Water → HCID 58096727, compound

HRID 1971031Notes

Reaction equation

HRID 1971031 reaction equation
[CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.[H-].[Na+].[I-].[Na+].[OH2:35].O1[CH2:41][CH2:40][O:39][CH2:38]C1>>[C:40]([O:39][CH2:38][N:26]1[C:24]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=4[Cl:8])[CH2:10][CH2:11]3)[CH:25]=2)[CH2:30][CH2:29][C:27]1=[O:28])(=[O:35])[CH2:41][CH2:22][CH2:21][CH2:20][CH2:25][CH2:24][CH2:23][CH2:30][CH3:29]

Participants

6

Reactant 5

HCID 962WaterHCID 5238Sodium IodideHCID 24758Sodium hydrideHCID 312751,4-DioxaneHCID 60795Aripiprazole2×

Product 1

HCID 58096727HCID 58096727, compoundYield 70%

Procedure

The chloromethyl ester above is dried over 4 Å molecular sieves. A solution of aripiprazole (45 grams, 0.1 mol) in 1,4-dioxane (800 mL) was sonicated to dissolve the aripiprazole completely, and then treated with NaH (38 g, 0.95 mol, 60% dispersion) in one portion. After stirring this reaction mixture for 15 minutes at room temperature, the reaction mixture was treated dropwise with chloromethyl ester (0.3 mol.) and a catalytic amount of sodium iodide (0.05 mol.). The resultant cloudy mixture was heated to 90° C. for 2 hours, cooled to ambient temperature and poured into water. The product was extracted with ethyl acetate, and the combined ethyl acetate layers washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography over silica gel provided the desired product (12.5 gram, 70% yield). 1H NMR (CDCl3, 300 MHz) δ 0.87 (t, 3H), 1.20 (m, 12H), 1.63 (m, 2H), 1.70 (m, 2H), 1.83 (m, 2H), 2.35 (t, 2H), 2.50 (t, 2H), 2.68 (m, 6H), 2.86 (t, 2H), 3.08 (m, 4H), 3.97 (t, 2H), 5.92 (s, 2H), 6.58 (dd, 1H), 6.61 (d, 1H), 6.94 (dd, 1H), 7.06 (d, 1H), 7.14-7.17 (m, 2H); m/z (M+H) 632.88.

Workup

  1. dry with materialThe chloromethyl ester above is dried over 4 Å molecular sieves
  2. temperatureThe resultant cloudy mixture was heated to 90° C. for 2 hours
  3. temperaturecooled to ambient temperature
  4. extractionThe product was extracted with ethyl acetate
  5. washthe combined ethyl acetate layers washed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-45d46ea38dc548839e33f3d726b85eef
Source dataset
uspto-grants-2013_04
Patent number
US08431576B2

Reaction notes

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