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Preparation process of doxycycline hydrochloride

A technology of doxycycline hydrochloride and preparation process, applied in the field of preparation of doxycycline hydrochloride, can solve the problems of poor stereospecificity, low yield and the like

Active Publication Date: 2010-07-28
扬州联博药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, it is generally believed that the heterogeneous catalyst Pd / C is used for hydrogenation reduction, and the yield is low and the stereospecificity is poor, while the use of a homogeneous catalyst such as a rhodium complex catalyst can increase the yield to about 85%.

Method used

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  • Preparation process of doxycycline hydrochloride
  • Preparation process of doxycycline hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Add 60ml of 60% ethanol to the hydrogenation tank, add metronidazole 0.0062g, 4-picoline 0.018g and 2,4-dihydroxyquinoline 0.063g solution in 5ml methanol, 5% palladium / carbon 0.8 g, stirred for 20 minutes, added 10 g of 11α-chloro-6-methine oxytetracycline p-toluenesulfonate, stirred for 30 minutes, and sealed. Vacuumize and change nitrogen for 3 times, then change hydrogen for 3 times, heat up, and react with hydrogen at 65°C, keeping the pressure at 6.5kg / cm 2 , After the completion of the reaction was confirmed by thin-plate chromatography, the reaction was stopped. Filter, wash with ethanol and water successively, combine the filter and washing liquid, add 5-sulfosalicylic acid, stir at 40°C for 1 hour, stand at 20°C for 6 hours, filter, wash with ethanol, and drain to obtain α-6-deoxy Oxytetracycline 5-sulfosalicylate 8.6g (dried).

Embodiment 2

[0033] Put 60ml of 60% ethanol into the hydrogenation kettle, add metronidazole 0.0057g, 4-picoline 0.016g and 2,4-dihydroxyquinoline 0.058g solution in 5ml methanol, 5% palladium / carbon 0.8 g, stirred for 20 minutes, added 10 g of 11α-chloro-6-methine oxytetracycline p-toluenesulfonate, stirred for 30 minutes, and sealed. Vacuumize and change nitrogen for 3 times, then change hydrogen for 3 times, heat up, and react with hydrogen at 65°C, keeping the pressure at 5.5kg / cm 2, After the completion of the reaction was confirmed by thin-plate chromatography, the reaction was stopped. Filter, wash with ethanol and water successively, combine the filter and washing liquid, add 5-sulfosalicylic acid, stir at 40°C for 1 hour, stand at 20°C for 6 hours, filter, wash with ethanol, and drain to obtain α-6-deoxy Oxytetracycline 5-sulfosalicylate 9.3g (dried).

Embodiment 3

[0035] Put 30ml of 60% ethanol and 10g of α-6-deoxyoxytetracycline 5-sulfosalicylate into the reactor successively, stir, add ammonia water dropwise at 10°C until the pH is 5.9, continue stirring for 15 minutes, and keep the pH at 5.9 No change, stop dripping ammonia water. Raise the temperature to 35°C, stir for 30 minutes, keep warm for 4 hours, filter, wash with 60% ethanol, and drain to obtain 6.0 g of α-6-deoxyoxytetracycline base (dried).

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Abstract

The invention provides a preparation process of doxycycline hydrochloride. In the preparation process, 5-hydroxy-6-demethyl-6-desoxy-6-methylene-11-chlorotetracycline is pressurized and hydrogenated with hydrogen in the presence of catalyst-palladium / carbon (Pd / C) and adjuvant and then reacts with 5-sulfosalicylic acid to obtain alpha-6-doxycycline 5-sulfosalicylate; then alpha-6-doxycycline base is generated after basification; and finally the doxycycline hydrochloride is generated through salt transformation. The preparation process of the doxycycline hydrochloride has the advantages that the productivity and stereoselectivity are improved, the content of related substances in the finished product is reduced, and the high-quality finished product is obtained.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, more specifically, to a preparation process of doxycycline hydrochloride. Background technique [0002] Doxycycline hydrochloride is a broad-spectrum semi-synthetic tetracycline antibiotic, effective against gram-positive bacteria, gram-negative bacteria and chlamydia, clinically used for respiratory tract infection, biliary tract infection, tonsillitis, lymphadenitis, cellulitis , the treatment of chronic bronchitis in the elderly, mycoplasma pneumonia, syphilis, gonorrhea, typhus, cholera, relapsing fever, the prevention of malignant malaria and leptospirosis, and short-term use as a preventive drug for traveler's diarrhea. The dosage forms of doxycycline hydrochloride clinically used include tablets, capsules, oral suspensions, injections and various slow and controlled release preparations. [0003] Blackwood et al. isolated the pure doxycycline α-isomer for the first time in US Patent US3...

Claims

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Application Information

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IPC IPC(8): C07C309/60C07C303/32C07C237/26C07C231/12
Inventor 陆波苏令
Owner 扬州联博药业有限公司
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