Water → HCID 12017110, compound

HRID 2268088Notes

Reaction equation

HRID 2268088 reaction equation
[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:13][C:14]([NH:16][N:17]=[C:18]=[O:19])=O.P(Cl)(Cl)(Cl)=O.O>C(#N)C.CCOCC>[CH2:29]([O:28][C:22]1[CH:21]=[C:20]([CH:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH2:13][C:14]2[O:19][CH:18]=[N:17][N:16]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH3:30]

Participants

6

Reactant 3

HCID 962WaterHCID 24813Phosphorus oxychlorideHCID 87483168HCID 87483168, compound

Product 1

HCID 12017110HCID 12017110, compoundYield 43.5%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6342AcetonitrileSolvent

Procedure

A mixture of 3-(1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (3.0 g, 8.1 mmol) and carbonyidiimidazole (1.45 g, 8.94 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 hours. To the solution was added formic hydrazide (644 mg, 10.7 mmol). The mixture was stirred for 18 hours. The resulting suspension was filtered and washed with ether. The isolated solid was stirred in a mixture of ethyl acetate (40 mL) and water (10 mL) for 1 hour. The suspension was filtered and washed with water and ether to give crude 3-(1,3-dioxoisoindolin-2-yl)-N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)propanamide (1.3 g, 39% yield). A solution of 3-(1,3-dioxoisoindolin-2-yl)-N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)propanamide (600 mg, 1.46 mmol) and phosphorus oxychloride (POCl3, 0.54 mL, 5.8 mmol) in acetonitrile (20 mL) was heated to reflux for 2 hours. This solution was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography gave an oil. The oil was slurried in ether (10 mL). The resulting suspension was filtered to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]isoindoline-1,3-dione as a white solid (250 mg, 43% yield): mp, 132.0-134.0° C.; 1H NMR (CDCl3); δ 1.46 (t, J=6.9 Hz, 3H, CH3), 2.82 (dd, J=6.0, 15.6 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.11 (q, J=7.0 Hz, 2H, CH2), 4.37 (dd, J=10.3, 15.7 Hz, 1H, CHH), 5.81 (dd, J=6.0, 10.3 Hz, 1H, NCH), 6.62 (d, J=7.9 Hz, 1H, Ar), 7.13-7.17 (m, 2H, Ar), 7.67-7.72 (m, 2H, Ar), 7.75-7.62 (m, 2H, Ar), 8.29 (s, 1H, Ar); 13C NMR (CDCl3)δ 14.69, 27.70, 51.85, 55.90, 64.42, 111.32, 112.51, 120.32, 123.44, 130.14, 13163, 134.13, 148.39, 143.43, 153.03, 163.99, 167.93; Anal Calcd for C21H29N3O5: C, 64.12; H, 4.87; N, 10.68. Found: C, 63.84; H, 4.90; N, 10.48.

Workup

  1. temperatureto reflux for 2 hours
  2. extractionThe aqueous layer was extracted with ethyl acetate (2×50 mL)
  3. washThe combined organic layers were washed with sodium hydrogen carbonate (50 mL, sat), brine (50 mL)
  4. dry with materialdried over magnesium sulfate
  5. customRemoval of solvent and chromatography
  6. customgave an oil
  7. filtrationThe resulting suspension was filtered

Sources & evidence

ORD record
ord-83259eaef55b473c8cdf14d7451424db
Source dataset
uspto-grants-2001_12
Patent number
US06326388B1

Reaction notes

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