Triethylamine → (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester

HRID 1261499Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1261499
Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([NH2:13])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C[O:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH2:25]Br.C(N(CC)CC)C>C(#N)C.O>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([N:13]1[CH2:25][C:19]2[C:18](=[CH:23][CH:22]=[CH:21][C:20]=2[F:24])[C:17]1=[O:16])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1

Komponenten

6

Edukt 3

HCID 8471TriethylamineHCID 19788116Methyl 2-(bromomethyl)-3-fluorobenzoateHCID 22861687methyl (2S)-2-amino-3-cyclohexylpropanoate hydrochloride

Produkt 1

HCID 70945620(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl esterAusbeute 57,2 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittelHCID 6342AcetonitrileLösungsmittel

Reaktionsbedingungen

Temperatur
82 °C

Versuchsvorschrift

A solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester hydrochloride (Novabiochem, 500 mg, 2.25 mmol) in acetonitrile (20 mL) was placed in a flask and treated with 2-bromomethyl-3-fluoro-benzoic acid methyl ester (557 mg, 2.25 mmol) and triethylamine (660 μL, 4.74 mmol). The reaction mixture was then heated at reflux (82° C.) overnight for 16 h. After this time, the reaction mixture was diluted with water (5 mL) and concentrated in vacuo to remove the acetonitrile. The remaining material was then diluted with another portion of water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The crude material was purified using an Analogix Intelliflash 280 chromatography system (RS-40 silica gel column, 10-25% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (411 mg, 57%) as a clear colorless oil: [α]30D=−17.3° (c=0.30, methylene chloride); HR-ES(+) m/e calcd for C18H22NO3F [M+H]+ 320.1657, observed 320.1656; 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.63 (m, 2H), 7.42-7.54 (m, 1H), 4.96 (dd, J=4.53, 11.47 Hz, 1H), 4.49-4.65 (m, 2H), 3.63 (s, 3H), 1.48-1.99 (m, 7H), 0.74-1.23 (m, 6H).

Aufarbeitung

  1. temperatureThe reaction mixture was then heated
  2. concentrationconcentrated in vacuo
  3. customto remove the acetonitrile
  4. additionThe remaining material was then diluted with another portion of water (10 mL)
  5. extractionextracted with ethyl acetate (3×20 mL)
  6. dry with materialThe combined organic layers were then dried over magnesium sulfate
  7. filtrationfiltered
  8. customto remove the drying agent
  9. concentrationthe filtrate concentrated in vacuo
  10. customThe crude material was purified

Quellen und Nachweise

ORD-Eintrag
ord-4dd8cb7d8f6442eb90de73b58a2f1873
Quelldatensatz
uspto-grants-2013_06
Patentnummer
US08470866B2

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