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Synthetic method of bromamines muscle relaxant

A muscle relaxant and a synthesis method technology, applied in the production of steroids, bulk chemicals, organic chemistry, etc., can solve problems such as affecting product purity, improve product yield and product quality, reduce costs, and simplify operations. effect of steps

Inactive Publication Date: 2009-03-11
王加旺
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

We found that the ester at the 3-position is indeed easier to hydrolyze than the ester at the 17-position, but during the hydrolysis process, some of the ester at the 17-position is still hydrolyzed into the 17-OH, resulting in impurities that affect the purity of the product
[0022] Therefore, there are still many problems in the synthetic technique of ammonium bromide muscle relaxants, and further improvement is needed.

Method used

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  • Synthetic method of bromamines muscle relaxant
  • Synthetic method of bromamines muscle relaxant
  • Synthetic method of bromamines muscle relaxant

Examples

Experimental program
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Effect test

Embodiment 12

[0050] Example 12α, 3α, 16α, the synthesis of 17α-dioxyoxy-17-acetoxy-5-androstane (intermediate 4)

[0051] 1.1.5 Preparation of α-androst-2-en-17-one (interemediate 2)

[0052] Add 100g of epiandrosterone, 30ml of pyridine, 600ml of dichloromethane, 120g of p-toluenesulfonyl chloride into the reaction bottle, heat and reflux for 3h; Drying over sodium sulfate and concentrating under reduced pressure gave 144 g of the white body 2-p-phenylmethylsulfonyl-epiandrosterone (intermediate 1) with a yield of 92%;

[0053] Mix 60 g of the above-mentioned yellow-white solid and 80 ml of DMSO and heat to 120° C., and stir for 3 h. Stop heating, stand at room temperature for crystallization overnight, filter, wash the filter cake with water, and dry to obtain 31 g of a flesh-colored solid of 5α-androst-2-en-17one with a melting point of 102-105°C and a reaction yield of 87%.

[0054] 1.2.1 Synthesis of 7-acetoxy-5α-androst-2,16-diene (intermediate 3)

[0055] Add 50g of 5α-androst-2-...

Embodiment 2

[0058] The preparation of embodiment 2 rocuronium bromide

[0059] 2.1.2 Preparation of β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androst-3α-ol, 17β-acetate

[0060] Dissolve 10 g of 2α, 3α, 16α, 17α-diepoxy-17β-acetoxy-5-androstane (intermediate 4) prepared by the method in Example 1 above in 100 ml of methanol, add 10 ml of 4N sodium hydroxide , heated to reflux for 30 minutes, the solution was cooled to 40°C, 15 ml of tetrahydropyrrole was added and heated to reflux for 15 minutes, cooled, filtered, washed with water until neutral, and a white solid was obtained. Put the solid into a stainless steel pressure reactor, add 50ml of morpholine and 5ml of water into the reactor, and react at 140°C for 36 hours; after cooling, the solvent is evaporated under reduced pressure, and the residue is crystallized with acetone to obtain 4.5g of white crystals. This compound was identified as Intermediate 6A.

[0061] Add 4.5 g of the above-mentioned intermediate 6A into a 50 ml reacti...

Embodiment 3

[0073] The preparation of embodiment 3 vecuronium bromide

[0074] Preparation of 2β, 16β-dipiperidinyl-5α-androst-3α-ol-17-one (intermediate 8)

[0075] In a pressure reaction vessel lined with polytetrafluoroethylene, add 2α, 3α, 16α, 17α-diepoxy-17β-acetoxy-5-androstane 7g, 70ml of piperidine, and 7ml of water. Place in an oven at 150°C for 40 hours. Cool the reactor to room temperature, open the reactor, take out the reactant, evaporate the solvent under reduced pressure, dissolve the residue with 2N HCl and filter, adjust the filtrate to pH 8-10 with 10% NaOH, filter out the solid, wash it with water, dry it with acetone Crystallized to obtain 6 g of white crystals.

[0076] By 2β, 16β-dipiperidinyl-5α-androst-3α-ol-17-ketone (intermediate 8) can refer to the specific method of preparing vecuronium bromide (Zhu Baoquan. New Drug Synthesis Handbook. Beijing: Chemical Industry Press 2002.12).

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Abstract

The invention provides a bromide type muscle relaxant, which mainly comprises a method for synthesizing rocuronium bromide, vecuronium bromide, pancuronium bromide and pipecuronium bromide , and is mainly characterized by adopting a ketene as an acylating agent during the process of transforming 5Alpha-androstane -2-alkene-17-alkone to 17-acetoxyl group-5Alpha- androstane-2, and 16-diene, adopting a stress kettle as a reactor when realizing the step of ring-opening and condensation of the 2 Alpha and 3 Alpha-epoxy compound, and adding a solid catalyst and a desiccant in the last step of operation of rocuronium bromide to greatly improve the reaction yield and the quality of products. The technology provided by the invention can shorten the synthesis time of the bromide type muscle relaxant, simplify the operation steps, improve the quality of products and reduce the production cost.

Description

technical field [0001] The present invention relates to the synthesis of muscle relaxants, in particular to the synthesis of ammonium bromide muscle relaxants. Background technique [0002] Ammonium bromide muscle relaxants, especially rocuronium bromide, vecuronium bromide, pancuronium bromide, and pipecuronium bromide are commonly used muscle relaxants in surgical operations. [0003] In the prior art, epiandrosterone (epiandrosterone) is generally used as a starting material to synthesize intermediates 2α, 3α, 16α, 17α-diepoxy-17-acetoxy-5-androstane (intermediate 4, referred to as bicyclic Oxygen), and then the ammonium bromide muscle relaxant is prepared by reacting the intermediate with an amine compound. The synthetic route of the intermediate (diepoxy) can be carried out according to the following reaction equation, and details can be found in US3553212, US4171306, and US6090957 patents. [0004] [0005] Formula S [0006] The rout...

Claims

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Application Information

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IPC IPC(8): C07J43/00
CPCY02P20/55
Inventor 王加旺
Owner 王加旺
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