Process and intermediate compounds useful in the preparation of statins
There is provides a process for the preparation of a compound of formula ( 7 ): wherein R is an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group; provides that R is not a compound of Formula (a): wherein R a represents an alkyl group, such as a C 1-16 alkyl group, and preferably an isopropyl group; R b represents an aryl group, preferably a 4-fluorophenyl group; R c represents hydrogen, a protecting group or an alkyl group, such as a C 1-16 alkyl group, and preferably a methyl group; and Rd represents hydrogen, a protecting group or a SO 2 R e group where R e is an alkyl group, such as a C 1-16 alkyl group, and preferably a methyl group.
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 —OP 2 , in which P 2 represents hydrogen or a protecting group, to give a compound of formula (2):
b) oxidizing the compound of formula (2) to provide a compound of formula (3):
wherein W represents —OP 2 or ═O,
c) the process further comprising forming a compound of formula (2) or (3) in which W represents ═O by: oxidizing a compound of formula (2) or (3) wherein P 2 is hydrogen; or deprotecting and oxidizing a compound of formula (2) or (3) wherein P 2 is a protecting group;
d) coupling the compound of formula (3) wherein W represents ═O 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 give a compound of formula (5) wherein W represents ═O:
and
e) subjecting the compound of formula (5) 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. The process of claim 1 , wherein R is selected from:
and wherein
R 1 is a hydrogen, a protecting group or a substituted or unsubstituted hydrocarbyl group;
R 2 is a an optionally substituted acyl group;
R 3 is an optionally substituted acyl group;
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.
4. The process of claim 3 , wherein R 1 is an alkyl group and/or R 2 is an alkanoyl group.
5. The process of claim 4 , wherein R 1 is a C 1-6 alkyl group and/or R 2 is a C 1-8 alkanoyl group.
6. The process of claim 5 , wherein R 2 is a —C(O)CH(Me)CH 2 CH 3 or —C(O)C(Me) 2 CH 2 CH 3 group.
7. The process of claim 3 , wherein R 3 is an alkanoyl group.
8. The process of claim 7 , wherein R 3 is a C 1-8 alkanoyl group.
9. The process of claim 7 , wherein R 3 is a —C(O)CH(Me)CH 2 CH 3 or a —, C(O)C(Me) 2 CH 2 CH 3 group.
10. 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.
11. The process of claim 10 , wherein R 4 is a 4-fluorophenyl group and/or R 5 is a cyclopropyl group.
12. 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.
13. The process of claim 12 , wherein R 6 is a 4-fluorophenyl group and/or R 7 is an isopropyl group.
14. 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.
15. The process of claim 14 , wherein R 8 is a methyltetrazoyl group; R 9 is a 4-fluorophenyl group; and/or R 10 is a 4-fluorophenyl group.
16. The process of claim 3 , wherein Y is Cl or Br.
17. The process of claim 1 , wherein the process further comprises forming a compound of formula (2) in which W represents ═O by: oxidising a compound of formula (2) when W is OP 2 and P 2 is hydrogen; or deprotecting and oxidising a compound of formula (2) when W is OP 2 and P 2 is a protecting group.
18. The process of claim 1 , wherein the process further comprises forming a compound of formula (3) wherein W represents ═O by: oxidising a compound of formula (3) when W is —OP 2 and P 2 is hydrogen; or deprotecting and oxidising a compound of formula (3) when W is —OP 2 and P 2 is a protecting group.