HK1240571B - Synthetic intermediate of cytosines and synthetic intermediate of thionucleoside - Google Patents

Description

Synthetic intermediates of cytosine and thionucleosides

The present application is a divisional application of Chinese patent application No. 201380042642.1.3, filed on August 13, 2013, with a priority date of August 13, 2012, and entitled “Synthetic intermediates of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine and synthetic intermediates of thionucleosides and methods for producing the same.”

Technical Field

The present invention relates to compounds useful for the production of thionucleosides useful as pharmaceuticals, and methods for producing the same.

The present invention also relates to compounds useful for the production of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine, which is useful as an antitumor agent, and methods for producing the same.

Background Art

Thionucleosides in which oxygen atoms are replaced by sulfur atoms are known to exhibit antiviral and/or antitumor activities.

For example, it is known that 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine (hereinafter sometimes referred to as "Compound A") has excellent antitumor activity and is useful as a tumor therapeutic agent (Patent Document 1). As a method for producing Compound A, for example, a method using 1,2:5,6-di-O-isopropylidene-α-D-allose is known (Patent Document 1). In addition, a method using 5-O-benzyl-2,3-O-isopropylidene-L-lyxono-1,4-lactone is also known (Patent Document 2).

Also, known methods for producing sulfur-containing 5-membered ring compounds include a method of reacting a γ-haloester with potassium thioacetate (Non-Patent Document 1) and a method of reacting a γ-haloketone with sodium hydrosulfide (Non-Patent Document 2).

Prior art literature

Patent Literature

Patent Document 1: International Publication No. 1997/038001

Patent Document 2: International Publication No. 2011/074484 Pamphlet

Non-patent literature

Non-patent document 1: Journal of Medicinal Chemistry, 2003, Volume 46, Pages 389-398

Non-patent document 2: European Journal of Organic Chemistry, 2012, pp. 203-210

Summary of the Invention

Problems to be solved by the invention

However, the production method described in Non-Patent Document 1 has problems such as the reaction at an extremely low temperature (-78°C), the use of reagents requiring operational care, and low stereoselectivity. The production method described in Non-Patent Document 2 has problems such as the limited structure of the thionucleoside and low reactivity.

Furthermore, the production methods described in Patent Documents 1 and 2 have problems such as the large number of steps, the need for column chromatography, low yields, and the use of hazardous reagents.

Therefore, there is a strong demand for an industrial production method of thionucleosides and compound A that is short in time, high in reaction rate, high in stereoselectivity, and does not use reaction conditions or reagents that are not preferable for industrial production.

An object of the present invention is to provide a novel compound useful for the production of thionucleosides, and a method for producing the same.

Another object of the present invention is to provide a novel compound useful for, for example, the production of Compound A which is useful as an antitumor agent, and a method for producing the same.

Means for solving problems

The present inventors have conducted intensive studies to solve the above problems and have found that by reacting a compound represented by the general formula [1D] with a sulfur compound, a compound represented by the general formula [1E] can be obtained in a short time, at a high reaction rate, and with high stereoselectivity. Furthermore, they have found that a thionucleoside can be industrially produced from a compound represented by the general formula [4Aa] via a compound represented by the general formula [1Aa].

The present inventors have also found that the compound represented by the general formula [1] is a useful intermediate for producing compound A. The present inventors have further found that compound A can be industrially produced from the compound represented by the general formula [4] via the compound represented by the general formula [1] in a short time, with a high reaction rate and high stereoselectivity, without using reaction conditions or reagents that are not preferred for industrial production, thereby completing the present invention.

That is, according to the present invention, a method for producing a compound represented by the general formula [1E] is provided.

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A and R ^3B have the same meanings as those in the following groups).

It is characterized in that a compound represented by the general formula [1D] is reacted with a sulfur compound,

(wherein, R ^1A and R ^1B are the same or different and represent a hydrogen atom, a protected carboxyl group, a substituted C _1-6 alkyl group, a substituted C _2-6 alkenyl group, a substituted C _2-6 alkynyl group, a substituted aryl group or a substituted heterocyclic group; R ^2A and R ^2B are the same or different and represent a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an azido group, a protected amino group, a protected carboxyl group, a group represented by the general formula [15], a substituted C _1-6 alkyl group, a substituted C _2-6 alkenyl group, a substituted C _2-6 alkynyl group, a substituted C _1-6 alkoxy group, a substituted C _1-6 alkylthio group, a substituted aryl group, a substituted aryloxy group, a substituted arylthio group, a substituted heterocyclic group, a substituted heterocyclic oxy group or a substituted heterocyclic thio group; or R ^2A and R ^2B may together form a substituted C R ^3A and R ^3B are the same or different and represent a hydrogen atom, a _hydroxyl group, a halogen atom, a cyano group, an azido group, a protected amino group, a protected carboxyl group, a group represented by the general formula [16], a substituted C _1-6 alkyl group, a substituted C _2-6 alkenyl group, a substituted C _2-6 alkynyl group, a substituted C _1-6 alkoxy group, a substituted C _1-6 alkylthio group, a substituted aryl group, a substituted aryloxy group, a substituted arylthio group, a substituted heterocyclic group, a substituted heterocyclic oxy group or a substituted heterocyclic thio group; or R ^3A and R ^3B may together form a substituted C _1-6 alkylidene group; or R ^2A and R ^3A may together form a group represented by the general formula [17] or an atomic bond; or R ^2A , R ^2B , R ^3A and R ^3B can form a substituted aromatic ring together with the carbon atom to which they are bonded; X represents a leaving group;

-OR ^2a [15]

(wherein R ^2a represents a hydroxyl protecting group)

-OR ^3a [16]

(wherein R ^3a represents a hydroxyl protecting group)

-OY ¹ -O- [17]

(wherein, Y ¹ represents an optionally substituted C _1-6 alkylene group or an optionally substituted siloxane group; the atom on the left side is bonded to the carbon atom to which R ^2A is bonded).

Furthermore, the present invention also provides a method for producing a thionucleoside derivative represented by the general formula [11Aa].

(wherein, Base represents a protected nucleic acid base; R ^1A , R ^1B , R ^2A , R ^2B , R ^3A and R ^3B have the same meanings as those described below)

The method is characterized in that a compound represented by the general formula [4Aa] is reacted with a compound represented by the general formula [5] or a salt thereof to obtain a compound represented by the general formula [1Aa],

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A and R ^3B have the same meanings as the above groups)

H ₂ NOR ⁷ [5]

(wherein ^R7 represents a hydrogen atom, an optionally substituted _C1-6 alkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group or an optionally substituted silyl group)

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B and R ⁷ have the same meanings as the above groups),

Then, the compound represented by the general formula [1Ca] is obtained by the following method (1) or (2).

(1) A method of reacting a compound represented by the general formula [1Aa] with a halogenating agent in the presence of a base,

(2) A method of reacting a compound represented by the general formula [1Aa] with a compound represented by the general formula [6] in the presence of a base to obtain a compound represented by the general formula [1Ba], and then reacting the compound represented by the general formula [1Ba] with an alkali metal halide;

R ⁸ 5O ₂ X ¹ [6]

(wherein, R ⁸ represents a C _1-6 alkyl group which may be substituted or an aryl group which may be substituted; X ¹ represents a halogen atom)

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B , R ⁷ and R ⁸ have the same meanings as the above groups)

Then, the compound represented by the general formula [1Ca] is hydrolyzed to obtain the compound represented by the general formula [1Dd],

(wherein, R ^4a represents a halogen atom; R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B and R ⁷ have the same meanings as the above groups)

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B and R ^4a have the same meanings as the above groups)

Then, the compound represented by the general formula [1Dd] is reacted with a sulfur compound to obtain a compound represented by the general formula [1Ea],

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A and R ^3B have the same meanings as the above groups)

Then, the compound represented by the general formula [1Ea] is reacted with the compound represented by the general formula [7] or the compound represented by the general formula [8] to obtain the compound represented by the general formula [9Aa],

R ⁹ X ² [7]

(wherein, R ⁹ represents an acyl group which may be substituted, a C _1-6 alkylsulfonyl group which may be substituted, or an arylsulfonyl group which may be substituted; and X ² represents a halogen atom)

R ⁹ -OR ^g [8]

(wherein R ⁹ has the same meaning as the above groups)

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B and R ⁹ have the same meanings as the above groups),

Then, the compound represented by the general formula [9Aa] is reacted with a protected nucleic acid base and deprotected as needed.

Furthermore, the present invention also provides a method for producing a thionucleoside derivative represented by the general formula [11Ab].

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B and Base have the same meanings as the above groups)

The method is characterized in that the compound represented by the general formula [1Ba] is hydrolyzed to obtain the compound represented by the general formula [1De],

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B , R ⁷ and R ⁸ have the same meanings as the above groups)

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B and R ⁸ have the same meanings as the above groups)

Then, the compound represented by the general formula [1De] is reacted with a sulfur compound to obtain a compound represented by the general formula [1Eb],

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A and R ^3B have the same meanings as the above groups)

Then, the compound represented by the general formula [1Eb] is reacted with the compound represented by the general formula [7] or the compound represented by the general formula [8] to obtain the compound represented by the general formula [9Ab],

R ⁹ X ² [7]

(wherein, ^R9 and ^X2 have the same meanings as above)

R ⁹ -OR ⁹ [8]

(wherein R ⁹ has the same meaning as the above groups)

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B and R ⁹ have the same meanings as the above groups)

Then, the compound represented by the general formula [9Ab] is reacted with the protected nucleic acid base and deprotected as needed.

Furthermore, the present invention provides a method for producing 1-(2-deoxy-2-halogeno-4-thio-β-D-arabinofuranosyl)cytosine represented by the general formula [14].

(wherein R ³ has the same meaning as the above groups)

The method is characterized in that a compound represented by the general formula [4] is reacted with a compound represented by the general formula [5] or a salt thereof to obtain a compound represented by the general formula [1a],

(In the formula, R ^1a represents a hydroxyl protecting group; R ^2a represents a hydroxyl protecting group; or R ^1a and R ^2a may together form a C _1-3 alkylene group which may be substituted; and R ³ represents a halogen atom.)

H ₂ NOR ⁷ [5]

(wherein R ⁷ has the same meaning as the above groups)

(wherein, R ^1a , R ^2a , R ³ and R ⁷ have the same meanings as the above groups)

Then, the compound represented by the general formula [1c] is obtained by the following method (1) or (2),

(1) A method of reacting a compound represented by the general formula [1a] with a halogenating agent in the presence of a base,

(2) a method of reacting a compound represented by the general formula [1a] with a compound represented by the general formula [6] in the presence of a base to obtain a compound represented by the general formula [1b], and then reacting the compound represented by the general formula [1b] with an alkali metal halide;

R ⁸ SO ₂ X ¹ [6]

(In the formula, ^R8 represents a _C1-6 alkyl group which may be substituted or an aryl group which may be substituted; ^X1 represents a halogen atom.)

(wherein, R ^1a , R ^2a , R ³ , R ⁷ and R ⁸ have the same meanings as the above groups)

(wherein R ^4a represents a halogen atom; R ^1a , R ^2a , R ³ and R ⁷ have the same meanings as the above groups)

Then, the compound represented by the general formula [1c] is hydrolyzed to obtain a compound represented by the general formula [1d],

(wherein, R ^1a , R ^2a , R ³ and R ^4a have the same meanings as the above groups)

Then, the compound represented by the general formula [1d] is reacted with a sulfur compound to obtain a compound represented by the general formula [1e],

(wherein, R ^1a , R ^2a and R ³ have the same meanings as the above groups)

Then, the compound represented by the general formula [1e] is reacted with the compound represented by the general formula [7] or the compound represented by the general formula [8] to obtain the compound represented by the general formula [9].

R ⁹ X ² [7]

(In the formula, ^R9 represents an acyl group which may be substituted, a _C1-6 alkylsulfonyl group which may be substituted, or an arylsulfonyl group which may be substituted; ^X2 represents a halogen atom.)

R ⁹ -OR ⁹ [8]

(wherein R ⁹ has the same meaning as the above groups)

(wherein, R ^1a , R ^2a , R ³ and R ⁹ have the same meanings as the above groups)

Then, it is manufactured by any of the following methods (1) to (4),

(1) A method of reacting a compound represented by the general formula [9] with a protected cytosine or a protected N ⁴ -acylcytosine to obtain a compound represented by the general formula [11], and then deprotecting the compound represented by the general formula [11].

(wherein, R ¹⁰ represents a hydrogen atom or an acyl group which may be substituted; R ^1a , R ^2a and R ³ have the same meanings as those of the above groups)

(2) a method of reacting a compound represented by the general formula [9] with a protected cytosine to obtain a compound represented by the general formula [11a], then reacting the compound represented by the general formula [11a] with a compound represented by the general formula [12] or a compound represented by the general formula [13] to obtain a compound represented by the general formula [11b], and then deprotecting the compound represented by the general formula [11b].

(wherein, R ^1a , R ^2a and R ³ have the same meanings as the above groups)

R ^10a X ⁴ [12]

(In the formula, R ^10a represents an acyl group which may be substituted; X ⁴ represents a halogen atom.)

R ^10a -OR ^10a [13]

(wherein, R ^10a has the same meaning as the above groups)

(wherein, R ^1a , R ^2a , R ³ and R ^10a have the same meanings as the above groups)

(3) A method of halogenating a compound represented by the general formula [9] to obtain a compound represented by the general formula [10], reacting the compound represented by the general formula [10] with a protected cytosine or a protected N ⁴ -acylcytosine to obtain a compound represented by the general formula [11], and then deprotecting the compound represented by the general formula [11].

(wherein ^X3 represents a halogen atom; ^R1a , ^R2a and ^R3 have the same meanings as the above groups)

(wherein, R ^1a , R ^2a , R ³ and R ¹⁰ have the same meanings as the above groups)

(4) A method of halogenating a compound represented by the general formula [9] to obtain a compound represented by the general formula [10], then reacting the compound represented by the general formula [10] with a protected cytosine to obtain a compound represented by the general formula [11a], then reacting the compound represented by the general formula [11a] with a compound represented by the general formula [12] or a compound represented by the general formula [13] to obtain a compound represented by the general formula [11b], and then deprotecting the compound represented by the general formula [11b].

(wherein, R ^1a , R ^2a , R ³ and X ³ have the same meanings as the above groups)

(wherein, R ^1a , R ^2a and R ³ have the same meanings as the above groups)

R ^10a X ⁴ [12]

(wherein, R ^10a and X ⁴ have the same meanings as the above groups)

R ^10a -OR ^10a [13]

(wherein, R ^10a has the same meaning as the above groups)

(wherein, R ^1a , R ^2a , R ³ and R ^10a have the same meanings as the above groups).

In addition, the present invention also provides a compound represented by the general formula [1F], wherein:

(wherein, R ¹ represents a hydrogen atom or a hydroxyl protecting group; R ² represents a hydrogen atom or a hydroxyl protecting group; or R ¹ and R ² may together form a C _1-3 alkylene group which may be substituted; R ^3C represents a hydrogen atom, a halogen atom, a group represented by the general formula [16] or a C _1-6 alkyl group which may be substituted;

-OR ^3a [16]

(Wherein, R ^3a represents a hydroxyl protecting group.)

R ^3D represents a hydrogen atom, a halogen atom, a group represented by the general formula [16], or a C _1-6 alkyl group which may be substituted;

-OR ^3a [16]

(wherein, R ^3a has the same meaning as the above groups)

^R4 represents a halogen atom, a hydroxyl group, an optionally substituted _C1-6 alkylsulfonyloxy group or an optionally substituted arylsulfonyloxy group; ^R5 and ^R6 together represent a group represented by the general formula [2],

=Y [2]

(wherein, Y represents an oxygen atom or a group represented by the general formula [3],

=N-OR ⁷ [3]

(wherein, R ⁷ has the same meaning as the above groups);

or ^R4 and ^R5 together represent a sulfur atom; ^R6 represents a hydroxyl group. When ^R5 and ^R6 together represent a group represented by formula [2a], one of ^R3C and ^R3D is a halogen atom and the other is a hydrogen atom, and ^R4 is a halogen atom, an optionally substituted _C1-6 alkylsulfonyloxy group, or an optionally substituted arylsulfonyloxy group;

=O [2a]

When R ⁴ and R ⁵ together are a sulfur atom, and one of R ^3C and R ^3D is a hydrogen atom, the other is a halogen atom, a group represented by the general formula [16], or a C _1-6 alkyl group which may be substituted;

-OR ^3a [16]

(wherein, R ^3a has the same meaning as the above groups)

When R ⁴ and R ⁵ together are a sulfur atom, one of R ^3C and R ^3D is a hydrogen atom, and the other is a group represented by the general formula [16], R ² is a hydroxyl protecting group;

-OR ^3a [16]

(wherein R ^3a represents a hydroxyl protecting group)

When R ⁵ and R ⁶ together are a group represented by the general formula [3], one of R ^3C and R ^3D is a group represented by the general formula [16], the other is a hydrogen atom, and R ⁴ is an iodine atom, a hydroxyl group, an optionally substituted C _1-6 alkylsulfonyloxy group, or an optionally substituted arylsulfonyloxy group, R ¹ is an optionally substituted acyl group, and R ² is an optionally substituted acyl group;

=N-OR ⁷ [3]

(wherein R ⁷ has the same meaning as the above groups)

-OR ^3a [16]

(wherein, R ^3a has the same meaning as the above groups)

When R ⁵ and R ⁶ together represent a group represented by the general formula [3], R ^3C is a hydrogen atom, R ^3D is a hydrogen atom, and R ⁴ is a hydroxyl group, R ¹ is an optionally substituted aromatic acyl group, and R ² is an optionally substituted aromatic acyl group.

=N-OR ⁷ [3]

(wherein, R ⁷ has the same meaning as the above groups).

Furthermore, according to the present invention, there is also provided a compound represented by the general formula [1],

(wherein, ^R1 represents a hydrogen atom or a hydroxyl protecting group; ^R2 represents a hydrogen atom or a hydroxyl protecting group; or ^R1 and ^R2 may together form a _C1-3 alkylene group which may be substituted; ^R3 represents a halogen atom; ^R4 represents a halogen atom, a hydroxyl group, a _C1-6 alkylsulfonyloxy group which may be substituted, or an arylsulfonyloxy group which may be substituted; ^R5 and ^R6 may together form a group represented by the general formula [2],

=Y [2]

(wherein Y represents an oxygen atom or a group represented by the general formula [3]),

=N-OR ⁷ [3]

(wherein, R ⁷ represents a hydrogen atom, a C _1-6 alkyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted, or a silyl group which may be substituted);

or ^R4 and ^R5 together represent a sulfur atom; ^R6 represents a hydroxyl group. When ^R5 and ^R6 together represent a group represented by formula [2a], ^R4 represents a halogen atom, an optionally substituted _C1-6 alkylsulfonyloxy group, or an optionally substituted arylsulfonyloxy group,

=O [2a].

Furthermore, according to the present invention, there is also provided a compound represented by the general formula [1G].

(wherein, R ^1C represents a methyl group or an aryl group which may be substituted, R ^1D represents a hydrogen atom, R ^2C represents a hydrogen atom or an aryl group which may be substituted, R ^3E represents a hydrogen atom, a C _1-6 alkylthio group which may be substituted, an aryloxy group which may be substituted, an arylthio group which may be substituted, or a heterocyclic thio group which may be substituted, or R ^2C and R ^3E together represent a group or an atomic bond represented by the general formula [17],

-OY ¹ -O- [17]

(In the formula, ^Y1 represents an optionally substituted _C1-6 alkylene group or an optionally substituted siloxane group, and the atom on the left side is bonded to the carbon atom to which ^R2C is bonded.)

(wherein, when one of R ^1C and R ^1D is a methyl group, the other is a hydrogen atom, and R ^2C is a hydrogen atom, R ^3E is a C _1-6 alkylthio group which may be substituted, an aryloxy group which may be substituted, an arylthio group which may be substituted, or a heterocyclic thio group which may be substituted; or R ^1C is a hydrogen atom, R ^1D is a hydrogen atom, R ^2C is a hydrogen atom, and R ^3E is an aroylamino group which may be substituted; or R ^1C is a hydrogen atom, R ^1D is a hydrogen atom, R ^2C and R ^3E, together with the carbon atom to which they are bonded, form a benzene ring substituted with a protected hydroxyl group; or R ^1C is a protected carboxyl group, R ^1D is a protected carboxyl group, R ^2C is a hydrogen atom, and R ^3E is a hydrogen atom).

Effects of the Invention

The compound of the present invention is useful as an intermediate for producing thionucleosides, and the production method of the present invention is useful as a method for producing thionucleosides.

Furthermore, the compound of the present invention is useful as an intermediate for producing Compound A. The production method of the present invention is useful as a method for producing Compound A.

DETAILED DESCRIPTION

Hereinafter, the present invention will be described in detail.

In the present invention, unless otherwise specified, each term has the following meaning.

The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The C _1-6 alkyl group refers to a linear or branched C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl.

The C _2-6 alkenyl group refers to a linear or branched C _2-6 alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl.

The C _2-6 alkynyl group refers to a linear or branched C _2-6 alkynyl group such as ethynyl, propynyl, butynyl, pentynyl and hexynyl.

The C _3-8 cycloalkyl group refers to a C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Aryl refers to phenyl, naphthyl, etc.

The aryl C _1-6 alkyl group refers to aryl C _1-6 alkyl groups such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl and naphthylmethyl.

C _1-3 alkylene refers to methylene, ethylene or propylene.

The C _1-6 alkylidene group refers to a linear or branched C _1-6 alkylidene group such as a methine group, an ethylidene group, a propylidene group, a butylidene group, a pentylidene group, and a hexylidene group.

The C _1-6 alkoxy group refers to a linear or branched C _1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

Aryloxy refers to phenoxy, naphthoxy, and the like.

C _1-6 alkoxy C _1-6 alkyl refers to C _1-6 alkoxy C _1-6 alkyl such as methoxymethyl and 1-ethoxyethyl.

The C _2-6 alkanoyl group refers to a linear or branched C _2-6 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl.

Aroyl refers to benzoyl, naphthoyl, and the like.

The heterocyclic carbonyl group refers to nicotinoyl, thenoyl, pyrrolazinylcarbonyl, furoyl, and the like.

The (α-substituted) aminoacetyl group refers to an (α-substituted) aminoacetyl group derived from an amino acid (including amino acids such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine, tyrosine, tryptophan, proline, and hydroxyproline), the N-terminus of which may be protected.

Acyl groups include formyl, succinyl, glutaryl, maleoyl, phthaloyl, C _2-6 alkanoyl, aroyl, heterocyclic carbonyl, (α-substituted)aminoacetyl, and the like.

The C _2-6 alkanoyloxy group refers to a linear or branched C _2-6 alkanoyloxy group such as an acetyloxy group and a propionyloxy group.

The aroyloxy group refers to a benzoyloxy group, a naphthoyloxy group, or the like.

The acyloxy group means a C _2-6 alkanoyloxy group or an aroyloxy group.

The C _1-6 alkoxycarbonyl group refers to a linear or branched C _1-6 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl.

The aryloxycarbonyl group refers to a phenoxycarbonyl group, a naphthoxycarbonyl group, or the like.

The aryl C _1-6 alkoxycarbonyl group includes aryl C _1-6 alkoxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl and naphthylmethyloxycarbonyl.

The C _1-6 alkoxycarbonyloxy group refers to a linear or branched C _1-6 alkoxycarbonyloxy group such as a methoxycarbonyloxy group, an ethoxycarbonyloxy group, an isopropoxycarbonyloxy group, a tert-butoxycarbonyloxy group, and a 1,1-dimethylpropoxycarbonyloxy group.

The C _1-6 alkylamino group refers to a linear or branched C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino and hexylamino.

The di(C _1-6 alkyl)amino group refers to a linear or branched di(C 1-6 alkyl)amino group such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di(tert-butyl)amino, dipentylamino, dihexylamino, (ethyl)(methyl)amino and (methyl)( _propyl )amino.

The aroylamino group refers to an amino group substituted with an aroyl group such as a benzoylamino group.

The C _1-6 alkylthio group refers to a C _1-6 alkylthio group such as a methylthio group, an ethylthio group and a propylthio group.

The C _1-6 alkylsulfonyl group includes a C _1-6 alkylsulfonyl group such as a methylsulfonyl group, an ethylsulfonyl group and a propylsulfonyl group.

The arylsulfonyl group refers to a benzenesulfonyl group, a p-toluenesulfonyl group, a naphthylsulfonyl group, or the like.

The C _1-6 alkylsulfonyloxy group includes a C _1-6 alkylsulfonyloxy group such as a methylsulfonyloxy group, an ethylsulfonyloxy group and a propylsulfonyloxy group.

The arylsulfonyloxy group refers to a phenylsulfonyloxy group, a naphthylsulfonyloxy group, or the like.

The aromatic ring refers to a benzene ring, a naphthalene ring, or the like.

The siloxane group refers to a disiloxane group, a trisiloxane group, or the like.

The monocyclic nitrogen-containing heterocyclic group refers to a monocyclic nitrogen-containing heterocyclic group containing only nitrogen atoms as heteroatoms forming a ring such as azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, pyridinyl, homopiperidinyl, octylhydroazocinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, homopiperazinyl, triazolyl and tetrazolyl.

The monocyclic oxygen-containing heterocyclic group includes tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl and the like.

The monocyclic sulfur-containing heterocyclic group refers to thianthyl and the like.

The monocyclic nitrogen- and oxygen-containing heterocyclic group refers to a monocyclic nitrogen- and oxygen-containing heterocyclic group containing only nitrogen and oxygen atoms as heteroatoms forming the ring, such as oxazolyl, isoxazolyl, oxadiazolyl, and morpholinyl.

The monocyclic nitrogen- and sulfur-containing heterocyclic group refers to a monocyclic nitrogen- and sulfur-containing heterocyclic group containing only nitrogen and sulfur atoms as heteroatoms forming the ring, such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxidothiomorpholinyl, and 1,1-dioxidothiomorpholinyl.

The monocyclic heterocyclic group refers to a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, a monocyclic nitrogen- and oxygen-containing heterocyclic group, or a monocyclic nitrogen- and sulfur-containing heterocyclic group.

The bicyclic nitrogen-containing heterocyclic group refers to a bicyclic nitrogen-containing heterocyclic group containing only nitrogen atoms as heteroatoms forming the ring, such as dihydroindolinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, tetrahydroquinolyl, quinolyl, tetrahydroisoquinolyl, isoquinolyl, quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pteridinyl and quininyl.

The bicyclic oxygen-containing heterocyclic group refers to a bicyclic oxygen-containing heterocyclic group containing a heteroatom in the ring, such as 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodioxanyl, and 1,4-benzodioxanyl.

The bicyclic sulfur-containing heterocyclic group refers to a bicyclic sulfur-containing heterocyclic group containing only sulfur atoms as heteroatoms forming the rings such as 2,3-dihydrobenzothienyl and benzothienyl.

The bicyclic nitrogen- and oxygen-containing heterocyclic group refers to a bicyclic nitrogen- and oxygen-containing heterocyclic group containing only nitrogen atoms and oxygen atoms as heteroatoms forming the ring, such as benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzomorpholinyl, dihydropyranopyridinyl, dihydrodioxopyridinyl and dihydropyridoxazinyl.

The bicyclic nitrogen- and sulfur-containing heterocyclic group refers to a bicyclic nitrogen- and sulfur-containing heterocyclic group containing only nitrogen and sulfur atoms as heteroatoms forming the ring, such as benzothiazolyl, benzisothiazolyl, and benzothiadiazolyl.

The bicyclic heterocyclic group refers to a bicyclic nitrogen-containing heterocyclic group, a bicyclic oxygen-containing heterocyclic group, a bicyclic sulfur-containing heterocyclic group, a bicyclic nitrogen- and oxygen-containing heterocyclic group, or a bicyclic nitrogen- and sulfur-containing heterocyclic group.

The heterocyclic group refers to a monocyclic heterocyclic group or a bicyclic heterocyclic group.

The heterocyclic oxy group refers to a group in which a hydrogen atom (—H) bonded to a carbon atom forming the ring of a heterocyclic group is substituted with an oxygen atom (—O—).

The heterocyclic thio group means a group in which a hydrogen atom (—H) bonded to a carbon atom forming the ring of a heterocyclic group is substituted with a sulfur atom (—S—).

The silyl group refers to a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tributylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, or the like.

Silylation refers to replacing hydrogen atoms of a hydroxyl group, an amino group, a carboxyl group, an amide group, a mercapto group, or the like with a silyl group.

N ⁴ -Acylcytosine refers to cytosine whose amino group is protected with an acyl group which may be substituted, such as N ⁴ -formylcytosine, N ⁴ -acetylcytosine, N ⁴ -propionylcytosine, N ⁴ -pivaloylcytosine, N ⁴ -benzoylcytosine, N ⁴ -(4-methylbenzoyl)cytosine, N ⁴ -(4-bromobenzoyl)cytosine, N ⁴ -(4-nitrobenzoyl)cytosine, and N ⁴ -(4-methoxybenzoyl)cytosine.

Protected cytosine refers to cytosine protected with a silyl group, such as N ⁴ ,O-bis(trimethylsilyl)-4-amino-2-hydroxypyrimidine and N ⁴ ,O-bis(triethylsilyl)-4-amino-2-hydroxypyrimidine.

Protected N ⁴ -acylcytosine refers to N 4 -acylcytosine protected with a silyl group, such as 2-trimethylsilyloxy-4-acetylaminopyrimidine, N ⁴ ,O-bis(trimethylsilyl)-4-acetylamino-2-hydroxypyrimidine, 2-triethylsilyloxy-4-acetylaminopyrimidine, N ⁴ ,O-bis(triethylsilyl)-4-acetylamino-2-hydroxypyrimidine, 2-trimethylsilyloxy-4-benzoylaminopyrimidine, and N ⁴ ,O-bis(trimethylsilyl) ^-4 -benzoylamino-2-hydroxypyrimidine.

The nucleic acid base refers to a substituted adenine, a substituted guanine, a substituted cytosine, a substituted thymine or a substituted uracil.

The protected nucleic acid base refers to a nucleic acid base in which the amino group and/or the hydroxyl group is protected by a silyl group.

The leaving group is a halogen atom, a C _1-6 alkylsulfonyloxy group or an arylsulfonyloxy group. The C _1-6 alkylsulfonyloxy group and the arylsulfonyloxy group may be substituted with one or more groups selected from the substituent group A.

Examples of the hydroxyl-protecting group include all groups generally usable as hydroxyl-protecting groups, and examples thereof include those described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 16-366, 2007, John Wiley & Sons, Inc.

Specific examples include C _1-6 alkyl, C _2-6 alkenyl, aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, acyl, C _1-6 alkoxycarbonyl, C _1-6 alkylsulfonyl, arylsulfonyl, tetrahydrofuranyl, tetrahydropyranyl, and silanyl. These groups may be substituted with one or more groups selected from Substituent Group A.

The amino-protecting group includes all groups generally used as amino-protecting groups, and examples thereof include those described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696-926, 2007, John Wiley & Sons, Inc.

Specific examples include aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, acyl, C _1-6 alkoxycarbonyl, aryloxycarbonyl, C _1-6 alkylsulfonyl, arylsulfonyl, and silyl groups. These groups may be substituted with one or more groups selected from Substituent Group A.

The carboxyl-protecting group includes all groups generally usable as a carboxyl-protecting group, and examples thereof include those described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 533-646, 2007, John Wiley & Sons, Inc.

Specific examples include C _1-6 alkyl, C _2-6 alkenyl, aryl, aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, and silyl. These groups may be substituted with one or more groups selected from the substituent group A.

Substituent Group A: halogen atom, cyano group, nitro group, amino group which may be protected, hydroxy group which may be protected, carboxyl group which may be protected, carbamoyl group which may be substituted by one or more groups selected from Substituent Group B, sulfamoyl group which may be substituted by one or more groups selected from Substituent Group B, C _1-6 alkyl group which may be substituted by one or more groups selected from Substituent Group B, C _2-6 alkenyl group which may be substituted by one or more groups selected from Substituent Group B, C _2-6 alkynyl group which may be substituted by one or more groups selected from Substituent Group B, C _3-8 cycloalkyl group which may be substituted by one or more groups selected from Substituent Group B, aryl group which may be substituted by one or more groups selected from Substituent Group B, C _1-6 alkoxy group which may be substituted by one or more groups selected from Substituent Group B, aryloxy group which may be substituted by one or more groups selected from Substituent Group B, acyl group which may be substituted by one or more groups selected from Substituent Group B, C _1-6 acyloxy group which may be substituted by one or more groups selected from Substituent Group B, The present invention also includes a _{C 1-6} alkoxycarbonyl group, an aryloxycarbonyl group which may be substituted with one or more groups selected from Substituent Group B, a C _1-6 alkoxycarbonyloxy group which may be substituted with one or more groups selected from Substituent Group B, a C _1-6 alkylamino group which may be substituted with one or more groups selected from Substituent Group B, a di(C _1-6 alkyl)amino group which may be substituted with one or more groups selected from Substituent Group B, a C _1-6 alkylthio group which may be substituted with one or more groups selected from Substituent Group B, a C 1-6 alkylsulfonyl group which may be substituted with one or more groups selected from Substituent Group B, a _{C 1-6 alkylsulfonyloxy} group which may be substituted with one or more groups selected from Substituent Group B, a C _1-12 silyl group which may be substituted with one or more groups selected from Substituent Group B, a heterocyclic group which may be substituted with one or more groups selected from Substituent Group B, and an oxo group.

Substituent Group B: halogen atom, cyano group, nitro group, optionally protected amino group, optionally protected hydroxyl group, optionally protected carboxyl group, C _1-6 alkyl group, aryl group, C _1-6 alkoxy group, heterocyclic group, oxo group.

Examples of the aliphatic hydrocarbons include pentane, hexane, and cyclohexane.

Examples of the halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.

Examples of the alcohols include methanol, ethanol, propanol, 2-propanol, butanol, and 2-methyl-2-propanol.

Examples of the ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.

Examples of the esters include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate.

Examples of ketones include acetone, 2-butanone, and 4-methyl-2-pentanone.

Examples of the nitriles include acetonitrile and the like.

Examples of the amides include N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

Examples of the sulfoxides include dimethyl sulfoxide.

Examples of the carboxylic acid include acetic acid and the like.

Examples of the aromatic hydrocarbons include benzene, chlorobenzene, dichlorobenzene, nitrobenzene, toluene, and xylene.

Examples of ureas include 1,3-dimethyl-2-imidazolidinone and the like.

Examples of the base include organic bases and inorganic bases.

Examples of the organic base include triethylamine, pyridine, and N-methylimidazole.

Examples of the inorganic base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and sodium phosphate.

The C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl and heterocyclic groups represented by R ^1A and R ^1B may be substituted by one or more groups selected from Group A of Substituents.

The aryl group of R ^1C may be substituted by one or more groups selected from Substituent Group A.

The C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, aryl, aryloxy, arylthio, heterocyclic group, heterocyclicoxy and heterocyclicthio groups represented by R ^2A and R ^2B may be substituted by one or more groups selected from Substituent Group A.

The aryl group of R ^2C may be substituted by one or more groups selected from Substituent Group A.

The C _1-6 alkylidene group formed together with R ^2A and R ^2B may be substituted with one or more groups selected from Group A of Substituents.

The C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, aryl, aryloxy, arylthio, heterocyclic group, heterocyclicoxy and heterocyclicthio groups represented by R ^3A and R ^3B may be substituted by one or more groups selected from Substituent Group A.

The C _1-6 alkylidene group formed together with R ^3A and R ^3B may be substituted with one or more groups selected from Substituent Group A.

The C _1-6 alkyl group of R ^3C and R ^3D may be substituted with one or more groups selected from Substituent Group A.

The C _1-6 alkylthio group, aryloxy group, arylthio group, heterocyclic thio group and aroylamino group for R ^3E may be substituted by one or more groups selected from Substituent Group A.

The aromatic ring formed by R ^2A , R ^2B , R ^3A and R ^3B together with the carbon atom to which they are bonded may be substituted with one or more groups selected from Group A of Substituents.

The benzene ring formed by R ^2A , R ^2B , R ^3A and R ^3B together with the carbon atom to which they are bonded may be substituted with one or more groups selected from Group A of Substituents.

The C _1-6 alkylene group or the siloxane group which may be substituted for Y ¹ may be substituted with one or more groups selected from Group A of Substituents.

The nucleic acid base and the protected nucleic acid base may be substituted with one or more groups selected from Group A of Substituents.

The acyl group and aroyl group represented by R ¹ and R ² may be substituted by one or more groups selected from Substituent Group A.

The C _1-3 alkylene group formed together with R ¹ and R ² may be substituted with one or more groups selected from Substituent Group A.

The C _1-3 alkylene group formed together with R ^1a and R ^2a may be substituted with one or more groups selected from Substituent Group A.

The benzoyl group of R ^1a may be substituted by one or more groups selected from Substituent Group A.

The benzoyl group of R ^2a may be substituted with one or more groups selected from Substituent Group A.

The C _1-6 alkylsulfonyloxy group of R ⁴ may be substituted by one or more groups selected from Substituent Group A.

The arylsulfonyloxy group of R ⁴ may be substituted with one or more groups selected from Substituent Group A.

The C _1-6 alkyl group of R ⁷ may be substituted with one or more groups selected from Substituent Group A.

The aryl group of R ⁷ may be substituted with one or more groups selected from Substituent Group A.

The heterocyclic group of R ⁷ may be substituted by one or more groups selected from Substituent Group A.

The silyl group of R ⁷ may be substituted with one or more groups selected from Substituent Group A.

The C _1-6 alkyl group of R ⁸ may be substituted with one or more groups selected from Substituent Group A.

The aryl group of R ⁸ may be substituted with one or more groups selected from Substituent Group A.

The acyl group of R ⁹ may be substituted with one or more groups selected from Substituent Group A.

The C _1-6 alkylsulfonyl group of R ⁹ may be substituted with one or more groups selected from Substituent Group A.

The arylsulfonyl group of R ⁹ may be substituted with one or more groups selected from Substituent Group A.

The acyl groups of R ¹⁰ and R ^10a may be substituted with one or more groups selected from Substituent Group A.

Among the compounds represented by the general formula [1F], preferred compounds include the following compounds.

Preferred are compounds wherein R ¹ is a hydroxyl protecting group.

The compound wherein R ² is a hydroxyl protecting group is preferred.

Preferred are compounds wherein both R ¹ and R ² are hydroxyl protecting groups.

The hydroxy-protecting group for ^R1 or ^R2 is preferably a _C1-6 alkyl group which may be substituted by one or more groups selected from Substituent Group A, an aryl C1-6 alkyl group which may be substituted by one or more groups selected from Substituent Group A, an acyl group which may be substituted by one or more groups selected from Substituent Group A, a _C1-6 alkoxycarbonyl group which may be substituted by one or more groups selected from Substituent Group A, an aryl _C1-6 alkoxycarbonyl group which may be substituted by one or more groups selected from Substituent Group A, a silyl group _which may be substituted by one or more groups selected from Substituent Group A, a cinnamoyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group which may be substituted by one or more groups selected from Substituent Group A, and more preferably an aryl _C1-6 alkyl group which may be substituted by one or more groups selected from Substituent Group A, an acyl group which may be substituted by one or more groups selected from Substituent Group A, a _C1-6 alkoxycarbonyl group which may be substituted by one or more groups selected from Substituent Group A, an aryl C1-6 The present invention further preferably comprises a C _1-6 alkoxycarbonyl group, a silyl group which may be substituted by one or more groups selected from Substituent Group A, or a cinnamoyl group which may be substituted by one or more groups selected from Substituent Group A, further preferably a C _2-6 alkanoyl group which may be substituted by one or more groups selected from Substituent Group A, or an aroyl group which may be substituted by one or more groups selected from Substituent Group A, further preferably an acetyl group, a pivaloyl group, or a benzoyl group which may be substituted by one or more groups selected from Substituent Group A, further more preferably a benzoyl group which may be substituted by one or more groups selected from Substituent Group A, particularly preferably a benzoyl group, a 4-chlorobenzoyl group, a 2,4-dichlorobenzoyl group, a 4-nitrobenzoyl group, a 4-methoxybenzoyl group, a 4-(trifluoromethyl)benzoyl group, a 4-phenylbenzoyl group, a 3,5-dimethylbenzoyl group, or a 4-methylbenzoyl group, and most preferably a benzoyl group.

The compound wherein R ^3C is a hydrogen atom or a halogen atom is preferred, the compound wherein R ^3C is a hydrogen atom, a fluorine atom or a chlorine atom is more preferred, and the compound wherein R ^3C is a hydrogen atom or a fluorine atom is further preferred.

The compound wherein R ^3D is a hydrogen atom or a halogen atom is preferred, the compound wherein R ^3D is a hydrogen atom, a fluorine atom or a chlorine atom is more preferred, and the compound wherein R ^3D is a hydrogen atom or a fluorine atom is further preferred.

Preferred are compounds in which ^R4 is a halogen atom, a hydroxyl group, a _C1-6 alkylsulfonyloxy group which may be substituted with one or more groups selected from Substituent Group A, or an arylsulfonyloxy group which may be substituted with one or more groups selected from Substituent Group A. More preferred are compounds in which ^R4 is a chlorine atom, a bromine atom, a hydroxyl group, a methylsulfonyl group, a 2-nitrobenzenesulfonyloxy group, a 3-nitrobenzenesulfonyloxy group, a 4-nitrobenzenesulfonyloxy group, a 2,4,5-trichlorobenzenesulfonyloxy group, or a pentafluorobenzenesulfonyloxy group. Further preferred are compounds in which ^R4 is a hydroxyl group, a chlorine atom, a bromine atom, a methylsulfonyl group, or a 2,4,5-trichlorobenzenesulfonyloxy group.

When R ⁵ and R ⁶ together are a group represented by formula [2a],

=O [2a]

Preferred are compounds wherein one of ^R3C and ^R3D is a halogen atom and the other is a hydrogen atom, and more preferred are compounds wherein one of ^R3C and ^R3D is a fluorine atom and the other is a hydrogen atom. Preferred are compounds wherein ^R4 is a halogen atom, an optionally substituted _C1-6 alkylsulfonyloxy group, or an optionally substituted arylsulfonyloxy group.

When R ⁴ and R ⁵ together represent a sulfur atom and one of R ^3C and R ^3D represents a hydrogen atom, the compound in which the other is a halogen atom is preferred, and the compound in which the other is a fluorine atom is more preferred.

When ^R4 and ^R5 together are a sulfur atom, one of ^R3C and ^R3D is a hydrogen atom, and the other is a group represented by the general formula [16],

-OR ^3a [16]

(wherein R ^3a represents a hydroxyl protecting group)

The compound wherein R ² is a hydroxyl protecting group is preferred.

When R ⁵ and R ⁶ together are a group represented by the general formula [3], one of R ^3C and R ^3D is a group represented by the general formula [16], the other is a hydrogen atom, and R ⁴ is an iodine atom, a hydroxyl group, an optionally substituted C _1-6 alkylsulfonyloxy group, or an optionally substituted arylsulfonyloxy group,

=N-OR ⁷ [3]

(wherein R ⁷ has the same meaning as the above groups)

-OR ^3a [16]

(wherein, R ^3a has the same meaning as the above groups)

Preferred are compounds wherein R ¹ is an acyl group which may be substituted and R ² is an acyl group which may be substituted.

When R ⁵ and R ⁶ together are a group represented by the general formula [3], one of R ^3C and R ^3D is a hydrogen atom, the other is a hydrogen atom, and R ⁴ is a hydroxyl group,

=N-OR ⁷ [3]

(wherein R ⁷ has the same meaning as the above groups)

Preferred are compounds wherein R ¹ is an optionally substituted aroyl group and R ² is an optionally substituted aroyl group.

When Y is a group represented by the general formula [3],

=N-OR ⁷ [3]

(wherein R ⁷ has the same meaning as the above groups)

The compound wherein R ⁷ is a hydrogen atom, an optionally substituted C _1-6 alkyl group or an optionally substituted aryl group is preferred, the compound wherein R ⁷ is a hydrogen atom, a methyl group, a benzyl group or a phenyl group is more preferred, and the compound wherein R ⁷ is a methyl group or a benzyl group is further preferred.

When R ⁴ and R ⁵ together represent a sulfur atom, a compound wherein R ⁶ is a hydroxyl group is preferred.

Among the compounds represented by the general formula [1], the following compounds can be mentioned as preferred compounds.

Preferred are compounds wherein R ¹ is a hydroxyl protecting group.

The compound wherein R ² is a hydroxyl protecting group is preferred.

Preferred are compounds wherein both R ¹ and R ² are hydroxyl protecting groups.

^R1 and ^R2 may be the same or different.

The hydroxy-protecting group for ^R1 or ^R2 is preferably a _C1-6 alkyl group which may be substituted by one or more groups selected from Substituent Group A, an aryl C1-6 alkyl group which may be substituted by one or more groups selected from Substituent Group A, an acyl group which may be substituted by one or more groups selected from Substituent Group A, a _C1-6 alkoxycarbonyl group which may be substituted by one or more groups selected from Substituent Group A, an aryl _C1-6 alkoxycarbonyl group which may be substituted by one or more groups selected from Substituent Group A, a silyl group which may be substituted by one or more groups selected from Substituent Group A _, a cinnamoyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group which may be substituted by one or more groups selected from Substituent Group A, and more preferably an aryl _C1-6 alkyl group which may be substituted by one or more groups selected from Substituent Group A, an acyl group which may be substituted by one or more groups selected from Substituent Group A, a _C1-6 alkoxycarbonyl group which may be substituted by one or more groups selected from Substituent Group A, an aryl C1-6 The present invention further preferably comprises a C _1-6 alkoxycarbonyl group, a silyl group which may be substituted by one or more groups selected from Substituent Group A, or a cinnamoyl group which may be substituted by one or more groups selected from Substituent Group A, further preferably a C _2-6 alkanoyl group which may be substituted by one or more groups selected from Substituent Group A, or an aroyl group which may be substituted by one or more groups selected from Substituent Group A, further preferably an acetyl group, a pivaloyl group, or a benzoyl group which may be substituted by one or more groups selected from Substituent Group A, further more preferably a benzoyl group which may be substituted by one or more groups selected from Substituent Group A, particularly preferably a benzoyl group, a 4-chlorobenzoyl group, a 2,4-dichlorobenzoyl group, a 4-nitrobenzoyl group, a 4-methoxybenzoyl group, a 4-(trifluoromethyl)benzoyl group, a 4-phenylbenzoyl group, a 3,5-dimethylbenzoyl group, or a 4-methylbenzoyl group, and most preferably a benzoyl group.

The benzoyl group as a protecting group is easily deprotected and has the advantage of withstanding the reaction conditions of the production method of the present invention. In addition, the benzoyl group-protected compound obtained by the production method of the present invention has excellent crystallinity and is easy to purify.

The compound wherein R ³ is a fluorine atom or a chlorine atom is preferred, and the compound wherein R ³ is a fluorine atom is more preferred.

The compound in which ^R4 is a halogen atom, a hydroxyl group, or an arylsulfonyloxy group which may be substituted with one or more groups selected from Substituent Group A is preferred. The compound in which ^R4 is a chlorine atom, a bromine atom, a hydroxyl group, a 2-nitrobenzenesulfonyloxy group, a 3-nitrobenzenesulfonyloxy group, a 4-nitrobenzenesulfonyloxy group, a 2,4,5-trichlorobenzenesulfonyloxy group, or a pentafluorobenzenesulfonyloxy group is more preferred. The compound in which ^R4 is a hydroxyl group, a chlorine atom, a bromine atom, or a 2,4,5-trichlorobenzenesulfonyloxy group is further preferred.

When R ⁴ is a halogen atom, a hydroxyl group, an optionally substituted C _1-6 alkylsulfonyloxy group or an optionally substituted arylsulfonyloxy group, a compound in which R ⁵ and R ⁶ together are a group represented by the general formula [2] is preferred.

=Y [2]

(wherein, Y has the same meaning as the above groups)

More preferred are compounds wherein Y is an oxygen atom.

When Y is a group represented by the general formula [3], compounds wherein ^R7 is a hydrogen atom, an optionally substituted _C1-6 alkyl group, or an optionally substituted aryl group are preferred, compounds wherein ^R7 is a hydrogen atom, a methyl group, a benzyl group, or a phenyl group are more preferred, and compounds wherein ^R7 is a methyl group or a benzyl group are further preferred.

=N-OR ⁷ [3]

(wherein R ⁷ has the same meaning as the above groups)

When R ⁴ and R ⁵ together represent a sulfur atom, a compound wherein R ⁶ is a hydroxyl group is preferred.

Among the compounds represented by the general formula [1G], the following compounds can be mentioned as preferred compounds.

Preferred are compounds wherein R ^1C is a methyl group and R ^1D is a hydrogen atom.

It is preferred that R ^2C and R ^3E together represent a group or an atomic bond represented by the general formula [17].

-OY ¹ -O- [17]

(wherein, Y ¹ has the same meaning as the above groups)

Preferably, Y ¹ is a C _1-6 alkylene group which may be substituted.

Among the production methods of the present invention, the following production methods can be mentioned as preferable production methods.

The method for producing a compound in which R ^1A and R ^1B are identical or different and are a hydrogen atom, a protected carboxyl group, a C _1-6 alkyl group which may be substituted, or an aryl group which may be substituted is preferred. The method for producing a compound in which R ^1A and R ^1B are identical or different and are a hydrogen atom or a C _1-6 alkyl group which may be substituted with one or more groups selected from the substituent group A is more preferred. The method for producing a compound in which R ^1A and R ^1B are identical or different and are a hydrogen atom, a methyl group, or a group represented by the general formula [18] is further preferred.

-CH ₂ OR ^1a [18]

(wherein, R ^1a has the same meaning as the above groups)

The ring-closing reaction of the present invention preferably has high reactivity and high stereoselectivity, and therefore the effect is particularly large when at least one of R ^1A or R ^1B is a substituent.

Particularly preferred is a method for producing a compound in which one of R ^1A and R ^1B is a hydrogen atom and the other is a methyl group or a group represented by the general formula [18].

-CH ₂ OR ^1a [18]

(wherein, R ^1a has the same meaning as the above groups)

The method for producing a compound in which R ^1a is C _1-6 alkyl which may be substituted with one or more groups selected from Substituent Group A, aryl C _1-6 alkyl which may be substituted with one or more groups selected from Substituent Group A, acyl which may be substituted with one or more groups selected from Substituent Group A, C _1-6 alkoxycarbonyl which may be substituted with one or more groups selected from Substituent Group A, aryl C _1-6 alkoxycarbonyl which may be substituted with one or more groups selected from Substituent Group A, silanyl which may be substituted with one or more groups selected from Substituent Group A, cinnamoyl, tetrahydrofuranyl or tetrahydropyranyl which may be substituted with one or more groups selected from Substituent Group A is preferably used, and more preferably R ^1a is aryl C _1-6 alkyl which may be substituted with one or more groups selected from Substituent Group A, acyl which may be substituted with one or more groups selected from Substituent Group A, C _1-6 alkoxycarbonyl which may be substituted with one or more groups selected from Substituent Group A, aryl C 1-6 The present invention relates to a method for producing a compound wherein R 1a is a C _2-6 alkoxycarbonyl group, a silyl group which may be substituted with one or more groups selected from Substituent Group A, or a cinnamoyl group which may be substituted with one or more groups selected from Substituent Group A. The method for producing a compound wherein R ^1a is a C _2-6 alkanoyl group which may be substituted with one or more groups selected from Substituent Group A, or an aryl group which may be substituted with one or more groups selected from Substituent Group A is more preferred. The method for producing a compound wherein R ^{1a is an acetyl group, a pivaloyl group, or a benzoyl group which may be substituted with one or more groups selected from Substituent Group A is still more preferred. The method for producing a compound wherein R 1a} is a benzoyl group which may be substituted with one or more groups selected from Substituent Group A is still more preferred. The method for producing a compound wherein R ^1a is a benzoyl group which may be substituted with one or more groups selected from Substituent Group A is still more preferred. The method for producing a compound wherein R ^1a is a benzoyl group which may be substituted with one or more groups selected from Substituent Group A is particularly preferred. The method for producing a compound wherein ^{R 1a} is benzoyl, 4-chlorobenzoyl, 2,4-dichlorobenzoyl, 4-nitrobenzoyl, 4-methoxybenzoyl, 4-(trifluoromethyl)benzoyl, 4-phenylbenzoyl, 3,5-dimethylbenzoyl or 4-methylbenzoyl is most preferably a method for producing a compound wherein R ^1a is benzoyl.

The benzoyl group as a protecting group has the advantage of being easily deprotected and thus resistant to the reaction conditions of the production method of the present invention. In addition, the benzoyl-protected compound obtained by the production method of the present invention has excellent crystallinity and is easy to purify.

Preferably, a method for producing a compound in which R ^2A and R ^2B are identical or different and are a hydrogen atom, a halogen atom, a cyano group, a group represented by the general formula [15] or an aryl group which may be substituted is used.

-OR ^2a [15]

(wherein, R ^2a has the same meaning as the above groups)

More preferably, a method for producing a compound in which R ^2A and R ^2B are the same or different and are a hydrogen atom, a group represented by the general formula [15], or an aryl group which may be substituted is used.

-OR ^2a [15]

(wherein, R ^2a has the same meaning as the above groups)

More preferably, a method for producing a compound in which R ^2A and R ^2B are the same or different and are a hydrogen atom or a group represented by the general formula [15] is used.

-OR ^2a [15]

(wherein, R ^2a has the same meaning as the above groups)

Particularly preferred is a method for producing a compound in which one of R ^2A and R ^2B is a hydrogen atom and the other is a group represented by the general formula [15].

-OR ^2a [15]

(wherein, R ^2a has the same meaning as the above groups)

The method for producing a compound in which ^R2a is _C1-6 alkyl which may be substituted with one or more groups selected from Substituent Group A, aryl _C1-6 alkyl which may be substituted with one or more groups selected from Substituent Group A, acyl which may be substituted with one or more groups selected from Substituent Group A, _C1-6 alkoxycarbonyl which may be substituted with one or more groups selected from Substituent Group A, aryl _C1-6 alkoxycarbonyl which may be substituted with one or more groups selected from Substituent Group A, silanyl which may be substituted with one or more groups selected from Substituent Group A, cinnamoyl, tetrahydrofuranyl or tetrahydropyranyl which may be substituted with one or more groups selected from Substituent Group A is preferably used, and more preferably ^R2a is aryl _C1-6 alkyl which may be substituted with one or more groups selected from Substituent Group A, acyl which may be substituted with one or more groups selected from Substituent Group A, _C1-6 alkoxycarbonyl which may be substituted with one or more groups selected from Substituent Group A, aryl C1-6 The present invention relates to a method for producing a compound wherein R 2a is a C _2-6 alkoxycarbonyl group, a silyl group which may be substituted with one or more groups selected from Substituent Group A, or a cinnamoyl group which may be substituted with one or more groups selected from Substituent Group A. The method for producing a compound wherein R ^2a is a C _2-6 alkanoyl group which may be substituted with one or more groups selected from Substituent Group A or an aryl group which may be substituted with one or more groups selected from Substituent Group A is more preferred. The method for producing a compound wherein R ^{2a is an acetyl group, a pivaloyl group, or a benzoyl group which may be substituted with one or more groups selected from Substituent Group A is still more preferred. The method for producing a compound wherein R 2a} is a benzoyl group which may be substituted with one or more groups selected from Substituent Group A is still more preferred. The method for producing a compound wherein R ^2a is a benzoyl group which may be substituted with one or more groups selected from Substituent Group A is still more preferred. The method for producing a compound wherein R ^2a is a benzoyl group which may be substituted with one or more groups selected from Substituent Group A is particularly preferred. The method for producing a compound wherein ^{R 2a} is benzoyl, 4-chlorobenzoyl, 2,4-dichlorobenzoyl, 4-nitrobenzoyl, 4-methoxybenzoyl, 4-(trifluoromethyl)benzoyl, 4-phenylbenzoyl, 3,5-dimethylbenzoyl or 4-methylbenzoyl is most preferably a method for producing a compound wherein R ^2a is benzoyl.

The benzoyl group as a protecting group has the advantage of being easily deprotected and thus resistant to the reaction conditions of the production method of the present invention. In addition, the benzoyl-protected compound obtained by the production method of the present invention has excellent crystallinity and is easy to purify.

R ^1a and R ^2a may be the same or different.

Preferably, a method for producing a compound in which R ^3A and R ^3B are the same or different and are a hydrogen atom, a halogen atom, an amino group which may be protected, a group represented by the general formula [16], an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkylthio group, an optionally substituted aryloxy group, an optionally substituted arylthio group or an optionally substituted heterocyclic thio group is used.

-OR ^3a [16]

(wherein, R ^3a has the same meaning as the above groups)

More preferably, a method for producing a compound in which R ^3A and R ^3B are identical or different and are a hydrogen atom, a halogen atom, a group represented by the general formula [16], or an aryloxy group which may be substituted with one or more groups selected from the substituent group A is used.

-OR ^3a [16]

(wherein, R ^3a has the same meaning as the above groups)

A method for producing a compound preferably using a compound in which one of R ^3A and R ^3B is a hydrogen atom and the other is a halogen atom, a group represented by the general formula [16], or an aryloxy group which may be substituted with one or more groups selected from the substituent group A.

-OR ^3a [16]

(wherein, R ^3a has the same meaning as the above groups)

More preferably, a method for producing a compound wherein one of R ^3A and R ^3B is a hydrogen atom and the other is a halogen atom, or a group represented by the general formula [16] is used.

-OR ^3a [16]

(wherein, R ^3a has the same meaning as the above groups)

Preferably, a method for producing a compound in which R ^2A and R ^3A together represent a group or an atomic bond represented by the general formula [17] is used.

-OY ¹ -O- [17]

(wherein, Y ¹ has the same meaning as the above groups)

Preferably, a method for producing a compound in which Y ¹ is an optionally substituted C _1-6 alkylene group is used.

The method for producing a compound in which R ³ is a fluorine atom or a chlorine atom is preferably used, and the method for producing a compound in which R ³ is a fluorine atom is more preferably used.

The method for producing a compound in which ^R4 is a halogen atom, a hydroxyl group, or an arylsulfonyloxy group which may be substituted with one or more groups selected from Substituent Group A is preferred. The method for producing a compound in which ^R4 is a chlorine atom, a bromine atom, a hydroxyl group, a 2-nitrobenzenesulfonyloxy group, a 3-nitrobenzenesulfonyloxy group, a 4-nitrobenzenesulfonyloxy group, a 2,4,5-trichlorobenzenesulfonyloxy group, or a pentafluorobenzenesulfonyloxy group is more preferred. The method for producing a compound in which ^R4 is a hydroxyl group, a chlorine atom, a bromine atom, or a 2,4,5-trichlorobenzenesulfonyloxy group is even more preferred.

Preferably, the method for producing a compound wherein ^R4 is a halogen atom, a hydroxyl group, an optionally substituted _C1-6 alkylsulfonyloxy group or an optionally substituted arylsulfonyloxy group, and ^R5 and ^R6 together are a group represented by the general formula [2] is used.

=Y [2]

(wherein, Y has the same meaning as the above groups)

More preferably, a method for producing a compound in which Y is an oxygen atom is used.

When Y is a group represented by the general formula [3], the method for producing a compound wherein R ⁷ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted aryl group is preferably used, more preferably the method for producing a compound wherein R ⁷ is a hydrogen atom, a methyl group, a benzyl group, or a phenyl group is more preferably used, and even more preferably the method for producing a compound wherein R ⁷ is a methyl group or a benzyl group is used.

=N-OR ⁷ [3]

(wherein, R ⁷ has the same meaning as the above groups).

It is preferable to use a method for producing a compound in which R ⁴ and R ⁵ together represent a sulfur atom and R ⁶ represents a hydroxyl group.

The method for producing a compound in which R ⁹ is an acyl group which may be substituted is preferably used, the method for producing a compound in which R ⁹ is an acyl group is more preferred, and the method for producing a compound in which R ⁹ is an acetyl group is further preferred.

It is preferred to use a method for producing a compound in which X ³ is a bromine atom.

Preferably, a method for producing a compound in which the nucleic acid base is adenine which may be substituted with one or more groups selected from substituent group A, guanine which may be substituted with one or more groups selected from substituent group A, cytosine which may be substituted with one or more groups selected from substituent group A, thymine which may be substituted with one or more groups selected from substituent group A, or uracil which may be substituted with one or more groups selected from substituent group A is used. More preferably, a method for producing a compound in which the nucleic acid base is cytosine which may be substituted with one or more groups selected from substituent group A is used.

Preferably, a method for producing a compound in which the protected cytosine is N ⁴ ,O-bis(trimethylsilyl)-4-amino-2-hydroxypyrimidine is used.

Preferably, a method for producing a compound in which the protected N ⁴ -acylcytosine is 2-trimethylsilyloxy-4-acetylaminopyrimidine or N ⁴ ,O-bis(trimethylsilyl)-4-acetylamino-2-hydroxypyrimidine is used, and more preferably, a method for producing a compound in which the protected N ⁴ -acylcytosine is N ⁴ ,O-bis(trimethylsilyl)-4-acetylamino-2-hydroxypyrimidine is used.

The method for producing a compound in which R ^10a is formyl, optionally substituted C _2-6 alkanoyl, or optionally substituted aroyl is preferred, the method for producing a compound in which R ^10a is C _2-6 alkanoyl is more preferred, and the method for producing a compound in which R ^10a is acetyl is even more preferred.

In the step of producing a compound represented by the general formula [11b] from a compound represented by the general formula [11a], it is preferred to use a compound represented by the general formula [13].

The method for producing 1-(2-deoxy-2-halo-4-thio-β-D-arabinofuranosyl)cytosine from the compound represented by the general formula [9] is preferably the method (3) or (4), more preferably the method (4).

When the method of (3) is used, it is preferred to use protected N ⁴ -acylcytosine.

The compound represented by the general formula [11b] is preferably isolated in a solid form. The purity of compound A is improved by isolation.

Next, the production method of the present invention will be described.

Manufacturing method 1

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B and X have the same meanings as the above groups)

The compound represented by the general formula [1E] can be produced by reacting the compound represented by the general formula [1D] with a sulfur compound.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, ureas, and water. These solvents may also be used in the form of a mixture.

Preferred solvents include ethers, esters, nitriles, amides, and ureas, with amides being more preferred.

The amount of the solvent used is not particularly limited, as long as it is 1 to 50 times (v/w) the amount of the compound represented by the general formula [1D], and preferably 1 to 15 times (v/w).

Examples of the sulfur compound used in the reaction include hydrogen sulfide or a salt thereof.

Examples of the salt of hydrogen sulfide include sodium hydrosulfide, sodium sulfide, potassium hydrosulfide, calcium hydrosulfide, and magnesium sulfide, with sodium hydrosulfide being preferred.

The amount of the sulfur compound used may be 0.2 to 10 times the mole of the compound represented by the general formula [1D], preferably 0.5 to 2.0 times the mole, and more preferably 0.7 to 1.5 times the mole.

The reaction temperature may be -20 to 100°C, preferably -10 to 80°C, and more preferably -5 to 60°C.

The reaction time may be 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and even more preferably 5 minutes to 6 hours.

In this production method, it is presumed that after a sulfur compound is added to the formyl group of the compound represented by the general formula [1D], a nucleotropic substitution reaction proceeds, leading to ring closure. This allows for a short reaction time, high reactivity, and high stereoselectivity. However, the present invention is not limited to this reaction mechanism.

The compound represented by the general formula [1D] may be produced by a ring-opening reaction of a sugar or by other methods.

Manufacturing method 2

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B , R ^4a , R ⁷ , R ⁸ , R ⁹ , X ¹ , X ² and Base have the same meanings as the groups described above)

(Step 1)

As a compound represented by the general formula [4Aa], for example, ((2R,3R,4S)-3-benzoyloxy-4-fluoro-5-hydroxyoxolan-2-yl)methyl benzoate is known.

As the compound represented by the general formula [5] or a salt thereof, for example, O-methylhydroxylamine and O-benzylhydroxylamine are known.

The compound represented by the general formula [1Aa] can be produced by reacting a compound represented by the general formula [4Aa] with a compound represented by the general formula [5] or a salt thereof.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, nitriles, amides, sulfoxides, aromatic hydrocarbons, and water. These solvents may be mixed and used.

Preferred solvents include halogenated hydrocarbons, alcohols, nitriles, aromatic hydrocarbons, and water.

The amount of the solvent used is not particularly limited, and may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [4Aa], and preferably 1 to 15 times (v/w).

The amount of the compound represented by the general formula [5] or its salt used in the reaction may be 0.5 to 10 times the molar amount of the compound represented by the general formula [4Aa], preferably 0.8 to 5.0 times the molar amount, more preferably 1.0 to 2.0 times the molar amount.

When a salt of the compound represented by the general formula [5] is used, it is preferred to add a base.

Examples of the base include organic bases and inorganic bases, and triethylamine and sodium hydrogen carbonate are preferred.

The amount of the base used may be 0.1 to 10 times the mole of the salt of the compound represented by the general formula [5], preferably 0.2 to 2.0 times the mole, and more preferably 0.5 to 1.5 times the mole.

The reaction temperature may be -10 to 100°C, preferably -5 to 80°C, and more preferably 0 to 60°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(Step 2)

As the compound represented by the general formula [6], for example, 4-nitrobenzenesulfonyl chloride, 2,4,5-trichlorobenzenesulfonyl chloride, and pentafluorobenzenesulfonyl chloride are known.

The compound represented by the general formula [1Ba] can be produced by reacting the compound represented by the general formula [1Aa] with the compound represented by the general formula [6] in the presence of a base.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, and aromatic hydrocarbons. These solvents may be mixed and used.

Preferred solvents include esters, nitriles and aromatic hydrocarbons.

The amount of the solvent used is not particularly limited, and may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1Aa], and preferably 1 to 15 times (v/w).

Examples of the base used in the reaction include organic bases and inorganic bases, with triethylamine and N-methylimidazole being preferred.

The amount of the base used may be 0.5 to 10 times the mole of the compound represented by the general formula [1Aa], preferably 0.8 to 4.0 times the mole, and more preferably 1.0 to 3.0 times the mole.

The amount of the compound represented by the general formula [6] used in the reaction may be 0.5 to 10 times the molar amount of the compound represented by the general formula [1Aa], preferably 0.8 to 4.0 times the molar amount, and more preferably 1.0 to 2.0 times the molar amount.

The reaction temperature may be -10 to 100°C, preferably -5 to 80°C, and more preferably 0 to 60°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(Step 3)

The compound represented by the general formula [1Ca] can be produced by reacting the compound represented by the general formula [1Ba] with an alkali metal halide.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, and ureas. These solvents may be used in the form of a mixture.

Preferred solvents include ethers, esters, nitriles, amides, and ureas, with amides and ureas being more preferred.

The amount of the solvent used is not particularly limited, as long as it is 1 to 50 times (v/w) the amount of the compound represented by the general formula [1Ba], and preferably 1 to 15 times (v/w).

Examples of the alkali metal halide used in the reaction include lithium fluoride, sodium fluoride, potassium fluoride, lithium bromide, sodium bromide, potassium bromide, lithium chloride, sodium chloride, potassium chloride, lithium iodide, sodium iodide, and potassium iodide, with lithium bromide being preferred.

The amount of the alkali metal halide used may be 0.5 to 20 times the mole of the compound represented by the general formula [1Ba], preferably 0.8 to 8.0 times the mole, and more preferably 1.0 to 5.0 times the mole.

The reaction temperature may be -50 to 150°C, preferably -10 to 120°C, more preferably 0 to 100°C, and even more preferably 20 to 80°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(Other methods)

The compound represented by the general formula [1Ca] can be produced by reacting the compound represented by the general formula [1Aa] with a halogenating agent in the presence of a base.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, ureas, and water. These solvents may be mixed and used.

Preferred solvents include ethers, esters, nitriles, amides, aromatic hydrocarbons, and ureas, with amides being more preferred.

The amount of the solvent used is not particularly limited, and may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1Aa], and preferably 1 to 15 times (v/w).

Examples of the halogenating agent in this reaction include chlorinating agents and brominating agents.

Examples of the chlorinating agent include phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, Vilsmeier reagent (N,N-dimethylformamide-phosphorus pentachloride, N,N-dimethylformamide-phosphorus oxychloride, etc.), Rydon reagent (Ph ₃ PCl ₂ , triphenylphosphine-carbon tetrachloride), thionyl chloride, and sulfuryl chloride. Sulfuryl chloride is preferred.

Examples of the brominating agent include phosphorus tribromide, N,N-dimethylformamide-phosphorus tribromide, triphenylphosphine-carbon tetrabromide, and triphenylphosphine dibromide.

The amount of the halogenating agent used may be 0.1 to 10 times the mole of the compound represented by the general formula [1Aa], preferably 0.8 to 5.0 times the mole, and more preferably 1.0 to 2.0 times the mole.

Examples of the base used in the reaction include organic bases and inorganic bases, with triethylamine and pyridine being preferred.

The amount of the base used may be 0.5 to 50 times the mole of the compound represented by the general formula [1Aa], preferably 0.8 to 20 times the mole, and more preferably 1.0 to 10 times the mole.

In this reaction, it is preferred to add a salt.

Examples of the salt include lithium chloride, lithium bromide, sodium bromide, calcium bromide, and pyridine hydrochloride.

In this halogenation reaction, a mixture of epimers is generally obtained. In order to improve the optical purity of the compound of the general formula [1Ca], it is preferred to use sulfuryl chloride and lithium chloride in combination.

The amount of the salt used may be 0.5 to 20 times the mole of the compound represented by the general formula [1Aa], preferably 0.8 to 5.0 times the mole, and more preferably 1.0 to 3.0 times the mole.

The reaction temperature may be -50 to 80°C, preferably -40 to 60°C, and more preferably -30 to 40°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(Step 4)

The compound represented by the general formula [1Dd] can be produced by hydrolyzing the compound represented by the general formula [1Ca] in the presence of an acid.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, ureas, and water. These solvents may be mixed and used.

Preferred solvents include ethers, esters, nitriles, amides, and water, with ethers and water being more preferred.

The amount of the solvent used is not particularly limited, as long as it is 1 to 50 times (v/w) the amount of the compound represented by the general formula [1Ca], and preferably 1 to 15 times (v/w).

Examples of the acid used in the reaction include hydrochloric acid, sulfuric acid, toluenesulfonic acid, acetic acid, glyoxylic acid, and phosphoric acid, with glyoxylic acid being preferred.

The amount of the acid used may be 0.5 to 100 times the mole of the compound represented by the general formula [1Ca], preferably 1.0 to 60 times the mole, and more preferably 1.5 to 40 times the mole.

In this reaction, it is preferred to add a carbonyl compound.

Examples of the carbonyl compound include ketones such as acetone and 2-butanone, and aldehydes such as formaldehyde, benzaldehyde, glyoxal, and glyoxylic acid. Aldehydes are preferred, and glyoxylic acid is more preferred.

The amount of the carbonyl compound used may be 0.5 to 100 times the mole of the compound represented by the general formula [1Ca], preferably 1.0 to 60 times the mole, and more preferably 1.5 to 40 times the mole.

The reaction temperature may be -10 to 120°C, preferably 0 to 100°C, and more preferably 20 to 80°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(5th step)

The compound represented by the general formula [1Ea] can be produced by reacting the compound represented by the general formula [1Dd] with a sulfur compound.

This reaction may be carried out according to the method described in Production Method 1.

(Step 6)

As the compound represented by the general formula [7], for example, acetyl chloride, benzoyl chloride, benzenesulfonyl chloride, and methanesulfonyl chloride are known.

As the compound represented by the general formula [8], for example, acetic anhydride and propionic anhydride are known.

The compound represented by the general formula [9Aa] can be produced by reacting the compound represented by the general formula [1Ea] with the compound represented by the general formula [7] or the compound represented by the general formula [8].

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, and aromatic hydrocarbons. These solvents may be mixed and used.

Preferred solvents include ethers, esters, nitriles and amides, with ethers, nitriles and amides being more preferred.

The amount of the solvent used is not particularly limited, and may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1Ea], and preferably 1 to 15 times (v/w).

The amount of the compound represented by the general formula [7] or the compound represented by the general formula [8] used in the reaction may be 0.5 to 50 times the molar amount of the compound represented by the general formula [1Ea], preferably 0.8 to 20 times the molar amount, more preferably 1.0 to 10 times the molar amount.

It is preferred to add a base to this reaction. Examples of the base include organic bases and inorganic bases, with triethylamine being preferred.

The amount of the base used may be 0.5 to 50 times the mole of the compound represented by the general formula [1Ea], preferably 0.8 to 20 times the mole, and more preferably 1.0 to 15 times the mole.

The reaction temperature may be -10 to 100°C, preferably -5 to 80°C, and more preferably 0 to 60°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(Step 7)

The nucleic acid base or protected nucleic acid base is not particularly limited as long as it is a nucleic acid base that can be used in a glycosylation reaction.

The compound represented by the general formula [11Aa] can be produced by reacting the compound represented by the general formula [9Aa] with a nucleic acid base or a protected nucleic acid base in the presence of an acid.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, and aromatic hydrocarbons. These solvents may be mixed and used.

Preferred solvents include aliphatic hydrocarbons, halogenated hydrocarbons, nitriles, and aromatic hydrocarbons, with halogenated hydrocarbons and aromatic hydrocarbons being preferred.

The amount of the solvent used is not particularly limited, as long as it is 1.0 to 50 times (v/w) the amount of the compound represented by the general formula [9Aa], and preferably 1.0 to 15 times (v/w).

Examples of the acid used in the reaction include Lewis acids such as aluminum chloride, aluminum bromide, tin tetrachloride, titanium tetrachloride, titanium (IV) isopropoxide, zinc chloride, and trimethylsilyl trifluoromethanesulfonate.

Preferred examples of the acid include aluminum chloride, tin tetrachloride, and trimethylsilyl trifluoromethanesulfonate, with trimethylsilyl trifluoromethanesulfonate being more preferred.

The amount of the acid used is not particularly limited, and may be 0.0001 to 10 times the mole of the compound represented by the general formula [9Aa], and preferably 0.001 to 1.0 times the mole.

The amount of the nucleic acid base or protected nucleic acid base used in the reaction may be 1.0 to 50 times the molar amount of the compound represented by the general formula [9Aa], preferably 1.0 to 10 times the molar amount, and more preferably 1.0 to 5 times the molar amount.

The reaction temperature may be 20 to 150°C, and is preferably 20 to 100°C.

The reaction time may be 5 minutes to 50 hours, preferably 30 minutes to 24 hours, more preferably 1 hour to 10 hours.

When the compound represented by the general formula [11Aa] has a protecting group, thionucleoside can be produced by deprotection.

This method may be carried out according to the method described in Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons, INC. and the like.

Manufacturing method 3

(wherein, R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B , R ⁷ , R ⁸ , R ⁹ , X ² and Base have the same meanings as the groups described above)

(Step 1)

The compound represented by the general formula [1De] can be produced by hydrolyzing the compound represented by the general formula [1Ba] in the presence of an acid.

This method may be carried out according to the method described in Production Method 2 (Step 4).

(Step 2)

The compound represented by the general formula [1Eb] can be produced by reacting the compound represented by the general formula [1De] with a sulfur compound.

This reaction may be carried out according to the method described in Production Method 1.

(Step 3)

The compound represented by the general formula [9Ab] can be produced by reacting the compound represented by the general formula [1Eb] with the compound represented by the general formula [7] or the compound represented by the general formula [8].

This method may be carried out according to the method described in Production Method 2 (Step 6).

(Step 4)

The compound represented by the general formula [11Ab] can be produced by reacting the compound represented by the general formula [9Ab] with a nucleic acid base or a protected nucleic acid base in the presence of an acid.

This method may be carried out according to the method described in Production Method 2 (Step 7).

Manufacturing Method 4

(wherein, R ^1a , R ^2a , R ³ , R ^4a , R ⁷ , R ⁸ , R ⁹ , X ¹ and X ² have the same meanings as the above groups)

(Step 1)

As a compound represented by the general formula [4], for example, ((2R,3R,4S)-3-benzoyloxy-4-fluoro-5-hydroxyoxolan-2-yl)methyl benzoate is known.

As the compound represented by the general formula [5] or a salt thereof, for example, O-methylhydroxylamine and O-benzylhydroxylamine are known.

The compound represented by the general formula [1a] can be produced by reacting a compound represented by the general formula [4] with a compound represented by the general formula [5] or a salt thereof.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, nitriles, amides, sulfoxides, aromatic hydrocarbons, and water. These solvents may be mixed and used.

Preferred solvents include halogenated hydrocarbons, alcohols, nitriles, aromatic hydrocarbons, and water.

The amount of the solvent used is not particularly limited, as long as it is 1 to 50 times (v/w) the amount of the compound represented by the general formula [4], and preferably 1 to 15 times (v/w).

The amount of the compound represented by the general formula [5] or its salt used in this reaction may be 0.5 to 10 times the molar amount of the compound represented by the general formula [4], preferably 0.8 to 5.0 times the molar amount, more preferably 1.0 to 2.0 times the molar amount.

When a salt of the compound represented by the general formula [5] is used, it is preferred to add a base.

Examples of the base include organic bases and inorganic bases, and triethylamine and sodium hydrogen carbonate are preferred.

The amount of the base used may be 0.1 to 10 times the mole of the salt of the compound represented by the general formula [5], preferably 0.2 to 2.0 times the mole, and more preferably 0.5 to 1.5 times the mole.

The reaction temperature may be -10 to 100°C, preferably -5 to 80°C, and more preferably 0 to 60°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(Second step)

As the compound represented by the general formula [6], for example, 4-nitrobenzenesulfonyl chloride, 2,4,5-trichlorobenzenesulfonyl chloride, and pentafluorobenzenesulfonyl chloride are known.

The compound represented by the general formula [1b] can be produced by reacting the compound represented by the general formula [1a] with the compound represented by the general formula [6] in the presence of a base.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, and aromatic hydrocarbons. These solvents may be mixed and used.

Preferred solvents include esters, nitriles and aromatic hydrocarbons.

The amount of the solvent used is not particularly limited, and may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1a], and preferably 1 to 15 times (v/w).

Examples of the base used in the reaction include organic bases and inorganic bases, with triethylamine and N-methylimidazole being preferred.

The amount of the base used may be 0.5 to 10 times the mole of the compound represented by the general formula [1a], preferably 0.8 to 4.0 times the mole, and more preferably 1.0 to 3.0 times the mole.

The amount of the compound represented by the general formula [6] used in the reaction may be 0.5 to 10 times the molar amount of the compound represented by the general formula [1a], preferably 0.8 to 4.0 times the molar amount, and more preferably 1.0 to 2.0 times the molar amount.

The reaction temperature may be -10 to 100°C, preferably -5 to 80°C, and more preferably 0 to 60°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(Step 3)

The compound represented by the general formula [1c] can be produced by reacting the compound represented by the general formula [1b] with an alkali metal halide.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, and ureas. These solvents may be used in the form of a mixture.

Preferred solvents include ethers, esters, nitriles, amides, and ureas, with amides and ureas being preferred.

The amount of the solvent used is not particularly limited, and may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1b], and preferably 1 to 15 times (v/w).

Examples of the alkali metal halide used in the reaction include lithium fluoride, sodium fluoride, potassium fluoride, lithium bromide, sodium bromide, potassium bromide, lithium chloride, sodium chloride, potassium chloride, lithium iodide, sodium iodide, and potassium iodide, with lithium bromide being preferred.

The amount of the alkali metal halide used may be 0.5 to 20 times the mole of the compound represented by the general formula [1b], preferably 0.8 to 8.0 times the mole, and more preferably 1.0 to 5.0 times the mole.

The reaction temperature may be -50 to 150°C, preferably -10 to 120°C, more preferably 0 to 100°C, and even more preferably 20 to 80°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(Other methods)

The compound represented by the general formula [1c] can be produced by reacting the compound represented by the general formula [1a] with a halogenating agent in the presence of a base.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, ureas, and water. These solvents may be mixed and used.

Preferred solvents include ethers, esters, nitriles, amides, aromatic hydrocarbons, and ureas, with amides being more preferred.

The amount of the solvent used is not particularly limited, and may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1a], and preferably 1 to 15 times (v/w).

Examples of the halogenating agent in this reaction include chlorinating agents and brominating agents.

Examples of the chlorinating agent include phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, Vilsmeier reagent (N,N-dimethylformamide-phosphorus pentachloride, N,N-dimethylformamide-phosphorus oxychloride, etc.), Rydon reagent (Ph ₃ PCl ₂ , triphenylphosphine-carbon tetrachloride), thionyl chloride, and sulfuryl chloride. Sulfuryl chloride is preferred.

Examples of the brominating agent include phosphorus tribromide, N,N-dimethylformamide-phosphorus tribromide, triphenylphosphine-carbon tetrabromide, and triphenylphosphine dibromide.

The amount of the halogenating agent used may be 0.1 to 10 times the mole of the compound represented by the general formula [1a], preferably 0.8 to 5.0 times the mole, and more preferably 1.0 to 2.0 times the mole.

Examples of the base used in the reaction include organic bases and inorganic bases, with triethylamine and pyridine being preferred.

The amount of the base used may be 0.5 to 50 times the mole of the compound represented by the general formula [1a], preferably 0.8 to 20 times the mole, and more preferably 1.0 to 10 times the mole.

In this reaction, it is preferred to add a salt.

Examples of the salt include lithium chloride, lithium bromide, sodium bromide, calcium bromide, and pyridine hydrochloride.

In this halogenation reaction, a mixture of epimers is generally obtained. In order to improve the optical purity of the compound of the general formula [1c], it is preferred to use sulfuryl chloride and lithium chloride in combination.

The amount of the salt used may be 0.5 to 20 times the mole of the compound represented by the general formula [1a], preferably 0.8 to 5.0 times the mole, and more preferably 1.0 to 3.0 times the mole.

The reaction temperature may be -50 to 80°C, preferably -40 to 60°C, and more preferably -30 to 40°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(Step 4)

The compound represented by the general formula [1d] can be produced by hydrolyzing the compound represented by the general formula [1c] in the presence of an acid.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, ureas, and water. These solvents may be mixed and used.

Preferred solvents include ethers, esters, nitriles, amides, and water, with ethers and water being more preferred.

The amount of the solvent used is not particularly limited, and may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1c], and preferably 1 to 15 times (v/w).

Examples of the acid used in the reaction include hydrochloric acid, sulfuric acid, toluenesulfonic acid, acetic acid, glyoxylic acid, and phosphoric acid, with glyoxylic acid being preferred.

The amount of the acid used may be 0.5 to 100 times the mole of the compound represented by the general formula [1c], preferably 1.0 to 60 times the mole, more preferably 1.5 to 40 times the mole.

In this reaction, it is preferred to add a carbonyl compound.

Examples of the carbonyl compound include ketones such as acetone and 2-butanone, and aldehydes such as formaldehyde, benzaldehyde, glyoxal, and glyoxylic acid. Aldehydes are preferred, and glyoxylic acid is more preferred.

The amount of the carbonyl compound used may be 0.5 to 100 times the mole of the compound represented by the general formula [1c], preferably 1.0 to 60 times the mole, more preferably 1.5 to 40 times the mole.

The reaction temperature may be -10 to 120°C, preferably 0 to 100°C, and more preferably 20 to 80°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(5th step)

The compound represented by the general formula [1e] can be produced by reacting the compound represented by the general formula [1d] with a sulfur compound.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, ureas, and water. These solvents may be mixed and used.

Preferred solvents include ethers, esters, nitriles, amides, and ureas, with amides being more preferred.

The amount of the solvent used is not particularly limited, as long as it is 1 to 50 times (v/w) the amount of the compound represented by the general formula [1d], and preferably 1 to 15 times (v/w).

Examples of the sulfur compound used in the reaction include hydrogen sulfide or a salt thereof.

Examples of the salt of hydrogen sulfide include sodium hydrosulfide, sodium sulfide, potassium hydrosulfide, calcium hydrosulfide, and magnesium sulfide, with sodium hydrosulfide being preferred.

The amount of hydrogen sulfide or its salt used may be 0.2 to 10 times the mole of the compound represented by the general formula [1d], preferably 0.5 to 2.0 times the mole, more preferably 0.7 to 1.5 times the mole.

The reaction temperature may be -20 to 100°C, preferably -10 to 80°C, and more preferably -5 to 60°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

(Step 6)

As the compound represented by the general formula [7], for example, acetyl chloride, benzoyl chloride, benzenesulfonyl chloride, and methanesulfonyl chloride are known.

As the compound represented by the general formula [8], for example, acetic anhydride and propionic anhydride are known.

The compound represented by the general formula [9] can be produced by reacting the compound represented by the general formula [1e] with the compound represented by the general formula [7] or the compound represented by the general formula [8].

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, and aromatic hydrocarbons. These solvents may be mixed and used.

Preferred solvents include ethers, esters, nitriles and amides, with ethers, nitriles and amides being more preferred.

The amount of the solvent used is not particularly limited, and may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1e], and preferably 1 to 15 times (v/w).

The amount of the compound represented by the general formula [7] or the compound represented by the general formula [8] used in the reaction may be 0.5 to 50 times the molar amount of the compound represented by the general formula [1e], preferably 0.8 to 20 times the molar amount, more preferably 1.0 to 10 times the molar amount.

It is preferred to add a base in this reaction. Examples of the base include organic bases and inorganic bases, with triethylamine being preferred.

The amount of the base used may be 0.5 to 50 times the mole of the compound represented by the general formula [1e], preferably 0.8 to 20 times the mole, and more preferably 1.0 to 15 times the mole.

The reaction temperature may be -10 to 100°C, preferably -5 to 80°C, and more preferably 0 to 60°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

Method (1)

(wherein, R ^1a , R ^2a , R ³ , R ⁹ and R ¹⁰ have the same meanings as the above groups)

(Step 1)

Protected cytosine or protected N ⁴ -acylcytosine can be produced by reacting cytosine or N ⁴ -acylcytosine with a silanizing agent in the presence of a catalyst.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, nitriles, and aromatic hydrocarbons. These solvents may be used in the form of a mixture.

Preferred solvents include aliphatic hydrocarbons, halogenated hydrocarbons, and aromatic hydrocarbons. Aromatic hydrocarbons are preferred, and chlorobenzene and toluene are more preferred.

The amount of the solvent used is not particularly limited, as long as it is 1.0 to 50 times (v/w) the amount of cytosine or N ⁴ -acylcytosine, and preferably 1.0 to 15 times (v/w).

Examples of the silanizing agent used in the reaction include 1,1,1,3,3,3-hexamethyldisilazane.

The amount of the silanizing agent used is not particularly limited, as long as it is 1.0 to 50 times the mole of cytosine or N ⁴ -acylcytosine, and preferably 1.0 to 10 times the mole.

Examples of the catalyst used in this reaction include ammonium salts such as ammonium hydrogen sulfate.

The amount of the catalyst used may be 0.001 to 1 times the mole of cytosine or N ⁴ -acylcytosine, and preferably 0.01 to 0.1 times the mole.

The reaction temperature may be 20 to 150°C, and is preferably 50 to 150°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 10 hours, more preferably 5 minutes to 6 hours.

This reaction is preferably carried out under an inert gas (eg, nitrogen, argon) atmosphere.

The protected cytosine or protected N ⁴ -acylcytosine is preferably used directly in the next reaction without isolation.

The compound represented by the general formula [11] can be produced by reacting the compound represented by the general formula [9] with protected cytosine or protected N ⁴ -acylcytosine in the presence of an acid.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, and aromatic hydrocarbons. These solvents may be mixed and used.

Preferred solvents include aliphatic hydrocarbons, halogenated hydrocarbons, nitriles, and aromatic hydrocarbons, with halogenated hydrocarbons and aromatic hydrocarbons being preferred.

The amount of the solvent used is not particularly limited, as long as it is 1.0 to 50 times (v/w) the amount of the compound represented by the general formula [9], and preferably 1.0 to 15 times (v/w).

Examples of the acid used in the reaction include Lewis acids such as aluminum chloride, aluminum bromide, tin tetrachloride, titanium tetrachloride, isopropyl titanate, zinc chloride, and trimethylsilyl trifluoromethanesulfonate.

Preferred examples of the acid include aluminum chloride, tin tetrachloride, and trimethylsilyl trifluoromethanesulfonate, with trimethylsilyl trifluoromethanesulfonate being more preferred.

The amount of the acid used is not particularly limited, and may be 0.0001 to 10 times the mole of the compound represented by the general formula [9], and more preferably 0.001 to 1.0 times the mole.

The amount of protected cytosine or protected N ⁴ -acylcytosine used in the reaction may be 1.0 to 50 times the molar amount of the compound represented by the general formula [9], preferably 1.0 to 10 times the molar amount, and more preferably 1.0 to 5 times the molar amount.

The reaction temperature may be 20 to 150°C, and is preferably 20 to 100°C.

The reaction time may be 5 minutes to 50 hours, preferably 30 minutes to 24 hours, more preferably 1 hour to 10 hours.

(Second step)

The compound represented by the general formula [14] can be produced by deprotecting the compound represented by the general formula [11].

This method may be carried out according to the method described in Patent Document 1 or Protective Groups in Organic Synthesis, 4th edition, pp. 696-926, 2007, John Wiley & Sons, INC.

Preferred deprotection methods include methods using a base.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, and water. These solvents may be used in the form of a mixture.

Preferred solvents include alcohols and water, with alcohols being more preferred.

The amount of the solvent used is not particularly limited, as long as it is 1.0 to 50 times (v/w) the amount of the compound represented by the general formula [11], and preferably 1.0 to 15 times (v/w).

Examples of the base used in the reaction include inorganic bases such as sodium hydroxide and potassium hydroxide, ammonia, and metal alkoxides such as sodium methoxide and sodium ethoxide.

Preferred bases include ammonia and metal alkoxides, with ammonia and sodium methoxide being more preferred.

The amount of the base used is not particularly limited, and may be 0.001 to 10 times the mole of the compound represented by the general formula [11], and more preferably 0.01 to 1.0 times the mole.

The reaction temperature may be 0 to 100°C, and is preferably 10 to 70°C.

The reaction time may be 5 minutes to 7 days, and is preferably 1 to 24 hours.

Method (2)

(wherein, R ^1a , R ^2a , R ³ , R ⁹ , R ^10a and X ⁴ have the same meanings as the above groups)

(Step 1)

The compound represented by the general formula [11a] can be produced by reacting the compound represented by the general formula [9] with protected cytosine.

This method may be carried out according to Method 1 (first step).

The compound represented by the general formula [11a] is preferably used directly in the next reaction without isolation.

(Second step)

As the compound represented by the general formula [12], for example, acetyl chloride, propionyl chloride, pivaloyl chloride, and benzoyl chloride are known.

As the compound represented by the general formula [13], for example, acetic anhydride is known.

The compound represented by the general formula [11b] can be produced by reacting a compound represented by the general formula [11a] with a compound represented by the general formula [12] or a compound represented by the general formula [13] in the presence or absence of a base and in the presence or absence of a catalyst.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, and aromatic hydrocarbons. These solvents may be used in the form of a mixture.

Preferred solvents include aliphatic hydrocarbons, halogenated hydrocarbons, and aromatic hydrocarbons, with halogenated hydrocarbons and aromatic hydrocarbons being more preferred.

The amount of the solvent used is not particularly limited, as long as it is 1 to 50 times (v/w) the amount of the compound represented by the general formula [11a], and preferably 1 to 15 times (v/w).

When the compound represented by the general formula [12] is used, it is preferred to add a base.

Examples of the base include organic bases and inorganic bases, and organic bases are preferred.

The amount of the base used may be 0.5 to 10 times the mole of the compound represented by the general formula [11a], and is preferably 1.0 to 5 times the mole.

When the compound represented by the general formula [13] is used, it is preferred to add a catalyst.

Examples of the catalyst include organic bases, and dimethylaminopyridine is preferred.

The amount of the catalyst used may be 0.001 to 1.0 times the mole of the compound represented by the general formula [11a], and is preferably 0.01 to 1.0 times the mole.

The amount of the compound represented by the general formula [12] or the compound represented by the general formula [13] used may be 1.0 to 20 times the mole of the compound represented by the general formula [11a], and preferably 1.0 to 10 times the mole.

The reaction temperature may be -20 to 100°C, and is preferably -10 to 80°C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to 24 hours, more preferably 5 minutes to 6 hours.

In this reaction, it is preferred to isolate the compound represented by the general formula [11b] as a solid. By isolating the compound represented by the general formula [11b], the purity of the compound represented by the general formula [14] is improved.

(Step 3)

The compound represented by the general formula [14] can be produced by deprotecting the compound represented by the general formula [11b].

This method may be carried out according to the method (1) (second step).

Method (3)

(wherein, R ^1a , R ^2a , R ³ , R ⁹ , R ¹⁰ and X ³ have the same meanings as the above groups)

(Step 1)

The compound represented by the general formula [10] can be produced by halogenating the compound represented by the general formula [9].

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, carboxylic acids, ketones, nitriles, amides, and sulfoxides. These solvents may be mixed and used.

Preferred solvents include halogenated hydrocarbons, ethers, carboxylic acids, and nitriles, with halogenated hydrocarbons being more preferred.

The amount of the solvent used is not particularly limited, as long as it is 1 to 100 times (v/w) the amount of the compound represented by the general formula [9], and preferably 1 to 10 times (v/w).

Examples of the reagent used for halogenation include hydrogen halide, alkali metal halide, and halogenating agents.

Examples of the hydrogen halide include hydrogen chloride, hydrogen bromide and hydrogen iodide, with hydrogen bromide being preferred.

Examples of the alkali metal halide include lithium bromide, sodium bromide, potassium bromide, lithium chloride, sodium chloride, potassium chloride, lithium iodide, sodium iodide, and potassium iodide.

Examples of the halogenating agent in this reaction include phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, sulfuryl chloride, and phosphorus tribromide.

Preferred reagents include hydrogen halides, and hydrogen bromide is more preferred.

The amount of the reagent used may be 1 to 100 times the mole of the compound represented by the general formula [9], preferably 1 to 10 times the mole, more preferably 1 to 5 times the mole.

The reaction temperature may be -30 to 40°C, more preferably -5 to 10°C.

The reaction time may be 5 minutes to 10 hours, preferably 5 minutes to 3 hours, more preferably 5 minutes to 1 hour.

(Step 2)

The compound represented by the general formula [11] can be produced by reacting the compound represented by the general formula [10] with protected cytosine or protected N ⁴ -acylcytosine.

This method may be carried out according to Patent Document 1 or method (1) (first step).

(Step 3)

The compound represented by the formula [14] can be produced by deprotecting the compound represented by the general formula [11].

This method may be carried out according to the method (1) (second step).

Method (4)

(wherein, R ^1a , R ^2a , R ³ , R ⁹ , R ^10a , X ³ and X ⁴ have the same meanings as the above groups)

(Step 1)

The compound represented by the general formula [10] can be produced by halogenating the compound represented by the general formula [9].

This method may be carried out according to method (3) (first step).

(Step 2)

The compound represented by the general formula [11a] can be produced by reacting the compound represented by the general formula [10] with protected cytosine.

This method may be carried out according to method (3) (second step).

(Step 3)

As the compound represented by the general formula [12], for example, acetyl chloride, propionyl chloride, pivaloyl chloride, and benzoyl chloride are known.

As the compound represented by the general formula [13], for example, acetic anhydride is known.

The compound represented by the general formula [11b] can be produced by reacting the compound represented by the general formula [11a] with the compound represented by the general formula [12] or the compound represented by the general formula [13].

This method may be carried out according to method (2) (second step).

(Step 4)

The compound represented by the general formula [14] can be produced by deprotecting the compound represented by the general formula [11b].

This method may be carried out according to the method (1) (second step).

In the above-mentioned production method, the protecting groups of the hydroxyl group, amino group or carboxyl group may be appropriately combined and replaced.

The compound obtained by the above production method can also be isolated and purified by common methods such as extraction, crystallization, distillation or column chromatography. In addition, the compound obtained by the above production method can be used directly in the next reaction without isolation.

The compound having a formyl group obtained by the above-mentioned production method may contain hydrates or alcohol adducts, all of which are encompassed by the present invention.

The compound obtained by the above-mentioned production method may exist in tautomers or mirror image isomers, and the present invention also encompasses these isomers.

In addition, when crystal polymorphs, salts, hydrates or solvates exist, the present invention also includes all of the crystal polymorphs, salts, hydrates or solvates.

Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited to these.

Example

Unless otherwise specified, silica gel column chromatography used SNAP KP-Sil Cartridge manufactured by Biotage Japan, FR-260 Hi-Flash ^™ Column manufactured by YAMAZEN, or Wakogel C-200 manufactured by YAMAZEN.

The mixing ratio in the eluent is the volume ratio.

For example, "hexane/ethyl acetate = 90/10 to 50/50" means that the eluent of "hexane:ethyl acetate = 90:10" is changed to an eluent of "hexane:ethyl acetate = 50:50".

The ¹ H-NMR spectrum was measured using Bruker AV400N (Bruker) or Bruker AV300 (Bruker) using tetramethylsilane as an internal standard, and the total δ value was expressed in ppm.

The ¹⁹ F-NMR spectrum was measured using Bruker AV400N (Bruker), and the total δ value was expressed in ppm.

LC/MS analysis was performed under the following conditions.

Measurement equipment: Waters SQD

Column: Waters BEHC 18 1.7 μm, 2.1 × 30 mm

Solvent: Solution A: 0.1% formic acid/water

Solution B: 0.1% formic acid/acetonitrile

Gradient cycle: 0.00 min (solution A/solution B = 95/5), 2.00 min (solution A/solution B = 5/95), 3.00 min (solution A/solution B = 5/95), 3.01 min (solution A/solution B = 100/0), 3.80 min (solution A/solution B = 100/0)

Flow rate: 0.5 mL/min

Column temperature: room temperature

Ionization method: Electrospray ionization (detection of ESI positive and negative ion peaks)

Detection wavelength: 254nm

The abbreviations in the examples have the following meanings.

Ac：Acetyl

Bn: benzyl

Bz: benzoyl

Cbz: benzyloxycarbonyl

Et: ethyl

Me：methyl

Ms：Methylsulfonyl

Ph: phenyl

PMB: 4-methoxybenzyl

ⁱ Pr：isopropyl

TBDPS: tert-butyl(diphenyl)silyl

THP: Tetrahydropyranyl

TIPS: tri(propane-2-yl)silyl

Tol: (4-methylphenyl)carbonyl

DMSO-d ₆ : heavy dimethyl sulfoxide

RT(min): holding time (minutes)

Example 1

(1)

To 119 g of ((2R,3R,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl benzoate, 474 mL of methanol and 21.4 g of O-methylhydroxylamine hydrochloride were added dropwise. 35.7 mL of triethylamine was added dropwise at 0-10°C, and the mixture was stirred at room temperature for 5 hours. 400 mL of ethyl acetate and 400 mL of saturated sodium bicarbonate were added to the reaction mixture, and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 92.6 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl benzoate as a colorless oil. ^1H -NMR analysis showed a cis/trans ratio of 78:22.

¹ H-NMR (CDCl ₃ ) δ value:

3.05 (0.22H, d, J=5.6Hz), 3.11 (0.78H, d, J=6.0Hz), 3.83 (2.34H, s), 3.92 (0.66H, s), 4.35-4.49 (m, 2H), 4.55-4.68 (m, 1H), 5.42-5.54 (m, 0.78H), 5.48-5.67 (m, 0.78H), 5.74 (0.22H, ddd, J=28.0, 8.0, 1.6Hz), 6.06 (0.22H, ddd, J=46.4, 4.8, 1.6Hz), 6.84 (0.22H, dd, J =11.2, 4.8Hz), 7.38-7.48 (4.78H, m), 7.54-7.63 (2H, m), 8.00-8.10 (4H, m)

(2)

To a solution of 87.0 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl benzoate in 300 mL of ethyl acetate was added 64.4 g of 4-nitrobenzenesulfonyl chloride at 0-10°C, followed by the dropwise addition of 40.5 mL of triethylamine over 30 minutes at a temperature below 15°C, and the mixture was stirred at 26°C for 5 hours. To the reaction mixture was added 300 mL of a 5% aqueous sodium bicarbonate solution, and the mixture was stirred at the same temperature for 2 hours. The aqueous layer was removed, and the organic layer was washed sequentially with a mixture of 100 mL of 1 mol/L hydrochloric acid and 100 mL of a 10% aqueous sodium chloride solution, and then with a mixture of 100 mL of a 5% aqueous sodium bicarbonate solution and 100 mL of a 10% aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 126 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((4-nitrobenzene)sulfonyl)oxy)pentan-3-yl benzoate as a pale yellow solid. ¹ H-NMR analysis showed a cis/trans ratio of 1:2.

¹ H-NMR (CDCl ₃ ) δ value:

8.20-8.15 (2H, m), 8.10-8.05 (2H, m), 8.03-7.96 (2H, m), 7.92-7.86 (2H, m), 7.64-7.54 (2H, m), 7.48-7.38 (4.23H, m), 6.82 (0.77H, dd, J=11.2, 4.4Hz), 5.94 (0.77H, ddd, J=26.4, 6.0, 2.4Hz), 5.84 (0.77H, ddd, J=46.8, 4.4, 2.4Hz), 5.77 (0.23H, ddd, J=23.2, 5.6, 2.8Hz), 5.43 (0.23H, ddd, J=6.8, 5.6, 2.8Hz), 5.40 (0.77H, ddd, J=7.2, 6.0, 2.8Hz), 5.34 (0.23H, ddd, J=46.0, 6.8, 2.8Hz), 4.76 (0.23H, dd, J =12.4, 2.8Hz), 4.75 (0.77H, dd, J = 12.4, 2.8Hz), 4.52 (0.77H, dd, J = 12.4, 7.2Hz), 4.51 (0.23H, dd, J = 12.4, 6.8Hz), 3.89 (2.31H, s), 3.85(0.69H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-204.4--204.7(0.77F, m), -196.4--196.6(0.23F, m)

(3)

To a solution of 101.5 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((4-nitrobenzene)sulfonyl)oxy)pentan-3-yl benzoate in 350 mL of N,N-dimethylformamide, 153.4 g of anhydrous lithium bromide was added in six portions at 50-60°C, and the mixture was stirred at 57°C for 4 hours and 30 minutes. Ethyl acetate (400 mL) and 1 mol/L hydrochloric acid (250 mL) were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed sequentially with 1 mol/L hydrochloric acid and 250 mL of a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to yield 79.9 g of a brown oil.

Results of ¹ H-NMR measurement showed that the brown oil was a mixture of (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl benzoate and (2R,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl benzoate (87:13). The cis/trans ratio of (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl benzoate was 82:18.

(2S,3S,4R)-1-(Benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl benzoate

¹ H-NMR (CDCl ₃ ) δ value:

8.15-8.00 (4H, m), 7.65-7.55 (2H, m), 7.51-7.40 (4.82H, m), 6.87 (0.18H, dd, J=11.2, 4.8Hz), 6.07 (0.18H, ddd, J=46.8, 4.4, 3.2Hz), 5.94 (0.18H, ddd, J=24.4, 6.0, 3.2Hz), 5.82 (0.82H, ddd, J=16.4, 6.0, 2.8Hz), 5.52 (0.82H, dt, J=46.8, 6.0Hz), 4.84-4.71 (1H, m), 4.64-4.55 (2H, m), 3.89 (2.46H, s), 3.85 (0.54H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-193.3--193.5(0.82F, m),-203.1--203.4(0.18F, m)

(4)

To a solution of 79.9 g of the brown oil obtained in Example 1(3) in 255 mL of tetrahydrofuran was added 170 mL of a 50% aqueous solution of glyoxylic acid, and the mixture was stirred at 56°C for 12 hours. The reaction mixture was cooled to room temperature, 255 mL of ethyl acetate and 170 mL of a 10% aqueous sodium chloride solution were added, and the aqueous layer was removed. The organic layer was washed sequentially with 170 mL of a 10% aqueous sodium chloride solution and a mixture of 170 mL of a 5% aqueous sodium bicarbonate solution and 170 mL of a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 70.4 g of a brown oil.

The obtained oily substance was a mixture of (2S,3S,4S)-1-(benzoyloxy)-2-bromo-4-fluoro-5-pentanon-3-yl benzoate and its hydrate.

(5)

To a solution of 70.4 g of the brown oil obtained in Example 1(4) in 700 mL of N-methylpyrrolidone was added 26.7 g of sodium hydrosulfide x-hydrate (Wako Pure Chemical Industries, Ltd.) at 0-10°C. After stirring at the same temperature for 2 hours, 13.4 g of sodium hydrosulfide x-hydrate was added, and the mixture was stirred at 0-10°C for 3 hours. 1050 mL of ethyl acetate and 700 mL of a 10% aqueous sodium chloride solution were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed successively with a mixture of 700 mL of 1 mol/L hydrochloric acid and 350 mL of a 10% aqueous sodium chloride solution, and a mixture of 350 mL of a 5% aqueous sodium bicarbonate solution and 350 mL of a 10% aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain 52.1 g of ((2R,3S,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl benzoate as a light brown oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.08-7.97 (4H, m), 7.63-7.31 (6H, m), 6.05 (0.61H, ddd, J=12.0, 7.2, 5.6Hz), 5.83 (0.39H, ddd, J=12.4, 2.8, 2.0Hz), 5.64 (0.39H, ddd, J=9.6, 8.4, 2.0Hz), 5.49 (0.61H, m), 5.31 (0.39H, dt, J=47.6, 2.0Hz), 5.20 (0.61H, ddd, J=51.2, 7.2, 4.0Hz), 4.67 (0.61H, dd, J=11.6, 6.8Hz), 4.60 (0.61H, dd, J=11.6, 6.8Hz), 4.53-4.47 (0.78H, m), 4.21 (0.39H, tdd, J=8.0, 2.8, 1.2Hz), 3.75 (0.61H, td, J=6.8, 5.6Hz), 3.01 (0.61H, d, J=4.8Hz, -OH), 2.64 (0.39H, d, J=8.4Hz, -OH)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-183.6-183.9(0.61F, m), -192.3-192.6(0.39F, m)

(6)

To a solution of 52.1 g of ((2R,3S,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl benzoate in 210 mL of tetrahydrofuran was added 26.0 mL of acetic anhydride, and 58.0 mL of triethylamine was added dropwise at below 10°C. The mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 100 mL of ethyl acetate, 210 mL of a 5% aqueous sodium bicarbonate solution, and 100 mL of a 10% aqueous sodium chloride solution, and stirred for 1 hour. The aqueous layer was removed, and the organic layer was washed sequentially with a mixture of 150 mL of 1 mol/L hydrochloric acid and 100 mL of a 10% aqueous sodium chloride solution, and then with a mixture of 50 mL of a 5% aqueous sodium bicarbonate solution and 100 mL of a 10% aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from methanol to obtain 29.3 g of ((2R,3S,4S)-5-(acetyloxy)-3-(benzoyloxy)-4-fluorotetrahydrothiophen-2-yl)methyl benzoate as a white solid.

(7)

To a solution of 5.0 g of ((2R,3S,4S)-5-(acetyloxy)-3-(benzoyloxy)-4-fluorotetrahydrothiophen-2-yl)methyl benzoate in 20 mL of dichloromethane, under a nitrogen atmosphere and ice-cooling, was added 9.2 mL of a 30% hydrogen bromide/acetic acid solution, and the mixture was stirred at 5-7°C for 3 hours. 10 mL of a 30% aqueous sodium acetate solution was added dropwise to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layer and the extract were combined, washed with a 25% aqueous sodium bicarbonate solution, and the aqueous layer was extracted twice with dichloromethane. The organic layer and the extract were combined, washed with a 3% aqueous sodium bicarbonate solution, and the aqueous layer was extracted with dichloromethane. The organic layer and the extract were combined and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain 15 mL of a dichloromethane solution of ((2R,3S,4S)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydrothiophen-2-yl)methyl benzoate.

Separately, under a nitrogen atmosphere, to a suspension of 3.66 g of acetylcytosine in 15 mL of ethylbenzene were added 7.7 g of 1,1,1,3,3,3-hexamethyldisilazane and 15.8 mg of ammonium sulfate, and the mixture was stirred at 110-115°C for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain 7.5 g of a white solid.

To the obtained white solid was added 1.25 mL of N-ethylpyrrolidone, and 15 mL of the above-mentioned dichloromethane solution was added dropwise at 70-75°C, and stirred at this temperature for 1 hour. The reaction mixture was cooled to room temperature, 75 mL of dichloromethane, 4 mL of water and 5 g of diatomaceous earth were added, and stirred at 27-28°C for 2 hours. The insoluble matter was filtered off and the residue was washed with dichloromethane. The filtrate was combined with the washings, washed with 14.3 mL of a solution of 2.85 g of dipotassium hydrogen phosphate and 0.38 g of potassium dihydrogen phosphate in water, and the aqueous layer was extracted with dichloromethane. The organic layer was combined with the extract, the insoluble matter was filtered off, and the solvent was replaced with propyl acetate. The precipitated solid was collected by filtration and washed with propyl acetate to obtain 1.53 g of ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophen-2-yl)methyl 4-benzoate as a white solid.

(8)

To a solution of 2.03 g of ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophen-2-yl)methyl 4-benzoate in 40 mL of methanol was added 20 mL of 25% aqueous ammonia, and the mixture was stirred at room temperature for 12 hours. The solvent was concentrated under reduced pressure, and the precipitated solid was washed with methanol to obtain 374 mg of (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophene as a white solid.

The washings were concentrated under reduced pressure, and the precipitated solid was dissolved in 150 mL of ethyl acetate. 80 mL of the solvent was distilled off under reduced pressure, and the precipitated solid was collected by filtration and washed with ethyl acetate to obtain 491 mg of (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophene as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

7.99 (1H, d, J = 7.9Hz), 7.28-7.20 (2H, brs), 6.46 (1H, dd, J = 14.5, 5.3Hz), 5.88 (1H, d, J = 4.6Hz), 5.77 (1H, d, J = 7.9Hz), 5.25 (1H, t, J = 5.3Hz), 4.92 (1H, dt, J = 50.9, 5.3Hz), 4.30-4.19 (1H, m), 3.78-3.54 (2H, m), 3.23 (1H, q, J = 5.9Hz)

Example 2

(1)

Under a nitrogen atmosphere, to a suspension of 150 g of (3S,4R,5R)-4-(benzoyloxy)-5-((benzoyloxy)methyl)-3-fluorooxolan-2-yl benzoate in 105 mL of acetic acid was added dropwise 76 mL of 30% hydrogen bromide/acetic acid at room temperature, and the mixture was stirred at 25°C for 8 hours. To the reaction mixture were added 450 mL of toluene and 450 mL of water, and the mixture was stirred for 5 minutes, after which the aqueous layer was removed. The resulting organic layer was washed sequentially with 450 mL of water and 450 mL of a 5% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 136 g of ((2R,3R,4S)-3-(benzoyloxy)-5-bromo-4-fluorooxolan-2-yl)methyl benzoate as a colorless oil.

The results of ¹ H-NMR measurement showed that all the obtained compounds were α-isomers.

¹ H-NMR (CDCl ₃ ) δ value:

8.11 (2H, dd, J = 8.0, 0.8Hz), 8.07 (2H, dd, J = 8.0, 0.8Hz), 7.63 (1H, tt, J = 8.0, 0.8Hz), 7.56 (1H, tt, J = 8.0, 0.8Hz), 7.49 (2H, t, J=8.0Hz), 7.43 (2H, t, J=8.0Hz), 6.64 (1H, d, J=12.4Hz), 5.60 (1H, d, J=50.0Hz), 5.54 (1H, dd, J=22.0, 3.0Hz), 4.68-4.86 (3H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value: -165.8--166.1 (1F, m)

(2)

To 136 g of ((2R,3R,4S)-3-(benzoyloxy)-5-bromo-4-fluorooxolan-2-yl)methyl benzoate, 270 mL of acetonitrile and 300 mL of a 10% aqueous sodium bicarbonate solution were added, and the mixture was stirred at 50°C for 4 hours. 150 mL of toluene was added to the reaction mixture, and the aqueous layer was removed, followed by cooling to 25°C to obtain a toluene/acetonitrile solution of ((2R,3R,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl benzoate.

((2R,3R,4S)-3-(Benzoyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl benzoate was not isolated but directly used in the next reaction as a solution.

(3)

To a toluene/acetonitrile solution of ((2R,3R,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl benzoate, 135 mL of water and 40.2 g of O-methylhydroxylamine hydrochloride were added. 58.2 mL of triethylamine was added dropwise at 25-30°C, and the mixture was stirred for 6 hours. To the reaction mixture, 150 mL of toluene and 300 mL of a 10% aqueous sodium chloride solution were added, and the aqueous layer was removed. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 122 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl benzoate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 3:1.

¹ H-NMR (CDCl ₃ ) δ value:

8.10-8.00 (4H, m), 7.63-7.54 (2H, m), 7.48-7.38 (4.75H, m), 6.84 (0.25H, dd, J = 11.2, 4.8Hz), 6.06 (0.25H, ddd, J = 46.4, 4.8, 1.6Hz), 5.74 (0.25H, ddd, J=28.0, 8.0, 1.6Hz), 5.75 (0.75H, ddd, J=45.6, 6.8, 2.4Hz), 5.49 (0.75H, ddd, J=26.0, 8.4, 2.4Hz), 4.64 (0.75H, dd, J=12.0, 2.4Hz), 4.60 (0.25H, dd, J=11.2, 2.4Hz), 4.50-4.35 (2H, m), 3.91 (0 .75H, s), 3.82 (2.25H, s), 3.11 (0.75H, d, J = 6.0Hz), 3.05 (0.25H, d, J = 5.6Hz)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-199.9--200.2(0.75F, m),-207.3--207.5(0.25F, m)

Example 3

(1)

Under a nitrogen atmosphere, to a mixture of 30.0 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl benzoate in 150 mL of N,N-dimethylacetamide and 30 mL of pyridine was added 6.50 g of lithium chloride. Sulfuryl chloride (6.40 mL) was then added dropwise over 20 minutes at -20 to 0°C, followed by stirring at room temperature for 3 hours. To the reaction mixture were added 300 mL of ethyl acetate, 150 mL of a 20% aqueous sodium chloride solution, and 100 mL of water, and the aqueous layer was removed. The organic layer was washed twice with 150 mL of 1 mol/L hydrochloric acid, then washed with 150 mL of a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to obtain 34.2 g of (2S,3S,4R)-1-(benzoyloxy)-2-chloro-4-fluoro-5-(methoxyimino)pentan-3-yl benzoate as a colorless oil.

(2S,3S,4R)-1-(Benzoyloxy)-2-chloro-4-fluoro-5-(methoxyimino)pentan-3-yl benzoate was used directly in the next reaction without isolation.

A small amount of the reaction solution was diluted in heavy chloroform and measured by ¹ H-NMR. The result showed that the cis/trans ratio was 85:15.

¹ H-NMR (CDCl ₃ ) δ value:

3.84 (0.45H, s), 3.88 (2.55H, s), 4.54-4.74 (3H, m), 5.52 (0.85H, dt, J=46.4, 6.4Hz), 5.85 (0.85H, ddd, J=17.2, 5.9, 3.2Hz), 5.88-6.00 (0.15H, m), 5.95-6.12 (0.15H, m), 6.88 (0.15H, dd, J=11.2, 4.8Hz), 7.40-7.53 (4.85H, m), 7.55-7.66 (2H, m), 8.01-8.15 (4H, m)

(2)

Under a nitrogen atmosphere, a mixture of 30.6 g of (2S,3S,4R)-1-(benzoyloxy)-2-chloro-4-fluoro-5-(methoxyimino)pentan-3-yl benzoate obtained in Example 3(1), 183 mL of tetrahydrofuran, and 133 mL of glyoxylic acid was stirred at 60°C for 10 hours. To the reaction mixture were added 300 mL of ethyl acetate, 200 mL of a 20% aqueous sodium chloride solution, 300 mL of water, and 65.1 g of sodium bicarbonate, and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 27.3 g of a colorless oil.

The obtained oily substance was a mixture of (2S,3S,4S)-1-(benzoyloxy)-2-chloro-4-fluoro-5-pentanon-3-yl benzoate and its hydrate.

¹ H-NMR (CDCl ₃ ) δ value:

4.69-4.78 (3H, m), 5.37 (1H, dd, J=46.8, 4.0Hz), 5.85 (1H, dt, J=20.8, 3.6Hz), 7.39-7.53 (4H, m), 7.54-7.66 (2H, m), 8.01-8.12 (4H, m), 9.83 (1H, d, J=6.4Hz)

(3)

Under a nitrogen atmosphere, 96.2 mg of sodium monohydrosulfide n-hydrate was added to a solution of 350 mg of the colorless oil obtained in Example 3(2) in 5.25 mL of N-methylpyrrolidone, followed by stirring at room temperature for 5 hours. 7.90 mL of ethyl acetate, 5.25 mL of a 20% aqueous sodium chloride solution, and 5.25 mL of a saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to obtain 80.0 mg of ((2R,3S,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

3.74 (0.55H, q, J=6.8Hz), 4.17-4.23 (0.45H, m), 4.44-4.55 (0.90H, m), 4.56-4.64 (0.55H, m), 4.64-4.72 (0.55H, m), 5.20 (0.55H, ddd, J =51.5, 7.6, 4.0Hz), 5.32 (0.45H, dt, J = 47.6, 2.4Hz), 5.48 (0.55H, t, J = 4.4Hz), 5.64 (0.45H, dd, J = 8.411.2, 1.6Hz), 5.82 (0.45H, dt, J = 12.8, 3.2Hz), 6.04-6.12 (0.55H, m), 7.28-7.65 (6H, m), 7.94-8.16 (4H, m)

(4)

Under a nitrogen atmosphere, 39.5 mL of triethylamine and 17.9 mL of acetic anhydride were dropwise added to a solution of 10.3 g of ((2R,3S,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl benzoate in 20 mL of ethyl acetate, followed by stirring at room temperature for 4 hours. 50 mL of ethyl acetate, 20 mL of 20% aqueous sodium chloride, and 30 mL of saturated aqueous sodium bicarbonate were added to the reaction mixture, and the aqueous layer was removed. 30 mL of saturated aqueous ammonium chloride was added to the organic layer, and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1) to obtain 8.35 g of ((2R,3S,4S)-5-(acetyloxy)-3-(benzoyloxy)-4-fluorotetrahydrothiophen-2-yl)methyl benzoate as a brown oil.

¹ H-NMR (CDCl ₃ ) δ value:

2.12 (1.29H, s), 2.13 (1.71H, s), 3.74 (0.57H, q, J = 6.8Hz), 4.11 (0.43H, q, J = 6.8Hz), 4.43-4.59 (1.43H, m), 4.69 (0.57H, dd, J = 11.1, 6.0Hz), 5.31 (0.57H, ddd, J=50.8, 9.1, 4.8Hz), 5.39 (0.43H, dt, J=47.6, 3.2Hz), 5.85 (0.43H, dt, J=12.0, 4.0Hz), 6.08 (0.57H, dt, J=11.6, 8.4Hz), 6.18 (0.57H, d, J=4.8Hz), 6.24 (0.43H, dd, J=13.6, 2.0Hz), 7.28-7.36 (1.14H, m), 7.37-7.65 (4.86H, m), 7.92-7.98 (1.14H, m), 8.00-8.09 (2.86H, m)

Example 4

(1)

To a suspension of 17.2 g of O-benzylhydroxylamine hydrochloride in 86 mL of ethyl acetate was added 200 mL of 5% aqueous sodium bicarbonate solution. The aqueous layer was removed, and the solvent was then concentrated under reduced pressure. To the resulting residue were added 130 mL of dichloromethane, 19.4 g of ((2R,3R,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methylbenzoate, 13.6 g of sodium bicarbonate, and 1.36 g of pyridinium p-toluenesulfonate, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was cooled to room temperature, 100 mL of ethyl acetate, 100 mL of 20% aqueous sodium chloride solution, and 50 mL of saturated aqueous sodium bicarbonate solution were added, and the aqueous layer was removed. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1) to obtain 36.4 g of (2R,3R,4R)-3-(benzoyloxy)-5-((benzyloxy)imino)-4-fluoro-2-hydroxypentyl benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

2.88 (0.31H, s), 2.91 (0.69H, s), 4.33-4.46 (2H, m), 4.55-4.64 (1H, m), 5.06 (1.38H, s), 5.16 (0.62H, dd, J=6.8, 5.5Hz), 5.49 (0.69H, ddd, J=25.9, 7.6, 1.6Hz), 5.58 (0.69H, ddd, J=46.7, 6.4, 2.4Hz), 5.79 (0.31H, dd, J=27.5, 7.9Hz), 6.10 (0.31H, ddd, J=46.7, 4.8, 2.0Hz), 6.90 (0.31H, dd, J=11.2, 4.8Hz), 7.24 (5H, m), 7.38-7.53 (4.69H, m), 7.54-7.64 (2H, m), 7.99-8.10 (4H, m)

(2)

Under a nitrogen atmosphere, a mixture of 1.00 g of (2R,3R,4R)-3-(benzoyloxy)-5-((benzyloxy)imino)-4-fluoro-2-hydroxypentyl benzoate, 5.00 mL of N,N-dimethylformamide, and 1.00 mL of pyridine was cooled to -20°C. While maintaining the internal temperature below 0°C, 0.210 mL of sulfuryl chloride was added dropwise over 20 minutes, followed by stirring at room temperature for 3 hours. To the reaction mixture were added 10 mL of ethyl acetate, 5 mL of 20% aqueous sodium chloride solution, and 5 mL of water, and the aqueous layer was removed. 5 mL of 1 mol/L hydrochloric acid was added to the organic layer, and the removal of the aqueous layer was repeated twice. Next, 5 mL of saturated aqueous sodium bicarbonate solution was added to the organic layer, and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1) to obtain 1.01 g of (2S,3S,4R)-3-(benzoyloxy)-5-((benzyloxy)imino)-2-chloro-4-fluoropentyl benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

4.48-4.75 (3H, m), 5.07 (0.4H, s), 5.11 (1.6H, s), 5.52 (0.8H, dt, J=46.8, 6.0Hz), 5.84 (0.8H, ddd, J=16.4, 6.0, 3.2Hz), 5.89-6.00 (0.2H, m), 6.01-6.18 (0.2H, m), 6.92 (0.2H, dd, J=8.1, 3.6Hz), 7.25-7.34 (5H, m), 7.39-7.51 (4.8H, m), 7.53-7.64 (2H, m), 8.00-8.12 (4H, m)

(3)

Under a nitrogen atmosphere, a mixture of 0.610 g of (2S,3S,4R)-3-(benzoyloxy)-5-((benzyloxy)imino)-2-chloro-4-fluoropentyl benzoate, 3.00 mL of benzaldehyde, and 0.300 mL of concentrated sulfuric acid was stirred at room temperature for 1 hour. To the reaction mixture were added 5 mL of ethyl acetate, 5 mL of a 20% aqueous sodium chloride solution, and 5 mL of a saturated aqueous sodium bicarbonate solution, and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1) to obtain 0.260 g of a colorless oil.

The obtained oily substance was a mixture of (2S,3S,4S)-1-(benzoyloxy)-2-chloro-4-fluoro-5-pentanon-3-yl benzoate and its hydrate.

¹ H-NMR (CDCl ₃ ) δ value:

4.69-4.78 (3H, m), 5.37 (1H, dd, J=46.8, 4.0Hz), 5.85 (1H, dt, J=20.8, 3.6Hz, 7.39-7.53 (4H, m), 7.54-7.66 (2H, m), 8.01-8.12 (4H, m), 9.83 (1H, d, J=6.4Hz)

Example 5

(1)

A mixture of 1.70 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol, 30 mL of tetrahydrofuran, 4.24 mL of triethylamine, 2.8 mL of acetic anhydride, and 0.01 g of 4-dimethylaminopyridine was stirred at 25°C for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with aqueous sodium bicarbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 2.2 g of ((2R,3R,4S)-3-(acetyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl acetate as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ value:

5.28-5.12 (2H, m), 5.01 (1H, d, J = 4.0Hz), 4.31 (1H, dd, J = 3.6, 11.2Hz), 4.10-4.02 (2H, m), 3.34 (3H, s), 2.09 (3H, s), 2.23 (3H, s)

(2)

A mixture of 2.1 g of ((2R,3R,4S)-3-(acetyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl acetate, 9 mL of trifluoroacetic acid, and 1 mL of water was stirred at 50°C for 8 hours. Ethyl acetate and aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain ((2R,3R,4S)-3-(acetyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl acetate as a colorless oil.

A mixture of the obtained ((2R,3R,4S)-3-(acetyloxy)-4-fluoro-5-hydroxyoxolan-2-yl) methyl acetate, 10 mL of methanol, 0.85 g of O-methylhydroxylamine hydrochloride and 0.7 mL of triethylamine was stirred at 25 ° C for 0.5 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) to obtain 0.35 g of (2R,3R,4R)-1-(acetyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentane-3-yl acetate as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ value:

7.51 (0.75H, dd, J=6.8, 7.2Hz), 7.02 (0.25H, dd, J=4.8, 10.4Hz), 5.93-5.73 (1.25H, m), 5.36 (0.75H, ddd, J=2.8, 6.8, 45.6Hz), 5.12 (0.25H, ddd, J=1.6, 9.2, 29.6Hz), 4.97 (0.75H, ddd, J=2.4, 8.4, 26.4Hz), 4.05-3.85 (3H, m), 3.83 (0.75H, s), 3.80 (2.25H, s), 2.06 (2.25H, s), 2.04 (0.75H, s), 1.99 (3H.m)

(3)

A mixture of 0.35 g of (2R,3R,4R)-1-(acetyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl acetate, 5 mL of acetonitrile, 0.15 mL of N-methylimidazole, and 0.41 g of 2,4,5-trichlorobenzenesulfonyl chloride was stirred at 25°C for 5 hours. Furthermore, 0.10 g of 2,4,5-trichlorobenzenesulfonyl chloride was added, and the mixture was left at 25°C for 3 days. Next, 1.0 mL of N-methylimidazole was added, and the mixture was left at 25°C for 1 day. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed twice with dilute hydrochloric acid, then washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1) to obtain 0.44 g of a colorless solid. The obtained solid was recrystallized from methanol to obtain 0.29 g of (2R,3R,4R)-1-(acetyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl acetate as a colorless solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.33 (1.0H, m), 8.23 (1.0H, m), 7.55 (0.75H, dd, J = 6.0, 7.2Hz), 7.05 (0.25H, dd, J = 4.8, 11.2Hz), 5.81 (0.25H, ddd, J = 2.0, 4.8, 46.4Hz), 5.53 (0.25H, ddd, J = 2.4, 5.2, 28.4Hz), 5.49-5.33 (1.5H, m), 5.18-5.11 (1H, m), 4.35-4.12 (2H, m), 3.81 (3H, m), 2.07 (3H, m), 1.86-1.85 (3H,m)

Example 6

(1)

Under a nitrogen atmosphere, 0.53 mL of pentafluorobenzenesulfonyl chloride was added dropwise to a solution of 1.3 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl benzoate and 4.0 mL of triethylamine in 4 mL of ethyl acetate at 0-4°C. The mixture was stirred at 0°C for 2 hours and 40 minutes. 0.27 mL of triethylamine and 0.26 mL of pentafluorobenzenesulfonyl chloride were then added dropwise, and the mixture was stirred for 1 hour. 5.4 mL of saturated aqueous sodium bicarbonate and dimethylaminopyridine were added to the reaction mixture. After stirring at room temperature for 30 minutes, the aqueous layer was removed, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.8 g of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((pentafluorobenzene)sulfonyl)oxy)pentyl benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

3.86 (2.16H, s), 3.92 (0.84H, s), 4.57 (1H, dd, J = 13.2, 7.2Hz), 4.80 (0.72H, dd, J = 12.8, 2.8Hz), 4.81 (0.28H, dd, J = 12.8, 2.8Hz), 5.42 (0.72H, ddd, J=45.6, 6.4, 3.2Hz), 5.51-5.60 (1H, m), 5.83 (0.72H, ddd, J=22.8, 5.6, 3.2Hz), 5.90 (0.28H, ddd, J=46.8, 4.4, 2.4Hz), 6.00 (0.28H, ddd, J=26.0, 5.6, 2.4Hz), 6.84 (0.28H, dd, J=11.2, 4.4Hz), 7.38-8.07 (10.72H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-133.79 (2F, m), -142.45 (1F, m), -157.66 (2F, m), -196.43 (0.72F, ddd, J＝45.6, 22.8, 6.8Hz), -204.90 (0.28F, ddd, J＝46.8, 26.0, 11.2Hz)

(2)

Under a nitrogen atmosphere, 430 mg of anhydrous lithium bromide was added to a solution of 615 mg of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((pentafluorophenyl)sulfonyl)oxy)pentyl benzoate in 2.2 mL of dimethylimidazolidinone, and the mixture was stirred at room temperature for 2 hours. 3 mL of water and 3 mL of ethyl acetate were added to the reaction mixture, and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 379 mg of (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

3.85 (0.51H, s), 3.88 (2.49H, s), 4.52-4.65 (2H, m), 4.70-4.85 (1H, m), 5.52 (0.83H, ddd, J=46.8, 6.4, 6.4Hz), 5.82 (0.83H, ddd, J=16.4, 6.4, 2.8Hz), 5.94 (0.17H, ddd, J=24.4, 6.0, 2.8Hz), 6.07 (0.17H, ddd, J=47.2, 4.4, 2.8Hz), 6.87 (0.17H, dd, J=10.8, 4.4Hz), 7.41-8.16 (10.83H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-193.45 (0.83F, ddd, J＝46.8, 16.4, 6.4Hz), -203.28 (0.17F, ddd, J＝47.2, 24.4, 10.8Hz)

Example 7

(1)

Under a nitrogen atmosphere, 5.1 mL of 1-methylimidazole was added dropwise to a solution of 20.0 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl benzoate and 17.3 g of 2,4,5-trichlorobenzenesulfonyl chloride in 50 mL of acetonitrile at 0-4°C, followed by stirring at room temperature for 2 hours. 50 mL of saturated aqueous sodium bicarbonate and 50 mL of water were added to the reaction mixture, followed by stirring at room temperature for 1 hour. The solid was collected by filtration, washed twice with 50 mL of water and then twice with 25 mL of methanol, yielding 28.3 g of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentyl benzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

3.85 (2.22H, s), 3.91 (0.78H, s), 4.54 (1H, dd, J = 12.8, 6.4Hz), 4.73 (0.74H, dd, J = 12.8, 3.2Hz), 4.75 (0.26H, dd, J = 12.8, 2.8Hz), 5.37-5.52 (1.74H, m), 5.82 (0.74H, ddd, J=22.8, 5.6, 2.8Hz), 5.90 (0.26H, brs, J=48.0Hz), 6.00 (0.26H, ddd, J=26.0, 5.6, 2.0Hz), 6.83 (0.26H, dd, J＝11.2, 4.4Hz), 7.38-8.11 (12.74H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-196.70 (0.74F, ddd, J＝45.6, 22.8, 6.8Hz), -204.90 (0.26F, ddd, J＝48.0, 26.0, 11.2Hz)

(2)

Under a nitrogen atmosphere, 291 mg of anhydrous lithium bromide was added to a solution of 421 mg of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentyl benzoate in 1.34 mL of dimethylimidazolidinone, and the mixture was stirred at 40°C for 4 hours. Analysis of the reaction mixture by high-performance liquid chromatography revealed a reaction yield of 98% and the formation of (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl benzoate.

Example 8

(1)

Under a nitrogen atmosphere, 0.30 mL of 1-methylimidazole was added dropwise to a solution of 1.0 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl benzoate and 857 mg of 3-nitrobenzenesulfonyl chloride in 5.0 mL of acetonitrile at 0-4°C, followed by stirring at room temperature for 15 hours and 30 minutes. 5 mL of saturated aqueous sodium bicarbonate was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. 5.0 mL of ethyl acetate was added to the reaction mixture, and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.59 g of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((3-nitrobenzene)sulfonyl)oxy)pentyl benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

3.84 (2.01H, s), 3.89 (0.99H, s), 4.50 (1H, dd, J = 12.8, 6.4Hz), 4.73-4.80 (1H, m), 5.33 (0.67H, ddd, J = 45.6, 6.8, 3.2Hz), 5.39-5.48 (1H, m), 5.73-5.87 (1H, m), 5.95 (0.33H, ddd, J=26.4, 6.0, 2.4Hz), 6.80 (0.33H, dd, J=11.2, 4.4Hz), 7.30-8.75 (14.67H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-196.64 (0.67F, ddd, J＝45.6, 23.3, 6.8Hz), -204.77 (0.33F, ddd, J＝46.7, 26.4, 11.2Hz)

(2)

Under a nitrogen atmosphere, 73.6 mg of anhydrous lithium bromide was added to a solution of 103 mg of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((3-nitrobenzene)sulfonyl)oxy)pentyl benzoate in 0.34 mL of N,N-dimethylformamide, and the mixture was stirred at 60°C for 5 hours and 30 minutes. Analysis of the reaction mixture by high performance liquid chromatography revealed a reaction yield of 98% and the formation of (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl benzoate.

Example 9

(1)

Under a nitrogen atmosphere, 0.30 mL of 1-methylimidazole was added dropwise to a solution of 1.0 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl benzoate and 857 mg of 2-nitrobenzenesulfonyl chloride in 5.0 mL of acetonitrile at 0-4°C, followed by stirring at room temperature for 15 hours and 30 minutes. 5 mL of saturated aqueous sodium bicarbonate was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. 5.0 mL of ethyl acetate was added to the reaction mixture, and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.44 g of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((2-nitrobenzene)sulfonyl)oxy)pentyl benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

3.83 (2.13H, s), 3.90 (0.87H, s), 4.56 (1H, dd, J = 12.8, 6.0Hz), 4.84 (1H, dd, J = 12.8, 2.8Hz), 5.42 (0.71H, ddd, J = 45.6, 6.4, 3.2Hz), 5.39-5.55 (1.71H, m), 5.87 (0.71H, ddd, J=23.6, 6.0, 2.8Hz), 5.93 (0.29H, ddd, J=49.2, 4.4, 2.4Hz), 6.80 (0.29H, dd, J=11.2, 4.4Hz), 7.35-8.15 (14.71H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-197.12 (0.71F, ddd, J＝45.6, 23.6, 6.8Hz), -205.10 (0.29F, ddd, J＝49.2, 26.4, 11.2Hz)

(2)

Under a nitrogen atmosphere, 875 mg of anhydrous lithium bromide was added to a solution of 1.15 g of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((2-nitrobenzene)sulfonyl)oxy)pentyl benzoate in 4 mL of N,N-dimethylformamide, and the mixture was stirred at 60°C for 3 hours. Analysis of the reaction mixture by high-performance liquid chromatography revealed a reaction yield of 98% and the formation of (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl benzoate.

Example 10

(1)

A mixture of 800 mg of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol, 67 mg of tetrabutylammonium chloride, 4 mL of toluene, 481 mg of sodium hydroxide, 4 mL of water, and 1.56 g of 4-methylbenzoyl chloride was stirred at 5°C for 1 hour and then at room temperature for 2.5 hours. The organic layer was separated, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate/hexane = 1/10 to 1/2) to obtain 1.61 g of ((2R,3R,4S)-4-fluoro-5-methoxy-3-((4-methylphenyl)carbonyloxy)oxolan-2-yl)methyl 4-methylbenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.98-7.93 (4H, m), 7.25-7.20 (4H, m), 5.79 (1H, ddd, J=17.2, 6.0, 6.0Hz), 5.25 (1H, ddd, J = 52.4, 6.4, 4.4Hz), 5.07 (1H, d, J = 4.4Hz), 4.72 (1H, dd, J = 11.6, 6.4Hz), 4.56 (1H, dd, J = 11.6, 6.4Hz), 4.38-4.34(1H, m), 3.48(3H, s), 2.43(3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-206.73(1F,dd,J=52.1,17.5Hz)

(2)

A mixture of 800 mg of ((2R,3R,4S)-4-fluoro-5-methoxy-3-((4-methylphenyl)carbonyloxy)oxolan-2-yl)methyl 4-methylbenzoate, 2.2 mL of trifluoroacetic acid, and 268 mg of water was stirred at 50°C for 7 hours. 50 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed three times with a saturated aqueous sodium bicarbonate solution and once with a saturated aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate/hexane = 1/10 to 1/2) to obtain 720 mg of ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((4-methylphenyl)carbonyloxy)oxolan-2-yl)methyl 4-methylbenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.97-7.93 (4H, m), 7.24-7.21 (4H, m), 5.68 (1H, dd, J = 10.0, 3.6Hz), 5.47 (1H, dd, J = 22.0, 4.4Hz), 5.16 (1H, d, J = 49.2Hz), 4.74-4.67 (2H, m), 4.60-4.56 (1H, m), 2.93 (1H, dd, J = 3.4, 3.4Hz), 2.42 (3H, s), 2.40 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-190.09 (1F, ddd, J=49.3, 22.4, 10.4Hz)

(3)

In the same manner as in Example 1(1), (2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)-3-((4-methylphenyl)carbonyloxy)pentyl 4-methylbenzoate was obtained as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

7.97-7.89 (4H, m), 7.39 (0.80H, dd, J=6.8, 6.8Hz), 7.26-7.21 (4H, m), 6.83 (0.20H, dd, J=11.1, 4.7Hz), 6.05 (0.20H, ddd, J=46.4, 4.2, 1.5Hz), 5.70 (0.20H, dd, J=28.2, 1.9Hz), 5.56 (0.80H, ddd, J=45.4, 6.9, 2.3Hz), 5.44 (0.80H, ddd, J=26.0, 8.4, 2.4Hz), 4.61 (0.80H, dd, J=12.4, 3.2Hz), 4.57 (0.20H, dd, J=11.1, 1.9Hz), 4.45-4.34 (2H, m), 3.91 (0.60H, s), 3.83 (2.40H, s), 3.03 (0.80H, d, J=5.8Hz), 2.98 (0.20H, d, J＝2.4Hz), 2.42-2.41 (6H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-200.06 (0.8F, ddd, J＝45.2, 25.7, 6.9Hz), -207.4 (0.2F, ddd, J＝46.5, 28.2, 11.1Hz)

(4)

In the same manner as in Example 7(1), (2R,3R,4R)-2-fluoro-1-(methoxyimino)-5-((4-methylphenyl)carbonyloxy)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl 4-methylbenzoate was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.06 (1H, s), 7.83 (4H, dd, J=45.8, 8.2Hz), 7.41-7.39 (1.18H, m), 7.26-7.20 (4H, m), 6.83 (0.82H, dd, J=11.0, 4.6Hz), 6.00-5.91 (1.41H, m), 5.85-5.83 (0.41H, m), 5.77 (0.18H, ddd, 22.8, 5.9, 3.1Hz), 5.46 (0.09H, ddd, J=28.5, 6.5, 2.9Hz), 5.41-5.36 (0.91H, m), 4.72-4.65 (1H, m), 4.56-4.51 (1H, m), 3.90 (2.46H, s), 3.86 (0.54H, s), 2.42 (6H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-196.58 (0.18F, ddd, J＝45.6, 22.6, 6.7Hz), -204.85 (0.82F, ddd, J＝46.5, 26.3, 11.0Hz)

(5)

The same procedure as in Example 7(2) was carried out to obtain (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-3-((4-methylphenyl)carbonyloxy)pentyl 4-methylbenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.02-7.88 (4H, m), 7.47 (0.86H, dd, J=6.4, 6.4Hz), 7.28-7.19 (4H, m), 6.86 (0.14H, dd, J=11.2, 4.8Hz), 6.05 (0.14H, ddd, J=47.0, 4.7, 3.0Hz), 5.91 (0.14H, ddd, J = 24.8, 5.7, 3.1Hz), 5.79 (0.86H, ddd, J = 17.2, 5.7, 3.1Hz), 5.51 (0.86H, ddd, J = 46.8, 5.2, 5.3Hz), 4.79-4.70 (1.14H, m), 4.62-4.54 (1.86H, m), 3.88 (2.58H, m), 3.85 (0.42H, m), 2.43-2.40 (6H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-193.52 (0.86F, ddd, J＝46.7, 16.8, 6.3Hz), -203.30 (0.14F, ddd, J＝46.9, 24.6, 10.8Hz)

(6)

In the same manner as in Example 1(4), a mixture of (2S,3S,4S)-2-bromo-4-fluoro-3-((4-methylphenyl)carbonyloxy)-5-oxopentyl 4-methylbenzoate and its hydrate was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.81 (1H, d, J = 6.0Hz), 8.01-7.88 (4H, m), 7.26-7.18 (4H, m), 5.80-4.61 (5H, m), 2.42-2.34 (6H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-210.08(1F,ddd,J=47.1,20.8,6.5Hz)

(7)

The same procedure as in Example 1(5) was carried out to obtain ((2R,3S,4S)-4-fluoro-5-hydroxy-3-((4-methylphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methylbenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.01-7.87 (4H, m), 7.26-7.14 (4H, m), 6.03-5.97 (0.54H, m), 5.81 (0.46H, dt, J = 12.1, 4.6Hz), 5.62 (0.46H, dd, J = 9.6Hz), 5.49 (0.54H, dd, J=9.6, 5.2Hz), 5.37 (0.23H, m), 5.25 (0.50H, m), 5.12 (0.27H, m), 4.68-4.56 (1.1H, m), 4.48-4.46 (0.92H, m), 4.19-4.15 (0.46H, m), 3.74 (0.54H, dd, J=12.0, 6.8Hz), 2.81 (0.54H, dd, J=5.8, 1.4Hz), 2.45-2.37 (6.46H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-183.63 (0.54F, dd, J = 47.4, 11.4Hz), -192.74 (0.46F, ddd, J = 51.2, 11.5, 5.1Hz)

(8)

To a solution of 1.35 g of ((2R,3S,4S)-4-fluoro-5-hydroxy-3-((4-methylphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methylbenzoate in 8.1 mL of tetrahydrofuran were added 12 mg of dimethylaminopyridine and 622 mg of 2-methylpyridine. 511 mg of acetic anhydride was added at below 10°C, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed three times with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. Methanol was added to the resulting residue, and the solid was collected by filtration to obtain 546 mg of ((2R,3S,4S,5R)-5-acetyloxy-4-fluoro-3-((4-methylphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methylbenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.88 (4H, dd, J=28.0, 8.0Hz), 7.16 (4H, dd, J=32.0, 8.0Hz), 6.17 (1H, d, J=4.4Hz), 6.08-6.01 (1H, m), 5.30 (1H, ddd, J=50.8, 9.6, 4.5Hz), 4.66 (1H, dd, J = 11.2, 6.0Hz), 4.47 (1H, dd, J = 11.4, 6.6Hz), 3.72 (1H, dd, J = 13.4, 6.6Hz), 2.42 (3H, s), 2.36 (3H, s), 2.12 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-191.83(1F,dd,J=50.8,11.7Hz)

(9)

The same procedure as in Example 1 (7) was carried out to obtain ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-methylphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methylbenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.01-7.86 (4H, m), 7.27-7.20 (4H, m), 5.82-5.80 (0.5H, m), 5.77-5.75 (0.5H, m), 5.73-5.71 (1H, m), 5.68-5.67 (0.5H, m), 5.58-5.56 (0.5H, m), 4.66-4.60 (1H, m), 4.57-4.49 (1H, m), 4.34-4.28 (1H, m), 2.42 (3H,s),2.40(3H,s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-163.52(1F,dd,J＝46.9,14.4Hz)

(10)

Using a dichloromethane solution of ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-methylphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methylbenzoate, the same operation as in Example 22(2) was carried out to obtain ((2R,3S,4S,5R)-5-(4-acetamide-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-((4-methylphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methylbenzoate as a yellowish-brown solid.

m/z(ESI-positive)：540.5[M+H] ⁺

¹⁹ F-NMR (CDCl ₃ ) δ value:

-195.82(1F,ddd,J=49.0,23.5,9.2Hz)

(11)

The same operation as in Example 1 (8) was carried out to obtain (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophene.

Example 11

(1)

Except for changing the reaction time to 8 hours, the same operation as in Example 10(1) was carried out to obtain ((2R,3R,4S)-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl 4-chlorobenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.02-7.96 (4H, m), 7.45-7.26 (4H, m), 5.83 (1H, ddd, J = 17.2, 6.0, 6.0Hz), 5.25 (1H, ddd, J = 52.0, 6.4, 4.4Hz), 5.07 (1H, d, J = 4.4Hz), 4.73 (1H, dd, J = 11.6, 4.0Hz), 4.56 (1H, dd, J = 11.6, 6.4Hz), 4.37-4.33 (1H, m), 3.48 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-191.75(1F,dd,J=50.6,11.9Hz)

(2)

The same procedure as in Example 10(2) was carried out to obtain ((2R,3R,4S)-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl 4-chlorobenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.01-7.97 (4H, m), 7.45-7.39 (4H, m), 5.69 (1H, d, J = 10.0Hz), 5.46 (1H, dd, J = 21.8, 4.2Hz), 5.16 (1H, d, J = 49.2Hz), 4.76-4.59 (3H, m), 2.92(1H, brs)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-190.45(1F,ddd,J=49.1,21.9,10.1Hz)

(3)

In the same manner as in Example 1(1), (2R,3R,4R)-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentyl 4-chlorobenzoate was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.98-7.92 (4H, m), 7.58 (0.86H, dd, J=6.0, 6.0Hz), 7.45-7.39 (4H, m), 6.82 (0.14H, dd, J=11.2, 4.6Hz), 6.04 (0.14H, ddd, J=46.4, 4.6, 2.0Hz), 5.75 (0.14H, dd, J=8.2, 2.0Hz), 5.55-5.50 (1.72H, m), 4.63-4.54 (1H, m), 4.46-4.35 (2H, m), 3.91 (0.42H, s), 3.85 (2.58H, s), 3.08 (0.86H, d, J=6.6, 1.1Hz), 2.91 (0.25H, d, J=6.0Hz)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-200.31 (0.86F, ddd, J＝46.5, 23.6, 5.7Hz), -207.35 (0.14F, ddd, J＝45.2, 29.2, 10.4Hz)

(4)

In the same manner as in Example 7(1), (2R,3R,4R)-1-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentan-3-yl 4-chlorobenzoate was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.99 (1H, s), 7.96-7.89 (4H, m), 7.65 (1H, s), 7.44-7.40 (4H, m), 7.35 (1H, m), 5.62-5.58 (1H, m), 5.37-5.22 (2H, m), 4.84-4.79 (1H, m), 4.68-4.63 (1H, m), 3.83 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-190.52 (1F, ddd, J=47.4, 17.4, 6.5Hz)

(5)

The same procedure as in Example 7(2) was carried out to obtain (2S,3S,4R)-2-bromo-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)pentyl 4-chlorobenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.02-7.91 (4H, m), 7.46-7.40 (5H, m), 5.87 (1H, ddd, J = 6.1, 6.1, 1.7Hz), 5.14 (1H, ddd, J = 46.8, 27.2, 11.7Hz), 4.65-4.64 (2H, m), 4.53-4.48(1H, m), 3.81(3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-171.64(1F,ddd,J＝46.6,8.7,5.2Hz)

(6)

The reaction was carried out in the same manner as in Example 1(4), except that the reaction was carried out at 60°C for 7 hours and then at room temperature for 3 days, to obtain a mixture of (2S,3S,4S)-2-bromo-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-oxopentyl 4-chlorobenzoate and its hydrate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.80-9.78 (1H, m), 8.02-7.90 (4H, m), 7.48-7.39 (4H, m), 5.80-4.54 (5H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-194.14 (1F, ddd, J=47.3, 18.5, 4.4Hz)

(7)

Except for allowing the reaction to proceed at room temperature for 24 hours, the same operation as in Example 1(5) was carried out to obtain ((2R,3S,4S)-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl 4-chlorobenzoate as a yellowish brown solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.00-7.90 (4H, m), 7.44-7.31 (4H, m), 6.04-6.01 (0.56H, m), 5.79 (0.44H, dt, J=12.6, 5.3Hz), 5.68-5.62 (0.44H, m), 5.48 (0.54H, dd, J=8.8, 4.4Hz), 5.37-5.36 (0.22H, m), 5.27-5.24 (0.50H, m), 5.12-5.11 (0.28H, m), 4.65-4.59 (1.3H, m), 4.49-4.47 (0.7H, m), 4.20-4.15 (0.44H, m), 2.79 (0.54H, d, J = 4.0Hz), 2.37 (0.54H, d, J = 8.0Hz)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-183.81 (0.54F, dd, J = 46.7, 11.8Hz), -192.29 (0.46F, ddd, J = 51.6, 11.8, 4.2Hz)

(8)

The same procedure as in Example 10(8) was carried out to obtain ((2R,3S,4S,5R)-5-acetyloxy-3-((4-chlorophenyl)carbonyloxy)-4-fluorotetrahydrothiophen-2-yl)methyl 4-chlorobenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.96 (4H, dd, J = 14.0, 2.4Hz), 7.41 (4H, dd, J = 18.8, 8.4Hz), 6.23 (1H, dd, J = 14.0, 2.0Hz), 5.82 (1H, ddd, J = 12.0, 8.0, 3.0Hz), 5.38 (1H, ddd, J = 44.8, 3.4, 2.3Hz), 4.55-4.43 (2H, m), 4.10-4.07 (1H, m), 2.12(3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-191.76(1F,dd,J=50.8,11.7Hz)

(9)

The same procedure as in Example 1 (7) was carried out to obtain ((2R,3S,4S,5R)-5-bromo-3-((4-chlorophenyl)carbonyloxy)-4-fluorotetrahydrothiophen-2-yl)methyl 4-chlorobenzoate as a yellowish brown oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.01 (4H, dd, J = 16.8, 8.4Hz), 7.42 (4H, dd, J = 10.8, 8.4Hz), 5.82-5.80 (0.5H, m), 5.77-5.76 (0.5H, m), 5.74-5.73 (1H, m), 5.69 (0.5H, brs), 5.58-5.56 (0.5H, m), 4.65-4.50 (1H, m), 4.32-4.26 (1H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-163.51(1F,dd,J=47.2,14.5Hz)

(10)

The same procedure as in Example 22(2) was carried out to obtain ((2R,3S,4S,5R)-3-((4-chlorophenyl)carbonyloxy)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophen-2-yl)methyl 4-chlorobenzoate as a pale yellow solid.

m/z(ESI-positive)：580.4[M+H] ⁺

¹⁹ F-NMR (CDCl ₃ ) δ value:

-196.19(1F,ddd,J=49.1,23.9,8.7Hz)

(11)

The same operation as in Example 1 (8) was carried out to obtain (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophene.

Example 12

(1)

The same procedure as in Example 10(1) was carried out to obtain ((2R,3R,4S)-4-fluoro-5-methoxy-3-((4-methoxyphenyl)carbonyloxy)oxolan-2-yl)methyl 4-methoxybenzoate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

8.03-7.98 (4H, m), 6.93-6.88 (4H, m), 5.45 (1H, dd, J = 23.2, 4.8Hz), 5.21-5.03 (2H, m), 4.71 (1H, dd, J = 12.0, 3.6Hz), 4.60 (1H, dd, J=12.0, 4.4Hz), 4.47-4.50 (1H, m), 3.87 (3H, s), 3.85 (3H, s), 3.45 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-190.34(1F,ddd,J=49.3,23.1,10.5Hz)

(2)

The same procedure as in Example 10(2) was carried out to obtain ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((4-methoxyphenyl)carbonyloxy)oxolan-2-yl)methyl 4-methoxybenzoate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

8.03-7.97 (4H, m), 6.94-6.88 (4H, m), 5.68 (1H, dd, J = 10.4, 3.6Hz), 5.45 (1H, dd, J = 22.2, 4.2Hz), 5.15 (1H, d, J = 49.2Hz), 4.72-4.55 (3H, m), 3.34 (1H, dd, J = 3.4Hz)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-189.89--190.10 (1F, m)

(3)

In the same manner as in Example 1(1), (2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)-3-((4-methoxyphenyl)carbonyloxy)pentyl 4-methoxybenzoate was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.04-7.96 (4H, m), 7.39 (0.70H, dd, J=6.0, 6.0Hz), 6.94-6.89 (4H, m), 6.83 (0.30H, dd, J=11.0, 4.8Hz), 6.05 (0.30H, ddd, J=46.5, 4.8, 1.9Hz), 5.71-5.62 (0.30H, m), 5.56 (0.70H, ddd, J=45.4, 6.9, 2.3Hz), 5.42 (0.70H, ddd, J=26.0, 8.4, 2.3Hz), 4.62-4.54 (1H, m), 4.42-4.32 (2H, m), 3.91 (0.9H, s), 3.87-3.85 (6H, m), 3.83 (2.1H, s), 3.06 (0.7H, d, J = 2.4Hz), 3.01 (0.3H, d, J = 2.4Hz)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-200.11 (0.7F, ddd, J＝45.2, 26.0, 6.8Hz), -207.36 (0.3F, ddd, J＝46.5, 28.4, 10.9Hz)

(4)

The same procedure as in Example 7(1) was carried out to obtain (2R,3R,4R)-2-fluoro-1-(methoxyimino)-5-((4-methoxyphenyl)carbonyloxy)-4-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentan-3-yl 4-methoxybenzoate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

8.07-8.06 (1H, s), 7.98-7.82 (4H, m), 7.43-7.39 (1.73H, m), 6.93-6.88 (4H, m), 6.82 (0.27H, dd, J=11.0, 4.5Hz), 5.96-5.95 (0.27H, m), 5.87 (0.27H, ddd, 22.7, 5.3, 2.3Hz), 5.75 (0.73H, ddd, 22.9, 5.9, 3.1Hz), 5.50-5.47(0.36H, m), 5.42-5.36(1.36H, m), 4.70-4.64(1H, m), 4.53-4.48 (1H, m), 3.90-3.83 (9H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-196.63 (0.73F, ddd, J＝45.6, 23.0, 6.8Hz), -204.89 (0.27F, ddd, J＝46.5, 26.3, 11.0Hz)

(5)

The same procedure as in Example 7(2) was carried out to obtain (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-3-((4-methoxyphenyl)carbonyloxy)pentyl 4-methoxybenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.08-7.94 (4H, m), 7.46 (1H, dd, J = 6.5, 6.5Hz), 6.96-6.89 (4H, m), 5.77 (1H, ddd, J = 16.8, 6.0, 3.2Hz), 5.50 (1H, ddd, J = 46.8, 6.3, 6.3Hz), 4.75-4.69 (1H, m), 4.57-4.53 (2H, m), 3.88-3.84 (9H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-193.50(1F,ddd,J=46.1,16.9,6.2Hz)

(6)

The same procedure as in Example 1(4) was repeated except that the reaction was carried out at 60°C for 14 hours to obtain a mixture of (2S,3S,4S)-2-bromo-4-fluoro-3-((4-methoxyphenyl)carbonyloxy)-5-oxopentyl 4-methoxybenzoate and its hydrate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.85-9.70(1H,m), 8.02-7.91(4H,m), 6.94-6.86(4H,m), 6.07-4.38 (5H,m), 3.87-3.84(6H,m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-210.07 (1F, ddd, J=47.3, 20.9, 6.4Hz)

(7)

The same procedure as in Example 1(5) was repeated except that the reaction was allowed to proceed at room temperature for 5 hours to obtain ((2R,3S,4S)-4-fluoro-5-hydroxy-3-((4-methoxyphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methoxybenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.02-7.93 (4H, m), 6.93-6.82 (4H, m), 6.32-5.97 (0.54H, m), 5.80 (0.46H, dt, J = 12.2, 4.9Hz), 5.61 (0.46H, dt, J = 9.7, 9.7Hz), 5.48 (0.54H, dd, J=9.5, 5.0Hz), 5.36-5.35 (0.23H, m), 5.25-5.23 (0.50H, m), 5.14-5.09 (0.27H, m), 4.65-4.54 (1.3H, m), 4.47-4.45 (0.7H, m), 4.25-4.17 (0.46H, m), 3.87-3.83 (6H, m), 3.73 (0.54H, d, J = 12.3, 6.7Hz), 2.78 (0.54H, d, J = 5.3Hz), 2.69 (0.46H, d, J = 8.6Hz)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-183.54(0.54F,dd,J＝47.1,11.4Hz), -192.82(0.46F,ddd,J＝51.4,11.7,5.1Hz)

(8)

In the same manner as in Example 10(8), ((2R,3S,4S,5R)-5-acetyloxy-4-fluoro-3-((4-methoxyphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methoxybenzoate was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.98 (4H, dd, J = 9.8, 9.8Hz), 6.89 (4H, dd, J = 16.4, 8.8Hz), 6.22 (1H, dd, J = 13.6, 1.8Hz), 5.81 (1H, ddd, J = 12.3, 8.2, 3.0Hz), 5.37 (1H, ddd, J=45.0, 3.5, 2.2Hz), 4.54-4.40 (2H, m), 4.15-4.03 (1H, m), 3.87 (3H, s), 3.85 (3H, s), 2.11 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-191.95(1F,dd,J=50.8,11.7Hz)

(9)

The same procedure as in Example 1(7) was carried out to obtain ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-methoxyphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methoxybenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.03 (4H, dd, J = 20.9, 8.9Hz), 6.91 (4H, dd, J = 11.3, 8.9Hz), 5.81-5.79(0.5H,m), 5.76-5.74(0.5H,m), 5.72-5.71(1H,m), 5.68(0.5 H, brs), 5.58-5.56 (0.5H, m), 4.64-4.47 (1H, m), 4.33-4.27 (1H, m), 3.87 (3H,s),3.85(3H,s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-163.56 (1F, dd, J=47.2, 14.8Hz)

(10)

Using a dichloromethane solution of ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-methoxyphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methoxybenzoate, the same operation as in Example 22(2) was carried out to obtain ((2R,3S,4S,5R)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-((4-methoxyphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methoxybenzoate as a pale yellow solid.

m/z(ESI-positive)：572.5[M+H] ⁺

¹⁹ F-NMR (CDCl ₃ ) δ value:

-196.14 (1F, ddd, J=49.6, 23.7, 8.9Hz)

(11)

The same operation as in Example 1 (8) was carried out to obtain (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophene.

Example 13

(1)

In the same manner as in Example 10(1), ((2R,3R,4S)-4-fluoro-5-methoxy-3-((4-(trifluoromethyl)phenyl)carbonyloxy)oxolan-2-yl)methyl 4-(trifluoromethyl)benzoate was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.21-8.15 (4H, m), 7.68-7.75 (4H, m), 5.83 (1H, ddd, J = 17.2, 6.0, 6.0Hz), 5.28 (1H, ddd, J = 52.0, 6.4, 4.4Hz), 5.09 (1H, d, J = 4.4Hz), 4.78 (1H, dd, J = 12.0, 4.0Hz), 4.62 (1H, dd, J = 12.0, 6.4Hz), 4.41-4.37 (1H, m), 3.49 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-63.16(3F, s), -63.23(3F, s), -206.61(1F, dd, J＝52.3, 16.9Hz)

(2)

The same procedure as in Example 10(2) was carried out to obtain ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((4-(trifluoromethyl)phenyl)carbonyloxy)oxolan-2-yl)methyl 4-(trifluoromethyl)benzoate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

8.18 (4H, dd, J = 7.8, 7.8Hz), 7.73 (4H, dd, J = 12.4, 4.4Hz), 5.72 (1H, dd, J = 9.8, 2.6Hz), 5.51 (1H, dd, J = 21.6, 4.0Hz), 5.19 (1H, d, J=49.2Hz), 4.82-4.78 (1H, m), 4.72-4.64 (2H, m), 2.85 (1H, dd, J=3.2, 3.2Hz)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-63.16 (3F, s), -63.24 (3F, s), -190.66 (1F, dddd, J=49.0, 21.7, 9.6, 2.4Hz)

(3)

In the same manner as in Example 1(1), (2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)-3-((4-(trifluoromethyl)phenyl)carbonyloxy)pentyl 4-(trifluoromethyl)benzoate was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.19-8.11 (4H, m), 7.74-7.69 (4H, m), 7.40 (0.64H, dd, J=6.4, 6.4Hz), 6.83 (0.36H, dd, J=11.2, 4.4Hz), 6.10 (0.36H, ddd, J=46.4, 4.5, 2.0Hz), 5.82 (0.36H, dd, J=8.1, 1.9Hz), 5.65 (0.32H, dd, J=6.4, 2.4Hz), 5.57-5.48 (0.96H, m), 4.67-4.60 (1H, m), 4.51-4.41 (2H, m), 3.93 (1.08H, s), 3.82 (1.92H, s), 2.88 (0.64H, d, J = 5.8Hz), 2.83 (0.36H, d, J = 5.9Hz),

¹⁹ F-NMR (CDCl ₃ ) δ value:

-63.23 (3F, s), -63.28 (3F, s), -200.2 (0.64F, ddd, J = 45.2, 25.3, 7.2Hz), -207.4 (0.36F, ddd, J = 46.3, 27.5, 11.3Hz)

(4)

The same procedure as in Example 7(1) was carried out to obtain (2R,3R,4R)-2-fluoro-1-(methoxyimino)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)-5-((4-(trifluoromethyl)phenyl)carbonyloxy)pentan-3-yl 4-(trifluoromethyl)benzoate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

8.15-8.05 (5H, m), 7.75-7.70 (4H, m), 7.50 (1H, s), 7.41 (0.65H, dd, J=6.6, 6.6Hz), 6.81 (0.35H, dd, J=11.3, 4.4Hz), 6.02 (0.35H, ddd, J=25.7, 5.9, 2.5Hz), 5.95-5.93 (0.17H, m), 5.86-5.78 (0.82H, m), 5.51-5.38(1.65H, m), 4.81-4.74(1H, m), 4.63-4.57(1H, m), 3.92(1.95H, s), 3.83(1.05H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-63.23 (3F, s), -63.30 (3F, s), -196.6 (0.65F, ddd, J = 45.6, 21.9, 6.9Hz), -204.9 (0.35F, ddd, J = 46.9, 25.9, 11.4Hz)

(5)

The same procedure as in Example 7(2) was carried out to obtain (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-3-((4-(trifluoromethyl)phenyl)carbonyloxy)pentyl 4-(trifluoromethyl)benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.23-8.08 (4H, m), 7.76-7.66 (4H, m), 7.49 (0.82H, dd, J=6.4, 6.4Hz), 6.87 (0.18H, dd, J=11.2, 4.8Hz), 6.07 (0.18H, ddd, 47.0, 4.6, 3.3Hz), 5.93 (0.18H, ddd, 23.8, 5.7, 3.2Hz), 5.83 (0.82H, ddd, 15.6, 6.2, 3.0Hz), 5.53 (0.82H, ddd, 46.8, 6.3, 6.3Hz), 4.81-4.70 (1H, m), 4.81-4.74(1H, m), 4.65-4.58(1H, m), 3.90(2.46H, s), 3.88(0.54H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-63.24 (3F, s), -63.27 (3F, s), -193.37 (0.82F, ddd, J＝46.7, 15.4, 6.4Hz), -202.98 (0.18F, ddd, J＝47.1, 23.5, 10.7Hz)

(6)

The reaction was carried out in the same manner as in Example 1 (4), except that the reaction was carried out at 60°C for 8 hours and then at 70°C for 2 hours, to obtain a mixture of (2S,3S,4S)-2-bromo-4-fluoro-5-oxo-3-((4-(trifluoromethyl)phenyl)carbonyloxy)pentyl 4-(trifluoromethyl)benzoate and its hydrate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.84 (1H, d, J = 5.6Hz), 8.23-8.03 (4H, m), 7.78-7.57 (4H, m), 5.89-4.09 (5H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-63.28 (3F, s), -63.36 (3F, s), -210.07 (1F, ddd, J = 47.1, 20.1, 5.8Hz)

(7)

The same procedure as in Example 1(5) was repeated except that the reaction was allowed to proceed for 6 hours to obtain ((2R,3S,4S)-4-fluoro-5-hydroxy-3-((4-(trifluoromethyl)phenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-(trifluoromethyl)benzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.18-8.07(4H,m),7.75-7.58(4H,m),6.10-6.06(0.53H,m),5.84 (0.47H, dt, 13.0, 6.0Hz), 5.67 (0.47H, dd, J=10.2, 7.1Hz), 5.49 (0.53H, d d, J=8.4, 4.1Hz), 5.40-5.39 (0.23H, m), 5.30-5.27 (0.50H, m), 5.17-5.14 (0.27H, m), 5.17-4.65 (1.3H, m), 4.55-4.53 (0.7H, m), 4.22 (0.47H, m), 3.78 (0.53H, dd, J=13.0, 6.2Hz), 2.91 (0.53H, d, J=4.4Hz), 2.45 (0.47H, d, J=7.0Hz)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-63.28 (3F, s), -63.30 (3F, s), -184.00 (0.47F, dd, J＝47.4, 11.9Hz), -192.00 (0.53F, ddd, J＝51.4, 11.8, 3.7Hz)

(8)

Except for changing the solvent added to the obtained residue from methanol to hexane, the same operation as in Example 10 (8) was carried out to obtain ((2R,3S,4S,5R)-5-acetyloxy-4-fluoro-3-((4-(trifluoromethyl)phenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-(trifluoromethyl)benzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.05 (4H, dd, J=22.0, 8.0Hz), 7.62 (4H, dd, J=48.2, 8.2Hz), 6.19 (1H, d, J=4.4Hz), 6.11-6.04 (1H, m), 5.32 (1H, ddd, J=50.6, 9.1, 4.5Hz), 4.62 (1H, ddd, J = 55.6, 11.4, 6.6Hz), 3.78 (1H, dd, J = 13.6, 6.8Hz), 2.16 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-63.32(3F, s), -63.33(3F, s), -191.78(1F, dd, J＝50.6, 11.9Hz)

(9)

The same procedure as in Example 1 (7) was carried out to obtain ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-(trifluoromethyl)phenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-(trifluoromethyl)benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.19 (4H, dd, J = 15.8, 8.0Hz), 7.72 (4H, dd, J = 9.0, 9.0Hz), 5.87-5.85 (0.5H, m), 5.82-5.80 (0.5H, m), 5.76 (1H, brs), 5.71 (0.5H, brs), 5.61 (0.5H, brs), 4.68-4.59 (2H, m), 4.36-4.30 (1H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-63.20 (3F, s), -63.28 (3F, s), -163.52 (1F, dd, J = 46.9, 14.4Hz)

(10)

Using a dichloromethane solution of ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-(trifluoromethyl)phenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-(trifluoromethyl)benzoate, the same operation as in Example 22(2) was carried out to obtain ((2R,3S,4S,5R)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-((4-(trifluoromethyl)phenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-(trifluoromethyl)benzoate as a pale yellow solid.

m/z(ESI-positive): 648.5[M+H] ⁺

¹⁹ F-NMR (CDCl ₃ ) δ value:

-196.23 (1H, ddd, J=49.7, 24.5, 8.7Hz)

(11)

The same operation as in Example 1 (8) was carried out to obtain (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophene.

Example 14

(1)

In the same manner as in Example 10(1), ((2R,3R,4S)-4-fluoro-5-methoxy-3-((3-phenyl-2-acryloyl)oxy)oxolan-2-yl)methyl 3-phenyl-2-propenoate was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.74 (2H, dd, J = 16.0, 5.6), 7.54-7.51 (4H, m), 7.42-7.36 (6H, m), 6.47 (2H, dd, J = 16.0, 6.8Hz), 5.63 (1H, ddd, J = 17.2, 6.0, 6.0Hz), 5.20 (1H, dd, J = 52.4, 6.4, 4.4Hz), 5.05 (1H, d, J = 4.4Hz), 4.62 (1H, dd, J = 11.6, 4.0Hz), 4.40 (1H, dd, J = 11.6, 7.2Hz), 4.31-4.24 (1H, m), 3.52 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-206.91(1F,dd,J=52.3,16.9Hz)

(2)

The same operation as in Example 10(2) was carried out except that the reaction temperature was 70°C and the reaction time was 4 hours to obtain ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((3-phenyl-2-acryloyl)oxy)oxolan-2-yl)methyl 3-phenyl-2-acrylate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

7.75 (2H, dd, J = 16.0, 8.0Hz), 7.54-7.51 (4H, m), 7.41-7.37 (6H, m), 6.48 (2H, dd, J = 16.0, 4.4Hz), 5.67 (1H, dd, J = 10.4, 2.8Hz), 5.51 (1H, dd, J = 21.6, 4.0Hz), 5.32 (1H, dd, J = 22.2, 4.2Hz), 5.09 (1H, d, J = 49.2Hz), 4.65-4.58 (2H, m), 4.48-4.42 (1H, m), 3.15 (1H, brs)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-190.06(1F,ddd,J＝49.1,22.1,10.3Hz)

(3)

In the same manner as in Example 1(1), (2R,3R,4R)-2-fluoro-4-hydroxy-1-(methoxyimino)-5-((3-phenyl-2-acryloyl)oxy)pentan-3-yl 3-phenyl-2-propenoate was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.75 (2H, dd, J = 19.7, 16.1Hz), 7.53-7.50 (4H, m), 7.41-7.37 (6.77H, m), 6.85 (0.23H, dd, J = 11.2, 4.8Hz), 6.48 (2H, dd, J = 16.0, 14.8Hz), 6.01 (ddd, J=46.4, 4.8, 2.0Hz), 5.57 (ddd, J=28.4, 8.0, 2.0Hz), 5.53 (ddd, J=45.4, 6.6, 2.4Hz), 5.33 (ddd, J=26.0, 8.1, 2.5Hz), 4.50-4.40 (1H, m), 4.32-4.28 (2H, m), 3.94 (0.7H, s), 3.02-2.99 (1H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-200.15 (0.77F, ddd, J＝45.6, 26.0, 7.2Hz), -207.29 (0.23F, ddd, J＝46.7, 28.2, 11.3Hz)

(4)

The same procedure as in Example 7(1) was carried out to obtain (2R,3R,4R)-2-fluoro-1-(methoxyimino)-5-((3-phenyl-2-acryloyl)oxy)-4-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentan-3-yl 3-phenyl-2-propenoate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

8.17 (1H, s), 7.78-7.63 (3H, m), 7.54-7.50 (4H, m), 7.41-7.36 (6.77H, m), 6.81 (0.23H, dd, J=11.1, 4.4Hz), 6.33 (1.54H, dd, J=77.6, 16.0Hz), 6.32 (0.46H, dd, J=65.2, 16.0Hz), 5.89 (0.23H, m), 5.79 (0.23H, ddd, 19.0, 5.5, 2.4Hz), 5.66 (0.77H, ddd, 23.6, 6.4, 3.2Hz), 5.37 (0.77H, ddd, 45.8, 6.5, 3.1Hz), 5.29-5.25 (1H, m), 4.59-4.55 (1H, m), 4.43-4.38 (1H, m), 3.94 (0.69H, s), 3.89 (2.31H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-197.2 (0.77F, ddd, J＝45.6, 23.4, 6.9Hz), -205.2 (0.23F, ddd, J＝46.7, 26.4, 11.3Hz)

(5)

In the same manner as in Example 7(2), (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-1-((3-phenyl-2-acryloyl)oxy)pentan-3-yl 3-phenyl-2-propenoate was obtained as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

7.78 (2H, dd, J=28.0, 16.0Hz), 7.57-7.51 (4H, m), 7.46 (0.87H, dd, J=6.5, 6.5Hz), 7.41-7.37 (6H, m), 6.87 (0.13H, dd, J=11.0, 4.8Hz), 6.50 (2H, dd, J = 29.6, 16.0Hz), 6.03 (0.13H, dd, J = 47.2, 4.6, 3.3Hz), 5.75 (0.13H, dd, J = 25.1, 5.8, 3.1Hz), 5.65 (0.87H, ddd, 17.6, 5.6, 3.6Hz), 5.53 (0.82H, ddd, 46.8, 6.3, 6.3Hz), 4.66-4.44 (3H, m), 3.92 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-193.71 (1F, ddd, J=46.7, 17.3, 6.4Hz)

(6)

The reaction was carried out in the same manner as in Example 1 (4), except that the reaction was carried out at 40°C for 2 hours and then at 70°C for 13 hours, to obtain a mixture of (2S,3S,4S)-2-bromo-4-fluoro-5-oxo-1-((3-phenyl-2-acryloyl)oxy)pentan-3-yl 3-phenyl-2-propenoate and its hydrate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.86-9.79 (1H, m), 8.86-7.67 (2H, m), 7.58-7.26 (10H, m), 6.53-6.45 (2H, m), 5.79-4.11 (5H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-210.09—210.34 (1F, m)

(7)

The same operation as in Example 1(5) was carried out except that the reaction was allowed to proceed for 4 hours to obtain ((2R,3S,4S)-4-fluoro-5-hydroxy-3-((3-phenyl-2-acryloyl)oxy)tetrahydrothiophen-2-yl)methyl 3-phenyl-2-acrylate as a brown oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

7.76-7.69 (2H, m), 7.53-7.46 (4H, m), 7.41-7.31 (6H, m), 6.45 (0.94H, dd, J=15.8, 6.2Hz), 6.43 (1.06H, dd, J=22.8, 16.0Hz), 5.91-5.84 (0.53H, m), 5.70 (0.47H, dt, 11.9, 4.8Hz), 5.59 (0.47H, dd, 9.8, 9.8Hz), 5.45 (0.53H, dd, J=9.6, 4.8Hz), 5.30-5.29 (0.23H, m), 5.19-5.16 (0.50H, m), 5.06-5.04 (0.27H, m), 4.53-4.50 (1.3H, m), 4.55-4.53 (0.7H, m), 4.09-4.05 (0.47H, m), 3.62 (0.53H, dd, J=12.3, 6.7Hz), 2.88 (0.53H, d, J=5.4Hz), 2.52 (0.47H, d, J=9.0Hz)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-183.75 (0.48F, dd, J＝47.1, 11.5Hz), -192.65 (0.52F, ddd, J＝ 51.2, 11.8, 4.6Hz)

(8)

In the same manner as in Example 10(8), ((2R,3S,4S,5R)-5-acetyloxy-4-fluoro-3-((3-phenyl-2-acryloyl)oxy)tetrahydrothiophen-2-yl)methyl 3-phenyl-2-propenoate was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.71 (2H, dd, J = 33.8, 16.2Hz), 7.49-7.29 (10H, m), 6.42 (2H, dd, J = 43.2, 16.0Hz), 6.15 (1H, d, J = 4.0Hz), 5.23-5.86 (1H, m), 5.22 (1H, ddd, J = 50.8, 8.9, 4.5Hz), 4.46 (1H, ddd, J = 58.4, 11.3, 6.9Hz), 3.61 (1H, dd, J = 13.8, 7.0Hz), 2.18 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-192.04(1F, dd, J＝50.5, 12.0Hz)

(9)

The same procedure as in Example 1 (7) was carried out to obtain ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((3-phenyl-2-acryloyl)oxy)tetrahydrothiophen-2-yl)methyl 3-phenyl-2-propenoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.83-7.69 (2H, m), 7.55-7.45 (4H, m), 7.42-7.31 (6H, m), 6.51-6.38 (2H, m), 5.67-5.66 (1.5H, m), 5.63-5.61 (0.5H, m), 4.65-4.59 (1H, m), 4.54-4.38(2H, m), 4.23-4.18(1H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-163.52(1F,dd,J＝49.1,15.0Hz)

(10)

Using a dichloromethane solution of ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((3-phenyl-2-acryloyl)oxy)tetrahydrothiophen-2-yl)methyl 3-phenyl-2-acrylate, the same operation as in Example 22(2) was carried out to obtain ((2R,3S,4S,5R)-5-(4-acetamide-2-oxy-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-((3-phenyl-2-acryloyl)oxy)tetrahydrothiophen-2-yl)methyl 3-phenyl-2-acrylate as a yellowish-brown solid.

m/z(ESI-positive)：564.5[M+H] ⁺

¹⁹ F-NMR (CDCl ₃ ) δ value:

-195.90 (1F, ddd, J=49.0, 23.5, 9.2Hz)

(11)

The same operation as in Example 1 (8) was carried out to obtain (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophene.

Example 15

(1)

Except for changing the reaction time to 1 hour, the same operation as in Example 10(1) was carried out to obtain ((2R,3R,4S)-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl 2,4-dichlorobenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.89-7.81 (2H, m), 7.50-7.47 (2H, m), 7.34-7.29 (2H, m), 5.44 (1H, dd, J = 22.8, 4.8Hz), 5.20-5.02 (2H, m), 4.77 (1H, dd, J = 12.0, 3.6Hz), 4.61 (1H, dd, J=12.0, 3.6Hz), 4.49 (1H, dd, J=8.4, 3.6Hz), 3.44 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-190.42(1F,ddd,J=48.9,22.0,10.0Hz)

(2)

The same procedure as in Example 10(2) was carried out to obtain ((2R,3R,4S)-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl 2,4-dichlorobenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.87 (2H, dd, J = 15.6, 8.4Hz), 7.50 (2H, dd, J = 11.6, 2.0Hz), 7.35-7.29 (2H, m), 5.68 (1H, d, J = 10.0Hz), 5.46 (1H, dd, J = 21.2, 4.0Hz), 5.15 (1H, d, J = 48.8Hz), 4.77-4.67 (2H, m), 4.62-4.58 (1H, m), 2.87 (1H, brs)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-190.37 (1F, ddd, J=48.9, 21.4, 10.1Hz)

(3)

In the same manner as in Example 1(1), (2R,3R,4R)-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentyl 2,4-dichlorobenzoate was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.84 (2H, dd, J=12.0, 8.4Hz), 7.50-7.48 (2H, m), 7.44 (0.74H, dd, J=7.4, 6.2Hz), 7.33-7.30 (2H, m), 6.87 (0.26H, dd, J=11.3, 4.4Hz), 6.03 (ddd, J=46.4, 4.4, 2.0Hz), 5.82 (dd, J=8.4, 2.0Hz), 5.63-5.61 (0.37H, m), 5.54-5.45 (1.1H, m), 4.60-4.55 (1H, m), 4.48-4.39 (2H, m), 3.94 (0.8H, s), 3.86 (2.2H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-200.08 (0.74F, ddd, J＝44.8, 25.0, 7.3Hz), -207.25 (0.26F, ddd, J＝46.3, 28.0, 11.5Hz)

(4)

The same procedure as in Example 7(1) was carried out to obtain (2R,3R,4R)-1-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentan-3-yl 2,4-dichlorobenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.07 (1H, s), 7.83-7.75 (2H, m), 7.51-7.42 (3.76H, m), 7.35-7.26 (2H, m), 6.85 (0.24H, dd, J＝11.3, 4.4Hz), 6.00 (0.24H, ddd, J＝ 25.8, 5.8, 2.4Hz), 5.93-5.91 (0.12H, m) 5.84-5.76 (0.88H, m), 5.49-5.47 (0.38H, m), 5.38-5.29 (1.14H, m), 4.74-4.55 (2H, m), 3.93 (0.72H, s), 3.88 (2.28H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-197.30 (0.88F, ddd, J＝45.6, 21.6, 7.0Hz), -204.36 (0.12F, ddd, J＝46.7, 25.7, 11.4Hz)

(5)

The same procedure as in Example 7(2) was carried out to obtain (2S,3S,4R)-2-bromo-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)pentyl 2,4-dichlorobenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.88 (2H, dd, J=16.0, 9.6Hz), 7.51-7.45 (2.77H, m), 7.35-7.30 (2H, m), 6.88 (0.23H, dd, J=11.4, 4.6Hz), 6.11-6.09 (0.12H, m), 5.99-5.94 (0.23H, m), 5.90-5.88 (0.12H, m), 5.82 (0.77H, ddd, 16.0, 5.8, 3.4Hz), 5.50 (0.77H, ddd, 46.4, 6.2, 6.2Hz), 4.79-4.70 (1H, m), 4.60-4.54 (2H, m), 3.93 (0.7H, s), 3.90 (2.3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-193.48 (0.77F, ddd, J＝46.7, 15.9, 6.1Hz), -202.59 (0.23F, ddd, J＝47.1, 24.4, 11.2Hz)

(6)

The same procedure as in Example 1(4) was repeated except that the reaction was carried out at 70°C for 6 hours to obtain a mixture of (2S,3S,4S)-2-bromo-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-oxopentyl 2,4-dichlorobenzoate and its hydrate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.84 (1H, d, J=6.0Hz), 7.90-7.82 (2H, m), 7.50-7.45 (2H, m), 7.34-7.27 (2H, m), 5.89-4.05 (5H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-209.92(1F,ddd,J=46.5,20.6,5.7Hz)

(7)

The same procedure as in Example 1(5) was repeated except that the reaction was allowed to proceed for 4 hours to obtain ((2R,3S,4S)-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl 2,4-dichlorobenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.93-7.78 (2H, m), 7.50-7.44 (2H, m), 7.35-7.30 (2H, m), 6.01-5.95 (0.59H, m), 5.84 (0.41H, dt, 11.6, 4.3Hz), 5.63 (0.41H, dd, J=6.0, 6.0Hz), 5.49 (0.59H, dd, J=7.8, 3.8Hz), 5.37-5.36 (0.21H, m), 5.26-5.23 (0.50H, m), 5.13-5.10 (0.29H, m), 4.71-4.58 (1.2H, m), 4.53-4.43 (0.8H, m), 4.20-4.16 (0.41H, m), 3.74 (0.59H, dd, J=12.2, 6.7Hz), 2.84 (0.59H, dd, J=5.5, 1.2Hz), 2.56 (0.41H, d, J=9.0Hz)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-183.85(0.41F,dd,J＝47.1,11.1Hz), -192.53(0.59F,ddd,J＝51.2,11.3,4.9Hz)

(8)

The same procedure as in Example 10(8) was carried out to obtain ((2R,3S,4S,5R)-5-acetyloxy-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluorotetrahydrothiophen-2-yl)methyl 2,4-dichlorobenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.79 (2H, d, J = 8.4Hz), 7.46 (2H, dd, J = 22.8, 2.0Hz), 7.27 (2H, ddd, J = 30.4, 8.4, 2.0Hz), 6.16 (1H, d, J = 4.4Hz), 6.03-5.98 (1H, m), 5.29 (1H, ddd, J = 50.6, 8.8, 4.6Hz), 4.40 (1H, ddd, J = 7.06, 11.4, 6.4Hz), 3.73 (1H, dd, J = 13.6, 6.4Hz), 2.15 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-192.62(1F,dd,J=50.6,11.5Hz)

Example 16

(1)

2.2 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol was dissolved in 26.4 mL of pyridine. 6.1 g of 4-nitrobenzoyl chloride was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed twice with water and once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resulting residue, and the solid was collected by filtration to obtain 4.0 g of ((2R,3R,4S)-4-fluoro-5-methoxy-3-((4-nitrophenyl)carbonyloxy)oxolan-2-yl)methyl 4-nitrobenzoate as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.38 (4H, d, J = 8.6Hz), 8.25 (2H, d, J = 8.9Hz), 8.22 (2H, d, J = 8.9Hz), 5.72 (1H, td, J = 11.5, 5.8Hz), 5.52 (1H, ddd, J = 51.6, 6.5, 4.4Hz), 5.16 (1H, d, J = 4.3Hz), 4.70 (1H, d, J = 7.9Hz), 4.54-4.50 (2H, m), 3.35 (3H, s)

(2)

In the same manner as in Example 10(2), ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((4-nitrophenyl)carbonyloxy)oxolan-2-yl)methyl 4-nitrobenzoate was obtained as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.39 (2H, d, J = 5.9Hz), 8.36 (2H, d, J = 5.9Hz), 8.21 (2H, d, J = 5.9Hz), 8.19 (2H, d, J = 5.9Hz), 5.53 (1H, d, J = 10.9Hz), 5.43 (1H, dd, J=23.1, 5.0Hz), 5.18 (1H, d, J=49.2Hz), 4.67 (3H, tdd, J=19.2, 9.9, 4.0Hz), 3.31 (1H, s)

(3)

The same procedure as in Example 1(1) was carried out to obtain (2R,3R,4R)-3-((4-nitrophenyl)carbonyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentyl 4-nitrobenzoate as a colorless oily substance.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.33 (2H, d, J = 2.3Hz), 8.30 (2H, d, J = 2.6Hz), 8.17 (2H, d, J = 4.6Hz), 8.14 (2H, t, J = 3.8Hz), 7.63 (1H, dd, J = 8.3, 5.9Hz), 6.20 (1H, dd, J = 22.0, 7.1Hz), 6.10 (1H, d, J = 6.6Hz), 5.46 (1H, dd, J = 24.9, 8.4Hz), 4.40 (2H, dt, J = 14.0, 4.8Hz), 3.86 (1H, s), 3.71 (3H, s)

(4)

The same procedure as in Example 7(1) was carried out to obtain (2R,3R,4R)-3-((4-nitrophenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentyl 4-nitrobenzoate as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.36 (2H, d, J = 5.0Hz), 8.33 (2H, d, J = 5.0Hz), 8.23 (0.75H, s), 8.22 (0.25H, s), 8.18 (0.75H, s), 8.15 (0.25H, s), 8.11-8.06 (4H, m), 7.71 (0.25H, dd, J = 8.1, 5.8Hz), 7.51 (0.75H, dd, J = 8.9, 5.6Hz), 7.00 (0.25H, dd, J = 11.6, 4.6Hz), 6.14 (0.25H, dd, J = 45.2, 4.3Hz), 5.75-5.67 (1.50H, m), 4.85 (1H, dd, J = 12.4, 3.1Hz), 4.68 (2H, dt, J = 26.4, 9.1Hz), 3.79 (0.75H, s), 3.75 (2.25H, s)

(5)

In the same manner as in Example 7(2), (2S,3S,4R)-3-((4-nitrophenyl)carbonyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentyl 4-nitrobenzoate was obtained as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.39 (2H, d, J = 8.9Hz), 8.34 (2H, d, J = 8.9Hz), 8.20 (2H, d, J = 8.9Hz), 8.13 (2H, d, J = 8.9Hz), 7.78 (0.2H, t, J = 6.4Hz), 7.64 (0.8H, dd, J=7.6, 5.0Hz), 5.92-5.88 (1H, m), 5.35 (1H, dt, J=46.0, 7.3Hz), 5.15 (1H, dt, J=11.3, 4.0Hz), 4.72 (2H, dt, J=20.0, 8.8Hz), 3.84 (0.6H, s), 3.63 (2.4H, s)

(6)

The same procedure as in Example 1(4) was carried out to obtain a mixture of (2S,3S,4S)-3-((4-nitrophenyl)carbonyloxy)-2-bromo-4-fluoro-5-oxopentyl 4-nitrobenzoate and its hydrate as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ value:

9.67 (1H, d, J = 8.3Hz), 8.38 (2H, d, J = 6.9Hz), 8.34 (2H, d, J = 8.9Hz), 8.21 (2H, d, J = 8.9Hz), 8.12 (2H, d, J = 8.9Hz), 6.55 (1H, dd, J=21.3, 6.4Hz), 5.61 (1H, dd, J=45.4, 4.8Hz), 4.79 (2H, ddd, J=42.4, 21.1, 8.8Hz), 4.59-4.40 (1H, m)

Example 17

(1)

4.0 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol was dissolved in 40 mL of pyridine. 10.1 g of 2-naphthoyl chloride was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed three times with 1 mol/L hydrochloric acid and once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate/hexane = 1/9 to 5/5) to obtain 5.7 g of ((2R,3R,4S)-4-fluoro-5-methoxy-3-((2-naphthoyloxy)oxolan-2-yl)methyl 2-naphthoate) as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.67 (1H, s), 8.63 (1H, s), 8.14 (1H, d, J=7.9Hz), 8.07-8.00 (6H, m), 7.69-7.59 (5H, m), 5.55 (1H, dd, J=23.9, 4.8Hz), 5.38 (1H, d, J=18.2Hz), 5.28 (1H, d, J=20.5Hz), 4.76-4.68 (3H, m), 3.42 (3H, s)

(2)

The same procedure as in Example 10(2) was carried out to obtain ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((2-naphthoyl)oxy)oxolan-2-yl)methyl 2-naphthoate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

8.63 (2H, d, J = 7.3Hz), 8.10-8.03 (2H, m), 7.90 (6H, m), 7.56 (4H, m), 5.76 (1H, d, J = 10.9Hz), 5.61 (1H, dd, J = 22.1, 4.3Hz), 5.27 (1H, d, J = 49.2Hz), 4.83 (2H, dt, J = 11.7, 4.0Hz), 4.72 (1H, dd, J = 12.9, 6.3Hz), 3.09 (1H, s)

(3)

The same procedure as in Example 1(1) was carried out to obtain (2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)-3-(2-naphthoyloxy)pentyl 2-naphthoate as a colorless oily substance.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.33 (2H, d, J = 2.3Hz), 8.30 (2H, d, J = 2.6Hz), 8.17 (2H, d, J = 4.6Hz), 8.14 (2H, t, J = 3.8Hz), 7.63 (1H, dd, J = 8.3, 5.9Hz), 6.20 (1H, dd, J = 22.0, 7.1Hz), 6.10 (1H, d, J = 6.6Hz), 5.46 (1H, dd, J = 24.9, 8.4Hz), 4.40 (2H, dt, J = 14.0, 4.8Hz), 3.86 (1H, s), 3.71 (3H, s)

(4)

In the same manner as in Example 7(1), (2R,3R,4R)-4-fluoro-5-(methoxyimino)-3-(2-naphthoyloxy)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentyl 2-naphthoate was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.61 (1H, s), 8.49 (1H, s), 8.09 (0.3H, s), 8.08 (0.7H, s), 8.03-7.83 (8H, m), 7.65-7.53 (4H, m), 7.47 (0.7H, t, J=6.8Hz), 7.32 (0.3H, s), 6.89 (0.3H, dd, J = 11.1, 4.5Hz), 6.11 (0.7H, ddd, J = 26.3, 5.7, 2.7Hz), 5.92 (1H, dq, J = 22.9, 3.0Hz), 5.57 (1H, dq, J = 16.0, 3.1Hz), 5.48 (1H, dq, J=20.2, 3.2Hz), 4.84 (1H, ddd, J=12.6, 7.9, 3.0Hz), 4.67 (1H, dd, J=12.9, 6.3Hz), 3.94 (0.9H, s), 3.86 (2.1H, s)

(5)

The same procedure as in Example 7(2) was carried out to obtain (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-3-(2-naphthoyloxy)pentyl 2-naphthoate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

8.67 (0.2H, s), 8.61 (0.8H, s), 8.57 (0.2H, s), 8.11 (0.8H, t, J = 4.3Hz), 8.04 (1H, dd, J = 8.6, 1.7Hz), 7.92-7.87 (7H, m), 7.61-7.54 (5H, m), 6.93 (0.2H, dd, J=11.2, 4.6Hz), 6.04 (0.8H, dq, J=21.1, 3.1Hz), 5.92 (1H, dq, J=16.8, 3.0Hz), 5.61 (1H, dt, J=46.7, 6.2Hz), 4.88-4.82(1H, m), 4.78-4.66(2H, m), 3.89(2.4H, s), 3.86(0.6H, s)

(6)

The same procedure as in Example 1(4) was carried out to obtain a mixture of (2S,3S,4S)-2-bromo-4-fluoro-3-(2-naphthoyloxy)-5-oxopentyl 2-naphthoate and its hydrate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.88 (1H, d, J = 6.3Hz), 8.60 (2H, d, J = 14.5Hz), 8.02 (2H, td, J = 8.8, 1.8Hz), 7.92-7.84 (5H, m), 7.59-7.51 (5H, m), 5.95 (1H, dt, J=21.4, 3.8Hz), 5.56 (1H, d, J=4.0Hz), 5.41 (1H, d, J=4.0Hz), 4.81-4.69 (2H, m)

(7)

The same procedure as in Example 1(5) was carried out to obtain ((2R,3S,4S,5R)-4-fluoro-5-hydroxy-3-((2-naphthoyl)oxy)tetrahydrothiophen-2-yl)methyl 2-naphthoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.58 (1H, d, J = 20.8Hz), 8.49 (1H, d, J = 13.5Hz), 8.05 (0.5H, dd, J = 8.6, 1.7Hz), 7.97 (1H, dt, J = 8.3, 2.1Hz), 7.90-7.82 (4H, m), 7.71 (2H, td, J = 13.8, 5.9Hz), 7.60-7.46 (4H, m), 7.38 (0.5H, t, J = 7.6Hz), 6.23-6.14 (0.5H, m), 5.96-5.91 (0.5H, m), 5.67 (0.5H, d, J=10.6Hz), 5.42 (0.5H, dt, J=32.3, 3.1Hz), 5.32 (0.5H, t, J=6.4Hz), 5.19 (0.5H, dd, J=7.3, 4.0Hz), 4.75-4.67 (1H, m), 4.62 (1H, dd, J =14.5, 6.3Hz), 4.34 (0.5H, dd, J = 7.8, 4.1Hz), 3.88 (0.5H, dd, J = 13.4, 6.1Hz), 3.05 (0.5H, s), 2.67 (0.5H, s)

(8)

The same procedure as in Example 10(8) was carried out to obtain ((2R,3S,4S,5R)-5-acetyloxy-4-fluoro-3-((2-naphthoyl)oxy)tetrahydrothiophen-2-yl)methyl 2-naphthoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.60 (0.35H, s), 8.58 (0.35H, s), 8.53 (0.65H, s), 8.42 (0.65H, s), 8.03 (0.70H, d, J = 8.6Hz), 7.94 (1.30H, ddd, J = 13.2, 8.6, 1.7Hz), 7.87-7.47 (9.35H, m), 7.35 (0.65H, t, J=6.9Hz), 6.19-6.08 (2H, m), 5.56-5.28 (1H, m), 4.75 (0.70H, dd, J=11.4, 7.1Hz), 4.60 (1.30H, t, J=8.1Hz), 4.24-4.21 (0.35H, m), 3.88 (0.65H, q, J=6.8Hz), 2.16 (1.05H, s), 2.16 (1.95H, s)

(9)

The same procedure as in Example 1(7) was carried out to obtain ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((2-naphthoyl)oxy)tetrahydrothiophen-2-yl)methyl 2-naphthoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.65 (2H, d, J=27.6Hz), 8.11-7.80 (8H, m), 7.64-7.47 (4H, m), 5.96 (0.5H, brs), 5.91 (0.5H, brs), 5.82 (0.5H, brs), 5.78 (0.5H, brs), 5.74 (0.5H, brs), 5.66 (0.5H, brs), 4.76-4.62 (2H, m), 4.48-4.42 (1H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-163.66(1F,dd,J=48.0,14.5Hz)

(10)

The same procedure as in Example 22(2) was carried out to obtain ((2R,3S,4S,5R)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-((2-naphthoyl)oxy)tetrahydrothiophen-2-yl)methyl 2-naphthoate as a white solid.

m/z(ESI-positive)：664.6[M+H] ⁺

¹⁹ F-NMR (CDCl ₃ ) δ value:

-195.71 (1F, ddd, J=49.6, 22.7, 9.0Hz)

(11)

The same operation as in Example 1 (8) was carried out to obtain (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophene.

Example 18

(1)

2.5 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol was dissolved in 25 mL of pyridine. 7.2 g of 4-phenylbenzoyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, which was washed twice with water and once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate/hexane = 1/9 to 6/4) to obtain 3.3 g of ((2R,3R,4S)-3-(((1,1'-biphenyl)-4-carbonyl)oxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl (1,1'-biphenyl)-4-carboxylate as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.05 (4H, dd, J=8.4, 1.8Hz), 7.86 (2H, d, J=8.6Hz), 7.82 (2H, d, J=8.6Hz), 7.76-7.72 (4H, m), 7.50-7.45 (6H, m), 5.48 (1H, dd, J=23.8, 5.0Hz), 5.34 (1H, d, J=9.6Hz), 5.24 (1H, d, J=28.7Hz), 4.71-4.59 (3H, m), 3.40 (3H, s)

(2)

In the same manner as in Example 10(2), ((2R,3R,4S)-3-(((1,1'-biphenylyl)-4-carbonyl)oxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl(1,1'-biphenylyl)-4-carboxylate was obtained as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.06 (4H, t, J = 8.6Hz), 7.86 (2H, d, J = 8.6Hz), 7.81 (2H, d, J = 8.6Hz), 7.77-7.72 (4H, m), 7.52-7.45 (6H, m), 7.07 (1H, dd, J = 4.0, 2.6Hz), 5.54 (1H, dd, J=10.6, 4.3Hz), 5.44 (1H, dd, J=23.4, 4.6Hz), 5.15 (1H, d, J=49.9Hz), 4.68-4.58 (3H, m)

(3)

In the same manner as in Example 1(1), (2R,3R,4R)-3-(((1,1'-biphenylyl)-4-carbonyl)oxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentyl(1,1'-biphenylyl)-4-carboxylate was obtained as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.09-7.98 (4H, m), 7.88-7.68 (8H, m), 7.50-7.44 (6H, m), 7.12 (0.3H, dd, J = 10.6, 4.6Hz), 6.06 (1.7H, ddd, J = 32.5, 14.2, 5.6Hz), 5.54 (2H, tt, J=39.1, 7.7Hz), 5.15 (0.3H, d, J=48.9Hz), 4.69-4.57 (0.7H, m), 4.41-4.26 (2H, m), 3.88 (0.9H, s), 3.75 (2.1H, s)

(4)

The same operation as in Example 7(1) was carried out to obtain (2R,3R,4R)-3-(((1,1'-biphenyl)-4-carbonyl)oxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentyl(1,1'-biphenyl)-4-carboxylate as a colorless oily substance.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.14 (1H, s), 8.05 (2H, dd, J = 19.7, 11.1Hz), 7.97 (1H, s), 7.81 (8H, m), 7.50 (8H, m), 7.20 (0.5H, dd, J = 11.2, 4.6Hz), 6.09 (0.5H, dq, J=48.2, 3.1Hz), 5.86 (1H, dt, J=23.1, 3.8Hz), 5.68 (2H, tt, J=29.9, 9.4Hz), 4.70 (2H, dt, J=27.4, 9.7Hz), 3.79 (3H, s)

(5)

The same procedure as in Example 7(2) was carried out to obtain (2S,3S,4R)-3-(((1,1'-biphenyl)-4-carbonyl)oxy)-2-bromo-4-fluoro-5-(methoxyimino)pentyl(1,1'-biphenyl)-4-carboxylate as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.10-8.01 (2H, m), 7.95 (1H, d, J = 8.6Hz), 7.88-7.83 (3H, m), 7.80 (1H, d, J = 6.6Hz), 7.68 (5H, m), 7.47 (6H, m), 6.01-5.93 (1H, m), 5.46 (1H, dt, J=47.4, 6.9Hz), 5.05 (1H, t, J=45.2Hz), 4.71 (3H, ddd, J=25.6, 14.5, 7.8Hz), 3.86 (3H, s)

(6)

In the same manner as in Example 1(4), a mixture of (2S,3S,4S)-3-(((1,1'-biphenyl)-4-carbonyl)oxy)-2-bromo-4-fluoro-5-oxopentyl(1,1'-biphenyl)-4-carboxylate and its hydrate was obtained as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

9.69 (1H, d, J = 9.9Hz), 8.06 (2H, m), 8.00 (2H, d, J = 7.3Hz), 7.86 (2H, dd, J = 8.6, 2.6Hz), 7.77 (2H, dd, J = 8.4, 4.1Hz), 7.70 (3H, d, J = 12.6Hz), 7.53-7.43 (7H, m), 6.55 (1H, dd, J = 20.1, 5.9Hz), 6.06 (1H, ddd, J=22.1, 5.0, 3.3Hz), 5.82 (1H, dq, J=14.9, 4.0Hz), 5.01-4.95 (1H, m), 4.77-4.67 (1H, m)

(7)

In the same manner as in Example 1(5), ((2R,3S,4S)-3-(((1,1'-biphenylyl)-4-carbonyl)oxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl(1,1'-biphenylyl)-4-carboxylate was obtained as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.04 (2H, dd, J=8.6, 2.3Hz), 7.87 (2H, t, J=8.4Hz), 7.79 (2H, dd, J=8.6, 3.0Hz), 7.71-7.67 (2H, m), 7.63-7.39 (10H, m), 6.84 (1H, dd, J=6.1, 1.8Hz), 6.09 (0.5H, dt, J=14.2, 5.9Hz), 5.76 (0.5H, dd, J=14.5, 6.9Hz), 5.66 (0.5H, dt, J=14.4, 5.4Hz), 5.39-5.30 (1H, m), 5.18 (0.5H, dt, J=17.2, 5.1Hz), 4.48 (2H, ddd, J=29.3, 15.8, 9.3Hz), 4.18 (0.5H, dd, J=12.9, 7.3Hz), 3.83 (0.5H, dd, J=13.2, 7.3Hz)

(8)

In the same manner as in Example 10(8), ((2R,3S,4S)-3-(((1,1'-biphenylyl)-4-carbonyl)oxy)-5-acetyloxy-4-fluorotetrahydrothiophen-2-yl)methyl (1,1'-biphenylyl)-4-carboxylate was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.11 (0.5H, d, J=8.6Hz), 8.07 (2H, d, J=8.6Hz), 7.98 (1.5H, d, J=8.6Hz), 7.67-7.38 (14H, m), 6.25 (0.25H, t, J=6.9Hz), 6.14 (1.5H, tt, J=10.7, 3.7Hz), 5.89 (0.25H, td, J=8.5, 4.2Hz), 5.42 (0.25H, ddd, J=48.0, 4.0, 2.6Hz), 5.33 (0.75H, ddd, J=50.7, 9.1, 4.5Hz), 4.69 (1H, dd, J＝11.4, 6.8Hz), 4.54 (1H, dd, J＝10.9, 6.6Hz), 4.15 (0.25H, ddd, J=13.2, 6.8, 2.1Hz), 3.79 (0.75H, q, J=6.8Hz), 2.17 (2.25H, d, J=2.3Hz), 2.14 (0.75H, s)

(9)

The same operation as in Example 1 (7) was carried out to obtain ((2R,3S,4S,5R)-3-(((1,1'-biphenyl)-4-carbonyl)oxy)-5-bromo-4-fluorotetrahydrothiophen-2-yl)methyl (1,1'-biphenyl)-4-carboxylate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.14(2H,dd,J=21.0,8.4Hz),7.69-7.37(16H,m),5.89-5.70(0.5H,m),5.84-5.82(0.5H,m),5.78-5.77(0.5H,m),5.75(0.5H,brs),5.71 (0.5H, brs), 5.62-5.61 (0.5H, m), 4.70-4.56 (2H, m), 4.40-4.34 (1H, m)

¹⁹ F-NMR (282.37 MHz, CDCl ₃ ) δ value:

-163.62(1F, dd, J＝48.9, 14.3Hz)

(10)

Using a dichloromethane solution of ((2R,3S,4S,5R)-3-(((1,1'-biphenyl)-4-carbonyl)oxy)-5-bromo-4-fluorotetrahydrothiophen-2-yl)methyl(1,1'-biphenyl)-4-carboxylate, the same operation as in Example 22(2) was carried out to obtain ((2R,3S,4S,5R)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-(((1,1'-biphenyl)-4-carbonyl)oxy)tetrahydrothiophen-2-yl)methyl(1,1'-biphenyl)-4-carboxylate as a white solid.

m/z(ESI-positive): 612.6[M+H] ⁺

¹⁹ F-NMR (CDCl ₃ ) δ value:

-195.70 (1F, ddd, J=49.6, 22.7, 9.0Hz)

(11)

The same operation as in Example 1 (8) was carried out to obtain (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophene.

Example 19

(1)

Except for changing the reaction time to 2 hours, the same operation as in Example 10(1) was carried out to obtain ((2R,3R,4S)-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl trimethylacetate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

5.11-5.04 (2H, m), 4.80 (1H, d, J = 47.6Hz), 4.42 (1H, dd, J = 12.0, 3.6Hz), 4.27 (1H, dd, J = 12.0, 4.4Hz), 4.17 (1H, m), 3.39 (3H, s), 1.21 (18H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-190.55(1F,ddd,J=49.5,23.0,10.5Hz)

(2)

The same procedure as in Example 10(2) was carried out to obtain ((2R,3R,4S)-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl trimethylacetate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

5.57 (1H, dd, J = 10.4, 4.0Hz), 5.11 (1H, dd, J = 22.0, 3.6Hz), 4.92 (1H, d, J = 49.6Hz), 4.42-4.35 (2H, m), 4.27-4.23 (1H, m), 2.96 (1H, dd, J=11.8, 3.2Hz), 1.21 (9H, s), 1.20 (9H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-190.09 (1F, ddd, J=49.8, 22.6, 11.2, Hz)

(3)

In the same manner as in Example 1(1), (2R,3R,4R)-3-(2,2-dimethylpropionyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentyl trimethylacetate was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.29 (0.73H, dd, J=8.1, 6.4Hz), 6.75 (0.27H, dd, J=11.3, 4.6Hz), 5.91 (0.27H, ddd, J=46.5, 4.6, 1.8Hz), 5.43 (0.73H, ddd, J=45.3, 6.4, 2.3Hz), 5.38 (0.27H, ddd, J=28.6, 8.7, 1.8Hz), 4.74 (0.73H, ddd, J=25.7, 8.8, 2.4Hz), 4.27-3.91 (3H, m), 3.91 (0.80H, s), 3.88 (2.20H, s), 2.78 (0.73H, d, J = 6.4Hz), 2.73 (0.27H, d, J = 6.4Hz), 1.23 (9H, s), 1.22 (9H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-201.5 (0.7F, ddd, J = 43.5, 23.8, 6.2Hz), -208.1 (0.3F, ddd, J = 46.5, 28.7, 11.6Hz)

(4)

The same procedure as in Example 7(1) was carried out to obtain (2R,3R,4R)-5-(2,2-dimethylpropionyloxy)-2-fluoro-1-(methoxyimino)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl trimethylacetate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.16 (1H, s), 7.69 (1H, s), 7.22 (0.67H, dd, J=7.8, 6.4Hz), 6.64 (0.33H, dd, J=11.3, 4.4Hz), 5.73-5.67 (0.33H, m), 5.63-5.60 (0.33H, m), 5.36 (0.67H, ddd, J=51.9, 6.4, 3.6), 5.38-5.35 (0.34H, m), 5.19-5.53 (1H, m), 5.13-5.09 (0.33H, m), 4.44-4.40 (1H, m), 4.21-4.16 (1H, m), 3.90 (2.01H, s), 3.89 (0.99H, s), 1.19 (9H, s), 1.17 (9H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-199.40 (0.71F, ddd, J＝48.0, 26.2, 8.0Hz), -206.33 (0.29F, ddd, J＝49.9, 30.1, 12.4Hz)

(5)

The same procedure as in Example 7(2) was carried out to obtain (2S,3S,4R)-2-bromo-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-(methoxyimino)pentyl trimethylacetate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.38 (0.83H, dd, J=6.5, 6.5Hz), 6.75 (0.17H, dd, J=11.2, 4.7), 5.85 (0.17H, ddd, J=47.4, 4.7, 3.0), 5.64 (0.17H, m), 5.37-5.47 (2.25H, m), 5.23 (0.41H, m), 4.57-4.18 (2H, m), 3.91 (2.49H, s), 3.89 (0.51H, s), 1.27 (9H, s), 1.23 (9H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-194.50 (0.84F, ddd, J＝46.6, 16.6, 6.6Hz), -203.81 (0.16F, ddd, J＝47.3, 25.7, 11.2Hz)

(6)

The same procedure as in Example 1(4) was repeated except that the reaction was carried out at 60°C for 8 hours to obtain a mixture of (2S,3S,4S)-2-bromo-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-oxopentyltrimethylacetate and its hydrate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.72 (1H, d, J=6.6Hz), 5.58-4.56 (5H, m), 1.27-1.23 (18H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-210.77 (1F, ddd, J=46.8, 20.9, 6.5Hz)

(7)

The same procedure as in Example 1(5) was carried out to obtain ((2R,3S,4S)-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl trimethylacetate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

5.62-5.44 (1.5H, m), 5.41 (0.5H, m), 5.16 (0.25H, m), 5.06-5.03 (0.5H, m), 4.94-4.90 (0.25H, m), 4.38-4.28 (1H, m), 4.16-4.10 (1H, m), 3.85 (0.5H, dd, J=7.4, 7.4), 3.42 (0.5H, dd, J=13.1, 5.7), 2.97 (0.5H, brs), 2.46 (0.5H, brs), 1.23-1.21 (18H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-184.20 (0.54F, ddd, J＝47.1, 11.1, 11.1Hz), -193.48 (0.46F, ddd, J＝51.8, 10.9, 5.4Hz)

(8)

To a solution of 40 mg of ((2R,3S,4S)-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl trimethylacetate, 0.3 mg of dimethylaminopyridine, and 19 mg of 2-methylpyridine in 1.0 mL of tetrahydrofuran was added 14 mg of acetic anhydride at below 10°C, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography to obtain 44 mg of ((2R,3S,4S)-5-acetyloxy-3-(2,2-dimethylpropionyloxy)-4-fluorotetrahydrothiophen-2-yl)methyl trimethylacetate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

6.14 (0.41H, dd, J=13.8, 2.1Hz), 6.10 (0.59H, d, J=4.5), 5.64 (0.59H, ddd, J=16.5, 9.0, 7.7), 5.43 (0.41H, ddd, J=12.2, 3.4, 3.4), 5.18 (0.41H, ddd, J=47.4, 3.4, 2.1), 5.10 (0.59H, ddd, J=50.8, 9.0, 4.5), 4.36 (0.59H, dd, J=11.5, 4.7), 4.23 (0.41H, dd, J=11.2, 7.4), 4.12-4.07 (1H, m), 3.78 (0.41H, m), 3.42 (0.59H, ddd, J=7.7, 4.7, 4.7), 2.16 (1.77H, s), 2.10 (1.23H, s), 1.25 (5.31H, s), 1.23 (3.69H, s), 1.21 (5.31H, s), 1.20 (3.96H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-187.09 (0.44F, ddd, J＝50.5, 13.9, 13.9Hz), -192.57 (0.56F, dd, J＝50.9, 11.8Hz)

Example 20

(1)

Except for changing the reaction time to 1 hour, the same operation as in Example 10(1) was carried out to obtain ((2R,3R,4S)-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl 3,5-dimethylbenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.67-7.64 (4H, m), 7.22-7.17 (2H, m), 5.46 (1H, dd, J = 23.8, 4.8Hz), 5.22-5.03 (2H, m), 4.70 (1H, dd, J = 12.0, 4.0Hz), 4.62 (1H, dd, J=12.0, 4.8Hz), 4.52-4.49 (1H, m), 3.46 (3H, s), 2.36 (6H, s), 2.32 (6H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-190.21(1F,ddd,J＝49.1,23.1,10.7Hz)

(2)

The same procedure as in Example 10(2) was carried out to obtain ((2R,3R,4S)-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl 3,5-dimethylbenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.68 (2H, s), 7.65 (2H, s), 7.22 (1H, s), 7.17 (1H, s), 5.69 (1H, dd, J = 10.4, 3.8Hz), 5.46 (1H, dd, J = 21.8, 3.8Hz), 5.16 (1H, d, J =49.2Hz), 4.71-4.69 (3H, m), 2.36 (6H, s), 2.32 (6H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-190.45(1F,dddd,J＝49.3,22.3,10.9,2.4Hz)

(3)

In the same manner as in Example 1(1), (2R,3R,4R)-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentyl 3,5-dimethylbenzoate was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.67 (2H, s), 7.62 (2H, s), 7.40 (0.80H, dd, J = 6.8, 6.8Hz), 7.23 (1H, s), 7.20 (1H, s), 6.84 (0.20H, dd, J = 11.1, 4.6Hz), 6.06 (0.20H, ddd, J=46.4, 4.6, 2.0Hz), 5.70 (0.20H, ddd, J=28.5, 8.2, 1.9Hz), 5.57 (0.80H, ddd, J=45.2, 6.8, 2.4Hz), 5.43 (0.80H, ddd, J=26.0, 8.4, 2.4Hz), 4.60-4.51 (1H, m), 4.48-4.34 (2H, m), 3.92 (0.60H, s), 3.84 (2.40H, s), 3.03 (0.80H, d, J = 6.2Hz), 2.98 (0.20H, d, J = 13.7Hz), 2.36(6H, s), 2.35(6H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-200.07 (0.86F, ddd, J＝45.3, 26.0, 7.0Hz), -207.47 (0.14F, ddd, J＝46.3, 28.4, 4.6Hz)

(4)

In the same manner as in Example 7(1), (2R,3R,4R)-1-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentan-3-yl 3,5-dimethylbenzoate was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.05 (1H, s), 7.65 (2H, s), 7.51 (2H, s), 7.41 (1H, dd, J = 6.6, 6.6Hz), 7.37 (1H, s), 7.23 (1H, s), 7.20 (1H, s), 5.78 (1H, ddd, J =23.2, 6.1, 3.0Hz), 5.52-5.50 (0.50H, m), 5.44-5.38 (1.50H, m), 4.67 (1H, dd, J = 12.8, 2.9Hz), 4.53 (1H, dd, J = 12.9, 6.2Hz), 3.87 (3H, s), 2.36 (12H, m,)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-196.79 (1F, ddd, J=45.7, 23.3, 6.7Hz)

(5)

The same procedure as in Example 7(2) was carried out to obtain (2S,3S,4R)-2-bromo-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)pentyl 3,5-dimethylbenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.72 (2H, s), 7.65 (2H, s), 7.48 (1H, dd, J = 6.4, 6.4Hz), 7.23 (1H, s), 7.20 (1H, s), 5.80-5.75 (1H, m), 5.53 (1H, ddd, J = 46.8, 6.4, 6.2Hz), 4.76-4.69 (1H, m), 4.63-4.56 (2H, m), 3.89 (3H, s), 2.40 (6H, s), 2.35 (6H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-193.60 (1F, ddd, J=46.7, 17.3, 6.2Hz)

(6)

The same procedure as in Example 1 (4) was repeated except that the reaction was carried out at 60°C for 11 hours to obtain a mixture of (2S,3S,4S)-2-bromo-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-oxopentyl 3,5-dimethylbenzoate and its hydrate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.82 (1H, d, J = 6.3Hz), 7.65 (2H, s), 7.29 (2H, s), 7.23 (1H, s), 7.20 (1H, s), 5.82 (1H, ddd, J = 21.7, 3.5, 3.5Hz), 5.41 (1H, dd, J=46.9, 3.5, Hz), 4.61-4.19 (3H, m), 2.37-2.34 (12H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-210.09 (1F, ddd, J=46.8, 21.9, 6.7Hz)

(7)

The same procedure as in Example 1(5) was carried out to obtain ((2R,3S,4S)-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl 3,5-dimethylbenzoate as a yellow oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

7.65(1H,s), 7.61(1H,s), 7.59(1H,s), 7.57(1H,s), 7.21(0.50H, s), 7.19 (0.50H, s), 7.17 (0.50H, s), 7.12 (0.50H, s), 6.07-6.00 (0.50H, m), 5.80 (0.50H, ddd, J=12.4, 2.5, 2.5Hz), 5.61 (0.50H, ddd, J=9.3, 9.3, 6.1Hz), 5.48-5.46 (0.50H, m), 5.37-5.36 (0.25H, m), 5.26-5.23 (0.50H, m), 5.14-5.11 (0.25H, m), 4.65-4.56 (1.25H, m), 4.48-4.46 (0.75H, m), 4.22-4.16(0.50H, m), 3.77-3.72(0.50H, m), 2.34-2.33(6H, m), 2.32(3H, s), 2.25(3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-183.72 (0.50F, ddd, J＝47.7, 12.0, 12.0Hz), -192.40 (0.50F, ddd, J＝51.2, 11.3, 3.7Hz)

(8)

The same procedure as in Example 19(8) was carried out to obtain ((2R,3S,4S)-5-acetyloxy-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluorotetrahydrothiophen-2-yl)methyl 3,5-dimethylbenzoate as a yellow oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

7.64-7.61 (2.9H, m), 7.53 (1.1H, s), 7.45 (0.45H, s), 7.19 (0.55H, s), 7.16 (0.45H, s), 7.08 (0.55H, s), 6.23 (0.45H, dd, J=13.8, 2.3Hz), 6.16 (0.55H, d, J = 4.5Hz), 6.05 (0.55H, ddd, J = 16.2, 9.0, 7.3Hz), 5.82 (0.45H, ddd, J = 12.4, 4.0, 3.8Hz), 5.38 (0.45H, ddd, J = 47.7, 3.8, 2.3Hz), 5.29 (0.55H, ddd, J=50.7, 9.0, 4.5Hz), 4.66-4.62 (1H, m), 4.54-4.41 (1.55H, m), 4.13-4.07 (0.45H, m), 2.34-2.31 (9H, m), 2.23(3H,m)2.17-2.13(3H,m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-187.11 (0.5F, ddd, J = 48.1, 13.2, 13.2Hz), -191.86 (0.5F, dd, J = 53.8, 12.3Hz)

Example 21

(1)

Except for changing the reaction time to 5 hours, the same procedure as in Example 10(1) was carried out to obtain ((2R,3R,4S)-4-fluoro-5-methoxy-3-(methoxycarbonyloxy)oxolan-2-yl)methyl methyl formate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

5.11 (1H, d, J = 10.0Hz), 5.03-4.91 (2H, m), 4.50 (1H, dd, J = 11.6, 7.2Hz), 4.33 (1H, dd, J = 11.6, 5.2Hz), 4.31-4.29 (1H, m), 3.83 (3H, s), 3.81 (3H, s), 3.41 (3H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-191.20(1F,ddd,J=49.1,22.2,10.5Hz)

(2)

The same procedure as in Example 10(2) was carried out to obtain ((2R,3R,4S)-4-fluoro-5-hydroxy-3-(methoxycarbonyloxy)oxolan-2-yl)methyl methyl formate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

5.59 (0.84H, dd, J=10.0, 3.6Hz), 5.47-5.42 (0.16H, m), 5.20 (0.16H, ddd, J=17.2, 4.0, 4.0Hz), 5.02 (0.84H.d, J=48.8Hz), 5.05-4.98 (16H, m), 4.31-4.15(2H, m), 4.36-4.32(1H, m), 3.84(3H, s), 3.80(3H, s), 3.50(1H, brs)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-191.10 (0.88F, ddd, J＝48.9, 21.1, 10.2Hz), -206.53 (0.12F, ddd, J＝51.2, 16.9, 6.0Hz)

(3)

In the same manner as in Example 1(1), (2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)-3-(methoxycarbonyloxy)pentylmethyl formate was obtained as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

7.42 (0.78H, dd, J=6.8, 6.8Hz), 6.85 (0.22H, dd, J=11.2, 4.8Hz), 5.91 (0.22H, ddd, J=46.4, 4.8, 2.0Hz), 5.41 (0.78H, ddd, J=45.2, 6.8, 2.8Hz), 5.25-5.15 (0.22H, m), 5.00 (0.78H, ddd, J=24.2, 8.2, 2.8Hz), 4.52-4.19 (3H, m), 3.89 (3H, s), 3.83 (3H, s), 3.81 (3H, s), 3.08(1H,brs)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-199.93 (0.75F, ddd, J＝45.2, 24.3, 4.9Hz), -207.93 (0.25F, ddd, J＝46.3, 27.1, 10.5Hz)

(4)

The same procedure as in Example 7(1) was carried out to obtain (2R,3R,4R)-2-fluoro-1-(methoxyimino)-5-(methoxycarbonyloxy)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-ylmethyl formate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.13-8.08(1H,m),7.70-7.68(1H,m),7.39-7.30(0.87H,m),6.83-6.75 (0.13H, m), 5.80-5.66 (0.24H, m), 5.54-5.45 (0.13H, m), 5.36-5.27 (0.76H, m), 5.19-5.15 (0.50H, m), 5.12-5.01 (1.37H, m), 4.54-4.42 (1.13H, m), 4.34-4.26 (0.87H, m), 3.93-3.73 (9H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-196.34 (0.74F, ddd, J＝45.3, 20.9, 6.4Hz), -205.27 (0.26F, ddd, J＝46.7, 25.2, 11.1Hz)

(5)

The same procedure as in Example 7(2) was carried out to obtain (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-3-(methoxycarbonyloxy)pentylmethyl formate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

7.48-7.41 (0.80H, m), 6.96-6.83 (0.20H, m), 5.95 (0.12H, ddd, J = 47.0, 4.8, 3.4Hz), 5.45-5.09 (1.88H, m), 4.56-4.31 (3H, m), 3.94-3.80 (9H,m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

193.89 (0.71F, ddd, J = 46.1, 16.6, 6.0Hz), 203.12 (0.29F, ddd, J = 47.1, 24.5, 10.9Hz)

(6)

The same procedure as in Example 1 (4) was repeated except that the reaction was carried out at 60°C for 9 hours to obtain a mixture of (2S,3S,4S)-2-bromo-4-fluoro-3-(methoxycarbonyloxy)-5-oxopentylmethyl formate and its hydrate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.78(1H,m), 5.48-5.18(2H,m), 4.57-4.34(3H,m), 3.84-3.80 (6H,m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-210.73 (1F, ddd, J=47.3, 21.8, 6.2Hz)

(7)

The same procedure as in Example 1(5) was carried out to obtain ((2R,3S,4S)-4-fluoro-5-hydroxy-3-(methoxycarbonyloxy)tetrahydrothiophen-2-yl)methyl formate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

5.57-5.46 (1H, m), 5.38-5.35 (0.80H, m), 5.25-5.23 (0.20H, m), 5.12-5 .09 (0.70H, m), 4.99-4.97 (0.30H, m), 4.71-4.31 (1.30H, m), 4.23-4.19 (0.70H, m), 3.84 (3H, s), 3.81 (3H, s), 3.77-3.73 (1H, m)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-185.10 (0.43F, d, J＝46.7Hz), -192.12 (0.57F, dd, J＝51.5, 12.0Hz)

(8)

The same procedure as in Example 19(8) was carried out to obtain ((2R,3S,4S)-5-acetyloxy-4-fluoro-3-(methoxycarbonyloxy)tetrahydrothiophen-2-yl)methyl formate as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value:

6.12-6.06 (1H, m), 5.51 (0.60H, ddd, J=15.6, 8.8, 6.8Hz), 5.38-5.31 (0.60H, m), 5.23-5.19 (0.50H, m), 5.10-5.07 (0.30H, m), 4.45 (0.60H, dd, J=11.2, 5.6Hz), 4.32-4.20 (1.40, m), 3.95-3.84 (3.40H, m), 3.80-3.79 (3H, m), 3.54-3.51 (0.60H, m), 2.17 (1.80H, s), 2.12 (1.20H, s)

¹⁹ F-NMR (CDCl ₃ ) δ value:

-187.31 (0.37F, ddd, J＝47.8, 14.1, 14.1Hz), -191.72 (0.63F, dd, J＝50.5, 11.3Hz)

Example 22

(1)

To a solution of 100 g of ((2R,3S,4S)-5-acetyloxy-3-(benzoyloxy)-4-fluorotetrahydrothiophen-2-yl)methyl benzoate in 600 mL of dichloromethane was added 94 mL of a 30% hydrobromic acid/acetic acid solution at room temperature, and the mixture was stirred for 3 hours. 500 mL of water was added to the reaction mixture, and the mixture was stirred for 10 minutes. The organic layer was separated and washed with 600 mL of a 7% aqueous sodium bicarbonate solution to obtain 620 mL of a dichloromethane solution of ((2R,3S,4S)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydrothiophen-2-yl)methyl benzoate.

(2)

Under a nitrogen stream, 193 g of 1,1,1,3,3,3-hexamethyldisilazane was added to a suspension of 66.4 g of cytosine and 316 mg of ammonium sulfate in 200 mL of toluene. The mixture was stirred while heating under reflux until the reaction mixture became a homogeneous solution. 620 mL of a dichloromethane solution of ((2R,3S,4S)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydrothiophen-2-yl)methylbenzoate obtained in (1) was added dropwise at 70°C, and the mixture was stirred at 70°C for 12 hours while distilling off the dichloromethane. The reaction mixture was cooled to room temperature, 146 mg of 4-dimethylaminopyridine was added, and then 122 g of acetic anhydride was added dropwise at 60°C, and the mixture was stirred at or above 60°C for 1 hour. The reaction mixture was cooled to room temperature, and 2000 mL of dichloromethane and 600 mL of 2 mol/L hydrochloric acid were added. The organic layer was separated, and the dichloromethane was distilled off in an external bath at 45°C. To the resulting residue was added 1500 mL of propyl acetate, and the mixture was heated to 80°C with stirring until the distillation component ceased. The reaction mixture was cooled to 10°C, and the solid matter was collected by filtration to obtain 78.0 g of ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophen-2-yl)methyl benzoate.

(3)

To a suspension of 800 mg of ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophen-2-yl)methyl benzoate in 10 mL of methanol was added 60 mg of a 28% sodium methoxide/methanol solution at 22°C, and the mixture was stirred for 5 hours. The reaction mixture was cooled to 5°C, and 140 μL of methanesulfonic acid and 2.4 mL of water were added to dissolve the solid, and the solvent was then distilled off under reduced pressure. To the resulting residue was added 12.6 mL of acetone, and the mixture was stirred at 20°C for 90 minutes, then at 5°C for 1 hour. The solid matter was collected by filtration to obtain 478 mg of (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophene methanesulfonate as a white solid.

Example 23

(1)

To a solution of 10 g of ((2R,3S,4S)-5-acetyloxy-3-(benzoyloxy)-4-fluorotetrahydrothiophen-2-yl)methyl benzoate in 60 mL of dichloromethane was added 9.4 mL of a 30% hydrobromic acid/acetic acid solution at room temperature, and the mixture was stirred for 3 hours. 70 mL of water was added to the reaction mixture, and the mixture was stirred for 10 minutes. The organic layer was separated and washed with 70 mL of a 7% aqueous sodium bicarbonate solution to obtain 58 mL of a dichloromethane solution of ((2R,3S,4S)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydrothiophen-2-yl)methyl benzoate.

(2)

Under a nitrogen stream, 19.3 g of 1,1,1,3,3,3-hexamethyldisilazane was added to a suspension of 6.6 g of cytosine and 32 mg of ammonium sulfate in 20 mL of toluene. The mixture was heated under reflux and stirred until the reaction mixture became a homogeneous solution. 58 mL of a dichloromethane solution of ((2R,3S,4S)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydrothiophen-2-yl)methylbenzoate obtained in (1) was added dropwise at 70°C, and the mixture was stirred at 70°C for 10 hours while distilling off the dichloromethane. The reaction mixture was cooled to room temperature, 15 mg of 4-dimethylaminopyridine was added, and then 20 mL of isobutyric anhydride was added dropwise at 60°C, and the mixture was stirred at 70-80°C for 1 hour. The reaction mixture was cooled to room temperature, and 30 mL of dichloromethane and 30 mL of 2 mol/L hydrochloric acid were added. The organic layer was separated, 6 mL of triethylamine was added, and the dichloromethane was distilled off. The reaction mixture was cooled to 5°C, and the solid was collected by filtration to obtain 5.7 g of ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-(2-methylpropanecarboxamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophen-2-yl)methyl benzoate.

¹ H-NMR (DMSO-d ₆ ) δ value:

1.07 (dd, J=6.8, 1.2Hz, 6H), 2.71 (hept, J=6.8Hz, 1H), 4.07 (dd, J=12.0, 7.0Hz, 1H), 4.65 (dd, J=9.9, 6.5Hz, 1H), 4.74 (dd, 11.3, 7.5Hz, 1H), 5.71 (ddd, J＝49.4, 5.4, 5.4Hz, 1H), 5.99 (ddd, J＝11.1, 5.4, 5.4Hz, 1H), 6.63 (dd, J＝13.5, 5.4Hz, 1H), 7.31 (d, J＝7.6Hz, 1H), 7.48 (dd, J=7.8, 7.8Hz, 2H), 7.57 (dd, J=7.7, 7.7Hz, 2H), 7.66 (dd, J=7.5, 7.5Hz, 1H), 7.72 (dd, J=7.4, 7.4Hz, 1H), 7.95 (dd, J=1.3, 8.4Hz, 2H), 8.01 (dd, J=1.3, 8.4Hz, 2H), 8.45 (d, J=7.4Hz, 1H), 10.98 (brs, 1H)

Example 24

The same procedure as in Example 23 was carried out to obtain ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-(propanecarboxamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophen-2-yl)methyl benzoate.

¹ H-NMR (DMSO-d ₆ ) δ value:

1.04 (t, J=7.4Hz, 3H), 2.43 (q, J=7.4Hz, 2H), 4.07 (dd, J=11.9, 6.7Hz, 1H), 4.65 (dd, J=10.5, 6.8Hz, 1H), 4.74 (dd, 11.3, 7.4Hz, 1H), 5.72 (ddd, J=49.3, 5.5, 5.5Hz, 1H), 5.99 (ddd, J=11.1, 5.4, 5.4Hz, 1H), 6.62 (dd, J=13.1, 5.6Hz, 1H), 7.30 (d, J=7.4Hz, 1H), 7.48 (dd, J =7.8, 7.8Hz, 2H), 7.57 (dd, J=7.8, 7.8Hz, 2H), 7.66 (dd, J=7.4, 7.4Hz, 1H), 7.72 (dd, J=7.6, 7.6Hz, 1H), 7.95 (d, J=7.2Hz, 2H), 8.01(d, J＝7.3Hz, 2H), 8.48(d, J＝7.6Hz, 1H), 10.96(brs, 1H)

Example 25

The same procedure as in Example 23 was carried out to obtain ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-(butanecarboxamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorotetrahydrothiophen-2-yl)methyl benzoate.

¹ H-NMR (DMSO-d ₆ ) δ value:

0.89 (t, J=7.4Hz, 3H), 1.58 (qt, J=7.4, 7.4Hz, 2H), 2.39 (t, J=7.3Hz, 2H), 4.08 (dd, J=11.9, 7.0Hz, 1H), 4.65 (dd, J=10.1, 6.7Hz, 1H), 4.74 (dd, 11.4, 7.4Hz, 1H), 5.72 (ddd, J=49.3, 5.5, 5.5Hz, 1H), 5.99 (ddd, J=11.2, 5.5, 5.5Hz, 1H), 6.62 (dd, J=13.2, 5.5Hz, 1H), 7.31 (d, J=7.6Hz, 1H), 7.48 (dd, J=7.8, 7.8Hz, 2H), 7.57 (dd, J=7.8, 7.8Hz, 2H), 7.66 (dd, J=7.4, 7.4Hz, 1H), 7.72 (dd, J=7.5, 7.5Hz, 1H), 7.95 (dd, J=1.3, 8.3Hz, 2H), 8.01 (dd, J=1.3, 8.4Hz, 2H), 8.48 (d, J=7.7Hz, 1H), 10.97 (brs, 1H)

Example 26

(1)

To a solution of 727 mg of 2-deoxy-2-fluoro-1-O-methyl-D-arabinoside in 15 mL of N,N-dimethylformamide, 438 mg of 60% sodium hydride was added under ice-cooling. The mixture was stirred at the same temperature for 15 minutes, followed by the addition of 1.20 mL of benzyl bromide and stirring for 5 minutes. The mixture was further stirred at room temperature for 1.5 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 75/25) to obtain 1.35 g of 2-deoxy-2-fluoro-1-O-methyl-3,5-bis-O-benzyl-D-arabinoside as a colorless oil.

The results of ¹ H-NMR measurement showed that the anomer ratio was 1:1.

RT(min):1.80.

¹ H-NMR (CDCl ₃ ) δ value:

7.38-7.25 (10H, m), 5.11 (0.5H, dd, J=6.3, 4.3Hz), 4.96-4.92 (1.5H, m), 4.64 (2H, ABq, J=21.9, 11.2Hz), 4.57 (2H, s), 4.28-4.11 (2H, m), 3.62-3.50 (2H, m), 3.40 (3H, s)

(2)

To 1.35 g of 2-deoxy-2-fluoro-1-O-methyl-3,5-bis-O-benzyl-D-arabinoside, 1.26 mL of trifluoroacetic acid and 0.14 mL of water were added, and the mixture was stirred at 55-60°C for 3 hours. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated, washed once with water and twice with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 65/35) to obtain 954 mg of 2-deoxy-2-fluoro-3,5-bis-O-benzyl-D-arabinoside as a colorless oil.

The result of ¹ H-NMR measurement showed that the anomeric ratio was 8/2.

RT(min):1.54.

¹ H-NMR (CDCl ₃ ) δ value:

7.40-7.25 (10H, m), 5.48 (0.8H, dd, J=9.9, 6.6Hz), 5.30 (0.2H, dq, J=10.4, 2.1Hz), 4.96 (0.2H, dt, J=52.8, 4.6Hz), 4.95 (0.8H, dd, J=50.1, 1.3Hz), 4.69 (0.4H, dd, J=11.2, 2.6Hz), 4.62 (1H, d, 5.3Hz), 4.60 (0.6H, dd, J=3.3, 11.2Hz), 4.55 (2H, s), 4.52-4.43 (1H, m), 4.38-4.27(0.2H, m), 4.07-3.97(0.8H, m), 3.64-3.44(2H, m), 2.99(1H, m)

(3)

To a solution of 954 mg of 2-deoxy-2-fluoro-3,5-bis-O-benzyl-D-arabinoside in 10 mL of methanol were added 325 mg of O-methylhydroxyammonium chloride and 0.415 mL of triethylamine, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the resulting residue. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 70/30) to obtain 1.09 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis(benzyloxy)pentanal O-methyloxime as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 63:37.

RT(min):1.66.

¹ H-NMR (CDCl ₃ ) δ value:

7.51 (0.63H, t, J=6.9Hz), 7.40-7.20 (10H, m), 7.01 (0.37H, dd, J=11.9, 4.6Hz), 5.82 (0.37H, ddd, J=46.9, 4.6, 1.3Hz), 5.31 (0.63H, ddd, J=46.1, 6.6, 3.3Hz), 4.72-4.42 (4H, m), 3.97 (1H, brs), 3.91-3.56 (1H, m), 3.90 (1.11H, s,), 3.87 (1.89H, s), 3.71-3.64 (2H, m), 2.47 (1H,brs)

(4)

To a solution of 1.09 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis(benzyloxy)pentanal O-methyloxime in 10.4 mL of acetonitrile, 1.26 g of 2,4,5-trichlorobenzenesulfonyl chloride and 0.430 mL of 1-methylimidazole were added at room temperature, and the mixture was stirred at room temperature for 14.5 hours. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. After filtering out the solids, the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1.50 g of (2R,3R,4R)-2-fluoro-3,5-bis(benzyloxy)-4-(2,4,5-trichlorophenoxy)pentanal O-methyloxime as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 68:32.

RT(min):2.22.

¹ H-NMR (CDCl ₃ ) δ value:

8.09 (0.32H, s), 8.09 (0.68H, s), 7.43 (1H, s), 7.40 (0.68H, t, J=7.7Hz), 7.37-7.15 (10H, m), 6.88 (0.32H, dd, J=11.2, 4.6Hz), 5.61 (0.32H, ddd, J=47.6, 4.6, 2.4Hz), 5.14 (0.68H, ddd, J=46.4, 6.6, 4.0Hz), 4.88-4.75 (1H, m), 4.72-4.54 (2H, m), 4.45-4.25 (2.32H, m), 4.20-4.07 (0.68H, ddd, J=22.5, 5.3, 4.0Hz), 3.88 (3H, s), 3.86-3.75 (2H, m)

(5)

To a solution of 1.50 g of (2R,3R,4R)-2-fluoro-3,5-bis(benzyloxy)-4-(2,4,5-trichlorophenoxy)pentanal O-methyloxime in 6 mL of tetrahydrofuran and 5.4 mL of 1,3-dimethyl-2-imidazolidinone was added 430 mg of lithium bromide, and the mixture was stirred at 60°C for 6 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 75/25) to obtain 662 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal O-methyloxime as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 86:14.

RT(min):2.00.

¹ H-NMR (CDCl ₃ ) δ value:

7.42 (0.86H, t, J = 6.9Hz), 7.33 (10H, m), 6.90 (0.14H, dd, J = 11.2, 5.3Hz), 5.81 (0.14H, dq, J = 47.6, 2.6Hz), 5.32 (0.86H, dt, J = 46.9, 6.6Hz), 4.75 (1.72H, ABq, 40.3, 11.2Hz), 4.68 (0.28H, ABq, 19.8, 8.6Hz), 4.55 (0.28H, ABq, 12.6, 10.6Hz), 4.48 (1.72H, s), 4.33-4.21 (0.14H, m), 4.19-4.10 (1H, m), 4.09-3.98 (0.86H, m), 3.91 (2.58H, s), 3.90 (0.42H, m), 3.93-3.83 (1H, m), 3.83-3.76 (0.14H, m), 3.71 (0.86H,m)

(6)

To a solution of 662 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal O-methyloxime in 6.6 mL of tetrahydrofuran was added 3.3 mL of 50% aqueous glyoxylic acid solution, and the mixture was stirred at 70°C for 4.83 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with aqueous sodium bicarbonate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 655 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal and its hydrate as a colorless oil.

RT(min):1.54

(7)

To a solution of 655 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal and its hydrate in 6 mL of 1-methylpyrrolidone was added 289 mg of sodium monohydrosulfide n-hydrate under ice-cooling, and the mixture was stirred at the same temperature for 1.25 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless oily solution of 2-deoxy-2-fluoro-3,5-bis-O-benzyl-4-thio-D-arabinoside in 1-methylpyrrolidone.

The result of ¹ H-NMR measurement: the anomeric ratio was 57/43.

RT (min): 1.66, 1.68.

¹ H-NMR (CDCl ₃ ) δ value:

7.39-7.21 (10H, m), 6.14 (0.57H, d, J=5.9Hz), 5.77 (0.43H, d, J=7.9Hz), 5.51-5.40 (0.43H, m), 5.29-5.23 (0.57H, m), 5.08 (0.43H, ddd, J=50.2, 4.6, 3.3Hz), 4.96 (0.57H, ddd, J=52.2, 7.9, 4.0Hz), 4.77-4.57 (2H, m), 4.54 (1.14H, s), 4.50 (0.86, s), 4.42-4.31 (0.57H, m), 4.17-1.06 (0.43H, m), 3.88-3.51 (2H, m), 3.19-3.15 (1H, m), 3.08 (2H, t, J = 5.0Hz), 2.99 (1H, t, J = 6.6Hz)

(8)

To the 1-methylpyrrolidone solution of 2-deoxy-2-fluoro-3,5-bis(benzyloxy)-4-thio-D-arabinoside obtained in Example 26 (7) were added 5.4 mL of tetrahydrofuran, 0.293 mL of acetic anhydride, 0.541 mL of triethylamine, and a 4-dimethylaminopyridine tablet, and the mixture was stirred at room temperature for 1.25 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 95/5 to 60/40) to obtain 394 mg of 1-acetyl-2-deoxy-2-fluoro-3,5-bis-O-benzyl-4-thio-D-arabinoside as a colorless oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 55/45.

RT(min):1.89.

¹ H-NMR (CDCl ₃ ) δ value:

7.39-7.22 (10H, m), 6.05 (0.55H, t, J=4.5Hz), 6.02 (0.45H, dd, J=10.6, 3.3Hz), 5.20 (0.45H, ddd, J=50.1, 5.3, 3.3Hz), 5.14 (0.55H, ddd, J=51.0, 8.6, 4.6Hz), 4.80-4.46 (4H, m), 4.36-4.23 (0.55H, m), 4.21-4.09 (0.45H, m), 3.81-3.37 (3H, m), 2.11 (1.65H, s), 2.06 (1.35H, s)

(9)

To a solution of 116.2 mg of 1-acetyl-2-deoxy-2-fluoro-3,5-bis-O-benzyl-4-thio-D-arabinoside in 2.3 mL of dichloromethane was added 0.119 mL of a 30% hydrogen bromide-acetic acid solution and stirred at room temperature for 1 hour. Water was added to the reaction mixture. The organic layer was separated, washed with saturated sodium bicarbonate aqueous solution, and dried over magnesium sulfate to obtain a dichloromethane solution of 1-bromo-2-deoxy-2-fluoro-3,5-bis-O-benzyl-4-thio-D-arabinoside.

To 83 mg of cytosine, 0.521 mL of N,O-bistrimethylsilylacetamide was added at room temperature. After stirring at 80°C for 1.5 hours under a nitrogen atmosphere, a dichloromethane solution of 1-bromo-2-deoxy-2-fluoro-3,5-bis-O-benzyl-4-thio-D-arabinoside was added. The solvent was distilled off, and the mixture was further stirred at 80°C for 2.5 hours. Ethyl acetate and 2 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain 61.3 mg of 1-(3,5-bis-O-benzyl-2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine as a colorless oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 31/69.

RT(min):1.30.

¹ H-NMR (CDCl ₃ ) δ value:

7.99 (0.69H, dd, J=7.6, 1.7Hz), 7.83 (0.31H, d, J=7.3Hz), 7.40-7.24 (10H, m), 7.21-7.16 (1H, m), 6.68 (0.69H, dd, J=18.5, 4.6Hz), 6.34 (0.31H, dd, J = 15.9, 2.0Hz), 6.20-5.80 (1H, brs), 5.69 (0.31H, d, J = 7.3Hz), 5.60 (0.69H, d, J = 7.3Hz), 5.15 (0.31H, dt, J = 47.4, 2.5Hz), 5.11 (0.69H, dt, J=51.0, 4.5Hz), 4.61 (1.38H, ABq, J=12.6, 11.7), 4.52 (1.24H, brs), 4.48 (1.38H, ABq, 12.9, 4.8Hz), 4.26 (1H, m), 3.93 (0.31H, t, J=5.9Hz), 3.70-3.55 (2.38H, m), 3.53-3.47 (0.31H, m)

(10)

To a solution of 9.6 mg of 1-(3,5-bis-O-benzyl-2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in 1 mL of dichloromethane was added 0.065 mL of a 1 mol/L boron tribromide-dichloromethane solution under ice-cooling. The mixture was stirred for 2 hours while slowly warming to room temperature. Hexane was added to the reaction mixture, and the solid was collected by filtration. The resulting solid was washed with toluene and ethyl acetate to obtain 5.3 mg of 1-(2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine as a white solid.

The results of ¹ H-NMR measurement showed that the α/β ratio was 36/64.

RT (min): 0.22, 0.27.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.02-7.93 (1H, m), 7.40-7.15 (2H, m), 6.46 (0.64H, dd, J=14.5, 5.3Hz), 6.15 (0.36H, dd, J=17.2, 5.9Hz), 5.93 (0.36H, d, J=4.6Hz), 5.84 (0.64H, d, J=4.6Hz), 5.82-5.71 (1H, m), 5.26 (0.64H, t, J=5.3Hz), 5.06 (0.36H, dt, J=52.2, 5.9Hz), 5.03 (1H, dd, J=11.2, 4.6Hz), 4.91 (0.64H, dt, J=46.2, 5.3Hz), 4.29-4.18 (0.64H, m), 4.15-4.02 (0.36H, m), 3.8 2-3.67(0.36H,m), 3.65-3.54(1H,m), 3.51-3.28(1H,m), 3.26-3.15(0.64H,m)

Example 27

(1)

To a solution of 1.87 g of 3,5-bis-O-benzoyl-2-deoxy-2-fluoro-D-arabinoside in 37.5 mL of dichloromethane was added 0.941 mL of 3,4-dihydro-2H-pyran at room temperature. 49 mg of p-toluenesulfonic acid monohydrate was added under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 60/40) to obtain 2.33 g of 3,5-bis-O-benzoyl-2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-D-arabinoside as a colorless oil.

RT(min):1.96.

¹ H-NMR (CDCl ₃ ) δ value:

8.06 (4H, m), 7.51 (6H, m), 5.68 (1H, d, J = 10.6Hz), 5.59-5.48 (1H, dd, 21.9, 4.5Hz), 5.20 (1H, d, J = 49.5Hz), 5.06-5.02 (1H, m), 4.77-4.59 (2H, m), 4.53 (1H, q, 4.2Hz), 3.94-3.84 (1H, m), 3.64-3.53 (1H, m), 1.90-1.40 (6H, m)

(2)

To a methanol solution of 2.33 g of 3,5-bis-O-benzoyl-2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-D-arabinoside was added a 28% sodium methoxide/methanol solution, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and ethyl acetate and water were added to the resulting residue. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 50/50 to 0/100) to obtain 1.08 g of 2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-D-arabinoside as a colorless oil.

RT(min):0.69.

¹ H-NMR (CDCl ₃ ) δ value:

5.58-5.50 (1H, m), 5.03 (1H, brs), 4.94 (1H, dd, 44.7, 2.7Hz), 4.30-4.07 (3H, m), 3.92-3.52 (3H, m), 2.33 (1H, d, J = 9.2Hz), 2.14-2.08 (1H, m), 1.84-1.54 (7H, m)

(3)

To a solution of 1.08 g of 2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-D-arabinoside in 20 mL of N,N-dimethylformamide, 456 mg of 60% sodium hydride was added under ice-cooling. The mixture was stirred at the same temperature for 25 minutes, followed by 1.43 mL of 4-methoxybenzyl chloride and stirring for 1 hour. After further stirring at room temperature for 1 hour, the mixture was allowed to stand overnight at room temperature. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 60/40) to obtain 1.42 g of 2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-3,5-bis-O-(4-methoxybenzyl)-D-arabinoside as a colorless oil.

The results of ¹ H-NMR measurement showed that the anomeric ratio was 8:2.

RT(min):1.92.

¹ H-NMR (CDCl ₃ ) δ value:

7.25-7.20 (4H, m), 6.90-6.83 (4H, m), 5.49 (0.8H, d, J = 12.6Hz), 5.40-5.34 (0.2H, m), 5.12 (0.4H, d, J = 2.0Hz), 4.99-4.89 (1.6H, m), 4.64-4.62(4H, m), 4.22-4.15(1H, m), 4.12-3.84(2H, m), 3.81(3H, s), 3.80(3H, s), 3.75-3.63(3H, m), 1.89-1.43(6H, m)

(4)

To a solution of 1.42 g of 2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-3,5-bis-O-(4-methoxybenzyl)-D-arabinoside in 14.2 mL of acetone was added 1.42 mL of 2 mol/L hydrochloric acid, and the mixture was stirred at 50°C for 1.25 hours. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 50/50) to obtain 1.14 g of 2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-D-arabinoside as a colorless oil.

The results of ¹ H-NMR measurement showed that the anomeric ratio was 8:2.

RT(min):1.50.

¹ H-NMR (CDCl ₃ ) δ value:

7.29-7.17 (4H, m), 6.92-6.83 (4H, m), 5.46 (0.8H, dd, J = 10.2, 7.6Hz), 5.28 (0.2H, ddd, J = 11.4, 3.9, 1.2Hz), 4.94 (0.2H, dt, J = 52.8, 4.8Hz), 4.91 (0.8H, dd, J=50.4, 1.3Hz), 4.93-4.87 (0.2H, d, J=1.3Hz), 4.62-4.39 (4.8H, m), 4.10-3.91 (1H, m), 3.81 (3H, s), 3.81 (3H, s), 3.77-3.67(0.8H, m), 3.58-3.43(2.2H, m)

(5)

To a solution of 1.14 g of 2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-D-arabinoside in 11 mL of methanol were added 315 mg of O-methylhydroxyammonium chloride and 0.403 mL of triethylamine, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the resulting residue. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 95/5 to 50/50) to obtain 1.02 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 69:31.

RT(min):1.58.

¹ H-NMR (CDCl ₃ ) δ value:

7.47 (0.69H, t, J=6.9Hz), 7.29-7.21 (2H, m), 7.18-7.10 (2H, m), 7.00 (0.31H, dd, J=11.2, 4.6Hz), 6.87 (4H, m), 5.80 (0.31H, ddd, J =47.1, 4.6, 2.0Hz), 5.35 (0.69H, ddd, J = 46.2, 6.9, 3.0Hz), 4.56-4.34 (4H, m), 3.95-3.90 (1H, m), 3.90 (0.93H, m), 3.86 (2.07H, s), 3.82-3.78 (1H, m), 3.81 (3H, s), 3.80 (3H, s), 3.71 (0.31H, dd, J = 7.8, 3.3Hz), 3.64-3.56 (1.69H, m)

(6)

To a solution of 1.02 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in 20 mL of acetonitrile, 2.03 g of 2,4,5-trichlorobenzenesulfonyl chloride and 0.772 mL of 1-methylimidazole were added at room temperature. The mixture was stirred at room temperature for 1.75 hours and then at 40°C for 1.25 hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction mixture. The organic layer was separated and filtered to remove the solid matter. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 75/25) to obtain 1.15 g of (2R,3R,4R)-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)-4-(2,4,5-trichlorophenoxy)pentanal O-methyloxime as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 65:35.

RT(min):2.15.

¹ H-NMR (CDCl ₃ ) δ value:

8.08 (0.35H, s), 8.08 (0.65H, s), 7.43 (1H, s), 7.36 (0.65H, t, J=6.9Hz), 7.18-7.10 (4H, m), 6.92-6.80 (4.35H, m), 5.58 (0.35H, dq, J=47.6, 2.4Hz), 5.10 (0.65H, dq, J=46.6, 3.5Hz), 4.85-4.72 (1H, m), 4.62-4.46 (2H, m), 4.40-4.21 (2.35H, m), 4.08 (0.65H, dq, J=23.8, 2.9Hz), 3.87 (1.95H, s), 3.87 (1.05H, s), 3.81 (3.90H, s), 3.80 (2.10H, s), 3.81-3.72 (2H, m)

(7)

To a solution of 1.15 g of (2R,3R,4R)-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)-4-(2,4,5-trichlorophenoxy)pentanal O-methyloxime in 6 mL of tetrahydrofuran and 6 mL of 1,3-dimethyl-2-imidazolidinone was added 451 mg of lithium bromide, and the mixture was stirred at 65°C for 7 hours. Ethyl acetate and a 25% aqueous lithium bromide solution were added to the reaction mixture. The organic layer was separated, washed with a 12% aqueous lithium bromide solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 60/40) to obtain 857 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 82:18.

RT(min):1.92.

¹ H-NMR (CDCl ₃ ) δ value:

7.40 (0.82H, t, J=6.9Hz), 7.24 (4H, m), 6.92-6.83 (4.18H, m), 5.79 (0.18H, ddd, J=50.9, 6.0, 2.4Hz), 5.29 (0.82H, dt, J=46.9, 6.6Hz), 4.66 (1.64H, ABq, J=10.5, 24.3Hz), 4.58 (0.36H, ABq, J=18.0, 10.5Hz), 4.48 (0.36H, s), 4.42 (1.64H, ABq, J=12.0, 1.3Hz), 4.29-4.06 (1H, m), 3.98 (0.82H, dq, J=17.3, 3.3Hz), 3.90 (3H, s), 3.88-3.70 (0.18H, m), 3.81 (1H, s), 3.81 (3H, s), 3.80 (3H, s), 3.71-3.63 (1H, m)

(8)

To a solution of 857 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in 17 mL of acetone, 4.2 mL of 35% formaldehyde solution and 4.2 mL of 2 mol/L hydrochloric acid were added at room temperature, and the mixture was stirred for 1.75 hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 60/40) to obtain 598 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal and its hydrate as a colorless oil.

RT(min):1.66.

(9)

To a solution of 598 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal and its hydrate in 6 mL of 1-methylpyrrolidone was added 210 mg of sodium monohydrosulfide n-hydrate under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours. Ethyl acetate and saturated brine were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 30/70) to obtain 453 mg of 2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-4-thio-D-arabinoside as a colorless oil.

RT(min):1.58,1.61.

m/z(ESI-positive)：409.3[M+H] ⁺

(10)

To a solution of 453 mg of 2-deoxy-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)-4-thio-D-arabinoside in 9 mL of tetrahydrofuran were added 0.210 mL of acetic anhydride, 0.462 mL of triethylamine, and 5 mg of 4-dimethylaminopyridine at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 50/50) to obtain 447 mg of 1-acetyl-2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-4-thio-D-arabinoside as a colorless oil.

The result of ¹ H-NMR measurement showed that the anomeric ratio was 1/1.

RT(min):1.79,1.81.

¹ H-NMR (CDCl ₃ ) δ value:

7.25-7.18 (4H, m), 6.90-6.83 (4H, m), 6.03 (0.5H, t, J=3.3Hz), 6.01 (0.5H, J=13.8, 3.3Hz), 5.25 (0.5H, ddd, J=50.1, 5.1, 3.3Hz), 5.09 (0.5H, ddd, J=51.0, 8.4, 4.8Hz), 4.73-4.46 (2H, m), 4.46 (1H, s), 4.42 (1H, ABq, J=12.0, 3.3Hz), 4.30-4.07 (1H, m), 3.80 (6H, s), 3.79-3.55(1.5H, m), 3.50-3.31(1.5H, m), 2.10(1.5H, s), 2.07(1.5H, s)

(11)

To a solution of 47.2 mg of cytosine and 95.7 mg of 1-acetyl-2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-4-thio-D-arabinoside in 1 mL of acetonitrile was added 0.277 mL of N,O-bistrimethylsilylacetamide at room temperature. The mixture was stirred at 75°C for 2 hours under a nitrogen atmosphere. Then, 0.154 mL of trimethylsilyl trifluoromethanesulfonate was added, and the mixture was stirred at the same temperature for 1 hour. Dichloromethane and water were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol = 100/0 to 50/50), and then purified by silica gel column chromatography (NH column, chloroform/methanol = 100/0 to 90/10) to obtain 8.8 mg of 1-(2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-4-thio-D-arabinofuranosyl)cytosine as a colorless oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 53/47.

RT(min):1.30.

¹ H-NMR (CDCl ₃ ) δ value:

8.04 (0.47H, dd, J=7.3, 1.3Hz), 7.90 (0.53H, d, J=7.3Hz), 7.25-7.19 (3H, m), 7.13-7.07 (1H, m), 6.92-6.79 (4H, m), 6.68 (0.47H, dd, J=17.8, 4.6Hz), 6.36 (0.53H, dd, J=15.5, 2.3Hz), 5.58 (0.53H, d, J=7.9Hz), 5.52 (0.47H, d, J=7.3Hz), 5.13 (0.53H, dt, J=46.9, 2.6Hz), 3.81 (1.59H, s), 3.79 (3H, s), 3.64-3.42 (2H, m)

(12)

To a solution of 8.8 mg of 1-(2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-4-thio-D-arabinofuranosyl)cytosine in 2 mL of dichloromethane was added 0.2 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 1.5 hours. The solvent in the reaction mixture was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH column, chloroform/methanol = 90/10 to 60/40) to obtain 3.1 mg of 1-(2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine as a white solid.

The results of ¹ H-NMR measurement showed that the α/β ratio was 56/44.

RT(min):0.22.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.02-7.94 (1H, m), 7.34-7.15 (2H, m), 6.46 (0.44H, dd, J=14.5, 5.3Hz), 6.15 (0.56H, dd, J=17.8, 5.9Hz), 5.92 (0.56H, d, J=5.3Hz), 5.87 (0.44H, d, J=4.6Hz), 5.79 (0.56H, d, J=7.3Hz), 5.77 (0.44H, d, J=7.3Hz), 5.24 (1H, t, J=5.6Hz), 5.06 (0.56H, dt, J=52.2, 5.9Hz), 5.03 (1H, dd, J = 11.2, 4.6Hz), 4.91 (0.44H, dt, J = 46.2, 5.3Hz), 4.24 (0.44H, dt, J = 10.7, 5.3Hz), 4.09 (0.56H, dt, J = 2.7, 6.4Hz), 3.82-3.67 (0.66H, m), 3.65-3.54 (1H, m), 3.51-3.28 (1H, m), 3.26-3.15 (0.44H, m)

Example 28

(1)

Under a nitrogen atmosphere, 0.44 g of sodium hydride and 2.03 g of 4-methylbenzyl bromide were added to a solution of 0.70 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol in 7.0 mL of N,N-dimethylformamide under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of 2.5 mL of methanol, followed by the addition of ethyl acetate and hexane. The mixture was washed sequentially with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 60/40) to obtain 1.33 g of (3S,4R,5R)-3-fluoro-2-methoxy-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)oxolan-3-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.23-7.11 (8H, m), 5.10 (0.5H, dd, J=5.9, 4.3Hz), 4.93-4.91 (1.5H, m), 4.66-4.52 (4H, m), 4.23-4.09 (2H, m), 3.57-3.48 (2H, m), 3.40 (3H, s), 2.35 (3H, s), 2.34 (3H, s)

(2)

To 1.31 g of (3S,4R,5R)-3-fluoro-2-methoxy-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)oxolan-2-ol were added 9.8 mL of acetic acid, 3.3 mL of water, and 0.56 mL of concentrated sulfuric acid, and the mixture was stirred at 70°C for 2 hours. Ethyl acetate and hexane were added to the reaction mixture, which was washed sequentially with water and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 30/70) to obtain 0.74 g of (3S,4R,5R)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)oxolan-2-ol as a colorless oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 22:78.

¹ H-NMR (CDCl ₃ ) δ value:

7.21-7.12 (8H, m), 5.46 (0.78H, dd, J=10.1, 7.1Hz), 5.28 (0.22H, dd, J=10.6, 2.1Hz), 4.94 (0.22H, dt, J=52.6, 4.8Hz), 4.92 (0.78H, dd, J=50.4, 1.0Hz), 4.67-4.42 (5H, m), 4.30 (0.22H, dt, J=17.8, 4.8Hz), 4.00 (0.78H, ddt, J=19.0, 3.8, 1.0Hz), 3.92 (0.22H, dd, J=10.6, 1.3Hz), 3.57-3.42 (2H, m), 2.97 (0.78H, dd, J=7.1, 1.0Hz), 2.35 (6H, s)

(3)

Under a nitrogen atmosphere, 3.6 mL of methanol and 0.20 g of O-methylhydroxylamine hydrochloride were added to 0.72 g of (3S,4R,5R)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)oxolan-2-ol. Then, 0.34 mL of triethylamine was added dropwise, and the mixture was stirred at room temperature for 16 hours. 0.10 g of O-methylhydroxylamine hydrochloride and 0.25 mL of triethylamine were added to the reaction mixture, and the mixture was further stirred at 50°C for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 50/50) to obtain 0.65 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis((4-methylbenzyl)oxy)pentanal=O-methyloxime as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 67:33.

¹ H-NMR (CDCl ₃ ) δ value:

7.48 (0.67H, t, J=7.1Hz), 7.23-7.11 (8H, m), 7.00 (0.33H, dd, J=11.6, 4.6Hz), 5.81 (0.33H, ddd, J=46.2, 4.6, 1.8Hz), 5.28 (0.67H, ddd, J=46.2, 7.1, 3.1Hz), 4.58-4.28 (4H, m), 3.97-3.82 (4.33H, m), 3.74-3.60 (2.67H, m), 2.45 (0.33H, d, J=6.9Hz), 2.43 (0.67H, d, J =6.9Hz), 2.35(3H, s), 2.34(3H, s)

(4)

Under a nitrogen atmosphere, 6.4 mL of acetonitrile, 0.60 g of 2,4,5-trichlorobenzenesulfonyl chloride, and 0.21 mL of N-methylimidazole were added to 0.64 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis((4-methylbenzyl)oxy)pentanal=O-methyloxime, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 70/30) to obtain 1.01 g of (2R,3R,4R)-4-fluoro-5-(methoxyimino)-1,3-bis((4-methylbenzyl)oxy)pentan-2-yl 2,4,5-trichlorobenzenesulfonate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 66:34.

¹ H-NMR (CDCl ₃ ) δ value:

5.59 (0.34H, ddd, J = 47.6, 4.6, 2.6Hz), 5.12 (0.66H, ddd, J = 46.5, 6.9, 3.8Hz), 4.82 (0.66H, td, J = 5.3, 3.3Hz), 4.77 (0.34H, td, J = 5.6, 2.4Hz), 4.65-4.49 (2H, m), 4.40-4.23 (2.34H, m), 4.10 (0.66H, ddd, J=23.7, 5.3, 3.8Hz), 3.87 (3H, s), 3.85-3.82 (2H, m), 2.35-2.33 (6H, m)

(5)

Under a nitrogen atmosphere, 10 mL of 1,3-dimethyl-2-imidazolidinone and 0.82 g of anhydrous lithium bromide were added to 1.00 g of (2R,3R,4R)-4-fluoro-5-(methoxyimino)-1,3-bis((4-methylbenzyl)oxy)pentan-2-yl 2,4,5-trichlorobenzenesulfonate, and the mixture was stirred at 50°C for 17 hours. Ethyl acetate and n-hexane were added to the reaction mixture, which was washed sequentially with water, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 60/40) to obtain 0.56 g of (2R,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methylbenzyl)oxy)pentanal = O-methyloxime as a pale yellow oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 84:16.

¹ H-NMR (CDCl ₃ ) δ value:

7.40 (0.84H, t, J=6.6Hz), 7.23-7.11 (8H, m), 6.89 (0.16H, dd, J=11.2, 5.0Hz), 5.79 (0.16H, ddd, J=47.7, 5.0, 3.0Hz), 5.29 (0.84H, dt, J=47.2, 6.6Hz), 4.77-4.43 (4H, m), 4.28-4.08 (1.16H, m), 4.00 (0.84H, ddd, J=17.2, 6.6, 3.3Hz), 3.92-3.87 (3.16H, m), 3.83 (0.84H, dd, J =10.2, 7.3Hz), 3.77 (0.16H, ddd, J = 11.2, 5.9, 2.3Hz), 3.69 (0.84H, ddd, J = 10.2, 5.9, 2.3Hz), 2.35 (3H, s), 2.34 (3H, s)

(6)

Under a nitrogen atmosphere, 11 mL of acetone, 2.7 mL of 2 mol/L hydrochloric acid, and 1.0 mL of a 37% aqueous formaldehyde solution were added to 0.55 g of (2R,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methylbenzyl)oxy)pentanal = O-methyloxime, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, which was washed sequentially with water, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 50/50) to obtain 0.50 g of a colorless oil.

The obtained oily substance was a mixture of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methylbenzyl)oxy)valeraldehyde and its hydrate.

¹ H-NMR (CDCl ₃ ) δ value:

9.76 (1H, d, J=6.6Hz), 7.23-7.13 (8H, m), 5.06 (1H, dd, J=47.7, 3.8Hz), 4.66-4.48 (4H, m), 4.34 (1H, td, J=5.9, 4.8Hz), 4.22 (1H, ddd, J=22.6, 4.8, 3.8Hz), 3.94 (1H, dd, J=10.9, 5.4Hz), 3.76 (1H, ddd, J=10.9, 6.4, 2.5Hz), 2.35 (3H, s), 2.34 (3H, s)

(7)

To a solution of 0.50 g of the colorless oil obtained in Example 28 (6) in 4.8 mL of 1-methyl-2-pyrrolidone, 0.19 g of sodium hydrosulfide x hydrate was added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, 0.5 M hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 50/50) to obtain 0.36 g of (3S,4S,5R)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)tetrahydrothiophen-2-ol as a pale yellow oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 40:60.

¹ H-NMR (CDCl ₃ ) δ value:

7.23-7.13 (8H, m), 5.43 (0.40H, ddt, J = 12.2, 8.9, 1.3Hz), 5.20-5.03 (1.30H, m), 4.90 (0.30H, ddt, J = 7.3, 4.0Hz), 4.72-4.46 (4H, m), 4.36 (0.60H, dd, J=7.4, 1.8Hz), 4.31 (0.40H, dd, J=7.1, 4.6Hz), 3.95 (0.40H, t, J=7.9Hz), 3.66-3.37 (3.20H, m), 3.03 (0.40H, dd, J=12.2, 1.3Hz), 2.35(6H, s)

(8)

Under a nitrogen atmosphere, to a solution of 0.34 g of (3S,4S,5R)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)tetrahydrothiophen-2-ol in 3.4 mL of tetrahydrofuran was added 0.17 mL of acetic anhydride and 0.38 mL of triethylamine under ice-cooling, and the mixture was stirred at room temperature for 21 hours. Ethyl acetate was added to the reaction mixture, which was washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 60/40) to obtain 0.31 g of (3S,4S,5R)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)tetrahydrothiophen-2-yl acetate as a colorless oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 40:60.

¹ H-NMR (CDCl ₃ ) δ value:

7.21-7.12 (8H, m), 6.03 (0.40H, d, J=4.6Hz), 6.02 (0.60H, dd, J=16.7, 3.2Hz), 5.17 (0.60H, ddd, J=50.1, 5.4, 3.2Hz), 5.09 (0.40H, ddd, J=50.9, 8.6, 4.6Hz), 4.74-4.41 (4H, m), 4.26 (0.40H, ddd, J= 12.6, 8.6, 4.9Hz), 4.12 (0.60H, ddd, J=15.4, 6.9, 5.4), 3.74 (0.60H, ddd, J=6.9, 5.3, 1.1Hz), 3.66-3.60 (1H, m), 3.51-3.34 (1.40H, m), 2.35 (6H, s), 2.10 (1.80H, s), 2.06 (1.20H, s)

(9)

Under a nitrogen atmosphere, 0.14 mL of a 30% hydrogen bromide/acetic acid solution was added to a solution of 0.15 g of (3S,4S,5R)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)tetrahydrothiophen-2-yl acetate in 0.60 mL of dichloromethane, and the mixture was stirred at room temperature for 1.5 hours. Dichloromethane was added to the reaction mixture, and the mixture was washed sequentially with water and a saturated aqueous sodium bicarbonate solution, then dried over anhydrous sodium sulfate to obtain a dichloromethane solution containing (3S,4S,5R)-2-bromo-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)tetrahydrothiophene.

In a separate reaction vessel, 0.10 g of cytosine and 0.58 ml of N,O-bis(trimethylsilyl)acetamide were added under a nitrogen atmosphere, and the mixture was stirred at 80°C for 1.5 hours. After cooling, a dichloromethane solution containing (3S,4S,5R)-2-bromo-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)tetrahydrothiophene was added to the reaction mixture, and the mixture was stirred at 60°C for 2.5 hours. Dichloromethane was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol = 100/0 to 90/10) to obtain 72 mg of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)tetrahydrothiophene as a pale yellow solid.

The results of ¹ H-NMR measurement showed that the α/β ratio was 38:62.

¹ H-NMR (CDCl ₃ ) δ value:

8.08 (0.62H, dd, J=7.3, 1.7Hz), 7.95 (0.38H, d, J=7.3Hz), 7.23-7.05 (8H, m), 6.69 (0.62H, dd, J=18.0, 4.5Hz), 6.39 (0.38H, dd, J=15.2, 2.0Hz), 5.56 (0.38H, d, J=7.3Hz), 5.50 (0.62H, d, J=7.3Hz), 5.14 (0.38H, dt, J=46.6, 2.0Hz), 5.11 (0.62H, dt, J=50.5, 4.5Hz), 4.63-4.40 (4H, m), 4.29-4.15 (1H, m), 3.92 (0.38H, t, J=7.6Hz), 3.65-3.56 (2.24H, m), 3.49 (0.38H, ddd, J=9.2, 6.8, 2.0Hz), 2.37-2.34 (6H, m)

(10)

Under a nitrogen atmosphere, to a solution of 70 mg of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)tetrahydrothiophene in 4.6 mL of dichloromethane was added 3.0 mL of a 1 mol/L boron trichloride solution in dichloromethane under dry ice/acetone cooling, and the mixture was stirred at the same temperature for 3.5 hours. The reaction mixture was warmed to 0°C and stirred for 30 minutes. 3.0 mL of methanol was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration and purified by silica gel column chromatography (chloroform/methanol = 100/0 to 60/40) to obtain 63 mg of (2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrothiophen-3-ol as a white solid.

The results of ¹ H-NMR measurement showed that the α/β ratio was 24:76.

¹ H-NMR (DMSO-d ₆ ) δ value:

7.99 (0.76H, dd, J=7.3, 1.3Hz), 7.97 (0.24H, d, J=7.3Hz), 7.31-7.20 (2H, br), 6.46 (0.76H, dd, J=14.5, 5.0Hz), 6.15 (0.24H, dd, J=17.5, 5.9Hz), 5.95 (0.24H, d, J=5.0Hz), 5.90 (0.76H, d, J=5.0Hz), 5.80 (0.24H, d, J=7.3Hz), 5.78 (0.76H, d, J=7.3Hz), 5.26 (0.76H, t, J =5.3Hz), 5.18-4.82 (1.24H, m), 4.29-4.20 (0.76H, m), 4.14-4.03 (0.27H, m), 3.80-3.56 (2H, m), 3.25-3.19 (1H, m)

Example 29

(1)

Under a nitrogen atmosphere, 0.97 g of sodium hydride and 4.66 g of 4-chlorobenzyl bromide were added to a solution of 1.35 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol in 13 mL of N,N-dimethylformamide under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 5 mL of methanol was added to the reaction mixture to quench the reaction. Ethyl acetate and hexane were then added, and the mixture was washed sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 60/40) to obtain 3.32 g of (2R,3R,4S)-3-((4-chlorobenzyl)oxy)-2-(((4-chlorobenzyl)oxy)methyl)-4-fluoro-5-methoxyoxolan-3-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.33-7.20 (8H, m), 5.10 (0.5H, dd, J=6.1, 4.5Hz), 4.93-4.91 (1.5H, m), 4.68-4.52 (4H, m), 4.13-4.07 (2H, m), 3.59-3.49 (2H, m), 3.40 (3H, s)

(2)

To 3.32 g of (2R,3R,4S)-3-((4-chlorobenzyl)oxy)-2-(((4-chlorobenzyl)oxy)methyl)-4-fluoro-5-methoxyoxolane were added 27 mL of acetic acid, 6.6 mL of water, and 1.06 mL of concentrated sulfuric acid, and the mixture was stirred at 70°C for 2 hours. To the reaction mixture were added 4.5 mL of water and 0.53 mL of concentrated sulfuric acid, and the mixture was stirred at 70°C for 5 hours. Ethyl acetate and hexane were added to the reaction mixture, and the mixture was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 30/70) to obtain 2.92 g of (3S,4R,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorooxolane-2-ol as a colorless oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 18:82.

¹ H-NMR (CDCl ₃ ) δ value:

7.35-7.29 (4H, m), 7.25-7.20 (4H, m), 5.49 (0.82H, dd, J = 10.2, 6.3Hz), 5.31 (0.18H, ddd, J = 10.2, 3.8, 2.3Hz), 4.95 (0.18H, dt, J = 52.8, 4.6Hz), 4.95 (0.82H, dd, J=50.2, 1.3Hz), 4.68-4.48 (4H, m), 4.43 (0.82H, td, J=5.6, 4.3Hz), 4.26 (0.18H, dt, J=17.6, 4.6Hz), 4.10 (0.18H, dt, J=5.0, 3.8Hz), 3.99 (0.82H, ddt, J=19.8, 4.3, 0.9Hz), 3.70 (0.18H, dd, J=10.2, 1.5Hz), 3.62-3.48 (2H, m), 2.88 (0.82H, dd, J＝6.6, 1.3Hz)

(3)

Under a nitrogen atmosphere, 14 mL of methanol and 0.72 g of O-methylhydroxylamine hydrochloride were added to 2.89 g of (3S,4R,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorooxolan-2-ol. Then, 1.21 mL of triethylamine was added dropwise, and the mixture was stirred at room temperature for 12 hours. Ethyl acetate was added to the reaction mixture, which was washed sequentially with water and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 50/50) to obtain 3.09 g of (2R,3R,4R)-3,5-bis((4-chlorobenzyl)oxy)-2-fluoro-4-hydroxypentanal = O-methyloxime as a white solid.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 65:35.

¹ H-NMR (CDCl ₃ ) δ value:

7.47 (0.65H, t, J=6.9Hz), 7.35-7.13 (8H, m), 6.99 (0.35H, dd, J=11.6, 4.6Hz), 5.80 (0.35H, ddd, J=46.9, 4.6, 1.7Hz), 5.28 (0.65H, ddd, J=45.9, 6.9, 3.3Hz), 4.62-4.39 (4H, m), 4.00-3.83 (4.35H, m), 3.76-3.56 (2.65H, m), 2.42 (0.35H, d, J=6.6Hz), 2.40 (0.65H, d, J=6.6Hz)

(4)

Under a nitrogen atmosphere, 31 mL of acetonitrile, 2.81 g of 2,4,5-trichlorobenzenesulfonyl chloride, and 1.02 mL of N-methylimidazole were added to 3.08 g of (2R,3R,4R)-3,5-bis((4-chlorobenzyl)oxy)-2-fluoro-4-hydroxypentanal = O-methyloxime, and the mixture was stirred at room temperature for 4.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 70/30) to obtain 4.72 g of (2R,3R,4R)-1,3-bis((4-chlorobenzyl)oxy)-4-fluoro-5-(methoxyimino)pentan-2-yl 2,4,5-trichlorobenzenesulfonate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 68:32.

¹ H-NMR (CDCl ₃ ) δ value:

8.08 (0.32H, s), 8.07 (0.68H, s), 7.42 (1H, s), 7.37 (0.68H, t, J=6.7Hz), 7.33-7.27 (4H, m), 7.21-7.08 (4H, m), 6.87 (0.32H, dd, J =11.6, 4.6Hz), 5.58 (0.32H, ddd, J = 47.6, 4.6, 3.0Hz), 5.12 (0.68H, ddd, J = 46.5, 6.7, 4.2Hz), 4.84 (0.68H, ddd, J = 5.6, 4.8, 3.0Hz), 4.77 (0.32H, td, J=5.6, 2.3Hz), 4.68-4.53 (2H, m), 4.41-4.29 (2.16H, m), 4.25 (0.16H, dd, J=5.6, 2.3Hz), 4.10 (0.68H, td, J=23.1, 4.5Hz), 3.88 (3H, s), 3.86-3.73 (2H, m)

(5)

Under a nitrogen atmosphere, 47 mL of 1,3-dimethyl-2-imidazolidinone and 3.64 g of anhydrous lithium bromide were added to 4.71 g of (2R,3R,4R)-1,3-bis((4-chlorobenzyl)oxy)-4-fluoro-5-(methoxyimino)pentan-2-yl 2,4,5-trichlorobenzenesulfonate, and the mixture was stirred at 50°C for 14 hours. Ethyl acetate and hexane were added to the reaction mixture, which was washed sequentially with water, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 60/40) to obtain 2.78 g of (2R,3S,4S)-4-bromo-3,5-bis((4-chlorobenzyl)oxy)-2-fluoropentanal = O-methyloxime as a pale yellow oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 81:19.

¹ H-NMR (CDCl ₃ ) δ value:

7.42 (0.81H, t, J=6.6Hz), 7.34-7.21 (8H, m), 6.89 (0.19H, dd, J=11.6, 4.8Hz), 5.79 (0.19H, ddd, J=47.6, 4.8, 3.0Hz), 5.31 (0.81H, dt, J=47.2, 6.6Hz), 4.80-4.39 (4H, m), 4.30-4.11 (1.19H, m), 4.00 (0.81H, ddd, J=16.8, 6.6, 3.3Hz), 3.913 (2.43H, s), 3.905 (0.57H, s), 3.89-3.77 (1.19H, m), 3.70 (0.81H, ddd, J=10.2, 5.9, 2.3Hz)

(6)

Under a nitrogen atmosphere, 55 mL of acetone, 14 mL of 2 mol/L hydrochloric acid, and 4.80 mL of 37% aqueous formaldehyde were added to 2.75 g of (2R,3S,4S)-4-bromo-3,5-bis((4-chlorobenzyl)oxy)-2-fluoropentanal = O-methyloxime, and the mixture was stirred at room temperature for 5.5 hours. Ethyl acetate was added to the reaction mixture, which was washed sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 80/20 to 20/80) to obtain 2.56 g of a light yellow oil.

The obtained oily substance is a mixture of (2S,3S,4S)-4-bromo-3,5-bis((4-chlorobenzyl)oxy)-2-fluoropentanal and its hydrate.

¹ H-NMR (CDCl ₃ ) δ value:

9.80 (1H, d, J=5.9Hz), 7.35-7.15 (8H, m), 5.13 (1H, dd, J=47.6, 3.6Hz), 4.66-4.44 (4H, m), 4.37 (1H, dt, J=5.9, 5.1Hz), 4.22 (1H, ddd, J=23.0, 5.1, 3.6Hz), 3.94 (1H, dd, J=10.9, 5.3Hz), 3.78 (1H, ddd, J=10.9, 5.9, 2.5Hz)

(7)

To a solution of 2.50 g of the light yellow oil obtained in Example 29 (6) in 25 mL of 1-methyl-2-pyrrolidone, 0.91 g of sodium hydrosulfide x hydrate was added under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, 0.5 mol/L hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 50/50) to obtain 1.92 g of (3S,4S,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-ol as a light yellow oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 63:37.

¹ H-NMR (CDCl ₃ ) δ value:

7.42-7.19 (8H, m), 5.45 (0.37H, ddd, J = 11.6, 9.2, 1.2Hz), 5.15 (0.63H, ddd, J = 8.3, 3.6, 3.0Hz), 5.13 (0.37H, dt, J = 47.9, 1.2Hz), 5.01 (0.63H, ddd, J=52.2, 7.1, 4.1Hz), 4.72-4.41 (4H, m), 4.35-4.36 (1H, m), 3.93 (0.37H, t, J=7.8Hz), 3.59-3.34 (3.26H, m), 2.89 (0.37H, dd, J＝11.6, 1.0Hz)

(8)

To a solution of 1.89 g of (3S,4S,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-ol in 19 mL of tetrahydrofuran was added 0.86 mL of acetic anhydride and 1.90 mL of triethylamine under ice-cooling, and the mixture was stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 60/40) to obtain 1.77 g of (3S,4S,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl acetate as a pale yellow oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 40:60.

¹ H-NMR (CDCl ₃ ) δ value:

7.33-7.20 (8H, m), 6.04 (0.40H, d, J=4.3Hz), 6.02 (0.60H, dd, J=16.8, 3.0Hz), 5.19 (0.60H, ddd, J=50.0, 5.4, 3.0Hz), 5.11 (0.40H, ddd, J=50.9, 8.3, 4.3Hz), 4.76-4.41 (4H, m), 4.24 (0.40H, ddd, J= 12.2, 8.3, 6.6Hz), 4.12 (0.60H, ddd, J=15.4, 6.6, 5.4), 3.75 (0.60H, qd, J=6.6, 1.0Hz), 3.65-3.60 (1H, m), 3.50 (0.60H, dd, J=9.6, 6.6Hz), 3.47 (0.40H, ddd, J=9.7, 6.6, 1.0Hz), 3.37 (0.40H, q, J=6.6Hz), 2.11 (1.8H, s), 2.08 (1.2H, s)

(9)

Under a nitrogen atmosphere, 0.17 mL of a 30% hydrogen bromide/acetic acid solution was added to a solution of 0.20 g of (3S,4S,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl acetate in 0.80 mL of dichloromethane, and the mixture was stirred at room temperature for 2 hours. Dichloromethane was added to the reaction mixture, and the mixture was washed sequentially with water and a saturated aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate to obtain a dichloromethane solution containing (3S,4S,5R)-2-bromo-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorotetrahydrothiophene.

In a separate reaction vessel, 0.12 g of cytosine and 0.53 mL of N,O-bis(trimethylsilyl)acetamide were added under a nitrogen atmosphere and stirred at 80°C for 2 hours. After cooling, a dichloromethane solution containing (3S,4S,5R)-2-bromo-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorotetrahydrothiophene was added to the reaction mixture, and the mixture was stirred at 60°C for 2 hours. Dichloromethane was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol = 100/0 to 80/20) to obtain 0.18 g of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorotetrahydrothiophene as a pale yellow solid.

The results of ¹ H-NMR measurement showed that the α/β ratio was 36:64.

¹ H-NMR (CDCl ₃ ) δ value:

8.01 (0.64H, dd, J=7.6, 1.8Hz), 7.93 (0.36H, d, J=7.6Hz), 7.36-7.09 (8H, m), 6.73 (0.64H, dd, J = 19.2, 4.3Hz), 6.38 (0.36H, dd, J = 15.0, 2.3Hz), 5.54 (0.36H, d, J = 7.6Hz), 5.53 (0.64H, d, J = 7.6Hz), 5.20 (0.36H, dt, J=47.2, 2.3Hz), 5.14 (0.64H, dt, J=50.5, 4.3Hz), 4.65-4.41 (4H, m), 4.28-4.21 (1H, m), 3.95-3.89 (0.36H, m), 3.66-3.60 (2.28H, m), 3.54-3.48 (0.36H, m)

(10)

Under a nitrogen atmosphere, to a solution of 0.17 g of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorotetrahydrothiophene in 11 mL of dichloromethane was added 6.8 mL of a 1 mol/L boron trichloride solution in dichloromethane under dry ice/acetone cooling, and the mixture was stirred at this temperature for 3.5 hours. The reaction mixture was warmed to 0°C and stirred for 30 minutes. 7.5 mL of methanol was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration and washed sequentially with ethyl acetate and hexane. The obtained solid was purified by silica gel column chromatography (chloroform/methanol = 100/0 to 60/40) to obtain 63 mg of (2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrothiophen-3-ol as a white solid.

The results of ¹ H-NMR measurement showed that the α/β ratio was 27:73.

¹ H-NMR (DMSO-d ₆ ) δ value:

7.99 (0.73H, dd, J=7.3, 1.3Hz), 7.97 (0.27H, d, J=7.3Hz), 7.31-7.20 (2H, br), 6.46 (0.73H, dd, J=14.7, 5.3Hz), 6.15 (0.27H, dd, J=17.5, 5.9Hz), 5.95 (0.27H, d, J=5.3Hz), 5.89 (0.73H, d, J=5.3Hz), 5.80 (0.27H, d, J=7.3Hz), 5.78 (0.73H, d, J=7.3Hz), 5.26 (0.73H, t, J =5.3Hz), 5.18-4.82 (1.27H, m), 4.29-4.20 (0.73H, m), 4.14-4.03 (0.27H, m), 3.80-3.54 (2H, m), 3.25-3.19 (1H, m)

Example 30

(1)

Under a nitrogen atmosphere, 55 mL of dichloromethane and 2.60 mL of 1-methylimidazole were added to 1.37 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol. Then, 3.52 mL of (benzyloxy)phosgene was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed sequentially with water and saturated aqueous sodium bicarbonate, and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 95/5 to 70/30) to obtain 2.91 g of benzyl ((2R,3R,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl carbonate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.40-7.33 (10H, m), 5.33-5.22 (1H, m), 5.14 (0.5H, dd, J=5.6, 4.3Hz), 4.97-4.96 (1.5H, m), 4.53 (1H, dd, J=11.2, 4.0Hz), 4.31 (1H, dd, J＝11.2, 7.6Hz), 4.21 (1H, ddd, J＝7.6, 5.1, 4.0Hz), 3.45 (3H, s)

(2)

To 2.58 g of benzyl ((2R,3R,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl carbonate were added 21 mL of acetic acid, 5.2 mL of water, and 0.67 mL of concentrated sulfuric acid, and the mixture was stirred at 70°C for 8 hours. 0.30 mL of concentrated sulfuric acid was added to the reaction mixture, and the mixture was further stirred at 70°C for 7 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 95/5 to 50/50) to obtain 1.69 g of benzyl ((2R,3R,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl carbonate as a colorless oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 20:80.

¹ H-NMR (CDCl ₃ ) δ value:

7.40-7.33 (10H, m), 5.56 (0.80H, dd, J=10.2, 4.0Hz), 5.42 (0.20H, ddd, J=8.6, 6.6, 3.6Hz), 5.23-5.14 (4.20H, m), 5.03 (0.80H, dd, J =21.3, 4.1Hz), 5.02 (0.80H, dd, J = 48.2, 1.0Hz), 4.96 (0.20H, dt, J = 50.9, 3.6Hz), 4.53-4.43 (2H, m), 4.34 (0.80H, dd, J = 12.4, 6.8Hz), 4.17 (0.20H, dd, J = 5.9, 4.1Hz), 3.34 (0.20H, dd, J = 8.6, 2.0Hz), 2.70 (0.80H, dd, J = 4.0, 2.8Hz)

(3)

To 1.68 g of benzyl ((2R,3R,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl carbonate were added 8.4 mL of methanol and 0.37 g of O-methylhydroxylamine hydrochloride, followed by the dropwise addition of 0.61 mL of triethylamine, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, which was washed sequentially with water and a saturated aqueous sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 95/5 to 60/40) to obtain 1.66 g of dibenzyl ((2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)pentane-1,3-diyl) dicarbonate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 77:23.

¹ H-NMR (CDCl ₃ ) δ value:

7.41-7.33 (10.77H, m), 6.82 (0.23H, dd, J=11.2, 4.6Hz), 5.89 (0.23H, ddd, J=46.2, 4.6, 2.1Hz), 5.39 (0.77H, ddd, J=45.2, 6.4, 2.8Hz), 5.29-5.13 (4.23H, m), 5.01 (0.77H, ddd, J = 24.0, 8.0, 2.9Hz), 4.35-4.09 (3H, m), 3.89 (0.69H, s), 3.84 (2.31H, s), 2.62 (0.77H, d, J = 5.9Hz), 2.60 (0.23H, d, J = 6.9 Hz)

(4)

Under a nitrogen atmosphere, 10 mL of acetonitrile, 1.55 g of 2,4,5-trichlorobenzenesulfonyl chloride, and 0.87 mL of N-methylimidazole were added to 1.66 g of dibenzyl ((2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)pentane-1,3-diyl) dicarbonate, and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction mixture, which was washed sequentially with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 75/25) to obtain 2.40 g of dibenzyl ((2R,3R,4R)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentane-1,3-diyl) dicarbonate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 78:22.

¹ H-NMR (CDCl ₃ ) δ value:

8.11 (0.22H, s), 8.10 (0.78H, s), 7.51 (1H, s), 7.43-7.33 (10.78H, m), 6.78 (0.22H, dd, J=11.4, 4.5Hz), 5.71 (0.22H, ddd, J=46.9, 4.5, 2.8Hz), 5.54 (0.22H, ddd, J = 25.1, 5.8, 2.8Hz), 5.37 (0.78H, ddd, J = 21.5, 5.6, 4.0Hz), 5.31 (0.39H, dd, J = 6.3, 4.0Hz), 5.22-5.03 (5.17H, m), 5.00 (0.22H, td, J=5.8, 2.6Hz), 4.46-4.39 (1H, m), 4.36-4.30 (1H, m), 3.87 (0.66H, s), 3.85 (2.34H, s)

(5)

Under a nitrogen atmosphere, 24 mL of 1,3-dimethyl-2-imidazolidinone and 1.65 g of anhydrous lithium bromide were added to 2.40 g of dibenzyl ((2R,3R,4R)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentane-1,3-diyl) dicarbonate, and the mixture was stirred at 50°C for 9 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 80/20) to obtain 1.25 g of dibenzyl ((2R,3S,4S)-2-bromo-4-fluoro-5-(methoxyimino)pentane-1,3-diyl) dicarbonate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 79:21.

¹ H-NMR (CDCl ₃ ) δ value:

7.42-7.34 (10.79H, m), 6.82 (0.21H, dd, J=11.2, 4.8Hz), 5.94 (0.21H, ddd, J=46.9, 4.8, 3.1Hz), 5.47-5.16 (5.79H, m), 4.59-4.31 (3H, m), 3.89(3H,s)

(6)

Under a nitrogen atmosphere, 22 mL of acetone, 5.6 mL of 2 mol/L hydrochloric acid, and 1.87 mL of 37% aqueous formaldehyde were added to 1.11 g of dibenzyl ((2R,3S,4S)-2-bromo-4-fluoro-5-(methoxyimino)pentane-1,3-diyl) dicarbonate, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, which was washed sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 85/15 to 20/80) to obtain 1.07 g of a colorless oil.

The obtained oily substance was a mixture of dibenzyl((2R,3S,4S)-2-bromo-4-fluoro-5-pentanone-1,3-diyl)=dicarbonate and its hydrate.

¹ H-NMR (CDCl ₃ ) δ value:

9.74 (1H, d, J = 5.6Hz), 7.39-7.31 (10H, m), 5.38 (1H, dt, J = 22.0, 4.0Hz), 5.20-5.13 (5H, m), 4.62-4.31 (3H, m)

(7)

To a solution of 1.05 g of the colorless oil obtained in Example 30 (6) in 11 mL of 1-methyl-2-pyrrolidone, 0.37 g of sodium hydrosulfide x hydrate was added under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, 0.5 mol/L hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 40/60) to obtain 0.64 g of benzyl ((2R,3S,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl carbonate as a pale yellow oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 36:64.

¹ H-NMR (CDCl ₃ ) δ value:

7.40-7.31 (10H, m), 5.53-5.45 (1H, m), 5.40 (0.36H, dtd, J=10.2, 2.0, 1.0Hz), 5.34 (0.64H, t, J=4.0Hz), 5.27-5.10 (4.68H, m), 4.95 (0.32H, dd, J＝7.3, 4.0Hz), 4.46 (0.64H, dd, J＝10.6, 6.4Hz), 4.37 (0.64H, dd, J＝10.6, 6.4Hz), 4.22 (0.72H, dd, J＝7.3, 1.0Hz), 4.03-3.97 (0.36H, m), 3.54 (0.64H, td, J＝6.4, 5.3Hz)

(8)

To a solution of 0.64 g of benzyl ((2R,3S,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-hydroxytetrahydrothiophen-2-yl)methyl carbonate in 6.4 mL of tetrahydrofuran was added 0.28 mL of acetic anhydride and 0.61 mL of triethylamine under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, which was washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 40/60) to obtain 0.58 g of (3S,4S,5R)-4-(((benzyloxy)carbonyl)oxy)-5-((((benzyloxy)carbonyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl acetate as a pale yellow oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 40:60.

¹ H-NMR (CDCl ₃ ) δ value:

7.39-7.34 (10H, m), 6.08 (0.60H, dd, J=14.5, 1.7Hz), 6.05 (0.40H, d, J=4.3Hz), 5.51 (0.40H, ddd, J=11.9, 8.8, 7.1Hz), 5.38-5.03 (5.60H, m), 4.47 (0.40H, dd, J=11.1, 5.8Hz), 4.34-4.20 (1.60H, m), 3.89 (0.60H, q, J=6.4Hz), 3.51 (0.40H, q, J=6.5Hz), 2.11 (1.20H, s), 2.07 (1.80H, s)

(9)

Under a nitrogen atmosphere, 0.08 mL of a 30% hydrogen bromide/acetic acid solution was added to a solution of 100 mg of (3S,4S,5R)-4-(((benzyloxy)carbonyl)oxy)-5-(((benzyloxy)carbonyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl acetate in 0.40 mL of dichloromethane, and the mixture was stirred at room temperature for 2 hours. Dichloromethane was added to the reaction mixture, and the mixture was washed sequentially with water and a saturated aqueous sodium bicarbonate solution, then dried over anhydrous sodium sulfate to obtain a dichloromethane solution containing benzyl ((2R,3S,4S)-3-(((benzyloxy)carbonyl)oxy)-5-bromo-4-fluorotetrahydrothiophen-2-yl)methyl carbonate.

In a separate reaction vessel, 59 mg of cytosine and 0.36 ml of N,O-bis(trimethylsilyl)acetamide were added under a nitrogen atmosphere and stirred at 80°C for 1.5 hours. After cooling, a dichloromethane solution containing benzyl ((2R,3S,4S)-3-(((benzyloxy)carbonyl)oxy)-5-bromo-4-fluorotetrahydrothiophen-2-yl)methyl carbonate was added to the reaction mixture, and the mixture was stirred at 60°C for 3 hours. Dichloromethane was added to the reaction mixture, and the mixture was washed with water and then a saturated aqueous sodium bicarbonate solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol = 100/0 to 80/20) to obtain 15 mg of benzyl ((2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-(((benzyloxy)carbonyl)oxy)-4-fluorotetrahydrothiophen-2-yl)methyl carbonate as a white solid.

The results of ¹ H-NMR measurement showed that the α/β ratio was 24:76.

¹ H-NMR (CDCl ₃ ) δ value:

7.96 (0.76H, dd, J=7.3, 2.1Hz), 7.96 (0.24H, d, J=7.3Hz), 7.41-7.34 (10H, m), 6.82 (0.76H, dd, J=23.8, 4.0Hz), 6.35 (0.24H, dd, J= 15.2, 2.3Hz), 5.77-5.66 (1.24H, m), 5.43-5.07 (5.76H, m), 4.45-4.30 (2H, m), 4.08 (0.24H, t, J=7.6Hz), 3.80 (0.76H, t, J=7.6Hz)

(10)

To 15 mg of benzyl ((2R,3S,4S)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((benzyloxy)carbonyl)oxy)-4-fluorotetrahydrothiophen-2-yl)methyl carbonate was added 1.0 mL of a 7 mol/L ammonia/methanol solution, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol = 100/0 to 65/35) to obtain 6.6 mg of (2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrothiophen-3-ol as a white solid.

The results of ¹ H-NMR measurement showed that the α/β ratio was 26:74.

¹ H-NMR (DMSO-d ₆ ) δ value:

7.99 (0.74H, dd, J=7.3, 1.3Hz), 7.97 (0.26H, d, J=7.3Hz), 7.29-7.19 (2H, br), 6.46 (0.74H, dd, J = 14.5, 5.0Hz), 6.15 (0.26H, dd, J = 17.5, 5.9Hz), 5.94 (0.26H, d, J = 5.0Hz), 5.88 (0.74H, d, J = 5.0Hz), 5.79 (0.26H, d, J = 7.3Hz), 5.78 (0.74H, d, J = 7.3Hz), 5.26 (0.74H, t, J =5.3Hz), 5.17-4.82 (1.26H, m), 4.29-4.20 (0.74H, m), 4.14-4.03 (0.26H, m), 3.79-3.56 (2H, m), 3.25-3.19 (1H, m)

Example 31

(1)

A mixture of 1.15 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol, 20 mL of N,N-dimethylformamide, 5.33 mL of tert-butyldiphenylsilyl chloride, and 2.83 g of imidazole was stirred at room temperature for 1 hour and then allowed to stand at room temperature for 1 day. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 9/1) to obtain 3.15 g of (3S,4R,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluoro-2-methoxyoxolan-3-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.59-7.51 (8H, m), 7.41-7.24 (12H, m), 4.94 (1H, d, J = 5.3Hz), 4.92 (1H, ddd, J = 52.8, 5.9, 4.6Hz), 4.32 (1H, dt, J = 16.5, 5.3Hz), 4.13-4.07 (1H, m), 3.38 (2H, d, J = 5.3Hz), 3.29 (3H, s), 1.06 (9H, s), 0.97 (9H, s)

(2)

To a solution of 1.66 g of (3S,4R,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluoro-2-methoxyoxolane in 10 mL of dichloromethane was added dropwise 1.0 mL of 30% hydrogen bromide/acetic acid at room temperature, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was stirred for 5 minutes. The organic layer was separated, washed with a 10% aqueous sodium bicarbonate solution, and the solvent was evaporated under reduced pressure. To the resulting residue were added 10 mL of acetonitrile and 10 mL of a 10% aqueous sodium bicarbonate solution, stirred at room temperature for 3 hours, and then allowed to stand overnight. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 9/1) to obtain 0.65 g of (3S,4R,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorooxolan-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.65-7.24 (20H, m), 5.37 (1H, t, J = 9.2Hz), 4.76 (1H, dd, J = 50.2, 1.3Hz), 4.45 (1H, td, J = 5.4, 2.9Hz), 4.38-4.32 (1H, m), 3.47-4.43 (2H, m), 3.15 (1H, d, J=8.6z), 1.07 (9H, s), 0.91 (9H, s)

(3)

To 0.65 g of (3S,4R,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorooxolan-2-ol were added 0.13 g of O-methylhydroxylamine hydrochloride and 1.0 mL of methanol. Then, 0.19 mL of triethylamine was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 9/1) to obtain 0.32 g of (2R,3R,4R)-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoro-4-hydroxypentanal = O-methyloxime as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 4:1.

¹ H-NMR (CDCl ₃ ) δ value:

7.63-7.50 (8H, m), 7.46-7.28 (12.75H, m), 6.72 (0.25H, dd, J＝11.2, 4.6Hz), 5.73 (0.25H, ddd, J＝46.6, 4.6, 2.0Hz), 5.10 (0.75H, ddd, J=46.1, 7.3, 4.0Hz), 4.10 (0.25H, ddd, J=28.1, 6.3, 1.7Hz), 3.98-3.77 (2.75H, m), 3.76 (2.25H, s), 3.60-3.50 (1.75H, m), 2.66 (0.25H, dd, J=4.0, 1.3Hz), 2.55 (0.25H, ddd, J=28.1, 6.3, 1.7Hz), 1.01 (9H, s), 0.97 (6.75H, s), 0.94 (2.25H, s)

(4)

A mixture of 0.32 g of (2R,3R,4R)-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoro-4-hydroxypentanal = O-methyloxime, 2 mL of acetonitrile, 1 mL of tetrahydrofuran, 0.1 mL of N-methylimidazole, and 0.15 g of 2,4,5-trichlorobenzenesulfonyl chloride was stirred at room temperature for 8 hours and then allowed to stand at room temperature for 3 days. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 19/1) to obtain 0.24 g of (2R,3R,4R)-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoro-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentanal = O-methyloxime as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.01 (1H, s), 7.63-7.56 (8H, m), 7.46-7.28 (13H, m), 7.15 (1H, t, J=6.9Hz), 5.01 (1H, dt, J=47.6, 7.3Hz), 4.90 (1H, t, J=7.3Hz), 4.32 (1H, dd, J = 13.2, 6.6, 1.3Hz), 4.03 (1H, dd, J = 11.2, 5.9Hz), 3.83 (1H, dd, J = 11.2, 6.6Hz), 3.79 (3H, s), 0.99 (9H, s), 0.97 (9H, s)

(5)

To a solution of 236 mg of (2R,3R,4R)-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoro-4-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentanal = O-methyloxime in 1.0 mL of tetrahydrofuran were added 114 mg of anhydrous lithium bromide and 1.0 mL of 1,3-dimethyl-2-imidazolidinone, and the mixture was stirred at 50°C for 10 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 19/1) to obtain 173 mg of (2R,3S,4S)-4-bromo-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoropentanal = O-methyloxime as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.71-7.53 (8H, m), 7.46-7.29 (12H, m), 7.17 (0.86H, t, J=7.3Hz), 6.57 (0.14H, dd, J=10.6, 5.3Hz), 5.75 (0.14H, dt, J=47.3, 4.6Hz), 5.13 (0.86H, dt, J=46.9, 6.6Hz), 4.26-4.19 (1H, m), 4.08-4.00 (1H, m), 3.87-3.78 (4.58H, m), 3.65 (0.42H, s), 1.03 (9H, s), 1.00 (9H, s)

(6)

To a solution of 173 mg of (2R,3S,4S)-4-bromo-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoropentanal = O-methyloxime in 1.0 mL of acetone were added 0.18 mL of 37% aqueous formaldehyde, 0.20 mL of water, and 0.04 mL of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 48 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 7/3) to obtain 114 mg of a colorless oil.

The obtained oily substance is a mixture of (2R,3S,4S)-4-bromo-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoropentanal and its hydrate.

¹ H-NMR (CDCl ₃ ) δ value:

9.59 (1H, d, J=7.9Hz), 7.66-7.57 (8H, m), 7.44-7.27 (12H, m), 4.93 (1H, dd, J=46.9, 4.0Hz), 4.42 (1H, ddd, J=18.5, 4.0, 2.6Hz), 4.16-4.09 (2H, m), 3.88 (1H, ddd, J=12.9, 8.9, 2.6Hz), 1.03 (9H, s), 1.01 (9H, s)

(7)

To a solution of 114 mg of the colorless oil obtained in Example 31(6) in 0.5 mL of N,N-dimethylformamide was added 87 mg of a 15-18% aqueous sodium hydrosulfide solution at 0-10°C, and the mixture was stirred at the same temperature for 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed three times with a 10% aqueous sodium chloride solution. The solvent was distilled off under reduced pressure to obtain a light yellow oil containing (3S,4S,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-ol.

The light yellow oil was used directly in the next reaction.

¹ H-NMR (CDCl ₃ ) δ value:

7.74-7.22 (20H, m), 5.43-5.28 (1H, m), 4.96 (0.5H, d, J=48.2Hz), 4.86 (0.5H, ddd, J=51.5, 5.9, 4.0Hz), 4.60-4.53 (1H, m), 3.93 (0.5H, t, J=7.9Hz), 3.48-3.32 (2H, m), 3.26 (0.5H, dd, J=9.2, 5.3Hz), 1.08 (4.5H, s), 1.07 (4.5H, s), 0.92 (4.5H, s), 0.91 (4.5H, s)

(8)

To a 1.0 mL solution of the pale yellow oil obtained in Example 31 (7) in tetrahydrofuran was added 0.1 mg of dimethylaminopyridine and 0.1 mL of acetic anhydride, and the mixture was stirred at room temperature for 1 hour and allowed to stand overnight at room temperature. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 9/1) to obtain 67 mg of (3S,4S,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl acetate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.60-7.48 (8H, m), 7.44-7.23 (12H, m), 6.02 (0.5H, dd, J=4.6, 1.3Hz), 5.96 (0.5H, dd, J=16.2, 3.0Hz), 5.06 (0.5H, ddd, J=48.9, 5.0, 3.0Hz), 4.99 (0.5H, ddd, J=50.9, 8.6, 4.6Hz), 4.34-4.18 (1H, m), 3.84-3.77 (0.5H, m), 3.66-3.60 (1H, m), 3.41 (0.5H, td, J=7.6, 3.3Hz), 3.31-3.18 (1H, m), 2.12 (1.5H, s), 1.89 (1.5H, s), 1.03 (4.5H, s), 0.99 (4.5H, s), 0.95 (9H, s)

(9)

To a solution of 59 mg of (3S,4S,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl acetate in 1.0 mL of dichloromethane was added 0.03 mL of a 30% hydrogen bromide/acetic acid solution, and the mixture was stirred at room temperature for 2 hours. Dichloromethane and water were added to the reaction mixture. The organic layer was separated, washed with a 5% aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to obtain a light brown oil containing (3S,4S,5R)-2-bromo-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophene.

To the resulting light brown oil were added 24 mg of cytosine and 0.2 mL of N,O-bis(trimethylsilyl)acetamide, and the mixture was stirred at 80°C for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1) to obtain 43 mg of ((3S,4S,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl)cytosine as a colorless oil.

The results of ¹ H-NMR measurement showed that the α/β ratio was 15/85.

¹ H-NMR (CDCl ₃ +D ₂ O) δ value:

8.12 (0.15H, d, J=7.3Hz), 7.69-7.25 (20.85H, m), 6.89 (0.85H, dd, J=23.1, 4.0Hz), 6.26 (0.15H, dd, J=16.2, 2.3Hz), 5.71 (0.15H, d, J=7.3Hz), 5.55 (0.85H, d, J=7.3Hz), 5.02 (0.15H, dt, J=48.2, 2.6Hz), 4.85 (0.85H, dt, J=51.1, 3.3Hz), 4.42 (0.85H, d, J=7.3Hz), 4.30 (0.15H, dt, J=11.7, 3.0Hz), 3.88 (0.15H, t, J=6.6Hz), 3.65-3.48 (2.7H, m), 3.34 (0.15H, t, J=9.2Hz), 1.07 (7.65H, s), 0.99 (1.35H, s), 0.91 (9H, s)

(10)

To a solution of 43 mg of ((3S,4S,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl)cytosine in 1.0 mL of tetrahydrofuran was added 0.24 mL of a 1 mol/L tetrabutylammonium fluoride/tetrahydrofuran solution, followed by stirring at room temperature for 2 hours and then standing overnight. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol = 1/0 to 2/1) to obtain 14 mg of 1-(2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine as a white solid.

The results of ¹ H-NMR measurement showed that the α/β ratio was 16/84.

¹ H-NMR (DMSO-d ₆ ) δ value:

8.01-7.96 (1H, m), 7.30-7.22 (2H, br), 6.46 (0.84H, dd, J=14.5, 5.3Hz), 6.15 (0.16H, dd, J=17.2, 5.9Hz), 5.93 (0.16H, d, J=5.3Hz), 5.87 (0.84H, d, J=4.0Hz), 5.80-5.76 (1H, m), 5.25 (0.84H, t, J=5.3Hz), 5.17-4.82 (1.16H, m), 4.29-4.20 (0.84H, m), 4.15-4.06 (0.16H, m), 3.80-3.55 (2H, m), 3.25-3.16 (1H, m)

Example 32

(1)

To a suspension of 5.0 g of 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in 1.3 mL of acetic acid was added dropwise 2.9 mL of 30% hydrogen bromide/acetic acid at room temperature, followed by stirring at room temperature for 3 hours. To the reaction mixture were added 20 mL of toluene and 20 mL of water, stirred for 5 minutes, and the aqueous layer removed. The resulting organic layer was washed with 20 mL of 10% aqueous sodium bicarbonate solution, and the solvent was removed by vacuum distillation. To the resulting oily substance were added 10 mL of acetonitrile and 10 mL of 10% aqueous sodium bicarbonate solution, stirred at room temperature for 1 hour, and then allowed to stand overnight. To the reaction mixture were added 20 mL of toluene and 10 mL of water, stirred for 5 minutes, and the aqueous layer removed. The solvent was then removed by vacuum distillation to yield a colorless oil containing 2,3,5-tri-O-benzoyl-D-ribofuranose.

The colorless oil was used directly in the next reaction.

(2)

To the colorless oil obtained in Example 32 (1) were added 1.3 g of O-methylhydroxylamine hydrochloride and 5.0 mL of methanol, and 1.8 mL of triethylamine was added dropwise under ice-cooling, followed by stirring at room temperature for 3 hours. 10 mL of toluene and 10 mL of a 10% aqueous sodium chloride solution were added to the reaction mixture, and the solvent was removed under reduced pressure after removal of the aqueous layer. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 2/1) to obtain 2.7 g of (2R,3R,4S)-2-hydroxy-5-(methoxyimino)pentane-1,3,4-triyl tribenzoate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 4:1.

¹ H-NMR (CDCl ₃ ) δ value:

8.05-8.01 (4H, m), 7.99-7.94 (2H, m), 7.62-7.35 (9.8H, m), 6.92 (0.2H, d, J = 5.9Hz), 6.57 (0.2H, dd, J = 5.9, 2.6Hz), 6.16 (0.8H, dd, J=6.6, 3.3Hz), 5.87 (0.2H, dd, J=8.9, 3.0Hz), 5.81 (0.8H, dd, J=7.9, 3.3Hz), 4.68-4.62 (1H, m), 4.46-4.31 (2H, m), 4.03 (0.6H, s), 3.92(2.4H, s), 3.24(0.2H, brs), 3.06(0.8H, brs)

(3)

A mixture of 2.7 g of (2R,3R,4S)-2-hydroxy-5-(methoxyimino)pentane-1,3,4-triyl tribenzoate, 5 mL of acetonitrile, 0.5 mL of N-methylimidazole, and 1.7 g of 2,4,5-trichlorobenzenesulfonyl chloride was stirred at room temperature for 8 hours and then allowed to stand at room temperature for 3 days. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 3/1) to obtain 3.0 g of (2R,3R,4S)-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentane-1,3,4-triyl tribenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.08-7.96 (5H, m), 7.91-7.88 (2H, m), 7.64-7.33 (10.75H, m), 6.91 (0.25H, d, J=5.9Hz), 6.55 (0.25H, t, J=5.3Hz), 6.06-5.95 (1.75H, m), 5.55-5.49 (0.75H, m), 5.48-5.42 (0.25H, m), 4.91-4.84 (1H, m), 4.69-4.62 (1H, m), 3.97 (0.75H, s), 3.85 (2.25H, s)

(4)

To a solution of 3.0 g of (2R,3R,4S)-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentane-1,3,4-triyl tribenzoate in 4.0 mL of tetrahydrofuran were added 1.8 g of anhydrous lithium bromide and 4.0 mL of 1,3-dimethyl-2-imidazolidinone, and the mixture was stirred at 50°C for 2 hours. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 4/1) to obtain 1.5 g of (2S,3S,4S)-2-bromo-5-(methoxyimino)pentane-1,3,4-triyl tribenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.12-7.93 (6H, m), 7.65-7.36 (9.87H, m), 6.82 (0.13H, d, J=5.9Hz), 6.53 (0.13H, t, J=6.6Hz), 6.14-6.06 (0.13mH, m), 6.04-5.95 (1.74H, m), 4.84-4.54 (3H, m), 3.80 (0.39H, s), 3.70 (2.61H, s)

(5)

To a solution of 1.5 g of (2S,3S,4S)-2-bromo-5-(methoxyimino)pentane-1,3,4-triyl tribenzoate in 5.0 mL of acetonitrile was added 2.8 mL of 50% aqueous glyoxylic acid solution, and the mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the aqueous layer was removed. The organic layer was washed sequentially with 10% aqueous sodium bicarbonate solution and water, and the solvent was distilled off under reduced pressure to obtain 1.4 g of an oily substance.

The obtained oily substance is a mixture of (2S,3S,4S)-2-bromo-5-pentanone-1,3,4-triyl tribenzoate and its hydrate.

¹ H-NMR (CDCl ₃ ) δ value:

9.73 (1H, d, J = 9.2Hz), 8.13-7.98 (6H, m), 7.66-7.39 (9H, m), 6.03 (1H, dd, J = 7.3, 3.3Hz), 5.68 (1H, d, J = 7.3Hz), 4.85-1.74 (2H, m), 6.03 (1H, dd, J=10.6, 6.6Hz)

(6)

To a solution of 1.4 g of the oily substance obtained in Example 32(5) in 4.0 mL of N,N-dimethylformamide was added 1.2 g of a 15-18% aqueous sodium hydrosulfide solution at 0-10°C, and the mixture was stirred at the same temperature for 30 minutes. 15 mL of ethyl acetate and 15 mL of a 10% aqueous sodium chloride solution were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed twice with 15 mL of a 10% aqueous sodium chloride solution to obtain an ethyl acetate solution of 2,3,5-tri-O-benzoyl-4-thio-D-ribofuranose.

The ethyl acetate solution was directly used in the next reaction.

¹ H-NMR (CDCl ₃ ) δ value:

8.12-7.88 (6H, m), 7.63-7.29 (9H, m), 6.03 (1H, dd, J=7.9, 3.3Hz), 5.88 (1H, dd, J=4.0, 2.0Hz), 5.50 (1H, dd, J=4.6, 2.0Hz), 4.74 (1H, dd, J=11.6, 6.3Hz), 4.61 (1H, dd, J=11.9, 5.9Hz), 4.23 (1H, td, J=7.3, 5.5Hz), 2.64 (1H, d, J=4.6Hz)

(7)

To the ethyl acetate solution obtained in Example 32(6) were added 1.6 mg of dimethylaminopyridine and 0.28 mL of acetic anhydride, and the mixture was stirred at room temperature for 1 hour and allowed to stand at room temperature for 3 days. Water was added to the reaction mixture, the aqueous layer was removed, and the organic layer was washed with water. The solvent was then distilled off under reduced pressure. The resulting residue was recrystallized from methanol to obtain 402 mg of 1-O-acetyl-2,3,5-tri-O-benzoyl-4-thio-β-D-ribofuranose as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.08-8.02(2H,m),7.98-7.95(2H,m),7.91-7.88(2H,m),7.64-7.58(1H,m),7.55-7.44(4H,m),7.36-7.29(4H,m),6.06(1H,d,J＝ 2.0Hz), 5.99 (1H, dd, J=4.0, 2.0Hz), 5.91 (1H, dd, J=8.6, 4.0Hz), 4.73 (1H, dd, J=11.2, 5.9Hz), 4.53 (1H, dd, J=11.2, 5.9Hz), 4.25 (1H, dt, J=8.6, 5.9Hz), 2.12 (3H, s)

(8)

To a suspension of 208 mg of 1-O-acetyl-2,3,5-tri-O-benzoyl-4-thio-β-D-ribofuranosyl and 67 mg of cytosine in 2.0 mL of acetonitrile was added 0.44 mL of N,O-bis(trimethylsilyl)acetamide, and the mixture was stirred at 60°C for 1 hour. 0.22 mL of trimethylsilyl trifluoromethanesulfonate was added to the reaction mixture, and the mixture was stirred at 80°C for 4 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium bicarbonate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol = 1/0 to 4/1) to obtain 70 mg of 1-(2,3,5-tri-O-benzoyl-4-thio-β-D-ribofuranosyl)cytosine as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.14-7.95 (6H, m), 7.89 (1H, d, J = 7.3Hz), 7.63-7.36 (9H, m), 6.90 (1H, d, J = 5.9Hz), 5.94-5.89 (2H, m), 5.59 (1H, d, J = 7.9Hz), 4.79 (1H, dd, J = 11.9, 5.9Hz), 4.66 (1H, dd, J = 11.6, 5.0Hz), 4.10-4.05 (1H, m)

(9)

To a suspension of 70 mg of 1-(2,3,5-tri-O-benzoyl-4-thio-β-D-ribofuranosyl)cytosine in 2.0 mL of methanol was added 0.1 mL of a 28% sodium methoxide/methanol solution, and the mixture was stirred at room temperature for 1 hour and allowed to stand overnight. 0.2 mL of acetic acid was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol = 1/0 to 2/1) to obtain 18 mg of 1-(4-thio-β-D-ribofuranosyl)cytosine as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

7.97 (1H, d, J = 7.3Hz), 7.14 (2H, brd), 5.94 (1H, d, J = 6.6Hz), 5.76 (1H, d, J = 7.3Hz), 5.42 (1H, brs), 5.29 (1H, brs), 5.14 (1H, brs), 4.08-3.98 (2H, m), 3.69-3.51 (2H, m), 3.20 (1H, dd, J=9.2, 5.9Hz)

Example 33

(1)

To a solution of 6.58 g of 2-deoxy-1-O-methyl-D-furanoside in 44 mL of toluene, 22 mL of 20% aqueous sodium hydroxide solution and 617 mg of tetrabutylammonium chloride were added. Benzoyl chloride (10.8 mL) was then added at 10-25°C, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 70/30) to obtain 11.8 g of 2-deoxy-3,5-O-dibenzoyl-1-O-methyl-D-furanoside as a colorless oil.

The results of ¹ H-NMR measurement showed that the anomer ratio was 1:1.

RT (min): 1.73, 1.76.

¹ H-NMR (CDCl ₃ ) δ value:

5.20 (0.5H, d, J=4.6Hz), 4.70-4.45 (3H, m), 3.43 (1.5H, s), 3.37 (1.5H, s), 2.64-2.50 (1H, m), 2.36 (0.5H, td, J=9.6, 4.6Hz), 2.21 (0.5H, dd, J＝14.5, 1.3Hz)

(2)

To a solution of 6.49 g of 2-deoxy-3,5-O-dibenzoyl-1-O-methyl-D-furanoside in 32.4 mL of acetic acid, 32.4 mL of 1 mol/L hydrochloric acid was added, and the mixture was stirred at 55°C for 2.58 hours. 20 mL of acetic acid and 20 mL of 1 mol/L hydrochloric acid were added, and the mixture was stirred at the same temperature for 2.58 hours. Toluene and water were added to the reaction mixture. The organic layer was separated, washed with water and saturated sodium bicarbonate aqueous solution, and dried over anhydrous magnesium sulfate to obtain 6.23 g of 2-deoxy-3,5-O-dibenzoyl-D-furanoside as a colorless oil.

The results of ¹ H-NMR measurement showed that the anomeric ratio was 6:4.

RT(min):1.41,1.44.

¹ H-NMR (CDCl ₃ ) δ value:

8.11-7.99 (4H, m), 7.63-7.51 (2H, m), 7.51-7.37 (4H, m), 5.80-5.69 (1H, m), 5.67-5.60 (0.4H, m), 5.54-5.48 (0.6H, m), 4.76-4.47 (3H, m), 3.11-3.03 (0.4H, m), 2.86 (0.6H, t, J=5.3Hz), 2.62-2.48 (1H, m), 2.45-2.25 (1H, m)

(3)

To a solution of 6.23 g of 2-deoxy-3,5-O-dibenzoyl-D-furanoside in 62 mL of methanol, 1.98 g of O-methylhydroxyammonium chloride, 3.78 mL of triethylamine, and 3 mL of a 5-10% hydrochloric acid/methanol solution were added, and the mixture was stirred at room temperature for 11.7 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the resulting residue. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 6.65 g of (2R,3S)-2-hydroxy-5-(methoxyimino)pentane-1,3-diyl dibenzoate as a pale yellow oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 64:36.

RT(min):1.50.

¹ H-NMR (CDCl ₃ ) δ value:

8.04 (4H, d, J=7.9Hz), 7.62-7.54 (2H, m), 7.51-7.30 (4.64H, m), 6.85 (0.36H, t, J=5.9Hz), 5.47-5.37 (1H, m), 4.61 (1H, d, J=3.3Hz), 4.57 (1H, d, J=3.3Hz), 4.44 (0.64H, dd, J=5.9, 2.6Hz), 4.40 (0.36H, dd, J=5.9, 2.6Hz), 4.29-4.17 (1H, m), 3.87 (1.08, s), 3.78 (1.92H, s), 3.07-2.85 (1H, m), 2.82 (1H, t, J=5.9Hz)

(4)

To a solution of 6.65 g of (2R,3S)-2-hydroxy-5-(methoxyimino)pentane-1,3-diyl dibenzoate in 67 mL of acetonitrile, 5.51 g of 2,4,5-trichlorobenzenesulfonyl chloride and 2.14 mL of 1-methylimidazole were added at room temperature and stirred for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. 20 mL of ethyl acetate and 30 mL of hexane were added to the resulting residue, and the solid matter was filtered to remove. The solvent was removed by vacuum distillation to obtain 8.97 g of (2R,3S)-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentane-1,3-diyl dibenzoate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 54:46.

RT(min):2.06.

¹ H-NMR (CDCl ₃ ) δ value:

8.00-8.00 (1H, eachs), 7.93 (4H, t, J=7.6Hz), 7.64-7.54 (2H, m), 7.50-7.39 (5H, m), 7.34 (0.54H, d, J=4.0Hz), 6.80 (0.46H, t, J=5.6Hz), 5.56-5.49 (1H, m), 5.42-5.30 (1H, m), 4.63 (1H, brs), 4.61 (1H, s), 3.86 (1.38H, s), 3.77 (1.62H, s), 2.99-2.91 (1H, m), 2.90-2.83 (0.46H, m), 2.82-2.71 (0.54H, m)

(5)

To a solution of 8.97 g of (2R,3S)-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentane-1,3-diyl dibenzoate in 17.9 mL of tetrahydrofuran and 16.1 mL of 1,3-dimethyl-2-imidazolidinone was added 1.52 g of lithium bromide, and the mixture was stirred at 50°C for 3 hours. Ethyl acetate and a 25% aqueous lithium bromide solution were added to the reaction mixture. The organic layer was separated, washed with a 13% aqueous lithium bromide solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 75/25) to obtain 4.84 g of (2R,3S)-2-bromo-5-(methoxyimino)pentane-1,3-diyl dibenzoate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 55:45.

RT(min):1.87.

¹ H-NMR (CDCl ₃ ) δ value:

8.11-8.01 (4H, m), 7.64-7.54 (2H, m), 7.51-7.37 (4.55H, m), 6.78 (0.45H, t, J = 5.3Hz), 5.73-5.60 (1H, m), 4.77-4.67 (1H, m), 4.64-4.43 (2H, m), 3.86 (1.35H, s), 3.75 (1.65H, s), 3.09-2.87 (1H, m), 2.84 (1H, t, J = 6.3)

(6)

To a solution of 3.54 g of (2R,3S)-2-bromo-5-(methoxyimino)pentane-1,3-diyl dibenzoate in 35 mL of acetone, 7.1 mL of 35% aqueous formaldehyde, 4.3 mL of water, and 1.4 mL of concentrated hydrochloric acid were added at room temperature and stirred at 30°C for 1.5 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3.75 g of a colorless oil.

The obtained colorless oil was a mixture of (2R,3S)-2-bromo-5-pentanone-1,3-diyl dibenzoate and its hydrate.

RT(min):1.71,1.81.

(7)

To a solution of 3.75 g of the colorless oil obtained in Example 33 (6) in 33 mL of 1-methylpyrrolidone was added a solution of 720 mg of sodium monohydrosulfide n-hydrate in 5 mL of 1-methylpyrrolidone under ice-cooling, and the mixture was stirred at the same temperature for 1.42 hours. 249 mg of sodium monohydrosulfide n-hydrate was added, and the mixture was stirred at the same temperature for 0.58 hours. Ethyl acetate and brine were added to the reaction mixture. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a 1-methylpyrrolidone solution of 2-deoxy-3,5-O-dibenzoyl-4-thio-D-furan nucleoside.

RT(min):1.56.

m/z(ESI-positive): 341.1[M+H-H2O] ⁺

(8)

To the 1-methylpyrrolidone solution of 2-deoxy-3,5-O-dibenzoyl-4-thio-D-furan nucleoside obtained in Example 33 (7), 29.2 mL of tetrahydrofuran, 0.916 mL of acetic anhydride, and 10 mg of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0 to 75/25). 4 mL of methanol was added to the obtained solid, and the solid was filtered to obtain 0.942 g of 1-O-acetyl-2-deoxy-3,5-O-dibenzoyl-4-thio-β-D-furan nucleoside as a white solid.

RT(min):1.77.

¹ H-NMR (DMSO-d ₆ ) δ value:

7.96 (4H, dt, J=7.9, 1.3Hz), 7.71-7.61 (2H, m), 7.56-7.44 (4H, m), 6.11 (1H, dd, J=5.9, 3.3Hz), 5.77-5.69 (1H, m), 4.55-4.40 (2H, m), 3.99 (1H, qd, J=5.9, 1.3Hz), 2.76-2.54 (2H, m), 2.01 (3H, s)

(9)

To a solution of 111 mg of cytosine and 200 mg of 1-O-acetyl-2-deoxy-3,5-O-dibenzoyl-4-thio-β-D-furanoside in 2 mL of acetonitrile was added 0.700 mL of N,O-bistrimethylsilylacetamide at room temperature. The mixture was stirred at 60°C under a nitrogen atmosphere for 70 minutes, followed by 0.361 mL of trimethylsilyl trifluoromethanesulfonate. The mixture was stirred at the same temperature for 2.5 hours and then at 80°C for 2 hours. Dichloromethane and water were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol = 100/0 to 40/60) and then by HPLC to obtain 1-(2-deoxy-3,5-bis-O-benzoyl-4-thio-D-ribofuranosyl)cytosine as a brown oil.

The α/β ratio determined by ¹ H-NMR was 53:47.

The obtained brown oil was separated by high performance liquid chromatography to obtain 13.6 mg of 1-(2-deoxy-3,5-bis-O-benzoyl-4-thio-β-D-ribofuranosyl)cytosine.

HPLC conditions

Column: Sunfire prep C18OBD 10 μm, 19 mm × 150 mm (Waters)

Mobile phase: 0.1% formic acid-water/0.1% formic acid-acetonitrile (volume ratio: 70/30 to 55/45)

Flow rate: 17 mL/min

Detection: UV (254nm)

Temperature: Room temperature

Holding time: α body 7.34min, β body 8.50min

Beta body

RT(min):1.25.

¹ H-NMR (CDCl ₃ ) δ value:

8.09-8.02 (4H, m), 7.95 (1H, d, J = 7.3Hz), 7.63-7.54 (2H, m), 7.45 (4H, d, J = 7.9Hz), 6.71 (1H, t, J = 7.3Hz), 5.80 (1H, d, J = 7.3Hz), 5.75 (1H, q, J=3.7Hz), 4.59 (2H, d, 6.6Hz), 4.00 (1H, td, 6.6, 3.3Hz), 2.99-2.13 (2H, brs), 2.82 (1H, dq, 13.9, 3.5Hz), 2.44-2.33 (1H, m)

α-body

RT(min):1.19.

¹ H-NMR (CDCl ₃ ) δ value:

8.22 (1H, d, J=7.3Hz), 8.08 (2H, dd, J=7.9, 1.3Hz), 7.85 (2H, dd, J=7.9, 1.3Hz), 7.62-7.52 (2H, m), 7.50-7.36 (4H, m), 6.45 (1H, dd, J=7.3, 2.0Hz), 5.80 (1H, d, J=7.3Hz), 5.73-5.67 (1H, m), 4.56-4.38 (2H, m), 4.24 (1H, dt, J=6.9, 2.0Hz), 2.95-2.82 (1H, m), 2.66 (1H, dt, J＝15.2, 2.6Hz)

(10)

To a solution of 9.6 mg of 1-(2-deoxy-3,5-bis-O-benzoyl-4-thio-β-D-ribofuranosyl)cytosine in 1 mL of methanol was added 1 mL of a 7 mol/L ammonia/methanol solution, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol = 95/5 to 30/70) to obtain 4.7 mg of 1-(2-deoxy-4-thio-β-D-ribofuranosyl)cytosine as a white solid.

RT(min):0.27.

¹ H-NMR (DMSO-d ₆ ) δ value:

7.931H, d, J=7.3Hz), 7.19 (1H, brs), 7.12 (1H, brs), 6.35 (1H, dd, J=8.6, 6.6Hz), 5.78 (1H, d, J=7.3Hz), 5.23 (1H, d, J=3.3Hz), 5.12 (1H, t, J=5.3Hz), 4.36-4.29 (1H, m), 3.64-3.22 (3H, m), 2.28-2.01 (2H, m), 1.83 (1H, s)

Example 34

(1)

To a solution of 238 mg of 1-O-methyl-2,3,5-tri-O-benzoyl-L-lyxose in 1.0 mL of acetic acid was added dropwise 0.2 mL of 30% hydrogen bromide/acetic acid at room temperature, followed by stirring at room temperature for 2 hours. Dichloromethane and water were added to the reaction mixture, stirred for 5 minutes, and the aqueous layer removed. The resulting organic layer was washed with 10% aqueous sodium bicarbonate solution, and the solvent was removed under reduced pressure to yield a brown oil.

Separately, 0.2 mL of 30% hydrogen bromide/acetic acid was added dropwise to a solution of 238 mg of 1-O-methyl-2,3,5-tri-O-benzoyl-L-lyxose in 1.0 mL of dichloromethane at room temperature, followed by stirring at room temperature for 2 hours. Dichloromethane and water were added to the reaction mixture, stirred for 5 minutes, and the aqueous layer removed. The resulting organic layer was washed with a 10% aqueous sodium bicarbonate solution, and the solvent was removed by vacuum distillation. 2.0 mL of acetone and 2.0 mL of water were added to the resulting oil, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, and the solvent was removed by vacuum distillation to obtain a brown oil.

The brown oils obtained in the above two operations were combined and purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 3/1) to obtain 462 mg of a colorless oil containing 2,3,5-tri-O-benzoyl-L-lyxose.

(2)

To 462 mg of a mixture containing 2,3,5-tri-O-benzoyl-L-lyxose, 125 mg of O-methylhydroxylamine hydrochloride and 1.0 mL of methanol were added, followed by the dropwise addition of 0.18 mL of triethylamine under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 3/1) to obtain 201 mg of (2S,3R,4S)-2-hydroxy-5-(methoxyimino)pentane-1,3,4-triyl tribenzoate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 4:1.

¹ H-NMR (CDCl ₃ ) δ value:

8.08-7.98 (6H, m), 7.62-7.32 (9.8H, m), 6.91 (0.2H, d, J = 5.9Hz), 6.56 (0.2H, t, J = 6.3Hz), 6.06 (0.8H, t, J = 6.9Hz), 5.83-5.76 (1H, m), 4.58-4.44(2H, m), 4.39-4.35(1H, m), 3.88(0.6H, s), 3.74(2.4H, s)

(3)

To 201 mg of (2S,3R,4S)-2-hydroxy-5-(methoxyimino)pentane-1,3,4-triyl tribenzoate, 2.0 mL of ethyl acetate and 0.08 mL of triethylamine were added, followed by the dropwise addition of 0.04 mL of methanesulfonyl chloride under ice-cooling. The mixture was stirred at room temperature for 1 hour and then allowed to stand overnight. To the reaction mixture, 0.2 mL of triethylamine and 0.1 mL of methanesulfonyl chloride were added, followed by stirring at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 3/1) to obtain 197 mg of (2S,3S,4S)-5-(methoxyimino)-2-((methylsulfonyl)oxy)pentane-1,3,4-triyl tribenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.10-8.00 (6H, m), 7.62-7.41 (9.8H, m), 6.87 (0.2H, d, J=5.9Hz), 6.47 (0.2H, dd, J=5.9, 4.6Hz), 6.07-6.03 (1H, m), 5.95 (0.8H, t, J =6.3Hz), 5.47 (0.8H, dt, J = 7.5, 3.3Hz), 5.39 (0.2H, td, J = 6.3, 3.3Hz), 4.85-4.75 (1H, m), 4.69-4.60 (1H, m), 4.39-4.35 (1H, m), 3.91 (0.6H, s), 3.77 (2.4H, s), 3.05 (2.4H, s), 3.01 (0.6H, s)

(4)

To a solution of 197 mg of (2S,3S,4S)-5-(methoxyimino)-2-((methylsulfonyl)oxy)pentane-1,3,4-triyl tribenzoate in 1.0 mL of acetonitrile was added 0.35 mL of 50% aqueous glyoxylic acid solution, and the mixture was stirred at 70°C for 9 hours and then allowed to stand at room temperature overnight. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was removed. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 1/1) to obtain 130 mg of (2S,3S,4R)-2-((methylsulfonyl)oxy)-5-pentanone-1,3,4-triyl tribenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.73 (1H, s), 8.11-8.04 (6H, m), 7.66-7.42 (9H, m), 6.09 (1H, t, J=5.3Hz), 5.68 (1H, d, J=5.9Hz), 5.61-5.56 (1H, m), 4.81 (1H, dd, J＝12.6, 4.0Hz), 4.66 (1H, dd, J＝12.6, 6.6Hz), 3.05 (3H, s)

(5)

To a solution of 130 mg of (2S,3S,4R)-2-((methylsulfonyl)oxy)-5-pentanone-1,3,4-triyl tribenzoate in 0.5 mL of N,N-dimethylformamide was added 0.11 mL of a 15-18% aqueous sodium hydrosulfide solution at 0-10°C, and the mixture was stirred at the same temperature for 1 hour. 10 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed three times with 10 mL of a 10% aqueous sodium chloride solution to obtain an ethyl acetate solution of 2,3,5-tri-O-benzoyl-4-thio-D-ribofuranose.

To the resulting ethyl acetate solution, 0.1 mg of dimethylaminopyridine and 0.025 mL of acetic anhydride were added, and the mixture was stirred at room temperature for 1 hour and allowed to stand at room temperature for 4 days. The reaction mixture was washed with water, and the solvent was removed under reduced pressure. The resulting residue was recrystallized from 10 mL of methanol to obtain 28 mg of 1-O-acetyl-2,3,5-tri-O-benzoyl-4-thio-β-D-ribofuranose as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

8.06-8.02 (2H, m), 7.98-7.95 (2H, m), 7.91-7.88 (2H, m), 7.64-7.58 (1H, m), 7.55-7.44 (4H, m), 7.36-7.29 (4H, m), 6.06 (1H, d, J＝ 1.3Hz), 5.99 (1H, dd, J=3.6, 1.7Hz), 5.91 (1H, dd, J=8.6, 4.0Hz), 4.74 (1H, dd, J=11.2, 5.9Hz), 4.53 (1H, dd, J=11.2, 5.9Hz), 4.25 (1H, dt, J=8.6, 5.9Hz), 2.12 (3H, s)

Example 35

(1)

To a solution of 3.8 g of 5-methyl-3-phenoxyoxolan-2-one in 40 mL of toluene, 13.5 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise at -78°C and stirred for 15 minutes. To the reaction mixture was added 1 mL of methanol and 50 mL of a 20% aqueous solution of potassium sodium tartrate at room temperature. The mixture was stirred for 1 hour, and the aqueous layer was removed. The aqueous layer was extracted with 100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to yield 3.9 g of 5-methyl-3-phenoxyoxolan-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

6.85-7.30 (5H, m), 5.40-5.55 (1H, m), 4.70-4.80 (1H, m), 4.45-4.55 (1H, m), 3.15-3.40 (2H, m), 1.65-2.60 (2H, m), 1.35-1.40 (3H, m)

(2)

To 3.6 g of 5-methyl-3-phenoxy oxolane-2-ol as a colorless oil, 20 mL of methanol and 1.8 g of O-methylhydroxylamine hydrochloride were added, and 2.79 mL of triethylamine was added dropwise, and the mixture was stirred at room temperature for 5.5 hours. After the methanol was evaporated under reduced pressure, 100 mL of ethyl acetate and 100 mL of water were added, and the aqueous layer was removed. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 3.65 g of 5-(methoxyimino)-4-phenoxypentane-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

6.65-7.40(6H,m), 4.90-5.60(1H,m), 4.00-4.20(1H,m), 3.70-4.00 (3H,m), 1.50-2.50(3H,m), 1.20-1.30(3H,m)

(3)

To a solution of 3.6 g of 5-(methoxyimino)-4-phenoxypentan-2-ol in 36 mL of tetrahydrofuran was added 3.3 mL of triethylamine, 1.2 mL of methanesulfonyl chloride was added at 0-10°C, and the mixture was stirred at or below 15°C for 1 hour. 200 mL of ethyl acetate and 200 mL of water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 4/1) to obtain 4.4 g of 5-(methoxyimino)-4-phenoxypentan-2-yl methanesulfonate as a light yellow oil.

¹ H-NMR (CDCl ₃ ) δ value:

6.60-7.40(6H,m), 4.90-5.40(2H,m), 3.80-4.00(3H,m), 2.70-3.10 (3H,m), 1.90-2.40(2H,m), 1.45-1.55(3H,m)

(4)

To a mixture of 2.0 g of 5-(methoxyimino)-4-phenoxypentan-2-yl methanesulfonate, 4.8 mL of a 36% aqueous formaldehyde solution, and 60 mL of acetone was added 15 mL of 2 mol/L hydrochloric acid, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and 30 mL of ethyl acetate and 30 mL of water were added, and the aqueous layer was removed. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 4/1) to obtain 0.66 g of a mixture of 5-oxo-4-phenoxypentan-2-yl methanesulfonate and its hydrate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.71-9.76 (1H, m), 7.26-7.33 (2H, m), 7.01-7.04 (1H, m), 6.88-6.92 (2H, m), 5.05-5.15 (1H, m), 4.67-4.77 (1H, m), 3.00 (1.4H, s), 2.83(1.6H, s), 2.0-2.4(2H, m), 1.48-1.55(3H, m)

(5)

To a solution of 0.62 g of 5-oxo-4-phenoxypentan-2-yl methanesulfonate in 6 mL of N,N-dimethylformamide was added 0.53 g of sodium hydrosulfide x-hydrate (Wako Pure Chemical Industries, Ltd.) at 0-10°C and the mixture was incubated at the same temperature for 1 hour. 30 mL of ethyl acetate and 30 mL of water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed with 30 mL of water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 4/1) to obtain 0.34 g of 5-methyl-3-phenoxytetrahydrothiophen-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.25-7.35(2H,m), 6.90-7.00(3H,m), 5.40-5.55(1H,m), 4.90 (1H,m), 3.75-3.90(1H,m), 2.40-2.70(1H,m), 1.90-2.20(2H,m), 1.42-1.46(3H,m)

Example 36

To a solution of 400 mg of 2-chloromethyl-4,6-dibenzyloxybenzaldehyde in 4.5 mL of N,N-dimethylformamide, 1.83 g of a 15% aqueous sodium hydrosulfide solution was added at 0-10°C, and the mixture was stirred at 15°C for 1 hour. 40 mL of ethyl acetate and 20 mL of a 10% aqueous sodium chloride solution were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, 30 mL of hexane was added, and the solid was collected by filtration to obtain 206 mg of 5,7-bis(benzyloxy)-1,3-dihydrobenzothiophen-1-ol as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

7.30-7.45 (10H, m), 6.68 (1H, dd, J=2.1, 6.9Hz), 6.48 (1H, d, J=8.4Hz), 6.47 (1H, d, J=8.4Hz), 5.14 (H, d, J=12.3Hz), 5.09 (1H, d, J=12.3Hz), 5.03 (2H, s), 4.49 (1H, dd, J=2.1, 14.7Hz), 4.02 (1H, d, J=14.7Hz), 2.45 (1H, d=6.9Hz)

Example 37

(1)

To a solution of 13.8 g of 5-(hydroxymethyl)oxolan-2-one and 19.0 g of 2,4,6-tris(benzyloxy)-1,3,5-triazine in 150 mL of dioxane was added 2.1 mL of trifluoromethanesulfonic acid at 5-10°C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was added to a mixture of 400 mL of ethyl acetate and 300 mL of saturated aqueous sodium bicarbonate. The organic layer was separated, washed sequentially with 300 mL of water and 300 mL of saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 2/3 to 1/1) to obtain 22.4 g of 5-((benzyloxy)methyl)oxolan-2-one as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.33-7.28 (5H, m), 4.68-4.61 (1H, m), 4.572 (1H, s), 4.566 (1H, s), 3.68 (1H, dd, J = 10.8, 4.5Hz), 3.58 (1H, dd, J = 10.8, 4.2Hz), 2.57-2.42(2H,m), 2.35-2.06(2H,m)

(2)

To a solution of 9.9 g of 5-((benzyloxy)methyl)oxolan-2-one in 12 mL of ethanol and 48 mL of tetrahydrofuran was added 2.3 g of sodium tetrahydroborate at 5-10°C under a nitrogen atmosphere. A solution of 7.0 g of calcium chloride in 25 mL of ethanol was then added dropwise over 20 minutes. 25 mL of tetrahydrofuran was added to the reaction mixture, and the mixture was stirred at room temperature for 200 minutes. 200 mL of ethyl acetate was added to the reaction mixture, followed by the dropwise addition of 1 mol/L hydrochloric acid. The organic layer was separated, washed with 100 mL of saturated sodium bicarbonate solution, then washed twice with 100 mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 9.4 g of 5-(benzyloxy)pentane-1,4-diol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.35-7.31 (5H, m), 4.55 (2H, s), 3.89-3.81 (1H, m), 3.71-3.58 (2H, m), 3.49 (1H, dd, J = 9.3, 3.3Hz), 3.36 (1H, dd, J = 9.3, 7.8Hz), 2.92 (1H, brs), 2.55 (1H, brs), 1.67-1.41 (4H, m)

(3)

To a solution of 5.0 g of 5-(benzyloxy)pentane-1,4-diol in 50 mL of tetrahydrofuran was added 0.96 g of sodium hydride (60 wt% in oil) at 5-10°C under a nitrogen atmosphere. After stirring at room temperature for 30 minutes, 5.3 mL of triisopropylsilyl chloride was added dropwise at 5-10°C. The reaction mixture was stirred at room temperature for 1 hour and then added to a mixture of 100 mL of ethyl acetate and 100 mL of water. The organic layer was separated and washed sequentially with 100 mL of saturated sodium bicarbonate solution, 100 mL of water, and 100 mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/5 to 1/5) to obtain 5.4 g of 1-benzyloxy-5-(triisopropyl)silyloxy)pentane-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.35-7.26 (5H, m), 4.56 (2H, s), 3.85-3.79 (1H, m), 3.72 (2H, t, J=5.9Hz), 3.49 (1H, dd, J=9.3, 3.9Hz), 3.38 (1H, dd, J=9.3, 7.2Hz), 2.86 (1H, d, J = 3.3Hz), 1.76-1.45 (4H, m), 1.15-1.00 (21H, m)

(4)

To a solution of 1.5 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-ol and 0.7 mL of triethylamine in 15 mL of ethyl acetate was added dropwise 0.35 mL of methanesulfonyl chloride at 5-10°C, followed by stirring at room temperature for 1 hour. The reaction mixture was added to a mixture of 100 mL of ethyl acetate and 50 mL of 1 mol/L hydrochloric acid. The organic layer was separated and washed sequentially with 50 mL of saturated sodium bicarbonate solution, 50 mL of water, and 50 mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.8 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-yl methanesulfonate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.36-7.26 (5H, m), 4.92-4.83 (1H, m), 4.58 (1H, d, J = 17.6Hz), 4.54 (1H, d, J = 17.6Hz), 3.77-3.58 (4H, m), 3.02 (3H, s), 1.90-1.52 (4H, m), 1.15-1.00 (21H, m)

(5)

To a solution of 1.53 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-yl methanesulfonate in 20 mL of methanol was added 0.33 g of p-toluenesulfonic acid, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to a mixture of 50 mL of ethyl acetate and 30 mL of saturated aqueous sodium bicarbonate. The organic layer was separated, washed sequentially with 10 mL of water and 30 mL of saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 2/3 to 3/2) to obtain 0.8 g of 1-benzyloxy-5-hydroxypentan-2-yl methanesulfonate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.36-7.26 (5H, m), 4.93-4.84 (1H, m), 4.58 (1H, d, J = 12.0Hz), 4.53 (1H, d, J = 12.0Hz), 3.74-3.57 (4H, m), 3.02 (3H, s), 1.84-1.64 (4H, m)

(6)

To a solution of 200 mg of 1-benzyloxy-5-hydroxypentan-2-yl methanesulfonate in 2 mL of dichloromethane was added 440 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoyl-3(1H)-one (Dess-Martin Periodinane), and the mixture was stirred at room temperature for 1 hour. 100 mg of Dess-Martin Periodinane was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to a mixture of 50 mL of ethyl acetate and 30 mL of saturated aqueous sodium bicarbonate solution, and filtered through Celite. The organic layer was separated, washed twice with 30 mL of aqueous sodium thiosulfate solution, then with 30 mL of saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/2 to 1/1) to obtain 141 mg of 1-benzyloxy-5-pentanone-2-yl methanesulfonate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.79 (1H, s), 7.36-7.26 (5H, m), 4.89-4.80 (1H, m), 4.57 (1H, d, J = 13.5Hz), 4.52 (1H, d, J = 13.5Hz), 3.67-3.57 (2H, m), 3.01 (3H, s), 2.79-2.61(2H, m), 2.10-1.83(2H, m)

(7)

To a solution of 103 mg of 1-benzyloxy-5-pentanone-2-yl methanesulfonate in 3 mL of N,N-dimethylformamide was added 58 mg of sodium hydrosulfide n-hydrate at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to a mixture of 30 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate. The organic layer was separated, washed with 20 mL of saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/3 to 1/2) to obtain 49 mg of 5-((benzyloxy)methyl)tetrahydrothiophen-2-ol as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 50:50.

Additionally, approximately 20 mg of the reaction mixture was accurately weighed using a precision balance at 3, 30, 60, 90, and 120 minutes after the start of the reaction, and the remaining amount of the starting material, 1-benzyloxy-5-pentanone-2-yl methanesulfonate, was measured by HPLC. The result showed that the remaining amount after 3 minutes was 53%, and after 30 minutes, the starting material had been completely consumed.

¹ H-NMR (CDCl ₃ ) δ value:

7.38-7.26 (5H, m), 5.55-5.45 (1H, m), 4.59 (1H, s), 4.56 (0.5H, d, J = 12.0Hz), 4.45 (0.5H, d, J = 12.0Hz), 3.85-3.57 (2H, m), 3.42-3.31 (1H, m), 2.72 (0.5H, d, J = 6.90Hz), 2.29-1.87 (4.5H, m)

Example 38

(1)

To a mixture of 8.02 g of 2,3,5-tri(O-benzyl)-D-arabinofuranoside, 48 mL of acetonitrile, and 24 mL of water, 3.35 g of O-methylhydroxylamine hydrochloride was added, followed by the dropwise addition of 3.45 mL of triethylamine, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture were added 80 mL of ethyl acetate and 50 mL of an 8% aqueous sodium bicarbonate solution. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to yield 8.48 g of (2R,3R,4R)-1,3,4-tris(benzyloxy)-5-(methoxyimino)pentan-2-ol as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 78:22.

¹ H-NMR (CDCl ₃ ) δ value:

2.60 (0.22H, d, J = 1.5Hz), 2.68 (0.78H, d, J = 1.5Hz), 3.56-3.60 (2.22H, m), 3.67 (0.78H, dd, J = 7.1, 3.6Hz), 3.79 (0.22H, dd, J = 7.5, 3.0Hz), 3.85 (0.66H, s), 3.86 (2.34H, s), 3.97-4.04 (1H, m), 4.27 (0.78H, dd, J=7.8, 3.9Hz), 4.38-4.65 (6H, m), 4.93 (0.22H, dd, J =6.0, 3.0Hz), 6.90 (0.22H, d, J = 6.3Hz), 7.23-7.35 (15H, m), 7.43 (0.78H, dd, J = 8, 1, 0.6Hz)

(2)

To a solution of 3.33 g of (2R,3R,4R)-2,3,5-tris(benzyloxy)-4-hydroxypentanal = O-methyloxime in 33 mL of acetonitrile, 1.54 mL of triethylamine and 0.89 mL of N-methylimidazole were added dropwise, followed by 0.86 mL of methanesulfonyl chloride, and the mixture was stirred at room temperature for 1 hour. 40 mL of water and 80 mL of ethyl acetate were added to the reaction mixture. The organic layer was separated and washed sequentially with a mixture of 20 mL of 1 mol/L hydrochloric acid and 20 mL of a 10% aqueous sodium chloride solution, and then with a mixture of 20 mL of a 5% aqueous sodium bicarbonate solution and 20 mL of a 10% aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.16 g of (2R,3S,4R)-1,3,4-tris(benzyloxy)-5-(methoxyimino)pentan-2-yl methanesulfonate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 75:25.

¹ H-NMR (CDCl ₃ ) δ value:

2.93 (2.25H, s), 2.95 (0.75H, s), 3.80 (1H, dd, J = 11.4, 6.9Hz), 3.85 (0.75H, s), 3.86 (2.25H, s), 3.90 (1H, dd, J = 11.4, 2.1Hz), 3.98 (0.75H, t, J=4.5Hz), 4.16 (0.75H, ddd, J=7.7, 4.5, 0.6Hz), 4.41-4.62 (4.25H, m), 4.67 (2H, dd, J=20.4, 11.1Hz), 4.80 (0.25H, dd, J= 7.5, 4.5Hz), 4.99 (1H, m), 6.81 (0.25H, d, J=6.3Hz), 7.24-7.37 (15.75H, m)

(3)

To a solution of 2.06 g of (2R,3S,4R)-1,3,4-tris(benzyloxy)-5-(methoxyimino)pentan-2-yl methanesulfonate in 40 mL of acetone, 10 mL of 2 mol/L hydrochloric acid and 3.10 mL of 35% aqueous formaldehyde solution were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 hours. 40 mL of 10% aqueous sodium chloride solution and 40 mL of ethyl acetate were added to the reaction mixture. The organic layer was separated and washed with a mixture of 20 mL of 5% aqueous sodium bicarbonate solution and 20 mL of 10% aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.50 g of (2R,3S,4S)-1,3,4-tris(benzyloxy)-5-pentanone-2-yl methanesulfonate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

2.97 (1H, s), 3.76 (1H, dd, J = 11.4, 6.6Hz), 3.89 (1H, dd, J = 11.4, 3.0Hz), 4.04 (1H, dd, J = 3.3, 0.9Hz), 4.18 (1H, dd, J = 5.3, 3.3Hz), 4.47-4.60 (4H, m), 4.67 (2H, dd, J=22.2, 11.4Hz), 5.97 (1H, m), 7.20-7.25 (2H, m), 7.27-7.36 (13H, m)

(4)

To a solution of 0.10 g of (2R,3S,4S)-1,3,4-tris(benzyloxy)-5-pentanone-2-yl methanesulfonate in 2 mL of N,N-dimethylformamide was added 0.06 g of sodium hydrosulfide x-hydrate, and the mixture was stirred at room temperature for 12 hours. 2 mL of water and 5 mL of ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with 5 mL of a 10% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.02 g of (3S,4S,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrothiophen-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

3.69 (1H, d, J = 12.6Hz), 3.77-3.82 (3H, m), 4.19 (2H, m), 4.51-4.67 (6H, m), 5.26 (1H, d, J = 12.6Hz), 7.22-7.37 (15H, m)

Example 39

(1)

To 0.99 g of (2R,3R,4S)-2-hydroxy-5-(methoxyimino)pentane-1,3,4-triyl tribenzoate, 10 mL of ethyl acetate and 0.19 mL of methanesulfonyl chloride were added dropwise. Under ice cooling, 0.39 mL of triethylamine was added dropwise, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 0.19 mL of triethylamine and 0.39 mL of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 2 hours and allowed to stand at room temperature for 2 days. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 3/1) to obtain 1.02 g of (2R,3S,4S)-5-(methoxyimino)-2-((methylsulfonyl)oxy)pentane-1,3,4-triyl tribenzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.11-8.00 (6H, m), 7.64-7.41 (9.75H, m), 6.92 (0.25H, d, J=5.9Hz), 6.55 (0.25H, dd, J=5.3, 4.0Hz), 6.11 (0.25H, dd, J=5.9, 4.0Hz), 6.08-6.02 (1.5H, m), 5.53-5.46 (1H, m), 5.01-4.91 (1H, m), 4.59-4.47 (1H, m), 3.97 (0.75H, s), 3.88 (2.25H, s), 3.17 (2.25H, s), 3.13 (0.75H, s)

(2)

To a solution of 1.02 g of (2R,3S,4S)-5-(methoxyimino)-2-((methylsulfonyl)oxy)pentane-1,3,4-triyl tribenzoate in 3.0 mL of acetonitrile was added 1.8 mL of 50% aqueous glyoxylic acid solution, and the mixture was stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the aqueous layer was removed. The organic layer was washed sequentially with 10% aqueous sodium bicarbonate solution and water, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 1/1) to obtain 317 mg of a colorless oil.

The obtained oily substance was a mixture of (2R,3S,4R)-2-((methylsulfonyl)oxy)-5-pentanone-1,3,4-triyl tribenzoate and its hydrate.

¹ H-NMR (CDCl ₃ ) δ value:

9.74 (1H, s), 8.20-7.96 (6H, m), 7.66-7.42 (9H, m), 6.12 (1H, dd, J=7.9, 2.6Hz), 5.87 (1H, d, J=2.6Hz), 5.64-5.58 (1H, m), 4.96 (1H, dd, J = 13.2, 2.6Hz), 4.49 (1H, dd, J = 13.2, 5.3Hz), 3.13 (3H, s)

(3)

To a solution of 317 mg of the colorless oil obtained in Example 39(2) in 1.5 mL of N,N-dimethylformamide was added 0.27 mL of a 15-18% aqueous sodium hydrosulfide solution at 0-10°C, and the mixture was stirred at the same temperature for 1 hour. 10 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed three times with 10 mL of a 10% aqueous sodium chloride solution to obtain an ethyl acetate solution of 2,3,5-tri-O-benzoyl-4-thio-L-lyxose.

To the obtained ethyl acetate solution was added 0.4 mg of 4-dimethylaminopyridine and 0.061 mL of acetic anhydride, stirred at room temperature for 1 hour, and allowed to stand overnight at room temperature. The reaction mixture was washed with water, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/0 to 3/1) to obtain 107 mg of 1-O-acetyl-2,3,5-tri-O-benzoyl-4-thio-L-lyxose as a colorless oil. The obtained compound was a single end group isomer.

¹ H-NMR (CDCl ₃ ) δ value:

8.05-8.01 (2H, m), 7.96-7.92 (2H, m), 7.90-7.87 (2H, m), 7.64-7.31 (9H, m), 6.20 (1H, d, J = 4.0Hz), 6.09 (1H, dd, J = 5.9, 4.0Hz), 5.94 (1H, t, J = 3.6Hz), 4.77 (1H, dd, J = 11.2, 7.3Hz), 4.61 (1H, dd, J = 11.2, 7.3Hz), 4.37 (1H, q, J = 6.8Hz), 2.15 (3H, s)

Example 40

(1)

To a solution of 12.0 kg of (2R,3R,4S)-3,4,5-trihydroxy-2-hydroxymethyloxolane in 1200 mL of methanol, 720 mL of acetyl chloride was added dropwise over 30 minutes at below 15°C, and the mixture was stirred at 20-30°C for 1 hour. To the reaction mixture were added 2100 mL of a 28% sodium methoxide/methanol solution and 1000 mL of toluene, and the methanol was distilled off under reduced pressure to obtain 4500 mL of a toluene solution of (2R,3R,4S)-3,4-dihydroxy-2-hydroxymethyl-5-methoxyoxolane.

To 4500 mL of the resulting toluene solution, 2400 mL of a 50% aqueous sodium hydroxide solution, 6000 mL of toluene, and 72.0 g of tetrabutylammonium chloride were added at below 30°C. 3290 mL of 4-methylbenzoyl chloride was then added dropwise over 1 hour at below 15°C, and the mixture was stirred at 30°C for 3 hours. The aqueous layer was removed, and the organic layer was washed sequentially with 3000 mL of water and 3000 mL of a 10% aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 3.94 kg of ((2R,3S,4S)-3,4-bis((4-methylphenyl)carbonyloxy)-5-methoxyoxiran-2-yl)methyl 4-methylbenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

2.33-2.45 (9H, m), 3.49 (3H, s), 4.53-4.57 (1H, m), 4.60-4.76 (1H, m), 4.82 (1H, dd, J=3.2, 12.0Hz), 5.16 (1H, s), 5.44-5.48 (1H, m), 5.55 (1H, d, J = 5.6Hz), 7.08-7.26 (6H, m), 7.86-7.97 (6H, m)

(2)

To a mixture of 50.0 g of ((2R,3S,4S)-3,4-bis((4-methylphenyl)carbonyloxy)-5-methoxyoxiran-2-yl)methyl 4-methylbenzoate in 50 mL of acetic acid and 25 mL of toluene was added 50 mL of a 30% hydrogen bromide/acetic acid solution at 25°C, and the mixture was stirred at the same temperature for 2 hours. 100 mL of hexane was added to the reaction mixture, and the solid was collected by filtration to obtain 37.7 g of ((2R,3S,4S)-5-bromo-3,4-bis((4-methylphenyl)carbonyloxy)oxiran-2-yl)methyl 4-methylbenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

2.44(3H,s), 2.42(3H,s), 2.37(3H,s), 4.72-4.92(3H,m), 5.59(1H,d,J=4.4Hz), 5.92(1H,s), 6.19(1H,s), 7.08-7.30(6H, m),7.82-8.03(6H,m)

(3)

To a mixture of 400 g of ((2R,3S,4S)-5-bromo-3,4-bis((4-methylphenyl)carbonyloxy)oxiran-2-yl)methyl 4-methylbenzoate in 950 mL of toluene, 480 mL of water, and 600 mL of acetonitrile was added 71.0 g of sodium bicarbonate at 25°C, and the mixture was stirred at 55°C for 6 hours and 30 minutes. 500 mL of 10% aqueous sodium bicarbonate solution was added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed with 3 L of 10% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 361 g of ((2R,3S,4S)-3,4-bis((4-methylphenyl)carbonyloxy)-5-hydroxyoxiran-2-yl)methyl 4-methylbenzoate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

2.37-2.45(9H,m), 4.73-4.92(3H,m), 5.59(1H,d,J=4.4Hz), 5.92(1H,s), 6.59(1H,s), 7.04-7.26(6H,m), 7.83-8.03(6H,m)

(4)

To a solution of 361 g of ((2R,3S,4S)-3,4-bis((4-methylphenyl)carbonyloxy)-5-hydroxyoxiran-2-yl)methyl 4-methylbenzoate in 1080 mL of methanol were added 360 mL of pyridine, 180 g of p-toluenesulfonic acid dihydrate, and 106 g of O-methylhydroxylamine hydrochloride. Then, 176 mL of triethylamine was added dropwise at 25°C, and the mixture was stirred at the same temperature for 8 hours. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was removed. The organic layers were washed successively with a 10% aqueous sodium chloride solution twice, with hydrochloric acid twice, with a sodium bicarbonate solution once, and with a saturated aqueous sodium chloride solution once, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to obtain 394 g of (2R,3R,4R)-1,3-bis((4-methylphenyl)carbonyloxy)-2-hydroxy-5-(methoxyimino)pentan-4-yl 4-methylbenzoate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 75:25.

¹ H-NMR (CDCl ₃ ) δ value:

2.37-2.43 (9H, m), 3.40 (1H, d, J = 8.4Hz), 3.79 (2.25H, s), 4.11 (0.75H, s), 4.36-4.40 (1H, m), 4.53-4.59 (1H, m), 5.66 (0.75H, dd, J=3.2, 8.4Hz), 5.84 (0.25H, dd, J=2.8, 8.4Hz), 6.17 (0.75H, dd, J=3.2, 6.0Hz) 6.57 (0.25H, dd, J=2.8, 5.2Hz), 6.76 (0.25H, d, J=5.2Hz), 7.06-7.29 (6H, m), 7.45 (0.75H, d, J=6.0Hz), 7.89-8.03 (6H, m)

(5)

To a solution of 338 g of (2R,3R,4R)-1,3-bis((4-methylphenyl)carbonyloxy)-2-hydroxy-5-(methoxyimino)pentan-4-yl 4-methylbenzoate in 1200 mL of acetonitrile was added 195 g of (2,4,5-trichlorobenzene)sulfonyl chloride at 25°C. Then, 130 mL of N-methylimidazole was added dropwise at 0-10°C over 40 minutes, and the mixture was stirred at 10°C for 5 hours. 1500 mL of ethyl acetate and 1000 mL of water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed successively with a 10% aqueous sodium chloride solution twice, hydrochloric acid once, sodium bicarbonate solution once, and saturated aqueous sodium chloride solution once, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to obtain (2R,3R,4R)-1-(methoxyimino)-2,5-bis((4-methylphenyl)carbonyloxy)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl 4-methylbenzoate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 75:25.

¹ H-NMR (CDCl ₃ ) δ value:

2.37-2.49 (9H, m), 3.82 (2.25H, s), 3.96 (0.75H, s), 4.62-4.80 (2H, m), 5.35-5.51 (1H, m), 5.90-6.05 (1.75H, m), 6.30-6.38 (0.25H, m), 6.74-6.76 (0.25H, m), 7.15-7.35 (7H, m), 7.44-7.49 (0.75H, m), 7.75-7.99 (7H, m)

(6)

To a mixed solution of (2R,3R,4R)-1-(methoxyimino)-2,5-bis((4-methylphenyl)carbonyloxy)-4-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentan-3-yl 4-methylbenzoate in 450 mL of tetrahydrofuran and 370 mL of 1,2-dimethylimidazole was added 110 g of lithium bromide at below 10°C, and the mixture was stirred at 25°C for 6 hours. 800 mL of ethyl acetate and 800 mL of water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (2S,3S,4R)-2-bromo-1,4-bis((4-methylphenyl)carbonyloxy)-5-(methoxyimino)pentan-3-yl 4-methylbenzoate as a colorless oil.

The results of ¹ H-NMR measurement showed that the cis/trans ratio was 79:21.

¹ H-NMR (CDCl ₃ ) δ value:

2.34-2.41 (9H, m), 3.38 (2.37H, s), 3.88 (0.63H, s), 4.44-4.75 (3H, m), 6.04-6.11 (1.79H, m), 6.41-6.44 (0.21H, m), 6.75 (0.21H, d, J =5.6Hz), 7.11-7.26 (6H, m), 7.53 (0.79H, d, J = 5.2Hz), 7.78-7.96 (6H, m)

(7)

To a 900 mL solution of (2S,3S,4R)-2-bromo-1,4-bis((4-methylphenyl)carbonyloxy)-5-(methoxyimino)pentan-3-yl 4-methylbenzoate in acetonitrile was added 420 mL of a 50% aqueous solution of glyoxylic acid, and the mixture was stirred at 75°C for 12 hours. The reaction mixture was cooled to room temperature, and 600 mL of ethyl acetate and 200 mL of water were added, and the aqueous layer was removed. The organic layer was washed sequentially with a mixture of a 10% aqueous sodium chloride solution, an aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to yield 337 g of a brown oil.

The obtained oily substance was a mixture of (2S,3S,4S)-2-bromo-1,4-bis((4-methylphenyl)carbonyloxy)-5-pentanon-3-yl 4-methylbenzoate and its hydrate.

¹ H-NMR (CDCl ₃ ) δ value:

2.34-2.45 (9H, m), 4.55-4.85 (3H, m), 5.78-5.80 (1H, m), 5.95-6.00 (1H, m), 7.18-7.26 (6H, m), 7.89-7.96 (6H, m), 9.72 (1H, s)

(8)

To a solution of 337 g of the oily substance obtained in Example 40 (7) in 1000 mL of N,N-dimethylformamide, 584 mL of a 25% aqueous sodium hydrogensulfide solution was added dropwise at -10°C over 30 minutes, and the mixture was stirred at 15°C for 2 hours. 1000 mL of ethyl acetate and a saturated aqueous sodium chloride solution were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed three times with an aqueous sodium bicarbonate solution and then dried over anhydrous magnesium sulfate to obtain an ethyl acetate solution of ((2R,3S,4S)-3,4-bis((4-methylphenyl)carbonyloxy)-5-hydroxytetrahydrothiophen-2-yl)methyl 4-methylbenzoate.

To the resulting ethyl acetate solution was added 15.0 g of N,N-dimethyl-4-aminopyridine, followed by the addition of 180 mL of acetic anhydride in four portions at 0°C. The mixture was allowed to stand at room temperature for 16 hours. 400 mL of water was added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed four times with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was recrystallized from methanol to obtain 167 g of ((2R,3S,4S)-5-(acetyloxy)-3,4-bis((4-methylphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methylbenzoate as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

1.99 (1.50H, s), 2.04 (1.50H, s), 2.31-2.45 (9H, m), 3.78-3.87 (1H, m), 4.46-4.53 (1H, m), 4.64-4.71 (1H, m), 5.66-5.73 (1H, m), 6.08-6.21 (1H, m), 6.31 (0.50H, d, J = 4.4Hz), 6.40 (0.50H, d, J = 4.4Hz), 6.96-7.28 (6H, m), 7.76-7.96(6H, m)

(9)

To a solution of 25 g of ((2R,3S,4S)-5-(acetyloxy)-3,4-bis((4-methylphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methylbenzoate in 75 mL of trifluoroacetic acid was added 25 mL of triethylsilane, and the mixture was stirred at room temperature for 8 hours and 30 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from methanol to obtain 167 g of ((2R,3S,4S)-5-(acetyloxy)-3,4-bis((4-methylphenyl)carbonyloxy)tetrahydrothiophen-2-yl)methyl 4-methylbenzoate as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ value:

2.31-2.45 (9H, m), 3.18 (1H, dd, J=5.6, 16.0Hz), 3.52 (1H, d, J=4.8, 16.0Hz), 3.92 (1H, ddd, J=4.8, 9.2, 10.8Hz), 4.57 (1H, dd, J=9.2, 14.8Hz), 4.67 (1H, dd, J=10.8, 14.8), 5.72-5.77 (1H, m), 5.85-5.88 (1H, m), 7.15-7.26 (6H, m), 7.88-7.96 (6H, m)

Example 41

(1)

To a solution of 23.2 g of (2S,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxyoxolan-3-one in 100 mL of tetrahydrofuran, 92 mL of a 1 mol/L methylmagnesium bromide/tetrahydrofuran solution and 23 mL of a 3 mol/L methylmagnesium bromide/diethyl ether solution were added dropwise at -40°C, and the mixture was stirred at the same temperature for 30 minutes. The temperature was raised to 0°C over 1 hour, and 500 mL of a saturated aqueous ammonium chloride solution and 500 mL of ethyl acetate were added. The organic layer was separated, washed with 300 mL of a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 12.0 g of (2S,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolan-3-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.37-7.24 (10H, m), 4.80-4.48 (5H, m), 4.12 (1H, m), 3.53-3.42 (2H, m), 3.44 (3H, s), 3.38 (1H, d, J = 0.6Hz), 3.34 (1H, d, J = 4.2Hz), 1.31(3H, s).

(2)

To a solution of 7.2 g of (2S,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolan-3-ol in N,N-dimethylformamide, 1.2 g of sodium hydride was added, followed by the dropwise addition of 5.1 g of benzyl bromide at below 15°C, and the mixture was stirred at room temperature for 1.5 hours. 200 mL of water and 200 mL of ethyl acetate were added to the reaction mixture. The organic layer was separated and washed sequentially with 200 mL of 1 mol/L hydrochloric acid and 200 mL of saturated aqueous sodium chloride solution. The solvent was distilled off under reduced pressure to obtain 9.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolan-3-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.44-7.22 (15H, m), 4.82-4.46 (6H, m), 4.70 (1H, s), 4.27 (1H, q, J=3.9Hz), 3.59-3.43 (3H, m), 3.46 (3H, s), 1.34 (3H, s).

(3)

To a solution of 9.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolan-2 in 80 mL of acetic acid and 20 mL of water was added 4.9 g of concentrated sulfuric acid dropwise at room temperature, followed by stirring at 70°C for 3 hours. The reaction mixture was cooled to 30°C, and 200 mL of water and 200 mL of ethyl acetate were added. The organic layer was separated and washed sequentially with 200 mL of 1 mol/L hydrochloric acid and 200 mL of saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 5.5 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyloxolan-2-ol as a colorless oil.

¹ H-NMR (dmso-d ₆ ) δ value:

7.38-7.24 (15H, m), 6.56 (0.64H, d, J = 4.8Hz), 5.84 (0.36H, d, J = 6.9Hz), 5.01 (0.64H, d, J = 4.8Hz), 4.99 (0.36H, d, J = 6.9), 4.75-4.47 (6H, m), 4.17 (0.36H, m), 4.03 (0.64H, m), 3.79 (0.64H, d, J = 7.5Hz), 3.66 (0.36H, d, J = 6.0Hz), 3.61-3.49 (2H, m), 1.34 (1.92H, s), 1.33 (1.08H, s).

(4)

To a mixture of 2.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyloxolan-2-ol and 10 mL of methanol was added 0.69 g of O-methylhydroxylamine hydrochloride, followed by 0.56 g of triethylamine dropwise, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and 20 mL of ethyl acetate and 20 mL of water were added to the resulting residue. The organic layer was separated and washed twice with water, and the solvent was distilled off under reduced pressure to obtain 2.0 g of (2R,3R,4S)-1,3,4-tris(benzyloxy)-4-((methoxyimino)methyl)pentan-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.42(s(1H), 7.35-18(15H,m), 4.64-4.39(6H,m), 4.06(1H, m), 3.87(3H,s), 3.76-3.68(4H,m), 1.58(3H,s).

(5)

To a solution of 2.0 g of (2R,3R,4S)-1,3,4-tris(benzyloxy)-4-((methoxyimino)methyl)pentan-2-ol in 10 mL of acetonitrile were added 0.66 g of triethylamine and 0.53 g of N-methylimidazole, followed by the dropwise addition of 0.75 g of methanesulfonyl chloride, and the mixture was stirred at room temperature for 1 hour. 30 mL of water and 50 mL of ethyl acetate were added to the reaction mixture. The organic layer was separated and washed twice with 20 mL of 1 mol/L hydrochloric acid, then with 20 mL of saturated aqueous sodium bicarbonate solution and 20 mL of saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.7 g of (2R,3R,4S)-1,3,4-tris(benzyloxy)-5-(methoxyimino)-4-methylpentan-2-yl methanesulfonate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.35 (1H, s), 7.34-7.22 (15H, m), 5.23 (1H, m), 4.81-3.39 (6H, m), 3.96 (1H, d, J = 1.8Hz), 3.89-3.79 (2H, m), 3.87 (3H, s), 2.96 (3H, s), 1.48 (3H, s).

(6)

To a solution of 0.7 g of (2R,3R,4S)-1,3,4-tris(benzyloxy)-5-(methoxyimino)-4-methylpentan-2-yl methanesulfonate in 14 mL of acetone, under a nitrogen atmosphere, were added 3.5 mL of 2 mol/L hydrochloric acid and 1.12 g of a 35% aqueous formaldehyde solution. The mixture was stirred at room temperature for 22 hours. 1.2 g of a 35% aqueous formaldehyde solution and 2 mL of acetone were then added, and the mixture was stirred at 40°C for 5 hours. 15 mL of water and 20 mL of ethyl acetate were added to the reaction mixture. The organic layer was separated and washed sequentially with 20 mL of a saturated aqueous sodium bicarbonate solution and 20 mL of a saturated aqueous sodium chloride solution. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.31 g of (2R,3R,4R)-1,3,4-tris(benzyloxy)-4-methyl-5-pentan-2-yl methanesulfonate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.51 (1H, s), 7.38-7.24 (15H, m), 5.09 (1H, m), 4.77-4.43 (6H, m), 4.09 (1H, d, J = 4.5Hz), 3.96-3.77 (2H, m), 2.93 (3H, s), 1.43 (3H, s).

(7)

To a solution of 0.12 g of (2R,3R,4R)-1,3,4-tris(benzyloxy)-4-methyl-5-pentanone-2-yl methanesulfonate in N,N-dimethylformamide was added 0.035 g of sodium hydrosulfide x-hydrate, and the mixture was stirred at room temperature for 2 hours. Water and 5 mL of ethyl acetate were added to the reaction mixture. The organic layer was separated and washed with 5 mL of saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.05 g of (3R,4S,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyltetrahydrothiophen-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.37-7.22 (15H, m), 5.29 (1H, d, J = 6.0Hz), 4.75-4.37 (6H, m), 4.02 (1H, d, J = 6.3Hz), 3.94 (1H, dd, J = 9.3, 4.8Hz), 3.80 (1H, m), 3.70 (1H, dd, J=9.3, 8.1Hz), 1.95 (1H, d, J=6.3Hz), 1.48 (3H, s).

Example 42

(1)

190 mg of (2R,3R)-2-((benzoyloxy)methyl)-4,4-difluoro-5-hydroxyoxolan-3-ylbenzoate was dissolved in 4 mL of a mixed solvent of acetonitrile/water (3/1), followed by the addition of 83.5 mg of O-methylhydroxylamine hydrochloride and 0.09 mL of triethylamine, and the mixture was stirred for 2 hours. 82 mg of pyridinium p-toluenesulfonate was added to the reaction mixture, and the mixture was stirred for 69 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the aqueous layer was removed. The aqueous layer was extracted with ethyl acetate, and the organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless oil. 0.42 mL of triethylamine was added to a 3 mL solution of the oil in tetrahydrofuran, followed by the addition of 0.12 mL of methanesulfonyl chloride at 0°C, and the mixture was stirred for 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the aqueous layer was removed. The aqueous layer was extracted with ethyl acetate, the organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain 202 mg of (2R,3R,5E)-3-benzoyloxy-4,4-difluoro-2-(methylsulfonyloxy)-5-(methoxyimino)pentyl benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.10-8.05 (4H, m), 7.67-7.40 (7H, m), 6.17 (1H, ddd, 12.9Hz, 10.8Hz, 3.0Hz), 5.62 (1H, ddd, 8.4Hz, 3.0Hz, 2.7Hz), 4.89 (1H, dd, 12.6Hz, 2.7Hz), 4.60 (1H, dd, 12.6Hz, 8.4Hz), 3.90 (3H, s), 3.06 (3H, s)ppm.

(2)

To a solution of 202 mg of (2R,3R,5E)-3-benzoyloxy-4,4-difluoro-2-(methylsulfonyloxy)-5-(methoxyimino)pentyl benzoate in 4 mL of acetone were added 1 mol/L hydrochloric acid and 35% aqueous formaldehyde solution, and the mixture was stirred at room temperature for 72 hours. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was removed. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 2/3 to 1/4) to obtain 70.5 mg of (3R,4R)-5-benzoyloxy-2,2-difluoro-1,1-dihydroxy-4-(methylsulfonyloxy)pentan-3-yl benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.08-8.02 (4H, m), 7.64-7.36 (6H, m), 6.19 (1H, ddd, 12.9Hz, 12.9Hz, 2.7Hz), 5.70 (1H, ddd, 8.7Hz, 2.4Hz, 2.4Hz), 5.30 (1H, br), 4.93 (1H, br), 4.92 (1H, dd, 12.6Hz, 2.4Hz), 4.59 (1H, dd, 12.6Hz, 8.7Hz), 3.10 (1H, br), 3.08 (3H, s)ppm.

(3)

To a solution of 70.5 mg of (3R,4R)-5-benzoyloxy-2,2-difluoro-1,1-dihydroxy-4-(methylsulfonyloxy)pentan-3-yl benzoate in 1 mL of N,N-dimethylformamide was added 17 mg of sodium hydrosulfide n-hydrate, and the mixture was stirred at room temperature for 5 minutes. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was removed. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 5/1 to 0/1) to obtain 26.5 mg of (2R,3R)-2-((benzoyloxy)methyl)-4,4-difluoro-5-hydroxytetrahydrothiophen-3-yl benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.04 (2H, d, J=7.2Hz), 7.90 (0.6H, d, J=7.2Hz), 7.82 (1.4H, d, J=7.2Hz), 7.27-7.65 (6H, m), 5.98 (1H, m), 5.36-5.54, (1H, m), 4.62 (0.6H, d, J=7.5Hz), 4.55 (0.7H, dd, J=11.4, 8.1Hz), 4.44 (0.7H, d, J=11.4, 6.1Hz), 4.28 (0.7H, ddd, J=8.1Hz, 6.1Hz, 6.6Hz), 2.80-3.15 (1H, br).

Example 43

(1)

To a solution of 1.2 g of 5-methyl-4-phenyloxolan-2-one in 2 mL of ethanol and 20 mL of tetrahydrofuran was added 0.64 g of sodium tetrahydroborate under a nitrogen atmosphere at 5-10°C. A solution of 2.0 g of calcium chloride in 8 mL of ethanol was then added dropwise, and the mixture was stirred at room temperature for 200 minutes. To the reaction mixture was added 30 mL of ethyl acetate, followed by 20 mL of 3 mol/L hydrochloric acid. The organic layer was separated, washed with saturated sodium bicarbonate aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.05 g of 3-phenylpentane-1,4-diol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.35-7.15 (5H, m), 3.95 (1H, dqb, J=6.9Hz, 6.3H), 3.70-3.61 (1H, m), 3.57-3.46 (1H, m), 2.69 (1H, ddd, J=8.3Hz, 8.3Hz, 5.1Hz), 2.28-2.15 (1H, m), 2.00-1.80 (1H, m), 1.04 (3H, d, J=6.3Hz).

(2)

To a solution of 1.0 g of 3-phenylpentane-1,4-diol and 0.45 g of imidazole in 20 mL of N,N-dimethylformamide was added dropwise 1.25 mL of triisopropylsilyl chloride at 5-10°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 19 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/19 to 1/10) to obtain 1.2 g of 3-phenyl-5-((tri(propan-2-yl)silyl)oxy)pentan-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.33-7.12(5H,m), 4.00-3.89(1H,m), 3.76-3.68(1H,m), 3.63-3.53 (1H, m), 2.81-2.78 (1H, m), 2.75-2.67 (1H, m), 2.20-2.08 (1H, m), 1.99-1.88 (1, m), 1.15-1.00 (24H, m).

(3)

To a solution of 1.0 g of 3-phenyl-5-((tri(propan-2-yl)silyl)oxy)pentan-2-ol and 1.67 mL of triethylamine in 10 mL of ethyl acetate was added dropwise 0.46 mL of methanesulfonyl chloride at 5-10°C, followed by stirring at room temperature for 5.5 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.2 g of 3-phenyl-5-((tri(propan-2-yl)silyl)oxy)pentan-2-yl methanesulfonate as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.35-7.15 (5H, m), 4.90 (1H, dq, J=6.3Hz, 6.8Hz), 3.66-3.58 (1H, m), 3.46-3.35 (1H, m), 3.10-3.02 (1H, m), 2.85 (3H, s), 2.27-2.14 (1H, m), 1.94-1.81 (1H, m), 1.31 (3H, d, J=6.3Hz), 1.09-0.95 (21H, m).

(4)

To a solution of 1.05 g of 3-phenyl-5-((tri(propan-2-yl)silyl)oxy)pentan-2-yl methanesulfonate in 15 mL of methanol was added 0.24 g of p-toluenesulfonic acid monohydrate, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated, washed sequentially with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/4 to 1/1) to obtain 0.56 g of 5-hydroxy-3-phenylpentan-2-yl methanesulfonate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.38-7.16 (5H, m), 4.92 (1H, dq, J=7.8Hz, 6.3Hz), 3.62-3.53 (1H, m), 3.44-3.34 (1H, m), 3.05-2.95 (1H, m), 2.92 (3H, s), 2.29-2.16 (1H, m), 1.99-1.85 (1H, m), 1.28 (3H, d, J=6.3Hz).

(5)

To a solution of 490 mg of 5-hydroxy-3-phenylpentan-2-yl methanesulfonate in 5 mL of dichloromethane was added 1.2 g of 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoyl-3(1H)-one (Dess-Martin periodinane), and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated, washed sequentially with an aqueous sodium thiosulfate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/10 to 1/1) to obtain 414 mg of 5-oxo-3-phenylpentan-2-yl methanesulfonate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.69 (1H, m), 7.38-7.18 (5H, m), 4.93-4.85 (1H, m), 3.50-3.43 (1H, m), 3.15-3.04 (1H, m), 2.93-2.80 (4H, m), 1.31 (3H, d, J = 4.5Hz).

(6)

To a solution of 256 mg of 5-oxo-3-phenylpentan-2-yl methanesulfonate in 3 mL of N,N-dimethylformamide was added 240 mg of sodium hydrosulfide n-hydrate at room temperature, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed twice with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/19 to 1/9) to obtain 80 mg of 5-methyl-4-phenyltetrahydrothiophen-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

7.38-7.17(5H,m), 5.82-5.72(0.17H,m), 5.63-5.58(0.83H,m), 3.99-3.90 (0.83H, m), 3.82-3.51 (0.83H, m), 3.66-3.47 (0.34H, m), 2.75-2.68 (0.17H, m), 2.56-2.31 (1.83H, m), 1.10 (0.51H, d, J = 6.9Hz), 0.84 (2.49H, d, J = 6.9Hz).

Example 44

(1)

To a solution of 12.2 g of (3aR,6R,6aR)-2,2,6-trimethyltetrahydro-2H-furo(3,4-d)(1,3)dioxol-4-ol in 10 mL of ethanol and 120 mL of tetrahydrofuran was added 4.0 g of sodium tetrahydroborate under a nitrogen atmosphere at 5-10°C. A solution of 10.3 g of calcium chloride in 50 mL of ethanol was then added dropwise, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture were added 200 mL of ethyl acetate and 300 mL of water, the organic layer was separated, and the aqueous layer was extracted six times with 200 mL of ethyl acetate. The organic layer and the extract were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/4 to 1/1) to obtain 7.4 g of (1R)-1-((4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethan-1-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

4.34-4.27 (1H, m), 4.03-3.71 (4H, m), 2.73-2.62 (2H, m), 1.41 (3H, s), 1.36 (3H, s), 1.33 (3H, d, J=6.0Hz).

(2)

To a solution of 3.5 g of (1R)-1-((4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethan-1-ol and 1.63 g of imidazole in 50 mL of N,N-dimethylformamide was added dropwise 4.46 mL of triisopropylsilyl chloride under a nitrogen atmosphere at 5-10°C, and the mixture was stirred at room temperature for 23 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7.1 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tri(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolan-4-yl)ethan-1-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

4.29 (1H, ddd, J = 3.6, 5.1, 10.2Hz), 4.12 (1H, br), 4.02-3.94 (2H, m), 3.88 (1H, dd, J = 10.2, 10.2Hz), 3.67 (1H, dd, J = 3.6, 10.2Hz), 1.40-1.03 (30H, m).

(3)

To a solution of 1.6 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tri(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolan-4-yl)ethan-1-ol and 2.7 mL of triethylamine in 16 mL of ethyl acetate was added dropwise 0.75 mL of methanesulfonyl chloride at 5-10°C, followed by stirring at room temperature for 10 minutes. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated, washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.98 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tri(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolan-4-yl)ethyl methanesulfonate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

5.17 (1H, dq, J=3.3, 6.6Hz), 4.35-4.27 (2H, m), 3.94-3.82 (2H, m), 3.02 (3H, s), 1.51 (3H, d, J=6.6Hz), 1.47 (3H, s), 1.37 (3H, s), 1.17-1.03(21H, m).

(4)

To a solution of 1.98 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tri(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolan-4-yl)ethyl methanesulfonate in 24 mL of tetrahydrofuran was added 5.8 mL of a 1 mol/L tetrabutylammonium fluoride/tetrahydrofuran solution at 5-10°C, and the mixture was stirred at room temperature for 20 minutes. Saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.8 g of (1R)-1-((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate as a colorless oil.

The obtained oily substance contained fluorotri(propane-2-yl)silane and was used directly in the next reaction.

¹ H-NMR (CDCl ₃ ) δ value:

4.96 (1H, dq, J=6.3, 6.3Hz), 4.32 (1H, dt, J=4.5, 6.3Hz), 4.17-4.11 (1H, m), 3.90-3.79 (2H, m), 3.75 (1H, br), 3.06 (3H, s), 1.53 (3H, d, J=6.3Hz), 1.47 (3H, s), 1.38 (3H, s).

(5)

To a solution of 1.8 g of (1R)-1-((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate (containing fluorotri(propan-2-yl)silane) and 1.16 mL of pyridine in 20 mL of dichloromethane was added 3 g of 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoyl-3(1H)-one (Dess-Martin periodinane) at 5-10°C, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate, saturated aqueous sodium bicarbonate, and aqueous sodium thiosulfate were added to the reaction mixture. The organic layer was separated, washed sequentially with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.7 g of (1R)-1-((4S,5R)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate as a yellow oily substance.

The obtained oily substance contained fluorotri(propane-2-yl)silane and was used directly in the next reaction.

¹ H-NMR (CDCl ₃ ) δ value:

9.69 (1H, d, J = 3.0Hz), 4.99 (1H, dq, J = 5.1, 6.6Hz), 4.50-4.39 (2H, m), 3.02 (3H, s), 1.60 (3H, s), 1.50 (3H, d, J = 6.6Hz), 1.42 (3H, s).

(6)

To a solution of 0.85 g of (1R)-1-((4S,5R)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate (containing fluorotri(propan-2-yl)silane) in 8 mL of N,N-dimethylformamide was added 0.38 g of sodium hydrosulfide n-hydrate at 5-10°C, and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed twice with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/19 to 1/4) to obtain 0.11 g of (3aR,6S,6aS)-2,2,6-trimethyltetrahydro-2H-thieno(3,4-d)(1,3)dioxol-4-ol as a white solid.

¹ H-NMR (CDCl ₃ ) δ value:

5.21 (1H, s), 4.77-4.70 (2H, m), 3.82 (1H, dq, J=3.3, 6.9Hz), 1.76 (1H, br), 1.49 (3H, s), 1.38 (3H, d, J=6.9Hz), 1.33 (3H, s).

Example 45

(1)

To a solution of 1.0 g of 5-phenyloxolan-2-one in 12 mL of toluene was added dropwise 4.1 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution at -60°C, followed by stirring for 30 minutes. To the reaction mixture was added 1 mL of methanol, followed by 40 mL of a 20% aqueous sodium potassium tartrate solution at room temperature, and stirred for 1 hour. The aqueous layer was removed, and the solvent was distilled off under reduced pressure to yield 0.98 g of 5-phenyloxolan-2-ol as a colorless oil.

As a result of ¹ H-NMR measurement, the obtained oily substance was a mixture of isomer A and isomer B, with a ratio of A:B=56:54.

¹ H-NMR (CDCl ₃ ) δ value:

7.46-7.23 (5H+5H, m, A+B), 5.77-5.75 (1H, m, A), 5.64-5.62 (1H, m, B), 5.25 (1H, t, J=6.9Hz, A), 5.04-4.98 (1H, m, B), 2.98-2.92 (1H,m,B), 2.90-2.83(1H,m,B), 2.59-2.42(1H,m,A), 2.36-2.02 (1H+4H,m,A+B), 2.21-1.91(1H,m,A), 1.86-1.75(1H,m,A).

(2)

To 0.98 g of 5-phenyloxolane-2-ol was added 12 mL of acetonitrile, 6 mL of water, and 1.0 g of O-methylhydroxylamine hydrochloride, and 1.08 mL of triethylamine was added dropwise, and the mixture was stirred at room temperature for 0.5 hours. Hexane, ethyl acetate, and water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.10 g of 4-(methoxyimino)-1-phenylbutane-1-ol as a colorless oil.

As a result of ¹ H-NMR measurement, the obtained oily substance was a mixture of isomer A and isomer B, with a ratio of A:B=60:40.

¹ H-NMR (CDCl ₃ ) δ value:

7.41 (1H, t, J=5.9Hz, A), 7.38-7.25 (5H+5H, m, A+B), 6.68 (1H, t, J=5.7Hz, A), 4.77-4.71 (1H, m, A), 4.70-4.64 (1H, m, B), 3.87 (3H, s, B), 3.81 (3H, s, A), 2.54-2.25 (2H+2H, m, A+B), 2.20 (1H, d, J=3.6Hz, A), 2.17 (1H, d, J=3.6Hz, B), 2.06-1.80 (2H+2H, m, A+B).

(3)

To a solution of 0.39 g of 4-(methoxyimino)-1-phenylbutane-1-ol in 4 mL of acetonitrile was added 0.24 mL of N-methylimidazole, followed by 0.19 mL of methanesulfonyl chloride at 0-10° C., and the mixture was stirred at 5° C. or below for 1.5 hours. After adding 0.24 mL of methanesulfonyl chloride, ethyl acetate and water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting product was purified by silica gel column chromatography (hexane/ethyl acetate = 90/10 to 59/41) to obtain 0.07 g of (4-chloro-4-phenylbutyl)(methoxy)amine as a light yellow oil.

¹ H-NMR measurement results showed that the obtained oily substance was a mixture of isomer A and isomer B, with a ratio of A:B=58:42.

¹ H-NMR (CDCl ₃ ) δ value:

7.41-7.30 (6H+5H, m, A+B), 6.63 (1H, t, J=5.4Hz, B), 4.92 (1H, t, J=6.8Hz, A), 4.84 (1H, dd, J=6.2, 8.0Hz, B), 3.86 (3H, s, B), 3.82(3H,s,A), 2.53-2.20(4H+4H,m,A+B).

(4)

To a mixture of 82 mg of (4-chloro-4-phenylbutyl)(methoxy)amine, 0.32 mL of 36% aqueous formaldehyde solution, and 4 mL of acetone was added 0.1 mL of 2 mol/L hydrochloric acid, and the mixture was stirred at room temperature for 0.5 hours. Hexane and water were added to the reaction mixture, the aqueous layer was removed, and the solvent was distilled off under reduced pressure to obtain 61 mg of 4-chloro-4-phenylbutyraldehyde as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

9.78 (1H, t, J=0.9Hz), 7.41-7.28 (5H, m), 4.94 (1H, dd, J=6.6, 7.5Hz), 2.66 (2H, t, J=6.9Hz), 2.39 (2H, dd, J=6.6, 7.4Hz), 3.86 (3H, s, B), 3.82 (3H, s, A), 2.53-2.20 (4H+4H, m, A+B).

(5)

To a solution of 61 mg of 4-chloro-4-phenylbutyraldehyde in 1 mL of N,N-dimethylformamide was added 32 mg of anhydrous sodium hydrosulfide at 0-10°C, and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 85/15 to 60/40) to obtain 37 mg of 5-phenyltetrahydrothiophen-2-ol as a colorless oil.

¹ H-NMR measurement results showed that the obtained oily substance was a mixture of isomer A and isomer B, with a ratio of A:B=68:32.

¹ H-NMR (CDCl ₃ ) δ value:

7.45 (2H, brd, J=7.8Hz, A), 7.39-7.20 (3H+5H, m, A+B), 5.80 (1H, m, B), 5.64 (1H, t, J=4.2Hz, A), 4.80 (1H, dd, J=5.0, 7.1Hz, B), 4.56 (1H, dd, J=6.1, 10.5Hz, A), 2.65-2.00 (4H+4H, m, A+B).

Example 46

To a solution of 295 mg of diethyl 2-bromo-2-(3-oxopropyl)malonic acid in 3 mL of N,N-dimethylformamide was added 80 mg of sodium hydrosulfide x-hydrate at 0-10°C, followed by stirring at the same temperature for 15 minutes and then at room temperature for 15 minutes. To the reaction mixture were added 10 mL of ethyl acetate and 10 mL of water. The organic layer was separated and washed sequentially with 10 mL of 1 mol/L hydrochloric acid, 10 mL of saturated aqueous sodium bicarbonate, and 10 mL of saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 5/1) to obtain 29 mg of diethyl 5-hydroxydihydrothiophene-2,2(3H)-dicarboxylate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

1.23-1.31 (6H, m), 2.30 (2H, m), 2.58 (1H, m), 2.67 (1H, d, J=6.9Hz), 2.77 (1H, m), 4.15-4.30 (4H, m), 5.62 (1H, dt, J=6.9Hz, 3.3Hz).

Example 47

(1)

A mixture of 10 g of 3-bromo-2-oxoxolane, 6.6 g of benzylamine, 21 g of potassium carbonate, and 200 ml of acetonitrile was stirred at 70°C for 1 hour and 30 minutes. Then, 7.9 ml of 4-methylbenzoyl chloride was added dropwise at 5-10°C, and the mixture was stirred at room temperature for 2 hours. 400 mL of ethyl acetate and 200 mL of water were added to the reaction mixture. The organic layer was separated, washed with 100 mL of water and 100 mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 100 mL of ethyl acetate by heating. 100 mL of hexane was added dropwise at 50°C. The solid was filtered to obtain 11.2 g of N-benzyl-4-methyl-N-(2-oxoxolan-3-yl)benzoamide.

¹ H-NMR (CDCl ₃ ) δ value:

7.47-7.15 (9H, m), 4.85-4.50 (3H, m), 4.27-4.14 (1H, m), 4.06-3.89 (1H, m), 2.71-2.50 (1H, m), 2.34 (3H, s), 2.36-2.20 (1H, m)

(2)

To a solution of 2.0 g of N-benzyl-4-methyl-N-(2-oxoxolan-3-yl)benzoamide in 30 mL of toluene and 10 mL of dichloromethane, 4.4 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise at -60°C and stirred for 30 minutes. The reaction mixture was warmed to 15°C, and 6.6 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise at -60°C and stirred for 25 minutes. 1 mL of methanol was added to the reaction mixture, followed by 80 mL of a 20% aqueous sodium potassium tartrate solution at room temperature. The aqueous layer was removed, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 60/40 to 35/65) to obtain 0.89 g of N-benzyl-N-(2-hydroxyoxolan-3-yl)benzoamide as a colorless oil.

¹ H-NMR measurement results showed that the obtained oily substance was a mixture of isomer A and isomer B, with a ratio of A:B=61:39.

¹ H-NMR (CDCl ₃ ) δ value:

7.40-7.10 (9H+9H, m, A+B), 5.47 (1H, brs, A), 5.24 (1H, dd, J=5.1, 7.8Hz, B), 4.90-4.48 (2H+2H, m, A+B), 4.25-3.50 (3H+3H, m, A+B), 2.35 (3H, s, A), 2.32 (3H, s, B), 2.22-1.92 (2H+2H, m, A+B).

(3)

To 0.2 g of N-benzyl-N-(2-hydroxyoxolane-3-yl)benzoamide, 1.2 mL of acetonitrile, 0.6 mL of water, and 0.1 g of O-methylhydroxylamine hydrochloride were added, stirred at room temperature for 0.5 hours, and allowed to stand for 11 hours. Hexane, ethyl acetate, and water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 60/40 to 30/70) to obtain 99 mg of N-benzyl-N-(4-hydroxy-1-(methoxyimino)butane-2-yl)-4-methylbenzoamide as a colorless oil.

¹ H-NMR measurement results showed that the obtained oily substance was a mixture of isomer A and isomer B, with a ratio of A:B=80:20.

¹ H-NMR (CDCl ₃ ) δ value:

7.38-7.15 (10H+10H, m, A+B), 5.14 (1H, q, J=7.2Hz, B), 4.86 (1H, q, J=6.3Hz, A), 4.70-4.50 (2H+2H, m, A+B), 3.85 (3H, s, B), 3.79 (3H, s, A), 3.58 (2H+2H, brs, A+B), 3.36 (3H, s, B), 3.35 (3H, s, A), 2.22-1.88 (2H+2H, m, A+B).

(4)

To a solution of 99 mg of N-benzyl-N-(4-hydroxy-1-(methoxyimino)butan-2-yl)-4-methylbenzamide in 3 mL of tetrahydrofuran was added 0.083 mL of triethylamine, followed by 0.028 mL of methanesulfonyl chloride at 0-10°C, and then stirred below 5°C for 105 minutes. After adding 0.028 mL of methanesulfonyl chloride, ethyl acetate and water were added, and the aqueous layer was removed. The organic layer was washed with water and saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure to obtain 3-(N-benzyl-1-(4-methylphenyl)formamide)-4-(methoxyimino)butyl methanesulfonate.

As a result of ¹ H-NMR measurement, signals of methanesulfonate were observed at 2.90 ppm and 2.93 ppm.

(5)

To a mixture of the resulting 3-(N-benzyl-1-(4-methylphenyl)formamido)-4-(methoxyimino)butyl methanesulfonate, 0.23 mL of a 36% aqueous formaldehyde solution, and 3 mL of acetone was added 0.05 mL of 2 mol/L hydrochloric acid, and the mixture was stirred at room temperature for 75 minutes. Hexane, ethyl acetate, and water were added to the reaction mixture, the aqueous layer was removed, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain 3-(N-benzyl-1-(4-methylphenyl)formamido)-4-oxobutyl methanesulfonate.

As a result of ¹ H-NMR measurement, a signal of aldehyde was observed at 9.42 ppm.

(6)

To a 3 mL solution of 3-(N-benzyl-1-(4-methylphenyl)formamide)-4-oxobutyl methanesulfonate in N,N-dimethylformamide was added 29 mg of anhydrous sodium hydrosulfide at 0-10°C, and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 70/30 to 50/50) to obtain 46 mg of N-benzyl-N-(2-hydroxytetrahydrothiophen-3-yl)-4-methylbenzoamide as a colorless oil.

¹ H-NMR measurement results showed that the obtained oily substance was a mixture of isomer A and isomer B, with a ratio of A:B=57:43.

¹ H-NMR (CDCl ₃ ) δ value:

7.40-7.14(9H+9H,m,A+B),5.56(1H,brs,B),5.42(1H,brs,A),4.95-4.80(1H,m,B),4.80-4.54(2H+2H,m,A+B),4.16-4.07(1H, m, A), 3.10-2.95 (1H+1H, m, A+B), 2.77-2.64 (1H, m, A), 2.36 (3H, s, B), 2.34 (3H, s, A), 2.28-2.04 (2H+2H, m, A+B).

Example 48

(1)

To a solution of 4.3 g of 5-methyl-3-(pyridin-2-ylsulfonyl)oxolan-2-one in 100 mL of tetrahydrofuran was added dropwise 16.4 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution at -78°C and stirred for 7.5 hours. To the reaction mixture was added 15 mL of methanol and 100 mL of a saturated aqueous solution of potassium sodium tartrate at room temperature. The mixture was stirred for 30 minutes, and the aqueous layer was removed. The aqueous layer was extracted with 100 mL of ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 4/1) to yield 2.8 g of 5-methyl-3-(pyridin-2-ylsulfonyl)oxolan-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.36-8.43 (1H, m), 7.47-7.57 (1H, m), 7.20-7.32 (1H, m), 6.99-7.09 (1H, m), 5.61 (0.18H, t, J=5.1Hz), 5.43-5.55 (0.73H, m), 5.35 (0.28H, s), 5.16 (0.27H, d, J = 2.1Hz), 5.04 (0.39H, s), 4.86 (0.15H, d, J = 5.7Hz), 4.31-4.58 (1H, m), 4.01-4.28 (1H, m), 2.49-2.60 (0.40H, m), 2.37-2.47(0.16H,m), 1.74-2.27(1.02H,m), 1.49-1.62(0.42H,m), 1.23-1.42 (3H,m)

(2)

To 1.5 g of 5-methyl-3-(pyridin-2-ylsulfonyl)oxolane-2-ol was added 8.0 mL of methanol and 712 mg of O-methylhydroxylamine hydrochloride, followed by the dropwise addition of 1.1 mL of triethylamine and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, 50 mL of ethyl acetate and 50 mL of water were added, and the aqueous layer was removed. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone = 4/1) to obtain 1.74 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfonyl)pentane-2-ol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.37-8.45 (1H, m), 7.48-7.58 (1.76H, m), 7.14-7.30 (1H, m), 6.99-7.10 (1H, m), 6.76-6.82 (0.24H, m), 5.06-5.19 (0.88H, m), 4.69-4.79 (0.79H, m), 3.97-4.12 (1H, m), 3.82-3.87 (3H, m), 2.91-3.05 (0.33H, m), 1.76-2.22 (2H, m), 1.21-1.29 (3H, m)

(3)

To a solution of 1.7 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfaniloyl)pentan-2-ol in 7.0 mL of tetrahydrofuran was added 1.2 mL of triethylamine, followed by 602 μL of methanesulfonyl chloride at 0-10°C, and then stirred below 15°C for 1.5 hours. 50 mL of ethyl acetate and 50 mL of water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to obtain 2.12 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfaniloyl)pentan-2-yl methanesulfonate as a brown oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.39-8.45 (1H, m), 7.47-7.57 (1.8H, m), 7.16-7.23 (1H, m), 7.00-7.07 (1H, m), 6.89 (0.2H, d, J=7.5Hz), 4.95-5.16 (1H, m), 4.67-4.78 (1H, m), 3.79-3.91 (3H, m), 3.07 (0.87H, s), 3.01-3.04 (0.59H, m), 2.97 (1.54H, s), 2.39-2.51 (0.54H, m), 2.05-2.35 (1.46H, m), 1.48-1.55 (3H, m)

(4)

To a mixture of 2.1 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfonyl)pentan-2-yl methanesulfonate, 4.7 mL of a 36% aqueous formaldehyde solution, and 60 mL of acetone was added 14 mL of 2 mol/L hydrochloric acid, and the mixture was stirred at room temperature for 2 hours and at 50°C for 3 hours. The solvent was distilled off under reduced pressure, and 100 mL of ethyl acetate and 100 mL of water were added, and the aqueous layer was removed. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone = 3/1) to obtain 0.90 g of 5-oxo-4-(pyridin-2-ylsulfonyl)pentan-2-yl methanesulfonate as a colorless oil.

(5)

To a solution of 0.60 mg of 5-oxo-4-(pyridin-2-ylsulfonyl)pentan-2-yl methanesulfonate in 10 mL of N,N-dimethylformamide was added 0.74 g of sodium hydrosulfide (Wako Pure Chemical Industries, Ltd.) at 0-10°C, and the mixture was stirred at the same temperature for 1.5 hours. 30 mL of ethyl acetate and 30 mL of saturated aqueous sodium bicarbonate were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed sequentially with 30 mL of water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (hexane/ethyl acetate = 5/1) to yield 120 mg of 5-methyl-3-(pyridin-2-ylsulfonyl)tetrahydrothiophen-2-ol as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ value:

8.33-8.43(1H,m),7.48-7.58(1H,m),7.20-7.34(1H,m),6.99-7.09 (1H, m), 5.62-5.70 (0.37H, m), 5.50-5.59 (0.63H, m), 4.41-4.53 (0.36H, m), 4.22-4.30 (0.24H, m), 4.14-4.21 (0.20H, m), 3.85-3.94 (0.20H, m), 3.54-3.80 (1H, m), 2.45-2.68 (0.80H, m), 2.33-2.42 (0.31H, m), 2.22-2.30 (0.28H, m), 1.99-2.11 (0.42H, m), 1.77-1.88 (0.19H, m), 1.50 (0.97H, d, J = 6.8Hz), 1.44 (0.89H, d, J = 6.4Hz), 1.33-1.40 (1.14H, m)

Industrial applicability

The compound of the present invention is useful as an intermediate for producing thionucleosides, and the production method of the present invention is useful as a method for producing thionucleosides.

Claims (5)

1. Compounds represented by the general formula [1F] In general formula [1F], ^R1 represents a hydroxyl protecting group; ^R2 represents a hydroxyl protecting group; or ^R1 and ^R2 together can form a substituted _C1-3 alkylene group; ^R3C represents a hydrogen atom, a halogen atom, a group represented by general formula [16] or a substituted _C1-6 alkyl group; -OR ^3a [16] In general formula [16], R ^3a represents a hydroxyl protecting group; R ^3D represents a hydrogen atom, a halogen atom, a group represented by general formula [16], or a substituted _C1-6 alkyl group; -OR ^3a [16] In general formula [16], R ^3a has the same meaning as the above-mentioned groups; ^R4 represents a halogen atom, a hydroxyl group, a substituted _C1-6 alkylsulfonyloxy group, or a substituted arylsulfonyloxy group; ^R5 and ^R6 together form a group represented by general formula [2]; =Y [2] In general formula [2], Y represents an oxygen atom or a group represented by general formula [3]; =N-OR ⁷ [3] In general formula [3], ^R7 represents a hydrogen atom, a substituted _C1-6 alkyl group, a substituted aryl group, a substituted heterocyclic group, or a substituted silyl group; or ^R4 and ^R5 together represent a sulfur atom; ^R6 represents a hydroxyl group; Wherein, when ^R5 and ^R6 together are groups represented by formula [2a], one of ^R3C and ^R3D is a halogen atom, the other is a hydrogen atom, and ^R4 is a halogen atom, a _C1-6 alkylsulfonyloxy group that can be substituted, or an arylsulfonyloxy group that can be substituted; =O [2a] When ^R4 and ^R5 together are sulfur atoms, and one of ^R3C and ^R3D is a hydrogen atom, the other is a halogen atom or a substituted _C1-6 alkyl group; When ^R5 and ^R6 together are groups represented by general formula [3], one of ^R3C and ^R3D is a group represented by general formula [16], the other is a hydrogen atom, ^R4 is an iodine atom, hydroxyl group, a substituted _C1-6 alkylsulfonyloxy group or a substituted arylsulfonyloxy group, ^R1 is a substituted acyl group and ^R2 is a substituted acyl group; =N-OR ⁷ [3] In general formula [3], R ⁷ has the same meaning as the above-mentioned groups; -OR ^3a [16] In general formula [16], R ^3a has the same meaning as the above-mentioned groups; When ^R5 and ^R6 together are groups represented by general formula [3], one of ^R3C and ^R3D is a hydrogen atom and the other is a hydrogen atom, and ^R4 is a hydroxyl group, ^R1 is a substituted aryl group and ^R2 represents a substituted aryl group; =N-OR ⁷ [3] In general formula [3], R ⁷ has the same meaning as the above-mentioned groups. 2. The compound according to claim 1, wherein it is a compound represented by the following general formula [1], In general formula [1], ^R1 represents a hydroxyl protecting group; ^R2 represents a hydroxyl protecting group; or ^R1 and ^R2 together can form a substituted _C1-3 alkylene group; ^R3 represents a halogen atom; ^R4 represents a halogen atom, a hydroxyl group, a substituted _C1-6 alkylsulfonyloxy group, or a substituted arylsulfonyloxy group; ^R5 and ^R6 together form a group represented by general formula [2]; =Y [2] In general formula [2], Y represents an oxygen atom or a group represented by general formula [3]; =N-OR ⁷ [3] In general formula [3], R ⁷ represents a hydrogen atom, a substituted C _1-6 alkyl group, a substituted aryl group, a substituted heterocyclic group, or a substituted silyl group; Alternatively, ^R4 and ^R5 together represent a sulfur atom; ^R6 represents a hydroxyl group; wherein, when ^R5 and ^R6 together are groups represented by formula [2a], ^R4 is a halogen atom, a substituted _C1-6 alkylsulfonyloxy group, or a substituted arylsulfonyloxy group; =O [2a]. 3. The compound according to claim 2, wherein ^R1 is a hydroxyl protecting group, ^R2 is a hydroxyl protecting group, and ^R3 is a fluorine atom. 4. The compound according to claim 2 or 3, wherein ^R4 is a halogen atom, a hydroxyl group, a substituted _C1-6 alkylsulfonyloxy group, or a substituted arylsulfonyloxy group; ^R5 and ^R6 together are groups represented by general formula [2]. =Y [2] In general formula [2], Y represents an oxygen atom or a group represented by general formula [3]. =N-OR ⁷ [3] In general formula [3], ^R7 represents a hydrogen atom, a substituted _C1-6 alkyl group, a substituted aryl group, a substituted heterocyclic group, or a substituted silyl group. 5. The compound according to claim 2 or 3, wherein ^R4 and ^R5 together are sulfur atoms; and ^R6 is a hydroxyl group.