Process for the production of quinazolines

1. A process for the production of a compound of formula (A), or a pharmaceutically acceptable salt or solvate thereof,

wherein

R 1 represents C 1-4 alkoxy optionally substituted by one or more fluorine atoms;

R 2 represents H or C 1-6 alkoxy optionally substituted by one or more fluorine atoms;

R 3 represents a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally substituted by one or more groups selected from halogen, C 1-4 alkoxy, C 1-4 alkyl and CF 3 ;

R 4 is a 4-, 5-, 6- or 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C 1-4 alkyl, C 1-4 alkoxy, halogen, CONR 7 R 8 , SO 2 NR 7 R 8 , (CH 2 ) b NR 7 R 8 and NHSO 2 (C 1-4 alkyl), and when S is a member of the ring system, it may be substituted by 1 or 2 oxygen atoms;

R 7 and R 8 independently represent H or C 1-4 alkyl, or together with the N atom to which they are attached they may represent a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S; and

b represents 0, 1, 2 or 3;

the process comprising condensing a compound of formula (B),

wherein

R 1 to R 3 are as defined above;

with a compound of formula (C),

wherein

R 5 and R 6 taken together with the N atom to which they are attached represent a 4-, 5-, 6-, or 7-membered N-containing heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C 1-4 alkyl, C 1-4 alkoxy, halogen, CONR 7 R 8 , SO 2 NR 7 R 8 , (CH 2 ) b NR 7 R 8 and NHSO 2 (C 1-4 alkyl), and when S is a member of the ring system, it may be substituted by 1 or 2 oxygen atoms;

R 7 , R 8 and b are as defined above; and

where necessary or desired, converting the resulting compound of formula (A) into a pharmaceutically acceptable salt or solvate, or converting the resulting salt or solvate into a compound of formula (A).

2. A process as claimed in claim 1 , wherein R 1 represents methoxy.

3. A process as claimed in claim 1 , wherein R 2 represents methoxy.

4. A process as claimed in claim 1 , wherein R 3 represents an aromatic ring.

5. A process as claimed in claim 4 , wherein R 3 represents 2-pyridyl.

6. A process as claimed in claim 1 , wherein R 5 and R 6 together with the nitrogen to which they are attached, represent a saturated 6-membered N-containing ring which is fused to an optionally substituted benzene or pyridine ring.

7. A process as claimed in claim 6 , wherein R 5 and R 6 together with the nitrogen to which they are attached represent a group of formula

8. A process as claimed in claim 1 , wherein the reaction is carried out in a polar aprotic solvent.

9. A process as claimed in claim 1 , wherein the reaction is carried out at a temperature in the range 10–30° C.

10. A process as claimed in claim 1 , wherein the reaction is carried out in the presence of a base.

11. A process as claimed in claim 10 , wherein the base is an alkali metal alkoxide or an alkaline earth metal alkoxide.

12. A process as claimed in claim 11 , wherein the base is sodium t-pentoxide.

13. A process for the production of a compound of formula (C), as defined in claim 1 , which comprises reaction of a compound of formula (E),

HNR 5 R 6   (E)

or an acid addition salt thereof,

wherein R 5 and R 6 are as defined in claim 1 , with BrCN in the presence of an amine base.

14. A process as claimed in claim 13 , wherein the amine is N,N-diisopropylethyl amine.

15. A process for the production of a compound of formula (C), as defined in claim 1 , which comprises reaction of a compound of formula (F),

wherein R 5 and R 6 are as defined in claim 1 , with methanesuiphonyl chloride in the presence of pyridine.

16. A process as claimed in claim 13 , wherein the product is N-(2-cyano-1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide.

17. A process for the production of a compound of formula (B),

wherein

R 1 to R 3 are as defined in claim 1 ;

which comprises reaction of a compound of formula (D),

wherein;

R 1 and R 3 are as defined in claim 1 ;

R 9 is a leaving group;

with a pyridyl boronate.

18. A process as claimed in claim 17 , wherein R 9 is iodine.

19. A process as claimed in claim 17 , wherein the pyridine derivative is a 2-pyridyl boronate.

20. A process as claimed in claim 19 , wherein the reaction is carried out in a polar aprotic solvent.

21. A process as claimed in claim 20 , wherein the polar aprotic solvent is tetrahydrofuran.

22. A process as claimed in claim 21 , wherein the reaction is carried out in the presence of a palladium (0) catalyst.

23. A process as claimed in claim 17 , wherein the product is 6-amino-3,4-dimethoxy-2-(2-pyridyl)benzonitrile.

24. A compound of formula (B), as defined in claim 1 .

25. A compound of formula (C), as defined in claim 1 .

26. A process as claimed in claim 1 wherein R 2 represents methoxy and R 3 represents an aromatic ring.

27. A process as claimed in claim 26 wherein R 5 and R 6 together with the nitrogen to which they are attached, represent a saturated 6-membered N-containing ring which is fused to an optionally substituted benzene or pyridine ring.

28. A process as claimed in claim 27 wherein R 3 represents 2-pyridyl and R 5 and R 6 together with the nitrogen to which they are attached, represent a group of formula

29. A process as claimed in claim 28 wherein the reaction is carried out in a polar aprotic solvent at a temperature in the range 10–30° C. and in the presence of a base.

30. A process as claimed in claim 29 wherein the base is an alkali metal alkoxide or alkaline earth metal alkoxide.

31. A process as claimed in claim 22 wherein the product is 6-amino-3,4-dimethoxy-2-(2-pyridyl)benzonitrile.

32. A process as claimed in claim 15 wherein the product is N-(2-cyano-1,2,3,4-tetrahydro-5-isoquinolyl) methanesulfonamide.