5-amino-2-methylbenzonitrile

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

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

Procedure: 15.2 g (0.22 mol) of sodium nitrite are heated to 70° C. in 160 ml of concentrated sulphuric acid and the solution formed is added dropwise to a solution of 26.4 g (0.2 mol) of the compound from Example XV in 400 ml of glacial acetic acid at 20° C. to 40° C. A solution of 63.1 g (0.44 mol) of copper(I) bromide in 400 ml of concentrated hydrobromic acid is added dropwise to this solution at 10° C. to 20° C. and the mixture is stirred for 0.5 hour. The reaction mixture is introduced into 1 l of water, the precipitate which has separated out is filtered off with suction, washed with water and suspended in methylene chloride and the insoluble material is filtered off with suction. The filtrate is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to give 19.2 g of the title compound. the solution formed the precipitate which has separated out is filtered off with suction washed with water the insoluble material is filtered off with suction The filtrate is washed with saturated sodium chloride solution dried over sodium sulphate concentrated

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

Procedure: A suspension of 8.11 g (50 mmol) of 6-methyl-3-nitro-benzonitrile and 0.81 g of 10% of palladium-on-charcoal in 50 ml of ethanol and 50 ml of ethyl acetate is hydrogenated under 2.9 bar for 1 hour. The catalyst is filtered off, the filtrate is concentrated and the residue is crystallised from ether/petroleum ether. The catalyst is filtered off the filtrate is concentrated the residue is crystallised from ether/petroleum ether

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

Procedure: 15.2 g (0.22 mol) of sodium nitrite are heated to 70° C. in 160 ml of concentrated sulphuric acid and the solution formed is added dropwise to a solution of 26.4 g (0.2 mol) of the compound from Example XV in 400 ml of glacial acetic acid at 20° C. to 40° C. A solution of 63.1 g (0.44 mol) of copper(I) bromide in 400 ml of concentrated hydrobromic acid is added dropwise to this solution at 10° C. to 20° C. and the mixture is stirred for 0.5 hour. The reaction mixture is introduced into 11 of water, the precipitate which has separated out is filtered off with suction, washed with water and suspended in methylene chloride and the insoluble material is filtered off with suction. The filtrate is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to give 19.2 g of the title compound. the solution formed the precipitate which has separated out is filtered off with suction washed with water the insoluble material is filtered off with suction The filtrate is washed with saturated sodium chloride solution dried over sodium sulphate concentrated

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

Procedure: A suspension of 8.11 g (50 mmol) of 6-methyl-3-nitrobenzonitrile and 0.81 g of 10% of palladium-on-charcoal in 50 ml of ethanol and 50 ml of ethyl acetate is hydrogenated under 2.9 bar for 1 hour. The catalyst is filtered off, the filtrate is concentrated and the residue is crystallised from ether/petroleum ether. The catalyst is filtered off the filtrate is concentrated the residue is crystallised from ether/petroleum ether

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Water (13.5 mL), HBr (74%, 14.4 mL) and 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) was added to a flask and heated to 50° C. for 20 min. Then the mixture was cooled to 0˜5° C., and a solution of NaNO2 (1.2 g, 17.4 mmol) in water was added. The reaction mixture was stirred for 10 min at 0˜5° C., then was warmed to 40° C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and refluxed for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed by saturated NaHCO3 solution and brine, and dried over Na2SO4. The crude product was purified by flask chromatograph (PE:EA=50:1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (yield: 77%). 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 2.51 (s, 3H). was added to a flask Then the mixture was cooled to 0˜5° C. was warmed to 40° C refluxed for 2 h The mixture was extracted with AcOEt the organic layer was washed by saturated NaHCO3 solution and brine dried over Na2SO4 The crude product was purified by flask chromatograph (PE:EA=50:1)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Water (13.5 mL), HBr (74%, 14.4 mL) and 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) was added to a flask and heated to 50° C. for 20 min. Then the mixture was cooled to 0˜5° C., and a solution of NaNO2 (1.2 g, 17.4 mmol) in water was added. The reaction mixture was stirred for 10 min at 0˜5° C., then was warmed to 40° C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and refluxed for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed by saturated NaHCO3 solution and brine, and dried over Na2SO4. The crude product was purified by flask chomatograph (PE:EA=50:1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (yield: 77%). 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 2.51 (s, 3H). was added to a flask Then the mixture was cooled to 0˜5° C. was warmed to 40° C refluxed for 2 h The mixture was extracted with AcOEt the organic layer was washed by saturated NaHCO3 solution and brine dried over Na2SO4 The crude product was purified by flask chomatograph (PE:EA=50:1)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Water (13.5 mL), HBr (74%, 14.4 mL) and 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) was added to a flask and heated to 50° C. for 20 min. Then the mixture was cooled to 0˜5° C., and a solution of NaNO2 (1.2 g, 17.4 mmol) in water was added. The reaction mixture was stirred for 10 min at 0˜5° C., then was warmed to 40° C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and refluxed for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed by saturated NaHCO3 solution and brine, and dried over Na2SO4. The crude product was purified by flask chomatograph (PE:EA=50:1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (yield: 77%). 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 2.51 (s, 3H). was added to a flask Then the mixture was cooled to 0˜5° C. was warmed to 40° C refluxed for 2 h The mixture was extracted with AcOEt the organic layer was washed by saturated NaHCO3 solution and brine dried over Na2SO4 The crude product was purified by flask chomatograph (PE:EA=50:1)

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

Procedure: 4-[5-(4-Methoxy-benzoylamino)-2-methyl-benzylamino]-quinazoline-8-carboxylic acid amide was prepared according to example 4-{3-[(4-Methoxy-benzoyl)-methyl-amino]-benzylamino}-quinazoline-8-carboxylic acid amide, starting from 5-Amino-2-methyl-benzonitrile and 4-methoxy-benzoic acid:

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Keep the solution of 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) and HBr (74%, 14.4 mL) stirring for 20 min, then the mixture was cooled to 0˜5° C., and the solution of NaNO2 (1.2 g, 17.4 mmol) in water (13.5 mL) was added. The reaction mixture was stirred for 10 min at 0˜5° C., then was warmed to 40° C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and it was stirred for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed with saturated NaHCO3 solution, brine, and dried over Na2SO4. The crude product was purified by flask chromatograph (PE:EA=50:1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (Yield: 77%). 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1 H), 7.59 (d, J=8.0 Hz, 1 H), 7.19 (d, J=8.0 Hz, 1 H), 2.51 (s, 3 H). the mixture was cooled to 0˜5° C. was stirred for 2 h The mixture was extracted with AcOEt the organic layer was washed with saturated NaHCO3 solution, brine dried over Na2SO4 The crude product was purified by flask chromatograph (PE:EA=50:1)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Keep the solution of 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) and HBr (74%, 14.4 mL) stirring for 20 min, then the mixture was cooled to 0˜5° C., and the solution of NaNO2 (1.2 g, 17.4 mmol) in water (13.5 mL) was added. The reaction mixture was stirred for 10 min at 0˜5° C., then was warmed to 40° C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and it was stirred for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed with saturated NaHCO3 solution, brine, and dried over Na2SO4. The crude product was purified by flask chromatograph (PE:EA=50:1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (Yield: 77%). 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1 H), 7.59 (d, J=8.0 Hz, 1 H), 7.19 (d, J=8.0 Hz, 1 H), 2.51 (s, 3 H). the mixture was cooled to 0˜5° C. was stirred for 2 h The mixture was extracted with AcOEt the organic layer was washed with saturated NaHCO3 solution, brine dried over Na2SO4 The crude product was purified by flask chromatograph (PE:EA=50:1)

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

Procedure: 15.2 g (0.22 mol) of sodium nitrite are heated to 70° C. in 160 ml of concentrated sulphuric acid and the solution formed is added dropwise to a solution of 26.4 g (0.2 mol) of the compound from Example XV in 400 ml of glacial acetic acid at 20° C. to 40° C. A solution of 63.1 g (0.44 mol) of copper(I) bromide in 400 ml of concentrated hydrobromic acid is added dropwise to this solution at 10° C. to 20° C. and the mixture is stirred for 0.5 hour. The reaction mixture is introduced into 1 l of water, the precipitate which has separated out is filtered off with suction, washed with water and suspended in methylene chloride and the insoluble material is filtered off with suction. The filtrate is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to give 19.2 g of the title compound. the solution formed the precipitate which has separated out is filtered off with suction washed with water the insoluble material is filtered off with suction The filtrate is washed with saturated sodium chloride solution dried over sodium sulphate concentrated