2-Bromopyrimidine-4-carbonitrile

Preparation of (3S)-tert-butyI 3-((l-(2-chIorophenyl)-2-((3, 3- difluorocyclobutyl) amino)-2-oxoethyl)(3, 5-difluorophenyl)carbamoyl)-4-(4- cyanopyrimid -2-yl)-5-oxopiperazine-l-carboxylate (racemic) - Compound 98 A mixture of (3S)-tert-butyl3-((l -(2-chlorophenyl)-2-((3, 3-difluorocyclobutyl)amino)-2-oxoethyl) (3, 5-difluorophenyl)carbamoyl)-5-oxopiperazine-l-carboxylate (200 mg, 0.326 mmol), 2- bromopyrimidine-4-carbonitrile (0.489 mmol), Pd2(dba)3 (30.2 mg, 0.0323 mmol), XantPhos (19.1 mg, 0.03 mmol) and Cs2C03 (148.7 mg, 0.46 mmol) in 1, 4-dioxane (10 mL) was stirred at 80 C for 3 hr under N2. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by a standard method to afford the desired product. NMR (400 MHz, CDC13): delta 8.97 (d, J= 4.3 Hz, 1H), 7.85-7.55 (d, 1H), 7.51-7.39 (m, 2H), 7.25 (t, J= 7.6 Hz, 1H), 7.13-6.26 (m, 6H), 5.91 (d, J= 7.6 Hz, 1H), 4.92-4.08 (m, 5H), 3.38 (t, J= 14.9 Hz, 1H), 3.02 (s, 2H), 2.83-2.22 (d, 2H), 1.61 (s, 9H). MS : 716.1 (M+l)+.Step B: 2-Bromopyrimidine-4-carbonitrile A mixture of 2-hydroxy-4-carboxyaldehyde oxime (9 g, 28.8 mmol), tetrabutyl ammonium bromide (10 g, 71.9 mmol) and phosphorus pentoxide (2 g, 14.4 mmol) in toluene (300 mL) was stirred at 120 C. for 2 h. The resulting mixture was filtered and the filtrate was concentrated. The resulting residue was purified by column chromatography to give the desired compound as a yellow solid. 1H NMR (400 MHz, CDCl3): delta 8.82 (d, J=4.8 Hz, 1H), 7.66 (d, J=4.8 Hz, 1H). MS: 185.0 (M+1)+.General procedure: Preparation of (3S)-tert-butyl 3-((l-(2-chlorophenyl)-2-((3, 3- difluorocyclobutyl) amino)-2-oxoethyl)(3, 5-difluorophenyl)carbamoyl)-4-(4- cyanopyrimidin-2-yl)-5-oxopiperazine-l-carboxylate (racemic) - Compound 98 A mixture of (3S)-tert-butyl3-((l-(2-chlorophenyl)-2-((3, 3-difluorocyclobutyl)amino)-2-oxoethyl) (3, 5-difluorophenyl)carbamoyl)-5-oxopiperazine-l-carboxylate (200 mg, 0.326 mmol), 2- bromopyrimidine-4-carbonitrile (0.489 mmol), Pd2(dba)3 (30.2 mg, 0.0323 mmol), XantPhos (19.1 mg, 0.03 mmol) and Cs2C03 (148.7 mg, 0.46 mmol) in 1 , 4-dioxane (10 mL) was stirred at 80 C for 3 hr under N2. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by a standard method to afford the desired product. 1H NMR (400 MHz, CDC13): delta 8.97 (d, J = 4.3 Hz, 1H), 7.85-7.55 (d, 1H), 7.51-7.39 (m, 2H), 7.25 (t, J= 7.6 Hz, 1H), 7.13-6.26 (m, 6H), 5.91 (d, J= 7.6 Hz, 1H), 4.92-4.08 (m, 5H), 3.38 (t, J= 14.9 Hz, 1H), 3.02 (s, 2H), 2.83-2.22 (d, 2H), 1.61 (s, 9H). MS : 716.1 (M+l)+.A mixture of (3 S)-tert-butyl3 -((1 -(2-chlorophenyl)-2-((3 , 3 -difluorocyclobutyl)amino)-2-oxoethyl) (3, 5 -difluorophenyl)carbamoyl)-5 -oxopiperazine-1 -carboxylate(200 mg, 0.326 mmol), 2- bromopyrimidine-4-carbonitrile (0.489 mmol), Pd2(dba)3 (30.2 mg, 0.0323 mmol), XantPhos (19.1 mg, 0.03 mmol) and Cs2CO3 (148.7 mg, 0.46 mmol) in 1, 4-dioxane (10 mL)was stirred at 80C for 3 hr under N2. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified bya standard method to afford the desired product. 'H NMR (400 MHz, CDC13): 8.97 (d, J= 4.3 Hz, 1H), 7.85-7.55 (d, 1H), 7.51-7.39 (m, 2H), 7.25 (t, J= 7.6 Hz, 1H), 7.13-6.26 (m, 6H), 5.91 (d, J= 7.6 Hz, 1H), 4.92-4.08 (m, 5H), 3.38 (t, J= 14.9 Hz, 1H), 3.02 (s, 2H), 2.83-2.22 (d, 2H), 1.61 (s, 9H). MS : 716.1 (M+1).Step B: 2-Bromopyrimidine-4-carbonitrile. A mixture of 2-hydroxy-4-carboxyaldehyde oxime (9 g, 28.8 mmol), tetrabutyl ammonium bromide (10 g, 71.9 mmol) and phosphorus pentoxide (2 g, 14.4 mmol) in toluene (300 mL) was stirred at 120 C for 2 h. The resulting mixture was filtered and the filtrate was concentrated. The resulting residue was purified by column chromatography to give the desired compound as a yellow solid. FontWeight='Bold' FontSize='10' H NMR (400 MHz, CDC13): delta 8.82 (d, J= 4.8 Hz, 1H), 7.66 (d, J= 4.8 Hz, 1H). MS: 185.0 (M+l)+.A mixture of 2-hydroxy-4-carboxyaldehyde oxime (9 g, 28.8 mmol), tetrabutyl ammonium bromide (10 g, 71.9 mmol) and phosphorus pentoxide (2 g, 14.4 mmol) in toluene (300 mL) was stirred at 120 C for 2 h. The resulting mixture was filtered and the filtrate was concentrated. The resulting residuewas purified by column chromatographyto give the desired compound as a yellow solid. 'H NMR (400 MFTz, CDC13): 8.82 (d, J= 4.8 Hz, 1H), 7.66 (d, J= 4.8 Hz, 1H). MS: 185.0 (M+1).Step B: 2-Bromopyrimidine-4-carbonitrile. A mixture of 2-hydroxy-4-carboxyaldehyde oxime (9 g, 28.8 mmol), tetrabutyl ammonium bromide ( 10 g, 71 .9 mmol) and phosphorus pentoxide (2 g, 14.4 mmol) in toluene (300 mL) was stirred at 120 C for 2 h. The resulting mixture was filtered and the filtrate was concentrated. The resulting residue was purified by column chromatography to give the desired compound as a yellow solid. NMR (400 MHz, CDC13): delta 8.82 (d, J = 4.8 Hz, 1 H), 7.66 (d, J = 4.8 Hz, 1 H). MS: 185.0 (M+l )+.Step B: 2-Bromopyrimidine-4-carbonitrile A mixture of 2-hydroxy-4-carboxyaldehyde oxime (9 g, 28.8 mmol), tetrabutyl ammonium bromide (10 g, 71.9 mmol) and phosphorus pentoxide (2 g, 14.4 mmol) in toluene (300 mL) was stirred at 120 C. for 2 h. The resulting mixture was filtered and the filtrate was concentrated. The resulting residue was purified by column chromatography to give the desired compound as a yellow solid. 1H NMR (400 MHz, CDCl3): delta 8.82 (d, J=4.8 Hz, 1H), 7.66 (d, J=4.8 Hz, 1H). MS: 185.0 (M+1)+.Preparation of (3S)-tert-butyl 3-((1-(2-chlorophenyl)-2-((3, 3-difluorocyclobutyl)amino)-2-oxoethyl)(3, 5-difluorophenyl)carbamoyl)-4-(4-cyanopyrimidin-2-yl)-5-oxopiperazine-1-carboxylate (racemic)-Compound 98 A mixture of (3S)-tert-butyl3-((1-(2-chlorophenyl)-2-((3, 3-difluorocyclobutyl)amino)-2-oxoethyl)(3, 5-difluorophenyl)carbamoyl)-5-oxopiperazine-1-carboxylate (200 mg, 0.326 mmol), General Procedure for the Preparation of General Procedure for the Preparation of

Molecular Weight:183.99
XLogP3:1.3
Hydrogen Bond Acceptor Count:3
Exact Mass:182.94321
Monoisotopic Mass:182.94321
Topological Polar Surface Area:49.6
Heavy Atom Count:9
Complexity:138
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes