2-amino-3-fluoro-N-methylbenzamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,1′-Carbonyldiimidazole (1.946 g, 12.00 mmol) was added in one portion to 2-amino-3-fluorobenzoic acid (1.551 g, 10 mmol) in THF (25 mL) at room temperature and the resulting suspension stirred for 18 hours. A 2N solution of methylamine in THF (7.50 mL, 15.00 mmol) was added and the resulting solution stirred at room temperature for 1 hour. The mixture was evaporated and the residue dissolved in EtOAc (100 mL). The solution was washed sequentially with water (2×50 mL) and a saturated solution of NaCl (50 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was dissolved in EtOAc (100 mL) and the mixture washed sequentially with a 2M solution of NaOH (50 mL), water (50 mL), and then with a saturated solution of NaCl (50 mL). The organic layer was dried over MgSO4 and then evaporated to afford 2-amino-3-fluoro-N-methylbenzamide (1.349 g, 80% yield); 1H NMR spectrum: (300 MHz, CDCl3) δ 2.91 (3H, d), 5.52 (2H, s), 5.97 (1H, s), 6.49 (1H, td), 6.93-7.04 (2H, m); Mass spectrum: m/z (ESI+) (M+H)+ =169.34. the resulting solution stirred at room temperature for 1 hour The mixture was evaporated the residue dissolved in EtOAc (100 mL) The solution was washed sequentially with water (2×50 mL) The organic layer was dried over MgSO4 evaporated The residue was dissolved in EtOAc (100 mL) the mixture washed sequentially with a 2M solution of NaOH (50 mL), water (50 mL) The organic layer was dried over MgSO4 evaporated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium(II) acetate (35.9 mg, 0.16 mmol) was added to 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (139 mg, 0.24 mmol), cesium carbonate (2604 mg, 7.99 mmol), 2,5-dichloro-4-iodopyridine (1094 mg, 4.00 mmol) and 2-amino-3-fluoro-N-methylbenzamide (672 mg, 4.00 mmol) in dioxane (20 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 24 hours and then allowed to cool to room temperature. The mixture was evaporated and the residue dissolved in EtOAc (150 mL) and then washed sequentially with a saturated solution of NaHCO3 (100 mL), water (100 mL), and then with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were evaporated to afford 2-[(2,5-dichloropyridin-4-yl)amino]-3-fluoro-N-methylbenzamide (624 mg, 50% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1H NMR (300.132 MHz, DMSO) δ 2.74 (3H, d), 6.39 (1H, d), 7.42 (1H, td), 7.49-7.59 (2H, m), 8.25 (1H, s), 8.64 (1H, m), 9.31 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+ =314.20 and 316.20 and 318.17. to cool to room temperature The mixture was evaporated the residue dissolved in EtOAc (150 mL) washed sequentially with a saturated solution of NaHCO3 (100 mL), water (100 mL) The organic layer was dried over MgSO4 evaporated The residue was purified by chromatography on silica eluting with a gradient of 0-100% EtOAc in isohexane Fractions containing product were evaporated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium(II) acetate (35.9 mg, 0.16 mmol) was added to 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (139 mg, 0.24 mmol), cesium carbonate (2604 mg, 7.99 mmol), 2,5-dichloro-4-iodopyridine (1094 mg, 4.00 mmol) and 2-amino-3-fluoro-N-methylbenzamide (672 mg, 4.00 mmol) in dioxane (20 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 24 hours and then allowed to cool to room temperature. The mixture was evaporated and the residue dissolved in EtOAc (150 mL) and then washed sequentially with a saturated solution of NaHCO3 (100 mL), water (100 mL), and then with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were evaporated to afford 2-[(2,5-dichloropyridin-4-yl)amino]-3-fluoro-N-methylbenzamide (624 mg, 50% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1H NMR (300.132 MHz, DMSO) δ 2.74 (3H, d), 6.39 (1H, d), 7.42 (1H, td), 7.49-7.59 (2H, m), 8.25 (1H, s), 8.64 (1H, m), 9.31 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+ =314.20 and 316.20 and 318.17. to cool to room temperature The mixture was evaporated the residue dissolved in EtOAc (150 mL) washed sequentially with a saturated solution of NaHCO3 (100 mL), water (100 mL) The organic layer was dried over MgSO4 evaporated The residue was purified by chromatography on silica eluting with a gradient of 0-100% EtOAc in isohexane Fractions containing product were evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Amino-3-fluoro-N-methyl-benzamide (10.0 g, 59.5 mmol) was dissolved in acetic acid (100 mL, 176 mmol) and bromine (3.22 mL, 62.4 mmol) was added. The reaction was stirred at room temperature for 20 minutes and the precipitate was then collected by filtration and washed with ethyl ether. The white solid was dried overnight under high vacuum at 50° C. to obtain 2-amino-5-bromo-3-fluoro-N-methyl-benzamide; hydrobromide as a white solid (16.8 g, 86%). LCMS (m/e) 216 (M-NHCH3); 1H-NMR (d6-DMSO, 400 MHz) δ 8.49-8.38 (m, 1H), 7.83-7.46 (m, 3H), 7.54 (s, 1H), 7.43 (d, 1H, J=10.89 Hz), 2.72 (d, 3H, J=4.2 Hz); 19F-NMR (d6-DMSO, 400 MHz) δ 131. the precipitate was then collected by filtration washed with ethyl ether The white solid was dried overnight under high vacuum at 50° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-amino-3-fluoro-N-methyl-benzamide (625 mg, 3.72 mmol), 5-bromo-2,4-dichloro-pyrimidine (1025 mg, 4.498 mmol), and N,N-diisopropylethylamine (1250 uL, 7.18 mmol) in N-methylpyrrolidinone (10.0 mL) was heated at 100° C. overnight. Solvent was removed by rotary evaporation and the residue was triturated with DCM to afford 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide as a yellow solid (381 mg, 28%) that had the following properties: 1H-NMR (DMSO-d6, 400 MHz): δ 9.74 (s, 1H), 8.61 (m, 1H), 8.51 (s, 1H), 7.51-7.44 (m, 3H), 2.73 (d, J=4.4, 3H). Solvent was removed by rotary evaporation the residue was triturated with DCM

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-amino-3-fluoro-N-methyl-benzamide (625 mg, 3.72 mmol), 5-bromo-2,4-dichloro-pyrimidine (1025 mg, 4.498 mmol), and N,N-diisopropylethylamine (1250 uL, 7.18 mmol) in N-methylpyrrolidinone (10.0 mL) was heated at 100° C. overnight. Solvent was removed by rotary evaporation and the residue was triturated with DCM to afford 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide as a yellow solid (381 mg, 28%) that had the following properties: 1H-NMR (DMSO-d6, 400 MHz): δ 9.74 (s, 1H), 8.61 (m, 1H), 8.51 (s, 1H), 7.51-7.44 (m, 3H), 2.73 (d, J=4.4, 3H). Solvent was removed by rotary evaporation the residue was triturated with DCM

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared according to the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-amino-3-fluoro-N-methylbenzamide. 1H NMR (CDCl3, 400 MHz): δ=1.26 (t, J=7.07 Hz, 6 H), 2.92 (d, J=4.80 Hz, 3 H), 3.03-3.12 (m, 2 H), 3.86 (s, 3 H), 3.95-4.07 (m, 4 H), 6.21 (q, J=4.97 Hz, 1 H), 6.57 (d, J=9.09 Hz, 1 H), 6.81 (t, J=1.89 Hz, 1 H), 7.28-7.36 (m, 3 H), 7.73 (br. s., 1 H), 7.85 (br. s., 1 H), 8.34 (s, 1 H), 8.89 (br. s., 1 H). MS (ES+): m/z 586.14 [MH+] (TOF, polar).

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared according to the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-amino-3-fluoro-N-methylbenzamide. 1H NMR (CDCl3, 400 MHz): δ=1.26 (t, J=7.07 Hz, 6H), 2.92 (d, J=4.80 Hz, 3H), 3.03-3.12 (m, 2H), 3.86 (s, 3H), 3.95-4.07 (m, 4H), 6.21 (q, J=4.97 Hz, 1H), 6.57 (d, J=9.09 Hz, 1H), 6.81 (t, J=1.89 Hz, 1H), 7.28-7.36 (m, 3H), 7.73 (br. s., 1H), 7.85 (br. s., 1H), 8.34 (s, 1H), 8.89 (br. s., 1H). MS (ES+): m/z 586.14 [MH+] (TOF, polar).