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

HRID 1512810Notes

Reaction equation

HRID 1512810 reaction equation
CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([C:33]([OH:35])=O)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31].O[NH:37]/[C:38](=[N:55]\[H])/[C:39]1[CH:47]=[C:46]2[C:42]([C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:44][NH:45]2)=[CH:41][CH:40]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:33]2[O:35][N:55]=[C:38]([C:39]3[CH:47]=[C:46]4[C:42]([C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:44][NH:45]4)=[CH:41][CH:40]=3)[N:37]=2)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:31])[CH3:32]

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 2724141Tetrabutylammonium FluorideHCID 180705825-Chloro-6-isopropoxynicotinic acidHCID 178506487HCID 178506487, compound

Product 1

HCID 59146162Ethyl 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoateYield 73.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

EDCI (356 mg) and HOBT (306 mg) were added to a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (200 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) (383 mg) in THF (5 mL) was added and the reaction mixture was stirred at RT for 2 hours. TBAF (970 mg) 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 EtOAc 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-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D108) (310 mg) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.46 (6H, d), 2.74 (2H, t), 3.15 (2H, t), 4.15 (2H, q), 5.51 (1H, m), 7.17 (1H, d), 7.72 (1H, d), 7.93 (1H, dd), 8.20 (2H, d), 8.42 (1H, d), 8.89 (1H, d). MS (ES): C23H23ClN4O4 requires 454; found 455.2 (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 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 (20% EtOAc in hexane)

Sources & evidence

ORD record
ord-04f06323ae584789ad189bfafbbc4990
Source dataset
uspto-grants-2012_07
Patent number
US08217028B2

Reaction notes

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