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

HRID 1845559Notes

Reaction equation

HRID 1845559 reaction equation
[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[CH2:29][C@H:16]([NH:15][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:14])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 7163042,6-Difluoro-l-phenylalanineHCID 2733179PyBroPHCID 578264554-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic AcidHCID 670663202-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione

Product 1

HCID 57826715N-{(1S)-2-(2,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamideYield 46.2%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (222 mg, 0.80 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (331 mg, 0.78 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (1.0 g, 4.97 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (448 mg, 0.96 mmol) in chloroform (10 mL). DIEA (700 μL, 4.01 mmol) was added and the reaction stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (249 mg, 0.36 mmol, 46%): LC-MS (ES) m/z=507 (M+H)+.

Workup

  1. customprepared
  2. customprepared
  3. customaccording to the procedure of Preparation 18
  4. custompurified via column chromatography (25-75% EtOAc/Hex)

Sources & evidence

ORD record
ord-7c3b9f1331e04cdb961f20ecdb894675
Source dataset
uspto-grants-2015_02
Patent number
US08946278B2

Reaction notes

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