JP2014101330A - METHOD OF PRODUCING OPTICALLY ACTIVE α-SUBSTITUTED PROLINES - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrial method practically suitable for producing an optically active α-substituted prolines with short process and mild conditions.SOLUTION: A method of producing an optically active α-substituted prolines (6) includes (d) a step of obtaining an optically active N, α-substituted prolines (5) by hydrolysis of an optically active N, α-substituted proline amides (4), and (e) a step of obtaining an optically active α-substituted prolines (6) by eliminating the optically active N, and a protective group Rof the α-substituted prolines (5).

Description

  The present invention relates to an industrial method for producing optically active α-substituted prolines from a chain ketone compound. The optically active α-substituted prolines produced by the present invention are useful compounds in the structural chemistry of peptides and as pharmaceutical intermediates.

  Since optically active α-substituted prolines allow only a very limited twist angle in a peptide containing the optically active α-substituted proline, it is considered that only a peptide having a limited three-dimensional structure is generated with a low degree of rotational freedom. (For example, refer nonpatent literature 1.). Furthermore, it is considered to be useful as a highly selective pharmaceutical partial structure because of its less fluctuation structure, and it is actively used in drug discovery research.

  As a method for synthesizing optically active α-substituted prolines, a method is known in which L-proline is used as a raw material, an amino acid is protected with pivalaldehyde, and then alkylated using a strong base and an alkylating agent (for example, (See Non-Patent Document 2.) As an improved method, there is a method using chloral instead of pivalaldehyde (for example, see Non-Patent Document 3). However, either method requires the use of an expensive strong base such as LDA at an extremely low temperature of −78 ° C., which is not industrially suitable. In addition, these methods have a problem that only the S-form α-substituted proline can be produced from inexpensive L-proline.

  A method of synthesizing optically active α-substituted prolines using an amino acid such as L-alanine as a raw material by an intramolecular cyclization reaction is also known (see, for example, Non-Patent Document 4 and Patent Document 1). However, there is a problem that an expensive strong base such as potassium hexamethyldisilazide or lithium hexamethyldisilazide is required in the intramolecular cyclization reaction step. On the other hand, a method for carrying out a similar reaction using inexpensive potassium hydroxide (see Non-Patent Document 5) has also been reported, but an industrially difficult operation of grinding potassium hydroxide into powder is necessary. In addition, since 30 times volume of DMSO is used as a solvent, there remains a problem that productivity is low. Further, in any case, it is necessary to protect the carboxyl group and the amino group in the intramolecular cyclization reaction step, and there is a drawback that the entire production process is increased due to protection and deprotection.

  A catalytic asymmetric synthesis method using an optically active quaternary ammonium salt is also known (see, for example, Non-Patent Document 6). Although the stereoselectivity and yield of this method are very high, it is necessary to use tertiary butyl ester as a substrate, iodide as an alkylating agent, and cesium hydroxide as a base. All of these materials are industrially expensive, and this method is not suitable for intermediates for medical and agricultural chemicals that require inexpensive production.

  On the other hand, a method is also known in which racemic α-methylproline amide is enzymatically resolved to obtain optically active α-methylproline and optically active α-methylprolineamide (see Non-Patent Document 1). In this document, the enzymatic resolution itself is relatively efficient, but it requires multiple steps to synthesize racemic α-methylprolinamide as a raw material for the resolution. That is, four steps of imine formation of alaninamide and benzaldehyde, addition to acrylonitrile using sodium hydride, hydrolysis of imine, and hydrogenation are required. In addition, although ion exchange resin purification is used to separate (S) -α-methylproline and (R) -α-methylproline amide obtained by enzymatic resolution, the product is diluted with ion exchange resin purification as a dilute aqueous solution. Therefore, a large amount of energy and time are required for the concentration, which is not preferable as an inexpensive industrial production method.

  An example is also known in which α-methylproline is obtained by crystallization without performing ion exchange resin purification (see Non-Patent Document 7). In this document, α-methylproline precursor is reacted with hydrochloric acid to obtain a solution containing α-methylproline hydrochloride, and then reacted with propylene oxide in ethanol to obtain α-methylproline crystals. . However, as a result of investigations by the present inventors, α-methylproline obtained by reacting with propylene oxide in alcohol is not sufficient for use as a pharmaceutical intermediate that requires high purity in terms of purity. As another crystallization method, there is known an example of crystallization using methanol and ethyl acetate after purification of an ion exchange resin (see Non-Patent Documents 2 and 8).

  However, since these methods use ethyl acetate having a relatively low polarity as a solvent, these methods are suitable for removing highly polar α-methylproline optical isomers and impurities having properties close to those of α-methylproline. It is not considered. Moreover, the example of the crystallization using water which is a highly polar solvent is not known. This is because α-methylprolines have very high solubility in water, and it is considered that the recovery rate of α-methylprolines decreases when water is used.

  As a method for producing a racemic α-substituted proline amide in a short process, a method of synthesizing by hydrating 2-cyano-2-substituted pyrrolidines can be considered. Among 2-cyano-2-substituted pyrrolidines that are the key to this method, synthesis examples of 1- (1-phenylethyl) -2-cyano-2-methylpyrrolidine have been reported (see Non-Patent Document 9). ), A special aminonitrile is required, and the target product is obtained only in a low yield of 13%. On the other hand, in another paper of the same author (see Non-Patent Document 10), 2-cyanopyrrolidine having a bicyclo skeleton is obtained in a relatively high yield (up to 80%). The difference in this result is that 2-cyanopyrrolidine is obtained in a high yield in a system in which elimination of the cyano group is suppressed by the bicyclo skeleton, but in the case where such stabilization is not present, 2-cyanopyrrolidine is used. It is difficult to obtain in high yield. An example of synthesizing 2-cyanopyrrolidine having a bicyclo skeleton from 1,7-dichloro-4-heptanone has also been reported (see Non-Patent Document 11). In this example as well, it is clear that the bicyclo skeleton is essential for achieving a high yield. In this report, it is stated that the side reaction is remarkable in the reaction in the hydrous solvent using potassium cyanide, and it is necessary to react with non-aqueous system using acetone cyanohydrin or 2-amino-2-methylpropanenitrile. However, there is a risk of generating hydrocyanic acid gas due to thermal decomposition or the like, and it cannot be said that it is an industrially preferable production method.

  As a compound similar to the present invention, a method of synthesizing a proline derivative from an N-protected proline amide having a bicyclo skeleton is known (see Non-Patent Document 12). The 1-phenylethyl group is removed by hydrolyzing the amide with aqueous hydrochloric acid and then hydrogenating with palladium on carbon. In this document, the proline derivative as a product is purified using an ion exchange resin. Yes. As described above, in the conventional method, in order to remove the acid used in the hydrolysis of the amide and the ammonia to be produced, it is inevitable to purify the ion exchange resin with high production cost.

International Publication No. 2006/110816

Chem. Eur. J. et al. , 2009, 15, 8015. Org. Synth. 1995, 72, 62. Synlett, 1999, 33. J. et al. Am. Chem. Soc. 2006, 128, 15394. J. et al. Am. Chem. Soc. , 2008, 130, 4153. Tetrahedron, 2010, 66, 4900. Tetrahedron Asym. 1998, 9, 2769. J. et al. Poly. Sci. Poly. Chem. Ed. 1977, 15, 1413. Tetrahedron Asym. , 2007, 18, 290. Tetrahedron Asym. 2006, 17, 252. Heterocycles, 1997, 45, 1447. Tetrahedron Asym. , 2010, 21, 2868.

  An object of the present invention is to provide an industrially suitable industrial method for producing optically active α-substituted prolines under a short process and mild conditions.

  As a result of intensive studies by the present inventors in order to solve the above-mentioned problems, a step of hydrolyzing optically active N, α-substituted proline amides to obtain optically active N, α-substituted prolines, the optically active N, It has been found that optically active α-substituted prolines can be obtained by deprotecting a substituent on the nitrogen atom of α-substituted proline amides to obtain optically active α-substituted prolines. It came to be completed. The optically active N, α-substituted proline amide is obtained by reacting a linear ketone compound with a primary amine or a salt thereof, and a cyanating agent to form 2-cyanopyrrolidine, and further converting the 2-cyanopyrrolidine into It can be produced by a step of hydration to give N, α-substituted prolineamides and a step of splitting the N, α-substituted prolineamides into optically active N, α-substituted prolineamides.

That is, according to the present invention, the following inventions are provided.
[1] General formula (6) including the following steps (d) and (e)

(In the formula, R ¹ represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, and R ³ each independently represents a hydrogen atom, An optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted hydroxyl group, an optionally substituted amino group, and optionally substituted. A thiol group or a halogen atom, wherein two or more R ^{3 s} may form one or more ring structures, * represents an asymmetric carbon, and the configuration of the asymmetric carbon : S-form (molar ratio) = 90: 10 to 100: 0 or R-form: S-form (molar ratio) = 10: 90 to 0: 100)) or an optically active α-substituted proline thereof Salt production method;
(D) The following general formula (4)

(Wherein R ¹ , R ³ and * are as defined above, and R ² represents an amino-protecting group). Hydrolyzing the optically active N, α-substituted proline amides or salts thereof By doing so, the general formula (5)

(Wherein each symbol has the same meaning as described above) to obtain an optically active N, α-substituted proline or a salt thereof represented by: and (e) an optically active N represented by the general formula (5), By removing the protective group R ² of the α-substituted prolines or salts thereof, the general formula (6)

(Wherein each symbol has the same meaning as described above), an optically active α-substituted proline or a salt thereof is obtained.
[2] General formula (6) including the following steps (a) to (e)

(Wherein each symbol has the same meaning as in [1] above), a process for producing optically active α-substituted prolines or salts thereof represented
(A) General formula (1)

(Wherein R ¹ and R ³ are as defined above, and X represents a halogen atom or a sulfonyloxy group) a chain ketone compound represented by By reacting, general formula (2)

(Wherein each symbol has the same meaning as in the above [1]), 2-cyanopyrrolidines or salts thereof are obtained;
(B) By hydrating 2-cyanopyrrolidines represented by the general formula (2) or a salt thereof, the general formula (3)

(Wherein each symbol is as defined above), N, α-substituted proline amides or salts thereof are obtained;
(C) By dividing the N, α-substituted proline amides represented by the general formula (3) or a salt thereof, the general formula (4)

(Wherein each symbol has the same meaning as described above), an optically active N, α-substituted proline amide or a salt thereof is obtained;
(D) By hydrolyzing the optically active N, α-substituted proline amides represented by the general formula (4) or a salt thereof, the general formula (5)

(Wherein each symbol has the same meaning as described above) to obtain an optically active N, α-substituted proline or a salt thereof represented by: and (e) an optically active N represented by the general formula (5), By removing the protective group R ² of the α-substituted prolines or salts thereof, the general formula (6)

(Wherein each symbol has the same meaning as described above), an optically active α-substituted proline or a salt thereof is obtained.
[3] Furthermore, the general formula (5)

(Wherein each symbol has the same meaning as in the above [1]), the method according to claim 1 or 2, comprising a purification step of the optically active N, α-substituted proline or a salt thereof. The method wherein the purification method is extraction using a polar organic solvent, or crystallization of N, α-substituted prolines represented by the general formula (5) or a salt thereof as a metal salt.
[4] Furthermore, the general formula (6)

(Wherein each symbol has the same meaning as in the above [1]), a hydrogen halide salt of an optically active α-substituted proline represented by the formula is purified in the presence of an epoxy compound. The method according to 1 or 2.
[5] General formula (6)

(Wherein each symbol has the same meaning as in the above [1]), the optically active α-substituted prolines represented by crystallization from a solvent system containing water, A method for producing optically active α-substituted prolines represented by the general formula (6).
[6] Formula (7)

(Wherein, * represents an asymmetric carbon), or an optically active α-methyl-N- (1′-phenylethyl) proline or a salt thereof.

  According to the present invention, optically active α-substituted prolines that are useful as key synthetic intermediates for pharmaceuticals can be efficiently produced from inexpensive and readily available known compounds.

In the present invention, R ¹ represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.

The “alkyl group” of the “optionally substituted alkyl group” is a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, n A linear alkyl group having 1 to 10 carbon atoms such as butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group; isopropyl group, Examples thereof include branched alkyl groups having 3 to 10 carbon atoms such as 1-methylpropyl group and t-butyl group; cyclic alkyl groups having 3 to 10 carbon atoms such as cyclopropyl group, cyclopentyl group and cyclohexyl group.
Examples of the substituent that the alkyl group may have include a fluorine atom; an alkenyl group having 2 to 6 carbon atoms (eg, vinyl group); an alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group). Etc.]; C 1-6 alkyl group (eg, methyl group, ethyl group, isopropyl group, etc.), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 2-6 alkenyl group 6 to 10 carbon atoms optionally having 1 to 3 substituents selected from a group (eg, vinyl group, etc.), an alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group, etc.), etc. Aryl groups (eg, phenyl group, naphthyl group, etc.) and the like. Although the number of the said substituent is not specifically limited, 1-3 are preferable. When there are two or more substituents, the types of the substituents may be the same or different.
Specific examples of the substituted alkyl group include a benzyl group, a 4-methoxybenzyl group, an allyl group, and a 2-fluoroethyl group.

Examples of the “aryl group” of the “optionally substituted aryl group” include an aromatic hydrocarbon group having 6 to 10 carbon atoms, such as a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
Examples of the substituent that the aryl group may have include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, Isopropyl group, etc.); C2-C6 alkenyl group (eg, vinyl group, etc.); C1-C6 alkoxy group (eg, methoxy group, ethoxy group, etc.); Halogen atom (eg, fluorine atom, chlorine atom) , Bromine atom, iodine atom), alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group, etc.), alkenyl group having 2 to 6 carbon atoms (eg, vinyl group, etc.), An aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents selected from 6 alkoxy groups (eg, methoxy group, ethoxy group, etc.) (eg, phenyl group, naphthyl group, etc.) Etc. Although the number of the said substituent is not specifically limited, 1-3 are preferable. When there are two or more substituents, the types of the substituents may be the same or different.

The “heteroaryl group” of the “optionally substituted heteroaryl group” includes 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom as a ring constituent atom. 5- or 6-membered aromatic heterocyclic groups such as pyrrolyl (eg 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg 2-furyl, 3-furyl), thienyl (eg 2- Thienyl, 3-thienyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (eg, 3-isoxazolyl, 4 -Isoxazolyl, 5-isoxazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazo (Eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (1,2,3-triazol-4-yl, 1, 2,4-triazol-3-yl), oxadiazolyl (1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl), thiadiazolyl (1,2,4- Thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl), tetrazolyl, pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl) , Pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (eg, 2-pyrazinyl, 3-pyrazinyl) ), And the like.
Examples of the substituent that the heteroaryl group may have include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group) , Isopropyl group, etc.); C 2-6 alkenyl group (eg, vinyl group); C 1-6 alkoxy group (eg, methoxy group, ethoxy group, etc.); halogen atom (eg, fluorine atom, chlorine) Atom, bromine atom, iodine atom), alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group), alkenyl group having 2 to 6 carbon atoms (eg, vinyl group), carbon number 1 An aryl group having 6 to 10 carbon atoms (eg, phenyl group, naphthyl group, etc.) optionally having 1 to 3 substituents selected from ˜6 alkoxy groups (eg, methoxy group, ethoxy group, etc.) ) And the like. Although the number of the said substituent is not specifically limited, 1-3 are preferable. When there are two or more substituents, the types of the substituents may be the same or different.

Of these, R ¹ is preferably an optionally substituted alkyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an n-butyl group, a benzyl group, or an allyl group, and particularly preferably. Is a methyl group that exhibits the characteristics of an α-substituted proline with the simplest structure.

In the present invention, R ² represents an amino-protecting group.

  Specific examples of the protecting group for amino group include, but are not limited to, formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, propionyl group, Acyl groups such as benzoyl group and 4-chlorobenzoyl group; alkoxycarbonyl groups which may be substituted such as methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group and allyloxycarbonyl group; benzyl group 4-methoxybenzyl group, 4-bromobenzyl group, 1-phenylethyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl group, carboxyphenylmethyl group, carbamoylphenylmethyl group, 2 -Substituted such as hydroxy-1-phenylethyl group Optionally have an arylalkyl group; an allyl group, an optionally substituted aryl group such as crotyl, propargyl group; a methanesulfonyl group, p- toluenesulfonyl group, a sulfonyl group, such as 2-nitrobenzenesulfonyl group. When the amino-protecting group has an asymmetric point, it may be R-form, S-form, or racemic form.

Among these, R ² is preferably an optionally substituted arylalkyl group or an optionally substituted allyl group, more preferably an arylalkyl group having high stability under a wide range of reaction conditions, More preferred are a benzyl group, 1-phenylethyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl group and carbamoylphenylmethyl group which can be easily removed, and particularly preferred is industrial. In addition, they are a benzyl group, a 1-phenylethyl group, and a carbamoylphenylmethyl group that can be derived from an inexpensive primary amine or a salt thereof.

In the present invention, each R ³ is independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or optionally substituted. A hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, or a halogen atom is shown. If possible, two or more R ^{3 s} may form one or more ring structures.

The “alkyl group” of the “optionally substituted alkyl group” is a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, n A linear alkyl group having 1 to 10 carbon atoms such as butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group; isopropyl group, Examples thereof include branched alkyl groups having 3 to 10 carbon atoms such as 1-methylpropyl group and t-butyl group; cyclic alkyl groups having 3 to 10 carbon atoms such as cyclopropyl group, cyclopentyl group and cyclohexyl group.
Examples of the substituent that the alkyl group may have include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); an alkenyl group having 2 to 6 carbon atoms (eg, vinyl group); carbon C 1-6 alkoxy group (eg, methoxy group, ethoxy group, etc.); C 1-6 alkyl group (eg, methyl group, ethyl group, isopropyl group, etc.), halogen atom (eg, fluorine atom, chlorine atom) , A bromine atom, an iodine atom), 1 to 3 selected from a C 2-6 alkenyl group (eg, vinyl group, etc.), a C 1-6 alkoxy group (eg, methoxy group, ethoxy group, etc.), etc. And an aryl group having 6 to 10 carbon atoms (eg, phenyl group, naphthyl group, etc.) and the like which may have a substituent. Although the number of the said substituent is not specifically limited, 1-3 are preferable. When there are two or more substituents, the types of the substituents may be the same or different.
Specific examples of the substituted alkyl group include a benzyl group, a 4-methoxybenzyl group, an allyl group, and a 2-chloroethyl group.

Examples of the “aryl group” of the “optionally substituted aryl group” include an aromatic hydrocarbon group having 6 to 10 carbon atoms, such as a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
Examples of the substituent that the aryl group may have include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, Isopropyl group, etc.); C2-C6 alkenyl group (eg, vinyl group, etc.); C1-C6 alkoxy group (eg, methoxy group, ethoxy group, etc.); Halogen atom (eg, fluorine atom, chlorine atom) , Bromine atom, iodine atom), alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group, etc.), alkenyl group having 2 to 6 carbon atoms (eg, vinyl group, etc.), An aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents selected from 6 alkoxy groups (eg, methoxy group, ethoxy group, etc.) (eg, phenyl group, naphthyl group, etc.) Etc. Although the number of the said substituent is not specifically limited, 1-3 are preferable. When there are two or more substituents, the types of the substituents may be the same or different.

The “heteroaryl group” of the “optionally substituted heteroaryl group” includes 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom as a ring constituent atom. 5- or 6-membered aromatic heterocyclic groups such as pyrrolyl (eg 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg 2-furyl, 3-furyl), thienyl (eg 2- Thienyl, 3-thienyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (eg, 3-isoxazolyl, 4 -Isoxazolyl, 5-isoxazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazo (Eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (1,2,3-triazol-4-yl, 1, 2,4-triazol-3-yl), oxadiazolyl (1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl), thiadiazolyl (1,2,4- Thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl), tetrazolyl, pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl) , Pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (eg, 2-pyrazinyl, 3-pyrazinyl) ), And the like.
Examples of the substituent that the heteroaryl group may have include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group) , Isopropyl group, etc.); C 2-6 alkenyl group (eg, vinyl group); C 1-6 alkoxy group (eg, methoxy group, ethoxy group, etc.); halogen atom (eg, fluorine atom, chlorine) Atom, bromine atom, iodine atom), alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group), alkenyl group having 2 to 6 carbon atoms (eg, vinyl group), carbon number 1 An aryl group having 6 to 10 carbon atoms (eg, phenyl group, naphthyl group, etc.) optionally having 1 to 3 substituents selected from ˜6 alkoxy groups (eg, methoxy group, ethoxy group, etc.) ) And the like. Although the number of the said substituent is not specifically limited, 1-3 are preferable. When there are two or more substituents, the types of the substituents may be the same or different.

Examples of the optionally substituted hydroxyl group include a hydroxyl group and a protected form thereof; methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-decyloxy group, 1-methylethoxy group, 1,1-dimethylethoxy group. Alkoxy groups having 1 to 10 carbon atoms such as cyclopropyloxy group and cyclohexyloxy group; aryloxy groups having 6 to 10 carbon atoms such as phenyloxy group and 2-naphthyloxy group; 2-thienyloxy group and 3-pyridyl group A heteroaryloxy group such as an oxy group, and the alkoxy group, aryloxy group and heteroaryloxy group are each a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); Alkyl group (eg, methyl group, ethyl group, isopropyl group, etc.); alkenyl group having 2 to 6 carbon atoms (eg, vinyl group, aryl group) Alkoxy group (e.g. having 1 to 6 carbon atoms, a methoxy group, an ethoxy group, etc.); group) an arylalkyl group (e.g., may have any substituent selected from a benzyl group). Although the number of the said substituent is not specifically limited, 1-3 are preferable. When there are two or more substituents, the types of the substituents may be the same or different.
In addition, the protective group used as a protective group for the hydroxyl group is not particularly limited as long as it can be removed under normal conditions, but specific examples thereof include formyl group, acetyl group, chloroacetyl group, propionyl group, benzoyl group and the like. Acyl group; arylalkyl group which may be substituted such as benzyl group, 4-methoxybenzyl group, 4-bromobenzyl group, 1-phenylethyl group; acetal such as methoxymethyl group, ethoxyethyl group, benzyloxymethyl group Type protecting groups; silyl groups such as trimethylsilyl and t-butyldimethylsilyl groups.

The optionally substituted amino group may have one or two arbitrary substituents and / or protecting groups.
Specific examples of the substituent include, but are not limited to, alkyl groups having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group, etc.); alkenyl having 2 to 6 carbon atoms Group (eg, vinyl group, allyl group, etc.); hydroxyl group; C 1-6 alkoxy group (eg, methoxy group, ethoxy group, etc.); arylalkyl group (eg, benzyl group, etc.).
Specific examples of the protecting group include, but are not limited to, formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, propionyl group, benzoyl group, Acyl groups such as 4-chlorobenzoyl group; alkoxycarbonyl groups which may be substituted such as methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, allyloxycarbonyl group; benzyl group, 4- An arylalkyl group which may be substituted such as a methoxybenzyl group, a 4-bromobenzyl group and a 1-phenylethyl group; and a sulfonyl group such as a methanesulfonyl group, a p-toluenesulfonyl group and a 2-nitrobenzenesulfonyl group.

Examples of the thiol group which may be substituted include a thiol group and a protected form thereof; methylthio group, ethylthio group, n-propylthio group, n-butylthio group, n-decylthio group, 1-methylethylthio group, 1,1- C 1-10 alkylthio groups such as dimethylethylthio group, cyclopropylthio group, cyclohexylthio group; arylthio groups having 6-10 carbon atoms such as phenylthio group, 2-naphthylthio group; 2-thienylthio group, 3-pyridylthio A heteroarylthio group such as a group, and the alkylthio group, arylthio group and heteroarylthio group are halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); alkyl group having 1 to 6 carbon atoms (Eg, methyl group, ethyl group, isopropyl group, etc.); C 2-6 alkenyl group (eg, vinyl group, Le group); an alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, etc.); an arylalkyl group (e.g., may have any substituent selected from a benzyl group). Although the number of the said substituent is not specifically limited, 1-3 are preferable. When there are two or more substituents, the types of the substituents may be the same or different.
In addition, the protective group used as a thiol group protector is not particularly limited as long as it can be removed under normal conditions, but specific examples thereof include formyl group, acetyl group, chloroacetyl group, propionyl group, benzoyl group, etc. An acyl group which may be substituted such as benzyl group, 4-methoxybenzyl group, 4-bromobenzyl group, 1-phenylethyl group; methoxymethyl group, ethoxyethyl group, benzyloxymethyl group, etc. Acetal type protecting group; silyl groups such as trimethylsilyl group and t-butyldimethylsilyl group are exemplified.

Specific examples of the halogen atom are a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Of these, R ³ is preferably a hydrogen atom.

  In the present invention, X represents a halogen atom or a sulfonyloxy group.

  Specific examples of the halogen atom are a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  Specific examples of the sulfonyloxy group include, but are not limited to, an alkylsulfonyloxy group which may be substituted such as a methanesulfonyloxy group, a chloromethanesulfonyloxy group, and a trifluoromethanesulfonyloxy group. An arylsulfonyloxy group which may be substituted, such as a p-toluenesulfonyloxy group, a p-chlorobenzenesulfonyloxy group and a 2-nitrobenzenesulfonyloxy group;

  Among these, X is preferably a halogen atom, more preferably the corresponding chain ketone compound is an industrially inexpensive chlorine atom.

  The chain ketone compound represented by the general formula (1) is a compound having a leaving group such as a halogen atom at the 4-position of 1-substituted-1-butanone.

  Specific examples of the chain ketone compound represented by the general formula (1) include 5-fluoro-2-pentanone, 5-chloro-2-pentanone, 5-bromo-2-pentanone, and 5-iodo-2- Pentanone, 5- (methanesulfonyloxy) -2-pentanone, 5- (chloromethanesulfonyloxy) -2-pentanone, 5- (toluenesulfonyloxy) -2-pentanone, 6-chloro-3-hexanone, 6-bromo -3-hexanone, 1-chloro-4-octanone, 6-chloro-2-methyl-3-hexanone, 4-chloro-1-cyclopropyl-1-butanone, 4-chloro-1-cyclohexyl-1-butanone, 4-bromo-1-cyclohexyl-1-butanone, 7-chloro-1-hepten-4-one, 4-chloro-1-phenyl-1-butanone, 4 Bromo-1-phenyl-1-butanone, 4-chloro-1- (4-methoxyphenyl) -1-butanone, 4-chloro-1- (4-chlorophenyl) -1-butanone, 4-chloro-1- ( 2-thienyl) -1-butanone, 4-chloro-1- (3-pyridyl) -1-butanone.

The 2-cyanopyrrolidines represented by the general formula (2) are compounds having a substituent and a cyano group at the 2-position of pyrrolidine and having an amino-protecting group on the nitrogen atom of pyrrolidine.
The 2-cyanopyrrolidines represented by the general formula (2) have an asymmetric point at the 2-position carbon atom of pyrrolidine. When there is no other asymmetric point in the molecule, it may be a racemate or an optically active form of S form or R form having any optical purity of less than 80% ee. The optical purity in this case is preferably 70% ee or less, more preferably 60% ee or less, and particularly preferably 50% ee or less.

  Moreover, when it has a plurality of asymmetric points in the molecule, it may be a diastereomer or a diastereomer mixture having any stereochemistry. In this case, the diastereomeric purity may be any value, and generally, diastereoisomer having an arbitrary ratio of R-form: S-form (molar ratio) = 10: 90 to 90:10 with respect to the stereochemistry at the 2-position of pyrrolidine. Or a mixture of diastereomers. Preferably, for the stereochemistry of pyrrolidine 2-position, R-form: S-form (molar ratio) = 15: 85-85: 15, more preferably R-form: S-form (molar ratio) = 20: 80-80: 20, Particularly preferably, R-form: S-form (molar ratio) = 25: 75 to 75:25. Further, a mixture having a lower ratio of R-form to S-form is preferred because it can be synthesized more easily.

  Specific examples of the 2-cyanopyrrolidines represented by the general formula (2) include 1-benzyl-2-cyano-2-methylpyrrolidine, 2-cyano-2-methyl-1- (1-phenylethyl) Pyrrolidine, 2-cyano-2-methyl-1- (1- (1-naphthyl) ethyl) pyrrolidine, 2-cyano-2-methyl-1- (1- (2-naphthyl) ethyl) pyrrolidine, 1- (carbamoyl) Phenylmethyl) -2-cyano-2-methylpyrrolidine, 2-cyano-2-ethyl-1- (1-phenylethyl) pyrrolidine, 2-butyl-2-cyano-1- (1-phenylethyl) pyrrolidine, 2 -Cyano-2- (1-methylethyl) -1- (1-phenylethyl) pyrrolidine, 2-cyano-2-cyclopropyl-1- (1-phenylethyl) pyrrolidine, 2-cyano 2-cyclohexyl-1- (1-phenylethyl) pyrrolidine, 2-allyl-2-cyano-1- (1-phenylethyl) pyrrolidine, 2-cyano-2-phenyl-1- (1-phenylethyl) Pyrrolidine, 2-cyano-2- (4-methoxyphenyl) -1- (1-phenylethyl) pyrrolidine, 2- (4-chlorophenyl) -2-cyano-1- (1-phenylethyl) pyrrolidine, 2-cyano Examples include -1- (1-phenylethyl) -2- (2-thienyl) pyrrolidine and 2-cyano-1- (1-phenylethyl) -2- (3-pyridyl) pyrrolidine.

  The N, α-substituted proline amides represented by the general formula (3) and the optically active N, α-substituted proline amides represented by the general formula (4) are substituted at the 2-position of pyrrolidine. And a carbamoyl group and an amino-protecting group on the nitrogen atom of pyrrolidine.

  The N, α-substituted proline amides represented by the general formula (3) have an asymmetric point at the carbon atom at the 2-position of pyrrolidine to which the carbamoyl group is bonded. When there is no other asymmetric point in the molecule, it may be a racemate or an optically active form of S form or R form having any optical purity of less than 80% ee. The optical purity in this case is preferably 70% ee or less, more preferably 60% ee or less, and particularly preferably 50% ee or less.

  Moreover, when it has a plurality of asymmetric points in the molecule, it may be a diastereomer or a diastereomer mixture having any stereochemistry. In this case, the diastereomeric purity may be any value, and generally, diastereoisomer having an arbitrary ratio of R-form: S-form (molar ratio) = 10: 90 to 90:10 with respect to the stereochemistry at the 2-position of pyrrolidine. Or a mixture of diastereomers. Preferably, for the stereochemistry of pyrrolidine 2-position, R-form: S-form (molar ratio) = 15: 85-85: 15, more preferably R-form: S-form (molar ratio) = 20: 80-80: 20, Particularly preferably, R-form: S-form (molar ratio) = 25: 75 to 75:25. Further, a mixture having a lower ratio of R-form to S-form is preferred because it can be synthesized more easily.

  The optically active N, α-substituted proline amides represented by the general formula (4) have an asymmetric point at the pyrrolidine 2-position carbon atom to which the carbamoyl group is bonded. When there is no other asymmetric point in the molecule, any optically active form of S form or R form having any optical purity of 80% ee or more may be used. The optical purity in this case is preferably 90% ee or higher, more preferably 95% ee or higher. In the case of a pharmaceutical product and its intermediate, high optical purity is required, and particularly preferably 99% ee or higher.

  Moreover, when it has a plurality of asymmetric points in the molecule, it may be a diastereomer or a diastereomer mixture having any stereochemistry. In this case, the diastereomeric purity may be any value, and usually R-form: S-form (molar ratio) = 90: 10 to 100: 0 or R-form: S-form (mol) for the stereochemistry at the 2-position of pyrrolidine. Ratio) = 10: 90 to 0: 100, and the higher the purity, the smaller the purification load in the subsequent step. Therefore, R form: S form (molar ratio) = 97.5: 2.5-100 : 0 or R-form: S-form (molar ratio) = 2.5: 97.5 to 0: 100. In the case of pharmaceuticals and intermediates thereof, high optical purity is required, so R form: S form (molar ratio) = 99: 1 to 100: 0 or R form: S form (molar ratio) = 1: 99-0: 100, particularly preferably R-form: S-form (molar ratio) = 99.5: 0.5-100: 0 or R-form: S-form (molar ratio) = 0.5: 99.5-0 : 100.

  Specific examples of the N, α-substituted proline amides represented by the general formula (3) and the optically active N, α-substituted proline amides represented by the general formula (4) include N-benzyl. -Α-methylprolinamide, α-methyl-N- (1-phenylethyl) prolinamide, α-methyl-N- (1- (1-naphthyl) ethyl) prolinamide, α-methyl-N- (1- (2-naphthyl) ethyl) prolinamide, N- (carbamoylphenylmethyl) -α-methylprolinamide, α-ethyl-N- (1-phenylethyl) prolinamide, α-butyl-N- (1-phenylethyl) ) Prolinamide, α- (1-methylethyl) -N- (1-phenylethyl) prolinamide, α-cyclopropyl-N- (1-phenylethyl) prolinamide, α-cyclohex Ru-N- (1-phenylethyl) prolinamide, α-allyl-N- (1-phenylethyl) prolinamide, α-phenyl-N- (1-phenylethyl) prolinamide, α- (4-methoxyphenyl) ) -N- (1-phenylethyl) prolinamide, α- (4-chlorophenyl) -N- (1-phenylethyl) prolinamide, N- (1-phenylethyl) -α- (2-thienyl) prolinamide N- (1-phenylethyl) -α- (3-pyridyl) prolinamide.

  The above compound may have a basic functional group and may form a salt. Such salts include inorganic acid salts (eg, hydrochloride, sulfate, nitrate, phosphate, etc.); organic acid salts (eg, acetate, propionate, methanesulfonate, 4-toluenesulfonate, Oxalate, maleate, etc.); tartaric acids (L-tartaric acid, D-tartaric acid, (2S, 3S) -dibenzoyltartaric acid, (2R, 3R) -dibenzoyltartaric acid, (2S, 3S) -di (p-toluoyl) ) Tartaric acid, (2R, 3R) -di (p-toluoyl) tartaric acid, etc.]; mandelic acids ((S) -mandelic acid, (R) -mandelic acid etc.); amino acid derivatives (N-acetyl-L-alanine, N -Acetyl-L-phenylglycine, N-acetyl-D-phenylglycine, N-benzyl-L-phenylglycine, N-benzyl-D-phenylglycine, N-acetyl-L-phenylaracine , N-acetyl-L-glutamic acid, N-acetyl-L-aspartic acid, etc.); optically active sulfonic acid ((S) -10-camphorsulfonic acid, (R) -10-camphorsulfonic acid, (S)- 1-phenylethanesulfonic acid, (R) -1-phenylethanesulfonic acid and the like). Among these, a salt with an optically active acid that can be expected to have a large solubility difference between diastereomeric salts, more preferably a salt with tartaric acids and mandelic acids, and particularly preferably an inexpensive salt. It is a salt with L-tartaric acid, D-tartaric acid, (S) -mandelic acid, (R) -mandelic acid.

  Of the optically active N, α-substituted proline amides represented by the general formula (4), N- (1′-phenylethyl) -α-methylprolinamide, an optically active acid and / or an achiral acid Specific examples of the salt of (2S, 1'S) -N- (1'-phenylethyl) -α-methylprolinamide D-tartrate, (2S, 1'S) -N- (1 ' -Phenylethyl) -α-methylprolinamide L-tartrate, (2S, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide D-tartrate, (2S, 1 ′ R) -N- (1′-phenylethyl) -α-methylprolinamide L-tartrate, (2R, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide D- Tartrate, (2R, 1′R) -N- (1′-phenylethyl) α-methylprolinamide, L-tartrate, (2R, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide, D-tartrate, (2R, 1 ′S) -N— (1′-Phenylethyl) -α-methylprolinamide · L-tartrate, (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide · (S) -mandelate , (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide, (R) -mandelate, (2S, 1′R) -N- (1′-phenylethyl) -Α-methylprolinamide • (S) -mandelate, (2S, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide • (R) -mandelate, (2R, 1′R) -N- (1′-phenylethyl) -α-methylproline amino (S) -mandelate, (2R, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide, (R) -mandelate, (2R, 1 ′S) —N -(1'-Phenylethyl) -α-methylprolinamide, (S) -mandelate, (2R, 1'S) -N- (1'-phenylethyl) -α-methylprolinamide, (R) -Mandelate, (2S, 1'S) -N- (1'-phenylethyl) -α-methylprolinamide 4-toluenesulfonate, (2R, 1'R) -N- (1'- Phenylethyl) -α-methylprolinamide 4-toluenesulfonate, (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide oxalate, (2R, 1 ′ R) -N- (1′-phenylethyl) -α-methylprolinamide It includes oxalate.

  The optically active N, α-substituted prolines represented by the general formula (5) are compounds having a substituent and a carboxyl group at the 2-position of pyrrolidine and an amino-protecting group on the nitrogen atom of pyrrolidine. is there. Further, the optically active N, α-substituted prolines represented by the general formula (5) are optically active substances having an asymmetric point at the carbon atom to which the carboxyl group is bonded, and other asymmetry is present in the molecule. When it does not have a point, any of S body and R body may be sufficient. The optical purity may be any value, but is preferably 80% ee or more, more preferably 90% ee or more, and still more preferably 95% ee or more. In the case of pharmaceuticals and intermediates thereof, high optical purity is required. Particularly preferably, it is 99% ee or more.

  When it has a plurality of asymmetric points in the molecule, it may be a diastereomer or diastereomer mixture having any stereochemistry. The diastereomeric purity and / or optical purity may be any value, but for the stereochemistry at the 2-position of pyrrolidine, preferably R-form: S-form (molar ratio) = 90: 10-100: 0 or R-form: S Body (molar ratio) = 10: 90 to 0: 100, more preferably R body: S body (molar ratio) = 97.5: 2.5 to 100: 0 or R body: S body (molar ratio) = 2 5: 97.5 to 0: 100, more preferably R-form: S-form (molar ratio) = 99: 1 to 100: 0 or R-form: S-form (molar ratio) = 1: 99 to 0: 100 is there. In the case of pharmaceuticals and intermediates thereof, since high optical purity is required, R-form: S-form (molar ratio) = 99.5: 0.5 to 100: 0 or R-form: S-form (molar ratio) ) = 0.5: 99.5 to 0: 100.

  Specific examples of the optically active N, α-substituted prolines represented by the general formula (5) include (S) -N-benzyl-α-methylproline and (R) -N-benzyl-α-methylproline. (2S, 1 ′S) -α-methyl-N- (1′-phenylethyl) proline, (2S, 1′R) -α-methyl-N- (1′-phenylethyl) proline, (2R, 1 ′S) -α-methyl-N- (1′-phenylethyl) proline, (2R, 1′R) -α-methyl-N- (1′-phenylethyl) proline, (2S, 1 ′S) -Α-methyl-N- (1 '-(1-naphthyl) ethyl) proline, (2S, 1'R) -α-methyl-N- (1'-(1-naphthyl) ethyl) proline, (2R, 1 ′S) -α-methyl-N- (1 ′-(1-naphthyl) ethyl) proline, (2R, 1′R -Α-methyl-N- (1 '-(1-naphthyl) ethyl) proline, (2S, 1'S) -α-methyl-N- (1'-(2-naphthyl) ethyl) proline, (2S, 1′R) -α-methyl-N- (1 ′-(2-naphthyl) ethyl) proline, (2R, 1 ′S) -α-methyl-N- (1 ′-(2-naphthyl) ethyl) proline (2R, 1′R) -α-methyl-N- (1 ′-(2-naphthyl) ethyl) proline, (2S, 1 ′S) -N- (carbamoylphenylmethyl) -α-methylproline, 2S, 1′R) -N- (carbamoylphenylmethyl) -α-methylproline, (2R, 1 ′S) -N- (carbamoylphenylmethyl) -α-methylproline, (2R, 1′R) -N -(Carbamoylphenylmethyl) -α-methylproline, (2S, 1 ′ S) -α-ethyl-N- (1′-phenylethyl) proline, (2S, 1′R) -α-ethyl-N- (1′-phenylethyl) proline, (2R, 1 ′S) -α -Ethyl-N- (1'-phenylethyl) proline, (2R, 1'R) -α-ethyl-N- (1'-phenylethyl) proline, (2S, 1'S) -α-butyl-N -(1'-phenylethyl) proline, (2S, 1'R) -α-butyl-N- (1'-phenylethyl) proline, (2R, 1'S) -α-butyl-N- (1 ' -Phenylethyl) proline, (2R, 1′R) -α-butyl-N- (1′-phenylethyl) proline, (2S, 1 ′S) -α- (1-methylethyl) -N- (1 '-Phenylethyl) proline, (2S, 1'R) -α- (1-methylethyl) -N- (1'-F Nylethyl) proline, (2R, 1 ′S) -α- (1-methylethyl) -N- (1′-phenylethyl) proline, (2R, 1′R) -α- (1-methylethyl) -N -(1'-phenylethyl) proline, (2S, 1'S) -α-cyclopropyl-N- (1'-phenylethyl) proline, (2S, 1'R) -α-cyclopropyl-N- ( 1′-phenylethyl) proline, (2R, 1 ′S) -α-cyclopropyl-N- (1′-phenylethyl) proline, (2R, 1′R) -α-cyclopropyl-N- (1 ′ -Phenylethyl) proline, (2S, 1'S) -α-cyclohexyl-N- (1'-phenylethyl) proline, (2S, 1'R) -α-cyclohexyl-N- (1'-phenylethyl) Proline, (2R, 1 ′S) -α-cyclohe Xyl-N- (1′-phenylethyl) proline, (2R, 1′R) -α-cyclohexyl-N- (1′-phenylethyl) proline, (2S, 1 ′S) -α-allyl-N— (1′-phenylethyl) proline, (2S, 1′R) -α-allyl-N- (1′-phenylethyl) proline, (2R, 1 ′S) -α-allyl-N- (1′- Phenylethyl) proline, (2R, 1′R) -α-allyl-N- (1′-phenylethyl) proline, (2S, 1 ′S) -α-phenyl-N- (1′-phenylethyl) proline (2S, 1′R) -α-phenyl-N- (1′-phenylethyl) proline, (2R, 1 ′S) -α-phenyl-N- (1′-phenylethyl) proline, (2R, 1′R) -α-phenyl-N- (1′-phenylethyl) proline (2S, 1 ′S) -α- (4-methoxyphenyl) -N- (1′-phenylethyl) proline, (2S, 1′R) -α- (4-methoxyphenyl) -N- (1 ′ -Phenylethyl) proline, (2R, 1'S) -α- (4-methoxyphenyl) -N- (1'-phenylethyl) proline, (2R, 1'R) -α- (4-methoxyphenyl) -N- (1'-phenylethyl) proline, (2S, 1'S) -α- (4-chlorophenyl) -N- (1'-phenylethyl) proline, (2S, 1'R) -α- ( 4-chlorophenyl) -N- (1′-phenylethyl) proline, (2R, 1 ′S) -α- (4-chlorophenyl) -N- (1′-phenylethyl) proline, (2R, 1′R) -Α- (4-chlorophenyl) -N- (1'-phenylethyl) Rollin, (2S, 1 ′S) -N- (1′-phenylethyl) -α- (2-thienyl) proline, (2S, 1′R) -N- (1′-phenylethyl) -α- ( 2-thienyl) proline, (2R, 1 ′S) -N- (1′-phenylethyl) -α- (2-thienyl) proline, (2R, 1′R) -N- (1′-phenylethyl) -Α- (2-thienyl) proline, (2S, 1'S) -N- (1'-phenylethyl) -α- (3-pyridyl) proline, (2S, 1'R) -N- (1 ' -Phenylethyl) -α- (3-pyridyl) proline, (2R, 1 ′S) -N- (1′-phenylethyl) -α- (3-pyridyl) proline, (2R, 1′R) -N -(1'-phenylethyl) -α- (3-pyridyl) proline.

The above compound may have a basic or acidic functional group, and may form a salt. Examples of such salts include inorganic acid salts (for example, hydrochloride, sulfate, nitrate, phosphate, etc.); organic acid salts (for example, acetate, propionate, methanesulfonate, 4-toluenesulfonate) , Oxalate, maleate, etc.); tartaric acids (L-tartaric acid, D-tartaric acid, (2S, 3S) -dibenzoyltartaric acid, (2R, 3R) -dibenzoyltartaric acid, (2S, 3S) -di (p- Toluoyl) tartaric acid, (2R, 3R) -di (p-toluoyl) tartaric acid, etc.); mandelic acids ((S) -mandelic acid, (R) -mandelic acid etc.); amino acid derivatives (N-acetyl-L-alanine, N-acetyl-L-phenylglycine, N-acetyl-D-phenylglycine, N-benzyl-L-phenylglycine, N-benzyl-D-phenylglycine, N-acetyl-L-pheny Alanine, N-acetyl-L-glutamic acid, N-acetyl-L-aspartic acid, etc.); optically active sulfonic acid ((S) -10-camphorsulfonic acid, (R) -10-camphorsulfonic acid, (S)- 1-phenylethanesulfonic acid, (R) -1-phenylethanesulfonic acid, etc.); alkali metal salts (for example, sodium salts, potassium salts, etc.); alkaline earth metal salts (for example, calcium salts, magnesium salts, barium salts, etc.) Organic base salts (for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.) and the like.
Among these, a salt of a carboxylic acid and a base such as an alkali metal salt, an alkaline earth metal salt, or an organic base salt is more preferable, and an alkali that generally has low solubility in water and can be purified from an aqueous solution. An earth metal salt, particularly preferably a calcium salt or a barium salt.

  Specific examples of the salt of the optically active N, α-substituted proline represented by the general formula (5) include (S) -N-benzyl-α-methylproline calcium and (S) -N-benzyl-α. -Methylproline barium, (R) -N-benzyl-α-methylproline calcium, (R) -N-benzyl-α-methylproline barium, (2S, 1'S) -α-methyl-N- (1 ' -Phenylethyl) proline calcium, (2S, 1'S) -α-methyl-N- (1'-phenylethyl) proline barium, (2S, 1'R) -α-methyl-N- (1'-phenyl) Ethyl) proline calcium, (2S, 1′R) -α-methyl-N- (1′-phenylethyl) proline barium, (2R, 1 ′S) -α-methyl-N- (1′-phenylethyl) Proline calcium, (2 , 1 ′S) -α-methyl-N- (1′-phenylethyl) proline barium, (2R, 1′R) -α-methyl-N- (1′-phenylethyl) proline calcium, (2R, 1 'R) -α-methyl-N- (1′-phenylethyl) proline barium.

The optically active α-substituted prolines represented by the general formula (6) are compounds having a substituent and a carboxyl group at the 2-position of pyrrolidine.
The optically active α-substituted prolines represented by the general formula (6) are optically active substances having an asymmetric point at the carbon atom to which the carboxyl group is bonded, and other asymmetric points are present in the molecule. When it does not have, either S body and R body may be sufficient. The optical purity may be any value, but is preferably 80% ee or more, more preferably 90% ee or more, and still more preferably 95% ee or more. In the case of pharmaceuticals and intermediates thereof, since high optical purity is required, it is particularly preferably 99% ee or higher.

  When it has a plurality of asymmetric points in the molecule, it may be a diastereomer or diastereomer mixture having any stereochemistry. The diastereomeric purity may be any value, but the stereochemistry at the 2-position of pyrrolidine is preferably R-form: S-form (molar ratio) = 90: 10 to 100: 0 or R-form: S-form (molar ratio). = 10: 90 to 0: 100, more preferably R form: S form (molar ratio) = 97.5: 2.5 to 100: 0 or R form: S form (molar ratio) = 2.5: 97. 5-0: 100, more preferably R-form: S-form (molar ratio) = 99: 1-100: 0 or R-form: S-form (molar ratio) = 1: 99-0: 100. In the case of pharmaceuticals and intermediates thereof, since high optical purity is required, R-form: S-form (molar ratio) = 99.5: 0.5 to 100: 0 or R-form: S-form (molar ratio) ) = 0.5: 99.5 to 0: 100.

  The purity of the optically active α-substituted prolines represented by the general formula (6) may be any value, but is generally 90 weight percent or more and / or 90 Area% or more by HPLC analysis. In the case of pharmaceuticals and intermediates thereof, since high purity is required, preferably 95 weight percent or more, and / or 95 Area% or more by HPLC analysis, more preferably 98 weight percent or more, and / or 98 Area by HPLC analysis. % Or more, particularly preferably 99 weight percent or more, and / or 99 Area% or more by HPLC analysis.

  Specific examples of the optically active α-substituted prolines represented by the general formula (6) include (S) -α-methylproline, (R) -α-methylproline, (S) -α-ethylproline, (R) -α-ethylproline, (S) -α-butylproline, (R) -α-butylproline, (S) -α- (1-methylethyl) proline, (R) -α- (1- Methylethyl) proline, (S) -α-cyclopropylproline, (R) -α-cyclopropylproline, (S) -α-cyclohexylproline, (R) -α-cyclohexylproline, (S) -α-allyl Proline, (R) -α-allylproline, (S) -α-phenylproline, (R) -α-phenylproline, (S) -α- (4-methoxyphenyl) proline, (R) -α- ( 4-methoxyphenyl) proline, (S -Α- (4-chlorophenyl) proline, (R) -α- (4-chlorophenyl) proline, (S) -α- (2-thienyl) proline, (R) -α- (2-thienyl) proline, ( S) -α- (3-pyridyl) proline and (R) -α- (3-pyridyl) proline.

The above compound has a basic or acidic functional group and may form a salt. Examples of such salts include inorganic acid salts (for example, hydrochloride, sulfate, nitrate, phosphate, etc.); organic acid salts (for example, acetate, propionate, methanesulfonate, 4-toluenesulfonate) , Oxalate, maleate, etc.); tartaric acids (L-tartaric acid, D-tartaric acid, (2S, 3S) -dibenzoyltartaric acid, (2R, 3R) -dibenzoyltartaric acid, (2S, 3S) -di (p- Toluoyl) tartaric acid, (2R, 3R) -di (p-toluoyl) tartaric acid, etc.); mandelic acids ((S) -mandelic acid, (R) -mandelic acid etc.); amino acid derivatives (N-acetyl-L-alanine, N-acetyl-L-phenylglycine, N-acetyl-D-phenylglycine, N-benzyl-L-phenylglycine, N-benzyl-D-phenylglycine, N-acetyl-L-pheny Alanine, N-acetyl-L-glutamic acid, N-acetyl-L-aspartic acid, etc.); optically active sulfonic acid ((S) -10-camphorsulfonic acid, (R) -10-camphorsulfonic acid, (S)- 1-phenylethanesulfonic acid, (R) -1-phenylethanesulfonic acid, etc.); alkali metal salts (for example, sodium salts, potassium salts, etc.); alkaline earth metal salts (for example, calcium salts, magnesium salts, barium salts, etc.) Organic base salts (for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.) and the like.
In addition, when the optically active α-substituted proline represented by the general formula (6) is used as a pharmaceutical intermediate, in the case of an acid or base salt, neutralization is required. It is preferable that the optically active α-substituted prolines represented by (1) do not form a salt.

The optically active α-methyl-N- (1′-phenylethyl) proline represented by the above formula (7) has a methyl group and a carboxyl group at the 2-position of pyrrolidine, and 1-phenyl on the nitrogen atom of pyrrolidine. A compound having an ethyl group.
The optically active α-methyl-N- (1′-phenylethyl) proline has two asymmetric points, the 2-position of pyrrolidine and the substituent (1′-position) on the pyrrolidine nitrogen atom. It may be a diastereomer or a mixture of diastereomers having chemistry. Since the asymmetric carbon of the substituent on the pyrrolidine nitrogen atom (position 1 ') is derived from the primary amine or its salt α-methylbenzylamine used in the corresponding step (a), it is epimerized during the reaction. When there is no, the optical purity of the α-methylbenzylamine used is an asymmetric purity at the 1 ′ position. The absolute configuration at the 1 ′ position may be any of R, S, and racemate, and the asymmetric purity may be any value, but the isomer about the pyrrolidine 2 position is determined by the asymmetry at the 1 ′ position. Since it can be divided, it is preferably high, and R-form: S-form (molar ratio) = 90: 10 to 100: 0 or R-form: S-form (molar ratio) = 10: 90-0: 100, more preferably R isomer: S isomer (molar ratio) = 97.5: 2.5 to 100: 0 or R isomer: S isomer (molar ratio) = 2.5: 97.5 to 0: 100, especially Preferably, R form: S form (molar ratio) = 99.5: 0.5 to 100: 0 or R form: S form (molar ratio) = 0.5: 99.5 to 0: 100.
The absolute configuration at the 2-position of pyrrolidine may be any of R-form, S-form and racemate, and the asymmetric purity thereof may be any value. -Since it becomes the optical purity of methylproline, it is preferably high, and R-form: S-form (molar ratio) = 90: 10-100: 0 or R-form: S-form (molar ratio) = 10: 90- 0: 100, more preferably R-form: S-form (molar ratio) = 97.5: 2.5 to 100: 0 or R-form: S-form (molar ratio) = 2.5: 97.5-0: 100 Particularly preferably, R-form: S-form (molar ratio) = 99.5: 0.5 to 100: 0 or R-form: S-form (molar ratio) = 0.5: 99.5 to 0: 100.

The optically active α-methyl-N- (1′-phenylethyl) proline represented by the above formula (7) has a basic amino group and an acidic carboxyl group, and forms a salt. Also good. Examples of such salts include inorganic acid salts (for example, hydrochloride, sulfate, nitrate, phosphate, etc.); organic acid salts (for example, acetate, propionate, methanesulfonate, 4-toluenesulfonate) , Oxalate, maleate, etc.); tartaric acids (L-tartaric acid, D-tartaric acid, (2S, 3S) -dibenzoyltartaric acid, (2R, 3R) -dibenzoyltartaric acid, (2S, 3S) -di (p- Toluoyl) tartaric acid, (2R, 3R) -di (p-toluoyl) tartaric acid, etc.); mandelic acids ((S) -mandelic acid, (R) -mandelic acid etc.); amino acid derivatives (N-acetyl-L-alanine, N-acetyl-L-phenylglycine, N-acetyl-D-phenylglycine, N-benzyl-L-phenylglycine, N-benzyl-D-phenylglycine, N-acetyl-L-pheny Alanine, N-acetyl-L-glutamic acid, N-acetyl-L-aspartic acid, etc.); optically active sulfonic acid ((S) -10-camphorsulfonic acid, (R) -10-camphorsulfonic acid, (S)- 1-phenylethanesulfonic acid, (R) -1-phenylethanesulfonic acid, etc.); alkali metal salts (for example, sodium salts, potassium salts, etc.); alkaline earth metal salts (for example, calcium salts, magnesium salts, barium salts, etc.) Organic base salts (for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.) and the like.
Among these, a salt of a carboxylic acid and a base such as an alkali metal salt, an alkaline earth metal salt, or an organic base salt is more preferable, and an alkali that generally has low solubility in water and can be purified from an aqueous solution. An earth metal salt, particularly preferably a calcium salt or a barium salt.

  Specific examples of the optically active α-methyl-N- (1′-phenylethyl) proline represented by the above formula (7) and salts thereof include (2S, 1 ′S) -α-methyl-N- (1 '-Phenylethyl) proline, (2S, 1'R) -α-methyl-N- (1'-phenylethyl) proline, (2R, 1'S) -α-methyl-N- (1'-phenylethyl) ) Proline, (2R, 1′R) -α-methyl-N- (1′-phenylethyl) proline, (2S, 1 ′S) -α-methyl-N- (1′-phenylethyl) proline calcium, (2S, 1 ′S) -α-methyl-N- (1′-phenylethyl) proline barium, (2S, 1′R) -α-methyl-N- (1′-phenylethyl) proline calcium, (2S , 1′R) -α-methyl-N- (1′-phenylethyl) pro Nbarium, (2R, 1 ′S) -α-methyl-N- (1′-phenylethyl) proline calcium, (2R, 1 ′S) -α-methyl-N- (1′-phenylethyl) proline barium, (2R, 1′R) -α-methyl-N- (1′-phenylethyl) proline calcium, (2R, 1′R) -α-methyl-N- (1′-phenylethyl) proline barium, and the like. .

Step (a)
The 2-cyanopyrrolidines represented by the general formula (2) can be synthesized by reacting the chain ketone compound represented by the general formula (1) with a primary amine or a salt thereof and a cyanating agent. .
As the chain ketone compound represented by the general formula (1), 5-chloro-2-pentanone, 4-chloro-1-phenyl-1-butanone and the like can be purchased as reagents. Other compounds can be optionally produced by methods such as Friedel-Crafts reaction of 3-chloropropionic acid chloride and aromatic compounds, Claisen condensation of γ-butyrolactone and esters, and subsequent treatment with hydrogen halide ( For example, see Chem. Pharm. Bull., 1989, 37, 958.).

The primary amine or salt thereof used in step (a) may be any compound that can provide a primary amine in the reaction system, and specific examples thereof are listed below, but are not limited thereto. , Benzylamine, 4-methoxybenzylamine, 4-bromobenzylamine, α-methylbenzylamine, 1- (1-naphthyl) ethylamine, α-phenylglycine, α-phenylglycinamide, α-phenylglycinol, allylamine, Primary amines such as propargylamine; and salts thereof. You may mix and use 2 or more types chosen from these primary amine or its salt. The primary amine or a salt thereof may be a salt such as hydrochloride, acetate, carbonate or the like, and if it has an asymmetric point, it may be R-form, S-form, racemate. There may be. Among these, an inexpensive benzylamine, (S) -α-methylbenzylamine and (R) -α-methylbenzylamine which can be reacted diastereoselectively by having an asymmetric point are preferable. is there.
The amount of the primary amine or salt thereof used is 0.5 to 10 equivalents, preferably 0.7 to 3 equivalents, more preferably 0.8 to the chain ketone compound represented by the general formula (1). -1.5 equivalents.

Specific examples of the cyanating agent used in the step (a) are listed below, but are not limited thereto, but inorganic cyanides such as sodium cyanide, potassium cyanide, copper cyanide; trimethylsilyl cyanide, tetrabutyl Organic cyanides such as ammonium cyanide and tributyltin cyanide; cyanic acid; cyanohydrins such as acetone cyanohydrin; and aminonitrile compounds such as 2-amino-2-methylpropanenitrile. A plurality of cyanating agents selected from these may be mixed and used. In addition, when the cyanating agent to be used is an aminonitrile compound, it can also serve as a primary amine or a salt thereof. Among these, inorganic cyanides that are less likely to generate highly toxic hydrocyanic acid gas by natural decomposition are preferable, and industrially inexpensive sodium cyanide and potassium cyanide are more preferable.
The excessive use of the cyanating agent is not preferable because it generates a high concentration of cyan waste liquid, and is 1 to 3 equivalents, preferably 1.0 to 1.5 equivalents, with respect to the chain ketone compound represented by the general formula (1). More preferably, it is 1.0 to 1.2 equivalents.

  In the step (a), it is preferable to add an acidic substance for the purpose of making the inside of the reaction system weakly acidic to weakly alkaline. The addition of the acidic substance is carried out for the purpose of suppressing side reactions such as cyclopropanation that can occur due to strong alkalinity and allowing the reaction to proceed smoothly. Therefore, it may be a compound such as a carboxylic acid ester that generates an acid by hydrolysis or the like in the reaction system even if it is not acidic at the time of addition, or may be a salt of a weak base such as an ammonium salt and an acid. Specific examples thereof include, but are not limited to, mineral acids such as hydrochloric acid, sulfuric acid and nitric acid; carboxylic acids such as acetic acid, formic acid, trifluoroacetic acid, benzoic acid and oxalic acid; methanesulfonic acid Sulfonic acids such as toluenesulfonic acid; phosphoric acids such as phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and disodium hydrogen phosphate; carboxylic acid esters such as ethyl acetate, methyl acetate, and methyl benzoate; Mineral acid ammonium salts such as ammonium chloride, ammonium sulfate, ammonium hydrogen sulfate, ammonium nitrate; inorganic acid ammonium salts such as ammonium carbonate, ammonium hydrogen carbonate, monoammonium phosphate, diammonium hydrogen phosphate; ammonium acetate, ammonium formate, ammonium citrate And organic acid ammonium salts such as A plurality of acidic substances selected from these may be mixed and used.

Among these acidic substances, preferred are weakly acidic carboxylic acids, carboxylic acid esters, or phosphoric acids having a high buffer capacity that can keep the reaction solution weakly acidic even when hydrogen chloride is generated by the reaction. More preferred are carboxylic acids, and particularly preferred are acetic acid and formic acid which are industrially inexpensive.
The amount of the acidic substance used may be such that it can be partially neutralized so as not to be strongly alkaline, and is 0.01 to 10 equivalents, preferably 0.1 to the chain ketone compound represented by the general formula (1). -5 equivalents, more preferably 0.3-3 equivalents.

  The solvent used in the step (a) is not particularly limited as long as it does not adversely affect the reaction. Specifically, hydrocarbon solvents such as hexane, heptane, benzene, toluene, etc .; ethyl ether, propyl ether, cyclopentyl methyl ether Ether solvents such as t-butyl methyl ether and tetrahydrofuran; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene; ester solvents such as ethyl acetate and butyl acetate; acetone, methyl ethyl ketone and methyl isobutyl ketone Ketone solvents; Amide solvents such as dimethylformamide and N-methylpyrrolidone; Carbonate ester solvents such as dimethyl carbonate and diethyl carbonate; Nitrile solvents such as acetonitrile; Sulfur containing substances such as dimethyl sulfoxide and sulfolane Solvent; methanol, ethanol, 2-propanol, alcohol solvents such t- butanol; water and the like. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio. Preferred solvents include tetrahydrofuran, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, alcohol that dissolves the chain ketone compound represented by the general formula (1), the primary amine or a salt thereof, and / or a cyanating agent. System solvent, water, and a mixed solvent containing these, more preferably, sodium cyanide and potassium cyanide which are preferable cyanating agents, and acidic substances and the like which are preferably added are relatively well dissolved, and the inside of the reaction system is Alcohol solvents that can suppress side reactions by making them weakly acidic to weakly alkaline, water, and mixed solvents containing these are particularly preferable, and mixed solvents containing water and water are particularly preferable. Moreover, as a usage-amount of a solvent, although arbitrary quantity of solvents can be used, it is 1-50 times volume amount normally with respect to the chain ketone compound represented by the said General formula (1), Preferably it is 1 -20 times volume, more preferably 2-10 times volume.

  The reaction temperature in step (a) is not particularly limited as long as it does not adversely affect the reaction, but is usually -20 to 120 ° C, preferably 10 to 80 ° C, more preferably 30 to 70 ° C. is there.

  The reaction time in the step (a) is not particularly limited as long as it does not adversely affect the reaction, but it is preferably performed in the range of 10 minutes to 24 hours from the viewpoint of suppressing the production cost, more preferably 1 to 10 hours.

  The 2-cyanopyrrolidines represented by the general formula (2) obtained in the step (a) can be purified by a method such as crystallization, extraction and / or distillation, and the step (b) without purification. It can also be used for the hydration reaction. At this time, sufficient extraction and water removal can be achieved only by extraction, so that no further purification operation is performed, and if necessary, the concentration operation is performed and then used in the next step to simplify work and increase productivity. It is preferable because it increases.

  The solvent used for extraction is not particularly limited, but hydrocarbon solvents such as hexane, heptane, benzene and toluene; ether solvents such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether and tetrahydrofuran; dichloromethane, chloroform , Halogenated hydrocarbon solvents such as dichloroethane and chlorobenzene; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; carbonate solvents such as dimethyl carbonate and diethyl carbonate; methanol, ethanol And alcohol solvents such as 2-propanol, 1-butanol and t-butanol. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio, or only the reaction solvent may be used as the extraction solvent without adding the solvent during extraction. When the reaction solvent is only water, the extraction may be performed by removing the separated aqueous layer without using an organic solvent. Preferable extraction solvents include hexane, heptane, toluene, ethyl acetate, t-butanol, a reaction solvent, or a mixed solvent thereof, and it is more preferable to perform extraction without adding an organic solvent in order to increase productivity.

Step (b)
The N, α-substituted proline amides represented by the general formula (3) can be synthesized by hydrating the 2-cyanopyrrolidines represented by the general formula (2).

The hydration reaction in step (b) can be carried out in the presence of a catalyst that promotes the hydration reaction from nitrile to amide. Specific examples of the catalyst used in the hydration reaction include, but are not limited to, hydrogen peroxide; hydroperoxides such as t-butyl hydroperoxide; peracetic acid, metachloroperbenzoic acid. Organic peracids such as persulfuric acid and periodic acid; inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; organic acids such as trifluoromethanesulfonic acid, methanesulfonic acid and trifluoroacetic acid Inorganic bases such as sodium hydroxide, potassium hydroxide and potassium carbonate; complex catalysts such as [{Rh (OMe) (cod)} ₂ ] PCy ₃ , {PtH (PMe ₂ OH) (PMe ₂ O) ₂ H} An enzyme having nitrile hydratase activity, and the like. A plurality of catalysts selected from these may be mixed and used.
Among these, a preferable catalyst varies depending on a substituent on nitrogen of the 2-cyanopyrrolidine represented by the general formula (2), but R ² may be an arylalkyl group which may be substituted or a substituted group. In the case of an allyl group, an inorganic acid, an organic acid, a complex catalyst, and an enzyme that can suppress side reactions such as decomposition of an unstable substrate are preferable, and an industrially inexpensive inorganic acid is more preferable.
On the other hand, when R ² is an acetyl group or a t-butoxycarbonyl group, a preferred catalyst is a combination of a hydrogen peroxide solution and an inorganic base, a complex catalyst, and an enzyme capable of performing a hydration reaction under mild conditions. More preferred is a combination of an industrially inexpensive hydrogen peroxide solution and an inorganic base.
The preferred amount of use varies depending on the activity of the catalyst used, but is generally 0.01 to 100 equivalents, preferably 0.02 to 20 equivalents, more preferably 2-cyanopyrrolidines represented by the general formula (2). Is 0.1 to 10 equivalents.

  In the step (b), a solvent may be used as necessary. The solvent to be used is not particularly limited as long as it does not adversely affect the reaction, and specifically, hydrocarbon solvents such as hexane, heptane, benzene, toluene, etc .; ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl Ether solvents such as ether and tetrahydrofuran; Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene; Ester solvents such as ethyl acetate and butyl acetate; Ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; Amide solvents such as formamide and N-methylpyrrolidone; Carbonate ester solvents such as dimethyl carbonate and diethyl carbonate; Nitrile solvents such as acetonitrile; Sulfur-containing solvents such as dimethyl sulfoxide and sulfolane; Lumpur, ethanol, 2-propanol, alcohol solvents such t- butanol; water and the like. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio. Preferred solvents include toluene, ethyl acetate, tetrahydrofuran, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, alcohol solvents, water, and mixed solvents thereof, more preferably alcohol solvents, water, and mixtures thereof. It is a solvent. Moreover, as a usage-amount of a solvent, although arbitrary quantity of solvents can be used, it is 0-50 times volume amount normally with respect to 2-cyanopyrrolidines represented with the said General formula (2), Preferably It is 0-20 times volume, More preferably, it is 0-10 times volume. In particular, in the case where the catalyst is a preferred inorganic acid, an excess solvent reduces the activity of the catalyst, so the preferred amount of solvent used is 0 to 5 times volume, more preferably 0 to 1 times volume.

  The reaction temperature in step (b) is not particularly limited as long as it does not adversely affect the reaction, but is usually -20 to 120 ° C, preferably 10 to 80 ° C, more preferably 30 to 70 ° C. is there.

  The reaction time in step (b) is not particularly limited as long as it does not adversely affect the reaction, but it is preferably performed in the range of 10 minutes to 24 hours from the viewpoint of suppressing production cost, more preferably 1 to 10 hours.

  The N, α-substituted proline amides represented by the general formula (3) obtained in the step (b) can be purified by a method such as extraction, distillation and / or crystallization, and the step without purification. It can also be used in the resolution reaction of (c).

  The solvent used for extraction and / or crystallization is not particularly limited, but is a hydrocarbon solvent such as hexane, heptane, cyclohexane, benzene, toluene; ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether, tetrahydrofuran, etc. Ether solvents such as: dichloromethane, chloroform, dichloroethane, chlorobenzene and other halogenated hydrocarbon solvents; ethyl acetate, butyl acetate and other ester solvents; methyl ethyl ketone, methyl isobutyl ketone and other ketone solvents; dimethyl carbonate, diethyl carbonate, etc. Carbonic acid ester solvents; alcohol solvents such as 1-butanol, 2-butanol, and 1-hexanol are listed. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio. Preferred extraction solvents include hexane, heptane, cyclohexane, toluene, ethyl acetate, 1-butanol or a mixed solvent thereof.

  Crystallization here refers to the addition of a poor solvent, acid, base, or the like to the solution, or the normal crystallization of taking out the target product as crystals by lowering the solubility by azeotropic removal of a rich solvent such as water. It also includes recrystallization in which the obtained crude crystals are dissolved in a suitable solvent and then recrystallized. The crystals obtained here may be α-substituted proline amides not containing an acid or base component, or α-substituted proline amides and acid or base salts.

Step (c)
An N, α-substituted prolinamide isomer mixture represented by the above general formula (3), wherein the stereochemistry at the 2-position of pyrrolidine is R-form: S-form (molar ratio) = 90: 10 to 10:90. By splitting, the stereochemistry of the 2-position of pyrrolidine is R-form: S-form (molar ratio) = 90: 10-100: 0 or R-form: S-form (molar ratio) = 10: 90-0: 100 The optically active N, α-substituted proline amides represented by the general formula (4) can be obtained.
Although it will not specifically limit if it is a method which can be divided | segmented efficiently, Specifically, (f) Separation by diastereomeric salt formation; (g) Separation by column chromatography is mentioned. The dividing step of the present invention may be either a single step of step (f) or (g), or may combine the steps of step (f) or (g).

Step (f): Resolution by diastereomeric salt formation The resolution by diastereomeric salt formation in step (f) means that the N, α-substituted prolineamide isomer mixture represented by the general formula (3) is pyrrolidine. When there is no asymmetric point other than the 2-position, an optically active acid or an N, α-substituted prolineamide isomer mixture is a diastereomeric mixture having a plurality of asymmetric points. This is a method in which an acid is allowed to act and the produced crystalline and / or amorphous salt is separated by a method such as filtration. By this operation, the stereochemistry at the 2-position of pyrrolidine is R-form: S-form (molar ratio) = 90: 10 to 100: 0 or R-form: S-form (molar ratio) = 10: 90 to 0: 100. Optically active N, α-substituted proline amides represented by the above general formula (4) are obtained.

Specific examples of the optically active acid used in the step (f) are listed below, but are not limited thereto. L-tartaric acid, D-tartaric acid, (2S, 3S) -dibenzoyltartaric acid, (2R, 3R) -dibenzoyltartaric acid, (2S, 3S) -di (p-toluoyl) tartaric acid, tartaric acids such as (2R, 3R) -di (p-toluoyl) tartaric acid; (S) -mandelic acid, (R) -mandel Mandelic acids such as acids; N-acetyl-L-alanine, N-acetyl-L-phenylglycine, N-acetyl-D-phenylglycine, N-benzyl-L-phenylglycine, N-benzyl-D-phenylglycine, Amino acid derivatives such as N-acetyl-L-phenylalanine, N-acetyl-L-glutamic acid, N-acetyl-L-aspartic acid; (S) -10-camphor Acid, (R)-10-camphorsulfonic acid, (S)-1-phenyl-ethanesulfonic acid, (R)-1-optically active acid such as phenyl ethanesulfonic acid. Of these, tartaric acids and mandelic acids which are industrially inexpensive and generally exhibit high resolution are preferred.
Specific examples of the achiral acid used in the step (f) are listed below, but are not limited thereto, but mineral acids such as hydrochloric acid, sulfuric acid, nitric acid; acetic acid, formic acid, trifluoroacetic acid, benzoic acid, Examples thereof include carboxylic acids such as oxalic acid, maleic acid and succinic acid; and sulfonic acids such as methanesulfonic acid and toluenesulfonic acid. Of these, hydrochloric acid, acetic acid, benzoic acid, oxalic acid, maleic acid, succinic acid, and toluenesulfonic acid are preferable because they are industrially inexpensive and generally have high salt crystallinity.
In addition, when the optically active acid and / or achiral acid used is a divalent or higher acid having a plurality of acidic groups, the diastereomeric salt to be generated may be a one-to-one salt or a one-to-two or more salt. There may be.
The amount of the optically active acid and / or achiral acid used is 0.1 to 10 equivalents with respect to the N, α-substituted prolineamide isomer mixture represented by the general formula (3), and the excess use is a crystal. In order to prevent the formation, the amount is preferably 0.2 to 3 equivalents, more preferably 0.3 to 1 equivalents. In addition, the usage-amount here is the equivalent of the acid used for salt formation.

The solvent used in the step (f) is not particularly limited, but is a hydrocarbon solvent such as hexane, heptane, benzene, and toluene; an ether solvent such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether, and tetrahydrofuran. Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; dimethyl carbonate, diethyl carbonate and the like Carbonate ester solvents; Nitrile solvents such as acetonitrile; Sulfur-containing solvents such as dimethyl sulfoxide and sulfolane; Methanol, ethanol, 2-propanol, 1-butanol, 2-butanol Alcohol solvents such as t- butanol; water and the like. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio.
Preferable solvents include N, α-substituted prolineamide isomer mixtures represented by the above general formula (3), diastereoisomers having sufficient solubility in optically active acids or achiral acids. It is preferable that the solubility of the Mer salt is sufficiently low, and ether solvents such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether and tetrahydrofuran; ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate; methanol, Alcohol solvents such as ethanol, 2-propanol, 1-butanol, 2-butanol, and t-butanol, and mixed solvents of these solvents and arbitrary solvents, more preferably esters such as ethyl acetate, isopropyl acetate, and butyl acetate System solvents and mixed solvents of these solvents and optional solvents. .
Moreover, you may accelerate | stimulate crystallization by adding the solvent with low solubility of a diastereomeric salt to a reaction solution. Examples of the solvent used at this time include hydrocarbon solvents such as hexane, heptane, benzene, and toluene; ester solvents such as ethyl acetate, isopropyl acetate, and butyl acetate.
The amount of the solvent used is usually 1 to 50 times the volume of the N, α-substituted prolineamide isomer mixture represented by the general formula (3), and the fluidity of the precipitated diastereomeric salt is Since the amount which can be ensured is required and the productivity is higher when the amount used is smaller, it is preferably 2 to 20 times volume, more preferably 3 to 10 times volume.

  A seed crystal may be added to induce crystallization. The diastereomeric salt obtained in step (f) can be used as a seed crystal. Further, after dissolving an optically active N, α-substituted prolineamide represented by the above general formula (4) and an optically active acid or an achiral acid, the solution is concentrated to dryness, cooled, physically It may be obtained by performing an operation such as impact.

  Although the temperature of a process (f) does not have limitation in particular, Usually, -20-120 degreeC, Preferably it is -10-80 degreeC, More preferably, it is 0-70 degreeC. In the case of using a seed crystal, it is preferable to add the seed crystal at a high temperature with relatively high solubility and gradually cool it in order to obtain a crystal with high purity.

  In step (f), resolution may be achieved by increasing the diastereomeric purity and / or optical purity of the filtrate. However, since it is generally easy to increase the purity of the crystals, the diastereoisomers obtained as crystals It is preferred to achieve resolution by increasing the diastereomeric purity of the mer salt. In addition, when the diastereomeric purity and / or optical purity of the optically active N, α-substituted proline amides represented by the above general formula (4) is insufficient, the purity can be increased by a method such as recrystallization. It is preferable to increase.

  The diastereomeric purity and / or optical purity of the optically active N, α-substituted proline amides represented by the general formula (4) obtained in the step (f) may be any value, but the purity is low. Since it is necessary to increase the purity outside this step, the stereochemistry at the 2-position of pyrrolidine is preferably R-form: S-form (molar ratio) = 90: 10 to 100: 0 or R-form: S-form (molar ratio). = 10: 90 to 0: 100, more preferably R form: S form (molar ratio) = 97.5: 2.5 to 100: 0 or R form: S form (molar ratio) = 2.5: 97. It is preferable that it is 5-0: 100. In the case of pharmaceuticals and intermediates thereof, high optical purity is required, so R form: S form (molar ratio) = 99: 1 to 100: 0 or R form: S form (molar ratio) = 1: 99-0: 100, particularly preferably R-form: S-form (molar ratio) = 99.5: 0.5-100: 0 or R-form: S-form (molar ratio) = 0.5: 99.5-0 : 100.

The diastereomeric salt of the optically active N, α-substituted proline amides represented by the above general formula (4) obtained in the step (f) can be obtained by combining the optically active α-substituted proline amides with the optically active α-substituted proline amides by a method such as extraction. Acid and / or achiral acid can be separated. The separated optically active acid and / or achiral acid may be recovered and reused.
When the reaction is continued after step (f), the diastereomeric salt may be used as a raw material, and an optical compound represented by the general formula (4) in which an optically active acid and / or an achiral acid is separated. Active N, α-substituted proline amides may be used as a raw material.

Step (g): Separation by Column Chromatography Separation by column chromatography in step (g) means that the N, α-substituted prolinamide isomer mixture represented by the above general formula (3) In some cases, each diastereomer is separated by passing through a column packed with an achiral packing. By this operation, optically active α-substituted proline amides represented by the general formula (4) are obtained.

Examples of column chromatography used in step (g) include, but are not limited to, silica gel column chromatography using spherical silica gel (neutral) and spherical silica gel (acidic); 18, reverse phase column chromatography using silica gel to which a linear alkyl group having 8 carbon atoms or the like is bonded; column chromatography using a styrene-divinylbenzene synthetic adsorbent, and the like. Specific examples of the synthetic adsorbent include HP20, HP21, SP70, SP207, SP700, SP825, and SP850 manufactured by Mitsubishi Chemical Corporation. Among these, preferred are silica gel column chromatography that is inexpensive and easy to use repeatedly, and column chromatography that uses a synthetic adsorbent, more preferably a synthetic adsorbent that can use an inexpensive aqueous solvent as an eluent. Column chromatography using
The separation method may be batch column chromatography for completely eluting the charged sample each time, or continuous column chromatography using a simulated moving bed.

The solvent used in the step (g) is not particularly limited, but is a hydrocarbon solvent such as hexane, heptane, benzene or toluene; an ether solvent such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether or tetrahydrofuran. Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; dimethyl carbonate, diethyl carbonate and the like Carbonate ester solvents; Nitrile solvents such as acetonitrile; Sulfur-containing solvents such as dimethyl sulfoxide and sulfolane; Methanol, ethanol, 2-propanol, 1-butanol, 2-butanol Alcohol solvents such as t- butanol; water and the like. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio.
The preferred solvent varies depending on the type of column chromatography used, but in the case of preferred column chromatography using a synthetic adsorbent, a ketone solvent; a nitrile solvent; an alcohol solvent; water is preferred, and an inexpensive acetone is more preferred. Methanol and water.
Moreover, you may add the additive for pH adjustment as needed. Specific examples of the additive include acids such as acetic acid and formic acid; salts such as ammonium acetate, sodium acetate, and ammonium chloride; bases such as ammonia and sodium hydroxide, and the like. May be.

  When the optically active α-substituted proline amide represented by the general formula (4) obtained in the step (g) has an asymmetric point only on the carbon atom to which the carbamoyl group is bonded, the optically active α-substituted proline amide should be 80% ee or more. Is preferable, 90% ee is more preferable, and 95% ee or more is further preferable. In the case of pharmaceuticals and intermediates thereof, high optical purity is required, so 99% ee or more is particularly preferable. In addition, when there are a plurality of asymmetric points in the molecule, R-form: S-form (molar ratio) = 90: 10 to 100: 0 or R-form: S-form (molar ratio) for the stereochemistry at the 2-position of pyrrolidine = 10: 90 to 0: 100, R-form: S-form (molar ratio) = 97.5: 2.5-100: 0 or R-form: S-form (molar ratio) = 2.5: More preferably, it is 97.5-0: 100. In the case of pharmaceuticals and intermediates thereof, high optical purity is required, so R form: S form (molar ratio) = 99: 1 to 100: 0 or R form: S form (molar ratio) = 1: 99.5-0: 100, R-form: S-form (molar ratio) = 99.5: 0.5-100: 0 or R-form: S-form (molar ratio) = 0.5: 99.5 A ratio of 0: 100 is particularly preferable.

Step (d)
The optically active N, α-substituted proline represented by the general formula (5) is obtained by replacing the optically active N, α-substituted proline amide represented by the general formula (4) with one equivalent or more of water. Below, it can be synthesized by hydrolysis.

The hydrolysis reaction in the step (d) can be performed in the presence of a catalyst and / or a reaction reagent for hydrolyzing the amide to a carboxylic acid. Specific examples of the catalyst and / or reaction reagent used in the hydrolysis reaction include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; trifluoromethanesulfone Examples include acids, organic acids such as methanesulfonic acid and trifluoroacetic acid; inorganic bases such as sodium hydroxide, potassium hydroxide and potassium carbonate; enzymes having amidase activity. A plurality of catalysts selected from these may be mixed and used.
Of these, preferred catalysts and / or reaction reagents are industrially inexpensive inorganic acids, organic acids, inorganic bases and enzymes, and more preferred are inorganic acids.
The preferred amount to be used varies depending on the activity of the catalyst and / or reaction reagent to be used, but is generally 0.01 to 100 equivalents with respect to the optically active N, α-substituted prolinamides represented by the general formula (4), preferably Is 0.02 to 20 equivalents, more preferably 0.1 to 10 equivalents.

  In the step (d), a solvent may be used as necessary. The solvent to be used is not particularly limited as long as it does not adversely affect the reaction, and specifically, hydrocarbon solvents such as hexane, heptane, benzene, toluene, etc .; ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl Ether solvents such as ether and tetrahydrofuran; Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene; Ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; Sulfur-containing solvents such as dimethyl sulfoxide and sulfolane; Methanol Alcohol solvents such as ethanol, 2-propanol, 1-butanol and t-butanol; water and the like. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio. Preferable solvents include toluene, tetrahydrofuran, acetone, dimethyl sulfoxide, alcohol solvents, water, and mixed solvents thereof, and alcohol solvents, water, and mixed solvents thereof are more preferable. Moreover, as a usage-amount of a solvent, although arbitrary quantity of solvents can be used, it is 0-50 times normally with respect to optically active N, (alpha)-substituted prolinamides represented by the said General formula (4). Volume amount, preferably 0 to 20 times volume, more preferably 0 to 10 times volume. In particular, in the case where the catalyst is a preferred inorganic acid, an excess solvent reduces the activity of the catalyst, so the preferred amount of solvent used is 0 to 5 times volume, more preferably 0 to 1 times volume.

  The reaction temperature in step (d) is not particularly limited as long as it does not adversely affect the reaction, but is usually -20 to 120 ° C, preferably 10 to 80 ° C, more preferably 30 to 70 ° C. is there.

  The reaction time in step (d) is not particularly limited as long as it does not adversely affect the reaction, but it is preferably performed in the range of 10 minutes to 24 hours from the viewpoint of suppressing production cost, more preferably 1 to 10 hours.

  The optically active N, α-substituted prolines represented by the general formula (5) obtained in the step (d) can be used in the next step without purification, but the purification load in the subsequent steps is reduced. Therefore, it is preferable to purify. In particular, when an inorganic acid which is a preferred catalyst and / or reaction reagent is used, it is preferable to remove the salt in the step (d) because an inorganic acid and a salt of ammonia produced by the reaction are mixed. The purification method is not particularly limited as long as it can efficiently remove salts and impurities. Specific examples include extraction with a polar organic solvent and crystallization as a metal salt.

The solvent used for extraction with a polar organic solvent is not particularly limited, but ether solvents such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether, and tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, and chlorobenzene Solvents; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; carbonate solvents such as dimethyl carbonate and diethyl carbonate; nitrile solvents such as acetonitrile and propionitrile; Examples include alcohol solvents such as butanol, 2-butanol, and 1-hexanol. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio. A preferable extraction solvent is an alcohol solvent excellent in extraction of a highly polar substance, and more preferably 1-butanol.
In addition, for the purpose of increasing the recovery rate of the optically active N, α-substituted prolines represented by the general formula (5), it is preferable to repeatedly extract the separated aqueous layer with an organic solvent. The number of re-extraction is preferably 1 to 10 times, more preferably 2 to 6 times, and if the number of repetitions is large, the working time increases and becomes complicated, so 2 to 4 times is particularly preferable.

  It is preferable to appropriately control the pH during extraction in order to increase the extraction efficiency of optically active N, α-substituted prolines having both a carboxyl group and an amino group. The range of preferable pH is 2-7, More preferably, it is 3-6, Most preferably, it is 4-5.

  Although the solvent used for crystallization is not particularly limited, specifically, hydrocarbon solvents such as hexane, heptane, benzene and toluene; ether systems such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether and tetrahydrofuran Solvent; Halogenated hydrocarbon solvent such as dichloromethane, chloroform, dichloroethane, chlorobenzene; Ketone solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone; Sulfur-containing solvent such as dimethyl sulfoxide, sulfolane; Methanol, ethanol, 2-propanol, Examples include alcohol solvents such as 1-butanol and t-butanol; water and the like. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio.

  When a preferred inorganic acid is used for the hydrolysis reaction, the reaction solution contains inorganic acid and ammonia generated by hydrolysis, so these can be dissolved. Water or a mixture of water and a solvent miscible with water A solvent or the like is preferable, and an alcohol solvent, water, or a mixed solvent thereof is more preferable. Moreover, as a usage-amount of a solvent, although arbitrary amounts of a solvent can be used, it is 1-50 times volume normally with respect to the optically active N, (alpha)-substituted proline represented by the said General formula (5). Amount, preferably 2 to 20 times volume, more preferably 3 to 10 times volume.

Crystallization here refers to the addition of a poor solvent, acid, base, or the like to the solution, or the normal crystallization of taking out the target product as crystals by lowering the solubility by azeotropic removal of a rich solvent such as water. It also includes recrystallization in which the obtained crude crystals are dissolved in a suitable solvent and then recrystallized. The crystals obtained here may be optically active N, α-substituted prolines that do not contain an acid or base component, or optically active N, α-substituted prolines and an acid or base salt.
The optically active N, α-substituted prolines represented by the general formula (5) have high solubility in water, which is a preferable solvent for crystallization, or a mixed solvent of water and a mixed solvent of water. It is preferable to crystallize active N, α-substituted prolines as metal salts. In general, since alkaline earth metal salts of carboxylic acids are sparingly soluble in water and other solvents, it is more preferable to precipitate crystals as alkaline earth metal salts, and crystals as calcium salts and barium salts. It is particularly preferred.
As a preferred method for crystallizing a metal salt of optically active N, α-substituted prolines, a metal hydroxide and / or a solution thereof may be added to a solution containing optically active N, α-substituted prolines. After making the solution alkaline, a neutral salt such as metal chloride and / or a solution thereof may be added. Further, a solution containing optically active N, α-substituted prolines may be added to a solution containing a metal.

  A metal salt of optically active N, α-substituted prolines obtained by crystallization as a metal salt can be converted to an optically active N, α-substituted proline containing no salt by reacting with an acid. The method is not particularly limited as long as the salt can be removed, but it is suspended in a solvent, the salt is exchanged by adding a stronger acid than the optically active N, α-substituted prolines, and the metal of the added acid that is normally precipitated It is preferable to remove the salt by filtration or the like because optically active N, α-substituted prolines can be obtained more easily than extraction or the like.

The acid used for removing the salt is not particularly limited as long as it is stronger than the optically active N, α-substituted prolines capable of salt exchange. Specifically, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid; Carboxylic acids such as formic acid, acetic acid, propionic acid, butanoic acid, hexanoic acid, trifluoroacetic acid, benzoic acid and oxalic acid; sulfonic acids such as methanesulfonic acid and toluenesulfonic acid; phosphoric acid, sodium dihydrogen phosphate, phosphoric acid Examples thereof include phosphoric acids such as potassium dihydrogen and disodium hydrogen phosphate. A plurality of acids selected from these may be mixed and used.
Among these acids, preferred are carboxylic acids that do not form a salt with optically active N, α-substituted prolines even when added in excess, and more preferred are formic acid, acetic acid, propionic acid, butanoic acid, and hexanoic acid. Particularly preferred are industrially inexpensive acetic acid and propionic acid.
The usage-amount of an acidic substance is 0.8-10 equivalent with respect to optically active N, (alpha)-substituted proline metal salt, Preferably it is 1.0-5 equivalent, More preferably, it is 1.1-2 equivalent.

The solvent used for removing the salt is not particularly limited. Specifically, hydrocarbon solvents such as hexane, heptane, benzene and toluene; ethers such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether and tetrahydrofuran Solvents: Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene; Ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate; Ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; Dimethyl sulfoxide and sulfolane And other sulfur-containing solvents such as methanol, ethanol, 2-propanol, 1-butanol, and t-butanol. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio.
Among these solvents, preferred are ether solvents, ester solvents, ketone solvents, alcohol solvents with high solubility of optically active N, α-substituted prolines produced by salt exchange, and more preferred are the following: Alcohol solvents which are preferable solvents in the step (e) are methanol, and ethanol is particularly preferable. Moreover, as a usage-amount of a solvent, although arbitrary amounts of a solvent can be used, it is 1-50 times volume normally with respect to the optically active N, (alpha)-substituted proline represented by the said General formula (5). Amount, preferably 2 to 20 times volume, more preferably 3 to 10 times volume.

  The solution of the optically active N, α-substituted prolines obtained by removing the salt may be used in the next step after concentration to obtain crystals, but may be used in the next step as it is, This is preferable for simplifying the operation.

Step (e)
The optically active α-substituted proline represented by the general formula (6) removes the protecting group of the optically active N, α-substituted proline represented by the general formula (5), that is, the substituent R ² is removed. It can be synthesized by converting to a hydrogen atom.

The reaction for removing the protecting group in the step (e) varies depending on the kind of the protecting group used. In the case of an arylalkyl group in which R ² is a more preferred protecting group, a hydrogenation reaction using a metal catalyst, Examples include a reaction using a Lewis acid such as boron tribromide, a reaction using an oxidizing agent such as 2,3-dichloro-5,6-dicyanoparabenzoquinone, and the like. Among these, a hydrogenation reaction using a metal catalyst in which impurities derived from the raw material do not remain after filtration of the catalyst is preferable.

Specific examples of the metal catalyst used include, but are not limited to, palladium catalysts such as palladium carbon and palladium hydroxide carbon; platinum catalysts such as platinum carbon and platinum oxide; Raney nickel and nickel carbon And a nickel catalyst. Among these, a palladium catalyst that is inexpensive and easy to recover is preferable.
The amount of the metal catalyst used is usually 0.0001 to 1 equivalent, preferably 0.001 to 0.2 equivalent, more preferably the optically active N, α-substituted proline represented by the general formula (5). Is 0.005 to 0.1 equivalent.

The solvent used in the step (e) is not particularly limited as long as it does not adversely influence the reaction. Specifically, hydrocarbon solvents such as hexane, heptane, benzene, toluene, etc .; ethyl ether, propyl ether, cyclopentyl methyl ether Ether solvents such as t-butyl methyl ether and tetrahydrofuran; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; dimethylformamide, dimethylacetamide, N An amide solvent such as methylpiperidinone; a sulfur-containing solvent such as dimethyl sulfoxide and sulfolane; an alcohol solvent such as methanol, ethanol, 2-propanol, 1-butanol and t-butanol; Etc. The. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio. Preferable solvents are alcohol solvents having high solubility of the optically active N, α-substituted proline as a raw material and the optically active α-substituted proline as a product, more preferably methanol and ethanol.
Moreover, as a usage-amount of a solvent, although arbitrary amounts of a solvent can be used, it is 1-50 times volume normally with respect to the optically active N, (alpha)-substituted proline represented by the said General formula (5). Amount, preferably 2 to 20 times volume, more preferably 3 to 10 times volume.

  The reaction temperature in step (e) is not particularly limited as long as it does not adversely affect the reaction, but is usually -20 to 120 ° C, preferably 10 to 80 ° C, more preferably 30 to 70 ° C. is there.

  The reaction time of the step (e) is not particularly limited as long as it does not adversely affect the reaction, but it is preferably performed in the range of 10 minutes to 24 hours from the viewpoint of suppressing the production cost, more preferably 1 to 10 hours.

  When a preferable metal catalyst is used in the step (e), it can be purified with an ion exchange resin or the like. However, after removing the catalyst by filtration, the optically active α- represented by the above general formula (6) is obtained by crystallization. It is industrially simple and preferable to obtain substituted prolines. For the purpose of removing impurities including residual metals, crystallization may be performed after treatment with activated carbon or the like. In addition, when the optically active α-substituted proline represented by the general formula (6) forms a salt with a hydrogen halide, the optically active α-substituted without salt is reacted with an epoxy compound. Crystallization as a proline is preferable because it is not necessary to neutralize the hydrogen halide salt when used as a pharmaceutical intermediate.

  Examples of the hydrohalide salt of the optically active α-substituted proline represented by the general formula (6) include hydrofluoride, hydrochloride, hydrobromide, and hydroiodide. Among these, preferred are hydrochlorides with little fear of coloring and the like and toxicity.

The epoxy compound used here is not particularly limited as long as the hydrogen halide forming the salt can be efficiently removed, and specifically, an aliphatic epoxy compound such as ethylene oxide, propylene oxide, isobutylene oxide; styrene oxide , Aromatic epoxy compounds such as divinylbenzene oxide, and the like, preferably an aliphatic epoxy compound having a low boiling point and easy to remove by a concentration operation, and more preferably an industrially inexpensive and low boiling point liquid at room temperature. Easy to handle propylene oxide.
Moreover, as the usage-amount of an epoxy compound, although arbitrary quantity can be used, Usually 1-50 times volume amount with respect to the optically active alpha-substituted proline represented by the said General formula (6), Preferably Is 2 to 20 times volume, more preferably 3 to 10 times volume.

Although the solvent used for crystallization is not particularly limited, specifically, hydrocarbon solvents such as hexane, heptane, benzene and toluene; ether systems such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether and tetrahydrofuran Solvents: Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate, butyl acetate; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; dimethyl carbonate, diethyl carbonate Carbonic ester solvents such as acetonitrile; Nitrile solvents such as acetonitrile; Amides solvents such as dimethylformamide, dimethylacetamide, N-methylpiperidinone; Sulfur-containing systems such as dimethyl sulfoxide and sulfolane Medium; methanol, ethanol, 2-propanol, 1-butanol, alcohol solvents such t- butanol; water and the like. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio. Preferred solvents are ether solvents, ketone solvents, nitrile solvents, amide solvents, sulfur-containing solvents, alcohol solvents, water and mixed solvents thereof, more preferably ether solvents, ketone solvents, A mixed solvent of at least one solvent selected from a nitrile solvent, an amide solvent, a sulfur-containing solvent, and an alcohol solvent and water, more preferably an ether solvent, a ketone solvent, a nitrile solvent, and A mixed solvent of at least one solvent selected from sulfur-containing solvents, an alcohol solvent, and water, and particularly preferably a mixed solvent that selects one or more of each from a ketone solvent, an alcohol solvent, and water. .
Further, as a method for adding the solvent, the optically active α-substituted proline is preferably dissolved after dissolving the optically active α-substituted proline in an alcohol solvent and water having a moderately high solubility in the optically active α-substituted proline or a mixed solvent thereof. A method of adding a ketone solvent that has relatively low solubility in substituted prolines and that dissolves other impurities relatively well is preferable.
As a use amount of the solvent, an arbitrary amount of the solvent can be used, but usually 1 to 50 times by volume, preferably 1 to 50 times the volume of the optically active α-substituted proline represented by the general formula (6). It is 2 to 20 times volume, more preferably 3 to 10 times volume. Further, the amount of water preferably added as a mixed solvent is too small if the effect of removing impurities is small. On the other hand, if too large, the recovery rate of optically active α-substituted prolines is significantly reduced. 0.01 to 5 times volume, preferably 0.1 to 3 times volume, more preferably 0.2 to 1 times volume with respect to the optically active α-substituted proline represented by formula (6) is there.

  Here, crystallization is a normal crystal in which a poor solvent, an acid, a base, or the like is added to a solution or a rich solvent such as water is removed azeotropically to lower the solubility of the target product and the target product is taken out as crystals. In addition to the analysis, it also includes recrystallization in which the obtained crude crystals are dissolved in a suitable solvent and then recrystallized. The crystal obtained in the present invention may be an optically active α-substituted proline containing no acid or base component, or may be a salt of an optically active α-substituted proline and an acid or base.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these.

[Example 1]
Production of 1-benzyl-2-cyano-2-methylpyrrolidine (in the above general formula (2), R ¹ = Me, R ² = Bn, R ³ = H; Step (a) benzylamine, using acetic acid, t- (Butanol-water reaction)

In a flask, 0.57 ml (5.0 mmol) of 5-chloro-2-pentanone, 270 mg (5.5 mmol) of sodium cyanide, 1.64 ml (15 mmol) of benzylamine, 0.86 ml (15 mmol) of acetic acid, 2.5 ml of water, 2.5 ml of t-butanol was charged and reacted at 50 ° C. for 2 hours. After adding 10 ml of ethyl acetate and 1.2 ml of 50 w / v% NaOH aqueous solution to the reaction solution, the aqueous layer was removed. The organic layer was concentrated to obtain 2.15 g of a light brown oily substance. From the results of NMR analysis, this oily substance was found to contain 47% by weight of 1-benzyl-2-cyano-2-methylpyrrolidine (1.01 g, quantitative), 48% by weight of benzylamine, 2% by weight of ethyl acetate, t -A mixture containing 3% by weight of butanol.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.56 (3H, s), 1.74-1.95 (3H, m), 2.30-2.45 (2H, m), 2.99 (1H , Ddd, J = 9.8, 8.3, 3.3 Hz), 3.35 (1H, d, J = 13.1 Hz), 4.02 (1H, d, J = 13.1 Hz), 7. 24-7.37 (5H, m).

[Example 2]
Production of 1-benzyl-2-cyano-2-methylpyrrolidine (in the above general formula (2), R ¹ = Me, R ² = Bn, R ³ = H; Step (a) Reaction in ethyl acetate-water solvent )
To the flask, 2.28 ml (20 mmol) of 5-chloro-2-pentanone, 1.08 g (22 mmol) of sodium cyanide, 2.40 ml (22 mmol) of benzylamine, 1.26 ml (22 mmol) of acetic acid, 4.6 ml of water, ethyl acetate 9.1 ml was charged and reacted at 50 ° C. for 3 hours. After adding 50 w / v% NaOH aqueous solution 0.8 ml (10 mmol) and sodium cyanide 0.50 g (10 mmol) to the reaction solution, the mixture was further reacted at 50 ° C. for 2 hours. After cooling to room temperature, the aqueous layer was removed and the organic layer was concentrated to give 4.30 g of a light brown oily substance. As a result of NMR analysis, this oily substance was found to contain 78% by weight (3.35 g, 84% yield) of 1-benzyl-2-cyano-2-methylpyrrolidine, 2% by weight of 5-chloro-2-pentanone, a chain. It was a mixture containing 12% by weight of 2-benzylamino-5-chloro-2-cyanopentane, 6% by weight of benzylamine, and 1% by weight of ethyl acetate.

[Example 3]
Production of 1-benzyl-2-cyano-2-methylpyrrolidine (in the above general formula (2), R ¹ = Me, R ² = Bn, R ³ = H; step (a) reaction in toluene-water solvent)
In a flask, 0.57 ml (5.0 mmol) of 5-chloro-2-pentanone, 270 mg (5.5 mmol) of sodium cyanide, 0.60 ml (5.5 mmol) of benzylamine, 0.32 ml (5.5 mmol) of acetic acid, water 1.1 ml and 2.3 ml of toluene were charged and reacted at 50 ° C. for 2 hours. After adding sodium cyanide 0.17g (3.5mmol) to the reaction liquid, it was made to react at 50 degreeC for 4 hours. The reaction solution was analyzed by NMR. As a result, 5-chloro-2-pentanone as a raw material, 1-benzyl-2-cyano-2-methylpyrrolidine as a target product, and 2-benzylamino-5 as a chain intermediate were obtained. -Chloro-2-cyanopentane was present in a ratio of 0.04: 1: 0.27.

[Example 4]
Production of N-benzyl-α-methylprolinamide (in the above general formula (3), R ¹ = Me, R ² = Bn, R ³ = H; Step (a) Reaction in ethanol-water solvent, Step (b ) Hydration with sulfuric acid)

  In a flask, 0.57 ml (5.0 mmol) of 5-chloro-2-pentanone, 270 mg (5.5 mmol) of sodium cyanide, 0.60 ml (5.5 mmol) of benzylamine, 0.32 ml (5.5 mmol) of acetic acid, water 1.1 ml and 1.1 ml of ethanol were charged and reacted at 40 ° C. for 3 hours. After adding 0.16 ml (1.5 mmol) of benzylamine to the reaction solution, the mixture was further reacted at 40 ° C. for 2 hours. The reaction solution was analyzed by NMR. As a result, 5-chloro-2-pentanone as a raw material, 1-benzyl-2-cyano-2-methylpyrrolidine as a target product, and 2-benzylamino-5-as a chain intermediate were obtained. Chloro-2-cyanopentane and 5-chloro-2-cyano-2-pentanol, which is a raw material cyanohydrin, were present in a ratio of 0.02: 1: 0.02: 0.08. To this reaction solution was added 0.40 ml (5.0 mmol) of a 50 w / v% aqueous NaOH solution, followed by extraction with toluene, and the organic layer was concentrated to obtain 1.44 g of an orange oily substance.

In a separate flask, 0.090 ml of water and 1.47 g (15 mmol) of sulfuric acid were charged, and 1.44 g of the orange oily substance was added under ice cooling, followed by washing with 0.30 ml of toluene. After reacting at 60 ° C. for 3 hours, 0.57 ml of water and 2.4 ml of 28% ammonia water were slowly added under ice cooling. Extraction with ethyl acetate was performed, and the organic layer was concentrated to obtain 2.0 g of an orange oily substance. When analyzed by HPLC, 770 mg (3.52 mmol, yield 70%) of N-benzyl-α-methylprolinamide was contained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, s), 1.68-1.89 (3H, m), 2.13-2.22 (1H, m), 2.40 (1H , Td, J = 9.1, 7.3 Hz), 2.97-3.03 (1H, m), 3.35 (1H, d, J = 13.1 Hz), 3.88 (1H, d, J = 13.1 Hz), 5.36 (1H, brs), 7.24-7.37 (5H, m), 7.55 (1H, brs).

[Example 5]
Production of N-benzyl-α-methylprolinamide (in the above general formula (3), R ¹ = Me, R ² = Bn, R ³ = H; step (a) reaction in aqueous solvent, step (b) sulfuric acid Hydration by)
A flask was charged with 6.03 g (50 mmol) of 5-chloro-2-pentanone, 2.7 g (55 mmol) of sodium cyanide, 6.0 ml (55 mmol) of benzylamine, 3.2 ml (55 mmol) of acetic acid, and 11.4 ml of water. The reaction was carried out at 40 ° C. for 3 hours. After adding 4.0 ml (50 mmol) of 50 w / v% NaOH aqueous solution to the reaction solution, the reaction was further allowed to react at 60 ° C. for 1 hour. When the reaction solution was analyzed by NMR, it was almost the target product, 1-benzyl-2-cyano-2-methylpyrrolidine. The aqueous layer was separated to give a light brown oil.

  In a separate flask, 14.7 g (150 mmol) of sulfuric acid was charged, and the light brown oily substance was added under ice cooling, followed by washing with 2.0 ml of toluene. After reacting at 60 ° C. for 7 hours and at 70 ° C. for 2 hours, at an internal temperature of 50 ° C. or less, 50 ml of water, 6.0 ml of toluene, and 32 ml of 50 w / v% NaOH aqueous solution were slowly added to adjust the pH to 10. The resulting crystals were filtered, washed with water, and dried under reduced pressure to obtain 8.67 g of N-benzyl-α-methylprolinamide as a light brown solid. As a result of HPLC analysis, the purity was 98 wt% (39.0 mmol, yield 78%).

[Example 6]
Production of 1-benzyl-2-cyano-2-methylpyrrolidine (in the above general formula (2), R ¹ = Me, R ² = Bn, R ³ = H; Step (a) No acetic acid addition, ethanol-water solvent Reaction)
A flask was charged with 0.57 ml (5.0 mmol) of 5-chloro-2-pentanone, 270 mg (5.5 mmol) of sodium cyanide, 0.60 ml (5.5 mmol) of benzylamine, 1.1 ml of water, and 1.1 ml of ethanol. , Reacted at 50 ° C. for 1.5 hours. The reaction solution was analyzed by NMR. As a result, it was found that 5-chloro-2-pentanone as a raw material, 1-benzyl-2-cyano-2-methylpyrrolidine as a target product, and cyclopentyl methyl ketone by-produced from the raw material were 0.02%. : 1: 0.32. In this example, the system became stronger basic than in Example 20 to which acetic acid was added, and cyclopentylmethylketone was produced as a by-product, but the target product, 1-benzyl-2-cyano-2, was obtained. -Methylpyrrolidine was obtained as the main product.

[Example 7]
Production of 1-benzyl-2-cyano-2-methylpyrrolidine (in the above general formula (2), R ¹ = Me, R ² = Bn, R ³ = H; Step (a) No acetic acid addition, ethyl acetate-water Reaction with solvent)
In a flask, 0.57 ml (5.0 mmol) of 5-chloro-2-pentanone, 270 mg (5.5 mmol) of sodium cyanide, 0.60 ml (5.5 mmol) of benzylamine, 1.1 ml of water, and 2.3 ml of ethyl acetate. The mixture was charged and reacted at 50 ° C. for 4.5 hours. The reaction solution was analyzed by NMR. As a result, 5-chloro-2-pentanone as a raw material, 1-benzyl-2-cyano-2-methylpyrrolidine as a target product, and 2-benzylamino-5 as a chain intermediate were obtained. -Chloro-2-cyanopentane was present in a ratio of 0.02: 1: 0.06 and no cyclopentyl methyl ketone was observed. In this example, no acid was added as in Example 22 described later. However, since ethyl acetate was hydrolyzed to produce acetic acid, the system was not strongly basic, and a cyclopentyl methyl ketone by-product was produced. Is considered to be suppressed.

[Example 8]
(2R, 1′R) -1- (1′-phenylethyl) -2-cyano-2-methylpyrrolidine and (2S, 1′R) -1- (1′-phenylethyl) -2-cyano-2 -Production of methylpyrrolidine (in the above general formula (2), R ¹ = Me, R ² = (R) -1-phenylethyl, R ³ = H; step (a) (R) -α-methylbenzylamine used , Reaction with water solvent)

In a flask, 1.14 ml (10 mmol) of 5-chloro-2-pentanone, 0.54 g (11 mmol) of sodium cyanide, 1.4 ml (11 mmol) of (R) -α-methylbenzylamine, 0.63 ml (11 mmol) of acetic acid, 2.3 ml of water was charged and reacted at 40 ° C. for 3 hours. After adding 0.80 ml (10 mmol) of a 50 w / v% NaOH aqueous solution to the reaction solution, the mixture was further reacted at 60 ° C for 1 hour. After cooling to room temperature, the mixture was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and the organic layer was concentrated to obtain 2.35 g of a light brown oily substance. As a result of NMR analysis, the oily substance was found to be (2R, 1′R) -1- (1′-phenylethyl) -2-cyano-2-methylpyrrolidine and (2S, 1′R) -1- (1′- Phenylethyl) -2-cyano-2-methylpyrrolidine 83 wt% (1.95 g, 91% yield), 5-chloro-2-pentanone 2 wt%, (R) -α-methylbenzylamine 11 The diastereomeric ratio was (2R, 1′R) :( 2S, 1′R) = 7: 3. The stereochemistry at the 2-position was determined by induction on optically active α-methylproline (see Reference Example 2).
(2R, 1′R) -1- (1′-phenylethyl) -2-cyano-2-methylpyrrolidine
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.02 (3H, s), 1.48 (3H, d, J = 6.8 Hz), 1.79-1.92 (3H, m), 2.22 -2.32 (1H, m), 2.75-2.83 (1H, m), 3.18-3.25 (1H, m), 3.92 (1H, q, J = 6.8 Hz) , 7.21-7.39 (5H, m).
(2S, 1′R) -1- (1′-phenylethyl) -2-cyano-2-methylpyrrolidine
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.48 (3H, d, J = 6.8 Hz), 1.67 (3H, s), 1.69-1.78 (2H, m), 1.92 -1.99 (1H, m), 2.32-2.39 (1 H, m), 2.47 (1 H, dt, J = 9.6, 8.1 Hz), 2.84-2.91 ( 1H, m), 3.84 (1H, q, J = 6.8 Hz), 7.21-7.39 (5H, m).

[Example 9]
Preparation of (2R, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide and (2S, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide ( In the above general formula (4), R ¹ = Me, R ² = (R) -1-phenylethyl, R ³ = H; Step (a) (R) -α-methylbenzylamine used, reaction in aqueous solvent Step (b) Hydration with sulfuric acid, Step (g) Separation by silica gel column chromatography)

  In a flask, 1.25 ml (11 mmol) of 5-chloro-2-pentanone, 0.54 g (11 mmol) of sodium cyanide, 1.28 ml (10 mmol) of (R) -α-methylbenzylamine, 0.63 ml (11 mmol) of acetic acid, 2.0 ml of water was charged and reacted at 40 ° C. for 3 hours. After adding 0.80 ml (10 mmol) of a 50 w / v% NaOH aqueous solution to the reaction solution, the reaction solution was further reacted at 60 ° C. for 2 hours. After cooling to room temperature, the aqueous layer was separated to obtain a light brown oily substance.

  In a separate flask, 3.9 g (40 mmol) of sulfuric acid was charged, and the light brown oily substance was added on a water bath, and washed with 1.0 ml of toluene. After reacting at 60 ° C. for 6 hours, 2.0 ml of water and 6.4 ml of 50 w / v% NaOH aqueous solution were slowly added on the water bath to adjust the pH to 10. The mixture was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and the organic layer was concentrated. The concentrated residue was purified by silica gel column chromatography, and (2R, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide and (2S, 1′R) -N- (1′- Two fractions of phenylethyl) -α-methylprolinamide were obtained. The stereochemistry at the 2-position was determined by induction on optically active α-methylproline (see Reference Example 2).

Fraction 1: 0.48 g. As a result of NMR analysis, (2R, 1′R) :( 2S, 1′R) = 96: 4, purity 85%, 1.75 mmol, and yield 18%.
Fraction 2: 1.52 g. As a result of NMR analysis, (2R, 1′R) :( 2S, 1′R) = 60: 40, purity 88%, 5.80 mmol, yield 58%.
(2R, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.30 (3H, d, J = 6.6 Hz), 1.37 (3H, s), 1.64-1.73 (2H, m), 1.80 -1.88 (1H, m), 2.16-2.32 (2H, m), 2.69-2.75 (1H, m), 3.62 (1H, q, J = 6.6 Hz) , 5.45 (1H, brs), 7.22-7.28 (1H, m), 7.28-7.35 (4H, m), 7.45 (1H, brs).
(2S, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.41 (3H, s), 1.42 (3H, d, J = 6.8 Hz), 1.66 to 1.89 (3H, m), 2.12 -2.22 (1H, m), 2.90-3.00 (1H, m), 3.09-3.15 (1H, m), 4.04 (1H, q, J = 6.8 Hz) 5.17 (1H, brs), 7.02 (1H, brs), 7.20-7.27 (1H, m), 7.29-7.35 (4H, m).

[Reference Example 1]
Production of (R) -α-methylprolinamide (removal of 1-phenylethyl group)

  In a flask, 0.48 g (1.75 mmol, diastereomer ratio 96) of (2R, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide of fraction 1 obtained in Example 9: 4) 0.11 ml (1.9 mmol) of acetic acid, 2.0 ml of methanol, 21 mg (0.0090 mmol) of 10% palladium carbon (manufactured by NE Chemcat, PE-type, 55% water-containing product) were added. The reaction was carried out at 60 ° C. for 2 hours under a normal pressure hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain 0.40 g of (R) -α-methylprolinamide as a colorless oily substance. As a result of NMR analysis, the purity was 58 wt% (quantitative).

[Reference Example 2]
Production of (R) -α-methylproline (in the above general formula (6), R ¹ = Me, R ³ = H; amide hydrolysis, determination of absolute configuration of α-methylproline)

  The flask was charged with 0.40 g (purity 58 wt%, 1.78 mmol) of (R) -α-methylprolinamide obtained in Reference Example 1 and 2.0 ml of 6 mol / l hydrochloric acid, and reacted at 90 ° C. for 4 hours. As a result of HPLC analysis, it contained 204 mg (1.58 mmol, yield 90%) of (R) -α-methylproline having an optical purity of 89% ee.

[Example 10]
Preparation of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide ( In the above general formula (3), R ¹ = Me, R ² = (S) -1-phenylethyl, R ³ = H; Step (a) (S) -α-methylbenzylamine used, reaction in aqueous solvent Step (b) Hydration with sulfuric acid)

  Into the flask, 13.3 g (110 mmol) of 5-chloro-2-pentanone, 5.4 g (110 mmol) of sodium cyanide, 12.1 g (100 mmol) of (S) -α-methylbenzylamine, 6.3 ml (110 mmol) of acetic acid, 24 ml of water was charged and reacted at 40 ° C. for 3 hours. After adding 8.0 ml (100 mmol) of 50 w / v% NaOH aqueous solution to the reaction solution, the reaction was further allowed to proceed at 60 ° C. for 2 hours. After cooling to room temperature, the aqueous layer was separated to obtain a light brown oily substance.

  In another flask, 39 g (400 mmol) of sulfuric acid was charged, and the light brown oily substance was added on a water bath, and washed with 6.0 ml of toluene. After reacting at 60 ° C. for 3 hours and at 70 ° C. for 3 hours, 36 ml of water, 60 ml of 28% aqueous ammonia and 60 ml of ethyl acetate were slowly added to adjust the pH to 9. Extracted with ethyl acetate, the organic layer was washed three times with water and once with saturated brine, and the organic layer was concentrated to give (2S, 1 ′S) -N- (1′-phenyl) as a light brown oil. Ethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1′-phenylethyl) -α-methylprolineamide 23.8 g were obtained. As a result of HPLC analysis, the purity was 80 wt%, 81.4 mmol, yield 81%, (2S, 1'S) :( 2R, 1'S) = 7: 3).

[Example 11]
Preparation of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide ( In the general formula (4), R ¹ = Me, R ² = (S) -1-phenylethyl, R ³ = H; Step (g) Separation by silica gel column chromatography)
(2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1′-phenyl) obtained according to the method of Example 10 Acetic acid 2.5 ml (44 mmol) is added to ethyl) -α-methylprolinamide (pure 9.80 g, 42.2 mmol), and silica gel 100 g (silica gel 60N (spherical, neutral) particle size 63 manufactured by Kanto Chemical Co., Inc.) (210 μm) and (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1 Two fractions of '-phenylethyl) -α-methylprolinamide were obtained (eluent / hexane: ethyl acetate (w: w) = 2: 1 to 1: 1).
Fraction 1: 6.71 g. As a result of NMR analysis, (2S, 1 ′S) :( 2R, 1 ′S) = 100: 0, purity 72%, 20.8 mmol, yield 49%, including 20 wt% acetic acid and 8 wt% ethyl acetate It was out.
Fraction 2: 3.11 g. As a result of NMR analysis, (2R, 1 ′S) :( 2S, 1 ′S) = 87: 13, purity 82%, 11.0 mmol, yield 25%, including 13 wt% acetic acid and 5 wt% ethyl acetate It was out.

[Example 12]
Production of (2S, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide D-tartrate (in the general formula (4), R ¹ = Me, R ² = (R) -1-phenylethyl, R ³ = H; step (f) diastereomeric salt resolution with D-tartaric acid)

(2R, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide and (2S, 1′R) -N- (1 ′) from fraction 2 obtained in Example 9 in a vial. -Phenylethyl) -α-methylprolinamide 48.4 mg (0.21 mmol, (2R, 1′R) :( 2S, 1′R) = 60: 40), D-tartaric acid 31.3 mg (0.21 mmol) Then, 0.20 ml of ethyl acetate and 0.10 ml of methanol were added and heated to 50 ° C. to dissolve. After cooling to room temperature, the resulting crystals were filtered and dried under reduced pressure to obtain 18.9 mg of white crystals. As a result of HPLC analysis and NMR analysis, the obtained crystals were obtained as a 1: 1 salt of (2S, 1′R) -N- (1′-phenylethyl) -α-methylprolinamide and D-tartaric acid (0.049 mmol). The yield was 24% and (2S, 1′R) :( 2R, 1′R) = 20: 1).
¹ H-NMR (400 MHz, DMSO-d6) δ 1.28 (3H, s), 1.35 (3H, d, J = 6.8 Hz), 1.62-1.79 (3H, m), 1. 95-2.03 (1H, m), 2.83-2.91 (1H, m), 3.05-3.12 (1H, m), 3.99-4.06 (1H, m), 4.26 (2H, s), 6.96 (2H, brs), 7.19-7.24 (1H, m), 7.28-7.34 (2H, m), 7.35-7. 39 (2H, m).

[Example 13]
(2R, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide L-tartrate and (2S, 1 ′S) -N- (1′-phenylethyl) -α-methyl Production of proline amide (in the above general formula (4), R ¹ = Me, R ² = (S) -1-phenylethyl, R ³ = H; Step (f) diastereomeric salt resolution with L-tartaric acid)

  A flask was charged with 0.18 g (1.2 mmol) of L-tartaric acid and 0.60 ml of methanol, and heated to 60 ° C. to dissolve. (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1 ′) prepared according to the method of Example 10 -Phenylethyl) -α-methylprolinamide in ethyl acetate solution 2.24 g (purity 32 wt%, 3.0 mmol, (2S, 1 ′S) :( 2R, 1 ′S) = 7: 3), methanol 0. 40 ml and 3.0 ml of ethyl acetate were added and stirred under ice cooling. The resulting crystals were filtered, washed with ethyl acetate, dried under reduced pressure, and 314 mg of (2R, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide · L-tartrate as white crystals ( 0.82 mmol, yield 27%, (2R, 1 ′S) :( 2S, 1 ′S) = 94: 6) was obtained. The filtrate was concentrated, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, the aqueous layer was removed, the organic layer was dried over magnesium sulfate and concentrated to give (2S, 1'S as a pale yellow oily substance). ) -N- (1′-phenylethyl) -α-methylprolinamide 683 mg was obtained. As a result of HPLC analysis, the purity was 77 wt%, 2.26 mmol, the yield was 73%, and (2S, 1'S) :( 2R, 1'S) = 95: 5.

[Example 14]
Production of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide · (S) -mandelate (in the general formula (4), R ¹ = Me, R ² = (S) -1-phenylethyl, R ³ = H; Step (f) (Acquisition of (S) -mandelate seed crystal)

50 mg of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide fraction 1 obtained in Example 11 in a vial (purity 72%, 0.16 mmol, (2S, 1 ′S) :( 2R, 1 ′S) = 100: 0), (S) -mandelic acid 32.7 mg (0.22 mmol) and ethyl acetate 0.20 ml were added and dissolved by heating. The mixture was left open at room temperature to evaporate ethyl acetate. Two weeks later, the resulting crystals were suspended in ethyl acetate, filtered and dried under reduced pressure to obtain 41 mg (0.11 mmol, yield 69%) of white crystals. As a result of HPLC and NMR analysis, the obtained crystal was (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide · (S) -mandelate (1: 1). It was.
¹ H-NMR (400 MHz, acetone-d6) δ 1.28 (3H, s), 1.28 (3H, d, J = 6.6 Hz), 1.65 to 1.81 (3H, m), 2. 07-2.18 (1H, m), 2.29 (1H, q, J = 8.5 Hz), 2.68-2.75 (1H, m), 3.66 (1H, q, J = 6) .6 Hz), 5.20 (1 H, s), 7.20-7.25 (1 H, m), 7.27-7.34 (3 H, m), 7.34-7.39 (2 H, m) ), 7.42-7.47 (2H, m), 7.49-7.53 (2H, m).

[Example 15]
Production of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide · (S) -mandelate (in the general formula (4), R ¹ = Me, R ² = (S) -1-phenylethyl, R ³ = H; Step (f) (S) -Diastereomeric salt resolution with mandelic acid)
(2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1′-) produced according to the method of Example 10 were added to the flask. Phenylethyl) -α-methylprolinamide in ethyl acetate solution 2.23 g (purity 32 wt%, 3 mmol, (2S, 1 ′S) :( 2R, 1 ′S) = 7: 3), (S) -mandelic acid 456 mg (3.0 mmol) was added and dissolved by heating at 40 ° C. (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide · (S) -mandelate seed crystal produced according to the method of Example 14 after cooling to 30 ° C. When a very small amount of was added, crystals were precipitated. After cooling to 20 ° C., the crystals were filtered, washed with ethyl acetate, dried under reduced pressure, and (2S, 1 ′S) —N— (1′-phenylethyl) -α-methylprolinamide. 753 mg (1.96 mmol, yield 64%, 94.2% de) of S) -mandelate was obtained.

[Example 16]
Production of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide · (S) -mandelate (in the general formula (4), R ¹ = Me, R ² = (S) -1-phenylethyl, R ³ = H; Step (f) (S) -Diastereomeric salt resolution with mandelic acid)
(2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1′-) produced according to the method of Example 10 were added to the flask. 7.26 g of phenylethyl) -α-methylprolinamide in ethyl acetate (purity 32 wt%, 10.0 mmol, (2S, 1 ′S) :( 2R, 1 ′S) = 7: 3), (S) — Mandelic acid 1.22 g (8.0 mmol) was added and dissolved by heating at 40 ° C. A very small amount of seed crystals of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide · (S) -mandelate prepared at 40 ° C. according to the method of Example 14 When added, crystals precipitated. After stirring under ice-cooling, the crystals were filtered, washed with ethyl acetate, dried under reduced pressure, and (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide. 2.36 g of (S) -mandelate was obtained. (6.13 mmol, 61% yield, 96.6% de)

[Example 17]
Reverse phase of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide HPLC separation (step (g) separation by reverse phase HPLC)
(2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1′-phenylethyl) -α obtained in Example 10 -Methylprolinamide ((2S, 1'S) :( 2R, 1'S) = 7: 3) was analyzed under the following reverse phase HPLC conditions, and a large difference in retention time was observed. From this, it can be said that reverse phase column preparative chromatography including a simulated moving bed can be efficiently applied.
Reversed phase HPLC condition column: L-column (4.6 mm × 250 mm) manufactured by Chemical Substance Evaluation Research Organization, mobile phase: 20 mmol / l acetic acid—20 mmol / l ammonium acetate aqueous solution / methanol (w / w) = 40/60, flow rate : 1.0 ml / min, column temperature: 40 ° C., UV: 220 nm, retention time: (2R, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide 5.8 min, (2S , 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide 9.3 min

[Example 18]
Synthetic adsorption of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide Agent column chromatography separation (step (g) separation by synthetic adsorbent column chromatography)
(2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide and (2R, 1 ′S) -N- (1′-phenylethyl) -α obtained in Example 10 -Methylprolinamide ((2S, 1'S) :( 2R, 1'S) = 7: 3) was analyzed under HPLC conditions using the following synthetic adsorbent column, and a large difference in retention time was observed. It was. From this, it can be said that the synthetic adsorbent column preparative chromatography including the simulated moving bed can be efficiently applied.
HPLC condition column using a synthetic adsorbent column: MCI (registered trademark) -GEL CHP10M (4.6 mm × 150 mm) manufactured by Mitsubishi Chemical Corporation, mobile phase: 20 mmol / l acetic acid-20 mmol / l aqueous ammonium acetate solution / acetonitrile = 50 / 50, flow rate: 1.0 ml / min, column temperature: 40 ° C., UV: 220 nm, retention time: (2R, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide 3.7 minutes , (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide 5.1 min

[Example 19]
Production of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline hydrochloride (in the above general formula (5), R ¹ = Me, R ² = (S) -1-phenyl Ethyl, R ³ = H; step (d) hydrolysis reaction with hydrochloric acid)

  142 g (370 mmol, diastereomeric purity 99) of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide · (S) -mandelate prepared according to the method of Example 16 .9% de) and 711 ml of toluene, 285 ml of 10% aqueous sodium hydroxide solution was added dropwise and stirred at room temperature, followed by liquid separation and separation of the aqueous layer. To the obtained organic layer, 213 ml of 10% aqueous sodium hydroxide solution was again added dropwise and stirred at room temperature. After completion of the stirring, liquid separation was performed, the aqueous layer was separated, and the organic layer was recovered. To the obtained organic layer, 213 ml of 35% hydrochloric acid was added dropwise at room temperature and stirred. After stirring, the solution was separated and the aqueous layer was recovered. To the remaining organic layer, 213 ml of 35% hydrochloric acid was dropped again and stirred, and then the aqueous layer was collected again.

  The collected aqueous layers were combined and heated to reflux. The reaction time was 12 hours and the conversion reached 100%. After completion of the reaction, the reaction solution was cooled and concentrated under reduced pressure at an external temperature of 60 ° C. After concentration to 229 g, 427 ml of 2-propanol was added and concentrated under reduced pressure. After concentrating to 190 g, 427 ml of 2-propanol was added and concentrated under reduced pressure. After concentrating to 158 g, 356 ml of 2-propanol was added to the concentrated residue and cooled. After stirring at 9 ° C. for 1 hour, the precipitated solid was removed by filtration and washed with 71 ml of 2-propanol. The resulting filtrate was 453 g of a pale yellow solution containing (2S, 1'S) -N- (1'-phenylethyl) -α-methylproline hydrochloride.

[Example 20]
Production of (S) -α-methylproline (in the above general formula (6), R ¹ = Me, R ³ = H; Step (e) Deprotection reaction by hydrogenation using palladium carbon, using propylene oxide Purification)
400 g of the solution containing (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline hydrochloride obtained in Example 19 and 51.7 g of 5% palladium on carbon (manufactured by Johnson Matthey, Type 39) , 59.5% water-containing product), and hydrogenation was carried out under conditions of a temperature of 40 ° C. to 60 ° C. and a hydrogen pressure of 0.5 MPa. The reaction time was 14 hours and the conversion reached 99.5%. After completion of the reaction, palladium on carbon was removed by pressure filtration and washed with 66 ml of 2-propanol. The resulting filtrate was 489 g of a blue-green solution. To the filtrate, 4.4 g of activated carbon (manufactured by Nippon Enviro Chemicals, trade name: Shirasagi P) was added, stirred at room temperature for 1 hour, and filtered. Washing with 44 ml of 2-propanol gave 509 g of filtrate. The obtained filtrate was concentrated under reduced pressure at an external temperature of 40 ° C. until there was no distillate.

  To the resulting concentrated residue, 265 ml of 2-propanol was added to form a solution, and 141 g of propylene oxide was added dropwise at room temperature. After dropping, when the temperature was raised to 43 ° C., precipitation of crystals was confirmed. Again, 18 g of propylene oxide was added dropwise and stirred. After completion of stirring, the mixture was concentrated to 370 ml at an external temperature of 50 ° C. (distillate 137 g). The precipitated crystals were washed with 44 ml of 2-propanol and filtered to obtain 27.3 g of wet (S) -α-methylproline as the first crystal. As a result of HPLC analysis, the purity of the first crystal was 97.9 Area%. The mother washing solution was concentrated, and acetone was added dropwise to the concentrated residue to obtain a second crystal (9.02 g as a wet body). As a result of HPLC analysis, the purity of the second crystal was 54.0 Area%. The obtained wet body was collected and dried to obtain 23.1 g of crude (S) -α-methylproline.

  The obtained crude (S) -α-methylproline (23.0 g), water (10.4 g) and ethanol (58 ml) were charged, and the temperature was raised to 66 ° C. to complete dissolution. Subsequently, it cooled to 60 degreeC and 76 ml of acetone was dripped. After dropping, the mixture was stirred for 1 hour and cooled to 15 ° C. over 3 hours. After stirring at 15 ° C. for 1 hour, the crystals were filtered. The obtained crystals were washed with a mixed solution of ethanol (8.1 ml) and water (2.3 ml), dried under reduced pressure at 60 ° C., and white needle-like (S) -α-methylproline (16.0 g, 124 mmol, yield) was obtained. 38%). As a result of HPLC analysis, the purity was 99.9 Area% or more and the optical purity was 99.9% ee or more, and the result of content analysis based on a commercial product was 102%.

As described above, the purity of the crystals of (S) -α-methylproline obtained from 2-propanol after reacting with propylene oxide in 2-propanol was not sufficiently high. On the other hand, the crystals of (S) -α-methylproline obtained from a mixed solvent of water, ethanol and acetone have an HPLC purity of 99.9 Area% or higher and an optical purity of 99.9% ee or higher, and have a very high purity. there were. From this, it can be said that the crystallization from the solvent system containing water is effective in improving the purity.
The analysis conditions of HPLC are as follows.
Process analysis column: Unison UK-C18 (4.6 mm × 250 mm, 3 μm) manufactured by Intact Corporation, mobile phase: A: 10 mM ammonium acetate aqueous solution B: 10 mM ammonium acetate methanol solution, Gradient (B concentration): 0 min 0% → 5 minutes 0% → 25 minutes 90% → 35 minutes 90%, flow rate: 1.0 ml / min, column temperature: 40 ° C., detection wavelength: UV 210 nm
Content analysis column: CLC-D (4.6 mm × 150 mm, 5 μm) manufactured by ASTEC, mobile phase: 2 mM CuSO ₄ aqueous solution, flow rate: 1.0 ml / min, column temperature: 45 ° C., detection wavelength: UV 254 nm

[Example 21]
Production of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline (in the general formula (5), R ¹ = Me, R ² = (S) -1-phenylethyl, R ³ = H; step (d) hydrolysis with hydrochloric acid, extracted and purified using 1-butanol)

  69.2 g (180 mmol, diastereomer) of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide · (S) -mandelate prepared according to the method of Example 16 138 ml of a 10% aqueous sodium hydroxide solution was added dropwise to a mixed solution of 346 ml of toluene and a purity of 99.9% de or more) and toluene, and the mixture was separated at room temperature, and the aqueous layer was separated. To the obtained organic layer, 104 ml of a 10% aqueous sodium hydroxide solution was added again and stirred at room temperature. After stirring, the mixture was separated and the aqueous layer was separated. The organic layer was concentrated and (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide as a pale tan oily substance. 42.1 g (181 mmol, yield 100%) was obtained.

The obtained (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide 20 g (86.1 mmol) and 35% hydrochloric acid 132 ml were charged and heated to reflux. The reaction time was 11 hours and the conversion reached 100%. After completion of the reaction, the reaction solution was concentrated under reduced pressure at an external temperature of 75 ° C. to obtain 62 g of a concentrated residue. A 50% aqueous sodium hydroxide solution was added dropwise thereto to adjust the pH to 8.8, and then 99 ml of 1-butanol was added and stirred at 10 ° C. Acetic acid was added dropwise thereto to adjust the pH to 4.5, and then the mixture was separated to recover the organic layer. Similarly, the aqueous layer was re-extracted three times with 66 ml of 1-butanol while adjusting the pH to 4.5 with acetic acid while stirring at 10 ° C. The obtained organic layers were combined and concentrated under reduced pressure at an external temperature of 70 ° C. until the water content became 1000 ppm or less. 100 ml of methanol was added to 90 g of the concentrated residue (water content: 573 ppm), and the mixture was stirred at 15 ° C. for 1 hour. Thereafter, the solid was removed by filtration, washed with 17 ml of 1-butanol / methanol = 1/1 (v / v) solution, and (2S, 1 ′S) -N- (1′-phenylethyl) -α-. 174 g of a methylproline / 1-butanol / methanol solution was obtained. As a result of HPLC analysis, it contained 69 mmol of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline, and the yield was 80%.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.59 (3H, d, J = 6.5 Hz), 1.65 (3H, s), 1.65 to 1.85 (2H, m), 1.90 -1.98 (1H, m), 2.45-2.57 (2H, m), 2.95-2.97 (1H, m), 3.93-3.94 (1H, m), 7 .28-7.43 (5H, m).

[Example 22]
Production of (S) -α-methylproline (in general formula (6), R ¹ = Me, R ³ = H; step (e) deprotection reaction by hydrogenation using palladium carbon)
The autoclave was charged with 108 g (43 mmol) of the (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline / 1-butanol / methanol solution obtained in Example 21 and 5% of water. 1.0 g of palladium carbon (manufactured by Johnson Matthey, Type 434, 54.7% water-containing product) was added and stirred. Thereafter, the reaction solution was adjusted to 35 to 45 ° C., and the inside of the reactor was replaced with 0.8 MPa of nitrogen three times, and then the inside of the reactor was replaced with hydrogen of 0.8 MPa three times with hydrogen. After completion of the hydrogen replacement, a dephenethyl reaction was performed under conditions of a hydrogen pressure of 0.5 MPa and 35 to 45 ° C. The reaction time was 8 hours and the conversion reached 99.5%. After completion of the reaction, the reaction solution was cooled, palladium carbon was removed by suction filtration, and washed with 10 ml of 50% aqueous methanol solution. The obtained filtrate was concentrated under reduced pressure at an external temperature of 60 ° C. After concentration to 40 ml, 50 ml of acetone was added and stirred for 1 hour under ice cooling. Thereafter, the crystals were collected by suction filtration and washed with 5.0 ml of acetone. The obtained crystals (5.44 g) were dried under reduced pressure to obtain crude (S) -α-methylproline (39 mmol, yield 91%) as a white powder. As a result of HPLC analysis, the purity of the crude product was 91.3 Area%.
[Example 23]

  0.80 g of crude (S) -α-methylproline produced according to the method of Example 22 (HPLC 95.8 Area%, 6.2 mmol as 100 wt% purity) and 2.4 ml of 80% 2-propanol aqueous solution (2-propanol 1.92 ml, water 0.48 ml) was added and heated to reflux. Thereafter, 3.2 ml of acetone was added dropwise at 50 ° C., and then cooled to 7 ° C. After stirring at 7 ° C. for 1 hour, the mixture was suction filtered and washed with 1 ml of cold 2-propanol. The obtained crystals were dried under reduced pressure to obtain 0.68 g (5.3 mmol, yield 86%) of (S) -α-methylproline as a white powder. As a result of HPLC analysis, the purity was 99.9 Area% or more.

[Example 24]
Production of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline calcium (in the above general formula (5), R ¹ = Me, R ² = (S) -1-phenylethyl R ³ = H; Step (d) Crystallization purification with calcium salt)

  70 ml (52 mmol, diastereomeric purity 99.9%) of a hydrolysis reaction solution of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide prepared according to the method of Example 19 About 130 ml of a 50% aqueous sodium hydroxide solution was added dropwise to the pH of 11-12. At 30 to 40 ° C., 91.8 g (62.4 mmol) of 5% calcium chloride aqueous solution was dropped to perform calcium chloride. After completion of dropping, the mixture was cooled to 0 to 10 ° C., stirred for 1 hour, and filtered. This was washed with 100 ml of water and 50 ml of ethanol, dried under reduced pressure at 40 ° C., and 13.9 g (1S) of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline calcium as a white powder. / 54 calcium salt as quantitative calcium salt).

[Example 25]
Production of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline barium (in the above general formula (5), R ¹ = Me, R ² = (S) -1-phenylethyl R ³ = H; Step (d) Crystallization purification with barium salt)
20 ml (15 mmol, diastereomeric purity 99.9%) of a hydrolysis reaction solution of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylprolinamide prepared according to the method of Example 19 50% sodium hydroxide aqueous solution was added dropwise to at least de) to adjust the pH to 11-12. 5% barium hydroxide aqueous solution was dropped at 30 to 40 ° C. to carry out barium chloride. After completion of dropping, the mixture was cooled to 0 to 10 ° C., stirred for 1 hour, and filtered. This was washed with 50 ml of water and 30 ml of ethanol, dried under reduced pressure at 50 ° C., and 0.40 g of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline barium as a white powder ( 1.3 mmol as a 1/2 barium salt, yield 9%).

[Example 26]
Production of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline (in the general formula (5), R ¹ = Me, R ² = (S) -1-phenylethyl, R ³ = H; Step (d) Free calcium salt)
(2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline calcium 5.0 g (19.8 mmol as a 1/2 calcium salt) obtained in Example 24 and 50 ml of ethanol were charged, Stir at 35-45 ° C. A solution of 1.8 g (25 mmol) of propionic acid in ethanol (10 ml) was added dropwise thereto and stirred at 35 to 45 ° C. for 1 hour. Then, it cooled to 5-15 degreeC and stirred for further 1 hour. After stirring, the solid was filtered off, washed with 5.0 ml of ethanol, and the resulting solution was concentrated under reduced pressure to 25 ml at 50 ° C. to give (2S, 1 ′S) -N- (1′-phenylethyl). ) -Α-methylproline in ethanol solution 20.2 g was obtained.

[Example 27]
Production of (S) -α-methylproline (in general formula (6), R ¹ = Me, R ³ = H; step (e) deprotection reaction by hydrogenation using palladium carbon)
20.2 g of an ethanol solution of (2S, 1 ′S) -N- (1′-phenylethyl) -α-methylproline obtained in Example 26 was charged into an autoclave, and 0.21 g of 5% palladium on carbon (Johnson Matthey). (Product Type, Type 434, 54.7% water-containing product) was added and stirred. Thereafter, the reaction solution was adjusted to 35 to 45 ° C., and the inside of the reactor was replaced with 0.8 MPa of nitrogen three times, and then the inside of the reactor was replaced with hydrogen of 0.8 MPa three times with hydrogen. After completion of the hydrogen replacement, a dephenethyl reaction was performed under conditions of a hydrogen pressure of 0.5 MPa and 35 to 45 ° C. The reaction time was 7 hours and the conversion reached 99.5%. After completion of the reaction, the reaction mixture was cooled, palladium carbon was removed by suction filtration, and washed with 5.0 ml of ethanol. The obtained filtrate was concentrated under reduced pressure at an external temperature of 50 ° C. After concentrating to 9.63 g, 25 ml of 1-butanol was added and concentrated under reduced pressure at an external temperature of 60 ° C. to obtain 11.1 g of a concentrated residue. To the concentrated residue, 25 ml of acetone was added dropwise at room temperature and stirred. After completion of dropping, the mixture was cooled with ice water and further stirred for 1 hour. Thereafter, the crystals were collected by suction filtration and washed with 5.0 ml of acetone. The obtained wet crystals were dried under reduced pressure to obtain 1.36 g (10.5 mmol, 53% yield) of white powder crude (S) -α-methylproline.

[Reference Example 3]
Preparation of α-methylprolinamide hydrochloride In a flask, 95.9 g (1.25 mol) of ammonium acetate, 100 ml of water, 200 ml of ethyl acetate, 50 g (0.42 mol) of 5-chloro-2-pentanone, 12.2 g of sodium cyanide (0.25 mol) was charged and heated to 60 ° C. The reaction was carried out while adding 28.8 g of 28% ammonia water in portions and adjusting the pH to 7.4 to 7.6. After 3 hours, 12.2 g (0.25 mol) of sodium cyanide was added, and the reaction was further continued for 3 hours. After cooling to room temperature, the aqueous layer was removed to obtain an ethyl acetate solution of 2-cyano-2-methylpyrrolidine.
In another flask, 40.7 g (0.42 mol) of sulfuric acid was charged, and the obtained ethyl acetate solution of 2-cyano-2-methylpyrrolidine was added dropwise under ice cooling. After standing, the ethyl acetate layer was removed, and the sulfuric acid layer was washed twice with 50 ml of cyclohexane. Further, 81.4 g (0.83 mol) of sulfuric acid was added and reacted at 40 to 60 ° C. for 4 hours. The reaction solution was ice-cooled, and 180 ml of water and 151 g of 28% aqueous ammonia were slowly added. After adding 330 ml of 1-butanol to the obtained solution, the aqueous layer was removed, and the aqueous layer was re-extracted with 165 ml of 1-butanol to obtain a 1-butanol solution of α-methylprolinamide. The solution was concentrated to remove water, and the precipitated solid was filtered off. Concentrated hydrochloric acid 27.3 g (0.26 mol) and cyclohexane 50 ml were added, and azeotropic dehydration was performed with Dean Stark under normal pressure heating and reflux. After cooling to room temperature, the crystals were filtered, washed with 1-butanol and ethyl acetate, and dried under reduced pressure to obtain 29.7 g of α-methylprolinamide hydrochloride as pale yellow crystals. As a result of HPLC analysis, the purity was 94 wt%, 0.171 mol, and the yield was 41%.

[Reference Example 4]
Production of (S) -α-methylproline A 500 ml Erlenmeyer flask was charged with 32.2 g (purity 97 wt%, 190 mmol) of α-methylprolinamide hydrochloride produced according to the method of Reference Example 3, and 34.7 ml of water. The pH was adjusted to 7.0 with 5% aqueous sodium hydroxide solution. Peptidase R (trade name, manufactured by Amano Enzyme Co., Ltd., Rhizopus oryzae) 2.3 g of water (15.5 ml) was added to the mixture, and the mixture was reacted at 40 ° C. and a stirring rate of 250 rpm for 60 hours. As a result of HPLC analysis, the pure content of (S) -α-methylproline was 10.5 g (81.0 mmol, yield 342.7%), and the optical purity was 99.0% ee. 50 ml of water and 15 g of activated carbon were added to the obtained reaction solution, and the mixture was shaken at 25 ° C. for 1 hour. Activated carbon was removed by Celite filtration, and the resulting aqueous solution was passed through an ion exchange resin (Amberlyst (registered trademark) A-26 (OH)), and then water was passed through (R) -α-methylprolinamide. Was recovered. As a result of HPLC analysis, 12.6 g (98.5 mmol, yield 52%, 87.1% ee) of (R) -α-methylprolinamide was recovered. Further, 1 mol / l acetic acid aqueous solution was passed through to elute (S) -α-methylproline, and (S) -α-methylproline 11.3 g (87.6 mmol, yield 46%, 99.0% ee, HPLC analysis) was collected.

[Example 28]
(S) -α-methylproline (189.6 g, chemical purity: 79.9 wt%, optical purity: 97.8% ee) prepared according to the method of Reference Example 4 was placed in the flask, and 80 ml of water and 400 ml of ethanol were added. After heating to 50 ° C. and dissolving, 500 ml of acetone was added dropwise. During the dropping, crystals were precipitated and the solution became cloudy. Further, the temperature was gradually lowered, and the mixture was stirred at 6-8 ° C. for about 30 minutes. Thereafter, the precipitated crystals were suction filtered and washed with 60 ml of a mixed solution of ethanol and acetone (ethanol / acetone (v / v) = 1/5) cooled to 10 ° C. or lower. The obtained crystal was dried at 60 ° C. until it became a constant weight (5 hours or more), and 116.5 g (yield 76.9%) of (S) -α-methylproline was obtained as a white crystal. As a result of HPLC analysis, the chemical purity was 98.9 wt% and the optical purity was 99.8% ee. The results are shown in Table 1. In Table 1, (S) -α-methylproline is expressed as AMP.

[Example 29]
Put (S) -α-methylproline (17.34 g, chemical purity: 70.5 wt%, optical purity: 95.2% ee) into the flask, add water (4 ml) and ethanol (20 ml), and warm to 55 ° C to dissolve. Then, 70 ml of acetone was added dropwise. During the dropping, crystals were precipitated and the solution became cloudy. Further, the temperature was gradually lowered, and the mixture was stirred at 4 to 7 ° C. for about 30 minutes. Thereafter, the precipitated crystals were suction filtered, and washed with 4 ml of a mixed solution of ethanol and acetone (ethanol / acetone (v / v) = 1/7) cooled to 10 ° C. or lower. The obtained crystal was dried at 60 ° C. until it became a constant weight (for 5 hours or more) to obtain 11.8 g (yield 96.2%) of (S) -α-methylproline as a white crystal. As a result of HPLC analysis, the chemical purity was 96.5 wt% and the optical purity was 98.6% ee. The results are shown in Table 1.

[Example 30]
(S) -α-Methylproline 17.62 g (chemical purity 63.0 wt%, optical purity 95.2% ee), 6 ml of water, 50 ml of ethanol, 50 ml of acetone It was. The results are shown in Table 1.

[Example 31]
(S) -α-methylproline 5.28 g (chemical purity 62.1 wt%, optical purity 98.0% ee), 1 ml of water, 3 ml of ethanol, 9 ml of acetone It was. The results are shown in Table 1.

[Example 32]
(S) -α-Methylproline 3.67 g (chemical purity 82.0 wt%, optical purity 98.0% ee), water 1.5 ml, ethanol 5 ml, acetone 6 ml were used, as in Example 28 Went to. The results are shown in Table 1.

[Example 33]
(S) -α-methylproline 2.21 g (chemical purity 56.9 wt%, optical purity 98.0% ee), 1 ml of water, 5 ml of ethanol, 5 ml of acetone It was. The results are shown in Table 1.

  As shown in Table 1, by crystallization in an organic solvent containing water, the chemical purity and optical purity can be increased to a level that can be almost satisfied with a single crystallization even for a sample with low chemical purity. it can. As for chemical purity, what was 56.9-82.0 wt% before crystallization is improved to 96.5-99.2 wt% after crystallization. Except for Example 29 where the recovery rate was particularly high, all were 98 wt% or more. Also, the optical purity was 95.2-98.0% ee before crystallization, but improved to 98.6-99.8% ee after crystallization. Excluding Example 29 where the recovery rate was particularly high, all were 99.6 ee% or more. Further, in Example 29, the chemical purity was changed from 70.5 wt% to 96.5 wt%, and the optical purity was changed from 95.2% ee to 98.6%, although the recovery rate was very high as 96.2%. It has improved to ee. Moreover, also in Examples 28 and 30 to 33, the recovery rate was sufficiently high at 61.3 to 80.5%. As described above, (S) -α-methylproline (AMP) can be efficiently purified by crystallization containing water. On the other hand, as shown in Example 20, when crystallization is performed from a solvent system that does not contain water, the chemical purity cannot be sufficiently improved.

[Example 34]
Production of 1- (carbamoylphenylmethyl) -2-cyano-2-methylpyrrolidine (in the above general formula (2), R ¹ = Me, R ² = carbamoylphenylmethyl, R ³ = H; Step (a) D- (Using phenylglycinamide hydrochloride, reaction in ethyl acetate-water solvent)

Into the flask, 0.60 g (5.0 mmol) of 5-chloro-2-pentanone, 0.37 g (7.5 mmol) of sodium cyanide, 0.93 g (5.0 mmol) of D-phenylglycinamide hydrochloride, 0. 43 ml (7.5 mmol), 50 w / v% NaOH aqueous solution 0.40 ml (5.0 mmol), water 1.2 ml and ethyl acetate 2.4 ml were charged and reacted at 40 ° C. for 2 hours and at 50 ° C. for 2 hours. To the reaction solution, 0.20 ml (2.5 mmol) of 50 w / v% NaOH aqueous solution was added and reacted at 60 ° C. for 2 hours, and then cooled to room temperature. After adding 0.20 ml (2.5 mmol) of 50 w / v% NaOH aqueous solution and 0.086 ml (1.5 mmol) of acetic acid to the reaction solution, the crystals were filtered, washed with water and ethyl acetate, and dried under reduced pressure. As a white crystal, 0.96 g (3.9 mmol, yield 79%) of 1- (carbamoylphenylmethyl) -2-cyano-2-methylpyrrolidine was obtained. In addition, since it was a racemate when it induced | guided | derived to (alpha) -methylproline, it is thought that epimerization of the carbamoylphenylmethyl group advanced during this reaction (refer the reference example 5).
^{In 1} H-NMR, a 7: 3 diastereomer mixture was observed.
Main products: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.62 (3H, s), 1.74-1.99 (3H, m), 2.29-2.41 (2H, m), 2 .78-2.84 (1H, m), 4.51 (1H, s), 5.81 (1H, brs), 6.97 (1H, brs), 7.31-7.44 (5H, m) ).
By-products: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.85 (3H, s), 1.74-1.99 (3H, m), 2.29-2.41 (1H, m), 2 70-2.78 (1H, m), 3.43-3.50 (1H, m), 4.19 (1H, s), 5.58 (1H, brs), 6.15 (1H, brs) ), 7.31-7.44 (3H, m), 7.52-7.58 (2H, m).

[Example 35]
Production of N- (carbamoylphenylmethyl) -α-methylprolinamide (in the above general formula (3), R ¹ = Me, R ² = carbamoylphenylmethyl, R ³ = H; step (b) hydration with sulfuric acid)

The flask was charged with 0.30 g (1.23 mmol) of 1- (carbamoylphenylmethyl) -2-cyano-2-methylpyrrolidine obtained in Example 34 and 1.0 g (10 mmol) of sulfuric acid at 50 ° C. for 2 hours. After the reaction, water and 28% aqueous ammonia were added on a water bath. Extraction with ethyl acetate was performed, and the organic layer was dried over magnesium sulfate and concentrated to obtain 0.50 g of a crude product of N- (carbamoylphenylmethyl) -α-methylprolinamide as a colorless oily substance. As a result of NMR analysis, the diastereomer ratio was> 5: 1. In addition, the stereochemistry of the obtained diastereomer has not been confirmed.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.45 (3H, s), 1.63-1.72 (1H, m), 1.80-1.94 (2H, m), 2.19-2 .27 (1H, m), 2.99-3.05 (1H, m), 3.42-3.49 (1H, m), 4.48 (1H, s), 5.31 (1H, brs) ), 5.38 (1H, brs), 5.58 (1H, brs), 6.97 (1H, brs), 7.29-7.47 (5H, m).

[Reference Example 5]
Production of α-methylproline (in the above general formula (6), R ¹ = Me, R ³ = H; removal of carbamoylphenylmethyl group, amide hydrolysis)
In a flask, 0.50 g of a crude product of N- (carbamoylphenylmethyl) -α-methylprolinamide obtained in Example 35, 0.070 ml (1.2 mmol) of acetic acid, 10% palladium carbon (manufactured by NE Chemcat) , PE-type, 55% water-containing product) 29 mg (0.012 mmol) and methanol 2.0 ml were added, and the mixture was reacted at 60 ° C. for 2 hours in an atmospheric hydrogen atmosphere. The reaction solution was filtered through celite and concentrated to obtain a crude product of α-methylprolinamide. To this crude product, 1.0 ml of water and 0.26 ml (4.9 mmol) of sulfuric acid were added and refluxed for 5 hours. After hydrolysis of the amide, the reaction mixture was analyzed by chiral HPLC. α-Methylproline was produced.

[Example 36]
Production of 1- (carbamoylphenylmethyl) -2-cyano-2-methylpyrrolidine (in the above general formula (2), R ¹ = Me, R ² = carbamoylphenylmethyl, R ³ = H; Step (a) D- Reaction with DMSO solvent using phenylglycinamide hydrochloride)
In a flask, 0.25 ml (2.2 mmol) of 5-chloro-2-pentanone, 0.29 g (6.0 mmol) of sodium cyanide, 0.37 g (2.0 mmol) of D-phenylglycinamide hydrochloride, 0. 34 ml (6.0 mmol), DMSO 1.0 ml and water 0.20 ml were charged and reacted at room temperature for 6 hours. After adding 3.8 ml of water to the reaction solution, the crystals were filtered, washed with water, and dried under reduced pressure. As a light brown crystal, 0.32 g (1.3 mmol, yield 67%) of 1- (carbamoylphenylmethyl) -2-cyano-2-methylpyrrolidine was obtained. In addition, since it was a racemate when it induced | guided | derived to (alpha) -methylproline like Example 35 and the reference example 5, it is thought that epimerization of the carbamoylphenylmethyl group advanced during this reaction.

[Example 37]
Production of 1-benzyl-2-cyano-2-phenylpyrrolidine (in the above general formula (2), R ¹ = Ph, R ² = Bn, R ³ = H; Step (a) 4-chloro-1-phenyl- 1-butanone, benzylamine and acetic acid used, reaction with t-butanol-water solvent)

In a flask, 0.32 ml (2.0 mmol) of 4-chloro-1-phenyl-1-butanone, 0.11 g (2.2 mmol) of sodium cyanide, 0.66 ml (6.0 mmol) of benzylamine, and 0.34 ml of acetic acid. (6.0 mmol), 1.0 ml of water and 1.0 ml of t-butanol were charged and reacted at 50 ° C. for 9 hours. To the reaction solution, 0.48 ml of 50 w / v% NaOH aqueous solution and sodium chloride were added, extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate. The solvent was distilled off to obtain 1.05 g of a pale yellow oily substance.
As a result of NMR analysis, this oily substance was found to contain 45% by weight (0.47 g, 90% yield) of 1-benzyl-2-cyano-2-phenylpyrrolidine, 46% by weight of benzylamine, and 9% by weight of ethyl acetate. It was a mixture containing.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.91-2.28 (4H, m), 2.52-2.60 (1H, m), 3.16-3.23 (1H, m), 3 .28 (1H, d, J = 12.9 Hz), 3.74 (1 H, d, J = 13.1 Hz), 7.23-7.39 (6H, m), 7.41-7.46 ( 2H, m), 7.73-7.77 (2H, m).

Claims (6)

General formula (6) including the following steps (d) and (e)
(In the formula, R ¹ represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, and R ³ each independently represents a hydrogen atom, An optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted hydroxyl group, an optionally substituted amino group, and optionally substituted. A thiol group or a halogen atom, wherein two or more R ^{3 s} may form one or more ring structures, * represents an asymmetric carbon, and the configuration of the asymmetric carbon : S-form (molar ratio) = 90: 10 to 100: 0 or R-form: S-form (molar ratio) = 10: 90 to 0: 100)) or an optically active α-substituted proline thereof Salt production method;
(D) The following general formula (4)
(Wherein R ¹ , R ³ and * are as defined above, and R ² represents an amino-protecting group). Hydrolyzing the optically active N, α-substituted proline amides or salts thereof By doing so, the general formula (5)
(Wherein each symbol has the same meaning as described above) to obtain an optically active N, α-substituted proline or a salt thereof represented by: and (e) an optically active N represented by the general formula (5), By removing the protective group R ² of the α-substituted prolines or salts thereof, the general formula (6)
(Wherein each symbol has the same meaning as described above), an optically active α-substituted proline or a salt thereof is obtained. General formula (6) including the following steps (a) to (e)
(Wherein each symbol has the same meaning as in claim 1), and a method for producing optically active α-substituted prolines or salts thereof;
(A) General formula (1)
(Wherein R ¹ and R ³ are as defined above, and X represents a halogen atom or a sulfonyloxy group) a chain ketone compound represented by By reacting, general formula (2)
(Wherein each symbol has the same meaning as in claim 1), 2-cyanopyrrolidines or salts thereof are obtained;
(B) By hydrating 2-cyanopyrrolidines represented by the general formula (2) or a salt thereof, the general formula (3)
(Wherein each symbol is as defined above), N, α-substituted proline amides or salts thereof are obtained;
(C) By dividing the N, α-substituted proline amides represented by the general formula (3) or a salt thereof, the general formula (4)
(Wherein each symbol has the same meaning as described above), an optically active N, α-substituted proline amide or a salt thereof is obtained;
(D) By hydrolyzing the optically active N, α-substituted proline amides represented by the general formula (4) or a salt thereof, the general formula (5)
(Wherein each symbol has the same meaning as described above) to obtain an optically active N, α-substituted proline or a salt thereof represented by: and (e) an optically active N represented by the general formula (5), By removing the protective group R ² of the α-substituted prolines or salts thereof, the general formula (6)
(Wherein each symbol has the same meaning as described above), an optically active α-substituted proline or a salt thereof is obtained. Furthermore, the general formula (5)
(Wherein each symbol has the same meaning as in claim 1), the method according to claim 1 or 2, comprising a purification step of the optically active N, α-substituted proline or a salt thereof. A method wherein the purification method is extraction using a polar organic solvent, or crystallization of N, α-substituted prolines represented by the general formula (5) or a salt thereof as a metal salt. Furthermore, the general formula (6)
(Wherein each symbol has the same meaning as in claim 1), a hydrogen halide salt of an optically active α-substituted proline represented by the formula is purified in the presence of an epoxy compound. Or the method of 2. General formula (6)
(Wherein each symbol has the same meaning as in claim 1), wherein the optically active α-substituted prolines are purified by crystallization from a solvent system containing water. A method for producing optically active α-substituted prolines represented by formula (6). Formula (7)
(Wherein * represents an asymmetric carbon), or an optically active α-methyl-N- (1′-phenylethyl) proline or a salt thereof.