Diethyl (ethoxymethylene)malonate → 2-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-1-ethoxy-2-pyridin-2-yl-ethyl]-malonic acid diethyl ester

HRID 1192387Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1192387
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1CN1CCNCC1.[Li]CCCC.[CH2:39]([O:41][CH:42]=[C:43]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:40]>C1COCC1.O>[CH2:52]([O:51][C:49](=[O:50])[CH:43]([CH:42]([O:41][CH2:39][CH3:40])[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:53]

Komponenten

7

Edukt 4

HCID 6871Diethyl (ethoxymethylene)malonateHCID 8087141-[(Pyridin-2-yl)methyl]piperazineHCID 10062065Tert-butyl 4-(pyridin-2-ylmethyl)piperazine-1-carboxylateHCID 178418339Butyllithium

Produkt 1

HCID 675375522-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-1-ethoxy-2-pyridin-2-yl-ethyl]-malonic acid diethyl esterAusbeute 67 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittel2×

Versuchsvorschrift

To a solution of 4-Pyridin-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from 1-Pyridin-2-ylmethyl-piperazine according to the literature: J. Med. Chem. (1993), 36, 2984) (2.00 g, 7.21 mmol) in THF (15 mL) was added n-BuLi (1.6 M in hexanes, 5.0 mL, 7.9 mmol) at −78° C. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The solution was then cooled to −78° C. and a solution of diethyl ethoxymethylenemalonate (1.72 g, 7.93 mmol) in THF (2 mL) was added dropwise. The reaction mixture was allowed to warm to 0° C. over 1 hour and stirred at 0° C. for 1 hour. The reaction was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 8:1 to 1; 1) to give 2-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-1-ethoxy-2-pyridin-2-yl-ethyl]-malonic acid diethyl ester (2.40 g, 67%) as a mixture of diastereomers. Diastereomer 1: 1H NMR (CDCl3, 400 MHz) δ 8.55 (d, J=4.4 Hz, 1H), 7.63 (td, J=7.6 Hz, J=1.6 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.16 (dd, J=7.6 Hz, J=1.6 Hz, 1H), 4.74 (m, 1H), 4.16 (m, 5H), 3.75 (q, J=7.2 Hz, 2H), 3.52 (d, J=4.4 Hz, 1H), 3.38 (m, 4H), 2.67 (m, 2H), 2.44 (m, 2H), 1.40 (s, 9H), 1.22 (m, 6H), 1.44 (t, J=7.2 Hz, 3H). LCMS (APCI+) m/z 494 [M+H]+; Rt=3.61 min. Diastereomer 2: 1H NMR (CDCl3, 400 MHz) δ 8.58 (d, J=4.8 Hz, 1H), 7.59 (td, J=7.6 Hz, J=1.6 Hz, 1H), 7.15 (dd, J=7.6 Hz, J=1.6 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 4.91 (m, 1H), 4.16 (m, 5H), 3.53 (m, 1H), 3.22 (m, 6H), 2.50 (m, 2H), 2.19 (m, 2H), 1.34 (s, 9H), 1.24 (m, 6H), 0.69 (t, J=7.2 Hz, 3H). LCMS (APCI+) m/z 494 [M+H]+; Rt=3.62 min.

Aufarbeitung

  1. temperatureThe solution was then cooled to −78° C.
  2. temperatureto warm to 0° C. over 1 hour
  3. stirringstirred at 0° C. for 1 hour
  4. extractionextracted with EtOAc
  5. washThe combined organic layers were washed with brine
  6. customdried
  7. concentrationconcentrated
  8. customThe residue was purified by column chromatography (hexanes:EtOAc, 8:1 to 1; 1)

Quellen und Nachweise

ORD-Eintrag
ord-9e8d70daf58a49d3847d65d1a04223ac
Quelldatensatz
uspto-grants-2014_03
Patentnummer
US08680114B2

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