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

A technology of methylene steroid and synthesis method, applied in steroids, organic chemistry and other directions, can solve the problems of high production cost, difficult impurities, low yield and the like, and achieves low cost, easy source and high yield. Effect

Inactive Publication Date: 2012-05-02
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, the reaction is relatively difficult. , the yield is low, only about 40%, and the impurities caused by the side reaction of this step are difficult to remove by crystallization, making the production cost higher

Method used

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

Examples

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Embodiment 1

[0041] Preparation of 1,3-dipyrrolidinandrost-3,5-dien-17-one and 3-pyrrolidine-androst-1,3,5-triene-17-one Under argon protection, 1 , 10.0 g of 4-diene-3,17-dione-androstol was dissolved in 100 ml of ethanol / methanol (95:5), and then sequentially added 6 ml of tetrahydrofuran, 0.2 ml of glacial acetic acid, and 35.4 ml of tetrahydropyrrole, and heated to 40 °C, stirred for 48 hours. After the reaction was completed, it was concentrated to dryness, and distilled twice with isopropyl ether 30ml×2. Then add 20ml of absolute ethanol, stir evenly, put it into the refrigerator for crystallization, and freeze for 24 hours. Filter, fully rinse with 15ml of frozen ethanol × 2, pump dry, and vacuum dry at 40°C for 6 hours to obtain 11.7g of a yellow solid, which is 1,3-dipyrrolidandrost-3,5-dien-17-one and The mixture of 3-pyrrolidine-androst-1,3,5-trien-17-one, the two are directly carried out to the next step reaction without separation.

Embodiment 2

[0043] Preparation of 6-methylphenylamine methylene-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 with 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 once with 50ml of dichloromethane, combine the organic layers, and wash with saturated bicarbonate Sodium solution (50ml×2) was washed until neutral, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness at 40°C to obtain 4.4g of a yellow solid with a weight yield of 88%.

Embodiment 3

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

[0047] Under the protection of argon, 5.0 g of 1,3-dipyrrolidandrost-3,5-dien-17-one made according to US3274176 was suspended in 50 ml of absolute ethanol with stirring, and then 1.41 ml of N-methylaniline and 5.94ml of 40% formaldehyde aqueous solution were stirred and reacted at 15°C for 4 hours. The aftertreatment was the same as above to obtain 3.5 g of a 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 follow, 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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Patent Type & Authority Patents(China)
IPC IPC(8): C07J1/00
Inventor 李金亮赵楠
Owner JIANGSU CHUANGUO PHARMA CO LTD