Method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol

A methylene and steroid technology, applied in the field of 6β, can solve the problems of high cost of environmental protection, lengthy reaction steps, expensive reaction reagents, etc., and achieve the effect of cheap raw materials, easy preparation, and few reaction steps

Inactive Publication Date: 2010-06-16
XIAN UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Regardless of the pure chemical synthesis method or the fermentation route, the reaction steps are lengthy, the reagents are expensive, the total yield is low, and the cost of environmental protection is high.
CN101177446A has reported a new method for stereoselectively synthesizing 6β by Winstein cyclopropanation method, 7β-methylene structure, but this method still needs 7-position allylic oxidation, and reaction reagent is expensive, reaction step is long, and total Low yield, etc.

Method used

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  • Method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol
  • Method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol
  • Method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol

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Experimental program
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Embodiment 1

[0028] At room temperature, Δ 4，6 - Add sodium borohydride (537 mg, 14.2 mmol) to a solution of androsdiene-3,17-dione (1.0 g, 3.5 mmol) in absolute ethanol (100 mL), and keep stirring overnight. After the reaction was completed, the solvent was removed by vacuum extraction to obtain a white solid. The white solid was placed in water and stirred for 30 min. It was then extracted with dichloromethane (3 x 100 mL). The organic layer was washed successively with aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered, concentrated, recrystallized from ethyl acetate / n-hexane (1:2), and dried in vacuo to obtain Δ 4，6 -Androsdiene-3β, 17β-diol, white crystal, 630mg (63%, 2.2mmol); mp: 155~158℃; IR(cm-1): 3400, 2960, 1670, 1460; 1 H-NMRδ: 3.62~3.66 (1H, m, H-3), 5.60 (1H, d, J=9.8Hz, H-6), 5.96 (1H, dd, J=2.4Hz, 10.0Hz, H-7 ).

Embodiment 2

[0030] At room temperature, m-chloroperoxybenzoic acid (m-CPBA, 600 mg, 3.5 mmol) was added to Δ 4，6 - Androsdiene-3β, 17β-diol (500mg, 1.7mmol) in dichloromethane (50mL) solution, kept stirring overnight. After the reaction was completed, water (50 mL) was added and stirred for 30 min. The aqueous layer was separated, and the aqueous layer was extracted (3 x 50 mL) with dichloromethane. The organic layers were combined, washed successively with aqueous sodium sulfite (10%), aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered, concentrated, column separated or recrystallized with ethyl acetate / n-hexane (1:2) , 4β,5β-epoxy-Δ was obtained after vacuum drying 6 -Androstene-3β, 17β-diol, white crystals, 332mg (65%, 1.1mmol); mp: 146~148°C; IR (cm -1 ): 3405, 2933, 1455; 1 H-NMR δ: 3.57~3.80 (2H, m, H-3, H-17), 4.17 (1H, d, J=3.2Hz, H-4), 5.32 (1H, dd, J=2.2Hz, 6.4 Hz, H-7), 5.64 (1H, d, J = 2.2 Hz, H-6).

Embodiment 3

[0032] 4β,5β-epoxy-Δ 6 -Androstene-3β, 17β-diol (10.5g, 34.5mmol) was added to anhydrous THF (300mL) / LiAlH 4 (5.7g, 150mmol) in suspension. The reaction was stirred at room temperature until the reaction was completed (TLC followed the reaction, about 40 min). The reaction feed solution was placed on an ice-water bath, continued to stir, and methanol was added dropwise until no gas was released, and then 10% aqueous hydrochloric acid (1000 mL) was added with stirring. Extract with isopropyl ether (3×100mL), wash the ether layer with water successively, dry over anhydrous magnesium sulfate, remove the solvent by vacuum extraction, recrystallize with ether, filter, and dry in vacuum to obtain Δ 6 -Androstene-3β, 5β, 17β-triol, white crystalline powder, 9.8g (93%, 32.1mmol); mp: 110-113°C.

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Abstract

The invention discloses a method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol, comprising the following steps of: preparing steride-4,6-dien-3beta-ol by using steride-4,6-dien-3beta-one as the raw material through a reductive reaction; preparing 4beta,5beta-epoxy steride-6-alkenyl-3beta-ol by the steride-4,6-dien-3beta-ol through epoxidation; preparing the intermediate steride-6-alkenyl-3beta,5beta-diol by the 4beta,5beta-epoxy steride-6-alkenyl-3beta-ol through a reductive ring opening reaction, and preparing the aimed compound 6beta,7beta-methylene-steride-3beta,5beta-diol by the intermediate through cyclopropanation reaction addition or directly preparing the aimed compound 6beta,7beta-methylene-steride-3beta,5beta-diol by the 4beta,5beta-epoxy steride-6-alkenyl-3beta-ol through cyclopropanation reaction. The invention has the advantages of low cost and easy availability of raw material, easy preparation of 4beta,5beta-epoxy steride-6-alkenyl-3beta-ol, high stereoselectivity for constructing 6beta,7beta-methylene structural unit, less reaction steps, simple operation and high yield, therefore, the method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of 6β, 7β-methylene-steroid-3β, 5β-diol. Background technique [0002] 6β, 7β-methylene-steroid-3β, 5β-diol is a key intermediate in the synthesis of a new type of steroidal progestin Drospirenone (Drospirenone). The classical chemical methods for the construction of 6β, 7β-methylene structural units all use the Δ of conjugated diene compounds 6 Micheal addition to the -ene position with Corey methyleneating reagents; or Simmons-Smith addition using Zn-Cu / dihalomethane. Later, it was improved to achieve Simmons-Smith addition directed by 5β-hydroxyl orientation, and its stereoselectivity and yield were greatly improved. But the introduction of 5β-hydroxy-Δ 6 The -alkene structural unit must be obtained through group protection, allylic oxidation, selective reduction, 5β, 6β-epoxidation, halogenation and elimination; or...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J53/00
Inventor 贺诗华
Owner XIAN UNIV OF SCI & TECH
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