Exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and preparation method and application thereof

A technology of methylene androster and ethylenedioxy, which is applied in the direction of chemical instruments and methods, steroids, ketal steroids, etc., can solve the problems of low total yield, large pollution, and expensive Jones reagent, and achieve Raw materials are easily available, the process route is simple and the cost is low

Inactive Publication Date: 2015-11-25
SHAOXING UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The raw material dehydrotestosterone (6) of this method is more expensive, and the Jones reagent is expensive, pollutes a lot, and the total yield is low, so it is not suitable for industrialized production

Method used

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  • Exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and preparation method and application thereof
  • Exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and preparation method and application thereof
  • Exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: the preparation of androstienone ethylene glycol ketal (2)

[0026] Under nitrogen protection, 28.4 grams of 1,4-androstenedione (0.10mol), 14.4 grams of ethylene glycol (0.24mol), 0.4 grams of p-toluenesulfonic acid (0.002mol) and 150 milliliters of toluene were added to 250 milliliters of In a four-necked reaction flask, heated to reflux with water, followed by high-performance liquid chromatography to detect the reaction, and the reaction was completed in about 12 hours. Add 50 ml of aqueous solution containing 1 gram of sodium bicarbonate for neutralization, separate layers, dry over anhydrous magnesium sulfate, recover the solvent under reduced pressure, recrystallize from ethanol to obtain 30.2 grams of light yellow crystals, liquid phase content 99.1%, yield 91.2% .

[0027] Product structure verification:

[0028] 1 HNMR (δ, ppm, 400MHz, CDCl 3 ): 7.062(d, J=10.0Hz, 1H, CH=CH); 6.315(d, J=10.0Hz, 1H, CH=CH); 6.070(s, 1H, CH=C); 3.817-3.925(m ,...

Embodiment 2

[0030] Embodiment 2: the preparation of 6-methylene androstienone ethylene glycol ketal (1)

[0031] Under the protection of nitrogen, 3.0 grams of paraformaldehyde (0.10mol) (according to formaldehyde conversion molar weight), 4.1 grams of dimethylamine hydrochloride (0.05mol) and 150 milliliters of isoamyl alcohol were added to 250 milliliters of the four-port reaction bottle, heated to reflux with water for 2 hours. Then add 3.28 grams of androstienone ethylene glycol ketal (0.01mol), insulate and stir the reaction at 140°C, track and detect the reaction by high-performance liquid chromatography, the reaction is completed in about 15 hours, cool to room temperature, add 100 milliliters of water to wash, and separate layers , after drying over anhydrous magnesium sulfate, the solvent was recovered under reduced pressure, and silica gel column chromatography (eluent: ethyl acetate:petroleum ether=4:6) gave 1.2 grams of white solid, liquid phase content 98.3%, yield 34.7%, mel...

Embodiment 3～8

[0036] Embodiment 3~8: Mannich reaction under different conditions prepares 6-methylene androstienone ethylene glycol ketal (1)

[0037]Under the protection of nitrogen, sequentially add paraformaldehyde, dimethylamine hydrochloride and 150 ml of isoamyl alcohol into a 250 ml four-necked reaction flask, and heat to reflux with water for 2 hours. Then add 3.28 grams of androstienone ethylene glycol ketal (0.01mol), stir the reaction at a certain temperature, track and detect the reaction by high performance liquid chromatography to the end of the reaction, cool to room temperature, add 100ml of water for washing, layering, anhydrous sulfuric acid After the magnesium was dried, the solvent was recovered under reduced pressure, silica gel column chromatography (eluent: ethyl acetate:petroleum ether=4:6), weighed, the liquid phase content was measured, and the yield was calculated. The results are shown in the following table.

[0038] Table 1: Prepared with different amounts of p...

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Abstract

The invention discloses an exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and its preparation method and application. Most existing methods have low overall yield and are not suitable for industrial production. The invention provides an exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone with a new structural formula. The preparation method comprises the following steps: firstly, dimethylamine hydrochloride and paraformaldehyde undergo reflux carrying water in isoamyl alcohol; and then, androstadienone ethylene glycol ketal is added to carry out an Mannich reaction so as to prepare 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone, and 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone is hydrolyzed to prepare exemestane. The method is simple and has industrial value.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to an exemestane intermediate 17,17-ethylenedioxy-6-methyleneandrost-1,4-dien-3-one and its preparation methods and applications. Background technique [0002] Exemestane, whose chemical name is 6-methylene-androst-1,4-diene-3,17-dione, is a second-generation aromatase inhibitor, clinically used in the treatment of metastatic breast cancer Cancer and as an adjuvant therapy for early breast cancer, it has definite curative effect, good tolerance and relatively few side effects. There are two main methods of synthesis: [0003] 1. Using androst-4-ene-3,17-dione (4) as a raw material, the Mannich reaction with dimethylamine hydrochloride and paraformaldehyde produces 6-methylene compound (5), and then Exemestane (3) can be prepared by oxidative dehydrogenation with oxidizing agents such as DDQ or chloranil. Its synthetic route is as follows: [0004] [0005] The yie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J21/00C07J1/00
CPCC07J21/008C07J1/0011
Inventor 沈润溥吴国锋曹瑞伟宋小华陈钢俞永浩杨建锋吴美玲
Owner SHAOXING UNIVERSITY
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