Ethyl Acetate → HCID 67244304, compound

HRID 2423407Notes

Reaction equation

HRID 2423407 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[C:25]([C:32]2[C:37](Cl)=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:26][O:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:25]1[C:24]([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium Carbonate2×HCID 592648754-(Chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropylisoxazole2×HCID 59321463Methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate

Product 1

HCID 67244304HCID 67244304, compoundYield 54.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
50 °C

Procedure

A mixture of 14.5 g (51.9 mmol) of methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate, 31.6 g (104 mmol) of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole and 21.5 g (156 mmol) of K2CO3 in 100 mL of DMF was stirred at 50° C. for 20 hr. Additional 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (15.8 g, 52 mmol), DMF (50 mL), and K2CO3 (14.5 g, 105 mmol) was added and the reaction was heated for an additional 7 hours at 70° C. and at 60° C. for another 12 hours. The reaction was allowed to cool to room temperature and was stirred for 2 days. EtOAc was added then the mixture washed with three portions of H2O, then brine. The aqueous layers were extracted with EtOAC. The combined organic layers were dried over Na2SO4, filtered, then concentrated. The crude material was dissolved in hot EtOAc and diluted with hexane. The mixture was placed in the freezer for three hours then filtered to yield the desired product (14.46 g) as a light brown solid. The filtrate was concentrated and the residue purified by silica gel chromatography (330 g of silica gel eluting with 0-80% EtOAc in hexanes over 45 minutes). Fractions containing the product were combined, concentrated, and recrystallized to give 16.82 g (59%) of methyl 7-[4-({[3-(2-chlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate. 1H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 8.60 (s, 1H), 8.14 (s, 1H), 7.99 (m, 2H), 7.60 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.33 (m, 1H), 6.92 (d, J=9 Hz, 2H), 4.80 (s, 2H), 4.06 (s, 3H), 3.36 (septet, 1H, J=7 Hz), 1.44 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.

Workup

  1. temperaturethe reaction was heated for an additional 7 hours at 70° C. and at 60° C. for another 12 hours
  2. temperatureto cool to room temperature
  3. stirringwas stirred for 2 days
  4. washthe mixture washed with three portions of H2O
  5. extractionThe aqueous layers were extracted with EtOAC
  6. dry with materialThe combined organic layers were dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. dissolutionThe crude material was dissolved in hot EtOAc
  10. additiondiluted with hexane
  11. waitThe mixture was placed in the freezer for three hours
  12. filtrationthen filtered

Sources & evidence

ORD record
ord-cd37512d24324d98ab119dab738c76a9
Source dataset
uspto-grants-2011_06
Patent number
US07960552B2

Reaction notes

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