Diisopropylethylamine → (S)-3-fluoro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

HRID 69732Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 69732
O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:22]([NH:24][CH3:25])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[F:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1)[C:22]([NH:24][CH3:25])=[O:23]

Komponenten

6

Edukt 4

HCID 81531DiisopropylethylamineHCID 10514344(Cyanomethyl)trimethylphosphanium iodideHCID 58324378(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-oneHCID 66775588HCID 66775588, Verbindung

Produkt 1

HCID 46864525(S)-3-fluoro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamideAusbeute 64,3 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 7854PropionitrileLösungsmittel

Reaktionsbedingungen

Temperatur
105 °C

Versuchsvorschrift

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (125 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-fluoro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (128.5 mg, 0.293 mmol, 64.2% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-2.03 (m, 3 H) 2.09-2.25 (m, 1 H) 2.50 (m, 4 H) 2.75 (d, J=4.29 Hz, 3 H) 2.96-3.14 (m, 4 H) 3.35-3.45 (m, 3 H) 3.53-3.65 (m, 1 H) 3.93-4.05 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.04 (t, J=8.59 Hz, 1 H) 7.51-7.67 (m, 3 H) 8.27-8.38 (m, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C23H27FN6O2, 439; found, 439.

Aufarbeitung

  1. temperatureIt was cooled to room temperature
  2. concentrationconcentrated in vacuo
  3. dissolutiondissolved in DMSO (2 mL)
  4. custompurified
  5. concentrationThe fractions were concentrated in vacuo
  6. customthe resulting solid was recrystallized from water-MeOH (2:1, 6 mL)
  7. customdried in vacuum

Quellen und Nachweise

ORD-Eintrag
ord-85ec30afee2b40588688ee94dc412381
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08822470B2

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