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Preparation method of rocuronium bromide intermediate

A technology for rocuronium bromide and intermediates, which is applied in the field of preparation of rocuronium bromide intermediates, can solve the problems of unindustrialization, high production cost, dark product color, etc., and reduce the loss of main products, by-products, and three wastes The effect of reducing emissions

Active Publication Date: 2021-11-23
福安药业集团重庆博圣制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The boiling point of 2,4,6-collidine is 171°C at normal pressure. In industrial production, steam heating is not easy to reach the reflux temperature, the production operation is difficult, and it cannot be industrialized; 2,4,6-Collidine is irritating, and its Acute toxicity LD50 is 400mg / kg (oral for rats), 1000-2000mg / kg (percutaneous for guinea pigs), not suitable for industrial application; 2,4,6-collidine is expensive and has high production costs
[0006] The preparation method of this patent is to carry out process telescoping on the traditional process, which improves the production efficiency, but this process uses expensive triflate such as lanthanum triflate or ytterbium triflate, At the same time, the product obtained by using toluene for a long time dehydration reaction at high temperature has a deep color, and needs to be recrystallized to remove the by-products introduced in the high temperature reaction

Method used

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  • Preparation method of rocuronium bromide intermediate
  • Preparation method of rocuronium bromide intermediate
  • Preparation method of rocuronium bromide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 15.6g (0.11mol) of phosphorus pentoxide and methanesulfonic acid (156g) into a clean 250mL three-neck flask, stir at room temperature for 2 hours, then add epiandrosterone (29.0g, 0.10mol), heat up to 110°C, and react At 6 hours, TLC showed no starting material. The reaction solution was lowered to room temperature, poured into 500mL of water, extracted with 500mL of dichloromethane, the organic phase was washed twice with 250ml of 5% sodium carbonate aqueous solution, washed twice with 250ml of purified water, dried over anhydrous sodium sulfate, filtered, Dichloromethane was recovered by concentration under reduced pressure to obtain a dark brown oil, which was crystallized with methanol to obtain 21.6 g of an off-white solid with an HPLC purity greater than 95% and a molar yield of 79.4%. The chromatographic results are shown in Table 1 below. figure 1 shown.

[0031] Table 1 Example 1 prepared 5α-androst-2-en-17-one purity HPLC data sheet

[0032]

[0033] ...

Embodiment 2

[0035] Add 15.6g (0.11mol) of phosphorus pentoxide and methanesulfonic acid (156g) into a clean 250mL three-neck flask, stir at room temperature for 2 hours, then add epiandrosterone (29.0g, 0.10mol), heat up to 40°C, and react At 17 hours, TLC showed no starting material. The reaction solution was lowered to room temperature, poured into 500mL of water, extracted with 500mL of dichloromethane, the organic phase was washed twice with 250ml of 5% sodium carbonate aqueous solution, washed twice with 250ml of purified water, dried over anhydrous sodium sulfate, filtered, Concentrate under reduced pressure and reclaim dichloromethane, obtain 24.3g off-white solid, HPLC purity 96.7%, molar yield 89.3%, its detection chromatography result is shown in Table 2 below, and chromatogram is as follows figure 2 shown.

[0036] Table 2 Example 2 prepared 5α-androst-2-en-17-one purity HPLC data sheet

[0037]

Embodiment 3

[0039] Add phosphorus pentoxide (15.6g, 0.11mol), methanesulfonic acid (15.6g, 0.16mol), dichloromethane (300mL) into a clean 500mL single-necked bottle, stir at room temperature for 2 hours, then add epiandrosterone (29.0 g, 0.10mol), reflux reaction for 17 hours. The reaction solution was lowered to room temperature, poured into 500mL of water, added 200mL of dichloromethane, the organic phase was washed twice with 250mL of 5% sodium carbonate aqueous solution, washed twice with 250ml of purified water, dried over anhydrous sodium sulfate, and filtered 1. Concentrate under reduced pressure to recover dichloromethane to obtain 24.6 g of off-white solid with a molar yield of 90.4%, an HPLC purity of 97.1%, and a water content of less than 0.1%. Its detection chromatogram result is shown in table 3 below, and chromatogram is as follows image 3 shown.

[0040] Table 3 Example 3 prepared 5α-androst-2-en-17-one purity HPLC data sheet

[0041]

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a rocuronium bromide intermediate. The preparation method comprises the following steps: by taking epiandrosterone as shown in a formula I as a raw material, carrying out dehydration reaction under the catalysis of an Eaton reagent, and then washing, extracting and concentrating to obtain the rocuronium bromide intermediate (5alpha-androstane-2-ene-17-ketone). According to the preparation method, the reaction temperature is reduced to 40 DEG C, byproducts of high-temperature reaction are reduced, white-like solids can be obtained by simply washing, extracting and concentrating reaction liquid, and main product loss caused when the byproducts are removed through recrystallization is reduced. And the process is simpler, the yield is lower, and the emission of three wastes is less.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of a rocuronium bromide intermediate. Background technique [0002] 5α-Androst-2-en-17-one is an important intermediate in the synthesis of non-depolarizing steroidal muscle relaxants such as pancuronium bromide, rocuronium bromide, vecuronium bromide, and pipecuronium bromide. Sterol ammonium bromide drugs including rocuronium bromide and vecuronium bromide are a new type of non-depolarizing muscle relaxants that have emerged in recent years. They are used as anesthesia auxiliary drugs for endotracheal intubation and surgery. Muscle relaxation, has the characteristics of fast onset, short duration, no accumulation, no tachycardia and blood pressure changes, no release of histamine, etc. Most of the existing common methods for preparing 5α-androst-2-en-17-one use epiandrosterone as a raw material and prepare it through a two-step method of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J11/00
CPCC07J11/00
Inventor 朱微袁明华陈新丁东周忠辉洪荣川徐华诚
Owner 福安药业集团重庆博圣制药有限公司
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