(S)-Tert-butyl 2-(((5-bromopyridin-3-YL)oxy)methyl)azetidine-1-carboxylate → HCID 21345212, compound

HRID 2185727Notes

Reaction equation

HRID 2185727 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]=[C:16](Br)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Cl)[CH2:22][CH3:23]>C1COCC1.C(OCC)C>[CH2:21]([C:16]1[CH:15]=[C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=[N:18][CH:17]=1)[CH2:22][CH3:23]

Participants

5

Reactant 2

HCID 10688713(S)-Tert-butyl 2-(((5-bromopyridin-3-YL)oxy)methyl)azetidine-1-carboxylateHCID 178455855HCID 178455855, compound

Product 1

HCID 21345212HCID 21345212, compoundYield 22%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)-3-bromopyridine (1.50 g, 4.37 mmol, Example 12a above) in THF (30 mL) at 0° C. was added [1,3-bis(diphenylphosphino)-propane]nickel(II) (14.0 mg) followed by propylmagnesium chloride (5.50 mL of a 2 M solution in diethyl ether, Aldrich). The reaction mixture was refluxed for 3 h, cooled to ambient temperature and then quenched with saturated aqueous ammonia chloride. The desired product was extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and concentrated. The residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 1:1) to afford 5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine as an oil (292 mg, 22%): MS (CI/NH3) m/z: 307 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ0.95 (t, J=8.3 Hz, 3H), 1.42 (s, 4.5H), 1.46 (s, 4.5H), 1.60-1.70 (m, 2H), 2.22-2.40 (m, 2H), 2.56 (t, J=8.3 Hz, 2H), 3.70-3.80 (m, 2H), 3.90 (m, 1H), 4.13 (m, 1H), 4.51 (m, 1H), 7.04 (s, 1H), 8.06 (s, 1H), 8.18 (d, J=3.3 Hz, 1H). To a 0° C. solution of 5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (290 mg, 0.950 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). After stirring for 30 min the reaction mixture was basified with 15% aqueous NaOH and extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by chromatography (silica gel; CH2Cl2/MeOH, 10:0.5) afforded the free base of the title compound as an oil (103 mg, 53%): MS (CI/NH3) m/z: 207 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ0.94 (t, J=8.3 Hz, 3H), 1.58-1.70 (m, 2H), 2.30-2.48 (m, 2H), 2.55 (t, J=8.3 Hz, 2H), 3.57 (m, 1H), 3.76 (q, J=8.3 Hz, 1H), 4.04-4.10 (m, 2H), 4.39 (m, 1H), 7.03 (t, J=3.0 Hz, 1H), 8.04 (s, 1H), 8.14 (d, J=3.3 Hz, 1H). The free base was dissolved in Et2O and a saturated solution of HCl in Et2O was added dropwise carefully. The solvent was removed, and the resultant solid was recrystallized from MeOH/Et2O to afford the title compound as a yellow hygroscopic solid: mp 79-80° C.; MS (CI/NH3) m/z: 207 (M+H)+; 1H NMR (D2O, 300 MHz) δ1.01 (t, J=3.05 Hz, 3H), 1.68-1.80 (m, 2H), 2.62-2.78 (m, 2H), 2.80 (t, J=7.1 Hz, 2H), 4.04-4.21 (m, 3H), 4.44-4.60 (m, 2H), 7.40 (s, 1H), 8.04 (s, 1H), 8.14 (s, 1H). Anal. Calcd for C12H18N2O.2 HCl.H2O: C, 48.49; H, 7.46; N, 9.43. Found: C, 48.35; H, 7.23; N, 9.48.

Workup

  1. temperatureThe reaction mixture was refluxed for 3 h
  2. customquenched with saturated aqueous ammonia chloride
  3. extractionThe desired product was extracted with CH2Cl2
  4. dry with materialThe organic phase was dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 1:1)

Sources & evidence

ORD record
ord-34d0fb926097454d9d19b0d759320fd4
Source dataset
uspto-grants-2002_06
Patent number
US06403575B1

Reaction notes

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