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Preparation method of 7-amino-6-demethylation-6-deoxy tetracycline and minocycline hydrochloride

A technology of minocycline hydrochloride and deoxytetracycline, which is applied in the preparation of carboxylic acid amides, the preparation of organic compounds, organic chemical methods and other directions, can solve the problems of small safety risk and complicated process operation.

Active Publication Date: 2021-04-13
台州达辰药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Compared with the existing synthetic methods, the method of the present invention solves the problem of cumbersome process operation, avoids the risk of heterogeneity exceeding the standard caused by the finished product passing through the column, and the post-purification treatment is simple, economical and environmentally friendly, and avoids the use of expensive and toxic reagents and catalyst, which greatly improves the yield and purity, reduces the cost, and is easy to realize large-scale production. It is a synthetic method with low safety risk and excellent advantages

Method used

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  • Preparation method of 7-amino-6-demethylation-6-deoxy tetracycline and minocycline hydrochloride
  • Preparation method of 7-amino-6-demethylation-6-deoxy tetracycline and minocycline hydrochloride
  • Preparation method of 7-amino-6-demethylation-6-deoxy tetracycline and minocycline hydrochloride

Examples

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preparation example Construction

[0172] The present invention provides a kind of preparation method of 7-amino-6-desmethyl-6-deoxytetracycline, described method comprises steps:

[0173]

[0174] (1) 6-demethyl-6-deoxytetracycline reacts with a chlorinated reagent to obtain a chlorinated product; the chlorinated product reacts with an azo reagent to obtain a chlorinated product containing 7-p-benzenesulfonate Acid azo-11a-chloro-6-demethyl-6-deoxytetracycline reaction solution;

[0175] (2) adding a reducing agent to the reaction solution containing 7-p-benzenesulfonic acid azo-11a-chloro-6-demethyl-6-deoxytetracycline obtained in step (1), and reacting to obtain 7 -Amino-6-desmethyl-6-deoxytetracycline.

[0176] In the preparation method of 7-amino-6-demethyl-6-deoxytetracycline of the present invention, 6-demethyl-6-deoxytetracycline also includes the form of its salt, preferably, the 6 - demethyl-6-deoxytetracycline includes 6-desmethyl-6-deoxytetracycline sulfate.

[0177] In a preferred example of ...

Embodiment 1

[0324] Example 1: Synthesis of 7-amino-6-demethyl-6-deoxytetracycline

[0325] Add 30g of 6-desmethyl-6-deoxytetracycline sulfate and 9.38g of N-chlorosuccinimide to 330ml of water, stir and react at 20-30°C for 1h, cool down to 0-5°C, and pour into the reaction system Add 31g diazonium salt of p-aminobenzenesulfonate, through NaHCO 3 Adjust the pH to 6.6-7.4 to obtain a reaction solution containing the product 7-azo-p-benzenesulfonate-11a-chloro-6-demethyl-6-deoxytetracycline, and then add hydrochloric acid dropwise to adjust the pH of the reaction solution=2.0~ 3.0, add 39.6g of stannous chloride, and react at 20-30°C for 3 hours to obtain a reaction solution, adjust the pH of the reaction solution to 6.8-7.2 with sodium hydroxide, use membrane separation equipment, and select a filter with a molecular weight of figure 1 shown.

Embodiment 2

[0326] Embodiment 2: the synthesis of minocycline hydrochloride

[0327] (1) In a clean four-necked bottle, add 80mL of ethylene glycol monomethyl ether and 20g of 7-amino-6-desmethyl-6-deoxytetracycline prepared in Example 1, add 13.8g of concentrated hydrochloric acid dropwise, and stir thoroughly Dissolve, transfer all the solution to a hydrogenation tank, add 12g of 5wt% Pd / C (50%), control the temperature at 20-25°C, and pass hydrogen (the hydrogen pressure is 7.0-9.0kg / cm 2 reaction liquid level), after adding 42.0 g of formaldehyde aqueous solution (the weight fraction of formaldehyde is 40%), heat preservation and pressure reaction for 3 hours, the reaction is completed, and the reaction liquid is obtained.

[0328] (2) In a clean four-neck bottle, add 1L of clean water, cool down to 0-10°C, add the reaction solution obtained in step (1), add ammonia water dropwise to adjust pH=3.8-4.0, crystallize at 0-10°C for 2 hours, pump Filter, obtain minocycline hydrochloride c...

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Abstract

The invention relates to a preparation method of 7-amido-6-demethylation-6-deoxy tetracycline and minocycline hydrochloride, and particularly provides a preparation method of 7-amido-6-demethylation-6-deoxy tetracycline. The preparation method comprises the following steps: (1) carrying out chlorination reaction on 6- preparation method-6-deoxy tetracycline and a chlorination reagent, and obtaining a chlorination product; carrying out azo reaction on the chlorination product and an azo reagent to obtain a reaction solution containing 7-p-benzenesulfonic acid azo group-11a-chloro-6-demethylation-6-deoxy tetracycline; and (2) adding a reducing reagent into the reaction solution containing the 7-p-benzenesulfonic acid azo group-11a-chloro-6-demethylation-6-deoxy tetracycline obtained in the step (1), and carrying out a reaction to obtain the 7-amido-6-demethylation-6-deoxy tetracycline. The synthesis method of minocycline hydrochloride has the advantages of simple synthesis process, high yield, high purity, easiness in large-scale production and the like.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of 7-amino-6-desmethyl-6-deoxytetracycline and minocycline hydrochloride. Background technique [0002] Minocycline hydrochloride, also known as minocycline or minocycline, is a broad-spectrum antibacterial tetracycline antibiotic. It can combine with t-RNA to achieve antibacterial effect. Minocycline has a broader antibacterial spectrum than similar drugs and has antibacterial activity. The antibacterial spectrum is similar to that of tetracycline, and it has a strong effect on Gram-positive bacteria including tetracycline-resistant Staphylococcus aureus, Streptococcus and Neisseria gonorrhoeae in Gram-negative bacteria; it also has a strong effect on Chlamydia trachomatis and Mycoplasma urealyticum Good inhibitory effect. [0003] Minocycline hydrochloride, Minocycline hydrochloride, CAS: 13614-98-7, light yellow-orange amorphous solid, soluble in water, sl...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C237/26
CPCC07C231/12C07C2603/46C07B2200/07C07C237/26
Inventor 周魏魏曹俊爽张盛荣谢彪李明霞
Owner 台州达辰药业有限公司
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