Reacción #156781

Ecuación de reacción

N,N-diisopropylethylamine

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

3-fluoro-4-(piperazin-1-yl)benzonitrile

(cyanomethyl)trimethylphosphonium iodide

→

(S)-3-fluoro-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)benzonitrile

Rendimiento 21.6%

Disolventes

DMSO

propionitrile

Condiciones de reacción

Tratamiento posterior

1. 1
   TemperaturaIt was cooled to room temperature
2. 2
   Otropurified
3. 3
   workup.ADDITIONThe fractions containing product
4. 4
   Concentraciónwere concentrated in vacuo
5. 5
   Otrocrystallized with water (3 mL)
6. 6
   FiltraciónThe precipitate was filtered
7. 7
   Otrodried in vacuum

Procedimiento

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (150 mg, 0.684 mmol), 3-fluoro-4-(piperazin-1-yl)benzonitrile (140 mg, 0.684 mmol), (cyanomethyl)trimethylphosphonium iodide (249 mg, 1.026 mmol) and N,N-diisopropylethylamine (0.597 ml, 3.42 mmol) were suspended in propionitrile (2 ml) and heated in a closed vial at 90° C. for 2 h. The reaction mixture became a clear dark brown solution. It was cooled to room temperature, diluted with DMSO (2 mL) and purified using preparative HPLC (25-95% acetonitrile in water, NH4HCO3 buffered). The fractions containing product were concentrated in vacuo and crystallized with water (3 mL). The precipitate was filtered and dried in vacuum to afford (S)-3-fluoro-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)benzonitrile (60.2 mg, 0.148 mmol, 21.65% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.83-2.03 (m, 3 H) 2.11-2.24 (m, 1 H) 2.44-2.49 (m, 4 H) 3.07-3.22 (m, 4 H) 3.34-3.42 (m, 3 H) 3.53-3.65 (m, 1 H) 3.93-4.03 (m, 1 H) 6.97 (d, J=2.02 Hz, 1 H) 7.11 (t, J=8.72 Hz, 1 H) 7.56 (dd, J=8.46, 1.64 Hz, 1 H) 7.61 (d, J=2.02 Hz, 1 H) 7.69 (dd, J=13.39, 2.02 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C22H23FN6O, 407; found, 407; melting point 226° C.

Fuente