Water → n-{2-[1-(4-Difluoromethoxy-3-ethoxy-phenyl)-3-morpholin-4-yl-3-oxo-propyl]-1,3-dioxo-2,3-dihydro-1h-isoindol-4-yl}-acetamide

HRID 1784997Notes

Reaction equation

HRID 1784997 reaction equation
[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([OH:19])=O)[C:9]2=[O:14])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.O>O1CCCC1>[F:28][CH:27]([F:29])[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]([N:8]2[C:7](=[O:33])[C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:1](=[O:3])[CH3:2])[C:9]2=[O:14])[CH2:16][C:17]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:19])=[CH:21][C:22]=1[O:30][CH2:31][CH3:32]

Participants

6

Reactant 4

HCID 962WaterHCID 8083MorpholineHCID 682631,1'-CarbonyldiimidazoleHCID 10411999HCID 10411999, compound

Product 1

HCID 10324743n-{2-[1-(4-Difluoromethoxy-3-ethoxy-phenyl)-3-morpholin-4-yl-3-oxo-propyl]-1,3-dioxo-2,3-dihydro-1h-isoindol-4-yl}-acetamideYield 44%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (400 mg, 0.86 μmmol) in tetrahydrofurane was added carbonyldiimidazole (160 mg, 1 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added morpholine (0.12 ml, 1.3 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-3-morpholin-4-yl-3-oxo-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (200 mg, 44%): mp, 109-111° C.; 1H NMR (CDCl3): 1.44 (t, J=7.5 Hz, 3H, OCH2CH3), 2.26 (s, 3H, CH3CO), 3.02 (dd, J=5, 17.5 Hz, 1H, CHHCO), 3.49-3.68 (m, 8H, morpholine ring), 3.9 (dd, J=7.5, 17.5 Hz, 1H, CHHCO), 4.09 (q, J=7.5 Hz, 2H, OCH2CH3), 5.84 (dd, J=5, 10 Hz, 1H, CHN), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 7.11-7.16 (m, 3H, Ar), 7.45 (d, J=7.5 Hz, 1H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.75 (d, J=7.5 Hz, 1H, Ar), 9.50 (s, 1H, NHCO). 13C NMR (CDCl3): 15.3, 25.6, 35.1, 42.7, 46.6, 51.9, 65.5, 67.2, 67.5, 112.6, 114.4, 115.9, 116.7, 118.6, 120.8, 120.9, 123.5, 125.5, 131.9, 136.6, 138.2, 138.5, 140.6, 151.3, 168.6, 168.7, 169.9, 170.6; Anal. Calcd. for C26H27F2N3O7: C, 58.75; H, 5.12; N, 7.91; Found: C, 58.48; H, 5.09; N, 7.79;

Workup

  1. stirringThe resulted mixture was stirred at room temperature for 2 hours
  2. customTHF was removed in vacuo
  3. washThe organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml)
  4. dry with materialwas dried over magnesium sulfate
  5. customThe solvent was removed in vacuo
  6. customThe resulted oil was purified by HPLC (acetonitrile:water=45:55)

Sources & evidence

ORD record
ord-3b3ba999033c4e63acf2ce7a8ef5dff3
Source dataset
uspto-grants-2009_03
Patent number
US07504427B2

Reaction notes

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