JP2007063267A - Method for producing optically active diphenylalanine compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an optically active diphenylalanine compound. <P>SOLUTION: An optically active diphenylalanine compound (e.g., L-2-acetylamino-3,3-diphenylpropanoic acid) is obtained by reacting a diphenylalanine compound (e.g., 2-acetylamino-3,3-diphenylpropanoic acid) with an optically active amine compound (e.g., (R)-(+)-1-(4-methylphenyl)ethylamine) in the presence of an organic solvent to obtain a diastereomer and treating the diastereomer under an acidic condition. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing an optically active diphenylalanine compound useful as a synthetic intermediate for anti-HIV drugs, dipeptidyl peptidase inhibitors and the like, and a diastereomeric salt of the compound useful for the production of the compound.

  An optically active diphenylalanine compound (including a protected amino group) is a compound useful as an intermediate for the synthesis of a pharmaceutical compound. For example, an anti-HIV drug (Patent Document 1), a dipeptidyl peptidase inhibitor (Patent Document) It is used as a synthetic intermediate of 2).

  As a method for producing optically active 3,3-diphenylalanine, as shown in the following reaction scheme, N- (diphenylmethylene) glycine ester synthesized from benzophenone imine and glycine ester is reacted with diphenylbromomethane, A method is described in which a racemate of 3-diphenylalanine is synthesized to form a diastereomeric salt with cinchonidine to perform optical resolution (Patent Document 3). However, as a result of the inventors reexamining the optical resolution method, the optical purity of the obtained D-3,3-diphenylalanine was 86% ee.

  As another method, Non-Patent Document 1 and Non-Patent Document 2 describe an asymmetric synthesis method of N-Boc-diphenylmethylalanine. However, these methods use an asymmetric source of stoichiometric amount, have a large number of steps, and additionally require expensive reagents such as a low-temperature reaction tank and KHMDS for reaction at −78 ° C. The cost is high and it is difficult to say that this is an industrially advantageous method.

International Publication No. 04/056764 pamphlet International Publication No. 03/002531 Pamphlet US Pat. No. 5,198,548 Heterocycles, 57, 6, pp. 2002 (HETEROCYCLES, 57, 6, 2002) Tetrahedron Letter, 33, 23, 3293, 1992 (Tetrahedron Letter, 33, 23, 3293, 1992)

  The present invention has been made in view of such a situation, and a problem to be solved is to provide a production method capable of obtaining an optically active diphenylalanine compound industrially advantageously in high yield. .

As a result of intensive studies to solve the above problems, the present inventors have formed an optically active N-protected diphenylalanine compound by forming a diastereomeric salt with a specific optically active phenylethylamine compound. The inventors have found that phenylalanine compounds can be optically resolved efficiently, and have completed the present invention.

That is, the present invention includes the following contents.
[1] The following formula (3):
[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, a nitro group or a hydroxyl group, and n represents an integer of 1 to 5 independently. , P ¹ represents an amino-protecting group, * represents an asymmetric carbon atom, and the configuration is S or R. ]
A method for producing an optically active diphenylalanine compound represented by the following formula (1):
[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, a nitro group or a hydroxyl group, and n represents an integer of 1 to 5 independently. , P ¹ represents an amino-protecting group. ]
A diphenylalanine compound represented by the following formula (2):
Wherein, R ³ is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a cyano group, a nitro group or an acyl group, or adjacent two of R ³ is a benzene ring to form a condensed ring N represents an integer of 1 to 5, * represents an asymmetric carbon atom, and the configuration is S or R. ]
A method for producing an optically active diphenylalanine compound, which comprises reacting with an optically active amine compound represented by the formula (I) and resolving the generated diastereomeric salt.
[2] The optically active amine compound is 1-phenylethylamine, 1- (4-methylphenyl) ethylamine, 1- (4-ethylphenyl) ethylamine, 1- (4-propylphenyl) ethylamine, 1- (4-isopropyl). Phenyl) ethylamine, 1- (4-methoxyphenyl) ethylamine, 1- (4-bromophenyl) ethylamine, 1- (4-chlorophenyl) ethylamine, 1- (4-fluorophenyl) ethylamine, 1- (4-hydroxyphenyl) ) Ethylamine, 1- (4-cyanophenyl) ethylamine, 1- (4-nitrophenyl) ethylamine, 1- (4-acetylphenyl) ethylamine, 1- (1-naphthyl) ethylamine and 1- (2-naphthyl) ethylamine One or more selected from the group consisting of optically active substances The production method according to [1] above, which is the above.
[3] The optically active amine compound is (−)-1-phenylethylamine, (+)-1-phenylethylamine, (−)-1- (4-methylphenyl) ethylamine, (+)-1- (4- Methylphenyl) ethylamine, (−)-1- (4-isopropylphenyl) ethylamine, (+)-1- (4-isopropylphenyl) ethylamine, (−)-1- (4-methoxyphenyl) ethylamine, (+) -1- (4-methoxyphenyl) ethylamine, (-)-1- (4-bromophenyl) ethylamine, (+)-1- (4-bromophenyl) ethylamine, (-)-1- (4-chlorophenyl) Ethylamine, (+)-1- (4-chlorophenyl) ethylamine, (−)-1- (1-naphthyl) ethylamine, (+)-1- (1-naphthyl) Triethanolamine, (-) - 1- (2-naphthyl) ethylamine and (+) - 1- (2-naphthyl) is at least one selected from the group consisting of ethylamine, the [1] The method according.
[4] The optically active amine compound is (−)-1-phenylethylamine, (+)-1-phenylethylamine, (−)-1- (4-methylphenyl) ethylamine, and (+)-1- (4- The production method of the above-mentioned [1], which is one or more selected from the group consisting of methylphenyl) ethylamine.
[5] Resolution is water, methanol, ethanol, 2-propanol, ethyl acetate, benzene, toluene, xylene, cyclohexane, methylcyclohexane, 1,2-dichloroethane, tert-butyl methyl ether, isobutyl methyl ketone, butyl acetate, chlorobenzene Diastereomeric salts are crystallized in one or more solvents selected from the group consisting of N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and acetonitrile. The production method according to any one of the above [1] to [4], which is carried out by separating by the method.
[6] After obtaining the optically active diphenylalanine compound represented by formula (3) according to the production method described in any one of [1] to [5] above, the protecting group for the amino group of the compound is removed. The following formula (4):
[Wherein R ¹ , R ² , * and n are as defined above] ]
The manufacturing method of the optically active diphenylalanine compound or its salt represented by these.
[7] The production method according to any one of [1] to [6], wherein R ¹ and R ² are each independently a fluorine atom or a hydrogen atom, and P ¹ is an acetyl group.
[8] The following formula (5):
[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, a nitro group or a hydroxyl group, and R ³ represents a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group. A group, a hydroxyl group, a cyano group, a nitro group, or an acyl group, or two adjacent R ³ may be condensed to form a benzene ring, and each n independently represents an integer of 1 to 5. , P ¹ represents an amino-protecting group, * represents an asymmetric carbon atom, and the configuration is S or R. ]
A diastereomeric salt represented by
[9] The following formula (6a):
[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, a nitro group, or a hydroxyl group, and n independently represents an integer of 1 to 5. . ]
An optically active N-acetyldiphenylalanine compound represented by the formula: (R)-(+)-1- (4-methylphenyl) ethylamine salt.
[10] The following formula (6b):
[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, a nitro group, or a hydroxyl group, and n independently represents an integer of 1 to 5. . ]
An optically active N-acetyldiphenylalanine compound represented by the formula: (S)-(−)-1- (4-methylphenyl) ethylamine salt.
[11] The salt according to [9] or [10] above, wherein R ¹ and R ² are each independently a fluorine atom or a hydrogen atom.

  According to the present invention, a highly pure optically active diphenylalanine compound can be easily produced in high yield.

  Hereinafter, the present invention will be described in detail. First, definitions of symbols in each formula used in this specification will be described.

Examples of the halogen atom in R ^{1, R 2} and ^{R 3,} a chlorine atom, a bromine atom, a fluorine atom is preferable, a fluorine atom is particularly preferred.

The alkyl group in R ¹ , R ² and R ³ is a linear or branched alkyl group having preferably 1 to 10, more preferably 1 to 7, and further preferably 1 to 4 carbon atoms. . Specific examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group and the like. A methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group and the like are preferable. In addition, the alkyl group may be substituted with one or more halogen atoms (for example, chlorine atom, bromine atom, fluorine atom), hydroxyl group, C 1-6 alkoxy group (for example, methoxy group) and the like. . In the present invention, the alkyl group includes a substituted alkyl group.

As the alkoxy group for R ¹ , R ² and R ^3, an alkoxy group in which the alkyl portion is the alkyl group described above is preferable. Specific examples include a methoxy group, an ethoxy group, a propoxy group, an isobropoxy group, a butoxy group, and a tert-butoxy group, and among them, a methoxy group and an ethoxy group are more preferable. In addition, the alkoxy group may be substituted with one or more halogen atoms (for example, chlorine atom, bromine atom, fluorine atom), hydroxyl group, C 1-6 alkoxy group (for example, methoxy group) and the like. . In the present invention, the alkoxy group includes a substituted alkoxy group.

The amino group in R ¹ and R ² may be mono- or di-substituted with the alkyl group, aryl group or aralkyl group described above, and may be substituted with a protecting group for the amino group in P ¹ described later. In the present invention, the amino group includes a substituted amino group. As an aryl group, C6-C14 (preferably 6-8) aryl groups, such as a phenyl group and a tolyl group, are mentioned. Examples of the aralkyl group include a benzyl group.
In addition, the hydroxyl group in R ¹ , R ² and R ³ may be similarly substituted with a protecting group exemplified by the protecting group for the amino group in P ¹ described later. In the present invention, the hydroxyl group includes a protected hydroxyl group.

Examples of the protecting group for the amino group in P ¹ include substituents described in Protecting Groups in Organic Chemistry 2nd edition (John Wiley & Sons, Inc. 1991). Specific examples include an acyl group, an alkyl group, an aralkyl group, and a silyl group. As an acyl group, C1-C8 acyl groups, such as a formyl group, an acetyl group, a phenylacetyl group, are mentioned, for example. As an alkyl group and an aralkyl group, the alkyl group and aralkyl group mentioned above are mentioned, for example. Examples of the silyl group include trisubstituted silyl groups such as a trimethylsilyl group, a triethylsilyl group, and a tert-butyldimethylsilyl group. In addition, methoxymethyl group, methylthiomethyl group, benzyloxymethyl group, methoxyethoxymethyl group, tetrahydropyranyl group, methoxycarbonyl group (Moc group), 9-fluorenylmethoxycarbonyl group (Fmoc group), 2,2, Examples include 2-trichloroethoxycarbonyl group, benzyloxycarbonyl group (Cbz group), tert-butoxycarbonyl group (Boc group), and the like.

Examples of the acyl group for R ³ include the same acyl groups as those exemplified as the amino-protecting group for P ¹ .

Particularly preferred embodiments for each symbol are as follows.
R ¹ and R ² are preferably a hydrogen atom, a halogen atom, or an alkyl group having 1 to 10 carbon atoms, more preferably a hydrogen atom or a halogen atom, and particularly preferably a hydrogen atom or a fluorine atom. Incidentally, R ¹ and R ² may be the same or different.
P ¹ is preferably an acyl group having 1 to 8 carbon atoms, a Moc group, an Fmoc group, a Cbz group, or a Boc group, and an acetyl group is particularly preferable.
R ³ includes a hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, bromine atom, chlorine atom, fluorine atom, hydroxy group, cyano group, nitro group, acetyl group, or two adjacent R ³ groups. Are preferably condensed to form a benzene ring, and further a hydrogen atom, methyl group, isopropyl group, methoxy group, bromine atom, chlorine atom or two adjacent R ³ are condensed to form a benzene ring. In some cases, a hydrogen atom and a methyl group are particularly preferable.

  Further, the compound represented by the formula (4) may be an acid addition salt, for example, an inorganic acid salt (for example, hydrochloride, sulfate), an organic acid salt (for example, acid salt, trifluoroacetate salt). , Tosylate, mesylate) and the like.

Next, the manufacturing method of this invention is demonstrated.
The diphenylalanine compound represented by the formula (1) is a compound to be subjected to optical resolution, and typically includes a racemic diphenylalanine compound, but an optically active diphenylalanine compound having low optical purity. Can also be used to increase its optical purity. As an optically active diphenylalanine compound having a low optical purity, for example, an optical purity of 80% e.e. e. The following mixture of (R) body and (S) body is mentioned.

  In the present invention, a diphenylalanine compound represented by formula (1) (hereinafter referred to as “compound (1)”) and an optically active amine compound represented by formula (2) (hereinafter referred to as “compound (2)”). The diastereomeric salt represented by the formula (5) (hereinafter referred to as “diastereomeric salt (5)”) is separated, and the salt is optically represented by the formula (3). Conversion into a diphenylalanine compound (hereinafter referred to as “compound (3)”) yields compound (3).

  The reaction is usually carried out in an organic solvent. Any organic solvent can be used as long as it does not inhibit this reaction, but an alcoholic organic solvent is preferably used. Examples of the alcohol organic solvent include methanol, ethanol, 1-propanol, 2-propanol, and t-butanol, and methanol is particularly preferable. In addition, these organic solvents can be used individually or in combination of 2 or more types. Further, these alcohol organic solvents may be used by mixing water or a non-alcohol organic solvent. Non-alcoholic organic solvents include ethyl acetate, isopropyl acetate, toluene, xylene, cyclohexane, methylcyclohexane, 1,2-dichloroethane, tert-butyl methyl ether, isobutyl methyl ketone, butyl acetate, chlorobenzene, tetrahydrofuran, N, N-dimethyl Examples include formamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, and acetonitrile. Although the usage-amount of an organic solvent can be suitably selected according to the kind of compound, it is 1-20 times weight normally with respect to a compound (1), Preferably it is 3-10 times weight.

  The amount of compound (2) to be used is generally 0.5 to 1.5 equivalents, preferably 0.5 to 1.0 equivalents, relative to compound (1). The reaction temperature is 40 to 70 ° C, preferably 50 to 60 ° C. The reaction time is 0.1 to 2 hours, preferably 0.5 to 1 hour.

  The generated diastereomeric salt (5) is divided by separating the diastereomeric salt (5) by crystallization in a solvent.

  Examples of the solvent used for the resolution of the diastereomeric salt (5) include the same solvents as the above reaction solvent. Among them, water, methanol, ethanol, 2-propanol, ethyl acetate, benzene, toluene, xylene, cyclohexane, methylcyclohexane, 1,2-dichloroethane, tert-butyl methyl ether, isobutyl methyl ketone, butyl acetate, chlorobenzene, tetrahydrofuran, One or more solvents selected from the group consisting of N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and acetonitrile are preferred. In particular, methanol is preferable.

  Crystallization can be performed, for example, under the following conditions. After the reaction is complete, first slowly cool the reaction solution slowly. The slow cooling time is 1 to 10 hours, preferably 2 to 5 hours. Cooling attainment temperature is 0-30 degreeC, Preferably it is 20-30 degreeC. Thereafter, crystallization is performed by stirring at that temperature. The stirring time is 0.5 to 24 hours, preferably 1 to 5 hours. The diastereomeric salt (5) is obtained by filtering the precipitated crystals. You may use a seed crystal as needed.

  After obtaining a crystal of the diastereomeric salt (5), the salt is converted into the compound (3), and the compound (3) is isolated. Conversion and isolation can be performed, for example, by extracting the diastereomeric salt (5) with an aprotic organic solvent under acidic conditions.

  Conversion and isolation can be carried out by a conventionally known method. For example, a diastereomeric salt (5), a mixed solvent of an aprotic organic solvent (for example, ethyl acetate, isopropyl acetate, toluene, etc.) and water. Among them, a method of adding an acid (for example, hydrochloric acid, sulfuric acid, etc.) can be mentioned. Extraction is made after acidification (usually pH 0.5-3, preferably 1-2). The obtained organic layer is washed with water, and then concentrated or a nonpolar organic solvent is added to obtain compound (3).

  Although the removal of the protecting group of the amino group of compound (3) can be performed by a well-known method, methods, such as an acid treatment and catalytic reduction, are mentioned, for example. For example, in the acid treatment, an acid (for example, hydrochloric acid or sulfuric acid) is added to the compound (3), and usually at 80 to 100 ° C. (preferably 90 to 100 ° C.), usually 1 to 16 hours (preferably 3 to 6 hours). This is done by reacting. Here, compound (4) may be obtained as an acid addition salt. For example, when concentrated hydrochloric acid is used 2 to 20 times by weight (preferably 5 to 7 times by weight) as the acid, the hydrochloride of compound (4) is precipitated, so it is filtered and dried to give compound (4) Can be obtained. The catalytic reduction is performed by a conventionally known method, for example, by introducing hydrogen into the compound (4) in the presence of a reduction catalyst such as palladium carbon.

  According to the present invention, an optical purity of 90% e.e. e. Or more, preferably 95% e.e. e. Or more, more preferably 98% e.e. e. The above compound (4) can be obtained.

  Preferred compounds (2) in the present invention include 1-phenylethylamine, 1- (4-methylphenyl) ethylamine, 1- (4-ethylphenyl) ethylamine, 1- (4-propylphenyl) ethylamine, 1- (4 -Isopropylphenyl) ethylamine, 1- (4-methoxyphenyl) ethylamine, 1- (4-bromophenyl) ethylamine, 1- (4-chlorophenyl) ethylamine, 1- (4-fluorophenyl) ethylamine, 1- (4- Hydroxyphenyl) ethylamine, 1- (4-cyanophenyl) ethylamine, 1- (4-nitrophenyl) ethylamine, 1- (4-acetylphenyl) ethylamine, 1- (1-naphthyl) ethylamine and 1- (2-naphthyl) ) Selected from the group consisting of ethylamine optically active substances It can include one or more members.

More preferred compounds (2) include (−)-1-phenylethylamine, (+)-1-phenylethylamine, (−)-1- (4-methylphenyl) ethylamine, (+)-1- (4- Methylphenyl) ethylamine, (−)-1- (4-isopropylphenyl) ethylamine, (+)-1- (4-isopropylphenyl) ethylamine, (−)-1- (4-methoxyphenyl) ethylamine, (+) -1- (4-methoxyphenyl) ethylamine, (-)-1- (4-bromophenyl) ethylamine, (+)-1- (4-bromophenyl) ethylamine, (-)-1- (4-chlorophenyl) Ethylamine, (+)-1- (4-chlorophenyl) ethylamine, (-)-1- (1-naphthyl) ethylamine, (+)-1- (1-naphthyl) Ethylamine, (-) - 1- (2-naphthyl) ethylamine and (+) - 1- (2-naphthyl) can be exemplified one or more selected from the group consisting of ethylamine.

Particularly preferred compounds (2) include (−)-1-phenylethylamine, (+)-1-phenylethylamine, (−)-1- (4-methylphenyl) ethylamine, and (+)-1- (4- Mention may be made of one or more selected from the group consisting of (methylphenyl) ethylamine.

The following formula (5) of the present invention obtained by the production method of the present invention:
[Wherein each symbol has the same meaning as described above. ]
The diastereomeric salt represented by is a novel compound.

Particularly preferred diastereomeric salts (5) include the following formula (6a):
[Wherein each symbol has the same meaning as described above. ]
An optically active N-acetyldiphenylalanine compound represented by the formula (R)-(+)-1- (4-methylphenyl) ethylamine salt, and the following formula (6b):
[Wherein each symbol has the same meaning as described above. ]
And an optically active N-acetyldiphenylalanine compound (S)-(−)-1- (4-methylphenyl) ethylamine salt represented by the formula: These are also novel compounds.

  The diphenylalanine compound represented by the formula (1) in the present invention conforms to a known method described in US Pat. No. 5,198,548, HETEROCYCLES, 57, 6, 2002 or Tetrahedron Letter, 33, 23, 3293, 1992. However, it can be more preferably produced by the method shown in the following scheme.

[Wherein, X represents a halogen atom, R ⁴ and R ⁵ each independently represents an alkyl group or an aralkyl group, or R ⁴ and R ⁵ together form an alkylene group; The symbols have the same meaning as above. ]

As a halogen atom in X, a chlorine atom, a bromine atom, or an iodine atom is preferable, and a chlorine atom or a bromine atom is particularly preferable.
Examples of the alkyl group in R ⁴ and R ⁵ include the same alkyl groups as in R ¹ , R ² or R ³ .
The aralkyl group in R ⁴ and R ⁵ refers to an alkyl group substituted with an aryl group. Carbon number of this alkyl group becomes like this. Preferably it is 1-6, More preferably, it is 1-3, and a methyl group, an ethyl group, a propyl group, an isopropyl group etc. are mentioned specifically ,. As this aryl group, C6-C14 (preferably 6-8) is preferable, and a phenyl group, a naphthyl group, etc. are mentioned specifically ,. The total carbon number of the aralkyl group is preferably 7-20, more preferably 7-11. Specific examples include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, etc. Among them, a benzyl group is preferable. The aralkyl group includes a halogen atom (for example, fluorine atom), an alkoxy group having 1 to 6 carbon atoms (for example, methoxy group), a haloalkyl group (for example, trifluoromethyl group), a haloalkoxy group (for example, trifluoro). It may be substituted with one or more methoxy groups).
Examples of the alkylene group formed by combining R ⁴ and R ⁵ include linear or branched alkylene groups having preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Specific examples include an ethylene group, a trimethylene group, a propylene group, and a tetramethylene group, and among them, a trimethylene group and a tetramethylene group are preferable.

Step (a)
Step (a) includes a diphenylmethylene halide compound represented by formula (7) (hereinafter referred to as “compound (7)”) and a malonic acid diester compound represented by formula (8) (hereinafter referred to as “compound (7)”). 8) ") is selected from organic solvents selected from N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone and N, N-dimethylformamide, and alkali metal hydrides and t-butoxy alkali metals. This is a step of reacting in the presence of a base to obtain a diester compound represented by formula (9) (hereinafter referred to as “compound (9)”).

The reaction in the step (a) is performed in the presence of a base selected from an alkali metal hydride and a t-butoxy alkali metal. Here, examples of the alkali metal hydride include lithium hydride, potassium hydride, sodium hydride and the like, and sodium hydride and potassium hydride are particularly preferable. Examples of the t-butoxy alkali metal include t-butoxy sodium and t-butoxy potassium, and t-butoxy potassium is particularly preferable. The amount of the base used is generally 1 to 1.5 equivalents, preferably 1.1 to 1.3 equivalents, relative to compound (8).

  The above reaction can also be performed in the presence of an iodine compound or a bromine compound in order to promote the reaction. In this case, when X is a chlorine atom, it is carried out in the presence of an iodine compound and / or a bromine compound, and preferably in the presence of an iodine compound. When X is a bromine atom, the reaction is carried out in the presence of an iodine compound.

  As the iodine compound, metal iodide and quaternary ammonium iodide are preferably used. As the metal iodide, an alkali metal iodide is preferable, and examples thereof include lithium iodide, potassium iodide, and sodium iodide. Of these, potassium iodide and sodium iodide are particularly preferable. Examples of quaternary ammonium iodide include tetrabutylammonium iodide and tetraheptylammonium iodide, with tetrabutylammonium iodide being particularly preferred. As the bromine compound, metal bromide and quaternary ammonium bromide are preferably used. As the metal bromide, an alkali metal bromide is preferable, and examples thereof include lithium bromide, potassium bromide, and sodium bromide, and potassium bromide and sodium bromide are particularly preferable. Examples of the quaternary ammonium bromide include tetrabutylammonium bromide and tetraheptylammonium bromide, with tetrabutylammonium bromide being particularly preferred. The usage-amount of an iodine compound or a bromine compound is 0.05-1.0 equivalent normally with respect to a compound (7), Preferably it is 0.5-1.0 equivalent.

  The reaction of step (a) is carried out under an organic solvent selected from N-methyl-2-pyrrolidone (also known as N-methylpyrrolidinone or 1-methylpyrrolidinone), N-ethyl-2-pyrrolidone and N, N-dimethylformamide. Done. From the viewpoint of improving the yield, N-methyl-2-pyrrolidone and N-ethyl-2-pyrrolidone are preferable, and N-methyl-2-pyrrolidone is particularly preferable. N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone and N, N-dimethylformamide may be used as a mixture of two or more thereof. Further, a solvent other than N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, and N, N-dimethylformamide may be mixed and used within a range in which the effect of this reaction is exhibited. As such a solvent, an aprotic organic solvent is preferably used, and examples thereof include dimethyl sulfoxide, hexamethylphosphoric triamide, acetonitrile, toluene and the like. Although the usage-amount of an organic solvent can be suitably selected according to the kind of compound, it is 3-20 times weight normally with respect to a compound (7), Preferably it is 5-10 times weight.

  The amount of compound (8) to be used is generally 1-1.5 equivalents, preferably 1.1-1.3 equivalents, relative to compound (7). When the amount of compound (8) used is less than the above range, the reaction tends to be insufficient.

  As reaction conditions, when the base is an alkali metal hydride, the reaction temperature is usually 30 to 60 ° C., preferably 40 to 50 ° C., and the reaction time is usually 1 to 16 hours, preferably 3 to 6 hours. is there. When the base is t-butoxy alkali metal, the reaction temperature is usually 30 to 80 ° C., preferably 60 to 70 ° C., and the reaction time is usually 3 to 24 hours, preferably 3 to 8 hours. After completion of the reaction, an organic solvent (for example, hydrocarbons such as toluene) and water are added to the reaction liquid and the mixture is separated, and the resulting organic layer is washed with water and concentrated to give compound (9). Can be obtained. Alternatively, after the completion of the reaction, the step (b) can be continuously performed in the same reaction vessel without performing the above-described post-treatment.

Step (b)
Step (b) is a step of obtaining compound (1) by subjecting compound (9) to hydrolysis and decarboxylation. Thereby, a compound (1) can be easily obtained with a sufficient yield.

  Hydrolysis and decarboxylation can be carried out by a conventionally known method. For example, the compound (9) is mixed with a base (for example, hydroxylated) in an alcoholic organic solvent (for example, ethanol) or a mixed solvent thereof with water. Sodium). The above reaction is usually carried out within the range of the reflux temperature of the solvent used from 80 ° C. (preferably 85 to 90 ° C.), and the reaction time is usually 1 to 16 hours, preferably 3 to 6 hours. After completion of the reaction, an organic solvent (for example, hydrocarbons such as toluene) and water are added to the reaction liquid and the mixture is separated. Acetic acid esters (for example, isopropyl acetate) and water are added to the obtained aqueous layer, and an acid is further added. (For example, hydrochloric acid and sulfuric acid) are added to make it acidic (usually pH 0.5 to 3, preferably 1 to 2), followed by extraction. The obtained organic layer is washed with water and then concentrated, whereby the compound (1) can be obtained.

  Step (a) and step (b) can also be carried out continuously in the same reaction vessel. For example, after completion of the reaction in the step (a), a method of adding a base (for example, sodium hydroxide, potassium hydroxide, or an aqueous solution thereof) and reacting them can be mentioned. This reaction is usually carried out within the range of the reflux temperature of the solvent used from 50 ° C. (preferably 60 to 70 ° C.), and the reaction time is usually 1 to 16 hours, preferably 3 to 6 hours.

  After completion of the reaction, the mixture is separated and acid (eg, hydrochloric acid, sulfuric acid) is added to the resulting aqueous layer to make it neutral (usually pH 6-8, preferably 7-8), followed by acetate esters (eg, acetic acid). Ethyl and isopropyl acetate) are added, and further acid (for example, hydrochloric acid and sulfuric acid) is added to make it acidic (usually pH 0.5 to 3, preferably 1 to 2), followed by extraction. The obtained organic layer is washed with an acid (for example, hydrochloric acid) and saturated saline, and then concentrated to obtain the compound (1).

  The property of the compound (1) obtained by the concentration is amorphous, but after performing the concentration to some extent without performing the concentration, the acetate solution is cooled as it is, or a specific poor solvent ( For example, crystallization can be performed by adding toluene) to obtain compound (1) as crystals.

  Examples of the present invention will be described in detail below, but the present invention is not limited to these examples.

<Reference Example 1>
Synthesis of 2-acetylamino-3,3-diphenylpropanoic acid To a solution of diethyl acetamidomalonate (13.33 g, 61.8 mmol) in N-methyl-2-pyrrolidone (40 mL, 1.25 M), t-butoxypotassium (7 .20 g, 64.3 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and then diphenylmethylene chloride (10.0 g, 49.3 mmol) and potassium iodide (4.10 g, 24.7 mol) were added thereto. For 6 hours. After completion of the reaction, 2M aqueous sodium hydroxide solution (45 mL) was added to the reaction solution, and the mixture was stirred at 60 ° C. for 5 hours. After cooling to room temperature, liquid separation was performed, and concentrated aqueous hydrochloric acid (4.4 mL) was added to the aqueous layer to adjust the pH to 7.0, ethyl acetate (30 mL) was added, and concentrated hydrochloric acid (6.9 mL) was further added to add water. The layer was extracted. The aqueous layer was further extracted with ethyl acetate (40 mL), and the organic layers were combined, washed 3 times with 2M hydrochloric acid (20 mL), washed with saturated brine (10 mL), and concentrated. Toluene (30 mL) was added to the concentrate, and the mixture was concentrated at 50 ° C., further toluene (30 mL) was added, and the mixture was stirred for 30 min. Then, white crystals precipitated by cooling to 0 ° C. over 5 hours. The crystals were filtered and dried under reduced pressure to give 11.69 g of the title compound. The powder X-ray (Cu-Kα ray) of the dry crystals showed characteristic peaks at 5.8 °, 11.5 °, 21.6 °, 23.2 ° and 28.7 °.

<Reference Example 2>
Synthesis of 2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid N-methyl-2-pyrrolidone (18.2 mL, 1.25 M) of diethyl acetamidomalonate (5.17 g, 23.80 mmol) To the solution was added t-butoxypotassium (2.77 g, 24.69 mmol), and the mixture was stirred at room temperature for 1 hour, and then a toluene solution of bis (4-fluorophenyl) methylene chloride (4.54 g, 19.02 mmol) (21 .79 g) and potassium iodide (3.19 g, 19.10 mol) were added, and the mixture was stirred at 70 ° C. for 6 hours. After completion of the reaction, 2M aqueous sodium hydroxide solution (45 mL) was added to the reaction solution, and the mixture was stirred at 60 ° C. for 5 hours. After cooling to room temperature, liquid separation was performed, and concentrated aqueous hydrochloric acid (4.4 mL) was added to the aqueous layer to adjust the pH to 7.0, ethyl acetate (30 mL) was added, and concentrated hydrochloric acid (6.9 mL) was further added to add water. The layer was extracted. The aqueous layer was further extracted with ethyl acetate (6 mL), the organic layers were combined, and the content of the title compound was examined by HPLC. As a result, it was found that 5.678 g was contained in the organic solvent. The organic layer was washed 3 times with 2M hydrochloric acid (9 mL), washed with saturated brine (4.5 mL), and concentrated. Toluene (13.5 mL) was added to the concentrate, and the mixture was concentrated at 50 ° C., and further toluene (13.5 mL) was added and stirred for 30 minutes. Then, white crystals precipitated by cooling to 0 ° C. over 5 hours. The crystals were filtered to obtain wet crystals. Powder X-rays of wet crystals (Cu-Kα ray) are 17.1 °, 17.6 °, 18.8 °, 20.7 °, 21.8 °, 22.0 °, 22.7 °, 23 Characteristic peaks were shown at .1 ° and 25.4 °. The wet crystals were dried under reduced pressure to give 5.39 g of the title compound as dry crystals. Powder X-ray (Cu-Kα ray) of dry crystals shows characteristic peaks at 17.1, 21.8, 22.0, 22.7, 23.1 and 25.4 degrees. It was.
Melting point 187 ° C
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.25-3.35 (m, 2H), 4.35 (d, 1H, J = 7.2 Hz), 5.13 (dd, 2H, J = 5.6 Hz, 10.7 Hz), 6.68 -7.39 (m, 13H), 8.52 (d, 1H, J = 5.6 Hz)
¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 172.49, 170.04, 162.53, 160.16, 160.12, 137.57, 137.39, 136.39, 130.45, 130.38, 130.30, 129.02, 128.29, 126.47, 115.60, 115.44, 115.39, 115.23, 55.67 , 51.82, 42.18
MS (FAB) m / z 396 [M + + H]

Synthesis of L-2-acetylamino-3,3-diphenylpropanoic acid (R)-(+)-1- (4-methylphenyl) ethylamine salt 2-acetylamino-3,3-diphenylpropanoic acid (1. 0 g, 3.5 mmol) in methanol (3 mL) was heated to 60 ° C. and (R)-(+)-1- (4-methylphenyl) ethylamine (508 μL, 3.5 mmol) was added and stirred. The mixture was cooled to 20 ° C. over 4 hours and stirred for 16 hours. The precipitated crystals were filtered and dried to obtain 456 mg of the title compound.

Synthesis of L-2-acetylamino-3,3-diphenylpropanoic acid L-2-acetylamino-3,3-diphenylpropanoic acid (R)-(+)-1- (4-methylphenyl) ethylamine salt ( 418 mg, 1.0 mmol) was added 2M sulfuric acid (1 mL) and ethyl acetate (3 mL), the aqueous layer was extracted, washed with 2M sulfuric acid (1 mL) and saturated brine, concentrated, dried in vacuo, and optical purity The title compound (270 mg) of 96.6% ee (SUMICHIRAL OA-4100, hexane: methanol: 2-propanol: trifluoroacetic acid = 92: 4: 4: 0.2, 210 nm, 1.0 mL / min, rt) Obtained.

Synthesis of L-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid / (R)-(+)-1- (4-methylphenyl) ethylamine salt 2-acetylamino-3,3- A methanol solution (10 mL) of bis (4-fluorophenyl) propanoic acid (4.59 g, 14.4 mmol) was heated to 60 ° C., and (R)-(+)-1- (4-methylphenyl) ethylamine (2 (.09 mL, 14.4 mmol) was added, seed crystals were added, and the mixture was stirred for 1 hour, then cooled to 20 ° C. over 4 hours with stirring, and stirred for 16 hours. The precipitated crystals were filtered and dried to obtain 2.9 g of the title compound.

Synthesis of L-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid L-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid · (R)-(+) To 1- (4-methylphenyl) ethylamine salt (2.0 g, 4.4 mmol), 1M hydrochloric acid (4 mL) and ethyl acetate (8 mL) were added, the aqueous layer was extracted, 1M hydrochloric acid (2 mL) and saturated brine Washed with, concentrated, vacuum dried, optical purity 99.5% ee (SUMICHIRAL OA-4100, hexane: methanol: 2-propanol: trifluoroacetic acid = 92: 4: 4: 0.2, 210 nm, 1 (0 mL / min, rt) of the title compound (1.40 g).

Synthesis of L-2-amino-3,3-bis (4-fluorophenyl) propanoic acid hydrochloride L-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid (1.65 g, 5. 2 mmol) of concentrated hydrochloric acid (10 mL) was stirred at 90 ° C. for 16 hours, and then ice-cooled to precipitate a solid. The solid was filtered and dried to give 1.32 g of the title compound.

Synthesis of L-2-t-butoxycarbonylamino-3,3-bis (4-fluorophenyl) propanoic acid L-2-amino-3,3-bis (4-fluorophenyl) propanoic acid (1.27 g, 4 , 05 mmol, 95.7% ee) aqueous solution of sodium bicarbonate was added to adjust pH to 8-9, methanol (1.0 mL) and di-t-butyl dicarbonate (1.3 g, 5 26 mmol) and stirred at 37 ° C. for 16 hours. Thereafter, the reaction solution was returned to room temperature, the pH was adjusted to 2 with 6N hydrochloric acid, ethyl acetate was added, the layers were separated, and the target product was extracted into the organic layer. After the organic layer was concentrated, heptane was added and the mixture was stirred overnight, whereby crystals were precipitated. The crystals were filtered, dried and 99% ee (SUMICHIRAL OA-4100, hexane: methanol: 2-propanol: trifluoroacetic acid = 98: 1: 1: 0.1, 220 nm, 1.0 mL / min, rt) 1.24 g of the title compound was obtained.

Synthesis of L-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid L-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid · (R)-(+) To 1- (4-methylphenyl) ethylamine salt (2.40 g, 5.3 mmol), 2M sulfuric acid (9.6 mL) and ethyl acetate (19.2 mL) were added, the aqueous layer was extracted, and 2M sulfuric acid (9. 6 mL) and saturated brine, concentrated, solvent-substituted with t-butanol, added water (4.8 mL) and sulfuric acid (0.8 mL), stirred at 100 ° C. for 14.5 hours, After adding sodium oxide and adjusting pH to 8-9, methanol (12 mL) and di-t-butyl dicarbonate (1.46 g, 6.34 mmol) were added to this, and it stirred at 35 degreeC for 16 hours. Thereafter, the reaction solution was returned to room temperature, the pH was adjusted to 2 with 6N hydrochloric acid, ethyl acetate was added, the layers were separated, and the target product was extracted into the organic layer. After the organic layer was concentrated, heptane was added and the mixture was stirred overnight, whereby crystals were precipitated. The crystals were filtered, dried and 99% ee (SUMICHIRAL OA-4100, hexane: methanol: 2-propanol: trifluoroacetic acid = 98: 1: 1: 0.1, 220 nm, 1.0 mL / min, rt) Of the title compound was obtained.

Synthesis of L-2-acetylamino-3,3-diphenylpropanoic acid / (R)-(+)-1- (4-methylphenyl) ethylamine salt 2-acetylamino-3,3-diphenylpropanoic acid (283 mg, 1.0 mmol) in methanol (1 mL) was heated to 60 ° C., (R)-(+)-1- (4-methylphenyl) ethylamine (145 μL, 1.0 mmol) was added and stirred for 4 hours. The mixture was cooled to 20 ° C. and stirred for 16 hours. The precipitated crystals were filtered and dried to obtain 126 mg of the title compound.

Synthesis of L-2-acetylamino-3,3-diphenylpropanoic acid L-2-acetylamino-3,3-diphenylpropanoic acid (R)-(+)-1- (4-methylphenyl) ethylamine salt ( 1 mg hydrochloric acid (1 mL) and ethyl acetate (2 mL) were added to 126 mg, 0.30 mmol), the aqueous layer was extracted, washed with 1M hydrochloric acid (1 mL) and saturated brine, concentrated, dried in vacuo, and optical purity 96.9% ee (SUMICHIRAL OA-4100, hexane: methanol: 2-propanol: trifluoroacetic acid = 90: 5: 5: 0.2, 210 nm, 1.0 mL / min, rt) of the title compound (66.9 mg) )

Synthesis of D-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid / (S)-(−)-1- (4-methylphenyl) ethylamine salt 2-acetylamino-3,3- A methanol solution (10 mL) of bis (4-fluorophenyl) propanoic acid (4.85 g, 15.3 mmol) was heated to 60 ° C., and (S)-(−)-1- (4-methylphenyl) ethylamine (2 .19 mL, 15.3 mmol) was added, and the mixture was cooled to 20 ° C. over 4 hours with stirring and stirred for 16 hours. The precipitated crystals were filtered and dried to obtain 2.96 g of the title compound.

Synthesis of D-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid D-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid · (S)-(−) To 1- (4-methylphenyl) ethylamine salt (2.96 g, 6.5 mmol), 2 M sulfuric acid (6 mL) and ethyl acetate (24 mL) were added, the aqueous layer was extracted, 2 M sulfuric acid (6 mL) and saturated brine , Concentrated, vacuum dried, optical purity 95% ee (SUMICHIRAL OA-4100, hexane: methanol: 2-propanol: trifluoroacetic acid = 90: 5: 5: 0.2, 210 nm, 1.0 mL / Min, rt) of the title compound (1.97 g) was obtained.
[Comparative Example 1]

Synthesis of D-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid / (−)-cinchonidine salt 2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid (317 mg, 1.0 mmol) methanol solution (1.0 mL) was heated to 60 ° C., (−)-cinchonidine (295 mg, 1.0 mmol) was added, cooled to 20 ° C. over 4 hours with stirring, and stirred for 16 hours. did. The precipitated crystals were filtered and dried to obtain 244 mg of the title compound.
[Comparative Example 2]

Synthesis of D-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid D-2-acetylamino-3,3-bis (4-fluorophenyl) propanoic acid / (−)-cinchonidine salt ( 1M hydrochloric acid (1 mL) and ethyl acetate (2 mL) were added to 224 g, 0.40 mmol), and the aqueous layer was extracted, washed with 1M hydrochloric acid (1 mL) and saturated brine, concentrated, vacuum dried, and optical purity. The title compound (129 mg) was obtained as 86% ee (SUMICHIRAL OA-4100, hexane: methanol: 2-propanol: trifluoroacetic acid = 90: 5: 5: 0.2, 210 nm, 1.0 mL / min, rt). .
[Comparative Example 3]

Synthesis of D-2-acetylamino-3,3-bis (phenyl) propanoic acid / (-)-cinchonidine salt Methanol of 2-acetylamino-3,3-bis (phenyl) propanoic acid (283 mg, 1.0 mmol) The solution (1 mL) was heated to 60 ° C., (−)-cinchonidine (301 mg, 1.0 mmol) was added, cooled to 20 ° C. over 4 hours with stirring, and stirred for 16 hours. The precipitated crystals were filtered and dried to obtain 203 mg of the title compound.
[Comparative Example 4]

Synthesis of D-2-acetylamino-3,3-bis (phenyl) propanoic acid D-2-acetylamino-3,3-bis (phenyl) propanoic acid / (−)-cinchonidine salt (203 mg, 0.35 mmol) 1M hydrochloric acid (1 mL) and ethyl acetate (2 mL) were added, and the aqueous layer was extracted, washed with 1M hydrochloric acid (2 mL) and saturated brine, concentrated, dried in vacuo, and optical purity 62% ee (SUMICHIRAL OA). -4100, hexane: methanol: 2-propanol: trifluoroacetic acid = 90: 5: 5: 0.2, 210 nm, 1.0 mL / min, rt) to give the title compound (93.6 mg).

According to the present invention, a highly pure optically active diphenylalanine compound useful as a synthetic intermediate such as an anti-HIV drug or a dipeptidyl peptidase inhibitor can be easily produced with high yield.

Claims (11)

Following formula (3):
[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, a nitro group or a hydroxyl group, and n represents an integer of 1 to 5 independently. , P ¹ represents an amino-protecting group, * represents an asymmetric carbon atom, and the configuration is S or R. ]
A method for producing an optically active diphenylalanine compound represented by the following formula (1):
[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, a nitro group or a hydroxyl group, and n represents an integer of 1 to 5 independently. , P ¹ represents an amino-protecting group. ]
A diphenylalanine compound represented by the following formula (2):
Wherein, R ³ is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a cyano group, a nitro group or an acyl group, or adjacent two of R ³ is a benzene ring to form a condensed ring N represents an integer of 1 to 5, * represents an asymmetric carbon atom, and the configuration is S or R. ]
A method for producing an optically active diphenylalanine compound, which comprises reacting with an optically active amine compound represented by the formula (I) and resolving the generated diastereomeric salt. The optically active amine compound is 1-phenylethylamine, 1- (4-methylphenyl) ethylamine, 1- (4-ethylphenyl) ethylamine, 1- (4-propylphenyl) ethylamine, 1- (4-isopropylphenyl) ethylamine. 1- (4-methoxyphenyl) ethylamine, 1- (4-bromophenyl) ethylamine, 1- (4-chlorophenyl) ethylamine, 1- (4-fluorophenyl) ethylamine, 1- (4-hydroxyphenyl) ethylamine, 1- (4-cyanophenyl) ethylamine, 1- (4-nitrophenyl) ethylamine, 1- (4-acetylphenyl) ethylamine, 1- (1-naphthyl) ethylamine and 1- (2-naphthyl) ethylamine optics One or more selected from the group consisting of actives The method according to claim 1, wherein. The optically active amine compound is (-)-1-phenylethylamine, (+)-1-phenylethylamine, (-)-1- (4-methylphenyl) ethylamine, (+)-1- (4-methylphenyl) Ethylamine, (−)-1- (4-isopropylphenyl) ethylamine, (+)-1- (4-isopropylphenyl) ethylamine, (−)-1- (4-methoxyphenyl) ethylamine, (+)-1- (4-methoxyphenyl) ethylamine, (−)-1- (4-bromophenyl) ethylamine, (+)-1- (4-bromophenyl) ethylamine, (−)-1- (4-chlorophenyl) ethylamine, ( +)-1- (4-Chlorophenyl) ethylamine, (−)-1- (1-naphthyl) ethylamine, (+)-1- (1-naphthyl) ethylamine The production method according to claim 1, which is at least one selected from the group consisting of N, (−)-1- (2-naphthyl) ethylamine and (+)-1- (2-naphthyl) ethylamine. Optically active amine compounds are (-)-1-phenylethylamine, (+)-1-phenylethylamine, (-)-1- (4-methylphenyl) ethylamine and (+)-1- (4-methylphenyl). The manufacturing method of Claim 1 which is 1 or more types selected from the group which consists of ethylamine. Resolution is water, methanol, ethanol, 2-propanol, ethyl acetate, benzene, toluene, xylene, cyclohexane, methylcyclohexane, 1,2-dichloroethane, tert-butyl methyl ether, isobutyl methyl ketone, butyl acetate, chlorobenzene, tetrahydrofuran, Diastereomeric salts are separated by crystallization in one or more solvents selected from the group consisting of N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and acetonitrile. The manufacturing method of any one of Claims 1-4 performed by this. According to the production method of any one of claims 1 to 5, after obtaining the optically active diphenylalanine compound represented by the formula (3), the amino protecting group of the compound is removed. The following formula (4):
[Wherein R ¹ , R ² , * and n have the same meaning as in claim 1. ]
The manufacturing method of the optically active diphenylalanine compound or its salt represented by these. The production method according to any one of claims 1 to 6, wherein R ¹ and R ² are each independently a fluorine atom or a hydrogen atom, and P ¹ is an acetyl group. Following formula (5):
[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, a nitro group or a hydroxyl group, and R ³ represents a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group. A group, a hydroxyl group, a cyano group, a nitro group, or an acyl group, or two adjacent R ³ may be condensed to form a benzene ring, and each n independently represents an integer of 1 to 5. , P ¹ represents an amino-protecting group, * represents an asymmetric carbon atom, and the configuration is S or R. ]
A diastereomeric salt represented by Following formula (6a):
[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, a nitro group, or a hydroxyl group, and n independently represents an integer of 1 to 5. . ]
An optically active N-acetyldiphenylalanine compound represented by the formula: (R)-(+)-1- (4-methylphenyl) ethylamine salt. Following formula (6b):
[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, a nitro group, or a hydroxyl group, and n independently represents an integer of 1 to 5. . ]
An optically active N-acetyldiphenylalanine compound represented by the formula: (S)-(−)-1- (4-methylphenyl) ethylamine salt. The salt according to claim 9 or 10, wherein R ¹ and R ² are each independently a fluorine atom or a hydrogen atom.