Pyridine → 3-(3-Benzyloxy-phenyl)-3-(cyclobutanecarbonyl-amino)-2-oxo-propionic acid ethyl ester

HRID 17975

Reaction equation

HRID 17975 reaction equation
[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:19][C:20]([CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:21])C(O)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:32]([O:34][C:35](=[O:39])[C:36](Cl)=[O:37])[CH3:33].[O-]CC.[Na+]>CN(C1C=CN=CC=1)C.C1COCC1.CCO>[CH2:32]([O:34][C:35](=[O:39])[C:36](=[O:37])[CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[NH:19][C:20]([CH:22]1[CH2:25][CH2:24][CH2:23]1)=[O:21])[CH3:33]

Participants

8

Reactant 4

HCID 1049PyridineHCID 20884Ethoxalyl chlorideHCID 2723922Sodium ethoxideHCID 68588161(3-Benzyloxy-phenyl)-(cyclobutanecarbonyl-amino)-acetic acid

Product 1

HCID 585926253-(3-Benzyloxy-phenyl)-3-(cyclobutanecarbonyl-amino)-2-oxo-propionic acid ethyl ester

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 702EthanolSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

A slurry of (3-benzyloxy-phenyl)-(cyclobutanecarbonyl-amino)-acetic acid (4.77 g, 14.1 mmol), pyridine (3.4 mL, 42.2 mmol) and DMAP (cat.) in anhydrous THF (26 mL) was charged dropwise with chloro-oxo-acetic acid ethyl ester (3.13 mL, 28.1 mmol) and heated to reflux for 1.5 h. The white precipitate was filtered through a fritted glass Buchner funnel into a flask containing H2O and EtOAc and the aqueous phase was separated from the organic phase. The aqueous was washed with EtOAc (3×) and the combined EtOAc layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a yellow/orange oil. The oil was dissolved in anhydrous EtOH (28 mL) and a solution of 21 wt % of sodium ethoxide (NaOEt) in EtOH (2.0 mnL) was added at 0° C. and warmed to rt. The reaction mixture was concentrated in vacuo and the crude material was chromatographed on silica gel [eluting with 2% EtOAc in CHCl3], yielding the title compound as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 1.26 (t, J=7.2 Hz, 3H), 1.80-2.04 (m, 2H), 2.09 (m, 4H), 3.06 (quint, J=8.4 Hz, 1H) 4.17-4.30 (m, 2H), 5.04 (s, 2H), 6.18-6.32 (m, 2H), 6.86-7.00 (m, 3H), 7.22-7.48 (m, 5H); MS (ES+): m/z 396.03 (100) [MH+]; HPLC: tR=3.09 min (MicromassZQ, nonpolar—5 min).

Workup

  1. temperatureheated
  2. temperatureto reflux for 1.5 h
  3. filtrationThe white precipitate was filtered through a fritted glass Buchner funnel into a flask
  4. additioncontaining H2O and EtOAc
  5. customthe aqueous phase was separated from the organic phase
  6. washThe aqueous was washed with EtOAc (3×)
  7. washthe combined EtOAc layers were washed with brine (1×)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customresulting in a yellow/orange oil
  12. concentrationThe reaction mixture was concentrated in vacuo
  13. customthe crude material was chromatographed on silica gel [eluting with 2% EtOAc in CHCl3]

Sources & evidence

ORD record
ord-9bab4d3612fb4f8abb0611fb1c56e770
Source dataset
uspto-grants-2010_06
Patent number
US07741324B2

Linked notes

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