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Preparation method of betamethasone intermediate

A technology for betamethasone and intermediates, which is applied in the field of preparation of the side chain at the 17-position of betamethasone intermediates, can solve the problems of many side reactions in the cyanation reaction, restricting industrial production, poor product quality and the like, and achieves increased reaction steps, The effect of shortened reaction time and increased product quality

Active Publication Date: 2018-05-18
江西赣亮医药原料有限公司
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  • Application Information

AI Technical Summary

Problems solved by technology

[0008] For these two synthetic routes, the construction of the 17-position side chain by the cyanation method requires the use of highly toxic sodium cyanide, which limits its industrial production, and due to the presence of 16β-methyl, the cyanation reaction has many side reactions and yields Low rate, poor product quality

Method used

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  • Preparation method of betamethasone intermediate
  • Preparation method of betamethasone intermediate
  • Preparation method of betamethasone intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Example 1: Preparation of 17α-hydroxy-16β-methyl-17β-cyano-1,4,9(11)-trien-3-one

[0023] Silicocyanation reaction:

[0024] At room temperature, add 30g of 16β-methyl-1,4,9(11)-triene-3,17-dione to a clean and dry 250ml three-necked round-bottomed flask equipped with a thermometer and mechanical stirring, dissolve in 120ml of dichloro Add 0.5g of zinc iodide and 10.9g of trimethylsilyl cyanide to methane, keep the temperature at 25°C for 3 hours, and complete the reaction in TLC (developer: acetone / petroleum ether = 1:4), add 60ml of 5% sodium bicarbonate aqueous solution Terminate the reaction, separate the organic layer, extract the aqueous phase with 30 ml of dichloromethane, combine the organic phases and wash with 100 ml of water, dry the organic phase with anhydrous sodium sulfate, rise to 40 ° C and concentrate under reduced pressure to a small volume, and bring to Without dichloromethane, it was stirred and filtered with suction, and the solid was dried at 40°...

Embodiment 2

[0029] Example 2: Preparation of 9,17α-hydroxy-16β-methyl-17β-cyano-4,9(11)-dien-3-one

[0030] Silicocyanation reaction:

[0031] At room temperature, add 54g of 9α-hydroxyl-16β-methyl-4,9(11)-diene-37-dione to a 500ml three-necked round-bottomed flask equipped with a thermometer and mechanically stirred, which is clean and dry, and dissolve in 270ml of dichloro In methane, add 1.1g cuprous iodide, 19.1g trimethylsilyl cyanide, 30 ℃ heat preservation reaction for 2h, TLC control reaction is complete (developer: acetone / petroleum ether = 1:4), add 50ml 10% bicarbonate The reaction was terminated by sodium aqueous solution, the organic layer was separated, the aqueous phase was extracted with 40ml of dichloromethane, the organic phase was combined and washed with 100ml of water, the organic phase was dried with anhydrous sodium sulfate, raised to 40°C and concentrated under reduced pressure to a small volume, and then washed with petroleum ether Take until there is no dichloro...

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Abstract

The invention discloses a preparation method of a betamethasone intermediate. The method includes the steps: taking a compound II as a substrate; performing silicon cyanide reaction to obtain a compound III; performing hydrolysis reaction to remove silicon alkyl groups to obtain a compound IV; performing transposition rearrangement reaction to prepare a compound I. According to the method, trimethylsilyl cyanide replaces sodium cyanide, the silicon cyanide reaction between the trimethylsilyl cyanide and the substrate is performed, the hydrolysis reaction and the transposition rearrangement reaction are performed to build 17 beta-CN, reaction steps are increased, reaction routes are simple, total reaction time is shortened, and the method is easy to operate and suitable for industrial production. More importantly, synthetic routes are achieved, side reaction is few, production yield and product quality are obviously increased, and production cost is greatly reduced.

Description

technical field [0001] The invention relates to a preparation method of a betamethasone intermediate, in particular to a preparation method of the 17-position side chain of the betamethasone intermediate. Background technique [0002] Steroid hormone drugs (steroid hormone drugs) refer to hormone drugs containing steroidal structure in their molecular structure, which is an important class of clinically important drugs, mainly including adrenal cortex hormones and sex hormones. As an important adrenocortical hormone drug, betamethasone is an isomer of dexamethasone. It has the same effect as prednisolone and dexamethasone. It has anti-inflammatory, anti-rheumatic, anti-allergic and immunosuppressive properties Pharmacological effects, betamethasone and its analogues have become one of the most widely used drugs in clinic. Pharmacological studies have shown that the efficacy of betamethasone and C 17 The side chain is closely related to the development of betamethasone C 1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J3/00
CPCC07J3/005
Inventor 蒋青锋杨坤于传云
Owner 江西赣亮医药原料有限公司
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