3-Boc-6-oxa-3-aza-bicyclo[3.1.0]hexane

To a solution of Compound 1 (4.0 g, 0.024 mmol) in CHExample 5 Preparation of N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2, 2-dimethylpropyl]-N-{[(3R, 4R)-4-hydroxypyrrolidin-3-yl]methyl}-1, 4'-bipiperidine-1'-carboxamide (83) and N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2, 2-dimethylpropyl]-N-{[(3S, 4S)-4-hydroxypyrrolidin-3-yl]methyl}-1, 4'-bipiperidine-1'-carboxamide (84) Step A: Epoxidation To a 100 mL round bottom flask was added 5.0 g (29.5 mmol) 2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester, 11.7 g (67.9 mmol) 3-chloroperoxybenzoic acid, and 70 mL of DCM. The mixture was stirred at ambient temperature under nitrogen for 20 h. Excess 1N NaOH was then added and the reaction mixture was extracted with DCM (.x.3). The product was determined by thin layer chromatography (4:1 hexanes:EtOAc) using ninhydrin stain. The organic layers were combined, dried over MgSO6-Oxa-3-aza-bicyclor3.1.01hexane-3-carboxylic acid tert-butyl ester (B); B[00452] 2, 5-Dihydro-pyrrole-l-carboxylic acid tert-butyl ester (46g, 65percent purity) was dissolved in CH[00148] 6-Oxa-3-aza-bicvclor3.1.01hexane-3-carboxylic acid tert-butyl ester (B)B[00149] 2, 5-Dihydro-pyrrole-l-carboxylic acid tert-butyl ester (46g, 65percent purity) was dissolved in CHTo a solution of compound 7 (34.52 g, 0.204 mol) in DCM (500 mL) was added 3-chloroperoxybenzoic acid (75percent, 108 g, 0.47 mol). The mixture was stirred at ambient temperature for 4 days. The suspension was concentrated. The crude product was purified by silica gel column chromatography to obtain compound 8 as a yellow oil (31.17 g, 83percent). To a suspension of compound 8 (2.66 g, 0.0144 mol) and copper(I) cyanide (0.129 g, 0.00144 mol) in THF anhydrous (40 mL) at -78 °C was added dropwise 1M solution of vinylmagnesium bromide in THF (45.3 mL, 0.0453 mol). The resulting suspension was allowed to warm slowly to ambient temperature and stirred for 7 h. The reaction mixture was quenched with saturated NH(PY-BOC) -3, 4-OXIDE. TO A STIRRED SOLUTION OF N-BOC-3-PYRROLINE (OKADA, T.; SATO, K H.; Tsuji, T.; Tsushima, T.; Nakai, H.; Yoshida, T.; Matsuura, S. Chem. Pharm. Bull. 1993, 41, 132-138; Jin, Y.; GHAFFARI, M. A.; Schwartz, M. A. Tetrahedron Lett. 2002, 43, 7319-7321. ) (1.69 g, 10 MMOL) in CH2CI2 (20 mL) was added a solution of MCPBA (-85percent purity, 5.2 g) in CH2CI2 (20 mL) dropwise and stirring was continued at rt overnight. The mixture was extracted with sat. NAHCO3, sat. NA2S03 and sat. NAHCO3 solutions successively. The organic layer was dried over NA2SO4 and filtered. After evaporation of the solvent, the residue was purified by flash chromatography (20percent ethyl acetate in hexane) to give N- Boc-pyrroline-3, 4-oxide as an oil (1.54 g, 82percent) : 1 H NMR (300 MHz, CDCI3) 6 3.77 (dd, J=22, 13 Hz, 2H), 3.66 (BRS, 2H), 3.31 (dd, J=13, 3 Hz, 2H), 1.44 (s, 9H).To a stirred solution of N-Boc-3-pyrroline (1.69 g, 10 mmol) in CHTo a stirred solution of tert-butyl 2, 5-dihydro-1H-pyrrole-1-carboxylate (130 g, 0.77 mol) in CHm-CPBA (48 g, 0.28 mol) was added to a solution of tert-butyl 2H-pyrrole- l(5H)-carboxylate (15 g, 0.07 mol) in DCM (500 niL) in portions at 0°C. The reaction was stirred at RT overnight. The mixture was filtered and the filtrate was washed with aqueous NaStir a mixture of 2, 5-dihydropyrrole-l-carboxylic acid tert-butyl ester (2 g, 11.8 mmol), 3-chloroperoxybenzoic acid (77percent, 3.1 g, 14.2 mmol) and 3-tert-butyl-4-hydroxy- 5-methylsulfide (254 mg, 0.7 mmol) in 1, 2-dichloroethane (50 mL) at 85 3: tert-butyl 3, 4-Epoxypyrrolidine-i-carboxylate (9); m-CPBA (44.3 g, 180 mmol) is added to a solution of olefin 8 (13.7 g, 81 mmol) in CHINTERMEDIATE 66-Oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tβr/-butyl esterTo a solution of tert-buty\ 2, 5-dihydro-lH-pyrrole-l-carboxylate (10 g, 0.059 mol) in DCM (200 mL) was added MCPBA (14.5 g, 0.065 mol) and the mixture stirred for 18 h. After this time the mixture was washed with water (50 mL) and sodium bicarbonate solution (50 mL), dried (NaCompound 96 (7.28 g, 43.0 mmol) was dissolved in CHA mixture of N-Boc-2, 5-dihydro-pyrrole (21.2 g, 125.4 mmol)and 70percent MCPBA (54.1 g, 314 mmol) in toluene (500 ml.) was stirred at rt for 24 h, after which the suspension was filtered and concentrated. The residue was dissolved in ether, and washed sequentially with 10percent sodium hydrogen sulfite, 1 M NaOH, and brine. The solution was then dried with magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 85:15 hexanes/ethy lacetate, to provide 8.85 g (38percent) of the title compound as a colorless oil.Preparation Example 1-114-16-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 3.0 g (43.40 mmol) of 2, 5-dihydro-1H-pyrrole and 14.21 g (65.10 mmol) of di tert-butyl dicarbonate were diluted with 10 mL of dichloromethane and stirred at room temperature for 2 hours. The reaction solution was distilled in vacuo and purified by column chromatography using a mixed solution of hexane and ethyl acetate in the ratio of 5:1. 7 g of the purified compound was dissolved in 20 mL of dichloromethane and cooled to 0° C. To the solution was added 14.98 g (86.80 mmol) of 3-chloro-benzenecarboperoxic acid and stirred at room temperature for 12 hours. The reaction mixture was distilled in vacuo, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate (MgSOWas synthesised according to published methods:. Tert-butyl 2, 5-dihydro-1H-pyrrole-1-carboxylate(5g, 29.59 mmol) was dissolved in dichloromethane (20 mL), m-chloroperbenzoic acid (7 g, 40.70 mmol) was added, reacted at room temperature for 3 hours, suction filtered, and the filtrate was extracted with saturated sodium bicarbonate solution. The organic phase was dried and concentrated to give the title compound (5 g).DI-TERT-BUTYL dicarbonate (0.015 mol) was added in portions to a solution of 3- pyrroline (0.01 mol, 65 percent pure) in 20 mL MeOH at 0 °C. The reaction mixture was then stirred at room temperature for 24 h. (TLC monitored using 9: 1 hexanes/EtOAc). After evaporation of the solvent, the residue was dissolved in 30 mL CH2CL2. The reaction mixture was cooled to 0 °C and M-CPBA (0. 013 mol, maximum 77 percent pure) was added in portions. After stirring the mixture at room temperature for 48 h, 20 percent NA2S03 was added and two layers were separated. The aqueous layers were extracted with CH2C12 (20 mL X 2). The combined organic extracts were washed with 20 percent NA2S03 (30 mL X 2) and water (30 mL X 2). The solvent was then removed IL I vacuo. The residue was purified by column chromatography (silica gel, hexanes: EtOAc, 7: 3) to give pure product (71 percent).Figure 4 illustrates various schemes (A, B, and C) for synthesizing exemplary compounds (A) 4 and (B) 5 of the present invention.A round-bottomed flask equipped with a stir bar was charged with 3-pyrroline (S37) (1.83 g, contained 45 molpercent pyrrolidine by 1H NMR analysis, 15.5 mmol). MeOH (17 mL) was added, and the solution was cooled to 0 °C. A second flask was charged with di-tert-butyl dicarbonate (8.61 g, 39.5 mmol) and cooled to 4 °C.MeOH (7 mL) was added, and the resulting solution was added dropwise to the amine over ca. 23 min. The reaction was then stirred for 2 h at 4 °C followed by overnight at room temperature. Solvent was removed via rotary evaporation. The crude product mixture was dissolved in CH2Cl2 (24 mL) and cooled to 0 °C. m-Chloroperbenzoic acid (5.78 g, 77percent max, 25.8 mmol) was added, and the reaction was stirred for 10 min at 0 °C followed by 22 h at room temperature. Additional m-chloroperbenzoic acid (4.57 g, 77percent max, 20.4 mmol) was added, and the reaction was stirred for 20 h at room temperature. The reaction was filtered to remove precipitated mchlorobenzoicacid, and the filtrate was washed with saturated NaHCO3 (100 mL), 1 M Na2SO3(100 mL), saturated NaHCO3 (100 mL), and brine, respectively. After drying over Na2SO4, solvent was removed via rotary evaporation. The crude product was purified by flash chromatography on silica gel (30percent EtOAc/hexanes). The fractions containing the volatile product were concentrated via rotary evaporation, and the remaining solvent was distilled away via Kügelrohr distillation at 51 mmHg. Isolated 1.59 g (55percent) of a clear liquid.Step 4) 3-(tert-butoxycarbonyl)-6-oxa-3-azabicvclo[3.1.01hexane [0184] A solution of 4-bromo-l-(tert-butoxycarbonyl)pyrrolidin-3-ol (2.5 g, 9.4 mmol) in 2 M NaOH/THF (20 mL/10 mL) was stirred at rt for 2 h. The mixture was diluted with H

Molecular Weight:185.22
XLogP3:0.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:185.10519334
Monoisotopic Mass:185.10519334
Topological Polar Surface Area:42.1
Heavy Atom Count:13
Complexity:224
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes