Preparation of fluorometholone and derivatives thereof

Abstract

The invention relates to a preparation method of a steroid compound, in particular to the preparation of fluorometholone and the derivative thereof, which takes 6-methyl-17-hydroxyl-1, 4, 9-triene-pregna-3, 20-diketone as the initiator to design a brand new process line for synthesizing the fluorometholone and the derivative (III) thereof and further provides the application of a compound (I) in the preparation of the fluorometholone and the derivative (III) thereof. As the production process adopts the existing intermediate of the company as the initiator, the line is concise, the material is easy to obtain, expensive auxiliary materials are saved, and the yield and the cost are obviously superior to the historical synthetic method of the prednisolone and the derivative thereof; in addition, the adoption of the existing intermediate realizes the doubling production of the hexamethylprednisolone products and the fluorometholone products, thus greatly reducing the production cost and industrial conditions. Meanwhile, in the line for preparing a fluorometholone esterified ester, the disadvantages of easy esterification of 11th and too much side products are avoided. R1 is equal to the alkyl with less than 5 carbon atoms; R2 is equal to H, OH, the alkyl with less than 5 carbon atoms; R3 is equal to H, COR4, wherein, R4 is equal to the alkyl with less than 11 carbon atoms.

Description

technical field [0001] The present invention relates to a kind of preparation method of steroid compound, especially relates to the preparation of fluorometholone and its derivatives. Background technique [0002] Fluorometholone and its derivatives are a very useful class of glucocorticoid drugs, the literature Antibiotic Med Clin Ther.1959 August; 6:575-7. and Proc Soc Exp Biol Med.1959 Oct-Sep pointed out that fluorometholone and Its derivatives have good anti-inflammatory effects, and can be used on the skin, eyes and other parts, and are widely used in dermatitis, eczema, and inflammatory eye diseases. The literature AnnOphthalmol.1975 Jan; 7 (1): 139-42 pointed out that clinical studies of fluorometholone and dexamethasone used in patients' eyes showed that fluorometholone had less effect on intraocular pressure than dexamethasone. The literature Arch Ophthalmol.1982 Apr; 100(4):640-1 points out that the derivative of fluorometholone, fluorometholone-17-acetate, is us...

AI Technical Summary

Problems solved by technology

The disadvantage of this reaction is that the by-product is relatively large, because while the 17-position is esterified, the 11-position hydroxyl group also has a small amount of esterification

Later, Upjohn improved the 17-position esterification process, see U.S. Patent No. 4,346,037A1, using enol ester, and carrying out 17-position esterification under the catalysis of a strong base, but the same problem is that the 11-position hydroxyl group will also Esterified

First of all, the source of the raw material 6-methylfluorocortisone is complicated, which is reported in JACS, 79:1515 (1957), and can be traced back to the initial raw material 11α, 17, 21-trihydroxyl, i.e. epihydrocortisone, Hydrocortisone is obtained by fermentation. The fermentation process is relatively complicated and the yield is low, which restricts industrialization and cost control

Secondly, the document JACS, 79: 1515 (1957) provides that the raw material 6-methylfludrocortisone is obtained by fermentation of 11α, 17, 21-trihydroxyl, dehydration of 11α hydroxyl, β hydroxylation of 11, 9 , 11-position epoxy, then ring-opening fluorine at 9 and 11 positions, and methyl at 6-position, etc. The process route is complicated and the cost is high

Finally, the by-products of the esterification process of fluorometholone are too large, resulting in increased recrystallization and separation strength of the finished esterified product, low yield and high cost

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