Industrial preparation method of ropivacaine hydrochloride monohydrate

A technology for ropivacaine hydrochloride and monohydrate, which is applied in the field of compound synthesis, can solve the problems of high risk of triphosgene use and storage, unsuitable for industrial production, and environmental pollution, and reduces the output and reaction of three wastes. The effect of short route and wide source of raw materials

Active Publication Date: 2021-07-13
HEBEI YIPIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses chiral starting materials, which are expensive and have limited commercial availability
The use of acylating reagents such as triphosgene, phosphorus pentachloride or thionyl chloride produces more waste gas and waste liquid, and there are environmental pollution problems. In addition, the use and storage of triphosgene is dangerous and not suitable for industrial production.

Method used

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  • Industrial preparation method of ropivacaine hydrochloride monohydrate
  • Industrial preparation method of ropivacaine hydrochloride monohydrate
  • Industrial preparation method of ropivacaine hydrochloride monohydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] a. Prepare the DMF solution of 1-propylpiperidine-2-propyl carboxylate (3)

[0040] Add 500ml of DMF, 100g (0.77mol) of 2-piperidinecarboxylic acid, 237g (1.93mol) of 1-bromopropane and 319g (2.31mol) of potassium carbonate into a 2L four-necked flask, stir and raise the temperature to 70°C to 80°C, and control the The reaction was continued at low temperature for 2 to 3 hours. After TLC detected that the reaction was complete, the reaction was cooled to room temperature and suction filtered to obtain a DMF solution of 1-propylpiperidine-2-propyl carboxylate.

[0041] b. Preparation of N-(2,6-dimethylphenyl)-1-n-propylpiperidine-2-carboxamide (5)

[0042] Add 129.6g (1.16mol) potassium tert-butoxide and 400ml DMF to another 2L four-necked flask, stir until dissolved, add 112g (0.92mol) dimethylaniline at 20°C to 30°C with temperature control, and then raise the temperature to 90 ℃~100℃, add the DMF solution of 1-propylpiperidine-2-propyl carboxylate dropwise at this t...

Embodiment 2

[0051] a. Preparation of NMP solution of 1-propylpiperidine-2-propyl carboxylate (3)

[0052] Add 500ml NMP, 87g (0.67mol) 2-piperidinecarboxylic acid, 206.2g (1.68mol) 1-bromopropane, 277.5g (2.00mol) potassium carbonate and 6.6g (0.04mol) potassium iodide in 2L four-necked flask, stir Raise the temperature to 70°C-80°C, and control the temperature to continue the reaction for 1.5-3 hours. After TLC detected that the reaction was complete, the reaction was cooled to room temperature and suction filtered to obtain an NMP solution of propyl 1-propylpiperidine-2-carboxylate.

[0053] b. Preparation of N-(2,6-dimethylphenyl)-1-n-propylpiperidine-2-carboxamide (5)

[0054] Add 36.7g (0.94mol) sodium amide and 200ml NMP into another 2L four-neck flask, stir until dissolved, add 97.4g (0.80mol) dimethylaniline at 20°C to 30°C with temperature control, and then raise the temperature to 75°C At ~85°C, add the NMP solution of 1-propylpiperidine-2-propyl carboxylate dropwise at this t...

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Abstract

The invention discloses an industrial synthesis method of ropivacaine hydrochloride monohydrate. The method comprises the following steps: dissolving racemized 2-piperidinecarboxylic acid serving as a starting material in an organic solvent, and carrying out alkylation reaction, transesterification, chiral resolution and salification refining to obtain a target product. The raw materials are cheap and easy to obtain, a one-pot method is adopted, organic reagents are easy to recycle and reuse, the reaction safety coefficient is high, the technological operation is simple, few three wastes are generated, and the obtained ropivacaine hydrochloride monohydrate is high in yield and high in purity.

Description

technical field [0001] The invention relates to the field of compound synthesis, in particular to a preparation method of medicinal ropivacaine hydrochloride monohydrate. Background technique [0002] Ropivacaine hydrochloride is a sodium channel blocker first listed by AstraZeneca in 1996. It belongs to aminoamide local anesthetics and is used for surgery, labor and postoperative analgesia. Compared with similar amide local anesthetics such as bupivacaine, it has a longer duration of use and is less toxic to the heart. Its pharmacological characteristics are low cardiotoxicity, obvious separation of sensory block and motor block, and peripheral vasoconstriction. [0003] Ropivacaine hydrochloride is ropivacaine hydrochloride monohydrate, chemical name: (-)-(S)-N-(2,6-dimethylphenyl)-1-n-propylpiper Pyridine-2-carboxamide hydrochloride monohydrate, the molecular formula is: C 17 h 26 N 2 O·HCl·H 2 O, structural formula: [0004] At present, the synthetic methods of ro...

Claims

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Application Information

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IPC IPC(8): C07D211/60C07B57/00
CPCC07D211/60C07B57/00C07B2200/07
Inventor 张辑马福民张晓彩赵翠然程瑶李铭皓李强李婷婷齐晓林啜振华
Owner HEBEI YIPIN PHARMA
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