JP2010037206A - Method for producing optically active o-methylserine or its salt - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing O-methylserine or its salt useful as an intermediate of medicines from a readily available starting material and using a low-cost reagent, which method can easily and efficiently be practiced in an industrial scale. <P>SOLUTION: Optically active O-methylserine or its salt is prepared by subjecting a readily available optically-active N,N-dibenzylserine to O-methylation, hydrolyzing the reaction product depending on the need therefor, and further debenzylating the reaction product. Thereby, O-methylserine or its salt can efficiently be produced. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to optically active O-methylserine or a salt thereof useful as a pharmaceutical intermediate and a compound useful for the production thereof, in particular, (R) -2-acetamido-N-benzyl-3-methoxy useful as a therapeutic agent for epilepsy and pain. The present invention relates to a method for producing (R) -O-methylserine or a salt thereof useful in the synthesis of propionamide (lacosamide).

The following is known as a method for producing optically active O-methylserine or a salt thereof.
(1) (R) -N-benzyloxycarbonyl-serine methyl ester is allowed to react with 5-fold molar amount of silver oxide and 10-fold molar amount of methyl iodide for 3 days. O-methylserine methyl ester is produced. Subsequently, after hydrolysis, a method of producing (R) -O-methylserine by hydrogenation in the presence of a palladium catalyst (Non-patent Document 1).
(2) Optically active N-benzyl-O-methyl serinamide is prepared by optical resolution of racemic 1-benzylaziridine-2-carboxamide with amidase and then treatment with methanol in the presence of Lewis acid catalyst. . Subsequently, a method for producing (S) -O-methylserine hydrochloride by debenzylation by hydrogenation in the presence of a palladium catalyst and further hydrolysis (Non-patent Document 2).
(3) (R) -N-chloroacetyl-O-methylserine is produced by chloroacetylating racemic O-methylserine and asymmetric hydrolysis using N-acetylamino acid amide hydrolase derived from pig kidney. . Then, the method of manufacturing (R) -O-methylserine hydrochloride by hydrolyzing with hydrochloric acid (patent document 1).

However, the method described in Non-Patent Document 1 has a problem in that methylation is performed using expensive silver and highly toxic methyl iodide, and the reaction requires a long time. The method described in Non-Patent Document 2 uses an expensive starting material, and is unsuitable for implementation on an industrial scale because of the long process. Since the method described in Patent Document 1 is a racemic resolution, it has problems in that productivity is low and N-chloroacetyl-O-methylserine has high water solubility, which requires a large amount of extraction solvent. ing.
JP-B 61-36838 Tetrahedron Asymmetry 1998, 9, 3841-3854. Organic Letters 2007, 9 (3), 521-524.

  In view of the above, an object of the present invention is a method capable of conveniently and efficiently implementing an optically active O-methylserine or a salt thereof useful as a pharmaceutical intermediate on an industrial scale from an easily available starting material using an inexpensive reagent. Is to provide.

  As a result of intensive studies, the present inventor obtained optically active O-methylserine efficiently by a simple method of O-methylation and further debenzylation of optically active N, N-dibenzyl-serine, which is easily available. It came to develop the manufacturing method.

  That is, the present invention provides the following formula (2):

（式中、Ｒは水素原子、アルカリ金属、炭素数１〜１２のアルキル基、炭素数２〜１２のアルケニル基、炭素数７〜１２のアラルキル基、又は炭素数６〜１２のアリール基を表し、＊は不斉炭素原子を表す。）で表される光学活性なＮ，Ｎ−ジベンジル−セリン誘導体またはその塩をＯ−メチル化することにより、下記式（１）；

(In the formula, R represents a hydrogen atom, an alkali metal, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an aryl group having 6 to 12 carbon atoms. , * Represents an asymmetric carbon atom.) O-methylation of an optically active N, N-dibenzyl-serine derivative represented by the following formula (1);

（式中、Ｒ、＊は前記に同じ。）で表される光学活性なＮ，Ｎ−ジベンジル−Ｏ−メチルセリン誘導体またはその塩を製造した後、必要に応じて加水分解を行って、下記式（３）；

(Wherein, R and * are the same as defined above), an optically active N, N-dibenzyl-O-methylserine derivative or a salt thereof is produced, and then hydrolyzed as necessary to obtain the following formula: (3);

（式中、＊は前記に同じ。）で表されるＮ，Ｎ−ジベンジル−Ｏ−メチルセリンまたはその塩を製造し、更に脱ベンジル化することを特徴とする、下記式（４）；

(Wherein, * is the same as above), N, N-dibenzyl-O-methylserine or a salt thereof is produced and further debenzylated;

（式中、＊は前記に同じ。）で表される光学活性なＯ−メチルセリンまたはその塩の製造法に関する。

(Wherein, * is the same as above), and relates to a method for producing optically active O-methylserine or a salt thereof.

  The present invention also provides the following formula (3):

（式中、＊は不斉炭素原子を表す。）で表されるＮ，Ｎ−ジベンジル−Ｏ−メチルセリンの酸またはアルカリ水溶液に、塩基または酸を添加してｐＨを３〜７に調整することにより前記化合物（３）を結晶として取得することを特徴とする、前記式（３）で表されるＮ，Ｎ−ジベンジル−Ｏ−メチルセリンの単離精製法に関する。

(In the formula, * represents an asymmetric carbon atom) The pH is adjusted to 3 to 7 by adding a base or acid to an acid or alkaline aqueous solution of N, N-dibenzyl-O-methylserine represented by the formula: The present invention relates to a method for isolating and purifying N, N-dibenzyl-O-methylserine represented by the formula (3), wherein the compound (3) is obtained as a crystal.

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

（式中、Ｒは水素原子、アルカリ金属、炭素数１〜１２のアルキル基、炭素数２〜１２のアルケニル基、炭素数７〜１２のアラルキル基、又は炭素数６〜１２のアリール基を表し、＊は不斉炭素原子を表す。）で表される光学活性なＮ，Ｎ−ジベンジル−Ｏ−メチルセリン誘導体またはその塩に関する。

(In the formula, R represents a hydrogen atom, an alkali metal, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an aryl group having 6 to 12 carbon atoms. , * Represents an asymmetric carbon atom), and an optically active N, N-dibenzyl-O-methylserine derivative or a salt thereof.

  According to the method of the present invention, optically active O-methylserine or a salt thereof useful as a pharmaceutical intermediate is simply and efficiently carried out on an industrial scale using inexpensive reagents from readily available starting materials. Is possible.

  First, the starting materials and products used in the present invention will be described.

  The optically active N, N-dibenzyl-serine derivative or a salt thereof as a starting material of the present invention is represented by the following formula (2):

で表される。

It is represented by

  Here, R represents a hydrogen atom, an alkali metal, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an aryl group having 6 to 12 carbon atoms. Specifically, for example, hydrogen atom, lithium, sodium, potassium, cesium, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group, vinyl Group, allyl group, methallyl group, benzyl group, 1-phenethyl group, phenyl group, naphthyl group and the like. Preferably they are a hydrogen atom, lithium, sodium, potassium, a methyl group, an ethyl group, a benzyl group, and a phenyl group, More preferably, they are a hydrogen atom or a methyl group.

  * Represents an asymmetric carbon atom. It should be noted that, of both objects, any object that is excessive in one object is included in the present invention.

  Specific examples of the salt include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, perchlorate; formate, acetate, pivalate, oxalate, lactate, Organic acid salts such as mandelate, tartrate, dibenzoyl tartrate, methanesulfonate, p-toluenesulfonate, camphorsulfonate and the like can be mentioned. When R is a hydrogen atom, amine salts such as ammonium salt, dicyclohexylamine salt, 1-phenethylamine salt, 1- (1-naphthyl) ethylamine salt, ephedrine salt, cinchonidine salt, triethylamine salt, pyridine salt are also included in the present invention. included.

  The compound (2) is exemplified by J.I. Chem. Soc. Perkin Trans I, 1995, 3073. Can be obtained by producing optically active serine and benzyl chloride by reacting them with potassium hydroxide in the presence of a phase transfer catalyst. Alternatively, as described in WO2006 / 038872, an optically active serine ester and benzyl bromide may be reacted in the presence of sodium hydrogen carbonate.

  Next, an optically active N, N-dibenzyl-O-methylserine derivative or a salt thereof obtained by the method according to the present invention is represented by the following formula (1);

で表される。ここで、Ｒ、＊、塩は前記に同じである。

It is represented by Here, R, *, and salt are the same as described above.

  The optically active N, N-dibenzyl-O-methylserine or a salt thereof obtained by the method according to the present invention is represented by the following formula (3);

で表される。ここで、＊、塩は前記に同じである。

It is represented by Here, * and the salt are the same as described above.

  The compounds (1) and (3) are novel compounds not described in the literature.

  The optically active O-methylserine or a salt thereof finally obtained by the method according to the present invention is represented by the following formula (4);

で表される。ここで、＊、塩は前記に同じである。

It is represented by Here, * and the salt are the same as described above.

  Then, the manufacturing method concerning this invention is demonstrated.

  First, the optically active N, N— represented by the formula (1) is obtained by O-methylating the optically active N, N-dibenzyl-serine derivative represented by the formula (2) or a salt thereof. A process for producing a dibenzyl-O-methylserine derivative or a salt thereof will be described.

  Examples of the O-methylation method include a method using a methylating agent such as silver oxide and methyl iodide, or a method in which a methylating agent is allowed to act in the presence of a base. It is good to carry out by making a methylating agent act in presence.

  Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide; ammonium hydroxides such as tetrabutylammonium hydroxide and benzyltrimethylammonium hydroxide; sodium carbonate and potassium carbonate Alkali metal carbonates such as sodium hydride, alkali metal hydrides such as potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; sodium Metal amides such as amide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide; n-butylmagnesium chloride, tert-butylmagnesium chloride, Examples include Grignard reagents such as phenylmagnesium bromide; lithium reagents such as methyllithium, n-butyllithium, and sec-butyllithium. Preferably sodium hydroxide, potassium hydroxide, tetrabutylammonium hydroxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium hexamethyldisilazide, or n-butyllithium, more preferably hydrogenated Sodium, sodium tert-butoxide, or potassium tert-butoxide. The amount of the base used is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to the compound (2).

  Examples of the methylating agent include methyl halides such as methyl chloride, methyl bromide and methyl iodide; methyl sulfonates such as dimethyl sulfate, methyl methanesulfonate and methyl p-toluenesulfonate; trimethyloxonium tetrafluoroborate and the like. Trimethyloxonium salt; trimethyl phosphate and the like. Preferred is methyl iodide or dimethyl sulfate, and more preferred is dimethyl sulfate. The amount of the methylating agent to be used is preferably 0.5 to 10-fold mol amount, more preferably 1 to 3-fold mol amount based on Compound (2).

  Examples of the reaction solvent that can be used in this reaction include ether solvents such as tetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether; ester solvents such as ethyl acetate and isopropyl acetate; hydrocarbon solvents such as benzene, toluene, and hexane. Solvents; Ketone solvents such as acetone and methyl ethyl ketone; Nitrile solvents such as acetonitrile and propionitrile; Halogen solvents such as methylene chloride and chloroform; Amides solvents such as N, N-dimethylformamide and N, N-dimethylacetamide Sulfoxide solvents such as dimethyl sulfoxide; urea solvents such as dimethylpropylene urea; phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide. Preferably, tetrahydrofuran, toluene, or N, N-dimethylacetamide is used. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. The amount of the reaction solvent to be used is preferably 50 times or less by weight, more preferably 5 to 20 times by weight with respect to the compound (2).

  The reaction temperature is preferably −50 to 50 ° C., more preferably −10 to 40 ° C. from the viewpoint of shortening the reaction time and improving the yield.

  The reaction time is preferably 5 minutes to 20 hours, more preferably 30 minutes to 5 hours from the viewpoint of improving the yield.

  There are no particular restrictions on the method and order of addition of compound (2), base, methylating agent, and solvent during the reaction.

  What is necessary is just to perform the general process for acquiring a product from a reaction liquid as a process after reaction. For example, the reaction solution after completion of the reaction is neutralized by adding water or an acid aqueous solution such as hydrochloric acid, sulfuric acid, acetic acid or the like. Next, a general extraction solvent such as ethyl acetate, diethyl ether, methyl tert-butyl ether, methylene chloride, toluene, hexane or the like is added to carry out the extraction operation. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained. The target product thus obtained has a sufficient purity, but may be purified by a general purification method such as crystallization, fractional distillation, column chromatography or the like for the purpose of further increasing the purity.

  When R of the compound (2), which is the starting material for this reaction, is a hydrogen atom or an alkali metal, the hydroxyl group of the compound (2) is methylated at the same time as the carboxyl group is methylated. The compound (1) in which is a methyl group may be produced, and this is also included in the scope of the present invention.

  Next, by hydrolyzing the optically active N, N-dibenzyl-O-methylserine derivative represented by the above formula (1) or a salt thereof, the N, N-dibenzyl- represented by the above formula (3) is obtained. The process for producing O-methylserine or a salt thereof will be described.

  This hydrolysis step is performed when R is not a hydrogen atom in the optically active N, N-dibenzyl-O-methylserine derivative represented by the above formula (1) or a salt thereof.

  Hydrolysis may be performed using either acid or alkali.

  The acid is not particularly limited, but hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, trifluoroacetic acid and the like are preferable, and the alkali is not particularly limited, but lithium hydroxide, sodium hydroxide, Potassium hydroxide, potassium carbonate and the like are preferable. The amount of the acid or alkali used is preferably 0.5 to 30 times the molar amount, more preferably 1 to 5 times the molar amount relative to the compound (1).

  The amount of water used for hydrolysis is preferably 50 times or less, more preferably 5 to 20 times the weight of the compound (1). Further, for the purpose of accelerating the reaction, a solvent compatible with water may be added.

  Examples of the solvent include methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran and the like. Methanol or ethanol is preferred. The amount of the solvent to be used is preferably 50 times or less, more preferably 5 to 20 times the weight of the compound (1).

  The reaction temperature is preferably 0 to 120 ° C., more preferably 20 to 80 ° C. from the viewpoint of shortening the reaction time and improving the yield.

  The reaction time is preferably 5 minutes to 48 hours, more preferably 30 minutes to 24 hours, from the viewpoint of improving the yield.

  There are no particular restrictions on the method and order of addition of the compound (1), acid or alkali, water, and solvent during the reaction.

  What is necessary is just to perform the general process for acquiring a product from a reaction liquid as a process after reaction. For example, the reaction solution after completion of the reaction is neutralized by adding an acid such as hydrochloric acid, sulfuric acid or acetic acid, or a base such as sodium hydroxide, potassium carbonate, sodium hydrogen carbonate, ammonia or triethylamine. Next, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like is added to carry out the extraction operation. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained. The target product thus obtained has a sufficient purity, but may be purified by a general purification method such as crystallization, fractional distillation, column chromatography or the like for the purpose of further increasing the purity. Further, salt formation and crystallization may be performed by forming a salt with an acid such as hydrochloric acid, sulfuric acid, acetic acid, oxalic acid or methanesulfonic acid, or a salt with an amine such as triethylamine, dicyclohexylamine or 1-phenethylamine.

  More preferably, the treatment after the reaction is a method of isolating N, N-dibenzyl-O-methylserine represented by the formula (3) as a crystal by neutralization crystallization. For example, when the reaction solution after the reaction is alkaline, an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, citric acid, preferably acetic acid is added to adjust the pH to 3 to 7, preferably pH 4 to 6. As a result, the compound (3) is precipitated as crystals. If the reaction solution after the reaction is acidic, a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, ammonia or triethylamine, preferably sodium hydroxide is added to adjust the pH. By adjusting to 3-7, preferably pH 4-6, the compound (3) precipitates as crystals. Precipitated crystals are separated by filtration under reduced pressure, pressure filtration, or centrifugation, washed with water or an organic solvent such as hexane, toluene, methyl tert-butyl ether as necessary, and dried by heating under reduced pressure. The compound (3) with improved purity can be obtained.

  Subsequently, N, N-dibenzyl-O-methylserine represented by the above formula (3) or a salt thereof is debenzylated, whereby the optically active O-methylserine represented by the above formula (4) or a salt thereof. The process of manufacturing the will be described.

  Examples of the debenzylation method include a method of hydrogenation in the presence of a transition metal catalyst. The transition metal catalyst is preferably palladium, rhodium, or platinum, and more preferably palladium. Palladium is preferably palladium black, palladium / carbon, palladium hydroxide / carbon, and more preferably palladium / carbon. The amount of the transition metal catalyst used is 0.1 times the molar amount or less, more preferably 0.05 to 0.0001 times the molar amount relative to the compound (3).

Preferably the hydrogen pressure in this step is 1 to 100 kg / cm ^2, more preferably from 1 to 30 kg / cm ^2.

  As a reaction solvent, water; alcohol solvents such as methanol, ethanol and isopropanol; ether solvents such as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; ester solvents such as ethyl acetate and isopropyl acetate; benzene, toluene, Hydrocarbon solvents such as hexane; halogen solvents such as methylene chloride and chloroform; amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxide solvents such as dimethyl sulfoxide; dimethylpropylene urea and the like Urea solvents; phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide may be used, and these may be used alone or in combination of two or more. Preferred is water; alcohol-based solvents such as methanol, ethanol, isopropanol, and more preferred are water, methanol, or a mixed solvent of water and methanol. The amount of the solvent to be used is preferably 50 times or less by weight, more preferably 5 to 20 times by weight with respect to the compound (3).

  The reaction temperature is preferably 0 to 100 ° C., more preferably 10 to 60 ° C. from the viewpoint of shortening the reaction time and improving the yield.

  The reaction time is preferably 30 minutes to 48 hours, more preferably 1 to 24 hours, from the viewpoint of yield improvement.

  There are no particular restrictions on the method and order of addition of the compound (3), transition metal catalyst, hydrogen, and solvent during the reaction.

  What is necessary is just to perform the general process for acquiring a product from a reaction liquid as a process after reaction. For example, after removing the transition metal catalyst from the reaction liquid after completion of the reaction by vacuum filtration or pressure filtration, the reaction solvent is distilled off by an operation such as heating under reduced pressure to obtain the desired product. The target product thus obtained has sufficient purity that can be used in the subsequent step, but for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, crystallization, The purity may be further increased by a general purification method such as fractional distillation or column chromatography.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

Reference Example 1 Production of (R) -N, N-dibenzyl-serine A solution consisting of 37.80 g (450 mmol) of sodium hydrogen carbonate, 32 mL of water, 80 mL of acetonitrile and 34.20 g (200 mmol) of benzyl bromide was heated to 50 ° C. Then, 15.55 g (100 mmol, 100% ee) of (R) -serine methyl ester hydrochloride was added thereto in 15 minutes. After stirring this solution at 50 ° C. for 16 hours, the reaction solution was cooled to room temperature, and the precipitated inorganic salt was filtered off under reduced pressure. This inorganic salt was washed with 20 mL of toluene, and the washing solution was combined with the filtrate. Further, 40 mL of toluene and 20 mL of water were added to the mixture of the washing solution and the filtrate for extraction. The organic layer was washed with 40 mL of saturated brine, and the solvent was distilled off under reduced pressure to obtain 41.51 g of a colorless oil. To this oily substance, 100 mL of water, 50 mL of methanol, and 16.00 g (120 mmol) of 30 wt% aqueous sodium hydroxide solution were added, and the mixture was stirred at 50 ° C. for 16 hours. After methanol was distilled off under reduced pressure, acetic acid was added to adjust the pH to 5, whereby crystals were precipitated. After cooling to 5 ° C. and stirring for 30 minutes, the crystals were filtered off under reduced pressure and dried in vacuo at 50 ° C. to give the title compound as white crystals (28.07 g, yield 97%).

Example 1 Production of (R) -N, N-dibenzyl-O-methylserine A 60% sodium hydride 400 mg (10 mmol) solution containing 20 mL of tetrahydrofuran was cooled to 5 ° C. and produced in Reference Example 1 (R) -N, N-dibenzyl-serine 1.441 g (5 mmol) was added and the temperature was raised to 25 ° C. After stirring for 1 hour, the mixture was cooled again to 5 ° C., and 1.260 g (10 mmol) of dimethyl sulfate was added. The temperature was raised to 25 ° C. and the mixture was stirred for 2 hours. Tetrahydrofuran was distilled off under reduced pressure, acetic acid was added to the residue to adjust the pH to 4.5, and 20 mL of methyl tert-butyl ether was added for extraction. The organic layer was washed twice with 10 mL of water and then concentrated under reduced pressure to obtain 1.9878 g of a colorless oil. As a result of analysis, this oily substance was a mixture of (R) -N, N-dibenzyl-O-methylserine and (R) -N, N-dibenzyl-O-methylserine methyl ester in a molar ratio of 1: 3.6. there were.

Methanol (5 mL), water (5 mL), and 30 wt% aqueous sodium hydroxide solution (1.33 g, 10 mmol) were added to the oily product, and the mixture was stirred at 50 ° C. for 20 hours. Methanol was distilled off under reduced pressure, and then acetic acid was added to adjust the pH to 4.5 to precipitate crystals. After cooling to 5 ° C. and stirring for 30 minutes, the crystals were filtered off under reduced pressure and dried in vacuo at 50 ° C. to give the title compound as white crystals (1.2916 g, purity 82.8 wt%, yield 71%). ).
¹ H-NMR (CDCl ₃ , 400 MHz / ppm): δ 3.38 (3H, s), 3.55 (1H, m), 3.78-4.16 (3H, m), 3.90 (4H, dd), 5.7 (1H, brs), 7.26-7.34 (10H, m)

Example 2 Production of (R) -O-methylserine (R) -N, N-dibenzyl-O-methylserine 722 mg (2 mmol) produced in Example 1, methanol 10 mL, water 5 mL, 10 wt% palladium / carbon ( A solution comprising 60 mg of a 50% water-containing product was stirred at 25 ° C. for 20 hours under a normal pressure hydrogen atmosphere. The palladium was filtered off under reduced pressure, washed with 10 mL of water, and the filtrate was concentrated under reduced pressure. Ethanol 10mL was added to the residue, and it concentrated under reduced pressure, and when ethanol 10mL was added to the residue, the crystal | crystallization precipitated. After cooling to 5 ° C. and stirring for 30 minutes, the crystals were filtered off under reduced pressure and dried in vacuo at 50 ° C. to give the title compound as white crystals (185.8 mg, yield 78%). The optical purity of this product was measured (column: SUMICHIRAL OA5000 4.6 × 150 mm, eluent: 2 mM copper sulfate aqueous solution, column temperature: 35 ° C., flow rate: 1.0 mL / min, detector: UV254 nm, retention time: (S) Body = 7.9 minutes, (R) body = 11.2 minutes), it was 99.5% ee.
¹ H-NMR (D ₂ O, 400 MHz / ppm): δ 3.23 (3H, s), 3.62-3.64 (2H, m), 3.75-3.77 (1H, m)

Claims (6)

Following formula (2);

(In the formula, R represents a hydrogen atom, an alkali metal, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an aryl group having 6 to 12 carbon atoms. , * Represents an asymmetric carbon atom.) O-methylation of an optically active N, N-dibenzyl-serine derivative represented by the following formula (1);

(Wherein, R and * are the same as defined above), an optically active N, N-dibenzyl-O-methylserine derivative or a salt thereof is produced, and then hydrolyzed as necessary to obtain the following formula: (3);

(Wherein, * is the same as above), N, N-dibenzyl-O-methylserine or a salt thereof is produced and further debenzylated;

(Wherein * is the same as above), a method for producing optically active O-methylserine or a salt thereof.   The production method according to claim 1, wherein the O-methylation is performed by reacting a base and dimethyl sulfate.   The manufacturing method of Claim 1 or 2 whose R is a hydrogen atom or a methyl group. Following formula (3);

(In the formula, * represents an asymmetric carbon atom) The pH is adjusted to 3 to 7 by adding a base or acid to an acid or alkaline aqueous solution of N, N-dibenzyl-O-methylserine represented by the formula: The method for isolating and purifying N, N-dibenzyl-O-methylserine represented by the formula (3), wherein the compound (3) is obtained as a crystal. Following formula (1);

(In the formula, R represents a hydrogen atom, an alkali metal, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an aryl group having 6 to 12 carbon atoms. , * Represents an asymmetric carbon atom)), or an optically active N, N-dibenzyl-O-methylserine derivative or a salt thereof.   The optically active N, N-dibenzyl-O-methylserine derivative or a salt thereof according to claim 5, wherein R is a hydrogen atom or a methyl group.