1,2-Dichloroethane → 6-chloro-4-(5-(4-hydroxy-4-methylpiperidine-1-carbonyl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one

HRID 449592Notes

Reaction equation

HRID 449592 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH3:20][C:21]1([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:24]3[CH2:25][CH2:26][C:21]([OH:27])([CH3:20])[CH2:22][CH2:23]3)=[O:17])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1

Participants

7

Reactant 5

HCID 111,2-Dichloroethane2×HCID 757711-Hydroxybenzotriazole2×HCID 81531DiisopropylethylamineHCID 156491744-Methylpiperidin-4-ol2×HCID 667425116-(6-Chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinic acid

Product 1

HCID 667423526-chloro-4-(5-(4-hydroxy-4-methylpiperidine-1-carbonyl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-oneYield 13%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
100 °C

Procedure

In a 250 mL round-bottomed flask, 6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinic acid (195 mg, 695 μmol), 4-methylpiperidin-4-ol (80.0 mg, 695 μmol), HOBT (138 mg, 903 μmol) and Hunig's base (269 mg, 364 μl, 2.08 mmol) were combined with DMF (13 ml) to give a light yellow suspension. EDC (173 mg, 903 μmol) was added and the reaction mixture was heated to 100° C. and stirred for 24 h. Additional 4-methylpiperidin-4-ol (80.0 mg, 695 μmol), HOBT (106 mg, 695 μmol) and EDC (133 mg, 695 μmol) were added with 2 ml DMF. The reaction mixture was heated to 100° C. and stirred for 24 h. The reaction was cooled to 25° C. and quenched with water. The aqueous layer was back-extracted with EtOAc (3×75 mL). The organic layers were combined, washed with sat NaCl (1×50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was taken up in DCM/MeOH 9:1 and filtered. The filtrate was conc. in vacuo to give a light yellow solid. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to afford 0.033 g (13%) of the title compound as a yellow solid. (M+H)+=378/380 m/e.

Workup

  1. customto give a light yellow suspension
  2. temperatureThe reaction mixture was heated to 100° C.
  3. stirringstirred for 24 h
  4. temperatureThe reaction was cooled to 25° C.
  5. customquenched with water
  6. extractionThe aqueous layer was back-extracted with EtOAc (3×75 mL)
  7. washwashed with sat NaCl (1×50 mL)
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated in vacuo
  10. filtrationfiltered
  11. customto give a light yellow solid
  12. customThe crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM)

Sources & evidence

ORD record
ord-ecd1efea4352495ba2b03bdd8f3328d4
Source dataset
uspto-grants-2013_07
Patent number
US08481540B2

Reaction notes

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