2-fluoro-5-methylaniline

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: In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-fluoro-5-methylaniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-fluoro-5-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.11 (dd, 1H, J=1.8 and 8.1 Hz), 7.94 (d, 1H, J=2.7 Hz), 7.08-6.84 (m, 4H), 6.74-6.67 (m, 1H), 6.64-6.59 (m, 1H), 4.27 (s, 4H), 2.28 (s, 3H); 19F NMR (282 MHz, CDCl3): −38659, −47267; LCMS: purity: 100%; MS (m/e): 371 (MH+). were reacted

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

Procedure: 2,4-Dichloropyrimidine (7.0 g, 47 mmol) was dissolved in n-butanol (5 ml), followed by addition of DIPEA (9.0 ml, 51.7 mmol), then 2-fluoro-5-methylaniline (5.3 ml, 47 mmol). The mixture was heated at 100° C. overnight, and then allowed to cool to ambient temperature. The mixture was evaporated to give an oil, which was taken up in DCM (250 ml) and washed with water (3×50 ml), brine (50 ml), dried over MgSO4 and evaporated to give an orange oil. This was purified by column chromatography eluting with EtOAc:isohexane (10:90) to give the title product as a white solid (2.40 g, 21%). NMR (300 MHz): 2.3 (s, 3H), 6.7 (d, 1H), 7.0 (m, 1H), 7.2 (m, 1H), 7.5 (d, 1H), 8.1 (d, 1H), 9.7 (s, 1H); m/z: (ES+) 237.9 (MH+). to cool to ambient temperature The mixture was evaporated to give an oil, which washed with water (3×50 ml), brine (50 ml) dried over MgSO4 evaporated to give an orange oil This was purified by column chromatography eluting with EtOAc:isohexane (10:90)

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

Procedure: To a slurry of 2-fluoro-5-metylaniline (6.75 g, 54 mmol) and CaCO3 (10 g, 100 mmol) in CH2Cl2 (1 L) and MeOH (400 mL) was added a solution of Benzyltrimethylammonium tribromide (22.3 g, 57 mmol) in CH2Cl2 (180 mL) and MeOH (70 mL). The solution was added dropwise and the mixture was stirred over night. The solution was a light orange/tan color. The mixture was filtered and the solvent was removed under reduced pressure. The resulting slurry was diluted with H2O (100 mL) and extracted with Et2O (3×200 mL). The mixture was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O) to provide (9 g, 69.5% yield) the product as a white solid. 1H-NMR (DMSO-d6) δ 7.23 (d, J=10.8 Hz, 1H), 6.74 (d, J=10.8 Hz, 1H), 5.27 (s, 2H), 2.20 (s, 3H). The solution was added dropwise The mixture was filtered the solvent was removed under reduced pressure The resulting slurry was diluted with H2O (100 mL) extracted with Et2O (3×200 mL) The mixture was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O)

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

Procedure: To a slurry of 2-fluoro-5-methylaniline (6.75 g, 54 mmol) and CaCO3 (10 g, 100 mmol) in CH2Cl2 (1 L) and MeOH (400 mL) was added a solution of Benzyltrimethylammonium tribromide (22.3 g, 57 mmol) in CH2Cl2 (180 mL) and MeOH (70 mL). The solution was added dropwise and the mixture was stirred over night. The solution was a light orange/tan color. The mixture was filtered and the solvent was removed under reduced pressure. The resulting slurry was diluted with H2O (100 mL) and extracted with Et2O (3×200 mL). The mixture was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O) to provide (9 g, 69.5% yield) the product as a white solid. 1H-NMR (DMSO-d6) δ 7.23 (d, J=10.8 Hz, 1H), 6.74 (d, J=10.8 Hz, 1H), 5.27 (s, 2H), 2.20 (s, 3H). The solution was added dropwise The mixture was filtered the solvent was removed under reduced pressure The resulting slurry was diluted with H2O (100 mL) extracted with Et2O (3×200 mL) The mixture was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O)

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

Procedure: To a slurry of 2-fluoro-5-methylaniline (6.75 g, 54 mmol) and CaCO3 (10 g, 100 mmol) in CH2Cl2 (1 L) and MeOH (400 mL) was added a solution of Benzyltrimethylammonium tribromide (22.3 g, 57 mmol) in CH2Cl2 (180 mL) and MeOH (70 mL). The solution was added dropwise and the mixture was stirred over night. The solution was a light orange/tan color. The mixture was filtered and the solvent was removed under reduced pressure. The resulting slurry was diluted with H2O (100 mL) and extracted with Et2O (3×200 mL). The mixture was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O) to provide (9 g, 69.5% yield) the product as a white solid. 1H-NMR (DMSO-d6) δ 7.23 (d, J=10.8 Hz, 1H), 6.74 (d, J=10.8 Hz, 1H), 5.27 (s, 2H), 2.20 (s, 3H). The solution was added dropwise The mixture was filtered the solvent was removed under reduced pressure The resulting slurry was diluted with H2O (100 mL) extracted with Et2O (3×200 mL) The mixture was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O)

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

Procedure: In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.250 g, 0.546 mmol) obtained in Example 145, step 2 and 2-fluoro-5-methylphenylamine (0.150 mL, 1.37 mmol), the title compound (0.155 g, 52%) was obtained.

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

Procedure: In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.24 g, 0.54 mmol) obtained in step 2 and 2-fluoro-5-methylaniline (0.1 g, 0.82 mmol), the title compound (0.25 g, 88%) was obtained.

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

Procedure: In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.10 g, 0.23 mmol) obtained in Example 120, step 2 and 2-fluoro-5-methylaniline (0.043 g, 0.34 mmol), the title compound (0.108 g, 90%) was obtained.

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

Procedure: In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.10 g, 0.23 mmol) obtained in Example 120, step 2 and 2-fluoro-5-methylaniline (0.043 g, 0.34 mmol), the title compound (0.108 g, 90%) was obtained.

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

Procedure: In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.070 g, 0.160 mmol) obtained in step 2 and 2-fluoro-5-methylaniline (0.030 g, 0.240 mmol), the title compound (0.074 g, 87%) was obtained.