4-Methylmorpholine → HCID 21035332, compound

HRID 1832107Notes

Reaction equation

HRID 1832107 reaction equation
FC(F)(F)[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:16](=[O:29])[C:15]=1[Cl:30].CN1CCOCC1.[S:43]1[CH:47]=[CH:46][C:45]([CH2:48]O)=[CH:44]1.[H-].[Na+]>CC(N(C)C)=O.C(O)(=O)C>[Cl:30][C:15]1[C:16](=[O:29])[N:17]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[CH2:9][NH:8][C:3](=[O:4])[O:5][CH2:48][C:45]1[CH:46]=[CH:47][S:43][CH:44]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 24758Sodium hydrideHCID 123570Thiophene-3-methanolHCID 22051057HCID 22051057, compound

Product 1

HCID 21035332HCID 21035332, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
60 °C

Procedure

To a cooled (0° C.) solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one trifluoroacetate (0.26 g, 0.50 mmol) and 1,1-carbonyldiimidazole (0.10 g, 0.60 mmol) in DMA (2.0 mL) was added 4-methylmorpholine (0.06 mL, 0.55 mmol). After 1 h at RT, 3-thiophenemethanol (0.09 mL, 0.99 mmol) was added. No product was observed after 2 h at RT. NaH (0.01 g, 0.50 mmol) was added and the reaction stirred at 60° C. Reaction was complete after 20 min. The reaction mixture was cooled (0° C.) and acetic acid added to quench the reaction. Solvent removed by distillation. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (30 mL) and extracted in DCM (3×25 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to a white foam, dried in vacuo (0.20 g, 73%). 1H NMR (CD3OD/400 MHz) δ 7.61 (m, 1H), 7.52 (m, 1H), 7.34 (s, 2H), 7.23 (t, 3H, J=8.4 Hz), 7.10 (m, 2H), 6.71 (s, 1H), 5.40 (s, 2H), 5.07 (s, 2H), 4.43 (s, 2H), 2.10 (s, 3H). ES HRMS m/z 549.0858 (M+H calculated for C26H21ClF3N2O4S requires 549.0857).

Workup

  1. waitNo product was observed after 2 h at RT
  2. customReaction
  3. waitwas complete after 20 min
  4. additionadded
  5. customto quench
  6. customthe reaction
  7. customSolvent removed by distillation
  8. customCrude product purified by preparatory HPLC
  9. customAcetonitrile was evaporated
  10. washthe solution washed with 5% NaHCO3 (30 mL)
  11. extractionextracted in DCM (3×25 mL)
  12. dry with materialThe organic extracts were dried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated to a white foam
  15. customdried in vacuo (0.20 g, 73%)

Sources & evidence

ORD record
ord-3b2a543f411a43059c67154db1b21a3c
Source dataset
uspto-grants-2006_06
Patent number
US07067540B2

Reaction notes

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