DCC mediated coupling for halofenate manufacture

1. A process for preparing a compound of formula (IV)

where R is C 1-6 alkylC(O)NHC 1-6 alkyl or arylC(O)NHC 1-6 alkyl, comprising the step of contacting (−)-halofenic acid with a compound of the formula ROH and N,N′-dicyclohexylcarbodiimide in an aprotic solvent in the absence of base under conditions sufficient to form the compound of formula (IV).

2. The process of claim 1 where the step is carried out in the absence of an N-hydroxy based agent.

3. The process of claim 1 where the aprotic solvent is selected from the group consisting of toluene, xylenes, cyclohexane, di-isopropyl ether, isopropyl acetate, tetrahydrofuran, hexanes, methyl tert-butyl ether, and combinations thereof.

4. The process of claim 3 where the aprotic solvent is toluene.

5. The process of claim 1 where the mole ratio of N,N′-dicyclohexylcarbodiimide to (−)-halofenic acid is 1.05:1 to 1.15:1, and the mole ratio of the compound of the formula ROH to (−)-halofenic acid is 1.02:1 to 1.7:1.

6. The process of claim 5 where the mole ratio of N,N′-dicyclohexylcarbodiimide to (−)-halofenic acid is 1.1:1, and the mole ratio of the compound of the formula ROH to (−)-halofenic acid is 1.5:1.

7. A process for the preparation of (−)-halofenate, comprising the step of contacting (−)-halofenic acid with N-acetylethanolamine and N,N′-dicyclohexylcarbodiimide in an aprotic solvent in the absence of base under conditions sufficient to form the (−)-halofenate.

8. The process of claim 7 where the step is carried out in the absence of an N-hydroxy based agent.

9. The process of claim 8 where the aprotic solvent is selected from the group consisting of toluene, xylenes, cyclohexane, di-isopropyl ether, isopropyl acetate, tetrahydrofuran, hexanes, methyl tert-butyl ether, and combinations thereof.

10. The process of claim 9 where the aprotic solvent is toluene.

11. The process of claim 7 where the mole ratio of N,N′-dicyclohexylcarbodiimide to (−)-halofenic acid is 1.05:1 to 1.15:1, and the mole ratio of N-acetylethanolamine to (−)-halofenic acid is 1.02:1 to 1.7:1.

12. The process of claim 11 where the mole ratio of N,N′-dicyclohexylcarbodiimide to (−)-halofenic acid is 1.1:1, and the mole ratio of N-acetylethanolamine to (−)-halofenic acid is 1.5:1.

13. A process for the preparation of (−)-halofenate, comprising the steps of:

contacting a solution comprising N-acetylethanolamine in toluene free of base with a solution comprising (−)-halofenic acid in toluene free of base;

cooling the resulting solution at about 0° C.;

contacting a solution of N,N′-dicyclohexylcarbodiimide in toluene free of base with the cooled resulting solution for a sufficient period of time to form (−)-halofenate.

14. The process of claim 13 where the steps are carried out in the absence of an N-hydroxy based agent.

15. The process of claim 14 , further comprising the step of separating N,N′-dicyclohexylurea as a precipitate from the (−)-halofenate-containing reaction mixture, leaving a filtrate.

16. The process of claim 15 , further comprising the step of washing the precipitate with toluene.

17. The process of claim 15 , further comprising the steps of adding cyclohexane to the filtrate, washing the filtrate with water and azeotropically distilling water from the filtrate, and crystallizing and isolating the (−)-halofenate.

18. The process of claim 17 where the isolated (−)-halofenate has an enantiomeric excess of 98% or greater before purification.

19. The process of claim 18 where the isolated (−)-halofenate has an enantiomeric excess of 99% or greater before purification.

20. The process of claim 19 where the isolated (−)-halofenate has an enantiomeric excess of 99.5% or greater before purification.