Sodium hydride → 1-methylcyclopropyl 4-[(1R,2S)-2-(2-{[5-(1H-1,2,4-triazol-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate

HRID 1850753Notes

Reaction equation

HRID 1850753 reaction equation
[OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]2([CH3:19])[CH2:18][CH2:17]2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].[N:22]1([C:27]2[CH:28]=[CH:29][C:30](O)=[N:31][CH:32]=2)[CH:26]=[N:25][CH:24]=[N:23]1>CN(C=O)C>[N:22]1([C:27]2[CH:28]=[CH:29][C:30]([O:1][CH2:2][CH2:3][C@@H:4]3[CH2:6][C@@H:5]3[CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]4([CH3:19])[CH2:18][CH2:17]4)=[O:14])[CH2:9][CH2:8]3)=[N:31][CH:32]=2)[CH:26]=[N:25][CH:24]=[N:23]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 708189561-methylcyclopropyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylateHCID 178516235HCID 178516235, compound

Product 1

HCID 708559651-methylcyclopropyl 4-[(1R,2S)-2-(2-{[5-(1H-1,2,4-triazol-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a stirred solution of 1-methylcyclopropyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (100 mg, 0.37 mmol) in DMF (5 mL) was added NaH (22 mg, 0.56 mmol) in small portions. After total addition, the grey solution was stirred at RT for 10 minutes and then cooled to −26° C. via dry ice/methanol bath. A solution of 5-(1H-1,2,4-triazole-1-yl)pyridin-2-ol (120 mg, 0.74 mmol) in DMF (0.5+0.5 mL) was added via syringe drop-wise and the resulting mixture was stirred for 30 minutes. The reaction was quenched with a cold solution of NH4Cl (10 mL) via syringe. Water (10 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The organics were combined, dried by MgSO4, filtered, and concentrated under reduced pressure. The residue was purified via flash column chromatography (80 g silica gel, ISCO, eluant 5% methanol in DCM) to afford the product after being concentrated to dryness under reduced pressure. LC/MS (m/z): 412 (M+H)±. LC/MS (m/z): 424 (M+H)+. GPR119 Human EC50: 0.88 nM

Workup

  1. additionAfter total addition
  2. temperaturecooled to −26° C. via dry ice/methanol bath
  3. stirringthe resulting mixture was stirred for 30 minutes
  4. customThe reaction was quenched with a cold solution of NH4Cl (10 mL) via syringe
  5. additionWater (10 mL) was added
  6. extractionthe mixture was extracted with EtOAc (2×30 mL)
  7. dry with materialdried by MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified via flash column chromatography (80 g silica gel, ISCO, eluant 5% methanol in DCM)
  11. customto afford the product
  12. concentrationafter being concentrated to dryness under reduced pressure

Sources & evidence

ORD record
ord-349a592b2c6e41bbbe6ea9f2b977c3b0
Source dataset
uspto-grants-2015_02
Patent number
US08957062B2

Reaction notes

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