Novel synthesis process of ubenimex

A technology of ubimethoxine and a synthesis process, which is applied in the field of novel synthesis technology of ubimethoxine, can solve the problems of high activity of the protective agent, low purity and yield, complicated operation, etc., achieves easy high-volume industrial production and improves yield. efficiency and purity, reducing safety risks

Active Publication Date: 2015-03-25
西安万隆制药股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] With the increase of global consumption, it is obvious that the production of Ubenimex by fermentation can no longer meet the demand of drugs, therefore, the pharmaceutical industry research teams as well as scientific research and academic institutions have spent a lot of effort to find a feasible route to produce this drug
[0004] The existing synthesis method of Ubenimex is to use (2S,3R)-3-amino-2-hydroxy-4-phenylbutyric acid as raw material, and use a highly active thiobenzyloxycarbonyl protecting agent to protect the amino group to prepare intermediate In body I, the protective agent used has high activity, but poor stability and complicated operation; in the process of preparin

Method used

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  • Novel synthesis process of ubenimex
  • Novel synthesis process of ubenimex
  • Novel synthesis process of ubenimex

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of Intermediate I

[0039]Add 15g of the raw material (2S, 3R)-3-amino-2-hydroxy-4-phenylbutyric acid, 150mL of water to adjust the pH to 8.5 by adding 2mol / L aqueous sodium hydroxide solution dropwise at room temperature, and the system is dissolved and clarified. Add 15ml Acetone and 5g di-tert-butyl dicarbonate, stir for 10 minutes and add 2mol / l sodium hydroxide aqueous solution to adjust the pH to 8.5, then add 5g di-tert-butyl dicarbonate, add 2mol / L hydrogen after stirring for 10 minutes Adjust the pH to 8.5 with aqueous sodium oxide solution, add di-tert-butyl dicarbonate 4 times in total, 20 g in total, continue to stir for 2 hours until the reaction of the raw materials is complete, adjust the pH to 1.5 with 2 mol / L hydrochloric acid in an ice bath, and use 150 ml of ethyl acetate Extract twice, wash the ethyl acetate phase with 100ml saturated brine, dry over anhydrous sodium sulfate, concentrate, add 50mL of petroleum ether to crystallize, filter...

Embodiment 2

[0049] Preparation of Intermediate I

[0050] Add 15g of the raw material (2S, 3R)-3-amino-2-hydroxy-4-phenylbutyric acid, 150ml of water at room temperature, add dropwise 2mol / L sodium carbonate aqueous solution to adjust the pH to 9, the system is dissolved and clarified, add 15ml of methanol And 5g di-tert-butyl dicarbonate, stir for 10 minutes and add 2mol / l sodium carbonate aqueous solution to adjust the pH to 8.5, then add 5g di-tert-butyl dicarbonate, add 2mol / l sodium carbonate aqueous solution after stirring for 10 minutes Adjust the pH to 8.5, add di-tert-butyl dicarbonate 4 times in total, a total of 20g, continue to stir for 2 hours until the raw materials are completely reacted, adjust the pH to 2 with 2mol / L hydrochloric acid in an ice bath, and extract twice with 150ml ethyl acetate , the ethyl acetate phase was washed with 100ml of saturated brine, dried over anhydrous sodium sulfate, concentrated and added with 50ml of petroleum ether to crystallize, and filte...

Embodiment 3

[0057] Preparation of Intermediate I

[0058] The raw material (2S, 3R)-3-amino-2-hydroxy-4-phenylbutyric acid 15g, 150ml of water was added dropwise at room temperature with triethylamine to adjust the pH to 10, the system was dissolved and clarified, and 15ml of triethylamine and 5g Di-tert-butyl dicarbonate, stirred for 10 minutes and added triethylamine to adjust the pH to 8.5, then added 5g of di-tert-butyl dicarbonate, stirred for 10 minutes, added triethylamine to adjust the pH to 8.5, added 4 times in total Di-tert-butyl carbonate, a total of 20g, continue to stir for 2 hours until the raw materials are completely reacted, adjust the pH to 2 with 2mol / L hydrochloric acid under ice bath, extract twice with 150ml ethyl acetate, wash the ethyl acetate phase with 100ml saturated saline , dried over anhydrous sodium sulfate, concentrated and added 50ml of petroleum ether to crystallize, filtered to obtain solid intermediate I: 21.00g, the appearance was white or off-white c...

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Abstract

The invention discloses a novel synthesis process of ubenimex. The synthesis process comprises the following steps: enabling a raw material, namely (2S,3R)-3-amino-2-hydroxy-4-phenyl butyric acid, to react with di-tert-butyl dicarbonate ester so as to prepare an intermediate I, wherein di-tert-butyl dicarbonate ester is added in multiple batches; reacting the intermediate I with L-leucine tert-butyl ester hydrochloride so as to obtain an intermediate II, wherein L-leucine tert-butyl ester hydrochloride is preferred and is conducive to the improvement of yield and purity of the intermediate II; and respectively removing protecting groups, namely tert-butyloxy carbonyl and tert-butyl ester, of the intermediate II in an acid-base system, wherein through the operation, the protecting groups are effectively removed by regulating pH value by virtue of the acid-base system, so that the yield and purity of the finished ubenimex are improved.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically refers to a novel synthesis process of ubenimex. Background technique [0002] Ubenimex (foreign name Ubenimex, Bestalin) is a dititanium compound isolated from the culture solution of Streptomyces ofivorecticui, which can competitively inhibit aminopeptidase B (aminopeptidase B) and leucine Acid peptidase (Leucineamino Peptidase) and caspase (Caspase), enhance the function of T cells, enhance the killing activity of NK cells, and increase the synthesis of colony-stimulating factor to stimulate the regeneration and differentiation of bone marrow cells, which can interfere with Metabolism of tumor cells, inhibition of tumor cell proliferation, apoptosis of tumor cells, activation of human cellular immune function, stimulation of cytokine production and secretion, and promotion of anti-tumor cell production and proliferation. It can be used in conjunction with chemotherapy, radiother...

Claims

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Application Information

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IPC IPC(8): C07C237/20C07C231/12
CPCY02P20/55
Inventor 张卓赵林吉蒋诗敏
Owner 西安万隆制药股份有限公司
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