Sodium Carbonate → Racemic 4-(trans-2,5-dimethylpiperazine-1-yl)-1-phenylpyrido[3,4-d]pyridazine

HRID 1514382Notes

Reaction equation

HRID 1514382 reaction equation
[C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:17]1[N:22]=[N:21][C:20]([N:23]2[CH2:28][C@@H:27]([CH3:29])[NH:26][CH2:25][C@@H:24]2[CH3:30])=[C:19]2[CH:31]=[N:32][CH:33]=[CH:34][C:18]=12>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][C@H:24]1[CH2:25][NH:26][C@H:27]([CH3:29])[CH2:28][N:23]1[C:20]1[N:21]=[N:22][C:17]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:18]2[CH:34]=[CH:33][N:32]=[CH:31][C:19]=12

Participants

5

Reactant 3

HCID 10340Sodium CarbonateHCID 66827Phenylboronic AcidHCID 876275031-Chloro-4-(rac-2,5-trans-dimethylpiperazine-1-yl)pyrido[3,4-d]pyridazine

Product 1

HCID 68796083Racemic 4-(trans-2,5-dimethylpiperazine-1-yl)-1-phenylpyrido[3,4-d]pyridazineYield 93.2%

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
100 °C

Procedure

Tetrakis(triphenylphosphine)palladium (146 mg, 126 μmol), phenylboronic acid (461 mg, 3.78 mmol), 2 M sodium carbonate (2520 μl, 5.04 mmol), and 1-chloro-4-(trans-2,5-dimethylpiperazine-1-yl)pyrido[3,4-d]pyridazine 43 (700 mg, 2.52 mmol) were added to a round bottom flask. The reaction vessel was purged with nitrogen and toluene (25 mL) was added. The reaction was heated to 100° C. overnight. After cooling to RT, the reaction was diluted with 250 mL of ethyl acetate and washed with 1×50 mL of sat. NaHCO3 and 1×50 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (10:0.5:0.1 CH2Cl2:MeOH, Et3N) afforded racemic 4-(trans-2,5-dimethylpiperazine-1-yl)-1-phenylpyrido[3,4-d]pyridazine 44 (750 mg, 93% yield). 1H-NMR (400 MHz, CDCl3): δ 9.76 (d, J=1.2 Hz, 1H), 8.94 (d, J=5.5 Hz, 1H), 7.84 (dd, J=5.9, 1.2 Hz, 1H), 7.78 (m, 2H), 7.57 (m, 2H), 3.83 (dqd, J=10.2, 5.9, 3.1 Hz, 1H), 3.47 (dd, J=12.1, 2.7 Hz, 1H), 3.30 (dqd, J=9.8, 6.3, 2.7 Hz, 1H), 3.25 (dd, J=12.5, 3.1 Hz, 1H), 2.94 (dq J=12.1, 10.2 Hz, 1H), 2.73 (dd, J=12.1, 9.8 Hz, 1H), 1.17 (d, J=6.3 Hz, 1H), 1.11 (d, J=6.6 Hz, 1H). MS 319.2 (calc'd) 320.2 (M+H, found).

Workup

  1. customThe reaction vessel was purged with nitrogen and toluene (25 mL)
  2. additionwas added
  3. temperatureAfter cooling to RT
  4. additionthe reaction was diluted with 250 mL of ethyl acetate
  5. washwashed with 1×50 mL of sat. NaHCO3 and 1×50 mL of brine
  6. dry with materialThe organic layer was dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification by column chromatography (10:0.5:0.1 CH2Cl2:MeOH, Et3N)

Sources & evidence

ORD record
ord-ece8357287fb46deafe8e9f8339aead6
Source dataset
uspto-grants-2012_07
Patent number
US08222251B2

Reaction notes

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