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 one of the following:
and wherein
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;
said process 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 , wherein 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):
wherein when W is —OP 2 , removing at least a portion of the P 2 protecting group and oxidizing the compound of formula (5) to provide a compound of formula (6):
and
d) subjecting the compound of formula (5) when W is ═O, or the compound of formula (6) to ring-opening, removing at least a portion of the P 1 protecting group, and optionally removing at least a portion of additional protecting groups to provide a compound of formula (7).
2. A process for the preparation of a compound of Formula (8):
wherein:
(i) a compound of formula (7), prepared according to claim 1 , is hydrogenated to provide a compound of formula (8);
(ii) a compound of formula (5) prepared according to steps (a) to (c) of claim 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);
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 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).