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Synthesis method of pidotimod

A technology of pidotimod and a synthesis method, which is applied in the field of chemical drug synthesis, can solve problems such as reducing racemization, inability to solve the problem of racemization, and achieves the effects of solving the problem of racemization, improving the yield, and reducing the feeding ratio.

Inactive Publication Date: 2018-06-15
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent CN201410658117.9 discloses a production process of pidotimod, which synthesizes pidotimod through a one-pot method of thiazolidinic acid or ester, pyroglutamic acid and condensing agent, but the problem of racemization still cannot be solved
The rest, such as patents CN201510167302.2, CN201110384747.8, CN201110236724.2, etc., although the synthesis methods are different, are all based on the original reaction mechanism, only to reduce the racemization or increase the yield, and there is no real solution to the problem of racemization. Rotate the problem, to achieve the purpose of improving product quality and reducing costs

Method used

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  • Synthesis method of pidotimod
  • Synthesis method of pidotimod
  • Synthesis method of pidotimod

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Experimental program
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Effect test

Embodiment 1

[0030] Example 1, a synthetic method of pidotimod: the method uses carboxyl R group protected L-thiazolidine-4-carboxylate or L-thiazolidine-4-carboxylic acid and nitrogen R1 protected coke Under the enzyme catalyst, glutamic acid is condensed to form the target compound pidotimod shown in the general formula III:

[0031]

[0032] III

[0033] Described R is selected from: H, OtBu, Bn, cHX, Mpe, 2-phlpr, TEGbn, Damb, Al, pNB, pTMSE or Dmnb;

[0034] Described R1 is selected from: H, Z, Boc, Cl-Z, Fmoc, oNBS, dNBS, Troc, Dts, pNZ, oNZ, NVOC, NPPOC, HFA, Ddz, Bpoc, Nps, Nsc, Bsmoc, α-Nsmoc , ivDde, Fmoc*, MTT or Alloc.

Embodiment 2

[0035] Embodiment 2, the synthetic method of a kind of pidotimod described in embodiment 1 is characterized in that: described substituted benzene ring is selected from 3 fluorine substitutions, 3, 5 fluorine substitutions, 3 chlorine substitutions, three Fluoromethyl substituted benzene ring.

Embodiment 3

[0036] Embodiment 3, the synthetic method of two kinds of pidotimod described in embodiment 1 or 2, its specific steps are as follows:

[0037] (1) Stir the pyroglutamic acid, enzyme and buffer solution protected by nitrogen R1 together; the buffer solution is potassium phosphate;

[0038] (2) Add L-thiazolidine-4-carboxylate or L-thiazolidine-4-carboxylic acid protected by carboxyl R group, continue stirring reaction;

[0039] (3) After the reaction finishes, the reaction solution is filtered to remove the enzyme to obtain the filtrate;

[0040] (4) When the raw material uses carboxyl R group protected L-thiazolidine-4-carboxylic acid, nitrogen unprotected pyroglutamic acid, the filtrate is hydrolyzed with sodium hydroxide or potassium hydroxide solution, and then the acid is directly adjusted to the acid To a large amount of white precipitate, filter to obtain the crude product of pidotimod;

[0041] When the raw material is L-thiazolidine-4-carboxylate protected by carboxyl...

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Abstract

The invention discloses a synthesis method of pidotimod. According to the synthesis method, L-thiazolidine-4-carboxylate with a protected carboxyl R group or L-thiazolidine-4-carboxylic acid and pyroglutamic acid with protected nitrogen R1 carry out condensation reactions in the presence of an enzyme catalyst to form a target compound namely pidotimod represented by the formula III. Enzymes are taken as the catalyst, the conventional oxazolone racemate generation mechanism is avoided totally; the reaction mechanism is completely different from a conventional synthesis and activation principleand mechanism, the racemization problem is radically solved, the feed ratio is greatly reduced, moreover, the yield and product quality are largely improved, and the synthesis method is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of pidotimod, which belongs to the field of chemical drug synthesis. technical background [0002] Pidotimod, whose chemical name is (4R)-3-[[(2S)-5-oxo-2-pyrrolidinyl]carbonyl]-4-thiazolidinecarboxylic acid, is a brand new chemically synthesized immune The regulator is suitable for patients with low immune function, and can be used to prevent acute infection, shorten the course of disease, and reduce the severity of the disease, and can be used as an auxiliary drug in the acute infection period. The original research company is the Italian Poli Chemical Industry Company, and it was launched as an oral preparation in 1993. It can activate natural killer cells, promote the proliferation of lymphocytes caused by mitogens, and make helper T cells (CD4+) and suppressive T cells with low immune function. The ratio of cells (CD8+) increased and returned to normal. It exerts significant antibacterial and antiviral...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P21/02C07K5/078C07K1/14
CPCY02P20/55C12P21/02C07K5/06173
Inventor 徐峰周金玉伏帅苏军柳铎芳孙美禄
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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