Preparation method of ropivacaine hydrochloride

Abstract

The invention discloses a preparation method of ropivacaine hydrochloride, the preparation method comprises the following specific steps: 1) in the presence of a reducing agent and an aprotic solvent, carrying out reductive amination reaction on (S)-piperidine-2-formic acid and propionaldehyde to obtain an intermediate 1; 2) in the presence of N, N-dimethylformamide and an aprotic solvent, carrying out acylation reaction on the intermediate 1 obtained in the step 1) and an acylation reagent to obtain an intermediate 2; 3) in the presence of N, N-dimethylformamide and under an alkaline condition, carrying out condensation reaction on the intermediate 2 obtained in the step 2) and 2, 6-dimethylaniline to obtain an intermediate 3; (4) salifying the intermediate 3 obtained in the step (3) with hydrochloric acid to obtain a ropivacaine hydrochloride crude product, and (5) purifying the ropivacaine hydrochloride crude product to obtain a ropivacaine hydrochloride competitive product. The purity of the prepared product is larger than 99.99%, and the synthetic process is mild in reaction condition, simple in preparation process, low in cost, safe, environmentally friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemistry, in particular to the technical field of synthesis of a novel long-acting amide local anesthetic, and in particular to a preparation method of ropivacaine hydrochloride. Background technique [0002] The chemical name of ropivacaine is ropivacaine hydrochloride. It is a pure L-body long-acting amide analgesic and local anesthetic. It is suitable for surgical anesthesia. Like other local anesthetics, it inhibits nerve cells Sodium ion channels, block nerve excitation and conduction, have dual effects of anesthesia and analgesia, large doses can produce surgical anesthesia, and small doses can produce sensory block (analgesia) only accompanied by limited non-progressive motor nerve block Ropivacaine was developed and widely promoted by AstraZeneca plc in 1996. It is the first new pure L-body long-acting amide local anesthetic in the world. It was approved in the U.S. in October 1996, followed by ...

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Problems solved by technology

[0018] Chinese patent CN201710470848.4 discloses a method for preparing ropivacaine hydrochloride, as described in Route 5, which uses 2-piperidinecarboxylic acid as the starting material, and hydrochloric acid is gas-formed in toluene and chloroform solution to form a salt, and the reaction Heterogeneous phase, poor salt-forming effect, self-condensed by-products, and then acylation, condensation, and alkylation to obtain the target product ropivacaine. This method uses carcinogenic solvent chloroform, and adopts ultrasonic reaction, which is not conducive to industrial production

[0021] Chinese patent 201910029895.4 discloses a method for the preparation and purification of a ropivacaine hydrochloride intermediate, as shown in Route 6, which uses L-piperidine-2-carboxylic acid hydrochloride as the starting The intermediates with a purity as low as 94% can be obtained through chemical reaction and condensation, which are refined with low-boiling point solvents such as diethyl ether and isopropyl ether, which are not suitable for industrial production

[0022] In summary, the preparation process for the production of ropivacaine hydrochloride listed in the prior art has certain defects in industrial production, so it is imminent to find a new scheme for the synthesis of ropivacaine which is green and environmentally friendly

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