Triethylamine → 2,2-difluoro-N'-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3-methoxyquinolin-6-yl)acetohydrazide

HRID 1513799Notes

Reaction equation

HRID 1513799 reaction equation
FC(F)(C1C=C2C(=CC=1)N=CC(OC)=C2)C(NNC1C=C(C2C=NN(C)C=2)C=CC=1F)=O.[F:33][C:34]([F:50])([C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][C:42]([O:48][CH3:49])=[CH:41]2)[C:35]([OH:37])=O.S(Cl)(Cl)=O.C(N(CC)CC)C.[F:62][C:63]1[C:64]([NH:75][NH2:76])=[N:65][CH:66]=[C:67]([C:69]2[CH:70]=[N:71][N:72]([CH3:74])[CH:73]=2)[CH:68]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CO.CN(C=O)C>[F:50][C:34]([F:33])([C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][C:42]([O:48][CH3:49])=[CH:41]2)[C:35]([NH:76][NH:75][C:64]1[C:63]([F:62])=[CH:68][C:67]([C:69]2[CH:70]=[N:71][N:72]([CH3:74])[CH:73]=2)=[CH:66][N:65]=1)=[O:37]

Participants

10

Reactant 5

HCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 576912392,2-Difluoro-2-(3-methoxyquinolin-6-yl)acetic acidHCID 675032383-fluoro-2-hydrazinyl-5-(1-methyl-1H-pyrazol-4-yl)pyridineHCID 675037092,2-difluoro-N'-(2-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-(3-methoxyquinolin-6-yl)acetohydrazide

Product 1

HCID 576913272,2-difluoro-N'-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3-methoxyquinolin-6-yl)acetohydrazideYield 33.1%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

2,2-difluoro-N′-(2-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-(3-methoxyquinolin-6-yl)acetohydrazide. A round bottom flask was charged with 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid (389 mg, 1536 μmol) and DMF (8 mL). The solution was cooled to 0 C, thionyl chloride (224 μl, 3073 μmol), was added and the resulting solution was maintained 1 h at 0° C. Then, triethylamine (641 μl, 4609 μmol) was added via syringe, followed by 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (382 mg, 1844 μmol) and 4-(dimethylamino)pyridine (18.8 mg, 154 μmol); both added as solids. The heterogeneous solution was stirred at 0° C. for 1 h, then allowed to warm to rt and stir for 18 h. The mixture was quenched with saturated aqueous NaHCO3 (50 mL) and the resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were concentrated (heating to 50° C.) and the residue purified by SiO2 chromatography solvent system: CH2Cl2:MeOH 99%:1% gradient 90:10 CH2Cl2 to yield 2,2-difluoro-N′-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3-methoxyquinolin-6-yl)acetohydrazide (225 mg, 33.1% yield) as a brown amorphous solid.

Workup

  1. additionwas added
  2. additionboth added as solids
  3. temperatureto warm to rt
  4. stirringstir for 18 h
  5. customThe mixture was quenched with saturated aqueous NaHCO3 (50 mL)
  6. extractionthe resulting mixture was extracted with CH2Cl2 (3×50 mL)
  7. concentrationThe combined organic layers were concentrated
  8. temperature(heating to 50° C.)
  9. customthe residue purified by SiO2 chromatography solvent system

Sources & evidence

ORD record
ord-59e02c4018874f648e8fabdce6e02ecd
Source dataset
uspto-grants-2012_07
Patent number
US08217177B2

Reaction notes

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