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Method for purifying etomidate

A technology of etomidate and purification method, applied in the direction of organic chemistry and the like, can solve the problems of increased production cost, decreased process yield and high impurity content, and achieves the effects of low production cost, high process yield and high product quality

Pending Publication Date: 2022-03-18
燃点(南京)生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in the course of the research, it was found that using isopropyl ether to refine etomidate, the purification effect is very poor, the impurity content is relatively high, and the product color is darker; in addition, it is necessary to repeatedly refine the product to control the quality of the product. within range
However, after repeated refining, the process yield is significantly reduced, it takes a long time, and a large amount of waste liquid is generated, resulting in a significant increase in the overall production cost

Method used

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  • Method for purifying etomidate
  • Method for purifying etomidate
  • Method for purifying etomidate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The object that present embodiment handles is etomidate crude product (HPLC purity 97.93%, maximum simple and complex 0.78%), and it is prepared by the following steps, specifically:

[0044] a) Take 60g of R-(+)-α-methylbenzylamine, 50g of triethylamine, 65g of ethyl chloroacetate, and 100mL of toluene, add them into the reaction bottle, start stirring; react at about 70°C for 8 hours. Cool down, filter, and wash the filtrate three times with water.

[0045] b) Add the filtrate after washing with water into the reaction flask, add 67g of formic acid, reflux and divide the water for 3 hours. The temperature was lowered, the reaction solution was washed three times with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a yellow liquid.

[0046] c) Add the yellow liquid obtained in step b) into a reaction flask, add 500 mL of toluene, 35 g of sodium ethoxide, and 100 g of ethyl formate. Reaction at room temperature ...

Embodiment 2

[0064] The refining process of etomidate crude product in the present embodiment is as follows:

[0065] Step 1) Add 10 g of crude etomidate, 20 mL of a mixed solvent of DMSO and water into the reaction bottle, start stirring, raise the temperature to about 70 ° C, stir and dissolve to obtain a solution, and the volume ratio of DMSO and water in the mixed solvent is 1:2 .

[0066] Step 2) Cool down the solution obtained in step 1) to about 5° C., and keep it warm for 1 hour for crystallization. Filtrate, wash, and dry to obtain 8.6 g of etomidate as a white solid, with a yield of 86%.

[0067] Using the same detection conditions as in Example 1 to detect the related substances of the product, the HPLC purity was 99.86%, and the maximum simple impurity was 0.05%.

Embodiment 3

[0069] The refining process of etomidate crude product in the present embodiment is as follows:

[0070] Step 1) Add 10 g of crude etomidate, 15 mL of a mixed solvent of N,N-dimethylformamide and water into the reaction bottle, start stirring, raise the temperature to about 70°C, stir and dissolve to obtain a solution, the N,N- The volume ratio of dimethylformamide and water is 4:3.

[0071] Step 2) Cooling the solution obtained in step 1) to about 45° C., adding seed crystals (crude etomidate) in an amount of 0.5% of the weight of the crude etomidate. The temperature was lowered to about 10°C, and the crystallization was carried out by heat preservation for 1 hour. Filtration, washing, and drying yielded 8.5 g of etomidate in the form of a white solid. Yield 85%.

[0072] Using the same detection conditions as in Example 1 to detect the related substances of the product, the HPLC purity was 99.92%, and the maximum simple impurity was 0.04%.

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Abstract

The invention belongs to the field of chemical pharmacy, and particularly relates to a purification method of etomidate. The purification method comprises the following steps: adding a crude etomidate product into a mixed solvent of an organic solvent and water, stirring and mixing, heating and dissolving, and cooling and crystallizing to obtain etomidate. The organic solvent is any one of N, N-dimethyl formamide, N, N-dimethyl acetamide, N, N-dimethyl propionamide, dimethyl sulfoxide, acetonitrile or acetone. The purification method disclosed by the invention has a very good impurity removal effect on the etomidate crude product, the product quality is high, the crystallinity is good, the purification effect is good, repeated refining is not needed, the process yield is high, the production cost is low, and the purification method is more suitable for industrial production.

Description

Technical field [0001] The invention belongs to the field of chemical pharmaceuticals, and specifically relates to a purification method of etomidate. Background technique [0002] Etomidate is an anesthetic drug that is mainly used for induction of general anesthesia and can also be used for short-term surgical anesthesia. Etomidate has been used clinically for 30 years. Etomidate is a non-barbiturate intravenous sedative and is the hydroxylated salt of imidazole. Its structural formula is as follows, molecular formula C 14 H 16 N 2 O 2 , molecular weight 244.29. The chemical name is (+)-1-(α-methylbenzyl)imidazole-5-carboxylic acid ethyl ester. It is easily soluble in ethanol or chloroform, insoluble in water, and soluble in dilute hydrochloric acid. Its structural formula is as follows: [0003] [0004] The document "Direct synthesis of etomidate using the optically active compound R-(+)-α-methylbenzylamine" (Modern Applied Pharmacy, 1997, 01: 30-31) reports a ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/90
CPCC07D233/90
Inventor 秦勇赵维王勇周超
Owner 燃点(南京)生物医药科技有限公司
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