Triphenylphosphine → (S)-Tert-butyl 2-(((5-bromopyridin-3-YL)oxy)methyl)azetidine-1-carboxylate

HRID 2185720Notes

Reaction equation

HRID 2185720 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])=[O:38])([CH3:35])([CH3:34])[CH3:33].[Br:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50](O)[CH:51]=1>C1COCC1>[Br:45][C:46]1[CH:51]=[C:50]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH:49]=[N:48][CH:47]=1

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 5995293-Bromo-5-hydroxypyridineHCID 5462977Diethyl azodicarboxylateHCID 10511797tert-butyl (2S)-2-(hydroxymethyl)azetidine-1-carboxylate

Product 1

HCID 10688713(S)-Tert-butyl 2-(((5-bromopyridin-3-YL)oxy)methyl)azetidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Triphenylphosphine (4.01 g, 15.3 mmol) and DEAD (2.43 mL, 15.3 mmol) were dissolved in 30 mL of THF at 0° C., and the mixture was stirred for 10 minutes. Samples of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol (2.86 g, 15.3 mmol, Step 7c above) and 3-bromo-5-hydroxypyridine.(1.51 g, 10.2 mmol, Step 10c above) were added, and the mixture was stirred for 40 hours at room temperature. The volatile components were removed under vacuum, and the residue was triturated with hexane. The separated hexane fraction was concentrated, and the residue was chromatographed (silica gel; hexane/ether, 10:1 to 10:2) to afford 5-bromo-3-((1-t-butyloxycarbonyl-(2S)-azetidinyl)methoxy)pyridine as a colorless oil (1.669 g): 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.31 (m, 2H), 3.89 (m, 2H), 4.12 (m, 1H), 4.322 (m, 1H), 4.52 (m, 1H), 7.43 (m, 1H), 8.29 (m, 2H); MS (CI/NH3) m/z 344 (M+H)+. The 5-bromo-3-(2-(1-BOC-2-(S)-azetidinyl)methoxy)pyridine was treated with with 4 M HCl in dioxane to give the free base of the title compound. This was converted to the dihydrochloride salt and recrystallized from methanol/ether to provide the title compound: mp 163-165° C.; [α]25D −5.1 (c 0.57, methanol); 1H NMR (D2O, 300 MHz) δ8.36 (d, J=1.8 Hz, 1H), 8.32 (d, J=2.6 Hz, 1H), 7.84 (dd, J=1.8, 2.6 Hz, 1H), 4.98-4.90 (m, 1H), 4.43 (d, J=4.0 Hz, 2H), 4.20-4.02 (m, 2H), 2.67 (q, J=8.5 Hz, 2H); MS (CI/NH3) m/z 243/246 (M+H)+, 260/262 (M+NH4)+. Anal. calcd for C9H13N2OBrCl2: C, 34.21; H, 4.15; N, 8.86. Found: C, 34.18; H, 4.17; N, 8.89.

Workup

  1. addition(1.51 g, 10.2 mmol, Step 10c above) were added
  2. stirringthe mixture was stirred for 40 hours at room temperature
  3. customThe volatile components were removed under vacuum
  4. customthe residue was triturated with hexane
  5. concentrationThe separated hexane fraction was concentrated
  6. customthe residue was chromatographed (silica gel; hexane/ether, 10:1 to 10:2)

Sources & evidence

ORD record
ord-4318b1cdfc14493db775fbb798230d00
Source dataset
uspto-grants-2002_06
Patent number
US06403575B1

Reaction notes

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