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Synthetic method of flumethasone

A synthetic method, flumetasone technology, applied in the direction of steroids, organic chemistry, etc., can solve the problems of high production cost, non-compliance with energy conservation and environmental protection, and deterioration of production environment, so as to reduce production cost, increase yield, shorten The effect of the reaction step

Pending Publication Date: 2022-04-22
HENAN LIHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] It can be seen from the above synthesis process that the auxiliary materials such as pyridine, acetonitrile, and benzoyl chloride used in the synthesis process have the problem of deteriorating the production environment and producing a large amount of waste water with high ammonia nitrogen, which does not meet the concept of energy saving, environmental protection, and green development. Expensive selective fluorine reagent, high production cost

Method used

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  • Synthetic method of flumethasone
  • Synthetic method of flumethasone
  • Synthetic method of flumethasone

Examples

Experimental program
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Effect test

Embodiment 1

[0079] S11. Add 50g of undehydrogenated 8DM, 100ml of ethylene glycol, and 80ml of triethyl orthoformate into the reaction flask, stir and heat up to 30°C, add 2g of p-toluenesulfonic acid, and keep the reaction for 8 hours. TLC detects that the raw materials have reacted completely, and add The reaction was terminated by triethylamine, the temperature was lowered to 0°C, the material was discharged, washed with 20ml of methanol, sucked dry, and dried at 80°C for 8 hours to obtain 57.5g of ketal product, the yield was about 115%, the HPLC content was 97.3%, and the largest impurity was 1.3 %.

[0080] S12. Prepare peracid: Add 45g of phthalic anhydride, 200ml of ethyl acetate, and 100ml of hydrogen peroxide into the reaction bottle, stir and react at room temperature for 8 hours, after dissolving, separate the water layer, and wash the organic layer with ammonium sulfate solvent to separate layers;

[0081] Add 55g of ketal and 400ml of dichloromethane into the reaction flask,...

Embodiment 2

[0090] S21. Add 50g of undehydrogenated 8DM, 100ml of ethylene glycol, and 80ml of triethyl orthoformate into the reaction flask, stir and heat up to 32°C, add 2g of p-toluenesulfonic acid, and keep the reaction for 8 hours. TLC detects that the raw materials have reacted completely, and add Triethylamine terminates the reaction, cools down to 2°C, discharges, washes with 20ml of methanol, drains, and dries at 85°C for 8 hours to obtain 58.5g of ketal product with a yield of about 117%, HPLC content of 97.1%, and maximum impurity of 1.1 %.

[0091] S22. Configure peracid: add 45g phthalic anhydride, 200ml ethyl acetate, and 100ml hydrogen peroxide into the reaction bottle, stir and react at room temperature for 8 hours, after dissolving, separate the water layer, and wash the organic layer with ammonium sulfate solvent to separate layers;

[0092] Add 55g of ketal product and 400ml of dichloromethane into the reaction flask, cool down to 0°C, add the prepared peracid dropwise, a...

Embodiment 3

[0101] S31. Add 50g of undehydrogenated 8DM, 100ml of ethylene glycol, and 80ml of triethyl orthoformate into the reaction flask, stir and heat up to 35°C, add 2g of p-toluenesulfonic acid, and keep the reaction for 8 hours. TLC detects that the raw materials have reacted completely, and add Triethylamine terminated the reaction, lowered the temperature to 5°C, discharged, washed with 20ml of methanol, drained, and dried at 90°C for 8 hours to obtain 58g of ketal product, the yield was about 116%, the HPLC content was 97.0%, and the largest impurity was 1.1%. .

[0102] S32. Prepare peracid: add 45g of phthalic anhydride, 200ml of ethyl acetate, and 100ml of hydrogen peroxide into the reaction bottle, stir and react at room temperature for 8 hours, after dissolving, separate the water layer, and wash the organic layer with ammonium sulfate solvent to separate layers;

[0103] Add 55g of ketal and 400ml of dichloromethane into the reaction flask, cool down to 0±3°C, add the pre...

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Abstract

The invention relates to the technical field of pharmacy, in particular to a flumethasone synthesis method which comprises the following steps: performing ketal reaction on undehydrogenated 8DM and ethylene glycol to obtain a ketal substance; carrying out epoxy reaction on the ketal substance and peroxy acid to obtain an epoxy substance; performing fluorination reaction on the epoxy substance and hydrofluoric acid to obtain a fluorination substance; carrying out elimination transposition on the fluorinated substance under an alkaline condition to obtain undehydrogenated flumethasone; the undehydrogenated flumethasone is dehydrogenated to obtain the flumethasone. According to the synthesis method, the reaction steps are shortened, the use of toxic and harmful solvents such as pyridine, acetonitrile and benzoyl chloride is avoided, the 6 site and the 9 site are fluorinated in the same system, deprotection can be realized, energy is saved, consumption is reduced, the yield is improved, the production cost is reduced on the premise that the environmental pollution caused by production is reduced, and the concept of green development is met.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a method for synthesizing flumetasone. Background technique [0002] Flumethasone, whose chemical name is 6a,9a-difluoro-11β,17a,21-trihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione, is a topical corticosteroid anti Inflammatory medicine, has anti-inflammatory, anti-allergic effects, etc. It is often used to compound with salicylic acid to prepare compound flumetasone ointment. [0003] At present, compound flumetasone ointment is one of the first-choice medicines for the clinical treatment of psoriasis, but studies have shown that long-term use can cause occasional skin redness at the medication site, and itching, contact allergies, skin pigmentation, masking infection, burning Sensation, irritation, dryness and other adverse reactions have seriously affected the normal life of patients. [0004] In addition, flumetasone is also a very important intermediate for the synthesis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J7/00
CPCC07J7/008
Inventor 陈玉真王海波王瑞玲李合兴张海涛金晓慧
Owner HENAN LIHUA PHARMA
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