Granted Patent B2

US 12,692,266 · App. 19/281,069 · Granted Jul 28, 2026

Inventors: Andrew Thomas Parsons (Cambridge, MA); Brian McNeil Cochran (San Diego, CA); William Powazinik, IV (Thousand Oaks, CA); Marc Anthony Caporini (Belmont, MA)

Assignee: AMGEN INC.

C07D471/04C07C69/76C07C309/24C07B57/00

Abstract

Claims (12)

1 . A process of preparing a compound of Formula (9):

or a pharmaceutically acceptable salt thereof, comprising:

admixing 7-chloro-6-fluoro-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione with POCl 3 and N,N-diisopropylethylamine to form 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, wherein the 7-chloro-6-fluoro-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione is stereoisomerically enriched with 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

2 . The process of claim 1 , comprising admixing 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one with tert-butyl (3S)-3-methylpiperazine-1-carboxylate, and N,N-diisopropylethylamine to form tert-butyl (3S)-4-{7-chloro-6-fluoro-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate.

3 . The process of claim 1 , comprising admixing tert-butyl (3S)-4-{7-chloro-6-fluoro-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate, potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and potassium acetate to form tert-butyl (3S)-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate.

4 . The process of claim 1 , comprising admixing tert-butyl (3S)-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate and trifluoroacetic acid to form 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2S)-2-methylpiperazin-1-yl]-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidin-2(1H)-one.

5 . The process of claim 1 , comprising admixing 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2S)-2-methylpiperazin-1-yl]-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidin-2(1H)-one with acryloyl chloride to form 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(11H)-one.

6 . The process of claim 1 , comprising:

admixing 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one with tert-butyl (3S)-3-methylpiperazine-1-carboxylate, and N,N-diisopropylethylamine to form tert-butyl (3S)-4-{7-chloro-6-fluoro-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate;

admixing tert-butyl (3S)-4-{7-chloro-6-fluoro-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate, potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and potassium acetate to form tert-butyl (3S)-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate;

admixing tert-butyl (3S)-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate and trifluoroacetic acid to form 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2S)-2-methylpiperazin-1-yl]-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidin-2(1H)-one; and

admixing 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2S)-2-methylpiperazin-1-yl]-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidin-2(1H)-one with acryloyl chloride to form 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(11H)-one.

Assignments (1)

Continuity (5)

References Cited (400)