Synthesis of 1,4-diene-6-methylene steroids and midbody thereof

A technology of methylene steroid and synthesis method, applied in the directions of steroids, organic chemistry, etc., can solve the problems of high production cost, difficult impurities, difficult reaction, etc., and achieve the effects of low cost, easy source and cheap source.

Inactive Publication Date: 2009-05-13
JIANGSU CHUANGUO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The above synthetic routes all use 4-en-3-one compounds as starting materials. After the 6-position methylene is introduced, no matter whether the 1-ene is introduced by dehydrobromination or dehydrogenation

Method used

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  • Synthesis of 1,4-diene-6-methylene steroids and midbody thereof
  • Synthesis of 1,4-diene-6-methylene steroids and midbody thereof
  • Synthesis of 1,4-diene-6-methylene steroids and midbody thereof

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0039] Example 1

[0040] Preparation of 1,3-dipyrrolidine androsta-3,5-diene-17-one and 3-pyrrolidine-androsta-1,3,5-trien-17-one

[0041] Under the protection of argon, dissolve 10.0g of 1,4-diene-3,17-dione-androst in 100ml of ethanol / methanol (95:5), and then add 6ml of tetrahydrofuran, 0.2ml of glacial acetic acid, 35.4ml in sequence Tetrahydropyrrole, heated to 40°C, stirred for 48 hours. After the reaction is completed, it is concentrated to dryness, and entrained and distilled twice with isopropyl ether 30ml×2. Then add 20ml of absolute ethanol, stir well, put it into the refrigerator to crystallize, and freeze for 24 hours. Filter, rinse with 15ml×2 of frozen ethanol, drain, vacuum dry at 40℃ for 6h to obtain 11.7g of yellow solid, which is 1,3-dipyrrolidine androsta-3,5-diene-17-one and 3 -A mixture of pyrrolidine-androst-1,3,5-trien-17-one, the two are directly subjected to the next reaction without separation.

Example Embodiment

[0042] Example 2

[0043] Preparation of 6-methylphenylaminomethylene-androst-1,4-diene-3,17-dione

[0044] Under the protection of argon, 5.0 g of the solid obtained in Example 1 was suspended in 50 ml of absolute ethanol under stirring, and then 1.41 ml of N-methylaniline and 5.94 ml of 40% formaldehyde aqueous solution were added successively, and the reaction was stirred at 20°C for 3.5 hours. After the reaction, concentrate to dryness at 40°C, dissolve the residue with 50ml of dichloromethane, wash 3 times with 50ml of 1% dilute sulfuric acid, combine the aqueous layers, back-extract with 50ml of dichloromethane, combine the organic layers, and use saturated hydrogen carbonate Sodium solution 50ml×2 was washed until neutral, dried with anhydrous sodium sulfate, filtered, and concentrated to dryness at 40°C to obtain 4.4g of yellow solid with a weight yield of 88%.

Example Embodiment

[0045] Example 3

[0046] Preparation of 6-methylphenylaminomethylene-androst-1,4-diene-3,17-dione

[0047] Under the protection of argon, 5.0g of 1,3-dipyrrolidine androsta-3,5-dien-17-one prepared according to US3274176 was suspended in 50ml of absolute ethanol under stirring, and then 1.41ml of N was added in sequence. -Methylaniline and 5.94ml 40% formaldehyde aqueous solution, stirred at 15°C for 4 hours. The post-treatment is the same as above to obtain 3.5 g of yellow solid with a weight yield of 70%.

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Abstract

The invention discloses a method for synthesizing a 1, 4-diene-6-methylene steroid as formula (I) and an intermediate. The method comprises the following steps: substituting the first position and the third position or only the third position of a 1, 4-diene-androstane compound as a raw material by pyrrolidine to generate 5, 6-ethylenic linkage compound; and introducing 6-methylene to the compound through Mannich reaction and elimination reaction to obtain the compound in the formula (I). Particular reaction formulas are shown as the above, and the method has the advantages of cheap and easily obtained raw materials, easily controlled process operation, high yield and low cost, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a synthesis method and an intermediate for synthesizing 1,4-diene-6-methylene steroid compounds such as formula (I). Background technique [0002] Among the 1,4-diene-6-methylene steroids, the representative one is Exemestane, and the chemical name of Exemestane is 6-methylene-androst-1,4 -diene-3,17-dione, the structural formula is as follows: [0003] [0004] Exemestane is a second-generation aromatase inhibitor developed by Pharmacia & Upjohn in Italy. It can irreversibly bind to aromatase to inactivate it, thereby preventing the biosynthesis of estrogen. It is clinically used for the treatment of metastatic breast cancer and as an adjuvant therapy for early breast cancer, with definite curative effect, good tolerance and relatively few side effects. [0005] At present, the synthetic route of exemestane mainly contains the following two routes: ...

Claims

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Application Information

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IPC IPC(8): C07J1/00
Inventor 李金亮赵楠
Owner JIANGSU CHUANGUO PHARMA CO LTD
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