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

HRID 1512845Notes

Reaction equation

HRID 1512845 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:36][C:37]1[C:45](/[C:46](/[NH:49]O)=[N:47]/[H])=[C:44]2[C:40]([C:41]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:42][NH:43]2)=[CH:39][CH:38]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:47]=[C:46]([C:45]3[C:37]([F:36])=[CH:38][CH:39]=[C:40]4[C:44]=3[NH:43][CH:42]=[C:41]4[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:49]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]

Participants

6

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 180705825-Chloro-6-isopropoxynicotinic acidHCID 178506517HCID 178506517, compound

Product 1

HCID 59146095Ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoateYield 18.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To the solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (1.39 g) in tetrahydrofuran (50 mL) were added EDCI (1.69 g) and HOBT (1.35 g). The resulting solution was stirred at room temperature for 1 hour. Then ethyl 3-{6-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D145) (1.72 g) was added and the solution was stirred at room temperature for another 2 hours. THF was removed in vacuo and the residue was dissolved in ethyl acetate (50 mL), washed with water (2×10 mL), dried over sodium sulphate and concentrated. The residue was dissolved in THF (3 mL), TBAF (6.13 g) was added and the reaction solution was stirred in the microwave (120° C., 2.5 hours). The reaction solution was poured into ethyl acetate (100 mL), washed with water (3×20 mL) and dried over sodium sulphate. The organic solution was concentrate and the residue was purified by column chromatography to afford ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D149) (520 mg) as a white solid. MS (ES): C23H22ClFN4O4 requires 472; found 473.2 (M+H+)

Workup

  1. stirringthe solution was stirred at room temperature for another 2 hours
  2. customTHF was removed in vacuo
  3. dissolutionthe residue was dissolved in ethyl acetate (50 mL)
  4. washwashed with water (2×10 mL)
  5. dry with materialdried over sodium sulphate
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in THF (3 mL)
  8. additionTBAF (6.13 g) was added
  9. stirringthe reaction solution was stirred in the microwave (120° C., 2.5 hours)
  10. additionThe reaction solution was poured into ethyl acetate (100 mL)
  11. washwashed with water (3×20 mL)
  12. dry with materialdried over sodium sulphate
  13. concentrationThe organic solution was concentrate
  14. customthe residue was purified by column chromatography

Sources & evidence

ORD record
ord-6adea8224ff646bf87a2ff14260c277c
Source dataset
uspto-grants-2012_07
Patent number
US08217028B2

Reaction notes

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