Preparation method of ropivacaine hydrochloride

A technology of ropivacaine hydrochloride and hydrochloric acid, applied in the field of chemistry, can solve problems such as being unfavorable for industrialized production, unsuitable for industrialized production, poor salt-forming effect, etc., avoiding protection and deprotection, and inhibiting the generation of quaternary ammonium salt impurities , easy-to-control effects

CN113735760AActive Publication Date: 2021-12-03JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2021-12-03

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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.
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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 ...

Examples

Embodiment 1

[0058] Embodiment 1 prepares ropivacaine hydrochloride

[0059] Step 1: Preparation of Intermediate 1

[0060] Add (S)-piperidine-2-carboxylic acid (100.00g, 0.77mol) in the 2000mL reaction flask, propionaldehyde (104.32g, 2.32mol) and dichloromethane (800mL), nitrogen replaces the air in the reaction flask, and then Add sodium cyanoborohydride (111.90g, 2.30mol) and react at 35°C for 10 hours. After the reaction is completed, quench with saturated aqueous sodium bicarbonate (500mL), separate the organic phase, and wash the aqueous phase with dichloromethane (500mL*2) extraction, combined organic phases, dried over anhydrous magnesium sulfate, concentrated under reduced pressure at 40°C-45°C to obtain 125g of intermediate 1, yield 94.3%.

[0061] Step 2: Preparation of Intermediate 2

[0062] Add intermediate 1 (100.00g, 0.58mol), dichloromethane (600mL) and N,N-dimethylformamide (2mL) into a 2000mL reaction flask, cool down to an internal temperature of 5°C in an ice-water ...

Embodiment 2

[0071] Embodiment 2 prepares ropivacaine hydrochloride

[0072] Step 1: Preparation of Intermediate 1

[0073] Add (S)-piperidine-2-carboxylic acid (100.00g, 0.77mol) in the 2000mL reaction flask, propionaldehyde (104.32g, 2.32mol) and dichloromethane (800mL), nitrogen replaces the air in the reaction flask, and then Add sodium acetate borohydride (380.69g, 2.32mol) and react at 35°C for 10 hours. After the reaction, quench with saturated aqueous sodium bicarbonate (500mL), separate the organic phase, and wash the aqueous phase with dichloromethane (500mL *2) extraction, combined organic phases, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at 40°C to 45°C to obtain 110g of intermediate 1 with a yield of 83.0%.

[0074] Step 2: Preparation of Intermediate 2

[0075] Add Intermediate 1 (100.00g, 0.58mol), dichloromethane (600mL) and N,N-dimethylformamide (2mL) into a 2000mL reaction flask, cool down to an internal temperature of 10°C in an ic...