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Method for preparing tetraene acetate and derivatives thereof

A technology of tetraene acetate and derivatives, applied in the direction of steroids, organic chemistry, etc., can solve the problems of environmental pollution, unsuitable for large-scale production, high production cost, etc., and achieve easy control of reaction conditions, low cost, and simple operation Effect

Inactive Publication Date: 2016-06-01
湖南成大生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Among them, the oxidation process is catalyzed by noble metals, the production cost is high, and it brings certain environmental pollution, so it is not suitable for large-scale production

Method used

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  • Method for preparing tetraene acetate and derivatives thereof
  • Method for preparing tetraene acetate and derivatives thereof
  • Method for preparing tetraene acetate and derivatives thereof

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preparation example Construction

[0035] One embodiment of the preparation method of tetraenyl acetate and its derivative V includes the following steps. The structural formula of tetraenyl acetate and its derivative V is shown in the following formula, wherein R 1 = H, F or CH 3 , R 2 , R 3 =H, OH or double bond, R 4 = H or CH 3 . Among them, R 2 , R 3 =H, OH or double bond represents: R 2 = H or OH, R 3 =H or OH, or R 2 , R 3 = double bond.

[0036]

[0037] Step S100: Under a protective gas atmosphere, compound I is used as a raw material, and compound I is etherified with an etherification reagent to obtain compound II, wherein R 5 , R 6 = H or double bond, R 7 =CH 3 or CH 2 CH 3 , R 1 = H, F or CH 3 , R 2 , R 3 =H, OH or double bond, R 4 = H or CH 3 .

[0038]

[0039] The preparation method uses compound I as a raw material, which is easy to obtain and has low cost.

[0040] Under the action of the etherifying reagent, compound I undergoes an etherification reaction with th...

Embodiment 1

[0104] The structural formulas of raw material compound I and product acetate tetraenyl and its derivative V are shown in the following formula, wherein R 1 = H, R 2 , R 3 = double bond, R 4 = H, R 5 = H, R 6 =H.

[0105]

[0106] Step S100: Under nitrogen protection, add 100 g of compound I, 100 mL of triethyl orthoformate, 200 mL of tetrahydrofuran and 2 g of p-toluenesulfonic acid into a three-neck reaction flask, heat to 40-45° C. and stir for 2 h, and TLC monitors that compound I basically disappears. A mixed solution containing compound II was obtained. Cool the mixture containing compound II to 20-25°C and keep it warm for 30min, add it to 1000mL of ice water to precipitate a solid, keep it warm at 0-10°C and stir for 3h, filter and wash with water to obtain the crudely purified compound II. Dissolve the crudely purified compound II in 300mL of dichloromethane, add 2g of triethylamine to keep it alkaline, add 100mL of methanol, start to concentrate the dichloro...

Embodiment 2

[0111] The specific steps of embodiment 2 are similar to those of embodiment 1, and only the specific steps of step S200 are given below. The difference between embodiment 2 and embodiment 1 is that the structural formulas of the raw material compound I of embodiment 2 and product acetate tetraenyl and derivatives thereof V are shown in the following formula, R 1 = H, R 2 , R 3 = double bond, R 4 =CH 3 , R 5 = H, R 6 =H.

[0112]

[0113] Step S200: under nitrogen protection, add 60mL reagent A (wherein R 8 =CH 2 CH 3 ) and 400mL of THF, cool down to -45°C, slowly add 240mL of butyllithium dropwise, and keep the temperature not higher than -30°C, continue stirring for 30min after the addition of butyllithium is complete, add 100g of compound II, stir, keep warm- Addition reaction occurred at 45° C. for 3 h, and the reaction of compound II was monitored by TLC to obtain a reaction solution containing intermediate IIa. Under the protection of nitrogen, slowly add th...

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Abstract

The invention relates to a method for preparing tetraene acetate and derivatives thereof. The method comprises the steps of obtaining a compound II through etherification reaction of a compound I and an etherification agent in the atmosphere of protective gases, obtaining a compound III through addition reaction of the compound II and a reagent A under the action of strong base and hydrolysis and elimination reaction of the compound II and the reagent A in the presence of an acid solution, obtaining a compound IV through substitution reaction and rearrangement reaction of the compound III and acetate, and conducting 1 position dehydrogenation and 2 position dehydrogenation on the compound IV to obtain the tetraene acetate and derivatives thereof. According to the method, the compound I is taken as the raw material and subjected to carbonyl etherification, addition, hydrolysis, elimination, rearrangement and dehydrogenation reaction to obtain the product, the raw material compound I is easy to obtain, cost is low, no precious metal is needed during preparation, reaction conditions are easy to control, operation is convenient, the method is suitable for large-scale industrial production, and the obtained tetraene acetate is an important intermediate for synthesis of dexamethasone, budesonide, betamethasone and other steroidal drugs.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a preparation method of tetraenyl acetate and derivatives thereof. Background technique [0002] Tetraenyl acetate and its derivatives are very important intermediates for the synthesis of steroidal drugs such as dexamethasone, budesonide and betamethasone. Tetraenyl acetate (wherein R = H or CH 3 ), its 9(11), 16(17) double bonds can be modified according to requirements, and the 20-position carbonyl and 21-position acetate groups on its 17-position side chain are also very important functional groups in the synthesis of many steroid hormone drugs. For example, dexamethasone can be synthesized by using tetraenyl acetate as raw material through epoxy reaction, methyl Grignard oxidation reaction and fluorine reaction. [0003] [0004] In the traditional synthetic route of tetraenyl acetate, the steroid intermediate of the 17-position acetyl group is generally used...

Claims

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Application Information

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IPC IPC(8): C07J13/00
CPCC07J13/005
Inventor 刘喜荣唐杰
Owner 湖南成大生物科技有限公司
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