3-(4-chlorophenyl)propan-1-amine

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

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(1-methylpiperidin-4-yl)-7-trifluoromethanesulfonyloxynaphthalene (0.25 g, 0.67 mmol), triethylamine (0.373 mL, 2.68 mmol), 3-(4-chlorophenyl)propylamine (0.341 mL, 2.01 mmol), and bis(triphenylphosphine)palladium chloride (0.025 g, 0.033 mmol) was blanketed with an atmosphere of carbon monoxide (balloon) and heated to 105° C. for 16 hours (h) . The reaction was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water and brine, dried and concentrated. The residue was flash chromatographed on silica gel (1×3 inches packed with 75% ethyl acetate/hexane). Elution proceeded as follows: 75% ethyl acetate/hexane, 150 mL, nil; ethyl acetate, 150 mL, nil; 2% methanol/1% triethylamine/ethyl acetate, 200 mL and 2% methanol/1% triethylamine/ethyl acetate, 150 mL, 0.196 g of a yellow-oil which slowly crystallized. This material was recrystallized from chloroform/ether to give 0.064 g (23%) of 1-(1-methylpiperidin-4-yl)-7-naphthalene carboxylic acid 3-(4-chlorophenyl)propyl amide as white crystals which had mp 132°-133.5° C.; 1H NMR (250 MHz, CDCl3) δ 8.66 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.58-7.46 (m, 3H), 7.27-7.23 (m, 2H partially obscurred by the NMR solvent), 7.15 (long range coupled d, J=8.5 Hz, 2H), 6.23 (br t, 1H), 3.55 (q, J=6.5 Hz, 2H), 3.39 (sym m, 1H), 3.02 (br d, J=12 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.36 (s, 3H), 2.23 (sym m, 2H), 2.04-1.89 (m, 6H). Analysis calculated for C26H29ClN2O·0.25 H2O: C, 73.40; H, 6.99; N, 6.58. Found: C, 73.30; H, 7.12; N, 6.56. filtered through celite The filtrate was washed with water and brine dried concentrated chromatographed on silica gel (1×3 inches packed with 75% ethyl acetate/hexane) Elution 2% methanol/1% triethylamine/ethyl acetate, 200 mL and 2% methanol/1% triethylamine/ethyl acetate, 150 mL, 0.196 g of a yellow-oil which slowly crystallized This material was recrystallized from chloroform/ether

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

Procedure: An equal molar amount of 3-(4-chlorophenyl)propylamine (prepared in a similar fashion from 4-chlorobenzaldehyde as above) 3′-methoxyacetophenone and 1.25 molar equivalents titanium(IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of I M, 5 mmol). Work-up and chromatography afforded N-[3-(4-chlorophenyl)propyl]-1-(3-methoxyphenyl)ethylamine, 6V, as an oil; m/z (rel. int.) 303 (M+, 8), 288 (91), 196 (4), 164 (10), 135 (100), 125 (61), 103 (21), 91 (21), 77 (18). were mixed 4 hr at rt

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

Procedure: 4-(6-Chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid (Preparation 1) (67 mg, 0.18 mmol) was diluted with DCM (1 mL) followed by the addition of oxalyl chloride in DCM (2M) (98 μl, 0.20 mmol) and DMF (1 drop). After stirring for 10 minutes, 3-(4-chlorophenyl)propan-1-amine (33 mg, 0.20 mmol) and DIEA (68 μl, 0.39 mmol) were added and the reaction was stirred at ambient temperature for 2 hours. The reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate (80 mg, 0.15 mmol, 85% yield). the reaction was stirred at ambient temperature for 2 hours eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes

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

Procedure: 4-(6-Chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid (Preparation 1) (67 mg, 0.18 mmol) was diluted with DCM (1 mL) followed by the addition of oxalyl chloride in DCM (2M) (98 μl, 0.20 mmol) and DMF (1 drop). After stirring for 10 minutes, 3-(4-chlorophenyl)propan-1-amine (33 mg, 0.20 mmol) and DIEA (68 μl, 0.39 mmol) were added and the reaction was stirred at ambient temperature for 2 hours. The reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate (80 mg, 0.15 mmol, 85% yield). the reaction was stirred at ambient temperature for 2 hours eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes

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

Procedure: 4-(6-Chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid (Preparation 1) (67 mg, 0.18 mmol) was diluted with DCM (1 mL) followed by the addition of oxalyl chloride in DCM (2M) (98 μl, 0.20 mmol) and DMF (1 drop). After stirring for 10 minutes, 3-(4-chlorophenyl)propan-1-amine (33 mg, 0.20 mmol) and DIEA (68 μl, 0.39 mmol) were added and the reaction was stirred at ambient temperature for 2 hours. The reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate (80 mg, 0.15 mmol, 85% yield). the reaction was stirred at ambient temperature for 2 hours eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes

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

Procedure: 2-Amino-5-benzoyloxazole (3.0 g, 16 mmol) was combined with p-chlorophenylpropylamine (2.7 g, 16 mmol) in 15 ml of water and t-butanol (2:1) and heated under reflux in nitrogen for 16 hours. The solvents were removed in a vacuum, and the residue was treated with hot acetonitrile and filtered. After concentration in vacuum, the filtrate was chromatographed on silica gel using hexane and ethyl acetate (1:1) as eluent to give 0.24 mg (4.4%) of the title compound as an oil. NMR (CDCl3): 1.8-2.0 (m, 2H), 2.4-2.7 (m, 2H), 3.1-3.4 (m, 2H), 5.0 (b s, 1H), 7.0-7.5 (m, 7H), 7.8 (s, 1H), 7.9-8.0 (m, 2H). heated under reflux in nitrogen for 16 hours The solvents were removed in a vacuum the residue was treated with hot acetonitrile filtered After concentration in vacuum the filtrate was chromatographed on silica gel

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

Procedure: 2-Amino-5-benzoyloxazole (3.0 g, 16 mmol) was combined with p-chlorophenylpropylamine (2.7 g, 16 mmol) in 15 ml of water and t-butanol (2:1) and heated under reflux in nitrogen for 16 hours. The solvents were removed in a vacuum, and the residue was treated with hot acetonitrile and filtered. After concentration in vacuum, the filtrate was chromatographed on silica gel using hexane and ethyl acetate (1:1) as eluent to give 0.24 mg (4.4%) of the title compound as an oil. NMR (CDCl3): 1.8-2.0 (m, 2H), 2.4-2.7 (m, 2H), 3.1-3.4 (m, 2H), 5.0 (b s, 1H), 7.0-7.5 (m, 7H), 7.8 (s, 1H), 7.9-8.0 (m, 2H). heated under reflux in nitrogen for 16 hours The solvents were removed in a vacuum the residue was treated with hot acetonitrile filtered After concentration in vacuum the filtrate was chromatographed on silica gel

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

Procedure: 16.7 g (0.1 mol) of dichloromaleic anhydride and 17.0 g (0.1 mol) of 3-(4-chlorophenyl)-propylamine are stirred in 100 ml of glacial acetic acid under reflux for 4 hours. 50 ml of water are added and the mixture is cooled to 20° C. The product is filtered off with suction and dried. 26.1 g (82% of theory) of dichloromaleic acid N-[3-(4-chlorophenyl)-propyl]-imide of melting point 72°-73° C. are obtained. under reflux for 4 hours The product is filtered off with suction dried

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

Procedure: 4-(6-Chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid (Preparation 1) (67 mg, 0.18 mmol) was diluted with DCM (1 mL) followed by the addition of oxalyl chloride in DCM (2M) (98 μl, 0.20 mmol) and DMF (1 drop). After stirring for 10 minutes, 3-(4-chlorophenyl)propan-1-amine (33 mg, 0.20 mmol) and DIEA (68 μl, 0.39 mmol) were added and the reaction was stirred at ambient temperature for 2 hours. The reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate (80 mg, 0.15 mmol, 85% yield). the reaction was stirred at ambient temperature for 2 hours eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes

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

Procedure: 4-(6-Chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid (Preparation 1) (67 mg, 0.18 mmol) was diluted with DCM (1 mL) followed by the addition of oxalyl chloride in DCM (2M) (98 μl, 0.20 mmol) and DMF (1 drop). After stirring for 10 minutes, 3-(4-chlorophenyl)propan-1-amine (33 mg, 0.20 mmol) and DIEA (68 μl, 0.39 mmol) were added and the reaction was stirred at ambient temperature for 2 hours. The reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate (80 mg, 0.15 mmol, 85% yield). the reaction was stirred at ambient temperature for 2 hours eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(1-methylpiperidin-4-yl)-7-trifluoromethanesulfonyloxynaphthalene (0.25 g, 0.67 mmol), triethylamine (0.373 mL, 2.68 mmol), 3-(4-chlorophenyl)propylamine (0.341 mL, 2.01 mmol), and bis(triphenylphosphine)palladium chloride (0.025 g, 0.033 mmol) was blanketed with an atmosphere of carbon monoxide (balloon) and heated to 105° C. for 16 hours (h) . The reaction was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water and brine, dried and concentrated. The residue was flash chromatographed on silica gel (1×3 inches packed with 75% ethyl acetate/hexane). Elution proceeded as follows: 75% ethyl acetate/hexane, 150 mL, nil; ethyl acetate, 150 mL, nil; 2% methanol/1% triethylamine/ethyl acetate, 200 mL and 2% methanol/1% triethylamine/ethyl acetate, 150 mL, 0.196 g of a yellow-oil which slowly crystallized. This material was recrystallized from chloroform/ether to give 0.064 g (23%) of 1-(1-methylpiperidin-4-yl)-7-naphthalene carboxylic acid 3-(4-chlorophenyl)propyl amide as white crystals which had mp 132°-133.5° C.; 1H NMR (250 MHz, CDCl3) δ 8.66 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.58-7.46 (m, 3H), 7.27-7.23 (m, 2H partially obscurred by the NMR solvent), 7.15 (long range coupled d, J=8.5 Hz, 2H), 6.23 (br t, 1H), 3.55 (q, J=6.5 Hz, 2H), 3.39 (sym m, 1H), 3.02 (br d, J=12 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.36 (s, 3H), 2.23 (sym m, 2H), 2.04-1.89 (m, 6H). Analysis calculated for C26H29ClN2O·0.25 H2O: C, 73.40; H, 6.99; N, 6.58. Found: C, 73.30; H, 7.12; N, 6.56. filtered through celite The filtrate was washed with water and brine dried concentrated chromatographed on silica gel (1×3 inches packed with 75% ethyl acetate/hexane) Elution 2% methanol/1% triethylamine/ethyl acetate, 200 mL and 2% methanol/1% triethylamine/ethyl acetate, 150 mL, 0.196 g of a yellow-oil which slowly crystallized This material was recrystallized from chloroform/ether