Ethyl Acetate → Benzyl[2-[2-[1-[[6-bromo-4-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydro-2-pyrazinyl]amino]cyclopropyl]phenoxy]ethyl]methylcarbamate

HRID 869816Notes

Reaction equation

HRID 869816 reaction equation
[CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH:5]([Mg]Cl)([CH3:7])[CH3:6].[CH:10]1([NH-])[CH2:12][CH2:11]1.Cl[Mg+].C(OC([CH2:26][NH:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1([NH:40][C:41]2[C:42](=[O:60])[N:43]([C:48]3[CH:49]=[C:50]([CH:55]=[C:56]([F:59])[C:57]=3[CH3:58])[C:51]([O:53]C)=O)[CH:44]=[C:45]([Br:47])[N:46]=2)[CH2:39][CH2:38]1)=O)C1C=CC=CC=1.[C:61]([O:64][CH2:65]C)(=[O:63])C>C1COCC1>[Br:47][C:45]1[N:46]=[C:41]([NH:40][C:37]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29][CH2:28][N:27]([CH3:26])[C:61](=[O:63])[O:64][CH2:65][C:12]3[CH:10]=[CH:7][CH:5]=[CH:6][CH:11]=3)[CH2:38][CH2:39]2)[C:42](=[O:60])[N:43]([C:48]2[CH:49]=[C:50]([C:51](=[O:53])[NH:4][CH:1]3[CH2:3][CH2:2]3)[CH:55]=[C:56]([F:59])[C:57]=2[CH3:58])[CH:44]=1

Participants

7

Reactant 5

HCID 8857Ethyl AcetateHCID 69828CyclopropylamineHCID 66713357methyl 3-[3-[1-[2-[2-[(benzyloxycarbonyl)methylamino]ethoxy]phenyl]cyclopropylamino]-5-bromo-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methylbenzoateHCID 178418918HCID 178418918, compoundHCID 178507068HCID 178507068, compound

Product 1

HCID 58072137Benzyl[2-[2-[1-[[6-bromo-4-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydro-2-pyrazinyl]amino]cyclopropyl]phenoxy]ethyl]methylcarbamate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of cyclopropylamine (261.9 μL, 3.70 mmol) in dry THF (2 mL) under an inert atmosphere was chilled in an ice-water bath and freshly titrated isopropylmagnesium chloride (1.46 M in THF, 1.27 mL, 1.85 mmol) was added. A portion of this chloromagnesium cyclopropylamide solution (0.524 M in THF, 2.12 mL, 1.11 mmol) was added via syringe to a stirred solution of methyl 3-[3-[1-[2-[2-[(benzyloxycarbonyl)methylamino]ethoxy]phenyl]cyclopropylamino]-5-bromo-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methylbenzoate (Preparation 4d, 125.7 mg, 185 μmol) in dry THF (2 mL) under an inert atmosphere. After 30 min, ethyl acetate (1 mL) was added before the reaction mixture was poured into ice-cold saturated aq. ammonium chloride (10 mL) and extracted with diethyl ether (3×10 mL). The organic extracts were combined, washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC on silica, eluting with ethyl acetate/isohexane/methanol (50:50:1 v/v), to afford benzyl [2-[2-[1-[[6-bromo-4-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydro-2-pyrazinyl]amino]cyclopropyl]phenoxy]ethyl]methylcarbamate (79.4 mg) as a white foam.

Workup

  1. extractionextracted with diethyl ether (3×10 mL)
  2. washwashed with brine (30 mL)
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by preparative TLC on silica
  6. washeluting with ethyl acetate/isohexane/methanol (50:50:1 v/v)

Sources & evidence

ORD record
ord-c435206250694047a578778ec3eb0161
Source dataset
uspto-grants-2015_03
Patent number
US08969350B2

Reaction notes

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