JP2007314426A - New method for producing 2-methylglycidyl ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing 2-methylglycidyl ester important as a synthetic intermediate for medicines and physiologically active substances, especially its optically active substance, in a high yield and economically. <P>SOLUTION: The method for producing 2-methylglycidyl ester comprises letting a basic reagent such as sodium hydroxide, potassium hydroxide, etc., act on a 3-halogeno-2-methyl-1,2-propanediol, performing an intramolecular ring closure to give 2-methylglycidol and reacting 2-methylglycidol with an acylating agent such as acetic anhydride, propionic anhydride, butyric anhydride, etc., in the presence of a base. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to 2-methylglycidyl ester important as a synthetic intermediate for pharmaceuticals and physiologically active substances and a method for producing an optically active substance thereof.

2-Methyl glycidyl ester is an important synthetic intermediate in the production of various pharmaceuticals. This 2-methylglycidyl ester has an asymmetric carbon and has optical isomerism.
In recent years, in the development of pharmaceuticals composed of optically active compounds, studies have been conducted on each optically active substance. That is, the establishment of a method for easily producing an optically active isomer of these series of compounds with high optical purity is a very important issue, but almost no method for producing optically active 2-methylglycidyl ester has been reported. ) Method by kinetic optical resolution of 2-methylglycidyl ester (see non-patent document 1), ii) Method by kinetic optical resolution of 2-methylglycidol (see non-patent document 2), iii) Methallyl ester Reaction by asymmetric epoxidation of (see Non-Patent Document 3) is known.
However, the methods i) and ii) have low selectivity, and are not efficient methods for producing high optical purity 2-methylglycidyl ester. In the method iii), the methallyl ester as a raw material needs to be prepared according to the target compound, and there is a problem in versatility.
J. Am. Chem. Soc., 1984, 106, 7250-7251. Tetrahedron Asymmetry, 1993, 4 (1), 85-90. J. Am. Chem. Soc., 1995, 117, 6412-6413.

  In solving the above-mentioned problems, the present invention provides a high yield from 3-halogeno-2-methyl-1,2-propanediol, and 3-halogeno-2-methyl-1,2-propanediol is an optically active substance. In this case, the object is to provide a method for producing 2-methylglycidyl ester without impairing its optical purity.

（式中、Ｘはハロゲン原子を意味する。）
で表される３−ハロゲノ−２−メチル−１，２−プロパンジオールに塩基性試剤を作用させ、分子内閉環させることにより、下記式（２）

で表される２−メチルグリシドールとし、次いで、下記式（３a）または（３b）

（式中、Ｒは炭素数１〜６のアルキル基を意味し、Ｙはハロゲン原子を意味する。）
で表されるアシル化剤と塩基存在下において反応させることを特徴とする、下記式（４）

（式中、Ｒは前掲と同じ基を意味する。）
で表される２−メチルグリシジルエステルの製造法に関する。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have made a basic agent act on 3-halogeno-2-methyl-1,2-propanediol to cause intramolecular cyclization, and then the presence of a base. It has been found that the target compound can be obtained efficiently by reacting with a lower acylating agent, and the present invention has been completed.
That is, the present invention

(In the formula, X means a halogen atom.)
A basic reagent is allowed to act on 3-halogeno-2-methyl-1,2-propanediol represented by the following formula (2):

2-methylglycidol represented by the following formula (3a) or (3b)

(In the formula, R means an alkyl group having 1 to 6 carbon atoms, and Y means a halogen atom.)
The reaction is carried out in the presence of a base with an acylating agent represented by the following formula (4):

(In the formula, R means the same group as described above.)
The manufacturing method of 2-methylglycidyl ester represented by these.

  According to the present invention, when 3-halogeno-2-methyl-1,2-propanediol is an optically active substance, the yield is high from 3-halogeno-2-methyl-1,2-propanediol. 2-methylglycidyl ester can be produced without impairing optical purity.

The present invention will be described in further detail.
A 2-methylglycidol represented by the formula (2) is obtained by an intramolecular cyclization reaction of 3-halogeno-2-methyl-1,2-propanediol represented by the general formula (1).

  The raw material 3-halogeno-2-methyl-1,2-propanediol represented by the general formula (1) may be obtained by any method. For example, racemic 3-chloro-2-methyl-1,2-propanediol in which X is a chlorine atom oxidizes methallyl chloride with peracetic acid or the like to methyl epichlorohydrin, and hydrates and cleaves it in the presence of an acid. It is well known. Further, the optically active substance is synthesized by, for example, synthesizing from dibutyl L-tartrate and β-methallyl alcohol (Japanese Patent Application Laid-Open No. 63-150234), or utilizing chiral resolution by microorganisms (Japanese Patent Application No. 2005-000116). Can be obtained according to

  Examples of the halogen atom represented by the substituent X of 3-halogeno-2-methyl-1,2-propanediol represented by the formula (1) include a chlorine atom, a bromine atom, and an iodine atom. Chlorine and bromine atoms.

  Specific examples of the 3-halogeno-2-methyl-1,2-propanediol (1) include 3-chloro-2-methyl-1,2-propanediol, 3-bromo-2-methyl-1,2 -Propanediol etc. are mentioned, and 3-chloro-2-methyl-1,2-propanediol is particularly preferably used.

  Basic reagents used include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, sodium methylate Alkali metal alcoholates such as sodium ethylate, sodium benzyl oxide, sodium phenoxide, potassium tert-butoxide, alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium amide, magnesium Alkali metal or alkaline earth metal amides such as amide, 1,1,3,3-tetramethylguanidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5. 4.0] -7- Amines such as ndecene are mentioned, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alcoholates such as sodium methylate, sodium ethylate and potassium tert-butoxide are more preferred. Is sodium hydroxide, potassium hydroxide, potassium tert-butoxide.

  The preferred amount of the basic reagent to be used is 0.5 to 5 equivalents relative to 3-halogeno-2-methyl-1,2-propanediol (1), more preferably 0.9 to 2. 0 equivalents.

  In addition, this reaction can use an additive as needed. Examples of additives that can be used include 4-dimethylaminopyridine, crown ethers such as 15-crown-5 and 18-crown-6, alkali metal iodides such as sodium iodide and potassium iodide, sodium bromide, odor A reagent such as an alkali metal bromide salt such as potassium halide can be used, and the reaction is accelerated by adding 0.1 to 10 mol%.

  Solvents that can be used include aqueous solvents, alcohol solvents such as methanol, ethanol, isopropanol, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl ether, and the like. Ether solvents, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and acetonitrile, chlorine solvents such as dichloromethane, chloroform and 1,2-dichloroethane, hydrocarbon solvents such as hexane, heptane, benzene and toluene, or These mixed solvents are mentioned. The amount of these solvents used is not particularly limited.

  The reaction temperature is usually from −80 ° C. to the reflux temperature of the solvent, preferably from −10 to 50 ° C. The reaction pressure is usually a normal pressure, but can be performed under pressure and reduced pressure as necessary.

  By acylation of 2-methylglycidol represented by formula (2), 2-methylglycidyl ester represented by general formula (4) is obtained.

  Acylating agents used in the acylation include acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride and other carboxylic acid anhydrides, acetyl chloride, acetyl bromide, propionyl chloride. And carboxylic acid halides such as butyryl chloride. Preferred acylating agents include butyryl chloride, acetic anhydride, butyric anhydride and the like.

  The amount of the acylating agent to be used is preferably 1.0 to 5.0 equivalents, more preferably 1.1 to 2 with respect to 3-halogeno-2-methyl-1,2-propanediol (1). 0.0 equivalents.

  Examples of the base that can be used include tertiary amines such as triethylamine, ethyldiisopropylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, picoline, lutidine, collidine, and preferably pyridine. . Pyridine can also be used as a solvent.

  The amount of the base used is preferably 1.0 to 6.0 equivalents, more preferably 1.1 to 2.5 equivalents, relative to 3-halogeno-2-methyl-1,2-propanediol (1). is there.

  This reaction is promoted by adding 0.1 to 10 mol% of 4-dimethylaminopyridine with respect to 3-halogeno-2-methyl-1,2-propanediol (1) as necessary. .

  Solvents that can be used include hydrocarbon solvents such as hexane, heptane, benzene, toluene, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, diethyl ether, diisopropyl ether, tetrahydrofuran, tert -Ether solvents such as butyl methyl ether and 1,4-dioxane, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, halogen solvents such as dichloromethane and 1,2-dichloroethane, and mixed solvents thereof. It is done. Preferred solvents are toluene, tert-butyl methyl ether, 1,2-dichloroethane. The amount of these solvents used is not particularly limited.

  The reaction temperature is usually from −80 ° C. to the reflux temperature of the solvent, preferably from −10 to 40 ° C.

  Although the present invention comprises two steps as described above, 2-methylglycidol obtained by the reaction in the first step can be directly subjected to the second step by adding an acylating agent without performing isolation and purification. In other words, one-pot operation is possible. In that case, the base added in the second step can be added in advance in the first step.

  After completion of the reaction, the solvent in the reaction solution is washed with basic water, washed with acid water, washed with water, distilled off under reduced pressure, the residue is extracted with an organic solvent, and the distilled solvent in the organic layer is distilled off under reduced pressure. The target product can be easily obtained by purification treatment such as distillation or silica gel column chromatography.

  When optically active 3-halogeno-2-methyl-1,2-propanediol is used as a raw material, no significant racemization occurs and the desired optically active 2-methylglycidyl ester is obtained.

EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to these Examples.
[Production Example 1]
100 ml (pH 7.0) of a medium composed of 10 g / L of peptone, 10 g / L of yeast extract, and 10 g / L of glycerin was placed in a 500 mL Erlenmeyer flask with a baffle and autoclaved at 121 ° C. for 15 minutes. Next, Pseudomonas sp.DS-SI-5 strain previously grown on the same nutrient medium plate was inoculated into one platinum loop and cultured aerobically at 30 ° C. for 24 hours. The obtained culture broth was centrifuged to collect the cells.
In the above Erlenmeyer flask, 100 mL of bacterial cells are suspended in 20 mM potassium phosphate buffer (pH 7.0), and 2.5% of racemic 3-chloro-2-methyl-1,2-propanediol is suspended in the suspension. (V / v) and 3.6% CaCO3 were added and reacted at 30 ° C. and 120 rpm for 48 hours. After completion of the reaction, the reaction solution was taken out and the cells were removed by centrifugation to obtain a supernatant. The supernatant was concentrated with an evaporator and extracted with ether. Subsequently, after dehydration with anhydrous magnesium sulfate, ether was removed under reduced pressure, and S form 3-chloro-2-methyl-1,2-propanediol (racemic 3-chloro-2-methyl-1,2- The residual ratio from propanediol was 40.9%, and the optical purity was 99% ee).

[Example 1]
Preparation of (R) -2-methylglycidyl acetate (4a) (S) -3-Chloro-2-methyl-1,2-propanediol 12.45 g (100 mmol), toluene 50 mL, pyridine 15.82 g (200 mmol) The mixture was ice-cooled, and potassium tert-butoxide (10.66 g, 95 mmol) was successively added so that the internal temperature did not exceed 10 ° C., and the mixture was stirred as it was for 1.5 hours under ice-cooling. ) Was added dropwise, and after stirring for 1 hour, 2.44 mg (0.2 mmol) of 4-dimethylaminopyridine was added and further stirred for 2.5 hours, and then twice with 40 mL of pure water and 39.5 g of 14% aqueous potassium carbonate solution. , Washed with 26.1 g of 14% hydrochloric acid and 33.2 g of pure water and concentrated to obtain 12.10 g of crude oil. The crude oil was purified by vacuum distillation, and 10.67 g (82.0%) of (R) -2-methylglycidyl acetate was 99% e.e. e. Obtained with an optical purity of

[Example 2]
Production of (R) -2-methylglycidyl butyrate (4b) (S) -3-chloro-2-methyl-1,2-propanediol 12.46 g (100 mmol), toluene 50 mL, pyridine 15.82 g (200 mmol) The mixture was ice-cooled, and potassium tert-butoxide (10.66 g, 95 mmol) was successively added so that the internal temperature did not exceed 10 ° C., and the mixture was stirred as it was for 2 hours under ice-cooling. Was added dropwise, and after stirring for 1 hour, 2.44 mg (0.2 mmol) of 4-dimethylaminopyridine was added and the mixture was further stirred for 2.5 hours, and then twice with 40 mL of pure water and 39.5 g of 14% aqueous potassium carbonate solution, It was washed with 26.1 g of 14% hydrochloric acid and 33.2 g of pure water and concentrated to obtain 15.45 g of crude oil. The crude oil was purified by vacuum distillation and 12.90 g (81.5%) of (R) -2-methylglycidyl butyrate was 99% e. e. Obtained with an optical purity of

[Example 3]
Production of (R) -2-methylglycidyl butyrate (4b) (S) -3-chloro-2-methyl-1,2-propanediol 12.46 g (100 mmol), toluene 45 mL, pyridine 15.82 g (200 mmol) The mixture was cooled on ice, 11.78 g (105 mmol) of potassium tert-butoxide was added so that the internal temperature did not exceed 15 ° C., and stirred for 2 hours, and 11.73 g (110 mmol) of butyryl chloride was added dropwise. After stirring for 2 hours, it was washed twice with 40 mL of pure water, 33.0 mL of 7% aqueous sodium hydrogen carbonate solution, 36.0 mL of 5% hydrochloric acid and 33 mL of pure water, and concentrated to obtain 16.13 g of crude oil. The crude oil was purified by vacuum distillation and 11.82 g (74.7%) of (R) -2-methylglycidyl butyrate was 99% e. e. Obtained with an optical purity of

Claims (5)

Following formula (1)

(In the formula, X means a halogen atom.)
A basic reagent is allowed to act on 3-halogeno-2-methyl-1,2-propanediol represented by the following formula (2):

2-methylglycidol represented by the following formula (3a) or (3b)

(In the formula, R means an alkyl group having 1 to 6 carbon atoms, and Y means a halogen atom.)
The reaction is carried out in the presence of a base with an acylating agent represented by the following formula (4):

(In the formula, R means the same group as described above.)
The manufacturing method of 2-methylglycidyl ester represented by these.   The process for producing 2-methylglycidyl ester according to claim 1, wherein 3-halogeno-2-methyl-1,2-propanediol is 3-chloro-2-methyl-1,2-propanediol.   The method for producing a 2-methylglycidyl ester according to claim 1 or 2, wherein the acylating agent is at least one selected from the group consisting of acetic anhydride, propionic anhydride, and butyric anhydride.   The method for producing a 2-methylglycidyl ester according to claim 1 or 2, wherein the acylating agent is at least one selected from the group consisting of acetyl chloride, propionyl chloride, and butyryl chloride.   The process for producing an optically active 2-methylglycidyl ester according to any one of claims 1 to 4, wherein 2-methyl-1,2-propanediol is an optically active substance.