Preparation method of cisatracurium besilate impurity O

A technology of cisatracurium besylate and impurities, which is applied in the field of organic synthesis of medicines, can solve problems such as lack of and unfavorable research on impurities of cisatracurium besylate, and achieve simple preparation methods, cheap and easy-to-obtain reagents, and high yields. rate effect

Pending Publication Date: 2022-05-27
武汉绿合医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The technical problem to be solved by this invention is to provide a kind of preparation method of cisatracurium besylate impurity O, aiming at overcoming the lack of preparation of high-purity impurity O method in the prior art and being unfavorable for the cisatracurium besylate Insufficiency of impurity research

Method used

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  • Preparation method of cisatracurium besilate impurity O
  • Preparation method of cisatracurium besilate impurity O
  • Preparation method of cisatracurium besilate impurity O

Examples

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Embodiment 1

[0031] A kind of preparation method of cisatracurium besylate impurity O, it comprises the steps:

[0032] S1. Take (1R)-1-[(3,4-dimethoxyphenyl)-methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl Oxycarbonylethyl-isoquinoline 5.00g, methyl benzenesulfonate 4.00g, sodium bicarbonate 0.61g, acetonitrile 20mL in a reaction flask, react at 15-25°C for more than 48h, a large amount of white solids are precipitated during the reaction , the ratio of the peak areas of the two configurations in liquid phase detection is 3:1, suction filtration, and the filter cake is slurried with acetonitrile until the purity of impurity D is ≥98%, and finally 3.77g of impurity D (purity 98.21%) is obtained;

[0033] S2. Take 3.00g of impurity D, 2.59g of 1,5-pentanediol, 2.37g of benzenesulfonic acid, and 15mL of dichloromethane in a reaction flask, heat to reflux for more than 8h, and HPLC detects that the raw materials have basically reacted, and the products are mainly Impurity F and a small amo...

Embodiment 2

[0040] A kind of preparation method of cisatracurium besylate impurity O, it comprises the steps:

[0041] S1. Take (1R)-1-[(3,4-dimethoxyphenyl)-methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl Oxycarbonylethyl-isoquinoline 5.00g, methyl benzenesulfonate 3.80g, sodium carbonate 0.77g, acetonitrile 20mL in a reaction flask, react at 15-25°C for more than 48h, a large amount of white solids are precipitated during the reaction, The ratio of the peak areas of the two configurations in liquid phase detection is 3:1, suction filtration, and the filter cake is slurried with acetonitrile until the purity of impurity D is ≥98%, and finally 3.56g of impurity D (purity 98.18%) is obtained;

[0042] S2. Take 3.00g of impurity D, 3.49g of 1,5-pentanediol, 2.87g of trifluoroacetic acid, and 15mL of dichloromethane in a reaction flask, heat to reflux for more than 8h, and HPLC detects that the raw materials have basically reacted, and the products are mainly Impurity F and a small amount...

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Abstract

The invention relates to a preparation method of a cisatracurium besylate impurity O. The preparation method comprises the following steps: S1, taking (1R)-1-[(3, 4-dimethoxyphenyl)-methyl]-1, 2, 3, 4-tetrahydro-6, 7-dimethoxy-2-methoxycarbonyl ethyl-isoquinoline, methyl benzenesulfonate, acetonitrile and a catalyst to react, so as to obtain a cisatracurium besylate impurity D; s2, taking the impurity D, 1, 5-pentanediol, dichloromethane and a catalyst to react to obtain an impurity F; s3, taking the impurity F, acryloyl chloride, dichloromethane and a catalyst to react to obtain an impurity O crude product; and S4, preparing a purified impurity O pure product through a liquid phase. According to the method, the defect that an effective method for preparing the cisatracurium besylate impurity O is lacked in the prior art is overcome, the purity of the prepared impurity O is high, the preparation method is simple, the used reagent is low in price and easy to obtain, the yield is high, and the impurities D and F can be prepared in the synthesis route.

Description

technical field [0001] The invention relates to the field of organic synthesis of medicines, in particular to a preparation method of cisatracurium besylate impurity O. Background technique [0002] Cisatracurium besylate, molecular formula C 53 H 72 N 2 O 12 ·2(C 6 H 5 O 3 S), is one of the 10 isomers that constitute the racemic mixture of atracurium, can compete with the cholinergic receptors of the motor endplate, and has a similar muscle relaxant effect to atracurium and Metabolic mode, its muscle relaxant strength is 3 times that of atracurium, and the onset and recovery are rapid, without releasing histamine, with little effect on cardiovascular, no accumulation effect, no toxicity and muscle relaxant effect of metabolites, can be used in Widely used clinically. [0003] Some impurities that may exist in cisatracurium besylate are listed in European Pharmacopoeia 10.0, among which the impurity code-named O, its English name is: [0004] (1R,2R)-1-[(3,4-dimetho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20
CPCC07D217/20Y02P20/55
Inventor 刘志恒王大鹏尹家平秦志平万梦
Owner 武汉绿合医药科技有限公司
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