Process for the preparation of caprolactam CGRP antagonist

1. A process for the preparation of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one, said process comprising the steps of:

(1) hydrogenating a (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium salt, in the presence of a cis-selective catalyst, to form a (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium salt; and

(2) reacting the (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium salt with R 3 N, wherein each R is independently C 1-4 alkyl, and a hydroxyl nitrobenzaldehyde.

2. A process for the preparation of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one hydrochloride, said process comprising the steps of:

(1) hydrogenating a (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium salt, in the presence of a cis-selective catalyst, to form a (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium salt;

(2) reacting the (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium salt with R 3 N, wherein each R is independently C 1-4 alkyl, and a hydroxyl nitrobenzaldehyde, to form (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one; and

(3) reacting (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one with HCl.

3. A process for the preparation of the intermediate (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one, comprising the steps of:

(1) reacting 3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3,4,7-tetrahydro-2H-azepin-2-one with 2-hydroxy-5-nitrobenzaldehyde and a chiral acid to form an (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium salt;

(2) hydrogenating a (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium salt, in the presence of a cis-selective catalyst, to form a (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium salt; and,

(3) reacting the (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium salt with R 3 N, wherein each R is independently C 1-4 alkyl, and a hydroxyl nitrobenzaldehyde, to form (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one.

4. A process for the preparation of the intermediate (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one hydrochloride, comprising the steps of:

(1) reacting 3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3,4,7-tetrahydro-2H-azepin-2-one with 2-hydroxy-5-nitrobenzaldehyde and ditoluoyl-L-tartaric acid to form an (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium salt;

(2) hydrogenating (3S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,7-tetrahydro-1H-azepin-3-ammonium di-toluoyl tartrate salt, in the presence of a cis-selective palladium catalyst, to form (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium di-toluoyl tartrate salt;

(3) reacting (3S,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ammonium di-toluoyl tartrate salt with Et 3 N and 2-hydroxy-5-nitrobenzaldehyde to form (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one; and

(4) reacting (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one with HCl.

5. The process of claim 1 , wherein the ammonium salt of claim 1 , steps (1) and (2) is a di-toluoyl tartrate salt.

6. The process of claim 1 , wherein the cis-selective catalyst of claim 1 , step (1) is a cis-selective palladium catalyst.

7. The process of claim 1 , wherein each R group of step (2) is ethyl.

8. The process of claim 2 , wherein the ammonium salt of claim 1 , steps (1) and (2) is a di-toluoyl tartrate salt.

9. The process of claim 2 , wherein the cis-selective catalyst of claim 1 , step (1) is a palladium catalyst.

10. The process of claim 2 , wherein each R group of step (2) is ethyl.

11. The process of claim 3 , wherein the chiral acid of step (1) is di-toluoyl-L-tartaria acid and the ammonium salt of steps (1) and (2) is a di-toluoyl tartrate salt.

12. The process of claim 3 , wherein the cis-selective catalyst of claim 1 , step (1) is a cis-selective palladium catalyst.

13. The process of claim 3 , wherein each R group of step (3) is ethyl.

14. The process of claim 3 , further comprising the step of

(4) reacting (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one with HCl to form (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one hydrochloride.