Potassium Hydroxide → Nemiralisib

HRID 880394Notes

Reaction equation

HRID 880394 reaction equation
[OH-].[K+].[NH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:20]=[C:19]4[C:15]([CH:16]=[N:17][N:18]4S(C4C=CC=CC=4)(=O)=O)=[C:14]([C:30]4[O:31][C:32]([CH2:35][N:36]5[CH2:41][CH2:40][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]5)=[CH:33][N:34]=4)[CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CC1CCCO1>[NH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:20]=[C:19]4[C:15]([CH:16]=[N:17][NH:18]4)=[C:14]([C:30]4[O:31][C:32]([CH2:35][N:36]5[CH2:37][CH2:38][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:40][CH2:41]5)=[CH:33][N:34]=4)[CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1

Participants

5

Reactant 2

HCID 14797Potassium HydroxideHCID 666957552-(6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole

Product 1

HCID 49784002Nemiralisib

Reagents, catalysts & solvents 2

HCID 5974Hexadecyltrimethylammonium BromideCatalystHCID 73012-MethyltetrahydrofuranSolvent

Conditions

Temperature
79 °C

Procedure

Potassium hydroxide (0.483 wt, 5 eq, 242 g) is added to a suspension of 2-(6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole (1 wt, 1 eq, 501 g), and CTAB (cetyltrimethylammonium bromide) (0.031 wt, 0.05 eq, 15.5 g) in 2-methyltetrahydrofuran (10 vols, 5.01 L) then heated at reflux (79° C.) for at least 4 hrs until the reaction is complete. The mixture is cooled to 50° C. and washed at 50° C. with water (2×10 vols, 2×5 L). The solution is diluted with 2-methyl tetrahydrofuran (5 vols, 2.5 L) and filtered while at 50° C. to remove precipitated palladium residues. The organic solution is then distilled (100 mbar, 20° C.) down to 2 vols (1 L), diluted with 2-methyl tetrahydrofuran (1 vol, 0.5 L) and 3-pentanone (3 vols, 1.5 L) and distilled (100 mbar, 30° C.) down to 2 vols (1 L). The solution is again diluted with 3-pentanone (3 vols, 1.5 L) and distilled (80 mbar, 25° C.) down to 2 vol (1 L). The solution is again diluted with 3-pentanone (3 vols (1.5 L) and distilled (100 mbar, 30° C.) down to 3 vols (1.5 L). The suspension is cooled to 20° C. over 1 hr and aged at 20° C. for at least 2 hrs. The product is filtered under vacuum, washed with 3-pentanone (1 vol, 0.5 L) and dried under vacuum at 60° C. to afford 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole as a tan solid.

Workup

  1. temperaturethen heated
  2. temperatureThe mixture is cooled to 50° C.
  3. washwashed at 50° C. with water (2×10 vols, 2×5 L)
  4. additionThe solution is diluted with 2-methyl tetrahydrofuran (5 vols, 2.5 L)
  5. filtrationfiltered while at 50° C.
  6. customto remove
  7. customprecipitated palladium residues
  8. distillationThe organic solution is then distilled (100 mbar, 20° C.) down to 2 vols (1 L)
  9. additiondiluted with 2-methyl tetrahydrofuran (1 vol, 0.5 L) and 3-pentanone (3 vols, 1.5 L)
  10. distillationdistilled (100 mbar, 30° C.) down to 2 vols (1 L)
  11. additionThe solution is again diluted with 3-pentanone (3 vols, 1.5 L)
  12. distillationdistilled (80 mbar, 25° C.) down to 2 vol (1 L)
  13. additionThe solution is again diluted with 3-pentanone (3 vols (1.5 L)
  14. distillationdistilled (100 mbar, 30° C.) down to 3 vols (1.5 L)
  15. temperatureThe suspension is cooled to 20° C. over 1 hr
  16. waitaged at 20° C. for at least 2 hrs
  17. filtrationThe product is filtered under vacuum
  18. washwashed with 3-pentanone (1 vol, 0.5 L)
  19. customdried under vacuum at 60° C.

Sources & evidence

ORD record
ord-5b04defc70664caf87369e1b46668183
Source dataset
uspto-grants-2015_03
Patent number
US08993576B2

Reaction notes

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