Water → Sufugolix

HRID 23257Notes

Reaction equation

HRID 23257 reaction equation
C([N:3]([CH2:6]C)CC)C.Cl.[CH3:9][O:10]N.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:44][C:22]3[N:23]([CH2:35][C:36]4[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=4[F:43])[C:24](=[O:34])[N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:26](=[O:27])[C:21]=3[C:20]=2[CH2:45][N:46]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH3:47])=[CH:15][CH:14]=1.[OH2:55]>CN(C)C=O.O1CCCC1>[CH2:48]([N:46]([CH2:45][C:20]1[C:21]2[C:26](=[O:27])[N:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:24](=[O:34])[N:23]([CH2:35][C:36]3[C:37]([F:43])=[CH:38][CH:39]=[CH:40][C:41]=3[F:42])[C:22]=2[S:44][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:6]([NH:3][O:10][CH3:9])=[O:55])=[CH:18][CH:17]=1)[CH3:47])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1

Participants

7

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 521874O-Methylhydroxylamine hydrochlorideHCID 109190521-(2,6-difluorobenzyl)-6-(4-aminophenyl)-5-((benzyl(methyl)amino)methyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

Product 1

HCID 3038517SufugolixYield 92.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent3×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

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%).

Workup

  1. customTo a solution obtained
  2. temperaturecooling
  3. temperaturewhile maintaining below 30° C
  4. temperatureThen, while maintaining below 30° C.
  5. customa solution obtained
  6. additionwas added dropwise
  7. additionwhich was added dropwise to the reaction mixture for 4 minutes
  8. temperatureThe mixture was cooled to 25° C.
  9. stirringthe mixture was stirred at 20-30° C. for 15 hours
  10. filtrationThe crystals were filtered
  11. washwashed with water (10 L) three times
  12. customUnder vacuum, the crystals were dried at 50° C. for 8 hours
  13. customto 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. filtrationfiltered
  15. concentrationThe filtrate was concentrated to about 15 L under reduced pressure
  16. concentrationThe filtrate was concentrated under reduced pressure while ethanol (15 L)
  17. stirringThe filtrate was stirred at 20-30° C. for 15 hours and 30 minutes
  18. filtrationThe crystals were filtered
  19. washwashed with ethanol (2 L)
  20. customThe crystals were dried under vacuum at 50° C. for 23 hours

Sources & evidence

ORD record
ord-000faabe4f20452f9fd35e634079aaeb
Source dataset
uspto-grants-2005_02
Patent number
US06849738B2

Reaction notes

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