5-(Chloromethyl)-2-methoxypyridine → HCID 86682409, compound

HRID 2365260Notes

Reaction equation

HRID 2365260 reaction equation
Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1.Br[C:12]1[CH:21]=[C:20]2[C:22](=[O:41])[N:23]([C@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]3[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:24]([CH3:26])([CH3:25])[C:19]2=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>O1CCCC1.[Cl-].[NH4+].[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Si:34]([O:33][C@H:28]1[CH2:29][CH2:30][CH2:31][CH2:32][C@@H:27]1[N:23]1[C:24]([CH3:26])([CH3:25])[C:19]2[C:20](=[CH:21][C:12]([CH2:2][C:3]3[CH:8]=[N:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=3)=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[C:22]1=[O:41])([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:36])[CH3:35]

Participants

7

Reactant 2

HCID 137528915-(Chloromethyl)-2-methoxypyridineHCID 86682410HCID 86682410, compound

Product 1

HCID 86682409HCID 86682409, compound

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 178418851HCID 178418851, compoundCatalystHCID 8028TetrahydrofuranSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 5-(chloromethyl)-2-methoxypyridine (0.117 g, 0.745 mmol) in 0.3 mL of tetrahydrofuran under an atmosphere of nitrogen was added Rieke zinc (0.76 M, 0.98 mL, 0.74 mmol). The mixture was heated at 90° C. for 2 h and then cooled to 0° C. 5-Bromo-8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one (0.075 g, 0.15 mmol) and bis(tri-tert-butylphosphine)palladium(0) (2.3 mg, 0.0045 mmol) were added and the mixture was stirred at ambient temperature for 30 min. The mixture was diluted with saturated aqueous ammonium chloride and extracted 2× with dichloromethane. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC followed by purification via silica gel chromatography, eluting with 0-10% methanolic ammonium hydroxide (10%) in dichloromethane, to provide 8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-methoxypyridin-3-yl)methyl]-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one.

Workup

  1. temperaturecooled to 0° C
  2. extractionextracted 2× with dichloromethane
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried with magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified via preparative reverse phase HPLC
  8. customfollowed by purification via silica gel chromatography
  9. washeluting with 0-10% methanolic ammonium hydroxide (10%) in dichloromethane

Sources & evidence

ORD record
ord-19d93f77c59c44b1bd89135e6d6a5eb1
Source dataset
uspto-grants-2014_04
Patent number
US08697690B2

Reaction notes

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