DD250537A1 - PROCESS FOR PREPARING 3-SUBSTITUTED 5 BETA, 6 BETA-EPOXY-1,2-DEHYDROSTEROIDES - Google Patents

Abstract

The invention relates to a process for the preparation of 3-substituted 5b, 6b-epoxy-1,2-dehydro-steroids of the general formula II in which R 1 is an acyl radical, an alkyl radical or a trialkylsilyl radical, R 2 is hydrogen or a hydroxyl group and R 3 is a hydroxyl, Ester or ethylene ketal group, a Bisnorcholansaeurerest which mean cholestane or a protected dihydroxyacetone side chain. They are valuable intermediates for the synthesis of steroidal agents. The starting materials used are 3-substituted 1,5-dieno-stholes of general formula I in which R 1, R 2 and R 3 have the abovementioned meaning. The new compounds according to the invention are obtained by reaction with organic peracids in the presence of an inert organic solvent.

Description

embodiments Example 1 .

Sweet-acetyloxy-sweet ^ ß-epoxy-cholest-i-en

In 104 ml of chloroform are dissolved with stirring 3.0 g (7.03m mol) of Sß-Acetyloxy-cholesta-i ^ -diene and the resulting solution was cooled to 0 ⁰ C in a cooling bath. With stirring at 0 ° C., a solution consisting of 1.66 g (9.61 mmol) of m-chloroperbenzoic acid in 112 ml of chloroform is added dropwise thereto over the course of 60 minutes. After further stirring for 5 hours at ^{0 0} C, the reaction solution is washed three times with 250 ml of saturated sodium bicarbonate solution, the separated organic phase washed neutral with water, dried over sodium sulfate and concentrated to dryness in a vacuum rotary evaporator. The residue is recrystallized from ethanol. 2.48 g of sweet acetyloxy-Sß ^ ß-epoxy-cholesM-ene are obtained.

Melting point: 85 to 92 °; Omax (cm ^-1 , CHCl ₃ ): 1040, 1270, 1735;

[a] g °: + 37 ° (c = 1, CHCl ₃ );

NMR (δ ppm; CDCl ₃ ): 0.66 (3H, S, 18H), 1.08 (3H, S, 19H), 2.06 (3H, S, -COOCH ₃ ), 3 , 06 (1H, S, broad, 6-H), 5.37 (1H, m, 3a-H), 5.50 (1H, d, J = 10Hz, 1-H), 5.84 (1H, dd, J = 10 and 2Hz, 2H)

Example 2

SßBenzoyloxy-SjS.eß-epoxy-cholest-i-en

2.0 g of 3-hydroxy-cholesta-1,5-diene are dissolved in 10 ml of dry pyridine. With stirring and cooling with an ice bath, it is added dropwise 2.4 ml of benzoyl chloride. The reaction mixture then remains overnight at room temperature and is then decomposed, starting with the addition of 50 g of ice and 20 ml of water with stirring. It is then extracted with chloroform, the chloroform extract washed with 10% hydrochloric acid and water until neutral, dried over sodium sulfate and concentrated to dryness in a vacuum rotary evaporator. The crude product is recrystallized from acetone. This gives 2.15 g of 3/3-benzoyloxy-cholesta-1,5-diene.

Melting point: 148 to 158 ° C; Q max (cm ^-1 , KBr): 1035, 1275, 1465, 1725;

[a] g °: + 63 ° (c = 1, CHCl ₃ ); NMR (δ ppm, CDCl ₃ ): 0.72 (3H, S, 18H), 1.15 (3H, S, 19H), 5.53 (2H, m, 6H, and 3a). H), 5.60 (1H, d, J = 10Hz, 1-H), 5.93 (1H, dd, J = 10 and 2Hz, 2-H).

Dissolve 2.15 g (4.39 m mol) of 3/3-Benzoyloxy-cholesta-1,5-diene with stirring in 43 ml of chloroform and the resulting solution is cooled to 0 ⁰ C from. To this is added dropwise within 45 minutes with stirring at ^{0 0} C, a solution consisting of 0.849 g (4.92m mol) of m-chloroperbenzoic acid in 65 ml of chloroform. Thereafter, the reaction mixture remains for another 4 hours at 0 ⁰ C, the reaction is monitored by thin layer chromatography. After complete reaction of the starting material, the reaction solution is washed three times with 100 ml of saturated sodium bicarbonate solution. The separated organic phase is then washed neutral with water, dried over sodium sulfate and concentrated to dryness in vacuo. The residue obtained is recrystallized from acetone. This gives 1.77 g of Sß-Benzoyloxy-ö / S ^ / Sepoxy-cholest-i-ene.

Melting point: 150 to 157 ° C; ömax (cm ^-1 , KBr): 1035, 1120, 1280, 1295, 1460, 1730;

Hg ⁰ : + 68 ° (c = 1, CHCl ₃ ); ·

NMR (δ ppm, CDCl ₃ ): 0.68 (3H, S, 18-H), 1.07 (3H, S, 19-H), 3.14 (1H, S.W., 6-H ), 5.66 (1H, d, J = 10.5Hz), 5.68 (1H, m, 3a-H), 5.93 (1H, dd, J = 10.5 and 2Hz, 2 H).

Example 3

S / S TrimethylsMyloxy SSS ^ / S-epoxy-cholesM-en

Dissolve 3.0 g of Sß-hydroxy-cholesta-i ^ -diene in 6 ml of dry pyridine and 3 ml of dry dimethylformamide. 7.2 ml of freshly distilled trimethylchlorosilane are added dropwise, while cooling with an ice bath, to the reaction solution while stirring and then allowed to react at room temperature for 12 hours. After the reaction time, the mixture is poured onto ice, the precipitated crude product is filtered off with suction, washed with water and dried over calcium chloride in a vacuum desiccator. By recrystallization of the crude product from acetone to obtain 2.67 g of Sß-trimethylsilyloxy-cholesta-i ^ -diene.

Melting point: 128 to 130 ^° C; ömax (cm ^-1 , KBr): 850, 910, 1085;

[a] § °: + 25.5 ° (c = 1, CHCI ₃ );

NMR (δ ppm, CDCl ₃ ): 0.70 (3H, S, 18H), -1.09 (3H, S, 19H), 4.22 (1H, m, 3aH) , 5.38 (1H, m, 6-H), 5.75 (1H, d, J = 10Hz, 1-H), 5.73 (1H, dd, J = 10 and 2Hz, 2- H).

2.5 g (5.47 mmol) of 3/3-trimethylsilyloxy-cholesta-1,5-diene are dissolved in 50 ml of benzene, p.A. solved.

Are added at +15 ⁰ C, with stirring, 1,059g (6,13mMol) m-chloroperbenzoic acid in 95ml of benzene, pA to this solution.

The dripping time is 45 minutes. Then allowed to stir the reaction solution for a further 2 hours at +15 ⁰ C. After the reaction time, the reaction solution is washed three times with 100 ml of saturated sodium bicarbonate solution, once with 100 ml of water, the organic phase is dried over sodium sulfate and then concentrated to dryness in vacuo. The residue obtained is recrystallized from acetone. 1.88 g of SjS-trimethylsilyloxy-6-yl-epoxy-cholest-1-ene are obtained.

Melting point: 102 to 110 ° C; 135 to 140 ° C; Ornax (cm ^-1 , KBr): 1110, 1260, 1475; [a] g °: + 35.5 ° (C = 1, CHCl ₃ );

NMR (δ; ppm CDCl ₃ ): 0.65 (3H, S, 18H), 1.05 (3H, S, 19H), 3.01 (1H, S.Breit, 6H) , 4.35 (1H, m, 3 -H), 5.51 (1H, d, J = 10Hz, 1-H), 5.71 (1H, dd, J = 10 and 2Hz, 2- H).

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Claims (4)

Invention claim: 1. A process for the preparation of 3-substituted 5 / 3,6 / 3-epoxy-1,2-dehydro steroids of the general formula II in which R ^{1 is} an acyl radical, an alkyl radical or a trialkylsilyl group, R ^{2 is} hydrogen or a Hydroxyl group and R ^{3 is} a hydroxyl, ester or ethylene ketal group, a
Bisnorcholansäurerest, the cholestane or a protected dihydroxyacetone side chain, characterized in that 3-substituted 1,5-dienoic acid of the general formula I, in which R ¹ , R ² and R ^{3 have} the abovementioned meaning, with organic peracids in the presence of reacted inert organic solvent. 2. The method according to item 1, characterized in that preferably as organic peracids
Peracetic acid, perbenzoic acid or m-chloroperbenzoic acid can be used. 3. The method according to item 1, characterized in that as the inert organic solvent
Halogenated hydrocarbons, preferably chloroform or dichloromethane, or aromatic
Hydrocarbons, preferably benzene or toluene, are used. 4. The method according to item 1, characterized in that the reaction at temperatures between -30 ° C and the boiling point of the solvent used, preferably at 0 ⁰ C to
Room temperature, is performed. For this 1 page formulas Field of application of the invention The invention relates to a process for the preparation of novel 3-substituted 5 / 3,6j8-epoxy-1,2-dehydro steroids of
general formula II in which R ^{1 is} preferably an acyl group, an alkyl group or a trialkylsilyl group, R ^{2 is} hydrogen or a hydroxyl group and R ^{3 is} a hydroxyl, ester or ethylene ketal group, a bisnorcholanic acid residue, the cholestane or a protected dihydroxyacetone side chain. The compounds of the invention serve as valuable intermediates for the synthesis of steroid drugs with
Calcium metabolism regulating or anti-inflammatory properties or find themselves as active ingredients application. Characteristic of the known technical solutions The compounds prepared according to the invention are therefore new and ways for their preparation are therefore not known.
It is known, however, that starting from 3/3-hydroxy or 3/3-acetoxy-cholesta-1,5-serve by epoxidation with 1.0 to
1.5 moles of a suitable Epoxidationsreagenzes between O ⁰ C and the boiling point of the solvent used to the corresponding 3/3-hydroxy or SßAcetyloxy-ia ^ a-epoxy-cholest B-enes passes. As suitable oxidation reagents
Preferably, peracids or hydrogen peroxide are used. The reactions are carried out in halogenated hydrocarbons, e.g. As chloroform or dichloromethane or aromatic hydrocarbons, eg. B. Benzene or toluene, (Howard Jones, Robert A. Frankshun US Patent 4046760). Object of the invention The aim of the invention is, starting from 3-substituted 1,5-diene steroids to synthesize the previously unproduced 3-substituted 5 / 3,6 / 3-epoxy-1,2-dehydro steroids. Explanation of the essence of the invention It has now surprisingly been found that 3-substituted / 3,6 / 3-epoxy-1,2-dehydro steroids of the general formula II in which R ^{1 is} an acyl radical, an alkyl radical or a trialkylsilyl group, R ^{2 is} hydrogen or a hydroxy group and R ^{3 represents} a hydroxyl, ester or ethylene ketal group, a bisnorcholanic acid residue, which is a cholestane or a protected dihydroxyacetone side chain, can be prepared by reacting 3-substituted 1,5-dieno-steroids of the general formula I in which R ¹ , R ² and R ^{3 have} the abovementioned meaning, with organic peracids in the presence of an inert organic
Implemented solvent. It has also been found that preferably peracetic acid, perbenzoic acid or mChlorperbezoesäure brings as organic peracids used as inert organic solvents, halocarbons, preferably chloroform or dichloromethane, or aromatic hydrocarbons, preferably benzene or toluene and the reaction between -30 ⁰ C and Boiling point of the solvent used, preferably between 0 ⁰ C and
Room temperature, performs.