3-(2-Chloro-phenoxy)-4-(3,3-difluoro-1-methoxycarbonyl-propylamino)-but-2-enoic acid ethyl ester → 2-[4-(2-Chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-butyric acid methyl ester

HRID 19324Notes

Reaction equation

C([O:3][C:4](=O)[CH:5]=[C:6]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[CH2:7][NH:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:11]([F:13])[F:12])C>C(#N)C>[CH3:17][O:16][C:14](=[O:15])[CH:9]([N:8]1[CH2:7][C:6]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:5][C:4]1=[O:3])[CH2:10][CH:11]([F:13])[F:12]

Participants

Conditions

Temperature: 180 °C

Procedure

A solution of 3-(2-chloro-phenoxy)-4-(3,3-difluoro-1-methoxycarbonyl-propylamino)-but-2-enoic acid ethyl ester (1.19 g, 3.04 mmol) in acetonitrile (4 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 180° C. for 3 h. The mixture was then cooled to room temperature and concentrated in vacuo with silica gel (3 g). Purification by Biotage flash chromatography (Aspire 40 g column, 16% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-butyric acid methyl ester (794 mg, 40% over two steps) as an amber oil: HR-ES-MS m/z calculated for C15H14NO4ClF2 [M+H]+ 346.0652, observed 346.0651.

Workup

temperatureThe mixture was then cooled to room temperature
concentrationconcentrated in vacuo with silica gel (3 g)
customPurification by Biotage flash chromatography (Aspire 40 g column, 16% ethyl acetate/hexanes to 50% ethyl acetate/hexanes)

Sources & evidence

ORD record: ord-90a5dcacdd6f4055a3c6ec6c70342227
Source dataset: uspto-grants-2010_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07741327B2

Reaction notes

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