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Diisopropylethylamine → (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide

HRID 18989
Notes
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Reaction equation

HRID 18989 reaction equation
[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[N:22]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(C[C@H](N2CC(OC)=CC2=O)C(NC2C=CN(CC(OC)(C)C)N=2)=O)CCCC1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([NH:20][C:21]2[CH:25]=[CH:24][N:23]([CH2:26][C:27]([OH:29])([CH3:28])[CH3:30])[N:22]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 44252907(S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamideHCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-olHCID 66894651(S)-3-cyclohexyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid

Product 1

HCID 57920092(S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of (S)-3-cyclohexyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (138 mg, 0.52 mmol), 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 98 mg, 0.63 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (326 mg, 0.75 mmol), N,N-diisopropylethylamine (200 mg, 1.54 mmol) in dichloromethane (10 mL) was stirred for 18 h under nitrogen at 23° C. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g silica gel; 0% to 10% methanol/dichloromethane) to afford, (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (123 mg, 59%) as a white foam, LR-ES-MS m/z calculated for C21H32N4O4 [M]+ 404, observed [M+H]+ 405; 1H NMR (300 MHz, CDCl3) δ ppm 0.78-1.31 (m, 7H) 1.15 (s, 6H) 1.55-1.77 (m, 5H) 1.77-1.95 (m, 2H) 3.82 (s, 3H) 3.87 (d, J=17.8 Hz, 1H) 3.94 (s, 2H) 4.05 (d, J=17.8 Hz, 1H) 4.92 (dd, J=9.5, 5.9 Hz, 1H) 5.14 (s, 1H) 6.67 (d, J=2.1 Hz, 1H) 7.28 (d, J=2.1 Hz, 1H) 8.72 (br. s., 1H).

Workup

  1. washwashed with 2N aqueous hydrochloric acid, saturated sodium chloride solution
  2. customdried
  3. concentrationThe organic layer was concentrated
  4. customthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g silica gel; 0% to 10% methanol/dichloromethane)
  5. customto afford

Sources & evidence

ORD record
ord-26411151e6a145f6abd6990de06e794a
Source dataset
uspto-grants-2010_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07741327B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes