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Preparation method of 16 Alpha-methyl steroidal compound

A compound, the technology of methylmagnesium bromide, applied in the field of preparation of steroid compounds, can solve the problems of difficult purification of impurities, low yield of 16α-methyl steroid compounds, easy dissociation of ester bonds and the like

Active Publication Date: 2010-06-30
TIANJIN JINYAO GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the above-mentioned synthetic route is only disclosed in this application. Through our experiments, we found that in the process of carrying out the Grignard reaction, due to the strong basicity of the Grignard reagent, the ester bond at the 21-position is easily dissociated, so that according to the above-mentioned method and process The yield of the 16α-methyl steroid compound obtained is low, and the impurities are difficult to purify

Method used

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  • Preparation method of 16 Alpha-methyl steroidal compound
  • Preparation method of 16 Alpha-methyl steroidal compound
  • Preparation method of 16 Alpha-methyl steroidal compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] 1) Combine 5.0 g of Pregna-1,4,16-triene-3,11,20-trione (compound (I-1)) with 0.02 times of cuprous dimethyl sulfide bromide, 1.2 times of trimethyl Add chlorosilane and 2 times hexamethylphosphoric triamide to 60ml tetrahydrofuran, slowly add 1.2 times methylmagnesium bromide dissolved in tetrahydrofuran to carry out the Grignard reaction, the reaction temperature is -30~-20℃, the reaction time N 2 After the reaction, it is diluted with water, separated and dried to obtain Grignard compound (Compound (II-1));

[0018] 2) The above-mentioned Grignard is reacted with 3 times potassium bicarbonate and 1.5 times m-chloroperoxybenzoic acid in dichloromethane at a reaction temperature of -30 to -25° C., and the reaction is complete. Use hydrochloric acid to adjust the pH of the solution to 1, concentrate under reduced pressure, cool, separate, and dry to obtain compound (III-1) with a total yield of 78.2%

[0019]

Embodiment 2

[0021] 1) Combine pregna-1,4,16-triene-3,20-dione (compound (I-2)) with 0.05 times cuprous bromide, 1.5 times trimethylchlorosilane, 3 times hexamethyl Phosphorus triamide was dissolved in 40ml tetrahydrofuran, and 1.4 times methylmagnesium bromide dissolved in tetrahydrofuran was slowly added to carry out the Grignard reaction. 2 After the reaction, it is diluted with water, separated and dried to obtain Grignard compound (compound (II-2));

[0022] 2) Reacting the above-mentioned Grignard compound with 1.1 times sodium hydroxide and 2.5 times m-chloroperoxybenzoic acid in chloroform at a reaction temperature of -25 to -20°C, and the reaction is complete. Adjust the pH of the solution to 2 with hydrochloric acid, concentrate and separate under reduced pressure, cool and separate, and dry to obtain compound (III-3) with a total yield of 80.5%

[0023]

Embodiment 3

[0025] 1) Pregnancy-1,4,9(11),16-tetraene-3,20-dione (compound (I-3)) 5.0g, 0.08 times cuprous chloride, 1.5 times trimethyl chloride Silane and 4-fold hexamethylphosphoric triamide were dissolved in 30ml tetrahydrofuran, and 1.4-fold methylmagnesium chloride dissolved in tetrahydrofuran was slowly added for Grignard reaction. The reaction temperature was -25~-15℃, and N was passed during the reaction. 2 After the reaction, it is diluted with water, separated and dried to obtain Grignard compound (Compound (II-3));

[0026] 2) Reacting the above-mentioned Grignard compound with 1.5 times sodium carbonate and 3 times m-chloroperoxybenzoic acid in chloroform at a reaction temperature of -20 to -15°C, and the reaction is complete. The pH value of the solution was adjusted to 3 with sulfuric acid, separated and dried to obtain compound (III-3) with a total yield of 77.9%.

[0027]

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Abstract

A preparation method of a 16 Alpha-methyl steroidal compound comprises: taking a formula (I) compound as a substrate, reacting with 0.2 to 0.1 time catalyst, 1 to 1.5 times trimethyl chlorosilane, 1 to 1.5 times Grignard reagent and 2 to 4 times triamine phosphate in organic solvent to obtain a formula (I) compound, and taking the formula (I) compound to react with 1 to 5 times alkali and 1 to 3 times meta-chloroperoxybenzoic acid in organic solvent to obtain a formula (III) compound.

Description

Technical field: [0001] The invention relates to a preparation method of steroids, in particular to a preparation method of 16α-methyl steroids. Background technique: [0002] The introduction of 16α-methyl into steroidal drug molecules can greatly reduce the retention of sodium ions and improve anti-inflammatory activity. At present, common adrenal corticosteroids with 16-α methyl include dexamethasone, diflumethasone, etc. Important and potent adrenal cortex hormones, the World Intellectual Property Organization patent application WO8707612 discloses a synthesis process of 16α-methyl steroids, using the compound of formula (1) under the catalysis of copper (II) salt, and trimethyl The chlorosilyl ether and the Grignard reagent undergo the Grignard reaction to obtain formula (2). However, the application only discloses the above-mentioned synthetic route. Through our experiments, we found that during the Grignard reaction, the 21-position ester bond is easily dissociated due to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
Inventor 孙亮陈松赵琳
Owner TIANJIN JINYAO GRP
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