1-AMINOCYCLOHEPTANECARBONITRILE synthesis

Yield:123193-99-7 96%

Reaction Conditions:

with ammonia;ammonium chloride in water at 20; for 72 h;

Steps:

1

Preparation of 3-(1-Carbamoyl-cycloheptylamino)-1-propanesulfonic acid (Compound OU); To a 250 mL 1 neck flask containing 30% NH₄OH (120 mL) was added NaCN (15.34 g, 0.31 mol) and NH₄Cl (19.75 g, 0.37 mol) with vigorous stirring. The corresponding ketone was added dropwise within 20 minutes at room temperature. The mixture was stirred for 3 days at room temperature follwed by extraction with dichloromehtnae (50 mL). The organic layer was separated and dried over anhydrous sodium sulfate for 2 hours. The sodium sulfate was removed by filtration, the solvent was removed under reduced pressure to yield the crude aminonitrile. The desired material was obtained as light yellow oil (33.09 g, 239 mmol, 96% crude yield). An attempt to purify it further by distillation under reduced pressure was not effective. The material obtained after the distillation was less pure than the crude product by was used as such in the nest step. ¹H NMR (500 MHz, DMSO-d₆) δ 1.41-67 (m, 10H), 1.91-95 (m, 2H), 2.47 (s, 2H); ¹³C NMR (125 MHz, DMSO-d₆) 21.8, 27.4, 40.1, 53.8, 125.8 To 10 g of concentrated sulfuric acid stirred in an ice cooled water bath was added dropwise a solution of the aminonitrille (41 mmol) in 30 mL CH₂Cl₂, maintaining the internal temperature at 15° C. Then the bath was removed and the mixture heated to 40° C. for 1 hour. The mixture was cooled in ac ice bath and poured onto 200 g of crushed ice. The mixture was made pH 7-8 with 28% aqueous NH₃ and extracted with EtOAc (3×100 mL). The extracts were collected, dried (MgSO₄), and evaporated to dryness. The crude solid was recrystallized in EtOAc/Hex. The desired material was obtained as a white solid 2.15 g, 13.8 mmol, 31%. ¹H NMR (500 MHz, DMSO-d₆) δ 1.34-1.38 (m, 2H), 1.49 (br s, 8H), 1.74 (s, 2H), 1.88-1.93 (m, 2H), 6.76 (br s, 1H), 7.27 (br s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) 22.4, 29.6, 39.1, 59.6, 181.1 A solution of 1,3-propane sultone (1M, 5.20 mL) in toluene was added to a solution of 2-amino-2-methylpropaneamide (0.4350 g, 4.26 mmol) in MTBK (5 mL) and ethanol (0.5 mL). The mixture was heated to reflux for 4 hours then cooled to room temperature. The solid was collected by suction filtration, rinsed with acetone (2×5 mL). The solid was dried 18 hours at 60° C. in the vacuum oven (0.62 g). The solid was recrystallized in ethanol (5 mL) and water (5 mL). After drying, the title compound was obtained as a fine white solid (0.39 g, 1.40 mmol, 27%). ¹H NMR (500 MHz, DMSO-d₆) δ 1.53 (br s, 6H), 1.65-1.69 (m, 2H), 1.83-1.88- (m, 2H), 1.97 (qt, J=6.7 Hz, 2H), 2.06-2.11 (m, 2H), 2.61 (t, J=6.6 Hz, 2H), 2.91 (br s, 2H), 7.57 (s, 1H0, 7.79 (s, 1H), 8.75 (br s, 2H); ¹³C NMR (125 MHz, DMSO-d₆) 21.8, 22.2, 29.1, 33.1, 43.0, 49.1, 68.3, 172.0; ES-MS 277 (M-H)

References:

US2006/223855,2006,A1 Location in patent:Page/Page column 157-158