JP4437648B2 - Process for producing optically active 1- (2-trifluoromethylphenyl) ethylamine - Google Patents

Description

  The present invention relates to a process for producing optically active 1- (2-trifluoromethylphenyl) ethylamine, which is an important intermediate for pharmaceuticals and agricultural chemicals.

  The optically active 1- (2-trifluoromethylphenyl) ethylamine targeted in the present invention is an important intermediate for pharmaceuticals and agricultural chemicals.

  As a method for producing optically active 1- (2-trifluoromethylphenyl) ethylamine, 1) a method by asymmetric reduction of O-methyloxime of 2-trifluoromethylacetophenone (Non-Patent Document 1, Non-Patent Document 2), 2) Regioselective of bis (α-methylbenzyl) amine having a trifluoromethyl group at the 2-position synthesized from 2-trifluoromethylacetophenone and optically active 1-phenylethylamine by two steps of dehydration condensation and asymmetric reduction A method by hydrogenolysis (Patent Document 1, Non-Patent Document 3) has been reported.

In the present invention, 1- (2-trifluoromethylphenyl) ethyl alcohol is converted to a sulfonic acid ester by reacting with a sulfonylating agent in the presence of a base, and reacted with optically active 1-phenylethylamine. To produce an optically active secondary amine by deriving the secondary amine into a salt thereof and recrystallizing and purifying the optically active secondary amine or a salt thereof by hydrogenolysis. A method for producing optically active 1- (2-trifluoromethylphenyl) ethylamine or a salt thereof has not been reported yet.
US Patent Application Publication No. 2002/103400 J. et al. Am. Chem. Soc. (USA), 1990, Vol. 112, No. 15, p. 5741-5747 J. et al. Chem. Soc. Perkin Trans. , (UK), 1985, No. 1, p. 2039-2044 Organic Letters, (USA), 2003, Vol. 5, No. 7, p. 1007-1010

  An object of the present invention is to provide an industrial process for producing optically active 1- (2-trifluoromethylphenyl) ethylamine, which is an important intermediate for pharmaceuticals and agricultural chemicals.

  In the method using asymmetric reduction described in Non-Patent Document 1 and Non-Patent Document 2, the chemical yield and optical purity of the target optically active 1- (2-trifluoromethylphenyl) ethylamine are 16% and 76%, respectively. e. e. (Enantiomeric excess) and extremely low.

  In addition, in the method by regioselective hydrogenolysis described in Patent Document 1 and Non-Patent Document 3, steric hindrance of the trifluoromethyl group at the 2-position is limited to a substrate having a trifluoromethyl group at the 2-position. For this reason, the dehydration condensation in the first step and the asymmetric reduction in the second step did not proceed well, and bis (α-methylbenzyl) amine having a trifluoromethyl group at the 2-position could not be obtained in good yield. . Further, unlike bis (α-methylbenzyl) amine having a trifluoromethyl group at the 3, 4 or 3,5 position, a salt purification method is specific for a substrate having a trifluoromethyl group at the 2 position. No optically active 1- (2-trifluoromethylphenyl) ethylamine having high optical purity cannot be obtained, and a practical synthesis method of optically active 1- (2-trifluoromethylphenyl) ethylamine It was hard to say.

  Thus, a method capable of industrially producing optically active 1- (2-trifluoromethylphenyl) ethylamine has been strongly desired.

  As a result of intensive studies to solve the above problems, the present inventors have found means for solving the problems as described below.

  That is, 1- (2-trifluoromethylphenyl) ethyl alcohol is converted to a sulfonic acid ester by reacting with a sulfonylating agent in the presence of a base, and trinated to the 2-position by reacting with optically active 1-phenylethylamine. It has been found that bis (α-methylbenzyl) amine (secondary amine) having a fluoromethyl group can be obtained in good yield.

Then, the secondary amine is converted into a salt thereof (referred to as a salt formed between an amine and an inorganic acid or an organic acid, the same shall apply hereinafter) and recrystallized to obtain a high diastereomeric excess optical activity. It was found that it can be purified to a secondary amine salt . In particular, by using hydrochloride or optically active mandelate, the relative configuration of the stereochemistry of the optically active secondary amine can be efficiently purified to the R-S or S-R diastereomer, while hydrobromide. It was found that the relative configuration of the stereochemistry of the optically active secondary amine can be efficiently purified to an R—R or S—S diastereomer. Furthermore, it has been clarified that by combining these salt purifications, both diastereomers can be recovered in good yield with a very high diastereomeric excess.

  Finally, both the diastereomers (RR-form / RS-form and SR-form / SS-form) of the optically active secondary amine or salts thereof are subjected to hydrogenolysis to obtain optically active 1 It was found that both optically active forms (R-form and S-form) of-(2-trifluoromethylphenyl) ethylamine or salts thereof can be obtained with high optical purity and high yield.

  Further, in the production method of optically active 1- (2-trifluoromethylphenyl) ethylamine, a useful sulfonic acid ester, and in the purification step, as a salt of optically active secondary amine, the hydrochloride, the hydrobromide, and the An optically active mandelate was found.

  The present inventors have found a novel method for producing optically active 1- (2-trifluoromethylphenyl) ethylamine as described above, and completed the present invention.

  This production method is highly effective for industrially producing optically active 1- (2-trifluoromethylphenyl) ethylamine because it has high selectivity in each reaction step and hardly produces impurities that are difficult to separate. It is.

  That is, the present invention provides the formula [1]

[Wherein the stereochemistry at the benzylic position (position 1) is R, S or racemic] 1- (2-trifluoromethylphenyl) ethyl alcohol represented by the general formula [2 ]

[Wherein R represents an alkyl group, an aryl group or a haloalkyl group, and X represents a halogen], or the general formula [3]

[Wherein R represents an alkyl group, an aryl group or a haloalkyl group], and is reacted with a sulfonylating agent represented by the general formula [4]

[Wherein the stereochemistry at the benzylic position (position 1) is R, S or racemic, and R represents an alkyl group, an aryl group or a haloalkyl group]. 5]

[Wherein * represents an asymmetric carbon, and the stereochemistry thereof is R or S form], by reacting with optically active 1-phenylethylamine represented by the formula [6]

[Wherein, the stereochemistry at the benzyl position (position 1) on the side where the trifluoromethyl group is substituted with an aromatic ring is R, S or racemic, * represents an asymmetric carbon, and the stereochemistry is R Or S-form] is produced , and the secondary amine is converted into a salt thereof and recrystallized and purified.

[Wherein * represents an asymmetric carbon, its stereochemistry R isomer or S-isomer optically active secondary amine obtained represented by the optically active secondary amine salt thereof (amine and an inorganic acid or an organic This refers to a salt formed between acids, the same applies hereinafter), and recrystallized and purified to give a formula [7]

[Wherein * represents an asymmetric carbon and the stereochemistry is R or S form], and the optically active secondary amine salt or the salt thereof is purified. By hydrogenolysis of the optically active secondary amine obtained by neutralization , the formula [8]

[Wherein * represents an asymmetric carbon, and the stereochemistry is R or S]], and provides a method for producing an optically active 1- (2-trifluoromethylphenyl) ethylamine or a salt thereof. .

  The present invention also provides an optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the formula [8], wherein a hydrochloride is used as the secondary amine salt represented by the formula [6] in the above production method. Alternatively, a method for producing a salt thereof is provided.

The present invention also provides a stereochemistry of the salt of the optically active secondary amine represented by the formula [7] obtained by purification in the production method using the hydrochloride of the secondary amine salt represented by the formula [6]. Provides a method for producing an optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the formula [8], or a salt thereof, wherein the relative configuration of is an R-S or S-R form.

  The present invention also provides an optically active 1- (2-trifluoromethyl) represented by the formula [8], wherein a hydrobromide is used as the secondary amine salt represented by the formula [6]. A method for producing phenyl) ethylamine or a salt thereof is provided.

Further, the present invention provides an optically active secondary amine salt represented by the formula [7] obtained by purification in the production method using a hydrobromide as the secondary amine salt represented by the formula [6]. A method for producing an optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the formula [8] or a salt thereof, in which the relative configuration of the stereochemistry of the compound is R—R or S—S.

Further, the present invention provides an optically active 1- (2-trifluoromethyl) represented by the formula [8], wherein an optically active mandelate is used as the secondary amine salt represented by the formula [6] in the production method described above. A method for producing phenyl) ethylamine or a salt thereof is provided.

Further, the present invention is a salt of secondary salt of the amine in the manufacturing method using an optically active mandelic acid salt, optically active secondary amine represented by the formula obtained by purification [7] represented by the above formula [6] A method for producing an optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the formula [8] or a salt thereof, wherein the relative configuration of the stereochemistry of R is the R-S form or the S-R form.

  Further, the present invention provides an optically active 1- (1) represented by the formula [8], wherein a salt of the secondary amine represented by the formula [6] is used in combination with a hydrochloride and a hydrobromide. A method for producing both optically active forms (R-form and S-form) of 2-trifluoromethylphenyl) ethylamine or a salt thereof is provided.

  The present invention also provides the optical activity represented by the formula [8], wherein the secondary amine salt represented by the formula [6] is used in combination with an optically active mandelate and hydrobromide in the production method described above. Provided is a method for producing both optically active forms (R-form and S-form) of 1- (2-trifluoromethylphenyl) ethylamine or a salt thereof.

  The present invention also provides a general formula [4].

[Wherein the stereochemistry at the benzylic position (position 1) is R, S or racemic, and R represents an alkyl group, an aryl group or a haloalkyl group].

  The present invention also provides a sulfonate ester in which R of the sulfonate ester represented by the general formula [4] is a methyl group in the above compound.

  In addition, the present invention provides formula [7]

[In the formula, * represents an asymmetric carbon, and the stereochemistry is R or S form], among the optically active secondary amines represented by R, S or R form. However, the hydrochloride salt is provided.

  In addition, the present invention provides formula [7]

[In the formula, * represents an asymmetric carbon, and the stereochemistry thereof is R or S form]. Among the optically active secondary amines represented by the formula, the relative configuration of stereochemistry is R or R or S form. However, the hydrobromide salt is provided.

  In addition, the present invention provides formula [7]

[In the formula, * represents an asymmetric carbon, and the stereochemistry is R or S form], among the optically active secondary amines represented by R, S or R form. An optically active mandelate salt is provided.

  Provided is an industrially advantageous process for producing optically active 1- (2-trifluoromethylphenyl) ethylamine, which is an important intermediate for pharmaceuticals and agricultural chemicals.

  The production method of the optically active 1- (2-trifluoromethylphenyl) ethylamine of the present invention will be described in detail. The production process of the present invention comprises 4 steps: 1) sulfonylation, 2) condensation, 3) salt purification, and 4) hydrogenolysis (see Scheme 1).

  The correlation of the stereochemistry of each compound according to the present invention is summarized in the following scheme 2.

   First, the sulfonylation in the first step will be described in detail. The sulfonylation in the first step consists of reacting 1- (2-trifluoromethylphenyl) ethyl alcohol with a sulfonylating agent in the presence of a base. By this step, a sulfonate ester represented by the general formula [4] can be obtained.

  As the stereochemistry at the benzyl position (position 1) of 1- (2-trifluoromethylphenyl) ethyl alcohol represented by the formula [1], an R-form, S-form or racemic form can be taken and employed. The optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the target formula [8] or a salt thereof may be properly used depending on the stereochemistry.

  The optical purity when the stereochemistry at the benzyl position (position 1) of 1- (2-trifluoromethylphenyl) ethyl alcohol represented by the formula [1] is R or S is 10% e. e. The above may be used, usually 20% e.e. e. Or more, particularly 30% e.e. e. The above is more preferable.

  The present invention has a great feature in that salt purification of the secondary amine represented by the formula [6] can be efficiently performed in the third step. For this reason, the optical activity represented by the formula [8], which is the final target product, is used without using one having high optical purity as the 1- (2-trifluoromethylphenyl) ethyl alcohol represented by the formula [1]. 1- (2-Trifluoromethylphenyl) ethylamine or a salt thereof can be obtained with high optical purity. Therefore, as 1- (2-trifluoromethylphenyl) ethyl alcohol represented by the formula [1], 30% e.e. e. Even if it is less than this, it can be satisfactorily used for the reaction, and this is often economically preferable. However, 90% e.e. e. Or 99% e. e. In this case, the secondary amine represented by the formula [6] can be obtained with a high diastereomeric excess without depending on the salt purification. The optically active 1- (2-trifluoromethylphenyl) ethylamine or a salt thereof represented by the formula [8] is obtained in such a high yield when considered based on 1- (2-trifluoromethylphenyl) ethyl alcohol. An active form can be obtained.

  1- (2-Trifluoromethylphenyl) ethyl alcohol represented by the formula [1] is a known compound, and the method for producing an optically active substance and a racemate is disclosed in Non-Patent Document 1 described above. Can be manufactured.

  Examples of the base include trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, dimethyllaurylamine, dimethylaminopyridine, N, N-dimethylaniline, dimethylbenzylamine, 1,8-diazabicyclo (5,4 , 0) undecene-7,1,4-diazabicyclo (2,2,2) octane, pyridine, 2,4,6-trimethylpyridine, pyrimidine, pyridazine, 3,5-lutidine, 2,6-lutidine, 2, Organic bases such as 4-lutidine, 2,5-lutidine and 3,4-lutidine, sodium hydride, potassium hydride, lithium hydride, calcium hydride, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, hydrogen carbonate Inorganic bases such as sodium and potassium bicarbonate It is. Among them, organic bases are preferable, and triethylamine, diisopropylethylamine, dimethylaminopyridine, 1,8-diazabicyclo (5,4,0) undecene-7, pyridine and 2,6-lutidine are more preferable.

  The amount of the base used may be 1 mol or more with respect to 1 mol of 1- (2-trifluoromethylphenyl) ethyl alcohol represented by the formula [1]. 1-5 mol is more preferable.

The alkyl group or haloalkyl group in the group R of the sulfonylating agent represented by the general formula [2] or the general formula [3] is not particularly limited, but for example, a straight chain or branched chain having 1 to 6 carbon atoms The halogen (F, Cl, Br, I) constituting the haloalkyl group is particularly preferably F and Cl. That is, as the alkyl group and haloalkyl group, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, trifluoromethyl group, pentafluoroethyl group And a heptafluoropropyl group, a nonafluorobutyl group, a trichloromethyl group, a pentachloroethyl group, a heptachloropropyl group, and a nonachlorobutyl group. On the other hand, examples of the aryl group include a phenyl group, a tolyl group (o-, m-, p-), and a xylyl group.

  As the group X (F, Cl, Br, I) of the sulfonylating agent represented by the general formula [2], F and Cl are particularly preferable.

  Examples of the sulfonylating agent represented by the general formula [2] or the general formula [3] include methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl fluoride, trifluoromethanesulfonyl chloride, pentafluoroethanesulfonyl fluoride, and pentafluoroethanesulfonyl. Examples thereof include chloride, monochloromethanesulfonyl chloride, dichloromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride, and p-toluenesulfonic anhydride. Among these, methanesulfonyl chloride, monochloromethanesulfonyl chloride and p-toluenesulfonyl chloride are preferable, and methanesulfonyl chloride and p-toluenesulfonyl chloride are more preferable.

  The amount of the sulfonylating agent represented by the general formula [2] or the general formula [3] is 1 mol or more with respect to 1 mol of 1- (2-trifluoromethylphenyl) ethyl alcohol represented by the formula [1]. May be used, and usually 1 to 10 mol is preferable, and 1 to 5 mol is more preferable.

  Examples of the reaction solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene, methylene chloride, chloroform, 1,2- Halogenated hydrocarbons such as dichloroethane, ethers such as diethyl ether, tetrahydrofuran, t-butyl methyl ether and 1,4-dioxane, esters such as ethyl acetate and n-butyl acetate, nitriles such as acetonitrile and propionitrile And the like. Among these, n-heptane, toluene, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, t-butyl methyl ether and ethyl acetate are preferable, and toluene, methylene chloride, 1,2-dichloroethane and t-butyl methyl ether are particularly preferable. . These reaction solvents can be used alone or in combination.

  The amount of the reaction solvent used may be 0.01 L (liter) or more with respect to 1 mol of 1- (2-trifluoromethylphenyl) ethyl alcohol represented by the formula [1]. -20L is preferable, and 0.1-10L is more preferable especially.

  As temperature conditions, it is -60- + 100 degreeC, Usually, -50- + 90 degreeC is preferable, and -40- + 80 degreeC is especially more preferable.

  The reaction time is 0.1 to 48 hours, but it varies depending on the reaction conditions, so the progress of the reaction is traced by analysis means such as gas chromatography, liquid chromatography, NMR, etc. The end point is preferred.

  Although there is no restriction | limiting in particular as post-processing, The target crude product of the sulfonate ester shown by General formula [4] can be obtained by performing normal post-processing operation after completion | finish of reaction. The crude product is subjected to purification operations such as activated carbon treatment, distillation, recrystallization, column chromatography, etc., if necessary, to obtain the target sulfonate ester represented by the general formula [4] with high chemical purity. be able to. On the other hand, a solution obtained by removing the reaction-finished solution directly or by-passing salt by filtration without performing any post-treatment operation can be used as it is for the second step condensation. Depending on the reaction conditions, 1- (2-trifluoromethylphenyl) ethyl halide reacts continuously with the salt formed as a by-product of the desired general formula [4] produced in the reaction system. However, the 1- (2-trifluoromethylphenyl) ethyl halide has the same reactivity as the sulfonate ester represented by the general formula [4]. Can be used.

  Next, the condensation in the second step will be described in detail. The condensation in the second step consists of reacting the sulfonic acid ester produced by the sulfonylation in the first step with optically active 1-phenylethylamine.

  As the stereochemistry of the asymmetric carbon of the optically active 1-phenylethylamine represented by the formula [5], an R-form or an S-form can be adopted, and the salt purification method to be employed and the target optical formula represented by the formula [8] What is necessary is just to use suitably according to the stereochemistry of active 1- (2-trifluoromethylphenyl) ethylamine or its salt.

  The optical purity of the optically active 1-phenylethylamine represented by the formula [5] is 95% e.e. e. Or more, usually 97% e.e. e. Or more, particularly 99% e.e. e. The above is more preferable.

  The amount of the optically active 1-phenylethylamine represented by the formula [5] may be 1 mol or more per 1 mol of the sulfonic acid ester represented by the general formula [4], and usually 1 to 10 mol. In particular, 1 to 5 mol is more preferable.

  This condensation can also be carried out in the presence of a base, and the base and the amount used thereof are the same as those disclosed in the sulfonylation in the first step.

  Examples of the reaction solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene, methylene chloride, chloroform, 1,2- Halogenated hydrocarbons such as dichloroethane, ethers such as diethyl ether, tetrahydrofuran, t-butyl methyl ether, 1,4-dioxane, esters such as ethyl acetate and n-butyl acetate, hexamethylphosphoric triamide, N, Examples thereof include amides such as N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide. Among them, n-heptane, toluene, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, t-butyl methyl ether, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile and dimethyl Sulfoxides are preferred, and toluene, 1,2-dichloroethane, tetrahydrofuran, t-butyl methyl ether, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile and dimethyl sulfoxide are particularly preferred. These reaction solvents can be used alone or in combination.

  As a usage-amount of the reaction solvent, 0.01 L or more should just be used with respect to 1 mol of sulfonic acid ester shown by General formula [4], Usually 0.05-20L is preferable, Especially 0.1-10L Is more preferable.

  As temperature conditions, it is -20- + 200 degreeC, Usually, -10- + 175 degreeC is preferable, and 0- + 150 degreeC is especially more preferable.

  The reaction time is 0.1 to 72 hours, but it varies depending on the reaction substrate and reaction conditions, so the progress of the reaction is tracked by analytical means such as gas chromatography, liquid chromatography, and NMR, and the raw materials are almost lost. Preferably, the end point is the end point.

Although there is no restriction | limiting in particular as a post-processing, The target crude product of the secondary amine shown by Formula [6] can be obtained by performing normal post-processing operation after completion | finish of reaction. In particular, the optically active 1-phenylethylamine represented by the unreacted formula [5] is obtained by washing the reaction-terminated liquid or the target organic layer containing the secondary amine represented by the formula [6] with an aqueous solution of ammonium chloride. Can be selectively removed. The crude product is obtained by subjecting it to purification treatment such as activated carbon treatment, distillation, recrystallization, column chromatography, etc., if necessary, to obtain the desired secondary amine represented by the formula [6] with high chemical purity. Can do. Since this condensation generally proceeds by an S _N 2 substitution reaction, the stereochemistry of the sulfonate ester represented by the general formula [4] used for the reaction substrate is inverted, but the degree of the inversion varies depending on the reaction substrate and reaction conditions. . The stereochemistry at the benzyl position (position 1) on the side where the trifluoromethyl group of the secondary amine represented by the formula [6] is substituted with an aromatic ring can be R, S or racemic, and the secondary The relative configuration of the stereochemistry of the amine is RR, RS, SR, or SS, and the secondary amine having any stereochemistry is a salt of the third step. Can be used for purification.

  Next, the salt purification in the third step will be described in detail. The salt purification in the third step consists of recrystallizing and refining the secondary amine produced by the condensation in the second step to its salt.

In order to obtain the optically active secondary amine represented by the formula [7] with a particularly high diastereomeric excess, 10% d. e. (Diastereomer excess) It is preferable to use one more than 20% d. e. More preferably, 30% d. e. The above is even more preferable. However, as the secondary amine represented by the formula [6], a steric stereochemistry (0% de) at the benzyl position (position 1) on the side where the trifluoromethyl group is substituted with the aromatic ring is used. This is also possible (Examples 3 to 5), and in this case too, the following d. e. % Of an optically active secondary amine salt represented by the formula [7] can be obtained. By repeating the same salt purification on the optically active secondary amine represented by the formula [7] obtained by the salt purification, an even higher d. e. % Of an optically active secondary amine salt represented by the formula [7] can be obtained (Examples 8 and 9). Thus, by repeating the salt purification, the secondary amine d. e. %, High d. e. % Of the optically active secondary amine salt of the formula [7] can be obtained.

  Examples of the acid used in this step include inorganic acids and organic acids.

  Examples of the inorganic acid include carbonic acid, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, boric acid, perchloric acid and the like. Of these, hydrochloric acid and hydrobromic acid are particularly preferred. By using hydrochloride for refining this salt, the diastereomeric salt of the R-S or S-R diastereomeric compound is preferentially precipitated as the stereochemistry of the secondary amine, while hydrobromide Is used, the diastereomeric salt of the R—R or S—S form of the stereochemistry of the secondary amine preferentially precipitates as crystals.

  By this method, among the optically active secondary amines represented by the formula [7], the hydrochloride of which the stereochemical relative configuration is the R-S form or the S-R form and the optical system represented by the formula [7] Among the active secondary amines, hydrobromide salts whose stereochemical relative configurations are R-R or S-S can be obtained.

  Examples of the organic acid include aliphatic carboxylic acids such as acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, hexanoic acid, heptanoic acid, cyclohexanecarboxylic acid, octanoic acid, phenylacetic acid, and 3-phenylpropionic acid, Haloalkylcarboxylic acids such as chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, bromoacetic acid, iodoacetic acid, 2-chloropropionic acid, 3-chloropropionic acid, acrylic acid, crotonic acid, citraconic acid Unsaturated carboxylic acids such as maleic acid, fumaric acid, cis or trans-cinnamic acid, benzoic acid, o-, m- or p-toluic acid, o-, m- or p-fluorobenzoic acid, o-, m- or p-chlorobenzoic acid, o-, m- or p-bromobenzoic acid, o-, m-ma Is p-iodobenzoic acid, o-, m- or p-hydroxybenzoic acid, o-, m- or p-anisic acid, o-, m- or p-aminobenzoic acid, o-, m- or p- Nitrobenzoic acid, o-, m- or p-cyanobenzoic acid, o-, m- or p-benzenedicarboxylic acid (phthalic acid, isophthalic acid, terephthalic acid), α-, β- or γ-picolinic acid, 2 , 6-pyridinedicarboxylic acid, aromatic carboxylic acids such as 1- or 2-naphthoic acid, methanesulfonic acid, chloromethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-phenolsulfonic acid Sulfonic acids such as lactic acid, malic acid, tartaric acid, dibenzoyltartaric acid, 2-phenylpropionic acid, mandelic acid, camphoric acid, cis-2-benzamido Optically active carboxylic acids such as cyclohexanecarboxylic acid, optically active sulfonic acids such as phenylethanesulfonic acid and 10-camphorsulfonic acid, optically active phosphoric acids such as 2,2 ′-(1,1′-binaphthyl) phosphoric acid, 4 -Optically active amino acids such as aminobutyric acid, phenylglycine, aspartic acid, pyroglutamic acid, N-acetyl-3,5-dibromo-tyrosine, N-acyl-phenylalanine, N-acyl-aspartic acid, N-acylglutamic acid, N -Optically active N-acylamino acids such as acylproline (N-acyl group represents acetyl group, benzyloxycarbonyl group, benzoyl group, benzenesulfonyl group, p-toluenesulfonyl group, etc.) and other organic acids Formic acid, oxalic acid, malonic acid, succinic acid, adipic acid, pimeli Acid, cyanoacetic acid, citric acid, glycolic acid, glyoxylic acid, pyruvic acid, levulinic acid, oxaloacetic acid, mercaptoacetic acid, phenoxyacetic acid, and the like picric acid. There are optical isomers in optically active carboxylic acids, optically active sulfonic acids, optically active phosphoric acids, optically active amino acids and optically active N-acylamino acids, but both optical isomers can be used. Of these, optically active mandelic acid is particularly preferred. By using an optically active mandelate for the purification of the salt, a diastereomeric salt of the R—S or S—R form of the stereochemistry of the secondary amine is preferentially precipitated as crystals. The R-S form of secondary amine tends to precipitate a salt with (R) -mandelic acid, while the S-R form of secondary amine tends to precipitate a salt with (S) -mandelic acid.

  By this method, “the optically active mandelate of the optically active secondary amine represented by the formula [7] whose relative configuration in stereochemistry is the R—S or S—R isomer” can be obtained.

  The amount of the acid used may be 0.1 mol or more with respect to 1 mol of the secondary amine represented by the formula [6], usually 0.2 to 5 mol, and particularly preferably 0.3 to 3 mol. Mole is more preferred.

  The method for preparing the salt may be appropriately determined depending on the combination of the secondary amine represented by the formula [6] and the acid, and usually the secondary amine represented by the formula [6] and the acid are directly added to the recrystallization solvent and mixed. Or by preparing each solution in advance and mixing the solutions. Crystal precipitation can be performed directly from the prepared salt solution, or can be performed after the prepared salt solution is concentrated once and dissolved again in the recrystallization solvent.

  The recrystallization solvent is not particularly limited as long as it does not react with the secondary amine represented by the formula [6], an acid, or a salt prepared from these, but the diastereomeric excess before purification or the target What is necessary is just to determine suitably by the diastereomeric excess rate and recovery rate etc. after refinement | purification to perform.

  Examples of the recrystallization solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene and mesitylene, methylene chloride, chloroform, 1 Halogenated hydrocarbons such as 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, t-butyl methyl ether, 1,4-dioxane, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, n acetate Examples thereof include ester systems such as butyl, nitrile systems such as acetonitrile and propionitrile, alcohol systems such as methanol, ethanol, n-propanol, i-propanol and n-butanol, and water. Among them, n-hexane, n-heptane, toluene, methylene chloride, tetrahydrofuran, t-butyl methyl ether, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, methanol, ethanol, n-propanol, i-propanol, n-butanol and water are included. Particularly preferred are n-hexane, n-heptane, toluene, methanol, ethanol, n-propanol, i-propanol, n-butanol and water. These recrystallization solvents can be used alone or in combination.

  The amount of the recrystallization solvent used is not particularly limited as long as the salt before purification is completely or partially dissolved when heated, but the diastereomeric excess before purification or the target after purification. What is necessary is just to determine suitably by the diastereomeric excess of this, recovery, etc. What is necessary is just to use 0.01L or more with respect to 1 mol of salts of the secondary amine shown by Formula [6] before refinement | purification, 0.05-30L is preferable normally, and 0.1-20L is especially more preferable.

  This salt refining can deposit a crystal | crystallization smoothly and efficiently by adding a seed crystal.

  The diastereomeric excess of the seed crystal is 95% d. e. The above may be used, usually 97% d. e. Or more, particularly 99% d. e. The above is more preferable.

  The amount of the seed crystal used may be 0.001 g or more with respect to 1 mol of the secondary amine salt represented by the formula [6] before purification, and is usually preferably 0.005 to 20 g, particularly 0. 0.01 to 10 g is more preferable.

  The temperature condition can be appropriately determined depending on the boiling point and freezing point of the recrystallization solvent to be used. Usually, the salt before purification is dissolved from room temperature (25 ° C.) to a temperature near the boiling point of the recrystallization solvent, and the temperature is gradually lowered. It is preferable to sufficiently crystallize at -30 to + 30 ° C. Usually, it is preferable to add the seed crystal while the temperature is lowered.

  In this salt purification, when the diastereomeric excess of precipitated crystals is improved, a salt with a high diastereomeric excess can be obtained by collecting the precipitated crystals by filtration or the like. On the other hand, when the diastereomeric excess of the mother liquor is improved, a solution containing a salt with a high diastereomeric excess can be obtained by removing the precipitated crystals by filtration or the like. Further, by repeating these purification operations, it can be purified to a higher diastereomeric excess.

  For the hydrogenolysis in the fourth step, the obtained salt can be used as it is or after neutralization to return to the free base. As a method for returning to the free base, the free base can be efficiently recovered by neutralization with a basic aqueous solution of an inorganic base and extraction with an organic solvent.

  Finally, the hydrogenolysis in the fourth step will be described in detail. The hydrogenolysis in the fourth step is performed by hydrogenolysis of the optically active secondary amine purified by the salt purification in the third step or a salt thereof.

  In this hydrogenolysis, the optically active 1- (2-trifluoro) represented by the formula [8] is obtained from the RR form or RS form of the optically active secondary amine represented by the formula [7] or a salt thereof. The R form of methylphenyl) ethylamine or a salt thereof can be obtained without impairing the optical purity. On the other hand, the S form can be obtained from the S form or S form without impairing the optical purity.

  This hydrogenolysis can be carried out in a hydrogen atmosphere using a Group VIII metal catalyst. Group VIII metal catalysts include platinum catalysts such as platinum oxide, platinum / activated carbon, platinum black, nickel catalysts such as reduced nickel, Raney nickel, Raney nickel with platinum, cobalt catalysts such as Raney cobalt, ruthenium oxide, ruthenium / activated carbon, etc. Ruthenium catalyst, rhodium / activated carbon, rhodium / alumina, rhodium catalyst such as rhodium-platinum oxide, iridium catalyst such as iridium black, palladium / activated carbon, palladium hydroxide, palladium black, palladium / barium sulfate, palladium / strontium carbonate, palladium / Calcium carbonate, palladium / calcium carbonate-lead diacetate, palladium / barium sulfate-quinoline, palladium / alumina, palladium sponge, palladium chloride, palladium acetate, palladium acetylacetonate, bis (dibenzylide) Acetone) palladium, tetrakis (triphenylphosphine) palladium, dichloro [bis (triphenylphosphine)] palladium, dichloro [bis (diphenylphosphino) methane] palladium, dichloro [bis (diphenylphosphino) ethane] palladium, dichloro [1 , 3-bis (diphenylphosphino) propane] palladium, dichloro [1,4-bis (diphenylphosphino) butane] palladium, dichloro (1,5-cyclooctadiene) palladium, dichloro [bis (benzonitrile)] palladium And palladium catalysts such as dichloro [bis (acetonitrile)] palladium and acetic acid [bis (triphenylphosphine)] palladium. Among them, platinum catalyst, nickel catalyst, ruthenium catalyst, rhodium catalyst and palladium catalyst are preferable, and platinum / activated carbon, Raney nickel, ruthenium / activated carbon, rhodium / activated carbon and palladium / activated carbon are more preferable. These Group VIII metal catalysts can be used alone or in combination. When using a catalyst in which a metal is supported on a carrier, the supported amount is 0.1 to 50% by weight, usually 0.5 to 30% by weight is preferable, and 1 to 20% by weight is more preferable. preferable. Moreover, what was preserve | saved in water or mineral oil can also be used in order to improve the safety of handling, or to prevent the oxidation of a metal surface.

  The amount of the group VIII metal catalyst used may be a catalytic amount with respect to 1 mol of the optically active secondary amine represented by the formula [7] or a salt thereof, and usually 0.001 to 20 g in terms of metal. Particularly preferred is 0.005 to 10 g.

  The amount of hydrogen used may be 1 mol or more per 1 mol of the optically active secondary amine represented by the formula [7] or a salt thereof. Usually, the reaction is carried out in a hydrogen atmosphere, and a large excess is required. use.

  The hydrogen pressure is 5 MPa or less, usually 0.01 to 3 MPa, and more preferably 0.05 to 2 MPa.

  This hydrogenolysis can also be carried out in the presence of an acid.

  Examples of the acid include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, hexanoic acid, heptanoic acid and the like. Among these, acetic acid, propionic acid and butyric acid are preferable, and acetic acid and propionic acid are more preferable.

  The amount of the acid used may be 0.1 mol or more with respect to 1 mol of the optically active secondary amine represented by the formula [7] or a salt thereof, and usually 0.2 to 20 mol is preferable. 0.3-10 mol is more preferable.

  Examples of the reaction solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene and mesitylene, diethyl ether, tetrahydrofuran, t- Ethers such as butyl methyl ether and 1,4-dioxane, esters such as ethyl acetate and n-butyl acetate, methanol, ethanol, n-propanol, i-propanol, n-butanol, n-pentanol and n-hexanol , Cyclohexanol, n-heptanol, alcohols such as n-octanol, carboxylic acids such as acetic acid, propionic acid, butyric acid, hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc. Examples include acidic aqueous solutions and water. Among them, toluene, tetrahydrofuran, ethyl acetate, methanol, ethanol, n-propanol, i-propanol, n-butanol, acetic acid, acidic aqueous solution of hydrochloric acid and acidic aqueous solution of hydrobromic acid are preferable, and methanol, ethanol, n-propanol are particularly preferable. I-propanol, n-butanol, acetic acid, acidic aqueous solution of hydrochloric acid and acidic aqueous solution of hydrobromic acid are more preferable. These reaction solvents can be used alone or in combination.

  The amount of the reaction solvent used may be 0.01 L or more with respect to 1 mol of the optically active secondary amine represented by the formula [7] or a salt thereof, usually 0.05 to 20 L, particularly preferably 0. .1 to 10 L is more preferable.

  As temperature conditions, it is 0-200 degreeC, Usually, 10-175 degreeC is preferable and especially 20-150 degreeC is more preferable.

  The reaction time is usually 0.1 to 48 hours, but it varies depending on the reaction substrate and reaction conditions. Therefore, the reaction progress is traced by analysis means such as gas chromatography, liquid chromatography, NMR, etc. The end point is preferably the point at which almost disappeared.

  The post-treatment is not particularly limited, but after the completion of the reaction, the usual optical treatment 1- (2-trifluoromethylphenyl) ethylamine represented by the formula [8] or a salt thereof can be obtained by performing a general post-treatment operation. The crude product can be obtained. When the reaction is carried out using the salt of the optically active secondary amine represented by the formula [7] as the reaction substrate, the reaction is carried out in the presence of an acid, or the reaction solvent is a carboxylic acid type or an acidic aqueous solution of an acid. When the reaction is carried out, the optically active 1- (2-trifluoromethylphenyl) represented by the target formula [8] is obtained by neutralizing with a basic aqueous solution of an inorganic base and extracting with an organic solvent. ) Ethylamine can be efficiently recovered as a free base. The crude product is subjected to a purification operation such as activated carbon treatment, distillation, recrystallization, column chromatography, etc., if necessary, so that the optically active 1- (2-trifluoromethyl) represented by the target formula [8] is obtained. Phenyl) ethylamine can be obtained with high chemical purity.

  Hereinafter, the embodiments of the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.

Example 1 Sulfonylation-1
Following formula

A solution of 15.47 g (81.35 mmol, 1.00 eq) of racemic 1- (2-trifluoromethylphenyl) ethyl alcohol and 10.30 g (101.79 mmol, 1.25 eq) of triethylamine (used with toluene) To the amount (325 ml), 11.18 g (97.60 mmol, 1.20 eq) of methanesulfonyl chloride was added under ice cooling, and the mixture was stirred at the same temperature for 5 hours and 10 minutes. The conversion rate of the reaction was determined by gas chromatography and was 100%. Water was added to the reaction completed solution, extracted with toluene, and the recovered organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and vacuum dried.

22.88 g of a sulfonic acid ester crude product represented by the formula (1) was obtained. The organic product recovery of the crude product was quantitative. ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum are shown below.
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ), δ ppm: 1.72 (d, 6.4 Hz, 3H), 2.82 (s, 3H), 6.10 (q, 6.4 Hz) , 1H), 7.47 (Ar-H, 1H), 7.66 (Ar-H, 2H), 7.76 (Ar-H, 1H).
¹⁹ F-NMR (reference material: C ₆ F ₆ , solvent: CDCl ₃ ), δ ppm: 103.42 (s, 3F).

Example 2 Condensation-1
The total amount of the crude product of the sulfonate ester produced in Example 1 (22.88 g, 81.35 mmol, 1.00 eq) in a toluene solution (toluene usage 85 ml) was added to (R) -1-phenylethylamine 31.00 g. (255.82 mmol, 3.14 eq) was added, and the mixture was stirred at 130 ° C. for 17 hours 30 minutes. The conversion rate of the reaction was determined by gas chromatography and was 100%. The reaction completed solution was washed with 1.5M aqueous ammonium chloride solution, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and vacuum dried.

16.45 g of a secondary amine crude product represented by the formula (1) was obtained. The total organic recovery rate of the two-step crude product organic matter of Example 1 and Example 2 was 69%. The gas chromatographic purity of the crude product was 88.5%. ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum are shown below.
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ),
RR isomer / δ ppm: 1.24 (d, 6.4 Hz, 6H), 1.69 (br, 1H), 3.48 (q, 6.4 Hz, 1H), 4.07 (q, 6 .4 Hz, 1H), 7.10-7.95 (Ar-H, 9H).
S-R form / δ ppm: 1.32 (d, 6.4 Hz, 3H), 1.36 (d, 6.4 Hz, 3H), 1.59 (br, 1H), 3.63 (q, 6 .4Hz, 1H), 4.34 (q, 6.4Hz, 1H), 7.10-7.75 (Ar-H, 9H).
¹⁹ F-NMR (reference substance: C ₆ F ₆ , solvent: CDCl ₃ ),
RR-form / δ ppm: 103.28 (s, 3F).
S-R form / δ ppm: 103.42 (s, 3F).

Example 3 Salt Purification-1
A portion of the crude product of the secondary amine prepared in Example 2 (2.00 g, 6.82 mmol, 1.00 eq) and (S) -mandelic acid (1.04 g, 6.84 mmol, 1.00 eq) -12 ml of propanol and 12 ml of n-heptane were added and dissolved by heating at 80 ° C. The temperature was gradually lowered while stirring, and the mixture was cooled to room temperature (25 ° C.) overnight. The precipitated crystals are filtered, dried under reduced pressure, and vacuum dried.

1.20 g of a crude crystal of an optically active secondary amine salt represented by formula (1) was obtained. ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum are shown below.
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ), δ ppm: 1.40 (d, 6.4 Hz, 3H), 1.48 (d, 6.4 Hz, 3H), 3.91 (q , 6.4 Hz, 1H), 4.31 (q, 6.4 Hz, 1H), 4.91 (s, 1H), 5.80 (br, 3H), 7.15-7.75 (Ar-H) , 14H).
¹⁹ F-NMR (reference material: C ₆ F ₆ , solvent: CDCl ₃ ), δ ppm: 103.33 (s, 3F).
The total amount of this crude crystal 1.20 g was neutralized with 1N aqueous sodium hydroxide solution and extracted with toluene. The recovered organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and vacuum dried.

0.79 g of a crude product of the optically active secondary amine free base represented by the formula (1) was recovered. The recovery rate of the secondary amine with respect to the S-R form was 79%. When the diastereomeric excess was determined from the ¹ H-NMR spectrum of the free base obtained from the crude crystals, it was 90.0% d. e. (S-R form). The ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum of the free base were the same as those described in Example 2.

  The total amount of the recrystallized mother liquor was concentrated under reduced pressure and dried in vacuo. The residue was neutralized with 1N aqueous sodium hydroxide solution and extracted with toluene. The recovered organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Vacuum dried, the following formula

1.08 g of a crude recovered product of the optically active secondary amine free base represented by the formula (1) was recovered. The recovery rate of the secondary amine with respect to the R—R form was 108%. When the diastereomeric excess was determined from the ¹ H-NMR spectrum of the free base obtained from the recrystallized mother liquor, it was 89.3% d. e. (RR form). The ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum of the free base were the same as those described in Example 2.

[Example 4] Salt purification-2
To a part of the secondary amine crude product produced in Example 2, 2.00 g (6.82 mmol, 1.00 eq) was added 1 M hydrochloric acid methanol 10 ml (10.00 mmol, 1.47 eq) at room temperature (25 ° C. ), Concentrated under reduced pressure, vacuum dried,

2.41 g of a crude product of a secondary amine salt represented by the formula: To 2.41 g of the total amount of the secondary amine salt, 15 ml of toluene and 10 ml of n-heptane were added and dissolved by heating at 90 ° C. The temperature was gradually lowered while stirring, and the mixture was cooled to room temperature (25 ° C.) overnight. The precipitated crystals are filtered, dried under reduced pressure, and vacuum dried.

As a result, 0.60 g of a crude crystal of an optically active secondary amine salt represented by the formula (1) was obtained. The recovery rate of the secondary amine with respect to the S-R form was 54%. When the diastereomeric excess was determined from the ¹⁹ F-NMR spectrum of this crude crystal, it was 92.5% d. e. (S-R form). ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum are shown below.
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ), δ ppm: 1.81 (d, 6.8 Hz, 3H), 1.84 (d, 6.8 Hz, 3H), 4.12 (q , 6.8 Hz, 1H), 4.71 (br, 1H), 7.16-7.60 (Ar-H, 8H), 8.36 (Ar-H, 1H), 9.82 (br, 1H) ), 10.67 (br, 1H).
¹⁹ F-NMR (reference material: C ₆ F ₆ , solvent: CDCl ₃ ), δ ppm: 103.66 (s, 3F).

[Example 5] Salt purification-3
1.00 g (89.3% de, RR form, 3.41 mmol, 1.00 eq) of a portion of the crude recovered product of the optically active secondary amine free base recovered from the recrystallized mother liquor in Example 3. ) And 47% hydrobromic acid 0.59 g (3.43 mmol, 1.01 eq), add 3 ml of methanol, stir at room temperature (25 ° C.), concentrate under reduced pressure, vacuum dry,

A crude product of an optically active secondary amine salt represented by 30 ml of i-propanol and 6 ml of n-heptane were added to the total amount of the salt of the optically active secondary amine, and dissolved by heating at 80 ° C. The temperature was gradually lowered while stirring, and the mixture was cooled to room temperature (25 ° C.) overnight. The precipitated crystals were filtered, dried under reduced pressure, and dried under vacuum to obtain 0.77 g of crude crystals of the optically active secondary amine salt represented by the above formula. The recovery rate of the optically active secondary amine with respect to the RR form was 64%. ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum are shown below.
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ), δ ppm: 2.00 (d, 6.8 Hz, 3H), 2.04 (d, 6.8 Hz, 3H), 4.17 (br 1H), 4.56 (br, 1H), 7.25-7.85 (Ar-H, 8H), 8.64 (Ar-H, 1H), 10.14 (br, 1H), 10. 31 (br, 1H).
¹⁹ F-NMR (reference material: C ₆ F ₆ , solvent: CDCl ₃ ), δ ppm: 102.46 (s, 3F).

When the diastereomeric excess was determined from the ¹ H-NMR spectrum of the free base obtained from the crude crystals, it was 98.9% d. e. (RR form).

Example 6 Sulfonylation-2
Following formula

A toluene solution of 50.00 g (262.94 mmol, 1.00 eq) of racemic 1- (2-trifluoromethylphenyl) ethyl alcohol and 33.30 g (329.08 mmol, 1.25 eq) of triethylamine represented by To an amount of 1050 ml), 36.15 g (315.58 mmol, 1.20 eq) of methanesulfonyl chloride was added under ice cooling, followed by stirring at the same temperature for 1 hour and 15 minutes. The conversion rate of the reaction was determined by gas chromatography and was 100%. Water was added to the reaction completed solution, extracted with toluene, and the recovered organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, vacuum dried,

81.82 g of a sulfonic acid ester crude product represented by the formula (1) was obtained. The organic product recovery of the crude product was quantitative. ^{The 1} H-NMR spectrum and the ¹⁹ F-NMR spectrum were the same as those described in Example 1.

Example 7 Condensation-2
The total amount of the crude product of sulfonic acid ester produced in Example 6 was 81.82 g (262.94 mmol, 1.00 eq) in a toluene solution (toluene use amount 270 ml), and (R) -1-phenylethylamine 47.80 g (394.45 mmol, 1.50 eq) was added and stirred under reflux conditions for 17 hours. The conversion rate of the reaction was determined by gas chromatography and was 99%. The reaction completed solution was washed with 1.5M aqueous ammonium chloride solution, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and vacuum dried.

As a result, 39.69 g of a secondary amine crude product was obtained. The total organic yield of the two-step crude product of Example 6 and Example 7 was 51%. ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum were the same as those described in Example 2.

[Example 8] Salt purification-4
A portion of the crude product of the secondary amine prepared in Example 7 (36.96 g, 126.00 mmol, 1.00 eq) and (S) -mandelic acid, 19.17 g (125.99 mmol, 1.00 eq), were -120 ml of propanol and 120 ml of n-heptane were added and dissolved by heating. The temperature was gradually lowered while stirring, and the mixture was cooled to room temperature (25 ° C.) overnight. The precipitated crystals are filtered, dried under reduced pressure, and vacuum dried.

21.94 g of the first recrystallized product of the salt of the optically active secondary amine represented by ^{The 1} H-NMR spectrum and the ¹⁹ F-NMR spectrum were the same as those described in Example 3. When the diastereomeric excess was determined from the ¹⁹ F-NMR spectrum of the first recrystallized product, it was found to be 73.2% d. e. (S-R form). 100 ml of i-propanol and 100 ml of n-heptane were added to 21.94 g of the total amount of the first recrystallized product and dissolved by heating. The temperature was gradually lowered while stirring, and the mixture was cooled to room temperature (25 ° C.) overnight. The precipitated crystals were filtered, dried under reduced pressure, and vacuum dried to obtain 14.10 g of a second recrystallized product of the salt of the optically active secondary amine represented by the above formula. When the diastereomeric excess was determined from the ¹⁹ F-NMR spectrum of the second recrystallized product, it was found to be 93.7% d. e. (S-R form). 70 ml of i-propanol and 70 ml of n-heptane were added to 14.10 g of the total amount of the second recrystallized product and dissolved by heating. The temperature was gradually lowered while stirring, and the mixture was cooled to room temperature (25 ° C.) overnight. The precipitated crystals were filtered, dried under reduced pressure, and vacuum dried to obtain 12.35 g of a third recrystallized product of the optically active secondary amine salt represented by the above formula. When the diastereomeric excess was determined from the ¹⁹ F-NMR spectrum of the third recrystallized product, it was 99.0% d. e. (S-R form). The total recovery rate of salt purification (three times of recrystallization) for the S-R form of the secondary amine was 44%.

[Example 9] Salt purification-5
The total amount of the first recrystallized mother liquor of Example 8 (including RR form in the major) was concentrated under reduced pressure, dried in vacuo, and the residue was neutralized with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, and recovered. The organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum.

17.17 g of a roughly recovered optically active secondary amine represented by the following formula was recovered. The recovery rate of the secondary amine with respect to the R-R form was 93%. When the diastereomeric excess was determined from the ¹ H-NMR spectrum of the free base obtained from the recrystallized mother liquor, it was 66.8% d. e. (RR form). The ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum of the free base were the same as those described in Example 2. The total amount of the optically active secondary amine recovered from the first recrystallization mother liquor was 17.17 g (66.8% de, RR form, 58.53 mmol, 1.00 eq) and 47% bromide. Add 11.08 g (64.36 mmol, 1.10 eq) of hydrogen acid, stir at room temperature (25 ° C.), concentrate under reduced pressure, vacuum dry,

A crude product of an optically active secondary amine salt represented by To the total amount of the optically active secondary amine salt, 180 ml of i-propanol and 150 ml of n-heptane were added and dissolved by heating. The temperature was gradually lowered while stirring, and the mixture was cooled to room temperature (25 ° C.) overnight. The precipitated crystals were filtered, dried under reduced pressure, and vacuum dried to obtain 13.63 g of a first recrystallized product of the salt of the optically active secondary amine represented by the above formula. ^{The 1} H-NMR spectrum and the ¹⁹ F-NMR spectrum were the same as those described in Example 5. When the diastereomeric excess was determined from the ¹⁹ F-NMR spectrum of the first recrystallized product, it was 98.5% d. e. (RR form). To the total amount of the first recrystallized product 13.63 g, 250 ml of i-propanol, 40 ml of methanol and 150 ml of n-heptane were added and dissolved by heating. The temperature was gradually lowered while stirring, and the mixture was cooled to room temperature (25 ° C.) overnight. The precipitated crystals were filtered, dried under reduced pressure, and vacuum dried to obtain 9.90 g of a second recrystallized product of the salt of the optically active secondary amine represented by the above formula. When the diastereomeric excess was determined from the ¹⁹ F-NMR spectrum of the second recrystallized product, it was 99.1% d. e. (RR form). The total recovery rate of the salt purification (recrystallization twice) for the RR form of the secondary amine was 54%.

Example 10 Hydrogenolysis-1
In 27 ml of methanol, the salt of optically active secondary amine purified in Example 8 (S-R (S) -mandelate, third recrystallized product, chemical purity> 99.0%, diastereomeric excess 99.0% de) Total amount 12.35 g (27.72 mmol, 1.00 eq) and 5% Pd / C (50 wt.% Wet) (palladium-carbon on which 5 g of Pd metal was supported per 95 g of activated carbon “Powder” was mixed with water of the same weight as this, and the humidity was adjusted. The same applies hereinafter. 0.62 g (Pd (metal conversion) 0.56 g / substrate 1.00 mol) was added, and the hydrogen pressure was 0.5 MPa. And stirred at 60 ° C. for 16 hours and 15 minutes. The conversion rate of the reaction was determined by gas chromatography and was 100%. The reaction mixture was filtered through celite, concentrated under reduced pressure and dried in vacuo. The residue was neutralized with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, and the recovered organic layer was washed with saturated brine, and anhydrous sodium sulfate. Dried under vacuum, concentrated under reduced pressure, vacuum dried,

3.10 g of a crude product of optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the formula: The total amount of the crude product 3.10 g was simply distilled (59 ° C./1330 Pa) to obtain 2.38 g of a distilled purified product of optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the above formula. The yield was 45%. The enantiomeric excess is derived from the benzamide derivative and is determined by chiral liquid chromatography, 99.0% e. e. (S body). ¹ H-NMR spectrum is shown below.
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ), δ ppm: 1.41 (d, 6.6 Hz, 3H), 1.56 (br, 2H), 4.56 (q, 6.6 Hz) , 1H), 7.33 (Ar-H, 1H), 7.57 (Ar-H, 1H), 7.61 (Ar-H, 1H), 7.74 (Ar-H, 1H).

Example 11 Hydrogenolysis-2
Optically active secondary amine salt purified in Example 9 (R-R hydrobromide, second recrystallized product, chemical purity> 99.0%, diastereomeric excess 99.1% d. e.) A total of 9.90 g (26.45 mmol, 1.00 eq) was neutralized with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, the collected organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and vacuum Dry and the following formula

7.76 g of a purified product of the optically active secondary amine free base represented by In 26 ml of methanol, 7.76 g (26.45 mmol, 1.00 eq) of the purified product of the free base of the optically active secondary amine, 7.94 g (132.22 mmol, 5.00 eq) of acetic acid and 5% Pd / C (50 wt.% Wet) 0.39 g (Pd (metal conversion) 0.37 g / substrate 1.00 mol) was added, the hydrogen pressure was set to 0.5 MPa, and the mixture was stirred at 60 ° C. for 18 hours and 15 minutes. The conversion rate of the reaction was determined by gas chromatography and was 100%. The reaction mixture was filtered through celite, concentrated under reduced pressure, and dried under vacuum. The residue was neutralized with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, and the recovered organic layer was washed with saturated brine, and anhydrous sodium sulfate. Dried under vacuum, concentrated under reduced pressure, vacuum dried,

3.96 g of a crude product of optically active 1- (2-trifluoromethylphenyl) ethylamine represented by A total of 3.96 g of this crude product was subjected to simple distillation (67 ° C./1870 Pa) to obtain 2.26 g of a purified product of optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the above formula. The yield was 45%. Enantiomeric excess is derived from benzamide derivatives and determined by chiral liquid chromatography,> 99.0% e. e. (R-form). ¹ H-NMR spectrum was similar to that described in Example 10.

Claims (14)

Formula [1]
[Wherein the stereochemistry at the benzylic position (position 1) is R, S or racemic] 1- (2-trifluoromethylphenyl) ethyl alcohol represented by the general formula [2 ]
[Wherein R represents an alkyl group, an aryl group or a haloalkyl group, and X represents a halogen], or the general formula [3]
[Wherein R represents an alkyl group, an aryl group or a haloalkyl group], and is reacted with a sulfonylating agent represented by the general formula [4]
[Wherein the stereochemistry at the benzylic position (position 1) is R, S or racemic, and R represents an alkyl group, an aryl group or a haloalkyl group]. 5]
[Wherein * represents an asymmetric carbon, and the stereochemistry thereof is R or S form], by reacting with optically active 1-phenylethylamine represented by the formula [6]
[Wherein, the stereochemistry at the benzyl position (position 1) on the side where the trifluoromethyl group is substituted with an aromatic ring is R, S or racemic, * represents an asymmetric carbon, and the stereochemistry is R give the secondary amine represented by the body or S-isomer, recrystallized by inducing the secondary amine to a salt thereof (refers to salts formed between the amine and inorganic or organic acids. hereinafter the same) By purification, the formula [7]
[Wherein * represents an asymmetric carbon and the stereochemistry is R or S form], and the optically active secondary amine salt or the salt thereof is purified. By hydrogenolysis of the optically active secondary amine obtained by neutralization , the formula [8]
[Wherein * represents an asymmetric carbon, and the stereochemistry is R or S]] a process for producing optically active 1- (2-trifluoromethylphenyl) ethylamine or a salt thereof. The method for producing an optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the formula [8] or a salt thereof using a hydrochloride as the salt of the secondary amine represented by the formula [6] in claim 1 . The relative configuration of the stereochemistry of the salt of the optically active secondary amine represented by the formula [7] obtained by purification according to claim 2 is the R-S form (the stereochemistry shown before the hyphen is that the trifluoromethyl group is aromatic. This represents the stereochemistry of the benzyl position (position 1) on the side substituted with the ring, and the stereochemistry shown after the hyphen represents the stereochemistry of the benzyl position (position 1) derived from optically active 1-phenylethylamine. Alternatively, a method for producing an optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the formula [8] or a salt thereof which is an S-R form. The optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the formula [8] or a salt thereof, wherein a hydrobromide is used as the secondary amine salt represented by the formula [6] in claim 1 How to manufacture. The optical compound represented by the formula [8] according to claim 4, wherein the stereochemical relative configuration of the salt of the optically active secondary amine represented by the formula [7] obtained by purification is an RR form or an SS form. A method for producing active 1- (2-trifluoromethylphenyl) ethylamine or a salt thereof. The optically active 1- (2-trifluoromethylphenyl) ethylamine represented by the formula [8] or a salt thereof, wherein an optically active mandelate is used as the secondary amine salt represented by the formula [6] in claim 1 . How to manufacture. The optical compound represented by the formula [8] according to claim 6, wherein the stereochemical relative configuration of the salt of the optically active secondary amine represented by the formula [7] obtained by purification is R-S or S-R. A method for producing active 1- (2-trifluoromethylphenyl) ethylamine or a salt thereof. The optically active 1- (2-trifluoromethylphenyl) represented by the formula [8] according to claim 1, wherein the salt of the secondary amine represented by the formula [6] is used in combination with a hydrochloride and a hydrobromide. A method for producing both optically active forms (R-form and S-form) of ethylamine or a salt thereof. The optically active 1- (2-trifluoro) represented by the formula [8] according to claim 1, wherein the salt of the secondary amine represented by the formula [6] is used in combination with an optically active mandelate and hydrobromide. A method for producing both optically active forms (R-form and S-form) of methylphenyl) ethylamine or a salt thereof. General formula [4]
[Wherein the stereochemistry at the benzylic position (position 1) is R, S or racemic, and R represents an alkyl group, aryl group or haloalkyl group]. The sulfonate ester according to claim 10, wherein R of the sulfonate ester represented by the general formula [4] is a methyl group. Formula [7]
[In the formula, * represents an asymmetric carbon, and the stereochemistry is R or S form], among the optically active secondary amines represented by R, S or R form. Though hydrochloride. Formula [7]
[In the formula, * represents an asymmetric carbon, and the stereochemistry thereof is R or S form]. Among the optically active secondary amines represented by the formula, the relative configuration of stereochemistry is R or R or S form. However, hydrobromide. Formula [7]
[In the formula, * represents an asymmetric carbon, and the stereochemistry is R or S form], among the optically active secondary amines represented by R, S or R form. However, optically active mandelate.