4-(3-AMINO-PHENYL)-PIPERIDINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER

A mixture of tert-butyl [4- (3-AMINOPHENYL)-3, ] 6-dihydro- [1] [(2H)-PYRIDINECARBOXYLATE] (3.10 g, 11.3 mmol) and 10percent Pd/C (1.00 g) in ethanol (100 [ML)] was hydrogenated at room temperature using the balloon method for 2 days. The reaction mixture was filtered through Celite and washed with ethanol. The combined ethanol extracts were concentrated in vacuo and the residue was chromatographed on silica (dichloromethane: methanol: isopropylamine 95: 5: 1) to give the desired product (2.63 g, [84percent). 1H] NMR (400 MHz, [CDC13)] [8] 7.10 (t, 1H, J = 7.6 [HZ), ] 6.62 (d, 1H, J [=] 8.4 Hz), 6.60-6. 59 (m, 2H), 4.27-4. 18 (m, 2H), 3.62-3. 58 (m, 2H), 2.80-2. 72 (m, 2H), 2.62-2. 59 (m, 1H), 1.89-1. 52 (m, 4H), 1.49 (s, 9H); ESMS m/e: [277.] 2 (M + H) [+.]A mixture of 3.10 g of tert-butyl 4-(3-aminophenyl)-1, 2, 3, 6-tetrahydropyridine-1-carboxylate (11.3 mmol) and 1.0 g of 10percent Pd/C in 200 mL of ethanol was hydrogenated at room temperature using the balloon method for 2 days. The reaction mixture was filtered and washed with ethanol. The combined ethanol extracts were concentrated in vacuo and the residue was chromatographed on silica (dichloromethane:methanol 95:5 with 1percent isopropylamine added to protect the BOC group from hydrolysis) to give 2.63 g of the desired product (84percent). A mixture of tert-butyl 4-(3-aminophenyl)-3, 6-dihydro-1(2H)-pyridinecarboxylate (3.10 g, 11.3 mmol) and 10percent Pd/C (1.00 g) in ethanol (100 mL) was hydrogenated at room temperature using the balloon method for 2 days. The reaction mixture was filtered through Celite and washed with ethanol. The combined ethanol extracts were concentrated in vacuo and the residue was chromatographed on silica (dichloromethane:methanol:isopropylamine 95:5:1) to give the desired product (2.63 g, 84percent). 1H NMR (400 MHz, CDCl3) ' 7.10 (t, 1H, J=7.6 Hz), 6.62 (d, 1H, J=8.4 Hz), 6.60-6.59 (m, 2H), 4.27-4.18 (m, 2H), 3.62-3.58 (m, 2H), 2.80-2.72 (m, 2H), 2.62-2.59 (m, 1H), 1.89-1.52 (m, 4H), 1.49 (s, 9H); ESMS m/e: 277.2 (M+H)+.TERT-BUTYL 4-[3-(AMINO)PHENYL]-1-PIPERIDINECARBOXYLATE: A mixture OF TERT-BUTYL 4- (3-AMINOPHENYL)-3, 6-DIHYDRO-1 (2H) -pyridinecarboxylate (3.30 g, 12.03 mmol) and 1.0 g of 10percent Pd/C in 200 mL ethanol was hydrogenated at rt for 2 days. The reaction mixture was filtered and washed with ethanol. The combined ethanol extracts were concentrated in vacuo to afford the desired product (2.1 g, 63percent). LC-MS M+H 276.7, RT 2. 0.5 1H NMR (DMSO): 6 6.9 (s, 1H), 6.4 (m, 3H), 4.9 (s, 2H), 4.0 (m, 2H), 2.7 (m, 2H), 1.7 (d, 2H), 1.4 (s, 9H).Step 2; 4-(3-Amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester; A mixture of 4-(3-Nitro-phenyl)-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butylester (Step 1, 950mg, 3.12mmol) and 10percentPd/C (catalytic amount) inmethanol (20ml) was stirred at 35°C for 3h under a hydrogen atmosphere. Thecatalyst was filtered off and the filtrate was concentrated in vacua to give a grey solid.Small amounts of diethyl ether (2x5ml) were added to the solid. After decantation andremoval of the solvent, the solid was dried in vacua to give title compound Example12 Step 2 as a white solid (800mg, 2.90mmol, 86percent).LCMS: Rt = 2.49min, m/z [M+23]Weigh 4- (3-nitrophenyl) piperidine-1-carboxylate (4c)(2.4g, 7.8mmol), placed in100 ml round-bottom flask, the reaction flask was added 40mL methanol, are stirred hook. to the reaction flask was added palladium on carbon (0. 4g, 10percent w / w), stirred at room temperature for 4 hours. the methanol was removed under reduced pressure, column chromatography [(petroleum ether / ethyl acetate (v / ν) = 15: 1)] to give a white solid of 4- (3-aminophenyl) piperidine-1-carboxylate (intermediate 4) (2.0g, 92percent yield).Weigh N- [3 _ [[4- chloro-5- (trifluoromethyl) pyrimidin-2-yl] amino] phenyl] acrylamide (3B) (1.0g, 3mml), placed in 100mL round-bottomed flask. To the reaction flask was added sequentially N, N- dimethylformamide (10mL), Nu, N- diisopropylethylamine (1. OmL, 6mmol), 4- (3- aminophenoxy) piperidine - 1- carboxylic acid tert-butyl ester (intermediate 1) (0. 84g, 3mmol). The reaction was heated to 90 C under stirring for 48 hours. after concentration under reduced pressure column chromatography (petroleum ether / ethyl acetate (nu / nu) = 3: 1) to give yellow solid 4- (3- ((2- ((3-acrylamido-phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl ) piperidine-1-carboxylate (7Beta) (0 · 80g, 45% yield).Weigh 4- (3-nitrophenyl) piperidine-1-carboxylate (4c)(2.4g, 7.8mmol), placed in100 ml round-bottom flask, the reaction flask was added 40mL methanol, are stirred hook. to the reaction flask was added palladium on carbon (0. 4g, 10% w / w), stirred at room temperature for 4 hours. the methanol was removed under reduced pressure, column chromatography [(petroleum ether / ethyl acetate (v / nu) = 15: 1)] to give a white solid of 4- (3-aminophenyl) piperidine-1-carboxylate (intermediate 4) (2.0g, 92% yield).Weigh N-[ 3 -[[ 2-chloro-5 - (trifluoromethyl) pyrimidin-4-yl] amino] phenyl] acrylamide (intermediate 3) (0.68g, 2mmol), the 100 ml round-bottom flask, the reaction bottle was added 1, 4-dioxane (10 ml). he reaction flask was added successively tertbutyl-4-(3-aminophenoxy)piperidine-1-carboxylate (intermediate 1) (0.55g, 2mmol), trifluoroacetic acid in 1, 4-dioxane solution (1mol/L, 0.4 ml). Reaction to 50 C lower stirring overnight. Removing the reaction solvent under reduced pressure, column chromatography separation (ethyl acetate) of the pink solid from tert-butyl-4-(3-((4-((3-acrylamidophenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (6B) (0.44g, yield 38%).

Molecular Weight:276.37
XLogP3:2.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:276.183778013
Monoisotopic Mass:276.183778013
Topological Polar Surface Area:55.6
Heavy Atom Count:20
Complexity:330
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes