JP2012036093A - Method for manufacturing (s)-1-phenyl-1,2,3,4-tetrahydroisoquinoline - Google Patents

Abstract

PROBLEM TO BE SOLVED: To inexpensively and efficiently produce (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline useful as an intermediate for a medicine and having high optical purity.SOLUTION: The (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline having the high optical purity can be produced by forming a salt from the easily available (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline having low optical purity and an inexpensive acid such as acetic acid and p-toluenesulfonic acid, and crystallizing the salt.

Description

  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, e. e. (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / (S) -2- (4-chlorophenyl) -3-methylbutyric acid salt (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 Journal of Medicinal Chemistry, 2005, 48, 6597-6606.

  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 always advantageous methods for industrial implementation. That's not true.

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

  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 present invention relates to the following formula (1) containing (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline as an impurity:

で表される（Ｓ）−１−フェニル−１，２，３，４−テトラヒドロイソキノリンを、と、所定の非光学活性な酸から塩を形成させて、晶析することにより、下記式（２）：

(S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the following formula (2): ):

（式中、Ａ⁻は非光学活性なカルボキシレートアニオン、非光学活性なスルホネートアニオン、非光学活性なホスホネートアニオン、クロロアニオン、ブロモアニオン、ナイトレートアニオン、ハイドロジェンサルフェートアニオン、又はパークロレートアニオンを表す。）で表される（Ｓ）−１−フェニル−１，２，３，４−テトラヒドロイソキノリンの塩結晶を製造し、続いて該塩結晶を塩基で処理することを特徴とする、光学純度の向上した前記式（１）で表される（Ｓ）−１−フェニル−１，２，３，４−テトラヒドロイソキノリンの製造法に関する。

(In the formula, A ⁻ represents a non-optically active carboxylate anion, a non-optically active sulfonate anion, a non-optically active phosphonate anion, a chloro anion, a bromo anion, a nitrate anion, a hydrogen sulfate anion, or a perchlorate anion. And (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline salt crystal represented by the following formula, and then treating the salt crystal with a base: The present invention relates to an improved process for producing (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the formula (1).

  Further, the present invention provides the following formula (3);

で表されるラセミの１−フェニル−１，２，３，４−テトラヒドロイソキノリンとＬ−酒石酸から塩を形成させ、（Ｒ）−１−フェニル−１，２，３，４−テトラヒドロイソキノリン／Ｌ−酒石酸塩を結晶として析出させて分離した後、得られた母液を塩基で処理することを特徴とする、下記式（１）：

A salt is formed from racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline and L-tartaric acid represented by the formula: (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / L -After depositing and separating the tartrate salt as crystals, the resulting mother liquor is treated with a base, the following formula (1):

で表される（Ｓ）−１−フェニル−１，２，３，４−テトラヒドロイソキノリンの製造法に関する。

(S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by formula (1).

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

（式中、Ａ’⁻は非光学活性なカルボキシレートアニオン、又は非光学活性なスルホネートアニオンを表す。）で表される（Ｓ）−１−フェニル−１，２，３，４−テトラヒドロイソキノリン塩にも関する。

(Wherein, A ^'-. Is non optically active carboxylate anion, or a non-optically active sulfonate anion) represented by (S) -1- phenyl-1,2,3,4-tetrahydroisoquinoline salt Also related.

  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.

  The present invention is described in detail below.

  First, (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline containing (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline as an impurity as a starting material of the present invention. explain.

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

で表される（以下、「化合物（１）」とする場合がある）。

(Hereinafter sometimes referred to as “compound (1)”).

  Here, a method for producing (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline containing (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline as an impurity as a starting material Examples thereof include a method of hydrogenating 1-phenyl-3,4-dihydroisoquinoline described in JP-A-2005-281144 in the presence of an optically active ruthenium catalyst. According to this method, approximately 60-90% e.e. e. (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline can be obtained.

  As another method, the following formula (3):

で表されるラセミの１−フェニル−１，２，３，４−テトラヒドロイソキノリン（以下、「化合物（３）」とする場合がある）とＬ−酒石酸から塩を形成させ、（Ｒ）−１−フェニル−１，２，３，４−テトラヒドロイソキノリン／Ｌ−酒石酸塩を結晶として析出させて分離した後、得られた母液を塩基で処理することにより製造する方法が挙げられ、本方法が好ましく用いられる。

A salt is formed from racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (hereinafter sometimes referred to as “compound (3)”) and L-tartaric acid represented by formula (R) -1 -Phenyl-1,2,3,4-tetrahydroisoquinoline / L-tartrate is precipitated as crystals and separated, and then the resulting mother liquor is treated with a base, and this method is preferred. Used.

  Specifically, for example, the compound (3) is preferably added in an amount of 1 to 50 times by weight, more preferably 5 to 20 times by weight of methanol, ethanol, water, or a mixed solvent thereof. Preferably 0.5 to 1.5 times the molar amount, more preferably 0.8 to 1.2 times the molar amount of L-tartaric acid is dissolved. When compound (3) is added here, crystals precipitate. This is preferably stirred at −10 to 30 ° C., preferably for 1 hour or longer, and then the crystals of (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / L-tartrate are separated.

  When the mother liquor obtained at this time is added with sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate in an amount of preferably 0.5 to 10 times the amount of compound (3), the formula (1) The represented (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline is liberated. The precipitated solid may be filtered off as it is, or may be extracted and recovered by adding an organic solvent such as toluene, ethyl acetate or methyl tert-butyl ether.

  The optical purity of the (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline thus obtained is about 70-90% e.e. e. It is.

  Next, the product (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline salt will be described.

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

で表される（以下、「化合物（２）」とする場合がある）。ここで、式中、Ａ⁻は非光学活性なカルボキシレートアニオン、非光学活性なスルホネートアニオン、非光学活性なホスホネートアニオン、クロロアニオン、ブロモアニオン、ナイトレートアニオン、ハイドロジェンサルフェートアニオン、又はパークロレートアニオンを表す。非光学活性なカルボキシレートアニオンとしては、具体的には例えば、ホルメートアニオン、アセテートアニオン、シアノアセテートアニオン、ジクロロアセテートアニオン、トリフルオロアセテートアニオン、プロピオネートアニオン、ブタノエートアニオン、イソブタノエートアニオン、ピバレートアニオン、フェニルアセテートアニオン、ベンゾエートアニオン、アクリレートアニオン、シンナメートアニオン、オキサレートアニオン、マロネートアニオン等が挙げられる。非光学活性なスルホネートアニオンとしては、具体的には、メタンスルホネートアニオン、トリフルオロメタンスルホネートアニオン、エタンスルホネートアニオン、ベンゼンスルホネートアニオン、ｐ−トルエンスルホネートアニオン、ｐ−クロロベンゼンスルホネートアニオン、ｐ−ニトロベンゼンスルホネートアニオン等が挙げられる。好ましくはアセテートアニオン、ｐ−トルエンスルホネートアニオンであり、更に好ましくはアセテートアニオンである。なお、Ａ⁻が非光学活性なカルボキシレートアニオン、または、非光学活性なスルホネートアニオンである式（２’）：

(Hereinafter, it may be referred to as “compound (2)”). Wherein A ⁻ is a non-optically active carboxylate anion, a non-optically active sulfonate anion, a non-optically active phosphonate anion, a chloro anion, a bromo anion, a nitrate anion, a hydrogen sulfate anion, or a perchlorate anion. Represents. 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 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. Acetate anions and p-toluenesulfonate anions are preferred, and acetate anions are more preferred. In the formula (2 ′), A ⁻ is a non-optically active carboxylate anion or a non-optically active sulfonate anion:

で表わされる化合物は文献未記載の新規化合物である。

Is a novel compound not described in any literature.

  Then, the manufacturing method of this invention is demonstrated.

  First, (S) -1-phenyl-1,2, represented by the above formula (1) having low optical purity and containing (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline as an impurity. By forming a salt from 3,4-tetrahydroisoquinoline and a non-optically active acid and crystallization, (S) -1-phenyl-1,2,3,4- represented by the above formula (2) is obtained. A process for producing a salt crystal of tetrahydroisoquinoline will be described.

  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 chloro anion, a bromo 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; methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid And sulfonic acids such as 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 preferably 0.5 to 10 times the molar amount, more preferably 1 to 5 times the molar amount relative to the compound (1).

  When mixing the said acid and the said compound (1), it implements normally using a solvent. As the solvent, 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, and the like. 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. Preferably, methyl tert-butyl ether, ethyl acetate, toluene, and hexane are used.

  The amount of the solvent used is not particularly limited, but if it is too much, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times or less, more preferably 20 times or less, with respect to the compound (1). It is.

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 the compound (1) by mixing it with a non-optically active acid in a solvent.
(B) A method in which the compound (1) and a non-optically active acid are mixed in a solvent and then cooled and crystallized.
(C) A method in which the compound (1) and a non-optically active acid are mixed in a solvent and then crystallized by adding a poor solvent such as hexane.
(D) A method in which the compound (1) and a non-optically active acid are mixed in a solvent and then crystallized by concentration under reduced pressure.
(E) A method in which the compound (1) and a non-optically active acid are mixed in a solvent and then crystallized by concentration substitution with a poor solvent such as hexane.

  Further, these methods (a) to (e) can be crystallized by appropriately combining them. A seed crystal may be added during crystallization. Further, when the target quality is not reached by one crystallization, the optical purity is improved by recrystallization such as cooling and crystallization by heating and dissolving the salt of the compound (1) in a solvent. Can do.

  Although the implementation temperature in the crystallization methods of (a) to (e) is not particularly limited, it may be appropriately selected depending on the type of salt and the type of solvent used, and preferably the solvent type or mixed solvent type used. It is good to set it according to the target precipitation amount and the quality of the crystal below the temperature at which the salt of the compound (1) is dissolved.

  The salt of the compound (1) 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 crystals obtained as described above are usually dried. There is no particular limitation on the method for drying the crystal, but it is desirable to dry under reduced pressure (vacuum drying) at about 60 ° C. or less while avoiding thermal decomposition and melting.

  The optical purity of the salt of the compound (1) thus obtained, that is, the compound (2) is usually 95% e.e. e. 99% e.e. by optimizing crystallization conditions. e. It is also possible to obtain the above.

  Next, the salt of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the formula (2) is treated with a base to improve the optical purity of the formula (1). The process for producing (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the following formula:

  In this step, first, the compound (2) is dissolved in water, and then the base is added.

  The amount of water used may be an amount that dissolves the compound (2), preferably 50 times or less, more preferably 5 to 20 times.

  The base is preferably a metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide or magnesium hydroxide; a metal carbonate such as sodium carbonate, potassium carbonate or magnesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate or the like A metal hydrogen carbonate; amines such as ammonia and triethylamine, and sodium hydroxide or potassium hydroxide is more preferable from the economical viewpoint.

  The amount of the base used is preferably 0.5 to 20 times the molar amount, more preferably 1 to 5 times the molar amount relative to the compound (2). Or you may set the usage-amount according to the pH of water. In any case, the pH is preferably 7 or more, more preferably 10 to 13. The base dissolved in water may be used.

  As a method for recovering the compound (1) thus obtained, for example, an organic solvent such as ethyl acetate, toluene or methyl tert-butyl ether is added and extracted, and the solvent is distilled off by an operation such as heating under reduced pressure. A method is mentioned. Or the method of depositing the crystal | crystallization of the said compound (1) from a reaction liquid, and isolate | separating and acquiring is more preferable.

  Examples of the method for precipitating crystals include a method of slowly adding a base to the aqueous solution of the compound (2). 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 crystal separation method include vacuum filtration, pressure filtration, and centrifugal separation. 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 crystals obtained as described above are usually dried. There is no particular limitation on the method for drying the crystal, but it is desirable to dry under reduced pressure (vacuum drying) at about 60 ° C. or less while avoiding thermal decomposition and melting.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated further in detail, these Examples do not limit this invention at all.

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

Column manufactured by Daicel Chemical Industries, Ltd. {CHIRALCEL OD-H 250 × 4.6 mm}, mobile phase: hexane / isopropyl alcohol = 3/7 (volume ratio), flow rate: 0.5 ml / min, detector: UV254 nm, column temperature: 30 ℃
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 Preparation of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline A solution consisting of 1726 mg (1 equivalent) of L-tartaric acid and 10 mL of methanol was added to a solution of racemic 1-phenyl-1,2,3. When a methanol solution (10 mL) of 2,750 mg (87.4 wt%, 11.5 mmol) of 2,4-tetrahydroisoquinoline was added dropwise and cooled to 5 ° C., crystals were precipitated. After stirring for 1 hour, the precipitated salt crystals of (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / L-tartaric acid were filtered off under reduced pressure. When the optical purity of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline in the mother liquor obtained was measured, it was 83% e. e. Met. 20 mL of water was added here, and methanol was distilled off under reduced pressure. When a 30 wt% 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 were filtered off under reduced pressure, washed with 20 mL of water and dried in vacuo to give the title compound as white crystals (1092 mg, yield 42%, optical purity 82% e.e. e.).

Example 2 Production of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / acetate 82% e. e. To (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline (780 mg, 3.7 mmol) in ethyl acetate (6 mL) was added 200 mg (1 equivalent) of acetic acid, and the mixture was heated 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 the title compound as white crystals (670 mg, yield 68%, 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), 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) -1-phenyl-1,2,3,4-tetrahydroisoquinoline (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / acetic acid produced in Example 2 640 mg of salt and water (8 ml) were mixed and cooled to 5 ° C. 640 mg (2 equivalents) of 30% 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 dried in vacuo to give the title compound as white crystals (480 mg, yield 97%, optical purity 99% ee).

Example 4 Preparation of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / acetate To a solution of 751 mg (1 equivalent) of L-tartaric acid and 1 mL of water, racemic 1-phenyl-1, When an ethanol solution (9 mL) of 1,197 mg (87.4% by weight, 5 mmol) of 2,3,4-tetrahydroisoquinoline was added dropwise and cooled to 5 ° C., crystals were precipitated. After stirring for 1 hour, the precipitated salt crystals of (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / L-tartaric acid were filtered off 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 toluene was added, and a 30 wt% aqueous sodium hydroxide solution was further added until pH 13 was reached. After separating the aqueous layer, the organic layer was washed with 5 mL of saturated brine and concentrated under reduced pressure to give a colorless oil. This was dissolved in 5 mL of toluene, 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 off under reduced pressure. The crystals were washed with hexane and dried in vacuo at 40 ° C. to give the title compound as white crystals (535 mg, yield 40%, optical purity 93% ee).

Example 5 Preparation of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / acetate salt A solution of 751 mg (1 equivalent) of L-tartaric acid and 1 mL of water was added to racemic 1-phenyl-1, When an ethanol solution (9 mL) of 1,197 mg (87.4% by weight, 5 mmol) of 2,3,4-tetrahydroisoquinoline was added dropwise and cooled to 5 ° C., crystals were precipitated. After stirring for 1 hour, the precipitated salt crystals of (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / L-tartaric acid were filtered off 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 weight aqueous sodium hydroxide solution was further added until pH 13 was reached. After separating the aqueous layer, the organic layer was washed with 5 mL of saturated brine and concentrated under reduced pressure to give a colorless oil. 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 off under reduced pressure. The crystals were washed with hexane and dried in vacuo at 40 ° C. to give the title compound as white crystals (564 mg, yield 42%, optical purity 98% ee).

Example 6 Preparation of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / p-toluenesulfonate 67% e.e. e. 158 mg (1 equivalent) of p-toluenesulfonic acid monohydrate was added to an ethyl acetate solution (5 mL) of 173 mg (0.83 mmol) of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline. Crystals precipitated when stirred at 25 ° C. for 16 hours. The crystals were filtered under reduced pressure and dried in vacuo to give the title compound as white crystals (280 mg, 89% yield, optical purity 76% ee).

To 250 mg 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 off under reduced pressure and dried in vacuo to give the title compound as white crystals (209 mg, 84% yield, 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. 10 mL of hexane was added to 542 mg (2.6 mmol) of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline, and dissolved by heating 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 off under reduced pressure and dried in vacuo to give the title compound as white crystals (362 mg, yield 65%, optical purity 67% ee).

Comparative Example 2 Preparation of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline 73% e. e. 3 mL of ethyl acetate was dissolved in 542 mg (2.6 mmol) of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline. 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 off under reduced pressure and dried in vacuo to give the title compound as white crystals (168 mg, 31% yield, optical purity 30% ee).

Example 7
FIG. 1 shows the X-ray crystallographic spectrum of (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / acetate prepared in Example 2. 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 are 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

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

Claims (7)

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

By forming a salt from (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the formula (I) and a predetermined non-optically active acid and crystallizing, the following formula (2):

(In the formula, A ⁻ represents a non-optically active carboxylate anion, a non-optically active sulfonate anion, a non-optically active phosphonate anion, a chloro anion, a bromo anion, a nitrate anion, a hydrogen sulfate anion, or a perchlorate anion. And (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline salt crystal represented by the following formula, and then treating the salt crystal with a base: Process for producing improved (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline.   The production method according to claim 1, wherein the non-optically active acid is acetic acid or p-toluenesulfonic acid. Following formula (3):

A salt is formed from racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline and L-tartaric acid represented by the formula: (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline / L -After depositing and separating the tartrate salt as crystals, the resulting mother liquor is treated with a base, the following formula (1):

A process for producing (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the formula:   The production method according to claim 1, wherein (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline produced in claim 3 is used as a raw material. The following formula (2 ′):

(Wherein, A ^'-. 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 A ^'- is acetate anion, or p- toluenesulfonate anion, (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline salt according to claim 5. Wherein A ^'- is acetate anion, 2 [Theta] = 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 5, having an X-ray powder analysis pattern showing specific peaks at °, 21.5 °, 23.4 °, and 26.7 °. , 4-tetrahydroisoquinoline salt.

Images