Phenol → 6-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-oxazolo[4,5-d]azepine

HRID 1529576Notes

Reaction equation

HRID 1529576 reaction equation
N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:17][C:18]1[CH:37]=[CH:36][C:21]([C:22]([N:24]2[CH2:30][CH2:29][C:28]3[O:31][C:32]([CH2:34][OH:35])=[N:33][C:27]=3[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1.[C:38]1(O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]2[CH2:30][CH2:29][C:28]3[O:31][C:32]([CH2:34][O:35][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:33][C:27]=3[CH2:26][CH2:25]2)=[O:23])=[CH:36][CH:37]=1

Participants

6

Reactant 4

HCID 996PhenolHCID 11776TriphenylphosphineHCID 97268Di-tert-butyl azodicarboxylateHCID 666088636-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepine-2-methanol

Product 1

HCID 569414846-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-oxazolo[4,5-d]azepineYield 8.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Di-tert-butyl azodicarboxylate (0.024 g, 0.10 mmol) was added portionwise to a stirred solution of 6-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepine-2-methanol (0.02 g, 0.069 mmol), phenol (0.01 g, 0.10 mmol) and triphenylphosphine (0.027 g, 0.10 mmol) in DCM (0.5 mL) at 0° C. The mixture was stirred at room temperature for 10 minutes and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 40/60). The desired fractions were collected and concentrated in vacuo. The product was further purified by flash column chromatography (silica; AcOEt in heptane 50/50 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo and purified by reverse phase HPLC performed on a C18 XBridge 30×100 mm, 5 μm column (0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 in ethyl acetate 80/20 to 0/100) to yield 6-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-oxazolo[4,5-d]azepine (2.07 mg, 8% yield) as an oil. C21H19FN2O3. (Mixture of rotamers ˜60:40) 1H NMR (400 MHz, CDCl3) δ ppm 2.66 (br. s., 1.2 H), 2.78 (br. s., 0.8 H), 3.00 (br. s., 0.8 H), 3.12 (br. s., 1.2 H), 3.62 (br. s., 2.1 H), 3.93 (br. s., 1.9 H), 5.05 (s, 2 H), 6.97-7.04 (m, 1 H), 7.02 (d, J=7.4 Hz, 2 H), 7.12 (t, J=8.7 Hz, 2 H), 7.31 (dd, J=9.1, 7.1 Hz, 2 H), 7.39 (dd, J=8.8, 5.3 Hz, 2 H).

Workup

  1. customthe solvent was evaporated in vacuo
  2. customThe crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 40/60)
  3. customThe desired fractions were collected
  4. concentrationconcentrated in vacuo
  5. customThe product was further purified by flash column chromatography (silica; AcOEt in heptane 50/50 to 100/0)
  6. customThe desired fractions were collected
  7. customthe solvents evaporated in vacuo
  8. custompurified by reverse phase HPLC

Sources & evidence

ORD record
ord-702204cf5c254f729a861a6c1a2b78bf
Source dataset
uspto-grants-2015_07
Patent number
US09090632B2

Reaction notes

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