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A kind of preparation method of mivacurium chloride and injection thereof

A technology of mivacurium chloride and injection, which is applied to medical preparations with non-active ingredients, medical preparations containing active ingredients, and pharmaceutical formulas, and can solve problems such as stability and safety issues that have not been properly resolved

Active Publication Date: 2021-04-30
朗天药业(湖北)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the mivacurium chloride in this injection is prepared by existing technology, and the stability and safety problems after long-term storage have not been properly solved; therefore, it is necessary to continue to develop a new mivacurium chloride and its Preparation method of injection, further reducing impurity content and improving its stability

Method used

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  • A kind of preparation method of mivacurium chloride and injection thereof
  • A kind of preparation method of mivacurium chloride and injection thereof
  • A kind of preparation method of mivacurium chloride and injection thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] A kind of synthetic method of mivacurium chloride, comprises the steps:

[0053] Step 1: Asymmetric Catalytic Reduction

[0054]

[0055] The crude product (100g) of the compound of formula VI was dissolved in tetrahydrofuran (1000ml), ultrasonically degassed, replaced with nitrogen for 5 minutes, added metal chiral catalyst RuCl-Ts-DPEN (2500mg), formic acid-triethylamine (V / V= 5:3, 15 mL), reacted at 15°C for 2.5 hours. Add saturated NaHCO 3 Aqueous solution (3000mL) was quenched, extracted continuously 3 times with ethyl acetate (2000ml), combined extracts; washed extracts 2 times with saturated brine (500ml) and dried, concentrated dry extract The R form of the compound of formula I (91.9 g) was obtained.

[0056] Step 2: Methylation and purification of amines

[0057]

[0058] Add the compound of formula I (100 g) and sodium borohydride (120 g) into 1500 ml of ethyl acetate, then add 1200 ml of 37% formaldehyde solution, and reflux until the reaction is c...

Embodiment 2

[0067] A kind of synthetic method of mivacurium chloride, comprises the steps:

[0068] Step 1: Asymmetric Catalytic Reduction

[0069] The crude product (100g) of the compound of formula VI was dissolved in dichloromethane (1000ml), ultrasonically degassed, replaced with nitrogen for 5 minutes, added metal chiral catalyst RuCl-Ts-DPEN (2200mg), formic acid-triethylamine (V / V=9:4, 20 mL), reacted at 0°C for 7.5 hours. Add saturated NaHCO 3 Aqueous solution (3000mL) was quenched, extracted continuously 3 times with dichloromethane (2000ml), combined extract; After washing extract with saturated brine (500ml) 2 times, dried, concentrated dry extract obtained the formula I compound of R type ( 90.3g).

[0070] Step 2: Methylation and purification of amines

[0071] Add the compound of formula I (100 g) and sodium borohydride (95 g) into 1500 ml of tetrahydrofuran, and then add 1400 ml of 30% formaldehyde solution, and reflux until the reaction is complete. After cooling to ...

Embodiment 3

[0077] A kind of synthetic method of mivacurium chloride, comprises the steps:

[0078] Step 1: Asymmetric Catalytic Reduction

[0079]The crude product (100g) of the compound of formula VI was dissolved in methyl tert-butyl ether (1000ml), ultrasonically degassed, replaced with argon for 5 minutes, and added metal chiral catalyst RuCl-Ts-DPEN (2000mg), formic acid-triethyl Amine (V / V=3:2, 18 mL), react at 4°C for 6.5 hours. Add saturated NaHCO 3 Quench with aqueous solution (2500mL), extract continuously with methyl tert-butyl ether (2000ml) for 3 times, combine the extracts; wash the extract with saturated brine (500ml) for 2 times and dry, then concentrate and dry the extract to obtain the R-type formula Compound I (91.1 g).

[0080] Step 2: Methylation and purification of amines

[0081] Add the compound of formula I (100 g) and sodium borohydride (90 g) into 1500 ml of dichloromethane, then add 800 ml of 40% formaldehyde solution, and reflux until the reaction is comp...

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Abstract

The invention belongs to the technical field of biomedicine, and specifically relates to a preparation method of mivacurium chloride and an injection thereof, wherein the mivacurium chloride uses R-5'-methoxylabdansin and fumaric acid as raw materials , through amine alkylation, transesterification and other reactions, finally get high-purity mivacurium chloride. The impurity of mivacurium chloride of the present invention is less, the product is easy to separate and purify, avoids the formation and discharge of a large amount of (S)-5-methoxylaudansu simultaneously, the injection liquid impurity that this raw material is made is smaller ,more stable.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of mivacurium chloride and an injection thereof. Background technique [0002] Muscle relaxants are important adjuvant drugs in clinical general anesthesia. Their main function is to enable patients to maintain a state of muscle relaxation under light anesthesia, so as to meet the needs of surgery, tracheal intubation and other operations. These drugs belong to N2 receptor antagonists, also known as neuromuscular blocking drugs. According to their pharmacological blocking methods, they can be divided into two categories: non-depolarizing and depolarizing. Depolarizing forms have poor selectivity and significant side effects; therefore, nondepolarizing agents are generally considered safer and more clinically desirable than depolarizing agents. [0003] Mivacurium chloride was developed by Abbott lab and first launched in the United States in 1992...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/20A61K31/4725A61K9/08A61K47/18A61K47/12A61P21/02
CPCA61K9/0019A61K9/08A61K31/4725A61K47/12A61K47/183A61P21/02C07D217/20
Inventor 陈景丽蔡翔黎翩余帮海皮培培张友民闵清彭平肖红敏陈从富
Owner 朗天药业(湖北)有限公司
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