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Method for preparing dexamethasone and series products thereof

A technology of dexamethasone and dexamethasone sodium phosphate, which is applied to a preparation field of steroid compounds, can solve the problems of difficult industrialization, complicated process, expensive raw materials, etc., and achieves reduction of production cost and industrialization conditions, easy availability of raw materials, Simple line effect

Inactive Publication Date: 2009-04-01
TIANJIN TIANYAO PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The route of the document GB869511A is long, and many ketones are protected, and the process is more complicated
The synthetic route of dexamethasone provided by document ES8800260A, the starting material 9α-fluoro-11β,21-dihydroxypregna-1,4,16-triene-3,20-dione-11β,21-diethyl ester raw material More expensive, the column purification method is used in the Grignard reaction, the yield is low, and it is not easy to industrialize

Method used

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  • Method for preparing dexamethasone and series products thereof
  • Method for preparing dexamethasone and series products thereof
  • Method for preparing dexamethasone and series products thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] The preparation of embodiment one dexamethasone acetate

[0064] Grignard reaction: 17α-hydroxy-16α-methyl-1,4,9-triene-pregna-3,20-dione;

[0065] Preparation of Grignard reagent: add 60ml tetrahydrofuran to the reaction bottle, add 6g magnesium flakes and 8g iodine in turn, adjust the temperature to 50±5°C, add 20g methyl bromide and 80ml tetrahydrofuran solution dropwise, control the temperature at 40±5°C, add After incubation for 1 hour, the Grignard reagent was obtained.

[0066] 12 g of 1,4,9,16-tetraene-pregna-3,20-dione and 50 ml of tetrahydrofuran were added to the reaction flask. Cool down to -30±5°C, add Grignard reagent dropwise until the sampling HPLC test is qualified. Add 20ml of ammonium chloride, 40ml of hydrogen peroxide and react at 0±5°C for 2 hours until the sample is qualified by HPLC. Separate the layers, concentrate at 60±5°C, cool down to 0±5°C, filter and dry to obtain 10 g of Grignard compound (1).

[0067] Epoxy reaction: 9β, 11β-epoxy-17...

Embodiment 2

[0075] The preparation of embodiment two dexamethasone acetate

[0076] Grignard reaction: 17α-hydroxy-16α-methyl-1,4,9-triene-pregna-3,20-dione;

[0077] Preparation of Grignard reagent: add 60ml tetrahydrofuran to the reaction bottle, add 6g magnesium flakes and 8g iodine in turn, adjust the temperature to 50±5°C, add 20g methyl bromide and 80ml tetrahydrofuran solution dropwise, control the temperature at 40±5°C, add After incubation for 1 hour, the Grignard reagent was obtained.

[0078] 12 g of 1,4,9,16-tetraene-pregna-3,20-dione and 50 ml of tetrahydrofuran were added to the reaction flask. Cool down to -30±5°C, add Grignard reagent dropwise until the sampling HPLC test is qualified. Add 20ml of ammonium chloride, add 30ml of sodium peroxide solution and react at 0±5°C for 2 hours until the sampling HPLC test is qualified. Separate the layers, concentrate at 60±5°C, cool down to 0±5°C, filter and dry to obtain 10 g of Grignard compound (1).

[0079] Epoxy reaction: 9...

Embodiment 3

[0087] The preparation of embodiment three dexamethasone acetate

[0088] Grignard reaction: 17α-hydroxy-16α-methyl-1,4,9-triene-pregna-3,20-dione;

[0089] The method is the same as the Grignard reaction method in Example 1 to obtain 10 g of Grignard substance (1).

[0090] Iodine reaction: 21-diiodo-17α-hydroxy-16α-methyl-1,4,9-triene-pregna-3,20-dione;

[0091] The method is the same as the iodine reaction method in Example 1 to obtain the wet product iodide (7). This product is unstable and does not need to be dried. The storage time should not be too long and it is ready for use.

[0092] Replacement reaction: 17α-hydroxy-16α-methyl-1,4,9-triene-pregna-3,20-dione-21-acetate

[0093] The method was the same as the replacement method in Example 1 to obtain 10.1 g of replacement product (8).

[0094] Epoxy reaction: 9β,11β-epoxy-17α-hydroxy-16α-methyl-1,4-diene-pregna-3,20-dione-21-acetate

[0095] The method is the same as the epoxy method in Example 1 to obtain 8.8g of...

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Abstract

The invention provides a completely new process route for synthesizing dexamethasone and series products thereof. The invention adopts 1, 4, 9, 16-tetraene-pregna-3, 20-diketone as the original material which is modified by 9, 11bits, 16, 17 bits and 21 bits so as to obtain the dexamethasone and the series products thereof such as dexamethasone acetate and dexamethasone sodium phosphate and the like. The process has the advantage that the invention adopts the existing intermediates of manufacturers as the original material; the route is simple; the materials are available; the use of expensive accessories is avoided; the yield and the cost are dramatically better than that of the prior methods used for synthesizing the dexamethasone and derivatives thereof; moreover, the adoption of the existing intermediates realizes the combined-line prodction of the betamethasone series products and the dexamethasone series products, thus greatly reducing the manufacturing cost and the industrial manufacturing condition.

Description

technical field [0001] The invention relates to a preparation method of steroidal compounds, in particular to a preparation method of dexamethasone and its series products. Background technique [0002] Dexamethasone and its series of products are long-acting adrenal cortex hormone drugs, which are widely used in clinical practice. Its products include: dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate and so on. Among them, dexamethasone is a glucocorticoid drug, mainly used for collagen diseases, such as rheumatoid arthritis, lupus erythematosus, rheumatic heart disease, rheumatic fever, dermatomyositis and other diseases. Dexamethasone acetate is mainly used for collagen diseases, such as rheumatoid arthritis, lupus erythematosus, rheumatic heart disease, rheumatic fever, dermatomyositis, etc. Its anti-inflammatory effect is 28-40 times stronger than hydrocortisone, With few side effects and mild sodium retention, it is considered to be one of the drug...

Claims

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Application Information

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IPC IPC(8): C07J5/00C07J7/00
Inventor 王福军周金萍蒋基平李健
Owner TIANJIN TIANYAO PHARM CO LTD
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