Process for preparing 3-aminothienopyridone derivatives

1. A compound of formula (2):

wherein R is a —CN, —NO 2 , —CO 2 Alk 2 , —COC 1-6 alkyl or —CONHet 2 group;

Alk 2 is an optionally substituted alkyl, arylalkyl, aryl, aryloxyalkyl, alkanoyloxyalkyl or aroyloxyalkyl group;

NHet 2 is an optionally substituted 4- to 6-membered heterocycloalkyl group attached through a nitrogen atom to the group —CO;

R 1 is an optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl group; and

each R y , which may be the same or different, is each a hydrogen atom or a hydrogen atom precursor;

or a salt, protected derivative, or N-oxide thereof.

2. A compound according to claim 1 in which R 1 is an optionally substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, indolyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

3. A compound according to claim 2 wherein R 1 is an optionally substituted phenyl or cyclopropyl group.

4. A compound according to claim 1 in which each R y is a hydrogen atom.

5. A compound according to claim 1 in which Alk 2 is a C 1-6 alkyl group.

6. A compound according to claim 1 wherein R is a —CN, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —COCH 3 or —CONHet 2 group.

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

wherein R is a —CN, —NO 2 , —CO 2 Alk 2 , —COC 1-6 alkyl or —CONHet 2 group;

Alk 2 is an optionally substituted alkyl, arylalkyl, aryl, aryloxyalkyl, alkanoyloxyalkyl or aroyloxyalkyl group;

NHet 2 is an optionally substituted 4- to 6-membered heterocycloalkyl group attached through a nitrogen atom to the group —CO;

R 1 is an optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl group;

each R y , which may be the same or different, is a hydrogen atom or a hydrogen atom precursor; and

T is a halogen atom;

which comprises diazotization of a compound of formula (2)

followed by halide displacement.

8. A process according to claim 7 wherein the reaction is carried out in the presence of an alkyl nitrite or a metal nitrite in the presence of an acid, followed by addition of a copper salt, in the presence of a solvent.

9. A process for the manufacture of a compound of formula (1A):

wherein R is a —CN, —NO 2 , —CO 2 Alk 2 , —COC 1-6 alkyl or —CONHet 2 group;

Alk 2 is an optionally substituted alkyl, arylalkyl, aryl, aryloxyalkyl, alkanoyloxyalkyl or aroyloxyalkyl group;

NHet 2 is an optionally substituted 4- to 6-membered heterocycloalkyl group attached through a nitrogen atom to the group —CO;

R 1 is an optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl group;

each R y , which may be the same or different, is a hydrogen atom or a hydrogen atom precursor; and

Ar is an optionally substituted aromatic or heteroaromatic group;

which comprises reacting a compound of formula (2):

with a compound ArQ,

wherein Q is a leaving group,

in the presence of a transition metal catalyst.

10. A process according to claim 9 wherein the reaction is carried out in the presence of a solvent, using a palladium catalyst, a phosphine ligand and a base.

11. A process according to claim 9 wherein the reaction is carried out in the presence of a copper catalyst.

12. A process for the manufacture of a compound of formula (2):

wherein R is a —CN, —NO 2 , —CO 2 Alk 2 , —COC 1-6 alkyl or —CONHet 2 group;

Alk 2 is an optionally substituted alkyl, arylalkyl, aryl, aryloxyalkyl, alkanoyloxyalkyl or aroyloxyalkyl group;

NHet 2 is an optionally substituted 4- to 6-membered heterocycloalkyl group attached through a nitrogen atom to the group —CO;

R 1 is an optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl group;

each R y , which may be the same or different, is a hydrogen atom or a hydrogen atom precursor;

which comprises the steps of:

a) reacting a compound of formula (2a) or (2b):

wherein R c is an optionally substituted alkyl group, and

W is a hydrogen atom, a metal ion or an amine salt;

with a compound of formula (3):

b) followed by reaction with a compound of formula (5):

wherein Z is a leaving group.

13. The process according to claim 12 wherein W is a metal ion.

14. The process according to claim 12 wherein step a) is performed in the presence of a base.

15. The process according to claim 14 wherein the base is selected from a lithium base, a silazane, a carbonate, an alkoxide, a hydroxide, a hydride, an organic amine, and a cyclic amine.

16. The process according to claim 12 wherein the reaction is carried out in an organic solvent.

17. The process according to claim 16 wherein step a) and step b) are each carried out in an organic solvent, which may be the same or different in each step, selected from an amide, an ether, an alcohol and acetonitrile.

18. The process according to claim 12 wherein an intermediate of formula (4) is isolated after step a):

19. A compound of formula (4):

wherein R 1 is an optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl group;

each R y , which may be the same or different, is a hydrogen atom or a hydrogen atom precursor; and

W is a hydrogen atom, a metal ion or an amine salt.

20. The process according to claim 12 wherein an intermediate of formula (6) is isolated during step b):

21. A compound of formula (6):

wherein R is a —CN, —NO 2 , —CO 2 Alk 2 , —COC 1-6 alkyl or —CONHet 2 group;

Alk 2 is an optionally substituted alkyl, arylalkyl, aryl, aryloxyalkyl, alkanoyloxyalkyl or aroyloxyalkyl group;

NHet 2 is an optionally substituted 4- to 6-membered heterocycloalkyl group attached through a nitrogen atom to the group —CO;

R 1 is an optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl group; and

each R y , which may be the same or different, is a hydrogen atom or a hydrogen atom precursor.