Diisopropylethylamine → tert-Butyl 1-(3-{[4,4,4-trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoyl]amino}benzyl)cyclopropanecarboxylate

HRID 877257Notes

Reaction equation

HRID 877257 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[F:19][C:20]([F:46])([F:45])[CH:21]([CH3:44])[CH:22]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][C:39]=3[F:42])[C:34]2=[O:43])=[CH:28][CH:27]=1)[C:23](O)=[O:24].O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:46][C:20]([F:19])([F:45])[CH:21]([CH3:44])[CH:22]([C:26]1[CH:27]=[CH:28][C:29]([CH2:32][N:33]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][C:39]=3[F:42])[C:34]2=[O:43])=[CH:30][CH:31]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8][CH2:7]1)=[O:24]

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 27960291-Hydroxybenzotriazole hydrateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58136514tert-Butyl 1-(3-aminobenzyl)cyclopropanecarboxylateHCID 581367454,4,4-Trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoic acid

Product 1

HCID 58136669tert-Butyl 1-(3-{[4,4,4-trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoyl]amino}benzyl)cyclopropanecarboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

110.8 mg (0.41 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were added to a solution of 129.0 mg (0.33 mmol) of 4,4,4-trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoic acid and 52.9 mg (0.39 mmol) of 1-hydroxy-1H-benzotriazole hydrate in 1 ml of DMF. At 0° C., 142 μl (0.82 mmol) of DIEA and then, a little at a time, 136.5 mg (0.36 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and stirred at RT for 2.5 h. The mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 97.4 mg (47.6% of theory) of the title compound.

Workup

  1. extractionextracted three times with ethyl acetate
  2. dry with materialThe combined organic phases were dried over magnesium sulfate
  3. concentrationconcentrated under reduced pressure
  4. customThe crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient)

Sources & evidence

ORD record
ord-4c38c5f9bc584aaf9d83229306163b46
Source dataset
uspto-grants-2015_03
Patent number
US08987256B2

Reaction notes

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