3-(methylamino)propanenitrile

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:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 19.08 g of sodium carbonate are added to a solution of 16.3 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 10 g of N-methyl-N-(β-cyanoethyl)amine in 160 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 4 hours at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 50 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 19.17 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(β-cyanoethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps. The suspension obtained is heated to reflux washed with 3 times 50 cm3 of water The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C

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

Procedure: To N-methyl-β-alaninenitrile (50 g, mmol in acetonitrile was added piperonyl chloride (50 g, mmol). After stirring for 18 h, the solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with aqueous carbonate, dried (MgSO4), and the solvent was removed in vacuo. The residue was dissolved in methanol saturated with ammonia (600 mL) and Raney nickel (10 g) was added. After shaking under an atmosphere of hydrogen at 20 psi for 6 h, the reaction was filtered through celite and the solvent was removed in vacuo to give 65 g of N-(1,3-benzodioxol-5-ylmethyl)-N-methyl-1,3-propanediamine. the solvent was removed in vacuo The residue was dissolved in CH2Cl2 washed with aqueous carbonate dried (MgSO4) the solvent was removed in vacuo The residue was dissolved in methanol saturated with ammonia (600 mL) and Raney nickel (10 g) was added After shaking under an atmosphere of hydrogen at 20 psi for 6 h the reaction was filtered through celite the solvent was removed in vacuo

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

Procedure: A solution of 116 g of p-chlorocinnamyl bromide in 500 ml of methylene chloride is added dropwise with stirring to a mixture of 42 g of 3-methylamino-propionitrile and 8.9 g of benzyl-tri-(n-butyl)ammonium bromide in 1 liter of methylene chloride and 500 ml of 2 N sodium hydroxide solution at room temperature and under a nitrogen atmosphere, and the emulsion stirred for 65 hours at room temperature. The organic phase is separated, washed with water, dried over sodium sulphate and evaporated to yield 3-[N-(p-chlorocinnamyl)-methylamino]-propionitrile. M.P. 143° [hydrogen oxalate form] The organic phase is separated washed with water dried over sodium sulphate evaporated

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

Procedure: A solution of 116 g of p-chlorocinnamyl bromide in 500 ml of methylene chloride is added dropwise with stirring to a mixture of 42 g of 3-methylamino-propionitrile and 8.9 g of benzyl-tri-(n-butyl)ammonium bromide in 1 liter of methylene chloride and 500 ml of 2 N sodium hydroxide solution at room temperature and under a nitrogen atmosphere, and the emulsion stirred for 65 hours at room temperature. The organic phase is separated, washed with water, dried over sodium sulphate and evaporated to yield 3-[N-(p-chlorocinnamyl)-methylamino]-propionitrile. M.P. 143° [hydrogen oxalate form] The organic phase is separated washed with water dried over sodium sulphate evaporated

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

Procedure: To Isatoic Anhydride (4.60 g, 28.2 mmol) in N,N-Dimethylformamide (30 mL) was added 3-Methylamino-propionitrile (3.00 mL, 32.1 mmol) and the reaction was stirred under an atmosphere of Nitrogen. After 6 h, the mixture was poured into 200 mL water, then extracted 3×100 mL DCM, washed with 100 mL satd. sodium bicarbonate, which was back extracted with 50 mL DCM. The combined organics were washed with brine (100 mL) and dried over sodium sulfate, then conc. in vacuo afforded 2-Amino-N-(2-cyano-ethyl)-N-methyl-benzamide as an oil in quantitative yield. 1H-NMR: 7.18 (dd, 1H, J=9.0, 9.0 Hz), 7.13 (d, 1H, J=7.3 Hz), 6.74 (m, 2H), 4.31 (br s, 2H), 3.76 (t, 2H, J=6.6 Hz), 3.15 (s, 3H), 2.75 (t, 2H, J=6.6 Hz). extracted 3×100 mL DCM washed with 100 mL sodium bicarbonate, which was back extracted with 50 mL DCM The combined organics were washed with brine (100 mL) dried over sodium sulfate

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

Procedure: 50 gms, 0.208 moles of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 21.2 gms, 0.252 moles of 3-methylaminopropionitrile were charged in a round bottom flask containing 350 ml hexamethylphosphoramide. The reaction mass was stirred at about 100° C. for 9 hours, cooled to a temperature of 25° C. and then charged with 250 ml isopropanol. The reaction mass was further stirred for 15 minutes, filtered and washed with 50 ml isopropanol and subjected to drying at 50° C. for 7-8 hours to yield N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine hydrochloride (43 gms). cooled to a temperature of 25° C. The reaction mass was further stirred for 15 minutes filtered washed with 50 ml isopropanol to drying at 50° C. for 7-8 hours

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

Procedure: 50 gms, 0.208 moles of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 21.2 gms, 0.252 moles of 3-methylaminopropionitrile were charged in a round bottom flask containing 350 ml hexamethylphosphoramide. The reaction mass was stirred at about 100° C. for 9 hours, cooled to a temperature of 25° C. and then charged with 250 ml isopropanol. The reaction mass was further stirred for 15 minutes, filtered and washed with 50 ml isopropanol and subjected to drying at 50° C. for 7-8 hours to yield N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine hydrochloride (43 gms). cooled to a temperature of 25° C. The reaction mass was further stirred for 15 minutes filtered washed with 50 ml isopropanol to drying at 50° C. for 7-8 hours

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

Procedure: 50 gms, 0.208 moles of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 21.2 gms, 0.252 moles of 3-methylaminopropionitrile were charged in a round bottom flask containing 350 ml dimethylformamide. The reaction mass was stirred at about 100° C. for 6 hours, cooled to 25° C. and charged with 250 ml isopropanol. The reaction mass was further stirred for 15 minutes, filtered and washed with 50 ml isopropanol and subjected to drying at 50° C. for 7-8 hours to yield N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine hydrochloride (50 gms). cooled to 25° C. The reaction mass was further stirred for 15 minutes filtered washed with 50 ml isopropanol to drying at 50° C. for 7-8 hours

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

Procedure: The patent 007' teaches the preparation of alfuzosin or a salt thereof by reacting 4-amino-2-chloro-6,7-dimethoxy quinazoline of formula (II) with 3-methylaminopropionitrile of formula (III) in the presence of isoamyl alcohol to obtain N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine of formula (IV) which is further hydrogenated in the presence of Raney-Nickel using 15% ammoniacal ethanol by applying 80 Kg pressure at 70° C. for 96 hours to obtain N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methylpropylenediamine of formula (V) which is then converted to the hydrochloride salt. The obtained N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methylpropylenediamine hydrochloride is then treated with carbonyldiimidazole-activated tetrahydrofuroic acid by adding a diamine compound in the presence of carbonyldiimidazole to obtain alfuzosin base which is then converted into alfuzosin hydrochloride salt.