A novel synthesis process of ubenimex

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 fluid of Streptomycesofivorecticui, which can competitively inhibit aminopeptidase B (aminopeptidase B) and leucine 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 factors to stimulate the regeneration and differentiation of bone marrow cells, which can interfere with tumors Cell metabolism, 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, radiotherapy and com...

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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 preparing intermediate I, intermediate I is condensed with leucine benzyl ester to obtain intermediate II, and intermediate II is hydrogenated under the catalysis of palladium carbon Ubenimex was prepared by deprotection, in which palladium carbon hydrogenation catalysis was used in the deprotection process, the cost was high, and the safety was poor, and there were small polar impurities with high ultraviolet absorption in the residual impurities, which could not be thoroughly detected by existing international detection methods out

[0005] In view of the low purity and yield of Ubenimex prepared by the existing synthesis process, carry out further research on the new synthesis process of Ubenimex

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