反应详情

温度

90 °C

A slurry of 6-methoxyisoquinolone (116 g, 662 mmol) in phosphorous oxychloride (200 mL, 2.14 mol) was charged to a rotavap flask. The resulting thick paste was heated on the rotovap to 90° C. for ˜30 min. The reaction thinned to a thick black solution with gas evolution then became pasty again, heated continuously at 90° C. for an additional 30 min and checked by TLC. An additional quantity of POCl3 (100 mL, 1.07 mol) was added and heated continuously for another 2 h. The reaction was complete (checked by TLC; complete consumption of starting material with some production of a polar impurity) so the excess POCl3 was stripped off under high vacuum to leave a solid mass of crude product. This solid mass was triturated with ethyl acetate (500 mL) at 0° C. for 3.5 h. The solid product was filtered off and washed with cold ethyl acetate (250 mL). Mother liquors contained essentially no product and were discarded. The weight of this crude solid salt was −208 grams. This salt was dissolved in a mixture of cold ethyl acetate (1000 mL) and water (1000 mL) and neutralized to pH=6.75 with NaHCO3 (209 g, 2.49 mol, 3.75 eq based on starting material). The phases were split, and the aqueous phase was back extracted with ethyl acetate (500 mL) and combined with the first product containing ethyl acetate phase. The ethyl acetate was stripped off to yield 110.8 g crude residue. In order to remove the polar impurity, this residue was dissolved in a mixture of ethyl acetate 200 mL and heptanes 100 mL and passed through a silica gel plug (500 g) and eluted with a mixture of ethyl acetate/heptanes 1:1. The product containing fractions was concentrated to a residue to provide pinkish-yellow solids. These solids were recrystallized from hot (˜75° C.) heptanes (1000 mL) and cooled to rt then to 0° C. Filtration and washing with cold heptanes (250 mL) followed by drying under vacuum provided purified 83E as a off-white crystalline solid. (98.02 g, 506 mmol, 76.5%).

1. customThe reaction thinned to a thick black solution with gas evolution
2. temperatureheated continuously at 90° C. for an additional 30 min
3. temperatureheated continuously for another 2 h
4. customcomplete consumption of starting material with some production of a polar impurity) so the excess POCl3
5. customto leave a solid mass of crude product
6. customThis solid mass was triturated with ethyl acetate (500 mL) at 0° C. for 3.5 h
7. filtrationThe solid product was filtered off
8. washwashed with cold ethyl acetate (250 mL)
9. dissolutionThis salt was dissolved in a mixture of cold ethyl acetate (1000 mL) and water (1000 mL)
10. customThe phases were split
11. extractionthe aqueous phase was back extracted with ethyl acetate (500 mL)
12. additioncontaining ethyl acetate phase