Potassium phosphate, tribasic, monohydrate → 5-{4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-[(4-methyl phenyl)sulfonyl]-1H-indazol-6-yl}-2-(methyloxy)-3-pyridinamine

HRID 38857Notes

Reaction equation

HRID 38857 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[O:22][C:23]([CH2:26][N:27]3[CH2:32][C@H:31]([CH3:33])[O:30][C@H:29]([CH3:34])[CH2:28]3)=[N:24][N:25]=2)[CH:3]=1.[CH3:35][O:36][C:37]1[C:42]([NH2:43])=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:34][C@H:29]1[O:30][C@@H:31]([CH3:33])[CH2:32][N:27]([CH2:26][C:23]2[O:22][C:21]([C:4]3[CH:3]=[C:2]([C:40]4[CH:41]=[C:42]([NH2:43])[C:37]([O:36][CH3:35])=[N:38][CH:39]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[N:25][N:24]=2)[CH2:28]1

Participants

7

Reactant 3

HCID 22031701Potassium phosphate, tribasic, monohydrateHCID 595579202-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine2×HCID 666957066-Bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazole

Product 1

HCID 666936135-{4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-[(4-methyl phenyl)sulfonyl]-1H-indazol-6-yl}-2-(methyloxy)-3-pyridinamineYield 43.6%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

6-Bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazole (680 mg, 1.244 mmol) was dissolved in 1,4-dioxane (15 ml) and water (1.5 ml). 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (311 mg, 1.244 mmol), bis(diphenylphosphino)ferrocene palladium dichloride (182 mg, 0.249 mmol) and tripotassium phosphate monohydrate (860 mg, 3.73 mmol) were added and the reaction mixture heated at 80° C. for 2 h. 2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (0.1 eq, 31 mg) was added and the reaction mixture heated at 80° C. for a further 18 h. The solvent was removed in vacuo and the residue partitioned between DCM (50 ml) and water (50 ml). The layers were separated (hydrophobic frit), the organic concentrated in vacuo and the residue purified by column chromatography, loading in dichloromethane and purified on a silica cartridge (100 g), using a 0-30% methanol(+1% triethylamine)-dichloromethane over 40 mins. The appropriate fractions were combined and concentrated in vacuo to a brown gum. This was purified again by column chromatography, loading in dichloromethane and purified on a silica cartridge (50 g) using a 0-100% ethyl acetate-cyclohexane+0-20% methanol over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (320 mg).

Workup

  1. temperaturethe reaction mixture heated at 80° C. for a further 18 h
  2. customThe solvent was removed in vacuo
  3. customthe residue partitioned between DCM (50 ml) and water (50 ml)
  4. customThe layers were separated (hydrophobic frit)
  5. concentrationthe organic concentrated in vacuo
  6. customthe residue purified by column chromatography, loading in dichloromethane
  7. custompurified on a silica cartridge (100 g)
  8. customover 40 mins
  9. concentrationconcentrated in vacuo to a brown gum
  10. customThis was purified again by column chromatography, loading in dichloromethane
  11. custompurified on a silica cartridge (50 g)
  12. customover 40 mins
  13. customevaporated in vacuo

Sources & evidence

ORD record
ord-e120ac370a5042a6b1b5bb261b7a7f83
Source dataset
uspto-grants-2013_09
Patent number
US08524751B2

Reaction notes

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