Potassium Carbonate → 6-(1-(2,2-Difluoroethyl)piperidin-4-yl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

HRID 1778070Notes

Reaction equation

HRID 1778070 reaction equation
Cl.[CH3:2][O:3][CH:4]([O:21][CH3:22])[C:5]1[N:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[F:23][CH:24]([F:27])[CH2:25]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:23][CH:24]([F:27])[CH2:25][N:18]1[CH2:17][CH2:16][CH:15]([C:6]2[CH:7]=[C:8]3[C:13](=[N:14][C:5]=2[CH:4]([O:3][CH3:2])[O:21][CH3:22])[NH:12][CH2:11][CH2:10][CH2:9]3)[CH2:20][CH2:19]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 38335651,1-Difluoro-2-iodoethaneHCID 1180364207-(Dimethoxymethyl)-6-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride2×

Product 1

HCID 1180363536-(1-(2,2-Difluoroethyl)piperidin-4-yl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 7-(dimethoxymethyl)-6-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride (Intermediate 342, 0.78 g, 2.14 mmol), 1,1-difluoro-2-iodoethane (0.63 g, 3.22 mmol) and K2CO3 (0.89 g, 6.43 mmol) in DMF (20 ml) was stirred at 70° C. After 16 h, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. The crude material was purified by reverse phase chromatography (Reprosil C18/250×30 mm/5 um, 35 ml/min, 0.1% TFA in H2O/acetonitrile 95:5 to 40:60 in 25 min, then to 5:95 in 1 min). The product-containing fractions were treated with NaHCO3 and then concentrated to remove acetonitrile. The watery residue was diluted with H2O and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4 and evaporated to give the title compound as a yellow solid. (UPLC-MS 3) tR 0.41; ESI-MS 356.2 [M+H]+.

Workup

  1. temperaturethe reaction mixture was cooled to room temperature
  2. extractionextracted with EtOAc (3×)
  3. washThe combined organic phases were washed with brine
  4. dry with materialdried over Na2SO4
  5. customevaporated
  6. customThe crude material was purified by reverse phase chromatography (Reprosil C18/250×30 mm/5 um, 35 ml/min, 0.1% TFA in H2O/acetonitrile 95:5 to 40:60 in 25 min
  7. waitto 5:95 in 1 min)
  8. additionThe product-containing fractions were treated with NaHCO3
  9. concentrationconcentrated
  10. customto remove acetonitrile
  11. additionThe watery residue was diluted with H2O
  12. extractionextracted with EtOAc (2×)
  13. dry with materialThe combined organic phases were dried over Na2SO4
  14. customevaporated

Sources & evidence

ORD record
ord-b8d779363227490a827a8efb91eb754c
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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