Processes for preparing benzimidazole thiophenes

1. A process for preparing a compound of formula (X):

wherein:

R 3 is F, Cl, Br, alkyl or haloalkyl;

R 10 is H or alkyl;

or a pharmaceutically acceptable salt thereof;

comprising the steps of:

a) reacting 3-bromo-5-nitrobenzaldehyde:

with an amine of formula:

to prepare a compound of formula (III-a) or a salt thereof:

b) cross-coupling the compound of formula (III-a) or a salt thereof with a compound of formula (IV-a) or a salt thereof:

c) in the presence of a palladium catalyst to prepare a compound of formula (V-a) or a salt thereof:

d) reducing the compound of formula (V-a) or a salt thereof to prepare a compound of formula (VI-a) or a salt thereof:

e) cyclizing the compound of formula (VI-a) or a salt thereof in the presence of an orthoester and an acid catalyst to prepare a compound of formula (IX) or a salt thereof:

 and

f) converting the ester compound of formula (IX), or salt thereof to the amide compound of formula (X).

2. A process for preparing 5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide:

said process comprising the steps of:

a) reacting 3-bromo-5-nitrobenzaldehyde:

 with N-methyl piperazine:

 to prepare 1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine or a salt thereof:

b) cross-coupling 1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine or a salt thereof with methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate or a salt thereof:

in the presence of a palladium catalyst to prepare methyl 5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate or a salt thereof:

c) reducing methyl 5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate or a salt thereof to prepare methyl 5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate or a salt thereof:

d) cyclizing methyl 5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate or a salt thereof to prepare methyl 5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate or a salt thereof:

 and

e) reacting methyl 5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate or a salt thereof with formamide and a base to prepare 5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide.

3. The process according to claim 2 , wherein said steps c) of reducing and d) of cyclizing are combined.

4. The process according to claim 2 , wherein:

said step a) comprises preparing 1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine HCl;

said step b) comprises cross-coupling 1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine HCl with methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate or a salt thereof in the presence of a palladium catalyst to prepare methyl 5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate HCl;

said step c) comprises reducing methyl 5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate HCl to prepare methyl 5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate HCl;

said step d) comprises cyclizing methyl 5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate HCl to prepare methyl 5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate HCl; and

said step e) comprises reacting methyl 5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate HCl with formamide and sodium methoxide to prepare 5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide.