Diisopropylethylamine → 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

HRID 2392267Notes

Reaction equation

HRID 2392267 reaction equation
[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH3:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH3:16]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 578264495-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic AcidHCID 58226866(S)-2-(2-amino-3-(3-fluorophenyl)propyl)isoindoline-1,3-dione

Product 1

HCID 578266495-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamideYield 42.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a 500 mL round-bottomed flask was added 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (6.8 g, 26.5 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (8.69 g, 29.1 mmol), N,N-diisopropyl ethylamine (14 mL, 80 mmol) and Pybrop (18.52 g, 39.7 mmol) in dichloromethane (DCM) (100 mL). After stirring at RT for 1 h, the reaction solution was washed with H2O (2×100 mL) and the organic layer was dried Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with (EtOAc/hexanes, 1:1) to give the title compound (6.1 g, 42.9%) as a white solid: LCMS (ES) m/z 537 (M+H)+.

Workup

  1. washthe reaction solution was washed with H2O (2×100 mL)
  2. filtrationfiltered
  3. concentrationconcentrated
  4. additionThe crude product was added to a silica gel column
  5. washwas eluted with (EtOAc/hexanes, 1:1)

Sources & evidence

ORD record
ord-37a8f187b07a45408ad2fc39084406d4
Source dataset
uspto-grants-2012_09
Patent number
US08273782B2

Reaction notes

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