cyclobutylmethanamine

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

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

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

Procedure: Using a procedure similar to that described in Example 15, but starting with 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (3.4 g) in dichloromethane (100 cc) and cyclobutylmethylamine (4.5 g), and after recrystallization in isopropyl ether, N-cyclobutylmethyl-10-[(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (1.7 g) is obtained in the form of white crystals, m.p. 133° C. after recrystallization in isopropyl ether

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

Procedure: By working in a manner similar to that described below in Example 103, but starting with 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonyl chloride hydrochloride (3.4 g) in dichloromethane (100 cc) and with cyclobutylmethylamine (4.5 g), N-(cyclobutylmethyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (1.7 g) is obtained, after recrystallization in isopropyl ether, in the form of white crystals, m.p. 133° C.

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

Procedure: Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (200 mg, 0.654 mmol) and HATU (372 mg, 0.98 mmol) in DMF (3 mL) was added triethylamine (198 mg, 1.961 mmol). Then cyclobutylmethanamine (0.784 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction mixture was purified by preparative HPLC to give the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.70-8.65 (m, 2H), 8.45-8.40 (m, 2H), 8.13 (d, J=7.6 Hz, 2H), 7.78 (d, J=7.6 Hz, 2H), 3.31 (m, 2H), 2.56-2.53 (m, 1H), 2.05-2.00 (m, 2H), 1.85-1.82 (m, 2H), 1.75-1.72 (m, 2H). MS m/Z [M+H]+ 374.1. The reaction mixture was purified by preparative HPLC

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

Procedure: Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (200 mg, 0.654 mmol) and HATU (372 mg, 0.98 mmol) in DMF (3 mL) was added triethylamine (198 mg, 1.961 mmol). Then cyclobutylmethanamine (0.784 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction mixture was purified by preparative HPLC to give the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.70-8.65 (m, 2H), 8.45-8.40 (m, 2H), 8.13 (d, J=7.6 Hz, 2H), 7.78 (d, J=7.6 Hz, 2H), 3.31 (m, 2H), 2.56-2.53 (m, 1H), 2.05-2.00 (m, 2H), 1.85-1.82 (m, 2H), 1.75-1.72 (m, 2H). MS m/Z [M+H]+ 374.1. The reaction mixture was purified by preparative HPLC

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

Procedure: Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (200 mg, 0.654 mmol) and HATU (372 mg, 0.98 mmol) in DMF (3 mL) was added triethylamine (198 mg, 1.961 mmol). Then cyclobutylmethanamine (0.784 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction mixture was purified by preparative HPLC to give the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.70-8.65 (m, 2H), 8.45-8.40 (m, 2H), 8.13 (d, J=7.6 Hz, 2H), 7.78 (d, J=7.6 Hz, 2H), 3.31 (m, 2H), 2.56-2.53 (m, 1H), 2.05-2.00 (m, 2H), 1.85-1.82 (m, 2H), 1.75-1.72 (m, 2H). MS m/Z [M+H]+ 374.1. The reaction mixture was purified by preparative HPLC

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

Procedure: Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (200 mg, 0.654 mmol) and HATU (372 mg, 0.98 mmol) in DMF (3 mL) was added triethylamine (198 mg, 1.961 mmol). Then cyclobutylmethanamine (0.784 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction mixture was purified by preparative HPLC to give the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.70-8.65 (m, 2H), 8.45-8.40 (m, 2H), 8.13 (d, J=7.6 Hz, 2H), 7.78 (d, J=7.6 Hz, 2H), 3.31 (m, 2H), 2.56-2.53 (m, 1H), 2.05-2.00 (m, 2H), 1.85-1.82 (m, 2H), 1.75-1.72 (m, 2H). MS m/Z [M+H]+ 374.1. The reaction mixture was purified by preparative HPLC

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

Procedure: (Aminomethyl)cyclobutane was prepared by lithium aluminum hydride reduction of cyclobutanecarboxamide according to the procedure of Shatkina, T. N.: Reutov, O. A., Dokl. Akad. Nauk. SSSR. (1975) 219:1148 [Chem. Abs. 82: 139453m]. Cyclobutanecarboxamide was prepared as follows: a solution of commercially available cyclobutanecarboxylic acid chloride (10 g) in ethyl ether (500 ml) was stirred at 0° while ammonia gas was introduced, resulting in a white precipitate. This material was collected by filtration and redissolved in 50 ml of ethanol/water (4:1, v/v). This solution was applied to a column containing 75 grams of AG 1-X8 ion exchange resin (hydroxide ion form) (obtained from Bio-Rad Company), and elution was continued with ethanol (1 liter). Evaporation of the eluate provided a quantitative yield (8.36 g) of cyclobutanecarboxamide. was introduced resulting in a white precipitate This material was collected by filtration redissolved in 50 ml of ethanol/water (4:1 containing

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

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

Procedure: Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example Eb) and cyclobutylmethanamine as an off-white solid (67%). MS 414 (MH+).

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

Procedure: Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (237 mg, 0.680 mmol) and cyclobutylmethyl amine (0.205 mL of a 4M/MeOH solution, 0.816 mmol) in 3 mL of EtOH containing TEA (0.140 mL, 1.02 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent. Yield: 262 mg (93%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.83 (m, 2H), 1.97 (m, 1H), 2.02 (m, 1H), 2.20 (m, 2H), 2.73 (m, 1H), 3.37 (m, 2H), 4.27 (m, 4H), 6.93 (d, J=8.98 Hz, 1H), 7.53 (d, J=8.79 Hz, 1H), 8.24 (m, 1H), 8.30 (m, 1H); MS (ESI) 413.95 (MH+). The product was purified by flash chromatography on silica gel using 3:1/hexanes