Preparation method of dehydroxymethasone intermediate

A technology for deoxymethasone and intermediates, which is applied in the field of preparation of deoxymethasone intermediates, can solve problems such as long reaction routes and unsatisfactory product yields, and achieve high economic value, low price, and reduced production costs. Effect

Pending Publication Date: 2022-04-05
JIANGSU YUANDA XIANLE PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the existing preparation technology including the above-mentioned patents still has a long reaction route and the product yield is not satisfactory

Method used

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  • Preparation method of dehydroxymethasone intermediate
  • Preparation method of dehydroxymethasone intermediate
  • Preparation method of dehydroxymethasone intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0028] The preparation of embodiment 1 compound II

[0029] Dissolve 50g of compound I (21-hydroxypregna-1,4,9(11),16-tetraene-3,20-dione-21-acetate) in 500ml of acetone, cool to 10°C and add 10mL of Chloric acid and 100 mL of water. Add 30g NBS in two batches, TLC (ethyl acetate:methanol=4:1) after the reaction is detected, add 40% NaOH solution (80gNaOH+200mL water) dropwise, raise the temperature to 35°C, and pour in 1000mL water after the insulation reaction is complete. Filtration and drying yielded 49.7 g of compound II.

Embodiment 2

[0030] The preparation of embodiment 2 compound III solution

[0031] Under the protection of nitrogen, put 400ml of tetrahydrofuran into the dry reaction tank, drop in 40g of compound II, cool down to 0-2°C, put in 4g of cuprous chloride, continue to cool down to -15--10°C, and dropwise add 150ml of Grignard reagent ( 1mol / L methylmagnesium bromide (tetrahydrofuran), heat the reaction until TLC (ethyl acetate:methanol=4:1) detects that the reaction is complete, continue to add dropwise for 10-15 minutes, stir, at -15~-10°C Incubate for more than 15 minutes to obtain a compound III solution.

Embodiment 3

[0032] The preparation of embodiment 3 compound IV

[0033] Prepare sodium hydroxide / methanol solution: under the protection of nitrogen, take 20g of sodium hydroxide and put it into 140ml of methanol, stir for later use.

[0034] Under the protection of nitrogen, add 8ml of glacial acetic acid to the compound III solution prepared in step S2 for neutralization, and the measured pH is 6-7; add sodium hydroxide / methanol solution dropwise, and set the dropwise temperature condition to -13~-10 ℃, the dropping time is controlled at 20-40 minutes, after the dropping is completed, keep warm for 1-2 hours, and perform TLC (benzene:acetone=4:1) detection. After the reaction is complete, neutralize with 30ml of glacial acetic acid, press into 1000ml of ice-purified water for water analysis, add 400ml of chloroform for extraction, filter the organic layer and emulsified layer, add 30g of neutral alumina to the filter; use 400ml for the water layer Chloroform was used for three extracti...

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Abstract

The invention provides a preparation method of a dehydroxymethasone intermediate, which comprises the following steps: by taking 21-hydroxypregna-1, 4, 9 (11), 16-tetraene-3, 20-diketone-21-acetate as a starting material, sequentially carrying out bromine hydroxylation, epoxidation, methylation and hydrolysis reaction, so as to obtain the dehydroxymethasone intermediate 9beta, 11 beta-epoxy-21-hydroxy-16 alpha-methyl progesterone-1, 4-diene-3, 20-diketone. The preparation process route provided by the invention has fewer reaction steps, the quality and yield of the product have obvious competitiveness, dangerous chemical processes are not involved, the method is green and clean, and the atom economy is improved; the preparation process has a wide industrial application prospect.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and medicinal chemistry, and in particular relates to a preparation method of a deoxymethasone intermediate. Background technique [0002] Dexamethasone is a very useful class of glucocorticoid drugs, belonging to the class of topical corticosteroids, mainly used to treat skin disorders. Dexamethasone was first developed by Russell (Roussel). The main synthesis literature is found in U.S. Patent US3099654A1. The synthesis method is based on 16α-methyl-11α, 21-dihydroxy-1,4-pregnane-3,20-dione-21-acetate as the starting material. At positions 9, 11 and 21, deoxymethasone was obtained through six steps of modification. The whole synthetic route is relatively long, and the yield from the starting material to the final product is about 28%, and the starting material is not easy to obtain. [0003] Chinese patent CN101397322A discloses a preparation method of dexamethasone, using 1,4,9,16-t...

Claims

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Application Information

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IPC IPC(8): C07J71/00
CPCY02P20/55
Inventor 张和明蔡成平赵百合冯永华刘新言
Owner JIANGSU YUANDA XIANLE PHARMA
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