IE44933B1

IE44933B1 - Butenolide compounds

Info

Publication number: IE44933B1
Application number: IE1205/80A
Authority: IE
Original assignee: Upjohn Co
Priority date: 1976-05-24
Filing date: 1977-05-23
Publication date: 1982-05-19
Also published as: IE44933L

Description

The compounds to which this invention relates are of formula I: Y q Λ wherein the dotted line indicates the presence of either a Δ or A double bond; 10 Y is hydrogen or C3_5 alkyl; and R is hydrogen or Chalky!. The compound 5,7adihydro-2(4H)-benzofuranone is disclosed, as formula VII, as a likely intermediate - 2 <4933 in the preparation of phenylacetic acid, in Tetrahedron Letters 45 (1968) 47394742 (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^_^ alkyl or Y is ^.galkyb In the invention, it is preferred that Y is Cg_g alkyl and R is 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-3-enyl)alkanoic acid or ester of formula II: Y CHR 1 1 COOR wherein R^ is hydrogen or Cpg alkyl and R and Y are as defined above. By reacting a compound of formula II with a catalytic amount, e.g. 1 to 10K, of a sulphonic or phosphonic acid at 75 to 130°C in a non-polar .azeotroping solvent, while removing water from the reaction mixture during the reaction, a mixture of the compounds of ]c formula I is formed in which the compound is predominant. By reacting a compound of formula II with acetic anhydride in the presence of an acid-scavenging base which does not destroy the reactants, e.g. potassium carbonate or pyridine, at room temperature, an unstable intermediate of the formula: - 3 440 33 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 £ 3 compound is predominant.

Suitable sulphonic and phosphonic acids, and suitable non-polar, azeotroping solvents are described in Acceptance No. 44232 . The same specification described 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 2-arylalkanoic acid or ester. Similarly, treatment of a compound of formula I with a sulphonic or phosphonic and at 75 to 130°C while removing water from the reaction mixture during the reaction, causes conversion to 2-arylalkanoic acids.

The following Example illustrates the invention.

EXAMPLE To a 15 ml, one necked flask equipped with a Dean-Stark trap and condenser, 0.0937 gm of ^-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-(420 isobutyl-2-oxo-3-cyclohexenyl)-propionic acid, and a major amount of two butenolide intermediates which has been identified as: isolation of these compounds can be accomplished by extracting the cooled reaction mixture with 5 percent aqueous sodium bicarbonate, washing the toluene wiase with water, drying it over sodium sulphate and evaporating off the toluene.

Tne residual oil containing mostly (B) and a minor amount of (A) is chromatographed ever silica gel giving, as oils, pure A and B having the following physical properties: A: MHz (CDClj) 0.87 sextet (6H); 1.83 doublet (5H) resolves into a 2H singlet and 3H triplet on addition of Eu(F0D)3: 5.22 singlet IH, 5.64 ppm singlet (IH). IR (CHC13) 1750, 1700 cm1. λ max Me°H 213 <7’5θθ): 278 sh (ε δ74) mass spectrum: 206 (m +), 177, 149.

B: 60 MHz NMR (CDClg) 0.90 (6H), 1.80 (5H), 4.96 quartet (IH) 5.45 quartet ' (IH) IR 1750, 1695 cm-1. λ maxMe°H 220 m/x ( e 5850) mass spectrum: 206 (m+), 177, 163, 149.

Subjecting each of the intermediates to p-toluenesulphonic acid in refluxing toluene produces ibuprofen.

Claims

CLAIMS 3 λ

1. A process for preparing a mixture of & and, predominantly, Δ compounds of formula I J <5 Z wherein the dotted line indicates the presence of either a Δογ i double bond; Y is hydrogen or Cg_ 5 alkyl; and R is hydrogen or C-|_ 4 alkyl; the process comprising reacting a compound of formula II ro QOOR 1 i wherein R is hydrogen or C^_ 5 alkyl and R and Y are as defined above, with a catalytic amount of a sulphonic or phosphonic acid at 75 to 130°C in a non-polar, azeotroping solvent, while removing water from the reaction mixture during the reaction. λ -a

2. A process for preparing a mixture of A and, predominantly, Δ compounds of formula I as defined in Claim 1, the process comprising reacting a - 6 O S 3 3 compound of formula II as defined in Claim 1 with acetic anhydride in the presence cf an acid-scavenging base which does not destroy the reactants at room temperature, to produce an unstable intermediate of the formula i.nerei'n fl and Y are as defined above, and heating the intermediate to from 75 to I,iO°C.

3. A process according to Claim 1 or Claim 2 wherein Y is C^g alkyl and R 'is C._ 4 alkyl.

4. A process according to Claim 3 wherein Y is isobutyi and R is methyl.

5. A process according to Claim 1 substantially as described in the Example.

6. A compound of formula I as defined in Claim 1 wherein Y is Cg_g alkyl.

7. A compound of formula I as defined in Claim 1 wherein R is C·^ alkyl.

8. A compound of formula I as defined in Claim 1 wherein Y is C 3 _ 5 alkyl and R ι s C-| _.4 al kyl.

9. A compound as claimed in Claim 3 wherein Y is isobutyl and R is methyl.