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

HRID 1845639Notes

Reaction equation

HRID 1845639 reaction equation
[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](CF)=[CH:35][CH:34]=1)[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(C(C)C)CC)(C)C.[F:50][P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([F:50])=[CH:37][CH:38]=3)[CH2:20][N:21]3[C:22](=[O:31])[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]3=[O:30])=[O:16])[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 578266384-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acidHCID 670661952-{(2S)-2-amino-3-[4-(fluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione

Product 1

HCID 578266004-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-ethyl-2-thiophenecarboxamideYield 92%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (250 mg, 1.0 mmol), 2-{(2S)-2-amino-3-[4-(fluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (313 mg, 1.05 mmol) [prepared according to the procedure of Preparation 6] and diisopropylethylamine (0.52 ml, 3 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (746 mg, 1.6 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding the title compound as a yellow solid (490 mg, 0.92 mmol, 92% yield) as a yellow foam: LCMS (ES) m/e 531 (M+H)+.

Workup

  1. customwas then partitioned between H2O-DCM
  2. washThe aqueous phase was washed several times with DCM
  3. dry with materialthe combined organic fractions were dried over Na2SO4
  4. concentrationconcentrated
  5. custompurified via column chromatography (silica, 30-70% EtOAc in hexanes)

Sources & evidence

ORD record
ord-31835e8240bb4fb882c7c45ad2dfc5fb
Source dataset
uspto-grants-2015_02
Patent number
US08946278B2

Reaction notes

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