3-Methyl-5-(trimethylstannyl)isothiazole → 4-((8-Fluoro-6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline

HRID 40262

Reaction equation

HRID 40262 reaction equation
Cl[C:2]1[CH:3]=[C:4]([F:25])[C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:60][C:61]1[CH:65]=[C:64]([Sn](C)(C)C)[S:63][N:62]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[F:25][C:4]1[C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=[C:2]([C:64]2[S:63][N:62]=[C:61]([CH3:60])[CH:65]=2)[CH:3]=1

Participants

6

Reactant 3

HCID 100383203-Methyl-5-(trimethylstannyl)isothiazole2×HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl2×HCID 675022054-((6-Chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline

Product 1

HCID 576911514-((8-Fluoro-6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinolineYield 51.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Dioxane (3.6 mL) was added to 4-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (175 mg, 488 μmol), X-Phos (32.6 mg, 68.3 μmol), 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol), palladium acetate (7.67 mg, 34.1 μmol). The flask was purged with argon and sealed. The reaction mixture was stirred at 80° C. for 2d. More X-Phos (32.6 mg, 68.3 μmol), palladium acetate (7.67 mg, 34.1 μmol) and 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol) were added and stirring was continued at 80° C. overnight. The reaction mixture was cooled at RT, concentrated in vacuo and urified by MPLC (CH2Cl2/MeOH: 100/0 to 90/10). Further purification by MPLC (ISCO, EtOAc/MeOH:9/1, isocratic) afforded the title compound (105 mg, 51% yield). MS m/z=422.0 [M+H]+. Calc'd for C21H16FN5O2S: 421.46

Workup

  1. customThe flask was purged with argon
  2. customsealed
  3. stirringstirring
  4. temperatureThe reaction mixture was cooled at RT
  5. concentrationconcentrated in vacuo
  6. customFurther purification by MPLC (ISCO, EtOAc/MeOH:9/1, isocratic)

Sources & evidence

ORD record
ord-9c298b46450d4c90a7692cf842cc61ee
Source dataset
uspto-grants-2013_09
Patent number
US08524900B2

Linked notes

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