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 , to achieve the effect of good long-term storage stability, less impurities, and less impurity components

Active Publication Date: 2020-07-31
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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  • Preparation method of mivacurium chloride and injection thereof
  • Preparation method of mivacurium chloride and injection thereof
  • Preparation method of mivacurium chloride and injection thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] A method for synthesizing micuronium chloride, including the following steps:

[0053]

[0054] Step 1: Asymmetric catalytic reduction

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

[0056] Step 2: Methylation and purification of amine

[0057] In 1500 ml of ethyl acetate, the compound of formula I (100 g), sodium borohydride (120 g), and 1200 ml of 37% formaldehyde solution were added, and refluxed until the reaction was complete....

Embodiment 2

[0063] A method for synthesizing micuronium chloride, including the following steps:

[0064] Step 1: Asymmetric catalytic reduction

[0065] The crude product (100g) of the compound of formula VI was dissolved in dichloromethane (1000ml), degassed ultrasonically, replaced with nitrogen for 5 minutes, and added with the metal chiral catalyst RuCl-Ts-DPEN (2200mg), formic acid-triethylamine (V / V=9:4, 20mL), reacted at 0°C for 7.5 hours. Add saturated NaHCO 3 The aqueous solution (3000 mL) was quenched, and extracted with dichloromethane (2000 mL) for 3 consecutive times, and the extracts were combined; the extract was washed twice with saturated brine (500 mL) and dried to obtain the R-type compound of formula I (90.3 g).

[0066] Step 2: Methylation and purification of amine

[0067] Add formula I compound (100g) and sodium borohydride (95g) to 1500ml of tetrahydrofuran, then add 1400ml of 30% formaldehyde solution, and reflux until the reaction is complete. After cooling to room t...

Embodiment 3

[0073] A method for synthesizing micuronium chloride, including the following steps:

[0074] Step 1: Asymmetric catalytic reduction

[0075] The crude product (100g) of the compound of formula VI was dissolved in methyl tert-butyl ether (1000ml), degassed ultrasonically and replaced with argon for 5 minutes, added with the metal chiral catalyst RuCl-Ts-DPEN (2000mg), formic acid-triethyl Amine (V / V=3:2, 18mL), reacted at 4°C for 6.5 hours. Add saturated NaHCO 3 The aqueous solution (2500mL) was quenched, and the extracts were continuously extracted with methyl tert-butyl ether (2000ml) for 3 times, and the extracts were combined; the extracts were washed twice with saturated brine (500ml) and dried to obtain the R-type compound of formula I (91.1g) ).

[0076] Step 2: Methylation and purification of amine

[0077] Add the compound of formula I (100g) and sodium borohydride (90g) to 1500ml of dichloromethane, and then add 800ml of 40% formaldehyde solution, and reflux until the reac...

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PUM

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Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to mivacurium chloride and a preparation method of an injection thereof. The mivacurium chloride is prepared from R-5'-methoxy laudanosine and trans-octenedioic acid as raw materials through amine alkylation, ester exchange and other reactions, and finally high-purity mivacurium chloride is obtained. Themivacurium chloride is less in impurity generation, the product is easy to separate and purify, meanwhile, formation and discharge of a large amount of (S)-5-methoxy laudanosine are avoided, and the injection prepared from the raw materials is less in impurity and stabler.

Description

Technical field [0001] The present invention relates to the technical field of medicinal chemistry, in particular to a preparation method of micuronium chloride and its injection. Background technique [0002] Muscle relaxants are important auxiliary drugs in clinical general anesthesia. Their main role is to enable patients to maintain muscle relaxation under light anesthesia, so as to meet the surgical needs of surgery and tracheal intubation. Such drugs belong to N2 receptor antagonists, also known as neuromuscular blockers. According to the way they block pharmacologically, they are divided into two categories: non-depolarizing and depolarizing. The depolarizing type has poor selectivity and obvious side effects; therefore, non-depolarizing drugs are generally considered safer than depolarizing drugs and more clinically desirable. [0003] Micuronium chloride was developed by Abbott lab. It was first used in the United States in 1992. It is a short-term benzyl isoquinoline non...

Claims

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Application Information

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Patent Type & Authority Applications(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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