Water → N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-3-morpholin-4-yl-3-oxo-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide

HRID 1367092Notes

Reaction equation

HRID 1367092 reaction equation
[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([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](O)=[O:18])[CH2:10]2)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.O>O1CCCC1>[F:29][CH:27]([F:28])[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]([N:11]2[C:12](=[O:14])[C:13]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=3[NH:4][C:1](=[O:3])[CH3:2])[CH2:10]2)[CH2:16][C:17]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:18])=[CH:21][C:22]=1[O:30][CH2:31][CH3:32]

Participants

6

Reactant 4

HCID 962WaterHCID 8083MorpholineHCID 682631,1'-CarbonyldiimidazoleHCID 104788263-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid

Product 1

HCID 10346488N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-3-morpholin-4-yl-3-oxo-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamideYield 72.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (300 mg, 0.67 mmol) in tetrahydrofurane was added carbonyldiimidazole (130 mg, 0.80 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added morpholine (0.1 ml, 1.0 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]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (250 mg, 72%): mp, 164-166° C.; 1HNMR (CDCl3): 1.43 (t, J=7.5 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 3.04 (dd, J=6, 10 Hz, 1H, CHHCO), 3.54-3.72 (m, 9H, morpholine ring+CHHCO), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.27 (d, J=17 Hz, 1H, CHHN), 4.44 (d, J=17 Hz, 1H, CHHN), 5.54-5.59 (m, 1H, CHN), 6.85 (t, JH-F=75 Hz, 1H, OCF2H), 6.94-7.16 (m, 3H, Ar), 7.14 (d, J=8 Hz, 1H, Ar), 7.46 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=7.5 Hz, 1H, Ar), 10.60 (s, 1H, NHCO). 13C NMR (CDCl3): 15.3, 25.6, 36.5, 42.8, 46.9, 49.8, 54.7, 65.5, 67.2, 67.4, 112.6, 114.1, 116.7, 117.6, 118.3, 118.4, 119.9, 120.8, 123.5, 133.9, 138.5, 140.5, 142.2, 151.5, 166.7, 169.7, 170.4; Anal. Calcd. for C26H29F2N3O6: C, 60.34; H, 5.65; N, 8.12. Found: C, 60.04; H, 5.71; N, 8.19.

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-2076b3a885be4a84a646b09751d143d4
Source dataset
uspto-grants-2011_02
Patent number
US07893102B2

Reaction notes

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