Production process for preparing cinchonaine hydrochloride by one-pot method

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a production process for preparing cinchonaine hydrochloride by a one-pot method. The method comprises the following steps: mixing 2-butoxyquinoline-4-carboxylic acid serving as an initial raw material with a solvent, heating to carry out acylation reaction to obtain 2-butoxyquinoline-4-formyl chloride, carryingout amidation reaction on the 2-butoxyquinoline-4-formyl chloride and N, N-diethylethylenediamine, regulating the pH value of the solution, washing, removing the solvent, adding isopropanol and crystallizing with hydrochloric acid to obtain thecinchonaine hydrochloride. The whole preparation process has the advantages of being easy and convenient to operate, good in controllability and good in large-scale test result, and is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a production process for preparing dibucaine hydrochloride by a one-pot method. Background technique [0002] Dibucaine hydrochloride is a local anesthetic in the perioperative series of drugs, the local anesthetic effect is 22-25 times greater than that of procaine, and the duration is longer; it is far more stable than procaine in the tissue, so the duration of anesthesia is longer. About 3 times that of procaine. In addition, although there is an amide in the chemical structure of Dibucaine Hydrochloride, it is still the same as an ester local anesthetic, and can be hydrolyzed by plasma cholinesterase, which can be used to identify the effect of the esterase clinically. [0003] Patent US4839366 uses intermediate 2-hydroxy-4-carboxyquinoline and phosphorus pentachloride for acylation and chlorination, evaporates volatile substances and adds n-hexane for crystall...

AI Technical Summary

Problems solved by technology

This step of amidation uses N,N-diethylethylenediamine both as a reactant and as an acid-binding agent, which leads to an increase in the amount of N,N-diethylethylenediamine, because N,N-diethylethylenediamine The price of diamine is relatively expensive, which will inevitably lead to a substantial increase in the raw material cost of dibucaine hydrochloride

In addition, in this method, the intermediate 2-chloro-N-[2-(diethylamino)ethyl]-4-quinoline carboxamide needs to be separated, purified and dried, which increases the production steps such as crystallization, centrifugation and drying. The operation time is long, which prolongs the production cycle and further increases the production cost

[0005] Patent CN107586277A also uses 2-hydroxy-4-carboxyquinoline as raw material to obtain N-(2-(diethyl)aminoethyl) through chlorination and amidation )-2-Chloro-4-quinoline carboxamide, directly carry out the amidation reaction without treatment, but the use of solvents, reaction conditions, operations, etc. are different, and the final effect is also different. The single-step yield in this patent is only 85%

[0006] patent CN106496120A and patent CN107586277A both used highly dangerous metal sodium when preparing dibucaine, which is not suitable for industrial production; and the single-step yield is 87.3% respectively and 65% lower

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