JP2007284358A - Method for producing optically active piperazine compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing optically active 1-methyl-3-phenylpiperazine and optically active 1-(3-hydroxymethyl-2-pyridyl)-4-methyl-2-phenylpiperazine useful for producing a medicine such as optically active mirtazapine, etc. <P>SOLUTION: An optically active phenylglycine derivative is used as a raw material and passed through N-chloroacetylphenylglycine, N-methylaminoacetylphenylglycine, a methyl ester thereof, 1-methyl-3-phenylpiperazine-2,5-dione, 1-methyl-3-phenylpiperazine, 1-(3-cyano-2-pyridyl)-4-methyl-2-phenylpiperazine and 1-(3-formyl-2-pyridyl)-4-methyl-2-phenylpiperazine to produce the optically active piperazine compound. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an optically active piperazine compound useful as a synthetic intermediate for pharmaceuticals such as optically active mirtazapine and a method for producing the intermediate.

  Mirtazapine is a useful drug as an antidepressant. Recently, optically active mirtazapine has been developed as a therapeutic agent for insomnia and the like, and a production method from (S) -1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine Is described in Patent Document 1.

  In Patent Document 1, optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine is obtained by an asymmetric synthesis method, an optical resolution method using a racemic chiral acid, or the like. Although it is described that it can be manufactured, there is no description about the specific manufacture.

  Racemic 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine is known to be prepared from racemic 1-methyl-3-phenylpiperazine (eg, patents). References 2 and 3).

It is known that racemic 1-methyl-3-phenylpiperazine is produced from N- (2-hydroxyethyl) -N-methyl-α-hydroxy-β-phenethylamine (for example, Patent Document 4). reference).
In addition, racemic 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine is obtained from racemic 1-methyl-3-phenylpiperazine to racemic 1- (3-formyl- It is also known to produce via 2-pyridyl) -4-methyl-2-phenylpiperazine (see, for example, Patent Document 5).

International Publication No. 2005/005410 Pamphlet US Pat. No. 4,062,848 US Pat. No. 6,852,855 US Pat. No. 6,495,685 Japanese Patent Application No. 2001-122874

  The present inventors advantageously synthesized optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine by using optically active 1-methyl-3-phenylpiperazine. I thought I could do it. However, although the above document discloses a racemic 1-methyl-3-phenylpiperazine, no optically active substance is disclosed in any document. The optically active substance is first considered to be obtained by optical resolution of a racemate. However, this method is economically disadvantageous because half of the undesired enantiomers can be formed, and further means of racemization recovery may be taken, but it is also economically disadvantageous, such as an increase in the number of steps.

  If optically active 1-methyl-3-phenylpiperazine can be easily produced from an inexpensive raw material, it will be economically advantageous for the production of pharmaceuticals such as optically active mirtazapine.

従って、光学活性な１−メチル−３−フェニルピペラジンから、立体配置を保持できるような方法で光学活性な１−（３−ヒドロキシメチル−２−ピリジル）−４−メチル−２−フェニルピペラジンを製造することができれば、光学活性なミルタザピン等の医薬品の製造には非常に有利になると考えられる。 In producing optically active mirtazapine using optically active 1-methyl-3-phenylpiperazine, the present inventors have carried out the same method as the method described in Patent Documents 2 and 3 (method in a racemate), When optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine was produced from optically active 1-methyl-3-phenylpiperazine, its configuration was not retained. The knowledge that it isomerizes was obtained.

Therefore, optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine is produced from optically active 1-methyl-3-phenylpiperazine by a method capable of maintaining the configuration. If possible, it would be very advantageous for the production of pharmaceuticals such as optically active mirtazapine.

  The present invention relates to a method and an intermediate for producing optically active 1-methyl-3-phenylpiperazine and salts thereof useful for the production of pharmaceuticals such as optically active mirtazapine, and optically active 1- (3-hydroxymethyl- It is an object of the present invention to provide a method for producing 2-pyridyl) -4-methyl-2-phenylpiperazine.

  As a result of studying the above problems, the present inventors have found that optically active 1-methyl-3-phenylpiperazine can be easily produced if optically active phenylglycine, which can be obtained at low cost, is used as a starting material. The present invention has been completed.

In addition, production of optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine from optically active 1-methyl-3-phenylpiperazine is carried out by the production of optically active 1- (3- It was found that the configuration could be maintained by a method via formyl-2-pyridyl) -4-methyl-2-phenylpiperazine, and the present invention was completed.

That is, the present invention is as follows.
[1] A method for producing optically active N-methylaminoacetylphenylglycine, comprising reacting optically active N-haloacetylphenylglycine with methylamine.
[2] The production method according to [1], wherein the optically active N-haloacetylphenylglycine is optically active N-chloroacetylphenylglycine.
[3] The production method according to any one of [1] to [2] above, wherein all the compounds are in the (S) form.
[4] A method for producing optically active N-methylaminoacetylphenylglycine methyl ester, comprising reacting optically active N-methylaminoacetylphenylglycine with thionyl chloride in methanol.
[5] The production method according to the above [4], wherein the compounds are all in the (S) form.
[6] A method for producing optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine, which comprises the following steps:
(Step 1) Step of producing optically active N-chloroacetylphenylglycine by chloroacetylating optically active phenylglycine;
(Step 2) A step of reacting optically active N-chloroacetylphenylglycine with methylamine to produce optically active N-methylaminoacetylphenylglycine;
(Step 3) A step of reacting optically active N-methylaminoacetylphenylglycine with thionyl chloride in methanol to produce N-methylaminoacetylphenylglycine methyl ester;
(Step 4) a step of cyclizing optically active N-methylaminoacetylphenylglycine methyl ester to produce optically active 1-methyl-3-phenylpiperazine-2,5-dione;
(Step 5) A step of producing optically active 1-methyl-3-phenylpiperazine by reducing optically active 1-methyl-3-phenylpiperazine-2,5-dione with a metal hydride compound;
(Step 6) An optically active 1- (3-cyano-2-pyridyl) -4-methyl-2 is prepared by reacting optically active 1-methyl-3-phenylpiperazine with 2-chloro-3-cyanopyridine. -Manufacturing a phenylpiperazine;
(Step 7) Optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine is reduced to give optically active 1- (3-formyl-2-pyridyl) -4-methyl. A step of producing 2-phenylpiperazine; and (Step 8) reduction of optically active 1- (3-formyl-2-pyridyl) -4-methyl-2-phenylpiperazine to give optically active 1- (3 -Hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine.
[7] The production method of the above-mentioned [6], wherein all the compounds are in the (S) form.
[8] Optically active N-methylaminoacetylphenylglycine or a salt thereof.
[9] The compound according to [8] above, wherein the optically active N-methylaminoacetylphenylglycine or a salt thereof is (S) -N-methylaminoacetylphenylglycine or a salt thereof.
And so on.

  ADVANTAGE OF THE INVENTION According to this invention, the optically active piperazine compound useful for manufacture of pharmaceuticals, such as an optically active mirtazapine, can be manufactured simply and economically from an inexpensive raw material.

In addition, production of optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine from optically active 1-methyl-3-phenylpiperazine is carried out while maintaining its configuration. can do.

Hereinafter, the present invention will be described in detail.
The optical activity of the present invention means that the content of any optical isomer exceeds 50%, but in order to obtain the target optically active piperazine compound or a salt thereof with high optical purity, it is 80% or more. Further, it is preferably 90% or more, particularly 95% or more.

In the present invention, optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine or a salt thereof can be produced by the following method.
Method

(In the formula, X represents a halogen atom, and the carbon atom indicated by * indicates an asymmetric carbon atom)

(Step 1) Step of haloacetylation of optically active phenylglycine
An optically active compound (formula 3) can be produced by reacting a haloacetylating agent (formula 1) with an optically active phenylglycine (formula 2).
Examples of X in (Formula 1) include a chlorine atom and a bromine atom. Specific examples of the haloacetylating agent include chloroacetyl chloride, bromoacetyl chloride, bromoacetyl bromide, and the like. Acetyl chloride is preferred.
The reaction method is not particularly limited, but a method in which a haloacetylating agent is dropped into an optically active phenylglycine solution is preferable.
The amount of the haloacetylating agent to be used is generally 1.1 to 2 mol, preferably 1.2 to 1.7 times mol, based on 1 mol of optically active phenylglycine.
Examples of the reaction solvent usually include water, tetrahydrofuran (THF), methanol, acetone, and mixed solvents thereof, and water is preferable from the viewpoints of reactivity, post-treatment methods, and the like.
The amount of reaction solvent used is usually 100 to 500 ml, preferably 200 to 400 ml, with respect to 100 g of optically active phenylglycine.
A base is usually used for the reaction of haloacetylating optically active phenylglycine. Examples of the base include inorganic bases such as caustic soda, caustic potassium, sodium carbonate and potassium carbonate, and organic bases such as triethylamine. Caustic soda is preferable from the viewpoints of economy and gas generation.
The amount of the base used is usually 3 to 10 mol, preferably 6 to 8 mol, per 1 mol of optically active phenylglycine. The base is added in an amount for dissolving optically active phenylglycine, for example. The amount thereof may be an amount that makes the pH in the system alkaline when haloacetylated, preferably in the range of pH 10-13.

As reaction temperature, it is 20 degrees C or less normally, Preferably it is 10 to 0 degreeC.
Although the reaction time depends on the reaction temperature and the amount of reagent used, the reaction is usually completed at the end of the addition of the haloacetylating agent.
The completion of the reaction can be confirmed by disappearance of the raw material by a usual method such as TLC or HPLC.
The target product is taken out from the reaction solution by ordinary post-treatment. For example, it is alkaline (pH 9 to 10) and washed with a solvent such as ethyl acetate. The aqueous layer is adjusted to be acidic (for example, pH is 1 to 2) using an inorganic acid such as hydrochloric acid.
The aqueous layer adjusted to be acidic is extracted with an organic solvent such as ethyl acetate.
The optically active haloacetylphenylglycine (formula 3) may be used in the reaction with methylamine after concentrating the solvent, but may be purified by means such as recrystallization or column chromatography if desired.

(Step 2) Production of optically active N-methylaminoacetylphenylglycine Optically active N-methylaminoacetyl by reacting haloacetylated optically active phenylglycine (formula 3) with methylamine. Phenylglycine can be obtained.
Examples of the solvent for reacting the compound of formula (3) with methylamine include water, methanol, THF and a mixed solvent thereof, and water is preferable from the viewpoint of economy.
The amount of the solvent is not particularly limited, but is usually 1 to 5 ml with respect to 1 g of optically active N-methylaminoacetylphenylglycine.
Methylamine may be in the form of an aqueous solution, an alcohol solution such as methanol or ethanol, or a gaseous form, but an aqueous solution is preferred from the viewpoint of economy.
The amount of methylamine to be used is usually 3 to 10 mol, preferably 5 to 8 mol, per 1 mol of haloacetylated optically active phenylglycine (Formula 3).
As reaction temperature, it is 20-50 degreeC normally, Preferably it is the range of 30-40 degreeC.
The reaction time is not particularly limited, but is usually 1 to 5 hours depending on the reaction temperature and the amount of reagent used.
The end point of the reaction is, for example, when the raw material disappears by HPLC or the like.

The optically active N-methylaminoacetylphenylglycine (formula 4) may be usually used as it is in the methyl esterification reaction, but may be purified by means such as recrystallization or column chromatography if desired. For example, it is adsorbed with an ion exchange resin such as (Amberlyst (Rohm & Haas) ion exchange resin), eluted with an alkali such as ammonia, and concentrated to obtain optically active N-methylaminoacetylphenylglycine. Can do.

Optically active N-methylaminoacetylphenylglycine may form an inorganic acid salt such as hydrochloride, an organic amine salt such as methylamine salt, or an alkali metal salt such as sodium salt.

(Step 3) Production of optically active N-methylaminoacetylphenylglycine methyl ester Optically active N-methylaminoacetylphenylglycine (formula 4) reacts with thionyl chloride in methanol to produce optically active N-methyl. Aminoacetylphenylglycine methyl ester (Formula 5) can be obtained. Further, optically active N-methylaminoacetylphenylglycine (formula 4) may be added to a solution in which methanol and thionyl chloride are mixed.

The amount of methanol used is usually 5 to 30 ml, preferably 15 to 25 ml, with respect to 1 g of optically active N-methylaminoacetylphenylglycine.
The amount of thionyl chloride to be used is generally 10-30 mol, preferably 15-20 mol, per 1 mol of optically active N-methylaminoacetylphenylglycine.
The reaction temperature is generally −20 to 0 ° C., preferably −15 to −5 ° C.
After the thionyl chloride is added, the reaction is completed by further stirring, for example, at a temperature of 10 to 30 ° C. for 1 to 4 hours.
The reaction time is usually 10 minutes to 10 hours, preferably 1 to 5 hours, although it depends on the reaction temperature and the amount of reagent used.
The end point of the reaction can be confirmed by measuring disappearance of the raw material by, for example, HPLC.
The optically active N-methylaminoacetylphenylglycine methyl ester can be converted to optically active 1-methyl-3-phenylpiperazine-2,5-dione (formula 6) by performing a cyclization reaction as it is without purification. However, it can be recrystallized if desired.

(Step 4) Production of optically active 1-methyl-3-phenylpiperazine-2,5-dione In this step, optically active N-methylaminoacetylphenylglycine methyl ester is cyclized to form optically active 1 -Methyl-3-phenylpiperazine-2,5-dione can be produced.

  The cyclization method includes (i) a method of cyclization by heating, (ii) a method of cyclization by reduced pressure, (iii) a method of cyclization by base treatment, (iv) a method of cyclization by acid treatment, or These combinations and the like can be mentioned.

  In the method by heating of (i), it is normally performed at 20 to 100 ° C, preferably 25 to 80 ° C. If this temperature is less than 20 ° C., the reaction rate becomes slow, and if it exceeds 100 ° C., by-products may be generated, which is not preferable. Although depending on the reaction temperature and the like, the reaction time is usually 1 hour to 4 days, preferably 2 hours to 1 day. This method can be carried out without solvent.

  In the method (ii) using reduced pressure, the reaction is usually performed at 0.13 to 13.3 kPa, preferably 0.7 to 6.7 kPa. When the degree of vacuum is less than 0.13 kPa, it is difficult to implement industrially. On the other hand, when it exceeds 13.3 kPa, the reaction rate is decreased, which is not preferable. The reaction time is usually 1 hour to 4 days, preferably 2 hours to 1 day, depending on the degree of vacuum. This method can be carried out without solvent.

  In the method (iii) based on base treatment, treatment is performed with an organic base (for example, triethylamine), an aqueous sodium bicarbonate solution, an aqueous sodium carbonate solution, an aqueous potassium carbonate solution, or the like. The amount of the base used is not particularly limited, but may be an amount that liberates the optically active compound (Formula 6).

  In this method, the above base may be used as a solvent, or a solvent may be used separately. Examples of the solvent include ether solvents such as THF, dimethoxyethane, diethoxymethane, dioxane, tert-butyl methyl ether, cyclopentyl methyl ether; hydrocarbon solvents such as toluene, xylene, heptane, hexane; methanol, ethanol, propanol, Examples include alcohol solvents such as isopropanol and butanol; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as methyl isobutyl ketone; and mixed solvents thereof.

  Although the usage-amount of a solvent is 0.5-5L normally with respect to 1 mol amount of optically active compounds (Formula 5), Preferably it is 1-3L, It does not specifically limit.

  As reaction temperature, it is 20-100 degreeC normally, Preferably it is 25-80 degreeC. If the reaction temperature is less than 20 ° C, the reaction rate becomes slow. Conversely, if the reaction temperature exceeds 100 ° C, a by-product may be generated, which is not preferable. While the reaction time varies depending on the reaction temperature, the amount of base used, etc., it is generally 1 hour to 4 days, preferably 2 hours to 1 day.

  Depending on the reaction conditions, post-treatment conditions, and the like of step 3, the reaction of step 4 may proceed after step 3.

  (Iv) In the method of cyclization by acid treatment, treatment is performed with polyphosphoric acid, sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, zinc chloride, aluminum chloride, etc., among others, from the viewpoint of the selectivity of the reaction, Polyphosphoric acid, sulfuric acid, phosphoric acid, zinc chloride, etc. are preferably used.

  The usage-amount of an acid is 0.1-1.0 mol amount normally with respect to 1 mol amount of optically active compounds (Formula 5), Preferably it is 0.2-0.5 mol amount. When the amount of the acid used is less than 0.1 mol, the raw material remains unreacted and the yield may decrease. On the other hand, when the amount exceeds 1.0 mol, there is no improvement in yield corresponding to the amount, which is not economical.

  In this method, the above acid may be used as a solvent, or a separate solvent may be used. Examples of the solvent include acid solvents such as acetic acid, ether solvents such as THF, dimethoxyethane, diethoxymethane, dioxane, and cyclopentyl methyl ether; hydrocarbon solvents such as toluene, xylene, heptane, hexane; methanol, ethanol, propanol, Examples include alcohol solvents such as isopropanol and butanol; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as methyl isobutyl ketone; and mixed solvents thereof.

  Although the usage-amount of a solvent is 2-20L with respect to 1 mol amount of optically active compounds (Formula 5) normally, Preferably it is 4-8L, It does not specifically limit.

The reaction temperature is usually 0 to 50 ° C., preferably 10 to 30 ° C. If the reaction temperature is less than 0 ° C., the reaction rate becomes slow. Conversely, if the reaction temperature exceeds 50 ° C., by-products may be generated, which is not preferable. While the reaction time varies depending on the reaction temperature, the amount of acid used, etc., it is generally 0.5 hr to 5 hr, preferably 1 hr to 2 hr.

Isolation of the optically active 1-methyl-3-phenylpiperazine-2,5-dione produced in this way is carried out by post-treatment of the reaction solution by a conventional method (for example, neutralization, extraction, washing with water, crystallization, etc.) It can be done by attaching. Optically active 1-methyl-3-phenylpiperazine-2,5-dione can be purified by recrystallization, extraction purification, adsorption treatment of activated carbon, silica, alumina, etc., and chromatographic methods such as silica gel column chromatography. However, no particular purification is performed, for example, the extraction solution itself or the residue after evaporation of the solvent may be subjected to the next step without particular purification.

(Step 5) Production of optically active 1-methyl-3-phenylpiperazine In this step, optically active 1-methyl is reduced by reducing optically active 1-methyl-3-phenylpiperazine-2,5-dione. -3-Phenylpiperazine or a salt thereof can be produced.

  The reduction is preferably performed using a reducing agent. The order of addition of the optically active 1-methyl-3-phenylpiperazine-2,5-dione and the reducing agent is not particularly limited. Usually, the optically active 1-methyl-3 is added to a reducing agent solution or suspension. -Phenylpiperazine-2,5-dione is added.

  Examples of the reducing agent include lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride, sodium borohydride, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex and the like.

  The amount of active hydrogen in the reducing agent is usually 5 to 50 equivalents, preferably 10 to 25 equivalents, per 1 mol amount of optically active 1-methyl-3-phenylpiperazine-2,5-dione or a salt thereof. . If the amount of active hydrogen in the reducing agent is less than 5 equivalents, the raw material may remain unreacted and the yield may be reduced. On the contrary, when it exceeds 50 equivalents, there is no improvement in yield corresponding to it and it is not economical.

  The reduction is usually performed in the presence of a solvent. Examples of the solvent include ether solvents such as THF, dimethoxyethane, diethoxymethane, dioxane, tert-butylmethyl ether, cyclopentylmethyl ether; toluene, xylene, heptane, Hydrocarbon solvents such as hexane; mixed solvents thereof and the like.

  The usage-amount of a solvent is 1-10L normally with respect to 1 mol amount of optically active 1-methyl-3-phenyl piperazine-2,5-dione or its salt, Preferably it is 2-7L. If the amount of the solvent used is less than 1 L, the stirring may not be sufficient. Conversely, if it exceeds 10 L, the reaction may be delayed, which is not preferable.

The reduction temperature is usually 0 to 100 ° C., preferably 25 to 70 ° C. When the reduction temperature is less than 0 ° C., the reduction rate is slow, and when it exceeds 100 ° C., by-products may be generated, which is not preferable. Although the reduction time depends on the reduction temperature, the amount of active hydrogen in the reducing agent, etc., it is usually 0.5 to 10 hours, preferably 1 to 5 hours.

  Isolation of the optically active 1-methyl-3-phenylpiperazine produced in this way is carried out by subjecting the reaction solution to post-treatment by a conventional method (for example, filtration, neutralization, extraction, washing with water, crystallization, distillation, etc.). It can be done by attaching. Optically active 1-methyl-3-phenylpiperazine can be purified by recrystallization, extraction purification, adsorption treatment of activated carbon, silica, alumina, etc., and chromatography methods such as silica gel column chromatography. Further, it can be purified by crystallization as a salt.

In the reactions of Steps 1 to 5, the steric configuration of the optically active compound is substantially retained. That is, if S form (L form) is used as optically active phenylglycine (Formula 2), (S) -1-methyl-3-phenylpiperazine can be produced, and R form (D form) is used. Then, (R) -1-methyl-3-phenylpiperazine can be produced, and an enantiomeric excess is preferably 95% ee or more, more preferably 99% ee or more. .

(Step 6) Production of optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine In this step, optically active 1-methyl-3-phenylpiperazine (formula 7) and 2-halogeno-3-cyanopyridine in the presence of a base to produce optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 8) Can be manufactured.

  Examples of 2-halogeno-3-cyanopyridine include 2-chloro-3-cyanopyridine and 2-bromo-3-cyanopyridine, and 2-chloro-3-cyanopyridine is preferable from the viewpoint of availability.

  The amount of 2-halogeno-3-cyanopyridine used is usually 1.0 to 2.0 mol, preferably 1., based on 1 mol of optically active 1-methyl-3-phenylpiperazine (Formula 7). The amount is 3 to 1.6 mol. If the amount of 2-halogeno-3-cyanopyridine used is less than 1.0 mol, the raw material may remain unreacted and the yield may be reduced. On the other hand, when the amount exceeds 2.0 mol, there is no improvement in yield corresponding to the amount, which is not economical.

  Examples of the base include organic bases such as triethylamine, trimethylamine, and tributylamine.

  The amount of the base used is usually 1.0 to 2.0 mol, preferably 1.2 to 1.6 mol, per 1 mol of optically active 1-methyl-3-phenylpiperazine (Formula 7). It is. If the amount of the base used is less than 1.0 mol, the raw material may remain unreacted and the yield may be reduced. On the other hand, when the amount exceeds 2.0 mol, there is no improvement in yield corresponding to the amount, which is not economical.

  The reaction is usually carried out in the presence of a solvent. Examples of the solvent include dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMI), and dimethyl sulfoxide (DMSO). A mixed solvent thereof and the like. Among these, DMF is preferable from the viewpoint of reaction time and economy.

  The amount of the solvent to be used is generally 0.1 to 2 L, preferably 0.2 to 1 L, relative to 1 mol of optically active 1-methyl-3-phenylpiperazine (Formula 7). If the amount of the solvent used is less than 0.1 L, the stirring may not be sufficient, whereas if it exceeds 2 L, the reaction may be delayed, which is not preferable.

  The reaction temperature is usually 100 to 150 ° C, preferably 120 to 140 ° C. If the reaction temperature is less than 100 ° C., the reaction rate becomes slow. Conversely, if the reaction temperature exceeds 150 ° C., a by-product may be generated, which is not preferable. The reaction time is usually 5 to 50 hours, preferably 8 to 20 hours, although it depends on the reaction temperature and the amount of each raw material used.

  When optically active 1-methyl-3-phenylpiperazine (formula 7) is used in the form of a salt, if the salt is not preferred for the reaction, it is better to liberate the salt in advance by adding a base. .

  Isolation of the optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 8) produced in this manner is carried out by subjecting the reaction solution to a post-treatment by a conventional method (for example, Filtration, neutralization, extraction, washing with water, crystallization, distillation, etc.). Moreover, it can refine | purify by chromatographic methods, such as recrystallization, extraction purification, adsorption processing of activated carbon, a silica, an alumina, etc., silica gel column chromatography. It can also be obtained as a salt with an acid such as succinic acid, but it is not particularly purified, for example, the extraction solution itself or the residue after evaporation of the solvent may be subjected to the next step without any particular purification. .

(Step 7) Production of optically active 1- (3-formyl-2-pyridyl) -4-methyl-2-phenylpiperazine In this step, optically active 1- (3-cyano-2-pyridyl) -4- Production of optically active 1- (3-formyl-2-pyridyl) -4-methyl-2-phenylpiperazine (Formula 9) by reducing methyl-2-phenylpiperazine (Formula 8) with a reducing agent. Can do.

  The order of addition of the optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 8) and the reducing agent is not particularly limited, but usually the optically active 1- ( A reducing agent is added to a solution of 3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine (Formula 8).

  The reducing agent is not particularly limited as long as it can reduce a cyano group to a formyl group, and examples thereof include diisobutylaluminum hydride, diisopropylaluminum hydride, and dihexylaluminum hydride. Among these, diisobutylaluminum hydride is preferable because it is easily available. The reducing agent is preferably used by dissolving it in an organic solvent (preferably toluene) in advance, and in particular, a toluene solution of diisobutylaluminum hydride is preferably used.

  The amount of the reducing agent used is usually 1.7 to 3.0 mol with respect to 1 mol of the optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 8). Amount, preferably 2.0-2.5 molar. If the amount of the reducing agent used is less than 1.7 mol, the raw material may remain unreacted and the yield may be reduced. On the other hand, when the amount exceeds 3.0 mol, there is no improvement in yield corresponding to the amount, which is not economical.

  The reduction is usually performed in the presence of a solvent. Examples of the solvent include ether solvents such as THF, dimethoxyethane, diethoxymethane, dioxane, tert-butylmethyl ether, cyclopentylmethyl ether; toluene, xylene, heptane, Hydrocarbon solvents such as hexane; mixed solvents thereof and the like. Of these, toluene is preferable from the viewpoints of reaction time and economy.

  The amount of the solvent used is usually 500 to 2000 parts by weight, preferably 1000 parts per 100 parts by weight of optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine (Formula 8). ˜1500 parts by weight. If the amount of the solvent used is less than 500 parts by weight, the stirring may not be sufficient, while if it exceeds 2000 parts by weight, the reaction may be delayed, which is not preferable.

  The reduction is preferably performed in an inert gas atmosphere such as nitrogen gas or argon gas.

  The reduction temperature is usually preferably from -70 to -10 ° C. The reduction time is usually 0.5 to 12 hours, preferably 1 to 3 hours, depending on the reduction temperature, the amount of reducing agent used, and the like.

  When optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 8) is used in the form of a salt, if the salt is not preferred for the reaction, a base is used. In addition, the salt should be liberated beforehand.

  Reduction of the optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine (Formula 8) can be stopped by adding, for example, a lower alcohol to the reaction solution. . As a lower alcohol, C1-C4 monohydric alcohols, such as ethanol, can be used conveniently. The amount of the lower alcohol is usually about 2 to 10 moles relative to 1 mole of the optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 8). .

  After the reduction reaction is completed, it is preferable to mix the resulting reaction mixture with water in order to decompose the reducing agent and to hydrolyze the produced imide to form an aldehyde. The amount of water is usually about 200 to 1000 parts by weight per 100 parts by weight of optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 8). preferable.

  Thereafter, if necessary, an aqueous alkaline solution can be added to the reaction mixture in order to dissolve the reducing agent remaining in the reaction mixture. Examples of the alkaline aqueous solution include an aqueous solution of an alkali metal hydroxide such as a sodium hydroxide aqueous solution and a potassium hydroxide aqueous solution.

  Next, the aqueous layer is separated from the reaction mixture, and a mineral acid such as sulfuric acid is added to the organic layer to make it acidic to about pH 1. Next, an aqueous alkali solution is added to make it alkaline, and the solution is separated.

  Isolation of the optically active 1- (3-formyl-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 9) produced in this manner is carried out by subjecting the reaction solution to a post-treatment by a conventional method (for example, Filtration, neutralization, extraction, washing with water, crystallization, distillation, etc.). Optically active 1- (3-formyl-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 9) is recrystallized, extracted and purified, activated carbon, silica, alumina and other adsorption treatment, silica gel column chromatography. For example, the extraction solution itself or the residue after evaporation of the solvent may be subjected to the next step without further purification. Examples of the salt of optically active 1- (3-formyl-2-pyridyl) -4-methyl-2-phenylpiperazine include, for example, optically active 1- (3-formyl-2-pyridyl) -4-methyl-2. -Phenyl piperazine succinate, hydrochloride, methanesulfonate and the like.

(Step 8) Production of optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine In this step, optically active 1- (3-formyl-2-pyridyl) -4 -Methyl-2-phenylpiperazine (Formula 9) is reduced with a reducing agent to produce optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine (Formula 10) can do.

  The order of addition of the optically active 1- (3-formyl-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 9) and the reducing agent is not particularly limited, but usually the optically active 1- ( A reducing agent is added (preferably dividedly added) to a solution of 3-formyl-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 9).

  The reducing agent is not particularly limited as long as it can reduce a formyl group to a hydroxymethyl group, and examples thereof include sodium borohydride, sodium cyanoborohydride, lithium borohydride and the like. Among these, sodium borohydride is preferable from the viewpoint of easy availability and economy.

  The amount of the reducing agent to be used is usually 1.5 to 3 mol, preferably 1 to 3 mol, preferably 1 mol of optically active 1- (3-formyl-pyridyl) -4-methyl-2-phenylpiperazine (formula 9). 2 to 2.5 molar amount. If the amount of the reducing agent used is less than 1.5 mol, the raw material may remain unreacted and the yield may be reduced. On the other hand, when the amount exceeds 3 mol, there is no improvement in yield corresponding to the amount, which is not economical.

  The reduction is usually performed in the presence of a solvent. Examples of the solvent include lower alcohols such as methanol and ethanol, water-containing solvents thereof, and two layers of a hydrophobic organic solvent such as toluene and ethyl acetate and water. It is possible to use a system solvent in which a phase transfer catalyst such as tetrabutylammonium bromide is present. Of these, methanol is preferable.

The amount of the solvent used is usually 400 to 2000 parts by weight, preferably 500 to 1000 parts per 100 parts by weight of optically active 1- (3-formyl-pyridyl) -4-methyl-2-phenylpiperazine (formula 9). Parts by weight. If the amount of the solvent used is less than 400 parts by weight, stirring may not be sufficient, while if it exceeds 2000 parts by weight, the reaction may be delayed, which is not preferable.
The reduction temperature is usually −10 to 50 ° C., preferably 0 to 10 ° C. If the reduction temperature is less than −10 ° C., the reduction rate is slow. Conversely, if the reduction temperature exceeds 50 ° C., by-products may be generated, which is not preferable. The reduction time is usually 0.5 to 5 hours, preferably 1 to 2 hours, although depending on the reduction temperature, the amount of reducing agent used, and the like.

  In addition, when optically active 1- (3-formyl-pyridyl) -4-methyl-2-phenylpiperazine (formula 9) is used in the form of a salt, if the salt is not preferred for the reaction, a base is added. It is preferable to liberate the salt in advance.

  Isolation of the optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 10) produced in this manner is carried out by subjecting the reaction solution to a post-treatment by a conventional method (for example, Filtration, neutralization, extraction, washing with water, crystallization, distillation, etc.). Further, optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 10) is recrystallized, extracted and purified, activated carbon, silica, alumina, etc. adsorption treatment, silica gel column chromatography. Although it can be purified by a chromatographic method such as chromatography, it may be subjected to the next step without any particular purification, for example, the extraction solution itself or the residue after evaporation of the solvent without any particular purification.

Production of optically active mirtazapine In this step, optically active mirtazapine is obtained by cyclization of optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine (formula 10). Can be manufactured.

  The cyclization method can be carried out in accordance with the methods described in Patent Document 1 and US Pat. No. 6,376,668.

In the reaction of each of the above steps, the configuration of the optically active compound is almost retained. That is, if S form (L form) is used as optically active 1-methyl-3-phenylpiperazine (formula 7), (S) -mirtazapine can be produced, and R form (D form) can be used. For example, (R) -mirtazapine can be produced, and an enantiomeric excess is preferably 95% ee or more, more preferably 99% ee or more.
The compound in the above step and the optically active mirtazapine may form a salt. Examples of the salt include alkali metals (eg, sodium, potassium, etc.); alkaline earth metals (eg, calcium, magnesium, etc.); bases such as organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, etc.) Salts and inorganic acids (eg hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid); organic acids (eg formic acid, acetic acid, oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, apples) Acid addition salts such as acid, succinic acid, tartaric acid, trifluoroacetic acid and the like.

EXAMPLES Next, although an Example is given and this invention is demonstrated concretely, this invention is not limited to these Examples at all.

Method from chloroacetyl chloride and (S) -phenylglycine Manufacturing scheme

(In the formula, the carbon atom indicated by * indicates an asymmetric carbon atom)

Example 1 (S) -N-Chloroacetylphenylglycine
(S) -phenylglycine (30.0 g, 0.199 mol) was suspended in water (50 ml), and an aqueous solution prepared by dissolving caustic soda (8.73 g, 0.218 mol) in water (50 ml) was added and dissolved. Chloracetyl chloride (33.63 g, 0.298 mol) and 40% aqueous sodium hydroxide solution (125 ml) were added dropwise simultaneously at 10 ° C. or lower and at a pH of 10-13. The mixture was washed with ethyl acetate (150 ml) under weak alkalinity (pH 9 to 10), and the aqueous layer was adjusted to pH 1.5 with concentrated hydrochloric acid and extracted with ethyl acetate (150 ml × 2). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain (S) -N-chloroacetylphenylglycine (45.08 g, quantitative) as a low melting solid.
¹ H-NMR (ppm, CDCl 3): δ 4.00 (m, 2 H, J = 10.5 Hz, CH ₂ ), 5.56 (d, 1 H, J = 6.8 Hz, CH), 7.25-7.70 (m, 5 H, aromatic ).

Example 2 (S) -1-Methyl-3-phenylpiperazine-2,5-dione
40% methylamine aqueous solution (2.0 g, 0.026 mol) was added to (S) -N-chloroacetylphenylglycine (1.00 g, 0.0044 mol), and the mixture was kept at 30 to 40 ° C. for 1.5 hours. Once, the aqueous methylamine solution was distilled off under reduced pressure, adsorbed onto an Amberlyst (Rohm & Haas) ion exchange resin column (15 ml), washed with water and eluted with 10% aqueous ammonia. The solvent was distilled off under reduced pressure to obtain a solid residue.

(S) -N-methylaminoacetylphenylglycine
¹ H-NMR (ppm, D ₂ O): δ 2.63 (S, 3H, NMe), 3.70-3.90 (m, 2H, CH ₂ ), 5.10 (S, 1H, CH), 7.20-7.40 (m, 5H, aromatic).

Thionyl chloride (8.90 g, 0.075 mol) was added to methanol (20 ml) at −10 ° C. or lower, and this was poured into the solid residue before stirring at room temperature for 2 hours. A part of the reaction solution was collected and analyzed.

(S) -N-methylaminoacetylphenylglycine methyl ester
¹ H-NMR (ppm, CDCl ₃ ): δ 2.52 (S, 3H, NMe), 3.48 (S, 2H, CH ₂ ), 3.73 (S, 3H, CO ₂ Me), 5.60 (d, 1H, J = 7.7Hz, CH), 7.30-7.40 (m, 5H, aromatic).

The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (15 ml) was added to the residue, and the mixture was extracted with THF (10 ml × 3). The solvent of the organic layer was distilled off under reduced pressure, and the residue was heated as it was at 60 to 70 ° C. for 3 hours. The crystals were washed with heptane-diethyl ether (1: 1, 10 ml) to obtain 0.40 g (yield 44.6%) of (S) -1-methyl-3-phenylpiperazine-2,5-dione.
(S) -N-methylaminoacetylphenylglycine methyl ester
¹ H-NMR (ppm, CDCl ₃ ): δ 2.95 (S, 3H, NMe), 3.92 and 4.11 (2d, 2H, J = 17.6 Hz, CH ₂ ), 5.10 (d, 1H, J = 2.8 Hz) , CH), 6.95 (brS, 1H, NH), 7.30-7.43 (m, 5H, aromatic).

Example 3 (S) -1-methyl-3-phenylpiperazine (S) -1-methyl-3-phenylpiperazine was added to a suspension of lithium aluminum hydride (0.24 g, 6.3 mmol) in THF (10 ml) under a nitrogen stream. -2,5-dione (0.26 g, 1.27 mmol) was added and then refluxed for 1.5 hours. The mixture was ice-cooled, ethyl acetate (5 ml), methanol (5 ml) and water (10 ml) were added, and the mixture was once evaporated under reduced pressure. Toluene (20 ml) and 10% aqueous sodium hydroxide solution (10 ml) were added, insoluble matter was filtered through celite, and the toluene layer was separated. Again, toluene (10 ml) was added and extracted, and the toluene layer was separated. When the solvent of the extraction layer was distilled off under reduced pressure, (S) -1-methyl-3-phenylpiperazine (0.209 g, 93.3%) was obtained ((S) :( R) = 96.8: 3.2 from chiral HPLC analysis).
(S) -1-Methyl-3-phenylpiperazine
¹ H-NMR (ppm, CDCl ₃ ): δ1.99 (t, 1H, J = 10.3Hz, CH), 2.14 (dt, 1H, J = 10.3and3.9Hz, CH), 2.31 (S, 3H, NMe ), 2.75-2.90 (m, 2H, CH 2), 3.00-3.15 (m, 2H, CH 2), 3.87 (dd, 1H, J = 10.3and2.4Hz, CH), 7.20-7.42 (m, 5H, aromatic).

Example 4 (S) -1-methyl-3-phenylpiperazine To a suspension of lithium aluminum hydride (0.46 g, 12.1 mmol) in THF (15 ml) under a nitrogen atmosphere was added (S) -1-methyl-3. -After adding phenylpiperazine-2,5-dione (0.5 g, 2.45 mmol), the mixture was refluxed for 1.5 hours. The mixture was ice-cooled, ethyl acetate (5 ml), methanol (5 ml) and water (10 ml) were added, and the solvent was once distilled off under reduced pressure. Toluene (20 ml) and 10% aqueous NaOH solution (10 ml) were added, and the mixture was filtered through Celite to remove insoluble matters, and the toluene layer was separated. The aqueous layer was extracted again with toluene (20 ml). The toluene layers were combined and the solvent was removed in vacuo to give the title compound oil (0.43 g, quantitative, chiral HPLC analysis (S) :( R) = 99.9: 0.1).

Example 5 (S) 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine succinate (S) -1-methyl-3-phenylpiperazine (S: R = 97.5: 2 .5) 2.4 g (12.5 mmol), N, N-dimethylformamide (4.5 g), 2.7 g (19.5 mmol) of 2-chloro-3-cyanopyridine, and triethylamine (1.9 g, 18. 8 mmol), and the mixture was stirred at 120 to 125 ° C. for 17 hours under a nitrogen stream. N, N-dimethylformaluminide was distilled off under reduced pressure at a bath temperature of 90 ° C., then cooled to 70 ° C., and 3.6 ml of water was introduced. The mixture was further cooled to 40 ° C., adjusted to pH 8.0 with 0.7 ml of 25% sodium hydroxide, and then extracted with 11 ml of ethyl acetate. After separation of the aqueous layer, the ethyl acetate layer was washed with 2.4 ml of 5% brine, and then 3.6 ml of methanol was introduced. 1.7 g of oxalic acid dihydrate was added in portions while keeping the temperature at 40 ° C. After confirming crystallization, the mixture was stirred for 1 hour, further cooled to 30 ° C., and stirred for 1 hour. The crystals were filtered, and the substance on the filter was washed with 7.7 ml of an ethyl acetate-methanol mixture (75:25). The obtained crystals were dried under reduced pressure at a bath temperature of 40 ° C. to give 3.2 g (yield 66. 7%) of the title compound was obtained.

HPLC conditions;
Daicel Chiralcel OD-H 250 × 4.6mm
n-hexane (0.1% diethylamine): 2-propanol (0.1% diethylamine) = 95: 5
0.5ml / min, 40 ° C, 254nm

Example 6 (S) -1- (3-Formyl-2-pyridyl) -4-methyl-2-phenylpiperazine Toluene 5 ml, water 3.5 ml, caustic potash 0.31 g (5.5 mmol) was charged and stirred. (S) -1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine oxalate (S form: R form = 96.53: 3.47) 1.0 g (2.6 mmol) ) And stirred at an outer bath of 25-30 ° C. for 1 hour. The toluene layer was separated by separation, washed with 5 ml of 5% brine, and the toluene solution was dried with 0.3 g of anhydrous magnesium sulfate (stirred at room temperature for 1 hour). Then, magnesium sulfate was filtered and washed with 5 ml of toluene to obtain a toluene solution of (S) -1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine free. This was charged into a 100 ml four-necked flask, cooled to −60 ° C. in a dry ice bath, and then 4 ml (6.1 mmol) of diisobutylaluminum hydride (DIBAL-H, manufactured by Wako Pure Chemical Industries, Ltd .: 25% strength toluene solution) in a nitrogen stream. ) Was dropped with a syringe over 7 minutes (−67 to −52.4 ° C.). The mixture was aged and stirred for 2 hours (−64 to −44.1 ° C.), sampled, and it was confirmed by HPLC that the reaction was almost complete.

  After the reaction, in order to decompose excess diisobutylaluminum hydride, 2 ml of ethanol was added dropwise while paying attention to foaming. Next, caustic soda water (caustic soda 0.85 g / water 5 ml) was added and stirred at 30 ° C. for 1 hour. The toluene layer was separated, and diluted sulfuric acid (sulfuric acid 0.42 g / water 5 ml) was added to the toluene layer. In addition, the mixture was stirred at 45 to 50 ° C. for 1 hour. After cooling to 25 ° C., caustic soda water (caustic soda 0.85 g / water 5 ml) was added and stirred for 10 minutes. After separation, the toluene layer was washed with 5 ml of water and dried over anhydrous magnesium sulfate 0.6 g. After removing magnesium sulfate by filtration, the bath temperature was set to 40 ° C., toluene was distilled off under reduced pressure with an evaporator, and the mixture was further swept at the same temperature for 1 hour using a vacuum pump to obtain 0.71 g of the title compound (yield). The rate was 91.8%, S-form: R-form = 96.2: 3.8).

In addition, R body / S body ratio was performed on the following HPLC analysis conditions.
Column: CHIRALCEL OD-H (0.46 cmφ × 25 cmL, mobile phase manufactured by Daicel Chemical Industries, Ltd. A liquid: 0.1% diethylamine-containing 2-propanol B liquid: 0.1% diethylamine-containing n-hexane flow rate A liquid: 0.025 ml / min
Liquid B: 0.475 ml / min (constant composition, constant flow rate)
Column temperature: 40 ° C
Wavelength: 254 nm

Example 7 (S) -1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine (S) -1- (3-formyl-2-pyridyl) obtained in Example 6 After dissolving 0.65 g (2.2 mmol) of -4-methyl-2-phenylpiperazine in 5.3 ml of methanol, the solution was cooled to 5 ° C. or less in an ice water bath. NaBH ₄ (Wako) 0.2 g (5.3 mmol) was added in portions over 30 minutes while maintaining 5 ° C. or lower, sampling for reaction check was performed, and the mixture was stirred for 30 minutes. After confirming the reaction by HPLC, 3.5 ml of water was added dropwise, and 1.7 ml of 35% hydrochloric acid was added dropwise over 10 minutes (foaming vigorously). After further stirring for 5 minutes, it was confirmed that it was acidic with a universal test paper, and then neutralized with sodium bicarbonate (required 0.7 g). Thereafter, the solution was concentrated at a bath temperature of 40 ° C. under reduced pressure using a rotary evaporator, 14 ml of toluene and 7 ml of water were added, and the mixture was dissolved by heating and stirring in a 40 ° C. bath. Toluene was separated, and the aqueous layer was further extracted with 14 ml of toluene twice, and the three toluene layers were combined. This toluene layer was washed with 3.5 ml of water, separated, and dried over 0.3 g of anhydrous magnesium sulfate (stirred at room temperature for 30 minutes). After removing magnesium sulfate by filtration, the pressure was reduced with a rotary evaporator at a bath temperature of 40 ° C. Toluene was distilled off to obtain 0.48 g of the title compound. Yield 73.3%, S-form: R-form = 99.93: 0.07 (however, R-form is a blade).

  The optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine thus obtained is optically active mirtazapine according to the method described in Patent Document 1 and US Pat. No. 6,376,668. Can lead to.

Claims (9)

A process for producing optically active N-methylaminoacetylphenylglycine, which comprises reacting optically active N-haloacetylphenylglycine with methylamine. The production method according to claim 1, wherein the optically active N-haloacetylphenylglycine is optically active N-chloroacetylphenylglycine. The manufacturing method in any one of Claims 1-2 whose compounds are all (S) bodies. A process for producing optically active N-methylaminoacetylphenylglycine methyl ester, comprising reacting optically active N-methylaminoacetylphenylglycine with thionyl chloride in methanol. The manufacturing method of Claim 4 whose compounds are all (S) bodies. A process for producing optically active 1- (3-hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine, which comprises the following steps:
(Step 1) Step of producing optically active N-chloroacetylphenylglycine by chloroacetylating optically active phenylglycine;
(Step 2) A step of reacting optically active N-chloroacetylphenylglycine with methylamine to produce optically active N-methylaminoacetylphenylglycine;
(Step 3) A step of reacting optically active N-methylaminoacetylphenylglycine with thionyl chloride in methanol to produce N-methylaminoacetylphenylglycine methyl ester;
(Step 4) a step of cyclizing optically active N-methylaminoacetylphenylglycine methyl ester to produce optically active 1-methyl-3-phenylpiperazine-2,5-dione;
(Step 5) A step of producing optically active 1-methyl-3-phenylpiperazine by reducing optically active 1-methyl-3-phenylpiperazine-2,5-dione with a metal hydride compound;
(Step 6) An optically active 1- (3-cyano-2-pyridyl) -4-methyl-2 is prepared by reacting optically active 1-methyl-3-phenylpiperazine with 2-chloro-3-cyanopyridine. -Manufacturing a phenylpiperazine;
(Step 7) Optically active 1- (3-cyano-2-pyridyl) -4-methyl-2-phenylpiperazine is reduced to give optically active 1- (3-formyl-2-pyridyl) -4-methyl. A step of producing 2-phenylpiperazine; and (Step 8) reduction of optically active 1- (3-formyl-2-pyridyl) -4-methyl-2-phenylpiperazine to give optically active 1- (3 -Hydroxymethyl-2-pyridyl) -4-methyl-2-phenylpiperazine. The manufacturing method of Claim 6 whose all compounds are (S) bodies. Optically active N-methylaminoacetylphenylglycine or a salt thereof. The compound according to claim 8, wherein the optically active N-methylaminoacetylphenylglycine or a salt thereof is (S) -N-methylaminoacetylphenylglycine or a salt thereof.