4-fluoro-3-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:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N′-Hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide (35 mg, 0.13 mmol) was stirred in 1,4-dioxane (2 mL) and 6 N hydrogen chloride solution (4 mL) was added. The solution was cooled to 0° C. and a solution of sodium nitrite (11 mg, 0.16 mmol) in water (3 mL) was slowly added. The mixture was stirred for 1 hour at 0° C. and evaporated. Dry 1,4-dioxane (2 mL) was added and the mixture evaporated two more times. A solution of 4-fluoro-3-methylaniline [Aldrich, product #559415] (25 mg, 0.20 mmol) in ethanol (2 mL) was added and the mixture was stirred for 1 hour. Purification by preparative LCMS (pH 2) gave the desired compound (17 mg, 27%). LCMS calculated for C13H18FN6O4S (M+H): m/z=373.1. 1H NMR (400 MHz, DMSO-d6): δ 11.25 (s, 1H), 8.61 (s, 1H), 7.18 (m, 1H), 6.91 (m, 1H), 6.72 (m, 1H), 6.58 (m, 1H), 6.24 (s, 1H), 3.32 (m, 2H), 3.11 (m, 2H), 2.89 (s, 3H), 2.05 (s, 3H). evaporated Dry 1,4-dioxane (2 mL) was added the mixture evaporated two more times the mixture was stirred for 1 hour Purification by preparative LCMS (pH 2)

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

Procedure: In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-methylaniline were reacted to provide 2-chloro-5-fluoro-N4-(4-fluoro-3-methylphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.06 (d, 1H, J=2.4 Hz), 7.48-7.43 (m, 1H), 7.39 (dd, 1H, J=2.7 and 6.3 Hz), 7.03 (t, 1H, J=9.0 Hz), 6.84 (bs, 1H), 2.30 (d, 1H, J=1.8 Hz); 19F NMR (282 MHz, CDCl3): −34285, −44676; LCMS: purity: 95%; MS (m/e): 257 (MH+). were reacted

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-3-methyl-phenylamine (10 g, 79.9 mmol) was mixed with trifluoroacetic acid (100 mL) in a 250 mL flask. After the mixture was cooled to 0° C., concentrated hydrochloric acid (10 mL) was added slowly, followed by addition of a solution of sodium nitrite (6.95 g, 100.67 mmol) in water (5 mL) dropwise over 20 minutes at 0° C. The mixture was stirred for another 10 minutes, and then poured into a stirred mixture of acetic acid (120 mL), sulfurous acid (0.94 N aqueous sulfur dioxide solution, 120 mL), copper(II) chloride (13.6 g, 79.9 mmol) and copper(I) chloride (100 mg) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 15 hours, and then poured into water (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (20% ethyl acetate in petroleum ether) to afford 4-fluoro-3-methyl-benzenesulfonyl chloride (5.2 g, 31.2%) (reference: Cherney, R. J. et al., J. Med. Chem. 46 (2003) 1811). 1H NMR (400 MHz, CDCl3) δ ppm 7.96-7.90 (m, 2 H), 7.284-7.229 (m, 1 H), 2.42 (d, J=1.6 Hz, 3 H). to warm to room temperature stirred for 15 hours The aqueous layer was extracted with ethyl acetate (100 mL×3) The combined organic layers were dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography (20% ethyl acetate in petroleum ether)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-3-methyl-phenylamine (10 g, 79.9 mmol) was mixed with trifluoroacetic acid (100 mL) in a 250 mL flask. After the mixture was cooled to 0° C., concentrated hydrochloric acid (10 mL) was added slowly, followed by addition of a solution of sodium nitrite (6.95 g, 100.67 mmol) in water (5 mL) dropwise over 20 minutes at 0° C. The mixture was stirred for another 10 minutes, and then poured into a stirred mixture of acetic acid (120 mL), sulfurous acid (0.94 N aqueous sulfur dioxide solution, 120 mL), copper(II) chloride (13.6 g, 79.9 mmol) and copper(I) chloride (100 mg) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 15 hours, and then poured into water (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (20% ethyl acetate in petroleum ether) to afford 4-fluoro-3-methyl-benzenesulfonyl chloride (5.2 g, 31.2%) (reference: Cherney, R. J. et al., J. Med. Chem. 46 (2003) 1811). 1H NMR (400 MHz, CDCl3) δ ppm 7.96-7.90 (m, 2 H), 7.284-7.229 (m, 1 H), 2.42 (d, J=1.6 Hz, 3 H). to warm to room temperature stirred for 15 hours The aqueous layer was extracted with ethyl acetate (100 mL×3) The combined organic layers were dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography (20% ethyl acetate in petroleum ether)

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

Procedure: Into a solution of 4-fluoro-3-methylaniline (8.75 g, 70 mmol) in methanol (65 mL) and water (65 mL) was added sodium bicarbonate (5.88 g, 70 mmol) followed by portionwise addition of powdered I2 (17.78 g, 70 mmol). The mixture was stirred at room temperature overnight then treated with water (300 mL). The aqueous mixture was extracted with CH2Cl2 (3×200 mL). The organics were combined and washed with sat. aq. sodium thiosulfate, water, and brine. The mixture was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane to give 4-fluoro-2-iodo-5-methylaniline (12.1 g, 69%), which contained ˜10% of the undesired isomer (4-fluoro-2-iodo-3-methylaniline). The aqueous mixture was extracted with CH2Cl2 (3×200 mL) washed with sat. aq. sodium thiosulfate, water, and brine The mixture was dried over Na2SO4 concentrated The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane

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

Procedure: Into a solution of 4-fluoro-3-methylaniline (8.75 g, 70 mmol) in methanol (65 mL) and water (65 mL) was added sodium bicarbonate (5.88 g, 70 mmol) followed by portionwise addition of powdered I2 (17.78 g, 70 mmol). The mixture was stirred at room temperature overnight then treated with water (300 mL). The aqueous mixture was extracted with CH2Cl2 (3×200 mL). The organics were combined and washed with sat. aq. sodium thiosulfate, water, and brine. The mixture was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane to give 4-fluoro-2-iodo-5-methylaniline (12.1 g, 69%), which contained ˜10% of the undesired isomer (4-fluoro-2-iodo-3-methylaniline). The aqueous mixture was extracted with CH2Cl2 (3×200 mL) washed with sat. aq. sodium thiosulfate, water, and brine The mixture was dried over Na2SO4 concentrated The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane

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-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine (0.10 g, 0.23 mmol) obtained in Example 81, step 2 and 4-fluoro-3-methylaniline (0.044 g, 0.35 mmol), the title compound (0.119 g, 99%) 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-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.24 mmol) obtained in Example 19, step 4 and 4-fluoro-3-methylaniline (46 mg, 0.36 mmol), the title compound (120 mg, 99%) was obtained.

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

Procedure: To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline in 30 mL of acetonitrile was added 7.64 g (3.93 mmol) of 4-methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of NaHCO3(s). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of H2O and extracted with diethyl ether (2×30 mL). The combined ether layers were back extracted with brine (1×30 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 97.5:2.5 hexanes:ethyl acetate, to give 2.56 g (35%) of a pale yellow oil. at reflux for 24 hours extracted with diethyl ether (2×30 mL) The combined ether layers were back extracted with brine (1×30 mL) dried over MgSO4 filtered concentrated to an oil This was purified via silica gel chromatography eluting with 97.5:2.5 hexanes