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A kind of synthetic method of minocycline and its derivatives

A technology of aminominocycline and nitrominocycline, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc.

Active Publication Date: 2022-03-08
JIHENG PHARMA HENGSHUI CITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But iodination itself produces isomers
In addition, it is a very attractive method to directly replace the chlorine on demeclotetracycline with dimethylamine, although there have been attempts on demeclotetracycline derivatives (Liu Qing, an anti-gynecological Tumor compound and its preparation method and application, Chinese patent, CN107200739), because the amine substitution of chlorine is not an easy reaction, so there is no literature report on demeclotetracycline so far

Method used

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  • A kind of synthetic method of minocycline and its derivatives
  • A kind of synthetic method of minocycline and its derivatives
  • A kind of synthetic method of minocycline and its derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Embodiment 1: the preparation of 9-nitrodemeclotetracycline

[0017] Demeclotetracycline hydrochloride (25.0 grams, 50 mmoles) was added in 180 milliliters of vitriol oil under the cooling of ice liquid, then control temperature of reaction, potassium nitrate (6.0 grams, 60 mmols) was added in batches, ice The mixture was stirred and reacted for 1 hour under liquid cooling, then poured into isopropyl ether cooled by ice liquid, a solid was precipitated, filtered, and the filter cake was washed with isopropyl ether to obtain 9-nitronoruretetracycline as a khaki solid. m / z: 509. 1 H NMR(DMSO-d6,500MHz)δ8.40(s,1H),4.75(s,1H),3.3(m,1H),3.23(m,6H),3.0-3.1(m,3H),3.0( m,3H), 2.59(m,2H), 2.4(m,2H), 1.7(m,1H).

Embodiment 2

[0018] Example 2: Synthesis of 6-hydroxyl-9-nitrominocycline

[0019] Add N,N-dimethylformamide (7 molar ratio), potassium hydroxide (2.5 molar ratio) and 9-nitronorautetracycline (10 mM Moore). After sealing, the reaction was stirred at 100°C for 24 hours. After cooling, the mixture was diluted with ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x100ml). The combined extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. 6-Hydroxy-9-nitrominocycline is obtained. m / z: 518. 1 H NMR(DMSO-d6,500MHz)δ8.40(s,1H),4.75(s,1H),3.44(m,6H),3.3(m,1H),3.23(m,6H),3.0-3.1( m,3H), 3.0(m,3H), 2.59(m,2H), 2.4(m,2H), 1.7(m,1H).

Embodiment 3

[0020] Example 3: Synthesis of 6-hydroxyl-9-aminominocycline

[0021] 50 grams of urea was added to 200 milliliters of distilled water, stirred to dissolve it, 6-hydroxyl-9-nitrominocycline (26 grams, 50 mmoles) was added, and then the pH value was adjusted to 8.5 with sodium hydroxide solution, 6-Hydroxy-9-nitrominocycline is completely dissolved, the reaction solution is transferred to a 500ml autoclave, 0.4 g of 5% Pd / C catalyst is added, the mouth of the tank is sealed, and the air in the tank is replaced with nitrogen for three times, and finally Press hydrogen to tank pressure of 0.7 MPa, maintain this pressure by adjusting the hydrogen valve, and stir at room temperature for 6 hours. The gas in the tank was replaced with nitrogen three times, the reaction solution was poured out and the pH was adjusted to 1.0 with hydrochloric acid, and filtered. The filtrate was adjusted to pH=5.5 with sodium hydroxide solution. The obtained crystals were filtered to obtain a yellow pr...

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Abstract

The invention relates to a synthesis method of minocycline and substituted minocycline, in particular to the synthesis of 9-aminominocycline. 9‑Aminominocycline is an important variant of tigecycline, which is used for the control of multidrug-resistant bacteria. The raw material of the invention is easy to obtain, the synthesis route is short, the reaction conditions are mild, the yield is high, the process is simple, and the method is suitable for large-scale production.

Description

technical field [0001] The invention relates to a synthesis method of tetracycline antibiotics, in particular to the synthesis of minocycline and 9-aminominocycline. 9-aminominocycline is an important simplified form of tigecycline, and tigecycline is used for the control of multidrug-resistant bacteria (Sha Qi et al., Synthesis of tigecycline, Chinese Journal of Antibiotics, 2013, 38(7), 520-523). [0002] The object of the present invention is to provide a synthetic method of tetracycline antibiotics represented by minocycline and tigecycline with low raw material price, short synthetic route, low production cost, environmental protection and suitable for large-scale production. Background technique [0003] Minocycline is a semi-synthetic tetracycline antibiotic with strong antibacterial effect and similar antibacterial spectrum to doxycycline. It has the characteristics of high efficiency and broad spectrum, rapid oral absorption, and wide distribution in the body. It w...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/12C07C231/14C07C237/26
CPCC07C231/12C07C231/14C07C2603/46C07C237/26
Inventor 李玮杨安雅杨尚金
Owner JIHENG PHARMA HENGSHUI CITY
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