2,6-difluoro-3,5-dimethoxyaniline

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

Procedure: To a stirred slurry of 2,6-difluoro-3,5-dimethoxyaniline (1.00 g, 5.29 mmol) in 6.0 M hydrogen chloride in water (9.00 mL, 54.0 mmol), a solution of sodium nitrite (0.383 g, 5.55 mmol) in water (2 mL) was added dropwise over 15 minutes at 0° C. After another 15 minutes, the resulting orange-red slurry was added to a solution of potassium iodide (3.50 g, 21.1 mmol) in water (5 mL) in small portions at 0° C. After addition, the reaction mixture was allowed to warm to room temperature and then it was stirred for 1 hour. Solid precipitated which was filtered out. The solid was washed with water and dried under vacuum to give the desired product (1.15 g, 70%). 1H NMR (400 MHz, CDCl3): δ 6.68 (t, J=8.0 Hz, 1H), 3.88 (s, 6H) ppm. After addition Solid precipitated which was filtered out The solid was washed with water dried under vacuum

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

Procedure: In a 1-L round bottom flask, 10.00 g (0.0528 mol) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 12.42 g (0.0523 mol) of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 500 mL of toluene with 3.65 g (0.0157 mol) of camphorsulfonic acid was fitted with a Dean Stark trap and heated at reflux. During the day, the toluene was drained three times from the finger and continued heating at reflux under nitrogen atmosphere overnight. The toluene was concentrated in vacuo and dried to give 25.30 g (quantitative) of the title compound. No further purification was necessary. MS (APCI) (m+1)/z 409.2. heated at reflux continued heating at reflux under nitrogen atmosphere overnight The toluene was concentrated in vacuo dried

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

Procedure: In a 1-L round bottom flask, 10.00 g (0.0528 mol) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 12.42 g (0.0523 mol) of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 500 mL of toluene with 3.65 g (0.0157 mol) of camphorsulfonic acid was fitted with a Dean Stark trap and heated at reflux. During the day, the toluene was drained three times from the finger and continued heating at reflux under nitrogen atmosphere overnight. The toluene was concentrated in vacuo and dried to give 25.30 g (quantitative) of the title compound. No further purification was necessary. MS (APCI) (m+1)/z 409.2. heated at reflux continued heating at reflux under nitrogen atmosphere overnight The toluene was concentrated in vacuo dried

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

Procedure: To a solution of the 7.00 g (33.4 mmol) of 4-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 500 mL of toluene was added 6.33 g 33.4 mmol, 1 equivalent) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 1.94 g (8.36 mmol, 0.25 equivalents) of camphorsulfonic acid. The reaction was warmed to reflux and the formed water was removed with the aid of a Dean-Stark trap. After reacting for 48 hours, the reaction was concentrated in vacuo. The residue was stirred with ether and filtered. The filter pad was dissolved in dichloromethane, stirred with silica gel, and concentrated in vacuo. The residue was placed in the sample injection module of a Biotage FLASH 75 chromatographic apparatus. Chromatography of the crude material down a Biotage 500 g silica gel column with 2:1 hexane/ethyl acetate, then 1:1 hexane/ethyl acetate and finally 9:1 ethyl acetate/ethanol gave 8.92 g (70%) of title compound as a solid: mp 172° C.–174° C. MS (APCI) (m+1)/z 381.0 Analysis calculated for C17H18aF2N4SO2: C, 53.67; H, 4.77; N, 14.73. Found: C, 53.54; H, 4.58; N, 14.61. The reaction was warmed to reflux the formed water was removed with the aid of a Dean-Stark trap the reaction was concentrated in vacuo filtered The filter pad was dissolved in dichloromethane stirred with silica gel concentrated in vacuo

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

Procedure: In a 500-mL round bottom flask, 3.00 g (15.86 mmol) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 3.13 g (15.86 mmol) of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 150 mL of toluene with 1.11 g (4.76 mmol) of camphorsulfonic acid was fitted with a Dean Stark trap and heated at reflux. During the day, the toluene was drained 3 times from the finger, replenished with 100 mL of the solvent and continued heating at reflux under nitrogen atmosphere overnight. The toluene was concentrated in vacuo and dried to give 7.19 g (quantitative) of the title compound. No further purification was necessary. MS (APCI) (m+1)/z 369.1. heated at reflux continued heating at reflux under nitrogen atmosphere overnight The toluene was concentrated in vacuo dried

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

Procedure: In a 500-mL round bottom flask, 3.00 g (15.86 mmol) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 3.13 g (15.86 mmol) of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 150 mL of toluene with 1.11 g (4.76 mmol) of camphorsulfonic acid was fitted with a Dean Stark trap and heated at reflux. During the day, the toluene was drained 3 times from the finger, replenished with 100 mL of the solvent and continued heating at reflux under nitrogen atmosphere overnight. The toluene was concentrated in vacuo and dried to give 7.19 g (quantitative) of the title compound. No further purification was necessary. MS (APCI) (m+1)/z 369.1. heated at reflux continued heating at reflux under nitrogen atmosphere overnight The toluene was concentrated in vacuo dried

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

Procedure: To 34.6 g (0.12 mol) of (2,6-difluoro-3,5-dimethoxy-phenyl)-carbamic acid tert-butyl ester, 120 mL of trifluoroacetic acid was added to give a homogeneous solution which was stirred at room temperature for 30 minutes. After 30 min., the reaction mixture was concentrated in vacuo. To the residue, a saturated solution of sodium bicarbonate was carefully added to pH 8. The resulting suspension was extracted twice with diethylether. Combined diethylether layers were washed once with brine, dried over sodium sulfate, filtered and evaporated to give 22 g (97%) of title compound. MS (APCI) (m+1)/z 190.1. to give a homogeneous solution which After 30 min. the reaction mixture was concentrated in vacuo To the residue, a saturated solution of sodium bicarbonate was carefully added to pH 8 The resulting suspension was extracted twice with diethylether Combined diethylether layers were washed once with brine dried over sodium sulfate filtered evaporated

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Benzyl-2,6-difluoro-3,5-dimethoxyaniline (6.0 g, 21.5 mmol) was dissolved in THF (40 mL) and the solution hydrogenated over 20% palladium hydroxide on carbon catalyst (0.6 g) at 20° C.–25° C. 48–50 psi hydrogen pressure for 16 hours. The mixture was filtered, the catalyst washed with THF (2×15 mL) and the combined filtrates concentrated to a solid. This was recrystallized from heptane (10 mL) and toluene (4.5 mL). The mixture was cooled to −10° C. before filtering. The crystals were washed with heptane (2×10 ML) and vacuum dried at 35° C. to give 2,6-difluoro-3,5-dimethoxyaniline as off-white needles (3.85 g, 20.4 mmol). mp: 78° C.–79° C. The mixture was filtered the catalyst washed with THF (2×15 mL) the combined filtrates concentrated to a solid This was recrystallized from heptane (10 mL) and toluene (4.5 mL) before filtering The crystals were washed with heptane (2×10 ML) and vacuum dried at 35° C.

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

Procedure: To a stirred slurry of 2,6-difluoro-3,5-dimethoxyaniline (6.00 g, 31.7 mmol) in 6.0 M hydrogen chloride in water (54 mL, 324 mmol), a solution of sodium nitrite (2.30 g, 33.3 mmol) in water (12 mL) was added drop-wise over 15 min. at 0° C. After an additional 15 min., the result orange-red slurry was added to a solution of potassium iodide (21.0 g, 126 mmol) in water (30 mL) in small-portion at 0° C. The mixture was then allowed to stir at r.t. for 1 h. The precipitates were collected by filtration, washed with water, and dried under reduced pressure. The filtrate was neutralized with 6 N NaOH to pH˜7, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated Na2S2O3 aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The residue combined with the precipitates collected previously was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (6.1 g, 64%). 1H-NMR (300 MHz, CDCl3): 6.68 (t, J=8.0 Hz, 1H), 3.88 (s, 6H). The precipitates were collected by filtration washed with water dried under reduced pressure extracted with ethyl acetate (3×20 mL) The combined organic layers were washed with saturated Na2S2O3 aqueous solution dried over MgSO4 filtered concentrated under reduced pressure collected previously was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%)

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

Procedure: To a stirred slurry of 2,6-difluoro-3,5-dimethoxyaniline (1.00 g, 5.29 mmol) in 6.0 M hydrogen chloride in water (9.00 mL, 54.0 mmol), a solution of sodium nitrite (0.383 g, 5.55 mmol) in water (2 mL) was added dropwise over 15 minutes at 0° C. After another 15 minutes, the resulting orange-red slurry was added to a solution of potassium iodide (3.50 g, 21.1 mmol) in water (5 mL) in small portions at 0° C. After addition, the reaction mixture was allowed to warm to room temperature and then it was stirred for 1 hour. Solid precipitated which was filtered out. The solid was washed with water and dried under vacuum to give the desired product (1.15 g, 70%). 1H NMR (400 MHz, CDCl3): δ 6.68 (t, J=8.0 Hz, 1H), 3.88 (s, 6H) ppm. After addition Solid precipitated which was filtered out The solid was washed with water dried under vacuum

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

Procedure: In a 1-L round bottom flask, 10.00 g (0.0528 mol) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 12.42 g (0.0523 mol) of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 500 mL of toluene with 3.65 g (0.0157 mol) of camphorsulfonic acid was fitted with a Dean Stark trap and heated at reflux. During the day, the toluene was drained three times from the finger and continued heating at reflux under nitrogen atmosphere overnight. The toluene was concentrated in vacuo and dried to give 25.30 g (quantitative) of the title compound. No further purification was necessary. MS (APCI) (m+1)/z 409.2. heated at reflux continued heating at reflux under nitrogen atmosphere overnight The toluene was concentrated in vacuo dried

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

Procedure: To a solution of the 7.00 g (33.4 mmol) of 4-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 500 mL of toluene was added 6.33 g 33.4 mmol, 1 equivalent) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 1.94 g (8.36 mmol, 0.25 equivalents) of camphorsulfonic acid. The reaction was warmed to reflux and the formed water was removed with the aid of a Dean-Stark trap. After reacting for 48 hours, the reaction was concentrated in vacuo. The residue was stirred with ether and filtered. The filter pad was dissolved in dichloromethane, stirred with silica gel, and concentrated in vacuo. The residue was placed in the sample injection module of a Biotage FLASH 75 chromatographic apparatus. Chromatography of the crude material down a Biotage 500 g silica gel column with 2:1 hexane/ethyl acetate, then 1:1 hexane/ethyl acetate and finally 9:1 ethyl acetate/ethanol gave 8.92 g (70%) of title compound as a solid: mp 172° C.–174° C. MS (APCI) (m+1)/z 381.0 Analysis calculated for C17H18aF2N4SO2: C, 53.67; H, 4.77; N, 14.73. Found: C, 53.54; H, 4.58; N, 14.61. The reaction was warmed to reflux the formed water was removed with the aid of a Dean-Stark trap the reaction was concentrated in vacuo filtered The filter pad was dissolved in dichloromethane stirred with silica gel concentrated in vacuo