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Preparation method of rocuronium bromide intermediate and rocuronium bromide

A technology for rocuronium bromide and intermediates, which is applied in the field of preparation of rocuronium bromide intermediates and rocuronium bromide, and can solve problems such as troublesome handling operations

Active Publication Date: 2020-02-14
重庆仁泽医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The post-treatment operation of this method is cumbersome, involves a large amount of acidic wastewater, and has a greater risk of environmental pollution

Method used

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  • Preparation method of rocuronium bromide intermediate and rocuronium bromide
  • Preparation method of rocuronium bromide intermediate and rocuronium bromide
  • Preparation method of rocuronium bromide intermediate and rocuronium bromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Into a dry and clean 250ml three-neck flask, add 10g of the compound of formula II, add 150ml of toluene, 30.6IIDQ, 5.4g of glacial acetic acid, and heat up to reflux for 5 hours. The temperature was lowered to 10-20°C, crystals were precipitated, filtered, and dried to obtain 7.1 g of compound (Formula III), with a molar yield of 64.9% and a purity of >99.9%.

[0043] Into a dry and clean 100ml three-neck flask, add 7g of compound of formula III, 50ml of absolute ethanol, 0.5g of sodium carbonate, 7g of 3-bromopropene, react at 35°C for 4 hours, filter under reduced pressure to remove sodium carbonate, and slowly drop the filtrate to 700ml Stir and crystallize in methyl tert-butyl ether, filter under nitrogen protection, and dry under reduced pressure at 40°C overnight to obtain 7 g of rocuronium bromide (Formula I), with a molar yield of 80.1% and a purity of >99.0%.

Embodiment 2

[0045] To a dry and clean 250ml three-neck flask, add 10g of the compound of formula II (2β, 3α, 5α, 16β, 17β)-2-(4-morpholine)-16-(1-pyrrole)-androster-3,17 -diol, add 150ml toluene, 30.6gIIDQ, 5.4g glacial acetic acid, heat up to reflux reaction for 5 hours. Cool down to 10-20°C, precipitate crystals, filter, and dry to obtain 6.8 g of compound (Formula III), with a molar yield of 62.2% and a purity of >99.9%;

[0046]To a dry and clean 100ml three-neck flask, add 6g of the compound of formula III (2β, 3α, 5α, 16β, 17β)-2-(4-morpholine)-16-(1-pyrrole)-androsta-3,17 -diol-17-acetate, 50ml absolute ethanol, 0.5g sodium carbonate, 6g 3-bromopropene, react at 35°C for 4 hours, filter under reduced pressure to remove sodium carbonate, and slowly drop the filtrate into 700ml methyl tert-butyl ether , stirred and crystallized, filtered under nitrogen protection, and dried under reduced pressure at 40°C overnight to obtain 5.9 g of rocuronium bromide (Formula I), with a molar yield...

Embodiment 3

[0048] Into a dry and clean 2000ml three-neck flask, add 50g of the compound of formula II, add 0.5L of acetone, 124.6g of EEDQ, and 26.9g of glacial acetic acid, raise the temperature to reflux for 4 hours, and then add 0.75L of acetonitrile. Then slowly lower the temperature to room temperature, heat and crystallize for 2 hours, and filter to obtain 48 g of white crystalline powder (Formula III), with a molar yield of 87.7% and a purity of >99.9%;

[0049] Into a dry and clean 1000ml three-necked flask, add 45g of the compound of formula III, 900ml of tert-butanol, 10g of alumina, 50g of 3-bromopropene, react at 45°C for 6 hours, filter under reduced pressure to remove the alumina, and slowly drop the filtrate to 5L without Stir and crystallize in water ether, filter under nitrogen protection, and dry under reduced pressure at 40°C overnight to obtain 50 g of rocuronium bromide (Formula I), with a molar yield of 89.3% and a purity of >99.0%.

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Abstract

The invention discloses a preparation method of a rocuronium bromide intermediate and rocuronium bromide. According to the method, (2beta,3alpha,5alpha,16beta,17beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol is used as an initial raw material, and is subjected to selective acetylation with glacial acetic acid under the action of a condensing agent to obtain (2beta,3alpha,5alpha,16beta,17beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol-17-acetate, and then (2beta,3alpha,5alpha,16beta,17beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol-17-acetate issubjected to salt formation with 3-bromopropene in a protic solvent under the action of a basic catalyst to obtain rocuronium bromide. The preparation method adopted in the invention is mild in reaction conditions, simple in post-treatment, and suitable for large-scale industrial application.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a rocuronium bromide intermediate and a preparation method of rocuronium bromide. Background technique [0002] Rocuronium Bromide (Rocuronium Bromide) is a new type of non-depolarizing sterol muscle relaxants, researched and developed by the Netherlands Organon (Organon), in June 1994 for the first time listed in the United States. As an adjuvant drug for anesthesia, this product is used for endotracheal intubation during anesthesia and muscle relaxation during surgery. It has the characteristics of quick onset, short duration, and rapid recovery. The drug is currently the most widely used muscle relaxant in the world. At present, the commonly used synthesis method of rocuronium bromide is to use the commercially available compound of formula II as the starting material, and obtain the compound of formula III through conventional esterification, and then react the compound of formula II...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00
CPCC07J43/003
Inventor 吴科赖开智肖波许娟
Owner 重庆仁泽医药科技有限公司
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