DD272854A1 - METHOD FOR PRODUCING 3 BETA-SUBSTITUTED (20S) -20-ARYL-SULFONYLMETHYL-PREGNA-5,7-DIENES - Google Patents

Abstract

The invention relates to a novel process for the preparation of 3b-substituted (20S) -20-arylsulfonylmethyl-pregna-5,6-diene of general formula 1, in which R 1 is hydrogen, alkyl, acyl, aroyl and silyl and R 2 is aryl. The compounds prepared according to the invention serve as valuable intermediates for the synthesis of steroidal agents, in particular for the synthesis of steroidal agents with calcium metabolism-regulating properties. The starting materials used are 3b-substituted (20S) -20-arylsulfonylmethyl-pregn-5-en-7-ones of the general formula 2 in which R1 and R2 have the meanings given above, which are reacted with p-tosylhydrazine in the corresponding p -Tosylhydrazone of the general formula 3, in which R1 and R2 have the meanings given above, überfuehrt and then reacted with lithium hydride or lithium aluminum hydride to the corresponding 5,7-dieno derivatives of the general formula 1, in which R1 and R2 have the meanings given above, implemented become.

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a novel process for preparing 3β-substituted (20S) -20-arylsulfonylmethyl-pregna-5,7-diene of the general formula 1 (formula scheme) in which R 'is hydrogen, alkyl, acyl, aroyl and SiIyI and R ² aryl mean. The compounds prepared according to the invention serve as valuable intermediates for the synthesis of steroidal agents, in particular for the synthesis of steroidal agents with calcium metabolism-regulating properties.

Characteristic of the known state of the art

It is known that 3β-substituted (20S) -20-arylsulfonylmethyl-pregna-5,7-dienes of general formula 1 (formula scheme) in which R 'and R ^{2 have} the meanings mentioned above are selected from 3β- To this end, the 5,7-diene system must first be prepared by reacting with phthalazine-1,4-dione (DD-WP 247008) or 4-phenyl-1,2,4 -triazolin-1-i-dione (EP-PS 0045524) to the corresponding Azd Diels-Alder adduct, followed by ozonolysis of the 22,23 double bond and reduction of the ozonide to the 5,7-protected 22-alcohol.

Conversion of the 22-alcohol to the corresponding 22-halo or 22-alkylsulfonyloxy compounds, reaction with a sulfinic acid salt, and regeneration of the 5,7-diene system eventually leads to the 3β-substituted- (20 S) -20-arylsulfonyloxy-pegna-5,7 serve (DD-WP 247008).

This procedure is gekirkzeichnet by a versatile synthesis sequence, which adversely affects the overall yield. Furthermore, the use of protective groups is required and for the recovery of the intermediates and the target product complex purification operations are required.

Object of the invention

The object of the invention is to provide readily accessible 3β-substituted (20S) -20-arylsulphonylmethyl-pregn-5-en-7-ones of the general formula 2 (formula scheme) in which R ¹ and R ^{3 have} the abovementioned meaning which are obtainable by allylic oxidation of (20S) -20-arylthiomethyl-pregn-5-enes according to an earlier law corresponding 3β-substituted (20S) -20-arylsulfonylmethyl-pregna-5,7-dienes of general formula 1 (formula scheme) , in which R 'and R ^{2 have} the meanings given above, to produce a shorter route of synthesis with significantly improved yield and bypassing expensive purification operations over the known method.

Explanation of the essence of the invention

The invention is based on the object, a simple method for the conversion of 3ß-substituted (20S) -20-Arylsulfonylmethyl-pregn-5-en-7-ones of the general formula 2 (formula scheme), in which R ¹ and R ^2, the above have given meanings in 3ß-substituted (20S) -20-arylsulphonylmethyl-pregna-5,7-dienes of the general formula 1 (formula scheme), in which R 'and R ^{2 have} the meanings given above, indicate.

According to the invention, 3β-substituted (20S) -20-arylsulfone / methyl-pregna-5,7-dienes of the general formula 1 (formula scheme) in which R ¹ and R ^{2 have} the meanings given above, are prepared by readily accessible 3ß-substituted (20S) -20-Arylsulfonylmethyl-pregn-5-en-7-one of the general formula 2 (formula scheme) in which R ¹ and R ^{2 have} the meanings given above, first with p-tosylhydrazine in organic solvents Exclusion of light to give tosylhydrazones of general formula 3 (formula scheme) in which R ¹ and R ^{2 have} the meanings given above, are reacted.

As organic solvents, methanol, tetrahydrofuran, benzene and toluene or mixtures thereof are preferably used. The reaction is carried out between + 5O ⁰ C and + 11O ⁰ C, preferably at the boiling point of the organic solvent or solvent mixture used.

Finally, according to the invention, the tosylhydrazones of the general formula 3 (formula scheme) in which R 'and R ^{2 have} the abovementioned meanings are converted into the 3β-substituted (20S) -20-alkylsulfonylmethyl-pregna-5,7-dienes of the general formula 1 (Formula scheme) in which R ¹ and R ^{2 have} the meanings given above, by reaction with lithium hydride or lithium aluminum hydride in organic solvents, preferably toluene, benzene or tetrahydrofuran or mixtures thereof.

The reaction is carried out in the absence of atmospheric oxygen at temperatures between +20 ³ C and 110 ° C, preferably at the boiling point of the solvent or Lösungsir / ielgemisches used.

embodiments

Example 1 (20S) -3β-Acetyloxy-20-benzenesulfonylmethyl-pregn-5,7-diene

a) (20S) -3β-Acetyloxy-20-benzenesulfonylmethyl-pregn-5-en-7-one p-toluenesulfonyl hydrazone

In a reaction flask, 5 g (20 S) -3β-acetyloxy-20-benzenesulfonylmethyl-pregn-5-en-7-one are dissolved in 250 ml of tetrahydrofuran (distilled over sodium hydride, water content 0.12%). Thereafter, 4.12 g of p-tosylhydrazine (recrystallized from aqueous methanol) are added and the mixture is heated for a total of 20 hours with stirring, with exclusion of light and with argon in an oil bath at reflux.

At the end of this reaction time, the starting material is completely converted into the corresponding tosylhydrazone. For workup, the reaction solution is concentrated to dryness in a vacuum rotary evaporator and the resulting residue is separated by column chromatography from excess p-tolylhydraziri. The chromotagraphy is carried out on silica gel (particle size 0.065-0.2 mm) with a benzene-ethyl acetate mixture (80:20).

A white solid is obtained.

Yield: 6.31 g to 6.64 g (95 to 100 molar proportions in%) C ₃₇ H ₄₈ N ₂ O ₈ S (680.94) NMR (δ, ppm, CDCl ₃ ): 0.59 (3H, S, 18-CH ₃ ); 1.03 (3H, S, 19-CH _3); 1.17 (3H, d, 21-CH ₃ ! (J = 7Hz); 1.99 (3H, S, 3-OCOCH ₃ ); 2.37 (3H, 8, -SO ₂ C ₆ H ₄ CH ₃ 4.56 (1H, m, 3α · Η) (HB = 24Hz), 5.97 (1H, S, 6 -Hj, 7.10 to 8.00 (9H, m, -SO ₂ C ₆ H ₁ and -SO ₂ C ₆ H ₄ CH ₃ ).

b) (20Sj-3β-Acetyloxy-2C-benzenesulfonylmethyl-pregna-5,7-diene

Dissolve 6,64 g of (20S) -3β-acetyloxy-20-benzenesulfonylmethyl-pregn-5-en-7-one, J-toluenesulfonylhydreOn in 660 ml of absolute and oxygen-free toluene (distilled over lithium hydride and the distillate with argon for 15 minutes fumigated).

Thereafter, 3.70 g of lithium chloride are added in portions over 5 minutes, and the mixture is refluxed for one hour under argon in an oil bath.

After the reaction time, the excess lithium hydride is filtered off, the filter residue is washed with toluene and the filtrate after washing with water ir.i vacuum rotary evaporator at a Bfidtemperatur of 6O ⁰ C to Troc !: ne concentrated and the residue from chloroform / methanol recrystallized. (20S) -3β-Acetyloxy-20-bis-sulfonylmethyl-pregna-5,7-diene is obtained.

Yield: 3.38 g (70 molar proportions in%)

Melting range: 180 to 19O ⁰ C (Z)

UV: ε ₂₇₂ = 12375; ε ₂₈₂ = 12250; C ₂₉₄ = 6750 (methanol)

C ₃₀ H ₄₀ O ₄ S (496.71)

NMR (δ, ppm, CDCl ₃ ): 0.575 (1H, S, 18 -CH ₃ ); 0.906 (1H, s, 19-CH _3); 1.20 (3H, d, 21-CH ₃₎ (J = 6.5Hz); 2.00 (3H, S, 3-OCOCH ₃ ); 4.66 (1H, m, 3σ-Η) (HB = 18Hz); 5.43 (2H, dd, 6-H and 7-H) (J = 6.5Hz); 7.40-8.00 (5H, m, -SO ₂ C ₆ H ₅ ).

SO.R

SO ₂ R

Claims (5)

1. A process for the preparation of 3β-substituted (20S) -20-arylsulfonylmethyl-pregna-5,7-compounds of the general formula 1, in which R ^{1 is} hydrogen, alkyl, acyl, aroyl and SiIyI and R ^{2 is} aryl, characterized in that 3β-substituted (20S) -20-arylsulphonylmethyl-pregn-5-en-7-ones of the general formula 2 in which R ^{1 is} hydrogen, alkyl, acyl, aroyl and SiIyI and R ^{2 is} aryl and p is tosylhydrazine in organic solvents Tosyüv / drazone of general formula 3, in which fl ¹ and R ^{2 have} the meanings mentioned above, and the compounds of general formula 3 with lithium hydride or lithium aluminum hydride in organic solvents to give the 5,7-dieno steroids of general formula 1, in which R ¹ and R ^{2 have} the abovementioned meanings, are reacted. 2. The method according to claim 1, characterized in that are used as the organic solvent for the formation of the tosylhydrazones preferably methanol, tetrahydrofuran, benzene and toluene or mixtures thereof. 3. Process according to claims 1 and 2, characterized in that the reaction for forming the Tosylhydrazone between + 5O ⁰ C and + 11O ⁰ C, preferably at the boiling point of the solvent or solvent mixture used. 4. The method according to claim 1 to 3, characterized in that the reaction ofTosylhydrazone organic oxygen-free solvents, preferably toluene, benzene or tetrahydrofuran or mixtures thereof, are used. 5. Process according to claims 1 to 4, characterized in that the reaction of Tosylhydrazone between +20 ⁰ C and +110 ⁰ C / orzugsweise at the boiling point of the solvent or solvent mixture used, with the exclusion of oxygen, is performed.