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Method for preparing clonidine hydrochloride

A technology of clonidine hydrochloride and formic acid, applied in the field of medicine and chemical industry, can solve the problems of low purity and low yield of clonidine hydrochloride, and achieve the effects of reducing cost, energy consumption and pollution, improving purity and yield, and having strong controllability.

Inactive Publication Date: 2018-04-17
KUNMING YUANRUI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The invention provides a preparation method of clonidine hydrochloride, the purpose of which is to solve the problems of low purity and low yield of clonidine hydrochloride in industrial production by optimizing the preparation process

Method used

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  • Method for preparing clonidine hydrochloride
  • Method for preparing clonidine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0045] A. Synthesis of Intermediate 1

[0046] Add 188ml of formic acid and 100.0g of 2,6-dichloroaniline raw materials into the reaction flask, heat and stir in an oil bath to dissolve, stir and reflux at 95°C-100°C for 5h, then cool to room temperature, then cool to 0°C, stir and crystallize for 2h, Suction filtered and dried to obtain 92.0 g of white solid with a yield of 78.4%.

[0047] B. Synthesis of Intermediate 2

[0048]Add 70ml of thionyl chloride and 92g of intermediate 1 into the reaction flask, stir, cool down to 0°C in an ice-water bath, and add a mixed solution of 141ml of thionyl chloride and 156ml of sulfonyl chloride. After the addition, the temperature was naturally raised to room temperature, and then heated to 40°C and stirred for 20 hours. After the system was dissolved, it was distilled under reduced pressure until there was no distillate. Chloromethane solution, after dropping, naturally warm up to room temperature, stop the reaction for 2 hours, and ...

Embodiment 2

[0052] A. Synthesis of Intermediate 1

[0053] Add 200ml of formic acid and 120.0g of 2,6-dichloroaniline raw materials into the reaction flask, heat and stir in an oil bath to dissolve, stir and reflux at 95°C for 6h, then cool to room temperature, then cool to 0°C, stir and crystallize for 2.5h, and filter with suction , and dried to obtain 100.0 g of white solid with a yield of 80.2%.

[0054] B. Synthesis of Intermediate 2

[0055] Add 80ml of thionyl chloride and 100g of intermediate 1 into the reaction flask, stir, cool down to 0°C in an ice-water bath, and add a mixture of 160ml of thionyl chloride and 160ml of sulfuryl chloride. After the addition, the temperature was naturally raised to room temperature, then raised to 45°C and stirred for 18 hours. After the system was dissolved, it was distilled under reduced pressure until there was no distillate. Added 320ml of dichloromethane, cooled to 5°C in an ice-water bath, and added 150g of ethylenediamine distillate dropw...

Embodiment 3

[0059] A. Synthesis of Intermediate 1

[0060] Add 210ml of formic acid and 130.0g of 2,6-dichloroaniline raw materials into the reaction flask, heat and stir in an oil bath to dissolve, stir and reflux at 100°C for 6.5h, then cool to room temperature, then cool to 0°C, stir and crystallize for 3.5h, pump It was filtered and dried to obtain 110 g of white solid with a yield of 82%.

[0061] B. Synthesis of Intermediate 2

[0062] Add 85ml of thionyl chloride and 110g of intermediate 1 into the reaction flask, stir, cool down to 0°C in an ice-water bath, and add a mixture of 150ml of thionyl chloride and 150ml of sulfuryl chloride. After the addition, the temperature was naturally raised to room temperature, then raised to 60°C and stirred for 22 hours. After the system was dissolved, it was distilled under reduced pressure until there was no fraction. Chloromethane solution, after dripping, naturally warmed up to room temperature, and the reaction was stopped for 2 hours. Af...

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Abstract

The invention discloses a preparation method of clonidine hydrochloride, which includes three steps of synthesis of intermediate 1, synthesis of intermediate 2 and synthesis of clonidine hydrochloride. Acylation reaction to obtain intermediate 1, "one-pot method" to obtain clonidine free base, and finally salify with hydrogen chloride ethanol solution to obtain clonidine hydrochloride. A preparation method of high-purity clonidine hydrochloride is obtained by processing the synthesis process of the raw materials, firstly salifying and then adjusting the base in the purification of free base, and using ethyl acetate beating for the purification of clonidine hydrochloride. The method not only improves the product purity and yield, but also can effectively control impurities, greatly reduces the cost, simplifies the process, and is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a preparation method of clonidine hydrochloride. Background technique [0002] In September 2010, the US FDA approved clonidine hydrochloride 0.1mg and 0.2mg sustained-release tablets (Kapvay, Shionogi Inc) alone or in combination with stimulants for the treatment of children aged 6 to 17 with attention deficit hyperactivity disorder (ADHD). This product is the first clonidine preparation approved by the US FDA for the treatment of ADHD, and it is the only adjuvant drug for stimulant treatment of ADHD. [0003] Clonidine hydrochloride is also suitable for the treatment of high blood pressure, it can be used alone or in combination with other blood pressure lowering drugs. At present, there are clonidine transdermal patches in China for the treatment of children's voice and multiple motor tic disorders. Clonidine can also be used in combination with anesthesia during s...

Claims

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Application Information

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IPC IPC(8): C07D233/50
CPCC07D233/50
Inventor 王高华徐春霞牛树伟王艳昌
Owner KUNMING YUANRUI PHARMA
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