Dicyclohexylcarbodiimide → 2-[(3-{4-[3-(2-Fluoro-phenyl)ureido]-phenyl}-isoxazole-5-carbonyl)-amino]-3-methyl-butyric acid methyl ester

HRID 75817Notes

Reaction equation

HRID 75817 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([OH:24])=O)[O:19][N:18]=2)=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:52][O:53][C:54](=[O:60])[C@H:55]([CH:57]([CH3:59])[CH3:58])[NH2:56]>CN(C=O)C.O>[CH3:52][O:53][C:54](=[O:60])[CH:55]([NH:56][C:22]([C:20]1[O:19][N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:25])=[CH:16][CH:15]=2)[CH:21]=1)=[O:24])[CH:57]([CH3:59])[CH3:58]

Participants

7

Reactant 4

HCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 111190Methyl valinate hydrochlorideHCID 673539813-(4-(3-(2-Fluorophenyl)ureido)phenyl)isoxazole-5-carboxylic acid

Product 1

HCID 673524222-[(3-{4-[3-(2-Fluoro-phenyl)ureido]-phenyl}-isoxazole-5-carbonyl)-amino]-3-methyl-butyric acid methyl esterYield 82.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

3-(4-(3-(2-fluorophenyl)ureido)phenyl)isoxazole-5-carboxylic acid (1 g) was dissolved in DMF (20 ml). N,N′-Dicyclohexyl carbodiimide (906 mg) and 1-Hydroxy benzotriazole (396 mg) were added and the reaction mixture was stirred at RT for 15 minutes. L-Valine methyl ester hydrochloride (640 mg) was dissolved in DMF (5 ml), neutralized with TEA (0.53 ml) and added into the above reaction mixture, which was then stirred at RT for 16 h. DMF was removed under reduced pressure to get a pale brown solid which was taken in water and extracted with EtOAc. Organic layer was dried over Na2SO4 and concentrated to get a pale yellow solid which was purified by silica gel column chromatography in 2:8 EtOAc:CHCl3 to get off white solid which was crystallized from DCM/Pet ether to yield 1.1 gm (82%) white solid. 1HNMR (DMSO-d6, 300 MHz): δ 9.33 (s, 1H), 9.18 (d, 1H), 8.62 (s, 1H), 8.13 (m, 1H), 7.85 (d, 2H), 7.67 (s, 1H), 7.59 (d, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 7.02 (m, 1H), 4.29 (m, 2H), 3.66 (s, 3H), 2.2 (m, 1H), 0.95 (d, 6H); MS (ES+): m/z 455 (M+1).

Workup

  1. additionadded into the above reaction mixture, which
  2. stirringwas then stirred at RT for 16 h
  3. customDMF was removed under reduced pressure
  4. customto get a pale brown solid which
  5. extractionextracted with EtOAc
  6. dry with materialOrganic layer was dried over Na2SO4
  7. concentrationconcentrated
  8. customto get a pale yellow solid which
  9. customwas purified by silica gel column chromatography in 2:8 EtOAc
  10. customCHCl3 to get off white solid which
  11. customwas crystallized from DCM/Pet ether

Sources & evidence

ORD record
ord-6da1778bdb584939909a0d7ebb3cf1c6
Source dataset
uspto-grants-2014_09
Patent number
US08835428B2

Reaction notes

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