CN111099993B

CN111099993B - Preparation method of (S) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid

Info

Publication number: CN111099993B
Application number: CN201911402651.2A
Authority: CN
Inventors: 陈刚胜; 张晓瑜; 李佳
Original assignee: Changzhou Hengbang Pharmaceutical Co ltd; Jiangsu Hansoh Pharmaceutical Group Co Ltd
Current assignee: Changzhou Hengbang Pharmaceutical Co ltd; Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority date: 2019-12-30
Filing date: 2019-12-30
Publication date: 2022-03-29
Anticipated expiration: 2039-12-30
Also published as: CN111099993A

Abstract

The invention discloses a preparation method of (S) -2-hydroxy-3-methoxyl-3, 3-diphenyl propionic acid, and relates to the field of drug synthesis. The method comprises the steps of Resolving (RS) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid by using a resolving reagent (1S, 2S) -2-amino-1- (4-nitrophenyl) propane-1, 3-diol, cooling and crystallizing, collecting solids to obtain salts of S configuration diastereoisomers, adding water to the salts of S configuration diastereoisomers for redissolving, then acidifying, extracting, drying, concentrating and recrystallizing to obtain the (S) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid with high optical purity. The method uses the cheap and easily-obtained resolving agent with good safety, has the quality yield of more than 45 percent while reducing the cost, can be amplified to large-scale industrial production, and has good industrial prospect.

Description

Preparation method of (S) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid

Technical Field

The invention relates to the field of drug synthesis, in particular to a preparation method of (S) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid.

Background

Pulmonary hypertension is a malignant disease in which the body functions are extremely failing. Ambrisentan (Ambrisentan) has a chemical name of (+) - (2S) -2- [ (4, 6-dimethylpyrimidin-2-yl) -oxy ] -3-methoxy-3, 3-diphenyl propionic acid (the structural formula of which is shown in formula I), is an endothelin-1 (endothelin-1, ET-1) receptor antagonist, is clinically used for treating pulmonary hypertension, is developed by American Myogen biopharmaceutical company, is approved to be marketed by the American FDA in 6 months in 2007 (the trade name is Letairis), and is marketed in China in 2011 (the trade name is Van Ruike). Ambrisentan has been recommended by WHO at present as a first-line clinical drug for treating pulmonary hypertension patients with grade II and grade III pulmonary hypertension, and the market development potential is huge.

At present, most of the drug is synthesized by a 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid racemate intermediate, the intermediate is split to obtain a (S) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid monomer, and then the monomer reacts with 4, 6-dimethyl-2-methylsulfonyl pyrimidine to obtain ambrisentan. The intermediate resolution is a key step for synthesizing ambrisentan.

Chinese patent CN95195655.8 describes the synthesis of ambrisentan, which includes the synthesis of (S) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid. The method described in the patent comprises the steps of carrying out ring opening and hydrolysis on 3, 3-diphenyl-2, 3-epoxy propionate, adjusting the pH value of a reaction mixture to be acidic, extracting the reaction mixture by using an organic solvent to obtain 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid, recrystallizing the reaction mixture to improve the purity, and then using sodium methoxide as an acid-binding agent to carry out resolution by using L-proline methyl ester hydrochloride to obtain S-2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid.

The splitting route method is a method which is publicly used in the current pharmaceutical industry, but has the following defects of

(1) Since the unwanted salt of R configuration is precipitated in solid form during the resolution process, and the target salt of S configuration is dissolved in the filtrate, pH adjustment and extraction operations can introduce more impurities into the product.

(2) In order to ensure that the S-2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid reaches the quality standard, the raw material 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid needs to be recrystallized and purified for multiple times until the raw material can be used according to the requirements, so that the working period is long and the yield is low;

(3) an acid-binding agent (such as sodium methoxide) is required to be added in the resolution reaction to neutralize hydrochloric acid in the L-proline methyl ester hydrochloride, so that the production cost is increased, waste salt is difficult to remove, impurities are easy to form and precipitate together with the product, and the product purity is reduced.

The skilled worker is also working on a number of chemical resolving agents for the chiral resolution of 2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid. However, the resolving reagents still have the problems that the L-proline methyl ester has no ultraviolet absorption, is difficult to detect and is not beneficial to product quality control and recycling of the resolving reagents; the (S) -1- (4-nitrophenyl) ethylamine or the hydrochloride thereof has unstable property and high price, thereby increasing the production cost and the difficulty of quality control; the (S) -1- (4-chlorphenyl) ethylamine has limited resources and high price in China, needs mass import and is not beneficial to industrial production; l-phenylglycinamide is also costly. In addition, it is reported in US6559338 that (S) -2-hydroxypropionic acid derivatives and resolving agents such as methyl L-proline or (S) -1- (4-nitrophenyl) ethylamine are difficult to crystallize when the process is scaled up to 100kg, and a complicated process is required to achieve high chiral purity. Therefore, the chiral resolution of 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid is only a laboratory pilot plant and further research is needed to determine whether the further industrial production and application can be achieved.

Disclosure of Invention

In order to solve the technical problems and overcome the defects in amplification production, the invention provides a method for preparing single-configuration (S) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid by using (1S, 2S) -2-amino-1- (4-nitrophenyl) propane-1, 3-diol as a resolution reagent, and the method is simple and safe to operate, has very high purity of the obtained product, and simultaneously has low cost and high yield.

The invention is realized by the following technical scheme

A preparation method of (S) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid comprises the following steps:

(1) carrying out resolution reaction on a raw material (RS) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid and a resolution reagent (1S, 2S) -2-amino-1- (4-nitrophenyl) propane-1, 3-diol in a solvent to obtain a composite salt of two diastereomers;

(2) separating the two diastereomeric complex salts to obtain the S configuration diastereomeric salt;

(3) and (3) removing the resolving agent in the S configuration diastereoisomer salt to obtain the (S) -2-hydroxy-3-methoxyl-3, 3-diphenyl propionic acid with high optical purity.

Further, the molar ratio of the raw material to the resolving agent in the step (1) is 1: 1-1: 1.5, and the preferred molar ratio is 1: 1.1.

Further, the mass volume ratio of the raw materials to the solvent in the step (1) is 1: 60-1: 240 g/ml.

Further, the solvent in the step (1) is a mixture of acetonitrile and acetone.

Preferably, the volume ratio of the acetonitrile to the acetone is 5: 1-12: 1, and more preferably 8: 1.

Further, the specific operation of the step (1) is to dissolve the raw material into a solvent, then add a resolving agent, and perform the resolving reaction under stirring conditions.

Further, the temperature of the resolution reaction is controlled to be 20-50 ℃, and preferably 30-40 ℃.

Further, the stirring time is 2-8 hours, preferably 3-5 hours.

Further, the separation method in the step (2) is cooling crystallization.

Further, the cooling crystallization temperature is-20 ℃ to-5 ℃, and is preferably-10 ℃.

Further, the method for removing the resolution reagent in the step (3) is to dissolve the salt of the S configuration diastereoisomer by adding water, adjust the pH value of the solution to acidity, add an organic solvent for extraction, dry, concentrate and recover the solvent, and recrystallize.

Preferably, the organic solvent used for the extraction in step (3) includes ethyl acetate, tetrahydrofuran, n-butanol, methyl t-butyl ether or dimethylformamide.

Preferably, the pH value of the solution is adjusted to 1-5, preferably 2-3.

The method for preparing (S) -2-hydroxy-3-methoxyl-3, 3-diphenyl propionic acid comprises the following steps:

(1) mixing an acetonitrile/acetone solution of a racemic raw material (2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid) with (1S, 2S) -2-amino-1- (4-nitrophenyl) propane-1, 3-diol to obtain a solution in which an (R, S) -diastereomer complex salt is dissolved;

(2) cooling the solution dissolved with the (R, S) -diastereoisomer composite salt for crystallization, collecting the solid, and separating to obtain the S configuration diastereoisomer composite salt;

(3) re-dissolving the S configuration diastereoisomer composite salt, acidifying to enable the S configuration diastereoisomer to be free, extracting to obtain an organic phase, drying, concentrating, and recrystallizing to obtain the (S) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid with the chemical purity and the optical purity respectively higher than 99.9% and 99.95%.

The applicant finds that the solubility of two diastereoisomer salts formed by using (1S, 2S) -2-amino-1- (4-nitrophenyl) propane-1, 3-diol as a resolving agent and a racemic raw material is very different in a specific solvent, the high-purity S configuration diastereoisomer salt can be directly obtained by cooling and crystallizing for one time, and other solvents cannot realize good separation effect.

The preparation method provided by the invention has the following beneficial effects

1) The method uses (1S, 2S) -2-amino-1- (4-nitrophenyl) propane-1, 3-diol as a resolving agent to effectively resolve the 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid, and the obtained optical isomer with the S configuration has the purity of 99.95% and the mass yield of 45.3% -48.1%.

2) The resolving agent used by the invention is convenient to purchase and low in price, and solves the problems that the existing resolving agent such as (S) -1- (4-nitryl) phenethylamine and (S) -1- (4-chlorphenyl) ethylamine is high in price and limited in goods source.

3) The separation reagent used in the invention has very good crystallization effect with diastereomer salt formed by raw materials, and the yield and purity are basically not influenced when the separation reagent is enlarged to industrial production scale, thus having very good industrialization prospect.

4) The splitting reagent used in the invention has good safety, mild reaction conditions and safe and controllable process, does not generate wastewater polluting the environment, conforms to the concept of green environmental protection, avoids the subsequent wastewater treatment process and reduces the investment of process cost.

5) The separation of the salts of the two diastereoisomers in the resolution process is simple, an acid-binding agent is not needed, and the input of raw material cost is reduced.

The existing chiral amine resolution reagent is expensive, has limited source of goods and poor safety, and is not beneficial to large-scale industrial production, for example, (S) -1- (4-nitro) phenylethylamine and (S) -1-phenylethylamine have irritation, and (S) -1-phenylethylamine also has corrosiveness, and (S) -1- (4-chlorphenyl) ethylamine is toxic and harmful, and cannot be directly discharged into the environment. The resolving agent used in the invention has no bad information in the aspect of safety, and has the advantages of low cost, easy obtaining and good safety compared with the existing agent for resolving 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid.

Detailed Description

It will be understood by those skilled in the art, based upon the disclosure herein, that various modifications and improvements may be made to the invention without departing from the spirit and scope of the invention. They are intended to fall within the scope of protection of the patent as defined by the claims of the present application. Furthermore, it should be understood that the examples provided herein are for the purpose of illustrating the invention and should not be construed as limiting the invention.

Example 1:

(1) salifying:

adding 50.00g of raw material (RS) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid (0.18mol) into 3L of mixed solvent (the volume ratio of acetonitrile to acetone is 5: 1), then adding 38.20g of resolving agent (1S, 2S) -2-amino-1- (4-nitrophenyl) propane-1, 3-diol (0.18mol) for resolution reaction, and stirring for 4 hours at the temperature of 30 ℃;

(2) separation:

after the reaction is finished, cooling to-10 ℃, standing for crystallization, filtering, and collecting solids to obtain salts of S configuration diastereoisomers;

(3) acidifying:

the salt of the S configuration diastereomer was dissolved in water, the pH was adjusted to 2 with hydrochloric acid to free the S configuration diastereomer, extracted with ethyl acetate, the organic layer was separated, washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, the solvent was recovered by concentration, and then recrystallized from ethyl acetate to obtain 22.63g of (S) -2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid having an optical purity of 99.98 ee%.

The effects of the composition and amount of the resolving solvent and the amount of the resolving agent on the product yield and the product purity (ee value) were examined, respectively, by referring to example 1, setting examples 2 to 19, and the results are shown in Table 1.

TABLE 1

An example of the large-scale industrial production of (S) -2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid is given below:

example 20:

(1) salifying:

adding 100kg of raw material (RS) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid into a mixed solvent (the volume ratio of acetonitrile to acetone is 8: 1), then adding 77.93kg of resolving agent (1S, 2S) -2-amino-1- (4-nitrophenyl) propane-1, 3-diol for resolution reaction, and stirring for 4 hours at the temperature of 30 ℃;

(2) separation:

(3) acidifying:

the salt of the S configuration diastereomer was dissolved in water, the pH was adjusted to 2 with hydrochloric acid to free the S configuration diastereomer, extracted with ethyl acetate, the organic layer was separated, the organic layer was washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, the solvent was recovered by concentration, and then recrystallized from ethyl acetate to obtain 46.72kg of (S) -2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid with a yield of 46.72% and an optical purity of 99.98%.

Example 21:

(1) salifying:

adding 120kg of raw material (RS) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid into a mixed solvent (the volume ratio of acetonitrile to acetone is 8: 1), then adding 93.5kg of resolving agent (1S, 2S) -2-amino-1- (4-nitrophenyl) propane-1, 3-diol into the mixed solvent to carry out resolving reaction, and stirring the mixture for 6 hours at the temperature of 20 ℃;

(2) separation:

after the reaction is finished, cooling to-5 ℃, standing for crystallization, filtering, and collecting solids to obtain salts of S configuration diastereoisomers;

(3) acidifying:

the salt of the S configuration diastereomer was dissolved in water, the pH was adjusted to 2 with hydrochloric acid to free the S configuration diastereomer, extracted with ethyl acetate, the organic layer was separated, the organic layer was washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, the solvent was recovered by concentration, and then recrystallized from ethyl acetate to obtain 55.13kg of (S) -2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid with a yield of 45.94% and an optical purity of 99.98%.

Example 22:

(1) salifying:

adding 200kg of raw material (RS) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid into a mixed solvent (the volume ratio of acetonitrile to acetone is 8: 1), then adding 155.9kg of resolving agent (1S, 2S) -2-amino-1- (4-nitrophenyl) propane-1, 3-diol for resolution reaction, and stirring for 3 hours at the temperature of 40 ℃;

(2) separation:

after the reaction is finished, cooling to-20 ℃, standing for crystallization, filtering, and collecting solids to obtain salts of S configuration diastereoisomers;

(3) acidifying:

the salt of the S configuration diastereomer was dissolved in water, the pH was adjusted to 2 with hydrochloric acid to free the S configuration diastereomer, extracted with ethyl acetate, the organic layer was separated, the organic layer was washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, the solvent was recovered by concentration, and then recrystallized with ethyl acetate to obtain 93..65kg of (S) -2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid with a yield of 46.83% and an optical purity of 99.96%.

The feasibility of large scale production was demonstrated by examples 20-23, with product yield and purity still high when the production scale-up was over 100 kg.

Claims

A process for the preparation of (S) -2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid, comprising the steps of:

(1) carrying out resolution reaction on a raw material (RS) -2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid and a resolution reagent (1S, 2S) -2-amino-1- (4-nitrophenyl) propane-1, 3-diol in a solvent to obtain a composite salt of two diastereomers;

(2) separating the two diastereomeric complex salts to obtain the S configuration diastereomeric salt;

(3) and (3) removing the resolving agent in the S configuration diastereoisomer salt to obtain the (S) -2-hydroxy-3-methoxyl-3, 3-diphenyl propionic acid with high optical purity.
2. The preparation method according to claim 1, wherein the molar ratio of the raw material to the resolving agent in the step (1) is 1: 1 to 1: 1.5.
3. The process according to claim 1, wherein the molar ratio of the starting material to the resolving agent in step (1) is 1: 1.1.
4. The preparation method according to claim 1, wherein the mass-to-volume ratio of the raw material to the solvent in the step (1) is 1: 60 to 1: 240 g/ml.
5. The process according to claim 4, wherein the solvent used for the resolution is a mixture of acetonitrile and acetone.
6. The method according to claim 5, wherein the volume ratio of acetonitrile to acetone is 5: 1 to 12: 1.
7. The method according to claim 6, wherein the volume ratio of acetonitrile to acetone is 8: 1.
8. The preparation method according to any one of claims 1 to 7, wherein the specific operation of step (1) is to dissolve the starting material in a solvent, then add a resolving agent, and perform the resolving reaction under stirring.
9. The method according to claim 8, wherein the stirring time is 2 to 8 hours.
10. The method according to claim 9, wherein the stirring time is 3 to 5 hours.
11. The process according to claim 1, wherein the temperature of the resolution reaction is controlled to 20 to 50 ℃.
12. The process according to claim 11, wherein the temperature of the resolution reaction is controlled to 30 to 40 ℃.
13. The method according to claim 1, wherein the separation method in the step (2) is cooling crystallization.
14. The method according to claim 13, wherein the temperature for cooling and crystallizing is controlled to be-20 ℃ to-5 ℃.
15. The method according to claim 14, wherein the temperature for cooling and crystallizing is controlled to-10 ℃.
16. The process of any one of claims 1 to 7 or 11 to 15, wherein the resolution reagent is removed in step (3) by dissolving the salt of diastereomer of S configuration in water, adjusting the pH of the solution to acidity, extracting with an organic solvent, drying, concentrating to recover the solvent, and recrystallizing.
17. The preparation method according to claim 16, wherein the organic solvent used in the extraction in the step (3) comprises ethyl acetate, tetrahydrofuran, n-butanol, methyl tert-butyl ether or dimethylformamide.
18. The method according to claim 16, wherein the pH of the solution is adjusted to 1 to 5 in the step (3).
19. The method according to claim 18, wherein the pH of the solution is adjusted to 2 to 3 in the step (3).