N-ACETYLHOMOPIPERAZINE

Clear colorless to light yellow liquid

3-(2-bromoethy 1)- 1 -(4-(5-(difluoromethyl)- 1 , 3, 4-oxadiazol-2-yl)-2-fluorobenzyl)- 1 -p henylurea (0.050 g, 0. 107 mmol) and l-( l , 4-diazepan- l-yl)ethan- l-one (0.017 g, 0.1 17 mmol) were mixed at the room temperature in acetonitrile ( 1 mL) and then stirred at 100 C for 18 hr and cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02 plate, 20x20x 1 mm; methanol / dichloromethane = 10 %) to give 3-(2-(4-acetyl- 1 , 4-diazepan- 1 -yl)ethyl)- 1 -(4-(5-(difluoromethyl)- 1 , 3, 4-oxadiazol-2-yl)- 2- fluorobenzyl)- l -phenylurea as yellow oil (0.022 g, 38.9 %). [5674] NMR (700 MHz, CDC1, ) delta 7.89 (dt, 1 H, J = 7.9, 1.2 Hz), 7.75 - 7.67 (m, 2H), 7.43 - 7.37 (m, 2H), 7.37 - 7.30 (m, 1 H), 7.21 - 7.16 (m, 2H), 7.04 - 6.82 (m, 1 H). 5.10 - 5.02 (m, 1 H), 5.05 (s, 2H), 3.43 (t, 1 H, J = 6.3 Hz), 3.41 (t, 1H, J = 5.0 Hz), 3.33 (t, 1H, J = 6.3 Hz), 3.32 - 3.26 (m, 3H), 2.61 - 2.57 (m, 1 H), 2.57 - 2.4.7 (m, 5H), 2.08 - 2.04 (m, 3H), 1.71 (s, 1 H), 1.62 (dt, 2H, / = 12.0, 6.0 Hz); LRMS (ES) m/z 531.0 (M+ + 1 ).[ 1395] To a stirred solution of methyl 4-((phenylamino)methyl)benzoate (0.500 g, 2.072 mmol) in dichloromethane (20 mL) were added at 0 C triphosgene (0.492 g, 1.658 mmol) and N.N-diisopropylethylamine ( 1.810 mL, 10.361 mmol). The reaction mixture was stirred at the same temperature for 1 hr, treated at the room temperature with l-( l , 4-diazepan-l-yl)ethan-l -one (0.354 g, 2.487 mmol), and stirred for additional 2 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture w-as passed through a plastic frit to remove solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give the title compound methyl 4-((4-acetyl-N-phenyl- l , 4-diazepane- l -carboxamido)methyl)benzoate as pale yellow oil (0.844 g, 99.5 %).A solution of N-(4-(5-(difluoromethyl)- 1, 3 , 4-oxadiazol-2-yl)benzyl)-N-phenylethenesulfonamide (0.100 g, 0.255 mmol), N-acetylhomopiperazine (0.073 g, 0.511 mmol) and N, N-diisopropylethylamine (0.176 mL, 1.022 mmol) in dichioromethane (5 mL) was stilTed at the room temperature for 18 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; methanol / dichloromethane = 3 % to 5 %) to give2-(4-acetyl- 1 , 4-diazepan- 1 -yl)-N-(4-(5-(difluoromethyl)- 1, 3 , 4-oxadiazol-2-yl)benzyl)- N-phenylethane-1-sulfonamide as white solid (0.032 g, 23.5 %).?H NMR (700 MHz, CDC13) oe 8.04 - 8.00 (m, 2 H), 7.45 (d, 2 H, J = 8.3 Hz), 7.36 -7.27 (m, 5 H), 6.91 (t, 1 H, J= 51.7 Hz), 4.96 (s, 2 H), 3.68 - 3.66 (m, 1 H), 3.64- 3.59(m, 1 H), 3.56 - 3.51 (m, 2 H), 3.36 - 3.33 (m, 1 H), 3.32 - 3.27 (m, 1 H), 3.13 - 3.07(m, 2 H), 2.79-2.66 (m, 4 H), 2.11 -2.09 (m, 3 H), 1.97 (m, 1 H), 1.88 - 1.87 (m, 1H);LRMS (ES) mlz 534.3 (M+1).Example 97: Preparation of l-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]- benzofuran-3-ylmethyl}-[l, 4]diazepan-l-yl)-ethanone (97) To a solution of 97-1 (46 mg, 0.32 mmol) in a mixture of DCM (3 mL) and DMF (2 mL) is added glacial AcOH (12 mu, 0.21 mmol) and ZnCl2 (1.0 M in Et20, 0.27 mL). Next, G (60 mg, 0.13 mmol) and sodium triacetoxyborohydride (250 mg, 1.16 mmol) are added sequentially, and the resultant reaction is stirred at ambient temperature. After 1 h, additional amount of 97-1 (64 mg, 0.45 mmol) and sodium triacetoxyborohydride (75 mg, 0.35 mmol) are added. After 18 h, the reaction is diluted with EtOAc (50 mL), and washed with saturated aqueous NaHCC>3 (50 mL) and brine (20 mL). The aqueous layer is extracted with EtOAc (50 mL). The combined organic layers are dried over Na2S04, filtered and concentrated to give 97-2. To a solution of 97-2 (130 mg, 0.231 mmol) in DCM (5 mL) is added TFA (5 mL), and the reaction is stirred at ambient temperature for 2 h. The mixture is concentrated; the residue is dissolved in DCM (20 mL), and treated with a solution of 2M NH3 in MeOH (10 mL). The mixture is concentrated and the residue is purified by silica gel chromatography (0- 10% MeOH in DCM) to give the title product.

Molecular Weight:142.20
XLogP3:-0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:142.110613074
Monoisotopic Mass:142.110613074
Topological Polar Surface Area:32.3
Heavy Atom Count:10
Complexity:125
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes