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Preparation of rocuronium

A technology of rocuronium bromide and pyrrole bromide, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of low yield and achieve the effects of improving product quality, avoiding side reactions, and avoiding epoxy ring opening

Inactive Publication Date: 2008-12-17
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Second, compound 3 is acetylated, and its product is also a mixture, including: 2β-(4-morpholinyl)-16β-(1-tetrahydropyrrolyl)-5α-androstane-3α, 17β- Diol 17-acetate (4), 2β-(4-morpholinyl)-16β-(1-tetrahydropyrrolyl)-5α-androstane-3α, 17β-diol 3-acetate (11) , 2β-(4-morpholinyl)-16β-(1-tetrahydropyrrolyl)-5α-androstane-3α, 17β-diol 3,17-diacetate (12) and 2β-(4- Morpholinyl)-16β-(1-tetrahydropyrrolyl)-5α-androstane-3α, 17β-diol (3), after separation, the yield is low, and the reaction result is as shown in formula 3:

Method used

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  • Preparation of rocuronium
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Examples

Experimental program
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Embodiment 1

[0030] Preparation of 2α,3α-epoxy-16β-(1-tetrahydropyrrolyl)-5α-androstan-17-one

[0031] Sodium hydroxide solution (30ml; 4N) was added to 2α, 3α, 16α, 17α-diepoxy-5α-androstane-17β-ol acetate (30g) in methanol (500ml) solution, at 8-10°C Stir for 1 hour. Tetrahydropyrrole (45ml) was added, followed by reflux for 20 minutes. The reaction solution was cooled to about 10°C, added water (600ml), filtered, washed with water (3×200ml), dried, and recrystallized with acetone to obtain white crystals 2α, 3α-epoxy-16β-(1-tetrahydropyrrolyl )-5α-androstan-17-one (21 g).

Embodiment 2

[0033] Preparation of 3α-hydroxy-2β-(4-morpholinyl)-16β-(1-tetrahydropyrrolyl)-5α-androstan-17-one

[0034]Water (12ml) was added to a solution of 2α,3α-epoxy-16β-(1-tetrahydropyrrolyl)-5α-androstan-17-one (20g) in morpholine (120ml) and heated to reflux for 3 days. Poured into water (1000ml), filtered, washed with water, dried to obtain the crude product, and recrystallized from acetone to obtain pure 3α-hydroxy-2β-(4-morpholinyl)-16β-(1-tetrahydropyrrolyl )-5α-androstan-17-one (15 g).

Embodiment 3

[0036] Preparation of 3α-hydroxy-2β-(4-morpholinyl)-16β-(1-tetrahydropyrrolyl)-5α-androstan-17-one 3-O-tetrahydropyran-2-ether

[0037] Add p-toluenesulfonic acid (0.598g) in dichloromethane (130ml), stir at room temperature for 10 minutes, add 3α-hydroxyl-2β-(4-morpholinyl)-16β-(1-tetrahydropyrrolyl)-5α -Androstan-17-one (13g), after complete dissolution, add 2,3-dihydro-4H-pyran (4.84g) under stirring, and reflux for 48 hours. After completion of the reaction, cool to room temperature, add 5% sodium carbonate aqueous solution (26ml), stir until alkaline, wash with water three times (20ml×3), then wash once with 5% sodium carbonate aqueous solution. Concentrate under reduced pressure until there is almost no solvent, pour into methanol (pH7.5~8), continue to concentrate until almost no solvent, pour into methanol (pH7.5~8), continue to concentrate until almost no solvent, pour into methanol (13ml), cool overnight, Filter, wash with ice methanol, drain, and wash with water un...

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Abstract

The invention pertains to the medicinal chemosynthesis field and relates to the preparation method of 1-square bracket 17Beta-acetoxyl-3Alpha-oxhydryl-2Beta-(4-morpholinyl)-androstane-16Beta-group square bracket-1-(2-propenyl) pyrrole bromide (rocuronium). The preparation method adopts 2Alpha, 3Alpha, 16Alpha, 17Alpha-diepoxy-5Alpha-androstane-17Beta-glycol acetate as the raw material from which the rocuronium is obtained after seven reaction steps including hydrolysis, pyrrole reaction, morpholinyl reaction, etherification, reduction, acetylation, hydrolysis and quaterisation. The preparation method of the invention has the advantages that the hydrolysis of 16Alpha, 17Alpha-epoxy-17Beta-acetoxyl takes place at a comparatively low temperature, which can avoid the ring opening of the epoxy and further the inhibition of the formation of 17Alpha-(1-pyrrolidine)-16-ketone; the synthesis avoids the optional acetylation of site 3 and site 17 oxhydryls and clearly simplifies the separation after reaction.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and relates to compound 1-[17β-acetoxy-3α-hydroxyl-2β-(4-morpholinyl)-androstane-16β-yl]-1-(2-propenyl) Preparation method of pyrrole bromide. Background technique [0002] Rocuronium bromide, chemical name 1-[17β-acetoxy-3α-hydroxy-2β-(4-morpholinyl)-androstane-16β-yl]-1-(2-propenyl)pyrrole bromide It is a non-depolarizing sterol muscle relaxant with rapid onset of action. The relevant prior art discloses the synthetic route of rocuronium bromide. Savage D.S. was equal to the synthesis of rocuronium bromide in 1990, the synthetic route is as formula 1: [0003] [0004] Formula 1 [0005] The above-mentioned synthetic route is brief, and there are few steps, but there are relatively serious defects, one, by 2α, 3α; 16α, 17α-diepoxy-5α-androstane-17β-alcohol 17-acetate (1) by Its patent method is to reflux in methanol containing sodium hydroxide for 30 minutes, then add py...

Claims

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Application Information

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IPC IPC(8): C07J43/00
Inventor 张沪跃周志贵
Owner FUDAN UNIV
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