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US 2017/0233382 A1Published application
Processes for the preparation of a bace inhibitor
AssigneeMerck Sharp & Dohme Corp.
InventorsSteven P. Miller, Carmela Molinaro, David Thaisrivongs, Feng Xu, Richard Desmond, Hongming Li, Qinghao Chen, Andrew W. Stamford, Zhiguo Jake Song, Lushi Tan
Life of this patent
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Abstract
This invention provides processes for the preparation of verubecestat (Compound of Formula (I)), a potent inhibitor of BACE-1 and BACE-2. In addition, the invention provides certain synthetic intermediates which are useful, among other things, for the preparation of the Compound of Formula (I).
Claims32
A process for the preparation of a compound of Formula (I):
- comprising reacting amine of the Formula (7):
- with a cyanating agent to form the compound of Formula (I).
A process for preparing an amine of Formula (7):
- comprising reacting a PG-protected sulfonamide of Formula (6):
- wherein
- R1 is
- C1-C6 alkyl;
- or
- phenyl, wherein the phenyl is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, —O—C1-C4 haloalkyl, halo, and nitro;
- and
- PG is a protecting group;
- with trifluoroacetic acid or methane sulfonic acid to form the amine (7).
6 more elements
A process preparing a PG-protected sulfonamide of Formula (6):
- wherein
- R1 is
- C1-C6 alkyl;
- or
- phenyl, wherein the phenyl is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, —O—C1-C4 haloalkyl, halo, and nitro;
- and
- PG is a protecting group;
- comprising coupling
- an aryl fluoride of Formula (4)
- wherein
- R1 is
- C1-C6 alkyl;
- or
- phenyl, wherein the phenyl is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, —O—C1-C4 haloalkyl, halo, and nitro;
- R2 is:
- halo, selected from the group consisting of bromo, chloro and iodo;
- a group of the formula —O—S(O)2—R2a, wherein R2a is methyl, chloromethyl, dichloromethyl, phenyl, p-trifluoromethylbenzyl, p-toluenyl, p-bromophenyl, p-fluorophenyl, p-methoxyphenyl, 2-nitrophenyl, 4-nitrophenyl, and 2,4-dichlorophenyl;
- or
- a diazonium group;
- and
- PG is a protecting group;
- with 5-fluoropicolinamide in the presence of a copper or palladium reagent;
- a ligand;
- and a Brønsted base to form the PG-protected sulfonamide (6).
21 more elements
A compound according to the Formula (7):
A compound according to the Formula (6):
- or a salt thereof, wherein:
- R1 is C1-C6 alkyl;
- or phenyl, wherein the phenyl is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, —O—C1-C4 haloalkyl, halo, and nitro;
- and PG is a protecting group.
1 more element
A compound according to Formula (6A):
- wherein PG is a protecting group.
A salt according to Formula (7A):
- wherein A{circle around (−)} is a salt of:
- L-tartaric acid, L-(+)-mandelic acid, L-(−)-malic acid, (1S)-(+)-10-camphorsulfonic acid, (−)-di-O,O-p-toluyl-L-tartaric acid, (−)-O,O-dibenzoyl-L-tartaric acid, (+)-camphoric acid, L-pyroglutamic acid, (1S)-(−)-camphanic acid, L-valine, (1S)-(+)-3-bromocamphor-10-sulfonic acid hydrate, L-histidine, D-tartaric acid, D-(−)-mandelic acid, D-(+)-malic acid, (1R)-(−)-10-camphorsulfonic acid, (+)-Di-O,O-p-toluyl-D-tartaric acid, (+)-O,O-dibenzoyl-D-tartaric acid, (−)-camphoric acid, D-pyroglutamic acid, (1R)-(+)-camphanic acid, D-valine, (+)-naproxen, or L-isoleucine.
A compound of Formula (4):
- wherein
- R1 is:
- C1-C6 alkyl;
- or
- phenyl, wherein the phenyl is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, —O—C1-C4 haloalkyl, halo, and nitro;
- R2 is:
- halo, selected from the group consisting of bromo, chloro and iodo;
- a group of the formula —O—S(O)2—R2a, wherein R2a is methyl, chloromethyl, dichloromethyl, phenyl, p-trifluoromethylbenzyl, p-toluenyl, p-bromophenyl, p-fluorophenyl, p-methoxyphenyl, 2-nitrophenyl, 4-nitrophenyl, and 2,4-dichlorophenyl;
- or
- a diazonium group;
- and
- PG is a protecting group.
9 more elements
A compound of Formula (4A):
- wherein
- R2 is:
- halo, selected from the group consisting of bromo, chloro and iodo;
- a group of the formula —O—S(O)2—R2a, wherein R2a is methyl, chloromethyl, dichloromethyl, phenyl, p-trifluoromethylbenzyl, p-toluenyl, p-bromophenyl, p-fluorophenyl, p-methoxyphenyl, 2-nitrophenyl, 4-nitrophenyl, and 2,4-dichlorophenyl;
- or
- a diazonium group;
- and
- PG is a protecting group.
5 more elements
A compound of Formula (8):
- wherein R1 is C1-C6 alkyl;
- or phenyl, wherein the phenyl is unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, —O—C1-C4 haloalkyl, halo, and nitro.
A compound of Formula (5):
A compound of Formula (9):
- wherein R2 is:
- a group of the formula —O—S(O)2—R2a, wherein R2a is methyl, chloromethyl, dichloromethyl, phenyl, p-trifluoromethylbenzyl, p-toluenyl, p-bromophenyl, p-fluorophenyl, p-methoxyphenyl, 2-nitrophenyl, 4-nitrophenyl, and 2,4-dichlorophenyl;
- or
- a diazonium group.
1 more element
Dependencies are inferred from the claim text.