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 2176558Notes

Reaction equation

HRID 2176558 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 purified 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. custompurified by MPLC(CH2Cl2/MeOH: 100/0 to 90/10)
  7. customFurther purification by MPLC (ISCO, EtOAc/MeOH:9/1, isocratic)

Sources & evidence

ORD record
ord-e5695b11408543d3a48fa83caff48c31
Source dataset
uspto-grants-2015_06
Patent number
US09066954B2

Reaction notes

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