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Preparation method of doxycycline hydrochloride

A technology for doxycycline hydrochloride and benzylsulfonate, which is applied in the field of preparation of doxycycline hydrochloride, can solve the problems of many process steps and low overall yield of doxycycline hydrochloride, etc., and achieves simple and convenient process steps, The effect of improving selectivity and yield and simplifying the preparation process

Active Publication Date: 2018-08-24
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the yield of these methods hydrogenation reaction is higher, there are still many overall process steps, and the overall yield of doxycycline hydrochloride is not high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] The preparation of embodiment 1 doxycycline sulfosalicylate

[0058] Add 150 ml of 50% ethanol aqueous solution into the hydrogenation kettle, add 2.5 g of palladium carbon (dried) under stirring, 0.05 g of methylthiouracil, 4.5 g of quinoline, 0.04 g of pyridine, and 0.15 g of sulfamethazine, and start Heat to 55°C and keep stirring for 30min. Add 50.0 g of 11a-chloro-6-methine oxytetracycline p-toluenesulfonate, nitrogen replacement 3 times, hydrogen replacement 3 times, hydrogen pressure 2kg / cm 2 , Stirring reaction 8 ~ 10h. After the reaction is complete, filter out the palladium carbon, cool to room temperature, add 45.0 g of sulfosalicylic acid, stir and crystallize at room temperature, filter, wash the filter cake with ethanol, and blow dry at 40-50 ° C to obtain 46.9 g of a yellow powdery solid , yield 92.0%.

Embodiment 2

[0059] The preparation of embodiment 2 doxycycline hydrochloride

[0060] Add 40.0 g of the α-6-deoxyoxytetracycline sulfosalicylate obtained above into 270 ml of 8% hydrogen chloride ethanol solution, heat and stir until dissolved, add 18 ml of purified water, stir and crystallize for 2 hours, and cool to room temperature , stirred for 16h. After filtering, the filter cake was washed with ethanol, and air-dried at 40-50° C. to obtain 27.8 g of a yellow powdery solid with a yield of 89.8% and a purity of 99.6%.

Embodiment 3

[0062] Add 150ml of 50% ethanol aqueous solution into the hydrogenation kettle, add 2.5g of palladium carbon (dried) under stirring, 4.5g of quinoline, 0.04g of pyridine, and 0.25g of sulfamethazine, start heating to 55°C, and keep stirring 30min. Add 50.0 g of 11a-chloro-6-methine oxytetracycline p-toluenesulfonate, nitrogen replacement 3 times, hydrogen replacement 3 times, hydrogen pressure 2kg / cm 2 , Stir the reaction for 8-10h. After the reaction is complete, filter out the palladium carbon, cool to room temperature, add 45.0 g of sulfosalicylic acid, stir and crystallize at room temperature, filter, wash the filter cake with ethanol, and blow dry at 40-50 ° C to obtain 37.3 g of a yellow powdery solid , yield 73.0%.

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PUM

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Abstract

The invention provides a preparation method of doxycycline hydrochloride. The preparation method provided by the invention comprises the following steps: carrying out hydrogenation reaction on 11a-chloro-6-methenyloxytetracycline p-toluenesulfonate under the conditions of a catalyst and a toxic agent; then reacting with sulfosalicylic acid to obtain alpha-6-deoxytetracycline sulfosalicylate; afterreacting with a hydrogen chloride-ethanol solution, adding and stirring to separate out a crystal, so as to obtain the doxycycline hydrochloride, wherein the toxic agent contains a mixture of an organic matter containing sulfur and an organic matter containing nitrogen. According to the method provided by the invention, the yield and stereoselectivity of the doxycycline hydrochloride can be improved and high-quality crude drugs are obtained.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of doxycycline hydrochloride. Background technique [0002] Doxycycline hydrochloride (Doxycycline, also known as doxycycline hydrochloride, deoxyoxytetracycline hydrochloride), is a broad-spectrum semi-synthetic tetracycline antibiotics. Inhibition of Rickettsia, Mycoplasma pneumoniae, Mycoplasma trachomatis, amoeba, etc., especially the common pathogenic bacteria in the respiratory tract of patients with chronic bronchitis are more sensitive to doxycycline hydrochloride, and doxycycline hydrochloride has Certain antitussive and expectorant effects. [0003] In recent years, researchers have found that doxycycline hydrochloride is more sensitive to anthrax bacteria, Vibrio cholerae, etc., and its mechanism of inhibiting microorganisms is: binding to the A site of the 30S small subunit of microorganisms, thereby interfering with aminoacyl tRNA and 30S smal...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C237/26
CPCC07C231/12C07C303/32C07C2603/46C07C237/26C07C309/60
Inventor 唐井元马贯军杨晓勇
Owner CHANGZHOU PHARMA FACTORY
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