反应详情

温度

107.5 °C

To a solution of [(R)-5-(5-amino-2-fluoro-phenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine (intermediate A12A) (40 mg, 69.5 μmol) in toluene (0.6 ml) in a sealable tube was added subsequently at 23° C. and under an argon atmosphere 4-bromobenzonitrile (25.3 mg, 139 μmol), sodium tert-butoxide (13.4 mg, 139 μmol), 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (2.95 mg, 6.95 μmol) and tris(dibenzylideneacetone) dipalladium chloroform adduct (2.16 mg, 2.08 μmol), the tube was sealed and heated to 105 to 110° C. for 17 h. The mixture was cooled to 23° C., partitioned between saturated aqueous NaHCO3 and ethyl acetate, the organic layer was dried and evaporated to give the crude product, which was purified by silica gel flash chromatography with n-heptane/ethyl acetate and trituration with diethyl ether/pentane to give the (R)-4-(3-(3-(bis(4-methoxyphenyl)(phenyl)methylamino)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenylamino)benzonitrile (23 mg, 49%) as a light yellow crystalline. MS (ISN): m/z=675.5 [M−H]−.

1. customthe tube was sealed
2. temperatureThe mixture was cooled to 23° C.
3. custompartitioned between saturated aqueous NaHCO3 and ethyl acetate
4. customthe organic layer was dried
5. customevaporated
6. customto give the crude product, which
7. customwas purified by silica gel flash chromatography with n-heptane/ethyl acetate and trituration with diethyl ether/pentane