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Exemestane intermediate oxime compound, and preparation method and application thereof

A technology of exemestane and compound, applied in the field of exemestane intermediate oxime compound and its preparation and application, can solve the problems of large pollution, low total yield, expensive Jones reagent, etc., and achieve simple and convenient process route, Easy to obtain raw materials and low cost

Inactive Publication Date: 2016-02-03
ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY +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 oxime compound, and preparation method and application thereof
  • Exemestane intermediate oxime compound, and preparation method and application thereof
  • Exemestane intermediate oxime compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: the preparation of androstienone oxime (2)

[0026] Under nitrogen protection, 28.4 grams of 1,4-androstenedione (0.1 moles), 9.75 grams of hydroxylamine hydrochloride (0.15 moles), 13.2 grams of sodium acetate (0.16 moles) and 200 milliliters of 50 % (volume ratio) ethanol aqueous solution. Heated to reflux with water, followed by high performance liquid chromatography to detect the reaction, and the reaction was completed in about 6 hours. Cool down, evaporate the solvent under reduced pressure, add 200 ml of dichloromethane and 100 ml of water to the residue, stir for half an hour, separate layers, evaporate the solvent in the lower dichloromethane layer, crystallize with 120 ml of acetone, filter and dry to obtain 25.5 g of white powdery solid, liquid chromatography content 99.0%, yield 84.4%.

[0027] Product structure verification:

[0028] 1 HNMR (δ, ppm, 400MHz, CDCl 3 ):8.602(s,1H,NOH); 7.056(d,J=10.0Hz,1H,CH=CH); 6.247(d,J=10.0Hz,1H,CH=CH); ...

Embodiment 2

[0030] Embodiment 2: Preparation of 6-methylene androstienone oxime (1)

[0031] Under nitrogen protection, 3.0 grams of paraformaldehyde (0.10mol), 4.1 grams of dimethylamine hydrochloride (0.05mol) and 150 milliliters of isoamyl alcohol were successively added to a 250 milliliter four-necked reaction flask, heated to reflux with water 2 hours. Then add 2.99 grams of androstienone oxime (0.01mol), insulate and stir the reaction at 140 DEG C, and the high-performance liquid chromatography will follow up and detect the reaction for about 15 hours. After drying over magnesium sulfate, the solvent was recovered under reduced pressure, and silica gel column chromatography (eluent: ethyl acetate:petroleum ether=6:4) gave 1.0 g of white solid, liquid phase content 97.1%, yield 31.2%, melting point 247-248 ℃.

[0032] Product structure verification (the product is the cis-trans isomer of oxime, the ratio is about 1:0.6, the main product is analyzed):

[0033] 1 HNMR (δ, ppm, 400M...

Embodiment 3～8

[0036] Embodiment 3~8: Mannich reaction under different conditions prepares 6-methylene androstienone oxime (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 2.99 grams of androstienone oxime (0.01mol), stir the reaction at a certain temperature, and the high-performance liquid chromatographic tracking detection reaction is completed to the end of the reaction, cooled to room temperature, added 100ml of water for washing, layered, dried over anhydrous magnesium sulfate, and reduced The solvent was recovered under 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 paraformaldehyde and di...

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Abstract

The invention discloses an exemestane intermediate 17-oximino-6-methyleneandrost-1,4-diene-3-one, and a preparation method and an application thereof. Most of existing methods have the defect of low total yield, and are not suitable for industrial production. The invention discloses the exemestane intermediate 17-oximino-6-methyleneandrost-1,4-diene-3-one with a novel structural formula. The preparation method comprises the following steps: dimethylamine hydrochloride and paraformaldehyde are refluxed with water in isoamyl alcohol; 17-oximino-androstadienone is added for carrying out a Mannich reaction, such that 17-oximino-6-methyleneandrost-1,4-diene-3-one is obtained; and exemestane can be prepared through the hydrolysis of 17-oximino-6-methyleneandrost-1,4-diene-3-one. The method is simple, and has high industrialization value.

Description

technical field [0001] The invention relates to an exemestane intermediate oxime compound 17-oximino-6-methyleneandrost-1,4-dien-3-one and a preparation method and application thereof. 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 yield of the first step of the method is low, the amou...

Claims

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Application Information

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IPC IPC(8): C07J41/00C07J1/00
Inventor 吴国锋曹瑞伟沈润溥陈钢俞永浩杨建锋宋小华盛国栋
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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