Potassium Phosphate, Tribasic → HCID 68157919, compound

HRID 2170800Notes

Reaction equation

HRID 2170800 reaction equation
Br[C:2]1[C:3](=[O:16])[CH:4]([CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5][C:6]=1[O:7][CH3:8].[CH3:17][N:18]1[C:26]2[CH:25]=[CH:24][C:23]([CH3:27])=[C:22](B(O)O)[C:21]=2[CH:20]=[N:19]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][N:18]1[C:26]2[C:21](=[C:22]([C:2]3[C:3](=[O:16])[CH:4]([CH2:9][CH:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[CH2:5][C:6]=3[O:7][CH3:8])[C:23]([CH3:27])=[CH:24][CH:25]=2)[CH:20]=[N:19]1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 44119487HCID 44119487, compoundHCID 66926140HCID 66926140, compound

Product 1

HCID 68157919HCID 68157919, compoundYield 23.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent

Conditions

Temperature
140 °C

Procedure

To a stirred suspension of the 2-bromo-3-methoxy-5-(tetrahydro-pyran-4-ylmethyl)-cyclopent-2-enone (150 mg, 0.5 mmol), 1,5-dimethyl-1H-indazole-4-boronic acid (148 mg, 0.78 mmol) and freshly powdered potassium phosphate tribasic (221 mg, 1 mmol) in anhydrous, de-gassed toluene (1.5 ml) under a nitrogen atmosphere were added palladium acetate (6 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (21 mg, 0.05 mmol). The reaction was heated to 140° C. for 30 minutes in the microwave (using “normal” absorbtion). The reaction was diluted with water (10 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with brine (10 ml), dried over magnesium sulfate and evaporated to dryness under reduced pressure to give a brown oil. The crude product was purified by column chromatography (30% EtOAc/hexane to 100% EtOAc as eluent) to give 2-(1,5-Dimethyl-1H-indazol-4-yl)-3-methoxy-5-(tetrahydro-pyran-4-ylmethyl)-cyclopent-2-enone (41 mg). This material was dissolved in acetone (2 ml) and 2 M hydrochloric acid (2 ml) added. This solution was heated in the microwave (using “normal” absorbtion) for 1 h at 120° C. This solution was then extracted with dichloromethane (2×10 ml) and the organics dried over magnesium sulfate and reduced in vacuo. The crude material was purified by reverse phase preparative HPLC (eluting with acetonitrile/water) to give 2-(1,5-dimethyl-1H-indazol-4-yl)-4-(tetrahydro-pyran-4-ylmethyl)-cyclopentane-1,3-dione (4 mg).

Workup

  1. customde-gassed toluene (1.5 ml) under a nitrogen atmosphere
  2. extractionextracted with ethyl acetate (3×15 ml)
  3. washThe combined organic extracts were washed with brine (10 ml)
  4. dry with materialdried over magnesium sulfate
  5. customevaporated to dryness under reduced pressure
  6. customto give a brown oil
  7. customThe crude product was purified by column chromatography (30% EtOAc/hexane to 100% EtOAc as eluent)

Sources & evidence

ORD record
ord-877a9075ac294894b2604d74bfaa2c49
Source dataset
uspto-grants-2015_06
Patent number
US09051300B2

Reaction notes

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