Preparation of fluorometholone and derivatives thereof

A technology of fluorometholone and compounds, which is applied in the field of preparation of steroidal compounds, can solve the problems of increased recrystallization separation intensity, complex fermentation process, and low yield

Inactive Publication Date: 2009-04-01
TIANJIN PHARMA GROUP CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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 obta

Method used

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  • Preparation of fluorometholone and derivatives thereof
  • Preparation of fluorometholone and derivatives thereof
  • Preparation of fluorometholone and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] The preparation of embodiment one fluorometholone

[0049] 9,11-epoxy reaction

[0050] Add 10g of 6α-methyl-17α-hydroxyl-1,4,9-triene-pregna-3,20-dione (CN1896090) and 120ml of acetone into the reaction flask, stir, cool to 0°C, and Add 9g of NBS within 30 minutes, keep the reaction at 5-10°C for 2 hours, add 10% sodium carbonate aqueous solution to neutralize to PH=6.5, raise the temperature to 20±2°C, add 10% sodium hydroxide aqueous solution 15ml within 1 hour , controlled temperature at 20-25°C for 2 hours, neutralized with acetic acid to PH = 7, concentrated under reduced pressure until there was no acetone smell, diluted into ice water, filtered, and dried to obtain 11.2 g of 9,11-epoxide.

[0051] 9,11-ring opening reaction

[0052] Add 11.2g of 9,11-epoxy compound obtained by the reaction of 9,11-epoxy, 60ml of DMF into the reaction bottle, stir, cool down to -5°C, pass in hydrogen fluoride gas, and keep it at -5~0°C for 1 hour , diluted in ice water, adjust...

Embodiment 2

[0053] The preparation of embodiment two fluorometholone

[0054] 9,11-epoxy reaction

[0055] Add 10g of 6α-methyl-17α-hydroxyl-1,4,9-triene-pregna-3,20-dione (CN1896090) and 50ml of tetrahydrofuran into the reaction flask, stir, cool to 0°C, and Add 9g of NCS within 30 minutes, keep the reaction at 5-10°C for 2 hours, dilute in water, filter to obtain the halide wet product, and directly dissolve the solid in 100ml of acetone, raise the temperature to 20±2°C, and add 10% within 1 hour Potassium hydroxide aqueous solution 15ml, temperature control 20-25°C, react for 2 hours, neutralize with acetic acid to PH=7, concentrate under reduced pressure until there is no acetone smell, dilute into ice water, filter and dry to obtain 9,11-epoxy compound 10.9 g.

[0056] 9,11-ring opening reaction

[0057]Add 10.9g of 9,11-epoxy compound obtained by the reaction of 9,11-epoxy, 50ml of tetrahydrofuran into the reaction bottle, stir, cool down to -5°C, add 50ml of 47% hydrogen fluorid...

Embodiment 3

[0058] The preparation of embodiment three fluorometholone-17-acetates

[0059] 17-position esterification reaction

[0060] Add 10g of 6α-methyl-17α-hydroxyl-1,4,9-triene-pregna-3,20-dione (CN1896090) into the reaction flask, add 25ml of anhydrous acetic anhydride and 25ml of acetic acid, add 2.5 g of p-toluenesulfonic acid, kept at 75±2°C for 1 hour, diluted in ice water, filtered, and dried to obtain 11.1 g of 6α-methyl-17α-hydroxyl-1,4,9-triene- Pregna-3,20-dione-17-acetate.

[0061] 9,11-epoxy reaction

[0062] Add 11.1g of 6α-methyl-17α-hydroxyl-1,4,9-triene-pregna-3,20-dione-17-acetate, 50ml of tetrahydrofuran into the reaction flask, stir, and cool to 0 ℃, add 6.5 g of dibromocyanoacetamide within 30 minutes, keep the reaction at 5-10 ℃ for 2 hours, dilute in water, filter to obtain the halide wet product, and directly dissolve the solid in 40ml of methanol and 30ml of dichloromethane, Raise the temperature to 20±2°C, add 15ml of 10% potassium hydroxide aqueous sol...

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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...

Claims

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Application Information

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IPC IPC(8): C07J7/00
Inventor 王淑丽郑彤金玉鑫
Owner TIANJIN PHARMA GROUP CORP
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