TERT-BUTYL4-(AMINOCARBONYL)TETRAHYDROPYRIDINE-1(2H)-CARBOXYLATE

White powder

A mixture of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (220 mg, 2.88 mmol) , ammonium chloride (154 mg, 2.88 mmol) , EDCI (367 mg, 1.92 mmol) and HOAT (195 mg, 1.44 mmol) in DCM (10 mL) was stirred at 0 , and then DIPEA (1.0 mL, 5.77 mmol) was added dropwise. After the addition, the mixture was stirred at rt for 10 h and washed with water (10 mL × 3) . The organic layer was dried over anhydrous NaThe compound 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (220mg, 0.96mmol), ammoniumchloride (154mg, 2.88mmol), 1- ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (367mg, 1.92mmol) and N- hydroxy-7-aza-benzotriazole (195mg, 1.44 mmol) were dissolved in dichloromethane (10mL), and the conditions under 0 ° C, to this solution was added dropwise N, N- diisopropylethylamine(1.0mL, 5.77 mmol), stirred for 10H at room temperature, add water (10mL × 3) washing the organic phase wasdried over anhydrous Na 2 SO 4, the solvent was removed, the concentrate was subjected to columnChromatography (eluent: EtOAc), to give a white solid 160mg: 4-carbamoyl-piperidine-1-carboxylate, yield:73percent.To a mixture of l-(tert- butoxycarbonyl)piperidine-4-carboxylic acid 1 (2.29 g, 10 mmol), DIEA (3.87 g, 30 mmol) and HATU (4.18 g, 11 mmol) in DMF (50 mL) was added NHGeneral procedure: To a magnetically stirred solution of formamide (6.10 g, 130 mmol) inTHF (30 mL) was added MeONa (52 mmol, 12.8 mL of 4.05 M solutionin MeOH) at r.t. After 5 min, a solution of methyl cis/trans-1-phenethyl-4-(phenylamino)piperidine-3-carboxylate29 (4.60 g, 13 mmol) in THF (7 mL) was added in one portion and the stirring was continued at r.t. The initially clear solution became turbid after 1–3 h, followed by the gradual formation of a white precipitate. The reaction progress was monitored by TLC (reactant consumption; CH2Cl2–MeOH, 9:1). After 24 h, the mixture was concentrated (30 °C, 1 h, rotary evaporator) and the syrupy residue was partitioned between brine (75 mL) and CHCl3 (3 × 25 mL). The combined organic layers were concentrated by rotary evaporator, yielding the 1a/1b mixture (4.05 g, 96percent) as an off-white solid. The mixture was separated by flash column chromatography on silica gel (CH2Cl2–MeOH, 95:5).The ring nitrogen atom of isonipecotamide 1 (commercially available from Aldrich) was Boc-protected in 95percent isolated yield by using Boc20 in dioxane and NMO as the base.4-Carbamoyl-piperidine-l-carboxylic acid tert-butyl ester[0029] To a suspension of iosnipecotamide (255 g, 1.99 mol) and 4-dimethylamino- pyridine (204 mg, 1.82 mol) in methylene chloride (1500 mL) in a 5-lite of three-neck flask was added a solution of di-tert-butyl dicarbonate (502 g, 2.30 mol, 1.15 eq.) in methylene chloride (500 mL) drop wise at room temperature with mechanic stirring. A clear solution was reached at the end of the adding. After stirring at room temperature for two more hours, the solution was washed with phosphoric acid water solution (2.5v/vpercent, 500 mL), water (500 mL), half saturated sodium bicarbonate water solution (500 mL), and 10percent of brine (500 mL). The organic phase was dried over anhydrous sodium sulfate. During the course of removing of the methylene chloride, ethyl acetate (100 ml) and heptane (200 mL) was added. After removing the methylene chloride, the white solid formed was filtrated, washed with hexane, and dried to give 414 g (95percent) of product. TLC: dichloromethane-methanol 90: 10, Rf (product) = 0.28; Rf (starting material) = base line, iodine positive.To a suspension of iosnipecotamide (255 g, 1.99 mol) and 4-dimethylamino-pyridine (204 mg, 1.82 mol) in methylene chloride (1500 mL) in a 5-lite of three-neck flask was added a solution of di-tert-butyl dicarbonate (502 g, 2.30 mol, 1.15 eq.) in methylene chloride (500 mL) dropwise at room temperature with mechanic stirring. A clear solution was reached at the end of the adding. After stirring at room temperature for two more hours, the solution was washed with phosphoric acid water solution (2.5 v/v percent, 500 mL), water (500 mL), half saturated sodium bicarbonate water solution (500 mL), and 10percent of brine (500 mL). The organic phase was dried over anhydrous sodium sulfate. During the course of removing of the methylene chloride, ethyl acetate (100 ml) and heptane (200 mL) was added. After removing the methylene chloride, the white solid formed was filtrated, washed with hexane, and dried to give 414 g (95percent) of product.TLC: dichloromethane-methanol 90:10, Rf (product)=0.28; Rf (starting material)=base line, iodine positive.ISONIPECOTAMIDE (1) (28.8 g, 0.22 mol) was suspended in chloroform (288 mL). To this was added 4- (dimethylamino) pyridine (DMAP) (23 mg, catalytic) followed by dropwise addition of a solution of BOC-anhydride (56 g, 0.26 mol, 1.14 equiv. ) in chloroform (57 mL). The solution was stirred at room temperature for 1 h and then partitioned between chloroform and 10percent citric acid solution. The organic phase was washed with citric acid solution and back extracted with chloroform. The combined organic extracts were washed with water, 10percent brine and dried (MgSO4). Filtration followed by evaporation of the filtrate gave the crude product as a pink solid. Crystallisation from ethyl acetate/hexane gave the title compound (2) as a colourless solid in 4 crops (45.5 g, 0.20 mol, 89percent)Example 3N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)piperidine-4-carboxamideStep A: Preparation of tert-butyl 4-Carbamoylpiperidine-1-carboxylate. To a solution of isonipecotamide (500 mg, 3.90 mmol) in a mixture of 5percent aqueous sodium carbonate (7 ml) and 1, 4-dioxane (3 ml) was added Boc-anhydride (1.30 ml, 5.85 mmol) and stirred for 5 h at room temperature. The pH was adjusted to 5-6 with acetic acid and volatiles were evaporated under vacuo. The residue was triturated with n-pentane and diethyl ether to yield 740 mg (82.4percent) of tert-butyl 4-carbamoylpiperidine-1-carboxylate as a white solid.To a suspension of isonipecotamide (3.0 g, 23.4 mmol) and 4-dimethylaminopyridine (2.87 g, 23.4 mmol) in CHTo a solution of piperidine-4-carboxamide (2 g, 15.6 mmol) in acetonitrile (30 ml_), ferf-butyldicarbonate (4.4 g, 20.2 mmol, 1.3 eq) and DMAP (190 mg, 1.56 mmol, 0.1 eq) were added and the mixture was stirred at r.t. overnight. It was then concentrated under reduced pressure, taken up with DCM and washed with saturated aqueous NaHCC , saturated aqueous NH4CI, brine and water. The organic phase was dried over Na2S04 and evaporated to dryness. The residue was triturated with diethyl ether and the white solid was filtered and dried to give 2.65 g (74percent) of the title product.HPLC: Rtert-Butyl 4-carbamoylpiperidine-1-carboxylate

Molecular Weight:228.29
XLogP3:0.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:228.14739250
Monoisotopic Mass:228.14739250
Topological Polar Surface Area:72.6
Heavy Atom Count:16
Complexity:275
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes