Diisopropylethylamine → (S)-N-ethyl-3-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 69743Notes

Reaction equation

HRID 69743 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.[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([CH3:34])[CH:23]=1)[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:32][CH2:33]2)=[C:24]([CH3:34])[CH:23]=1)[CH3:19]

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 66775291N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride

Product 1

HCID 46864730(S)-N-ethyl-3-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)benzamideYield 62.8%

Reagents, catalysts & solvents 1

HCID 7854PropionitrileSolvent

Conditions

Temperature
105 °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), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride (129 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)—N-ethyl-3-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, 0.286 mmol, 62.8% 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 C25H32N6O2, 449; found, 449.

Workup

  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

Sources & evidence

ORD record
ord-d7651633ae0140ea80085a1a9c759183
Source dataset
uspto-grants-2014_09
Patent number
US08822470B2

Reaction notes

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