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Pidotimod synthesis method

A technology of pidotimod and synthetic method, which is applied in the field of chemical drug synthesis, can solve the problems of reducing racemization and no racemization, and achieves the effects of solving the racemization problem, increasing the yield, and shortening the synthesis cycle

Active Publication Date: 2017-05-10
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are still many other methods, but they are all based on the original reaction mechanism, or reduce racemization, or simply avoid other synthetic routes to achieve the purpose of obtaining authorized patents or publishing articles. Solve the problem of racemization to achieve the purpose of improving product quality and reducing costs

Method used

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Examples

Experimental program
Comparison scheme
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 Glutamic acid is condensed to form the target compound pidotimod shown in general formula III under the catalyst of R2 substituted boric acid:

[0031]

[0032] The R is selected from: H, Otbu, Bn, cHX, Mpe, 2-ph1pr, TEGbn, Damb, Al, pNB, pTMSE or Dmnb;

[0033] The 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;

[0034] The R2 is selected from: various benzene rings, substituted benzene rings, furan, thiophene, imidazole or diazole.

Embodiment 2

[0035] Example 2, a synthetic method of pidotimod described in Example 1: the substituted benzene ring is selected from 3-position fluorine substitution, 3,5-position fluorine substitution, 3-position chlorine substitution or trifluoromethyl substitution benzene ring.

[0036] The specific steps are as follows:

[0037] (1) Stir the pyroglutamic acid protected by nitrogen R1, boric acid substituted by R2, activated molecular sieve, and organic solvent together; the activated molecular sieve uses a molecular sieve with an activated particle diameter of 4Å; the organic solvent is anhydrous dichloro Methane or ethyl acetate;

[0038] (2) Add L-thiazolidine-4-carboxylate or L-thiazolidine-4-carboxylic acid protected by the carboxyl R group, and continue to stir and react;

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

[0040](4) When the raw material is L-thiazolidine-4-carboxylate protected by carboxyl R group or pyroglutamic...

Embodiment 3

[0048] Embodiment 3, in the synthetic method of a kind of pidotimod described in embodiment 1:

[0049] The molar ratio of pyroglutamic acid protected by nitrogen R1, L-thiazolidine-4-carboxylate or L-thiazolidine-4-carboxylic acid protected by carboxyl R group, and boric acid substituted by R2 is 1.5:1:0.3 ;

[0050] Volume ml of organic solvent and nitrogen R oNBS, dNBS, Troc, Dts, pNZ, oNZ, NVOC, NPPOC, HFA, Ddz, Bpoc, Nps, Nsc, Bsmoc, α-Nsmoc, ivDde, Fmoc*, MTT or Alloc;

[0051] The R2 is selected from: various benzene rings, substituted benzene rings, furan, thiophene, imidazole or diazole.

[0052] Example 2, a synthetic method of pidotimod described in Example 1: the substituted benzene ring is selected from 3-position fluorine substitution, 3,5-position fluorine substitution, 3-position chlorine substitution or trifluoromethyl substitution benzene ring.

[0053] The specific steps are as follows:

[0054] (1) Stir the pyroglutamic acid protected by nitrogen R1, bo...

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Abstract

The invention relates to a pidotimod synthesis method and belongs to pure liquid phase synthesis. The method comprises the step that carboxyl group R protected L-thiazolidine-4-carboxylic acid ester or L-thiazolidine-4-carboxylic acid and nitrogen R1 protected pyroglutamic acid are condensed under a catalyst, namely, R2-substituted boronic acid, and the target compound pidotimod as shown in the general formula III is formed. A high-purity product can also be obtained by recrystallization. The invention also discloses an application of R2-substituted boronic acid in synthesis of pidotimod. With the adoption of the method, the synthesis cycle is greatly shortened, the mechanism of formation of oxazolidinone from all polypeptides with a traditional method is avoided, the problem of racemization is solved completely, the catalyst can be reused, and accordingly, the cost is greatly reduced, the yield is high, the product purity is good, and the method is applicable to industrial production.

Description

technical field [0001] The invention relates to a synthesis method of pidotimod, which belongs to the field of chemical drug synthesis. Background technique [0002] The chemical name of Pidotimod is (4R)-3-[[(2S)-5-oxo-2-pyrrolidinyl]carbonyl]-4-thiazolidinecarboxylic acid, which is a brand-new chemically synthesized immune Accelerator, with anti-toxicity, anti-oxidation, anti-irritation, anti-infection and other characteristics. The original research company is Italian Poli Chemical Industry Company, and it was put into the market as an oral preparation in 1993. It is mainly used to prevent and treat recurrent respiratory infections (RRI) and chronic bronchitis in children. Satisfactory results have been obtained, so the compound It plays a very important role in medicine. [0003] There are many synthetic methods for this compound, but some methods have high cost, inconvenient operation, high toxicity of intermediates, and poor stability; some methods have stricter cond...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078
CPCC07K5/06173Y02P20/55
Inventor 徐峰谷海涛孙美禄李杰陈守菊
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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