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Method for preparing ropivacaine

A piperidine and direct technology, which is applied in the field of preparation of local anesthetic ropivacaine, can solve the problems of being dangerous and unsuitable for industrial production, and achieve the effects of simple operation, increased yield and reduced cost

Inactive Publication Date: 2013-05-08
SHANDONG INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] "Synthetic Chemistry" 2006, Volume 14, No. 4 "Synthesis of Ropivacaine Hydrochloride by Triphosgene Method" also reported the synthetic method of ropivacaine. The method uses triphosgene to prepare acid chloride, and triphosgene is stored and Dangerous to handle and also unsuitable for industrial production

Method used

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  • Method for preparing ropivacaine
  • Method for preparing ropivacaine
  • Method for preparing ropivacaine

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Mix 6.5g of L-piperidine-2-carboxylic acid with 100ml of toluene, and slowly inject HCl gas under stirring at room temperature until the pH of the reaction solution is 3. When the reaction solution is heated to 40°C, add 0.1ml of DMF, and dropwise add 6g of oxychloride at 40°C. Sulfone, after dropping, keep stirring at the temperature for 3 hours, add dropwise 20ml of toluene solution containing 12.1g 2,6-dimethylaniline, the reaction is exothermic, control the internal temperature not to exceed 60°C, add 7.3g bromopropane after 2 hours of reaction , 4.5gK 2 CO 3 , reacted at 50°C for 4 hours under stirring, filtered hot, and placed the filtrate at 0°C for crystallization. It was filtered and sucked dry, and dried to obtain 12 g of white solid.

[0030] Refining: heat-dissolve the crude product in 50ml of toluene, filter, cool, crystallize and filter to obtain 10g of fine product, with a total yield of 71%.

[0031] ES-MS m / z 275 [M+H + ], mp: 143~146°C, [α]25 D -80...

Embodiment 2

[0038] Mix 6.5g of L-piperidine-2-carboxylic acid with 100ml of toluene, slowly inject HCl gas under stirring at room temperature until the pH of the reaction solution is 3, heat the reaction solution to reflux, add 0.1ml of DMF, and add 6g of thionyl chloride dropwise while maintaining the reflux temperature, After dropping, keep stirring at this temperature for 3 hours, cool naturally to about 50°C, add dropwise 20ml of toluene solution containing 12.1g of 2,6-dimethylaniline, the reaction is exothermic, control the internal temperature not to exceed 60°C, and react for 2 hours Add 7.3g bromopropane, 4.5gK 2 CO 3 , reacted at 80°C for 4 hours under stirring, filtered hot, and placed the filtrate at 0°C for crystallization. It was filtered and sucked dry, and dried to obtain 12.5 g of white solid.

[0039] Refining: heat-dissolve the crude product with 50ml of toluene, filter, cool, crystallize and filter to obtain 10 g of fine product, with a total yield of 71%.

Embodiment 3

[0041] Mix 6.5g of L-piperidine-2-carboxylic acid with 100ml of toluene, and slowly inject HCl gas under stirring at room temperature until the pH of the reaction solution is 3. When the reaction solution is heated to 55°C, add 0.1ml of DMF, and add 6g of chlorinated chlorinated dropwise at 55°C. Sulfone, after dropping, keep stirring at the temperature for 3 hours, add dropwise 20ml of toluene solution containing 12.1g 2,6-dimethylaniline, the reaction is exothermic, control the internal temperature not to exceed 60°C, add 7.3g bromopropane after 2 hours of reaction , 4.5gK 2 CO 3 , reacted at 70°C for 4 hours under stirring, filtered hot, and placed the filtrate at 0°C for crystallization. It was filtered and sucked dry, and dried to obtain 13.5 g of white solid.

[0042] Refining: heat-dissolve the crude product in 50ml of toluene, filter, cool, crystallize and filter to obtain 11g fine product, with a total yield of 78%.

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Abstract

The invention relates to a one-pot method for preparing ropivacaine. According to the invention, L-piperidine-2-carbonyl chloride is prepared from L-piperidine-2-carboxylic acid; intermediate separation is not needed, and the material is directly subjected to a reaction with 2,6-dimethylaniline, and (S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide is prepared; intermediate separation is not needed, and the material is directly subjected to a reaction with bromopropane, such that ropivacaine is prepared. According to the invention, when the intermediate is prepared, no separation is needed, and reactions can be directly carried out. The method is green and environment-friendly. With the method, process operation is simplified, cost is reduced, and yield is improved. The method is more suitable for large-scale industrialized productions.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of local anesthetic ropivacaine. Background technique [0002] Ropivacaine is a single enantiomer (S-shaped) long-acting amide local anesthetic. Its mechanism of action is the same as that of other local anesthetics. It blocks nerve excitation and conduction by inhibiting nerve cell sodium ion channels. Since the discovery that long-acting local anesthetics can induce cardiac arrest, people have been looking for less fat-soluble and safer alternatives. Ropivacaine is such a new type of long-acting amide local anesthetic, which has a long duration of action and has anesthetic and analgesic effects. [0003] Ropivacaine is a product in which the third nitrogen atom of the piperidine ring of bupivacaine is replaced by a propyl group. It is a single enantiomer with an asymmetric structure, that is, the S-mirror body. It is a pure left-han...

Claims

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Application Information

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IPC IPC(8): C07D211/60
Inventor 赵思太任业明沈乃涛冯光玲张雯段崇刚
Owner SHANDONG INST OF PHARMA IND
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