Water → HCID 117701767, compound

HRID 1507445Notes

Reaction equation

HRID 1507445 reaction equation
[Br:1][C:2]1[C:3]([OH:24])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]1)=[C:8]([CH3:22])[C:7]2=[O:23].C(N(C(C)C)CC)(C)C.Cl[CH2:35][O:36][CH3:37].O>ClCCl>[Br:1][C:2]1[C:3]([O:24][CH2:35][O:36][CH3:37])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]1)=[C:8]([CH3:22])[C:7]2=[O:23]

Participants

6

Reactant 4

HCID 962WaterHCID 7864Chloromethyl Methyl EtherHCID 81531DiisopropylethylamineHCID 71666040HCID 71666040, compound

Product 1

HCID 117701767HCID 117701767, compoundYield 51%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 8-bromo-7-hydroxy-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (3.82 mol) obtained in Example 32 in dichloromethane (25 mL), diisopropylethylamine (1.32 mL, 7.66 mmol) and chloro(methoxy)methane (345 μL, 4.59 mmol) were added under cooling with ice, and the mixture was stirred for 1 hour under cooling with ice and then at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol=98/2) to obtain 847 mg of 8-bromo-7-(methoxymethoxy)-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (yield: 51%). Subsequently, 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (181 μL, 0.953 mmol), potassium carbonate (167 mg, 1.21 mmol), and a palladium chloride-dppf complex (40.7 mg) were added to a mixed solution of the obtained compound (104 mg, 0.24 mmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL), and the mixture was stirred at 90° C. for 14 hours under the nitrogen atmosphere. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=50/50→0/100) and then further purified by HPLC to obtain 38 mg of the title compound (yield: 40%) as an oil.

Workup

  1. temperatureunder cooling with ice
  2. temperatureunder cooling with ice
  3. waitat room temperature for 2 hours
  4. extractionfollowed by extraction with dichloromethane
  5. washThe organic layer was washed with saturated brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. distillationthe solvent was distilled off under reduced pressure
  8. customThe obtained residue was purified by silica gel column chromatography (dichloromethane/methanol=98/2)

Sources & evidence

ORD record
ord-e41fd36e82c6480a88c77d592775ab95
Source dataset
uspto-grants-2015_12
Patent number
US09221811B2

Reaction notes

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