4-AMINO-1-N-BUTOXYCARBONYL-4-METHYL-PIPERIDINE

White powder

A mixture of the compound of formula LE (2.48g, 7.1 lmmol) and 10percent palladium on carbon (200mg, Sigma-Aldrich) in methanol (2OmL) was stirred under a hydrogen atmosphere at a temperature of about 25Description 4.; tert-Butyl 4-a rboxylate (D4); To a solution of 1-benzyl-4-methylpiperidin-4-amine (D3, 4.5g, 22mmol) in MeOH (20 ml) was added AcOH (1.32g, 22mmol) and Pd(OH)Method Y: tert-butyl 4-amino-4-methylpiperidine-1-carboxylate 10334] Compound 3 (26 g, 107 mmol) was dissolved with CR3CN (200 mE) and 2N KOR (100 mE). Then 1, 3-di- bromo-5, 5-dimethylimidazolidine-2, 4-dione (15 g, 54 mmol) was added to the reaction and stirred overnight. Then the reaction pH was adjusted to 5 with 2N HC1 and extracted with EA to remove the impurity. The aqueous phase was adjusted to a pH of 10. The precipitate was collected to afford the desired product as a white solid (16 g, 69percent).Step 3: Dissolved the compound 3 (26g, 107 mmol) in acetonitrile (200 ml) and 5N KOH (100 ml). Then added l, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione (15g, 54 mmol) into the system. The mixture was stirred overnight. Concentrated to remove acetonitrile, adjusted the pH of the water phase to 5 with 2N HC1 while cooling the water phase in ice bath, extracted with EA and collected the organic layer. Then, the pH of water phase was adjusted to 10, and a white precipitate formed. The white solid as compound 4 was isolated by filtration (16 g, 69percent).Compound 3 (26 g, 107 mmoi) was dissolved with ACN (acetonitrile) (200 ml) and 5N KOH (10() ml). i, 3-dibronio5, 5dimethyhmidazohdine2.4dione (15 g, 54nunol) was then added into the system. The mixture was stined overnight and concentrated to remove the ACN. The pH of the water phase was adjusted to about 5 with 2N HC1 in an ice bath, extracted with EA and separated. The p1-I of water phase was ihen adjusted to 10. The precipitate was collected to yield compound 4 as a white solid (16 g, 69percent).Method Y: tert-butyl 4-amino-4-methylpiperidine-1-carboxylate A mixture of potassium hydroxide (400 mg, 7 mmol) and tert-butyl 4-isocyanato-4-methylpiperidine-1-carboxylate (560 mg, 2.3 mmol) in tetrahydrofuran (4 ml) and water (4 ml) was stirred at room temperature for 18 hours. The amine was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the desired compound (500 mg, quantitative yield). 1H NMR (CDCl3, 400 MHz) delta 1.17 (3H, s), 1.36-1.56 (4H, m), 1.47 (9H, s), 3.38-3.52 (4H, m).Step B. To a solution of the above solid from step A (1.69g) in THF (30ml) was addedpotassium trimethylsilanolate (2g) and the resulting mixture was stirred at room temperaturefor 18 hours. The reaction mixture was partitioned between dichloromethane and saturatedsodium bicarbonate. The organic extracts were dried (MgSO4) and evaporated to dryness togive the sub-title compound (1.21g) as an orange oil which was used without furtherpurification.NMR (CDC13): 1.2 (s, 3H), 1.4-1.7 (m, 13H), 3.4-3.6 (m, 4H).in room temperature, To compound 115b (750mg, 4.75mmol)To a mixture of Example 612a (110 mg, 0.5 mmol), g (170 mg, 0.5 mmol) and HATU (200 mg, 0.52 mmol) in DMF (1 mL) was added DIPEA at 0 C. The reaction mixture was warmed to rt overnight. The reaction mixture was quenched with 0.5 N HCl and extracted with EtOAc. The combined extracts was washed with brine, and concentrated under vacuum. The residues was dissolved in DCM (2 mL), then, TFA (1.5 mL) was added at 0 C. The mixture was warmed to rt for 2 hrs. The solvent was evaporated and purified by reverse phase chromatography eluted with ACN and water and dried using lyophilization to afford the title products as TFA-salt pink solids. ESI-MS, m/z 551.3 (M+23)+.A mixture containing A flask was charged with t-butyl 2-(5-(2-formyl-5-(trifluoromethyl)phenyl)-2, 5- diazabicyclo[2.2.llheptan-2-yl)acetate (320 mg, 0.830 mmol, 1.00 equiv), t-butyl 4-amino-4- methylpiperidine-1-carboxylate (713 mg, 3.33 mmol, 4.00 equiv), and methanol (20 ml). The mixture was stirred for 4 h at 60 C and sodium borohydride (127 mg, 3.36 mmol, 4.00 equiv) was added. The resulting solution was stirred overnight at 60 and quenched with water (20 mL). The resulting mixture was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 400 mg (82% yield) of t-butyl 4-((2-(5 -(2-(t-butoxy)-2-oxoethyl)-2, 5 -diazabicyclo[2. 2.1 ]heptan-2- yl)-4-(trifluoromethyl)benzyl)amino)-4-methylpiperidine- 1 -carboxylate as a yellow oil. LCMS (ESI, m/z): 583 [M+H].A round-bottom flask was charged with tert-butyl 1-(2-formyl-5- (trifluoromethyl)phenyl)piperidine-4-carboxylate (380 mg, 1.06 mmol, 1.00 equiv), methanol (10 mL), acetic acid (191 mg, 3.18 mmol, 3.00 equiv), and tert-butyl 4-amino-4- methylpiperidine-1-carboxylate (295 mg, 1.38 mmol, 1.30 equiv). The resulting solution was stirred for 30 mm at room temperature prior to addition of sodium cyanoborohydride (200 mg, 3.18 mmol, 3.00 equiv). The reaction mixture was stirred overnight at room temperature and quenched with water (10 mL). The resulting solution was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to yield 300 mg (51% yield) of tert-butyl 4-((2-(4-(tert- butoxycarbonyl)piperidin- 1 -yl)-4-(trifluoromethyl)benzyl)amino)-4-methylpiperidine- 1- carboxylate. LCMS (ESI, m/z): 556 [M+H].

Molecular Weight:214.30
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:214.168127949
Monoisotopic Mass:214.168127949
Topological Polar Surface Area:55.6
Heavy Atom Count:15
Complexity:238
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes