Process for preparing Substituted Indole Compounds

Patent metadata

Field	Value
Publication number	US-10131674-B2
Application number	US-201515524872-A
Country	US
Kind code	B2
Filing date	Nov 5, 2015
Priority date	Nov 6, 2014
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

The present invention is directed to a process for preparing Substituted Indole Compounds of Formula (I): wherein R 1 , R 2 , R 3 and R 4 are as defined herein. These indole compounds are useful as synthetic intermediates for making inhibitors of HCV NS5A.

First claim

What is claimed is:

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

wherein said process comprises the steps:
(A) preparing a solution, wherein said solution comprises: (a) compound of Formula (i):

(b) a photocatalyst, selected from fac-Ir(ppy) 3 , fac-Ir(dF-ppy) 3 , Ir(ppy) 2 (dtbpy), [Ir(dF-CF 3 -ppy) 2 (dtbpy)(PF 6 ), Ir(ppy) 3 , Ir(dF-CF 3 -ppy) 2 (dtbpy), [Ru(bpm) 3 ]Cl 2 , [Ru(bpy) 3 ]Cl 2 , [Ru(bpz) 3 ]Cl 2 and [Ru(phen)]Cl 2 , or a salt thereof, (c) an oxidizing agent, selected from an organic peroxyester, and (d) an organic solvent, selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide;
(B) exposing the solution of Step A to light having a wavelength in the UV/Visible spectrum, for a time and at a temperature sufficient to provide a compound of formula (I),

wherein:
R 1 represents up to 4 optional benzene ring substituents, which can be the same or different, and are each selected from C 1 -C 6 alkyl, halo, —OTf, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl;
R 2 is H or halo;
R 3 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl, 4 to 7-membered monocyclic heterocycloalkyl and 8 to 12-membered bicyclic heterocycloalkyl, wherein said C 3 -C 7 cycloalkyl group, said C 6 -C 10 aryl group, said 5 or 6-membered monocyclic heteroaryl group, said 9 or 10-membered bicyclic heteroaryl group, said 4 to 7-membered monocyclic heterocycloalkyl group and 8 to 12-membered bicyclic heterocycloalkyl group can be optionally substituted with one or more R 5 groups, which can be the same or different;
R 4 is selected from H, C 1 -C 6 alkyl and C(O)—(C 1 -C 6 alkyl), or when R 3 is phenyl, R 4 can be a group having the formula CH(R 6 )—O—, wherein the oxygen atom of the group of formula —CH(R 6 )—O— is attached to a meta carbon atom of said R 3 phenyl group;
each occurrence of R 5 is independently selected from C 1 -C 6 alkyl, halo, —OTf, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —CN, —O—(C 1 -C 6 alkyl), —O—(C 6 -C 10 aryl), —O—(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —N(R 8 ) 2 , —S—(C 1 -C 6 alkyl), —S(O) 2 —(C 1 -C 6 alkyl), —NHS(O) 2 —(C 1 -C 6 alkyl), —OC(O)R 7 , —C(O)OR 7 , —C(O)R 7 , —C(O)N(R 8 ) 2 , and —NHC(O)R 7 ;
R 6 is selected from C 1 -C 6 alkyl, phenyl and 5 or 6-membered heteroaryl, wherein said heteroaryl group can be optionally substituted with C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl;
each occurrence of R 7 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl and 5 or 6-membered monocyclic heteroaryl; and
each occurrence of R 8 is independently selected from H and C 1 -C 6 alkyl.

2. The process of claim 1 , wherein the organic peroxyester is tert-butyl peroxybenzoate.

3. The process of claim 1 , wherein in Step B, the UV-visible light has a wavelength of from 350 nm to 500 nm.

4. The process of claim 1 , wherein in Step B, the solution is exposed to the UV-visible light for a time period of from 10 minutes to 2 hours.

5. The process of claim 1 , wherein in Step B, the solution is exposed to the UV-visible light for a time period of from 30 minutes to 1 hour.

6. The process of claim 1 , wherein the solution of Step A is maintained at a temperature of from −20° C. to 25° C. throughout the entirety of Step B.

7. The process of claim 1 , wherein for the compounds of formulas (i) and (I), R 1 is halo.

8. The process of claim 1 , wherein for the compounds of formulas (i) and (I), R 2 is H.

9. The process of claim 1 , wherein for the compounds of formulas (i) and (I), R 3 is phenyl and R 4 is —CH(R 6 )—O—, wherein the oxygen atom of the group of formula —CH(R 6 )—O— is attached to a meta carbon atom of said phenyl group.

10. The process of claim 1 , wherein for the compounds of formulas (i) and (I), R 4 is selected from H, C 1 -C 6 alkyl and —C(O)—(C 1 -C 6 alkyl).

11. The process of claim 1 , wherein the compound of formula (i) has the formula (i′):

and the compound of formula (I) has the formula (I′):

wherein R 1 and R 5b are each halo, R 5a is H or F, and R a is phenyl or 5 or 6-membered heteroaryl, wherein said heteroaryl group is optionally substituted with C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl.

12. The process of claim 11 , wherein R 1 and R 5b are each Br, R 5a is H, and R a is phenyl.

13. The process of claim 11 , wherein R 1 and R 5b are each Br, R 5a is F, and R a is thiazolyl, optionally substituted with a cyclopropyl group.

Assignees

• Merck Sharp & Dohme

Inventors

• Dirocco Daniel A
• Davies Ian
• Peng Feng
• Mclaughlin Mark
• Campeau Louis-Charles
• Xu Yingju

Classifications

• B01J31/181

  Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• B01J2231/766

  of -CH-CH- or -C=C- to -C=C- or -C-C- triple bond species · CPC title

• B01J35/004

  Operations & Transport · mapped topic

• B01J2531/827

  Iridium · CPC title