The preparation method of (s)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid

Abstract

The invention discloses a preparation method of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid and relates to the field of drug synthesis. The method uses the resolving reagent (1S,2S)‑2‑amino‑1‑(4‑nitrophenyl)propane‑1,3‑diol to resolve (RS)‑2‑hydroxy‑3‑methoxy‑ 3,3-diphenylpropionic acid, through cooling and crystallization, collect the solid to obtain the salt of the S-configuration diastereomer, and acidify the salt of the S-configuration diastereoisomer after adding water to redissolve it , through extraction, drying, concentration and recrystallization to obtain (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid with high optical purity. The invention uses cheap, easy-to-obtain and high-safety resolution reagents, has a mass yield of more than 45% while reducing costs, and can be scaled up to large-scale industrial production, and has very good industrialization prospects.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid. Background technique [0002] Pulmonary hypertension is a malignant disease with extreme exhaustion of body functions. The chemical name of Ambrisentan is (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)-oxyl]-3-methoxy-3,3-di Phenylpropionic acid (its structural formula is as shown in formula I), is a kind of endothelin-1 (endothelin-1, ET-1) receptor antagonist, is clinically used in the treatment of pulmonary arterial hypertension, developed by American Myogen biopharmaceutical company, In June 2007, it was approved for marketing by the US FDA (trade name: Letairis), and it was launched in China in 2011 (trade name: Vanrik). Ambrisentan has been recommended by the WHO as the first-line clinical drug for the treatment of pulmonary arterial hypertension patients with pulmonary arterial hypertension grade II and g...

AI Technical Summary

Problems solved by technology

[0008] (2) In order to make S-2-hydroxyl-3-methoxyl-3,3-diphenylpropionic acid reach the quality standard, the raw material 2-hydroxyl-3-methoxyl-3,3-diphenyl Propionic acid undergoes repeated recrystallization and purification until it meets the requirements before it can be used, resulting in long construction period and low yield;

[0009] (3) Acid-binding agent (such as sodium methoxide) needs to be added in the resolution reaction to neutralize the hydrochloric acid in the L-proline methyl ester hydrochloride, which increases the production cost and also causes the waste salt to be difficult to remove, which is easy to form Impurities are precipitated together with the product, reducing the purity of the product

But these resolution reagents still have problems that cannot be ignored: L-proline methyl ester has no ultraviolet absorption, is difficult to detect, is not conducive to product quality control and resolution reagent recycling; (S)-1-(4-nitro Phenyl) ethylamine or its hydrochloride are unstable in nature and expensive, which increases the difficulty of production cost and quality control; (S)-1-(4-chlorophenyl) ethylamine is limited in domestic resources and expensive , needs to be imported in large quantities, which is not conducive to industrial production; L-phenylglycinamide also has a higher cost

In addition, according to U.S. Patent No. 6,559,338, (S)-2-hydroxypropionic acid derivatives and resolution reagent L-proline methyl ester or (S)-1-(4-nitrophenyl)ethylamine are used in process amplification It is difficult to crystallize up to 100kg, and complex processes are required to achieve high chiral purity

Therefore, the current chiral resolution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid is only a small laboratory test, and further research is needed on whether it can be further applied in industrial production

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