4-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidine-1-carbonitrile → 3-(methoxymethyl)-5-(4-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidin-1-yl)-1,2,4-oxadiazole

HRID 1850787Notes

Reaction equation

HRID 1850787 reaction equation
[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]#[N:24])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].[OH:25][NH:26][C:27](=N)[CH2:28][O:29][CH3:30]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:30][O:29][CH2:28][C:27]1[N:24]=[C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][O:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][N:9]=3)[CH2:22][CH2:21]2)[O:25][N:26]=1

Participants

5

Reactant 2

HCID 867112044-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidine-1-carbonitrileHCID 178496050HCID 178496050, compound

Product 1

HCID 665634813-(methoxymethyl)-5-(4-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidin-1-yl)-1,2,4-oxadiazole

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidine-1-carbonitrile (Step A, Example 98; 80 mg, 0.23 mmol) and N-hydroxy-2-methoxyacetimidamide (38 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (0.6 mL, 0.5 M in tetrahydrofuran, 0.3 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 30 min, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (10 g of silica gel) and eluted with a gradient of dichloromethane/CMA, 19:1, 500 mL; 4:1, 500 mL to provide the title compound as an off-white solid, 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=2.4 Hz, 1H), 8.03 (dd, J=2.5, 8.7 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 4.50 (t, J=7.2 Hz, 2H), 4.38 (s, 2H), 4.25-4.10 (m, 2H), 3.46 (s, 3H), 3.15-2.95 (m, 2H), 3.08 (s, 3H), 2.20-2.05 (m, 1H), 1.95-1.80 (m, 2H), 1.60-1.40 (m, 3H), 1.20-0.85 (m, 2H), 0.80-0.55 (m, 2H), −0.08 (q, J=4.6 Hz, 1H). MS (ESI) m/z 437 [M+H]+. MP: 68-70° C. GPR119 Human EC50: 7 nM

Workup

  1. temperatureThe mixture was refluxed for 2 h
  2. concentrationconcentrated to dryness under reduced pressure
  3. dissolutionThe residue was dissolved in 2 mL of 4N HCl ethanol
  4. temperatureThe solution was refluxed for 30 min
  5. temperaturecooled to RT
  6. concentrationconcentrated to dryness under reduced pressure
  7. dissolutionThe residue was dissolved in methanol (5 mL)
  8. additionneutralized by the addition of excess potassium carbonate
  9. additionmixed silica gel (2 g)
  10. concentrationconcentrated to dryness under reduced pressure
  11. washeluted with a gradient of dichloromethane/CMA, 19:1, 500 mL

Sources & evidence

ORD record
ord-cfb13033666e444bb0e0591d31e6a997
Source dataset
uspto-grants-2015_02
Patent number
US08957062B2

Reaction notes

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