Process and intermediate compounds useful in the preparation of statins, particularly rosuvastatin
There is provided a process for the preparation of a compound of formula (7) wherein R 1 represents an alkyl group; R 2 represents an aryl group; R 3 represents hydrogen, a protecting group or an alkyl group; and R 4 represents hydrogen, a protecting group or a SO 2 R 5 group where R 5 is an alkyl group, which comprises a) hydroxylating a compound of formula (1) wherein Y represents a halo group; P 1 represents hydrogen or a protecting group, and W represents ═O or —OP 2 , in which P 2 represents hydrogen or a protecting group, to give a compound of formula (2), b) oxidixing the compound of formula (2) to give a compound of formula (3), c) coupling the compound of formula (3) with a compound of formula (4), wherein R 3 represents a protecting group or an alkyl group; R 4 represents a protecting group or a SO 2 R 5 group where R 5 is an alkyl group; and R 6 represents (PR 7 R 8 )+X − or P(═O)R 7 R 8 in which X is an anion and R 7 and R 8 each independently is an alkyl, aryl.
1. A process for the preparation of a compound of formula (7):
wherein
R 1 represents an isopropyl group;
R 2 represents a 4-fluorophenyl group;
R 3 represents a methyl group; and
R 4 represents a SO 2 R 5 group where R 5 is a methyl group, comprising the steps of:
a) hydroxylating a compound of formula (1):
wherein Y represents a halo group; P 1 represents hydrogen or a protecting group selected from the group consisting of benzyl, benzoyl, methyl, silyl, and tetrahydropyranyl; and W represents —OP 2 , in which P 2 represents a protecting group selected from the group consisting of benzyl, benzoyl, methyl, silyl, and tetrahydropyranyl, to give a compound of formula (2):
b) oxidising the compound of formula (2) to give a compound of formula (3):
c) coupling the compound of formula (3) with a compound of formula (4):
wherein R 1 represents an isopropyl group; R 2 represents a 4-fluorophenyl group; R 3 represents a methyl group; R 4 represents SO 2 R 5 group where R 5 is a methyl group; and R 6 represents P(═O)R 7 R 8 in which R 7 and R 8 each independently is a C 1-6 alkyl, C 6-12 aryl, C 1-6 alkoxy, or C 6-12 aryloxy group, to give a compound of formula (5):
wherein R 3 represents a methyl group; and R 4 represents a SO 2 R 5 group where R 5 is methyl group;
d) removing the P 2 protecting group and oxidising the compound of formula (5) to give a compound of formula (6):
and
e) subjecting the compound of formula (6) to ring-opening and removing any P 1 protecting group, to give a compound of formula (7).
2. The process of claim 1 , wherein Y represents independently for each occurrence Cl or Br.
3. The process of claim 1 , wherein P 1 represents benzyl, benzoyl, methyl, or silyl.
4. The process of claim 1 , wherein P 1 represents benzyl or benzoyl.
5. The process of claim 1 , wherein P 1 represents a trialkylsilyl or a triarylsilyl.
6. The process of claim 1 , wherein P 1 represents a silyl selected from the group consisting of trimethylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl.
7. The process of claim 1 , wherein P 2 represents benzyl.
8. The process of claim 1 , wherein P 2 represents methyl.
9. The process of claim 1 , wherein R 7 and R 8 are each independently a C 6-12 aryloxy group.
10. The process of claim 1 , wherein R 7 and R 8 each independently is methyl, ethyl, phenyl, tolyl, naphthyl, methoxy, ethoxy or phenoxy.
11. The process of claim 1 , wherein R 7 and R 8 represent phenoxy.
12. The process of claim 1 , wherein P 1 represents benzyl or benzoyl; and R 7 and R 8 represent phenoxy.