Tetrahydrofuran → 4-(4-(Cyclopropyl(hydroxy)methyl)pyridin-3-yl)-2-methoxybenzonitrile

HRID 1897620Notes

Reaction equation

HRID 1897620 reaction equation
[CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][CH3:18])[CH:10]=1)=[O:2].[CH2:19]1[CH2:23]OC[CH2:20]1>>[CH:20]1([CH:1]([OH:2])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH2:19][CH2:23]1

Participants

3

Reactant 2

HCID 8028Tetrahydrofuran2×HCID 866748424-(4-Formylpyridin-3-yl)-2-methoxybenzonitrile

Product 1

HCID 532370744-(4-(Cyclopropyl(hydroxy)methyl)pyridin-3-yl)-2-methoxybenzonitrile

Conditions

Temperature
-36 °C

Procedure

To a solution of 4-(4-formylpyridin-3-yl)-2-methoxybenzonitrile (100 mg, 0.42 mmol) in THF (4 mL) at −36° C. was added 0.5M c-PrMgCl in THF (2.27 mL, 1.13 mmol) dropwise and the mixture was stirred at −36° C. for 1 hr. The mixture was quenched with water at −36° C., silica gel was added, and the mixture was concentrated in vacuo. The residue was purified by silica chromatography eluting with a 40 to 100% EtOAc-heptane gradient. The product obtained was re-purified by Xbridge C18 eluting with a 10 to 100% acetonitrile-water gradient to give 4-(4-(cyclopropyl(hydroxy)methyl)pyridin-3-yl)-2-methoxybenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.13-−0.05 (m, 1H), 0.20-0.29 (m, 1H), 0.29-0.41 (m, 2H), 0.91-1.06 (m, 1H), 3.95 (s, 3H), 4.16 (dd, J=6.6, 4.3 Hz, 1H), 5.39 (d, J=4.5 Hz, 1H), 7.12 (dd, J=7.8, 1.3 Hz, 1H), 7.27 (d, J=1.3 Hz, 1H), 7.66 (d, J=5.3 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 8.42 (s, 1H), 8.62 (d, J=5.3 Hz, 1H). HRMS: (ESI) m/z 281.1280 [(M+H)+ Calcd for C17H16N2O2 281.1290].

Workup

  1. customThe mixture was quenched with water at −36° C.
  2. additionsilica gel was added
  3. concentrationthe mixture was concentrated in vacuo
  4. customThe residue was purified by silica chromatography
  5. washeluting with a 40 to 100% EtOAc-heptane gradient
  6. customThe product obtained
  7. customwas re-purified by Xbridge
  8. washC18 eluting with a 10 to 100% acetonitrile-water gradient

Sources & evidence

ORD record
ord-a52934f3deaa43bc88e38e83548bc467
Source dataset
uspto-grants-2013_08
Patent number
US08519134B2

Reaction notes

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