Process and intermediates useful in the preparation of statins, particularly atorvastatin
There is provided a process for the preparation of a compound of formula (7) or salts thereof: wherein R 1 represents a hydrogen or a hydrocarbyl group, R 2 represents a hydrogen or substituent group, R 3 represents a hydrogen or a hydrocarbyl group, and X represents a hydrogen or substituent group which comprises a) cyanating a compound of formula (1): wherein Y represents a halo group, preferably CI or Br; 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) reducing the compound of formula (2) to give a compound of formula (3): coupling the compound of formula (3) with a compound of formula (4): to give a compound of formula (5): when W represents —OP 2 , deprotecting and then oxidizing the compound of formula (5) to give a compound of formula (6): and e) subjecting the compound of formula (5) when W represents ═O, or compound of formula (6) to ring-opening, and removal of any remaining protecting groups, to give a compound of formula (7) or salts thereof.
1. A process for the preparation of a compound of formula (7) or a salt thereof:
wherein
R 1 represents an alkyl group;
R 2 represents an aryl group;
R 3 represents an aryl group;
X represents a group of formula —COZ, wherein Z represents —OR 4 , in which R 4 represents alkyl, or —NR 5 R 6 , wherein R 5 and R 6 each independently represent H, alkyl, or aryl;
which comprises
a) cyanating a compound of formula (1):
wherein Y represents a halo group; P 1 represents hydrogen or a protecting group, and W represents —OP 2 , in which P 2 represents hydrogen or a protecting group, to give a compound of formula (2):
b) reducing 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):
to give a compound of formula (5):
d) deprotecting and then 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 removal of any remaining protecting groups, to give a compound of formula (7) or a salt thereof:
2. The process according to claim 1 , wherein R 1 is an isopropyl group, R 2 is a phenyl group, R 3 is a 4-fluorophenyl group, and X is —CO 2 Me, —CO 2 Et or —CONHPh.
3. The process of claim 1 , wherein Y represents Cl or Br.
4. The process of claim 1 , wherein R 1 represents a C 1-6 alkyl group.
5. The process of claim 1 , wherein R 1 represents an isopropyl group.
6. The process of claim 1 , wherein R 2 represents a phenyl group.
7. The process of claim 1 , wherein R 3 represents a 4-fluorophenyl group.
8. The process of claim 1 , wherein Z represents —OR 4 , in which R 4 represents alkyl.
9. The process of claim 1 , wherein Z represents —OR 4 , in which R 4 represents a methyl or ethyl group.
10. The process of claim 1 , wherein Z represents —NR 5 R 6 , wherein R 5 and R 6 each independently represent H, alkyl, or aryl.
11. The process of claim 1 , wherein Z represents —NR 5 R 6 , wherein R 5 is H, and R 6 is phenyl.
12. The process of claim 1 , wherein R 1 represents a C 1-6 alkyl group; and R 2 represents a phenyl group.
13. The process of claim 1 , wherein R 1 represents a C 1-6 alkyl group; R 2 represents a phenyl group; and R 3 represents a 4-fluorophenyl group.
14. The process of claim 1 , wherein R 1 represents a C 1-6 alkyl group; R 2 represents a phenyl group; R 3 represents a 4-fluorophenyl group; and Z represents —OR 4 , in which R 4 represents a methyl or ethyl group.
15. The process of claim 1 , wherein R 1 represents a C 1-6 alkyl group; R 2 represents a phenyl group; R 3 represents a 4-fluorophenyl group; and Z represents —NR 5 R 6 , wherein R 5 is H, and R 6 is phenyl.