Diisopropylcarbodiimide → 4-[2-(Cyclopropanecarbonyl-amino)-2-phenyl-acetyl]-morpholine-3-carboxylic acid {4-[3-(5-chloro-2-hydroxy-phenyl)-1-methyl-1H-pyrazol-4-ylethynyl]-phenyl}-amide

HRID 2075777Notes

Reaction equation

HRID 2075777 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH2:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1.[CH:42]1([C:45](O)=[O:46])[CH2:44][CH2:43]1.CC(C)N=C=NC(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH:38][C:45]([CH:42]4[CH2:44][CH2:43]4)=[O:46])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1

Participants

5

Reactant 3

HCID 12734DiisopropylcarbodiimideHCID 15655Cyclopropanecarboxylic acidHCID 1363466894-(2-Amino-2-phenyl-acetyl)-morpholine-3-carboxylic acid {4-[3-(5-chloro-2-hydroxy-phenyl)-1-methyl-1H-pyrazol-4-ylethynyl]-phenyl}-amide

Product 1

HCID 1363466904-[2-(Cyclopropanecarbonyl-amino)-2-phenyl-acetyl]-morpholine-3-carboxylic acid {4-[3-(5-chloro-2-hydroxy-phenyl)-1-methyl-1H-pyrazol-4-ylethynyl]-phenyl}-amideYield 49%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of compound 9D (4.0 g, 7.02 mmol) and cyclopropanecarboxylic acid (10D, (0.91 g, 10.53 mmol) in anhydrous CH2Cl2 (100 mL) was added DIPC (1.63 mL, 10.53 mmol). The reaction mixture was stirred at rt overnight. It was filtered to remove diisopropylurea. The filtrate was purified with silica column chromatography eluting with dichloromethane/EtOAc (v/v 1/1, 7/1, 4/1) to give the title compound (11D, 3.4 g, crude), which was recrystallized from hexanes/acetone to provide pure compound 11D (2.2 g) as white powder in 49% yield. 1H NMR (CDCl3, 500 MHz) δ 10.68 (s, 1H), 8.75 (s, 1H), 8.71 (s, 1H), 7.90 (d, 2H, J=8.5 Hz), 7.63 (s, 1H), 7.56 (d, 2H, J=9.0 Hz), 7.50 (m, 2H), 7.45 (m, 3H), 7.20 (dd, 1H, J=8.5, 2.5 Hz), 6.97 (d, 1H, J=9.0 Hz), 6.57 (s, 1H), 5.69 (d, 1H, J=5.5 Hz), 5.23 (s, 1H), 4.82 (d, 1H, J=12.0 Hz), 3.97 (s, 3H), 3.81 (d, 1H, J=11.5 Hz), 3.72 (d, 1H, J=12.5 Hz), 3.64 (t, 1H, J=12.0 Hz), 3.43 (dd, 1H, J=11.0, 3.0 Hz), 3.11 (t, 1H, J=11.5 Hz), 1.49 (m, 1H), 1.00 (m, 2H), 0.84 (m, 2H). LCMS (ESI) m/z 669.43 (MNa+), 638.39 (MH+), 437.28. HPLC: tR=4.98 min.

Workup

  1. filtrationIt was filtered
  2. customto remove diisopropylurea
  3. customThe filtrate was purified with silica column chromatography
  4. washeluting with dichloromethane/EtOAc (v/v 1/1, 7/1, 4/1)

Sources & evidence

ORD record
ord-94627a2a609945998a90d1ef59051c2c
Source dataset
uspto-grants-2011_04
Patent number
US07923004B2

Reaction notes

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