Diisopropylethylamine → methyl 3-[3-[1-[2-[2-[(benzyloxycarbonyl)methylamino]ethoxy]phenyl]cyclopropylamino]-5-bromo-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methylbenzoate

HRID 869815Notes

Reaction equation

HRID 869815 reaction equation
[NH2:1][C:2]1([C:5]2[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=2[O:7][CH2:8][CH2:9][N:10]([CH3:21])C(=O)OCC2C=CC=CC=2)[CH2:4][CH2:3]1.Br[C:27]1[C:28](=[O:46])[N:29]([C:34]2[CH:35]=[C:36]([CH:41]=[C:42]([F:45])[C:43]=2[CH3:44])[C:37]([O:39][CH3:40])=[O:38])[CH:30]=[C:31]([Br:33])[N:32]=1.C(N(CC)[CH:51]([CH3:53])[CH3:52])(C)C>O1CCOCC1>[CH2:40]([O:39][C:37]([CH2:21][NH:10][CH2:9][CH2:8][O:7][C:6]1[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=1[C:2]1([NH:1][C:27]2[C:28](=[O:46])[N:29]([C:34]3[CH:35]=[C:36]([CH:41]=[C:42]([F:45])[C:43]=3[CH3:44])[C:37]([O:39][CH3:40])=[O:38])[CH:30]=[C:31]([Br:33])[N:32]=2)[CH2:3][CH2:4]1)=[O:38])[C:52]1[CH:51]=[CH:53][CH:35]=[CH:34][CH:43]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 66689945methyl 3-(3,5-dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methylbenzoate2×HCID 66713005Benzyl[2-[2-(1-aminocyclopropyl)phenoxy]ethyl]methylcarbamate

Product 1

HCID 66713357methyl 3-[3-[1-[2-[2-[(benzyloxycarbonyl)methylamino]ethoxy]phenyl]cyclopropylamino]-5-bromo-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methylbenzoateYield 164.4%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A solution of benzyl [2-[2-(1-aminocyclopropyl)phenoxy]ethyl]methylcarbamate (Preparation 4b, 68.1% w/w, 102.2 mg, 204 μmol), methyl 3-(3,5-dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methylbenzoate (Preparation 1g, 94.5 mg, 225 μmol) and N,N-diisopropylethylamine (137 μL, 818 μmol) in 1,4-dioxane (3 mL) was heated to 90° C. (jacket temperature) in a sealed reaction tube for 3 h, before being left to stir overnight at ambient temperature. Further methyl 3-(3,5-dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methylbenzoate (8.6 mg, 20.4 μmol) was added and the reaction mixture re-heated to 90° C. (jacket temperature) for a further 90 min. The solution was then concentrated in vacuo before being purified by preparative TLC on silica, eluting with ethyl acetate/isohexane (1:2 v/v), to afford methyl 3-[3-[1-[2-[2-[(benzyloxycarbonyl)methylamino]ethoxy]phenyl]cyclopropylamino]-5-bromo-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methylbenzoate (125.7 mg) as a white foam.

Workup

  1. customin a sealed reaction tube for 3 h
  2. waitbefore being left
  3. temperaturethe reaction mixture re-heated to 90° C. (jacket temperature) for a further 90 min
  4. concentrationThe solution was then concentrated in vacuo
  5. custombefore being purified by preparative TLC on silica
  6. washeluting with ethyl acetate/isohexane (1:2 v/v)

Sources & evidence

ORD record
ord-0bbf22b3122545079c9eee3dab0f0c57
Source dataset
uspto-grants-2015_03
Patent number
US08969350B2

Reaction notes

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