Preparation method of cloperadine hydrochloride

A technology of cloperidine hydrochloride and salt formation, applied in the field of medicine, can solve the problems of reduced yield of target product, reduced utilization rate of chloroethanol, increased production cost of enterprises, etc., and is beneficial to large-scale industrial production, reduced extraction cost, and improved quality effect

Pending Publication Date: 2021-11-16
CHONGQING SANSHENG IND CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The defect of this synthetic method is that the total yield is on the low side, not as high as the yield of the convergent synthesis method, and 2-chloroethanol and 2-chloroethanol can also undergo etherification reaction under the effect of concentrated sulfuric acid, resulting in the utilization of chlorohydrin The yield decreases, and the by-product 2-chloroethyl ether is increased at the same time. 2-Chloroethyl ether and piperidine can also react to generate by-products, resulting in a decrease in the yield of the target product, an increase in impurities, and separation and purification difficulties. Products with high quality requirements will increase the production cost of enterprises

Method used

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  • Preparation method of cloperadine hydrochloride
  • Preparation method of cloperadine hydrochloride
  • Preparation method of cloperadine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Step 1: Add 20g (84.7mmol) of 4-chlorodiphenylchloromethane, 10.9g (84.7mmol) of 2-piperidineethanol and 80mL of dichloromethane to the three-necked reaction flask in sequence, and add 10.3g of triethylamine under stirring (101 mmol), then reacted at 20-30° C. for 3 hours, and TLC detected that the reaction of the raw materials was complete. The reaction solution was washed twice with water, and the organic phase was spin-dried to obtain compound (II) as an oil, which was directly used in the next step.

[0040] Step 2: Dissolve the oily substance obtained in the previous step in 60 mL of isopropyl acetate, feed hydrogen chloride gas at 20-30°C until the pH is less than 2, then stop stirring at 20-30°C for 1 hour, then cool down to 0-30°C Stir at 5°C for 1 hour, filter with suction, wash the filter cake with isopropyl acetate, and dry the wet product under reduced pressure to obtain 28.2 g of white powder with a yield of 91.2%, a purity of 99.8%, and a maximum single im...

Embodiment 2

[0042] Step 1: Add 20g (91.7mmol) of 4-chlorodiphenylmethanol, 13.5g (91.7mmol) of N-(2-chloroethyl)piperidine, and 0.2g of tetrabutylammonium iodide to the three-necked reaction flask in sequence and 80 mL of dichloromethane, and added 11.2 g (111 mmol) of triethylamine under stirring, and then reacted at 30-40° C. for 5 hours, and the reaction of raw materials was detected by TLC. The temperature was lowered to 30°C, washed with water twice and spin-dried to obtain compound (II) as an oil, which was directly used in the next step.

[0043] Step 2: Dissolve the oily substance obtained in the previous step in 60 mL of ethyl acetate, feed hydrogen chloride gas at 20-30°C until the pH is less than 2, stop, continue to stir at 20-30°C for 1 hour, and then cool down to 0-5 Stir at ℃ for 1 hour, filter with suction, wash the filter cake with ethyl acetate, and dry the wet product under reduced pressure to obtain 30.1 g of white powder with a yield of 89.8%, a purity of 99.8%, and a...

Embodiment 3

[0045]Step 1: In the three-necked reaction flask, add 4-chlorodiphenylmethanol 20g (91.7mmol), 2-piperidineethanol 11.8g, 13.5g (91.7mmol) and 80mL toluene in sequence, and add concentrated sulfuric acid 5.4g ( 55.1 mmol), and then reacted at 100-110° C. for 7 hours, and TLC detected that the reaction of the raw materials was complete. Cool down to 0-5°C to crystallize for 1 hour, filter with suction, adjust the pH to alkaline with lye (sodium hydroxide, potassium hydroxide, carbonate or bicarbonate), add 60 mL of ethyl acetate to extract, organic The phase was washed once and directly used in the next step for salt formation.

[0046] Step 2: Add hydrogen chloride gas to the ethyl acetate compound (II) solution obtained in the previous step at 20-30°C until the pH is less than 2, then stop, continue to stir at 20-30°C for 1 hour, and then cool down to 0-5°C Stir for 1 hour, filter with suction, wash the filter cake with isoethyl acetate, and dry the wet product under reduced...

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Abstract

The invention relates to a preparation method of cloperadine hydrochloride, which comprises the following steps: placing a formula VI and a formula III in a solvent or without a solvent, carrying out condensation or etherification reaction, and separating to obtain 1-[2-[(4-chloro-alpha phenyl benzyl) oxygen] ethyl] piperidine (II); and salifying the 1-[2-[(4-chloro-alpha phenyl benzyl) oxygen] ethyl] piperidine with hydrogen chloride or hydrochloric acid in a solvent to obtain the cloperadine hydrochloride. The method is mild in process condition, convenient and simple to operate and suitable for large-scale industrial production, the purity of the produced target product reaches 99.7% or above, and the single impurity is smaller than 0.1%.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of cloperidine hydrochloride. Background technique [0002] The chemical name of cloperidine hydrochloride is 1-[2-[(4-chloro-αphenylbenzyl)oxy]ethyl]piperidine hydrochloride, which is mainly used to suppress the cough center and antitussive, and also has a weak anti-organism effect. Amine effect, no dependence and tolerance. Cloperidine hydrochloride was developed by Mitsubishi Tanabe Pharmaceutical Co., Ltd., Japan, and was launched in Japan on May 10, 1965. It has been produced and used in my country since the 1970s. [0003] The synthetic route of cloperidine hydrochloride report is seldom, and patent CN104327014B reports to be raw material with 4-chlorodiphenylmethanol, first reacts with 2-chloroethanol under the catalysis of concentrated sulfuric acid to obtain 4-chlorodiphenyl chloroethyl ether, Then, it undergoes condensation reaction with piperidine under t...

Claims

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Application Information

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IPC IPC(8): C07D295/088
CPCC07D295/088
Inventor 彭磊罗骥潘呈恭黄雄鸠何伟张洪兰
Owner CHONGQING SANSHENG IND CO LTD
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