1-Pentyl-3-(trifluoroacetyl)indole.
1. A cooled (0 *C) suspension of NaH (60% dispersion in mineral oil, 68 g) in DMF (1000 ml) was treated with a solution of indole (100 g) in DMF (200 ml).
2. Warmed to rt, and stirred for 10 min.
3. The mixture was cooled to 0*C, treated slowly with the appropriate 1-bromopentane (135 g), warmed to rt, and stirred for 1 h.
4. The solution was cooled to 0 *C, treated with (CF3CO)2O (300 ml), warmed to rt, and stirred for 1 h.
5. The mixture was poured onto ice−water (6000 ml) and stirred vigorously.
6. The mixture was filtered, and the precipitate was dried to give the crude product as a red solid, which was used in the following step without purification, to yield 100%.
1-Pentylindole-3-carboxylic Acid.
1. To a refluxing solution of KOH (66 g) in MeOH (120 ml) was added, portionwise, a solution of the appropriate crude 1-pentyl-3-trifluoroacetylindole (100 g) in toluene (300 ml).
2. After heating at reflux for 2 h, the mixture was cooled to ambient temperature, and H2O (1000 ml) was added.
3. The layers were separated, and the organic layer was extracted with 1M NaOH (350 ml) aq.
4. The combined aqueous phases were acidified to pH 1 with 10M aq. HCl, extracted with Et2O (3x500 ml), and dried (MgSO4), and the solvent was removed under reduced pressure.
5. The crude solid was recrystallized from i-PrOH to give the appropriate 37 g 1-pentylindole-3-carboxylic acid as colorless crystals.
AB-PICA ((S)-N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indole-3-carboxamide).
1. A solution of the 1-Pentylindole-3-carboxylic Acid (100 g) in DMF (1000 ml) was treated with EDC (83 g), HOBt (59 g), DIPEA (190 g), L-valinamide (100 g) and stirred for 24 h.
2. The mixture was partitioned between and H2O (2000 ml) and EtOAc (1000 ml), the layers were separated, and the aqueous layer was extracted with EtOAc (2x500 ml).
3. The combined organic phases were dried (MgSO4), and the solvent was evaporated under reduced pressure.
4. The crude products were purified by recrystallization to get 116 g (81%) of a white solid.
1. A cooled (0 *C) suspension of NaH (60% dispersion in mineral oil, 68 g) in DMF (1000 ml) was treated with a solution of indole (100 g) in DMF (200 ml).
2. Warmed to rt, and stirred for 10 min.
3. The mixture was cooled to 0*C, treated slowly with the appropriate 1-bromopentane (135 g), warmed to rt, and stirred for 1 h.
4. The solution was cooled to 0 *C, treated with (CF3CO)2O (300 ml), warmed to rt, and stirred for 1 h.
5. The mixture was poured onto ice−water (6000 ml) and stirred vigorously.
6. The mixture was filtered, and the precipitate was dried to give the crude product as a red solid, which was used in the following step without purification, to yield 100%.
1-Pentylindole-3-carboxylic Acid.
1. To a refluxing solution of KOH (66 g) in MeOH (120 ml) was added, portionwise, a solution of the appropriate crude 1-pentyl-3-trifluoroacetylindole (100 g) in toluene (300 ml).
2. After heating at reflux for 2 h, the mixture was cooled to ambient temperature, and H2O (1000 ml) was added.
3. The layers were separated, and the organic layer was extracted with 1M NaOH (350 ml) aq.
4. The combined aqueous phases were acidified to pH 1 with 10M aq. HCl, extracted with Et2O (3x500 ml), and dried (MgSO4), and the solvent was removed under reduced pressure.
5. The crude solid was recrystallized from i-PrOH to give the appropriate 37 g 1-pentylindole-3-carboxylic acid as colorless crystals.
AB-PICA ((S)-N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indole-3-carboxamide).
1. A solution of the 1-Pentylindole-3-carboxylic Acid (100 g) in DMF (1000 ml) was treated with EDC (83 g), HOBt (59 g), DIPEA (190 g), L-valinamide (100 g) and stirred for 24 h.
2. The mixture was partitioned between and H2O (2000 ml) and EtOAc (1000 ml), the layers were separated, and the aqueous layer was extracted with EtOAc (2x500 ml).
3. The combined organic phases were dried (MgSO4), and the solvent was evaporated under reduced pressure.
4. The crude products were purified by recrystallization to get 116 g (81%) of a white solid.
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