(S)-3-BOC-AMINO-2-PIPERIDONE

(S)-tert-Ruiy (2-Oxopiperidin-3-yl)carbamate (133) To a solution of 0 64 g (2.75 mmol) of BOC-L-ORN-OH in 275 mL of DMF at a 10 mM concentration were added 1.22 g (2.75 mmol) of BOP and 1.16 g (20.0 mmol) of sodium bicarbonate. After 12 h stirring at room temperature, the mixture was concentrated to a small volume (around 5 mL) under reduced pressure. The concentrated mixture was diluted with water and saturated sodium bicarbonate solution (1 : 1, 100 mL) and extracted with three 100- mL portions of EtOAc. The combined organic extracts were washed with 300 mL of water and 300 mL of brine, dried over NaA slow stream of HCl (gas) was bubbled through a solution of (L)-omithine hydrochloride (20.2 g, 120 mmol; Aldrich) in methanol (400 mL) for 45 minutes at ambient temperature. After stirring for an additional 4 hours, the mixture was concentrated under reduced pressure to leave a brown oil. The brown oil was dissolved in methanol (300 mL) and treated with a solution of NaOCH3 (prepared from 6.9 g Na and 100 mL of methanol). After stirring at ambient temperature for 4 hours, the mixture was concentrated under reduced pressure to provide a brown semisolid. The semisolid was dissolved in dichloromethane (300 mL) and treated with triethylamine (50.1 g, 360 mmol) and di-tert-butyl dicarbonate (38.7 g, 180 mmol; Aldrich). After stirring for 60 hours at 20-25 °C, the mixture was concentrated under reduced pressure. The residue was taken up in dichloromethane (200 mL), washed successively with water (100 mL) and brine (100 mL), dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol:NH4OH, 95:5:0.5) to provide the title compound as a white solid (20.1 g, 78percent). MS (CI/NH3) m/z 215 (M+H)+.[00208] (S)-tert-Ruiy (2-Oxopiperidin-3-yl)carbamate (133) To a solution of 0 64 g (2.75 mmol) of BOC-L-ORN-OH in 275 mL of DMF at a 10 mM concentration were added 1.22 g (2.75 mmol) of BOP and 1.16 g (20.0 mmol) of sodium bicarbonate. After 12 h stirring at room temperature, the mixture was concentrated to a small volume (around 5 mL) under reduced pressure. The concentrated mixture was diluted with water and saturated sodium bicarbonate solution (1 : 1, 100 mL) and extracted with three 100- mL portions of EtOAc. The combined organic extracts were washed with 300 mL of water and 300 mL of brine, dried over NaA slow stream of HCl (gas) was bubbled through a solution of (L)-omithine hydrochloride (20.2 g, 120 mmol; Aldrich) in methanol (400 mL) for 45 minutes at ambient temperature. After stirring for an additional 4 hours, the mixture was concentrated under reduced pressure to leave a brown oil. The brown oil was dissolved in methanol (300 mL) and treated with a solution of NaOCH3 (prepared from 6.9 g Na and 100 mL of methanol). After stirring at ambient temperature for 4 hours, the mixture was concentrated under reduced pressure to provide a brown semisolid. The semisolid was dissolved in dichloromethane (300 mL) and treated with triethylamine (50.1 g, 360 mmol) and di-tert-butyl dicarbonate (38.7 g, 180 mmol; Aldrich). After stirring for 60 hours at 20-25 °C, the mixture was concentrated under reduced pressure. The residue was taken up in dichloromethane (200 mL), washed successively with water (100 mL) and brine (100 mL), dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol:NH4OH, 95:5:0.5) to provide the title compound as a white solid (20.1 g, 78percent). MS (CI/NH3) m/z 215 (M+H)+. (500 mg, 2.3 mmol), 5-Iodoisoquinoline (720 mg, 2.8 mmol), cuprous iodide (200 mg, 1.0 mmol), potassium phosphate (1.6 g, 4.7 mmol), ethylenediamine (5 mL), 4A molecular sieve (2 g) 1, 4-Dioxane (50 mL) was added, and the reaction was carried out at 120 C. overnight under a nitrogen atmosphere.After the reaction was completed by LCMS, the reaction solution was cooled to room temperature, 30 mL of water was added for washing, and the mixture was extracted by suction. The aqueous phase was extracted with methylene chloride. The combined methylene chloride phases were dried, filtered, and concentrated to obtain the target product (S). - tert-butyl (1-(isoquinolin-5-amino)-2-oxopiperidine-3-amino)carboxylic acid (520 mg, 40%).[00209] (.S)-Benzyl 2-(3-((teri-Butoxycarbonyl)amino)-2-oxopiperidin-l-yl)acetate (134). A solution of 0.36 g of 133 (1.68 mmol) in 5 mL of anhydrous THF was added to a suspension of 134 mg (3.36 mmol) of sodium hydride (60% dispersion in mineral oil) in 10 mL of anhydrous THF. The reaction was stirred at room temperature for 15 min, and 280 (403 mg, 1.76 mmol) of benzyl bromoacetate was added. After 5 h stirring at room temperature, 30 mL of EtOAc was added, followed by 20 mL of water. The organic phase was washed with 20 mL of brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to afford an oily residue. The residue was purified by chromatography on a silica gel column (10 chi 2 cm). Elution with 3: 1 hexanes-EtOAc afforded 134 as colorless oil: yield 353 mg (58%); Silica gel TLC 0.52 (3: 1 hexanes- EtOAc); H NMR (CDC13) delta 1.35 (s, 9H), 1.47-1.63 (m, 1H), 1.75-1.85 (m, 2H), 2.26- 2.38 (m, 1H), 3.17-3.34 (m, 2H), 4.01 (m AB system, 2H), 3.93-4.07 (m, 1H), 4.99-5.11 (m, 2H), 5.43 (br s, 1H) and 7.16-7.31 (m, 5H); 1 C NMR (CDC13) delta 20.8, 27.8, 28.3, 48.7, 48.9, 51.6, 66.8, 79.3, 128.2, 128.3, 128.5, 135.3, 155.8, 168.6 and 170.3.[00208] (S)-tert-Ruiy (2-Oxopiperidin-3-yl)carbamate (133) To a solution of 0 64 g (2.75 mmol) of BOC-L-ORN-OH in 275 mL of DMF at a 10 mM concentration were added 1.22 g (2.75 mmol) of BOP and 1.16 g (20.0 mmol) of sodium bicarbonate. After 12 h stirring at room temperature, the mixture was concentrated to a small volume (around 5 mL) under reduced pressure. The concentrated mixture was diluted with water and saturated sodium bicarbonate solution (1 : 1, 100 mL) and extracted with three 100- mL portions of EtOAc. The combined organic extracts were washed with 300 mL of water and 300 mL of brine, dried over Na2S04, filtered, and concentrated under reduced pressure to afford a 133 as a colorless solid: yield 0.37 g (62%); Silica gel TLC i 0.55 (10: 1 DCM-MeOH); Ti NMR CDCb, ) delta 1.32 (s, 9H), 1.45-1.64 (m, 1H), 1.65-1.84 (m, 2H), 2.10-2.30 (m, 1H), 3.15-3.25 (m, 2H), 3.79-4.05 (m, 1H), 5.62 (br s, 1H) and 6.99 (br s, 1H); 1 C NMR (CDC13) delta 27.7, 28.2, 36.56, 36.61, 41.5, 51.0, 79.5, 156.0 and 172.3.

Molecular Weight:214.26
XLogP3:0.8
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:214.13174244
Monoisotopic Mass:214.13174244
Topological Polar Surface Area:67.4
Heavy Atom Count:15
Complexity:258
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes