JP2006036760A - Method for producing n-carbonyl saturated heterocyclic compound and synthetic intermediate thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a N-carbonyl saturated heterocyclic compound and to provide a synthetic intermediate thereof and a method for producing the intermediate and to provide a method for using the N-carbonyl saturated heterocyclic compound. <P>SOLUTION: The invention relates to the formulas and reaction schemes disclosed in the specification. (In the formula, R<SP>1</SP>is H, an alkoxyl, a (substituted)phenyl, etc., R<SP>2</SP>is a halogen substituted phenyl, R<SP>3</SP>is H, OH, etc., G<SP>1</SP>is an alkylene, G<SP>2</SP>is a single bond or CH<SB>2</SB>, G<SP>3</SP>is an alkylene, etc., X is OH, etc., Y is a leaving group.). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to a novel process for producing N-carbonyl saturated heterocycles, and provides a novel compound for producing N-carbonyl saturated heterocycles, a process for producing the same and a method for using the same.

  N-carbonyl saturated heterocycles are useful as intermediates for producing neurokinin antagonists (see Patent Document 1), and such N-carbonyl saturated heterocycles are converted into intramolecular nucleophilic substitution reactions. In the case of synthesizing by the ring closure according to the above, it is necessary to deprotect the N-alkyl or sulfonyl group after the ring-closing reaction of the N-alkyl or N-sulfonyl protected chain compound, and then carbonylate the nitrogen atom. (Non-Patent Documents 1, 2 and 3).

  For this reason, in this method, there are many steps, and it was not suitable as a manufacturing method of an industrial N-carbonyl saturated heterocyclic ring.

Another method synthesizes the corresponding N-carbonyl saturated heterocycle from N-tert-butoxycarbonyl chain diol by Mitsunobu reaction using, for example, diethyl azodicarboxylate (DEAD) and triphenylphosphine (Ph ₃ P). There are known methods (see the following reaction formulas) (see Non-Patent Document 4 and Non-Patent Document 5).

(In the above formula, TBDMS is tert-butyldimethylsilyl and Boc is tert-butoxycarbonyl.)
However, in this method, diethyl hydrazine dicarboxylate and triphenylphosphine oxide are produced as by-products, which interfere with the separation and purification of the target product, so that it is difficult to produce an industrial N-carbonyl saturated heterocyclic ring. It was not suitable.

US Pat. No. 6,511,1975 Y. Jinbo et al., J. Med. Chem., 37, 2791 (1994) G. Bettoni, et al., Tetrahedron, 36, 409 (1980) RA Firestone, et al., J. Med. Chem., 27, 1037 (1984) T. Nishi et al., Tetrahedron: Asymmetry, 9, 3251 (1998) T. Nishi et al., Bioorg. Med. Chem. Lett., 10, 1665 (2000)

As a result of intensive studies aimed at solving these problems and establishing a novel method for producing N-carbonyl saturated heterocyclic rings, the present inventors have found that the following general formulas (1), (2) and (4) By scrutinizing the reaction conditions via the compound (1), it was found that saturated N-carbonyl heterocycles that were conventionally difficult to synthesize were obtained industrially in high yield, and the present invention was completed.

The present invention
(1) The following general formula (1)

(In the formula, R ¹ is a hydrogen atom, a C ₁ -C ₄ alkoxy group, a C ₇ -C ₁₁ aralkyloxy group which may be substituted with 1 to 3 groups selected from substituent group β, or a substituent. R represents a phenyl group which may be substituted with 1 to 3 groups selected from the group α, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, and R ³ represents hydrogen atom, hydroxyl group, protected hydroxyl group, C ₁ -C ₄ haloalkane sulfonyloxy group, C ₁ -C ₄ alkanesulfonyloxy group, or optionally substituted with 1 to 3 groups selected from substituent group β A good C ₆ -C ₁₀ arylsulfonyloxy group, G ¹ represents a C ₁ -C ₆ alkylene group, G ² represents a single bond or a methylene group, and G ³ represents a C ₂ -C ₃ alkylene group. , _C 2 -C ₃ alkenylene group Is represents a _C 2 -C ₃ alkynylene group, the α substituent group, hydroxyl _group, C 1 -C ₄ alkoxy _groups, C 1 -C ₄ represents the group consisting of halogenated alkyl groups and tetrazolyl, the substituent group beta, A compound having a nitro group, a halogen atom, a C ₁ -C ₄ alkyl group and a C ₁ -C ₄ halogenated alkyl group is represented by the following general formula (2)

(Wherein R ¹ , R ² , R ³ , G ¹ , G ² and G ³ are as defined above, Y represents a leaving group), By treating a compound having the formula (2) with a base, the following general formula (3)

(Wherein R ¹ , R ² , R ³ , G ¹ , G ² and G ³ are as defined above).

Among the above, the preferred method is
(2) the method wherein R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from a C ₁ -C ₄ alkoxy group or a substituent group α;
(3) The method wherein R ¹ is a phenyl group optionally substituted with ¹ to 3 groups selected from the substituent group α,
(4) The method wherein R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms,
(5) The method wherein R ³ is a hydroxyl group or a protected hydroxyl group, and G ³ is a C ₂ -C ₃ alkylene group,
(6) R ³ is a C ₆ -C ₁₀ arylsulfonyloxy group optionally substituted with 1 to 3 groups selected from the substituent group β, and G ³ is a C ₂ -C ₃ alkylene group. The way that is,
(7) The method wherein R ³ is a hydrogen atom and G ³ is a vinyl group,
(8) The method in which G ¹ is methylene or ethylene,
(9) The method wherein G ¹ is ethylene,
(10) The method wherein G ² is a single bond,
(11) the method wherein G ³ is ethylene, and
(12) The method wherein Y is chlorobenzenesulfonyloxy.

Furthermore, the present invention provides
(13) The following general formula (4)

(In the formula, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, and R ³ represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group, a C ₁ -C ₄ haloalkanesulfonyloxy group, C _1. A C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted with 1 to 3 groups selected from —C ₄ alkanesulfonyloxy group or substituent group β, and G ¹ represents C ₁ -C ₆ represents an alkylene group, G ³ represents a C ₂ -C ₃ alkylene group, a C ₂ -C ₃ alkenylene group or a C ₂ -C ₃ alkynylene group, and the substituent group β represents a nitro group, a halogen atom, C ₁ A compound having a —C ₄ alkyl group and a C ₁ -C ₄ halogenated alkyl group ”or a salt thereof, and the following general formula (5)

(In the formula, R ¹ is a hydrogen atom, a C ₁ -C ₄ alkoxy group, a C ₇ -C ₁₁ aralkyloxy group which may be substituted with 1 to 3 groups selected from the substituent group β, or a substituent. A phenyl group which may be substituted with 1 to 3 groups selected from the group α, G ² represents a single bond or a methylene group, X represents a hydroxyl group, a C ₁ -C ₄ alkylcarbonyloxy; _group, C 1 -C ₄ shows an alkoxycarbonyloxy group or a halogen atom, the α substituent group, a hydroxyl _group, C 1 -C ₄ alkoxy _group, a group consisting of C 1 -C ₄ halogenated alkyl group, and tetrazolyl. And a compound having the following general formula (1):

(Wherein R ¹ , R ² , R ³ , G ¹ , G ² and G ³ are as defined above), and the compound having the general formula (1) is represented by the following general formula: (2)

(Wherein R ¹ , R ² , R ³ , G ¹ , G ² and G ³ are as defined above, Y represents a leaving group), By treating a compound having the formula (2) with a base, the following general formula (3)

(Wherein R ¹ , R ² , R ³ , G ¹ , G ² and G ³ are as defined above).

Among the above, the preferred method is
(14) The method wherein R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from a C ₁ -C ₄ alkoxy group or a substituent group α,
(15) The method wherein R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from the substituent group α,
(16) The method wherein R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms,
(17) The method wherein R ³ is a hydroxyl group or a protected hydroxyl group, and G ³ is a C ₂ -C ₃ alkylene group,
(18) R ³ is a C ₆ -C ₁₀ arylsulfonyloxy group optionally substituted with 1 to 3 groups selected from the substituent group β, and G ³ is a C ₂ -C ₃ alkylene group. The way that is,
(19) The method wherein R ³ is a hydrogen atom and G ³ is a vinyl group,
(20) The method wherein G ¹ is methylene or ethylene,
(21) The method wherein G ¹ is ethylene,
(22) The method wherein G ² is a single bond,
(23) The method wherein G ³ is ethylene,
(24) The method wherein X is a chlorine atom or a bromine atom, and
(25) The method wherein Y is chlorobenzenesulfonyloxy.

Furthermore, the present invention provides
(26) The following general formula (4)

(Wherein R ² represents a phenyl group substituted with 1 or 2 halogen atoms, R ³ represents a hydroxyl group, a C ₁ -C ₄ haloalkanesulfonyloxy group, a C ₁ -C ₄ alkanesulfonyloxy group, Or a C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted with 1 to 3 groups selected from the substituent group β, G ¹ represents a C ₁ -C ₆ alkylene group, and G ³ Represents a C ₂ -C ₃ alkylene group, and the substituent group β represents a compound having a nitro group, a halogen atom, a C ₁ -C ₄ alkyl group and a C ₁ -C ₄ halogenated alkyl group) or About its salt.

Among the above, preferred compounds are
(27) The compound wherein R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms,
(28) The compound wherein R ³ is a hydroxyl group,
(29) The compound wherein G ¹ is methylene or ethylene,
(30) the compound wherein G ¹ is ethylene,
(31) The compound in which G ³ is ethylene, and (32) General formula (4) is represented by the following general formula (4 ′)

And the salts thereof (preferably hydrochlorides, sulfates or oxalates).

Of the above, particularly preferred compounds are:
(33) A compound wherein R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms, R ³ is a hydroxyl group, G ¹ is ethylene, and G ³ is ethylene Or its hydrochloride, sulfate or oxalate.

Furthermore, the present invention provides
(34) The following general formula (1)

(In the formula, R ¹ represents a hydrogen atom or a phenyl group optionally substituted by 1 to 3 groups selected from the substituent group α, and R ² represents 1 or 2 halogen atoms. R 1 represents a substituted phenyl group, and R ³ is selected from a hydroxyl group, a protected hydroxyl group, a C ₁ -C ₄ haloalkanesulfonyloxy group, a C ₁ -C ₄ alkanesulfonyloxy group, or a substituent group β A C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted with three groups, G ¹ represents a C ₁ -C ₆ alkylene group, G ² represents a single bond or a methylene group, G ³ represents a C ₂ -C ₃ alkylene group, a C ₂ -C ₃ alkenylene group or a C ₂ -C ₃ alkynylene group, and the substituent group α is a hydroxyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ halogen. Alkyl group and tetrazo Represents the group consisting of Le, the β substituent group, a nitro group, relates to a halogen atom, C ₁ -C ₄ alkyl and C ₁ -C ₄ compound having a.) Indicating the group consisting of halogenated alkyl groups.

Among the above, preferred compounds are
(35) The compound wherein R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from a C ₁ -C ₄ alkoxy group or a substituent group α,
(36) The compound wherein R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from substituent group α,
(37) The compound wherein R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms,
(38) The compound wherein R ³ is a hydroxyl group or a protected hydroxyl group,
(39) A compound wherein G ¹ is methylene or ethylene,
(40) the compound wherein G ¹ is ethylene,
(41) The compound wherein G ² is a single bond,
(42) the compound in which G ³ is ethylene, and
(43) General formula (1) is represented by the following general formula (1 ′)

It is a compound which is.

Of the above, particularly preferred compounds are:
(44) R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from substituent group α, and R ² is substituted with 1 or 2 fluorine atoms or chlorine atoms A compound in which R ³ is a hydroxyl group or a protected hydroxyl group, G ¹ is ethylene, G ² is a single bond, and G ³ is ethylene.

Furthermore, the present invention provides
(45) General formula (5), characterized by substantially consisting of the following step A, step B, and step C

(In the formula, R ¹ is a hydrogen atom, a C ₁ -C ₄ alkoxy group, a C ₇ -C ₁₁ aralkyloxy group which may be substituted with 1 to 3 groups selected from substituent group β, or a substituent. R 1 represents a phenyl group which may be substituted with 1 to 3 groups selected from the group α, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, and G ¹ represents C ¹ ₁ -C ₆ alkylene group, G ² represents a single bond or a methylene group, G ³ represents a C ₂ -C ₃ alkylene group, G ⁴ represents> C-OH or> S → O, The substituent group α represents a group consisting of a hydroxyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ halogenated alkyl group, and tetrazolyl, and the substituent group β represents a nitro group, a halogen atom, or C ₁ -C _4. shows the group consisting of alkyl groups and C ₁ -C ₄ halogenated alkyl group .) Compounds with or manufacturing method of a pharmacologically acceptable salt thereof:
{Here, step A is represented by the general formula (1)

[Wherein R ¹ , R ² , G ¹ , G ² and G ³ are as defined above, and R ³ represents a hydroxyl group, a protected hydroxyl group, a C ₁ -C ₄ haloalkanesulfonyloxy group, a C _1- A C ₄ alkanesulfonyloxy group, or a C ₆ -C ₁₀ arylsulfonyloxy group optionally substituted with 1 to 3 groups selected from the substituent group β, wherein the substituent group β is a nitro group, a halogen _atom, C 1 -C ₄ alkyl and _C 1 -C ₄ group consisting halogenated alkyl group. ]
A compound having the general formula (2)

[Wherein R ¹ , R ² , G ¹ , G ² and G ³ are as defined above, and R ³ and Y are a C ₁ -C ₄ haloalkanesulfonyloxy group and a C ₁ -C ₄ alkane, respectively. A sulfonyloxy group or a C ₆ -C ₁₀ arylsulfonyloxy group optionally substituted with 1 to 3 groups selected from the substituent group β, wherein the substituent group β is a nitro group, a halogen atom, shows the C ₁ -C ₄ alkyl and _C 1 -C ₄ group consisting halogenated alkyl group. A compound having the following formula:
In step B, compound (2) obtained in step A is treated with a base to give a general formula (3)

[Wherein R ¹ , R ² , G ¹ , G ² and G ³ are as defined above, and R ³ represents a C ₁ -C ₄ haloalkanesulfonyloxy group, a C ₁ -C ₄ alkanesulfonyloxy group, Or a C ₆ -C ₁₀ arylsulfonyloxy group optionally substituted by 1 to 3 groups selected from the substituent group β, wherein the substituent group β is a nitro group, a halogen atom, C ₁ -C _A group consisting of ₄ alkyl groups and C ₁ -C ₄ halogenated alkyl groups is shown. A compound having the following formula:
Step C includes the compound (3) obtained in Step B and the general formula (6).

[Wherein G ⁴ is as defined above. And a compound having the general formula (5) to produce a compound having the general formula (5). }

Among the above, the preferred method is
(46) The method wherein R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from a C ₁ -C ₄ alkoxy group or a substituent group α,
(47) The method wherein R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from substituent group α,
(48) The method wherein R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms,
(49) The method wherein R ³ of the compound (1) is a hydroxyl group or a protected hydroxyl group,
(50) The method wherein G ¹ is methylene or ethylene,
(51) The method wherein G ¹ is ethylene,
(52) The method wherein G ² is a single bond,
(53) A method in which G ³ is ethylene, and (54) a method in which R ³ and Y of compound (2) and compound (3) are chlorobenzenesulfonyloxy.


C ₇ -C ₁₁ aralkyl optionally substituted with 1 to 3 groups selected from “C ₁ -C ₄ alkoxy group” and “substituent group β, which is used for specifying the present invention "Oxy group", "phenyl group optionally substituted with 1 to 3 groups selected from substituent group α", "phenyl group substituted with 1 or 2 halogen atoms", "protected C which may be substituted with 1 to 3 groups selected from “hydroxyl group”, “C ₁ -C ₄ alkanesulfonyloxy group”, “C ₁ -C ₄ haloalkanesulfonyloxy group”, “substituent group β ₆ -C ₁₀ arylsulfonyloxy group "," _C 1 -C ₆ alkylene group "," _C 2 -C ₃ alkylene group "," _C 2 -C ₃ alkenylene group "," _C 2 -C ₃ alkynylene group "_"C 1 -C ₄ halogenated alkyl Group "," halogen atom "," _C 1 -C ₄ alkyl group ", the term" leaving group "," _C 1 -C ₄ alkylcarbonyloxy group "and" _C 1 -C ₄ alkoxycarbonyloxy group " Are defined as follows.

“C ₁ -C ₄ alkoxy group” in the definition of R ¹ and substituent group α may be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy, and R ¹ is preferably Is ethoxy or tert-butoxy, and the substituent group α is preferably a C ₁ -C ₃ alkoxy group (more preferably, methoxy or isopropoxy).

The “C ₇ -C ₁₁ aralkyloxy group optionally substituted by 1 to 3 groups selected from substituent group β” in the definition of R ¹ is 1 in which the aryl moiety is selected from substituent group β C ₆ -C ₁₀ aryl optionally substituted with 3 to 3 groups (preferably phenyl) and the alkoxy moiety is C ₁ -C ₄ alkoxy (preferably methoxy, ethoxy or propoxy, Particularly preferred is methoxy), preferably benzyloxy which may be substituted with 1 to 3 groups selected from substituent group β, and particularly preferably Benzyloxy or nitrobenzyloxy, most preferably benzyloxy.

The “phenyl group optionally substituted with 1 to 3 groups selected from the substituent group α” in the definition of R ¹ is preferably phenyl, 3-isopropoxyphenyl, 3,4,5-tri Methoxyphenyl or 3,5-bis (trifluoromethyl) phenyl, particularly preferably 3,4,5-trimethoxyphenyl or 3,5-bis (trifluoromethyl) phenyl, most preferably 3,4,5-trimethoxyphenyl.

The halogen atom of the “halogen atom” in the definition of the substituent groups β and X and the “phenyl group substituted with 1 or 2 halogen atoms” in the definition of R ² are a fluorine atom, a chlorine atom, a bromine atom or It is an iodine atom. As the substituent group β, a fluorine atom, a chlorine atom or a bromine atom is preferable, and a chlorine atom is more preferable. As X, a chlorine atom, a bromine atom or an iodine atom is preferable, and a chlorine atom is particularly preferable.

The “phenyl group substituted with 1 or 2 halogen atoms” in the definition of R ² is preferably a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms, and more preferably, 4-fluorophenyl, 4-chlorophenyl, 3,4-difluorophenyl or 3,4-dichlorophenyl, still more preferably 3,4-difluorophenyl or 3,4-dichlorophenyl, particularly preferably 3,4-dichlorophenyl.

The “protected hydroxyl group” in the definition of R ³ is generally a hydroxyl group protected with a hydroxyl protecting group in the field of synthetic organic chemistry, such as tert-butyl, 1,1-dimethyl. C ₃ -C ₆ branched alkyl groups such as propyl, 1,1,2-trimethylpropyl or 1,1-dimethylbutyl; C ₃ -C ₆ straight, such as allyl or 1-methyl-2-propenyl Chain or branched 2-alkenyl groups; formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7- Dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pen Tadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl A C ₁ -C ₂₁ alkanoyl group such as eicosanoyl or heneicosanoyl; a C ₂ -C ₄ halogenoalkanoyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl; C _1- such as methoxyacetyl A C ₄ alkoxy C ₂ -C ₄ alkanoyl group; an unsaturated alkanoyl group such as (E) -2-methyl-2-butenoyl; a C ₆ -C ₁₀ arylcarbonyl group such as benzoyl, 1-naphthoyl or 2-naphthoyl; ; 2-bro 2,4,6 _C 1 -C ₄ alkylated _C 6 _{-C 10} arylcarbonyl group such as trimethyl benzoyl or p- toluoyl; _C 6 _{-C 10} halogenoaryl carbonyl groups such as benzoyl or 4-chlorobenzoyl; 2-carboxybenzoyl, 3-carboxybenzoyl or 4-carboxyphenyl carboxylated _C 6 _{-C 10} arylcarbonyl group such as benzoyl; _C 1 -C ₄ alkoxylated _C 6 _{-C 10} arylcarbonyl group such as a p- anisoyl group ; 4-nitrobenzoyl or 2-nitrated _C 6 _{-C 10} arylcarbonyl group such as nitrobenzoyl; 2- (methoxycarbonyl) _C 1 -C ₄ alkoxycarbonyl of _C 6 _{-C 10} arylcarbonyl group such as benzoyl C ₆ such as 4-phenylbenzoyl -C ₁₀ aryl of _C 6 _{-C 10} arylcarbonyl group; tetrahydropyran-2-yl, 3-bromo-tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl or 4 A tetrahydropyranyl group or a tetrahydrothiopyranyl group such as methoxytetrahydrothiopyran-4-yl; a tetrahydrofuranyl group or a tetrahydrothiofuranyl group such as tetrahydrofuran-2-yl or tetrahydrothiofuran-2-yl; _C 1 -C ₄ alkoxylated _C 1 -C such as 2-methoxyethoxymethyl; methyl, ethoxymethyl, propoxymethyl, iso-propoxymethyl, _C 1 -C ₄ alkoxymethyl group such as butoxymethyl or tert- butoxymethyl ₄ Alkyki Cimethyl group; C ₁ -C ₄ halogenoalkoxymethyl group such as 2,2,2-trichloroethoxymethyl or bis (2-chloroethoxy) methyl; 1-methoxy-1-methylethyl, 1-ethoxyethyl or 1- A C ₁ -C ₄ alkoxylated ethyl group such as (isopropoxy) ethyl; 1 to Aralkyl groups consisting of _three C ₆ -C ₁₀ aryls and C ₁ -C ₃ alkyls; (4-methoxyphenyl) diphenylmethyl, bis (4-methoxyphenyl) phenylmethyl, diphenyl (p-tolyl) methyl, tri ( p- tolyl) _C 1 -C ₄ alkyl or _C 1 -C ₄ alkoxy group such as methyl A triarylmethyl group having one or more substituted aryl rings; 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4- C ₇ substituted aryl ring with C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, nitro or cyano group, such as nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-cyanobenzyl -C ₁₅ aralkyl group; methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl or _C 1 -C ₄ alkoxycarbonyl group such as isobutoxycarbonyl; 2,2,2-trichloroethoxycarbonyl such _C 1 -C ₄ halogenated Alkoxycarbonyl group; vinyloxycarbonyl or allyloxy C ₂ -C ₅ alkenyloxycarbonyl group such as carbonyl; benzyloxycarbonyl, such as 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl oxycarbonyl, 2-nitrobenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl A C ₇ -C ₁₅ aralkyloxycarbonyl group in which the aryl ring may be substituted with one or two C ₁ -C ₄ alkoxy or nitro groups; or trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethyl Silyl, diisopropylmethylsilyl, di-tert-butylmethylsilyl, triisopropylsilyl, methyldiphenylsilyl, butyldiphenylsilyl, isopropyldiphenylsilyl or diisopropylphenylsilyl It is a silyl group such as, _preferably, C 3 -C ₆ branched-chain alkyl group; a tetrahydropyranyl group; 1 or aralkyl consisting of three _C 6 _{-C 10} aryl and _C 1 -C ₃ alkyl A C ₇ -C ₁₅ aralkyl group in which the aryl ring is substituted with a C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy group, and more preferably tetrahydropyran-2-yl, triphenylmethyl , Trimethylsilyl or tert-butyldimethylsilyl, particularly preferably tetrahydropyran-2-yl or triphenylmethyl.

The “C ₁ -C ₄ alkanesulfonyloxy group” in the definition of R ³ is preferably methanesulfonyloxy or ethanesulfonyloxy, and particularly preferably methanesulfonyloxy.

The “C ₁ -C ₄ haloalkanesulfonyloxy group” in the definition of R ³ is a C ₁ -C ₄ alkanesulfonyloxy group substituted with the above “halogen atom” (preferably a fluorine atom), preferably , Trifluoromethanesulfonyloxy or pentafluoroethanesulfonyloxy, particularly preferably trifluoromethanesulfonyloxy.

The “C ₆ -C ₁₀ arylsulfonyloxy group optionally substituted with 1 to 3 groups selected from substituent group β” in the definition of R ³ has an aryl moiety selected from substituent group β A C ₆ -C ₁₀ arylsulfonyloxy group optionally substituted with 1 to 3 groups, and preferably 1 to 3 groups selected from substituent group β Preferred benzenesulfonyloxy groups, more preferably benzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, 4-nitrobenzenesulfonyloxy, 4-chlorobenzenesulfonyloxy, 4-methylbenzenesulfonyloxy or 4-trifluoromethylbenzenesulfonyloxy. Particularly preferred is 4-chlorobenzenesulfonyloxy.

“C ₁ -C ₆ alkylene group” in the definition of G ¹ is, for example, methylene, ethylene, trimethylene, propylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethylethylene, pentamethylene. , 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,2-dimethyltrimethylene, or a straight or branched alkylene group such as a hexamethylene group, preferably C _1- A C ₃ alkylene group, more preferably a C ₁ -C ₃ linear alkylene group, still more preferably methylene or ethylene, and most preferably ethylene.

The “C ₂ -C ₃ alkylene group” in the definition of G ³ is ethylene, trimethylene or propylene, preferably ethylene or trimethylene, and particularly preferably ethylene. When G ³ is a C ₂ -C ₃ alkylene group, R ³ is preferably a hydroxyl group, a protected hydroxyl group, a C ₁ -C ₄ haloalkanesulfonyloxy group, or a C ₁ -C ₄ alkanesulfonyloxy group. Or a C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted with 1 to 3 groups selected from substituent group β.

The “C ₂ -C ₃ alkenylene group” in the definition of G ³ is vinylene, 1-propenylene or 2-propenylene, and particularly preferably vinylene. When G ³ is a C ₂ -C ₃ alkenylene group, R ³ is preferably a hydrogen atom.

The “C ₂ -C ₃ alkynylene group” in the definition of G ³ is ethynylene, 1-propynylene or 2-propynylene, and particularly preferably ethynylene. When G ³ is a C ₂ -C ₃ alkenylene group, R ³ is preferably a hydrogen atom.

The “C ₁ -C ₄ halogenated alkyl group” in the definition of the substituent group α and the substituent group β is a C ₁ -C ₄ alkyl group substituted with the above “halogen atom”, preferably trifluoro Methyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl or 2 , 2-dibromoethyl, more preferably trifluoromethyl, trichloromethyl, difluoromethyl or fluoromethyl, and particularly preferably trifluoromethyl.

“C ₁ -C ₄ alkyl group” in the definition of substituent group β is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl, Particularly preferred is methyl.

The leaving group in the definition of Y is, for example, a halogen atom such as chlorine atom, bromine atom or iodine atom; C ₂ -C ₅ alkoxycarbonyloxy group such as methoxycarbonyloxy or ethoxycarbonyloxy; methanesulfonyloxy or ethane C ₁ -C ₄ alkanesulfonyloxy group such as sulfonyloxy; C ₁ -C ₄ haloalkanesulfonyloxy group such as trifluoromethanesulfonyloxy or pentafluoroethanesulfonyloxy; or benzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, 4 -Substituent groups β such as nitrobenzenesulfonyloxy, 4-chlorobenzenesulfonyloxy, 4-methylbenzenesulfonyloxy or 4-trifluoromethylbenzenesulfonyloxy Be a 1 to 3 of which may be substituted with a group C ₆ -C ₁₀ arylsulfonyloxy group are al selected, preferably, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, 4-nitrobenzene It is sulfonyloxy, 4-chlorobenzenesulfonyloxy or 4-methylbenzenesulfonyloxy, more preferably methanesulfonyloxy or 4-chlorobenzenesulfonyloxy, and particularly preferably 4-chlorobenzenesulfonyloxy.

_C 1 -C ₄ alkyl _C 1 -C ₄ alkylcarbonyloxy group in the definition of X includes _"C 1 -C ₄ alkyl group" in the definition of Substituent group β the same meaning, preferably pivaloyl group is there.

_C 1 -C ₄ alkoxy _C 1 -C ₄ alkoxycarbonyloxy groups in the definition of X are the same meanings as _"C 1 -C ₄ alkoxy group" in the definition of ^{R 1} and Substituent group alpha, preferably a tert-butoxycarbonyl group;


The salt of the compound having the general formula (4) and the salt of the compound having the general formula (4 ′) and the pharmacologically acceptable salt of the compound having the general formula (5) are, for example, hydrochloride, sulfate or An inorganic acid salt such as a phosphate; or an organic acid salt such as acetate, oxalate, fumarate or succinate, a compound having general formula (4) or general formula (4 ′) Preferably, the salt is a hydrochloride, sulfate or oxalate, and the pharmacologically acceptable salt of the compound having the general formula (5) is preferably hydrochloride or fumarate. is there.

The present invention is carried out according to the following <Method A>.
<Method A>

(Wherein R ¹ , R ² , R ³ , G ¹ , G ² , G ³ , X and Y are as defined above.)
The first step is a step of producing compound (1) by reacting compound (4) or a salt thereof and compound (5) in the presence of a base in an inert solvent.

  The inert solvent used is not particularly limited as long as it does not impair the reaction and dissolves the starting material. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene or Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate or Esters such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; acetone, ethyl Ketones such as ruketone, isobutyl methyl ketone, isophorone or cyclohexanone; nitro compounds such as nitroethane or nitrobenzene; nitriles such as acetonitrile, propionitrile or isobutyronitrile; formamide, N, N-dimethylformamide, Amides such as N, N-dimethylacetamide, N-methylpyrrolidinone or hexamethylphosphorotriamide; Sulfoxides or sulfones such as dimethyl sulfoxide or sulfolane; Alcohols such as methanol, ethanol, propanol or butanol; Water; Or a mixture thereof, preferably aromatic hydrocarbons, ethers, nitriles, water or a mixture thereof, more preferably toluene, tetrahydrofuran, acetonite. Le, water or mixtures thereof.

The base used is not particularly limited as long as it is used as a base in a normal reaction. For example, N-methylmorpholine, trimethylamine, triethylamine, tripropylamine, tributylamine, N, N-diisopropylethylamine, Dicyclohexylamine, N-methylpiperidine, N-methylpyrrolidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-dimethylaminopyridine, 2,6-di (tert-butyl) -4-methylpyridine, imidazole, N-methyl Imidazole, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2 ] Octane (DABCO) or 1,8-diazabicyclo [ .4.0] obtained an organic bases such as undec-7-ene (DBU), preferably triethylamine and N, an N- diisopropylethylamine, particularly preferably triethylamine.

The reaction temperature is usually −20 ° C. to 100 ° C. (preferably −5 ° C. to 10 ° C.), and the reaction time varies depending on the reaction temperature and the like, but usually 5 minutes to 24 hours (preferably 10 minutes to 2 hours).

In addition, when X is a hydroxyl group, it can also be achieved by reacting with a “condensation agent” in the presence or absence of the base in a solvent. The condensing agents used are phosphate esters such as diethyl phosphoryl cyanide and diphenyl phosphoryl cyanide; 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, 3- (3-dimethylaminopropyl) -1- Carbodiimides such as ethylcarbodiimide; combinations of the above carbonyldiimides with N-hydroxys such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide Carbonates such as N, N′-disuccinimidyl carbonate, di-2-pyridyl carbonate, S, S′-bis (1-phenyl-1H-tetrazol-5-yl) dithiocarbonate; N, N ′ -Bis (2-oxo-3-oxazo Phosphinic chlorides such as (diynyl) phosphinic chloride; N, N′-disuccinimidyl oxalate, N, N′-diphthalimido oxalate, 1,1′-bis (benzotriazolyl) oxalate Such oxalates; 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; 1,1′-oxalyldiimidazole, such as N, N′-carbonyldiimidazole Imidazoles; Phosphates such as phenyl dichlorophosphate and polyphosphate esters; Phosphonic acid cyclic anhydrides such as 1-propanephosphonic acid cyclic anhydrides; Halogenosulfonyl isocyanates such as chlorosulfonyl isocyanate; Trimethylsilyl chloride, Triethylsilyl Halogenosilanes such as luchloride; lower alkanesulfonyl halides such as methanesulfonyl chloride; phosphonic acid cyclic anhydrides or lower alkanesulfonyl halides are preferred.

The inert solvent used is not particularly limited as long as it does not impair the reaction and dissolves the starting material. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene or Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate or Esters such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; acetone, ethyl Ketones such as ruketone, isobutyl methyl ketone, isophorone or cyclohexanone; nitro compounds such as nitroethane or nitrobenzene; nitriles such as acetonitrile, propionitrile or isobutyronitrile; formamide, N, N-dimethylformamide, Mention may be made of amides such as N, N-dimethylacetamide, N-methylpyrrolidinone or hexamethylphosphorotriamide; sulfoxides or sulfones such as dimethyl sulfoxide or sulfolane.

The second step is a step for producing the compound (2) by converting the primary hydroxyl group of the compound (1) into a leaving group Y in an inert solvent in the presence or absence of a base.

  Inert solvents used are, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride or chloroform, carbon tetrachloride, Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; diethyl ether, diisopropyl ether, tert- Ethers such as butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; acetone, ethyl methyl ketone, isobutyl methyl ketone, isophorone or cyclohexane Ketones such as Sanone; nitro compounds such as nitroethane or nitrobenzene; nitriles such as acetonitrile, propionitrile or isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N Amides such as methylpyrrolidinone or hexamethylphosphorotriamide; sulfoxides or sulfones such as dimethyl sulfoxide or sulfolane; alcohols such as methanol, ethanol, propanol or butanol; water; or mixtures thereof Preferred are aromatic hydrocarbons, ethers, nitriles, water or a mixture thereof, and more preferred are toluene, tetrahydrofuran, acetonitrile, water or a mixture thereof.

Bases used are, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide or barium hydroxide; lithium carbonate Alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; alkaline earth metal carbonates such as calcium carbonate or barium carbonate; lithium hydride, sodium hydride or hydrogen Alkali metal hydrides such as potassium hydroxide; alkali metal phosphates such as tripotassium phosphate or trisodium phosphate; lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium Methoxide, potassium ester Alkali metal alkoxides such as toxide or potassium tert-butoxide; or N-methylmorpholine, trimethylamine, triethylamine, tripropylamine, tributylamine, N, N-diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, N-methylpyrrolidine Pyridine, 4-pyrrolidinopyridine, picoline, 4-dimethylaminopyridine, 2,6-di (tert-butyl) -4-methylpyridine, imidazole, N-methylimidazole, quinoline, N, N-dimethylaniline, N , N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [ 5.4.0] It obtained an organic amines such as dec-7-ene (DBU), preferably an alkali metal hydroxides, particularly preferably sodium hydroxide or potassium hydroxide.

The amount of the base used is preferably 2 to 60 equivalents, more preferably 10 to 25 equivalents relative to 1 equivalent of compound (4), and such base can be used at one time or Can be added gradually.

When alkali metal hydroxides are used as the base, the particle size is preferably 425 μm or less, more preferably 212 μm or less, and particularly preferably 180 μm or less.

As the reagent for forming the leaving group Y, a corresponding halide is used, and as such a reagent, methanesulfonyl chloride, benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 2- Nitrobenzenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride is preferable, and 4-chlorobenzenesulfonyl chloride is particularly preferable.

The reaction temperature is preferably −40 ° C. to 0 ° C. (more preferably −35 ° C. to −25 ° C. or −5 ° C. to 0 ° C., particularly preferably −35 ° C. to −25 ° C.). The time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 2 hours).

The third step is a step of producing compound (3) by cyclizing compound (2) in the presence of a base in an inert solvent.

  Inert solvents used are, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; diethyl ether, diisopropyl ether, tert- Ethers such as butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; acetone, ethyl methyl ketone, isobutyl methyl ketone, isophorone or cyclohexane Ketones such as non; nitro compounds such as nitroethane or nitrobenzene; nitriles such as acetonitrile, propionitrile or isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N Amides such as methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; sulfoxides or sulfones such as dimethyl sulfoxide or sulfolane; alcohols such as methanol, ethanol, propanol or butanol; water Or a mixture thereof, preferably aromatic hydrocarbons, ethers, nitriles, water or a mixture thereof, more preferably toluene, tetrahydrofuran, acetonitrile, water or a mixture thereof. .

Bases used are, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide or barium hydroxide; lithium carbonate Alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; alkaline earth metal carbonates such as calcium carbonate or barium carbonate; lithium hydride, sodium hydride or hydrogen Alkali metal hydrides such as potassium hydroxide; alkali metal phosphates such as tripotassium phosphate or trisodium phosphate; lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium Methoxide, potassium ester Alkali metal alkoxides such as toxide or potassium tert-butoxide; or N-methylmorpholine, trimethylamine, triethylamine, tripropylamine, tributylamine, N, N-diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, N-methylpyrrolidine Pyridine, 4-pyrrolidinopyridine, picoline, 4-dimethylaminopyridine, 2,6-di (tert-butyl) -4-methylpyridine, imidazole, N-methylimidazole, quinoline, N, N-dimethylaniline, N , N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [ 5.4.0] It obtained an organic amines such as dec-7-ene (DBU), preferably an alkali metal hydroxides, particularly preferably sodium hydroxide or potassium hydroxide.

The amount of the base used is preferably 2 to 60 equivalents, more preferably 10 to 25 equivalents relative to 1 equivalent of compound (4), and such base can be used at one time or Can be added gradually.

When alkali metal hydroxides are used as the base, the particle size is preferably 425 μm or less, more preferably 212 μm or less, and particularly preferably 180 μm or less.

The reaction temperature is usually −40 ° C. to 20 ° C. (preferably −40 ° C. to 0 ° C., more preferably −35 ° C. to −25 ° C. or −5 ° C. to 0 ° C., particularly preferably −35 ° C. The reaction time is usually 15 minutes to 24 hours (preferably 30 minutes to 6 hours), although it varies depending on the reaction temperature and the like.

The first, second, and third steps can be performed continuously without isolating the compound (1) and the compound (2).


A neurokinin receptor antagonist [compound (5)] can be produced by reacting the compound (3) according to the following <Method B>.
<Method B>

(In the formula, R ¹ , R ² , G ¹ , G ² , G ³ and G ⁴ are as defined above, and R ³ is a C ₁ -C ₄ haloalkanesulfonyloxy group, C ₁ -C ₄ alkanesulfonyl. An oxy group or a C ₆ -C ₁₀ arylsulfonyloxy group optionally substituted with 1 to 3 groups selected from the substituent group β, wherein the substituent group β is a nitro group, a halogen atom, C ₁ -C ₄ represents an alkyl group and _C 1 -C ₄ group consisting halogenated alkyl group.)
This step is a step of producing compound (5) by reacting compound (3) with compound (6) in the presence of a base in an inert solvent.

  The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, Esters such as butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diethylene glycol dimethyl ether; acetone, ethyl methyl ketone Ketones such as nitrogen, isobutyl methyl ketone, isophorone or cyclohexanone; nitro compounds such as nitroethane or nitrobenzene; nitriles such as acetonitrile, propionitrile or isobutyronitrile; formamide, N, N-dimethylformamide, Amides such as N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide; or sulfoxides or sulfones such as dimethyl sulfoxide or sulfolane, preferably Is an amide, an ether or a nitrile, more preferably a nitrile, and particularly preferably acetonitrile.

  The base to be used is not particularly limited as long as it is used as a base in a normal reaction. For example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; calcium carbonate or barium carbonate Alkaline earth metal carbonates such as; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; or alkaline earth metal hydroxides such as calcium hydroxide or barium hydroxide; or alternatively N-methylmorpholine, triethylamine , Tripropylamine, tri Tylamine, N, N-diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-dimethylaminopyridine, 2,6-di (tert-butyl) -4-methylpyridine, quinoline N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane ( DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), and can be organic bases, preferably inorganic bases, most preferably alkali metals. Hydrogen carbonates. For the purpose of promoting the reaction, it is also useful to add a catalytic amount of an alkali metal iodide such as potassium iodide or sodium iodide.

  The reaction temperature can be, for example, 0 ° C. to 150 ° C., and preferably 20 ° C. to 120 ° C.

The reaction time mainly varies depending on the reaction temperature, the raw material compound, the reaction reagent or the kind of the inert solvent used, but can be 30 minutes to 48 hours, and preferably 1 hour to 12 hours.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

  For example, it can be obtained by adding water to the reaction mixture and extracting with an immiscible organic solvent such as toluene, washing the extract with water or the like, drying with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

If necessary, the obtained compound can be separated and purified by a conventional method such as recrystallization, reprecipitation, or silica gel column chromatography.

In the above <Method A>, by using the optically active substance of compound (4), that is, compound (4 ′), the optically active substance of compound (1), compound (2) and compound (3) is produced. The optically active form of compound (5) can be produced by carrying out the reaction according to <Method B> using the optically active form of compound (3).

In the compound (4 ′), a compound in which R ³ is a hydroxyl group and G ³ is an ethylene group can be produced by, for example, the following <Method C>.
<Method C>

(In the formula, R ² and G ¹ are as defined above.)
The fourth step is a step of producing the 3-buten-1-ol compound (8) by reacting the propene derivative (7) with paraformaldehyde. This step is performed according to the method of Okachi et al. (Organic Letters 2002, 4, 1667-1669), or a trifluoroborane complex compound (for example, trifluoroborane; trifluoroborane / methyl ether complex, trifluoroborane Ethyl ether complexes, trifluoroborane / C ₁ -C ₄ alkyl ether complexes such as trifluoroborane / n-butyl ether complex; trifluoroborane / C ₁ -C ₄ alkyl sulfide complexes such as trifluoroborane / methyl sulfide complex Or a trifluoroborane · tetrahydrofuran complex, preferably a trifluoroborane · C ₁ -C ₄ alkyl ether complex, more preferably a trifluoroborane · ethyl ether complex) and a base (eg, Lithium hydroxide, sodium hydroxide or potassium hydroxide Alkali metal hydroxides such as lithium; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate; lithium hydride, sodium hydride or potassium hydride Alkali metal hydrides such as tripotassium phosphate or trisodium phosphate; lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, Alkali metal alkoxides such as potassium ethoxide or potassium tert-butoxide; or N-methylmorpholine, triethylamine, tributylamine, N, N-diisopropylethylamine, dicyclohexylamine, N-methylpi Peridine, pyridine, 4-pyrrolidinopyridine, picoline, 4-dimethylaminopyridine, 2,6-di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline or N, N-diethylaniline Such organic amines can be used, preferably alkali metal hydroxides, alkali metal alkoxides or organic amines, more preferably alkali metal alkoxides or organic amines, and particularly preferably. , Sodium methoxide or triethylamine) in the presence of propene derivative (7) and paraformaldehyde.

For the latter method, preferably the reaction is carried out in an inert solvent (eg aromatic hydrocarbons such as benzene, toluene or xylene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate). Nitriles such as acetonitrile, propionitrile or isobutyronitrile; or halogens such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, trichloromethylbenzene or trifluoromethylbenzene And is preferably halogenated hydrocarbons, more preferably dichloromethane.).

The amount of paraformaldehyde used is 1.0 to 10.0 equivalents (preferably 1.0 equivalent to 2.0 equivalents) per 1 equivalent of propene derivative (7). The amount of the roborane complex compound is 1.0 to 10.0 equivalents (preferably 1.0 equivalent to 3.0 equivalents) relative to 1 equivalent of the propene derivative (7). The amount is 0.1 equivalent to 1.0 equivalent (preferably 0.3 equivalent to 0.8 equivalent) with respect to 1 equivalent of propene derivative (7). The reaction temperature is usually −10 ° C. to 20 ° C. (preferably −5 ° C. to 5 ° C.), and the reaction time is usually 1 hour to 20 hours (preferably 1 hour to 8 hours). is there.

In the case of carrying out the former method (Okachi et al. Method), the molecular sieve must be used in the same amount as the weight of the propene derivative (7), and it is difficult to recover and reuse the molecular sieve. Since it becomes waste, the former method has a drawback that it is not suitable for industrial implementation. In contrast, the latter method is suitable for industrial implementation because the 3-buten-1-ol compound (8) can be produced without using a molecular sieve.

The fifth step is a step of producing compound (9) by asymmetric epoxidation of 3-buten-1-ol compound (8). This step is carried out according to the method of Okachi et al. (Organic Letters 2003, 5, 85-87), or in an inert solvent, molecular sieves and zirconium (IV) alkoxide (for example, zirconium (IV) ethoxide, zirconium ( IV) propoxide, zirconium (IV) isopropoxide, zirconium (IV) butoxide or zirconium (IV) tert-butoxide, preferably zirconium (IV) isopropoxide or zirconium (IV) tert-butoxide. ) And an optically active tartaric acid diester (eg, dimethyl tartrate, diethyl tartrate, diisopropyl tartrate, dibutyl tartrate or di-tert-butyl tartrate tartrate) in the presence of an asymmetric catalyst (eg, m-chloro Perbenzoic acid, 3,5-dinitro Benzoic acid, o-carboxyperbenzoic acid, peracetic acid, pertrifluoroacetic acid, perphthalic acid, cumene hydroperoxide, isopropyl cumyl hydroperoxide, preferably cumene hydroperoxide or isopropyl cumyl hydroperoxide Most preferred is cumene hydroperoxide.), And asymmetric epoxidation.

Inert solvents used are, for example, aromatic hydrocarbons such as benzene, toluene or xylene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; methylene chloride, chloroform, tetra Halogenated hydrocarbons such as carbon chloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether such as acetone or methyl ethyl ketone Ketones; nitriles such as acetonitrile, propionitrile or isobutyronitrile or the above mixed solvents, and more preferably aromatic hydrocarbons or halogenated hydrocarbons. , Particularly preferably, toluene.

The amount of molecular sieve used is 0.02 to 1 times the weight of the 3-buten-1-ol compound (8), preferably 0.05 to 0.15 times the weight. It is.

The amount of zirconium (IV) alkoxide used is 0.01 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of 3-buten-1-ol compound (8). is there.

The amount of the optically active tartaric acid diester used is 0.02 to 2.2 equivalents, preferably 0.21 to 1.1 equivalents to 1 equivalent of the 3-buten-1-ol compound (8). Is equivalent.

  The amount of the oxidizing agent used is preferably 0.5 to 10 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of the 3-buten-1-ol compound (8). .

The reaction temperature is usually 0 ° C. to 80 ° C. (preferably 10 ° C. to 30 ° C.), and the reaction time is usually 1 hour to 5 days (preferably 2 hours to 2 days).

In the sixth step, the asymmetric epoxy compound (9) and the amino alcohol compound (10) are mixed with an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene or xylene; ethyl formate, ethyl acetate, propyl acetate). Esters such as butyl acetate or diethyl carbonate; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitriles such as acetonitrile, propionitrile or isobutyronitrile; formamide, N, N-dimethyl Amides such as formamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide; can be sulfoxides or sulfones such as dimethyl sulfoxide or sulfolane, preferably Are aromatic hydrocarbons or halogenated hydrocarbons, and more preferably toluene.) In this step, compound (4′a) is produced by reaction in toluene.

The reaction temperature is usually −20 ° C. to 150 ° C. (preferably 30 ° C. to 80 ° C.), and the reaction time is usually 10 minutes to 3 days (preferably 30 minutes to 1 day). .

Furthermore, the compound (4), the compound (4 ′), the compound (4′a), the compound (5), and an optically active form thereof may be converted to an acid (for example, hydrogen chloride, sulfuric acid, or phosphoric acid). Or an organic acid such as acetic acid, oxalic acid, fumaric acid or succinic acid. Can lead to.

The compounds used as starting materials in the above <Method B> and <Method C> are, for example, US Pat. No. 6,159,967, US Pat. No. 6,511,975, and David ™ et al., J. Amer. Chem. Soc. 851 (1947) or can be readily prepared from the compounds disclosed therein.

According to the present invention, N-carbonyl saturated heterocycles that have been difficult to synthesize conventionally can be obtained industrially in high yield.

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

The enantiomeric excess in each example is a value based on analysis by high performance liquid chromatography (HPLC), and the enantiomeric excess was analyzed under the conditions of the following “HPLC conditions”.
<HPLC conditions>
Column: CHRALCEL AD (trade name, manufactured by Daicel Chemical Industries, Ltd.)
4.6φ × 250mm
Moving layer: Hexane: EtOH = 94: 6
Column temperature: 40 ° C
Detection: UV (220 nm)
Flow rate: 1 ml / min
Retention time: R-form: 11.2 min, S-form: 12.8 min

(Example)
Example 1 (3R) -3- (3,4-Dichlorophenyl) -4-[(2-hydroxyethyl) amino] -1,3-butanediol 2-[(2R) obtained in Reference Example 3 2- (3,4-Dichlorophenyl) oxilan-2-yl] ethanol in toluene was added with 98.62 g (1.61 mol) of 2-aminoethanol and stirred at 55 to 60 ° C. for 4 hours. After cooling to 20 to 25 ° C., a solution of sodium pyrosulfite 12.28 g (64.60 mmol) in 40 ml of water was added and stirred for 30 minutes. After cooling to 0 to 5 ° C., 280 ml of 6 mol / l hydrochloric acid was added dropwise, and the aqueous layer was separated. The aqueous layer separated with a 25% aqueous sodium hydroxide solution was made alkaline and extracted with cyclopentyl methyl ether. As a result of quantifying the separated organic layer by HPLC, it was shown that the title compound contained 36.72 g (yield: 86.5%). The organic layer was concentrated to a liquid volume of 80 ml and used in Example 2.
¹ H-NMR (400 MHz, CD ₃ OD) δ ppm: 1.97 (ddd, J = 14.4, 6.3, 4.9 Hz, 1H), 2.13 (ddd, J = 14.4, 7.9, 6.8 Hz, 1H), 2.65 (t , J = 5.4 Hz, 2H), 2.86 (d, J = 12.2 Hz, 1H), 2.91 (d, J = 12.2 Hz, 1H), 3.42 (ddd, J = 11.0, 6.8, 4.9 Hz, 1H), 3.58 (t, J = 5.4 Hz, 2H), 3.63 (ddd, J = 11.0, 7.9, 6.3 Hz, 1H), 7.36 (dd, J = 8.5, 2.2 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H).
¹³ C-NMR (100 MHz, CD ₃ OD) δ ppm: 43.40, 52.78, 58.68, 60.58, 61.56, 76.36, 126.34, 128.81, 131.24, 131.40, 133.15, 148.35.

(Example 2) (3R) -3- (3,4-Dichlorophenyl) -4-[(2-hydroxyethyl) amino] -1,3-butanediol.0.5 sulfate obtained in Example 1 To the solution, 240 ml of acetone and 40 ml of methanol were added and heated to 40 ° C. A solution of 7.41 g (74.04 mmol) of concentrated sulfuric acid in 80 ml of acetone was added dropwise, and the mixture was stirred at the same temperature for 1 hour or more. After cooling to 20 to 30 ° C., the mixture was stirred for 30 minutes or more, and the precipitated crystals were collected by filtration. It was dried at 50 ° C. under reduced pressure for 10 hours or more to obtain 42.2 g of the title compound (purity 96.8%, yield 82.4%).
¹ H-NMR (400 MHz, CD ₃ OD) δ ppm: 2.05 (ddd, J = 14.6, 5.1, 4.9 Hz, 1H), 2.26 (ddd, J = 14.6, 8.9, 5.6 Hz, 1H), 3.11 (t , J = 5.4 Hz, 2H), 3.32 (d, J = 12.7 Hz, 1H), 3.53 (d, J = 12.7 Hz, 1H), 3.53 (ddd, J = 11.0, 5.6, 5.1 Hz, 1H), 3.66 (ddd, J = 11.0, 8.9, 4.9 Hz, 1H), 3.79 (t, J = 5.4 Hz, 2H), 7.46 (dd, J = 8.5, 2.2 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H).
Anal.Calcd for C ₁₂ H ₁₇ Cl ₂ NO ₃・ 0.5H ₂ SO ₄ : C, 41.99; H, 5.29; N, 4.08; Cl, 20.66; S, 4.67. Found: C, 41.79; H, 5.29; N , 4.09; Cl, 20.36; S 4.90.

Example 3 (3R) -3- (3,4-Dichlorophenyl) -4-[(2-hydroxyethyl) amino] -1,3-butanediol hydrochloride (3R) -3- (3,4 -Dichlorophenyl) -4-[(2-hydroxyethyl) amino] -1,3-butanediol 8.03 g (27.3 mmol) in 100 ml of isopropyl acetate 10.3 ml of 3 mol / l HCl-isopropyl acetate solution ( 30.9 mmol) was added dropwise and concentrated under reduced pressure. To the obtained oily substance, 20 ml of acetone and 20 ml of isopropyl acetate were added and stirred at 20 to 30 ° C. An additional 20 ml of isopropyl acetate was added, and the mixture was stirred at the same temperature for 30 minutes or more, and the precipitated crystals were collected by filtration. To the crystal, 25 ml of acetone and 25 ml of isopropyl acetate were added and stirred at 40 ° C. for 30 minutes or more. The mixture was cooled to 20 to 30 ° C. and stirred for 30 minutes or more. The crystals were filtered and dried under reduced pressure at 50 ° C. for 10 hours or more to obtain 4.71 g (yield 52.2%) of the title compound.
¹ H-NMR (400 MHz, CD ₃ OD) δ ppm: 2.03 (ddd, J = 14.9, 4.9, 4.4 Hz, 1H), 2.24 (ddd, J = 14.9, 9.0, 5.4 Hz, 1H), 3.03-3.15 (m, 2H), 3.35 (d, J = 12.7 Hz, 1H), 3.45 (d, J = 12.7 Hz, 1H), 3.59 (ddd, J = 11.0, 5.4, 4.9 Hz, 1H), 3.67 (ddd, J = 11.0, 9.0, 4.4 Hz, 1H), 3.78 (t, J = 5.4 Hz, 2H), 7.45 (dd, J = 8.5, 2.2 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H).
Anal.Calcd for C ₁₂ H ₁₇ Cl ₂ NO ₃・ HCl: C, 43.59; H, 5.49; N, 4.24; Cl, 32.17.Found: C, 43.48; H, 5.58; N, 4.23; Cl, 31.92.

Example 4 (3R) -3- (3,4-Dichlorophenyl) -4-[(2-hydroxyethyl) amino] -1,3-butanediol oxalate (3R) -3- (3 4-dichlorophenyl) -4-[(2-hydroxyethyl) amino] -1,3-butanediol.0.5 sulfate (4.91 g, 14.3 mmol) was converted to the free base with 50 ml of 25% aqueous sodium hydroxide solution, Extraction was performed with 50 ml of cyclopentyl methyl ether. Further, the aqueous layer was extracted with 25 ml of cyclopentyl methyl ether. The organic layers were matched, washed with 25 ml of 20% aqueous sodium chloride solution and concentrated under reduced pressure. To the obtained oily substance, 50 ml of acetone and 0.2 ml of methanol were added and heated to 40 to 50 ° C. 1.84 g (14.6 mmol) of oxalic acid was added and stirred at the same temperature for 1 hour or more. The mixture was cooled to 20 to 30 ° C. and stirred for 30 minutes or more. The precipitated crystals were collected by filtration and dried at 50 ° C. under reduced pressure for 10 hours or more to obtain 4.35 g (purity 98.0%, yield 77.6%) of the title compound.
¹ H-NMR (400 MHz, CD ₃ OD) δ ppm: 2.03 (ddd, J = 14.6, 4.9, 4.4 Hz, 1H), 2.23 (ddd, J = 14.6, 9.0, 5.4 Hz, 1H), 3.02-3.12 (m, 2H), 3.34 (d, J = 12.7 Hz, 1H), 3.45 (d, J = 12.7 Hz, 1H), 3.58 (ddd, J = 11.0, 5.4, 4.9 Hz, 1H), 3.67 (ddd, J = 11.0, 9.0, 4.4 Hz, 1H), 3.77 (t, J = 5.4 Hz, 2H), 7.44 (dd, J = 8.5, 2.2 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H).
Anal. Calcd for C ₁₂ H ₁₇ Cl ₂ NO ₃・ (COOH) ₂ : C, 43.77; H, 4.98; N, 3.65; Cl, 18.46.Found: C, 43.58; H, 4.93; N, 3.67; Cl, 18.08.

Example 5 2-[(2R) -2- (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl 4-chlorobenzenesulfonate (3R) Triethylamine 5 was added to a solution of 9.56 g (27.9 mmol) of 3- (3,4-dichlorophenyl) -4-[(2-hydroxyethyl) amino] -1,3-butanediol 0.5 sulfate in 100 ml of acetonitrile. .64 g (55.7 mmol) was added, and the mixture was stirred at 20 to 25 ° C. for 10 minutes or more. After adding 5 ml of water to the mixture, it was cooled to 0 to 5 ° C. Next, a solution of 6.75 g (29.3 mmol) of trimethoxybenzoyl chloride in 34 ml of toluene was added dropwise at 5 ° C. or lower and stirred at 0 to 5 ° C. for 30 minutes. After cooling the mixture to −20 to −10 ° C., a solution of 12.05 g (57.1 mmol) of 4-chlorobenzenesulfonyl chloride in 50 ml of acetonitrile was added. Next, 5.57 g (139.3 mmol) of sodium hydroxide having a particle size of 180 μm or less was added at −5 ° C. or less. After cooling to −20 to −10 ° C., 16.71 g (417.8 mmol) of sodium hydroxide having a particle size of 180 μm or less was further added at −5 ° C. or less. After stirring at −15 ° C. for 2 hours, 120 ml of water was added dropwise at 5 ° C. or less, the insoluble matter was filtered, and the organic layer was separated. The organic layer was concentrated, and after adding 100 ml of toluene and 50 ml of water, the organic layer was separated. Next, the separated organic layer was concentrated to 25 ml and stirred at 50 ° C. for about 1 hour. After cooling at 0 to 5 ° C., the mixture was further stirred for 1 hour. The precipitated crystals were collected by filtration and dried at 50 ° C. under reduced pressure for 15 hours to obtain 14.6 g of the title compound (purity 99.1%, yield 80.5%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 2.00-2.25 (m, 1H), 2.25-2.50 (m, 1H), 3.30-3.90 (m, 6H), 3.86 (s, 9H), 4.00- 4.15 (m, 1H), 4.15-4.30 (m, 1H), 6.52 (s, 2H), 6.70-7.90 (m, 7H).

Example 6 2-[(2R) -2- (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl 4-chlorobenzenesulfonate (3R) Triethylamine 2 was added to a solution of 4.78 g (13.9 mmol) of 3- (3,4-dichlorophenyl) -4-[(2-hydroxyethyl) amino] -1,3-butanediol 0.5 sulfate in 50 ml of acetonitrile. .82 g (27.9 mmol) was added, and the mixture was stirred at 20 to 25 ° C. for 10 minutes or more. After adding 2.5 ml of water to the mixed solution, it was cooled to 0 to 5 ° C. Next, a solution of 3.37 g (14.6 mmol) of trimethoxybenzoyl chloride in 17 ml of toluene was added dropwise at 5 ° C. or lower and stirred at 0 to 5 ° C. for 30 minutes. After cooling this mixture to −30 to −35 ° C., a solution of 6.03 g (28.6 mmol) of 4-chlorobenzenesulfonyl chloride in 25 ml of acetonitrile was added. Next, while maintaining −35 to −25 ° C., 0.28 g (7.0 mmol) of sodium hydroxide having a particle size of 180 μm or less was added 40 times at intervals of 1.5 to 3 minutes. After stirring at −35 to −25 ° C. for 3 to 4 hours, 75 ml of water was added dropwise at 5 ° C. or less, the insoluble matter was filtered, and the organic layer was separated. The organic layer was concentrated, 50 ml of toluene and 25 ml of 5% sodium bicarbonate water were added, and the organic layer was separated. Next, the separated organic layer was concentrated to 30 ml and stirred at 50 ° C. for 1 hour. 10 ml of ethylcyclohexane was added and stirred at the same temperature for 1 hour. After cooling to 20 to 25 ° C. and stirring for 1 hour, the precipitated crystals were collected by filtration. The crystals were dried under reduced pressure at 50 ° C. for 15 hours to obtain 7.24 g of the title compound (purity 99.0%, yield 79.8%).

(Example 7) tert-butyl 2- (3,4-dichlorophenyl) -2- [2- (trityloxy) ethyl] morpholine-4-carboxylate To a mixed solution of 120 ml of toluene and 240 ml of acetone, 3- (3,4 -Dichlorophenyl) -3-butenyl trityl ether 28.2 g (61.4 mmol) was added followed by sodium bicarbonate 16.4 g (195.2 mmol). A solution of 40.0 g (65.0 mmol) of OXONE ^{™ in} 240 ml of water was added dropwise at 30 ° C. or lower. After stirring at 25 to 30 ° C. for 2 hours, a solution of sodium thiosulfate pentahydrate 3.23 g (13.0 mmol) in 30 ml of water was added and stirred for 10 minutes. The solution was concentrated under reduced pressure until the liquid volume reached 390 ml, and 240 ml of methylene chloride was added. After extraction, the organic layer was washed with 210 ml of water and concentrated under reduced pressure.

  Toluene was added to this mixture to adjust the liquid volume to 120 ml, and 90 ml of ethanol was added. Next, 15.6 g (97.2 mmol) of lithium perchlorate trihydrate and 19.6 ml (326.5 mmol) of 2-aminoethanol were added and refluxed for 7 hours. After cooling, 210 ml of toluene and 120 ml of water were added for extraction, and the organic layer was washed with 120 ml of water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

  One-sixth of the obtained oil was dissolved in 10 ml of toluene, 2.61 g (12.0 mmol) of di-tert-butyl dicarbonate was added, and the mixture was stirred at 25 to 30 ° C. for 1.5 hours. After cooling the mixture to −10 ° C. or lower, 1.69 g (16.7 mmol) of triethylamine was added, and a solution of 1.65 g (14.4 mmol) of methanesulfonyl chloride in 5 ml of toluene was added dropwise at 5 ° C. or lower. After stirring at −10 to 0 ° C. for 3 hours, the organic layer was washed successively with 25 ml of water at 0 to 1 ° C. and 25 ml of saturated aqueous sodium hydrogen carbonate solution at 0 to 1 ° C.

To the separated organic layer, 20 ml of ethanol at 0 to 1 ° C. and 37.5 ml of toluene at 0 to 1 ° C. were added, and the mixture was cooled to −15 to −10 ° C. 28% sodium methoxide-methanol solution (5.25 g, 27.2 mmol) was added dropwise at -10 ° C or lower. Warm to 20 ° C. and stir for 1.5 hours. The organic layer was separated by washing twice with 25 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was quantified by an absolute calibration curve method using HPLC. As a result, it was shown that 5.69 g (yield: 89.9%) of the title compound was contained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.42 (s, 9H), 1.80-2.00 (m, 1H), 2.05-2.25 (m, 1H), 2.45-2.65 (m, 1H), 2.95- 3.14 (m, 2H), 3.15-3.30 (m, 1H), 3.30-3.50 (m, 1H), 3.50-3.65 (m, 1H), 3.65-3.80 (m, 1H), 4.55-4.75 (m, 1H ), 7.06-7.48 (m, 18H).

Example 8 2-[(2R) -2- (3,4-Dichlorophenyl) -4- (phenylacetyl) morpholin-2-yl] ethyl 4-chlorobenzenesulfonate (3R) -3- (3,4 -Dichlorophenyl) -4-[(2-hydroxyethyl) amino] butane-1,3-diol.0.5 sulfate 14.3 g (41.8 mmol) in acetonitrile 225 ml solution 10.6 g (104.3 mmol) of triethylamine And 15 ml of water were added and the mixture was stirred at 20 to 25 ° C. for 10 minutes or more. Next, the mixture was cooled to 0 to 5 ° C., and a solution of 7.45 g (48.2 mmol) of phenylacetyl chloride in 75 ml of acetonitrile was added dropwise at 5 ° C. or lower. After stirring at 0-5 ° C. for 1 hour, the reaction mixture was concentrated. Extraction was performed with 225 ml of methylene chloride and 105 ml of 20% brine, and the organic layer was separated. The crude product obtained by concentrating the organic layer was purified by silica gel column chromatography, and N-[(2R) -2- (3,4-dichlorophenyl) -2,4-dihydroxybutyl] -N- (2- 11.6 g (yield 67.3%) of hydroxyethyl) -2-phenylacetamide was obtained.

To a 30 ml acetonitrile solution of 1.93 g (4.68 mmol) of the obtained acetamide, 2.07 g (9.83 mmol) of 4-chlorobenzenesulfonyl chloride was added and cooled to −20 to −15 ° C. 0.94 g (23.5 mmol) of sodium hydroxide having a particle size of 180 μm or less was added at 1 ° C. or less, and after cooling to −20 to −10 ° C., 2.80 g (70.0 mmol) of sodium hydroxide having a particle size of 180 μm or less was further added. Added at -5 ° C or lower. After stirring at −15 to −10 ° C. for 2 hours, 24 ml of water was added dropwise at 5 ° C. or lower, insoluble matters were filtered, and the organic layer was separated. The crude product obtained by concentrating the organic layer was purified by silica gel column chromatography to obtain 2.33 g (yield 87.6%) of the title compound.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 2.04 (ddd, J = 14.6, 7.1, 6.6 Hz, 1H), 2.14 (ddd, J = 14.6, 6.8, 6.3 Hz, 1H), 3.05-3.15 ( m, 1H), 3.24 (d, J = 13.9 Hz, 1H), 3.26-3.36 (m, 1H), 3.36-3.46 (m, 2H), 3.63 (d, J = 15.0 Hz, 1H), 3.68 (d , J = 15.0 Hz, 1H), 3.78 (ddd, J = 10.3, 7.1, 6.8 Hz, 1H), 4.05 (ddd, J = 10.3, 6.6, 6.3 Hz, 1H), 4.51 (d, J = 13.9 Hz, 1H), 6.94-7.01 (m, 2H), 7.12 (dd, J = 8.5, 2.2 Hz, 1H), 7.14-7.19 (m, 3H), 7.36 (d, J = 8.5 Hz, 1H), 7.38 (d , J = 2.2 Hz, 1H), 7.49-7.55 (m, 2H), 7.72-7.78 (m, 2H).

(Reference example)
(Reference Example 1) 3- (3,4-Dichlorophenyl) -3-buten-1-ol Under nitrogen flow, 1.27 g (22.3 mmol) of sodium methoxide was added to 85 ml of methylene chloride, and the temperature was adjusted to 0 to 1 ° C. Cooled down. After 9.41 ml (74.3 mmol) of boron trifluoride diethyl ether complex was added dropwise, 1.65 g (49.5 mmol) of paraformaldehyde was added, and then 9.10 g of 1,2-dichloro-4-isopropenylbenzene (48 .6 mmol) in 10 ml of methylene chloride was added dropwise. The mixture was stirred at 0 to 1 ° C. for 3.5 hours, and the reaction mixture was quantified by HPLC. The result showed that 6.77 g (yield 64.1%) of the title compound was contained.

(Reference Example 2) 3- (3,4-Dichlorophenyl) -3-buten-1-ol Under nitrogen flow, 1.33 g (13.18 mmol) of triethylamine was added to 45 ml of methylene chloride, and cooled to 0 to 1 ° C. . 6.67 ml (52.6 mmol) of boron trifluoride diethyl ether complex was added dropwise, then 0.878 g (26.3 mmol) of paraformaldehyde was added, and then 4.92 g (26 of 1,2-dichloro-4-isopropenylbenzene) .3 mmol) in 5 ml of methylene chloride was added dropwise. The mixture was stirred at 0 to 1 ° C. for 4.25 hours, and the reaction mixture was quantified by HPLC. The result showed that the title compound contained 4.52 g (yield 79.2%).

Reference Example 3 2-[(2R) -2- (3,4-Dichlorophenyl) oxiran-2-yl] ethanol Under nitrogen flow at 20 to 25 ° C., 240 ml of toluene and 4.0 g of molecular sieves 4A and D-tartaric acid 16.26 g (69.41 mmol) of diisopropyl was sequentially added and stirred for 30 minutes. Next, 12.52 g (32.30 mmol) of zirconium (IV) isopropoxide isopropanol complex was added and stirred for 1 hour. To this solution was added dropwise 36.86 g of cumene hydroxyperoxide (purity 80%, 19.37 mmol), followed by 35.05 g (161.45 mmol) of 3- (3,4-dichlorophenyl) -3-buten-1-ol. A 30 ml solution was added dropwise. After stirring at 20 to 25 ° C. for 24 hours and filtering the molecular sieve, the toluene solution was quantified by HPLC. As a result, the title compound contained 33.65 g (yield 89.4%, enantiomeric excess 88.9%). It was shown that. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.91 (s (br), 1H), 2.10 (ddd, J = 14.9, 6.6, 5.3 Hz, 1H), 2.46 (ddd, J = 14.9, 6.6, 5.6 Hz, 1H), 2.73 (d, J = 5.0 Hz , 1H), 3.12 (d, J = 5.0 Hz, 1H), 3.72 (m, 2H), 7.23 (dd, J = 8.3, 2.0 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 2.0Hz, 1H).

  According to the present invention, N-carbonyl saturated heterocycles that have been difficult to synthesize conventionally can be obtained industrially in high yield.

Claims (65)

The following general formula (1)

(In the formula, R ¹ is a hydrogen atom, a C ₁ -C ₄ alkoxy group, a C ₇ -C ₁₁ aralkyloxy group which may be substituted with 1 to 3 groups selected from substituent group β, or a substituent. R represents a phenyl group which may be substituted with 1 to 3 groups selected from the group α, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, and R ³ represents hydrogen atom, hydroxyl group, protected hydroxyl group, C ₁ -C ₄ haloalkane sulfonyloxy group, C ₁ -C ₄ alkanesulfonyloxy group, or optionally substituted with 1 to 3 groups selected from substituent group β A good C ₆ -C ₁₀ arylsulfonyloxy group, G ¹ represents a C ₁ -C ₆ alkylene group, G ² represents a single bond or a methylene group, and G ³ represents a C ₂ -C ₃ alkylene group. , _C 2 -C ₃ alkenylene group Is represents a _C 2 -C ₃ alkynylene group, the α substituent group, hydroxyl _group, C 1 -C ₄ alkoxy _groups, C 1 -C ₄ represents the group consisting of halogenated alkyl groups and tetrazolyl, the substituent group beta, A compound having a nitro group, a halogen atom, a C ₁ -C ₄ alkyl group and a C ₁ -C ₄ halogenated alkyl group is represented by the following general formula (2)

(Wherein R ¹ , R ² , R ³ , G ¹ , G ² and G ³ are as defined above, Y represents a leaving group), By treating a compound having the formula (2) with a base, the following general formula (3)

(Wherein R ¹ , R ² , R ³ , G ¹ , G ² and G ³ are as defined above).
The method according to claim ¹ , wherein R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from a C ₁ -C ₄ alkoxy group or a substituent group α. The method according to claim ¹ , wherein R ¹ is a phenyl group which may be substituted with 1 to 3 groups selected from substituent group α. The method according to any one of claims 1 to 3, wherein R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms. The method according to any one of claims 1 to 4, wherein R ³ is a hydroxyl group or a protected hydroxyl group, and G ³ is a C ₂ -C ₃ alkylene group. R ³ is a C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted with 1 to 3 groups selected from substituent group β, and G ³ is a C ₂ -C ₃ alkylene group. 5. A method according to any one of claims 1 to 4, selected from claims 1 to 4. The method according to any one of claims 1 to 4, wherein R ³ is a hydrogen atom, and G ³ is a vinyl group. G ¹ is a methylene or ethylene, as described in item 1 one selected from claims 1 to 7 methods. G ¹ is an ethylene, as described in item 1 one selected from claims 1 to 7 methods. METHOD G ² is a single bond, as described in item 1 one selected from claims 1 to 9. G ³ is ethylene, as described in item 1 one selected from claims 1 to 10 methods. The method according to any one of claims 1 to 11, wherein Y is chlorobenzenesulfonyloxy.
The following general formula (4)

(In the formula, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, and R ³ represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group, a C ₁ -C ₄ haloalkanesulfonyloxy group, C _1. A C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted with 1 to 3 groups selected from —C ₄ alkanesulfonyloxy group or substituent group β, and G ¹ represents C ₁ -C ₆ represents an alkylene group, G ³ represents a C ₂ -C ₃ alkylene group, a C ₂ -C ₃ alkenylene group or a C ₂ -C ₃ alkynylene group, and the substituent group β represents a nitro group, a halogen atom, C ₁ A compound having a —C ₄ alkyl group and a C ₁ -C ₄ halogenated alkyl group ”or a salt thereof, and the following general formula (5)

(In the formula, R ¹ is a hydrogen atom, a C ₁ -C ₄ alkoxy group, a C ₇ -C ₁₁ aralkyloxy group which may be substituted with 1 to 3 groups selected from the substituent group β, or a substituent. A phenyl group which may be substituted with 1 to 3 groups selected from the group α, G ² represents a single bond or a methylene group, X represents a hydroxyl group, a C ₁ -C ₄ alkylcarbonyloxy; _group, C 1 -C ₄ shows an alkoxycarbonyloxy group or a halogen atom, the α substituent group, a hydroxyl _group, C 1 -C ₄ alkoxy _group, a group consisting of C 1 -C ₄ halogenated alkyl group, and tetrazolyl. And a compound having the following general formula (1):

(Wherein R ¹ , R ² , R ³ , G ¹ , G ² and G ³ are as defined above), and the compound having the general formula (1) is represented by the following general formula: (2)

(Wherein R ¹ , R ² , R ³ , G ¹ , G ² and G ³ are as defined above, Y represents a leaving group), By treating a compound having the formula (2) with a base, the following general formula (3)

(Wherein R ¹ , R ² , R ³ , G ¹ , G ² and G ³ are as defined above).
The method according to claim 13, wherein R ¹ is a phenyl group which may be substituted with 1 to 3 groups selected from a C ₁ -C ₄ alkoxy group or a substituent group α. The method according to claim 13, wherein R ¹ is a phenyl group which may be substituted with 1 to 3 groups selected from substituent group α. The method according to any one of claims 13 to 15, wherein R ² is a phenyl group substituted with one or two fluorine atoms or chlorine atoms. The method according to any one of claims 13 to 16, wherein R ³ is a hydroxyl group or a protected hydroxyl group, and G ³ is a C ₂ -C ₃ alkylene group. R ³ is a C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted with 1 to 3 groups selected from substituent group β, and G ³ is a C ₂ -C ₃ alkylene group. 17. A method as claimed in any one of claims 13 to 16 selected. The method according to any one of claims 13 to 16, wherein R ³ is a hydrogen atom, and G ³ is a vinyl group. G ¹ is a methylene or ethylene, as described in item 1 one selected from claims 13 to claim 19 method. G ¹ is an ethylene, as described in item 1 one selected from claims 13 to claim 19 method. METHOD G ² is a single bond, as described in item 1 one selected from claims 13 to claim 21. G ³ is ethylene, as described in item 1 one selected from claims 13 to claim 22 method. The method according to any one of claims 13 to 23, wherein X is a chlorine atom or a bromine atom. 25. The method according to any one of claims 13 to 24, wherein Y is chlorobenzenesulfonyloxy.
The following general formula (4)

(In the formula, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, R ³ represents a hydroxyl group, a C ₁ -C ₄ haloalkanesulfonyloxy group, a C ₁ -C ₄ alkanesulfonyloxy group, Or a C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted with 1 to 3 groups selected from the substituent group β, G ¹ represents a C ₁ -C ₆ alkylene group, and G ³ Represents a C ₂ -C ₃ alkylene group, and the substituent group β represents a compound having a nitro group, a halogen atom, a C ₁ -C ₄ alkyl group and a C ₁ -C ₄ halogenated alkyl group) or Its salt.
R ² is 1 or 2 fluorine atoms or a phenyl group substituted with a chlorine atom, a compound or a salt thereof according to claim 26. R ³ is a hydroxyl group, compound or salt thereof according to claim 26 or claim 27. G ¹ is a methylene or ethylene, compound or a salt thereof as described in 1, wherein any one selected from claims 26 to claim 28. G ¹ is an ethylene, a compound or a salt thereof as described in 1, wherein any one selected from claims 26 to claim 28. G ³ is ethylene, a compound or a salt thereof as described in 1, wherein any one selected from claims 26 to claim 30. General formula (4) is the following general formula (4 ′)

32. The compound or a salt thereof according to any one of claims 26 to 31, which is: R ² is 1 or 2 fluorine atoms or a phenyl group substituted by a chlorine atom, R ³ is a hydroxyl group, G ¹ is ethylene, G ³ is an ethylene, claim 32 Or a hydrochloride, sulfate or oxalate thereof.
The following general formula (1)

(In the formula, R ¹ represents a hydrogen atom or a phenyl group optionally substituted by 1 to 3 groups selected from the substituent group α, and R ² represents 1 or 2 halogen atoms. R 1 represents a substituted phenyl group, and R ³ is selected from a hydroxyl group, a protected hydroxyl group, a C ₁ -C ₄ haloalkanesulfonyloxy group, a C ₁ -C ₄ alkanesulfonyloxy group, or a substituent group β A C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted with three groups, G ¹ represents a C ₁ -C ₆ alkylene group, G ² represents a single bond or a methylene group, G ³ represents a C ₂ -C ₃ alkylene group, a C ₂ -C ₃ alkenylene group or a C ₂ -C ₃ alkynylene group, and the substituent group α is a hydroxyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ halogen. Alkyl group and tetrazo It represents the group consisting of Le, the β substituent group, a nitro group, a halogen atom, C ₁ -C ₄ alkyl and C ₁ -C ₄ shows the group consisting of halogenated alkyl groups.) Compound having.
35. The compound according to claim 34, wherein R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from a C ₁ -C ₄ alkoxy group or a substituent group α. The compound according to claim 34, wherein R ¹ is a phenyl group which may be substituted with 1 to 3 groups selected from substituent group α. R ² is 1 or 2 fluorine atoms or a phenyl group substituted by a chlorine atom, the compound described in 1, wherein any one selected from claims 34 to claim 36. R ³ is a hydroxyl group or a protected hydroxyl group, compounds described in 1, wherein any one selected from claims 34 to claim 37. G ¹ is methylene or ethylene, compounds described in 1, wherein any one selected from claims 34 to claim 38. G ¹ is an ethylene, compounds described in 1, wherein any one selected from claims 34 to claim 38. G ² is a bond, compounds described in 1, wherein any one selected from claims 34 to claim 40. G ³ is ethylene, compounds described in 1, wherein any one selected from claims 34 to claim 41. General formula (1) is the following general formula (1 ′)

43. The compound according to any one of claims 34 to 42, wherein: R ¹ is a phenyl group which may be substituted with 1 to 3 groups selected from substituent group α, and R ² is a phenyl group substituted with 1 or 2 fluorine atoms or chlorine atoms 44. The compound of claim 43, wherein R ³ is a hydroxyl group or a protected hydroxyl group, G ¹ is ethylene, G ² is a single bond, and G ³ is ethylene.
The general formula (5) is characterized by substantially comprising the following step A, step B, and step C.

(In the formula, R ¹ is a hydrogen atom, a C ₁ -C ₄ alkoxy group, a C ₇ -C ₁₁ aralkyloxy group which may be substituted with 1 to 3 groups selected from substituent group β, or a substituent. R 1 represents a phenyl group which may be substituted with 1 to 3 groups selected from the group α, R ² represents a phenyl group substituted with 1 or 2 halogen atoms, and G ¹ represents C ¹ ₁ -C ₆ alkylene group, G ² represents a single bond or a methylene group, G ³ represents a C ₂ -C ₃ alkylene group, G ⁴ represents> C-OH or> S → O, The substituent group α represents a group consisting of a hydroxyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ halogenated alkyl group, and tetrazolyl, and the substituent group β represents a nitro group, a halogen atom, or C ₁ -C _4. shows the group consisting of alkyl groups and C ₁ -C ₄ halogenated alkyl group .) Compounds with or manufacturing method of a pharmacologically acceptable salt thereof:
{Here, step A is represented by the general formula (1)

[Wherein R ¹ , R ² , G ¹ , G ² and G ³ are as defined above, and R ³ represents a hydroxyl group, a protected hydroxyl group, a C ₁ -C ₄ haloalkanesulfonyloxy group, a C _1- A C ₄ alkanesulfonyloxy group, or a C ₆ -C ₁₀ arylsulfonyloxy group optionally substituted with 1 to 3 groups selected from the substituent group β, wherein the substituent group β is a nitro group, a halogen _atom, C 1 -C ₄ alkyl and _C 1 -C ₄ group consisting halogenated alkyl group. ]
A compound having the general formula (2)

[Wherein R ¹ , R ² , G ¹ , G ² and G ³ are as defined above, and R ³ and Y are a C ₁ -C ₄ haloalkanesulfonyloxy group and a C ₁ -C ₄ alkane, respectively. A sulfonyloxy group or a C ₆ -C ₁₀ arylsulfonyloxy group optionally substituted with 1 to 3 groups selected from the substituent group β, wherein the substituent group β is a nitro group, a halogen atom, shows the C ₁ -C ₄ alkyl and _C 1 -C ₄ group consisting halogenated alkyl group. A compound having the following formula:
In step B, compound (2) obtained in step A is treated with a base to give a general formula (3)

[Wherein R ¹ , R ² , G ¹ , G ² and G ³ are as defined above, and R ³ represents a C ₁ -C ₄ haloalkanesulfonyloxy group, a C ₁ -C ₄ alkanesulfonyloxy group, Or a C ₆ -C ₁₀ arylsulfonyloxy group optionally substituted by 1 to 3 groups selected from the substituent group β, wherein the substituent group β is a nitro group, a halogen atom, C ₁ -C _A group consisting of ₄ alkyl groups and C ₁ -C ₄ halogenated alkyl groups is shown. A compound having the following formula:
Step C includes the compound (3) obtained in Step B and the general formula (6).

[Wherein G ⁴ is as defined above. And a compound having the general formula (5) to produce a compound having the general formula (5). }.
R ¹ is a C ₁ -C ₄ alkoxy or 1 to 3 phenyl group which may be substituted with a group selected from Substituent group alpha, according to claim 45 methods. 46. The method according to claim 45, wherein R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from substituent group α. R ² is 1 or 2 fluorine atoms or a phenyl group substituted by a chlorine atom, as described in item 1 one selected from claims 45 to claim 47 method. The method according to any one of claims 45 to 48, wherein R ³ of the compound (1) is a hydroxyl group or a protected hydroxyl group. G ¹ is a methylene or ethylene, as described in item 1 one selected from claims 45 to claim 49 method. G ¹ is an ethylene, as described in item 1 one selected from claims 45 to claim 49 method. METHOD G ² is a single bond, as described in item 1 one selected from claims 45 to claim 51. G ³ is ethylene, as described in item 1 one selected from claims 45 to claim 52 method. R ³ and Y of the compound (2) and the compound (3) is chlorobenzene sulfonyloxy, the method described in any one selected from claims 45 to claim 53.
General formula (7)

(Wherein R ² represents a phenyl group substituted with 1 or 2 halogen atoms) and paraformaldehyde are reacted in the presence of a trifluoroborane complex compound and a base. (8)

(Wherein R ² is as defined above).
General formula (7)

(Wherein R ² represents a phenyl group substituted with 1 or 2 halogen atoms) and paraformaldehyde are reacted in the presence of a trifluoroborane complex compound and a base. (8)

(Wherein R ² has the same meaning as described above), and then the compound having the general formula (8) (wherein R ² has the same meaning as described above) In an active solvent, an oxidant is allowed to act in the presence of an asymmetric catalyst prepared from molecular sieves and zirconium (IV) alkoxide and an optically active tartaric acid diester, to give a compound of the general formula (9)

(Wherein R ² is as defined above).
R ² is one or two fluorine atoms or a phenyl group substituted with a chlorine atom, as claimed in claim 55 or claim 56 method. Trifluoroborane complex compounds are trifluoroborane · C ₁ -C ₄ alkyl ether complex, the method described in 1, wherein any one selected from claims 55 to claim 57. 58. The method according to any one of claims 55 to 57, wherein the trifluoroborane complex compound is a trifluoroborane-ethyl ether complex. 60. The method according to any one of claims 55 to 59, wherein the base is an alkali metal hydroxide, alkali metal alkoxide or organic amine. 60. The method according to any one of claims 55 to 59, wherein the base is an alkali metal alkoxide or an organic amine. 60. The method according to any one of claims 55 to 59, wherein the base is sodium methoxide or triethylamine. 63. The method according to any one of claims 56 to 62, wherein the zirconium (IV) alkoxide is zirconium (IV) isopropoxide or zirconium (IV) tert-butoxide. 64. The method according to any one of claims 56 to 63, wherein the optically active tartaric acid diester is diisopropyl tartrate. 65. A method according to any one of claims 56 to 64, wherein the oxidizing agent is cumene hydroperoxide or isopropyl cumyl hydroperoxide.