Cesium carbonate → (3R*,4R*)-N-(3,5-dichloropyridin-2-yl)-4'H-1-azaspiro[bicyclo[2.2.1]heptane-3,5'-oxazol]-2'-amine

Temperature

80 °C

To a solution of 3,5-dichloro-2-isothiocyanatopyridine (57 mg, 0.279 mmol) in N,N-dimethylformamide (2 mL) was added (3S*,4R*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride (60 mg, 0.279 mmol). The reaction was treated with cesium carbonate (227 mg, 0.697 mmol) and heated to 80° C. After 2 hours, the reaction was further treated with 1,3-diisopropylcarbodiimide (0.152 mL, 0.976 mmol). The reaction was heated at 80° C. for a further 18 hours and then cooled to room temperature. The reaction was poured into chloroform (20 ml) and water (20 ml). The organic was collected and purified by silica gel chromatography eluting with 5-40% (10% NH4OH/Methanol)/chloroform. The product fractions were collected and concentrated in vacuo followed by trituration in diethyl ether to yield (3R*,4R*)—N-(3,5-dichloropyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine (42 mg, 0.134 mmol, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (s, 1H) 8.16 (d, J=2.26 Hz, 1H) 7.97 (d, J=2.51 Hz, 1H) 3.79 (d, J=10.04 Hz, 1H) 3.58 (d, J=9.79 Hz, 1H) 2.71-2.98 (m, 2H) 2.56-2.71 (m, 4H) 2.37 (dd, J=10.04, 3.76 Hz, 1H) 1.83-2.00 (m, 1H) 1.48 (s, 1H). MS (LC/MS) R.T=1.423; (M+H=312.99).

1. temperatureThe reaction was heated at 80° C. for a further 18 hours
2. temperaturecooled to room temperature
3. customThe organic was collected
4. custompurified by silica gel chromatography
5. washeluting with 5-40% (10% NH4OH/Methanol)/chloroform
6. customThe product fractions were collected
7. concentrationconcentrated in vacuo

ORD record

ord-8d0a93693eac4450b19c12e044a4f1bd

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08278320B2