cyclohexanamine;hydrochloride

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

Procedure: A suspension of cyclohexylamine hydrochloride (310 mg, 2.28 mmol) and (2-methylphenyl)cyanamide (365 mg, 2.76 mmol) in dry chlorobenzene was heated at 125°-135° for 4 hrs. The solvent was evaporated in vacuo with heating, and the residue partitioned between CH2Cl2 and 20×8 ml 10% HCl. The aqueous extracts were made alkaline to pH 9-9.5, and the white precipitate collected after standing at 4° C. overnight. Two recrystallizations from EtOH/H2O gave 140 mg (22%) of white needles, mp 145°-146°, 1H (CD3OD) 1.149-2.054 (m, 10 H), 2.164 (s, 3 H), 3.50 (m, 1 H), 6.875 (d, 1H, J=7.5 Hz), 6.968 (t, 1H, J=7.5 Hz), 7.118 (t, 1H, J=7.5 Hz), 7.177 (d, 1H, J=7.5 Hz). Anal. Calcd for C14H21N3 : C, 72.69; H, 9.15; N, 18.16. Found: C, 72.72; H, 9.24; N, 18.18. was heated at 125°-135° for 4 hrs The solvent was evaporated in vacuo with heating the residue partitioned between CH2Cl2 and 20×8 ml 10% HCl the white precipitate collected Two recrystallizations from EtOH/H2O

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Adamantan-1-ylcyanamide (514 mg, 2.92 mmol), and cyclohexylamine hydrochloride (398 mg, 2.93 mmol) were finely ground together, and heated at 200° C. for 10 min. The resultant glassy solid was pulverized, and extracted twice with 50 ml boiling 5% HCl. The insoluble material was filtered, and dried. 346 mg, mp 264-270 (p.h.b. 240° C.). On cooling the combined aqueous extracts to 25°, a white ppt. formed, and was filtered off, 56 mg. Combined crude yield: 44%. Crystallization of a 50 mg sample of the crude product from EtOH/Et2O afforded white needles (25 mg, mp 269°-271° C. (p.h.b. 240°), lit. 268°-269° C.). 1H (CD3OD) 1.208-1.474 (m, 5H), 1.744 (s, 9H), 1.967 (s, 8H), 2.119 (5, 3H), 3.434 (m, 1H), 13C (CD3OD) (broad band decoupled) 25.55, 26.26, 30.96, 33.74, 36.74, 42.73. extracted twice with 50 ml The insoluble material was filtered dried 346 mg, mp 264-270 (p.h.b. 240° C.) On cooling the combined aqueous extracts to 25° formed was filtered off Crystallization of a 50 mg sample of the crude product from EtOH/Et2O afforded white needles (25 mg, mp 269°-271° C. (p.h.b. 240°), lit. 268°-269° C.)

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Adamantan-1-ylcyanamide (514 mg, 2.92 mmol), and cyclohexylamine hydrochloride (398 mg, 2.93 mmol) were finely ground together, and heated at 200° C. for 10 min. The resultant glassy solid was pulverized, and extracted twice with 50 ml boiling 5% HCl. The insoluble material was filtered, and dried. 346 mg, mp 264-270 (p.h.b. 240° C.). On cooling the combined aqueous extracts to 25°, a white ppt. formed, and was filtered off, 56 mg. Combined crude yield: 44%. Crystallization of a 50 mg sample of the crude product from EtOH/Et2O afforded white needles (25 mg, mp 269°-271° C. (p.h.b. 240°), lit. 268°-269° C.). 1H (CD3OD) 1.208-1.474 (m, 5H), 1.744 (s, 9H), 1.967 (s, 8H), 2.119 (5, 3H), 3.434 (m, 1H), 13C (CD3OD) (broad band decoupled) 25.55, 26.26, 30.96, 33.74, 36.74, 42.73. extracted twice with 50 ml The insoluble material was filtered dried 346 mg, mp 264-270 (p.h.b. 240° C.) On cooling the combined aqueous extracts to 25° formed was filtered off Crystallization of a 50 mg sample of the crude product from EtOH/Et2O afforded white needles (25 mg, mp 269°-271° C. (p.h.b. 240°), lit. 268°-269° C.)

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

Procedure: 2-[3-(Methylsulfanyl)phenoxy]nicotinic acid (200 mg, 0.77 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (427 ul, 3.07 mmol) was added followed by cyclohexylamine hydrochloride (88 ug, 0.77 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) and 1-hydroxybenzotriazole (114 mg, 0.84 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (50 ml) and diethyl diethyl ether (50 ml). The organic phase was washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 35:65) as eluant to give a white solid which was recrystallised from diethyl diethyl ether/pentane to give N-cyclohexyl-2-[3-(methylsulfanyl)phenoxy]nicotinamide (134 mg) as a white solid. the solvent was removed under reduced pressure The residue was partitioned between water (50 ml) and diethyl diethyl ether (50 ml) The organic phase was washed with brine dried over MgSO4 the solvent was removed under reduced pressure The residue was purified by flash column chromatography to give a white solid which was recrystallised from diethyl diethyl ether/pentane

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

Procedure: Following the procedure of Example 1, step 3, 1.00 g (6.93 mmol) of 1-methyl-3,4-dihydronaphthalene in 7 ml of acetic acid was reacted with 2.25 ml of 37% formaldehyde solution and 2.16 g of cyclohexylamine hydrochloride. Work up gave 2.41 g of crude 3-cyclohexyl-1,2,3,4,5,6-hexahydro-benz[f]isoquinoline. Following the procedure of Example 2, this was reacted with 0.397 g of lithium wire in 200 ml of liquid ammonia, 40 ml of anhydrous THF and 1 ml of aniline. Chromatography on silica, eluting with 5-10% methanol/dichloromethane, then on alumina, eluting with 5-7% ethyl acetate/petroleum ether gave 0.333 g (18%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent, the title product hydrochloride was obtained as a white solid, m.p. 281°-285° C. (dec). NMR δ(D2O) 1.16-1.96 (12H, m), 2.10 (2H, m), 2.69 (2H, m), 2.92-3.05 (3H, m), 3.20-3.31 (2H, m), 3.55 (1H, m), 3.69 (1H, m), 7.25-7.29 (3H, m), 7.35-7.36 (1H, m). m/z (CI+, NH3) 270 (M+H)+, 226.

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

Procedure: Following the procedure of Example 1, step 3, 1.00 g (6.93 mmol) of 1-methyl-3,4-dihydronaphthalene in 7 ml of acetic acid was reacted with 2.25 ml of 37% formaldehyde solution and 2.16 g of cyclohexylamine hydrochloride. Work up gave 2.41 g of crude 3-cyclohexyl-1,2,3,4,5,6-hexahydro-benz[f]isoquinoline. Following the procedure of Example 2, this was reacted with 0.397 g of lithium wire in 200 ml of liquid ammonia, 40 ml of anhydrous THF and 1 ml of aniline. Chromatography on silica, eluting with 5-10% methanol/dichloromethane, then on alumina, eluting with 5-7% ethyl acetate/petroleum ether gave 0.333 g (18%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent, the title product hydrochloride was obtained as a white solid, m.p. 281°-285° C. (dec). NMR δ(D2O) 1.16-1.96 (12H, m), 2.10 (2H, m), 2.69 (2H, m), 2.92-3.05 (3H, m), 3.20-3.31 (2H, m), 3.55 (1H, m), 3.69 (1H, m), 7.25-7.29 (3H, m), 7.35-7.36 (1H, m). m/z (CI+, NH3) 270 (M+H)+, 226.

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

Procedure: 2-[3-(Methylsulfanyl)phenoxy]nicotinic acid (200 mg, 0.77 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (427 ul, 3.07 mmol) was added followed by cyclohexylamine hydrochloride (88 ug, 0.77 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) and 1-hydroxybenzotriazole (114 mg, 0.84 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (50 ml) and diethyl diethyl ether (50 ml). The organic phase was washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 35:65) as eluant to give a white solid which was recrystallised from diethyl diethyl ether/pentane to give N-cyclohexyl-2-[3-(methylsulfanyl)phenoxy]nicotinamide (134 mg) as a white solid. the solvent was removed under reduced pressure The residue was partitioned between water (50 ml) and diethyl diethyl ether (50 ml) The organic phase was washed with brine dried over MgSO4 the solvent was removed under reduced pressure The residue was purified by flash column chromatography to give a white solid which was recrystallised from diethyl diethyl ether/pentane

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

Procedure: Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (45 mg, 0.16 mmol), cyclohexylamine hydrochloride (21.5 mg, 0.16 mmol) and ethanol (2.5 mL) except that after 1 h, the mixture was treated with triethylamine (0.022 mL, 0.16 mmol), and heating continued for 0.5 h, to afford 5-methyl-7-phenyl-N-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-2-amine (15 mg) as a yellow solid. MS m/z 310 (M+1). after 1 h heating

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

Procedure: Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (45 mg, 0.16 mmol), cyclohexylamine hydrochloride (21.5 mg, 0.16 mmol) and ethanol (2.5 mL) except that after 1 h, the mixture was treated with triethylamine (0.022 mL, 0.16 mmol), and heating continued for 0.5 h, to afford 5-methyl-7-phenyl-N-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-2-amine (15 mg) as a yellow solid. MS m/z 310 (M+1). after 1 h heating

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

Procedure: A suspension of cyclohexylamine hydrochloride (310 mg, 2.28 mmol) and (2-methylphenyl)cyanamide (365 mg, 2.76 mmol) in dry chlorobenzene was heated at 125°-135° for 4 hrs. The solvent was evaporated in vacuo with heating, and the residue partitioned between CH2Cl2 and 20×8 ml 10% HCl. The aqueous extracts were made alkaline to pH 9-9.5, and the white precipitate collected after standing at 4° C. overnight. Two recrystallizations from EtOH/H2O gave 140 mg (22%) of white needles, mp 145°-146°, 1H (CD3OD) 1.149-2.054 (m, 10H), 2.164 (s, 3H), 3.50 (m, 1H), 6.875 (d, 1H, J=7.5 Hz), 6.968 (t, 1H, J=7.5 Hz), 7.118 (t, 1H, J=7.5 Hz), 7.177 (d, 1H, J=7.5 Hz). Anal. Calcd for C14H21N3 : C, 72.69; H, 9.15; N, 18.16. Found: C, 72.72; H, 9.24; N, 18.18. was heated at 125°-135° for 4 hrs The solvent was evaporated in vacuo with heating the residue partitioned between CH2Cl2 and 20×8 ml 10% HCl the white precipitate collected Two recrystallizations from EtOH/H2O

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Adamantan-1-ylcyanamide (514 mg, 2.92 mmol), and cyclohexylamine hydrochloride (398 mg, 2.93 mmol) were finely ground together, and heated at 200° C. for 10 min. The resultant glassy solid was pulverized, and extracted twice with 50 ml boiling 5% HCl. The insoluble material was filtered, and dried. 346 mg, mp 264°-270° (p.h.b. 240° C.). On cooling the combined aqueous extracts to 25°, a white ppt. formed, and was filtered off, 56 mg. Combined crude yield: 44%. Crystallization of a 50 mg sample of the crude product from EtOH/Et2O afforded white needles (25 mg, mp 269°-271° C. (p.h.b. 240°), lit. 268°-269° C.). 1H (CD3OD) 1.208-1.474 (m, 5H), 1.744 (s, 9H), 1.967 (s, 8H), 2.119 (5, 3H), 3.434 (m, 1H), 13C (CD3OD) (broad band decoupled) 25.55, 26.26, 30.96, 33.74, 36.74, 42.73. extracted twice with 50 ml The insoluble material was filtered dried 346 mg, mp 264°-270° (p.h.b. 240° C.) On cooling the combined aqueous extracts to 25° formed was filtered off Crystallization of a 50 mg sample of the crude product from EtOH/Et2O afforded white needles (25 mg, mp 269°-271° C. (p.h.b. 240°), lit. 268°-269° C.)

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Adamantan-1-ylcyanamide (514 mg, 2.92 mmol), and cyclohexylamine hydrochloride (398 mg, 2.93 mmol) were finely ground together, and heated at 200° C. for 10 min. The resultant glassy solid was pulverized, and extracted twice with 50 ml boiling 5% HCl. The insoluble material was filtered, and dried. 346 mg, mp 264°-270° (p.h.b. 240° C.). On cooling the combined aqueous extracts to 25°, a white ppt. formed, and was filtered off, 56 mg. Combined crude yield: 44%. Crystallization of a 50 mg sample of the crude product from EtOH/Et2O afforded white needles (25 mg, mp 269°-271° C. (p.h.b. 240°), lit. 268°-269° C.). 1H (CD3OD) 1.208-1.474 (m, 5H), 1.744 (s, 9H), 1.967 (s, 8H), 2.119 (5, 3H), 3.434 (m, 1H), 13C (CD3OD) (broad band decoupled) 25.55, 26.26, 30.96, 33.74, 36.74, 42.73. extracted twice with 50 ml The insoluble material was filtered dried 346 mg, mp 264°-270° (p.h.b. 240° C.) On cooling the combined aqueous extracts to 25° formed was filtered off Crystallization of a 50 mg sample of the crude product from EtOH/Et2O afforded white needles (25 mg, mp 269°-271° C. (p.h.b. 240°), lit. 268°-269° C.)