Diisopropylethylamine → (S)-N,3-dimethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3',2'-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

HRID 69701Notes

Reaction equation

HRID 69701 reaction equation
O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[CH3:20][NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH3:20][NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([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][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 10514344(Cyanomethyl)trimethylphosphanium iodideHCID 58324368(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3',2'-e]pyrazin-6(6aH)-oneHCID 66775618N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride

Product 1

HCID 46864563(S)-N,3-dimethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3',2'-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamideYield 14.25%

Reagents, catalysts & solvents 1

HCID 7854PropionitrileSolvent

Conditions

Temperature
90 °C

Procedure

(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol), N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride (131 mg, 0.429 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143 mmol) were suspended in propiononitrile (Volume: 1287 μl) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature and purified using HPLC (NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from MeCN (5 mL), filtered off, washed with water (2 mL) and dried in vacuum to afford (S)—N,3-dimethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (27.4 mg, 0.061 mmol, 14.25% yield) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.57 (m, 3 H) 1.64 (d, J=11.87 Hz, 1 H) 1.85 (d, J=11.37 Hz, 1 H) 2.04 (d, J=11.87 Hz, 1 H) 2.25 (s, 3 H) 2.51-2.70 (m, 5 H) 2.56-2.70 (m, 2 H) 2.74 (d, J=4.29 Hz, 3 H) 2.87 (br. s., 4 H) 3.37-3.45 (m, 2 H) 3.84 (dd, J=11.24, 2.40 Hz, 1 H) 4.50 (d, J=13.14 Hz, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.01 (d, J=8.34 Hz, 1 H) 7.61 (dd, J=8.46, 1.64 Hz, 1 H) 7.65 (dd, J=12.25, 1.64 Hz, 2 H) 8.23 (q, J=4.13 Hz, 1 H) 10.48 (s, 1 H); [M+H] calc'd for C25H32N6O2, 449; found, 449.

Workup

  1. temperatureIt was cooled to room temperature
  2. custompurified
  3. concentrationThe fractions were concentrated in vacuo
  4. customthe resulting solid was recrystallized from MeCN (5 mL)
  5. filtrationfiltered off
  6. washwashed with water (2 mL)
  7. customdried in vacuum

Sources & evidence

ORD record
ord-560a8daa23424756a357e493102c5c28
Source dataset
uspto-grants-2014_09
Patent number
US08822470B2

Reaction notes

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