A kind of preparation method of besylate cisatracurium intermediate

Abstract

The invention discloses a preparation method of a cisatracurium besylate intermediate. The method is as follows: compound III is freed by adding alkali, reacts with tert-butyl acrylate under the catalysis of acetic acid, and then adds oxalic acid to form a salt to obtain the compound of formula VI; compound of formula VI is freed by adding alkali, and then firstly becomes salt, and then hydrolyze the tert-butyl ester in it into carboxylic acid under heating to obtain the compound of formula VII, and then carry out esterification reaction with 1,5-pentanediol in situ to generate an esterified product, after washing the excess compound of formula VII with water, add Alkali alkalization, and then salify with oxalic acid to obtain the intermediate of formula IV. The product of the present invention has high yield and high purity, can be directly put into the cisatracurium besylate for the last step reaction without refining to finally obtain the cisatracurium besylate, and has simple aftertreatment and is easy for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of a cisatracurium besylate intermediate. Background technique [0002] Cisatracurium besylate is a non-depolarizing neuromuscular blocking agent, which is a single-configuration isomer among the 10 isomers of atracurium besylate (1R,1' R, 2R, 2'R), has similar muscle relaxation effect and metabolic mode as atracurium besylate, but its muscle relaxation intensity is about 3 times that of atracurium, and does not release histamine. The vascular response is small, and it is an ideal non-depolarizing muscle relaxant with a medium-time effect. Since the drug was first launched in the UK in 1996, it has gradually replaced vecuronium bromide and atracurium and has become the mainstream product of clinical muscle relaxants. [0003] Cisatracurium besylate, chemical name: (1R,1'R,2'R,2R)-2,2'-(3,11-dioxo-4,10-dioxotridecylidene Methyl) bis(1...

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Problems solved by technology

[0007] But in the experiment we found that there are two shortcomings in this process: (1) when preparing formula II, because it contains two double bonds, it is very easy to produce polymerization because of being heated for a long time in the post-treatment decompression distillation purification operation process, and then Seriously affect the yield of formula II; (2) when preparing formula IV, in order to make the reaction complete as far as possible, reduce the generation amount of this impurity of single adduct (formula V), must R-tetrahydropapaverine excessive about 13% , although most of the excess tetrahydropapaverine can be removed by silica gel adsorption after the reaction, silica gel will also adsorb part of the product of formula IV at the same time, and after the oxalate is formed, there will still be more R-tetrahydropapaverine in the intermediate of formula IV Alkali raw material must be refined through twice recrystallization again, and these factors cause the yield of formula IV intermediate to only have about 60%

[0009] Although the preparation method of the process formula II disclosed in the patent WO2010 / 128518A2 has changed, it adopts the reaction of 1,5-pentanediol and methyl acrylate under the catalysis of p-toluenesulfonic acid, but still cannot avoid the final reduction mentioned in US545351. This disadvantage of pressure distillation purification operation leads to product polymerization, the yield is only about 50%

In addition, when formula IV is prepared, although the addition of acetic anhydride after the reaction can make excess R-tetrahydropapaverine acetylation beneficial for removal during crystallization, the final yield of formula IV is only about 60%, which is not higher than the above-mentioned The method yield adopted among the US5453510 improves to some extent

[0010] Although the synthetic method described in the patent CN107056699A has not been synthesized by formula II, the synthetic route used in it introduces quaternary ammonium salt prematurely, and the subsequent esterification reaction uses dichloromethane as a solvent, which has poor solubility, resulting in reaction Slower, and because the reaction produces a large amount of sodium salt insoluble in organic solvents, it is difficult to separate, resulting in complicated post-processing, which is not conducive to industrial production

Moreover, anion exchange will occur during the reaction, resulting in the doping of chloride ions in the final product, which will adversely affect the quality of the product.

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