JP2005023055A - New optically active amine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new optically active amine and its salt useful as an optical resolution agent for an optically active carboxylic acid having a specific structure and useful also as an asymmetric ligand, an asymmetry recognition agent, raw material of medicines and agrochemicals, a chiral building block, etc., and producible by an industrial means and provide a method for the production and use of these compounds. <P>SOLUTION: The invention provides a new optically active phenylethylamine derivative synthesizable by a conventional easy process. The optically active amine compound of the invention is useful as an excellent optical resolution agent for a carboxylic acid having a specific structure and useful also as an asymmetric ligand, an asymmetry recognition agent, raw material of medicines and agrochemicals and a chiral building block. It is producible on an industrial scale by a simple means. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  TECHNICAL FIELD The present invention relates to an optically active amine important as a pharmaceutical / pesticidal raw material, a chiral building block, an optical resolution agent, or the like, and in particular, a novel optically active amine and a salt thereof, the amine as an optical resolution agent, and an optical using the compound. The present invention relates to a method for producing an active carboxylic acid.

  An optically active amine is an important compound that is used as a raw material for pharmaceuticals and agricultural chemicals due to its unique physiological activity or as an optical resolving agent, an asymmetric ligand, a chiral building block or the like because of its chirality.

For example, optically active natural alkaloids having a tertiary amine structure such as morphine, brucine, quinidine, quinine, strychnine, cinchonine, ephedrine and the like have long been famous as optical resolution agents. However, since these alkaloids are difficult to synthesize and are toxic, optically active amines that can be substituted are demanded.
Optically active α-phenylethylamines are known as excellent optical resolution agents along with natural alkaloids, but optically active α-methylbenzylamine, α-naphthylethylamine, N-benzyl-α-methylbenzyl having a similar structure. Amines and the like are also used as useful optical resolution agents.
Particularly important optically active α-phenylethylamines can be obtained by optical resolution of racemic α-phenylethylamines (for example, see Non-Patent Documents 1 and 2). Racemic α-phenylethylamines can be easily produced by known methods, for example, from benzylamine and phenylacetaldehyde (see, for example, Non-patent Document 3), from benzaldehyde and phenylethylamine (for example, non-patented). It is obtained from benzyl alcohol and phenylethylamine (see, for example, Non-Patent Document 5), or a well-known method for reducing benzylidenephenylethylamine (for example, see Non-Patent Documents 6 and 7).
As described above, methods for producing racemic or optically active α-phenylethylamines are known per se. However, when these optically active amines are used for optical resolution, the function as an optical resolution agent is not always exhibited sufficiently, and it is difficult to foresee the function of optical resolution from the structure of the optically active amine. It is certain to actually perform optical resolution using a large number of optically active amines. For these reasons, α-phenylethylamine and optically active amines having similar structures have been synthesized and studied as optical resolution agents (see, for example, Patent Documents 1, 2, 3, 4, and 5).

A. W. Ingersoll, Organic Synthesis, Coll. Vol. 2, 506 (1943). The Chemical Society of Japan, Experimental Chemistry Course 18, Reactions of Organic Compounds II (top), p.539 (1957) Fischer, E., CHBEAM, Chem. Ber., 29 (1896), 211. Buth, Kuelz, Rosenmund, CHBEAM, Chem. Ber., 72 (1939) 19, 25. Kindler, JLACBF, Justus Liebigs Ann. Chem., 485 (1931) 113, 120. Thies, et al, ARPMAS, Arch.Pharm. (Weinheim Ger.), 291 (1958) 248, 255. Hess, Ulrich, Czapla, Sylvia, ZECEAL, Z.Chem., (German), 259 (1985), 334. JP 2001-106661 A US Pat. No. 6,476,268 JP 2001-213843 A JP 2001-294573 A JP 2002-30050 A

  An object of the present invention is an industrially practicable method, a novel optically active amine and salt thereof useful as an optical resolution agent, an asymmetric ligand, an asymmetric recognition agent, a pharmaceutical / agrochemical raw material, a chiral building block, or the like. Is to provide.

The present inventors have made intensive studies for the above problems, a novel optically active phenylethylamine derivatives which may be synthesized by a known and simple method, optically active carboxylic acids, tertiary having a substituent, for example hydroxyl group, It has been found that the carboxylic acid having a quaternary asymmetric structure is excellent in optical resolution. In addition, since optically active carboxylic acids can be easily produced using new optically active phenylethylamine derivatives, there is a way to provide new optical resolution agents, chiral recognition agents, raw materials for pharmaceuticals and agricultural chemicals, and chiral building blocks. Opened up and reached the present invention.

That is, the present invention provides a novel optically active amine represented by the general formula 1 and salts thereof represented by the general formula 1 shown in (1) to (9), the compound as an optical resolution agent, and production of an optically active carboxylic acid using the compound Regarding the method.
(1) An optically active amine represented by the general formula 1 and a salt thereof.
(1)
(However, R ₁ and R ₂ represent an alkyl group, an aryl group, or an aralkyl group that may have a substituent. Xn, X ₁ , X ₂ , X ₃ , and X ₄ are a hydrogen atom, a halogen atom, a hydroxyl group, Or an alkyl group, an aryl group, or an aralkyl group which may have a substituent, which may be the same or different, and may have a plurality of Xn. Represents a carbon atom, and the carbon atom to which the substituents R ₂ , X ₃ and X ₄ are linked may be an asymmetric center.)
(2) The optically active amine or salt thereof according to (1), wherein R _{1 in} formula 1 is a methyl group.
(3) In the general formula 1, R ₂ is 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 3,4 -Dimethylphenyl group, 3,5-dimethylphenyl group, 2,4,5-trimethylphenyl group, 2,4,6-trimethylphenyl group, 4-biphenyl group, 1-naphthyl group, 2-methoxyphenyl group, 3 -Methoxyphenyl group, 4-methoxyphenyl group, 2-chlorophenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 2-trifluoromethylphenyl group, or 4-trifluoromethylphenyl group, (1) Or the optically active amine and the salt thereof according to (2).
(4) The optically active amine and the salt thereof according to any one of (1) to (3), wherein Xn, X ₁ , X ₂ , X ₃ and X ₄ are all hydrogen atoms in the general formula 1. .
(5) In the general formula 1, all of Xn, X ₁ , X ₂ , X ₃ and X ₄ are hydrogen atoms, R ₁ is a methyl group, R ₂ is a 2-methylphenyl group, 3- Methylphenyl group, 4-methylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 2,4,5-trimethylphenyl Group, 2,4,6-trimethylphenyl group, 4-biphenyl group, 1-naphthyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-chlorophenyl group, 2-fluorophenyl group , A 4-fluorophenyl group, a 2-trifluoromethylphenyl group, or a 4-trifluoromethylphenyl group, the optically active amine and the salt thereof according to any one of (1) to (4)
(6) The optically active amine according to any one of (1) to (5), which is produced by reacting α-methylbenzylamine having optical activity with a carbonyl compound and reducing the resulting imine compound, and the amine Salt derived from.
(7) An optical resolution agent comprising the optically active amine according to any one of (1) to (6), and an optical resolution method using the amine.
(8) A method for producing an optically active carboxylic acid using the optically active amine described in (1) to (6) as an optical resolution agent.
(9) Optically active 2- (6-methoxy-2-naphthyl) propionic acid and 3,3,3-trifluoro-2 using the optically active amine described in (1) to (6) as an optical resolution agent -Method for producing hydroxy-2-methylpropionic acid.

  The novel optically active amine compound of the present invention is an excellent optical resolution agent for a carboxylic acid having a specific structure, and is useful as an asymmetric ligand, an asymmetric recognition agent, a pharmaceutical / agrochemical raw material, or a chiral building block. And it can be manufactured industrially by simple means.

Hereinafter, the present invention will be described in detail. In R _1, R ₂ in the general formula 1, alkyl group which may have a substituent, an aryl group or an aralkyl group, e.g., methyl group, ethyl group, n- propyl group, an isopropyl group, t- butyl Group, n-amyl group, i-amyl group, n-hexyl group, cyclohexyl group, phenyl group, benzyl group, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2-cumyl Group, 3-cumyl group, 4-cumyl group, 2-indenyl group, 3-indenyl group, 1-naphthyl group, 2-naphthyl group, 4-biphenyl group, phenyloxyphenyl group, 2-methylphenyl group, 3- Methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group 2,5-dimethylphenyl group, 2,6-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 2,3,4-trimethylphenyl group, 2,4,5-trimethylphenyl Group, 2,4,6-trimethylphenyl group, 3,4,5-trimethylphenyl group, 2,3,4,5-tetramethylphenyl group, 2,3,4,6-tetramethylphenyl group, 2, 3,5,6-tetramethylphenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-trifluoromethylphenyl Group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-metho Shifeniru group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, a 4-ethoxyphenyl group.

Xn, X ₁ , X ₂ , X ₃ , X ₄ are a hydrogen atom, a halogen atom, that is, a fluorine, chlorine, bromine, iodine atom, a hydroxyl group or an alkyl group that may have a substituent, an aryl group, Or it is an aralkyl group. In the general formula 1, R ₁ , R ₂ , Xn, X ₁ , X ₂ , X ₃ , and X ₄ may be the same or different from each other, and there may be a plurality of Xn. The substituents that R ₁ , R ₂ , Xn, X ₁ , X ₂ , X ₃ , X ₄ may have are fluorine, chlorine, bromine, iodine atom, hydroxyl group, trifluoromethyl group, trichloromethyl group, A methoxy group, an ethoxy group, a linear or branched alkyl group having 1 to 24 carbon atoms, an aryl group, an aralkyl group, and a pyridyl group. A plurality of these substituents may be present.

When the optically active carboxylic acid is optically resolved using the optically active amine represented by the general formula 1, for example, the surface of the optical resolution of carboxylic acids having a tertiary or quaternary asymmetric structure having a substituent such as a hydroxyl group. From the viewpoint of R ₁ , R ₁ is any _one of a methyl group, an ethyl group, an isopropyl group, and a 4-methylphenyl group, and R ₂ is a 2-methylphenyl group, a 2-fluorophenyl group, and a 4-fluorophenyl group. Group, 2-chlorophenyl group, 2-bromophenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2,4-dimethylphenyl group, 2 , 5-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 2,4,5-trimethylphenyl group, 2,4,6-trimethyl Butylphenyl group, 1,1'-biphenyl-4-yl group, 2-methoxyphenyl group, 3-methoxyphenyl group, a 4-methoxyphenyl group, either a 1-naphthyl group, and _{Xn, X} 1, X _This is a case where all of ₂ , X ₃ and X ₄ are hydrogen atoms.

The optically active amine and its salt of the present invention can be synthesized by a known method, and an imine compound obtained by reaction of an optically active α-methylbenzylamine derivative and a carbonyl compound such as benzaldehyde having a substituent can be reduced. By doing so, N-benzyl-α-phenylethylamine having various substituents can be obtained. In addition, for example, a mineral acid such as hydrochloric acid, sulfuric acid, and nitric acid can be used to form a salt of the amine compound.
In order to obtain the imine compound, the optically active α-methylbenzylamine used for the reaction with the carbonyl compound is a known compound and can be easily obtained or produced.

  Examples of the carbonyl compound include 2-methylbenzaldehyde, 3-methylbenzaldehyde, 4-methylbenzaldehyde, 2,4-dimethylbenzaldehyde, 2,5-dimethylbenzaldehyde, 3,4-dimethylbenzaldehyde, 3,5-dimethylbenzaldehyde, 2,4,6-trimethylbenzaldehyde, 2,4,5-trimethylbenzaldehyde, 4-phenylbenzaldehyde, 4-methoxybenzaldehyde, 1-naphthylaldehyde and the like are used, and these can be easily obtained.

  In the reaction, it is usually preferable to use a solvent, alcohols such as methanol, ethanol, isopropyl alcohol, diethyl ether, t-butyl methyl ether, n-butyl ether, isobutyl ether, tetrahydrofuran, etc., which are inert to the reaction. And ethers, aromatic hydrocarbons such as benzene, toluene, o-xylene, m-xylene, p-xylene and ethylbenzene, and halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and chlorobenzene. These solvents may be used alone or in combination of two or more.

The carbonyl compound used in the reaction is usually preferably 0.5 to 2 mol times, particularly preferably 1 to 1.5 mol times relative to the α-methylbenzylamine derivative.
The reaction temperature is usually in the range of 0 to 200 ° C, and particularly preferably in the range of 0 to 100 ° C. The reaction time is usually 0.5 to 30 hours, but the purpose can be sufficiently achieved in 0.5 to 10 hours. The imine compound obtained here can be subjected to the following reaction after isolation or without isolation.

As a reduction method for obtaining an amine compound from the imine compound, there are a method using a metal hydride such as lithium aluminum hydride, sodium borohydride and borane, and a catalytic reduction method using a catalyst such as nickel, platinum and palladium.
When the lithium aluminum hydride or sodium borohydride is used, the amount of the reducing agent used in the reduction method using a metal hydride is usually about 0.25 to 5 moles, preferably about 0.005 times the amount of the imine compound. A range of 25 to 2 mole times is suitable. When borane is used, the amount of borane used is usually in the range of 0.3 to 5 mol times, preferably 0.3 to 3 mol times, based on boron, with respect to the imine compound.

  Solvents used in the reduction reaction include ethers such as diethyl ether, t-butyl methyl ether, n-butyl ether, isopropyl ether and tetrahydrofuran which are inert to the reaction, benzene, toluene, orthoxylene, metaxylene, paraxylene, ethylbenzene, and the like. Aromatic hydrocarbons, and halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane or chlorobenzene are preferred. Moreover, when using sodium borohydride etc. as a reducing agent, in addition to the said solvent, lower alcohols, such as methanol, ethanol, isopropyl alcohol, can also be used. The solvents may be used alone or in combination of two or more. The amount of solvent used is not particularly limited.

  The reaction temperature is usually about −50 ° C. to 100 ° C., preferably in the range of −20 ° C. to 100 ° C. After completion of the reaction, the salt obtained by decomposing the unreacted reducing agent with water, acetic acid or mineral acid and then concentrating is collected by filtration, and the recovered salt is neutralized using a base such as sodium hydroxide. Alternatively, the target amine compound can be obtained by concentrating the organic layer separated under weakly basic conditions. Alternatively, after completion of the reaction, an unreacted reducing agent is decomposed with water, acetic acid or mineral acid, and then a base is used as necessary, and then the organic layer separated under neutral to weak basicity is concentrated. The obtained amine may be further purified by distillation, column chromatography using silica gel or the like.

  In the case of catalytic hydrogenation using Raney nickel, palladium carbon, palladium alumina, platinum carbon, platinum alumina, platinum dioxide, palladium black, platinum black, etc. as the catalyst, the amount of catalyst used is usually from 0.1 to the imine compound. The range is 100% by weight, and the preferred range is 0.5 to 50% by weight. In the reduction reaction, alcohols such as methanol, ethanol and isopropyl alcohol, ethers such as diethyl ether, t-butyl methyl ether, n-butyl ether, isopropyl ether and tetrahydrofuran, esters such as ethyl acetate, benzene, toluene, ortho It is preferable to use aromatic hydrocarbons such as xylene, meta-xylene, para-xylene, and ethylbenzene, or water. These solvents may be used alone or in combination of two or more, and there is no particular limitation on the amount used. The reaction temperature is usually −30 ° C. to 150 ° C., but a temperature range of −10 to 100 ° C. is preferable. The reaction pressure is usually about 0 to 10 MPa, preferably about 0 to 5 MPa.

  After completion of the catalytic reduction reaction, the catalyst is removed by filtration, and the filtrate is concentrated to obtain the desired optically active amine. In addition, you may refine | purify by column chromatography using distillation and a silica gel etc. as needed. The resulting amine can be derived into salts using various acids.

  The optically active amine obtained by the above is an optically active carboxylic acid, for example, a tertiary or quaternary asymmetric carboxylic acid having a substituent such as a hydroxyl group, such as 2- (6-methoxy-2-naphthyl) propion. It shows excellent performance in optical resolution of acid or 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid. In addition, the optically active amine can be easily produced from optically active α-methylbenzylamine which is generally available, which is advantageous in terms of industrial implementation. Furthermore, since it is an amine having a novel structure and a salt derived from the amine, it can be expected to be applied to new asymmetric recognition agents, raw materials for pharmaceuticals and agricultural chemicals and chiral building blocks.

Hereinafter, the present invention will be described in more detail with reference to examples.
Example 1
Preparation of (S) -N- (2,4-dimethylbenzyl) -α-methylbenzylamine (S) -α-methylbenzylamine 4.31 g (35.6 mmol) and 2,4-dimethylbenzaldehyde 4.78 g ( 35.6 mmol) was stirred in 30 ml of toluene at 50 ° C. for 2 hours, water generated with the solvent was removed, and 120 ml of methanol was added. Next, 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 2 hours.
After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 8.21 g (34.3 mmol) of (S) -N- (2 , 4-dimethylbenzyl) -α-methylbenzylamine was obtained (yield 96.3%).
NMR spectrum data (δppm, CDCl3)
1.36 (d) 3H; 1.50 (s) 1H; 2.22 (s) 3H;
2.28 (s) 3H; 3.55 (s) 2H; 3.81 (q) 1H;
6.94-7.37 (m) 8H

Example 2
Preparation of (S) -N- (2,5-dimethylbenzyl) -α-methylbenzylamine (S) -α-methylbenzylamine 4.31 g (35.6 mmol) and 2,5-dimethylbenzaldehyde 5.02 g ( 37.4 mmol) was stirred in 30 ml of toluene at 50 ° C. for 2 hours, then the water produced with the solvent was removed, and 150 ml of methanol was added. 1.48 g (39.1 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 2 hours. After the reaction, 12 ml of 36% hydrochloric acid and 50 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 8.09 g (33.8 mmol) of (S) -N- (2 , 5-dimethylbenzyl) -α-methylbenzylamine was obtained (yield 94.9%).
NMR spectrum data (δppm, CDCl3)
1.36 (d) 3H; 1.52 (s) 1H; 2.20 (s) 3H;
2.29 (s) 3H; 3.55 (s) 2H; 3.82 (q) 1H;
6.93-7.38 (m) 8H

Example 3
Preparation of (R) -N- (3,4-dimethylbenzyl) -α-methylbenzylamine (R) -α-methylbenzylamine 4.31 g (35.6 mmol) and 3,4-dimethylbenzaldehyde 4.78 g ( 35.6 mmol) was stirred in 30 ml of toluene at 60 ° C. for 30 min, the water produced with the solvent was removed, and 140 ml of methanol was added. 1.48 g (39.1 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 5 hours. After the reaction, 12 ml of 36% hydrochloric acid and 100 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, extracted with ethyl acetate, and the extract was dried over magnesium sulfate and concentrated to give 8.09 g (33.8 mmol) of (R) -N- (3 , 4-Dimethylbenzyl) -α-methylbenzylamine was obtained (yield 94.9%).
NMR spectrum data (δppm, CDCl3)
1.34 (d) 3H; 1.65 (s) 1H; 2.21 (s) 3H;
2.23 (s) 3H; 3.55 (dd) 2H; 3.80 (q) 1H;
6.98-7.35 (m) 8H

Example 4
Preparation of (R) -N- (3,5-dimethylbenzyl ) -α-methylbenzylamine 4.31 g (35.6 mmol) of (R) -α-methylbenzylamine and 4.78 g of 3,5-dimethylbenzaldehyde ( 35.6 mmol) was stirred in 30 ml of toluene at 70 ° C. for 1 hour, and then the water produced together with the solvent was removed, and 140 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 2 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 8.19 g (34.2 mmol) of (R) -N- (3 , 5-dimethylbenzyl) -α-methylbenzylamine was obtained (yield 96.1%).
NMR spectrum data (δppm, CDCl3)
1.36 (d) 3H; 1.70 (s) 1H; 2.28 (s) 6H;
3.55 (dd) 2H; 3.80 (q) 1H; 6.86 (s) 1H;
6.88 (s) 2H; 7.20-7.36 (m) 5H

Example 5
Preparation of (S) -N- (2,4,6-trimethylbenzyl) -α-methylbenzylamine (S) -α-methylbenzylamine 4.31 g (35.6 mmol) and 2,4,6-trimethylbenzaldehyde After stirring 5.81 g (39.2 mmol) in 30 ml of toluene at 70 ° C. for 2 hours, the water produced together with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 4 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 8.24 g (32.5 mmol) of (S) -N- (2 , 4,6-trimethylbenzyl) -α-methylbenzylamine was obtained (yield 91.3%).
NMR spectrum data (δppm, CDCl3)
1.36 (d) 3H; 1.48 (s) 1H; 2.22 (s) 3H;
2.26 (s) 6H; 3.53 (dd) 2H; 3.83 (q) 1H;
6.80 (s) 2H; 7.22 to 7.40 (m) 5H

Example 6
Preparation of (R) -N- (4-phenylbenzyl) -α-methylbenzylamine (R) -α-methylbenzylamine 4.31 g (35.6 mmol) and 4-biphenylaldehyde 6.49 g (35.6 mmol) Was stirred in 80 ml of toluene at 80 ° C. for 30 minutes, and then the water produced together with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 2 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 9.80 g (34.1 mmol) of (R) -N- (4 -Phenylbenzyl) -α-methylbenzylamine was obtained (yield 95.8%).
NMR spectrum data (δppm, CDCl3)
1.36 (d) 3H; 1.69 (s) 1H; 3.63 (dd) 2H;
3.81 (q) 1H; 7.21-7.57 (m) 14H

Example 7
Preparation of (R) -N- (2,4,5-trimethylbenzyl) -α-methylbenzylamine (R) -α-methylbenzylamine 4.31 g (35.6 mmol) and 2,4,5-trimethylbenzaldehyde After stirring 5.28 g (35.6 mmol) in 30 ml of toluene at 80 ° C. for 30 min, water produced with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 4 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of the crystal separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 8.49 g (33.5 mmol) of (R) -N- (2 , 4,5-trimethylbenzyl) -α-methylbenzylamine was obtained (yield 94.1%).
NMR spectrum data (δppm, CDCl3)
1.35 (d) 3H; 1.36 (s) 1H; 2.18 (s) 6H;
2.20 (s) 3H; 3.53 (s) 2H; 3.81 (q) 1H;
6.89 (s) 1H; 7.00 (s) 1H;
7.21 to 7.37 (m) 5H

Example 8
Preparation of (R) -N- (2-methylbenzyl) -α-methylbenzylamine (R) -α-methylbenzylamine 4.31 g (35.6 mmol) and 2-methylbenzaldehyde 4.28 g (35.6 mmol) Was stirred in 80 ml of toluene at 80 ° C. for 30 minutes, and then the water produced together with the solvent was removed, and 120 ml of methanol was added. 1.48 g (39.2 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 10 hours. After the reaction, 13 ml of 36% hydrochloric acid and 60 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 7.84 g (34.8 mmol) of (R) -N- (2 -Methylbenzyl) -α-methylbenzylamine was obtained (yield 97.8%).
NMR spectrum data (δppm, CDCl3)
1.37 (d) 3H; 1.42 (s) 1H; 2.24 (s) 3H;
3.58 (s) 2H; 3.81 (q) 1H;
7.08 to 7.38 (m) 9H

Example 9
Preparation of (S) -N- (3-methylbenzyl) -α-methylbenzylamine (S) -α-methylbenzylamine 4.31 g (35.6 mmol) and 3-methylbenzaldehyde 4.28 g (35.6 mmol) Was stirred in 30 ml of toluene at 50 ° C. for 1 hour, water generated with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 5 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 7.66 g (34.0 mmol) of (S) -N- (3 -Methylbenzyl) -α-methylbenzylamine was obtained (yield 95.5%).
NMR spectrum data (δppm, CDCl3)
1.34 (d) 3H; 1.57 (s) 1H; 2.32 (s) 3H;
3.57 (dd) 2H; 3.79 (q) 1H;
7.02 to 7.35 (m) 9H

Example 10
Preparation of (R) -N- (4-methylbenzyl) -α-methylbenzylamine (R) -α-methylbenzylamine 4.31 g (35.6 mmol) and 4-methylbenzaldehyde 4.28 g (35.6 mmol) Was stirred in 30 ml of toluene at 70 ° C. for 1 hour, water generated with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 6 hours. After the reaction, 11 ml of 36% hydrochloric acid and 50 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of the crystal separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 7.64 g (33.9 mmol) of (R) -N- (4 -Methylbenzyl) -α-methylbenzylamine was obtained (yield 95.2%).
NMR spectrum data (δppm, CDCl3)
1.34 (d) 3H; 1.57 (s) 1H; 2.31 (s) 3H;
3.57 (dd) 2H; 3.78 (q) 1H;
7.09 to 7.35 (m) 9H

Example 11
Preparation of (R) -N- (2-methoxybenzyl) -α-methylbenzylamine (R) -α-methylbenzylamine 4.31 g (35.6 mmol) and 2-methoxybenzaldehyde 4.31 g (35.6 mmol) Was stirred in 30 ml of toluene at 60 ° C. for 1 hour, and then the water produced together with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 5 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding a NaOH aqueous solution of the crystal separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 8.16 g (33.8 mmol) of (R) -N- (2 -Methoxybenzyl) -α-methylbenzylamine was obtained (yield 94.9%).
NMR spectrum data (δppm, CDCl3)
33 (d) 3H; 1.91 (s) 1H; 3.63 (dd) 2H
3.75 (q) 1H; 3.76 (s) 3H; 6.82 to 7.34 (m) 9H

Example 12
Preparation of (S) -N- (3-methoxybenzyl) -α-methylbenzylamine (S) -α-methylbenzylamine 4.31 g (35.6 mmol) and 3-methoxybenzaldehyde 4.31 g (35.6 mmol) Was stirred in 30 ml of toluene at 60 ° C. for 1 hour, and then the water produced together with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 5 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 8.42 g (34.9 mmol) of (S) -N- (3 -Methoxybenzyl) -α-methylbenzylamine was obtained (yield 98.0%).
NMR spectrum data (δppm, CDCl3)
35 (d) 3H; 1.58 (s) 1H; 3.57 (dd) 2H
3.75 (s) 3H; 3.79 (q) 1H; 6.75-7.35 (m) 9H

Example 13
Preparation of (R) -N- (4-methoxybenzyl) -α-methylbenzylamine (R) -α-methylbenzylamine 4.31 g (35.6 mmol) and 4-methoxybenzaldehyde 4.85 g (35.6 mmol) Was stirred in 30 ml of toluene at 60 ° C. for 2 hours, water generated with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 7 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 8.47 g (35.1 mmol) of (R) -N- (4 -Methoxybenzyl) -α-methylbenzylamine was obtained (yield 98.6%).
NMR spectrum data (δppm, CDCl3)
34 (d) 3H; 1.57 (s) 1H; 3.57 (dd) 2H
3.77 (s) 3H; 3.78 (q) 1H; 6.82-7.35 (m) 9H

Example 14
Preparation of (S) -N- (2-fluorobenzyl) -α-methylbenzylamine (S) -α-methylbenzylamine 4.31 g (35.6 mmol) and 2-fluorobenzaldehyde 4.42 g (35.6 mmol) Was stirred in 30 ml of toluene at 60 ° C. for 1 hour, and then the water produced together with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 5 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 8.03 g (35.0 mmol) of (S) -N- (2 -Fluorobenzyl) -α-methylbenzylamine was obtained (yield 98.3%).
NMR spectrum data (δppm, CDCl3)
1.34 (d) 3H; 1.61 (s) 1H; 3.66 (dd) 2H;
3.77 (q) 1H; 6.95-7.35 (m) 9H

Example 15
Preparation of (R) -N- (4-fluorobenzyl) -α-methylbenzylamine (R) -α-methylbenzylamine 4.31 g (35.6 mmol) and 4-fluorobenzaldehyde 4.42 g (35.6 mmol) Was stirred in 30 ml of toluene at 60 ° C. for 1 hour, and then the water produced together with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 5 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of the crystal separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 7.89 g (34.4 mmol) of (R) -N- (4 -Fluorobenzyl) -α-methylbenzylamine was obtained (yield 96.6%).
NMR spectrum data (δppm, CDCl3)
1.34 (d) 3H; 1.53 (s) 1H; 3.56 (dd) 2H;
3.77 (q) 1H; 6.96-7.32 (m) 9H

Example 16
Preparation of (R) -N- (2-chlorobenzyl) -α-methylbenzylamine (R) -α-methylbenzylamine 4.31 g (35.6 mmol) and 2-chlorobenzaldehyde 5.00 g (35.6 mmol) Was stirred in 30 ml of toluene at 60 ° C. for 1 hour, and then the water produced together with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 5 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of the crystal separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 8.65 g (35.2 mmol) of (R) -N- (2 -Chlorobenzyl) -α-methylbenzylamine was obtained (yield 98.9%).
NMR spectrum data (δppm, CDCl3)
1.37 (d) 3H; 1.80 (s) 1H; 3.70 (dd) 2H;
3.79 (q) 1H; 7.13-7.38 (m) 9H

Example 17
Preparation of (S) -N- (2-trifluoromethylbenzyl) -α-methylbenzylamine (S) -α-methylbenzylamine 4.31 g (35.6 mmol) and 2-trifluoromethylbenzaldehyde 6.20 g ( 35.6 mmol) was stirred in 30 ml of toluene at 60 ° C. for 1 hour, then the water produced together with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 5 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 9.13 g (32.7 mmol) of (S) -N- (1 -Naphthylmethyl) -α-methylbenzylamine was obtained (yield 91.9%).
NMR spectrum data (δppm, CDCl3)
1.35 (d) 3H; 1.58 (s) 1H; 3.77 (dd) 2H;
3.81 (q) 1H; 7.24-7.60 (m) 9H

Example 18
Preparation of (S) -N- (4-trifluoromethylbenzyl) -α-methylbenzylamine (S) -α-methylbenzylamine 4.31 g (35.6 mmol) and 4-trifluoromethylbenzaldehyde 6.20 g ( 35.6 mmol) was stirred in 30 ml of toluene at 60 ° C. for 1 hour, then the water produced together with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 5 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to obtain 9.75 g (34.9 mmol) of (S) -N- (1 -Naphthylmethyl) -α-methylbenzylamine was obtained (yield 98.0%).
NMR spectrum data (δppm, CDCl3)
1.36 (d) 3H; 1.59 (s) 1H; 3.66 (dd) 2H;
3.77 (q) 1H; 7.25 to 7.53 (m) 9H

Example 19
Preparation of (R) -N- (1-naphthylmethyl) -α-methylbenzylamine (R) -α-methylbenzylamine 4.31 g (35.6 mmol) and 1-naphthylbenzaldehyde 5.56 g (35.6 mmol) Was stirred in 30 ml of toluene at 60 ° C. for 1 hour, and then the water produced together with the solvent was removed, and 120 ml of methanol was added. 1.35 g (35.6 mmol) of sodium borohydride was added at room temperature and stirred at room temperature for 5 hours. After the reaction, 11 ml of 36% hydrochloric acid and 42 ml of water were added in an ice bath and concentrated under reduced pressure to obtain a white solid. Water was added to the concentrate, and a white solid slurry was filtered off. The solution was made basic by adding NaOH aqueous solution of crystals separated by filtration, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give 8.60 g (32.9 mmol) of (R) -N- (1 -Naphthylmethyl) -α-methylbenzylamine was obtained (yield 92.4%).
NMR spectrum data (δppm, CDCl3)
1.37 (d) 3H; 1.62 (s) 1H; 3.88 (q) 1H;
4.03 (dd) 2H; 7.24-7.99 (m) 12H

Example 20
Optical resolution of 2- (6-methoxy-2-naphthyl) propionic acid (S) -N- (2,4-dimethylbenzyl) -α-methylbenzylamine (0.479 g, 2 mmol) and racemic 2- ( 6-Methoxy-2-naphthyl) propionic acid (0.461 g, 2 mmol) was dissolved in 5 ml of t-butyl methyl ether at 60 ° C. Next, the solution was gradually cooled to 5 ° C. over 3 hours with stirring. The precipitated crystals are filtered, the filter cake is washed with t-butyl methyl ether and dried (S) -N- (2,4-dimethylbenzyl) -α-methylbenzylamine and (S) -2- A diastereomeric salt of (6-methoxy-2-naphthyl) propionic acid (0.250 g, 0.532 mmol) was obtained. The optical purity of (S) -2- (6-methoxy-2-naphthyl) propionic acid obtained by metathesis of the obtained crystals was 75.5% ee.
The obtained diastereomeric salt (0.200 g) was dissolved in 5 ml of methanol while heating, and then cooled to 5 ° C. with stirring. The precipitated crystals were filtered, washed with t-butyl methyl ether, and dried to obtain 0.148 g of a purified diastereomeric salt.
The resulting purified diastereomeric salt was decomposed by adding an excess of 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The aqueous layer was separated, acidified with excess 1N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, concentrated and dried to give (S) -2- (6-methoxy-2-naphthyl) propionic acid. The obtained (S) -2- (6-methoxy-2-naphthyl) propionic acid (0.070 g) had an optical purity of 95% ee and a theoretical yield of 38%.

Example 21
Optical resolution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (S) -N- (2,5-dimethylbenzyl) -α-methylbenzylamine (0.479 g, 2 mmol) and racemic 3,3,3-Trifluoro-2-hydroxy-2-methylpropionic acid (0.316 g, 2 mmol) was dissolved in 4 g of t-butyl methyl ether at 60 ° C. Next, the solution was gradually cooled to 5 ° C. over 3 hours with stirring. The precipitated crystals were filtered, and the filter cake was washed with t-butyl methyl ether and dried to give (S) -N- (2,5-dimethylbenzyl) -α-methylbenzylamine and (S) -3,3, A diastereomeric salt of 3-trifluoro-2-hydroxy-2-methylpropionic acid (0.307 g, 0.772 mmol) was obtained. The optical purity of (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid obtained by metathesis of the obtained crystal was 44.0% ee.
The obtained diastereomeric salt (0.250 g) was dissolved in 2.5 g of 2-propanol while heating, and then cooled to 5 ° C. with stirring. The precipitated crystals were filtered, washed with t-butyl methyl ether, and dried to obtain 0.162 g of a purified diastereomeric salt.
The resulting purified diastereomeric salt was decomposed by adding an excess of 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The aqueous layer was separated, acidified with excess 1N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, concentrated and dried to obtain (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid. The obtained (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.063 g) had an optical purity of 75.5% ee and a theoretical yield of 48.9%. It was.

Example 22
Optical resolution of 2- (6-methoxy-2-naphthyl) propionic acid (R) -N- (3,4-dimethylbenzyl) -α-methylbenzylamine (0.479 g, 2 mmol) and racemic 2- ( 6-Methoxy-2-naphthyl) propionic acid (0.461 g, 2 mmol) was dissolved in 5 ml of t-butyl methyl ether at 60 ° C. Next, the solution was gradually cooled to 5 ° C. over 3 hours with stirring. The precipitated crystals are filtered, the filter cake is washed with t-butyl methyl ether and dried and (R) -N- (3,4-dimethylbenzyl) -α-methylbenzylamine and (S) -2- The diastereomeric salt of (6-methoxy-2-naphthyl) propionic acid (0.198 g, 0.421 mmol) was obtained. The optical purity of (S) -2- (6-methoxy-2-naphthyl) propionic acid obtained by metathesis of the obtained crystals was 73.2% ee. The obtained diastereomeric salt (0. 180 g) was dissolved in 5 ml of methanol while heating, and then cooled to 5 ° C. with stirring. The precipitated crystals were filtered, washed with t-butyl methyl ether and dried to give 0.135 g of purified diastereomeric salt.
The resulting purified diastereomeric salt was decomposed by adding an excess of 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The aqueous layer was separated, acidified with excess 1N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, concentrated and dried to give (S) -2- (6-methoxy-2-naphthyl) propionic acid. The obtained (S) -2- (6-methoxy-2-naphthyl) propionic acid (0.064 g) had an optical purity of 93.5% ee and a theoretical yield of 30.6%.

Example 23
Optical resolution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (R) -N- (3,5-dimethylbenzyl) -α-methylbenzylamine (0.479 g, 2 mmol) and racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.316 g, 2 mmol) was dissolved in 2 g of 2-propanol at 60 ° C. Next, the solution was gradually cooled to 5 ° C. over 3 hours with stirring. The precipitated crystals are filtered, the filter cake is washed with t-butyl methyl ether and dried (R) -N- (3,5-dimethylbenzyl) -α-methylbenzylamine and (S) -3, The diastereomeric salt (0.219 g, 0.551 mmol) of 3,3-trifluoro-2-hydroxy-2-methylpropionic acid was obtained. The optical purity of (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid obtained by metathesis of the obtained crystals was 91.8% ee. Mer salt (0.200 g) was dissolved in 2.0 g of 2-propanol while heating, and then cooled to 5 ° C. with stirring. The precipitated crystals were filtered, washed with t-butyl methyl ether and dried to give 0.175 g of purified diastereomeric salt.
The resulting purified diastereomeric salt was decomposed by adding an excess of 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The aqueous layer was separated, acidified with excess 1N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, concentrated and dried to obtain (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid. The obtained (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.066 g) had an optical purity of 98.5% ee and a theoretical yield of 46.0%. It was.

Example 24
Optical resolution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (S) -N- (2,4,6-trimethylbenzyl) -α-methylbenzylamine (0.507 g, 2 mmol) And racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.316 g, 2 mmol) were dissolved in 4 g of t-butyl methyl ether at 60 ° C. Next, the solution was gradually cooled to 5 ° C. over 3 hours with stirring. The precipitated crystals are filtered, the filter cake is washed with t-butyl methyl ether and dried (S) -N- (2,4,6-trimethylbenzyl) -α-methylbenzylamine and (S)- The diastereomeric salt of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.256 g, 0.623 mmol) was obtained.
The optical purity of (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid obtained by metathesis of the obtained crystal was 12.5% ee.

Examples 25-37
Optical resolution of 2- (6-methoxy-2-naphthyl) propionic acid S1 in the case where R1 in general formula 1 is a methyl group, Xn, X1, X2, X3, and X4 are all hydrogen atoms and the substituent R2 is changed. -The results of optical resolution of the body are summarized in Table 1.

Claims (9)

An optically active amine represented by the general formula 1 and a salt thereof.
(1)
(However, R ₁ and R ₂ represent an alkyl group, an aryl group, or an aralkyl group that may have a substituent. Xn, X ₁ , X ₂ , X ₃ , and X ₄ are a hydrogen atom, a halogen atom, a hydroxyl group, Or an alkyl group, an aryl group, or an aralkyl group which may have a substituent, which may be the same or different, and may have a plurality of Xn. Represents a carbon atom, and the carbon atom to which the substituents R ₂ , X ₃ and X ₄ are linked may be an asymmetric center.) The optically active amine or a salt thereof according to claim ₁ , wherein R _{1 in} formula 1 is a methyl group. In the general formula 1, R ₂ is 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 3,4-dimethylphenyl. Group, 3,5-dimethylphenyl group, 2,4,5-trimethylphenyl group, 2,4,6-trimethylphenyl group, 4-biphenyl group, 1-naphthyl group, 2-methoxyphenyl group, 3-methoxyphenyl Or a 4-methoxyphenyl group, a 2-chlorophenyl group, a 2-fluorophenyl group, a 4-fluorophenyl group, a 2-trifluoromethylphenyl group, or a 4-trifluoromethylphenyl group. Item 3. The optically active amine and the salt thereof according to Item 2. The optically active amine and the salt thereof according to any one of claims 1 to 3, wherein in the general formula 1, all of Xn, X ₁ , X ₂ , X ₃ and X ₄ are hydrogen atoms. In General Formula 1, Xn, X ₁ , X ₂ , X ₃ , and X ₄ are all hydrogen atoms, R ₁ is a methyl group, R ₂ is a 2-methylphenyl group, and a 3-methylphenyl group. 4-methylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 2,4,5-trimethylphenyl group, 2 , 4,6-trimethylphenyl group, 4-biphenyl group, 1-naphthyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-chlorophenyl group, 2-fluorophenyl group, 4- The optically active amine and salt thereof according to any one of claims 1 to 4, which is a fluorophenyl group, a 2-trifluoromethylphenyl group, or a 4-trifluoromethylphenyl group.   The optically active amine according to any one of claims 1 to 5 and a salt derived from the amine, which are produced by reacting an optically active α-methylbenzylamine with a carbonyl compound and reducing the resulting imine compound. .   An optical resolution agent comprising the optically active amine according to claim 1, and an optical resolution method using the amine.   The manufacturing method of the optically active carboxylic acid which uses the optically active amine of Claim 1 to 6 as an optical resolution agent.   An optically active 2- (6-methoxy-2-naphthyl) propionic acid and 3,3,3-trifluoro-2-hydroxy-2-acid using the optically active amine according to claim 1 as an optical resolving agent A method for producing methylpropionic acid.