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Method for preparing rocuronium bromide midbody compound crystal

A technology of rocuronium bromide and compounds, applied in the field of pharmaceutical chemical synthesis, can solve the problems of large solution volume, complicated operation, high cost, etc., and achieve the effect of convenient and effective method, improved product quality and yield, and shortened reaction time

Active Publication Date: 2012-06-13
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To prepare rocuronium bromide with the foam-like compound (I) as an intermediate, it needs to be purified by column chromatography, the solution is large in volume, the operation is complicated, the working hours are long, the yield is low, and the cost is high

Method used

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  • Method for preparing rocuronium bromide midbody compound crystal
  • Method for preparing rocuronium bromide midbody compound crystal
  • Method for preparing rocuronium bromide midbody compound crystal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of compound 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstane-3α, 17β-diol-diacetate crystals:

[0039] In the reaction flask, add 120ml of dichloromethane, compound 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstane-3α, 30g of 17β-diol (II), and stir , cooled to 12°C, added 60ml of acetic anhydride, reacted at 15-20°C for 6 hours; Extract with dichloromethane, combine the organic layers, wash with water, separate layers, dehydrate the organic layer with anhydrous sodium sulfate; filter, and concentrate the filtrate to nearly dryness;

[0040] Add 90ml of dichloromethane to dissolve, add 150ml of n-hexane, concentrate to an appropriate amount, add 150ml of n-hexane, concentrate until a large amount of crystals precipitate, cool, filter, and obtain a wet product; dry to obtain compound 2β-(4- Morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstane-3α, 17β-diol-diacetate (I) 34.1g; mp: 138~140℃, [α] D 20 =+12.7°(10mg / ml CHCl 3 ), the HPLC purity is 99.3%. ...

Embodiment 2

[0042] Preparation of compound 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstane-3α, 17β-diol-diacetate (I) crystals:

[0043] In the reaction flask, add 120ml of dichloromethane, compound 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstane-3α, 30g of 17β-diol (II), and stir , cooled to 8°C, added 60ml of acetic anhydride, reacted at 10-15°C for 7 hours; poured into ice water, added 180ml of dichloromethane, stirred, cooled to below 5°C, neutralized with sodium carbonate solution, layered, The layers were extracted with dichloromethane, the organic layers were combined, washed with water, separated into layers, the organic layer was dehydrated with anhydrous sodium sulfate; filtered, and the filtrate was concentrated to nearly dryness;

[0044]Add 90ml of chloroform to dissolve, add 150ml of n-heptane, concentrate to an appropriate amount, add 150ml of n-heptane, concentrate until a large amount of crystals precipitate, cool, filter, and obtain a wet product; dry to obta...

Embodiment 3

[0046] Preparation of compound 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstane-3α, 17β-diol-diacetate (I) crystals:

[0047] In the reaction flask, add 120ml of dichloromethane, compound 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstane-3α, 30g of 17β-diol (II), and stir , cooled to 15°C, added 60ml of acetic anhydride, reacted at 20-25°C for 5 hours; Extract with dichloromethane, combine the organic layers, wash with water, separate layers, dehydrate the organic layer with anhydrous sodium sulfate; filter, and concentrate the filtrate to about 100ml;

[0048] Add 150ml of petroleum ether, concentrate to an appropriate amount, add 150ml of petroleum ether, concentrate until a large amount of crystals precipitate, cool, filter, and obtain a wet product; dry to obtain the compound 2β-(4-morpholinyl)-16β- (1-Pyrrolidinyl)-5α-androstane-3α, 17β-diol-diacetate (I) 33.7g; mp: 138~140℃, [α] D 20 =+13.0°(10mg / ml CHCl 3 ), the HPLC purity is 99.4%.

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Abstract

The invention discloses a method for preparing rocuronium bromide midbody compound crystal, which is characterized in that compound 2beta-(4-morpholinyl)-16beta-(1-pyrrolidyl)-5alpha-androstane-3alpha, 17beta-glycol is adopted as raw material to be proceeded with acylation reaction and then to be refined to obtain crystal powder compound 2beta-(4 - morpholinyl)-16beta-(1 - pyrrolidinyl)-5alpha-Androstane-3alpha, 17beta-diol - 2 acetate with high purity. With the method, the fallow crystal powder compound with high purity can be prepared, and conditions are created for synthesizing high-quality rocuronium bromide.

Description

technical field [0001] The invention relates to a method for chemically synthesizing medicine, in particular to a method for preparing rocuronium bromide intermediate compound crystals. Background technique [0002] Rocuronium Bromide, chemical name: 1-[17β-acetoxy-3α-hydroxy-2β-(4-morpholinyl)-5α-androstane-16β-yl]-1-(2 -propenyl)pyrrolidine bromide is a non-depolarizing sterol neuromuscular blocking agent, and is a non-depolarizing muscle relaxant with rapid and medium-term effects. Because of its rapid onset of action, no accumulation in the body, small adverse reactions, rapid recovery, and high safety, it is widely used in clinical surgery, and has now become the drug of choice in major surgery among muscle relaxants. [0003] Compound 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstane-3α, 17β-diol-diacetate (I) is an important intermediate in the synthesis of rocuronium bromide Body, the structural formula of compound (I) is as follows: [0004] [0005] One o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J43/00
Inventor 方伟明
Owner ZHEJIANG XIANJU PHARMA
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