benzyl 3-aminocyclobutylcarbamate

DIPEA (5.24 ml, 30.06 mmol) was added to a stirred mixture of ferf-butyl 3-(2-hydroxyethyl)piperazine-l-carboxylate (1.73 g, 7.51 mmol) and 7-bromo-4-chloro-5, 8-difluoroquinazoline (2.1 g, 7.51 mmol) in MeCN (100 ml) at room temperature. The resulting solution was stirred at room temperature for 3 hours, a suspension developed after ~30 minutes. The precipitate was collected by filtration, washed with MeCN (3 x 20 ml) and dried under vacuum to afford desired product, 2.64 g. On standing overnight a second crop of desired product, 300 mgs was isolated to afford ferf-butyl 4-(7-bromo-5, 8-difluoroquinazolin-4-yl)-3-(2-hydroxyethyl)piperazine-l-carboxylate (2.94 g, 83%), as a white solid, which was used without further purification. 1H NM R (400 MHz, DMSO, 30C) 1.43 (9H, s), 1.71 - 1.82 (2H, m), 2.86 (1H, s), 3.18 (1H, s), 3.37 - 3.51 (2H, m), 3.72 (1H, d), 3.97 (2H, d), 4.36 (1H, s), 4.70 (1H, s), 7.75 (1H, dd), 8.62 (1H, s) OH not observed, m/z (ES+), [M+H]+ 473, 475.Phenyl (4-chloro-3-fluorophenyl)carbamate (441 mg, 1.659 mmol) and tert-butyl 3-(2- hydroxyethyl)piperazine-l-carboxylate (382 mg, 1.659 mmol) were suspended in EtOH (5 niL) and heated in a Biotage Initiator using initial high setting to 100 C for 7 min. The reaction was concentrated under a stream of nitrogen at 50 C then dissolved in DCM (3 niL) and TFA (3 niL, 38.9 mmol). After 30 minutes the reaction was concentrated under a stream of nitrogen at 50 C. The residue was dissolved in DCM/MeOH and loaded onto a SCX-3 cartridge (2 g). The cartridge was washed with 3 volumes of MeOH, then eluted with 3 volumes of 2N NH3MeOH. The eluants were concentrated under a stream of nitrogen at 50 C followed by high vacuum, resulting in the isolation of N-(4-chloro-3-fluorophenyl)-2-(2 -hydro xyethyl)piperazine-l-carboxamide (494 mg, 1.637 mmol, 99 % yield) as a white solid.LC/MS (ESI): m/z 302.0 (M+H)+, 0.39 min (ret. time)A mixture of phenyl (5-chloro-4-(trifluoromethyl)thiazol-2-yl)carbamate (1.75 g, 4.34 mmol), (±) tert-butyl 3-(2-hydroxyethyl)piperazine-l-carboxylate (0.6 g, 2.61 mmol) and TEA (0.908 niL, 6.51 mmol) in ethanol (5 niL) was heated via microwave at 80C for 3min. The mixture was then cooled and concentrated in vacuo. The residue was purified by normal phase chromatography (40g ISCO gold silica gel column, 40mL/min flow rate, gradient 10-50% EtOAc/hexanes for 15 column volumes and 50% EtOAc/hexanes for 5 column volumes) to afford (±) tert-butyl 4-((5-chloro-4- (trifluoromethyl)thiazol-2-yl)carbamoyl)-3-(2-hydroxyethyl)piperazine-l-carboxylate (1.10 g, 2.157 mmol, 83 % yield) as a pale yellow solid. LC/MS: m/z 459.2 (M+H)+, 1.16 min (ret. time).1H NMR (400 MHz, DMSO-d6) delta 11.56 (br. s, 1H), 4.71 (br. s, 1H), 4.27-4.47 (m, 1H), 3.69-3.99 (m, 3H), 3.43 (m, 2H), 2.71-3.13 (m, 3H), 1.67 (m, 2H), 1.42 (s, 9H)Step 2: 3-(2-Hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.25 mmol) was dissolved in 4 mL of dichloromethane and 1 mL of DIPEA, and then triphosgene (27 mg, 0.09 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes, and the solvent was removed in vacuo. The residue was dissolved in 3 mL of dichloromethane and 1 mL of TFA. After the reaction mixture was stirred for 1 hour, the solvent was removed in vacuo to give hexahydro-pyrazino[1, 2-c][1, 3]oxazin-6-one trifluoro acetitic acid salt (Compound D) as a crude product which was used directly without further purification. LC/MS: calc'd 157 (MH+), exp 157 (MH+).Intermediate 11 2-[1-(5-Aminothiazolo[5, 4-d]pyrimidin-7-yl)piperazin-2-yl]ethanol trifluoracetate salt [0231] To a solution of Intermediate 4 (0.38 g, 2.06 mmol) in DMF (20 mL) were added

Molecular Weight:230.30
XLogP3:0.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:230.16304257
Monoisotopic Mass:230.16304257
Topological Polar Surface Area:61.8
Heavy Atom Count:16
Complexity:238
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes