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Preparation method of danazol

A technology for etherification of danazol and enol, applied in the directions of steroids, organic chemistry, etc., can solve the problems of low yield, long reaction time, increased solvent pollution, etc. The effect of shortening the reaction time

Active Publication Date: 2014-10-08
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 preparation methods of danazol and an intermediate thereof. The preparation method of danazol is prepared by the steps of taking androstenedione as a starting raw material, and carrying out 3-site enol etherification, 17-site carbonyl ethinylation, 3-site hydrolysis, 2-site methylidynel hydroxylation and oximation to obtain danazol. The 3-site enol etherification comprises firstly carrying out a reaction of androstenedione and triethyl orthoformate for 4-10 h in the presence of absolute ethyl alcohol and p-toluenesulfonic acid and at the temperature of 30-50 DEG C, then adding triethylamine at the temperature of 0-10 DEG C, and continuing to carry out a reaction for 0.2-1 h; the 17-site carbonyl ethinylation comprises firstly carrying out a reaction of a potassium hydroxide powder for 1-2 h in an acetylene airflow and at the temperature of 5-10 DEG C, and then carrying out a reaction with the 3-site enol etherified product for 2-4 h in the presence of tetrahydrofuran and a catalyst, at the temperature of 15-30 DEG C and in the acetylene airflow. The 3-site enol etherification is mild in reaction conditions and relatively high in yield, and the 17-site carbonyl ethynylation is relatively high in reaction yield and relatively short in 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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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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