Method for preparing D-cycloserine through one-pot method

A technology of cycloserine and serine, which is applied in the field of medicine, can solve the problems of many reagents, long reaction steps, unfavorable detection of D-cycloserine residues, etc., and achieve the effects of high liquid phase purity, mild reaction, and improved atom economy

Inactive Publication Date: 2019-08-30
山东诚汇双达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chen Huiru and others reported in "Chemical World" that D-serine was used as a raw material, and ethyl trifluoroacetate was used as a protecting group to protect the amino group, and D-cycloserine was obtained through a 5-step reaction; the reaction steps were relatively long, and triethyl Amines, methanesulfonyl chloride, DBU and petroleum ether; disadvantages of this method: longer reaction steps and more reagents used; wherein petroleum ether is a mixture of alkanes, which is unfavorable for the detection of organic residues in the product D-cycloserine

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (1) Preparation of Intermediate I:

[0033] Add 741g of toluene to a 2000ml dry four-neck round bottom bottle, add 123.5g of 3-chloro-D-serine under stirring and install a drying tube, add 142.8g of thionyl chloride dropwise at 20-30°C; 60-70 ° C to complete the reaction of raw materials. After the reaction, excess thionyl chloride was removed in vacuum to obtain intermediate I, ie, a toluene solution of 3-chloro-D-alanyl chloride hydrochloride.

[0034] (2) Preparation of crude D-cycloserine:

[0035]Pre-prepared aqueous sodium hydroxide solution with a concentration of 35% by mass: 160g of sodium hydroxide and 300g of deionized water, and lowered the temperature to below 0°C. Take 300g of 35% sodium hydroxide aqueous solution and put it into a 2000ml four-neck round bottom flask, control the temperature at -5-5°C, add the above toluene solution and stir evenly. Then control the temperature at -5-5°C and add dropwise a solution of 83.4g of hydroxylamine hydrochlorid...

Embodiment 2

[0039] (1) Preparation of Intermediate I:

[0040] Add 741g of toluene to a 2000ml dry four-neck round bottom bottle, add 123.5g of 3-chloro-D-serine under stirring and install a drying tube, add 178.5g of thionyl chloride dropwise at 20-30°C; 50-60 ° C to complete the reaction of raw materials. After the reaction, excess thionyl chloride was removed in vacuum to obtain intermediate I, ie, a toluene solution of 3-chloro-D-alanyl chloride hydrochloride.

[0041] (2) Preparation of crude D-cycloserine:

[0042] Pre-prepared aqueous sodium hydroxide solution with a concentration of 35% by mass: 160g of sodium hydroxide and 300g of deionized water, and lowered the temperature to below 0°C. Take 300g of 35% sodium hydroxide aqueous solution and put it into a 2000ml four-neck round bottom flask, control the temperature at -5-5°C, add the above toluene solution and stir evenly. Then control the temperature at -5-5°C and add dropwise a solution of 104.3g of hydroxylamine hydrochlor...

Embodiment 3

[0046] (1) Preparation of Intermediate I:

[0047] Add 741g of toluene to a 2000ml dry four-neck round bottom bottle, add 123.5g of 3-chloro-D-serine under stirring and install a drying tube, add 178.5g of thionyl chloride dropwise at 20-30°C; 50-60 ° C to complete the reaction of raw materials. After the reaction, excess thionyl chloride was removed in vacuum to obtain intermediate I, ie, a toluene solution of 3-chloro-D-alanyl chloride hydrochloride.

[0048] (2) Preparation of crude D-cycloserine:

[0049] Pre-prepared aqueous sodium hydroxide solution with a concentration of 35% by mass: 160g of sodium hydroxide and 300g of deionized water, and lowered the temperature to below 0°C. Take 300g of 35% sodium hydroxide aqueous solution and put it into a 2000ml four-neck round bottom flask, control the temperature at -5-5°C, add the above toluene solution and stir evenly. Then control the temperature at -5-5°C and add dropwise a solution of 104.3g of hydroxylamine hydrochlor...

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PUM

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Abstract

The invention discloses a method for preparing D-cycloserine through a one-pot method. The method comprises: carrying out a reaction on 3-chloro-D-serine and thionyl chloride in a solvent to obtain anintermediate 3-chloro-D-alanyl chloride hydrochloride solution; preparing a 35% sodium hydroxide aqueous solution, cooling to a temperature of less than 0 DEG C, controlling the temperature at -5 to5 DEG C, and adding the 3-chloro-D-alanyl chloride hydrochloride solution; uniformly stirring after completing the adding, controlling the temperature at -5 to 5 DEG C, and adding a hydroxylamine hydrochloride solution; slowly heating to a temperature of 20-30 DEG C after the adding, and adjusting the pH value of the solution to 10.5-12.0 by adding a 35% sodium hydroxide aqueous solution; carryingout standing liquid separation after completing the reaction; taking the water phase, and concentrating to achieve a near dry state; adding methanol, dissolving, and filtering to obtain a methanol solution; cooling to a temperature of -5 to 5 DEG C, and adjusting the pH value of the solution to 6.0-6.5 with a 60% acetic acid methanol solution; and carrying out stirring crystallization, carrying out centrifugation, drying the obtained wet product to obtain crude D-cycloserine, and refining to obtain the D-cycloserine finished product. According to the present invention, the product prepared bythe method has a liquid phase purity of more than 99.6% and a specific rotation of more than +110 DEG.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for preparing D-cycloserine by a one-pot method. Background technique [0002] D-cycloserine, chemical name D-4-amino-3-isoxazolone; is a product developed by Eli Lilly and Company in the early 1970s. In 1982, the FDA approved Eli Lilly's capsules for marketing. This product is suitable for the treatment of tuberculosis caused by tuberculosis that is sensitive to the drug and treated with first-line anti-tuberculosis drugs (such as streptomycin, isoniazid, rifampicin and ethambutol). Treatment of ineffective active pulmonary and extrapulmonary tuberculosis (including renal tuberculosis). Similar to other anti-tuberculosis drugs, this product is one of the main second-line drugs, usually in combination. This product can also be used for the treatment of acute urinary tract infection caused by sensitive Gram-positive and Gram-negative bacteria, especially En...

Claims

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Application Information

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IPC IPC(8): C07D261/04
CPCC07D261/04
Inventor 李跃东廖国志葛正全杨彦军任真真王志刚
Owner 山东诚汇双达药业有限公司
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