Formaldehyde → 3-(4-Piperidin-1-ylmethyl-phenyl)-6-(1H-imidazol-1-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole

HRID 1506038Notes

Reaction equation

HRID 1506038 reaction equation
[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:27]=[N:26][C:17]4[NH:18][C:19]5[CH:24]=[N:23][C:22]([NH2:25])=[CH:21][C:20]=5[C:16]=4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[CH:30]([CH:32]=O)=O.[Cl-].[NH4+:35].C(=O)(O)[O-].[Na+].[CH3:41]O>O1CCOCC1.O.C(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:27]=[N:26][C:17]4[NH:18][C:19]5[CH:24]=[N:23][C:22]([N:25]6[CH:32]=[CH:30][N:35]=[CH:41]6)=[CH:21][C:20]=5[C:16]=4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

10

Reactant 6

HCID 712FormaldehydeHCID 887MethanolHCID 7860GlyoxalHCID 25517Ammonium ChlorideHCID 516892Sodium BicarbonateHCID 58266504HCID 58266504, compound

Product 1

HCID 582664603-(4-Piperidin-1-ylmethyl-phenyl)-6-(1H-imidazol-1-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrroleYield 17%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-amine (101.1 mg, 0.283 mmol), paraformaldehyde (9.65 μL, 0.283 mmol), glyoxal (13.0 μL, 0.283 mmol) and 0.17M aqueous ammonium chloride (5.0 mL) in 1,4-dioxane (8.4 mL) and water (8.4 mL) was heated at 100° C. for 18 h. The cooled reaction mixture was treated with saturated sodium bicarbonate and diluted with 20% MeOH in DCM and water. The layers were separated, the aqueous phase extracted into 20% MeOH in DCM, and the combined organic phase was dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by preparative HPLC (0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min) to afford the title compound as a white solid (20 mg, 17%). NMR (DMSO-D6, 400 MHz): 12.37 (s, 1H), 8.96 (s, 2H), 8.82 (s, 1H), 8.67 (s, 1H), 8.49 (s, 1H), 7.94 (s, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.16 (s, 1H), 3.50 (s, 2H), 2.37 (m, 4H), 1.58-1.46 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=6.62 min, M+H+=409

Workup

  1. customThe cooled reaction mixture
  2. customThe layers were separated
  3. extractionthe aqueous phase extracted into 20% MeOH in DCM
  4. dry with materialthe combined organic phase was dried over sodium sulfate
  5. concentrationconcentrated in vacuo
  6. customThe resultant residue was purified by preparative HPLC (0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min)

Sources & evidence

ORD record
ord-4a5234a6261647ec9c36fd055773713d
Source dataset
uspto-grants-2015_12
Patent number
US09216980B2

Reaction notes

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