Sodium Carbonate → Racemic (4,4-difluorocyclohexyl)(trans-2,5-dimethyl-4-(1-phenylpyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone

HRID 1514383Notes

Reaction equation

HRID 1514383 reaction equation
[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[N:10]=[N:11][C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=12.CCN=C=NCCCN(C)C.[F:36][C:37]1([F:46])[CH2:42][CH2:41][CH:40]([C:43](O)=[O:44])[CH2:39][CH2:38]1.N1C2C(=NC=CC=2)N(O)N=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:36][C:37]1([F:46])[CH2:42][CH2:41][CH:40]([C:43]([N:6]2[CH2:7][C@@H:2]([CH3:1])[N:3]([C:9]3[N:10]=[N:11][C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:13]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=34)[CH2:4][C@@H:5]2[CH3:8])=[O:44])[CH2:39][CH2:38]1

Participants

8

Reactant 5

HCID 10340Sodium CarbonateHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 181649HOAtHCID 27791364,4-Difluorocyclohexanecarboxylic acidHCID 68796083Racemic 4-(trans-2,5-dimethylpiperazine-1-yl)-1-phenylpyrido[3,4-d]pyridazine

Product 1

HCID 25227134Racemic (4,4-difluorocyclohexyl)(trans-2,5-dimethyl-4-(1-phenylpyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To racemic trans 4-(2,5-dimethylpiperazine-1-yl)-1-phenylpyrido[3,4-d]pyridazine 44 (360 mg, 1127 μmol) dissolved in 4 mL of DMF was added EDCI (259 mg, 1.35 mmol), 4,4-difluorocyclohexanecarboxylic acid (204 mg, 1.24 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (184 mg, 1.35 mmol) (HOAT), and sodium carbonate (239 mg, 2.25 mmol). The reaction was stirred at RT for 4 h, and the solvent was removed in vacuo. The crude reaction mixture was dissolved in 100 mL of ethyl acetate and washed with 1×25 mL of water, 1×25 mL of sat. NaHCO3, and 1×25 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purified by column chromatography to isolate racemic (4,4-difluorocyclohexyl)(trans-2,5-dimethyl-4-(1-phenylpyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone 45. MS 465.2 (calc'd) 466.1 (M+H, found).

Workup

  1. customthe solvent was removed in vacuo
  2. customThe crude reaction mixture
  3. washwashed with 1×25 mL of water, 1×25 mL of sat. NaHCO3, and 1×25 mL of brine
  4. dry with materialThe organic layer was dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurified by column chromatography

Sources & evidence

ORD record
ord-2318a1ec2cac4411acaa94837c130da5
Source dataset
uspto-grants-2012_07
Patent number
US08222251B2

Reaction notes

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