Process and intermediate compounds useful in the preparation of statins

1. A process for the preparation of a compound of formula (7):

wherein:

R is a substituted or unsubstituted alkenyl or aryl group or any combination thereof,

or a substituted or unsubstituted heterocyclic group;

provided that R is not a compound of Formula (a):

wherein:

R a is an alkyl group;

R b is an aryl group;

R c is hydrogen, a protecting group or an alkyl group; and

R d is hydrogen, a protecting group or a SO 2 R e group, where R e is an alkyl group, which comprises:

a) hydroxylating a compound of formula (1):

wherein Y is a halo group, P 1 is hydrogen or a protecting group, and W is ═O or —OP 2 , in which P 2 is hydrogen or a protecting group, to provide a compound of formula (2):

b) oxidizing the compound of formula (2) to provide a compound of formula (3):

c) coupling the compound of formula (3) with a compound of formula (4):

wherein Z is (PR 11 R 12 ) + X − or P(═O)R 11 R 12 , wherein X is an anion and R 11 and R 12 each independently is an alkyl, aryl, alkoxy or aryloxy group, to provide a compound of formula (5):

d) when W is —OP 2 , removing any P 2 protecting group and oxidizing the compound of formula (5) to provide a compound of formula (6):

and

e) subjecting the compound of formula (5) when W is ═O, or compound of formula (6) to ring-opening, removal of any P 1 protecting groups, and optionally removing any additional protecting groups to provide a compound of formula (7).

2. The process of claim 1 , wherein Y is Cl or Br.

3. A process for the preparation of a compound of formula (7):

wherein R is one of the following:

and wherein:

R 4 is a substituted or unsubstituted hydrocarbyl group;

R 5 is a substituted or unsubstituted hydrocarbyl group;

R 6 is a substituted or unsubstituted hydrocarbyl group;

R 7 is a substituted or unsubstituted hydrocarbyl group;

R 8 is a substituted or unsubstituted hydrocarbyl group, or substituted or unsubstituted heterocyclic group;

R 9 is a substituted or unsubstituted hydrocarbyl group;

R 10 is a substituted or unsubstituted hydrocarbyl group;

which comprises:

a) hydroxylating a compound of formula (1):

wherein Y is a halo group, P 1 is hydrogen or a protecting group, and W is ═O or —OP 2 , in which P 2 is hydrogen or a protecting group, to provide a compound of formula (2):

b) oxidizing the compound of formula (2) to provide a compound of formula (3):

c) coupling the compound of formula (3) with a compound of formula (4):

wherein Z is (PR 11 R 12 ) + X − or P(═O)R 11 R 12 , wherein X is an anion and R 11 and R 12 are each independently an alkyl, aryl, alkoxy or aryloxy group, to provide a compound of formula (5):

d) when W is —OP 2 , removing any P 2 protecting group and oxidizing the compound of formula (5) to provide a compound of formula (6):

and

e) subjecting the compound of formula (5) when W is ═O, or compound of formula (6) to ring-opening, removal of any P 1 protecting groups, and optionally removing any additional protecting groups to provide a compound of formula (7).

4. The process of claim 3 , wherein R 4 is a substituted or unsubstituted aryl group and/or R 5 is a substituted or unsubstituted alkyl group.

5. The process of claim 3 , wherein R 6 is a substituted or unsubstituted aryl group and/or R 7 is a substituted or unsubstituted alkyl group.

6. The process of claim 3 , wherein R 8 is a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group; R 9 is a substituted or unsubstituted aryl group and/or R 10 is a substituted or unsubstituted aryl group.

7. The process of claim 3 , wherein Y is Cl or Br.

8. The process of claim 3 , wherein R 4 is a 4-fluorophenyl group and/or R 5 is a C 1-6 alkyl group.

9. The process of claim 3 , wherein R 6 is a 4-fluorophenyl group and/or R 7 is a C 1-6 alkyl group.

10. The process of claim 3 , wherein R 8 is a methyltetrazoyl group; R 9 is a 4-fluorophenyl group and/or R 10 is a 4-fluorophenyl group.

11. A process for the preparation of a compound of Formula (8):

wherein:

(i) a compound of formula (7), prepared according to claim 2 , is hydrogenated to provide a compound of formula (8); or

(ii) a compound of formula (5) prepared according to steps (a) to (c) of claim 1 or 2 , is hydrogenated to provide a compound of formula (9):

and when W is —OP 2 , removing the P 2 protecting group and oxidizing the compound of formula (9) to provide a compound of formula (10);

and subjecting the compound of formula (9) when W is ═O, or the compound of formula (10) to ring opening, removing the P 1 protecting group and optionally removing additional protecting groups to provide a compound of formula (8); or

(iii) a compound of formula (6), prepared according to steps (a) to (c) of claim 1 or 2 , is hydrogenated to provide a compound of formula (10); and subjecting the compound of formula (10) to ring-opening, removing the P 1 protecting group, and optionally removing additional protecting groups to provide a compound of formula (8).

12. A process for the preparation of a compound of formula (5):

which comprises coupling the compound of formula (3):

with a compound of formula (4):

wherein:

R is a substituted or unsubstituted alkenyl or aryl group or a substituted or unsubstituted heterocyclic group;

Z is (PR 11 R 12 ) + X − or P(═O)R 11 R 12 , wherein X is an anion and R 11 and R 12 each independently is an alkyl, aryl, alkoxy or aryloxy group;

P 1 is hydrogen or a protecting group; and

W is ═O or —OP 2 , in which P 2 is hydrogen or a protecting group; provided that R is not a compound of Formula (a):

wherein:

R a is an alkyl group;

R b is an aryl group;

R c is hydrogen, a protecting group or an alkyl group; and

R d is hydrogen, a protecting group or a SO 2 R e group, where R e is an alkyl group.

13. A process of claim 12 , wherein R is one of the following:

and wherein:

R 4 is a substituted or unsubstituted hydrocarbyl group;

R 5 is a substituted or unsubstituted hydrocarbyl group;

R 8 is a substituted or unsubstituted hydrocarbyl group, or substituted or unsubstituted heterocyclic group;

R 9 is a substituted or unsubstituted hydrocarbyl group; and

R 10 is a substituted or unsubstituted hydrocarbyl group.

14. The process of claim 13 , wherein R 4 is a substituted or unsubstituted aryl group and/or R 5 is a substituted or unsubstituted alkyl group.

15. The process of claim 13 , wherein R 8 is a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group; R 9 is a substituted or unsubstituted aryl group and/or R 19 is a substituted or unsubstituted aryl group.

16. The process of claim 13 , wherein Y is Cl or Br.

17. The process of claim 13 , wherein R 4 is a 4-fluorophenyl group and/or R 5 is a C 1-6 alkyl group.

18. The process of claim 13 , wherein R 8 is a methyltetrazoyl group; R 9 is a 4-fluorophenyl group and/or R 10 is a 4-fluorophenyl group.

19. A compound of formula (9):

wherein:

R is a substituted or unsubstituted alkenyl or aryl group or a substituted or unsubstituted heterocyclic group;

P 1 is hydrogen or a protecting group; and

W is —OP 2 , in which P 2 is hydrogen or a protecting group; provided that R is not a compound of Formula (a):

wherein:

R a is an alkyl group;

R b is an aryl group;

R c is hydrogen, a protecting group or an alkyl group; and

R d is hydrogen, a protecting group or a SO 2 R e group, where R e is an alkyl group, such as C 1-6 alkyl group, and preferably a methyl group.

20. A compound of formula (5)

wherein R is one of the following:

and wherein:

R 4 is a substituted or unsubstituted hydrocarbyl group;

R 5 is a substituted or unsubstituted hydrocarbyl group;

R 8 is a substituted or unsubstituted hydrocarbyl group, or substituted or unsubstituted heterocyclic group;

R 9 is a substituted or unsubstituted hydrocarbyl group; and

R 10 is a substituted or unsubstituted hydrocarbyl group;

P 1 is hydrogen or a protecting group; and

W is ═O or —OP 2 , in which P 2 is hydrogen or a protecting group; provided that R is not a compound of Formula (a):

wherein

R a is an alkyl group;

R b is an aryl group;

R c is hydrogen, a protecting group or an alkyl group; and

R d is hydrogen, a protecting group or a SO 2 R e group, where R e is an alkyl group, such as a C 1-6 alkyl group, and preferably a methyl group.

21. The compound of claim 20 , wherein R 4 is a substituted or unsubstituted aryl group and/or R 5 is a substituted or unsubstituted alkyl group.

22. The compound of claim 20 , wherein R 8 is a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group; R 9 is a substituted or unsubstituted aryl group and/or R 10 is a substituted or unsubstituted aryl group.

23. The compound of claim 20 , wherein R 4 is a 4-fluorophenyl group and/or R 5 is a C 1-6 alkyl group.

24. The compound of claim 20 , wherein R 8 is a methyltetrazoyl group; R 9 is a 4-fluorophenyl group and/or R 10 is a 4-fluorophenyl group.

25. A process for the preparation of a compound of formula (5):

which comprises coupling the compound of formula (3):

with a compound of formula (4):

wherein R is one of the following:

Z is (PR 11 R 12 ) + X − or P(═O)R 11 R 12 , wherein X is an anion and R 11 and R 12 each independently is an alkyl, aryl, alkoxy or aryloxy group;

P 1 is hydrogen or a protecting group;

W is ═O or —OP 2 , in which P 2 is hydrogen or a protecting group; and

R 1 is hydrogen, a protecting group or a substituted or unsubstituted hydrocarbyl group;

R 2 is a substituted or unsubstituted acyl group; and

R 3 is a substituted or unsubstituted acyl group.

26. The process of claim 25 , wherein R 1 is an alkyl group; and/or R 2 is an alkanoyl group; and/or R 3 is an alkanoyl group.

27. A compound of formula (5):

wherein R is one of the following:

P 1 is hydrogen or a protecting group;

W is ═O or —OP 2 , in which P 2 is hydrogen or a protecting group; and

R 1 is hydrogen, a protecting group or a substituted or unsubstituted hydrocarbyl group;

R 2 is a substituted or unsubstituted acyl group; and

R 3 is a substituted or unsubstituted acyl group.

28. The compound of claim 27 , wherein R 1 is an alkyl group; and/or R 2 is an alkanoyl group; and/or R 3 is an alkanoyl group.

29. The process of claim 12 , wherein R is:

and wherein

R 6 is a substituted or unsubstituted hydrocarbyl group;

R 7 is a substituted or unsubstituted hydrocarbyl group; and

W is OP 2 , in which P 2 is hydrogen or a protecting group.

30. The process of claim 29 , wherein R 6 is a substituted or unsubstituted aryl group and/or R 7 is a substituted or unsubstituted alkyl group.

31. The process of claim 29 , wherein R 6 is a 4-fluorophenyl group and/or R 7 is a C 1-6 alkyl group.

32. A compound of formula (5):

wherein

R is

R 6 is a substituted or unsubstituted hydrocarbyl group;

R 7 is a substituted or unsubstituted hydrocarbyl group;

P 1 is hydrogen or a protecting group; and

W is —OP 2 , in which P 2 is hydrogen or protecting group.

33. The compound of claim 32 , wherein R 6 is a substituted or unsubstituted aryl group and/or R 7 is a substituted or unsubstituted alkyl group.

34. The compound of claim 32 , wherein R 6 is a 4-fluorophenyl group and/or R 7 is a C 1-6 alkyl group.

35. A compound of formula (9)

wherein R is one of the following:

and wherein

R 4 is a substituted or unsubstituted hydrocarbyl group;

R 5 is a substituted or unsubstituted hydrocarbyl group;

R 6 is a substituted or unsubstituted hydrocarbyl group;

R 7 is a substituted or unsubstituted hydrocarbyl group;

R 8 is a substituted or unsubstituted hydrocarbyl group, or substituted or unsubstituted heterocyclic group;

R 9 is a substituted or unsubstituted hydrocarbyl group;

R 10 is a substituted or unsubstituted hydrocarbyl group;

P 1 is hydrogen or a protecting group; and

W is —OP 2 , in which P 2 is hydrogen or a protecting group.

36. The compound of claim 35 , wherein R 4 is a substituted or unsubstituted aryl group and/or R 5 is a substituted or unsubstituted alkyl group.

37. The compound of claim 35 , wherein R 6 is a substituted or unsubstituted aryl group and/or R 7 is a substituted or unsubstituted alkyl group.

38. The compound of claim 35 , wherein R 8 is a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group; R 9 is a substituted or unsubstituted aryl group and/or R 10 is a substituted or unsubstituted aryl group.

39. The compound of claim 35 , wherein R 4 is a 4-fluorophenyl group and/or R 5 is a C 1-6 alkyl group.

40. The compound of claim 35 , wherein R 6 is a 4-fluorophenyl group and/or R 7 is a C 1-6 alkyl group.

41. The compound of claim 35 , wherein R 8 is a methyltetrazoyl group; R 9 is a 4-fluorophenyl group and/or R 10 is a 4-fluorophenyl group.

42. A compound of formula (9)

wherein R is one of the following:

Z is (PR 11 R 12 ) + X − or P(═O)R 11 R 12 , wherein X is an anion and R 11 and R 12 each independently is an alkyl, aryl, alkoxy or aryloxy group;

P 1 is hydrogen or a protecting group;

W is ═O or —OP 2 , in which P 2 is hydrogen or a protecting group; and

R 1 is hydrogen, a protecting group or a substituted or unsubstituted hydrocarbyl group;

R 2 is a substituted or unsubstituted acyl group;

R 3 is a substituted or unsubstituted acyl group.

43. The process of claim 42 , wherein R 1 is an alkyl group; and/or R 2 is an alkanoyl group; and/or R 3 is an alkanoyl group.