WO2010071117A1

WO2010071117A1 - Method for manufacturing (s)-1-phenyl-1,2,3,4-tetrahydroisoquinoline

Info

Publication number: WO2010071117A1
Application number: PCT/JP2009/070853
Authority: WO
Inventors: 耕平森; 章西山
Original assignee: 株式会社カネカ
Priority date: 2008-12-15
Filing date: 2009-12-14
Publication date: 2010-06-24
Also published as: CN102245579A; JP2012036093A

Abstract

By forming a salt from a non-optically active acid and (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by formula (1): (1) that comprises (R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline as an impurity, and by crystallizing, salt crystals of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline that is represented by formula (2a): (2a) (in formula (2a), A^n- represents a non-optically active carboxylate anion, non-optically active sulfonate anion, non-optically active phosphonate anion, chloride anion, bromide anion, nitrate anion, hydrogen sulfate anion or perchlorate anion. The n of A^n- represents the valence of the anion) are manufactured. By then treating the salt crystals with a base, (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline is manufactured.

Description

Process for producing (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline

The present invention relates to a process for producing (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline useful as a pharmaceutical intermediate.

The following methods are known as methods for improving the optical purity of 1-phenyl-1,2,3,4-tetrahydroisoquinoline.
1) 51% e. e. By forming a salt from (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline and (S) -2- (4-chlorophenyl) -3-methylbutyric acid and crystallizing, 100% e. e. (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / (S) -2- (4-chlorophenyl) -3-methylbutyric acid salt (Patent Document 1).
2) Crystallization by forming a salt from racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline and D-tartaric acid in a mixed solvent of ethanol and water. e. (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / D-tartrate (Non-patent Document 1).

JP 2001-288171 A

However, (S) -2- (4-chlorophenyl) -3-methylbutyric acid and D-tartaric acid described in Patent Document 1 and Non-Patent Document 1 are very expensive acids, and are not necessarily advantageous methods for industrial implementation. That's not true.
Note that (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline may decrease the optical purity when simply recrystallized, and it is not easy to increase the optical purity.

An object of the present invention is to provide a method for efficiently and inexpensively producing (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline having high optical purity. *

As a result of intensive studies, the present inventors have formed (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline having a low optical purity by forming a salt with a non-optically active acid which is inexpensive and readily available. By crystallization, the optical purity was successfully improved and the present invention was completed.

That is, the process for producing (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline with improved optical purity according to the present invention comprises (R) -1-phenyl-1,2,3,4-tetrahydro. The following formula (1) containing isoquinoline as an impurity:

A salt is formed from (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the following formula and a non-optically active acid, followed by crystallization to give the following formula (2a):

(In the formula (2a), A ⁿ⁻ represents a non-optically active carboxylate anion, a non-optically active sulfonate anion, a non-optically active phosphonate anion, a chloride anion (Cl ⁻ ), a bromide anion (Br ⁻ ), a nitrate anion. (S 3) -1-phenyl-1,2,3,4-tetrahydro represented by (NO ₃ ⁻ ), hydrogen sulfate anion (HSO ₄ ⁻ ), or perchlorate anion (ClO ₄ ⁻ )) It is characterized in that a salt crystal of isoquinoline is produced and subsequently the salt crystal is treated with a base.

The n is preferably 1. The non-optically active acid is preferably acetic acid or p-toluenesulfonic acid.

Further, the present invention provides the following formula (1):

(S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the formula (especially containing (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline as an impurity ( S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline), which is represented by the following formula (3):

A salt is precipitated from racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline and L-tartaric acid represented by formula (I), and the resulting mother liquor is treated with a base.

Furthermore, the present invention provides the following formula (2b):

(In the formula (2b), B ⁻ represents a non-optically active carboxylate anion or a non-optically active sulfonate anion.) (S) -1-phenyl-1,2,3,4-tetrahydro Also related to isoquinoline salts.

Wherein B ^- is acetate anion, such as p- toluenesulfonate anion are preferred. Preferred salts (2b) is, B ^- is acetate anion, in its X-ray powder diffraction pattern, 2 [Theta] = 8.9 °, 11.0 °, 13.0 °, 13.7 °, 15.8 °, Specific peaks are shown at 17.9 °, 19.1 °, 20.0 °, 21.5 °, 23.4 °, and 26.7 °.

According to the method of the present invention, by crystallization by forming a salt from (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline, which is easily available and low in optical purity, and an inexpensive acid, (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline with high optical purity that can be used as a pharmaceutical intermediate can be produced.

1 is an X-ray powder analysis spectrum of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / acetate obtained in Example 7. FIG. The vertical axis represents the X-ray intensity (cps), and the horizontal axis represents the diffraction angle (2θ).

Hereinafter, the present invention will be described in detail.

(I) S-form material First, (S) -1-phenyl-1,2,3 containing (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline, which is a starting material of the present invention, as an impurity , 4-Tetrahydroisoquinoline (hereinafter sometimes referred to as “S-form material”) will be described. Examples of the S-form material include (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline and (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline, A mixture in which (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline is in excess of (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline can be used.

The optical purity of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline in the S-form raw material is, for example, 60 to 90% e. e. Degree, preferably 70-90% e.e. e. Degree, more preferably 80-85% e.e. e. Degree.

Note that (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline has the following formula (1):

It is represented by

The method for producing or obtaining the S-form material is not particularly limited. For example, as described in JP-A-2005-281144, 1-phenyl-3,4-dihydroisoquinoline is hydrogenated in the presence of an optically active ruthenium catalyst. The method of making it. According to this method, about 60-90% e. e. (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline can be obtained.

As another method, the following formula (3):

A racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the formula (hereinafter sometimes referred to as “racemic raw material”) is brought into contact with L-tartaric acid in the presence of a solvent, and a precipitate ( Usually a salt formed from a racemic raw material and L-tartaric acid, referred to herein as (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / L-tartrate, In some cases, it is abbreviated as “body tartrate. Preferably, it is a crystal of the salt”, and then the resulting mother liquor is treated with a base, and this method is preferably used.

The amount of L-tartaric acid is, for example, about 0.3 to 2 mol, preferably about 0.5 to 1.5 mol, more preferably about 0.8 to 1.2 mol, with respect to 1 mol of the racemic raw material. is there.

Examples of the solvent include water and water-soluble organic solvents (especially alcohols such as methanol and ethanol), and these may be used alone or in combination. A preferred solvent is C _1-2 alcohol or a mixed solvent of C _1-2 alcohol and water. When C _1-2 alcohol and water are mixed, the volume ratio (water / C _1-2 alcohol) is 50/50 or less, preferably 1/99 to 30/70, more preferably 5/95 to 20 / 80 or so.

The contact procedure of the racemic raw material and L-tartaric acid is not particularly limited, but usually, both the racemic raw material and L-tartaric acid are separately dissolved in a solvent, and then one is added to the other. Preferably, the racemic raw material solution is added to the L-tartaric acid solution. By contacting the racemic raw material with L-tartaric acid, the R-form tartrate is formed and precipitated as described above. The mixing temperature and time can be appropriately set according to the solvent to be used, but are, for example, −10 to 30 ° C. and 1 hour or longer.

The target S body material is dissolved in the mixed solution. By removing the R form tartrate by solid-liquid separation and collecting the liquid, an S form raw material solution can be obtained. This S-form material solution may be used as a starting material as it is, but it is usually used as a concentrated oil or solid after appropriate post-treatment such as base treatment, concentration, washing and solidification (crystallization). .

In the base treatment, for example, alkali such as sodium oxide, potassium hydroxide, sodium carbonate, potassium carbonate can be used. The amount of alkali is not particularly limited, but may be, for example, about 0.5 to 10 moles per mole of the racemic raw material. When a base is added directly to the S-form material solution, an S-form material is precipitated. This precipitate may be recovered by filtration as it is, or may be extracted and recovered by adding an organic solvent such as toluene, ethyl acetate, methyl tert-butyl ether or the like.

The optical purity of the S-form material thus obtained is about 70 to 90% e.e. e. Degree, preferably 75-88% e.e. e. Degree, more preferably 80-85% e.e. e. Degree.

(Ii) S Form Salt Crystal In the present invention, the S form raw material is sometimes referred to as (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline salt crystal (hereinafter referred to as “S form salt crystal”). ) To improve its optical purity.

The S-form salt crystal has the following formula (2a):

It is represented by Here, in the formula (2a), A ^n-non optically active carboxylate anions, non-optically active sulfonate anions, non-optically active phosphonate anion, chloride anion, bromide anion, nitrate anion, hydrogen sulfate anion, Or it represents a perchlorate anion. ^N in A ^n- represents the valence of the anion.

Specific examples of the non-optically active carboxylate anion include, for example, formate anion, acetate anion, cyanoacetate anion, dichloroacetate anion, trifluoroacetate anion, propionate anion, butanoate anion, isobutanoate Anion, pivalate anion, phenylacetate anion, benzoate anion, acrylate anion, cinnamate anion, oxalate anion, malonate anion, adipate anion and the like.

Specific examples of the non-optically active sulfonate anion include methanesulfonate anion, trifluoromethanesulfonate anion, ethanesulfonate anion, benzenesulfonate anion, p-toluenesulfonate anion, p-chlorobenzenesulfonate anion, p-nitrobenzenesulfonate anion, and the like. Can be mentioned.

Wherein A ^n- is such preferably non-optically active carboxylate anions, non-optically active sulfonate anions. N is preferably 1. The salt crystals formed by these preferred anions can be represented by the following formula (2b), and this compound is a novel compound not described in any literature.

(In formula (2b), B ⁻ represents a non-optically active carboxylate anion or a non-optically active sulfonate anion)
The most preferred A ^n- and B ^- is acetate anion, a p- toluenesulfonate anion, more preferably an acetate anion.

When A ⁿ⁻ or B ⁻ is an acetate anion, the X-ray powder analysis pattern of the S-form salt crystal represented by the formula (2a) or (2b) is 2θ = 8.9 °, 11.0 °, Specific peaks at 13.0 °, 13.7 °, 15.8 °, 17.9 °, 19.1 °, 20.0 °, 21.5 °, 23.4 °, and 26.7 ° Show. Further, when A ⁿ⁻ or B ⁻ is p-toluenesulfonic acid, the special peaks are 2θ = 8.7 °, 9.7 °, 11.0 °, 17.1 °, 17.5 °, 19 0.0 °, 19.9 °, 20.4 °, and 21.6 °.

The S-form salt crystal can be produced by forming a salt from the S-form material and a non-optically active acid (achiral acid) and crystallization.

Examples of the non-optically active acid include a non-optically active carboxylate anion, a non-optically active sulfonate anion, a non-optically active phosphonate anion, a chloride anion, a bromide anion, a nitrate anion, a hydrogen sulfate anion, or a perchlorate anion. There is no particular limitation as long as it causes the problem. Examples of such acids include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, perchloric acid, and phosphoric acid; formic acid, acetic acid, cyanoacetic acid, dichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, Carboxylic acids such as isobutyric acid, pivalic acid, phenylacetic acid, benzoic acid, acrylic acid, cinnamic acid, oxalic acid, malonic acid, adipic acid; methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include sulfonic acids such as toluenesulfonic acid, p-chlorobenzenesulfonic acid, and p-nitrobenzenesulfonic acid. From the viewpoint of obtaining a compound with high optical purity, acetic acid or p-toluenesulfonic acid is preferred, and acetic acid is more preferred.

The amount of the non-optically active acid used is, for example, about 0.5 to 10 mol, preferably about 0.9 to 7 mol, and more preferably about 1 to 5 mol, relative to 1 mol of the S-form material. Yes, it may be about 0.8 to 1.5 moles.

When the acid and the S-form material are mixed, a solvent is usually used. Examples of the solvent include water; alcohol solvents such as methanol, ethanol and isopropanol; ether solvents such as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether and methyl tert-butyl ether; ester solvents such as ethyl acetate and isopropyl acetate; Hydrocarbon solvents such as benzene, toluene, xylene and hexane; ketone solvents such as acetone and methyl ethyl ketone; nitrile solvents such as acetonitrile, propionitrile and benzonitrile; halogen solvents such as methylene chloride, chloroform and chlorobenzene; N Amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxide solvents such as dimethyl sulfoxide. These may be used alone or in combination of two or more. There. The mixing ratio when using two or more solvents in combination is not particularly limited. Preferable examples include methyl tert-butyl ether, ethyl acetate, toluene, and hexane.

The amount of the solvent used is not particularly limited, but too much is not preferable in terms of cost and post-treatment. Therefore, the amount of the solvent used is preferably 50 parts by mass or less, more preferably 20 parts by mass or less, with respect to 1 part by mass of the S-form material.

Although it does not specifically limit as a crystallization method of this process, For example, the following methods are mentioned.
(A) A method of crystallizing a salt of S form by mixing the S form raw material with a non-optically active acid in a solvent.
(B) A method in which the S-form raw material and a non-optically active acid are mixed in a solvent and then cooled to crystallize the salt of the S-form.
(C) A method of crystallizing a salt of S form by mixing the S form raw material and a non-optically active acid in a solvent and then adding a poor solvent such as hexane.
(D) A method of crystallizing a salt of S form by mixing the S form raw material and a non-optically active acid in a solvent and then concentrating under reduced pressure.
(E) A method of crystallizing a salt of S form by mixing the S form raw material and a non-optically active acid in a solvent and then concentrating and replacing with a poor solvent such as hexane.

Further, crystallization can be performed by appropriately combining the methods (a) to (e). A seed crystal may be added in the crystallization of the salt of the S form. Further, when the target quality is not reached by one crystallization, the optical purity can be increased by performing recrystallization such as cooling and crystallization by heating and dissolving the S-form salt crystal in a solvent.

The operating temperature in the method for crystallizing the S-form salt of (a) to (e) is not particularly limited, but may be appropriately selected depending on the type of salt and the type of solvent used, preferably the type of solvent used or the mixture It is preferable to set the solvent species according to the target precipitation amount and crystal quality at a temperature lower than the temperature at which the total amount of the S-form salt crystals dissolves.

The S-form salt crystals precipitated by the crystallization methods (a) to (e) can be separated and obtained by a method such as vacuum filtration, pressure filtration, or centrifugation. Further, when the mother liquor remains in the acquired crystal and the purity of the crystal is lowered, the quality can be improved by further washing with a solvent as necessary.

The S-form salt crystals obtained as described above are usually dried. There are no particular restrictions on the method for drying the crystals, but it is preferable to dry under reduced pressure (vacuum drying) at about 60 ° C. or less, avoiding thermal decomposition and melting of the S-form salt crystals.

The optical purity of the S-form salt crystal thus obtained is, for example, + 5% e. e. Or more, preferably + 10% e.e. e. Or more, more preferably + 15% e.e. e. It has been improved. The optical purity of the S-form salt crystal is, for example, 75% e.e. e. Or more, preferably 80% e.e. e. Or more, more preferably 95% e.e. e. That's it. 99% e.e. by optimizing crystallization conditions. e. It is also possible to obtain the above S-form salt crystals.

(Iii) S-form purified product The S-form purified product is obtained by treating the S-form salt crystals obtained as described above with a base. This S-form purified product has an optical purity equivalent to that of the S-form salt crystal, and there is no decrease in optical purity due to the base treatment of the S-form salt crystal.

When the S-form salt crystal is treated with a base, the S-form salt crystal is preferably dissolved in water, and then the base is added.

The water may be in an amount sufficient to dissolve a part of the S-form salt crystals and react with the base. The amount of water used is preferably 50 parts by mass or less, and more preferably 5 to 20 parts by mass with respect to 1 part by mass of S-form salt crystals.

Examples of the base include metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and magnesium hydroxide (particularly alkali metal or alkaline earth metal hydroxide); sodium carbonate, potassium carbonate, magnesium carbonate, and the like. Metal carbonates (especially alkali metal or alkaline earth metal carbonates); metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate (particularly alkali metal or alkaline earth metal hydrogen carbonates); ammonia, triethylamine, etc. Examples of the amines can be exemplified. The base is preferably sodium hydroxide or potassium hydroxide from an economical viewpoint.

The amount of the base used is determined based on the pH of water. The pH of the water after the base treatment is, for example, 7 or more, preferably about 10 to 13. The amount of the base used can be appropriately set within this pH range. For example, the amount is preferably 0.5 to 20 mol, more preferably 1 to 5 mol, per 1 mol of the S-form salt crystal. The base dissolved in water may be used.

The purified S-form obtained by removing the salt in this manner is recovered from the base treatment solution by an appropriate method. Examples of the recovery method include a method in which an organic solvent such as ethyl acetate, toluene, or methyl tert-butyl ether is added for extraction, and the solvent is distilled off by an operation such as heating under reduced pressure. Or the method of depositing the crystal | crystallization of S body refined | purified substance from a base processing liquid, and isolate | separating acquisition is more preferable.

Examples of the method for precipitating crystals include a method of slowly adding a base to the aqueous solution of the S-form salt crystals. For the purpose of improving quality, an organic solvent compatible with water, such as methanol, ethanol, isopropanol, acetone, and acetonitrile, may be further added.

Examples of the method for separating crystals of the purified S-form include vacuum filtration, pressure filtration, or centrifugation. Further, when the mother liquor remains in the acquired crystal and the purity of the crystal is lowered, the quality can be improved by further washing with a solvent as necessary.

The S-form purified product obtained as described above is usually dried. Although there is no restriction | limiting in particular as a drying method of S body refined | purified substance, It is desirable to dry under reduced pressure (vacuum drying) at about 60 degrees C or less avoiding thermal decomposition and a fusion | melting.

Hereinafter, the present invention will be described in more detail with reference to examples, but these examples do not limit the present invention in any way.

(I) Optical purity analysis method (isocratic method)
The optical purity of 1-phenyl-1,2,3,4-tetrahydroisoquinoline was measured by the following method.

Column: “CHIRALCEL OD-H” 250 × 4.6 mm, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane / isopropyl alcohol = 3/7 (volume ratio), flow rate: 0.5 ml / min, detector: UV254 nm, column temperature: 30 ° C
Retention time: (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline = 9.3 minutes, (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline = 11.7 minutes

Example 1 Production of S Form Raw Material In a solution consisting of 1726 mg (11.5 mmol, 1 equivalent) of L-tartaric acid and 10 mL of methanol, 2750 mg of racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (racemic raw material) ( When a methanol solution (10 mL) having a chemical purity of 87.4% by mass and 11.5 mmol) was added dropwise and cooled to 5 ° C., crystals were precipitated. After stirring for 1 hour, the precipitated (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / L-tartaric acid salt crystals (R-form tartrate crystals) were removed by vacuum filtration. The optical purity of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline (S-form material) in the mother liquor obtained was measured to be 83% e. e. Met. 20 mL of water was added here, and methanol was distilled off under reduced pressure. When a 30% by mass aqueous sodium hydroxide solution was added to the resulting solution (19.65 g) until pH 12 was reached, crystals were precipitated. After cooling to 5 ° C. and stirring for 30 minutes, the crystals are filtered under reduced pressure, washed with 20 mL of water, and dried under vacuum to obtain (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline (S body raw material) Was obtained as white crystals (1092 mg, chemical purity 93 mass%, 4.83 mmol, yield 42 mol%, optical purity 82% ee).

Example 2 Production of S-form salt crystals (acetate) 82% e.e. produced in Example 1. e. Into an ethyl acetate solution (6 mL) of 848 mg (chemical purity 93 mass%, (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline pure content 780 mg, 3.7 mmol) of 200 mg of acetic acid (3.3 mmol, 0.9 eq) was added and warmed to 60 ° C. When hexane (8 ml) was added and cooled to 25 ° C., crystals were precipitated. The crystals were filtered under reduced pressure and dried in vacuo to give (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / acetate (S-form salt crystals) as white crystals (670 mg, chemical purity) 98.9 mass%, 2.5 mmol, yield 68 mol%, optical purity 99% ee).
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.84 (s, 3H), 2.89-2.97 (m, 1H), 3.04-3.17 (m, 2H), 3. 26-3.32 (m, 1H), 5.29 (s, 1H), 6.76 (d, 1H), 7.05-7.35 (m, 8H), 8.12 (brs, 2H)

Example 3 Production of S Form Purified Product 647 mg of S form salt crystals produced in Example 2 (chemical purity 98.9% by mass, (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / acetic acid Pure salt (640 mg, 2.4 mmol) and water (8 ml) were mixed and cooled to 5 ° C. 640 mg (4.8 mmol, 2 equivalents) of a 30% by mass aqueous sodium hydroxide solution was added, and the mixture was stirred for 4 hours while raising the temperature from 5 ° C to 25 ° C. The precipitated crystals were filtered under reduced pressure and vacuum dried to obtain (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline (S-form purified product) as white crystals (480 mg, chemical purity 99). .4 mass%, 2.3 mmol, yield 97 mol%, optical purity 99% ee).

Example 4 Preparation of S-form salt crystal (acetate) L-tartaric acid 751 mg (5.0 mmol, 1 equivalent) was added to a solution of 1 mL of water and racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline ( Racemic raw material) 1197 mg (chemical purity 87.4% by mass, 5 mmol) of ethanol solution (9 mL) was added dropwise and cooled to 5 ° C. to precipitate crystals. After stirring for 1 hour, the precipitated (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / L-tartaric acid salt crystals (R-form tartrate) were removed by vacuum filtration. The salt crystals were washed with 3 mL of ethanol, and the washing solution was added to the mother liquor. When the optical purity of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline in the mother liquor obtained was measured, it was 84% e. e. Met. 10 mL of water was added here, and ethanol was distilled off under reduced pressure. To the resulting solution, 10 mL of toluene was added, and a 30% by mass aqueous sodium hydroxide solution was further added until pH 13 was reached. After the aqueous layer was separated, the organic layer was washed with 5 mL of saturated brine and concentrated under reduced pressure to obtain a colorless oil (S body raw material). This was dissolved in 5 mL of toluene, and then 180 mg (3 mmol) of acetic acid was added to precipitate crystals (S-form salt crystals). Further, 5 mL of hexane was added, the mixture was cooled to 5 ° C., stirred for 30 minutes, and then the crystals were filtered under reduced pressure. The crystals were washed with hexane and dried in vacuo at 40 ° C. to obtain (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / acetate (S-form salt crystals) as white crystals (535 mg). , Chemical purity 99 mass%, 2.0 mmol, yield 40 mol%, optical purity 93% ee).

Example 5 Preparation of S-form salt crystal (acetate) L-tartaric acid (751 mg, 5.0 mmol, 1 equivalent) and a solution of 1 mL of water were mixed with racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline ( When 1197 mg (87.4% by mass, 5 mmol) of an ethanol solution (9 mL) was added dropwise and cooled to 5 ° C., crystals were precipitated. After stirring for 1 hour, the precipitated (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / L-tartaric acid salt crystals (R-form tartrate) were filtered under reduced pressure and washed with 3 mL of ethanol. . When the optical purity of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline in the mother liquor obtained was measured, it was 84% e. e. Met. 10 mL of water was added here, and ethanol was distilled off under reduced pressure. To the obtained solution, 10 mL of ethyl acetate was added, and a 30% by mass aqueous sodium hydroxide solution was further added until the pH reached 13. After the aqueous layer was separated, the organic layer was washed with 5 mL of saturated brine and concentrated under reduced pressure to obtain a colorless oil (S body raw material). This was dissolved in 5 mL of ethyl acetate, and then 180 mg (3 mmol) of acetic acid was added to precipitate crystals. Further, 5 mL of hexane was added, the mixture was cooled to 5 ° C., stirred for 30 minutes, and then the crystals were filtered under reduced pressure. The crystals were washed with hexane and dried in vacuo at 40 ° C. to give (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / acetate (S-form salt crystals) as white crystals (564 mg). , Chemical purity 100 mass%, 2.1 mmol, yield 42 mol%, optical purity 98% ee).

Example 6 Preparation of S-form salt crystals (p-toluenesulfonate) 67% e.e. e. (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline (raw material of S-form) 173 mg (chemical purity 100 mass%, 0.83 mmol) in ethyl acetate solution (5 mL) was added p-toluenesulfonic acid 1 When 158 mg (0.83 mmol, 1 equivalent) of hydrate was added and stirred at 25 ° C. for 16 hours, crystals were precipitated. The crystals were filtered under reduced pressure and vacuum dried to obtain (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / p-toluenesulfonate (S-form salt crystals) as white crystals ( 280 mg, chemical purity 100 mass%, 0.74 mmol, yield 89 mol%, optical purity 76% ee).

To 250 mg (0.66 mmol) of the crystals, 5 mL of ethyl acetate was added and heated to 60 ° C. After stirring for 30 minutes, it was cooled to 25 ° C. and stirred for 30 minutes. The crystals were filtered under reduced pressure and dried in vacuo to give the title compound as white crystals (209 mg, chemical purity 100 mass%, 0.55 mmol, yield 84 mol%, optical purity 85% ee).
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.34 (s, 3H), 2.99 (m, 1H), 3.20 (m, 1H), 3.26 (m, 2H), 5 .56 (s, 1H), 6.71 (d, 1H), 7.05 (d, 2H), 7.10 (m, 2H), 7.1-7.4 (m, 8H), 9. 1-9.6 (brs, 2H)

Comparative Example 1 Preparation of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline 73% e.e. e. To (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline (542 mg) (chemical purity 100 mass%, 2.6 mmol) was added 10 mL of hexane, and the mixture was heated and dissolved at 50 ° C. When cooled to 25 ° C., crystals were precipitated, which was cooled to 5 ° C. and stirred for 30 minutes. The crystals were filtered under reduced pressure and dried in vacuo to give the title compound as white crystals (362 mg, chemical purity 98 mass%, 1.7 mmol, yield 65 mol%, optical purity 67% ee).

Comparative Example 2 Preparation of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline 73% e.e. e. (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline (542 mg) (chemical purity 100 mass%, 2.6 mmol) was dissolved in 3 mL of ethyl acetate. When 9 mL of hexane was added thereto, crystals were precipitated, which was cooled to 5 ° C. and stirred for 30 minutes. The crystals were filtered under reduced pressure and dried under vacuum to give the title compound as white crystals (168 mg, chemical purity 100 mass%, 0.81 mmol, yield 31 mol%, optical purity 30% ee).

Example 7
The X-ray crystallographic spectrum of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / acetate prepared in Example 2 is shown in FIG. 2θ is about 8.9 °, 11.0 °, 13.0 °, 13.7 °, 15.8 °, 17.9 °, 19.1 °, 20.0 °, 21.5 °, 23. The most prominent peaks were seen in XRD at 4 ° and 26.7 °.
X-ray powder crystal analyzer: MiniFlex-ll manufactured by Rigaku Corporation
Measurement conditions: CuK _α1 wire Tube voltage 30 kV
Current between 15 mA

Example 8
The (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / p-toluenesulfonate prepared in Example 6 was analyzed by X-ray crystal in the same manner as in Example 7. At 2θ of about 8.7 °, 9.7 °, 11.0 °, 17.1 °, 17.5 °, 19.0 °, 19.9 °, 20.4 °, and 21.6 °, The most prominent peak was seen in XRD.

The present invention is useful for increasing the optical purity of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline. This (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline is useful as a pharmaceutical intermediate.

Claims

The following formula (1) containing (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline as an impurity:

A salt is formed from (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the following formula and a non-optically active acid, followed by crystallization to give the following formula (2a):

(In the formula (2a), A n-non optically active carboxylate anions, non-optically active sulfonate anions, non-optically active phosphonate anion, chloride anion, bromide anion, nitrate anion, hydrogen sulfate anion, or Park perchlorate anions represents an .A n-n-is represented by showing the valence of anion) (S) -1- manufactured salt crystals phenyl-1,2,3,4-tetrahydroisoquinoline, followed by A process for producing (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline with improved optical purity, characterized by treating the salt crystal with a base.
The manufacturing method according to claim 1, wherein the n is 1.
After preparing a salt crystal of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the formula (2a), the salt crystal is re-processed prior to treatment with a base. The manufacturing method of Claim 1 or 2 which crystallizes.
The production method according to any one of claims 1 to 3, wherein the non-optically active acid is acetic acid or p-toluenesulfonic acid.
Following formula (3):

A salt is precipitated from the racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline and L-tartaric acid represented by formula (I) and separated, and the resulting mother liquor is treated with a base. Formula (1):

(S) -1-Phenyl-1,2,3,4-tetrahydroisoquinoline represented by the formula:
Following formula (3):

It is obtained by precipitating and separating a salt from racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline and L-tartaric acid represented by the formula (S). The production method according to any one of claims 1 to 4, wherein -1-phenyl-1,2,3,4-tetrahydroisoquinoline is used as a raw material.
Following formula (2b):

(In the formula (2b), B -. Is non optically active carboxylate anion, or represents a non-optically active sulfonate anion) represented by (S) -1- phenyl-1,2,3,4 Tetrahydroisoquinoline salt.
Wherein B - is an acetate anion, or p- toluenesulfonate anion, (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline salt according to claim 7.
B − is an acetate anion, 2θ = 8.9 °, 11.0 °, 13.0 °, 13.7 °, 15.8 °, 17.9 °, 19.1 °, 20.0 °. The (S) -1-phenyl-1,2,3 according to claim 8 having an X-ray powder analysis pattern showing specific peaks at 21.5 °, 23.4 ° and 26.7 °. 4-tetrahydroisoquinoline salt.
B − is a p-toluenesulfonate anion and 2θ = 8.7 °, 9.7 °, 11.0 °, 17.1 °, 17.5 °, 19.0 °, 19.9 °, 20 The (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline salt according to claim 8, having an X-ray powder analysis pattern showing specific peaks at .4 ° and 21.6 °.