4-Methylmorpholine → 6-[(3R,9aS)-8-[2-[4-(tetrazol-1-yl)phenyl]acetyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-3,4-dihydroisochromen-1-one

[6-(1H-Tetrazol-1-yl)pyridine-3-yl]acetic acid (82 mg, 0.40 mmol, 1.3 eq), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (83 mg, 0.43 mmol, 1.4 eq) and 1H-1,2,3-benzotriazol-1-ol hydrate (66 mg, 0.43 mmol, 1.4 eq) were dissolved in dichloromethane (3 mL) in a 16 mL reaction vial. The mixture was stirred at r.t. for 30 min under N2. To the above mixture was added the dichloromethane solution (2 mL) of (3R,9aS)-3-(1-oxo-3,4-dihydro-1H-isochromen-6-yl)octahydropyrazino[2,1-c][1,4]oxazin-8-ium chloride (100 mg, 0.31 mmol, 1.0 eq) that was neutralized with N-methylmorpholine (34 μL, 0.31 mmol, 1.0 eq). The reaction was stirred at r.t. for 18 h, diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution (2×10 mL), brine (5 mL) and water (5 mL). The organic phase was dried over MgSO4, filtered and concentrated to give the crude product. The desired product was obtained after purification by flash column chromatography (0-10% MeOH/CH2Cl2) followed by preparative TLC (NH4OH/MeOH/CHCl3: 0.5:4.5:95): LC-MS (IE, m/z): [(M+1)-28]+=448.5, [(M+Na]+=498.4: 1H NMR (500 MHz, CDCl3, δ in ppm): 9.41 (1H, m), 7.99 (2H, m), 7.81 (1H, m), 7.28 (2H, m), 4.55-4.75 (1H, m), 4.45-4.55 (2H, m), 3.93 (1H, dd, J=3.2 Hz, J=11.2 Hz), 3.70-3.92 (3H, m), 3.40-3.55 (2H, m), 3.01 (2H, t, J=6.0 Hz), 2.80-3.00 (3H, m), 2.33 (1H, t, J=2.6 Hz,), 2.15-2.30 (3H, m).

1. stirringThe reaction was stirred at r.t. for 18 h
2. washwashed with saturated sodium bicarbonate solution (2×10 mL), brine (5 mL) and water (5 mL)
3. dry with materialThe organic phase was dried over MgSO4
4. filtrationfiltered
5. concentrationconcentrated
6. customto give the crude product

ORD record

ord-a46faef50df04ae1bfe74f1de7fbb124

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09206199B2