Potassium Phosphate, Tribasic → 6,6-Dimethyl-2-(6-{[6-(1-methyl-1h-pyrazol-4-yl)pyridin-2-yl]oxy}-2,3-dihydro-4h-1,4-benzoxazin-4-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5h)-one

HRID 885986Notes

Reaction equation

HRID 885986 reaction equation
Br[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][N:14]([C:18]4[S:19][C:20]5[C:21](=[O:29])[NH:22][C:23]([CH3:28])([CH3:27])[CH2:24][C:25]=5[N:26]=4)[C:13]=3[CH:30]=2)[CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1>C1COCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][C:23]1([CH3:28])[NH:22][C:21](=[O:29])[C:20]2[S:19][C:18]([N:14]3[C:13]4[CH:30]=[C:9]([O:8][C:6]5[CH:5]=[CH:4][CH:3]=[C:2]([C:43]6[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=6)[N:7]=5)[CH:10]=[CH:11][C:12]=4[O:17][CH2:16][CH2:15]3)=[N:26][C:25]=2[CH2:24]1

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 873022572-{6-[(6-Bromopyridin-2-yl)oxy]-2,3-dihydro-4h-1,4-benzoxazin-4-yl}-6,6-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5h)-one

Product 1

HCID 668889066,6-Dimethyl-2-(6-{[6-(1-methyl-1h-pyrazol-4-yl)pyridin-2-yl]oxy}-2,3-dihydro-4h-1,4-benzoxazin-4-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5h)-oneYield 40%

Reagents, catalysts & solvents 4

HCID 74236Tetrabutylammonium BromideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
130 °C

Procedure

To a suspension of Example 382 (40 mg, 0.082 mmol) in THF (3 mL) and water (1 mL) was added tetra-n-butylammonium bromide (53 mg, 0.164 mmol), potassium phosphate (35 mg, 0.164 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (34 mg, 0.164 mmol) and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol). The reaction was heated at 130° C. under microwave irradiation for 20 minutes then cooled to r.t. The resulting mixture was partitioned between DCM (50 mL) and water (50 mL); the organic phase was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to yield the title compound (16 mg, 40%) as a white solid. δH (CDCl3) 8.00 (1H, d, J 2.6 Hz), 7.88 (1H, s), 7.83 (1H, s), 7.63 (1H, t, J 8.1 Hz), 7.16 (1H, d, J 7.5 Hz), 6.98 (1H, d, J 8.9 Hz), 6.90 (1H, dd, J 8.7 and 2.4 Hz), 6.61 (1H, d, J 8.3 Hz), 5.28 (1H, s), 4.40-4.34 (2H, m), 4.15-4.08 (2H, m), 3.91 (3H, s), 2.82 (2H, s), 1.36 (6H, s). LCMS (ES+) 487.0 (M+H)+, RT 3.25 minutes (Method 1).

Workup

  1. temperaturethen cooled to r.t
  2. customThe resulting mixture was partitioned between DCM (50 mL) and water (50 mL)
  3. washthe organic phase was washed with brine (50 mL)
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by preparative HPLC (Method 6)

Sources & evidence

ORD record
ord-86738bb68e594ef1841cdea0a4829d6c
Source dataset
uspto-grants-2012_08
Patent number
US08242116B2

Reaction notes

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