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Processes for preparing C-7 substituted 5-androstenes

A steroid, CH2 technology, applied in androstane derivatives, chemical instruments and methods, steroids, etc., can solve problems such as difficulty in preparing steroids

Inactive Publication Date: 2005-11-09
PHARMACIA & UPJOHN CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, 7-aryl derivatives are very difficult to use for the preparation of 7-carboxy substituted steroids

Method used

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  • Processes for preparing C-7 substituted 5-androstenes
  • Processes for preparing C-7 substituted 5-androstenes
  • Processes for preparing C-7 substituted 5-androstenes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Embodiment 1: the preparation of tricarbonate 2

[0105] To 3N 250 ml RBF was added triol 1 (Scheme I) (10.00 g, 31 mmol) dissolved in pyridine (100 ml). To this solution was added triethylamine (31ml, 218mmol), methoxycarbonylbenzotriazole (24.2g, 125mmol) and 4-N,N-dimethylaminopyridine (1.2g, 9.4mmol). The resulting slurry was stirred for 2 hours at which time all had dissolved. Additional methoxycarbonylbenzotriazole (12g, 62mmol) and triethylamine (10ml, 73mmol) were added. Once the solids dissolve, the reaction is complete. Water (300ml) was added slowly and the mixture was cooled in an ice bath. The precipitate was filtered off, washed with 10% HCl (2 x 35 ml) and hexane (3 x 50 ml), and dried in a vacuum oven for 24 hours to afford the title compound 2 (Scheme I). 13 C NMR (CDCl 3 )δ 217.78, 155.60, 155.23, 154.88, 144.48, 122.35, 78.58, 76.81, 75.39, 55.29, 54.93, 51.09, 49.47, 47.79, 38.48, 37.89, 36.19, 36.08, 27.96, 29.3

Embodiment 2

[0106] Example 2: Preparation of furan 3 (Scheme 1)

[0107] A solution of tricarbonate 2 (1.0 g, 2.02 mmol) in 7 mL of acetonitrile was treated with 2-methylfuran (0.2 mL, 2.22 mmol) and 0.298 g Sc(OTf) at room temperature 3 Process for 1 hour. TLC (30% EtOAc / Hex) showed the reaction was complete. Chromatography on silica gel with 25% EtOAc / Hex afforded 0.92 g (96% yield) of furan 3 . 13 C NMR (CDCl 3 )δ 217.88,171.08,155.34,154.93,152.38,151.49,140.72,123.98,110.56,106.45,77.50,75.89,60.51,54.98,54.71,47.45,46.57,38.73,37.66,36.21,35.91,27.96,22.22,19.14, 13.98, 13.77.

Embodiment 3

[0108] Example 3: Preparation of Diol 4 (Scheme 1)

[0109] A solution of dicarbonate 3 (1.0 g) in 10 mL of MeOH was treated with 500 mg K2CO 3 For processing, heat to 40 °C. The mixture was stirred as TLC showed the reaction was complete. After the reaction was complete the slurry was poured into water, the product was isolated with EtOAc and the organics were concentrated to give diol 4 as a viscous oil.

[0110] 1 H NMR (CDCl 3 )δ 5.7(s, H), 5.45(d, J=5.7Hz, 1H), 3.45(m, 1H), 3.29(t, J=5.1Hz, 1H), 2.09(s, 3H), 1.1(s , 3H), 0.75(s, 3H).

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Abstract

This invention relates to processes for the preparation of novel , substituted steroid compounds of Formula 1, wherein R1 is H or -COR2; R2 is C1-C6 alkyl or Ct-C6 alkoxy; Z1 is CH2, or wherein OR3 is in the alpha configuration; R3 is H or -COR2; Z2 is -CH-; or Z1 and Z2 may be taken together to form a carbon-carbon double bond; Q is or Y is -CN, -CH2-CH=CH2, C1-6- Alkyl C1-6 alkyl CHR4C (O)Ar, or CHR4 C (O)XC1-6 alkyl; CHR4(O)XAr, or CHR4 HC(O)XC1-6 alkyl; where R4 = O C1-6 alkyl or aryl X=O or S.

Description

Background of the invention [0001] Certain C-7 substituted steroids, such as eplerenone, are known to have aldosterone antagonist activity and are therefore useful in the treatment and prevention of circulatory disorders. Oxipregnone is the subject of several patents and applications, eg US4,559,332 and 5,981,744 and International Publications W098 / 25948 and W097 / 21720. The emergence of new and expanded clinical applications of oxigestrel has created a need for improved methods of preparing these and other related steroids. A major obstacle to the efficient synthesis of epoxypregnenone and related steroids is the introduction of a carboxyl group or a functional group convertible to a carboxyl group at C-7. [0002] It has been described that allyl derivatives, especially allyl acetate, benzoate, pivalate, etc. nuclear reagent reaction. Allylation reactions have been applied to many substances. For example, allyl glycosides, glycosyl cyanides and glycosyl azides (Yadav, J.S...

Claims

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Application Information

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IPC IPC(8): C07J1/00C07J21/00C07J43/00
CPCC07J43/00C07J1/0003C07J21/00C07J1/00
Inventor 彼得·GM·伍茨
Owner PHARMACIA & UPJOHN CO
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