Preparation method of ubenimex intermediate (2S,3R)-3-acetamido-2-hydroxyl-4-phenylbutyric acid

A technology of acetamido and phenylbutyric acid, applied in the preparation of carboxylic acid amide optical isomers, organic chemistry, etc., can solve the problems of complicated operation, low yield, unfavorable industrial production, etc., and achieves easy operation and reproducibility Good, the effect of improving productivity

Inactive Publication Date: 2017-08-29
CHANGZHOU AINUOXINRUI PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the resolution reaction uses S-1-phenylethylamine as the resolution reagent to resolve the racemate (compound 1), and selectively obtain the intermediate (2S,3R)-3-acetamido of Ubenimex -2-Hydroxy-4-phenylbutyric acid, but this resolution process can not stably obtain the high optical purity product, and the yield is low, which is not conducive to industrial production
[0008] Patent CN101891647 A discloses a method for splitting compound 1 by using L-lysine, L-arginine and L-histidine to obtain high-purity (2S,3R)-3-acetylamino-2-hydroxy -4-phenylbutyric acid, but this method needs to carry out repeatedly beating purification and crystallization, complicated operation, is unfavorable for suitability for industrialized production

Method used

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  • Preparation method of ubenimex intermediate (2S,3R)-3-acetamido-2-hydroxyl-4-phenylbutyric acid
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  • Preparation method of ubenimex intermediate (2S,3R)-3-acetamido-2-hydroxyl-4-phenylbutyric acid

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Experimental program
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Effect test

Embodiment 1

[0031] Compound 1 (2.4 g) and S-1-naphthylethylamine (1.8 g) were added into ethanol (10 ml), stirred and dissolved at 60°C. Cool the above solution to 25°C, filter to obtain 1.5 grams of white solid, which is the S-1-naphthylethylamine salt of (2S,3R)-3-acetamido-2-hydroxy-4-phenylbutyric acid. Add the salt to an aqueous solution (10 ml), stir to dissolve, add reagent hydrochloric acid (2 ml), stir to precipitate a solid, and separate to obtain (2S,3R)-3-acetylamino-2-hydroxy-4-phenylbutyric acid 0.85 g, yield 35.4%, ee value 99.8%.

Embodiment 2

[0033] Compound 1 (2.4 g) and S-1-naphthylethylamine (1.8 g) were added into ethanol (10 ml) and acetonitrile (3 ml), stirred at 60° C. to dissolve. Cool the above solution to 25°C, filter to obtain a white solid, which is the S-1-naphthylethylamine salt of (2S,3R)-3-acetamido-2-hydroxy-4-phenylbutyric acid, add this salt to into an aqueous solution (10 ml), stirred to dissolve, added reagent hydrochloric acid (2 ml), stirred to precipitate a solid, and separated to obtain 0.89 g of (2S,3R)-3-acetylamino-2-hydroxyl-4-phenylbutyric acid , yield 37.1%, ee value 99.6%.

Embodiment 3

[0035] Compound 1 (2.4 g) and (S)-1-(2-naphthyl)ethylamine (1.8 g) were added into tetrahydrofuran (20 ml), and stirred at 60°C to dissolve. Cool the above solution to 25°C, filter to obtain a white solid, which is the S-1-naphthylethylamine salt of (2S,3R)-3-acetamido-2-hydroxy-4-phenylbutyric acid, add this salt to into an aqueous solution (10 ml), stirred to dissolve, added reagent hydrochloric acid (2 ml), stirred to precipitate a solid, and separated to obtain 0.88 g of (2S,3R)-3-acetylamino-2-hydroxyl-4-phenylbutyric acid , yield 36.7%, ee value 99.6%.

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Abstract

The present invention provides a method for preparing an ubenimex intermediate (2S,3R)-3-acetamido-2-hydroxyl-4-phenylbutyric acid by using an organic alkali as a resolving agent, wherein the organic alkali is selected from S-1-naphthalene ethylamine, (S)-1-(2-naphthyl)ethylamine, L-phenylglycinol, and L-phenylalaninol. According to the present invention, the preparation method has advantages of good ubenimex intermediate purity, high yield, simple operation and good reproducibility, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of organic chemistry, in particular to a method for preparing an ubenimex intermediate (2S, 3R)-3-acetylamino-2-hydroxyl-4-phenylbutyric acid. Background technique [0002] Ubenimex, whose chemical name is N-[(2S,3R)-4-phenyl-3-amino-2-hydroxybutyryl]-L-leucine, has the following structural formula: [0003] [0004] Ubenimex is a peptide anti-tumor drug, which was discovered by H. Umezawa (US 4052449) et al. from the fermentation broth of Streptomyces olivine reticulum. It can promote the body's immune response and inhibit aminopeptidase B and leucine aminopeptidase. [0005] Clinical studies have shown that Ubenimex achieves its curative effect in cancer treatment by improving the cytotoxic activity of antineoplastic drugs. This product is used for the chemotherapy of tumor patients, adjuvant radiation therapy and senile immunodeficiency and other diseases. Indications include leukemia, multiple myeloma, myelo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/47C07C231/20
CPCC07C231/20
Inventor 张席妮资春鹏周涛熊志刚梁劲泮廷廷
Owner CHANGZHOU AINUOXINRUI PHARMA LTD
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