Sodium hydride → 3-[[(S)-N-(tert-Butoxycarbonyl)-2-azetidinyl]methoxy]-5-[(1S,25)-2-[(3-pyridyloxy)methyl]cyclopropyl]pyridine

HRID 2095311Notes

Reaction equation

HRID 2095311 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C@H:9]2[CH2:11][C@@H:10]2[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[N:16][CH:17]=2)[CH:2]=1.[H-].[Na+].[C:21]([O:25][C:26]([N:28]1[CH2:31][CH2:30][C@H:29]1[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:27])([CH3:24])([CH3:23])[CH3:22].[NH4+].[Cl-]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:21]([O:25][C:26]([N:28]1[CH2:31][CH2:30][C@H:29]1[CH2:32][O:18][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([C@H:10]2[CH2:11][C@@H:9]2[CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:13]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 11602568(S)-tert-Butyl 2-((tosyloxy)methyl)azetidine-1-carboxylateHCID 686121325-[(1s,2s)-2-[(3-Pyridyloxy)methyl]cyclopropyl]-3-pyridinol

Product 1

HCID 686119423-[[(S)-N-(tert-Butoxycarbonyl)-2-azetidinyl]methoxy]-5-[(1S,25)-2-[(3-pyridyloxy)methyl]cyclopropyl]pyridineYield 79%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
100 °C

Procedure

To a solution of 5-[(1S,2S)-2-[(3-pyridyloxy)methyl]cyclopropyl]-3-pyridinol (92 mg, 0.38 mmol) in anhydrous DMF (5 mL) in a 25 mL round-bottom flask was added NaH (60% dispersion in mineral oil, 23 mg, 0.57 mmol, 1.5 equiv.). The flask was equipped with a condenser, and the atmosphere was exchanged with Ar (3 times). The suspension was heated to 100° C. (oil bath) and stirred for 1 h. After cooling to room temperature, 1-(tert-butoxycarbonyl)-2(S)-[(4-toluenesulfonyloxy)methyl]azetidine (195 mg, 0.57 mmol, 1.5 equiv.) in dry DMF (2 mL) and tetra-n-butylammonium iodide (14 mg, 0.04 mmol, 0.1 equiv.) were added. The resulting mixture was again protected with Ar and stirred at 100° C. overnight. After the reaction mixture was cooled to room temperature, saturated NH4Cl solution (15 mL) was added to quench excessive NaH. The product was extracted into EtOAc (3×15 mL). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, and concentrated. The residue was purified by CC on SiO2 (10×1.0 cm, EtOAc) to give the crude product, which 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 22.0-23.2 min) to give a yellowish oil (123 mg, 79%). 1H NMR (CDCl3, 500 MHz) δ 8.35 (s, 1H), 8.26 (d, 1H, J=3.8 Hz), 8.18 (s, 1H), 8.10 (s, 1H), 7.29-7.22 (m, 2H), 6.95 (s, 1H), 4.53 (d, 1H, J=4.6 Hz), 4.33 (s, br, 1H), 4.15 (dd, 1H, J=10.0, 2.4 Hz), 4.10 (dd, 1H, J=9.9, 6.6 Hz), 4.03 (dd, 1H, J=9.8, 6.8 Hz), 3.92 (t, 2H, J=7.6 Hz), 2.39-2.28 (m, 2H), 2.02-1.97 (m, 1H), 1.67 (dd, 1H, J=12.6, 5.8 Hz), 1.44 (s, 9H), 1.19-1.13 (m, 2H).

Workup

  1. customThe flask was equipped with a condenser
  2. temperatureAfter cooling to room temperature
  3. stirringstirred at 100° C. overnight
  4. temperatureAfter the reaction mixture was cooled to room temperature
  5. customto quench excessive NaH
  6. extractionThe product was extracted into EtOAc (3×15 mL)
  7. washThe combined organic phases were washed with brine (15 mL)
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated
  10. customThe residue was purified by CC on SiO2 (10×1.0 cm, EtOAc)
  11. customto give the crude product, which
  12. customwas 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
  13. wait100% CH3CN for 20 min

Sources & evidence

ORD record
ord-dc000d87fc454e778f63a538efbfe6f7
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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