Method for preparing hydrochloric acid ropivacaine

A technology for ropivacaine hydrochloride and lev-ropivaca is applied in the field of chemistry and can solve the problems of high cost of raw materials, unsuitability for industrial production, racemization and the like

Active Publication Date: 2014-08-27
SHANDONG JINHE DRUG RES DEV
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  • Abstract
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Problems solved by technology

Although this method has a simple production process and relatively short reaction steps, the average price of commercially available L-2-piperidinecarboxylic acid is 4 to 5 times that of racemized 2-piperidinecarboxylic acid, and the cost of raw materials is too high. Racemization may occur in the process, which affects the optical purity of the product. For example, the US Patent US4695576 and the article "Synthesis of Ropivacaine Hydrochloride" in the 11th issue of "Chinese Journal of Medicine" in 2012 and Chinese patent CN201310041390.2 all adopt this method
[0008] "Synthesis of Ropivacaine Hydrochloride by Triphosgene Method" in "Synthetic Chemistry" 2006, Volume 14, No. 4, and Hunan University's master's thesis "Synthetic Technology Research of Ropivacaine Hydrochloride and Bupivacaine Hydrochloride" discloses another A method for synthesizing ropivacaine, using inexpensive racemized 2-piperidinecarboxylic acid as a raw material, and preparing ropivacaine hydrochloride through amidation, alkylation, etc., using triphosgene or thionyl chloride Acyl chlorides, but triphosgene is more dangerous during storage and post-treatment, and is not suitable for industrialized production; ) needs to be improved, and it is difficult to take into account high purity and high yield simultaneously under its test conditions, and according to the prior art, the separation of ropivacaine racemate is also not ideal

Method used

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  • Method for preparing hydrochloric acid ropivacaine
  • Method for preparing hydrochloric acid ropivacaine
  • Method for preparing hydrochloric acid ropivacaine

Examples

Experimental program
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experiment example 1

[0032] Experimental example 1, the selection of intermediate (I) separation pH (aqueous phase)

[0033] One, the purpose of the experiment: in the process of investigating the preparation of intermediate (I), 2-piperidinecarboxylic acid and 2,6-dimethylaniline react in toluene solution to generate the hydrochloride of intermediate (I) and then reduce it to intermediate ( After I), the impact of different pH values ​​on the yield of intermediate (I).

[0034]2. Method: 4 experiments in parallel——add 10.0g of 2-piperidinecarboxylic acid and 160ml of toluene into a 500ml reaction flask, feed HCl gas to pH 2-3, raise the temperature to 45-50°C, add 1.5ml of DMF (N,N -dimethylformamide), dropwise add 9.3g (1.0 equivalent) of the mixed solution of thionyl chloride and 20ml toluene, dropwise, keep warm at 50-55°C for 3h, add dropwise 37.5g, that is, dropwise add 4.0 equivalent of 2, Mixture of 6-dimethylaniline and 20ml of toluene, keep warm at 55-60°C for 3 hours, filter to obtain ...

experiment example 2

[0043] Experimental example 2, the selection of intermediate (I) separation extraction solvent

[0044] 1. Experimental purpose: To investigate the influence of different extraction reagents on the yield of intermediate (I) during the preparation of intermediate (I).

[0045] 2. Method: Four experiments in parallel——add 10.0g of 2-piperidinecarboxylic acid and 160ml of toluene into a 500ml reaction bottle, feed HCl gas to about pH2-3, raise the temperature to 45-50°C, add 1.5ml of DMF (N,N -Dimethylformamide), add dropwise 9.3g (1.0 equivalent) of the mixed solution of thionyl chloride and 20ml of toluene, dropwise, keep warm at 50-55°C for 3h, add dropwise 37.5g (ie 4.0 equivalent) of 2,6 - Mixture of dimethylaniline and 20ml of toluene, keep warm at 55-60°C for 3 hours, filter to obtain 65g of yellow-green wet product, dry to obtain 56g of gray solid, add the solid to 280ml of purified water, and stir to dissolve to obtain a reaction solution; Slowly add % NaOH solution to ...

experiment example 3

[0053] Experimental example 3, selection of catalyst in the resolution reagent in the preparation process of levopivacaine tartrate

[0054] 1. Purpose of the experiment: To investigate the separation results of different catalysts in the resolution reagent during the preparation of L-ropivacaine tartrate.

[0055] 2. Method: Four experiments in parallel—dissolve 14.8g of intermediate (I) in 60mlDMF, add 8.5gK 2 CO 3 , add 7.8g (1.0 equivalent) bromo-n-propane dropwise, after dropping, raise the temperature to 75-80°C, keep it warm for 2h; cool down to room temperature, filter, add the filtrate to 150ml ice water, precipitate a large amount of white solid, filter and dry , to obtain about 16.6g of white solid, yield 95%, which is intermediate (II) N-(2,6-dimethylphenyl)-1-n-propylpiperidine-2-carboxamide; 15g intermediate Compound (II) was dissolved in 100ml of isopropanol, heated to 40°C and stirred to dissolve; when completely dissolved, 0.1 equivalent of different catalys...

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Abstract

The invention provides a method for preparing hydrochloric acid ropivacaine. Part of parameters and conditions in the prior art are improved, and optimization is performed through the following steps that intermediate (I) separation pH and separation extracting solvent are selected; a catalyst and the usage quantity of the catalyst in a resolution agent are selected; refining solvent is selected. In this way, the yield and purity of the prepared hydrochloric acid ropivacaine are high, the purity reaches up to over 99% under the optimal condition, the percentage of dextrorotary isomer is reduced below 0.5%, standard requirements are completely met, and the hydrochloric acid ropivacaine is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of ropivacaine hydrochloride, which belongs to the technical field of chemistry. Background technique [0002] Ropivacaine (Ropivacaine) is a new type of pure L-body long-acting amide local anesthetic listed by Swedish Astra Pharmaceutical Company in 1996. It has dual effects of analgesia and anesthesia, and is widely used in nerve block anesthesia, local infiltration anesthesia and epidural anesthesia. Anesthesia, especially for postoperative analgesia and obstetric anesthesia. [0003] There is a chiral carbon atom on the piperidine ring in the structure of ropivacaine, which is a chiral compound. The left-handed isomer is less toxic than the right-handed isomer and has better effects. [0004] Ropivacaine hydrochloride is the hydrochloride salt of ropivacaine, chemical name: (-)-(S)-N-(2,6-dimethylphenyl)-1-n-propylpiperidine-2 -Formamide hydrochloride, the molecular formula is C 17 h 26 N 2 O HCl, ...

Claims

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Application Information

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IPC IPC(8): C07D211/60
CPCC07D211/60
Inventor 张栋彭坤马宁王京凯董玉波
Owner SHANDONG JINHE DRUG RES DEV
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