1-Methyl-2-pyrrolidinemethanol

a) (/?S)-(1 -Methylpyrrolidin-2-yl)methanoIA mixture of (RS)-pyrrolidin-2-ylmethanol (1.00 g, 9.90 mrnol, 1.0 eq), formaldehyde (35percent aqueous, 10 mL) and 10percent Pd/C (200 mg) was stirred under a balloon of hydrogen gas for 18 h. The mixture was filtered through a Celite pad, concentrated under reduced pressure and purification by silica gel chromatography (20percent MeOH/CHCIStep 3Diisobutylaluminum hydride (60 mL, 66 mmol) was added dropwise to 50 mL methyl 1-methylpyrrolidine-2-carboxylate 10c (4.7 g, 33 mmol) in methylene chloride. The reaction solution under ice bath is reacted for 6 hours, 10 mL of methanol. The reaction solution was concentrated under reduced pressure, to give the title product (1-methyl - pyrrolidin-2-yl) - methanol 10d (1.8 g, brown liquid), Yield: 47.4percent.Step 2 (2R)-1-Methylpyrrolidine-2-carbaldehyde Dimethyl sulfoxide (820 muL, 11.46 mmol) was dissolved in 5 mL of dichloromethane in a dry ice bath, followed by dropwise slowly addition of oxalyl chloride (968 mg, 7.64 mmol). After stirring for 45 minutes, a solution of Dimethyl sulfoxide (820 muL, 11.46 mmol) was dissolved in 5 mL of dichloromethane in a dry ice bath, followed by dropwise slowly addition of oxalyl chloride (968 mg, 7.64 mmol). After stirring for 45 minutes, a solution of Step 2 (2R)-1-Methylpyrrolidine-2-formaldehyde Dimethyl sulfoxide (820 muL, 11.46 mmol) was dissolved in 5 mL of dichloromethane in a dry ice bath, followed by the dropwise slow addition of oxalyl chloride (968 mg, 7.64 mmol). After stirring for 45 minutes, a solution of Under dry ice bath, dimethylsulfoxide (820 muL, 11.46 mmol) in 5 mL of methylene chloride was added slowly dropwise oxalyl chloride (968 mg, 7.64 mmol). React for 45 minutes. Add dropwise 2 mL To a mixture of(R)-(i-methylpyrrolidin-2-yl)methanol (450 mg, 3.00 mmol) in chloroform (6 mL) was added thionyl chloride (1.5 mL) drop-wise at 0C. The reaction was stirred at 65C overnight. The mixture was concentrated and washed with diethyl ether to give(R)-2-(chloromethyl)-i-methylpyrrolidine (410 mg, 80.35% yield) as yellow solid. LC-MS (ESI) found: 134 [M+H-56j.General procedure: and the mixture was refluxed for 1 hr. The mixture was concentrated and the residue was purified by prep-HPLC to give 25 (S)-(1-methylpyrrolidin-2-yl)methyl (4-(2-(4-((benzylcarbamoyl)oxy)piperidin-1-yl)thiazol-5-yl)-3-(N-(tert-butyl)sulfamoyl)phenyl)carbamate (19.87 mg, 28.8 umol, 15.7% yield, 99.3% purity) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) delta=10.06 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.71 (t, J=6.2 Hz, 1H), 7.60 (dd, J=2.3, 8.5 Hz, 1H), 7.37-7.14 (m, 7H), 6.94 (s, 1H), 4.81-4.71 (m, 1H), 4.16 (br d, J=6.2 Hz, 2H), 4.10-4.03 (m, 1H), 4.02-3.96 (m, 1H), 3.73-3.63 (m, 2H), 3.28 (br s, 2H), 2.94-2.87 (m, 1H), 2.44-2.37 (m, 1H), 2.30 (s, 3H), 2.18-2.05 (m, 1H), 1.99-1.82 (m, 3H), 1.68-1.52 (m, 5H), 1.12-1.03 (m, 9H). ESI [M+H]=685.2General procedure: and the mixture was refluxed for 1 hr. The mixture was concentrated and the residue was purified by prep-HPLC to give 25 (S)-(1-methylpyrrolidin-2-yl)methyl (4-(2-(4-((benzylcarbamoyl)oxy)piperidin-1-yl)thiazol-5-yl)-3-(N-(tert-butyl)sulfamoyl)phenyl)carbamate (19.87 mg, 28.8 umol, 15.7% yield, 99.3% purity) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) delta=10.06 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.71 (t, J=6.2 Hz, 1H), 7.60 (dd, J=2.3, 8.5 Hz, 1H), 7.37-7.14 (m, 7H), 6.94 (s, 1H), 4.81-4.71 (m, 1H), 4.16 (br d, J=6.2 Hz, 2H), 4.10-4.03 (m, 1H), 4.02-3.96 (m, 1H), 3.73-3.63 (m, 2H), 3.28 (br s, 2H), 2.94-2.87 (m, 1H), 2.44-2.37 (m, 1H), 2.30 (s, 3H), 2.18-2.05 (m, 1H), 1.99-1.82 (m, 3H), 1.68-1.52 (m, 5H), 1.12-1.03 (m, 9H). ESI [M+H]=685.2General procedure: The mixture of mollugin (0.35 mmol), alcohol (3.52 mmol), and catalytic p-TsOH (0.035 mmol) in2 mL microwave vial was placed in the cavity of microwave reactor, and then stirred for 3 h at 160 C.The produced brown mixture was dried under vacuum and subjected to purification (20 g silica gelcartridge, dichloromethane-MeOH) to give the title product.

Molecular Weight:115.17
XLogP3:0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:115.099714038
Monoisotopic Mass:115.099714038
Topological Polar Surface Area:23.5
Heavy Atom Count:8
Complexity:74.9
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes