Preparation method and application of cisatracurium besilate

A technology of cisatracurium besylate and reaction technology, which is applied in the field of preparation of cisatracurium besylate, can solve the problem of complex preparation of pentanediol diacrylate, reaction yield of less than 60%, large solvent consumption, etc. problems, to achieve the effect of easier control of residues, fewer types of impurities and lower costs

Active Publication Date: 2021-05-11
JIANGSU CHENGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] But this method has the following problems: the preparation of the reaction raw material pentylene glycol diacrylate is relatively complicated, and high-temperature rectification equipment is required, which cannot be produced in general ordinary production workshops; in the Michael addition reaction of the first step of the process, the production scale is explosive. Potential risks; two isomers are produced during the methylation process, resulting in less than 60% methylation reaction yield
Moreover, the removal of the isomer requires silica gel column chromatography purification, which consumes a lot of solvent and produces a large amount of solid waste silica gel; and the last step of the methylation process uses methyl benzenesulfonate, which is a genotoxic impurity, and there is a lot of residue in the finished product. Easy to exceed the standard

Method used

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  • Preparation method and application of cisatracurium besilate
  • Preparation method and application of cisatracurium besilate
  • Preparation method and application of cisatracurium besilate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] The present embodiment provides a kind of preparation method of cisatracurium besylate, and the reaction formula is as follows:

[0061]

[0062] Specific steps are as follows:

[0063] (1) Take R-tetrahydropapaverine-N-acetyl-L-leucine salt (50g, 0.0967mol) in toluene (250mL) and water (250mL) and use 20% sodium carbonate aqueous solution to adjust the pH to 9, divide liquid, the organic layer was concentrated under reduced pressure at 55°C until no dripping; then added acetonitrile (250mL) to dissolve, then added methyl 3-bromopropionate (19.4g, 0.116mol) and anhydrous sodium carbonate (12.3g, 0.116mol ), reacted at 80°C for 24h; after the reaction was completed, cooled to 20°C and filtered; the filtrate was concentrated under reduced pressure at 40°C until no dripping, added acetone (500mL) to dissolve, added oxalic acid (10.4g, 0.116mol) to form salt and crystallize , the wet product was dried to obtain Intermediate A (47.7g), yield: 95.0%;

[0064] (2) Take th...

Embodiment 2

[0076] The present embodiment provides a kind of preparation method of cisatracurium besylate, and the reaction formula is as follows:

[0077]

[0078] Specific steps are as follows:

[0079](1) Take R-tetrahydropapaverine-N-acetyl-L-leucine salt (50g, 0.0967mol) in toluene (250mL) and water (250mL) and use triethylamine to adjust the pH to 8, separate the liquids, The organic layer was concentrated under reduced pressure at 55°C until it did not drop; then acetonitrile (250mL) was added to dissolve, and then methyl 3-bromopropionate (16.2g, 0.0967mol) and triethylamine (9.8g, 0.0967mol) were added, and in React at 40°C for 28 hours; after the reaction is completed, cool to 20°C and filter; the filtrate is concentrated under reduced pressure at 40°C until it does not drop, add acetone (500mL) to dissolve, add oxalic acid (10.4g, 0.116mol) to form a salt and crystallize, wet product Intermediate A (47.1g) was obtained after drying, yield: 93.86%;

[0080] (2) Take the int...

Embodiment 3

[0084] The present embodiment provides a kind of preparation method of cisatracurium besylate, and the reaction formula is as follows:

[0085]

[0086] Specific steps are as follows:

[0087] (1) Take R-tetrahydropapaverine-N-acetyl-L-leucine salt (50g, 0.0967mol) in toluene (250mL) and water (250mL) to adjust the pH to 10 with aqueous sodium hydroxide solution, and separate the liquid , the organic layer was concentrated under reduced pressure at 55°C until it did not drop; then acetonitrile (250 mL) was added for dissolution, and then methyl 3-bromopropionate (22.6 g, 0.1354 mol) and sodium hydroxide (5.4 g, 0.1354 mol) were added, React at 90°C for 20h; after the reaction is complete, cool to 20°C and filter; the filtrate is concentrated under reduced pressure at 40°C until it does not drop, add acetone (500mL) to dissolve, add oxalic acid (10.4g, 0.116mol) to form a salt and crystallize, wet After drying the product, intermediate A (46.3g) was obtained, yield: 92.0%; ...

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Abstract

The invention provides a preparation method and application of cisatracurium besylate, and the preparation method comprises the following steps: (1) dissolving R-tetrahydropapaverine-N-acetyl-L-leucine salt, adjusting the pH value with an alkaline solution, and then mixing with methyl 3-bromopropionate and alkali for reaction to obtain an intermediate A; (2) mixing and reacting the intermediate A obtained in the step (1) with alkali to obtain an intermediate B; (3) mixing and reacting the intermediate B obtained in the step (2) with a methylation reagent to obtain an intermediate C; and (4) mixing and reacting the intermediate C obtained in the step (3), a catalyst and a dehydrating agent to obtain cisatracurium besylate. The preparation method provided by the invention is safe in production process, high in yield, few in isomer and low in maximum single impurity.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method and application of cisatracurium besylate, in particular to a preparation method and application of cisatracurium besylate with low toxicity. Background technique [0002] Atracurium besylate is a non-depolarizing muscle relaxant, which has the characteristics of quick onset, short duration of action, no effect on heart, liver, kidney function and no accumulation of therapeutic dose, and is widely used clinically to prevent and treat various diseases. A condition that requires muscle relaxation or controlled breathing. Cisatracurium besylate is a single isomer of atracurium benzoate, it is a new generation of muscle relaxant, its action strength is about 3 times that of atracurium, it is metabolized by non-hepatic and non-renal and does not release amine , with cardiovascular protection. [0003] CN107056699A discloses a preparation method of high-purity atrac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20A61P21/02
CPCC07D217/20A61P21/02Y02P20/582
Inventor 李斌李二军魏云亮谭从祥张建明何宝亮张晨晨邢飞李勇成陈倩
Owner JIANGSU CHENGXIN PHARMA
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