Diisopropylethylamine → (S)-N-cyclopropyl-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)b enzamide

HRID 69747Notes

Reaction equation

HRID 69747 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.[CH:19]1([NH:22][C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[C:26]([CH3:36])[CH:25]=2)[CH2:21][CH2:20]1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH:19]1([NH:22][C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][N:33]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][C@H:8]6[C:7](=[O:16])[NH:6][C:5]=5[CH:4]=4)[CH2:34][CH2:35]3)=[C:26]([CH3:36])[CH:25]=2)[CH2:21][CH2:20]1

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 66775049N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride

Product 1

HCID 46864776(S)-N-cyclopropyl-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)b enzamideYield 29.7%

Reagents, catalysts & solvents 1

HCID 7854PropionitrileSolvent

Conditions

Temperature
90 °C

Procedure

To a suspension of (S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (0.1 g, 0.456 mmol), N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (0.179 g, 0.538 mmol), and (cyanomethyl)trimethylphosphonium iodide (0.188 g, 0.775 mmol) in Propiononitrile (Volume: 2.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.556 mL, 3.19 mmol) at 23° C. The reaction was stirred at 90° C. for 8 hr. The reaction mixture was cooled to room temperature, filtered, and rinsed with propiononitrile (3×1 mL). The resulting solid was reconstituted in DMSO (Volume: 3.0 mL) and purified via preparative mass trigger LCMS using a gradient eluant of 25-65% ACN:10 mM NH4HCO3 (aq). The collected fractions were combined and the ACN was removed via rotary evaporation to furnish a suspension. The suspension was filtered, rinsed with H2O (3×10 mL), and the resulting solid was dried in vacuo to provide (S)—N-cyclopropyl-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 (0.0624 g, 0.135 mmol, 29.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.59 (m, 2 H) 0.60-0.70 (m, 2 H) 1.86-2.00 (m, 3 H) 2.14-2.20 (m, 1 H) 2.25 (s, 3 H) 2.47-2.50 (m, 4 H) 2.76-2.93 (m, 5 H) 3.34-3.44 (m, 3 H) 3.55-3.63 (m, 1 H) 3.93-4.02 (m, 1 H) 6.96-7.04 (m, 2 H) 7.56-7.67 (m, 3 H) 8.22 (d, J=4.29 Hz, 1 H) 10.45 (s, 1 H). ESI-MS: m/z 461.4 (M+H)+. mp=226.7-233.5° C.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. filtrationfiltered
  3. washrinsed with propiononitrile (3×1 mL)
  4. custompurified via preparative mass trigger LCMS
  5. customthe ACN was removed via rotary evaporation
  6. customto furnish a suspension
  7. filtrationThe suspension was filtered
  8. washrinsed with H2O (3×10 mL)
  9. customthe resulting solid was dried in vacuo

Sources & evidence

ORD record
ord-7c08ed4386974708b62f8936b90c684f
Source dataset
uspto-grants-2014_09
Patent number
US08822470B2

Reaction notes

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