JP2017137262A - Method for producing optically active dihydrothiazolecarboxylic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an optically active dihydrothiazolecarboxylic acid derivative, useful as a pharmaceutical, by a short process without using a reagent having genetic toxicity.SOLUTION: The method for producing an optically active dihydrothiazolecarboxylic acid derivative represented by formula (4) comprises: producing an optically active dihydrothiazole ester derivative by reacting (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid and a glycol monomethyl ether derivative in the presence of a base; and hydrolyzing the same. This is a production method of a dihydrothiazolecarboxylic acid derivative, useful as a pharmaceutical, which enables production of the same by a short process without using a reagent having genetic toxicity and reduces by-production of impurities.SELECTED DRAWING: None

Description

  The present invention relates to an industrially suitable method for producing optically active dihydrothiazole carboxylic acid derivatives useful as pharmaceuticals.

  The following methods are known as methods for producing optically active dihydrothiazole carboxylic acid derivatives.

  Non-Patent Document 1 describes (S) -4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazolecarboxylic acid and isopropyl iodide in the presence of diisopropylethylamine as N, N. -Isopropyl (S) -2- (2,4-dihydroxyphenyl) -4,5-dihydro-4-methyl-4-thiazolecarboxylate is prepared by reaction in dimethylformamide. Subsequently, this is condensed with tri (ethylene glycol) monomethyl ether using diisopropyl azodicarboxylate and triphenylphosphine, and finally isopropyl ester is alkali-hydrolyzed to produce an optically active dihydrothiazole carboxylic acid derivative. Is described.

  Patent Document 1 discloses that (S) -4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazolecarboxylic acid is ethyl esterified with ethyl iodide, (S) -4,5-dihydro-2- [2-hydroxy-4- (3,6,9-trimethyl) by reacting tri (ethylene glycol) monomethyl ether of tosylate with potassium carbonate under acetone reflux conditions. Oxydecyloxy) phenyl] -4-methyl-4-thiazolecarboxylate ethyl ester is prepared. Subsequently, a method for producing an optically active dihydrothiazole carboxylic acid derivative by hydrolysis with aqueous sodium hydroxide in methanol is described.

International Publication No. 2008/115433

Raymond J.M. Bergeron (University of Florida) et al. Med. Chem. 2006, 49, 2772-2783.

  None of the methods described in the background art is suitable for production of pharmaceuticals in that a low-boiling alkyl halide having mutagenicity and suspected carcinogenicity is used, and (S) -4, Three steps are required to produce the optically active dihydrothiazole carboxylic acid derivative which is the target product from 5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazole carboxylic acid.

  As a result of intensive studies, the present inventors use a low-boiling alkyl halide from (S) -4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazolecarboxylic acid. Instead, a method for producing an optically active dihydrothiazolecarboxylic acid derivative, which is the target product, was developed in two steps.

  That is, the present invention provides the following formula (1):

(S) -4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazolecarboxylic acid represented by the following formula (2);

(Wherein X represents a leaving group, n represents an integer of 1 to 5), and a glycol monomethyl ether derivative represented by the following formula (3) is reacted in the presence of a base:

(Wherein n represents an integer of 1 to 5), wherein an optically active dihydrothiazole ester derivative represented by the following formula (4) is produced:

(Wherein, n represents an integer of 1 to 5) is a method for producing an optically active dihydrothiazole carboxylic acid derivative.
The present invention also provides the following formula (3);

(Wherein n represents an integer of 1 to 5) and is also an optically active dihydrothiazole ester derivative.

  According to the present invention, an optically active dihydrothiazole carboxylic acid derivative useful as a pharmaceutical can be produced in a short process without using a genotoxic reagent. Further, according to the present invention, impurity by-products can be significantly reduced.

The method according to the present invention will be described in detail below. First, the raw materials, intermediate products, and target products used in the present invention will be described.
(S) -4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazolecarboxylic acid, which is a raw material of the present invention, has the following formula (1);

It is represented by As a method for producing the compound (1), for example, the method described in International Publication No. 2003/097582 may be followed. Specifically, (S) -2-methylcysteine hydrochloride, 2,4-dihydroxybenzonitrile, and triethylamine are reacted under ethanol reflux conditions and acidified in water to obtain a target solid. it can.

  Next, the glycol monomethyl ether derivative as another raw material has the following formula (2):

It is represented by Here, X represents a leaving group. Specifically, for example, halogen atoms such as chlorine atom, bromine atom and iodine atom; methanesulfonyloxy group, ethanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, p-nitrobenzenesulfonyloxy group, trifluoromethane Examples thereof include a sulfonyloxy group such as a sulfonyloxy group. Preferred are methanesulfonyloxy groups, ethanesulfonyloxy groups, benzenesulfonyloxy groups, p-toluenesulfonyloxy groups, p-nitrobenzenesulfonyloxy groups, sulfonylmethane groups such as trifluoromethanesulfonyloxy groups, and more preferably methane A sulfonyloxy group or a p-toluenesulfonyloxy group. Here, n represents an integer of 1 to 5, preferably 2 or 3, and more preferably 3. Examples of the method for producing the compound (2) include J.M. Am. Chem. Soc. 2012, 134 (45), 18809-18815. May be followed. Specifically, p-toluenesulfonic acid triethylene glycol monomethyl ether can be obtained by reacting triethylene glycol monomethyl ether, potassium hydroxide, and p-toluenesulfonyl chloride in methylene chloride.
The optically active dihydrothiazole ester derivative which is an intermediate product of the present invention has the following formula (3):

And n is the same as described above. The compound (3) is a novel compound not described in any literature.

  The optically active dihydrothiazole carboxylic acid derivative which is the target product of the present invention has the following formula (4);

And n is the same as described above.

Next, the manufacturing method of this invention is demonstrated. First, (S) -4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazolecarboxylic acid represented by the formula (1) and the formula (2). The glycol monomethyl ether derivative is reacted in the presence of a base to produce an optically active dihydrothiazole ester derivative represented by the above formula (3).

  The amount of the compound (2) used is preferably 1 to 10 equivalents, more preferably 2 to 5 equivalents, relative to the compound (1).

  Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; lithium carbonate, sodium carbonate Alkali metal carbonates such as potassium carbonate and cesium carbonate; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium methoxide; Alkali metal alkoxides such as sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; trimethylamine, triethyl Amine, tributylamine, diisopropylethylamine, N- methylpyrrolidine, N- methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine, quinoline, and the like amine imidazole and the like. 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. Preferred are alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and more preferred are sodium carbonate and potassium carbonate. The amount of the base used is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the compound (1).

  The solvent in this step is not particularly limited as long as it does not affect the reaction. Specifically, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and ethylene glycol are used. System solvents; ether solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile and propionitrile; ethyl acetate, n-propyl acetate, Ester solvents such as isopropyl acetate; Aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and methylcyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and mesitylene Solvents; Ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; Halogen solvents such as methylene chloride and 1,2-dichloroethane; Sulfoxide solvents such as dimethyl sulfoxide; N, N-dimethylformamide, N, N-dimethylacetamide Amide solvents such as N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-methyl-ε-caprolactam and hexamethylphosphoramide; urea systems such as dimethylpropylene urea Solvent: Phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide can be 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. Preferred alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol; tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether Ether solvents such as acetonitrile; nitrile solvents such as acetonitrile and propionitrile; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylacetamide Amide solvents such as N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-methyl-ε-caprolactam, hexamethylphosphoramide More preferably methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, N, N- dimethylformamide, N, an N- dimethylacetamide, particularly preferably acetone, or acetonitrile.

  If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore the upper limit is preferably 100 times weight, more preferably 50 times weight, relative to the compound (1). Particularly preferred is 20 times the weight. The lower limit is preferably 0.1 times the weight of the compound (1), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.

  The reaction temperature in this reaction is not particularly limited and may be set as appropriate. However, in order to reduce the production of by-products, the upper limit is preferably 150 ° C., more preferably 120 ° C., and particularly preferably 90 ° C. The lower limit is preferably −50 ° C., more preferably −20 ° C., and particularly preferably 10 ° C.

  The reaction time in this reaction is not particularly limited and may be appropriately set. However, the upper limit is preferably 300 hours, more preferably 200 hours, and particularly preferably 100 hours. The lower limit is preferably 0.1 hour, more preferably 1 hour, and particularly preferably 3 hours.

  There is no restriction | limiting in particular about the mixing order of the said compound (1) of this process, the said compound (2), a base, and a solvent.

  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, water is added to the reaction solution after completion of the reaction, and an extraction operation is performed by adding a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like. 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 obtained in this way has sufficient purity that can be used in the subsequent steps. However, in order to further increase the purity, the target product is obtained by a general purification method such as crystallization, fractional distillation, column chromatography or the like. Purity may be increased.

  Subsequently, the compound (3) is hydrolyzed to produce an optically active dihydrothiazolecarboxylic acid derivative represented by the formula (4).

  The hydrolysis method may be either acid hydrolysis or alkaline hydrolysis, preferably alkaline hydrolysis. The alkali is preferably lithium hydroxide, sodium hydroxide, or potassium hydroxide, and more preferably sodium hydroxide.

  The amount of the alkali used is preferably 0.1 to 50 equivalents, more preferably 1 to 30 equivalents, and particularly preferably 3 to 20 equivalents with respect to the compound (3).

  The amount of water used for the hydrolysis is preferably 100 times the weight, more preferably 50 times the weight, and particularly preferably 20 times the weight of the compound (3). The lower limit is preferably 0.1 times the weight of the compound (1), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.

  In order to secure the fluidity of the reaction and accelerate the reaction, an auxiliary solvent may be added. The auxiliary solvent is not particularly limited as long as it does not affect the reaction. Specifically, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and ethylene glycol are used. System solvents; ether solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile and propionitrile; ethyl acetate, n-propyl acetate, Ester solvents such as isopropyl acetate; Aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and methylcyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and mesitylene Solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; Halogen solvents such as methylene chloride and 1,2-dichloroethane; Sulfoxide solvents such as dimethyl sulfoxide; N, N-dimethylformamide and N, N-dimethyl Amide solvents such as acetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-methyl-ε-caprolactam, hexamethylphosphoramide; urea such as dimethylpropylene urea Solvents such as phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide can be 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. Preferred are alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol, and more preferred is methanol, ethanol, or isopropanol.

  If the amount of the auxiliary solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore the upper limit is preferably 100 times weight, more preferably 50 times weight, relative to the compound (3). And particularly preferably 20 times the weight. The lower limit is preferably 0.1 times the weight of the compound (3), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.

  The reaction temperature in this reaction is not particularly limited and may be set as appropriate. However, in order to reduce the production of by-products, the upper limit is preferably 120 ° C., more preferably 90 ° C., and particularly preferably 60 ° C. The lower limit is preferably −50 ° C., more preferably −30 ° C., and particularly preferably −10 ° C.

  The reaction time in this reaction is not particularly limited and may be set as appropriate. The upper limit is preferably 200 hours, more preferably 100 hours, and particularly preferably 50 hours. The lower limit is preferably 0.1 hour, more preferably 1 hour, and particularly preferably 3 hours.

  There is no restriction | limiting in particular about the mixing order of the said compound (3) of this process, an alkali, water, and an auxiliary | assistant solvent.

  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, water is added to the reaction solution after completion of the reaction, and the pH is adjusted to 3 or less with an acid such as hydrochloric acid, sulfuric acid or acetic acid, and then a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene or hexane is added. To perform 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 obtained in this way has sufficient purity that can be used in the subsequent steps. However, in order to further increase the purity, the target product is obtained by a general purification method such as crystallization, fractional distillation, column chromatography or the like. Purity may be increased.

In addition, the optically active dihydrothiazole carboxylic acid derivative represented by the above formula (4) produced according to the method described in Patent Document 1 includes the following formula (5);

(Wherein n represents an integer of 1 to 5). Since these impurities are very similar in physical properties to the product, it is difficult to remove them, and how to suppress by-products in the reaction process is an important point. According to the present invention, the amount of the by-product of the impurity (5) is remarkably reduced, so that the removal is easy, which is a great merit in producing a high-purity pharmaceutical product. The reason why the by-product of impurities decreases is that, in the process of producing the compound (3), the compound (3) is sterically complicated with respect to the compound (Ethyl ester) of Patent Document 1, so It is mentioned that it is further difficult to react with the compound (2).

  As described above, according to the present invention, an optically active dihydrothiazole carboxylic acid derivative useful as a pharmaceutical can be produced in a short process without using a genotoxic reagent. Further, according to the present invention, impurity by-products can be significantly reduced.

  Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 (S) -4,5-dihydro-2- [2-hydroxy-4- (3,6,9-trioxadecyloxy) phenyl] -4-methyl-4-thiazolecarboxylic acid 3, Preparation of 6,9-trioxadecyl (S) -4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazolecarboxylic acid (1.287 g, 98.4% by weight, 5 mmol), potassium carbonate (1.659 g, 12 mmol), p-toluenesulfonic acid triethylene glycol monomethyl ether (3.900 g, 89.8 wt%, 11 mmol), and acetone 40 mL are stirred for 48 hours under reflux conditions. did. After adding 20 mL of water, acetone was distilled off under reduced pressure, and 30 mL of ethyl acetate was added to the residue for extraction. The organic layer was washed twice with 10 mL of water and concentrated under reduced pressure to give the title compound as a brown oil (2.8573 g, 81.1 wt%, yield 85%).
¹ H NMR (CDCl ₃ ): δ 1.67 (s, 3H), 3.20 (d, 1H), 3.37 (s, 3H), 3.38 (s, 3H), 3.5-3. 8 (m, 19H), 3.8-3.9 (m, 2H), 4.14 (m, 2H), 4,44 (m, 2H), 6.48 (dd, 2H), 7.29 (D, 1H)

Example 2 Production of (S) -4,5-dihydro-2- [2-hydroxy-4- (3,6,9-trioxadecyloxy) phenyl] -4-methyl-4-thiazolecarboxylic acid (S) -4,5-dihydro-2- [2-hydroxy-4- (3,6,9-trioxadecyloxy) phenyl] -4-methyl-4-thiazolecarboxylic acid 3 prepared in Example 1 , 6,9-trioxadecyl (2.875 g, 81.1 wt%, 4.25 mmol), methanol 50 mL, 48 wt% aqueous sodium hydroxide solution (3.542 g, 42.5 mmol) at 25 ° C. After stirring for 16 hours, methanol was distilled off under reduced pressure. To the obtained brown liquid (10.65 g), 30 mL of saturated brine was added and washed with 30 mL of methyl tert-butyl ether. Concentrated hydrochloric acid was added to the aqueous layer to adjust to pH 2, followed by extraction with 30 mL of ethyl acetate three times. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (2.3241 g, 68.0 wt%, yield 94%). This includes 0 (S) -4,5-dihydro-2- [2,4-bis (3,6,9-trioxadecyloxy) phenyl] -4-methyl-4-thiazolecarboxylic acid as an impurity. Contained 2%. Further, this oily substance was purified by silica gel column chromatography to obtain the title compound as a yellow oily substance (1.0747 g, 91.0% by weight, yield 58%).
¹ H NMR (D ₂ O): δ 1.76 (s, 3S), 3.35 (s, 3H), 3.54-3.61 (m, 3H), 3.64-3.72 (m, 4H), 3.74-3.78 (m, 2H), 3.90-3.94 (m, 2H), 3.96 (d, 1H), 4.25-4.29 (m, 2H) 6.53 (d, 1H), 6.64 (dd, 1H), 7.61 (d, 1H)

Comparative Example 1 (S) -4,5-dihydro-2- [2-hydroxy-4- (3,6,9-trioxadecyloxy) phenyl] -4-methyl-4-thiazolecarboxylic acid (S ) -4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazolecarboxylic acid (3.014 g, 98.4 wt%, 11.7 mmol), dimethylformamide 30 mL, iodinated A solution consisting of ethyl (3.287 g, 21.1 mmol) and diisopropylethylamine (2.725 g, 21.1 mmol) was stirred at 25 ° C. for 24 hours. 30 mL of water and 60 mL of ethyl acetate were added, and after adjusting to pH 4 with concentrated hydrochloric acid, the aqueous layer was separated. The organic layer was further washed twice with 20 mL of water, and concentrated under reduced pressure to give ethyl (S) -4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazolecarboxylate as reddish brown Obtained as an oil (4.0642 g, yield quantitative).

  From this oil (11.7 mmol), potassium carbonate (1.990 g, 14.4 mmol), p-toluenesulfonic acid triethylene glycol monomethyl ether (4.680 g, 89.8 wt%, 13.2 mmol), acetone from 60 mL The resulting solution was stirred under reflux conditions for 20 hours. 30 mL of water was added to make a homogeneous solution, and acetone was distilled off under reduced pressure. Then, concentrated hydrochloric acid was added to the residue to adjust to pH 4. Extraction was performed by adding 60 mL of toluene, and the organic layer was washed twice with 30 mL of water and concentrated under reduced pressure to give (S) -4,5-dihydro-2- [2-hydroxy-4- (3,6,9-trio). Ethyl oxadecyloxy) phenyl] -4-methyl-4-thiazolecarboxylate was obtained as a light brown oil (5.4493 g, 78.4 wt%, yield 83%).

  A solution consisting of this oily substance (10 mmol), 100 mL of methanol, and 48 wt% aqueous sodium hydroxide solution (8.333 g, 100 mmol) was stirred at 25 ° C. for 16 hours, and then methanol was distilled off under reduced pressure. To the obtained brown liquid (29.28 g), 50 mL of saturated brine was added and washed with 50 mL of methyl tert-butyl ether. Concentrated hydrochloric acid was added to the aqueous layer to adjust to pH 2, followed by extraction twice with 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (4.4276 g, 76.7 wt%, yield 85%). This includes 6 (S) -4,5-dihydro-2- [2,4-bis (3,6,9-trioxadecyloxy) phenyl] -4-methyl-4-thiazolecarboxylic acid as an impurity. Contained 4%.

Example 3 (S) -4,5-dihydro-2- [2-hydroxy-4- (3,6,9-trioxadecyloxy) phenyl] -4-methyl-4-thiazolecarboxylic acid 3, Preparation of 6,9-trioxadecyl (S) -4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazolecarboxylic acid (1.287 g, 98.4% by weight, 5 mmol), potassium carbonate (1.659 g, 12 mmol), diethylene glycol (2-bromoethyl) methyl ether (2.498 g, 11 mmol), and acetone 40 mL were stirred for 48 hours under reflux conditions. After adding 20 mL of water, acetone was distilled off under reduced pressure, and 30 mL of ethyl acetate was added to the residue for extraction. The organic layer was washed twice with 10 mL of water and concentrated under reduced pressure to give the title compound as a pale yellow oil (2.3888 g, 81.9 wt%, yield 72%).

Example 4 Production of (S) -4,5-dihydro-2- [2-hydroxy-4- (3,6,9-trioxadecyloxy) phenyl] -4-methyl-4-thiazolecarboxylic acid (S) -4,5-dihydro-2- [2-hydroxy-4- (3,6,9-trioxadecyloxy) phenyl] -4-methyl-4-thiazolecarboxylic acid 3 prepared in Example 3 , 6,9-trioxadecyl (2.399 g, 81.9 wt%, 4.25 mmol), methanol 50 mL, 48 wt% aqueous sodium hydroxide solution (3.542 g, 42.5 mmol) at 25 ° C. After stirring for 16 hours, methanol was distilled off under reduced pressure. To the obtained pale yellow liquid (7.56 g), 30 mL of saturated brine was added and washed with 30 mL of methyl tert-butyl ether. Concentrated hydrochloric acid was added to the aqueous layer to adjust to pH 2, followed by extraction with 30 mL of ethyl acetate three times. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (1.8502 g, 71.4 wt%, yield 92%). This includes 0 (S) -4,5-dihydro-2- [2,4-bis (3,6,9-trioxadecyloxy) phenyl] -4-methyl-4-thiazolecarboxylic acid as an impurity. Contained 2%.

Claims (5)

Following formula (1);

(S) -4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methyl-4-thiazolecarboxylic acid represented by the following formula (2);

(Wherein X represents a leaving group, n represents an integer of 1 to 4), and a glycol monomethyl ether derivative represented by the following formula (3) is reacted in the presence of a base:

(Wherein n represents an integer of 1 to 5), wherein an optically active dihydrothiazole ester derivative represented by the following formula (4) is produced:

(In the formula, n represents an integer of 1 to 5.) A method for producing an optically active dihydrothiazolecarboxylic acid derivative represented by:   The production method according to claim 1, wherein n is 3.   The production method according to claim 1 or 2, wherein X is a methanesulfonyloxy group or a p-toluenesulfonyloxy group. Following formula (3);

(Wherein n represents an integer of 1 to 5), an optically active dihydrothiazole ester derivative. The optically active dihydrothiazole ester derivative according to claim 4, wherein n is 3.