Novel method for preparing rocuronium bromide

A synthesis method, the technology of pyrrole bromide, applied in the field of chemical pharmacy, can solve the problems of poor chemical selectivity, achieve high purity, easy post-processing purification, and avoid the effects of by-products

Inactive Publication Date: 2017-11-03
JIANGSU QINGJIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The synthesis of rocuronium bromide reported in European patent EP0287150, starting from 2α, 3α, 16α, 17α-diepoxy-17β-acetoxy-5α-androstane, tetrahydropyrrole attacks the 16,17-position ring Oxygen, ring-opening to introduce 16βpyrrolidinyl, and then use morpholine to attack the 2,3-position epoxy, ring-opening to introduce 2β-morpholinyl, then reduction, acetylation, reaction with allyl bromide, and quaternization to obtain Ro Curonium bromide, when tetrahydropyrrole attacks epoxy reaction in this route, there are 2 epoxy groups, and the chemoselectivity is poor

Method used

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  • Novel method for preparing rocuronium bromide
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  • Novel method for preparing rocuronium bromide

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Experimental program
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Embodiment 1

[0022] 1. Synthesis of compound 2 (2α, 3α-epoxy-17-one-5α-androstane).

[0023] Add 5α-androst-2-en-17-one (27.2g, 0.1mol) and chloroform (140ml) into a clean and dry 250ml three-neck flask, stir to dissolve, cool down to 0-5°C, and control The internal temperature is lower than 5°C, slowly add m-CPBA (16.0g, 0.102mol) in chloroform solution (32ml), control the internal temperature at 0-5°C, stir for 5-6h, and use 1.5mol / L for the reaction solution Wash with ammonia water (60ml*2), then wash with water until neutral, and use starch potassium iodide test paper to detect m-CPBA until it is completely removed. Wash the organic phase with saturated saline (30ml), and then add 5g of anhydrous sodium sulfate to dry for 4-5h. Filtrate, concentrate under reduced pressure to obtain 25.7g of oil, recrystallize from methanol, and dry in vacuo to obtain 22.4g of the target compound 2 (2α,3α-epoxy-17-one-5α-androstane), yield: 77.7%.

[0024] 2. Synthesis of compound 3 (2β-(4-morpholinyl)...

Embodiment 2

[0035] The product rocuronium bromide HPLC purity 99.79% of embodiment 1 gained, see figure 1 ;

[0036] Structure confirmation data: mp: 162-166°C, H-NMR (500MHz, DMSO): δ0.694-0.797 (m, 4H), δ0.902-1.030 (m, 4H), δ1.052-1.092 (m, 1H), δ1.075-1.390 (m, 6H), δ1.400-1.925 (m, 9H), δ1.930-2.170 (m, 6H), δ2.203 (s, 3H), δ2.300-2.490 (d, 4H), δ3.244 (s, 3H), δ3.533 (s, 5H), δ3.610-3.740 (m, 3H), δ3.900-4.100 (m, 2H), δ4.098 ( s, 1H), δ4.247-4.262 (dd, 1H), δ4.357 (s, 1H), δ5.074-5.093 (d, 1H), δ5.608-5.673 (m, 2H), δ6.131 -6.213 (m, 1H), see figure 2 .

[0037] Compared with the prior art, the present invention has the following advantages:

[0038]1. Using compound 1 (5α-androst-2-en-17-one) as a raw material, the morpholine ring is introduced by first opening the epoxy ring on the six-membered ring, and then introducing a functionalized five-membered ring ketone at the α-position four Hydrogen pyrrole avoids the problem of chemoselectivity of tetrahydropyrrole opening epo...

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Abstract

The invention relates to a novel method for preparing rocuronium bromide 1-[17beta-acetoxyl-3alpha-hydroxyl-2beta-(4-morpholinyl)-androstane-16beta-yl]-1-(2-propenyl) pyrrole bromide, the problem of chemoselectivity of pyrrolidine open epoxy in an original line is solved, generation of byproducts is avoided, reaction yield is greatly improved, the production cost is reduced, column chromatography separation is avoided, and aftertreatment purification is implemented easily.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and specifically relates to a rocuronium bromide (I) 1-[17β-acetoxy-3α-hydroxyl-2β-(4-morpholinyl)-androstane-16β-yl] -1-(2-propenyl)pyrrole bromide a new preparation method. Background technique [0002] Rocuronium bromide is a single-quaternary ammonium steroid medium-effect muscle relaxant developed by Organon in the Netherlands and first launched in the United States in 1994. As an adjuvant drug for anesthesia, this product is used for tracheal intubation during anesthesia and muscle relaxation during surgery. It has the characteristics of quick onset, short duration, rapid recovery, no tachycardia and blood pressure changes, and no histamine release. The drug is currently the most widely used muscle relaxant in the world. [0003] [0004] The synthesis of rocuronium bromide reported in European patent EP0287150, starting from 2α, 3α, 16α, 17α-diepoxy-17β-acetoxy-5α-androstane...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00
CPCC07J43/003
Inventor 孟繁柯谢福佳张勇
Owner JIANGSU QINGJIANG PHARMA
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