HK1261159A1

HK1261159A1 - Novel method for producing hydroxamic acid derivative, and intermediate thereof

Info

Publication number: HK1261159A1
Application number: HK19121036.8A
Authority: HK
Inventors: 长远裕介; 马场康隆
Original assignee: 富士胶片富山化学株式会社
Priority date: 2016-03-31
Filing date: 2017-03-30
Publication date: 2019-12-27

Description

Process for producing novel hydroxamic acid derivative and intermediate thereof

Technical Field

The present invention relates to a method for producing (2S) -2- ((4- ((4- ((1S) -1, 2-dihydroxyethyl) phenyl) ethynyl) benzoyl) (methyl) amino) -N-hydroxy-N', 2-dimethylmalonamide having an excellent inhibitory activity against Uridine Diphosphate (UDP) -3-O-acyl-N-acetylglucosaminyl deacetylase (LpxC), and an intermediate thereof.

Background

LpxC is an enzyme that acts as a synthesis of lipid a. Lipid a is an essential component for the formation of the outer membrane, and is essential for the survival of gram-negative bacteria, for example. Therefore, agents inhibiting the activity of LpxC are strongly expected to be effective as antibacterial agents against gram-negative bacteria including Pseudomonas aeruginosa.

For example, (2S) -2- ((4- ((4- ((1S) -1, 2-dihydroxyethyl) phenyl) ethynyl) benzoyl) (methyl) amino) -N-hydroxy-N', 2-dimethylmalonamide (formula [ a ]; hereinafter, also referred to as compound a.) having excellent LpxC inhibitory activity and a method for producing the same are known (patent document 1).

On the other hand, a method for producing an optically active diol compound is known (non-patent document 1).

Documents of the prior art

Patent document

Patent document 1: international publication No. 2014/142298 single file

Non-patent document

Non-patent document 1: tetrahedron: asymmetry 10, (1999), p.1843-1846

Disclosure of Invention

Problems to be solved by the invention

Non-patent document 1 describes a method for producing a compound represented by the general formula [ I ] by protecting a hydroxyl group of a compound represented by the general formula [ G ] and then subjecting the protected compound to an asymmetric reduction reaction. However, this manufacturing method has the following disadvantages.

(1) The compound represented by the general formula [ G ] is unstable.

(2) Therefore, the production of the compound represented by the general formula [ G ] is difficult.

(3) In order to produce the compound represented by the general formula [ H ], an unstable compound represented by the general formula [ G ] must be used.

Patent document 1 describes a method for producing compound a. However, this manufacturing method has the following disadvantages.

(1) Column chromatography is required for purification of the compound represented by the formula [ D ].

(2) In the post-treatment for producing the compound represented by the formula [ F ] from the compound represented by the formula [ D ], column chromatography is required.

(3) Column chromatography is required for purification of compound a.

Compound a has an asymmetric carbon within the molecule. Therefore, when compound a is used as a drug substance of a pharmaceutical, it is strongly required to provide a compound having high optical purity.

The present invention addresses the problem of providing an industrial production method for a compound A having high optical purity and excellent LpxC inhibitory activity, and an intermediate therefor.

Means for solving the problems

Under such circumstances, the present inventors have intensively studied and found an industrial production method of compound a having high optical purity. The preparation method is simple and safe to human body. The present inventors have further found useful intermediates used in the production, and have completed the present invention.

The present invention provides the following.

[1] A method for producing a compound represented by the formula [2], which comprises a step of deprotecting a compound represented by the general formula [1 ].

(in the formula, R¹Is represented by C_1-3An alkyl group; r²Is represented by C_1-3An alkyl group; r^3aRepresents a hydroxyl protecting group. )

[2] The production method according to [1], wherein the step of deprotecting the compound represented by the general formula [1] comprises the steps of:

(1) deprotecting a hydroxyl-protecting group of the compound represented by the general formula [1] to obtain a compound represented by the general formula [3 ]; and,

(2) A step of deprotecting the compound represented by the general formula [3] to obtain a compound represented by the formula [2 ].

(in the formula, R¹And R²Have the same meanings as described above. )

[3]According to [1]Or [2]]The production process described in (1), wherein R¹Is methyl; r²Is methyl.

[4]According to [1]～[3]The production process of any one of the above, wherein R^3aIs tetrahydropyranyl.

[5] A method for producing a compound represented by the formula [2], which comprises:

a step of reacting a compound represented by the general formula [4] with a compound represented by the general formula [5] to obtain a compound represented by the general formula [1 ]; and,

And deprotecting the obtained compound represented by the general formula [1 ].

(in the formula, R¹And R²Have the same meanings as described above. )

(in the formula, L¹Represents a leaving group; r^3aHave the same meanings as described above. )

(in the formula, R¹、R²And R^3aHave the same meanings as described above. )

[6] The production method according to [5], wherein the step of deprotecting the compound represented by the general formula [1] comprises the steps of:

(in the formula, R¹And R²Have the same meanings as described above. )

[7]According to [5]]Or [6]]The production process described in (1), wherein R¹Is methyl; r²Is methyl.

[8]According to [5]]～[7]The production process of any one of the above, wherein R^3aIs tetrahydropyranyl; l is¹Is an iodine atom.

[9] A method for producing a compound represented by the formula [2], which comprises:

a step of reducing the compound represented by the general formula [6] to obtain a compound represented by the general formula [7 ];

deprotecting the obtained compound represented by the general formula [7] to obtain a compound represented by the formula [8 ];

a step of reacting the compound represented by the formula [8] with a compound represented by the general formula [9] to obtain a compound represented by the general formula [10 ];

deprotecting the obtained compound represented by the general formula [10] to obtain a compound represented by the formula [11 ];

protecting the diol group of the obtained compound represented by the formula [11] to obtain a compound represented by the general formula [4 ];

a step of reacting the obtained compound represented by the general formula [4] with a compound represented by the general formula [5] to obtain a compound represented by the general formula [1 ]; and,

And deprotecting the obtained compound represented by the general formula [1 ].

(in the formula, R⁴Represents an optionally substituted acyl group. )

(in the formula, R⁴Have the same meanings as described above. )

(in the formula, R^5aRepresents a silyl group. )

(in the formula, R^5aHave the same meanings as described above. )

(in the formula, R¹And R²Have the same meanings as described above. )

(in the formula, R^3aAnd L¹Have the same meanings as described above. )

(in the formula, R¹、R²And R^3aHave the same meanings as described above. )

[10] The production method according to [9], wherein the step of deprotecting the compound represented by the general formula [1] comprises the steps of:

(in the formula, R¹And R²Have the same meanings as described above. )

[11]According to [9]]Or [10]]The production process described in (1), wherein R⁴Is acetyl; r^5aIs a trimethylsilyl group.

[12]According to [9]]～[11]The production process of any one of the above, wherein R¹Is methyl; r²Is methyl.

[13]According to [9]]～[12]The production process of any one of the above, wherein R^3aIs tetrahydropyranyl; l is¹Is an iodine atom.

[14] A method for producing a compound represented by the formula [8], which comprises:

a step of reducing the compound represented by the general formula [6] to obtain a compound represented by the general formula [7 ]; and,

And (3) deprotecting the obtained compound represented by the general formula [7 ].

(in the formula, R⁴Have the same meanings as described above. )

[15]According to [ 14)]The production process described in (1), wherein R⁴Is acetyl.

[16] A compound represented by the general formula [12],

(in the formula, R⁵Represents a hydrogen atom, a general formula [13 ]]A group of the formula [14]]A group shown; r¹And R²Have the same meanings as described above. )

(formula (II)In, R⁶Is represented by C_1-3An alkyl group; r⁷Is represented by C_1-3An alkyl group; or R⁶And R⁷Together represent C_3-6An alkylene group; denotes the bonding site. )

(in the formula, R³Represents a hydrogen atom or a hydroxyl-protecting group; denotes the bonding site. ).

[17]According to [16]The compound of (1), wherein R¹Is methyl; r²Is methyl; r⁵Is a hydrogen atom.

[18]According to [16]The compound of (1), wherein R¹Is methyl; r²Is methyl; r⁵Is represented by the general formula [14]The groups shown.

(in the formula, R³And have the same meanings as described above. )

[19]According to [18]]The compound of (1), wherein R³Is a hydrogen atom or a tetrahydropyranyl group.

The present invention also provides the following.

[A] A method for producing a compound represented by the general formula [4], which comprises:

deprotecting the obtained compound represented by the general formula [10] to obtain a compound represented by the formula [11 ]; and,

Protecting the diol group of the obtained compound represented by the formula [11 ].

(in the formula, R¹And R²Have the same meanings as described above. )

(in the formula, R^5aHave the same meanings as described above. )

[B]According to [ A ]]The production process described in (1), wherein R^5aIs a trimethylsilyl group.

[C]According to [ A ]]Or [ B]The production process described in (1), wherein R¹Is methyl; r²Is methyl.

[D] A method for producing a compound represented by the general formula [4], which comprises:

protecting the diol group of the compound represented by the formula [8] to obtain a compound represented by the general formula [15 ];

a step of reacting the obtained compound represented by the general formula [15] with a compound represented by the general formula [16] to obtain a compound represented by the general formula [17 ]; and

and deprotecting the obtained compound represented by the general formula [17 ].

(in the formula, R¹And R²Have the same meanings as described above. )

(in the formula, R⁶Is represented by C_1-3An alkyl group; r⁷Is represented by C_1-3An alkyl group; or R⁶And R⁷Together represent C_3-6An alkylene group. )

(in the formula, R¹、R²、R⁶And R⁷Have the same meanings as described above. )

[E]According to [ D ]]The production process described in (1), wherein R⁶Is methyl; r⁷Is methyl.

[F]According to [ D ]]Or [ E]The production process described in (1), wherein R¹Is methyl; r²Is methyl.

Effects of the invention

The production method of the present invention has the characteristics of easy handling of intermediates, simple and convenient operation, safety to human body, high optical purity of the obtained compound, and the like. Therefore, the production method of the present invention is useful as an industrial production method for compound a having high optical purity and excellent LpxC inhibitory activity.

The compound of the present invention is useful as an intermediate for industrial production of compound a having high optical purity and excellent LpxC inhibitory activity.

Drawings

Fig. 1 is a diagram showing an example of an infrared absorption spectrum (ATR method) of a form II crystal of a hydrate of compound a (example 16).

Fig. 2 is a diagram showing an example of a powder X-ray diffraction pattern of a form II crystal of a hydrate of compound a (example 16).

Fig. 3 is a diagram showing an example of an infrared absorption spectrum (ATR method) of a type III crystal of compound a (example 17).

FIG. 4 is a diagram showing an example of a powder X-ray diffraction pattern of a type III crystal of Compound A (example 17).

Detailed Description

The present invention will be described in detail below.

In the present invention, unless otherwise specified,% represents% by mass.

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

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

C_1-3Alkyl means methyl, ethyl, propyl or isopropyl.

C_1-6Alkyl refers to methyl, ethyl, propyl, isopropyl, butyl,Straight-chain or branched C such as sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl_1-6An alkyl group.

Aryl radical C_1-6Alkyl (アル C)_1-6アルキル radical) is an aryl radical C such as benzyl, diphenylmethyl, trityl, phenethyl, 2-phenylpropyl, 3-phenylpropyl and naphthylmethyl_1-6An alkyl group.

C_3-6The alkylene group is a straight or branched chain C such as methylethylene, trimethylene, ethylethylene, tetramethylene, pentamethylene or hexamethylene_3-6An alkylene group.

C_1-6The alkoxy group means a straight, branched or cyclic C group such as methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, pentyloxy and hexyloxy_1-6An alkyloxy group.

C_1-6Alkoxy radical C_1-6The alkyl group is a methoxymethyl group, a 1-ethoxyethyl group or the like C_1-6Alkyloxy C_1-6An alkyl group.

C_2-6The alkanoyl group is a straight or branched C group such as acetyl, propionyl, valeryl, isovaleryl or pivaloyl_2-6An alkanoyl group.

Aroyl refers to benzoyl or naphthoyl.

Acyl is formyl, C_2-6Alkanoyl or aroyl.

C_1-6Alkoxycarbonyl means a straight-chain or branched C-group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1, 1-dimethylpropoxycarbonyl_1-6An alkyloxycarbonyl group.

Aryl radical C_1-6Alkoxycarbonyl means an aryl group C such as benzyloxycarbonyl and phenethyloxycarbonyl_1-6An alkyloxycarbonyl group.

C_1-6Alkylsulfonyl means C such as methylsulfonyl, ethylsulfonyl and propylsulfonyl_1-6An alkylsulfonyl group.

Arylsulfonyl means phenylsulfonyl, p-toluenesulfonyl, or naphthylsulfonyl.

C_1-6The alkylsulfonyloxy group is C such as methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy_1-6An alkylsulfonyloxy group.

Arylsulfonyloxy means phenylsulfonyloxy, p-toluenesulfonyloxy or naphthalenesulfonyloxy.

Silyl means trimethylsilyl, triethylsilyl, tri (isopropyl) silyl, tributylsilyl or dimethyl (tert-butyl) silyl.

Examples of the hydroxyl-protecting group include all Groups which can be generally used as protecting Groups for hydroxyl Groups, such as グリ - ンズ. プ, テクティブ. グル - プス. イン. just ガ - ツク. シンセシス (Greene's Protective Groups in Organic Synthesis) 5 th edition, 17-471, 2014, ジョン. ワイリ - アンド. サンズ (John Wiley&Sons, INC.). Specifically, for example, C is mentioned_1-6Alkyl, aryl C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl, acyl, C_1-6Alkoxycarbonyl, aryl C_1-6Alkoxycarbonyl group, C_1-6Alkylsulfonyl, arylsulfonyl, silyl, tetrahydrofuranyl, or tetrahydropyranyl. These groups may be substituted with one or two or more groups selected from substituent group a.

Examples of the leaving group include a halogen atom and C_1-6Alkylsulfonyloxy or arylsulfonyloxy. C_1-6The alkylsulfonyloxy group and the arylsulfonyloxy group may be substituted with one or more groups selected from the substituent group a.

SubstitutionGroup A: halogen atom, nitro group, C_1-6Alkyl radical, C_1-6An alkoxy group.

The aliphatic hydrocarbon is pentane, hexane, heptane, cyclohexane, methylcyclohexane or ethylcyclohexane.

The halogenated hydrocarbon is dichloromethane, chloroform or dichloroethane.

The ethers mean diethyl ether, diisopropyl ether, methyl (tert-butyl) ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.

The alcohol is methanol, ethanol, propanol, 2-propanol, butanol, 2-methyl-2-propanol, ethylene glycol, propylene glycol or diethylene glycol.

Ketones are acetone, 2-butanone or 4-methyl-2-pentanone.

Esters are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate or butyl acetate.

Amides are N, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone.

Nitrile means acetonitrile or propionitrile.

Sulfoxides are dimethyl sulfoxide or sulfolane.

The aromatic hydrocarbon means benzene, toluene or xylene.

The inorganic base is sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydride, potassium carbonate, tripotassium phosphate, potassium acetate, cesium fluoride or cesium carbonate.

The organic base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU), pyridine, N-dimethyl-4-aminopyridine or 4-methylmorpholine.

The inorganic acid is hydrochloric acid, hydrobromic acid, nitric acid or sulfuric acid.

The organic acid is an organic carboxylic acid such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid, or an organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.

Examples of the salt of the compound represented by the general formulae [2] and [3] include salts of acidic groups such as hydroxyl groups, which are generally known.

Examples of the salt of an acidic group include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, ammonium salts, and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- β -phenethylamine, 1-diphenylhydroxymethylamine, and N, N' -dibenzylethylenediamine.

Among the above salts, preferable salts include pharmaceutically acceptable salts.

When an anhydride, a solvate, a hydrate, and crystals of various shapes are present in the compound used in the present invention, the present invention encompasses all of them.

In general, the diffraction angle (2 θ) in the powder X-ray diffraction causes an error in the range of ± 0.2 °. Therefore, in the present specification, the term "diffraction angle (2 θ) X °" means "diffraction angle (2 θ) ((X-0.2) to (X +0.2)) °", unless otherwise specified.

It is known that the relative strength in powder X-ray crystal diffraction varies depending on the crystal orientation, particle size, crystallinity, measurement conditions, and the like. Therefore, it should not be strictly interpreted.

Generally, the wave number (cm) in infrared absorption spectrum (ATR method)^-1) Will be within 2cm^-1In the range of (1) to produceAnd (4) error. Therefore, in this specification, reference is made to "wavenumber Ycm^-1"in case of (i) means" wave number ((Y-2) to (Y +2)) cm "unless otherwise specified^-1”。

Next, the compounds of the present invention will be described.

The compound of the present invention is a compound represented by the general formula [12 ].

(in the formula, R¹、R²And R⁵Have the same meanings as described above. ).

The compounds of the present invention are novel compounds which have not been known so far.

R¹Is C_1-3An alkyl group.

R¹Preferably methyl or ethyl, more preferably methyl.

R²Is C_1-3An alkyl group.

R²Preferably methyl or ethyl, more preferably methyl.

Further preferred is R¹Is methyl; r²Is methyl.

R⁵Is a hydrogen atom of the formula [13 ]]A group of the formula [14]]A group shown

(in the formula, R⁶、R⁷And have the same meanings as described above. )

(in the formula, R³And have the same meanings as described above. )

R⁵Preferably a hydrogen atom.

More preferably R¹Is methyl; r²Is methyl; r⁵Is a hydrogen atom.

In another embodiment, R⁵Preferably of the formula [13]The radicals shown are, for example,

(in the formula, R⁶、R⁷And have the same meanings as described above. ).

R⁶Is C_1-3An alkyl group; r⁷Is C_1-3An alkyl group; or R⁶And R⁷Together are C_3-6An alkylene group.

R⁶Preferably methyl.

R⁷Preferably methyl.

More preferably R⁶Is methyl; r⁷Is methyl.

Further preferred is R¹Is methyl; r²Is methyl; r⁶Is methyl; r⁷A methyl group.

In another embodiment, R⁵Preferably of the formula [14]The groups shown.

(in the formula, R³And have the same meanings as described above. )

R³Is a hydrogen atom or a hydroxyl protecting group.

R³Preferably a hydrogen atom.

More preferably R¹Is methyl; r²Is methyl; r³Is a hydrogen atom.

In another embodiment, R³Preferably a hydroxyl protecting group, more preferably a tetrahydropyranyl group.

Further preferred is R¹Is methyl; r²Is methyl; r³Is tetrahydropyranyl.

In another embodiment of the compound of the present invention, there are (4S) -4- (4-ethynylphenyl) -2, 2-dimethyl-1, 3-dioxolane, 4- (4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) -2-methyl-3-butyn-2-ol, (2S) -2- ((4- ((4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) ethynyl) benzoyl) (methyl) amino) -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide and (2S) -2- ((4- ((4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) ethynyl) benzoyl) (methyl) amino) -N-hydroxy-N', 2-dimethylmalonamide.

Next, a compound used in the production method of the present invention will be described.

R¹、R²、R³、R⁵、R⁶And R⁷Preferred groups of (a) are as described above.

R^3aIs a hydroxyl protecting group.

R^3aTetrahydropyranyl is preferred.

R⁴Is an optionally substituted acyl group.

R⁴Preferably an acyl group, more preferably C_2-6Alkanoyl group, and more preferably acetyl group.

As R⁴Examples of the substituent of the acyl group include one or two or more groups selected from substituent group a.

L¹Is a leaving group.

L¹Preferably a bromine atom or an iodine atom, more preferably an iodine atom.

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

[ production method 1]

(in the formula, R⁴Have the same meanings as described above. )

Examples of the compound represented by the general formula [6] include (2- (4-iodophenyl) -2-oxoethyl) acetate and the like.

The compound represented by the general formula [6] can be easily produced from the corresponding α -haloketone compound.

The compound represented by the general formula [7] can be produced by subjecting a compound represented by the general formula [6] to a reduction reaction.

(1-1)

The reduction reaction may be, for example, a hydrogenation reaction using a metal catalyst.

The solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, alcohols, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include amides, and more preferably N, N-dimethylformamide.

Examples of the metal catalyst used in this reaction include [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (p-cymene) ruthenium (II), [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (mesitylene) ruthenium (II), [ (R, R) -N- (2-amino-1, 2-diphenylethyl) pentafluorobenzenesulfonamide ] chloro (p-cymene) ruthenium (II), chloro [ (R, R) -N- [2- [2- (4-methylbenzyloxy) ethyl ] amino-1, 2-diphenylethyl ] -p-toluenesulfonamide ] ruthenium (II) and chloro [ (R, r) -N- [2- [2- (4-methylbenzyloxy) ethyl ] amino-1, 2-diphenylethyl ] -methanesulfonamide ] ruthenium (II) and the like, preferably [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (p-cymene) ruthenium (II).

The amount of the metal catalyst to be used may be 0.001 to 1 time by mol, preferably 0.001 to 0.01 time by mol, based on the compound represented by the general formula [6 ].

Examples of the reducing agent include 2-propanol; formic acid; formates such as sodium formate, ammonium formate and triethylammonium formate; and cyclohexene and cyclohexadiene, etc., with formic acid being preferred.

The amount of the reducing agent to be used may be 2 to 100 times by mol, preferably 2 to 10 times by mol, based on the compound represented by the general formula [6 ].

The base is preferably added to the reaction. Examples of the base to be used include inorganic bases and organic bases, and organic bases are preferable.

The amount of the base to be used may be 0.5 to 50 times by mol, preferably 2 to 5 times by mol, based on the compound represented by the general formula [6 ].

This procedure is particularly preferred: the reaction was carried out using [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (p-cymene) ruthenium (II) as a metal catalyst and formic acid as a reducing agent in the presence of an organic base. By using [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (p-cymene) ruthenium (II) as a metal catalyst, the use of hydrogen can be avoided, and the reaction can be performed safely.

The reaction is carried out at-50 to 200 ℃, preferably 10 to 50 ℃ for 10 minutes to 48 hours.

The reaction may be preferably carried out under an inert gas (e.g., nitrogen or argon) atmosphere.

The compound represented by the general formula [7] may be isolated or may be used in the next reaction without isolation.

(1-2)

The compound represented by the general formula [7] can be produced by subjecting the compound represented by the general formula [6] to a reduction reaction using borane or a borane complex in the presence of oxazaborolidine.

The solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include halogenated hydrocarbons, ethers, and aromatic hydrocarbons, and these may be used in combination. Preferred solvents include ethers, and tetrahydrofuran is more preferred.

Examples of the oxazaborolidine used in the reaction include (S) -5, 5-diphenyl-3, 4-propanol-1, 3, 2-oxazaborolidine, (S) -5, 5-diphenyl-2-methyl-3, 4-propanol-1, 3, 2-oxazaborolidine, (S) -5, 5-diphenyl-2-butyl-3, 4-propanol-1, 3, 2-oxazaborolidine and (S) -3, 3-diphenyl-1-o-tolyl-tetrahydropyrrolo (1, 2, c) (1, 3, 2) oxazaboroline, etc., with (S) -5, 5-diphenyl-2-methyl-3, 4-propanol-1 being preferred, 3, 2-oxazaborolidine.

The amount of the oxazaborolidine to be used may be 0.001 to 1 time by mol, preferably 0.01 to 0.1 time by mol, based on the compound represented by the general formula [6 ].

As the borane or borane complex used in this reaction, a borane complex is preferred.

Examples of the borane complex used in this reaction include borane-tetrahydrofuran complex, borane-dimethylsulfide complex, borane-1, 4-dioxane complex, borane-diethylaniline complex, and pyrocatechol borane, with borane-diethylaniline complex being preferred.

The amount of the borane or borane complex to be used may be 1 to 10 times by mol, preferably 1 to 5 times by mol, based on the compound represented by the general formula [6 ].

The reaction is carried out at-78 to 50 ℃, preferably 10 to 50 ℃ for 10 minutes to 48 hours.

(2)

The compound represented by the general formula [8] can be produced by subjecting a compound represented by the general formula [7] to deprotection reaction.

The reaction can be carried out, for example, by the method described in グリ - ンズ - プ, テクティブ - グル - プス - イン - ガ - ツク - シンセシス (Green's Protective Groups in Organic Synthesis), 5 th edition, pages 17-471, 2014, ジョン - ワイリ - アンド - サンズ (John Wiley & Sons, INC.).

The compound represented by the general formula [8] may be isolated or may be used in the next reaction without isolation.

[ production method 2]

(in the formula, R¹、R²And R^5aHave the same meanings as described above. )

(1)

Examples of the compound represented by the general formula [9] include trimethylsilylacetylene and the like.

The compound represented by the general formula [10] can be produced by reacting the compound represented by the general formula [8] with the compound represented by the general formula [9] in the presence or absence of a base, in the presence or absence of a copper catalyst, in the presence or absence of a ligand, or in the presence of a palladium catalyst.

The 4-position of the phenyl group of the compound represented by the general formula [8] is an iodo group. Therefore, the compound represented by the general formula [10] can be produced by reacting the compound represented by the general formula [8] with the compound represented by the general formula [9] under mild conditions.

The reaction may be carried out by the method described in International publication No. 2014/142298, unigram et al, or a method based thereon.

The solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, alcohols, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include ethers, and tetrahydrofuran is more preferred.

In this reaction, as the base to be used as desired, for example, an organic base and an inorganic base can be mentioned. Preferred bases include organic bases, and triethylamine is more preferred.

The amount of the base to be used may be 0.5 to 50 times by mol, preferably 2 to 5 times by mol, based on the compound represented by the general formula [8 ].

In this reaction, examples of the copper catalyst to be used as desired include copper (I) bromide and copper (I) iodide, and copper (I) iodide is preferable.

The amount of the copper catalyst to be used may be 0.01 to 50 times by mol, preferably 0.01 to 0.2 times by mol, based on the compound represented by the general formula [8 ].

Examples of the ligand to be used in the reaction according to need include tri-tert-butylphosphine, tricyclohexylphosphine, triphenylphosphine, tritolylphosphine, tributylphosphite, tricyclohexylphosphite, triphenyl phosphite, 1 '-bis (diphenylphosphino) ferrocene, 2' -bis (diphenylphosphino) -1, 1 '-binaphthyl, 2-dicyclohexylphosphino-2', 6 '-dimethoxybiphenyl, 2-dicyclohexylphosphino-2', 4 ', 6' -triisopropylbiphenyl, 2- (di-tert-butylphosphino) -2 ', 4', 6 '-triisopropylbiphenyl, 2- (dicyclohexylphosphino) -3, 6-dimethoxy-2', 4 ', 6' -triisopropyl-1, 1' -biphenyl and 2- (di-tert-butylphosphino) biphenyl, which may be used in combination.

The amount of the ligand to be used may be 0.00001 to 1 time by mol, preferably 0.001 to 0.1 time by mol, based on the compound represented by the general formula [8 ].

Examples of the palladium catalyst used in this reaction include metallic palladium such as palladium-carbon and palladium black; inorganic palladium salts such as palladium chloride and palladium (II) chloride sodium trihydrate; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride, bis (acetonitrile) palladium (II) dichloride, bis (benzonitrile) palladium (II) dichloride, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium (0), organopalladium complexes such as bis (dibenzylideneacetone) palladium (0), bis (tricyclohexylphosphine) palladium (II) dichloride, bis (tri-o-tolylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium (II) dichloride, (1, 3-bis (2, 6-diisopropylphenyl) imidazolidene (イミダゾリデシ)) (3-chloropyridyl) palladium (II) dichloride, allylpalladium (II) chloride dimer and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride; polymer immobilized organic palladium complexes such as polymer-supported bis (acetate) triphenylphosphine palladium (II) and polymer-supported bis (acetate) dicyclohexylphenylphosphinpalladium (II); and palladium-NHC complexes such as bis (1, 4-naphthoquinone) bis [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene ] dipalladium (0), and these may be used in combination. Preferred palladium catalysts include tetrakis (triphenylphosphine) palladium (0), bis (1, 4-naphthoquinone) bis [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene ] dipalladium (0), and bis (triphenylphosphine) palladium (II) dichloride is more preferred.

The amount of the palladium catalyst to be used may be 0.00001 to 1 time by mol, preferably 0.001 to 0.1 time by mol, based on the compound represented by the general formula [8 ].

The amount of the compound represented by the general formula [9] to be used may be 0.5 to 50 times by mol, preferably 0.8 to 5 times by mol, based on the compound represented by the general formula [8 ].

This procedure is particularly preferred: as the compound represented by the general formula [9], trimethylsilylacetylene was used. By using trimethylsilylacetylene, the deprotection reaction of the compound represented by the general formula [10] can be carried out under mild conditions.

The compound represented by the general formula [10] may be isolated or may be used in the next reaction without isolation.

(2)

The compound represented by the formula [11] can be produced by subjecting a compound represented by the general formula [10] to a deprotection reaction.

The reaction can be carried out, for example, by the method described in グリ - ンズ - プ, テクティブ - グル - プス - イン - ガ - ツク - シンセシス (Green's Protective Groups in Organic Synthesis), 5 th edition, pages 1194-1202, 2014, ジョン - ワイリ - アン Ω - サンズ (John Wiley & Sons, INC.).

The compound represented by the formula [11] may be isolated or used in the next reaction without isolation.

(3)

The compound represented by the general formula [4] can be produced by protecting the diol group of the compound represented by the formula [11 ].

The reaction can be carried out, for example, by the methods described in グリーンズ & プ, テクティブ & グル, プス & イン, ガ, ツク & シンセシス (Greene's Protective Groups in Organic Synthesis), 5 th edition, pages 17 to 471, 2014, ジョン & ワイリ, アンド & サンズ (John Wiley & Sons, INC.).

Specifically, the compound represented by the formula [11] can be produced by reacting a compound represented by the general formula [16] or a compound represented by the general formula [17] in the presence of an acid catalyst.

(in the formula, R¹And R²Have the same meanings as described above. )

(in the formula, R^aIs represented by C_1-3An alkyl group; r^bIs represented by C_1-3An alkyl group; r¹And R²Have the same meanings as described above. )

The solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, alcohols, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include amides, and more preferably N-methylpyrrolidone.

Examples of the acid used in the reaction include organic acids and inorganic acids. Preferred acids include organic acids, more preferably organic sulfonic acids, and still more preferably methanesulfonic acid.

The amount of the acid to be used may be 0.01 to 1 time by mol, preferably 0.05 to 0.2 time by mol, based on the compound represented by the formula [11 ].

The amount of the compound represented by the general formula [16] or the compound represented by the general formula [17] to be used may be 0.5 to 50 times by mol, preferably 1 to 5 times by mol, based on the compound represented by the general formula [11 ].

In this step, a compound represented by the general formula [17] is preferably used, and 2, 2-dimethoxypropane is particularly preferably used as the compound represented by the general formula [17 ].

The compound represented by the general formula [4] may be isolated or may be used in the next reaction without isolation.

The compound represented by the general formula [4] can also be produced by the following production method.

[ production method 3]

(1)

The compound represented by the general formula [18] can be produced by protecting the diol group of the compound represented by the general formula [8 ].

The reaction may be carried out according to the method described in production methods 2 and 3.

(2)

As the compound represented by the general formula [19], for example, 2-methyl-3-butyn-2-ol is known.

The compound represented by the general formula [20] can be produced by reacting a compound represented by the general formula [18] with a compound represented by the general formula [19 ].

The reaction may be carried out according to the method described in production Process 2 (1).

(3)

The compound represented by the general formula [4] can be produced by subjecting a compound represented by the general formula [20] to a deprotection reaction.

The reaction can be carried out, for example, by the method described in グリ - ンズ - プ, テクティブ - グル - プス - イン - ガ - ツク - シンセシス (Green's Protective Groups in Organic Synthesis), 5 th edition, pages 1194-1202, 2014, ジョン - ワイリ - アンド - サンズ (John Wiley & Sons, INC.).

[ production method 4]

(in the formula, R¹、R²、R^3aAnd L¹Have the same meanings as described above. )

The compound represented by the general formula [1] can be produced by reacting a compound represented by the general formula [4] with a compound represented by the general formula [5] in the presence or absence of a base, in the presence or absence of a copper catalyst, in the presence or absence of a ligand, or in the presence of a palladium catalyst.

As the compound of the general formula [5], for example, (2S) -2- ((4-iodobenzoyl) (methyl) amino) -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide and the like are known.

[ production method 5]

(in the formula, R¹、R²And R³a has the same meaning as described above. )

(1)

The compound represented by the general formula [3] can be produced by deprotecting a hydroxyl-protecting group of the compound represented by the general formula [1 ]. The reaction can be carried out, for example, by the method described in グリ - ンズ - プ, テクティブ - グル - プス - イン - ガ - ツク - シンセシス (Green's Protective Groups in Organic Synthesis), 5 th edition, pages 17-471, 2014, ジョン - ワイリ - アンド - サンズ (John Wiley & Sons, INC.).

For example, R^3aIn the case of tetrahydropyranyl, the formula [3]The compound can be represented by the general formula [1]]The compounds shown were made by applying an acid-based deprotection reaction.

The solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, alcohols, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include ethers, alcohols, ketones, and amides, and more preferred are alcohols and ketones.

Examples of the acid used in the reaction include organic acids and inorganic acids. Preferred acids include organic acids, and methanesulfonic acid is more preferred.

The amount of the acid to be used may be 0.01 to 1.0 time by mol, preferably 0.1 to 0.5 time by mol, based on the compound represented by the general formula [3 ].

The reaction is carried out at-50 to 200 ℃, preferably-10 to 10 ℃ for 10 minutes to 48 hours.

(2)

The compound represented by the formula [2] can be produced by deprotecting a compound represented by the general formula [3] with an acid. The reaction can be carried out, for example, by the method described in グリ - ンズ - プ, テクティブ - グル - プス - イン - ガ - ツク - シンセシス (Green's Protective Groups in Organic Synthesis), 5 th edition, pages 17-471, 2014, ジョン - ワイリ - アンド - サンズ (John Wiley & Sons, INC.).

The solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, alcohols, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferable solvents include ethers, alcohols, ketones, amides, and nitriles, and more preferable are alcohols and nitriles.

Examples of the acid used in the reaction include organic acids and inorganic acids. Preferred acids include inorganic acids, and hydrochloric acid is more preferred.

The amount of the acid to be used may be 0.1 to 10 times by mol, preferably 1 to 3 times by mol, based on the compound represented by the general formula [3 ].

The reaction is carried out at-50 to 200 ℃ and preferably 0 to 20 ℃ for 10 minutes to 48 hours.

General formula [1]]In the compounds shown, it is preferred that the protecting group for the diol group is in R^3aThe hydroxyl protecting group of (a) is deprotected under the conditions of deprotection.

It is particularly preferred that R¹Is methyl, R²Is methyl, R^3aIs tetrahydropyranyl.

R^3aThe tetrahydropyranyl group of (a) is deprotected under conditions such that the protecting group of the diol group is not deprotected.

In the step of deprotecting the compound represented by the general formula [1] to produce the compound represented by the general formula [2], the compound represented by the general formula [3] may be isolated or the compound represented by the general formula [3] may not be isolated as described above.

In order to produce a compound represented by the formula [2] with high purity, it is preferable to isolate the compound represented by the formula [3 ].

The compound represented by the formula [2] obtained by the above production method has high optical purity. The optical purity of the compound represented by the formula [2] can be measured by a conventional method using a chiral column, for example.

When a solvate, a hydrate, and a crystal having various shapes are present in the compound used in the above production method, the solvate, the hydrate, and the crystal having various shapes may be used.

Among the compounds used in the above production methods, for example, compounds having an amino group, a hydroxyl group, a carboxyl group, or the like are protected with a common protecting group in advance, and after the reaction, these protecting groups can be removed by a method known per se.

The compound obtained by the above production method can be derived into another compound by subjecting a compound to a reaction known per se, such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or a suitable combination of these reactions.

Examples

The present invention will be described with reference to reference examples and examples, but the present invention is not limited to these examples.

Unless otherwise specified, silica gel column chromatography is flash column chromatography, and the carrier is Kanto chemical Co., Ltd., silica gel 60.

The mixing ratio of the eluents is a volume ratio. For example, "hexane: gradient elution of ethyl acetate ═ 100: 0 → 50: 50 "refers to the final change of 100% hexane/0% ethyl acetate eluent to 50% hexane/50% ethyl acetate eluent.

In the NMR spectrum, for example, the description of [1.81], 1.82(3H, s) indicates that peaks of respective diastereomers derived from the diastereomer mixture are observed as single peaks at 1.81ppm and 1.82ppm, respectively, and the total number of protons is 3H.

Powder X-ray diffraction was measured using Ultima IV (Rigaku Corporation) under the following conditions.

Measurement conditions

Using X-ray CuK α

Tube voltage: 40kV

Tube current: 40mA

Scanning shaft: 2 theta

The moisture content was measured using a Karl Fischer moisture meter CA-100 (Mitsubishi chemical).

Reference example 1

To a mixture of 10.00g of 2-bromo-1- (4-iodophenyl) ethanone, 39mL of ethanol, 3.89g of sodium acetate and 19.5mL of water was added 2.03g of acetic acid under a nitrogen atmosphere, and the mixture was stirred at 70 to 75 ℃ for 3 hours. After the reaction mixture was cooled to room temperature, 19.5mL of water was added, and the mixture was stirred at the same temperature for 1 hour. The solid was collected by filtration, washed 2 times with 27mL of water, and 8.92g of (2- (4-iodophenyl) -2-oxoethyl) acetate was obtained as a pale yellow solid.

¹H-NMR(600MHz，CDCl₃) Delta value: 2.23(3H, s), 5.28(2H, s), 7.62(2H, d, J ═ 9.0Hz), 7.86(2H, d, J ═ 9.0Hz).

Example 1

0.62mL of formic acid, (1.00 g of 2- (4-iodophenyl) -2-oxoethyl) acetate, and 10.5mg of [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (p-isopropyltoluene) ruthenium (II) were sequentially added to a mixture of 5.0mL of N, N-dimethylformamide and 1.15mL of N, N-diisopropylethylamine at 0 to 10 ℃ under a nitrogen atmosphere, and the mixture was stirred at 20 to 30 ℃ for 6.5 hours. To the reaction mixture were added 10mL of ethyl acetate and 10mL of 20% aqueous sodium chloride solution. The organic layer was separated, washed 1 time with 5mL of 20% aqueous sodium chloride solution, 2 times with 5mL of 5% aqueous sodium bicarbonate solution, and 1 time with 5mL of 20% aqueous sodium chloride solution. To the obtained organic layer was added 0.10g of activated carbon, and the mixture was stirred at 20 to 30 ℃ for 40 minutes, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.99g of ((2S) -2-hydroxy-2- (4-iodophenyl) ethyl) acetate as a pale yellow oil.

¹H-NMR(600MHz，CDCl₃) Delta value: 2.10(3H, s), 2.72(1H, s), 4.10(1H, dd, J ═ 11.4, 7.8Hz), 4.24(1H, dd, J ═ 12.0, 3.6Hz), 4.90(1H, d, J ═ 7.8Hz), 7.14(2H, d, J ═ 8.4Hz), 7.70(2H, d, J ═ 8.4Hz).

Example 2

To a mixture of ((2S) -2-hydroxy-2- (4-iodophenyl) ethyl) acetate 0.48g and methanol 2.5mL, potassium carbonate 0.34g was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 10mL of methylene chloride, 5mL of water, 5mL of a saturated aqueous solution of sodium chloride, and 0.1mL of 2-methyl-2-propanol. The organic layer was separated, and the aqueous layer was extracted with a mixture of 10mL of methylene chloride and 0.1mL of 2-methyl-2-propanol. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue was added diisopropyl ether, and the solid was collected by filtration to obtain 0.30g of (1S) -1- (4-iodophenyl) ethane-1, 2-diol as a pale yellow solid.

The obtained solid was used as a seed crystal for example 3.

Example 3

To a mixture of 100mL of N, N-dimethylformamide and 17.0g of N, N-diisopropylethylamine were added 15.1g of formic acid, 20.0g of (2- (4-iodophenyl) -2-oxoethyl) acetate, and 0.21g of [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (p-isopropyltoluene) ruthenium (II) in this order at 0 to 10 ℃ under a nitrogen atmosphere, and the mixture was stirred at 15 to 20 ℃ for 22.5 hours. To the reaction mixture were added 300mL of ethyl acetate and 200mL of 20% aqueous sodium chloride solution. The organic layer was separated, washed 1 time with 100mL of 20% aqueous sodium chloride solution, 2 times with 100mL of 5% aqueous sodium bicarbonate solution, and 1 time with 100mL of 20% aqueous sodium chloride solution. 2.00g of activated carbon was added to the obtained organic layer, and the mixture was stirred at 20 to 30 ℃ for 1 hour. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure to obtain ((2S) -2-hydroxy-2- (4-iodophenyl) ethyl) acetate as a pale yellow oil.

To a mixture of the obtained ((2S) -2-hydroxy-2- (4-iodophenyl) ethyl) acetate and 100mL of methanol was added 13.64g of potassium carbonate under a nitrogen atmosphere, and the mixture was stirred at 20 to 30 ℃ for 1.5 hours. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. To the resulting residue were added 100mL of methanol and 70mL of water. After confirming the dissolution, 0.05g of seed crystal was added, and the mixture was stirred at 20 to 30 ℃ for 2 hours. 10mL of water and 11.3mL of 6mol/L hydrochloric acid were added to the reaction mixture, the pH was adjusted to 7-8, and then the mixture was stirred at 20-30 ℃ for 2 hours and allowed to stand overnight. 100mL of water was added to the reaction mixture over 1 hour, and the mixture was stirred at the same temperature for 2.5 hours. 100mL of water was added to the reaction mixture over 2 hours, and the mixture was stirred at the same temperature for 1.5 hours. 220mL of water was added to the reaction mixture over 1.5 hours, and the mixture was stirred at the same temperature for 1 hour. After cooling the reaction mixture to 0-10 ℃, stirring the reaction mixture at the same temperature for 1 hour. The solid was collected by filtration, washed 2 times with 40mL of a 10% aqueous methanol solution to obtain 15.4g of (1S) -1- (4-iodophenyl) ethane-1, 2-diol as a pale yellow solid.

Optical purity: 96.2% ee

HPLC measurement conditions

Measuring wavelength: 230nm

Column: CHIRALPAK ID (Daicel Corporation), particle diameter: 5 μm, inner diameter 4.6mm x length 250mm

Column temperature: 40 deg.C

Flow rate: 1.0 mL/min

Mobile phase: hexane/ethanol 970/30

¹H-NMR(600MHz，DMSO-d₆) Delta value: 3.35-3.44(2H, m), 4.48(1H, dd, J ═ 11.4, 5.4Hz), 4.73(1H, t, J ═ 6.6Hz), 5.31(1H, d, J ═ 4.2Hz), 7.15(2H, d, J ═ 7.8Hz), 7.66(2H, d, J ═ 8.4Hz).

Example 4

To a mixture of 10.0g of (1S) -1- (4-iodophenyl) ethane-1, 2-diol, 0.13g of bis (triphenylphosphine) palladium (II) dichloride, 0.11g of copper (I) iodide, 9.96g of triethylamine and 50mL of tetrahydrofuran was added a mixture of 4.09g of trimethylsilylacetylene and 20mL of tetrahydrofuran under a nitrogen atmosphere over 1 hour, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 100mL of ethyl acetate and 50mL of 5% aqueous ammonium sulfate solution. The organic layer was separated and washed with 50mL of 40% ammonium sulfate aqueous solution, 50mL of 10% N-acetylcysteine aqueous solution, 50mL of 5% sodium bicarbonate aqueous solution, and 50mL of a mixture of 5% sodium bicarbonate aqueous solution and 20% sodium chloride aqueous solution. To the resulting organic layer were added 20g of anhydrous sodium sulfate and 1.0g of SHSILICA, and the mixture was stirred at room temperature for 30 minutes. To the resulting mixture was added 0.5g of activated carbon, and the mixture was stirred at room temperature. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. To the residue were added heptane and isopropyl acetate, and the solid was collected by filtration and washed with a mixture of heptane and isopropyl acetate to obtain 7.10g of (1S) -1- (4- ((trimethylsilyl) ethynyl) phenyl) ethane-1, 2-diol as a white solid.

¹H-NMR(600MHz，CDCl₃) Delta value: 0.25(9H, s), 2.42-2.49(1H, m), 2.92-3.00(1H, m), 3.54-3.63(1H, m), 3.67-3.75(1H, m), 4.74-4.81(1H, m), 7.28(2H, d, J ═ 8.4Hz), 7.45(2H, d, J ═ 8.4Hz).

Example 5

To a mixture of 0.36g of (1S) -1- (4- ((trimethylsilyl) ethynyl) phenyl) ethane-1, 2-diol and 3mL of methanol was added 0.24g of potassium carbonate under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added 3mL of water, and the mixture was stirred at room temperature for 1 hour. Insoluble matter was filtered off, and methylene chloride was added. The organic layer was separated and the aqueous layer was extracted 3 times with dichloromethane. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue were added hexane and isopropyl acetate, and the solid was collected by filtration to obtain 0.14g of (1S) -1- (4-ethynylphenyl) ethane-1, 2-diol as a pale yellow solid.

The obtained solid was used as a seed crystal for example 6.

Example 6

Using 5.00g of (1S) -1- (4-iodophenyl) ethane-1, 2-diol, (1S) -1- (4- ((trimethylsilyl) was obtained as a pale yellow solid in the same manner as in example 4

Ethynyl) phenyl) ethane-1, 2-diol.

To a mixture of the obtained (1S) -1- (4- ((trimethylsilyl) ethynyl) phenyl) ethane-1, 2-diol and 25mL of methanol was added 3.93g of potassium carbonate under a nitrogen atmosphere, and the mixture was stirred at 20 to 30 ℃ for 1.5 hours. 0.50g of activated carbon was added to the reaction mixture, and the mixture was stirred at 20 to 30 ℃ for 1 hour. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. To the residue obtained, 6.2mL of methanol and 6.2mL of water were added at 20 to 30 ℃. After the dissolution was confirmed, 6mol/L hydrochloric acid was added to adjust the pH to 6-7. To the resulting mixture were added 7.8mL of water and 6.2mL of 25% aqueous sodium chloride solution at the same temperature, and after seeding, the mixture was stirred at the same temperature for 1.5 hours. To the resulting mixture was added 6.2mL of a 25% aqueous solution of sodium chloride, and the mixture was stirred at 20 to 30 ℃ for 1 hour. To the resulting mixture was added 6.2mL of a 25% aqueous solution of sodium chloride, and the mixture was stirred at the same temperature for 4 hours and allowed to stand overnight. The mixture is stirred at 0-10 ℃ for 1.5 hours. The solid was collected by filtration, washed 2 times with 6.2mL of cold water to obtain 2.63g of (1S) -1- (4-ethynylphenyl) ethane-1, 2-diol as a pale yellow solid.

Optical purity: > 99.9% ee

HPLC measurement conditions

Measuring wavelength: 230nm

Column temperature: 40 deg.C

Flow rate: 1.0 mL/min

Mobile phase: hexane/ethanol 970/30

To a mixture of 2.00g of the obtained (1S) -1- (4-ethynylphenyl) ethane-1, 2-diol and 40mL of ethyl acetate was added 0.20g of activated carbon under a nitrogen atmosphere, and the mixture was stirred at 20 to 30 ℃ for 1 hour. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. To the resulting residue was added 10mL of ethyl acetate. After confirming the dissolution, 10mL of heptane was added, and after seeding, the mixture was stirred at 20 to 30 ℃ for 3 hours and allowed to stand overnight. 15mL of heptane was added to the resulting mixture over 1 hour, and the mixture was stirred at 20 to 30 ℃ for 1 hour. To the resulting mixture was added 15mL of heptane over 1 hour, and the mixture was stirred at the same temperature for 1 hour. The mixture is cooled to 0-10 ℃ and stirred at the same temperature for 2 hours.

The solid was collected by filtration and washed with heptane to obtain 1.67g of (1S) -1- (4-ethynylphenyl) ethane-1, 2-diol as a white solid.

¹H-NMR(400MHz，DMSO-d₆) Delta value: 3.37-3.49(2H, m), 4.11(1H, s), 4.55(1H, dd, J-10.4, 5.6Hz), 4.74(1H, t, J-5.6 Hz), 5.33(1H, d, J-4.4 Hz), 7.35(2H, d, J-8.4 Hz), 7.42(2H, d, J-8.0 Hz).

Example 7

To a mixture of 5.00g of (1S) -1- (4-ethynylphenyl) ethane-1, 2-diol, 50mL of methylene chloride and 19mL of 2, 2-dimethoxypropane was added 1.17g of p-toluenesulfonic acid monohydrate, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 3.8mL of 2, 2-dimethoxypropane, and the mixture was stirred at room temperature for 1 hour, then 15mL of 2, 2-dimethoxypropane was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 50mL of saturated aqueous sodium bicarbonate, 20mL of water, and methylene chloride. The organic layer was separated, washed with 50mL of a saturated aqueous sodium chloride solution, and the aqueous layer was extracted with dichloromethane. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By silica gel column chromatography [ eluent; hexane: ethyl acetate ═ 8: the resulting residue was purified to obtain 6.03g of (4S) -4- (4-ethynylphenyl) -2, 2-dimethyl-1, 3-dioxolane as a pale yellow oil.

¹H-NMR(400MHz，CDCl₃) Delta value: 1.49(3H, s), 1.55(3H, s), 3.08(1H, s), 3.67(1H, t, J ═ 8.4Hz), 4.31(1H, dd, J ═ 8.4, 6.4Hz), 5.07(1H, dd, J ═ 7.6, 6.4Hz), 7.33(2H, d, J ═ 8.4Hz), 7.49(2H, d, J ═ 8.0Hz).

Example 8

To a mixture of (1S) -1- (4-iodophenyl) ethane-1, 2-diol 1.00g, N-methylpyrrolidone 3mL and 2, 2-dimethoxypropane 1.2mL was added methanesulfonic acid 25. mu.L, and the mixture was stirred at room temperature for 8 hours. To the reaction mixture were added isopropyl acetate, 20% aqueous sodium chloride solution, 5% aqueous sodium bicarbonate solution and water. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.35g of (4S) -4- (4-iodophenyl) -2, 2-dimethyl-1, 3-dioxolane as a pale yellow oil.

¹H-NMR(400MHz，CDCl₃) Delta value: 1.48(3H, s), 1.53(3H, s), 3.65(1H, t, J ═ 8.0Hz), 4.30(1H, dd, J ═ 8.3, 6.1Hz), 5.02(1H, dd, J ═ 7.7, 6.5Hz), 7.10-7.13(2H, m), 7.60-7.70(2H, m).

Example 9

To a mixture of (1S) -1- (4-iodophenyl) ethane-1, 2-diol (20 g), N-methylpyrrolidone (60 mL) and 2, 2-dimethoxypropane (19.7 g) was added methanesulfonic acid (0.49 mL), and the mixture was stirred at room temperature for 3 hours. After adding 23.0g of triethylamine, 0.40g of bis (triphenylphosphine) palladium (II) dichloride and 0.22g of copper (I) iodide to the reaction mixture, 7.00g of 2-methyl-3-butyn-2-ol and 5mL of N-methylpyrrolidone were added thereto at 25 to 40 ℃ for 30 minutes under a nitrogen atmosphere, and the mixture was stirred at 30 to 38 ℃ for 2 hours and 40 minutes. The reaction mixture was cooled to room temperature, and after adding 100mL of isopropyl acetate and 40mL of 40% aqueous ammonium sulfate solution, 6mol/L hydrochloric acid was added to adjust the pH to 8, and 80mL of water was added. The organic layer was separated, washed 1 time with 40mL of a 10% aqueous solution of N-acetylcysteine, and 2 times with a mixture of a 2.5% aqueous solution of sodium hydrogencarbonate and a 20% aqueous solution of sodium chloride. Anhydrous magnesium sulfate and activated carbon were added to the organic layer, and after stirring, insoluble matter was filtered off. The solvent was distilled off under reduced pressure, and purified by silica gel column chromatography [ eluent; hexane: gradient elution of ethyl acetate ═ 5: 1 → 3: 1 → 2: 1 → 1: the obtained residue was purified, heptane was added to the purified product, and the solid matter was collected by filtration to obtain 12.5g of 4- (4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) -2-methyl-3-butyn-2-ol as a white solid.

The obtained solid was used as a seed crystal in example 10.

Example 10

To a mixture of (1S) -1- (4-iodophenyl) ethane-1, 2-diol 10g, N-methylpyrrolidone 30mL and 2, 2-dimethoxypropane 11.3mL was added methanesulfonic acid 0.25mL, and the mixture was stirred at room temperature for 9 hours. After adding 5mL of N-methylpyrrolidone (11.5 g) as triethylamine, 213mg of bis (triphenylphosphine) palladium (II) dichloride and 115mg of copper (I) iodide to the reaction mixture, 3.82g of 2-methyl-3-butyn-2-ol and 1mL of N-methylpyrrolidone were added under a nitrogen atmosphere at 40 ℃ over 30 minutes, and the mixture was stirred at the same temperature for 3.5 hours. The reaction mixture was cooled to room temperature, and after adding 100mL of ethyl acetate and 50mL of 5% aqueous ammonium sulfate solution, 6mol/L hydrochloric acid and 25% aqueous sodium hydroxide solution were added to adjust pH 7.0. The organic layer was separated, washed 1 time with 50mL of 40% aqueous ammonium sulfate solution, 1 time with 50mL of 10% aqueous N-acetylcysteine solution, 2 times with 50mL of 2.5% aqueous sodium bicarbonate solution and 1 time with 50mL of 5% aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. To the residue obtained, seed crystals and heptane were added. The solid was collected by filtration to give 8.1g of 4- (4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) -2-methyl-3-butyn-2-ol as a pale yellow solid.

¹H-NMR(400MHz，CDCl₃) Delta value: 1.49(3H, s), 1.55(3H, s), 1.62(6H, s), 2.01(1H, s), 3.67(1H, td, J ═ 8.1, 0.6Hz), 4.30(1H, dd, J ═ 8.3, 6.3Hz), 5.06(1H, dd, J ═ 7.6, 6.6Hz), 7.30(2H, d, J ═ 8.5Hz), 7.41(2H, d, J ═ 8.0Hz).

Example 11

To 40mL of a 4.0g solution of 4- (4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) -2-methyl-3-butyn-2-ol in toluene was added 172mg of potassium tert-butoxide, and 3.4mL of the solvent was distilled off under reduced pressure (300 to 340 torr) at 78 to 85 ℃. To the reaction mixture were added 8mL of water and 8mL of ethyl acetate. The organic layer was separated, washed with 8mL of water, and the solvent was distilled off under reduced pressure to obtain 3.56g of (4S) -4- (4-ethynylphenyl) -2, 2-dimethyl-1, 3-dioxolane as a brown oil. The brown oil contained toluene, and the content thereof was 13%.

¹H-NMR(400MHz，CDCl₃) Delta value: 1.49(3H, s), 1.55(3H, s), 3.07(1H, s), 3.67(1H, t, J ═ 8.0Hz), 4.31(1H, dd, J ═ 8.3, 6.3Hz), 5.07(1H, dd, J ═ 7.9, 6.5Hz), 7.32(2H, d, J ═ 8.4Hz), 7.48(2H, d, J ═ 8.0Hz).

Example 12

(1)

To a mixture of 6.96g of (1S) -1- (4-ethynylphenyl) ethane-1, 2-diol and 21mL of N-methylpyrrolidone, 13.4g of 2, 2-dimethoxypropane and 279. mu.L of methanesulfonic acid were added under a nitrogen atmosphere, and the mixture was stirred at 20 to 30 ℃ for 5.5 hours to obtain a solution.

(2)

A mixture of 20.0g of (2S) -2- ((4-iodobenzoyl) (methyl) amino) -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide, 0.22g of bis (triphenylphosphine) palladium (II) dichloride, 0.12g of copper (I) iodide, 10.3g of triethylamine and 40mL of N-methylpyrrolidone was stirred at 30 to 40 ℃ for 1 hour under a nitrogen atmosphere. The solution obtained in (1) was added to the reaction mixture at the same temperature over 2.5 hours, and stirred at the same temperature for 3.5 hours to obtain a reaction mixture.

(3)

The same operations as in (1) to (2) above were carried out 3 times. All the reaction mixtures obtained were combined. After adding 200mL of 2-methyltetrahydrofuran and 300mL of 5% ammonium sulfate aqueous solution to the reaction mixture, 31mL of 6mol/L hydrochloric acid was added to adjust the pH to 6-8, and the organic layer was separated.

(4)

The same operations as in (1) to (2) above were carried out. Adding 200mL of 2-methyltetrahydrofuran into the obtained reaction mixture, and cooling to 0-10 ℃. After 100mL of a 5% ammonium sulfate aqueous solution was added to the obtained mixture, 17.7mL of 6 mol/hydrochloric acid was added to adjust the pH to 6-7, and the organic layer was separated.

(5)

The same operation as in (4) was carried out.

(6)

The organic layers obtained in (3), (4) and (5) were combined, washed 1 time with 500mL of 40% ammonium sulfate aqueous solution, 1 time with 450mL of 10% N-acetylcysteine aqueous solution, 2 times with 500mL of 2.5% sodium bicarbonate aqueous solution and 1 time with 500mL of 5% sodium chloride aqueous solution, and the solvent was distilled off under reduced pressure. 1200mL of isopropyl acetate was added to the resultant residue, and the solvent was distilled off under reduced pressure. To the residue was added isopropyl acetate, and after warming to 50 ℃, the mixture was cooled to 25 ℃ over 5 hours and allowed to stand overnight. The solid was collected by filtration, washed 2 times with cyclopentylmethyl ether, and 64.8g of (2S) -2- ((4- ((4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) ethynyl) benzoyl) (methyl) amino) -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide was obtained as a pale yellow solid.

The obtained solid was used as a seed crystal for example 13.

Example 13

(1)

To a mixture of 6.96g of (1S) -1- (4-ethynylphenyl) ethane-1, 2-diol and 21mL of N-methylpyrrolidone, 13.4g of 2, 2-dimethoxypropane and 279. mu.L of methanesulfonic acid were added under a nitrogen atmosphere, and the mixture was stirred at 20 to 30 ℃ for 5 hours to obtain a solution.

(2)

A mixture of 20.0g of (2S) -2- ((4-iodobenzoyl) (methyl) amino) -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide, 0.22g of bis (triphenylphosphine) palladium (II) dichloride, 0.12g of copper (I) iodide, 14.5g of triethylamine and 40mL of N-methylpyrrolidone was stirred at 30 to 40 ℃ for 1 hour under a nitrogen atmosphere. The solution obtained in (1) was added to the reaction mixture at the same temperature for 3 hours, and stirred at the same temperature for 2 hours. Adding 200mL of ethyl acetate into the reaction mixture, cooling to 0-10 ℃, adding 100mL of 5% ammonium sulfate aqueous solution, adding 14.5mL of 6mol/L hydrochloric acid and 4.5mL of 5% sodium bicarbonate aqueous solution, and adjusting the pH to 6-7. The organic layer was separated, washed 1 time with 100mL of 40% aqueous ammonium sulfate solution, 1 time with 100mL of 10% aqueous N-acetylcysteine solution, 2 times with 100mL of 5% aqueous sodium bicarbonate solution and 1 time with 100mL of water, and the solvent was distilled off under reduced pressure. 160mL of ethyl acetate was added to the obtained residue, and after dissolution was confirmed, the temperature was raised to 30 to 35 ℃. After 150mL of heptane was added to the resulting mixture, 100mg of seed crystal was added, and the mixture was stirred at the same temperature for 1 hour. To the resulting mixture was added 50mL of heptane, and the mixture was stirred at 30 to 35 ℃ for 1 hour. To the resulting mixture was added 200mL of heptane over 1 hour, and the mixture was stirred at the same temperature for 1 hour. And cooling the obtained mixture to 20-30 ℃, stirring for 30 minutes at the same temperature, and standing overnight. After the resulting mixture was cooled to 0 to 10 ℃ and stirred at the same temperature for 1 hour, the solid was collected by filtration, washed 2 times with 40mL of a mixed solvent of ethyl acetate and heptane (ethyl acetate: heptane ═ 1: 10), and 20.5g of (2S) -2- ((4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) ethynyl) benzoyl) (methyl) amino) -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide was obtained as a pale yellow solid.

¹H-NMR(600MHz，CDCl₃) Delta value: 1.50(3H, s), 1.52-1.74(3H, m), 1.56(3H, s), 1.75-1.90(3H, m), [1.81]，1.82(3H，s)，[2.84]，2.85(3H，d，J＝4.8Hz)，[3.17]，3.20(3H，s)，[3.53-3.60]，3.62-3.68(1H，m)，3.70(1H，t，J＝7.8Hz)，[3.83-3.91]，3.98-4.06(1H，m)，4.33(1H，dd，J＝8.4，6.0Hz)，[4.92-4.98]，4.98-5.03(1H，m)，5.09(1H，t，J＝6.0Hz)，[6.98-7.05]，7.61-7.67(1H，m)，7.37(2H，d，J＝8.4Hz)，7.47-7.55(4H，m)，7.58(2H，d，J＝8.4Hz)，[10.14]，10.54(1H，s).

Example 14

To a mixture of (2S) -2- ((4- ((4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) ethynyl) benzoyl) (methyl) amino) -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide 3.46g, acetone 3mL, and 2-propanol 21mL, methanesulfonic acid 121 μ L was added at 0 to 10 ℃ under a nitrogen atmosphere, and stirred at the same temperature for 48 hours. To the reaction mixture were added 60mL of 2-methyltetrahydrofuran, 60mL of 20% aqueous sodium chloride solution and 6mL of 5% aqueous sodium bicarbonate solution. The organic layer was separated, washed with 60mL of 20% aqueous sodium chloride solution, and then 0.30g of activated carbon was added thereto, followed by stirring at 20 to 30 ℃ for 2.5 hours. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. To the residue obtained, 12mL of acetonitrile and 3mL of water were added, the temperature was raised to 35 to 40 ℃ to confirm dissolution, and then 12.7mL of water was added, and the mixture was stirred at the same temperature for 1 hour. And cooling the obtained mixture to 20-30 ℃, stirring for 1 hour at the same temperature, and standing overnight. 47.9mL of water was added to the obtained mixture for 1 hour, and after stirring at 20 to 30 ℃ for 1 hour, the mixture was cooled to 0 to 10 ℃ and stirred at the same temperature for 3.5 hours. The solid was collected by filtration, washed 2 times with 6mL of a 10% acetonitrile aqueous solution, and 2.65g of (2S) -2- ((4- ((4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) ethynyl) benzoyl) (methyl) amino) -N-hydroxy-N', 2-dimethylmalonamide was obtained as a white solid.

¹H-NMR(600MHz，DMSO-d₆) Delta value: 1.41(3H, s), 1.47(3H, s), 1.62(3H, s), 2.65(3H, d, J ═ 4.8Hz), 3.01(3H, s), 3.59(1H, t, J ═ 8.4Hz),4.33(1H，dd，J＝8.4，7.2Hz)，5.11(1H，t，J＝6.6Hz)，7.44(2H，d，J＝8.4Hz)，7.59(4H，d，J＝8.4Hz)，7.65(2H，d，J＝8.4Hz)，8.47-8.57(1H，m)，8.98(1H，s)，10.97(1H，s).

example 15

To a mixture of (2S) -2- ((4- ((4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) ethynyl) benzoyl) (methyl) amino) -N-hydroxy-N', 2-dimethylmalonamide (180 g) and 2-propanol (900 mL) was added 360mL of 1mol/L hydrochloric acid at 18 to 20 ℃, followed by stirring at 20 to 26 ℃ for 10 hours and then standing overnight. 540mL of water was added to the reaction mixture at 24 to 25 ℃ and stirred at 25 ℃ for 45 minutes. The solid was collected by filtration and washed with 180mL of a 50% aqueous 2-propanol solution, 540mL of water and 540mL of an 80% aqueous 2-propanol solution in this order to obtain 114g of a hydrate of (2S) -2- ((4- ((4- ((1S) -1, 2-dihydroxyethyl) phenyl) ethynyl) benzoyl) (methyl) amino) -N-hydroxy-N', 2-dimethylmalonamide as a white solid.

The resulting solid was used as seed crystals for example 16.

Example 16

To a mixture of (2S) -2- ((4- ((4- ((4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) phenyl) ethynyl) benzoyl) (methyl) amino) -N-hydroxy-N', 2-dimethylmalonamide 2.00g and acetonitrile 20mL, 4mL of 1mol/L hydrochloric acid was added at 5 to 10 ℃, and stirred at the same temperature for 18.5 hours. A mixture of 0.34g of sodium bicarbonate and 8.1mL of water was added to the reaction mixture, and the temperature was raised to 50-60 ℃. After the dissolution was confirmed, the pH was adjusted to 5-6 with a 5% aqueous solution of sodium bicarbonate and 1mol/L hydrochloric acid. The resulting mixture was cooled to 35-40 ℃, 10mg of seed crystal was added, and stirred at the same temperature for 1 hour. The resulting mixture was cooled to 30 to 35 ℃, 47mL of water was added over 2 hours, and stirred at the same temperature for 1 hour. The obtained mixture is cooled to 22.5-27.5 ℃, stirred for 1 hour at the same temperature and then kept stand all night. The obtained mixture is cooled to 12.5-17.5 ℃, and stirred for 1 hour at the same temperature. The mixture is cooled to 0-5 ℃ and stirred at the same temperature for 3 hours. The solid was collected by filtration, washed 2 times with 2mL of a 10% acetonitrile aqueous solution, and 1.62g of hydrate of (2S) -2- ((4- ((4- ((1S) -1, 2-dihydroxyethyl) phenyl) ethynyl) benzoyl) (methyl) amino) -N-hydroxy-N', 2-dimethylmalonamide was obtained as a white solid. The solid was taken as form II crystals.

Fig. 1 shows an infrared absorption spectrum (ATR method).

The powder X-ray diffraction pattern is shown in fig. 2 and table 1.

Moisture content: 4.1 percent

IR(ATR)：1474，1605，1682，3132，3363cm-1

Optical purity: > 99% ee (> 99% de)

HPLC measurement conditions

Measuring wavelength: 290nm of

Column: CHIRALCEL OZ-H (Daicel corporation), particle diameter: 5 μm, inner diameter 4.6mm x length 250mm

Column temperature: 40 deg.C

Flow rate: 0.7 mL/min

Mobile phase: hexane/ethanol/acetic acid 650/350/5

¹H-NMR(600MHz，DMSO-d₆) Delta value: 1.62(3H, s), 2.65(3H, d, J ═ 3.6Hz), 3.01(3H, s), 3.40-3.51(2H, m), 4.53-4.62(1H, m), 4.77(1H, t,J＝5.4Hz)，5.36(1H，d，J＝4.2Hz)，7.41(2H，d，J＝7.8Hz)，7.53(2H，d，J＝7.8Hz)，7.58(2H，d，J＝7.8Hz)，7.64(2H，d，J＝8.4Hz)，8.52(1H，d，J＝4.2Hz)，8.98(1H，s)，10.97(1H，s).

[ Table 1]

Example 17

A suspension of 16.5g of form II crystals in 49.5mL of methanol was stirred at 20 to 30 ℃ for 3 hours. The solid was collected by filtration and washed with 33mL of methanol 2 times to obtain 12.0g of a white solid. The solid was taken as form III crystals.

The infrared absorption spectrum (ATR method) is shown in fig. 3.

The powder X-ray diffraction pattern is shown in fig. 4 and table 2.

The obtained solid was used as a seed crystal for example 18.

Moisture content: 0.3 percent of

IR(ATR)：1481，1607，1688，3286，3475cm-1

¹H-NMR(400MHz，DMSO-d₆) Delta value: 1.63(3H, s), 2.65(3H, d, J ═ 4.8Hz), 3.02(3H, s), 3.40-3.51(2H, m), 4.53-4.62(1H, m), 4.77(1H, t, J ═ 5.8Hz), 5.37(1H, d, J ═ 4.4Hz), 7.41(2H, d, J ═ 8.0Hz), 7.53(2H, d, J ═ 8.4Hz), 7.59(2H, d, J ═ 8.0Hz), 7.64(2H, d, J ═ 8.4Hz), 8.46-8.58(1H, m), 8.99(1H, d, J ═ 1.2Hz), 10.98(1H, s).

[ Table 2]

Example 18

1.00g of type II crystal was added to a mixture of 2mL of methanol and 0.5mL of dimethyl sulfoxide at 0 to 10 ℃ in a nitrogen atmosphere, and the mixture was stirred at the same temperature for 4 minutes. After confirming the dissolution, the temperature was raised to 20 to 25 ℃, 2mL of methanol and 2mL of ethyl acetate were added, and a seed crystal of type III crystal was added and stirred at the same temperature for 2 hours. To the reaction mixture, 8mL of ethyl acetate was added over 30 minutes at 20 to 25 ℃ and stirred at the same temperature for 1 hour. 10mL of heptane was added to the reaction mixture at 20 to 25 ℃ over 30 minutes, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture is cooled to 0-10 ℃ and stirred at the same temperature for 1 hour. The solid was collected by filtration and washed 2 times with 2mL of ethyl acetate to obtain 0.90g of form III crystals as a white solid.

The infrared absorption spectrum (ATR method) and powder X-ray diffraction pattern were in accordance with example 17.

Moisture content: 0.1 percent of

Optical purity: > 99% ee (> 99% de)

HPLC measurement conditions

Measuring wavelength: 290nm of

Column temperature: 40 deg.C

Flow rate: 0.7 mL/min

Mobile phase: hexane/ethanol/acetic acid 650/350/5

Industrial applicability

The production method of the present invention is useful as an industrial production method for a compound having an excellent LpxC inhibitory activity, and the compound of the present invention is useful as an intermediate used for industrial production.

Claims

1. A process for producing a compound represented by the formula [2], which comprises a step of deprotecting a compound represented by the general formula [1],

formula [1]In, R¹Is represented by C_1-3An alkyl group; r²Is represented by C_1-3An alkyl group; r^3aRepresents a hydroxyl protecting group.

2. The production method according to claim 1, wherein the step of deprotecting the compound represented by general formula [1] comprises the steps of:

(2) A step of deprotecting the compound represented by the general formula [3] to obtain a compound represented by the formula [2],

formula [3]In, R¹Is represented by C_1-3An alkyl group; r²Is represented by C_1-3An alkyl group, a carboxyl group,

3. the production method according to claim 1 or 2, wherein R¹Is methyl; r²Is methyl.

4. The production method according to any one of claims 1 to 3, wherein R is^3aIs tetrahydropyranyl.

5. A method for producing a compound represented by the formula [2], which comprises:

A step of deprotecting the obtained compound represented by the general formula [1],

formula [4]In, R¹Is represented by C_1-3An alkyl group; r²Is represented by C_1-3An alkyl group, a carboxyl group,

formula [5]]In, R^3aRepresents a hydroxyl protecting group; l is¹Represents a leaving group, and represents a leaving group,

formula [1]In, R¹、R²And R^3aHave the same meanings as described above.

6. The production method according to claim 5, wherein the step of deprotecting the compound represented by general formula [1] comprises the steps of:

7. the production method according to claim 5 or 6, wherein R¹Is methyl; r²Is methyl.

8. The production method according to any one of claims 5 to 7, wherein R is^3aIs tetrahydropyranyl; l is¹Is an iodine atom.

9. A method for producing a compound represented by the formula [2], which comprises:

formula [6]]In, R⁴Represents an optionally substituted acyl group,

formula [7]In, R⁴Has the same meaning as that of the above-mentioned,

formula [9]]In, R^5aRepresents a silyl group, and is represented by,

formula [10]In, R^5aHas the same meaning as that of the above-mentioned,

formula [1]In, R¹、R²And R^3aHave the same meanings as described above.

10. The production method according to claim 9, wherein the step of deprotecting the compound represented by general formula [1] comprises the steps of:

11. the production method according to claim 9 or 10, wherein R⁴Is acetyl; r^5aIs a trimethylsilyl group.

12. The production method according to any one of claims 9 to 11, wherein R is¹Is methyl; r²Is methyl.

13. The production method according to any one of claims 9 to 12, wherein R is^3aIs tetrahydropyranyl; l is¹Is an iodine atom.

14. A method for producing a compound represented by the formula [8], which comprises:

A step of deprotecting the obtained compound represented by the general formula [7],

formula [6]]In, R⁴Represents an optionally substituted acyl group,

formula [7]In, R⁴Have the same meanings as described above.

15. The manufacturing method according to claim 14, wherein R⁴Is acetyl.

16. A compound represented by the general formula [12],

formula [12]]In, R¹Is represented by C_1-3An alkyl group; r²Is represented by C_1-3An alkyl group; r⁵Represents a hydrogen atom, a general formula [13 ]]A group of the formula [14]]The radicals shown are, for example,

formula [13]In, R⁶Is represented by C_1-3An alkyl group; r⁷Is represented by C_1-3An alkyl group; or R⁶And R⁷Together represent C_3-6An alkylene group; the x represents the bonding position(s),

formula [14]In, R³Represents a hydrogen atom or a hydroxyl-protecting group; denotes the bonding site.

17. The compound of claim 16, wherein R¹Is methyl; r²Is methyl; r⁵Is a hydrogen atom.

18. The compound of claim 16, wherein R¹Is methyl; r²Is methyl; r⁵Is represented by the general formula [14]The radicals shown are, for example,

19. The compound of claim 18, wherein R³Is a hydrogen atom or a tetrahydropyranyl group.