反応 #51535

反応方程式

water

triethylamine

6-(4-aminophenyl)-5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione

O-methylhydroxylamine hydrochloride

→

5-(N-benzyl-N-methylaminomethyl)-l-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione

収率 92.2%

溶媒

tetrahydrofuran

dimethylformamide

dimethylformamide

dimethylformamide

反応条件

後処理

1. 1
   その他To a solution obtained
2. 2
   温度cooling
3. 3
   温度while maintaining below 30° C
4. 4
   温度Then, while maintaining below 30° C.
5. 5
   その他a solution obtained
6. 6
   workup.ADDITIONwas added dropwise
7. 7
   workup.ADDITIONwhich was added dropwise to the reaction mixture for 4 minutes
8. 8
   温度The mixture was cooled to 25° C.
9. 9
   workup.STIRRINGthe mixture was stirred at 20-30° C. for 15 hours
10. 10
    ろ過The crystals were filtered
11. 11
    洗浄washed with water (10 L) three times
12. 12
    その他Under vacuum, the crystals were dried at 50° C. for 8 hours
13. 13
    その他to give crystals of crude 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione (1532.7 g)
14. 14
    ろ過filtered
15. 15
    濃縮The filtrate was concentrated to about 15 L under reduced pressure
16. 16
    濃縮The filtrate was concentrated under reduced pressure while ethanol (15 L)
17. 17
    workup.STIRRINGThe filtrate was stirred at 20-30° C. for 15 hours and 30 minutes
18. 18
    ろ過The crystals were filtered
19. 19
    洗浄washed with ethanol (2 L)
20. 20
    その他The crystals were dried under vacuum at 50° C. for 23 hours

実験手順

To a solution obtained by dissolving N,N′-carbonyldlimidazole (584.3 g, 3.53 mmol) in dimethylformamide (1.75 L), was added triethylamine (360.9 g, 3.57 mol) dropwise for 6 minutes under ice-cooling while maintaining below 30° C. Then, while maintaining below 30° C., a solution obtained by dissolving O-methylhydroxylamine hydrochloride (304.0 g, 3.64 mol) in dimethylformamide (1.75 L) was added dropwise thereto for 15 minutes. 6-(4-aminophenyl)-5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione (1400.0 g, 2.35 mol) was dissolved in dimethylformamide (3.5 L), which was added dropwise to the reaction mixture for 4 minutes. The mixture was stirred at 20-30° C. for 1 hour and at 50° C. for 1 hour. The mixture was cooled to 25° C., water (7.5 L) was added thereto, and the mixture was stirred at 20-30° C. for 15 hours. The crystals were filtered, and washed with water (10 L) three times. Under vacuum, the crystals were dried at 50° C. for 8 hours to give crystals of crude 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione (1532.7 g). The resulting crystals were hot-dissolved in tetrahydrofuran (25 L) and filtered. The filtrate was concentrated to about 15 L under reduced pressure. The filtrate was concentrated under reduced pressure while ethanol (15 L) was continuously injected and, finally, adjusted to 15 L. The filtrate was stirred at 20-30° C. for 15 hours and 30 minutes. The crystals were filtered and washed with ethanol (2 L). The crystals were dried under vacuum at 50° C. for 23 hours to give crystals of 5-(N-benzyl-N-methylaminomethyl)-l-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione (1447.3 g, 2.17 mol, 92.2%).

出典