4-Methylmorpholine → Methyl 2-(3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl) isoxazole-5-carboxamido)propanoate

HRID 75806Notes

Reaction equation

HRID 75806 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:44][O:45][C:46](=[O:50])[C@H:47]([CH3:49])[NH2:48].CCN(CC)CC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:48][CH:47]([CH3:49])[C:46]([O:45][CH3:44])=[O:50])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 8471TriethylamineHCID 62365Isobutyl chloroformateHCID 2733257Alanine methyl ester hydrochlorideHCID 673522053-(4-(3-(2,6-Difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylic acid

Product 1

HCID 67353466Methyl 2-(3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl) isoxazole-5-carboxamido)propanoateYield 92%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

To a solution of 3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylic acid (1.0 equiv.) in 50 ml of THF was added N-methylmorpholine (1.0 equiv.) at RT. The reaction mixture was then cooled to −20° C. and isobutylchloroformate (1.0 equiv.) was added and stirred at −20° C. for 5 min. L-alanine methyl ester hydrochloride (1.1 equiv.) was neutralized with Et3N (1.1 equiv.) in 25 ml of THF and added to the above mixture. The mixture was stirred at −20° C. for 5 min and then gradually warmed to RT over a period of 1 hr. THF was evaporated under vacuum and the residue was triturated with EtOAc with minimum quantity of MeOH and collected by filtration. This yielded the title compound as a white solid (92%) after drying in vacuo. 1H NMR (300 MHz, DMSO-d6) δ: 1.38-1.41 (d, J=7.2 Hz, 3H), 2.32 (s, 3H), 3.64 (s, 3H), 4.47-4.51 (t, J=7.2 Hz, 1H), 7.12-7.17 (m, 2H), 7.25-7.32 (m, 1H), 7.61 (S, 1H), 7.67-7.70 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 8.05-8.08 (d, J=8.7 Hz, 1H), 8.34 (s, 1H), 8.67 (s, 1H), 9.35-9.37 (d, J=6.9 Hz, 1H); ms (ESI) m/z 459.1 [M+H]+.

Workup

  1. additionadded to the above mixture
  2. stirringThe mixture was stirred at −20° C. for 5 min
  3. temperaturegradually warmed to RT over a period of 1 hr
  4. customTHF was evaporated under vacuum
  5. customthe residue was triturated with EtOAc with minimum quantity of MeOH
  6. filtrationcollected by filtration

Sources & evidence

ORD record
ord-2ed298f440e2408eb782f81387428990
Source dataset
uspto-grants-2014_09
Patent number
US08835428B2

Reaction notes

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