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Preparation method of 1,4-dipregnene-16-beta-methyl-17-alpha-21-bihydroxy object

A technology of pregnane and hydroxy substances, applied in the direction of steroids and organic chemistry, can solve the problems of difficult separation of products and by-products, inconvenient follow-up reactions, complex processes, etc. high rate effect

Inactive Publication Date: 2007-04-18
ZHEJIANG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] 16β-methyl adrenocorticosteroids such as beclomethasone dipropionate and betamethasone have been relatively stable in the domestic and foreign drug markets and have relatively high profit margins. However, the traditional domestic methods for introducing 16β-methyl mainly Adopt Grignard reagent to break α-epoxy, but this method needs to protect 3,20-diketone, also can produce the by-product of 17α-methyl at the same time, the process is complicated, and product and by-product are separated difficultly, also bring to follow-up reaction A lot of inconvenience; in addition, after the introduction of 16β-methyl, the steric hindrance of introducing acetate at the 21-position is increased, and the total yield is less than 60%; it also brings great difficulty to the 1,2-position dehydrogenation process

Method used

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  • Preparation method of 1,4-dipregnene-16-beta-methyl-17-alpha-21-bihydroxy object
  • Preparation method of 1,4-dipregnene-16-beta-methyl-17-alpha-21-bihydroxy object

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Embodiment 1

[0021] 1) 1,4,16-gestrinene and cuprous bromide dimethyl sulfide complex of 0.025 times the amount of substance, trimethylchlorosilane of 1 times the amount of substance, chlorine of 1 times the amount of substance Methylmagnesium and 2 times the amount of hexamethyl

[0022] Triamine phosphate is subjected to Grignard reaction in tetrahydrofuran at a reaction temperature of -50 to -40°C and a reaction time of 3 hours to obtain a Grignard compound;

[0023] 2) React the above-mentioned Grignard substance with potassium bicarbonate of 1 times the amount of the substance and m-chloroperoxybenzoic acid of 1 times the amount of the substance in dichloromethane, the reaction temperature is -30~-25 ° C, and the reaction time is 1 hours; the pH value of the solution was adjusted to 1 with hydrochloric acid to obtain the product 1,4-pregnane-16β-methyl-17α,21-dihydroxy, with a total yield of 81.4%.

Embodiment 2

[0025] 1) 1,4,16-gestrinene and cuprous bromide of 0.1 times of substance amount, trimethylchlorosilane of 4 times of substance amount, methylmagnesium bromide of 1.5 times of substance amount and 4 Hexamethyltriamine phosphate in an amount twice the amount of the substance is subjected to a Grignard reaction in ether at a reaction temperature of -15 to -10°C and a reaction time of 15 hours to obtain a Grignard substance;

[0026] 2) react the above-mentioned Grignard substance with sodium bicarbonate of 10 times the amount of the substance, and m-chloroperoxybenzoic acid of 5 times the amount of the substance in chloroform, the reaction temperature is -10~-5°C, and the reaction time is 5 hours; The pH value of the solution was adjusted to 4 with hydrochloric acid to obtain the product 1,4-pregna-16β-methyl-17α,21-dihydroxy. The overall yield is 76%.

Embodiment 3

[0028] 1) Mix 1,4,16-gestrinene with cuprous chloride of 0.05 times the amount of the substance, trimethylchlorosilane of 1 to 4 times the amount of the substance, and methylmagnesium iodide of 1.25 times the amount of the substance and three times the amount of hexamethylphosphoric acid triamine in tetrahydrofuran for Grignard reaction, the reaction temperature is -30 ~ -25 ° C, the reaction time is 9 hours, to obtain the Grignard substance;

[0029] 2) React the above-mentioned Grignard substance with potassium carbonate of 5 times the amount of the substance and m-chloroperoxybenzoic acid of 4.5 times the amount of the substance in dichloroethane, the reaction temperature is -30~-25 ° C, and the reaction time is 3.5 hours; the pH value of the solution was adjusted to 3 with sulfuric acid to obtain the product 1,4-pregnane-16β-methyl-17α,21-dihydroxy. The overall yield is 78.8%.

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Abstract

The present invention relates to a preparation method of 1,4-pregnanediene-16beta-methyl-17alpha, 21-dihydroxyl compound. Said preparation method includes the following steps: (1), using 1,4,16-pregnanetriene compound, catalyst, trimethylchlorosilane, Grignard reapent and hexamethyl phosphoric triamide according to a certain weight ratio and making them produce Grignard reaction in ether solvent, its reaction temperature is-50-10deg.C, reaction time is 3-15 hr, so as to obtain Grignard compound; and (2), utilizing said Grignard compound, alkali and m-chlorobenzo-hydroperoxide according to a certain weight ratio and making them produce reaction in a salvent, its reaction temperature is-30-5deg.C and reaction time is 1-5 h; using acid to regulate solution pH value to 1-4 so as to obtain the invented product 1,4-pregnanediene-16 beta-methyl-17alpha, 21-dihydroxyl compound.

Description

technical field [0001] The invention relates to a preparation method of 1,4-pregnane-16β-methyl-17α,21-dihydroxy. Background technique [0002] 16β-methyl adrenocorticosteroids such as beclomethasone dipropionate and betamethasone have been relatively stable in the drug market at home and abroad, and have high profit margins. However, the current domestic traditional 16β-methyl introduction methods mainly Grignard reagents are used to break α-epoxy, but this method needs to protect 3,20-diketone, and also produces 17α-methyl by-products, the process is complicated, and the separation of products and by-products is difficult, which also brings Many inconveniences; in addition, the introduction of 16β-methyl increases the steric hindrance of introducing acetate at the 21st position, and the total yield is less than 60%. It also brings great difficulty to the 1,2-position dehydrogenation process. Therefore, it is of great significance to study a process method with strong spec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
Inventor 王海清关怡新姚善泾
Owner ZHEJIANG UNIV
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