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

HRID 1961094Notes

Reaction equation

HRID 1961094 reaction equation
[CH3:1][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][CH:11]=1.C(N(CC)C(C)C)(C)C.[NH2:25][C@@H:26]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH:40]1([CH2:39][C@H:26]([NH:25][C:7]([C:5]2[S:6][C:2]([CH3:1])=[C:3]([C:10]3[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=3)[CH:4]=2)=[O:9])[CH2:27][N:28]2[C:29](=[O:38])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]2=[O:37])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 2761473Boc-2-(trifluoromethyl)-L-phenylalanineHCID 578265125-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acidHCID 670661172-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione

Product 1

HCID 57826546N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamideYield 94%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (138 mg, 0.62 mmol), N,N-diisopropylethylamine (0.541 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 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, 50% EtOAc in hexanes) yielding N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (285 mg, 0.581 mmol, 94% yield) as a white foam: LCMS (ES) m/e 491, 493 (M, M+2)+.

Workup

  1. customaccording to the procedure of Preparation 6
  2. customat 25° C.
  3. customwas then partitioned between H2O-DCM
  4. washThe aqueous phase was washed several times with DCM
  5. dry with materialthe combined organic fractions were dried over Na2SO4
  6. concentrationconcentrated
  7. custompurified via column chromatography (silica, 50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-8fa06878085d4a9683c7c92747f99999
Source dataset
uspto-grants-2013_04
Patent number
US08410158B2

Reaction notes

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