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Preparation method of betamethasone rearrangement substance and betamethasone rearrangement substance

A betamethasone and rearrangement technology, applied in the chemical industry, can solve the problems of large environmental pollution, low yield, high process cost, etc., and achieve the effects of low preparation cost, high yield, and good selectivity

Inactive Publication Date: 2021-01-05
山东斯瑞药业有限公司 +1
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  • Abstract
  • Description
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Problems solved by technology

[0010] The present invention provides a preparation method of betamethasone rearrangement and betamethasone rearrangement to solve the problems of high process cost, low yield and large environmental pollution in the preparation method of betamethasone rearrangement in the prior art question

Method used

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  • Preparation method of betamethasone rearrangement substance and betamethasone rearrangement substance
  • Preparation method of betamethasone rearrangement substance and betamethasone rearrangement substance
  • Preparation method of betamethasone rearrangement substance and betamethasone rearrangement substance

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preparation example Construction

[0037] figure 1 It is a flow chart of the steps of a method for preparing a betamethasone rearrangement product provided by an embodiment of the present invention, and the method may include:

[0038] Step 101. Under the protection of an inert gas, use methanol, dimethyl sulfoxide, sodium methoxide, and compound (I) as shown in the structural formula (I) for the mixed reaction at a reaction temperature of 30°C to 45°C for 1 hour After ~3 hours, the reaction solution of compound (II) represented by structural formula (II) was obtained.

[0039] In the embodiment of the present invention, the compound (I) is 21-(phenylsulfinyl)pregna-16β-methyl-1,4,9(11)17(20), 20 as shown in the structural formula (I) - Pentaen-3-one, mixing compound (I) with methanol, dimethylsulfoxide (DMSO) and sodium methoxide for reaction, thereby performing double bond addition reaction on compound (I) to obtain compound (II), DMSO in the system significantly improves the nucleophilicity of sodium metho...

Embodiment 1

[0067] Under the protection of an inert gas, 100g of compound (I), 200mL of methanol, 300mL of DMSO, and 25.1g of sodium methoxide were uniformly mixed, and reacted at a reaction temperature of 30°C for 2 hours to obtain a reaction solution containing compound (II);

[0068] Under the protection of an inert gas, add 43.2g trimethyl phosphite to the reaction liquid, react for 8 hours at a reaction temperature of 50°C, then cool the temperature of the reaction liquid to 10°C, add 2000g of water to the reaction liquid to make the crystal Precipitated, filtered to obtain a solid product, washed the solid product with 100 mL of methanol at 0° C., and dried to obtain 79.0 g of betamethasone rearrangement (III), with a molar yield of 96.0%.

Embodiment 2

[0070] Under the protection of an inert gas, 100g of compound (I), 600mL of methanol, 100mL of DMSO, and 62.8g of sodium methoxide were mixed uniformly, and reacted for 1 hour at a reaction temperature of 40°C to obtain a reaction solution containing compound (II);

[0071] Under the protection of an inert gas, add 86.4g trimethyl phosphite to the reaction liquid, and react for 4 hours at a reaction temperature of 40°C, then cool the temperature of the reaction liquid to 20°C, add 1000g of water to the reaction liquid to make the crystal Precipitated, filtered to obtain a solid product, washed the solid product with 50 mL of methanol at 0° C., and dried to obtain 79.2 g of betamethasone rearrangement (III), with a molar yield of 96.2%.

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Abstract

The invention provides a preparation method and device of betamethasone rearrangement substance, and belongs to the field of chemical engineering. The preparation method of betamethasone rearrangementsubstance provided by the invention comprises the steps of under the protection of inert gas, mixing a compound (I), methanol, dimethyl sulfoxide and sodium methoxide, reacting at the reaction temperature of 30-45 DEG C for 1-3 hours to obtain a reaction solution of a compound (II), directly adding trimethyl phosphite to the reaction solution, and reacting at the reaction temperature of 40-50 DEGC for 4-8 hours to obtain the betamethasone rearrangement substance (III), and adding dimethyl sulfoxide into a reaction system, so that the reaction activity of sodium methoxide is remarkably improved, the reaction time is shortened, and the reaction energy consumption and cost are reduced; and heating reflux is not needed, pollution and waste caused by volatilization of a large amount of trimethyl phosphite are avoided at a low reaction temperature, the total molar yield of the betamethasone rearrangement substance (III) is high (can reach 96% or above), the reaction is more thorough, and the selectivity is good.

Description

technical field [0001] The invention relates to the field of chemical industry, and more specifically, to a preparation method of betamethasone rearrangement and betamethasone rearrangement. Background technique [0002] Betamethasone rearrangement is an important steroid drug intermediate, which can be used to synthesize betamethasone series, diflurasone series, beclomethasone dipropionate series, 21-methyl series, etc. Among them, the rearrangement of betamethasone is light yellow or off-white crystalline powder, and its structure is as follows: [0003] [0004] At present, betamethasone rearrangement is mainly prepared by the following synthetic route: [0005] [0006] Through the two-step synthesis reaction from compound (I) to compound (II) to betamethasone rearrangement (III), the molar yield of synthesis is about 85%. The method for preparing the betamethasone rearrangement by the above-mentioned synthetic route mainly includes the following problems: [00...

Claims

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Application Information

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IPC IPC(8): C07J7/00
CPCC07J7/0075
Inventor 米奇孙福锁陈新雨范海涛刘芳刘刚生
Owner 山东斯瑞药业有限公司
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