Acetic Acid → 2-(4-chloro-phenyl)-6-[3-fluoro-4-(1-methyl-azetidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one

HRID 2384913Notes

Reaction equation

HRID 2384913 reaction equation
C(O[C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[F:36])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C=O.CC(O)=O.[BH3-]C#N.[Na+]>C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[S:27][C:21]3[C:20](=[O:35])[N:19]([C:16]4[CH:17]=[CH:18][C:13]([O:12][CH:10]5[CH2:9][N:8]([CH3:6])[CH2:11]5)=[C:14]([F:36])[CH:15]=4)[CH:24]=[CH:23][C:22]=3[CH:25]=2)=[CH:29][CH:30]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 712FormaldehydeHCID 6422Trifluoroacetic acidHCID 5003444Sodium cyanoborohydrideHCID 689499923-{4-[2-(4-Chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-fluoro-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 248035802-(4-chloro-phenyl)-6-[3-fluoro-4-(1-methyl-azetidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-oneYield 74%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Dissolve 3-{4-[2-(4-chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-fluoro-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester (0.491 g, 0.932 mmol) in CH2Cl2 (10 mL) and treat with TFA (3 mL), with stirring at RT for 2 h. Remove the excess reagent and solvent in vacuo. Dissolve the crude material in CH3OH (15 mL), treat with formaldehyde (0.28 mL, 3.71 mmol, 37% aqueous solution), HOAc (0.21 mL, 3.71 mmol) and NaBH3CN (0.233 g, 3.71 mmol). Stir the mixture at RT for 30 min followed by reflux for 4 h. Quench the mixture with saturated NH4Cl solution (10 mL). Dilute with water (10 mL) and saturated NaHCO3 (30 mL). Extract with EtOAc (3×50 mL). Dry the combined organic layers with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 1% Et3N, 10% CH3OH/CHCl3 to give 2-(4-chloro-phenyl)-6-[3-fluoro-4-(1-methyl-azetidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one (0.3012 g, 0.683 mmol, 74%). Dissolve the free base (0.152 g, 344.7 μmoles) in CH2Cl2 (5 mL) and CH3OH (0.5 mL). Treat the mixture with 1.0 M HCl in EtOH (344.7 μmoles; 344.7 μL). Add Et2O (50 mL), filter, and wash with Et2O (2×20 mL). Dry in a vacuum oven at RT for 2 days to give 0.14 g (83%) of the title compound. LC-MS/ES m/z (35Cl) 441.0 [M+H]+.

Workup

  1. customRemove the excess reagent and solvent in vacuo
  2. dissolutionDissolve the crude material in CH3OH (15 mL)
  3. stirringStir the mixture at RT for 30 min
  4. temperatureby reflux for 4 h
  5. customQuench the mixture with saturated NH4Cl solution (10 mL)
  6. additionDilute with water (10 mL) and saturated NaHCO3 (30 mL)
  7. extractionExtract with EtOAc (3×50 mL)
  8. dry with materialDry the combined organic layers with Na2SO4
  9. filtrationfilter
  10. concentrationconcentrate
  11. customPurify the crude material by chromatography
  12. washeluting with 1% Et3N, 10% CH3OH/CHCl3

Sources & evidence

ORD record
ord-909d697d644d4bcba14600b721798d2d
Source dataset
uspto-grants-2012_09
Patent number
US08263772B2

Reaction notes

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