Acetonitrile--water (1/1) → HCID 67044596, compound

HRID 2367133Notes

Reaction equation

HRID 2367133 reaction equation
[Cl:1][C:2]1[C:3]([F:27])=[C:4]([N:8]2[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=3)([OH:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:26])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30](=[O:44])[C:31](/[N:33]=[C:34](/NC(=O)C(OC)=O)\SC)=[O:32].C(#N)C.O>C(O)CCC>[CH3:28][O:29][C:30](=[O:44])[C:31]([NH:33][C:34]1[NH:25][C:20]2[CH:19]=[C:18]([C:16]3([OH:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:26])[N:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:27])[CH:23]=[CH:22][C:21]=2[N:24]=1)=[O:32]

Participants

5

Reactant 3

HCID 18373917Acetonitrile--water (1/1)HCID 67045347HCID 67045347, compoundHCID 178501868HCID 178501868, compound

Product 1

HCID 67044596HCID 67044596, compoundYield 38%

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Procedure

A solution of 2-(3-chloro-2-fluorophenyl)-3-(3,4-diaminophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (0.10 g, 0.26 mmol) and methyl{[(1Z)-{[(methyloxy)(oxo)acetyl]amino}(methylthio)methylidene]amino}(oxo)acetate (67 mg, 0.26 mmol) in n-butanol (2.0 mL) was heated to 80° C. for 5 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The resulting crude product was purified by reverse phase preparative HPLC (CH3CN/25 mM aqueous ammonium acetate). The fractions were collected, and the solvent was concentrated. The aqueous residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an oily residue, which was lyophillized from a mixture of acetonitrile-water (5.0 mL) to give methyl({6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}amino)(oxo)acetate (48 mg, 38% yield. 1H NMR (400 MHz, DMSO-d6): 11.86 (d, 1H), 7.87 (d, 1H), 7.65 (m, 2H), 7.53 (t, 1H), 7.33 (t, 1H), 7.30 (d, 1H), 7.25 (s, 1H), 7.20 (t, 1H), 6.99 (d, 1H), 6.91 (d, 1H), 3.57 (s, 3H); 13C NMR (400 MHz, DMSO-d6): 67.0, 92.5, 110.0, 113.8, 114.1, 115.7, 120.8, 121.4, 123.9, 125.3, 125.6, 126.0, 126.2, 129.5, 129.8, 130.5, 130.7, 134.3, 134.8, 150.3, 155.7, 155.8, 163.5, 166.2; MS (EI) for C24H16ClFN4O4: 436 (M−CO2CH3).

Workup

  1. customthe solvent was evaporated
  2. customThe resulting crude product was purified by reverse phase preparative HPLC (CH3CN/25 mM aqueous ammonium acetate)
  3. customThe fractions were collected
  4. concentrationthe solvent was concentrated
  5. customThe aqueous residue was partitioned with ethyl acetate
  6. washThe organic layer was washed with saturated aqueous sodium bicarbonate, brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationFiltration and concentration
  9. customresulted in an oily residue, which

Sources & evidence

ORD record
ord-6456e72086694d49889b2c7f2b69a779
Source dataset
uspto-grants-2014_04
Patent number
US08697737B2

Reaction notes

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