A kind of efficient preparation method of doxycycline

The technology of doxycycline and oxytetracycline is applied in the field of high-efficiency preparation of doxycycline, and can solve the problems of low yield and ee value of alpha isomer, harsh production conditions of doxycycline, low production and operation safety, and the like, Achieve high effective isomer content, reduce harm to human body, and facilitate weighing and transportation.

Inactive Publication Date: 2019-05-31
GUANGDONG ZHONGNONGLIAN BIOLOGICAL PHARMCO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 1. Hydrofluoric acid dehydration: Hydrofluoric acid is slowly corrosive to the environment, equipment and operators during use, so the safety of production operations is low and it is harmful to the human body;
[0008] 2. Dechlorination and hydrogenation: Palladium carbon dechlorination and hydrogenation process has poor isomer selectivity. After dechlorination and hydrogenation, a mixture of a configuration and b configuration isomer is obtained. The target product is a configuration isomer. The content of b isomer is required to be less than 2%, but after dechlorination and hydrogenation, the yield of a configuration is only about 75%, and the ee value is less than 60%;
[0009] 3. Salt conversion: the original process utilizes the strong binding force of a configuration and sulfosalicylic acid to convert p-toluenesulfonate into sulfosalicylate to increase the ratio of a configuration, but it will lead to sulfonic acid in the reaction mother liquor There are a large amount of acids such as salicylic acid and p-toluenesulfonic acid, if not treated, it will cause great environmental pollution, there are literature reports that can be treated, but the cost of treatment is high, and it is difficult to realize industrialization, so a considerable part of the production Business shut down due to this issue
[0010] Therefore, the original synthesis process of doxycycline has problems such as harsh production conditions, low yield of a isomer and ee value, high cost and large environmental pollution.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Put 100g of methanol, 10g of oxytetracycline base and 0.1g of methanolic ammonia in the reaction flask in turn, stir at 20~30°C for 30min, then start cooling to -10~-15°C, add 5g of dry and crushed NBS at one time, stir for 15min, TLC monitored the complete reaction of the raw materials, and a large amount of solids precipitated out in the reaction bottle, which was filtered through a filter rejection machine, and the filter cake was washed with cold methanol to obtain oxytetracycline 11α-bromo-6,12-hemiketal, with a yield of 95%. Dry at low temperature until the dry content is about 90%. After fractional distillation of the mother liquor, the resulting methanol is used mechanically.

Embodiment 2

[0032]Add 500mL of anhydrous treated benzene into a reaction kettle with a dehydration device, blow nitrogen into the reaction kettle, slowly add 11α-bromo-6,12-hemiketal oxytetracycline 100g under stirring, and then add HZSM-5 20g, first stirred at room temperature for 2 hours, then slowly raised the temperature to reflux reaction and discharged the water generated by the reaction in time, after TLC monitored the complete reaction of the raw materials, slowly lowered the temperature to 50°C, filtered the reaction solution while it was hot, and filtered out Solid hydroxyl dehydrating agent, distill the filtrate to remove the reaction solvent benzene, dilute the raffinate with double the amount of ethanol, slowly add ammonia ethanol solution (7%), neutralize the reaction solution to pH 1~2, cool to 0 ℃, shake filter, wash with cold ethanol 50mL, add 50g p-toluenesulfonic acid to the filtrate, and add a small amount of seed crystals to precipitate crystals, cool to 0°C shake filt...

Embodiment 3

[0034] Add 500mL of anhydrous treated benzene into a reaction kettle with a dehydration device, blow nitrogen into the reaction kettle, slowly add 11α-bromo-6,12-hemiketal oxytetracycline 100g under stirring, and then add T-Al 2 o 3 20g, first stirred at room temperature for 2 hours, then slowly raised the temperature to reflux reaction and discharged the water generated by the reaction in time, after TLC monitored the complete reaction of the raw materials, slowly lowered the temperature to 50°C, filtered the reaction solution while it was hot, and filtered out the solid hydroxyl group Dehydrating agent, distill the filtrate to remove the reaction solvent benzene, dilute the raffinate with double the amount of ethanol, slowly add ammonia ethanol solution (7%), neutralize the reaction solution to a pH of 1~2, cool to 0°C, shake Filter, wash with 50 mL of cold ethanol, add 50 g of p-toluenesulfonic acid to the filtrate, and add a small amount of seed crystals to precipitate c...

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Abstract

The invention discloses a high-efficiency preparation method of doxycycline, and belongs to the technical field of medicine synthesizing. The high-efficiency preparation method of doxycycline is technically characterized in that the specific synthesizing route is shown in the description. The high-efficiency preparation method has the advantages that the cost of raw materials is low, the obtaining is easy, the technology operation is simple, the repeatability is good, and the yield rate is relatively high.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a high-efficiency preparation method of doxycycline. Background technique [0002] Antibiotics are the most extensive class of antibacterial drugs. In the early 1940s, the clinical application of penicillin G promoted the improvement of antibacterial drugs and accelerated the development of antibacterial drugs. Antibiotics, formerly known as antibiotics, are secondary metabolites or synthetic analogues of microorganisms, which can inhibit the growth and survival of microorganisms in vitro without causing serious toxic side effects on host cells. In clinical treatment, most antibiotics can inhibit bacterial infection and are used for the prevention and treatment of bacterial infectious diseases. In fact, it can not only kill viruses and bacteria, but also have good inhibitory and inactivation effects on mold, mycoplasma, chlamydia and other microorga...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/12C07C237/26
CPCC07C231/12C07D311/00C07C237/26
Inventor 徐桂清高原毛龙飞姜玉钦李伟
Owner GUANGDONG ZHONGNONGLIAN BIOLOGICAL PHARMCO
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