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

HRID 1512762Notes

Reaction equation

HRID 1512762 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[O:35][CH3:36])[CH3:24].[F:37][C:38]1[CH:46]=[CH:45][C:44](/[C:47](/[NH:50]O)=[N:48]/[H])=[C:43]2[C:39]=1[C:40]([CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:41][NH:42]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:37][C:38]1[CH:46]=[CH:45][C:44]([C:47]2[N:50]=[C:32]([C:29]3[CH:30]=[N:31][C:26]([O:25][CH:23]([CH3:22])[CH3:24])=[C:27]([O:35][CH3:36])[CH:28]=3)[O:34][N:48]=2)=[C:43]2[C:39]=1[C:40]([CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:41][NH:42]2

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 2724141Tetrabutylammonium FluorideHCID 670254146-[(1-Methylethyl)oxy]-5-(methyloxy)-3-pyridinecarboxylic acidHCID 178506502HCID 178506502, compound

Product 1

HCID 59146077ethyl 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoateYield 64.8%

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-(methyloxy)-3-pyridinecarboxylic acid (110 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) (199 mg) in THF (4 mL) was added, and the reaction mixture was stirred at RT overnight. TBAF (780 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-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D50) (158 mg) as a white solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.47 (6H, d), 2.76 (2H, t), 3.24 (2H, t), 4.01 (3H, s), 4.15 (2H, q), 5.55 (1H, m), 6.91 (1H, dd), 7.14 (1H, d), 7.76 (1H, d), 8.06 (1H, dd), 8.64 (1H, d), 9.69 (1H, br s). MS (ES): C24H25FN4O5 requires 468; found 469.2 (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-68a1d99e16854213ae0329ba22c0c8f9
Source dataset
uspto-grants-2012_07
Patent number
US08217028B2

Reaction notes

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