Diisopropylethylamine → (S)-3-chloro-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

HRID 2097804Notes

Reaction equation

HRID 2097804 reaction equation
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.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:22]#[N:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][N:30]([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)[CH2:29][CH2:28]1)[C:22]#[N:23]

Participants

6

Reactant 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 667753553-Chloro-4-(piperazin-1-yl)benzonitrile hydrochloride

Product 1

HCID 46864919(S)-3-chloro-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)benzonitrileYield 70.2%

Reagents, catalysts & solvents 1

HCID 7854PropionitrileSolvent

Conditions

Temperature
90 °C

Procedure

(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-chloro-4-(piperazin-1-yl)benzonitrile hydrochloride (118 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 propionitrile (2 ml) and heated in a closed vial at 90° C. for 2 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo and purified using flash column chromatography on silica gel (80 g SiO2, dichloromethane-methanol 100:0-95:5). The resulting solid was suspended in ether (7 mL), stirred until a fine suspension resulted, filtered and the solid was dried in vacuum to afford (S)-3-chloro-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 (135.4 mg, 0.320 mmol, 70.2% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.80-2.03 (m, 3 H) 2.10-2.25 (m, 1 H) 2.39-2.61 (m, 4 H) 2.94-3.19 (m, 4 H) 3.35-3.46 (m, 3 H) 3.51-3.65 (m, 1 H) 3.91-4.05 (m, 1 H) 6.97 (d, J=1.77 Hz, 1 H) 7.22 (d, J=8.59 Hz, 1 H) 7.62 (d, J=1.52 Hz, 1 H) 7.74 (dd, J=8.46, 1.89 Hz, 1 H) 7.93 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C22H23ClN6O, 423; found, 423. melting point 213-215° C.

Workup

  1. temperatureIt was cooled to room temperature
  2. concentrationconcentrated in vacuo
  3. custompurified
  4. customresulted
  5. filtrationfiltered
  6. customthe solid was dried in vacuum

Sources & evidence

ORD record
ord-04d0f6d1eee14c92ac378230772f91c1
Source dataset
uspto-grants-2013_05
Patent number
US08450323B2

Reaction notes

Loading…