Nitrogen → 3-[2-[5-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]-1-propanol

HRID 2095319Notes

Reaction equation

HRID 2095319 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Sn](C)(C)C)[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][CH2:33][OH:34].[F-].[Cs+].N#N>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][CH2:32][CH2:33][OH:34])[CH:17]=[N:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 947NitrogenHCID 25953Cesium fluorideHCID 105633953-(2-Iodophenyl)propan-1-olHCID 105744715-Iodo-A-85380, 5-trimethylstannyl N-boc derivative

Product 1

HCID 593715693-[2-[5-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]-1-propanol

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
130 °C

Procedure

3-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-(trimethylstannyl)pyridine (214 mg, 0.50 mmol) and 3-(2-iodophenyl)-1-propanol (131 mg, 0.50 mmol) were dissolved in anhydrous DMF (2 mL) in a 10 mL round-bottom flask with a magnetic stirrer. CsF (152 mg, 1.0 mmol, 2.0 equiv.), CuI (9.5 mg, 50 μmol, 0.1 equiv.) and Pd(PPh3)4 (29 mg, 25 μmol, 0.05 equiv.) were added. The flask was equipped with a condenser, and the atmosphere was exchanged with N2 (3 times). The mixture was stirred in a 130° C. oil bath for 26 h and cooled to room temperature. The solvent was evaporated (oil pump, 60° C.), and the residue was purified by CC on silica gel (28×1.0 cm, EtOAc) to give the crude product as a yellow oil. This material was further purified by preparative HPLC in two portions (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 23.4-24.5 min) to give, after evaporation, the product as a colorless glass (128 mg, 64%). [α]546−51.3; [α]589−43.3 (c 9.15 g/L, EtOAc). 1H NMR (CDCl3, 400 MHz) δ 8.34 (d, 1H, J=2.8 Hz), 8.19 (d, 1H, J=1.4 Hz), 7.37-7.32 (m, 2H), 7.29-7.23 (m, 2H), 7.20 (d, 1H, J=7.3 Hz), 4.56-4.49 (m, 1H), 4.40 (dd, 1H, J=10.0, 4.6 Hz), 4.61 (dd, 1H, J=10.1, 2.7 Hz), 3.90 (t, 2H, J=7.8 Hz), 3.55 (q, 2H, J=5.5 Hz), 2.70-2.64 (m, 2H), 2.42-2.28 (m, 2H), 1.80-1.71 (m, 2H), 1.39 (s, 9H).

Workup

  1. customThe flask was equipped with a condenser
  2. temperaturecooled to room temperature
  3. customThe solvent was evaporated (oil pump, 60° C.)
  4. customthe residue was purified by CC on silica gel (28×1.0 cm, EtOAc)

Sources & evidence

ORD record
ord-c744bf9e37994ac9950955f09422666c
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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