反应详情

Sodium hydride (60% suspension in oil, 1.8 g, 45.19 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (130 mL). Neat 3-methyl pyrazole (3.71 g, 45.19 mmol) was added dropwise at 0° C. After the gas evolution subsided the cooling bath was removed and stirring was continued at room temperature. The (2-chloro-4-fluorophenyl)-(6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone of Step D (8.11 g, 22.59 mmol) was added in one portion and the mixture was placed in an oil bath (preheated at 130° C.) for 2 hrs. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate, and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with a hexane-ethyl acetate gradient (from 95:5 to 3:2) provided the desired product along with some mixed fractions containing the title compound and its more polar 5-methylpyrazole regioisomer of Example 2. The title compound crystallized by sonication from hexane-ethanol as a white solid (6.4 g), m.p. 207° C.

1. customdried under nitrogen
2. customwas removed
3. customwas continued at room temperature
4. customthe mixture was placed in an oil bath
5. temperatureAfter cooling
6. customthe mixture was partitioned between water and ethyl acetate
7. dry with materialThe organic extracts were dried over sodium sulfate
8. customevaporated to dryness in vacuo
9. dissolutionThe residue was dissolved in dichloromethane
10. customabsorbed onto a silica Merck-60 flash column
11. washElution with a hexane-ethyl acetate gradient (from 95:5 to 3:2)