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

HRID 1512811Notes

Reaction equation

HRID 1512811 reaction equation
CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[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].O[NH:40]/[C:41](=[N:58]\[H])/[C:42]1[CH:50]=[C:49]2[C:45]([C:46]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:47][NH:48]2)=[CH:44][CH:43]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:24][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[O:34][N:58]=[C:41]([C:42]3[CH:50]=[C:49]4[C:45]([C:46]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:47][NH:48]4)=[CH:44][CH:43]=3)[N:40]=2)=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36])[CH3:22]

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 2724141Tetrabutylammonium FluorideHCID 670252766-[(1-Methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinecarboxylic acidHCID 178506487HCID 178506487, compound

Product 1

HCID 59146088Ethyl 3-(6-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoateYield 63.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

EDCI (385 mg) and HOBT (332 mg) were added to a solution of 6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinecarboxylic acid (250 mg) in THF (5 mL) at RT. The resulting solution was stirred for 30 mins. Ethyl 3-{6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D107) (413 mg) in THF (5 mL) was added and the reaction mixture was stirred at RT for 2 hours. TBAF (1.1 g) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 90 mins. After cooling, the reaction was quenched with water, and extracted with EA for 3 times. The combined organic solution was washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (20% EtOAc in hexane) to afford ethyl 3-(6-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D109) (310 mg) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.45 (6H, d), 2.74 (2H, t), 3.15 (2H, t), 4.16 (2H, q), 5.60 (1H, m), 7.17 (1H, t), 7.73 (1H, d), 7.94 (1H, dd), 8.21 (2H, dd), 8.64 (1H, t), 9.14 (1H, d). δF (CDCl3, 376 MHz): −64.3. MS (ES): C24H23F3N4O4 requires 488; found 489.2 (M+H+).

Workup

  1. stirringthe reaction mixture was stirred at RT for 2 hours
  2. customThe reaction vessel was sealed
  3. temperatureheated in Biotage Initiator
  4. customnormal to 120° C.
  5. customfor 90 mins
  6. temperatureAfter cooling
  7. customthe reaction was quenched with water
  8. extractionextracted with EA 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 (20% EtOAc in hexane)

Sources & evidence

ORD record
ord-7286614b555b4f5f99e699b90a9eaa2e
Source dataset
uspto-grants-2012_07
Patent number
US08217028B2

Reaction notes

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