Diisopropylethylamine → HCID 46864645, compound

HRID 69722Notes

Reaction equation

HRID 69722 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:36])[C:22]1[CH:27]=[C:26]([F:28])[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][C:23]=1[F:35])[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.ClCCl.CO>[CH2:18]([NH:20][C:21](=[O:36])[C:22]1[CH:27]=[C:26]([F:28])[C:25]([N:29]2[CH2:34][CH2:33][N:32]([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)[CH2:31][CH2:30]2)=[CH:24][C:23]=1[F:35])[CH3:19]

Participants

8

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 66775087N-ethyl-2,5-difluoro-4-(piperazin-1-yl)benzamide hydrochloride

Product 1

HCID 46864645HCID 46864645, compoundYield 36.8%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 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 (10.76 mg, 0.049 mmol), N-ethyl-2,5-difluoro-4-(piperazin-1-yl)benzamide hydrochloride (15 mg, 0.049 mmol), (cyanomethyl)trimethylphosphonium iodide (17.88 mg, 0.074 mmol) and N,N-diisopropylethylamine (0.043 mL, 0.245 mmol) were suspended in propiononitrile (Volume: 0.2 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, diluted with dichloromethane (2 mL) and methanol (0.3 mL), and purified using flash column chromatography on silica gel (12 g SiO2, dichloromethane-methanol 100:0-90:10). The resulting solid was suspended in ether (1 mL), stirred until a fine suspension resulted, filtered and the solid was recrystallized from MeOH-water (1:7, 4 mL) and dried in vacuum to afford (S)—N-ethyl-2,5-difluoro-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 (8.5 mg, 0.018 mmol, 36.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.20 Hz, 3 H) 1.76-1.97 (m, 3 H) 2.11 (m, J=6.44, 4.17 Hz, 1 H) 2.36-2.42 (m, 4 H) 3.03 (br. s., 4 H) 3.12-3.22 (m, 2 H) 3.28-3.37 (m, 3 H) 3.46-3.59 (m, 1 H) 3.86-3.97 (m, 1 H) 6.81 (dd, J=12.63, 7.07 Hz, 1 H) 6.91 (d, J=1.77 Hz, 1 H) 7.30 (dd, J=13.64, 6.82 Hz, 1 H) 7.55 (d, J=1.52 Hz, 1 H) 7.95-8.04 (m, 1 H) 10.38 (s, 1 H). [M+H] calc'd for C24H28F2N6O2, 471; found, 471.

Workup

  1. temperatureIt was cooled to room temperature
  2. custompurified
  3. customresulted
  4. filtrationfiltered
  5. customthe solid was recrystallized from MeOH-water (1:7, 4 mL)
  6. customdried in vacuum

Sources & evidence

ORD record
ord-47319f0ba7454566989befae63de6033
Source dataset
uspto-grants-2014_09
Patent number
US08822470B2

Reaction notes

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