Dimethylformamide → (S)-(4,4-difluoropiperidin-1-yl)(2-methyl-4-(1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone

HRID 1514385Notes

Reaction equation

HRID 1514385 reaction equation
CN(C=O)C.[CH3:6][C@@H:7]1[NH:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[N:15][C:16]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=23)[CH2:8]1.[F:33][C:34]1([F:52])[CH2:39][CH2:38][N:37]([C:40](OC2C=CC([N+]([O-])=O)=CC=2)=[O:41])[CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:33][C:34]1([F:52])[CH2:39][CH2:38][N:37]([C:40]([N:12]2[CH2:11][CH2:10][N:9]([C:13]3[N:14]=[N:15][C:16]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=34)[CH2:8][C@@H:7]2[CH3:6])=[O:41])[CH2:36][CH2:35]1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 57657602(S)-4-(3-methylpiperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazineHCID 576576134-Nitrophenyl 4,4-difluoropiperidin-1-carboxylate

Product 1

HCID 25227136(S)-(4,4-difluoropiperidin-1-yl)(2-methyl-4-(1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

DMF (3 mL) was added to (S)-4-(3-methylpiperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine 47 (150 mg, 402 μmol), 4-nitrophenyl 4,4-difluoropiperidin-1-carboxylate 41 (230 mg, 803 μmol), potassium carbonate (167 mg, 1.2 mmol), 4-dimethylaminopyridine (9.8 mg, 80 μmol). The reaction was heated to 75° C. for 72 h. The reaction was diluted with ethyl acetate (70 mL) and washed with 1×10 mL water, 1×10 mL NaHCO3, and 1×10 mL brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography afforded (S)-(4,4-difluoropiperidin-1-yl)(2-methyl-4-(1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone 48. MS 520.2 (calc'd) 521.2 (M+H, found).

Workup

  1. washwashed with 1×10 mL water, 1×10 mL NaHCO3, and 1×10 mL brine
  2. dry with materialThe organic layer was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customPurification by column chromatography

Sources & evidence

ORD record
ord-532844a2eef947ba9c3916ac82c4905c
Source dataset
uspto-grants-2012_07
Patent number
US08222251B2

Reaction notes

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