Method for producing benzimidazole derivative

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

or a pharmaceutically acceptable salt thereof, wherein

each R 1 is independently halogen, cyano, C 1-6 alkyl, or C 1-6 alkoxy, wherein the alkyl and the alkoxy may be optionally substituted with 1 to 5 independently selected halogen atoms;

n is 0, 1, 2, or 3;

R 2 and R 3 are independently hydrogen; C 1-6 alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of cyano, halogen, and hydroxy; or C 3-10 cycloalkyl;

R 4 is hydrogen; C 1-6 alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of cyano, halogen, and hydroxy; or C 3-10 cycloalkyl;

R 5 is C 6-10 aryl or 5- to 12-membered heteroaryl, wherein the aryl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen; C 1-4 alkyl which may be optionally substituted with 1 to 5 independently selected halogen atoms; and C 1-4 alkoxy which may be optionally substituted with 1 to 5 independently selected halogen atoms;

m is 1, 2, or 3; and

R 6 and R 7 are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, and C 3-7 cycloalkoxy, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, and C 3-7 cycloalkoxy may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen and hydroxy,

comprising reducing a compound of formula (2):

wherein the reduction is carried out with (i) an oxide-layer remover; and (ii) a reducing metal, a reducing metal salt, or a mixture of a reducing metal and a reducing metal salt; and

wherein the oxide-layer remover is lithium bromide, lithium chloride, or chlorotrimethylsilane; and

cyclizing the reduced product with a formate equivalent.

2. The process of claim 1 , further comprising a step of preparing the compound of formula (2) which comprises reacting a compound of formula (3):

wherein X 1 is hydroxy, halogen, alkylsulfonyloxy, or arylsulfonyloxy,

with a compound of (4):

and then

with R 5 —X 2 , wherein X 2 is halogen.

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

or a pharmaceutically acceptable salt thereof, wherein

each R 1 is independently halogen, cyano, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl and the C 1-6 alkoxy may be optionally substituted with 1 to 5 independently selected halogen atoms;

n is 0, 1, 2, or 3;

R 2 and R 3 are each independently hydrogen; C 1-6 alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of cyano, halogen, and hydroxy; or C 3-10 cycloalkyl;

R 4 is hydrogen; C 1-6 alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of cyano, halogen, and hydroxy; or C 3-10 cycloalkyl;

R 5 is C 6-10 aryl or 5- to 12-membered heteroaryl, wherein the aryl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen; C 1-4 alkyl which may be optionally substituted with 1 to 5 independently selected halogen atoms; and C 1-4 alkoxy which may be optionally substituted with 1 to 5 independently selected halogen atoms;

m is 1, 2, or 3; and

R 6 and R 7 are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, and C 3-7 cycloalkoxy, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, and C 3-7 cycloalkoxy may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen and hydroxy, comprising reacting a compound of formula (3):

wherein X 1 is hydroxy, halogen, alkylsulfonyloxy, or arylsulfonyloxy,

with a compound of (4):

and then

with R 5 —X 2 wherein X 2 is halogen, to prepare a compound of formula (2):

reducing the compound of formula (2), wherein the reduction is carried out (i) with an oxide-layer remover; and (ii) a reducing metal, a reducing metal salt, or a mixture of a reducing metal and a reducing metal salt and wherein the oxide-layer remover is lithium bromide, lithium chloride, or chlorotrimethylsilane; and cyclizing the reduced product with a formate equivalent to prepare the compound of formula (1).

4. The process of claim 1 , wherein the compound of formula (1) is a compound of formula (1′):

5. The process of claim 2 , wherein

n is 0;

R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;

R 4 is hydrogen or C 1-6 alkyl;

R 5 is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen; C 1-4 alkyl which may be optionally substituted with 1 to 5 independently selected halogen atoms; and C 1-4 alkoxy which may be optionally substituted with 1 to 5 independently selected halogen atoms;

m is 1;

R 6 and R 7 are independently hydrogen, deuterium, or C 1-4 alkyl;

X 1 is halogen; and

X 2 is fluorine or bromine.

6. The process of claim 1 , wherein

R 5 is pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl, wherein the pyridyl, the pyrazinyl, the pyrimidinyl, and the pyridazinyl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen; C 1-4 alkyl which may be optionally substituted with 1 to 5 independently selected halogen atoms; and C 1-4 alkoxy which may be optionally substituted with 1 to 5 independently selected halogen atoms.

7. The process of claim 1 , wherein the reduction reaction is carried out with a reducing metal.

8. The process of claim 7 , wherein the reducing metal is zinc or iron.

9. The process of claim 1 , wherein the reduction reaction is carried out with a catalyst for catalytic reduction under hydrogen atmosphere.

10. The process of claim 9 , wherein the catalyst for catalytic reduction is palladium-carbon or platinum sulfide on carbon.

11. The process of claim 1 , wherein the reduction reaction is carried out in the presence of an acid.

12. The process of claim 1 , wherein the formate equivalent is one or more selected from the group consisting of orthoformate triester, formic acid ester, and formate.

13. The process of claim 12 , wherein the formate equivalent is orthoformate triester.

14. The process of claim 1 , wherein the reduction and the cyclization are carried out in a one-pot reaction.

15. The process of claim 1 , wherein in the reduction and the cyclization, the nitro is reduced, followed by adding an acid and a formate equivalent to make cyclization.

16. The process of claim 1 , wherein in the reduction and the cyclization, the nitro is reduced in the presence of an acid and a formate equivalent to make cyclization in the reaction system after the reduction.

17. The process of claim 11 , wherein the acid is formic acid.