Hydrochloric Acid → 6-Bromo-3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one

HRID 1749382Notes

Reaction equation

HRID 1749382 reaction equation
[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:22])[N:7]([C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl[C:24]1[C:29]([F:30])=[CH:28][N:27]=[CH:26][N:25]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].Cl>O1CCCC1.O.COC(C)(C)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:24]3[C:29]([F:30])=[CH:28][N:27]=[CH:26][N:25]=3)([CH3:22])[N:7]([C@@H:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH3:13])[C:8]2=[O:11])=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 3251421Potassium bis(trimethylsilyl)amideHCID 178937134-Chloro-5-fluoropyrimidineHCID 904083936-Bromo-2-((R)-1-(4-methoxyphenyl)ethyl)-3-methylisoindolin-1-one

Product 1

HCID 904084426-Bromo-3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-oneYield 43%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 15413tert-Butyl methyl etherSolvent

Procedure

Dissolve 6-bromo-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one (2.814 mmol, 1.014 g) in tetrahydrofuran (28 mL). Add 4-chloro-5-fluoro-pyrimidine (5.628 mmol, 518 μL) and cool to 0° C. Add potassium hexamethyldisilazide (4.502 mmol, 9 mL, 0.5 M in toluene) over 7 minutes and stir for 1 hour, then warm to ambient temperature and stir for 90 minutes. Pour into methyl-tert-butyl ether and aqueous 1 M HCl, add water and separate the layers. Wash with aqueous 1 N HCl, filter, wash with saturated aqueous sodium chloride, dry over magnesium sulfate, filter through a 2 cm pad of silica gel, and evaporate under reduced pressure to provide an oil. Purify on silica gel with 20-40% ethyl acetate/hexane to give the title compound as a foam (547 mg, 43%). ES/MS m/z: 456 (M+H).

Workup

  1. stirringstir for 90 minutes
  2. customseparate the layers
  3. washWash with aqueous 1 N HCl
  4. filtrationfilter
  5. washwash with saturated aqueous sodium chloride
  6. dry with materialdry over magnesium sulfate
  7. filtrationfilter through a 2 cm pad of silica gel
  8. customevaporate under reduced pressure
  9. customto provide an oil
  10. customPurify on silica gel with 20-40% ethyl acetate/hexane

Sources & evidence

ORD record
ord-e7d90f2f2f12499caffd48d588f0cd14
Source dataset
uspto-grants-2015_10
Patent number
US09156824B2

Reaction notes

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