GB1563878A

GB1563878A - Butenolide compounds

Info

Publication number: GB1563878A
Application number: GB3578478A
Authority: GB
Original assignee: Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1976-05-24
Filing date: 1977-05-16
Publication date: 1980-04-02
Also published as: FR2352780B1; DE2719304A1; IE44932B1; IE44932L; CH631959A5; FR2352780A1; GB1563877A; JPS52144643A; CH636592A5

Description

( 21) Application No 35784/78

( 62) Divided Out of No 1563877 ( 22) Filed 16 May 1977 ( 31) Convention Application No 689366 ( 32) Filed 24 May 1976 ( 31) Convention Application No 777598 ( 32) Filed 15 March 1977 in ( 33) United States of America (US) ( 44) Complete Specification published 2 April 1980 ( 51) INT CL 3 C 07 D 307/83 ( 52) Index at acceptance C 2 C 1473 213 247 253 25 Y 305 30 Y 351 352386401 40 Y 625761 767 AA TU ( 54) BUTENOLIDE COMPOUNDS ( 71) We, THE UPJOHN COMPANY, a corporation organised and existing under the laws of the State of Delaware, United States of America, of 301 Henrietta Street, Kalamazoo, State of Michigan, United States of America, 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:-

British Patent Application No 20424/77 (Serial No 1563877) discloses and claims a process for the preparation of 2arylalkanoic acids and esters including the pharmaceutically active compound 2-(pisobutylphenyl)-propionic acid which is known as ibuprofen The present invention relates to compounds, most of which are novel, which are useful as starting materials for that process or as intermediates therein, and to process for preparing them.

The compounds to which this invention relates are of formula 1:

y I wherein the dotted line indicates the presence of either a,3 or _ 4 double bond: Y is hydrogen or C 3 _s alkyl: and R is hydrogen or C,4 alkyl The compound 5,7 a-dihydro2 ( 4 H)-benzofuranone is disclosed, as formula VII, as a likely intermediate in the preparation of phenylacetic acid, in Tetrahedron Letters 46 ( 1968) 4739-4742 (Palazzo and Baiocchi) The novel compounds of this invention are those of formula I in which R and Y are not both hydrogen i e R is C,4 alkyl or Y is C 3 _ 5 alkyl.

In the invention, it is preferred that Y is C 3 _s alkyl and R is C 4 alkyl More preferably, Y is isobutyl and R is methyl, the compound then being a precursor to ibuprofen.

The processes of this invention use, as starting material, a 2-( 2-oxocyclohex-3enyl)alkanoic acid or ester of formula 11:

y CR COOR 1 a wherein R' is hydrogen or C,6 alkyl and R and Y are as defined above By reacting a compound of formula II with a catalytic amount, e g 1 to 10 5, of a sulphonic or phosphonic acid at 75 to 130 C in a nonpolar, azeotroping solvent, while removing water from the reaction mixture during the reaction, a mixture of the compounds of formula I is formed in which the A 4 compound is predominant By reacting a compound of formula II with acetic anhydride in the presence of an acidscavenging base which does not destroy the reactants, e g potassium carbonate or pyridine, at room temperature, an unstable intermediate of the formula:

v Y PATENT SPECIFICATION ( 11) 1 563 878 1,563,878 wherein R and Y are as defined above, is formed and heating of that intermediate to from 75 to 130 C yields a mixture of compounds of formula I in which the A 3 compound is predominant.

Suitable sulphonic and phosphonic acids, and suitable non-polar, azeotroping solvents are described in Application No 20424/77 (Serial No 1563877) The same specification describes how treatment of a compound of formula I with a mineral acid such as sulphuric or hydrochloric acid in acetic acid causes aromatisation, to form a 2arylalkanoic acid or ester Similarly, treatment of a compound of formula I with a sulphonic or phosphonic and at 75 to C while removing water from the reaction mixture during the reaction, causes conversion to 2-arylalkanoic acids.

The following Example illustrates the invention.

3 H triplet on addition of Eu(FOD)3: 5 22 singlet I H, 5 64 ppm singlet (IH) IR (CHCI 3) 1750, 1700 cm'.

tma Me 213 ( 7,500); 278 mu sh (E 674) mass spectrum: 206 (m-), 177, 149.

B:

M Hz NMR (CDCI 3) 0 90 ( 6 H), 1 80 ( 5 H), 4 96 quartet (IH) 5 45 quartet (IH) IR 1750, 1695 cm'.

1,me O" 220 mi/o (e 5850) mass spectrum: 206 (m+), 177, 163, 149, Subjecting each of the intermediates to ptoluenesulphonic acid in refluxing toluene produces ibuprofen.

Claims

WHAT WE CLAIM IS:-

1 A process for preparing a mixture of A 3 and, predominantly, A 4 compounds of formula I Example To a 15 ml, one necked flask equipped with a Dean-Stark trap and condenser, 0 0937 gm of p-toluene sulphonic acid monohydrate, 0 9935 gm of crystalline 2 ( 4isobutyl 2 oxo 3 cyclohexenyl) propionic acid and 4 ml of toluene were added The mixture was heated to reflux under nitrogen After 5 hours of heating, TLC and GLC analysis of the reaction mixture showed minor amounts of ibuprofen and 2( 4-isobutyl-2-oxo-3-cyclohexenyl)-propionic acid, and a major amount of two butenolide intermediates which have been identified as:

CH 3-CH-CH 3 l H 2 CH 3-CH-CH 3 end lA) l 8) Isolation of these compounds can be accomplished by extracting the cooled reaction mixture with 5 percent aqueous sodium bicarbonate, washing the toluene phase with water, drying it over sodium sulphate and evaporating off the toluene.

The residual oil containing mostly (B) and a minor amount of (A) is chromatographed over silica gel giving, as oils, pure A and B having the following physical properties:

A:

M Hz (CDCI 3) 0 87 sextet ( 6 H): 1 83 doublet ( 5 H) resolves into a 2 H singlet and D O R wherein the dotted line indicates the presence of either a A 3 or A 4 double bond; Y is hydrogen or C 3,5 alkyl; and R is hydrogen or C 1 4 alkyl; the process comprising reacting a compound of formula IT CHR coop' wherein R' is hydrogen or C,_ 6 alkyl and R and Y are as defined above, with a catalytic amount of a sulphonic or phosphonic acid at to 130 C in a non-polar, azeotroping solvent, while removing water from the reaction mixture during the reaction.

2 A process for preparing a mixture of A 4 and, predominantly, _:\ 3 compounds of formula I as defined in claim I, the process comprising reacting a compound of formula 11 as defined in claim I with acetic anhydride in the presence of an acidscavenging base which does not destroy the reactants at room temperature, to produce an unstable intermediate of the formula 2 1,563,878 wherein R and Y are as defined above, and heating the intermediate to from 75 to C.

3 A process according to claim I or claim 2 wherein Y is C 3 _ 5 alkyl and R is C,_ 4 alkyl.

4 A process according to claim 3 wherein Y is isobutyl and R is methyl.

A process according to claim I substantially as described in the Example.

6 A compound of formula I as defined in claim I wherein Y is C,-5 alkyl.

7 A compound of formula I as defined in claim I wherein R is C,4 alkyl.

8 A compound of formula I as defined in claim I wherein Y is C 3 _s alkyl and R is C,_ 4 alkyl.

9 A compound as claimed in claim 8 wherein Y is isobutyl and R is methyl.

For the Applicants, GILL JENNINGS & EVERY, Chartered Patent Agents, 53/64 Chancery Lane, London WC 2 A IHN.

Printed for Her Maiesty's Stationery Office, by the Courier Press, Leamington Spa 1980 Published by The Patent Office 25 Southampton Buildings London WC 2 A IAY from which copies may be obtained.