Stereoselective synthesis of a 4,4-disubstituted cyclohexanepropanoic acid
View Patent ↗There is provided stereoselective route to a compound of formula I: wherein R represents H or an alkali metal, Ar 1 represents 4-chlorophenyl and Ar 2 represents 2,5-difluorophenyl.
1. A process for the preparation of a compound of formula (1):
wherein R represents H or an alkali metal, Ar 1 represents 4-chlorophenyl and Ar 2 represents 2,5-difluorophenyl;
comprising the steps of:
(a) stirring a mixture of a cis-sulfide of formula (2) and a trans-sulfide of formula (3):
with 4-chlorobenzenethiol in an acidic medium in which said mixture of sulfides is partially soluble, causing preferential crystallisation of cis-sulfide of formula (2);
(b) collecting the cis-sulfide of formula (2);
(c) oxidising the cis-sulfide of formula (2) to the corresponding sulfone; and optionally
(d) neutralising the product of step (c) with alkali.
2. A process according to claim 1 wherein said acidic medium comprises an acid selected from trifluoroacetic acid and C 1-4 alkylsulfonic acids in which one or more of the carbon atoms may optionally be perfluorinated.
3. The process according to claim 2 wherein the acid is trifluoroacetic acid, trifluoromethanesulfonic acid or methanesulfonic acid.
4. A process according to claim 2 wherein said acidic medium additionally comprises a solvent selected from n-heptane, methylcyclohexane, trifluoroethanol, hexafluorobenzene, trifluorotoluene, hexafluoropropan-2-ol, acetonitrile and mixtures thereof.
5. A process according to claim 1 wherein the acidic medium is methanesulfonic acid containing from about 5 to about 15% water by volume.
6. A process according to claim 1 wherein the mixture of cis-sulfide of formula (2) and trans-sulfide of formula (3) is generated by reaction of 4-chlorobenzenethiol with an olefin of formula (4):
wherein Ar 2 represents 2,5-difluorophenyl, said reaction being carried out in the acidic medium used in step (a) of the said process.
7. A process according to claim 1 wherein the mixture of cis-sulfide of formula (2) and trans-sulfide of formula (3) is generated by reaction of 4-chlorobenzenethiol with a carbinol of formula (5):
wherein Ar 2 represents 2,5-difluorophenyl, said reaction being carried out in the presence of a Lewis acid, and the mixture of sulfides being isolated prior to carrying out step (a) of the said process.
8. A process according to claim 1 wherein the mixture of cis-sulfide of formula (2) and trans-sulfide of formula (3) is generated by reaction of 4-chlorobenzenethiol with a carbinol of formula (5):
wherein Ar 2 represents 2,5-difluorophenyl, said reaction being carried out in the acidic medium used in step (a) of the said process.
9. A process according to claim 6 wherein the acidic medium comprises an acid and hexafluoropropan-2-ol together with a co-solvent selected from perfluorohexane and perfluorinated 2-butyltetrahydrofuran.
10. A process according to claim 9 wherein the acid is trifluoromethanesulfonic acid.
11. A process according to claim 6 wherein the acidic medium is methanesulfonic acid containing from about 5 to about 15% water by volume.
12. A process according to claim 7 wherein the carbinol of formula (5) is prepared by:
(a) conversion of carboxylic acid (6a) to magnesium salt (6b):
(b) reaction of (6b) with Ar 2 -M′; and
(c) treatment of the resulting product with acid;
wherein M′ represents Li, MgX or CeX 2 ;
X represents Cl, Br or I; and
Ar 2 represents 2,5-difluorophenyl.
13. The compound of formula (5):
where Ar 2 is 2,5-difluorophenyl.
14. The compound of formula (4):
wherein Ar 2 is 2,5-difluorophenyl.
15. The compound of formula (2):
where Ar 1 is 4-chlorophenyl and Ar 1 is 2,5-difluorophenyl.