4-chloro-3-[2-(dimethylamino)ethoxy]aniline

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

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

Procedure: To a suspension of 4-chloro-3-(2-dimethylaminoethoxy)aniline (D6, 1.22 g, 0.006 mol) in McOH (30 ml) containing dimethoxyethanal in MTBE (1.76 g, 0.17 mol) and glacial acetic acid (1.71 g) was added sodium cyanoborohydride (1.78 g, 0.03 mol) portionwise at 0 C. After addition, the reaction was left to stir at room temperature for 1 hour, and then 10% aqueous NaOH was added and the mixture was extraced with CH2Cl2 and the combined organic layers were dried (Na2SO4), and concentrated in vacuo to give a brown oil. Purification by FCC, eluting with CH2Cl2 gave the title compound (1.49 mg, 87% ) After addition the reaction was left the combined organic layers were dried (Na2SO4) concentrated in vacuo to give a brown oil Purification by FCC eluting with CH2Cl2

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

Procedure: To 4-chloro-3-(2-dimethylaminoethoxy)nitrobenzene (D5, 1.5 g, 0.006 mol) in EtOH (25 ml) at 60° C., was added SnCl2 (4.2 g) in concentrated hydrochloric acid (7.6 ml) dropwise. The mixture was then heated under reflux for 30 mins and after cooling to room temperature, diluted with water (50 ml), and basified by addition of 40% aq. sodium hydroxide. The mixture was then heated under reflux for 30 mins

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

Procedure: To a solution containing 4-aminoquinaldine (74 mg, 0.46 mmol) in anhydrous THF (5.0 Ml) was added triethylamine (0.2 Ml, 1.4 mmol). The solution was cooled to 0° C. followed by the addition of triphosgene (45.0 mg, 0.18 mmol). The reaction mixture was stirred at 0° C. for 10 minutes before the addition of a solution of 4-chloro-3-(2-dimethylamino-ethoxy)aniline (100.0 mg, 0.46 mmol, for its synthsis see Steps 1–3 for Example 1) in THF (2 Ml). The ice bath was removed and the mixture was heated at 65° C. for 2 hours before it was poured into a mixture of CH2Cl2/MeOH (20 Ml, 7:1 ratio). The resulting mixture was washed with 10% sodium bicarbonate (aq. 15.0 Ml). The organic layer was dried over MgSO4 and concentrated. The oily residue was chromatographed over silica gel (eluent: 20% MeOH in EtOAc) to give the desired product as an off-white solid (82.0 mg, 45% yield). The ice bath was removed the mixture was heated at 65° C. for 2 hours before it was poured into a mixture of CH2Cl2/MeOH (20 Ml, 7:1 ratio) The resulting mixture was washed with 10% sodium bicarbonate (aq. 15.0 Ml) The organic layer was dried over MgSO4 concentrated The oily residue was chromatographed over silica gel (eluent: 20% MeOH in EtOAc)

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

Procedure: To a solution containing 4-aminoquinaldine (74 mg, 0.46 mmol) in anhydrous THF (5.0 Ml) was added triethylamine (0.2 Ml, 1.4 mmol). The solution was cooled to 0° C. followed by the addition of triphosgene (45.0 mg, 0.18 mmol). The reaction mixture was stirred at 0° C. for 10 minutes before the addition of a solution of 4-chloro-3-(2-dimethylamino-ethoxy)aniline (100.0 mg, 0.46 mmol, for its synthsis see Steps 1–3 for Example 1) in THF (2 Ml). The ice bath was removed and the mixture was heated at 65° C. for 2 hours before it was poured into a mixture of CH2Cl2/MeOH (20 Ml, 7:1 ratio). The resulting mixture was washed with 10% sodium bicarbonate (aq. 15.0 Ml). The organic layer was dried over MgSO4 and concentrated. The oily residue was chromatographed over silica gel (eluent: 20% MeOH in EtOAc) to give the desired product as an off-white solid (82.0 mg, 45% yield). The ice bath was removed the mixture was heated at 65° C. for 2 hours before it was poured into a mixture of CH2Cl2/MeOH (20 Ml, 7:1 ratio) The resulting mixture was washed with 10% sodium bicarbonate (aq. 15.0 Ml) The organic layer was dried over MgSO4 concentrated The oily residue was chromatographed over silica gel (eluent: 20% MeOH in EtOAc)

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

Procedure: To a suspension of 4-chloro-3-(2-dimethylaminoethoxy)aniline (D6, 1.22 g, 0.006 mol) in McOH (30 ml) containing dimethoxyethanal in MTBE (1.76 g, 0.17 mol) and glacial acetic acid (1.71 g) was added sodium cyanoborohydride (1.78 g, 0.03 mol) portionwise at 0 C. After addition, the reaction was left to stir at room temperature for 1 hour, and then 10% aqueous NaOH was added and the mixture was extraced with CH2Cl2 and the combined organic layers were dried (Na2SO4), and concentrated in vacuo to give a brown oil. Purification by FCC, eluting with CH2Cl2 gave the title compound (1.49 mg, 87% ) After addition the reaction was left the combined organic layers were dried (Na2SO4) concentrated in vacuo to give a brown oil Purification by FCC eluting with CH2Cl2

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

Procedure: To a suspension of 4-chloro-3-(2-dimethylaminoethoxy)aniline (D6, 1.22 g, 0.006 mol) in McOH (30 ml) containing dimethoxyethanal in MTBE (1.76 g, 0.17 mol) and glacial acetic acid (1.71 g) was added sodium cyanoborohydride (1.78 g, 0.03 mol) portionwise at 0 C. After addition, the reaction was left to stir at room temperature for 1 hour, and then 10% aqueous NaOH was added and the mixture was extraced with CH2Cl2 and the combined organic layers were dried (Na2SO4), and concentrated in vacuo to give a brown oil. Purification by FCC, eluting with CH2Cl2 gave the title compound (1.49 mg, 87% ) After addition the reaction was left the combined organic layers were dried (Na2SO4) concentrated in vacuo to give a brown oil Purification by FCC eluting with CH2Cl2

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

Procedure: To 4-chloro-3-(2-dimethylaminoethoxy)nitrobenzene (D5, 1.5 g, 0.006 mol) in EtOH (25 ml) at 60° C., was added SnCl2 (4.2 g) in concentrated hydrochloric acid (7.6 ml) dropwise. The mixture was then heated under reflux for 30 mins and after cooling to room temperature, diluted with water (50 ml), and basified by addition of 40% aq. sodium hydroxide. The mixture was then heated under reflux for 30 mins

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

Procedure: 2-Bromo-4,5-dimethoxybenzenesulfonyl chloride To a cooled (0° C.) solution of 4-bromoveratrole (15 mL, 100 mmol) in dichloromethane (100 mL) was added dropwise chlorosufonic acid (26 mL, 400 mmol). The reaction was allowed to slowly warm to ambient temperature and maintained for 3 hours, at which time it was concentrated and diluted with ether (300 mL). The resultant solution was then washed with ice cold water (2×250 mL) and brine (100 mL), dried over magnesium sulfate, and concentrated to furnish a grayish powder (25 g, 78%). b) 2-Bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide To a solution of 3-[2-(N,N-dimethylamino)ethoxy]-4-chloroaniline (1.9 g, 8.8 mmol) in dichloroethane (50 mL) was added 2-bromo-3,4-dimethoxybenzenesulfonyl chloride (2.8 g, 8.8 mmol). The resultant solution was maintained at ambient temperature for 3 days, then concentrated. Crystallization from ethanol gave the title compound (3.4 g, 72%). MS (ES+) m/e 493 [M+H]+ c) 4,5-Dimethoxy-biphenyl-2-sulfonic acid [4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide To a solution of 2-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide (50 mg, 0.1 mmol) in dimethoxyethane/water (25:3, 2 mL) was added phenylboronic acid (120 mg, 1.0 mmol), cesium carbonate (820 mg, 2.5 mmol), and tetrakispalladium triphenylphosphine (6 mg, 0.005 mmol). The resultant mixture was heated at 90° C. for 16 hours, at which time it was diluted with ethyl acetate (10 mL) and washed with 5% sodium hydroxide (2×10 mL) and brine (10 mL). The solution was then dried over magnesium sulfate and concentrated to give a yellow oil. Purification by HPLC (gradient; 10% acetonitrile/water to 90% acetonitrile/water) furnished the title compound (15 mg, 31%) as a white solid. MS (ES+) m/e 491 [M+H]+ Example 20 was prepared as outlined in Example 19, substituting the appropriate starting materials. concentrated Crystallization from ethanol

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

Procedure: 2-Bromo-4,5-dimethoxybenzenesulfonyl chloride To a cooled (0° C.) solution of 4-bromoveratrole (15 mL, 100 mmol) in dichloromethane (100 mL) was added dropwise chlorosufonic acid (26 mL, 400 mmol). The reaction was allowed to slowly warm to ambient temperature and maintained for 3 hours, at which time it was concentrated and diluted with ether (300 mL). The resultant solution was then washed with ice cold water (2×250 mL) and brine (100 mL), dried over magnesium sulfate, and concentrated to furnish a grayish powder (25 g, 78%). b) 2-Bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide To a solution of 3-[2-(N,N-dimethylamino)ethoxy]-4-chloroaniline (1.9 g, 8.8 mmol) in dichloroethane (50 mL) was added 2-bromo-3,4-dimethoxybenzenesulfonyl chloride (2.8 g, 8.8 mmol). The resultant solution was maintained at ambient temperature for 3 days, then concentrated. Crystallization from ethanol gave the title compound (3.4 g, 72%). MS (ES+) m/e 493 [M+H]+ c) 4,5-Dimethoxy-biphenyl-2-sulfonic acid [4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide To a solution of 2-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide (50 mg, 0.1 mmol) in dimethoxyethane/water (25:3, 2 mL) was added phenylboronic acid (120 mg, 1.0 mmol), cesium carbonate (820 mg, 2.5 mmol), and tetrakispalladium triphenylphosphine (6 mg, 0.005 mmol). The resultant mixture was heated at 90° C. for 16 hours, at which time it was diluted with ethyl acetate (10 mL) and washed with 5% sodium hydroxide (2×10 mL) and brine (10 mL). The solution was then dried over magnesium sulfate and concentrated to give a yellow oil. Purification by HPLC (gradient; 10% acetonitrile/water to 90% acetonitrile/water) furnished the title compound (15 mg, 31%) as a white solid. MS (ES+) m/e 491 [M+H]+ Example 20 was prepared as outlined in Example 19, substituting the appropriate starting materials. concentrated Crystallization from ethanol

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

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

Procedure: A solution of 3-(2dimethylaminoethoxy)-4chloronitrobenzene (D57) (295 mg) in ethanol (5 ml) was heated to 60° C. and treated dropwise with a solution of stannous chloride (0.82 g) in concentrated hydrochloric acid (1.5 ml) with stiring. After heating to reflux for 1/2 h, the reaction mixture was cooled, diluted with water and basified with 40% NaOH, then extracted into dichloromethane. The dried (Na2SO4) organic phase was evaporated under reduced pressure to give the title compound as a yellow oil. (221 mg, 85%). After heating to reflux for 1/2 h the reaction mixture was cooled extracted into dichloromethane The dried (Na2SO4) organic phase was evaporated under reduced pressure