Method for preparing ropivacaine intermediate

A technology for ropivacaine and intermediates, which is applied in the field of preparation of intermediates, can solve problems such as being dangerous and unsuitable for industrial production, and achieve the effects of simple operation, increased yield, and simplified process

Pending Publication Date: 2019-03-08
SHANDONG KEYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] "Synthetic Chemistry" 2006, Volume 14, No. 4 "Synthesis of Pivacaine Hydrochloride by Triphosgene Method" also reported the synthetic method of ropivacaine intermediate, which uses triphosgene to prepare acid chloride, and triphosgene is stored There are dangers in post-processing, and it is also not suitable for industrial production

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Mix 2.65g of L-piperidine-2-carboxylic acid with 13ml of toluene, slowly inject HCl gas under stirring at room temperature until the pH of the reaction solution is 3, then add 2.42g of 26-dimethylaniline, and then dropwise add 9.2g of trichloro Oxyphosphorus, the dropwise addition is completed, and the temperature is raised to 50°C for 6 hours. After the reaction is completed, the temperature is lowered to 10°C, and then 13ml of purified water is added dropwise, and then the pH is adjusted to 12 with 40% sodium hydroxide solution, and then extracted with 13ml of ethyl acetate for 3 The second time, the organic phase was collected, concentrated and spin-dried, and dried at 40° C. to obtain a white solid 3.6 with a yield of 77%. The HPLC control was the same point.

Embodiment 2

[0025] Mix 2.65g of L-piperidine-2-carboxylic acid with 13ml of DMP, slowly inject HCl gas under stirring at room temperature until the pH of the reaction solution is 3, then add 2.42g of 26-dimethylaniline, and then dropwise add 9.2g of oxytrichloride Phosphorus, the dropwise addition is completed, the temperature rises to 50°C, TLC controls the formation of product spots, reacts for 3 hours, after the reaction is completed, cools down to 10°C, then adds 26ml of purified water dropwise, and then adjusts the pH to 5-6 with 40% sodium hydroxide solution. Then extract 3 times with 13ml of ethyl acetate, collect the aqueous phase, adjust the pH=12 with 40% sodium hydroxide solution, then crystallize at 0-5°C for 3h, collect the solid, and separate by chromatography column, DCM:MeOH=10: 1. Obtained 0.72 g of white solid with a yield of 15.4%. The HPLC control was the same point.

Embodiment 3

[0027] Mix 2.65g of L-piperidine-2-carboxylic acid with 13ml of dioxane, slowly inject HCl gas under stirring at room temperature until the pH of the reaction solution is 3, then add 2.42g of 26-dimethylaniline, and then dropwise add 9.2g Phosphorus oxychloride, after the dropwise addition was completed, the temperature was raised to 50°C, and the product point was generated as compared with TLC, and reacted for 12 hours. After the reaction was completed, the temperature was lowered to 10°C, and then 13ml of purified water was added dropwise, and then the pH was adjusted to 12 with 40% sodium hydroxide solution. , and then extracted 3 times with 13ml of ethyl acetate, collected the organic phase, concentrated and spin-dried, and dried at 40°C to obtain a white solid 3.6, with a yield of 77%. The HPLC control was the same point.

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Abstract

The invention discloses a method for preparing a ropivacaine intermediate. The method includes: using L-piperidine-2-formic acid to prepare L-piperidine-2-formate, directly allowing L-piperidine-2-formate without separation to be in one-step reaction with 2, 6-dimethylaniline and phosphorus oxychloride to directly prepare S-N-(2, 6-dimethylphenyl) piperidine-2-formamide. By the method, process operation is simplified, cost is lowered, yield is increased, and the intermediate is more suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of an intermediate 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 image. I...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07D211/60
Inventor 徐鹤伦立军邢辉张照兴杨波勇武立军阴启明任小亮
Owner SHANDONG KEYUAN PHARMA
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