2-(Boc-aminomethyl)-piperidine

White to tan solid

To a solution of 2-[2-[[2-(2, 6-dioxo-3-piperidyl)-1, 3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl methanesulfonate (500 mg, 1.14 mmol, synthesized via Steps 1-2 of Example 184) in CH3CN (20 mL) was added tert-butyl N-(2-piperidylmethyl) carbamate (488 mg, 2.28 mmol, CAS141774-61-0), NaHCO3 (287 mg, 3.41 mmol) and KI (18.9 mg, 114 umol). The mixture was stirred at 80 C. for 16 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reversed phase flash to give the title compound (450 mg, 71% yield) as yellow solid. LC-MS (ESI+) m/z 558.4 (M+H)+.A reaction flask charged with capsaicin (1 eq) and ethyl acetate, cooled to 0 - 10 C, and then DIPEA (3 eq) was added followed by the addition of nitrophenylchloroformate (1.0 eq) as a solution in ethyl acetate at 0 - 10 C. The resulting mixture was stirred at 0 - 10 C for 15 min. Next, HOBt (0.1 eq) was added, followed by A-1 free base (1.2 eq) at 0 - 10 C. The resulting mixture was stirred overnight after warming to room temperature. The reaction mixture was worked up by successive extractions with IM aq. NaOH (3x), IM aq. HCl, water and finally brine solution. The resulting organic layer was removed, dried over sodium sulfate and filtered to afford A-2 in an ethyl acetate solution. The crude product was used in the following reaction without further manipulation.A solution of 4-nitrophenyl(4-(5-(trifluoromethyl)-1, 2, 4-oxadiazol-3-yl)phenyl)carbamate (2.08 g), HATU (157 mg, 0.413 mmol)was added to a stirred solution of 2-(l -ethyl- lH-indol-2-yl)-l - methyl-lH-benzo[d]imidazole-5-carboxylic acid (110 mg, 0.344 mmol)in DMF (2 mL)followed by DIPEA (0.072 mL, 0.413 mmol). After 30 min of stirring at rt, (+l-)-tert- butyl (piperidin-2-ylmethyl)carbamate (81 mg, 0.379 mmol)was added to the reaction mixtureand this was stirred for 2 h at rt. The solvent was removed under reduced pressure and water (10 mL) was added to the residue. A cream white precipitate was filtered off and rinsed with water (2 x 5 mL). The precipitate was dried in a vacuum oven for 2 h, affording 220 mg (113%) of a cream solid (the Boc-protected product). The Boc-protected product was then taken up in DCM (5 mL)and treated with TFA (1.5 mL, 19.47 mmol). After 30 min of stirring at rt the solvent was removed under reduced pressure and the dark purple residue was loaded in MeOH on a 2 g SCX column (previously conditioned with MeOH). The column was washed with MeOH (3CV) and eluted with methanolic ammonia (2N) (3 CV). The ammonia fractions were combined and evaporated under reduced pressure. The residue (189 mg) was loaded in DCM on a 10 g SNAP silica column and purified by SP4 flash chromatography, eluting with a 0-10% methanolic ammonia (2N) in DCM(10 CV). The appropriate fractions were combined and evaporated in vacuo to give (+/-)-(2- (aminom ethyl )piperi din- 1 -yl)(2-( 1 -ethyl- lH-indol-2-yl)- 1 -methyl- lH-benzo[d]imidazol-5- yl)methanone (11.4 mg, 0.027 mmol, 7.97 % yield)as a whitesolid.LCMS (Method B): Rt = 0.80min, MH+ = 416.2.To a solution of Compound L (14.71 g, 46.7 mmol) in THF(250 mE) at -60 C. was added 0.5 M KHMDS solution inTHF (103 mE) dropwise. After stirring at -60 C. for 30 mithe reaction mixture was added to a solution of 4-nitrophenylchloroformate at -60 C. (9.41 g, 46.7 mmol) in THF (200This reaction mixture was then stirred for 30 mm at -60C., followed by addition of piperidine-2-yl-methylcarbamicacid tert-butyl ester, also referred to herein as (R, S)-piperi-dine-2-yl-methylcarbamic acid tert-butyl ester, (5.0 g, 23.3mmol) in portions. The reaction was allowed to warm toambient temperature and then stirred for 18 h. The reactionwas then concentrated under vacuum, and the residue dilutedwith EtOAc (500 mE). The mixture was then washed withwater (2x250 mE) and brine (250 mE). The organic layer wasseparated, dried over Na2504, and filtered. Removal of sol-vents under vacuum afforded crude Compound N. CrudeCompound N was purified by flash chromatography using100% EtOAc. Removal of solvent under vacuum affordedCompound N in 50% yield (6.5 g, 11.7 mmol) as a whitesolid. EC-MS [M+H] 556.1 (C30H41N307+H, calc: 555.3).

Molecular Weight:214.30
XLogP3:1.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:214.168127949
Monoisotopic Mass:214.168127949
Topological Polar Surface Area:50.4
Heavy Atom Count:15
Complexity:211
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes