GB1564807A - Cholestene derivatives - Google Patents

Description

PATENT SPECIFICATION ( 11) 1 564807

i ( 21) Application No 23139/77 ( 22) Filed 8 Oct 1976 0 ( 62) Divided out of No1 564 806 ( 19) ( 31) Convention Application No 621 319 O ( 32) Filed 10 Oct 1975 Il ( 31) Covention Application No 623 859 1 ( 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 4 X 4 DX 4 N 6 X 4 N 6 Y 6 E ( 54) CHOLESTENE DERIVATIVES ( 71) We, F HOFFMANN-LA ROCHE & CO, AKTIENGESELLSCHAFT, a Swiss Company of 124-184 Grensacherstrasse, 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

S and by the following statement: 5

The present invention is concerned with cholestane derivatives.

The cholestene derivatives provided by the present invention have the following general formula CH CH IH 3) wherein R, represents a hydroxy, lower alkoxy, phenyl-(lower alkoxy), lower 10 alkanoyloxy or benzoyloxy group.

The cholestene derivatives of formula I are useful in the preparation of the 23,24-epoxy-25-hydroxy-cholestane derivatives which are claimed per se in the specification of our copending Application for Letters Patent No 23140/77 (Serial

No 1564808) and which, in turn, are useful in the preparation of the cholesterol 15 derivatives which are claimed per se in the specification of our copending

Application for Letters Patent No 41938/76 (now Serial No 1564806).

As used in this description and in the claims appended hereto the term "lower alkoxy" refers to a monovalent substituent which consists of a lower alkyl group linked through an ether oxygen atom having its free valence bond from the ether 20 oxygen atom, the term "lower alkyl" referring to a straight-chain or branchedchain saturated monovalent substituent consisting solely of carbon and hydrogen and containing from I to 8 carbon atoms Examples of such lower alkyl groups are methyl, ethyl n-propyl, isopropyl, tert butyl, hexyl and octyl Examples of lower alkoxy groups referred to earlier are methoxy, ethoxy, isopropoxy, and tert butoxy 25 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" refers to the residue of a C,-C 8 alkanoic acid formed by removal of the hydrogen atom from the hydroxyl moiety of the carboxyl group Examples of lower 30 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 nucleus by one of these notations: namely, a solid line () indicating a substituent or hydrogen atom which has the p-configuration (i e above the plane of 35 2 1,564,807 2 the molecule), or a broken lilne ( 1 l Il) indicating a substituent or hydrogen atom which has the ra-configuration (i e below the plane of the molecule).

The formulae all shown the compounds in their absolute stereochemical confugurations Since the starting materials are derived from naturally occurring stigmasterol, the products exist in the single absolute configuration shown herein 5 The nomenclature adopted to define the stereochemistry about the 23, 24double bond and the absolute configuration of substituents bound to carbon atoms 23 and 24 of the steroid nucleus is described in the Journal of Organic Chemistry, 35, 2849 ( 1970) under the title "IUPAC Tentative Rules for the Nomenclature of Organic Chemistry Section E Fundamental Stereochemistry" 10 In the preferred embodiment of the present invention, R, in formula I represents a lower alkoxy group, especially the methoxy group Also preferred are cholestene derivatives of formula I in which the configuration of the 23, 24-double bone is cis (denoted herein by the symbol Z) or is trans (denoted herein by the symbol E) 15 The present invention is also concerned with a process for the preparation of a cholestene derivative of the general formula CH 13,, Cc H 3 > 4 j CH 3 (Ia) wherein R, has the significance given earlier, in which the configuration of the 23,24-double bond is trans (i e where the 23,24-double bond has the E 20 configuration), which process comprises contacting a compound of the general formula CH 3,, <CH 3 (II) lC O H ax wherein R, has the significance given earlier, with a complex metal hydride reducing agent in an inert organic solvent 25 The compounds of formula II and a process for their production are claimed in the specification of our letters Patent No 1 445 237 Alternatively, the compounds of formula II can be prepared from the corresponding 25-tetrahydropyranyl ethers, which are also claimed per se in the specification of our Letters Patent No.

1 445 237, by treatment with a catalytic amount of a strong acid in an appropriate 30 solvent For example, in order to prepare 25-hydroxy-6/3-methoxy-3 a,5cyclo-5 acholest-23-yne, a compound of formula II in which R, represents a methoxy group, methanol would be used as the appropriate solvent and sulphuric or a sulphonic acid such as benzenesulphonic acid or p-toluenesulphonic acid would be used as the catalytic strong acid 35 Suitable complex metal hydride reducing agents for the conversion of a compound of formula II into a compound of formula Ia include alkali metal aluminium hydride reducing agents such as lithium aluminium hydride, mono and di(lower alkoxy) alkali metal aluminium hydrides such as luthium mono(tert butoxy)aluminium hydride and lithium bis(tert butoxy)-aluminium hydride, 40 and sodium bis( 2-methoxyethoxy)aluminium hydride Suitable inert organic solvents for the reduction include ethereal solvents such as diethyl ether, dimethoxyethane, dimethoxyethoxyethane, tetrahydrofuran and dioxane The reduction is conveniently carried out at a temperature between 50 C and 70 C.

While the quantity of the complex metal hydride is not narrowly critical and 45 can vary between about 0 5 to 10 moles relative to the compound being reduced, it is generally preferred to use from 1 to 5 moles of the complex metal hydride relative to the substrate A molar ratio of complex metal hydride to substrate of about 2 is most preferred.

The stereospecific reduction of the 23,24 triple bond of a compound of 5 formula II is preferably carried out using an alkali metal aluminium hydride in a cyclic ethereal solvent at a temperature of from 50 C to 70 C It is most preferred to use lithium aluminium hydride in tetrahydrofuran at about 70 C.

During the reduction of the acetylenic linkage of a compound of formula II to a double bond of a compound of formula Ia, an alkanoyloxy or benzoyloxy group 10 denoted by R 1 in the 6-position of the i-steroid molecule may be partially reduced to the corresponding 6-hydroxy group The carbinol may be reacylated by wellknown methods after the reduction.

In yet a further aspect, the present invention is concerned with a process for the preparation of a cholestene derivative of the general formula 15 ll>; 1 CH 3 V"l,/ ' 3 MH 13 |(Ib) q H 3 wherein R, has the significance given earlier in which the configuration of the 23,24-double bond is cis (i e where the 23,24-double bond has the Zconfiguration), which process comprises treating a compound of the general formula C 111, CH 3 (II) 20 wherein R 1 has the significance given earlier, with hydrogen in the presence of a hydrogenation catalyst and an inert solvent.

Among catalysts suitable for the stereospecific hydrogenation are nickel and noble-metal catalysts such as, for example, platinum, palladium and rhodium which may be free or supported on a suitable carrier such as, for example, carbon, 25 calcium carbonate, strontium carbonate or alumina Also included among catalysts suitable for the stereospecific hydrogenation are partially deactivated catalysts composed of noble-metals, free or supported, and deactivated with a heavy metal and an aromatic nitrogen heterocycle such as, for example, a Lindear catalyst composed of palladium-on-calcium carbonate deactivated with lead diacetate and 30 quinoline Generally, a palladium catalyst is preferred.

The quantity of catalyst which may be used is not narrowly critical and the amount of catalyst, including the support, may vary from 0 01 to about 2 0 weight per cent relative to the compound being reduced Generally, it is preferred to use between 0 05 and 0 5 weight per cent of catalyst 35 Suitable solvents for the hydrogenation include, inter alia, ethers such as diethyl ether, tetrahydrofuran, dioxane dimethoxyethane and dimethoxyethoxyethane, alcohols such as ethanol, methanol and 2-propanol, esters such as methyl acetate and ethyl acetate and organic carboxylic acids such as acetic acid It is preferred to use methanol as the solvent 40 While the temperature and pressure for the partial catalytic hydrogenation of the acetylenic linkage are not narrowly critical, it is preferred to carry out the hydrogenation at a pressure within the range of from I atmosphere to 5 1,564,807 atmospheres of hydrogen and at a temperature from O C to 100 C depending upon solvent medium and the pressure Generally, it is preferred to carry out the hydrogenation at a pressure of 1 to 3 atmospheres of hydrogen and at a temperature between O C to 50 C.

The partial stereospecific hydrogenation of the acetylenic likage of a 5 compound of formula II to give a cholestene derivative of formula Ib having the Zconfiguration is most preferably carried out in the presence of the Lindlar catalyst described by H Lindlar and R Dubuis in "Organic Synthesis", Coll, Vol V, John Wiley and Sons, New York, N Y, 1973, pages 880-883.

In the following Examples, Example 1 illustrates the preparation of the starting 10 material and Examples 2 and 3 illustrate the processes aforesaid:

Example 1.

25-Hydroxy-6/3-methoxy-3 a,5-cyclo-5 a-cholest-23-yne A mixture of 5 00 g ( 0 0101 mol) of 6/-methoxy-25-( 2tetrahydropyranyloxy)3 a,5-cyclo-5 ac-cholest-23-yne, 0 1 g of p-toluenesulphonic acid monohydrate and 15 250 ml of methanol was stirred at O C for 1 hour 1 0 g of potassium carbonate was added and the mixture was stirred at 0 C After 0 5 hour, the solvent was evaporated under reduced pressure 200 ml of water were added to the residue and the mixture was extracted with two 100 ml portions of ethyl acetate The combined organic layers were washed with 100 ml of water and 100 ml of saturated sodium 20 chloride solution and dried over anhydrous magnesium sulphate Evaporation of the solvent under a vacuum, after filtration of the drying agent, gave 4 10 g ( 99 %) of 25-hydroxy-6 p-methoxy-3 a,5-cyclo-5 a-cholest-23-yne; lalD 5 = + 49 7 (c = 0 99 in chloroform).

Analysis calculated for C 28 H 4402 25 (MW 412 66): C, 81 50; H, 10 75.

Found: C, 81 31; H, 10 79.

Example 2.

25-Hydroxy-6 p-methoxy-3 a,5-cyclo-5 a-cholest-23 (E)-ene A mixture of 1 20 g ( 0 0029 mol) of 25-hydroxy-6/p-methoxy-3 a,5-cyclo-5 a 30 cholest-23-yne, 1 65 g ( 0 0063 mol) of lithium aluminium hydride and 50 ml of tetrahydrofuran was heated under reflux for 48 hours with stirring The mixture was cooled to O C, diluted with 100 ml of ether and 3 3 ml of water followed by 2 6 ml of % aqueous sodium hydroxide were added dropwise with stirring The mixture was stirred at O C for 1 hour The solids were collected, triturated with methylene 35 chloride and the mixture was filtered The combined filtrates were evaporated and the residue was dissolved in methylene chloride and filtered through a column of silica gel Evaporation of the eluent followed by recrystallisation of the residue from hexane gave 0 90 g ( 81 %) of 25-hydroxy-6/t-methoxy-3 a,5-cyclo-5 acholest-23 (E)-ene of melting point 126 -127 C; lal 25 = + 46 0 (c = 0 98 in chloroform) 40 Example 3.

25-Hydroxy-6/3-methoxy-3 a,5-cyclo-5 a-cholest-23 (Z)-ene A mixture of 0 312 g ( 0 00076 mol) of 25-hydroxy-6/p-methoxy-3 a,5-cyclo5 acholest-23-yne, 6 ml of methanol and 0 05 g of Lindlar catalyst (prepared from palladium supported on precipitated calcium carbonate, lead diacetate and 45 quinoline according to the procedure described in "Organic Syntheses", Coll, Vol.

V, John Wiley and Sons, New York, N Y, 1973, pages 880-883) was stirred under I atmosphere of hydrogen until the absorption of gas ceased This required 24 hours The mixture was filtered through diatomaceous earth and the filtrate was evaporated to dryness to yield 0 310 g ( 99 %) of 25-hydroxy-6/3-methoxy3 a,5-cyclo 50 a-cholest-23 (Z)-ene; lal 25 = + 374 O (c = 1 24 in chloroform).

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Claims (1)

1. WHAT WE CLAIM IS:-

   1 A cholestene derivative of the general formula (I) wherein R 1 represents a hydroxy, lower alkoxy, phenyl-(lower alkoxy), lower alkanoyloxy or benzoyloxy group.

   2 A cholestene derivative of formula I given in claim 1, wherein R, represents a lower alkoxy group.

   3 A cholestene derivative as set forth in claim 2, wherein R 1 represents a methoxy group.

   4 A cholestene derivative of formula I given in claim 1, wherein the configuration of the 23,24-double bond is cis (denoted by the symbol Z).

   A cholestene derivative of formula I given in claim 1, wherein the configuration of the 23,24-double bond is trans (denoted by the symbol E).

   6 A process for the preparation of a cholestene derivative of the general formula C,3 o, 3 t CN 3 N(Ia) wherein R 1 has the significance given in claim 1 and the configuration of the 23,24double bond is trans (i e where the 23,24-double bond has the Econfiguration), which process comprises contacting a compound of the general formula nlo (II) wherein R 1 has the significance given in claim 1, with a complex metal hydride reducing agent in an inert organic solvent.

   7 A process according to claim 6, wherein R 1 represents a lower alkoxy group.

   8 A process according to claim 7, wherein R 1 represents a methoxy group.

   9 A process according to any one of claims 6 to 8 inclusive wherein the complex metal hydride reducing agent is an alkali metal aluminium hydride.

   A process according to claim 9, wherein the alkali metal aluminium hydride is lithium aluminium hydride.

   11 A process according to any one of claims 6 to 10 inclusive, wherein the inert organic solvent is an ethereal solvent.

   12 A process according to claim 11, wherein the ethereal solvent is tetrahydrofuran.

   6 1 564 07 13 A process for the preparation of a cholestene derivative of the general fori-mula óH;CH 3 C Hs up C 83 H I{ 3 3 (Ib) wherein R 1 has the significance given in claim I and the configuration of the 23,24double bond is cis (i e wherein the 23,24-double bond has the Zconfiguration), 5 which process comprises treating a compound of the general formula CH //, CH 3 <CH 3 (II) R 1 wherein R, has the significance given in claim 1, with hydrogen in the presence of a hydrogenation catalyst and an inert solvent.

   14 A process according to claim 13, wherein R 1 represents a lower alkoxy 10 group.

   A process according to claim 14, wherein R, represents a methoxy group.

   16 A process according to any of claims 13 to 15 inclusive, wherein the hydrogenation catalyst is a noble-metal catalyst.

   17 A process according to claim 16, wherein the noble-metal catalyst is a 15 palladium catalyst.

   18 A process according to claim 17, wherein the palladium catalyst is a Lindlar catalyst.

   19 A process for the preparation of cholestene derivatives, substantially as hereinbefore described with reference to Example 2 or Example 3 20 A cholestene derivative, when prepared by the process claimed in any one of claims 6 to 19 inclusive or by an obvious chemical equivalent thereof.

   For the Applicants, CARMAELS & RANSFORD, Chartered Patent Agents, 43, Bloomsbury Square, LONDON, WCIA 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.

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