GB1564809A

GB1564809A - 24,25-epoxy-cholestane derivatives

Info

Publication number: GB1564809A
Application number: GB2314177A
Authority: GB
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1975-10-10
Filing date: 1976-10-08
Publication date: 1980-04-16
Also published as: JPS5246061A; IT1068692B; GB1564810A; NL7611155A; FR2351998A1; DE2645527A1; CH628907A5; ATA751376A; GB1564808A; FR2407941A1; FR2407941B1; GB1564806A; GB1564807A; FR2351998B1; AT355236B

Description

PATENT SPECIFICATION

X ( 21) Application No 23141/77 ( 22) Filed 8 Oct 1976 ( 62) Divided out of No 1 564 806 ( 31) Convention Application No 621 319 ( 32) Filed 10 Oct 1975 M ( 31) Convention Application No 623 859 _ ( 32) Filed 20 Oct 1975 in ( 33) United States of America (US) ( 44) Complete Specification published 16 April 1980 ( 51) INT CL 3 C 07 J 53/00 ( 52) Index at acceptance C 2 U 4 A 3 4 C 9 A 4 DX 4 N 6 X 4 N 6 Y ( 11) 1 564 809 ( 19) ( 54) 24,25-EPOXY-CHOLESTANE DERIVATIVES ( 71) We, F HOFFMANN-LA ROCHE & CO, AKTIENGESELLSCHAFT, a Swiss Company of 124-184 Grenzacherstrasse, Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-

The present invention is concerned with 24,25-epoxy-cholestane derivatives.

The 24,25-epoxy-cholestane derivatives provided by the present invention are compounds of the general formulae cif 3;s &X J (Ia) R 1 wherein R, represents a hydroxy, lower alkoxy, phenyl-(lower alkoxy), lower alkanoyloxy or benzyloxy group and the absolute configuration at C-24 is R, said compounds being substantially free of the 24 S epimer, C 113 1 A tit, 3 CH' "" 3 (Ib) IH wherein R, has the significance given earlier and the absolute configuration at C-24 is S, said compounds being substantially free of the 24 R epimer.

The 24,25-epoxy-cholestane derivatives of formulae la and lb are useful in the preparation of cholesterol derivatives (see the specification of our copending

Application for Letters Patent No 41938/76 (now Serial No 1,564,806).

As used in this description and in the claims appended hereto, the term "lower alkyl" refers to a straight-chain or branched-chain saturated monovalent substituent consisting solely of carbon and hydrogen and containing from I to 8 carbon atoms Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, lert butyl, hexyl and octyl The term "lower alkoxy" refers to a monovalent substituent which consists of a lower alkyl group linked through an 2 1,564,809 2 ether oxygen atom having its free valence bond from the ether oxygen atom.

Examples of lower alkoxy groups are methoxy, ethoxy, isopropoxy and tert butoxy.

The term "phenyl-(lower alkoxy)" refers to a lower alkoxy group which is substituted by a phenyl group Examples of phenyl-(lower alkoxy) groups are benzyloxy, 2-phenylethoxy' and 4-phenylbutoxy The term "lower alkanoyloxy" 5 refers to the residue of a Cl-C 8 alkanoic acid formed by removal of the hydrogen from the hydroxyl moiety of the carboxyl group Examples of lower alkanoyloxy groups are formyloxy, acetoxy, butyryloxy and hexanoyloxy.

In the formulae given in this description and in the accompanying claims, the various substituents and hydrogen atoms are shown as being joined to the steroid 10 nucleus by one of these notations: namely, a solid line (-) indicating a substituent or hydrogen atom which has the /3-configuration (i e above the plane of the molecule), a broken line (I 1 1 1) indicating a substituent or hydrogen atom which as the a-configuration (e g below the plane of the molecule) or a wavy line (v/) is indicating a substituent or hydrogen atom which may have the a or /3configuration 15 The formulae all show the compounds in their absolute stereochemical configurations Since the starting materials are derived from naturally occurring stigmasterol, the products exist in the single absolute configuration shown herein.

The nomenclature adopted to define the absolute configuration of substituents bound to carbon atom 24 of the steroid nucleus is described in The Journal of 20 Organic Chemistry, 35, 2849 ( 1970) under the title "IUPAC Tentative Rules for the Nomenclature of Organic Chemistry Section E Fundamental Sterochemistry".

In a preferred embodiment of the present invention, R 1 represents a lower alkoxy group.

The 24,25-epoxy-cholestane derivatives of formulae Ia and Ib hereinbefore 25 can be prepared by (a) contacting a cholesterol derivative of the general formula C 113 Y Ioro.

3 CH CH 3,,,3 (I Ib) wherein R, has the significance given earlier, with a compound of the general formula R 2-SO 2X (III) 30 wherein X represents a chlorine or bromine atom or the group R:5200 in which R 2 represents a lower alkyl or (lower alkyl)-phenyl group, in a solvent medium comprising an organic solvent and an acid acceptor to yield a compound of the general formula C 13 OSO 2-R 2 CH 3 35 C H 3 | H| (IV) '' wherein R, and R 2 have the significance given earlier and the configuration at C-24 is R or S, and (b) contacting a compound of formula IV with a base in an inert solvent to give a 24,25-epoxy-cholestane derivative of formula Ia or Ib in which the absolute configuration at C-24 is inverted 40 The compounds of formulae H Ia, Ib and IV are claimed per se in the specification of our copending Application for letters Patent No 41938/76 (now

Serial No 1,564,806).

The sulphonylation (step a) is conveniently carried out by treating a cholesterol derivative of formula I Ia or Ib with a lower alkyl or (lower alkyl) 5 phenylsulphonyl halide or anhydride of formula III hereinbefore in a suitable solvent medium comprising an organic solvent and an organic acid acceptor.

Among the suitable organic solvents which can be used there may be mentioned aromatic solvents such as benzene, toluene and xylene and heteroaromatic solvents, particularly nitrogen containing heteroaromatic solvents 10 such as pyridine, picoline, lutidine and collidine Among the suitable organic acid acceptors which can be used there may be mentioned acyclic aliphatic amines such as triethylamine and tripropylamine, alicyclic aliphatic amines such as 1, 4diazabicyclol 2 2 2 loctane and 1,5-diazabicyclol 3 4 10 lnon-5-ene, aliphatic aromatic amines such as dimethylaniline and diethylaniline and heteroaromatic amines such 15 as pyridine, picoline, lutidine and collidine It is preferred to use the same heteroaromatic amine as the organic solvent and acid acceptor It is most preferred to use pyridine as both the solvent and acid acceptor.

Since the C-24 sulphonyloxy group is displaced in step (b), the structure of the R 2 moiety of the leaving group is not critical Nevertheless, it is preferred to use 20 a sulphonyloxy i-steroid in which R 2 represents a lower alkyl or (lower alkyl)phenyl group It is most preferred to use a sulphonyloxy i-steroid in which R 2 represents a methyl group Accordingly, sulphonylating agents of formula III in which R 2 represents a lower alkyl or (lower alkyl)-phenyl group and X represents a chlorine atom or a methanesulphonyloxy group are preferred Methanesulphonyl 25 chloride is most preferred.

In order to prevent side reactions such as sulphonylation and/or dehydration of the C-25 hydroxy group, it is preferred to carry out the derivatisation of the C-24 hydroxy group at a temperature of from -25 C to 25 C The most preferred temperature is about O C 30 While the molar ratio of sulphonylating agent of formula III to cholesterol derivative of formula H Ia or I Ib is not critical, it is preferred to use a molar ratio of 10:1 A molar ratio of 6:1 is most preferred.

The cyclisation (step b) is readily carried out by treating a compound of formula IV with a metal hydride in a suitable organic solvent at a temperature of 35 from -25 C to 25 C, with a temperature of about O C being preferred.

Suitable organic solvents for the cyclisation include ethereal solvents such as diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane and aromatic solvents such as benzene, dimethoxyethoxyethane, toluene and xylene Ethereal solvents are preferred Tetrahydrofuran is most preferred 40 Metal hydrides suitable for the cyclisation include, inter alia, alkali metal hydrides such as sodium hydride and potassium hydride Sodium hydride is preferred A sodium hydride in oil emulsion is most preferred.

The following Examples illustrate the manner in which the 24,25-epoxycholestane derivatives provided by the present invention can be prepared: 45 Example 1.

(a) 25 Hydroxy 6/ methoxy 24 R methylsulphonyloxy 3 a,5 cyclo 5 ocholestane To a solution of 0 050 g ( 0 000116 mol) of 24 R,25-dihydroxy-6/1-methoxy35 a,5cyclo-5 a-cholestane in 0 5 ml of dry pyridine cooled to O C was added 0 05 ml 50 ( 0.00066 mol) of methanesulphonyl chloride and the mixture was stirred at O C for 0.5 hour 0 10 g of ice was added to destroy excess methanesulphonyl chloride and the mixture was stirred for a short period The solution was washed with two 10 ml portions of 10 % aqueous sulphuric acid and two 10 ml portions of saturated aqueous sodium bicarbonate solution The organic layer was dried over anhydrous 55 magnesium sulphate and, after removal of the drying agent by filtration, the filtrate was evaporated to dryness to yield 0 059 g ( 100 %) of 25-hydroxy-6/methoxy-24 Rmethylsulphonyloxy-3 a,5-cyclo-5 a-cholestane; lal 25 + 44 70 (c= 1 03 in chloroform).

(b) 24 S,25 Epoxy 6/3 methoxy 3 at,5 cyclo 5 a cholestane To a suspension of 0 024 g ( 0 0010 mol) of sodium hydride in I ml of 60 tetrahydrofuran cooled to O C was added dropwise with stirring a solution of 0 059 g ( 0 000116 mol) of 25-hydroxy-6/p-methoxy-24 R-methylsulphonyloxy-3 a,5cyclo1,564,809 illl 4 1,564809 a-cholestane in 0 5 ml of tetrahydrofuran After 0 5 hour, the mixture was diluted with 10 ml of water and the solution was extracted with three 10 ml portions of methylene chloride The combined organic extracts were washed with two 10 ml portions of water, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness Recrystallisation of the solid residue from methyl ethyl 5 ketone gave 0 041 g ( 91 %) of 24 S,25-epoxy-6/-methoxy-3 a,5-cyclo-5 acholestane of melting point 100 -102 C; ltl 25 = + 42 2 (c = 0 97 in chloroform).

Example 2.

(a) 25 Hydroxy 6/3 methoxy 24 S methylsulphonyloxy 3 a,5 cyclo 5 acholestane 10 Hydroxy 6/3 methoxy 24 S methylsulphonyloxy 3 a,5 cyclo 5 acholestane l lal 25 = + 39 5 (c = 0 80 in chloroforml was prepared in 100 % yield analogously to the procedure described in Example l(a).

(b) 24 R,25 Epoxy 6 p methoxy 3 a,5 cyclo 5 a cholestane 24 R,25-Epoxy-6 p-methoxy-3 a,5-cyclo-5 a-cholestane was prepared in 93 % 15 yield from 25-hydroxy-6/3-methoxy-24 S-methylsulphonyloxy-3 a,5-cyclo-5 acholestane analogously to the procedures described in Example l(b): melting point 126 0-127 C; lal 25 = + 58 0 (c= 1 08 in chloroform).

Claims

WHAT WE CLAIM IS:-

1 A compound of the general formula 20 3 3 | Nc Jla(Ia) wherein R, represents a hydroxy, lower alkoxy, phenyl-(lower alkoxy), lower alkanoyloxy or benzoyloxy group and the absolute configuration at C-24 is R, said compound being substantially free of the 24 S epimer.

2 A compound according to claim 1, wherein R, represents a lower alkoxy 25 group.

3 24 R,25-Epoxy-6 p-methoxy-3 a,5-cyclo-5 a-cholestane.

4 A compound of the general formula CHI CHN 31 N 3 (Ib) , E R 1 wherein R, represents a hydroxy, lower alkoxy, phenyl-(lower alkoxy), lower 30 alkanoyloxy or benzoyloxy group and the absolute configuration at C-24 is S, said compound being substantially free of the 24 R epimer.

A compound according to claim 4, wherein R, represents a lower alkoxy group.

6 24 S,25-Epoxy-6 p-methoxy-3 a,5-cyclo-5 a-cholestane.

1,564,809 1,564,809 5 For the Applicants, CARPMAELS & RANSFORD, Chartered Patent Agents, 43, Bloomsbury Square, London WC 1 A 2 RA.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1980.

Published by the Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.