Synthesis process of doxycycline hydrochloride intermediate 11alpha-chlorinated methacycline

A technology for chloromethyloxytetracycline and doxycycline hydrochloride, which is applied in the field of synthesis technology of doxycycline hydrochloride intermediate 11α-chloromethyloxytetracycline, can solve the problem of high production cost, environmental pollution, etc. problems, to achieve the effect of saving production costs, reducing unfavorable factors, and eliminating excessive fluoride ions

Inactive Publication Date: 2013-12-25
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the shortcomings of the original production process, such as serious environmental pollution and

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] mixed acid dehydration reaction

[0018] Take 130ml of formic acid in a 500ml four-neck bottle, add 86ml of concentrated sulfuric acid with a mass concentration of 98% dropwise at 10-15°C, and add 123ml of thionyl chloride dropwise after the dropwise addition. After the dropwise addition, stir to cool down To -25°C, stir for 1 hour and raise the temperature to -10°C, add 100g oxytetracycline chlorinate into the mixture, control the temperature and stir at -10°C for 4-10 hours to obtain a yellow 11α-chloromethacycline oxytetracycline solution .

Embodiment 2

[0020] Preparation of doxycycline hydrochloride intermediate 11α-chloromethene oxytetracycline p-toluenesulfonate

[0021] Add 300ml of isopropanol to the 11α-chloromethycin solution prepared in Example 1 to dilute, control the temperature at 15-25°C, stir for 10min, control the temperature at 15-25°C, and use ethanol-ammonia Adjust the pH of the solution to 2, add a mixture of 700ml of isopropanol, 300ml of acetone and 80g of p-toluenesulfonic acid, then add seed crystals, stir for 12 hours, filter with suction, wash with 300ml of cold acetone, and dry with low-temperature blast to obtain yellow crystals Solid doxycycline hydrochloride intermediate 11α-chloromethene oxytetracycline p-toluenesulfonate 113g, yield 86%.

Embodiment 3

[0023] Preparation of doxycycline hydrochloride intermediate 11α-chloromethene oxytetracycline p-toluenesulfonate

[0024] Add 300ml of isopropanol to the 11α-chloromethycin solution prepared in Example 1 for dilution, control the temperature below 30°C, stir for 10min, control the temperature below 30°C, and adjust the solution with ethanol-ammonia pH=18~2.2, add 700ml of isopropanol, 300ml of acetone and 80g of p-toluenesulfonic acid mixture, then add seed crystals, stir for 8~15 hours, filter with suction, wash with 300ml of cold acetone, and dry with low temperature blast to get yellow Crystalline solid doxycycline hydrochloride intermediate 11α-chloromethacin p-toluenesulfonate.

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PUM

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Abstract

The invention discloses a synthesis process of doxycycline hydrochloride intermediate 11alpha-chlorinated methacycline. The technical scheme key point of the invention is as follows: in the synthesis process of doxycycline hydrochloride intermediate 11alpha-chlorinated methacycline, mixed acid of formic acid and 98% concentrated sulfuric acid is selected as a dehydrating agent. According to the improved way, anhydrous hydrofluoric acid in the tradition production is replaced by concentrated sulfuric acid frequently used in industrial production, the harm of the anhydrous hydrofluoric acid to the human body is reduced according to the improved process, the requirement on production equipment is reduced, the production cost is saved, and solvents used in the production can be recycled. On the environment aspect, the produced waste water is less, and the problem that fluorinion in the waste water is out of limits is eliminated. On the production operation aspect, the harm to an operator is small, and the operation is simple. And the yield is higher than the traditional synthesis process on the yield aspect.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis process of doxycycline hydrochloride intermediate 11α-chloromethycin. Background technique [0002] Doxycycline hydrochloride is a good antibacterial drug. It is a long-acting broad-spectrum semi-synthetic tetracycline antibiotic processed by oxytetracycline. It has a broad antibacterial spectrum and strong antibacterial effect. In addition to the effect on Gram-positive bacteria and negative bacteria, it can also inhibit Rickettsia, Mycoplasma pneumoniae, Mycoplasma trachomatis, and amoeba. In particular, common bacteria in the respiratory tract of patients with chronic bronchitis are more sensitive to doxycycline. And the medicine has certain antitussive, expectorant and antiasthmatic effects. In addition, the drug is also widely used in veterinary medicine to treat infections caused by various germs. The market demand for do...

Claims

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Application Information

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IPC IPC(8): C07C237/26C07C231/12C07C309/30C07C303/32
Inventor 韩会娟李伟杨林张水苗李鹏任宝齐
Owner HENAN NORMAL UNIV
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