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Preparation method of chloroprocaine hydrochloride

A technology of chloroprocaine hydrochloride and o-chlorine, which is applied in the field of organic drug synthesis, can solve the problems of low production efficiency, long reaction period, reduced reaction energy consumption, etc., and achieves reduced production period, short reaction time, and improved reaction yield. rate effect

Inactive Publication Date: 2016-09-28
WUXI KAIFU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] For this reason, the technical problem to be solved by the present invention lies in the problems of long reaction cycle and low production efficiency in the preparation process of chloroprocaine hydrochloride in the prior art, and the reduction of reaction energy consumption

Method used

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  • Preparation method of chloroprocaine hydrochloride
  • Preparation method of chloroprocaine hydrochloride
  • Preparation method of chloroprocaine hydrochloride

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Embodiment 1

[0034] Such as image 3 As shown, step 1: under stirring at room temperature, dissolve 1 mol of o-chloro-p-nitrobenzoic acid and 3 mol of 2-diethylaminoethanol in xylene until the solution is clear, and then add p-toluenesulfonic acid. The reactant was heated to 138-142°C, refluxed, and reacted for 2 hours. After the reaction was completed, it was cooled to room temperature and filtered. The filtrates were washed 3 times with aqueous NaOH respectively. The organic phase was extracted twice with hydrochloric acid solution, and the combined extracts were adjusted to pH 3.4-4.0 to obtain an aqueous solution of intermediate 1 (nitrolocaine), which was set aside.

[0035] Step 2: Add the aqueous solution of intermediate 1 into the reaction flask, add ammonium chloride, and add reducing iron powder in batches. Heat to 68-70°C, stir for 2-3 hours. After the reaction is completed, filter while it is hot. After the filtrate is acidified, add a saturated solution of sodium sulfide d...

Embodiment 2

[0044] Step 1: Dissolve 1 mol of o-chloro-p-nitrobenzoic acid and 3 mol of 2-diethylaminoethanol in xylene under stirring at room temperature, and then add p-toluenesulfonic acid until the solution is clear. The reactant was heated to 138-142°C, refluxed, and reacted for 4 hours. After the reaction was completed, it was cooled to room temperature and filtered. The filtrates were washed 3 times with aqueous NaOH respectively. The organic phase was extracted twice with hydrochloric acid solution, and the combined extracts were adjusted to pH 3.4-4.0 to obtain an aqueous solution of intermediate 1 (nitrolocaine), which was set aside.

[0045] Step 2: Add the aqueous solution of intermediate 1 into the reaction flask, add ammonium chloride, and add reducing iron powder in batches. Heated to 80°C and stirred for 1h. After the reaction is completed, filter while it is hot. After the filtrate is acidified, add a saturated solution of sodium sulfide dropwise to make it alkaline and...

Embodiment 3

[0054] Step 1: Dissolve 1mol o-chloro-p-nitrobenzoic acid and 3mol 2-diethylaminoethanol in xylene under stirring at room temperature until the solution is clear, then add immobilized liquid acid HF / Al 2 O. The reactant was heated to 138-142°C, refluxed, and reacted for 6 hours. After the reaction was completed, it was cooled to room temperature and filtered. The filtrates were washed 3 times with aqueous NaOH respectively. The organic phase was extracted twice with hydrochloric acid solution, and the combined extracts were adjusted to pH 3.4-4.0 to obtain an aqueous solution of intermediate 1 (nitrolocaine), which was set aside.

[0055] Step 2: Add the aqueous solution of intermediate 1 into the reaction flask, add ammonium chloride, and add reducing iron powder in batches. 25 ° C, stirring the reaction for 4h. After the reaction is finished, filter, and the filtrate is acidified, and a saturated solution of sodium sulfide is added dropwise to make it alkaline, and then ...

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Abstract

The invention belongs to the technical field of organic drug synthesis and particularly relates to a preparation method of chloroprocaine. The preparation method includes the steps that 1, 2-chloro-4-nitrobenzoic acid and 2-diethylaminoethanol reaction raw materials are added into a xylene reaction solvent, para-toluenesulfonic acid or immobilized liquid acid or faintly acid metal salt is added to serve as a catalyst, heating is conducted till reflux is achieved, a reaction is carried out for a certain period of time, aftertreatment is carried out, and a water solution of nitrochlor cain is obtained; 2, ammonium chloride and iron powder are added into the water solution of nitrochlor cain, a heating reaction is carried out, aftertreatment is carried out, and crude chloroprocaine hydrochloride is obtained; refining is carried out, and chloroprocaine hydrochloride is obtained. The direct esterification reaction time is short, the production period is shortened by 30% or above, the total yield of the finished product is larger than 30%, and energy consumption is reduced by 25% or above. The content of chloroprocaine hydrochloride is not smaller than 99.0%, the content of related substances is not larger than 1.0%, and the content of a residual solvent (dimethylbenzene) does not exceed 0.1%. The preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic medicine synthesis, and in particular relates to a preparation method of chloroprocaine hydrochloride. Background technique [0002] Chloroprocaine hydrochloride is a local anesthetic of benzoate esters, which introduces a Cl group on the basis of the structure of procaine, which increases the anesthetic efficacy by 4 times relative to procaine, and its toxicity is equivalent to that of common The 0.5 of lucaine has the advantages of strong anesthesia effect and quick recovery after anesthesia in terms of chemical structure. According to a large number of literature reports, clinical trials have confirmed that chloroprocaine has shown perfect anesthesia effects in many surgical operations, not only has quick onset, long duration, rapid recovery of motor and sensory synchronization after drug withdrawal, but also can reduce sedation. The dosage of pain medicine is reduced, and the corresponding si...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/06C07C219/14C07C227/04C07C229/60C07C227/40C07C227/42
CPCC07C213/06C07C227/04C07C227/40C07C227/42C07C219/14C07C229/60
Inventor 刘骞陈伟华
Owner WUXI KAIFU PHARMA
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