2-amino-N-methylbenzenesulfonamide

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

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

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-amino-N-methyl-benzenesulfonamide (2.93, 15.75 mmol), 2,4,5 trichloropyrimidine (2.9 g, 15.84 mmol) and K2CO3 (4.5 g, 32.6 mmol) in dry DMF (25 mL) was stirred at 45° C. for 15 h. The solvent was removed and the residue was taken in water and was extracted twice from ethylacetate. Combined organic was washed with water and brine. After drying solvent was removed. Upon triturating with ether and filtration gave the product 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide 7 as a white solid (2.6 g, 50%); 1H NMR (400 MHz, CDCl3) δ9.61 (s, 1H), 8.6 (d=12.89 Hz, 1H), 8.53 (s, 1H), 8.27 (s, 1H), 7.68 (m, 1H), 7.27 (m, 1H0, 1.66 (br s, 1H0, 2.66 (s, 3H). The solvent was removed was extracted twice from ethylacetate Combined organic was washed with water and brine After drying solvent was removed Upon triturating with ether and filtration

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-amino-N-methyl-benzenesulfonamide (2.93, 15.75 mmol), 2,4,5 trichloropyrimidine (2.9 g, 15.84 mmol) and K2CO3 (4.5 g, 32.6 mmol) in dry DMF (25 mL) was stirred at 45° C. for 15 h. The solvent was removed and the residue was taken in water and was extracted twice from ethylacetate. Combined organic was washed with water and brine. After drying solvent was removed. Upon triturating with ether and filtration gave the product 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide 7 as a white solid (2.6 g, 50%); 1H NMR (400 MHz, CDCl3) δ9.61 (s, 1H), 8.6 (d=12.89 Hz, 1H), 8.53 (s, 1H), 8.27 (s, 1H), 7.68 (m, 1H), 7.27 (m, 1H0, 1.66 (br s, 1H0, 2.66 (s, 3H). The solvent was removed was extracted twice from ethylacetate Combined organic was washed with water and brine After drying solvent was removed Upon triturating with ether and filtration

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Preparation of 2,5,7-Trimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: A heterogeneous mixture of 4-Acetylamino-2,6-dimethyl-isophthalic acid 1-ethyl ester (5.39 g, 1.95 mmol), 2-amino-N-methyl-benzenesulfonamide (3.63 g, 1.95 mmol), and phosphorus trichloride (8.5 mL, 9.7 mmol) in toluene (220 mL) was heated at 140° C. (oil bath temperature) for 3.5 h. The reaction mixture was allowed to cool to room temperature and then evaporated in vacuo. Sufficient ethyl acetate was added to dissolve the residue and the solution was washed with saturated aqueous sodium hydrogen carbonate then brine, dried (Na2SO4) and evaporated in vacuo. Trituration of the residue with dichloromethane gave a white solid, which was removed by filtration. Evaporation of the filtrate solution followed by trituration with ethyl acetate provided a second crop of white solid. The evaporation-trituration procedure was repeated to give two further crops of white solid. The combined white solids were washed with ether and dried in vacuo to provide the title compound. to cool to room temperature evaporated in vacuo Sufficient ethyl acetate was added to dissolve the residue the solution was washed with saturated aqueous sodium hydrogen carbonate brine, dried (Na2SO4) evaporated in vacuo Trituration of the residue with dichloromethane gave a white solid, which was removed by filtration Evaporation of the filtrate solution provided a second crop of white solid The evaporation-trituration procedure to give two further crops of white solid The combined white solids were washed with ether dried in vacuo

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

Procedure: Preparation of 2-Benzyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: To a mechanically-stirred suspension of 4-(Benzyloxyacetyl)amino-2,6-dimethyl-isophthalic acid 1-ethyl ester (27 g, 0.07 mol), 2-amino-N-methyl-benzenesulfonamide (13 g, 0.07 mol) and anhydrous toluene (500 mL) in a three-necked round bottom flask is added phosphorus trichloride (51 mL, 0.56 mol) via an addition funnel. The reaction mixture is stirred at room temperature for 5 minutes and then heated to reflux. After 45 minutes LCMS analysis indicates that the reaction is complete. The suspension is cooled to room temperature and the solution phase is decanted from the solid material. The solution and solid material are worked-up separately. The toluene solution is partitioned between ethyl acetate and saturated aqueous NaHCO3 solution with vigorous stirring to give a clear biphasic solution. The organic and aqueous phases are separated and the aqueous phase is extracted (×2) with ethyl acetate. The organic phases are combined, dried over anhydrous Na2SO4, and evaporated in vacuo to give an orange oil. Similarly, the solid material is stirred, vigorously with ethyl acetate and saturated aqueous NaHCO3 solution to give a clear biphasic solution. The organic and aqueous phases are separated and the aqueous phase is extracted (×2) with ethyl acetate. The organic phases are combined, dried over anhydrous Na2SO4, and evaporated in vacuo to give an orange oil. Trituration of the orange oil with diethyl ether provides a yellow solid, which is removed by filtration, washed with diethyl ether and air-dried to provide the title compound. heated to reflux After 45 minutes LCMS analysis indicates that the reaction The suspension is cooled to room temperature the solution phase is decanted from the solid material The toluene solution is partitioned between ethyl acetate and saturated aqueous NaHCO3 solution with vigorous stirring to give a clear biphasic solution The organic and aqueous phases are separated the aqueous phase is extracted (×2) with ethyl acetate dried over anhydrous Na2SO4 evaporated in vacuo to give an orange oil to give a clear biphasic solution The organic and aqueous phases are separated the aqueous phase is extracted (×2) with ethyl acetate dried over anhydrous Na2SO4 evaporated in vacuo to give an orange oil is removed by filtration washed with diethyl ether air-dried

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

Procedure: Preparation of 2-Benzyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: To a mechanically-stirred suspension of 4-(Benzyloxyacetyl)amino-2,6-dimethyl-isophthalic acid 1-ethyl ester (27 g, 0.07 mol), 2-amino-N-methyl-benzenesulfonamide (13 g, 0.07 mol) and anhydrous toluene (500 mL) in a three-necked round bottom flask is added phosphorus trichloride (51 mL, 0.56 mol) via an addition funnel. The reaction mixture is stirred at room temperature for 5 minutes and then heated to reflux. After 45 minutes LCMS analysis indicates that the reaction is complete. The suspension is cooled to room temperature and the solution phase is decanted from the solid material. The solution and solid material are worked-up separately. The toluene solution is portioned between ethyl acetate and saturated aqueous NaHCO3 solution with vigorous stirring to give a clear biphasic solution. The organic and aqueous phases are separated and the aqueous phase is extracted (×2) with ethyl acetate. The organic phases are combined, dried over anhydrous Na2SO4, and evaporated in vacuo to give an orange oil. Similarly, the solid material is stirred vigorously with ethyl acetate and saturated aqueous NaHCO3 solution to give a clear biphasic solution. The organic and aqueous phases are separated and the aqueous phase is extracted (×2) with ethyl acetate. The organic phases are combined, dried over anhydrous Na2SO4, and evaporated in vacuo to give an orange oil. Trituration of the orange oils with diethyl ether provides yellow solids, which are removed by filtration, washed with diethyl ether and air-dried to provide the title compound (20 g, 0.037 mol, 53%). heated to reflux After 45 minutes LCMS analysis indicates that the reaction The suspension is cooled to room temperature the solution phase is decanted from the solid material with vigorous stirring to give a clear biphasic solution The organic and aqueous phases are separated the aqueous phase is extracted (×2) with ethyl acetate dried over anhydrous Na2SO4 evaporated in vacuo to give an orange oil to give a clear biphasic solution The organic and aqueous phases are separated the aqueous phase is extracted (×2) with ethyl acetate dried over anhydrous Na2SO4 evaporated in vacuo to give an orange oil are removed by filtration washed with diethyl ether air-dried

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

Procedure: Preparation of 2-Benzyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: To a mechanically-stirred suspension of 4-(Benzyloxyacetyl)amino-2,6-dimethyl-isophthalic acid 1-ethyl ester (27 g, 0.07 mol), 2-amino-N-methyl-benzenesulfonamide (13 g, 0.07 mol) and anhydrous toluene (500 mL) in a three-necked round bottom flask is added phosphorus trichloride (51 mL, 0.56 mol) via an addition funnel. The reaction mixture is stirred at room temperature for 5 minutes and then heated to reflux. After 45 minutes LCMS analysis indicates that the reaction is complete. The suspension is cooled to room temperature and the solution phase is decanted from the solid material. The solution and solid material are worked-up separately. The toluene solution is portioned between ethyl acetate and saturated aqueous NaHCO3 solution with vigorous stirring to give a clear biphasic solution. The organic and aqueous phases are separated and the aqueous phase is extracted (×2) with ethyl acetate. The organic phases are combined, dried over anhydrous Na2SO4, and evaporated in vacuo to give an orange oil. Similarly, the solid material is stirred vigorously with ethyl acetate and saturated aqueous NaHCO3 solution to give a clear biphasic solution. The organic and aqueous phases are separated and the aqueous phase is extracted (×2) with ethyl acetate. The organic phases are combined, dried over anhydrous Na2SO4, and evaporated in vacuo to give an orange oil. Trituration of the orange oils with diethyl ether provides yellow solids, which are removed by filtration, washed with diethyl ether and air-dried to provide the title compound (20 g, 0.037 mol, 53%). heated to reflux After 45 minutes LCMS analysis indicates that the reaction The suspension is cooled to room temperature the solution phase is decanted from the solid material with vigorous stirring to give a clear biphasic solution The organic and aqueous phases are separated the aqueous phase is extracted (×2) with ethyl acetate dried over anhydrous Na2SO4 evaporated in vacuo to give an orange oil to give a clear biphasic solution The organic and aqueous phases are separated the aqueous phase is extracted (×2) with ethyl acetate dried over anhydrous Na2SO4 evaporated in vacuo to give an orange oil are removed by filtration washed with diethyl ether air-dried

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

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

Conditions: temp:61.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-Dichloro-5-nitro-pyrimidine (1.94 g, 10 mmol) and 2-amino-N -methyl-benzenesulfonamide (1.86 g, 10 mmol) are dissolved in CHCl3 (30 mL). The reaction mixture is heated at 61° C. for 2 h. The solvent is evaporated and the residue is washed with ether to give the title product. Rf=0.5 (n-hexane:ethyl acetate=1:1). 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.67 (d, 3H), 4.6-4.7 (m, 2H), 7.41 (t 1H), 7.7 (t, 1H), 8.04 (d, 1H), 8.15 (d, 1H), 9.21 (s, 1H), 11.2 (s, 1H). The solvent is evaporated the residue is washed with ether

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

Procedure: A suspension of 5-bromo-2,4-dichloropyrimidine (684 mg, 3.0 mmol) and 2-amino-N-methyl-benzenesulfonamide (559 mg, 3.0 mmol) in N,N-dimethylformamide (10 mL) containing potassium carbonate (830 mg, 6.0 mmol) is stirred at room temperature for 23 hours. Saturated aqueous ammonium chloride is added and the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane-ethyl acetate gradient) to afford the title compound as a slightly yellow solid. extracted twice with ethyl acetate The organic layer is washed with brine dried over sodium sulfate evaporated in vacuo The residue is purified by silica gel column chromatography (n-hexane-ethyl acetate gradient)