Method for producing benzimidazole derivative

Patent metadata

Field	Value
Publication number	US-11242332-B2
Application number	US-201816494137-A
Country	US
Kind code	B2
Filing date	Mar 14, 2018
Priority date	Mar 15, 2017
Publication date	Feb 8, 2022
Grant date	Feb 8, 2022

Abstract

The present invention relates to a process to prepare a benzimidazole derivative useful as a medicament, an intermediate for preparing the medicament, and a process to prepare the intermediate.

First claim

The invention claimed is:

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 a

Assignees

• Sumitomo Dainippon Pharma Co Ltd

Inventors

• Mizushima Shingo
• Lee Shoukou
• Takahashi Yoko

Classifications

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• B01J31/04

  containing carboxylic acids or their salts {(B01J31/0277 - B01J31/0298 take precedence; multi-metal carboxylate complexes like Pd (II) acetate, i.e. Pd3 (OAc) 6 or Cr(II)acetate, i.e. Cr2(OAc)4 B01J31/2226)} · CPC title

• B01J23/44

  Palladium · CPC title

• C07D213/64

  attached in position 2 or 6 · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title