Water → N-[6-[5-Amino-6-(methyloxy)-3-pyridinyl]-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide

HRID 1695726Notes

Reaction equation

HRID 1695726 reaction equation
P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][O:10][C:11]1[C:16]([NH2:17])=[CH:15][C:14](B2OC(C)(C)CC(C)(C)O2)=[CH:13][N:12]=1.Br[C:29]1[CH:30]=[C:31]([NH:44][C:45]([C:47]2[N:48]=[C:49]([CH2:52][N:53]3[CH2:58][C@H:57]([CH3:59])[O:56][C@H:55]([CH3:60])[CH2:54]3)[S:50][CH:51]=2)=[O:46])[C:32]2[C:36]([CH:37]=1)=[N:35][N:34]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)[CH:33]=2.O>O1CCOCC1.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[NH2:17][C:16]1[CH:15]=[C:14]([C:29]2[CH:30]=[C:31]([NH:44][C:45]([C:47]3[N:48]=[C:49]([CH2:52][N:53]4[CH2:58][C@H:57]([CH3:59])[O:56][C@H:55]([CH3:60])[CH2:54]4)[S:50][CH:51]=3)=[O:46])[C:32]3[C:36]([CH:37]=2)=[N:35][N:34]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[CH:33]=3)[CH:13]=[N:12][C:11]=1[O:10][CH3:9]

Participants

7

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 58255813N-[6-Bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamideHCID 582558272-(Methyloxy)-5-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-3-pyridinamine

Product 1

HCID 58255790N-[6-[5-Amino-6-(methyloxy)-3-pyridinyl]-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamideYield 62%

Reagents, catalysts & solvents 2

HCID 178420574HCID 178420574, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
140 °C

Procedure

Tripotassium phosphate (910 mg, 4.29 mmol), chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (105 mg, 0.143 mmol) and 2-(methyloxy)-5-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-3-pyridinamine (453 mg, 1.715 mmol) were weighed to a 20 ml microwave vial. N-[6-Bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (764 mg, 1.429 mmol) was dissolved in 1,4-dioxane (10 mL) and added, followed by water (2.000 mL). The reaction was heated at 140° C. for 20 min. The reaction mixture was passed through a 10 g silica cartridge, eluting with methanol. The solvent was evaporated to dryness and the residue was partitioned between DCM 200 ml and water 200 ml. The DCM was collected and eluted through a hydrophobic frit, then evaporated to dryness. The residue was purified by chromatography on silica gel (100 g cartridge), eluting with 0-25% methanol in DCM over 40 mins, then on a further silica gel 100 g cartridge, eluting with 0-100% ethyl acetate in cyclohexane over 40 mins and then 0-25% methanol in DCM over 20 mins to afford the title compound (512 mg).

Workup

  1. additionadded
  2. washeluting with methanol
  3. customThe solvent was evaporated to dryness
  4. customthe residue was partitioned between DCM 200 ml and water 200 ml
  5. customThe DCM was collected
  6. washeluted through a hydrophobic frit
  7. customevaporated to dryness
  8. customThe residue was purified by chromatography on silica gel (100 g cartridge)
  9. washeluting with 0-25% methanol in DCM over 40 mins
  10. washon a further silica gel 100 g cartridge, eluting with 0-100% ethyl acetate in cyclohexane over 40 mins

Sources & evidence

ORD record
ord-7042a1311b094b4fb5f06733b910bfad
Source dataset
uspto-grants-2012_04
Patent number
US08163743B2

Reaction notes

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