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Synthetic method for preparing steroid compounds from 3,17-diketone steroids

A technology of steroid compound and synthesis method, applied in the field of drug synthesis, can solve the problems of not conforming to the concept of green chemistry, not meeting the requirements of green chemistry, restrictions on large-scale industrial production, etc. Effect

Inactive Publication Date: 2013-12-18
ZHENGZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method adopts 4-step synthesis, and the reaction conditions are mild, but it needs to use special phosphonium ylide reagent (Ph 3 P + -CH 2 CH 2 OAc Br - ) and toxic oxidant pyridine sulfur trioxide, these reagents are expensive, unstable, difficult to obtain, and do not meet the requirements of green chemistry
[0017] The above four methods all use special reagents, some are expensive, some are highly toxic, some are unstable, not easy to obtain, and do not conform to the concept of green chemistry, and are limited in scale industrial production
Wherein the alkynylation method and the isocyanation method also have the shortcoming that the reaction route is longer and the total yield is lower
The Wittig reaction method has the advantages of shorter routes, high yields, and high stereoselectivity, and is worthy of promotion and application, but there are still defects

Method used

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  • Synthetic method for preparing steroid compounds from 3,17-diketone steroids
  • Synthetic method for preparing steroid compounds from 3,17-diketone steroids
  • Synthetic method for preparing steroid compounds from 3,17-diketone steroids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] (1) Step 1: After mixing 1 part of androst-4-ene-3,17-dione (androstenedione, 4AD) with 2-20 parts of ethylene glycol, add 0.01-10% part of p-toluenesulfonic acid Hydrate (TsOH·H 2 O) Catalyst and solvent toluene 50mL, stir, heat reaction in oil bath medium 50-120℃ for 2-10h, stop reaction, cool down; pour into 1:20-50 parts of water, filter, wash solid with water. Purification was recrystallized from methanol. Yield 85%. The reaction was detected by TLC (PE:EtOAc=3:1, color developed by iodine fumigation, Rf=0.72).

[0060]

[0061] C 23 h 34 o 4 , white powdery solid. mp.160-162℃

[0062] =0.80 (petroleum ether (30–60) / EtOAc = 3 / 2).

[0063] 1 H NMR (400 MHz, CDCl 3 ) δ 5.36(s, 1H, H-6), 3.93(m, 8H, 2×OCH 2 CH 2 O), 2.57(d, 1H, J H-H =14Hz, H-9), 2.14-1.10(m, 18H, skeleton protons), 1.04(s, 3H, H-19), 0.87(s, 3H, H-18).

[0064] 13 C NMR (101 MHz, CDCl 3 ) δ 140.14, 121.93, 119.51, 109.44, 65.16, 64.57, 64.46, 64.22, 50.53, 49.50, 45.77, 41.81, 36...

Embodiment 2

[0108] (1) Step 1: Weigh 1 part of androstenedione and dissolve it in 10-100 parts of THF solution, and keep stirring, add 1-500 parts of absolute ethanol, 1-5 parts of triethyl orthoformate, 0.05-10% p-toluenesulfonic acid, N 2 Protection, the reaction solution is reacted at 25-50°C for 1-12h, after the reaction is complete, the reaction solution is poured into 50-100 parts of water, filtered, and the solid is recrystallized with pyridine / ethanol to obtain a white powdery solid, which is dried and weighed , the yield is about 95%. = 0.73 (petroleum ether(30-60℃) / EtOAc = 3 / 2).

[0109]

[0110] C 21 h 30 o 2 , white powdery solid. mp.144-146℃

[0111] =0.80 (petroleum ether (30–60) / EtOAc = 3 / 2).

[0112] 1 H NMR (400 MHz, CDCl 3 ) δ5.25 (s, 1H, H-6), 5.14(s,1H, H-4), 3.81-3.78 (t, 2H, OCH 2 CH 3 ), 2.52-2.45(m, 1H, H-9), 2.32-1.10(m,16H, skeleton protons), 1.32(t, 3H, OCH 2 CH 3 ), 1.02(s, 3H, H-19), 0.93(s, 3H, H-18).

[0113] 13 C NMR (101 MHz, CDCl 3 )...

Embodiment 3

[0146] Using 1,4-androstenedione (ADD) as a raw material, according to the method described in Example 1, a compound with the following structural formula was prepared:

[0147]

[0148] NMR data:

[0149] 1 HNMR (CDCl 3 ): δ=0.94 (3H, H-19), 1.18 (3H, H-18), 2.15 (3H, 21-OCOCH 3 ), 5.24(2H, H-21), 6.12(1H, H-4), 6.35(1H, H-1), 6.69(1H, H-2).

[0150] 13 CNMR (CDCl 3 ): Δ = 90.8, 48.0, 49.6, 33.2, 23.8, 185.7, 35.8, 30.3, 168.1, 124.2, 128.3, 155.4, 43.4, 52.3, 22.8, 32.9, 170.2, 206.8, 16.7, 18.7, 20.4.

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Abstract

The invention discloses a synthetic method of steroid type drugs and intermediates, in particular relates to a synthetic method for preparing 17-hydroxy-20-ketone steroid compounds from 3,17-diketone steroids, and belongs to the field of synthesis of drugs. The method takes 3,17-diketone steroids as raw materials and adopts a conventional, environment-friendly, low-toxicity reagent, and the steroid type drugs such as cortisone, hydrocortisone, metacortandracin, or hydroprednisone, or intermediates 17alpha-hydroxy-20-ketone compounds are prepared simply and conveniently at high yield by selective protection of C3 or (and) C11-ketone group, Wittig reaction of C17, selective oxidization of 17(20)-position double bonds and halogenating replacement. The aftertreatment is simple, few three wastes are generated, the reaction selectivity is good, the yield is high, and byproducts anti-pregnancy steroidal drugs and steroidal compounds can be obtained. The raw materials are easy to get, the cost is low and the synthetic process is simple; the synthetic method is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of steroid drugs and intermediates, in particular to a synthesis method for preparing 17-hydroxyl-20-ketone steroids from 3,17-diketone steroids, belonging to the field of drug synthesis. Background technique [0002] The product of microbial transformation of animal and plant sterols: androstenedione (AD) or 1,4-androstenedione (ADD) is an important intermediate for the synthesis of steroidal drugs such as cortisone and prednisone. Introducing a corticosteroid side chain containing two carbon atoms on the basis of the 17-steroid ketone raw material to form a structural feature of 17α-hydroxy-20-ketone is the key to using sterol as a raw material for synthesizing corticosteroids. [0003] At present, there are several methods for synthesizing 17α-hydroxyl-20-ketone compounds via 3,17-diketone steroid raw materials: [0004] 1. Alkynylation [0005] Nitta (Bulletin of the Chemical Society of Japan, 1985, 58(...

Claims

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Application Information

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IPC IPC(8): C07J5/00C07J7/00
Inventor 章亚东冯书晓
Owner ZHENGZHOU UNIV
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