A kind of preparation method of Hasinide

A technology of selecting and compounding, applied in the field of medicine, can solve problems such as low reaction yield, increased risk of genetic impurities, easy introduction of genotoxic impurities, etc., to improve reaction yield and quality, reduce environmental protection treatment pressure, and be environmentally friendly Effect

Active Publication Date: 2022-07-12
TIANJIN PHARMA GROUP CORP
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Problems solved by technology

[0003] Literature Ein neuartiges Verfahren zur Uberfuhrung von 11β,17a,21-Trihydroxy-20-oxo-Steroidinn die 21-Chlor-20-oxo- △ 9(11)16 -Derivate (LiebigsAnnalen der Chemie; nb.5; (1982); p.966-972) discloses a synthetic process of halcinonide, the starting material is 21-mesylate, which belongs to the commonly used 21-position hydroxyl After sulfonation, chlorination or bromination reaction is carried out. The disadvantage of this method is that sulfonation is required first, the reaction yield is low, and it is easy to introduce genotoxic impurities, which increases the risk of introducing genetic impurities into the product.

Method used

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  • A kind of preparation method of Hasinide
  • A kind of preparation method of Hasinide

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Experimental program
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Embodiment 1

[0022] Embodiment 1 chlorination reaction

Embodiment 1-1

[0024] 7.0 g of compound 1 (0.017 mol) was dissolved in 34 ml of pyridine, nitrogen gas was introduced, and the temperature was lowered to 5°C. 2.5g of chlorosuccinimide (0.018mol) was added, SO was added dropwise 2 / pyridine (15ml, 20%). After reacting for 1.5 h, the reaction solution was diluted into 500 ml of 0°C water, stirred for 1 h, filtered, and dried to obtain compound 2 (7.2 g, molar yield 97.6%, HPCL purity 98.6%).

Embodiment 1-2

[0028] 14.0 g (0.034 mol) of compound 1 was dissolved in 80 ml of dichloromethane, nitrogen was introduced, and the temperature was lowered to -8°C. Add 15ml of triethylamine, pass SO 2 (The weight ratio of the absorbed triethylamine was 20%), and 2.8 g of acetyl chloride (0.036 mol) was added. After 2 h of reaction, the reaction solution was diluted into 600 ml of 0°C water, stirred for 10 min, and then separated. The organic phase was distilled under reduced pressure to remove the solvent to obtain compound 2 (13.6 g, molar yield 92.2%, HPCL purity 96.4%).

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Abstract

The present invention provides a preparation method of halcinide, comprising: 1) chlorination reaction: in SO 2 In the presence of, compound 1 reacts with a chlorinating reagent selected from the group consisting of acetyl chloride, propionyl chloride, benzoyl chloride, lithium chloride, carbon tetrachloride, chlorosuccinimide, dichloride One or more of hydantoin; 2) ring-opening reaction: compound 2 reacts with hydrogen fluoride to obtain hacinide. The beneficial effects of the invention are that the reaction conditions are mild, the environment is friendly, the operation is easy, the cost is low, and it has industrial value, can effectively control side reactions, and improve the reaction yield and quality; no high-risk reactions are involved in the process design, and it is easy to realize industrialization; There is a high pollution reaction, which reduces the pressure of environmental protection treatment.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a preparation method of hacinide. Background technique [0002] Halcinonide (Halcinonide), also known as chloroflulosol, Harlot, chemical name is 16α, 17-[(1-methylethylene)bis(oxy)]-11β-hydroxy-21-chloro-9 - Fluogestal-4-ene-3,20-dione. Molecular formula: C 24 H 32 ClFO 5 , molecular weight: 454.9. Hacinide is a kind of fluorine-containing chlorine-containing synthetic topical potent glucocorticoid, which has mild anti-inflammatory, anti-allergic, antipruritic, and immune-suppressing effects. Topical application can reduce the permeability of capillary wall and cell membrane, reduce wet penetration, and can inhibit the formation and release of histamine and other inflammatory mediators. Its pharmacokinetic behavior after percutaneous absorption is the same as that of systemic application, that is, it is bound to plasma proteins to varying degrees, mainly excreted from the kidneys a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J71/00
CPCC07J71/0031
Inventor 韩昆颖李亚玲齐海迪耿磊
Owner TIANJIN PHARMA GROUP CORP
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