2-(benzenesulfonyl)ethanamine;hydrochloride

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 32.3 g (0.102 mole) of 2-[2-(phenylsulfonyl)ethyl]-1H-isoindole-1,3-(2H)-dione and 11.8 g (0.2 mole) of 85% hydrazine hydrate in 500 ml of absolute ethanol was refluxed for 6 hr. The reaction mixture was cooled to room temperature, filtered and concentrated. The concentrate was dissolved in chloroform and extracted with a 5% sodium hydroxide solution. The chloroform layer was dried and evaporated to give a clear oil. The oil (the free base of the title compound) was reacted with ethereal hydrogen chloride. Recrystallization of the precipitated salt from methanol-diethyl ether gave white crystalline product (40.5% yield), m.p. 151°-154° C. filtered concentrated The concentrate was dissolved in chloroform extracted with a 5% sodium hydroxide solution The chloroform layer was dried evaporated to give a clear oil

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound and its hydrochloride salt are prepared according to Procedure D utilizing 5-{4-[4-(3-fluoro-benzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furaldehyde (0.317 mmol, 0.15 g), Phenylsulfonylethyl amine hydrochloride salt (0.475 mmol, 0.105 g) in the presence of Et3N (0.51 mmol, 0.067 mL) and NaBH4 (0.79 mmol, 0.029 g) in THF/MeOH. 1H NMR (DMSO-d6) 11.76 (bs, 1H); 9.82 (bs, 2H); 9.59 (s, 1H); 8.91 (s, 1H); 8.37 (d, 1H); 8.04 (m, 1H); 7.98-7.89 (m, 3H); 7.78 (m, 2H); 7.67 (m, 2H); 7.48 (m, 1H); 7.37-7.27 (m, 4H); 7.19 (m, 1H); 6.78 (m, 1H); 5.31 (s, 2H); 4.41 (s, 2H); 3.89 (m, 2H); 3.27 (m, 2H). Electrospray MS 643.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared according to Procedure (I) utilizing 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoic acid (0.25 g, 0.45 mmol), 2-(phenylsulfonyl)-ethylamine hydrochloride (0.30 g, 1.36 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.26 g, 1.36 mmol) and diisopropylethylamine (0.55 mL, 3.18 mmol) in acetonitrile. Electrospray MS m/z 683 (MH+). Prepared

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The carboxylic acid from Step D (60.0 mg, 0.188 mmol), amine from Step G (41.6 mg, 0.188 mmol), EDC hydrochloride (43.2 mg, 0.225 mmol), HOBT (30.4 mg, 0.225 mmol), and N,N-diisopropylethylamine (0.163 mL, 0.938 mmol) were stirred in dry, degassed DMF (1 mL) at 25° C. for 16 hours. The crude product was purified by preparative HPLC using a gradient of 5%-95% acetonitrile/0.1% TFA; 95%-5%/0.1% aqueous TFA over 15 min. The title compound was isolated after conversion to the HCl salt. MS (es) m+1=439. 1H-NMR (CD3OD): δ7.87 (d, 2H, J=7.8 Hz); 7.71 (d, 2H, J=8.5 Hz); 7.70 (t, 1H, J=7.8 Hz); 7.59 (t, 2H, J=7.7 Hz); 7.49 (s, 1H); 7.17 (d, 2H, J=8.0 Hz); 6.24 (bd, 1H, J=7.7 Hz); 4.64 (dd, 1H, J=12.3, 8.9 Hz); 3.74 (d, 1H, J=12.3 Hz), 3.28-3.57 (m, 4H). in dry degassed DMF (1 mL) at 25° C. for 16 hours The crude product was purified by preparative HPLC

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The sulfone from Step F (1.20 g, 4.21 mmol) was dissolved in ethyl acetate (10 mL). The solution was saturated with hydrogen chloride gas and stirred for 1 hour, then concentrated in vacuo. The residue was partitioned between methylene chloride (10 mL) and water (10 mL). The layers were separated and the aqueous layer was washed with methylene chloride (3×10 mL) and concentrated in vacuo to provide the title compound as a white solid which was sufficiently pure for use in the next step. concentrated in vacuo The residue was partitioned between methylene chloride (10 mL) and water (10 mL) The layers were separated the aqueous layer was washed with methylene chloride (3×10 mL) concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The sulfone from Step F (1.20 g, 4.21 mmol) was dissolved in ethyl acetate (10 mL). The solution was saturated with hydrogen chloride gas and stirred for 1 hour, then concentrated in vacuo. The residue was partitioned between methylene chloride (10 mL) and water (10 mL). The layers were separated and the aqueous layer was washed with methylene chloride (3×10 mL) and concentrated in vacuo to provide the title compound as a white solid which was sufficiently pure for use in the next step. concentrated in vacuo The residue was partitioned between methylene chloride (10 mL) and water (10 mL) The layers were separated the aqueous layer was washed with methylene chloride (3×10 mL) concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 32.3 g (0.102 mole) of 2-[2-(phenylsulfonyl)ethyl]-1H-isoindole-1,3-(2H)-dione and 11.8 g (0.2 mole) of 85% hydrazine hydrate in 500 ml of absolute ethanol was refluxed for 6 hr. The reaction mixture was cooled to room temperature, filtered and concentrated. The concentrate was dissolved in chloroform and extracted with 5% sodium hydroxide. The chloroform layer was dried and evaporated to give a clear oil. The oil, the free base of the title compound, was reacted with ethereal hydrogen chloride. Recrystallization of the precipitated salt from methanol-diethyl ether gave white crystalline product, m.p. 151°-154° C. in 40.5% yield. filtered concentrated The concentrate was dissolved in chloroform extracted with 5% sodium hydroxide The chloroform layer was dried evaporated to give a clear oil

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound and its hydrochloride salt are prepared according to Procedure D utilizing 5-{4-[4-(3-fluoro-benzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furaldehyde (0.317 mmol, 0.15 g) , Phenylsulfonylethyl amine hydrochloride salt (0.475 mmol, 0.105 g) in the presence of Et3N (0.51 mmol, 0.067 mL) and NaBH4 (0.79 mmol, 0.029 g) in THF/MeOH. 1H NMR (DMSO-d6) 11.76 (bs, 1H); 9.82 (bs, 2H); 9.59 (s, 1H); 8.91 (s, 1H); 8.37 (d, 1H); 8.04 (m, 1H); 7.98-7.89 (m, 3H); 7.78 (m, 2H); 7.67 (m, 2H); 7.48 (m, 1H); 7.37-7.27 (m, 4H); 7.19 (m, 1H); 6.78 (m, 1H); 5.31 (s, 2H); 4.41 (s, 2H); 3.89 (m, 2H); 3.27 (m, 2H). Electrospray MS 643.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound and its hydrochloride salt are prepared according to Procedure D utilizing 5-{4-[4-(3-fluoro-benzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furaldehyde (0.317 mmol, 0.15 g) , Phenylsulfonylethyl amine hydrochloride salt (0.475 mmol, 0.105 g) in the presence of Et3N (0.51 mmol, 0.067 mL) and NaBH4 (0.79 mmol, 0.029 g) in THF/MeOH. 1H NMR (DMSO-d6) 11.76 (bs, 1H); 9.82 (bs, 2H); 9.59 (s, 1H); 8.91 (s, 1H); 8.37 (d, 1H); 8.04 (m, 1H); 7.98-7.89 (m, 3H); 7.78 (m, 2H); 7.67 (m, 2H); 7.48 (m, 1H); 7.37-7.27 (m, 4H); 7.19 (m, 1H); 6.78 (m, 1H); 5.31 (s, 2H); 4.41 (s, 2H); 3.89 (m, 2H); 3.27 (m, 2H). Electrospray MS 643.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared according to Procedure (I) utilizing 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]6-quinazolinyl}-2-furyl)-2-propenoic acid (0.25 g, 0.45 mmol), 2-(phenylsulfonyl)-ethylamine hydrochloride (0.30 g, 1.36 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.26 g, 1.36 mmol) and diisopropylethylamine (0.55 mL, 3.18 mmol) in acetonitrile. Electrospray MS m/z 683 (MH+). Prepared

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared according to Procedure (I) utilizing 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]6-quinazolinyl}-2-furyl)-2-propenoic acid (0.25 g, 0.45 mmol), 2-(phenylsulfonyl)-ethylamine hydrochloride (0.30 g, 1.36 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.26 g, 1.36 mmol) and diisopropylethylamine (0.55 mL, 3.18 mmol) in acetonitrile. Electrospray MS m/z 683 (MH+). Prepared

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound and its hydrochloride salt are prepared according to Procedure D utilizing 5-{4-[4-(3-fluoro-benzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furaldehyde (0.317 mmol, 0.15 g), Phenylsulfonylethyl amine hydrochloride salt (0.475 mmol, 0.105 g) in the presence of Et3N (0.51 mmol, 0.067 mL) and NaBH4 (0.79 mmol, 0.029 g) in THF/MeOH. 1H NMR (DMSO-d6) 11.76 (bs, 1H); 9.82 (bs, 2H); 9.59 (s, 1H); 8.91 (s, 1H); 8.37 (d, 1H); 8.04 (m, 1H); 7.98–7.89 (m, 3H); 7.78 (m, 2H); 7.67 (m, 2H); 7.48 (m, 1H); 7.37–7.27 (m, 4H); 7.19 (m, 1H); 6.78 (m, 1H); 5.31 (s, 2H); 4.41 (s, 2H); 3.89 (m, 2H); 3.27 (m, 2H). Electrospray MS 643.