The preparation method of danazol

A technology for the etherification of danazol and enol, which is applied in the direction of steroids and organic chemistry, can solve the problems of low yield, increased solvent pollution, and long reaction time, so as to improve the reaction yield, shorten the reaction time, The effect of increasing the yield

Active Publication Date: 2016-08-24
佳尔科生物科技南通有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The disadvantages of this method are: (1) The reaction temperature of the 3-position enol etherification is relatively high and the yield is low (the weight yield is less than 85% after repeated experiments)
(2) Potassium acetylide in the 17-carbonyl ethynylation is prepared by wet method, which not only increases solvent pollution, but also has a low weight yield of only 80%, and the reaction time is long

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0014] The preparation method of the danazol of the present embodiment has the following steps:

[0015] ①Etherification of 3-position enol: Add 55.0g of androstenedione, 50mL of triethyl orthoformate, 120mL of absolute ethanol and 0.8g of p-toluenesulfonic acid into a 250mL four-neck flask, stir and raise the temperature after adding To 40±2°C, keep stirring and react for 6.5h, then lower the temperature to 5°C, add 1.9mL of triethylamine, and keep stirring at 5±2°C for 0.5h after adding.

[0016] After the reaction is finished, the material is discharged, suction filtered, and the filter cake is soaked and washed with 60mL of frozen ethanol / triethylamine mixed solution, and suction filtered again. After the filter cake is dried, 53.4g of enol etherified (i.e. 4-androster En-3-enol ethyl ether-17-one), the weight yield is 97.0%, the water content is 0.03%, and the melting point is 130-150°C.

[0017] ② Ethynylation of the 17-position carbonyl group and hydrolysis of the 3-po...

Embodiment 2～ Embodiment 5）

[0025] Each embodiment is basically the same as embodiment 1, the difference lies in step ①, see Table 1 for details.

[0026] Table 1

[0027] Example 1 Example 2 Example 3 Example 4 Example 5 androstenedione 55.0g 55.0g 55.0g 55.0g 55.0g Triethyl orthoformate 50mL 50mL 50mL 40mL 60mL p-Toluenesulfonic acid 0.8g 0.6g 1.0g 0.8g 0.8g Enol ether compounds 53.4g 52.8g 53.1g 52.6g 53.0g weight yield 97.0% 96.0% 96.5% 95.6% 96.4%

Embodiment 6～ Embodiment 9）

[0035] Each embodiment is basically the same as embodiment 1, the difference lies in step ②, see Table 3 for details.

[0036] table 3

[0037] Example 1 Example 6 Example 7 Example 8 Example 9 Enol ether compounds 40g 40g 40g 40g 40g Potassium acetylide preparation temperature 8℃ 5℃ 10℃ 8℃ 8℃ Potassium Hydroxide Powder 600g 600g 600g 700g 500g 17α-acetylene testosterone boutique 34.6g 34.0g 34.2g 34.2g 34.4g weight yield 86.5% 85.0% 85.5% 85.5% 86.0% Purity (HPLC) 99.0% 98.5% 98.7% 98.8% 98.9%

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Abstract

The invention discloses a preparation method of danazol and its intermediate, which uses androstenedione as a starting material, undergoes etherification of 3-position enol, 17-position carbonyl acetylation, 3-position hydrolysis, 2-position Secondary hydroxylation and oximation to obtain danazol. The etherification of the 3-position enol is firstly reacted with androstenedione and triethyl orthoformate in the presence of absolute ethanol and p-toluenesulfonic acid at a temperature of 30-50°C for 4-10 hours; Add triethylamine at a temperature of 10°C to continue the reaction for 0.2~1h; the ethynylation of the 17-position carbonyl is to first react potassium hydroxide powder in an acetylene stream at a temperature of 5~10°C for 1~2h; and then react with the 3-position The enol etherification product is reacted in the acetylene gas stream at a temperature of 15-30° C. for 2-4 hours in the presence of tetrahydrofuran and a catalyst. The reaction conditions of the 3-position enol etherification reaction in the present invention are mild, and the yield is high, while the 17-position carbonyl ethynylation reaction has a high yield and a short time.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound and an intermediate thereof, in particular to a preparation method of danazol and an intermediate thereof. Background technique [0002] Danazol is a steroidal heterocyclic compound, a derivative of the androgen 17α-ethynyl testosterone. It is an androgen suppressant, without estrogen and progesterone effects, has anti-gonadotropic effects and mild androgenic effects, can promote the degradation of uterine endometrium and improve symptoms, and can also relieve certain infertility. Patient becomes pregnant. [0003] For the preparation of danazol: Lu Daoren et al., "Synthesis of Danazol Ester", Journal of Zhejiang Medical University, 1985, Vol. 14, No. 5, pages 208-211, 214 and British patent document GB905844 all disclose A method for preparing danazol by using 17α-acetylenic testosterone (also known as pregnancy hormone) as raw material, specifically comprising: ① 2-position ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J71/00C07J1/00
Inventor 蒋澄宇翁菊英汤志伟
Owner 佳尔科生物科技南通有限公司
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