Water → N-((3R,4S)-3,4-Dihydro-3-(((methylamino)carbonyl)oxy)-6-(4-(3-oxetanyl)-1-piperazinyl)-2H-1-benzopyran-4-yl)-4-fluorobenzamide

HRID 1516335Notes

Reaction equation

HRID 1516335 reaction equation
[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:28][O:27][CH2:26]5)[CH2:21][CH2:20]4)[CH:17]=3)[O:12][CH2:11][C@@H:10]2[OH:29])=[O:7])=[CH:4][CH:3]=1.[C:32](N1C=CN=C1)([N:34]1C=CN=[CH:35]1)=[O:33].CN.O>C1COCC1.C(OC)(C)(C)C>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH:25]5[CH2:28][O:27][CH2:26]5)[CH2:23][CH2:24]4)[CH:17]=3)[O:12][CH2:11][C@@H:10]2[O:29][C:32](=[O:33])[NH:34][CH3:35])=[O:7])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 962WaterHCID 6329MethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 672813934-Fluoro-N-[(3R,4S)-3-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]chroman-4-yl]benzamide

Product 1

HCID 67475270N-((3R,4S)-3,4-Dihydro-3-(((methylamino)carbonyl)oxy)-6-(4-(3-oxetanyl)-1-piperazinyl)-2H-1-benzopyran-4-yl)-4-fluorobenzamideYield 78.6%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 15413tert-Butyl methyl etherSolvent

Procedure

To a solution of 4-fluoro-N-[(3R,4S)-3-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]chroman-4-yl]benzamide (72.0 g, 168 mmol) in THF (648 mL) add 1,1′-carbonyldiimidazole (35.5 g, 219 mmol) and stir the solution at room temperature overnight. Cool the mixture to 5° C. and add a solution of 2 M methylamine in THF (210 mL, 421 mmol, 2.5 eq) dropwise over a period of 15 min. Stir for 30 min. and pour over a mixture of water (720 mL) and methyl tert-butyl ether (216 mL). Stir the mixture for 30 min. and decant the phases. Extract the aqueous phase with dichloromethane (3×216 mL). Wash the combined organic phases with brine (3×100 mL), dry over anhydrous sodium sulfate, and concentrate in vacuo. Suspend the residue in ethyl acetate (720 mL), heat at reflux for 2 hr. and cool to 10° C. Collect the solid by filtration and dry under vacuum overnight to obtain the title compound (64.0 g, 78%) as a white solid. LC-ES/MS m/z 485 [M+H]+.

Workup

  1. temperatureCool the mixture to 5° C.
  2. stirringStir for 30 min.
  3. stirringStir the mixture for 30 min.
  4. customdecant the phases
  5. extractionExtract the aqueous phase with dichloromethane (3×216 mL)
  6. washWash the combined organic phases with brine (3×100 mL)
  7. dry with materialdry over anhydrous sodium sulfate
  8. concentrationconcentrate in vacuo
  9. temperatureheat
  10. temperatureat reflux for 2 hr
  11. temperatureand cool to 10° C
  12. customCollect the solid
  13. filtrationby filtration
  14. customdry under vacuum overnight

Sources & evidence

ORD record
ord-bf58908067d347ac8dc8aae98f53003e
Source dataset
uspto-grants-2012_07
Patent number
US08227468B2

Reaction notes

Loading…