Tetrahydrofuran → 2-{1-[2-(2,4-difluorophenyl)ethyl]azetidin-3-yl}-N,N-dimethoxyacetamide

HRID 10217

Reaction equation

HRID 10217 reaction equation
CO[C:3](=[O:19])[CH2:4][CH:5]1[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH2:6]1.Cl.C[NH:22][O:23][CH3:24].C([Mg]Cl)(C)C.[Cl-].[NH4+].[O:32]1CCC[CH2:33]1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][N:7]1[CH2:6][CH:5]([CH2:4][C:3]([N:22]([O:32][CH3:33])[O:23][CH3:24])=[O:19])[CH2:8]1

Participants

6

Reactant 5

HCID 8028TetrahydrofuranHCID 25517Ammonium ChlorideHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 21978392Methyl{1-[2-(2,4-difluorophenyl)ethyl]azetidin-3-yl}acetateHCID 178418918HCID 178418918, compound

Product 1

HCID 219783682-{1-[2-(2,4-difluorophenyl)ethyl]azetidin-3-yl}-N,N-dimethoxyacetamideYield 54%

Conditions

Temperature
-20 °C

Procedure

A slurry of methyl{1-[2-(2,4-difluorophenyl)ethyl]azetidin-3-yl}acetate (Step 1, 0.5 g, 1.86 mmol) and N,O-dimethylhydroxylamine hydrochloride (272 mg, 2.79 mmol) in tetrahydrofuran (4 mL) was cooled to −20° C. under nitrogen. Isopropylmagnesium chloride (2M in tetrahydrofuran, 2.79 mL, 5.57 mmol) was added dropwise, maintaining the internal temperature between −20 and −5° C. The reaction was stirred at −20° C. for 30 minutes then at room temperature for 2.5 hours. Saturated ammonium chloride solution was added and the mixture stirred vigorously for 5 minutes then extracted with ethyl acetate (x3). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 7% methanol/dichloromethane, to give 2-{1-[2-(2,4-difluorophenyl)ethyl]azetidin-3-yl}-N,N-dimethoxyacetamide (297 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 7.16–7.10 (1H, m), 6.79–6.71 (2H, m), 3.67 (3H, s), 3.51–3.47 (2H, m), 3.14 (3H, s), 2.89–2.79 (3H, m), 2.71 (2H, d, J=6.8 Hz), 2.62 (4H, s); m/z (ES+) 299 (M+H)+.

Workup

  1. temperaturemaintaining the internal temperature between −20 and −5° C
  2. waitat room temperature for 2.5 hours
  3. stirringthe mixture stirred vigorously for 5 minutes
  4. extractionthen extracted with ethyl acetate (x3)
  5. dry with materialThe combined organic layers were dried over MgSO4
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by flash column chromatography on silica
  8. washeluting with 7% methanol/dichloromethane

Sources & evidence

ORD record
ord-2a9066dffd474d6f87e1d6731d6c6d43
Source dataset
uspto-grants-2006_08
Patent number
US07094777B2

Linked notes

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