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

HRID 1512758Notes

Reaction equation

HRID 1512758 reaction equation
C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.[F:36][C:37]1[CH:45]=[CH:44][C:43](/[C:46](/[NH:49]O)=[N:47]/[H])=[C:42]2[C:38]=1[C:39]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:40][NH:41]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:47]=[C:46]([C:43]3[CH:44]=[CH:45][C:37]([F:36])=[C:38]4[C:42]=3[NH:41][CH:40]=[C:39]4[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:49]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 2724141Tetrabutylammonium FluorideHCID 225977283-Chloro-4-(propan-2-yloxy)benzoic acidHCID 178506502HCID 178506502, compound

Product 1

HCID 59146093Ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoateYield 85.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

HOBT (166 mg) and EDCI (199 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (115 mg) in THF (4 mL). The reaction mixture was stirred at RT for 2 hours. Ethyl 3-{4-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D45) (205 mg) in THF (4 mL) was added. Then stirring continued overnight. TBAF (760 mg) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 3 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 (15% EtOAc in hexane) to afford ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D46) (216 mg) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.47 (6H, d), 2.76 (2H, t), 3.24 (2H, t), 4.14 (2H, q), 4.74 (1H, m), 6.91 (1H, dd), 7.09 (1H, d), 7.14 (1H, d), 8.04 (1H, dd), 8.10 (1H, dd), 8.28 (1H, d), 9.71 (1H, br s). MS (ES): C24H23ClFN3O4 requires 471; found 472.2 (M+H+).

Workup

  1. stirringThen stirring continued overnight
  2. customThe reaction vessel was sealed
  3. temperatureheated in Biotage Initiator
  4. customnormal to 120° C.
  5. customfor 3 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 (15% EtOAc in hexane)

Sources & evidence

ORD record
ord-25e96b5730114f4d83fc5c35f352dfb8
Source dataset
uspto-grants-2012_07
Patent number
US08217028B2

Reaction notes

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