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Preparation method of halcinonide

A technology of selecting and compounding, which is applied in the field of medicine, can solve the problems of easy introduction of genotoxic impurities, increased risk of genetic impurities, and low reaction yield, so as to reduce the pressure of environmental protection treatment, control side reactions, increase reaction yield and quality effect

Active Publication Date: 2019-01-15
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.

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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 was blown in, and the temperature was lowered to 5°C. Add 2.5g chlorosuccinimide (0.018mol), add dropwise SO 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, blown with nitrogen, and cooled to -8°C. Add 15ml of triethylamine, pass through SO 2 (20% by weight of triethylamine absorbed), 2.8 g of acetyl chloride (0.036 mol) was added. After 2 hours of reaction, the reaction solution was diluted to 600ml of 0°C water, stirred for 10 minutes and then separated. The organic phase was distilled off under reduced pressure to obtain compound 2 (13.6g, molar yield 92.2%, HPCL purity 96.4%).

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Abstract

The invention provides a preparation method of halcinonide. The method includes: (1) chlorination reaction: in the presence of SO2, reacting a compound 1 with a chlorination reagent to generate a compound 2, with the chlorination reagent being selected from one or more of acetyl chloride, propionyl chloride, benzoyl chloride, lithium chloride, carbon tetrachloride, chlorosuccinimide and dichloro dimethylhydantoin; and (2) ring-opening reaction: reacting the compound 2 with hydrogen fluoride to obtain halcinonide. The method provided by the invention has the beneficial effects of mild reactionconditions, friendly environment, easy operation and low cost, has industrialization value, can effectively control side reaction, and improve the reaction yield and quality; the process design does not involve high-risk reaction, and is easy to realize industrialization; high-pollution reaction does not exist, thus easing the pressure of environmental protection treatment.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of halcinonide. Background technique [0002] Halcinonide (Halcinonide), also known as Clofluxasone, Halet, chemical name 16α, 17-[(1-methylethylene) bis(oxygen)]-11β-hydroxy-21-chloro-9 - Flupregna-4-ene-3,20-dione. Molecular formula: C 24 h 32 ClFO 5 , molecular weight: 454.9. Halcinonide is a potent glucocorticoid for local application of a synthetic compound containing fluorine and chlorine, 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. Topical application is not easy to cause systemic side effects, and the treatment of psoriasis and eczematous dermatitis is outstanding. After percutaneous absorption, it...

Claims

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Application Information

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Patent Type & Authority Applications(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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