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Method for preparing steroid muscular relaxant and analogue thereof

A compound and steroid technology, applied in the field of preparation of steroid muscle relaxants and similar compounds, can solve the problems of low yield and the like, and achieve the effects of good selectivity, shortened reaction time, and reduced hydrolysis

Active Publication Date: 2009-10-14
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] USP2005 / 0159398A1 describes an improvement to the first method of USP4894369, using selective acylation in a solvent, selective hydrolysis of the 3-acyl group of the by-product diacylate with dilute acid, and then recrystallizing twice to obtain a high-purity formula III compound, but the yield is lower; and the bromination agent is salified to obtain the formula I compound

Method used

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  • Method for preparing steroid muscular relaxant and analogue thereof
  • Method for preparing steroid muscular relaxant and analogue thereof
  • Method for preparing steroid muscular relaxant and analogue thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: 1-[17β-Acetoxy-3α-hydroxy-2β-(4-morpholinyl)-5α-androstane-16β-yl]-1-(2-propenyl)pyrrolidine bromide (rocuronium bromide) preparation

[0029] 3.0g 1-[3α, 17β-diacetoxy-2β-(4-morpholinyl)-5α-androstane-16β-yl]-1-(2-propenyl)pyrrolidine bromide (acetyl Cucuronium bromide) was dissolved in 30ml of dichloromethane, added 9ml of 18% hydrobromic acid, stirred, heated, and reacted at 40°C for 4.5 hours; then, cooled to 2°C, added pre-cooled 5-10% bicarbonate Neutralize with sodium aqueous solution to make the PH value 7-8, let it stand in a timely manner, and separate layers; the water layer is extracted with dichloromethane several times to extract the product, and the extracted solutions are combined, and dehydrated with anhydrous sodium sulfate to clean. Concentrate to dryness under reduced pressure below 40°C to obtain 2.2 g of rocuronium bromide, with an HPLC percent area purity of 98.7%.

Embodiment 2

[0030] Example 2: 1-[17β-Acetoxy-3α-hydroxy-2β-(4-morpholinyl)-5α-androstane-16β-yl]-1-(2-propenyl)pyrrolidine bromide (rocuronium bromide) preparation

[0031] 3.0g 1-[3α, 17β-diacetoxy-2β-(4-morpholinyl)-5α-androstane-16β-yl]-1-(2-propenyl)pyrrolidine bromide (acetyl Cucuronium bromide) was dissolved in 9ml of 9% hydrobromic acid, and reacted at 25°C for 15 hours under stirring; then, 30ml of dichloromethane was added, cooled to 2°C, and neutralized by adding pre-cooled 2-5% ammonia solution , so that the pH value is 7-8, let it stand at the right time, and separate layers; the water layer is extracted with dichloromethane several times to extract the product, and the extraction solution is combined, and dehydrated with anhydrous sodium sulfate to the net. Concentrate to dryness under reduced pressure below 40°C to obtain 1.95 g of rocuronium bromide, with an HPLC percent area purity of 98.5%.

Embodiment 3

[0032] Example 3: 1-[17β-Acetoxy-3α-hydroxy-2β-(4-morpholinyl)-5α-androstane-16β-yl]-1-(2-propenyl)pyrrolidine bromide (rocuronium bromide) preparation

[0033] 3.0 g of 1-[3α, 17β-diacetoxy-2β-(4-morpholinyl)-5α-androstane-16β-yl]-1-(2-propenyl)pyrrolidine bromide (acetyl Rocuronium bromide) was dissolved in 30ml of acetone, 15ml of 27% hydrobromic acid was added, heated under stirring, and reacted at 50°C for 2 hours; then, 30ml of chloroform was added, cooled to 5°C, and pre-cooled 10 ~15% potassium bicarbonate aqueous solution is neutralized, so that the pH value is 7~8, it is allowed to stand in a timely manner, and the layers are separated; the water layer is extracted with chloroform several times to extract the product, and the extracted solution is combined, and dehydrated with anhydrous sodium sulfate to the net. Concentrate to dryness under reduced pressure below 40°C to obtain 2.1 g of rocuronium bromide, with an HPLC percent area purity of 98.5%.

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PUM

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Abstract

The invention provides a preparation method of a steroidal muscle relaxant drug and its similar compounds. The compound of formula II is used as a starting material, and the selective Hydrolyzing the 3-position acyl group of the compound of formula II, neutralizing it with a weak base, and extracting the product from the aqueous layer with an inert and water-immiscible solvent multiple times; compared with the prior art, the method of the present invention does not need to pass through column chromatography, The operation is simple, the HPLC percentage area purity of the obtained product can reach 98.5%, and the yield of the product can reach about 70%; the improvement and optimization of the prior art are realized.

Description

Technical field: [0001] The invention relates to a preparation method of steroidal muscle relaxants and similar compounds, belonging to the technical field of medicinal chemistry Background technique: [0002] Steroidal muscle relaxants are non-depolarizing neuromuscular blocking agents, which have replaced traditional muscle relaxants as the first choice for major surgery. Rocuronium Bromide (Rocuronium Bromide) is a non-depolarizing muscle relaxant drug with rapid and medium time effect. [0003] USP4894369 describes two methods for the preparation of compounds of formula I. [0004] The reaction formula of the first method is as follows: [0005] [0006] Because the compound of formula III is relatively difficult to prepare, that is, in 20 times of solvent, it is selectively acylated with an acylating agent of 1.12 to 1.13 molar equivalents, and then obtained by basic alumina column chromatography; while the compound of formula III and brominating agent form After ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J43/00C07J75/00
Inventor 朱秀燕方伟明徐顺广
Owner ZHEJIANG XIANJU PHARMA
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