4-Methylmorpholine → [(S)-1-(4-fluoro-2-phenylaminophenylcarbamoyl)-2-methoxyethyl]carbamic acid tert-butyl ester

HRID 242918

Reaction equation

HRID 242918 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][O:29][CH3:30])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:28][O:29][CH3:30])([CH3:19])([CH3:17])[CH3:18]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 7016354(2S)-2-(((tert-butoxy)carbonyl)amino)-3-methoxypropanoic acidHCID 214506204-Fluoro-2-phenylaminoaniline

Product 1

HCID 68157542[(S)-1-(4-fluoro-2-phenylaminophenylcarbamoyl)-2-methoxyethyl]carbamic acid tert-butyl esterYield 74%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (450 mg, 2.2 mmol), (S)-2-tertbutoxycarbonylamino-3-methoxypropionic acid (525 mg, 2.4 mmol), HOAt (330 mg, 2.4 mmol), 4-methylmorpholine (0.53 mL, 4.8 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (460 mg, 2.4 mmol) in DCM (10 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried (MgSO4) concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-1-(4-fluoro-2-phenylaminophenylcarbamoyl)-2-methoxyethyl]carbamic acid tert-butyl ester (0.655 g, 74%). A solution of the compound thus obtained (0.655 g) in AcOH (10 mL) was heated at 70° C. for 56 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford the title compound (227 mg, 28%). LCMS (Method J): RT 3.59 and 3.70 min [M+H]+ 386.2

Workup

  1. customThe reaction mixture was partitioned between DCM
  2. washThe organic phase was washed with brine
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. customthe resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane)

Sources & evidence

ORD record
ord-c126b6359c714b53b2d79d8abfd651ad
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Linked notes

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