Indole-2-carboxylic acid → HCID 69194055, compound

HRID 132137Notes

Reaction equation

HRID 132137 reaction equation
[CH:1]1([CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:26](OC(=O)[C@@H](N)CCC1CCCCC1)[CH3:27].N1C2C(=CC=CC=2)C=C1C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:26]([O:11][C:10](=[O:12])[C@@H:9]([NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:27]

Participants

7

Reactant 5

HCID 72899Indole-2-carboxylic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 16218419Ethyl 2-amino-4-cyclohexylbutanoate--hydrogen chloride (1/1)HCID 69196048HCID 69196048, compound

Product 1

HCID 69194055HCID 69194055, compoundYield 92%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

The title compound was prepared following the procedures of Example 22, except that in step D it uses 4-cyclohexyl-(2S)-[(1H-indole-2-carbonyl)-amino]-butyric acid instead of Methyl-(2S)-(3-methyl-benzoylamino)-pentanoic acid. The final compound is isolated as a mixture of diastereomers in a 1.5:1 ratio. HPLC-MS calcd. for C29H38N4O3 (M+H+) 491.3, found 491.5. 1H NMR (CDCl3, 400 MHz) δ 0.55-1.38 (m, 16H), 1.53-1.71 (m, 2H), 2.89 (m, 2H), 3.49 (s, 3H), 4.03 (m, 1H), 4.41 (m, 1H), 6.35-7.17 (m, 9H), 7.40 (1H, m), 9.48 (s, 1H) 4-Cyclohexyl-(2S)-[(1H-indole-2-carbonyl)-amino]-butyric acid is made by the following procedure: (+)-Ethyl-(S)-2-amino-4-cyclohexylbutyrate hydrochloride (1.643 g, 6.577 mmol, 1.0 equiv.), 2-indolecarboxylic acid (1.166 g, 7.235 mmol, 1.1 equiv.), HATU (2.750 g, 7.232 mmol, 1.1 equiv.), and CH2Cl2 (80 mL) were combined in a 100 mL r.b. flask with a magnetic stir-bar. The resulting cloudy white solution reaction was allowed to stir at room temperature for 20 minutes, upon which DIPEA (5.8 mL, 33.29 mmol, 4.6 equiv.) was added via syringe. The reaction mixture turned dark yellow in color. The resulting solution was allowed to stir at rt for 3 h. When the reaction was complete by LC/MS, it was extracted with 100 mL water, washed the organic layer with 50 mL saturated NaCl and dried over MgSO4. After evaporation of solvent, the crude mixture was purified by ISCO normal phase separation to provide (2.161 g, 6.062 mmol, 92% yield) of 4-cyclohexyl-(2S)-[(1H-indole-2-carbonyl)-amino]-butyric acid ethyl ester as a clear liquid. HPLC-MS calcd. for C21H28N2O3 (M+H+) 357.5, found 357.5.

Workup

  1. customThe resulting cloudy white solution reaction
  2. additionwas added via syringe
  3. extractionwas extracted with 100 mL water
  4. washwashed the organic layer with 50 mL saturated NaCl
  5. dry with materialdried over MgSO4
  6. customAfter evaporation of solvent
  7. customthe crude mixture was purified by ISCO normal phase separation

Sources & evidence

ORD record
ord-3ab66d00fb2948d5839ad1ea7e48be41
Source dataset
uspto-grants-2008_06
Patent number
US07384970B2

Reaction notes

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