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Preparation method of pidotimod

A technology of pidotimod and thiazolidine, applied in the field of drug synthesis, can solve the problems of irritation to eyes, skin and respiratory tract, low product yield and purity, prominent environmental problems, etc., and achieves good practicability, fewer synthesis steps, and reduced The effect of large-scale production costs

Inactive Publication Date: 2017-11-24
成都美域高制药有限公司
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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

Method used

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  • Preparation method of pidotimod

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] (1) Condensation reaction

[0042]In a 250mL reaction flask, dissolve 9.5g (0.05mol) of L-thiazolidine-4-carboxylate tert-butyl ester and 12g (0.050mol) of L-(tert-butoxycarbonyl)-pyroglutamic acid in 150ml of dichloromethane , stirred and cooled to 2°C, added dropwise 14ml (0.1mol) of triethylamine, followed by adding 10g (0.055mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 8 g (0.055 mol) of 1-hydroxybenzotriazole monohydrate, naturally warmed to room temperature and stirred for 12 hours, 300 ml of dichloromethane diluted the reaction solution, and then washed with 1N hydrochloric acid, saturated sodium bicarbonate, and saturated brine respectively, The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 19 g of yellow oil, (4R)-3-[[(2S)-5-oxo-2(tert-butoxycarbonyl)-2- Pyrrolidinyl]carbonyl]-4-thiazolidinecarboxylic acid tert-butyl ester, the yield is 9...

Embodiment 2

[0046] (1) Condensation reaction

[0047] In a 250mL reaction flask, dissolve (190g (1mol) of tert-butyl L-thiazolidine-4-carboxylate) and 240g (1mol) of L-(tert-butoxycarbonyl)-pyroglutamic acid in 3L of dichloromethane , stirred and cooled to 2°C, added dropwise 280ml (2mol) of triethylamine, followed by adding 200g (1.1mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1 -Hydroxybenzotriazole monohydrate 160g (1.1mol), naturally warming to room temperature and stirring for 12h, using 6L of dichloromethane to dilute the reaction solution, and then washing with 1N hydrochloric acid, saturated sodium bicarbonate, saturated brine, organic Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain 400 g of yellow oil, (4R)-3-[[(2S)-5-oxo-2(tert-butoxycarbonyl)-2-pyrrole Alkyl]carbonyl]-4-thiazolidinecarboxylic acid tert-butyl ester, the yield is 94.7%.

[0048] (2) Hydrolysis reaction

[0049] Disso...

Embodiment 3

[0051] (1) Condensation reaction

[0052] Take 190 g of (L-thiazolidine-4-carboxylate tert-butyl ester, 240 g of L-(tert-butoxycarbonyl)-pyroglutamic acid) and dissolve them in 3L of tetrahydrofuran solvent, stir and cool to 4°C, add three Ethylamine 280ml, then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 200g and 1-hydroxybenzotriazole monohydrate 160g, naturally warming up to room temperature, reaction 10 The reaction solution was washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, and saturated saline solution, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain yellow oil (4R)-3-[[ 386 g of tert-butyl (2S)-5-oxo-2(tert-butoxycarbonyl)-2-pyrrolidinyl]carbonyl]-4-thiazolidinecarboxylate, the yield was 91.4%.

[0053] (2) Hydrolysis reaction

[0054] Take (4R)-3-[[(2S)-5-oxo-2(tert-butoxycarbonyl)-2-pyrrolidinyl]carbonyl]-4-thiazolidinecarb...

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Abstract

The invention provides a preparation method of a pidotimod crude drug. The preparation method mainly comprises a condensation reaction and a hydrolysis reaction. The preparation method provided by the invention has the advantages of simplicity and convenience, easiness in operation, low environmental pollution, stable process, good repeatability, high product yield, high product purity and few impurities.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of pidotimod. Background technique [0002] The immunity of the human body includes specific immunity (refers to the targeted resistance of the human body to a certain pathogen) and non-specific immunity, which directly affects the health of the human body. In real life, due to one reason or another, the immunity of various groups of people is often low. The blood concentration of exogenous immunoglobulin in children over half a year old is low, the immune system is not yet fully developed, and recurrent upper respiratory tract infections often occur due to climate change, which affects the physical growth and psychological development of children to a certain extent. The immune system of the elderly is physiologically degraded, and the cellular immune function is low, which is prone to recurrent respiratory tract infections, cancer and other immuno...

Claims

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Application Information

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IPC IPC(8): C07K5/078C07K1/12
CPCC07K1/12C07K5/06139Y02P20/55
Inventor 王春燕陈志勇随裕敏
Owner 成都美域高制药有限公司
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