Process for producing 3-acylaminobenzofuran-2-carboxylic acid derivative

1. A process for preparing a compound of the formula [1]:

wherein X is a group of the formula: —N═ or —CH═; R 1 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cyano group or an amino group optionally substituted by a lower alkyl group; Ring A is a nitrogen-containing heterocyclic group; Ring B is an optionally substituted benzene ring or an optionally substituted pyridine ring; and R 3 is a hydrogen atom or a lower alkyl group, or a pharmaceutically acceptable salt thereof, which comprises:

(A)

1)-a) reacting a compound of the formula [II]:

wherein R 0 is a hydrogen atom or a lower alkyl group and X 1 is a leaving group with a compound of the formula [III]:

wherein Ring A is a nitrogen-containing heterocyclic group, or

1)-b) reacting a compound of the formula [IV]:

wherein the symbol is the same a defined above with a compound of the formula [V]:

wherein A′ is a group derived from a nitrogen-containing heterocyclic group with a nitrogen atom, removed, and X 2 and X 3 are leaving groups;

2) subjecting the resulting compound of the formula [VI]:

wherein the symbols are the same as defined above to catalytic reduction;

3) subjecting the resulting the compound of the formula [VII]:

wherein the symbols are the same as defined above to lower-alkyl esterification when COOR 0 is a carboxyl group, followed by isomerization to give a trans-form compound of the formula [VIII]:

wherein R 00 is a hydrogen atom or a lower alkyl group and the other symbol is the same as defined above; and separately,

(B)

1) cyanation of a compound of the formula [IX]:

wherein Ring B is an optionally substituted benzene ring or an optionally substituted pyridine ring and X 4 is a leaving group,

2) reacting the resulting compound of the formula [X]:

wherein the symbol is the same as defined above with a compound of the formula [XI]:

X 5 —CH 2 COOR 7

wherein R 7 is a hydrogen atom or a lower alkyl residue selected from a group consisting of methyl residue and ethyl residue and X 5 is a leaving group,

converting said lower alkyl residue to a hydrogen atom when R 7 is a lower alkyl residue,

and reacting the resulting compound of the formula [XII]:

wherein the symbols are the same as defined above with a compound of the formula [XIII]:

wherein R 3 is a hydrogen atom or a lower alkyl group, R 1 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cyano group or an amino group optionally substituted by a lower alkyl group and X is a formula: —N═ or —CH═,

3) cyclizing the resulting compound of the formula [XIV]:

wherein the symbols are the same as defined above to give a compound of the formula [XV]:

wherein the symbols are the same as defined above; and

(C)

reacting a compound of the formula [XV] with a compound of the formula [VIII] or an acid halide thereof; and

wherein each of the leaving groups of X 1 -X 5 includes a halogen atom and sulfonic acid ester residues selected from the group consisting of an arylsulfonyloxy group, a lower-alkylsulfonyloxy group and a perhalogenolower-alkylsulfonyloxy group.

2. The process according to claim 1 , wherein the reaction between the compound of the formula [II] and the compound of the formula [III] is carried out under nitrogen in the presence of a catalyst, a ligand and a base in an inert solvent.

3. The process according to claim 2 , wherein the catalyst includes homogeneous and heterogeneous catalysts.

4. The process according to claim 3 , wherein the homogenous catalyst includes palladium acetate and the heterogeneous catalyst includes a group VIII metal compound supported by a solid phase.

5. The process according to claim 2 , wherein the ligand includes diphenylphosphino compounds selected from the group of consisting of 2.2′-bis(diphenylphosphino)-1,1′-binaphthyl and 1,1′-bis(diphenylphosphino)ferrocene, triphenylphosphines.

6. The process according to claim 2 , wherein the base includes an inorganic base and an organic base.

7. The process according to claim 2 , wherein the palladium catalyst is used in an amount of approximately 0.001-0.1 equivalent, the ligand is used in an amount of approximately 0.002-0.2 equivalent, and the base is used in an amount of approximately 1-2 equivalent in relation to the compound of the formula [II].

8. The process according to claim 2 , wherein the reaction is carried out at 0° C.-200° C.

9. The process according to claim 1 , wherein the reaction between the compound of the formula [IV] and the compound of the formula [V] is carried out in the presence of a base in an inert solvent.

10. The process according to claim 9 , wherein the base is used in an amount of approximately 2-10 equivalent in relation to the compound of the formula [IV].

11. The process according to claim 9 , wherein the reaction is carried out at 0° C.-30° C.

12. The process according to claim 1 , wherein the catalytic reduction of the compound of the formula [VI] is carried out in the presence of a catalyst under hydrogen pressure in an inert solvent.

13. The process according to claim 12 , wherein the hydrogen pressure ranges from 7 to 30 atm.

14. The process according to claim 12 , wherein the catalyst includes a rhodium-carbon, and is used in an amount of approximately 0.01-0.1 equivalent in relation to the compound of the formula [VI].

15. The process according to claim 12 , wherein the reaction is carried out at −20 C.-120° C.

16. The process according to claim 1 , wherein the catalytic is carried out under a condition of pH 7-8.

17. The process according to claim 1 , wherein the lower-alkyl esterification of the compound of the formula [VII] is carried out by treating the compound with a lower alkanol in an acid condition in an inert solvent.

18. The process according to claim 1 , wherein the isomerization of the compound [VII] is carried out in the presence of a base in an appropriate solvent.

19. The process according to claim 18 , wherein the base includes alkali metal alkoxides and alkali metal amides, and the solvent includes an inert solvent.

20. The process according to claim 19 , wherein the base is used in an amount of approximately 1-2 equivalent in relation to the compound of the formula [VII].

21. The process according to claim 18 , wherein the isomerization reaction is carried out at −20° C.-150° C.

22. The process according to claim 1 , wherein the cyanation of the compound of the formula [IX] is carried out by treating the compound with a cyanizing agent in the presence of a catalyst, zinc and a ligand.

23. The process according to claim 22 , wherein the cyanizing agent includes zinc cyanide, copper cyanide, potassium cyanide, sodium cyanide, and acetone cyanohydrin.

24. The process according to claim 1 , wherein the reaction between the compound of the formula [X] and the compound of the formula [XI] is carried out in the presence of a halogenating agent and a base in an inert solvent.

25. The process according to claim 24 , wherein the reaction is carried out at 0° C.-60° C.

26. The process according to claim 1 , wherein the reaction between the compound of the formula [XII] and the compound of the formula [XIII] is carried out in the presence of a halogenating agent and a base in an inert solvent.

27. The process according to claim 1 , wherein the cyclization of the compound of the formula [XIV] is carried out in the presence of a base in an inert solvent.

28. The process according to claim 27 , wherein the base is used in an amount of approximately 0.05-2.2 equivalent in relation to the compound of the formula [XIV].

29. The process according to claim 27 , wherein the reaction is carried out at 0° C.-100° C.

30. The process according to claim 1 , wherein the reaction between the compound of the formula [XV] and the compound of the formula [VIII] or an acid halide thereof is carried out in the presence of a base in an inert solvent.

31. The process according to claim 30 , wherein the reaction is carried out at 15° C.-25° C.