Ethyl Acrylate → Ethyl 1-(3-ethoxy-3-oxopropyl)-4-(6-(trifluoromethyl)pyridin-2-yl)-piperazine-2-carboxylate

HRID 1184574Notes

Reaction equation

[F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].C(N(CC)C(C)C)(C)C>C(O)C>[CH2:27]([O:26][C:22](=[O:25])[CH2:23][CH2:24][N:12]1[CH2:13][CH2:14][N:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:20])[F:21])[N:8]=2)[CH2:10][CH:11]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:28]

Participants

Conditions

Temperature: 80 °C

Procedure

To a solution of Example 94A (10 g, 33.0 mmol) and ethyl acrylate (14.29 mL, 132 mmol) in dry ethanol (30 mL) was added N,N-diisopropylethylamine (2.85 mL, 16.49 mmol). The mixture was heated to 80° C. and stirred for 4 days. Excess ethyl acrylate and ethanol were removed under vacuum. The residue was purified on a silica gel column (hexane:ethyl acetate=1:3) and then purified again via HPLC (Gilson®, Xbridge™ 50×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/acetonitrile, UV=220 nm) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.20 (t, 3H, J=7 Hz) 1.26 (t, 3H, J=7 Hz), 2.52 (td, 2H, J=7, 3 Hz), 2.56-2.65 (m, 1 H), 2.83-3.07 (m, 2 H), 3.17 (ddd, 1H, J=12, 9, 3 Hz), 3.37 (ddd, 1H, J=12, 9, 3 Hz), 3.47-3.61 (m, 2 H), 3.86-3.95 (m, 1 H), 4.06-4.18 (m, 4 H), 4.29 (dd, 1H, J=13, 3 Hz), 6.92-7.01 (m, 2 H), 7.62-7.70 (m, 1 H); MS (DCI) m/z 404 (M+H)+.

Workup

customExcess ethyl acrylate and ethanol were removed under vacuum
customThe residue was purified on a silica gel column (hexane:ethyl acetate=1:3)
custompurified again via HPLC (Gilson®, Xbridge™ 50×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/acetonitrile, UV=220 nm)

Sources & evidence

ORD record: ord-75995f198f484dffb7a140ce3186a865
Source dataset: uspto-grants-2014_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08669255B2

Reaction notes

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