Hydrochloric Acid → (trans)-9-(3-bromo-4-fluorophenyl)-7-methyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione

HRID 478306Notes

Reaction equation

HRID 478306 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=[O:16])=[C:13]([CH3:19])[NH:12][C:11]3[CH2:20][O:21][CH:22]([CH3:25])[C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:10]3[C:23](=[O:24])[C@@H:22]([CH3:25])[O:21][CH2:20][C:11]=3[NH:12][C:13]3[CH2:19][O:17][C:15](=[O:16])[C:14]2=3)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 18000971methyl 4-(3-bromo-4-fluorophenyl)-2,6-dimethyl-5-oxo-4,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxylateHCID 21124087Pyridiniumtribromide

Product 1

HCID 70003743(trans)-9-(3-bromo-4-fluorophenyl)-7-methyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
-10 °C

Procedure

The product from Example 84D (1.0 g, 2.5 mmol) was dissolved in chloroform (15 mL) under a nitrogen atmosphere, cooled to −10° C., treated with pyridine (0.24 mL, 3.0 mmol) and pyridinium tribromide (0.97 g, 3.0 mmol), stirred at −10° C. for 20 minutes, diluted with dichloromethane (100 mL) and treated with 1M HCl (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, heated to 130° C. under nitrogen for 15 minutes and cooled to ambient temperature. The residue was purified by chromatography on silica gel eluting with 38:1:1:40 ethyl acetate:formic acid:water:hexane to provide the title compound as the faster moving diasteriomer which was crystallized from dichloromethane. 1H NMR (DMSO-d6) δ 1.22 (d, 3H), 4.12 (q, 1H), 4.48 (d, 1H), 4.65 (d, 1H), 4.68 (s, 1H), 4.86 (dd, 1H), 4.99 (d, 1H), 7.24-7.28 (m, 2H), 7.48 (dd, 1H), 10.42 (bs, 1H);

Workup

  1. customThe layers were separated
  2. extractionthe aqueous layer was extracted with dichloromethane (50 mL)
  3. dry with materialThe combined organic layers were dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. temperatureheated to 130° C. under nitrogen for 15 minutes
  7. temperaturecooled to ambient temperature
  8. customThe residue was purified by chromatography on silica gel eluting with 38:1:1:40 ethyl acetate

Sources & evidence

ORD record
ord-f430aede5dbe4ec79fb847f24686be3f
Source dataset
uspto-grants-2003_11
Patent number
US06642222B2

Reaction notes

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