2-amino-N-methoxybenzamide

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

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

Procedure: O-methylhydroxylamine hydrochloride (1.79 g) was added to isatoic anhydride (2.34 g) in THF (72 mL) and DIPEA (4 mL). The reaction was stirred for 3 hours and then heated to reflux overnight. The reaction was then cooled and concentrated in vacuo and the residue dissolved in EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The phases were separated and the organics were washed with saturated aqueous sodium bicarbonate solution (2×100 mL). The organics were extracted with 1 M HCl (4×25 mL), the aqueous phase basified with potassium carbonate (˜15 g) and the organics discarded. The aqueous was then extracted with EtOAc (3×75 mL). The combined organics were dried (MgSO4, 20 g) and concentrated. The product was dried overnight at 40° C. under vacuum to give 2-amino-N-methoxybenzamide (1.18 g, 50% yield). heated to reflux overnight The reaction was then cooled concentrated in vacuo the residue dissolved in EtOAc (100 mL) The phases were separated the organics were washed with saturated aqueous sodium bicarbonate solution (2×100 mL) The organics were extracted with 1 M HCl (4×25 mL) The aqueous was then extracted with EtOAc (3×75 mL) The combined organics were dried (MgSO4, 20 g) concentrated The product was dried overnight at 40° C. under vacuum

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.303 g, 0.52 mmol), palladium(II) acetate (0.059 g, 0.26 mmol), 2-amino-N-methoxybenzamide (1.479 g, 8.90 mmol), N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (2 g, 5.23 mmol) and cesium carbonate (3.41 g, 10.47 mmol) were weighed out in a round bottom flask. Dioxane (60 mL) was added and argon was bubbled through the mixture for 10 minutes. The suspension was stirred at 100° C. overnight. The reaction mixture was allowed to cool to room temperature with stirring, diluted with DCM and MeOH. Silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel (150 g) eluting with 0 to 5% MeOH in EtOAc/DCM (1:1). The solvent was evaporated to dryness, giving. 35 mL of tBuOMe was added and the resulting solution was stirred at room temperature for 3 hours. The resulting precipitate was collected by filtration, washed with tBuOMe and dried to a constant weight to afford the title compound (1.53 g, 3.64 mmol, 69.5%) as a white solid. This solid was taken up into a minimum of acetonitrile, heated to 100° C. and more acetonitrile was added until complete solubilisation was achieved. The solution was filtered and left to cool to room temperature overnight. The resulting crystals were collected by filtration and dried to constant weight under high vacuum (7.10−2 mbar) at 50° C. for 1 hour, to give the title compound (1.2 g, 2.63 mmol, 50.2%) as a crystalline white solid. argon was bubbled through the mixture for 10 minutes to cool to room temperature with stirring diluted with DCM and MeOH Silica gel was added the mixture was concentrated The crude product was purified by flash chromatography on silica gel (150 g) eluting with 0 to 5% MeOH in EtOAc/DCM (1:1) The solvent was evaporated to dryness giving the resulting solution was stirred at room temperature for 3 hours The resulting precipitate was collected by filtration washed with tBuOMe dried to a constant weight

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

Procedure: O-Methylhydroxylamine hydrochloride (1.253 g, 15.00 mmol) was added to 1H-3,1-benzoxazine-2,4-dione (isatoic anhydride) (1.631 g, 10 mmol) in THF (50 mL) containing DIPEA (2.79 ml, 16.00 mmol). The resulting solution was stirred at room temperature for 4 hours and then heated to reflux for 17 hours. The mixture was allowed to cool to room temperature, filtered and then evaporated. The residue was dissolved in MeOH (20 mL) and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a 7N solution of NH3 in MeOH. Fractions containing product were combined and then evaporated to afford 2-amino-N-methoxybenzamide (1.410 g, 85% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.67 (3H, s), 6.26 (2H, s), 6.48 (1H, m), 6.70 (1H, dd), 7.15 (1H, m), 7.31 (1H, dd), 11.36 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=167.41. heated to reflux for 17 hours to cool to room temperature filtered evaporated The residue was dissolved in MeOH (20 mL) The mixture was eluted first with MeOH Fractions containing product evaporated

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

Procedure: Palladium acetate (0.071 g, 0.32 mmol) was added under a nitrogen atmosphere to 2-amino-N-methoxybenzamide (1.32 g, 7.94 mmol) in dioxane (80 mL) containing 2,5-dichloro-4-iodopyridine (2.176 g, 7.94 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.276 g, 0.48 mmol) and cesium carbonate (5.18 g, 15.89 mmol). The resulting suspension was heated at 80° C. for 18 hours and then at 85° C. for a further 24 hours. The mixture was filtered through Celite and then concentrated in vacuo. The residue was diluted with MeOH and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a 7N solution of NH3 in MeOH. Fractions containing product were combined and then evaporated. The residue was triturated with Et2O to leave 2-[(2,5-dichloropyridin-4-yl)amino]-N-methoxybenzamide (0.823 g, 33% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.66 (3H, s), 7.02 (1H, s), 7.26 (1H, m), 7.38 (1H, m), 7.56-7.64 (2H, m), 8.27 (1H, s), 9.66 (1H, s), 11.88 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=311.93 and 313.96 and 315.92. The mixture was filtered through Celite concentrated in vacuo The residue was diluted with MeOH The mixture was eluted first with MeOH Fractions containing product evaporated The residue was triturated with Et2O

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

Procedure: A mixture of isatoic anhydride (5.0 g, 31 mmol) and methoxylamine hydrochloride (3.8 g, 46 mmol) in EtOH (100 mL) and H2O (10 mL) was charged with Triethylamine (6.4 mL, 46 mmol) and stirred at reflux for 4 h. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The obtained solid was washed with ether and hexanes to afford 4.5 g, 88% yield, of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (br. s., 1H), 7.30 (dd, J=1.14, 7.96 Hz, 1H), 7.09-7.19 (m, 1H), 6.70 (dd, J=0.76, 8.34 Hz, 1H), 6.45-6.52 (m, 1H), 6.30 (br. s., 2H), 3.67 (s, 3H); MS (ES+): m/z: 167.0783 [MH+]. HPLC: tR=0.83 min (UPLC TOF: polar—3 min). at reflux for 4 h The reaction mixture was concentrated in vacuo partitioned between EtOAc and water separated The aqueous layer was extracted with EtOAc (3×) the combined organic fractions were washed with brine dried over sodium sulfate filtered concentrated The obtained solid was washed with ether and hexanes to afford 4.5 g, 88% yield

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

Procedure: A mixture of isatoic anhydride (5.0 g, 31 mmol) and methoxylamine hydrochloride (3.8 g, 46 mmol) in EtOH (100 mL) and H2O (10 mL) was charged with Triethylamine (6.4 mL, 46 mmol) and stirred at reflux for 4 h. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The obtained solid was washed with ether and hexanes to afford 4.5 g, 88% yield, of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (br. s., 1H), 7.30 (dd, J=1.14, 7.96 Hz, 1H), 7.09-7.19 (m, 1H), 6.70 (dd, J=0.76, 8.34 Hz, 1H), 6.45-6.52 (m, 1H), 6.30 (br. s., 2H), 3.67 (s, 3H); MS (ES+): m/z: 167.0783 [MH+]. HPLC: tR=0.83 min (UPLC TOF: polar—3 min). at reflux for 4 h The reaction mixture was concentrated in vacuo partitioned between EtOAc and water separated The aqueous layer was extracted with EtOAc (3×) the combined organic fractions were washed with brine dried over sodium sulfate filtered concentrated The obtained solid was washed with ether and hexanes to afford 4.5 g, 88% yield

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

Procedure: The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (0.060 g, 0.13 mmol) and 2-amino-N-methoxybenzamide (Compound 259A, 0.0242 g, 0.145 mmol). The crude material was purified on an Isco Combiflash unit using 0-5% MeOH in DCM as eluent to afford 55.7 mg of the title compound (72%). 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.70 (br. s., 1H), 8.79 (br. s., 1H), 8.38 (s, 1H), 7.48-7.57 (m, 2H), 7.42 (t, J=7.71 Hz, 1H), 7.09 (t, J=7.33 Hz, 1H), 7.01 (s, 1H), 6.83 (td, J=2.02, 8.08 Hz, 1H), 3.91-4.04 (m, 4H), 3.76 (s, 3H), 3.70 (s, 3H), 3.18-3.28 (m, 2H), 1.19 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 585.1915 [MH+]. HPLC: tR=1.41 min (UPLC TOF MS: polar—3 min). The title compound was prepared The crude material was purified on an Isco Combiflash unit

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-chloro-4-iodo-nicotinonitrile (14 g, 53.03 mmole, 1 eq), 2-amino-N-methoxy-benzamide (7.96 g, 53.03 mmole, 1 eq) and K3PO4 (28.14 g, 132.57 mmole, 2.5 eq) in 1,4-dioxane (250 mL) was degassed with N2 for 1 h. To this mixture were added Pd(OAC)2 (0.238 g, 1.06 mmole, 0.02 eq) and DPEPhos (2.28 g, 4.24 mmole, 0.08 eq). The resulting reaction mixture was degassed with N2 for another 15 min after which the resulting reaction mixture was stirred at 110° C. overnight. After completion of reaction solid material was collected by filtration, dissolved in water (500 mL), and extracted with ethyl acetate (5×200 mL). Combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude material. It was purified by column chromatography over silica gel (60-120 mesh) using 0.2% methanolic ammonia (10% ammonia in MeOH) in dichloromethane as the eluant to give the title compound as a pale yellow solid (9 g, 59%). 1H-NMR (400 MHz, DMSO-d6): δ 2.75 (d, 3H, J=4.56 Hz), 7.09 (s, 1H), 7.25-7.35 (m, 1H), 7.53-7.60 (m, 2H), 7.72 (d, 1H, J=7.48 Hz), 8.56 (s, 1H), 8.69-8.79 (brs, 1H), 10.65 (s, 1H). LC-MS calculated for C14H11ClN4O (M+H) 287.06, found 286.9. was degassed with N2 for 1 h The resulting reaction mixture was degassed with N2 for another 15 min after which the resulting reaction mixture After completion of reaction solid material was collected by filtration dissolved in water (500 mL) extracted with ethyl acetate (5×200 mL) Combined organic layers were dried over sodium sulfate filtered concentrated under reduced pressure to give crude material It was purified by column chromatography over silica gel (60-120 mesh)

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

Procedure: A mixture of 5-bromo-2-chloro-4-iodo-pyridine (5 g, 15.72 mmole, 1 eq), 2-amino-N-methoxy-benzamide (2.61 g, 15.72 mmole, 1 eq) and K3PO4 (8.34 g, 39.3 mmole, 2.5 eq), and 1,4-dioxane (30 mL) was degassed with N2 for 1 h. To this was added DPEPhos (0.67 g, 1.25 mmole, 0.08 eq) and Pd(OAc)2 (0.07 g, 0.31 mmole, 0.02 eq) and this mixture was degassed again with N2 for 30 min. The resulting mixture was refluxed for overnight. After completion of reaction, solvent was removed under reduced pressure and residue was diluted with water (100 mL) and extracted with 5% MeOH-DCM (3×100 mL). Combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude compound. It was purified by column chromatography over silica gel (60-120 mesh) using 20% Ethyl acetate-hexane as the eluant to yield the title compound as off white solid (3.5 g, 62%). 1H-NMR (400 MHz, DMSO-d6): δ 3.56 (s, 3H), 6.88-6.98 (m, 1H), 7.08 (s, 1H), 7.17-7.25 (m, 1H), 7.26-7.35 (m, 1H), 7.82-7.90 (m, 1H), 8.23 (s, 1H), 12.86 (brs, 1H). LC-MS [M+H]+=356.30. was degassed with N2 for 1 h this mixture was degassed again with N2 for 30 min The resulting mixture was refluxed for overnight After completion of reaction, solvent was removed under reduced pressure and residue was diluted with water (100 mL) extracted with 5% MeOH-DCM (3×100 mL) Combined organic layers were dried over sodium sulfate filtered concentrated under reduced pressure to give a crude compound It was purified by column chromatography over silica gel (60-120 mesh)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,5-dichloro-4-iodo-pyridine (40 g, 146.5 mmole, 1 eq), 2-amino-N-methoxy-benzamide (24.32 g, 146.5 mmole, 1 eq) and K3PO4 (77.72 g 366.2 mmole, 2.5 eq) in 1,4-dioxane (600 mL) was degassed with N2 for 1 h. To this were added Pd(OAc)2 (0.657 g, 2.93 mmole, 0.02 eq), DPEPhos (6.31 g, 11.7 mmole, 0.08 eq) and again degassed for 15 min with N2. The resulting mixture was stirred at 110° C. for overnight. After completion of reaction, solid material was collected by filtration, dissolved in water (500 mL) and extracted with ethyl acetate (5×200 mL). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Solid compound so obtained was purified by washing with hexane to give the title compound as yellowish solid (40 g, 53%). 1H-NMR (400 MHz, DMSO-d6): δ 3.63 (s, 3H), 7.06 (s, 1H), 7.15-7.22 (m, 1H), 7.48-7.57 (m, 2H), 7.66-7.67 (d, 1H, J=7.48 Hz), 8.25 (s, 1H), 10.66-11.45 (brs, 1H). LC-MS [M+H]+=312.3. was degassed with N2 for 1 h again degassed for 15 min with N2 After completion of reaction, solid material was collected by filtration dissolved in water (500 mL) extracted with ethyl acetate (5×200 mL) Combined organic layer was dried over sodium sulfate filtered concentrated under reduced pressure Solid compound so obtained was purified by washing with hexane

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

Procedure: To a mixture of isatoic anhydride (40 g, 245.39 mmol, 1 eq) and o-methyl hyroxylamine hydrochloride (30.55 g, 368.09 mmole, 1.5 eq) in EtOH:H2O (9:1) (1000 mL) was added triethylamine (51.2 mL, 368.09 mmole, 1.5 eq) and resulting mixture was reflux for 4 h. After completion of reaction solvent was removed under reduced pressure and residue was diluted with water (500 mL), extracted with ethyl acetate (3×250 mL). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Solid compound so obtained was purified by washing with diethyl ether and hexane to give the title compound as brown solid (20 g, 49%). 1H-NMR (400 MHz, DMSO-d6): δ 3.67 (s, 3H), 6.20-6.40 (brs, 2H), 6.44-6.53 (m, 1H), 6.70 (d, 1H, J=7.76 Hz), 7.10-7.19 (m, 1H), 7.30 (d, 1H, J=7.6 Hz), 11.40 (s, 1H). LC-MS [M+H]+=167.2. resulting mixture was reflux for 4 h After completion of reaction solvent was removed under reduced pressure and residue was diluted with water (500 mL) extracted with ethyl acetate (3×250 mL) Combined organic layer was dried over sodium sulfate filtered concentrated under reduced pressure Solid compound so obtained was purified by washing with diethyl ether and hexane