1H-Indole-3-propanoic acid → HCID 46846819, compound

HRID 1187329Notes

Reaction equation

HRID 1187329 reaction equation
[C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:14]1.[CH3:27][C:28]1(C)[C:32](=[N:33]O)[CH2:31][C:30]2(CCNC[CH2:35]2)[O:29]1.ClCCl>C1COCC1>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][C:24]([O:26]/[N:33]=[C:32]2/[CH:28]([CH3:27])[O:29][C:30]3([CH2:35][CH2:9][N:8]([CH3:1])[CH2:12][CH2:11]3)[CH2:31]/2)=[O:25])=[CH:14]1

Participants

6

Reactant 4

HCID 37441H-Indole-3-propanoic acidHCID 6344DichloromethaneHCID 682631,1'-CarbonyldiimidazoleHCID 87228623HCID 87228623, compound

Product 1

HCID 46846819HCID 46846819, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Carbonyldiimidazole (CDI) (0.19 g, 1.2 mmol) was added to a solution of 3-indole propionic acid (0.22 g, 1.2 mmol) in dry THF (10 ml) under an argon atmosphere. The reaction mixture was stirred for 0.5 h at room temperature, then dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime (0.23 g, 1.2 mmol, prepared according to the procedure of Tsukamoto et. al. Chem. Pharma. Bull. 1995, 43, 842-852) was added. The reaction mixture was stirred for 4 h at room temperature and then for 8 h at 45° C. The reaction mixture was cooled to room temperature, dichloromethane (80 ml) was added and the mixture was washed with water (10 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (30 ml). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography in a Combi-Flash Companion system (Isco, Inc) (HP 12-gold silica column, CH2Cl2/MeOH/NH4OH 90/10/1) followed by further flash chromatography in a Combi-Flash Companion system (Isco, Inc) (HP 12-gold silica column, CH2Cl2/MeOH/NH4OH 120/10/1). The residue was triturated in ether to give AF733 (104 mg), obtained as a white solid. 1H NMR (CDCl3, 300 MHz) δ 8.17 (br s, 1H, NH-indole), 7.60 (d, J=7.73 Hz, 1H, CHC arom), 7.35 (d, J=7.98 Hz, 1H, CHC arom), 7.19 (app t, J=7.76 Hz, 1H, CHCH arom), 7.12 (app t, J=7.43 Hz, 1H, CHCH arom), 7.04 (d, J=2.11 Hz, 1H, CHNH arom), 5.56 (q, J=6.3 Hz, 1H, CHCH3), 3.18 (t, J=7.37 Hz, 2H, CH2), 2.83 (t, J=7.41 Hz, 2H, COCH2), 2.40 (ABq, J=18.6 Hz, 2H, CH2), 2.5-2.3 (m, 4H), 2.28 (s, 3H, NCH3), 1.74 (2m, 3H), 1.5 (m, 1H), 1.43 (d, J=6.36 Hz, 3H, CH3—CH) ppm; 13C NMR (CDCl3, 300 MHz) δ 173.4 (C), 171.0 (C), 136.5 (C), 127.3 (C), 122.2 (CH), 122.1 (CH), 119.5 (CH), 118.8 (CH), 114.5 (C), 111.4 (CH), 78.7 (C), 72.5 (CH), 52.5 (CH2), 52.2 (CH2), 46.1 (CH3), 40.0 (CH2), 37.4 (CH2), 34.4 (CH2), 33.7 (CH2), 20.9 (CH2), 19.5 (CH3) ppm.

Workup

  1. addition1995, 43, 842-852) was added
  2. stirringThe reaction mixture was stirred for 4 h at room temperature
  3. waitfor 8 h at 45° C
  4. temperatureThe reaction mixture was cooled to room temperature
  5. washthe mixture was washed with water (10 ml)
  6. customThe two phases were separated
  7. extractionthe aqueous phase was extracted with dichloromethane (30 ml)
  8. dry with materialdried with anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationthe filtrate was concentrated under reduced pressure
  11. customThe residue was purified by flash chromatography in a Combi-Flash Companion system (Isco, Inc) (HP 12-gold silica column, CH2Cl2/MeOH/NH4OH 90/10/1)
  12. customThe residue was triturated in ether
  13. customto give AF733 (104 mg)
  14. customobtained as a white solid

Sources & evidence

ORD record
ord-d02ecc8f90134c8d9d992644a661c2bb
Source dataset
uspto-grants-2014_03
Patent number
US08673931B2

Reaction notes

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