1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → Ethyl 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate

HRID 1512761Notes

Reaction equation

HRID 1512761 reaction equation
C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:22][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36])[CH3:24].[F:39][C:40]1[CH:48]=[CH:47][C:46](/[C:49](/[NH:52]O)=[N:50]/[H])=[C:45]2[C:41]=1[C:42]([CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:43][NH:44]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:39][C:40]1[CH:48]=[CH:47][C:46]([C:49]2[N:52]=[C:32]([C:29]3[CH:30]=[N:31][C:26]([O:25][CH:23]([CH3:22])[CH3:24])=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:28]=3)[O:34][N:50]=2)=[C:45]2[C:41]=1[C:42]([CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:43][NH:44]2

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 2724141Tetrabutylammonium FluorideHCID 670252766-[(1-Methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinecarboxylic acidHCID 178506502HCID 178506502, compound

Product 1

HCID 59146132Ethyl 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoateYield 60.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

HOBT (161 mg) and EDCI (203 mg) were added to a solution of 6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinecarboxylic acid (132 mg) in THF (4 mL). The resulting solution was stirred for 2 hours. Ethyl 3-{4-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D45) (210 mg) in THF (4 mL) was added, and the reaction mixture was stirred at RT overnight. TBAF (770 mg) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 2.5 hours. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (10% EtOAc in hexane) to afford ethyl 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D49) (162 mg) as a pale white solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.46 (6H, d), 2.76 (2H, t), 3.24 (2H, t), 4.15 (2H, q), 5.59 (1H, m), 6.92 (1H, dd), 7.15 (1H, d), 8.05 (1H, dd), 8.64 (1H, d), 9.17 (1H, d), 9.65 (1H, br s). MS (ES): C24H22F4N4O4 requires 506; found 507.2 (M+H+).

Workup

  1. stirringthe reaction mixture was stirred at RT overnight
  2. customThe reaction vessel was sealed
  3. temperatureheated in Biotage Initiator
  4. customnormal to 120° C.
  5. customfor 2.5 hours
  6. temperatureAfter cooling
  7. customthe reaction was quenched with water
  8. extractionextracted with EtOAc for 3 times
  9. washThe combined organic solution was washed with brine
  10. dry with materialdried over anhydrous sodium sulfate
  11. concentrationThe dried solution was concentrated
  12. customThe residue was purified by column chromatography (10% EtOAc in hexane)

Sources & evidence

ORD record
ord-623e9cd2ab31400e86b759e343cfaef3
Source dataset
uspto-grants-2012_07
Patent number
US08217028B2

Reaction notes

Loading…