Triethylamine → 6-Bromo-2-((R)-1-(4-methoxyphenyl)ethyl)-3-methylisoindolin-1-one

HRID 1749378Notes

Reaction equation

HRID 1749378 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12](Br)[CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:11]=[C:6]2[C:5]([CH:12]([CH3:13])[N:25]([C@@H:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[CH3:24])[C:7]2=[O:9])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 641449(R)-1-(4-Methoxyphenyl)ethylamineHCID 90408083Methyl 5-bromo-2-(1-bromoethyl)benzoate

Product 1

HCID 904083936-Bromo-2-((R)-1-(4-methoxyphenyl)ethyl)-3-methylisoindolin-1-oneYield 52.6%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
67 °C

Procedure

Add solid methyl 5-bromo-2-(1-bromoethyl)benzoate (1724 g, 5.35 mol) to a solution of commercially available (R)-1-(4-methoxyphenyl)ethanamine (BePharm, WZG111219-071; 974 g, 6.44 mol) and triethylamine (1710 mL, 12.26 mol) in methanol (12 L). Heat the mixture for 10 hours at 67° C. then evaporate to dryness under reduced pressure. Partition the residue with ethyl acetate (5 L) and aqueous 1 N HCl (10 L), separate the phases, wash the organic phase again with aqueous 1 N HCl (5 L), saturated sodium bicarbonate, saturated aqueous sodium chloride, then dry over sodium sulfate, filter, and evaporate under reduced pressure. Dissolve the dark red oil in methyl-tert-butyl ether (750 mL) and add petroleum ether (3 L) with vigorous stirring. Filter the solids, wash with methyl-tert-butyl ether/petroleum ether (1:8), petroleum ether, dry in open air to give the title compound as an off-white solid (1014 g, 52%). ES/MS m/z: 360 (M+H).

Workup

  1. customthen evaporate to dryness under reduced pressure
  2. customPartition the residue with ethyl acetate (5 L) and aqueous 1 N HCl (10 L)
  3. customseparate the phases
  4. washwash the organic phase again with aqueous 1 N HCl (5 L), saturated sodium bicarbonate, saturated aqueous sodium chloride
  5. dry with materialdry over sodium sulfate
  6. filtrationfilter
  7. customevaporate under reduced pressure
  8. dissolutionDissolve the dark red oil in methyl-tert-butyl ether (750 mL)
  9. additionadd petroleum ether (3 L) with vigorous stirring
  10. filtrationFilter the solids
  11. washwash with methyl-tert-butyl ether/petroleum ether (1:8), petroleum ether
  12. customdry in open air

Sources & evidence

ORD record
ord-eb2cb5845b7d4238ad0a9a459bed4d3b
Source dataset
uspto-grants-2015_10
Patent number
US09156824B2

Reaction notes

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