5-(Chloromethyl)-2-methoxypyridine → HCID 57941371, compound

HRID 1438030Notes

Reaction equation

HRID 1438030 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Cl[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][C:25]1[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1

Participants

6

Reactant 2

HCID 137528915-(Chloromethyl)-2-methoxypyridine2×HCID 57941350(4r,7s)-2-(2,4-Difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one2×

Product 1

HCID 57941371HCID 57941371, compoundYield 9%

Reagents, catalysts & solvents 3

HCID 67553Tetrabutylammonium IodideCatalyst2×HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 480 mg, 1.6 mmol), 5-chloromethyl-2-methoxy-pyridine (Intermediate 50; 995 mg, 6.3 mmol) and tetrabutylammonium iodide (583 mg, 1.6 mmol) in dimethylformamide (63 mL) was heated at 100° C. for 48 h. The solvent was evaporated and dichloromethane (150 mL) was added. The solution was washed with saturated aqueous sodium thiosulfate (200 mL), saturated aqueous sodium hydrogen carbonate (200 mL) and brine (200 mL), dried (sodium sulfate), filtered, evaporated and purified using a Biotage 40M system, eluting with 20-50% ethyl acetate/hexanes and then 2% methanol/dichloromethane, to give a crude product that contains some tetrabutylammonium iodide. This material was taken up in dichloromethane (50 mL) and washed with 5% dimethylformamide in water (2×100 mL) and water (5×100 mL). The organic phase was dried (sodium sulfate), filtered and evaporated to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-(6-methoxy-pyridin-3-ylmethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (59 mg, 9%). APCI(+)-MS (M+H) 426.

Workup

  1. customThe solvent was evaporated
  2. additiondichloromethane (150 mL) was added
  3. washThe solution was washed with saturated aqueous sodium thiosulfate (200 mL), saturated aqueous sodium hydrogen carbonate (200 mL) and brine (200 mL)
  4. dry with materialdried (sodium sulfate)
  5. filtrationfiltered
  6. customevaporated
  7. custompurified
  8. washeluting with 20-50% ethyl acetate/hexanes
  9. custom2% methanol/dichloromethane, to give a crude product that
  10. washwashed with 5% dimethylformamide in water (2×100 mL) and water (5×100 mL)
  11. dry with materialThe organic phase was dried (sodium sulfate)
  12. filtrationfiltered
  13. customevaporated

Sources & evidence

ORD record
ord-93c4b15515a948a49f33ca8aeb3ffb97
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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