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Method for preparing betamethasone and series products thereof

A technology for betamethasone and a compound is applied in the field of preparation of steroid compounds, which can solve problems such as long process routes, and achieve the effects of easy availability of raw materials, concise routes, and reduced production costs and industrialization conditions.

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

AI Technical Summary

Problems solved by technology

The process route is relatively long, in which multiple steps involve the protection of 3,20 keto groups, and the 16(17)-alkene Grignard reaction needs to be prepared into pyrazoline derivatives first, and the mixture of 16α and 16β methyl groups is obtained after the Grignard reaction

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] The preparation of embodiment one betamethasone acetate

[0062] Grignard reaction: 17α-hydroxy-16β-methyl-1,4,9-triene-pregna-3,20-dione;

[0063] 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.

[0064] 12 g of 1,4,9,16-tetraene-pregna-3,20-dione and 50 ml of tetrahydrofuran were added to the reaction flask. Raise the temperature to 50±5°C, add the Grignard reagent dropwise until the sampling HPLC test is qualified. Add 20ml of ammonium chloride, add 30ml of hydrogen peroxide and react at 20±5°C for 2 hours until the sampling HPLC test is qualified. Cool down to 0±5°C, filter, and dry to obtain 10 g of Grignard (1).

[0065] Epoxy reaction: 9β, 11β-epoxy-17α-hydroxy-16β-methyl-1,4-die...

Embodiment 2

[0073] The preparation of embodiment two betamethasone acetate

[0074] Grignard reaction: 17α-hydroxy-16β-methyl-1,4,9-triene-pregna-3,20-dione;

[0075] 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.

[0076] 12 g of 1,4,9,16-tetraene-pregna-3,20-dione and 50 ml of tetrahydrofuran were added to the reaction flask. Raise the temperature to 50±5°C, add the Grignard reagent dropwise until the sampling HPLC test is qualified. Add 20ml of ammonium chloride, add 30ml of sodium peroxide solution and react at 30±5°C for 2 hours until the sampling HPLC test is qualified. Cool down to 0±5°C, filter, and dry to obtain 10 g of Grignard (1).

[0077] Iodine reaction: 21-diiodo-17α-hydroxy-16β-methyl-1,4...

Embodiment 3

[0085] The preparation of embodiment three betamethasone

[0086] Grignard reaction: 17α-hydroxy-16β-methyl-1,4,9-triene-pregna-3,20-dione;

[0087] The method is the same as the Grignard reaction method in Example 1 to obtain the Grignard compound (1).

[0088] Epoxy reaction: 9β, 11β-epoxy-17α-hydroxy-16β-methyl-1,4-diene-pregna-3,20-dione;

[0089] The method is the same as the epoxy reaction method in Example 1 to obtain 10.5g epoxy (2).

[0090] Fluorine reaction: 9α-fluoro-11β, 17α-dihydroxy-16β-methyl-1,4-diene-pregna-3,20-dione;

[0091] The method is the same as the fluorine-on reaction method in Example 1 to obtain 10.8 g of fluorine-on compound (3).

[0092] Iodine reaction: 9α-fluoro-21-diiodo-11β, 17α-dihydroxy-16β-methyl-1,4-diene-pregna-3,20-dione;

[0093] The method is the same as the iodine reaction method in Example 1 to obtain the wet product iodide (4). This product is unstable and does not need to be dried. The storage time should not be too long, and...

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Abstract

The invention provides a completely new process route for synthesizing betamethasone 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, 11 bits, 16, 17 bits and 21 bits so as to obtain the betamethasone and the series products thereof such as betamethasone acetate and betamethasone 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 betamethasone and derivatives thereof; moreover, the adoption of the existing intermediates realizes the combined-line production of the betamethasone series products and 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 betamethasone and its series products. Background technique [0002] Betamethasone is a glucocorticoid drug. It has various pharmacological effects such as anti-inflammation, anti-allergy and immune suppression, and is widely used clinically. Its effect is the same as that of dexamethasone, but its anti-inflammatory effect is stronger than that of dexamethasone and triamcinolone. At present, there are many types of preparations of betamethasone and its derivatives clinically: there are betamethasone tablets, betamethasone ointment, betamethasone sodium phosphate injection, betamethasone compound injection, betamethasone acetate and Betamethasone valerate and other products. [0003] In the document US3053865A1, 3α-ether-16-pregnene-11,20-trione was used as the starting material, and betamethasone was obtained through 30 steps of modification...

Claims

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Application Information

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IPC IPC(8): C07J5/00C07J7/00
Inventor 邓磊何四春蒋晓芸陈继生
Owner TIANJIN TIANYAO PHARM CO LTD
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