反应详情

2-(10-chloro-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-2-yl)acetonitrile (Intermediate 155; 97 mg, 0.39 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 124 mg, 0.47 mmol) and p-toluenesulphonic acid monohydrate (148 mg, 0.78 mmol) were heated together in 4-methyl-2-pentanol (4 mL) at 100° C. for 24 hours. The reaction mixture was diluted with water and methanol and the solution loaded onto an SCX-2 (5 g) column pre-wet with methanol. The column was washed with methanol (×2) and eluted with 2M NH3/MeOH. Fractions containing product identified as the addition product of the solvent and nitrile group were combined and evaporated. To the residue was added 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220 62 mg, 0.24 mmol) and p-toluenesulphonic acid monohydrate (74 mg, 0.39 mmol) and the mixture heated by microwave irradiation in isopropanol (4 mL) for 20 minutes at 150° C. The cooled mixture was loaded onto an SCX-2 (5 g) column pre-wet with MeOH. The column was washed with MeOH and eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a light brown solid (21 mg, 9%).

1. washThe column was washed with methanol (×2)
2. washeluted with 2M NH3/MeOH
3. additionFractions containing product
4. customevaporated
5. washThe column was washed with MeOH
6. washeluted with 2M NH3/MeOH
7. additionProduct containing fractions
8. customevaporated
9. customthe resultant material purified by base modified reverse phase preparative HPLC