Synthesis method of pidotimod

A synthesis method and condensing agent technology, applied in the direction of peptides, etc., can solve problems such as equipment corrosion, low product yield and purity, and high ester toxicity

Inactive Publication Date: 2011-08-31
ZHEJIANG KINGLYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Pentachlorophenol, pentafluorophenol, 2,4,5-trichlorophenol, N-hydroxysuccinimide or N-hydroxyphthalimide can be used to prepare reactive esters, but the resulting reactive The ester toxicity is bigger, and the stability of the reactive ester of nitrogen substitution is very poor; And sulfur oxychloride, phosphorus pentachloride or oxalyl chloride etc. are usually used when preparing acyl chloride, but sulfur oxychloride, phosphorus pentachloride And oxalyl chloride etc. are all toxic and corrosive, can seriously irritate eyes, skin and respiratory tract, be used in production equipment corrosion is serious, pollution problem is serious, environmental problem is prominent, and their technology as chlorination reagent also has product yield and Problems such as low purity
In addition, the reaction between L-cysteine ​​hydrochloride and formaldehyde requires pyridine and ethanol, which is costly and seriously polluting.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: Preparation of L-thiazolidine-4-carboxylic acid methyl ester (III-1)

[0031] Into a 1000mL reaction flask, add 121.2g (1.0003mol) of L-cysteine ​​in turn, add 500mL of purified water and stir to dissolve, then add 86.9g of 38% formaldehyde solution (1.0996mol of formaldehyde), stir for 10h, and cool to 0°C , filtered to obtain colorless needle-like crystals, the filter cake was transferred to a 1000mL three-necked flask, 300mL of purified water was added, the temperature was raised to reflux, and kept stirring for 1h, then the temperature was lowered to 30°C and stirred to precipitate crystals, cooled to 0°C, filtered, and the filter cake After drying, 110.7 g of colorless needle crystals were obtained, that is, L-thiazolidinyl-4-carboxylic acid, and the yield was 83.1%.

[0032] Add 1200mL of anhydrous methanol to a 3000mL reaction bottle, stir and cool to -2°C, add 240g (3.0573mol) of acetyl chloride dropwise, after the dropwise addition, add 100g (0.75...

Embodiment 2

[0034] Embodiment 2: Preparation of L-thiazolidine-4-carboxylic acid methyl ester (III-1)

[0035] Change 240g of acetyl chloride into 120g (0.4044mol) of bis(trichloromethyl)carbonate, and others are the same as in Example 1, and react to obtain light yellow liquid: 875mL of dichloromethane solution of L-thiazolidine-4-carboxylic acid methyl ester , the mass concentration of L-thiazolidine-4-carboxylate methyl ester is 8.38%.

Embodiment 3

[0036] Embodiment 3: Preparation of L-thiazolidine-4-carboxylic acid methyl ester (III-1)

[0037] Into a 1000mL reaction flask, add 121.2g (1.0003mol) of L-cysteine ​​in turn, add 500mL of purified water and stir to dissolve, then add 33.1g (1.1022mol) of paraformaldehyde, stir for 10h, cool to 0°C, filter Colorless needle-like crystals were obtained, the filter cake was transferred into a 1000mL three-necked flask, 300mL of purified water was added, the temperature was raised to reflux for 1h, the temperature was lowered to stir and crystallize, cooled to 0°C, filtered, and dried to obtain colorless needle-like crystals L-thiazolidinyl- 112.8 g of 4-carboxylic acid, the yield was 84.7%.

[0038] Add 1200 mL of anhydrous methanol to a 3000 mL reaction bottle, stir and cool to -3°C, add 120 g (0.4044 mol) of bis(trichloromethyl)carbonate dropwise, after the addition is complete, add the L-thiazolidinyl-4- Carboxylic acid 100g (0.7509mol), slowly warming up to reflux reaction ...

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Abstract

The invention discloses a synthesis method of pidotimod. The synthesis method comprises the following steps: reacting L-cysteine with paraformaldehyde or formaldehyde to generate L-thiazolidine-4-carboxylic acid, performing esterification to generate L-thiazolidine-4-carboxylate, or reacting L-cysteine ester hydrochloride with paraformaldehyde or formaldehyde to generate L-thiazolidine-4-carboxylate; and then carrying out condensation reaction on L-thiazolidine-4-carboxylate and L-pyroglutamic acid to generate (4R)-3-[[(2S)-5-oxo-2-pyrrolidinyl]carbonyl]-4-thiazolidine carboxylate, and then synthesizing pidotimod through hydrolysis reaction. Compared with the prior art, the technology in the invention is simple, is easy to operate, has high product yield and low production cost, is environmentally friendly and is suitable for industrial production.

Description

(1) Technical field [0001] The invention relates to a method for synthesizing medicine, in particular to a method for synthesizing pidotimod, an immune function promoter. (2) Background technology [0002] Pidotimod (Pidotimod), the chemical name is (4R)-3-[[(2S)-5-oxo-2-pyrrolidinyl]carbonyl]-4-thiazolidinecarboxylic acid, produced by Italian Poli Chemical Industry The immune function promoter developed by the company has the characteristics of anti-toxicity, anti-irritation, anti-infection, anti-oxidation, anti-aging, etc. It can not only promote non-specific immune response, but also promote specific immune response; it is mainly used for prevention and treatment. It is used to treat recurrent respiratory infections, urinary tract infections, allergic rhinitis and asthma in children, to treat and prevent acute exacerbations of chronic bronchitis and upper respiratory tract infections, and to treat various viral infections, malignant tumors and other chronic diseases that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078
Inventor 范青明赵海龙孟宪华王英杰盛金火
Owner ZHEJIANG KINGLYUAN PHARMA
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