4-Oxo-1,2-piperidinedicarboxylicacid1-(tert-butyl)2-methylester

To a mixture of oxalyl chloride [( (15] mL, [30] mmol, 2 M dichloromethane) in [CH2C12] (100 mL) cooled to-78°C was added DMSO (4.5 mL, 63.4 mmol). The mixture was stirred at this temperature for 1 h, after which 4-hydroxy-piperidine-1, 2-dicarboxylic acid 1-tert- butyl ester 2-methyl ester (2.0 g, 7.71 mmol dissolved in [CH2CL2)] as added. The mixture stirred for a further 1 h and Et3N (20 mL) was then added and the mixture stirred for another 30 min. The mixture was then allowed to warm to-40°C and poured into a solution of 10percent [NAHS04.] The reaction mixture was then extracted with ethyl acetate. The organic extract was then washed with brine and dried over [MGS04] (anhydrous) and the solvent was removed in vacuo and the crude residue was purified by silica gel flash column chromatography giving 1.75 g [(88percent)] of the product as a yellow oil. 1H-NMR (CDC13), 8 (ppm): 4.85 (br, d, 1H), 4.02 (m, 1H), 3.61 (s, 3H), 3. [58] (br, 1H), 2.75 (m, 2H), 2.44 (br, 2H), 1.43 (br, s, 9H).To a solution of 1 -(tert-butyl) 2-methyl 4-oxopiperidine-1 , 2-dicarboxylate (0.6 g, 2.3 mmol, 1 equiv) in methanol (60 ml_) at 0 C was added portion wise ammonium acetate (1 .79 g, 23.3 mmol, 10 equiv ) and maintained for 1 h at room temperature. After that sodium cyanoborohydride (0.57 g, 9.2 mmol, 4 equiv) and acetic acid (2 drops, catalytic) were added and maintained for 48 h at room temperature. After consumption of the starting material (tic, 50 % EtOAc in hexane), the reaction mixture was concentrated, diluted with 10 % methanol in DCM (150 mL) and washed with 10% aqueous NaHC03 solution (20 mL), cold water ( 20 mL), the organic layer dried over anhydrous sodium sulphate, filtered and concentrated to obtain 1 -(tert-butyl) 2-methyl 4-aminopiperidine- 1 , 2-dicarboxylate (0.5 g, crude, 99.6% yield) as off white solid. LCMS (ES) m/z = 259.3 [M+H]+. NMR (400 MHz, DMSO-d6) delta ppm - crude.(±) 1-(tert-Butyl) 2-methyl (R)-4-oxopiperidine-1, 2-dicarboxylate (10 g, 38.9 mmol) was dissolved in MeOH (50 mL). N-Methylbenzylamine (8 mL, 62 mmol) was added, followed by acetic acid (1 mL, 17.4 mmol). The reaction was stirred at room temperature for 1 h. After cooling the mixture to 0 oC, NaBH3CN (3.7 g, 59 mmol) was added in one portion. The reaction was warmed to room temperature and stirred for 15 h. The mixture was partitioned between EtOAc and H2O. The organic layer was dried over MgSO4, filtered, and then concentrated under vacuum. Purification by silica chromatography (20-50% EtOAc in hexanes) yielded (±)1-(tert- butyl) 2-methyl (cis)-4-(benzyl(methyl)amino)piperidine-1, 2-dicarboxylate (A) (3.96 g, 28%) as the second-highest major component on TLC (when visualized with iodine stain), and (±) 1-(tert- butyl) 2-methyl (trans)-4-(benzyl(methyl)amino)piperidine-1, 2-dicarboxylate (B) (2.49 g, 18%) as the lowest major non-baseline TLC component. A: 1H NMR (methanol-d4) d: 7.20-7.40 (m, 5H), 4.49 (m, 1H), 3.70-3.85 (m, 2H), 3.67 (s, 3H), 3.35-3.50 (m, 1H), 3.30 (m, 1H), 2.45-2.60 (m, 2H), 2.10 (m, 1H), 2.07 (s, 3H), 1.93-2.00 (m, 1H), 1.70-1.78 (m, 1H), 1.47 (s, 9H). B: 1H NMR (methanol-d4) 1:1 mixture of rotamers d: 7.33 (d, J=4.3 Hz, 4H), 7.23-7.29 (m, 1H), 4.89-4.99 (m, 1H), 4.03-4.09 (m, 1H), 3.67-3.72 (m, 3H), 3.63 (s, 2H), 2.84-3.05 (m, 1H), 2.39- 2.50 (m, 2H), 2.23 (s, 3H), 1.70-1.92 (m, 2H), 1.51-1.57 (m, 1H), 1.46 (br d, 9H)

Molecular Weight:257.28
XLogP3:0.5
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:257.12632271
Monoisotopic Mass:257.12632271
Topological Polar Surface Area:72.9
Heavy Atom Count:18
Complexity:358
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes