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Preparation method of pidotimod

A technology based on pidotimod and time, which is applied in the field of pharmaceutical synthesis, can solve the problems of low solubility of pidotimod, high toxicity of reagent pentachlorophenol, unstable active ester, etc., so as to reduce production cost, low cost, The effect of easy operation and control

Active Publication Date: 2014-07-02
SHANDONG NEWTIME PHARMA
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0010] The L-pyroglutamic acid pentachlorophenol ester involved in this method has complicated synthetic operations, and the reagent pentachlorophenol is highly toxic, and the nitrogen-substituted active ester is unstable; the solvent used for the condensation reaction is DMF, which has a high boiling point and is difficult to recycle Utilization, high cost, not conducive to mass production
[0011] In addition, Li Xiuzhen, Wang Yun, Shang Zhicai, Yu Qingsen, "Synthetic Improvement of Immunopromoter Pidotimod" Chemical World, No. 9, 2005, 555-557] mentioned the use of mixed solvent isopropanol: methanol = 6:4 refined pidotimod, the two alcohols in the mixed solvent are not very soluble to pidotimod, resulting in a low refined yield, only 51%, and high cost

Method used

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  • Preparation method of pidotimod
  • Preparation method of pidotimod
  • Preparation method of pidotimod

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Embodiment 1

[0039] The preparation of embodiment 1 pidotimod

[0040] In a dry 2000mL three-necked round-bottom flask, add 50.0g (0.375mol) of L-pyroglutamic acid and 700ml of anhydrous tetrahydrofuran, stir, cool to -5~5°C, add 39.7g (0.375mol) of sodium carbonate, Add 40.7 g (0.375 mol) of ethyl chloroformate dropwise under temperature control -5 to 5°C. After the dropwise addition is completed, keep stirring and react for 20 minutes, add 49.9 g (0.375 mol) of L-thiazolidinyl-4-carboxylic acid, and continue to control Stir and react at -5~5°C for 20 minutes, raise the reaction temperature to room temperature, evaporate the reaction solution to dryness under reduced pressure, add 200ml of 50% ethanol to the residue, stir to dissolve it completely, and control the temperature at -20~-10 30ml of concentrated hydrochloric acid was added dropwise at ℃, after the dropwise addition was completed, the crystallization was carried out with stirring and heat preservation for 8 hours, filtered, and...

Embodiment 2

[0043] The preparation of embodiment 2 pidotimod

[0044] In a dry 2000mL three-neck round bottom flask, add 50.0g (0.375mol) of L-pyroglutamic acid and 700ml of anhydrous tetrahydrofuran, stir, cool down to -20~-10°C, add 39.7g (0.375mol) of sodium carbonate , add 40.7g (0.375mol) of ethyl chloroformate dropwise under temperature control at -20~-10°C, after the dropwise addition is complete, keep stirring for 10 minutes, then add 49.9g (0.375mol) of L-thiazolidinyl-4-carboxylic acid, Continue to control the temperature at -5 ~ 5 ° C and stir for 20 minutes, then raise the reaction temperature to room temperature, evaporate the reaction solution to dryness under reduced pressure, add 200 ml of 60% ethanol to the residue, stir to dissolve it completely, and control the temperature at -20 ~ Add 30ml of concentrated hydrochloric acid dropwise at -10°C, after the dropwise addition is completed, keep stirring and crystallize for 20h, filter, and dry to obtain 71.8g of crude pidotim...

Embodiment 3

[0047] The preparation of embodiment 3 pidotimod

[0048] In a dry 2000mL three-neck round bottom flask, add 50.0g (0.375mol) of L-pyroglutamic acid and 700ml of anhydrous tetrahydrofuran, stir, cool down to -20~-10℃, add 24.3g (0.412mol) of trimethylamine , add 40.7g (0.412mol) of ethyl chloroformate dropwise under temperature control at -20~-10°C, after the dropwise addition is completed, keep stirring for 10 minutes, then add 49.9g (0.375mol) of L-thiazolidinyl-4-carboxylic acid, Continue to control the temperature at -5 ~ 5 °C and stir for 20 minutes, then raise the reaction temperature to room temperature, evaporate the reaction solution to dryness under reduced pressure, add 200 ml of 30% ethanol to the residue, stir to dissolve it completely, and control the temperature at -20 ~ Add 30ml of concentrated hydrochloric acid dropwise at -10°C. After the dropwise addition, keep stirring and crystallize for 16h, filter, and dry to obtain 72.9g of crude pidotimod, with a yield...

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Abstract

The invention provides an improved preparation method of pidotimod. According to the improved preparation method, a mixed anhydride method is adopted, and the improved preparation method comprises the following steps: under alkaline conditions, enabling L-pyroglutamic acid, ethyl chloroformate and L-thiazolidine-4-carboxylic acid to react, then acidifying, refining and devitrifying to prepare pidotimod. The method has the advantages of simplicity and convenience in operation, high yield and high product purity, and is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation method of pidotimod. Background technique [0002] Pidotimod (pidotimod), the chemical name is (R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]-thiazolidinyl-4-carboxylic acid, from Italy in the late 1980s Developed by Poli Chemical Industry Company, and first listed in Italy under the trade name Polimod in 1993, it is used as an inhibitor of tumor cell growth and recurrent respiratory and urinary tract infections [Immunomodulator agent for cognition disorders[J].Drugs Fut, 1994, 19(12): 1133-1134.], the structural formula is as follows: [0003] [0004] Pidotimod is a brand-new chemically synthesized immune enhancer, which has the characteristics of anti-toxicity, anti-oxidation, anti-irritation, anti-infection, etc. It can not only promote non-specific immune response, but also promote specific immune response. Satisfactory results have been ach...

Claims

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Application Information

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IPC IPC(8): C07K5/078C07K1/14
Inventor 赵志全王秀娟郭彦玲包汉杰
Owner SHANDONG NEWTIME PHARMA
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