Hydroxylamine → HCID 10075088, compound

HRID 346918Notes

Reaction equation

HRID 346918 reaction equation
[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[CH2:27][C:26]3[C:21](=[C:22]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:34])[CH2:15][C:16]([OH:18])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:48][OH:49].O>O1CCCC1>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[C:20](=[O:34])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:27]2)[CH2:15][C:16](=[O:18])[NH:48][OH:49])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]

Participants

6

Reactant 4

HCID 787HydroxylamineHCID 962WaterHCID 682631,1'-CarbonyldiimidazoleHCID 10006005HCID 10006005, compound

Product 1

HCID 10075088HCID 10075088, compoundYield 55.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid (400 mg, 0.81 mmol) in tetrahydrofurane was added carbonyldiimidazole (200 mg, 1.21 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added hydroxylamine (120 mg, 1.6 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 dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give cyclopropanecarboxylic acid {2-[1-(3,4-bis-difluoromethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (230 mg, 46%): mp, 191–193° C.; 1HNMR (CDCl3): δ 0.88–0.93 (m, 2H, cyclopropyl ring CH2), 1.09–1.12 (m, 2H, cyclopropyl ring CH2), 1.64–1.67 (m, 1H, cyclopropyl ring CH), 2.84–2.92 (m, 1H, CHHCO), 3.38–3.48 (m, 1H, CHHCO), 4.18 (d, J=18 Hz, 1H, CHHN), 4.36 (d, J=18 Hz, 1H, CHHN), 5.47–5.49 (m, 1H, CHN), 6.52 (t, JH-F=75 Hz, 1H, OCF2H), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 6.99 (d, J=8 Hz, 1H, Ar), 7.25–7.31 (m, 3H, Ar), 7.45 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 9.20 (broad, 1H, NHOH), 10.35 (s, 1H, NHCO); 13C NMR (DMSO):30.82, 35.26, 38.47, 46.17, 47.50, 51.68, 112.50, 116.83, 117.01, 117.39, 117.66, 117.99, 120.56, 120.97, 121.73, 125.73, 133.41, 137.47, 138.38, 142.76, 146.83, 166.12, 168.68, 172.21, 179.98. Anal. Calcd. for C23H21F4N3O6: C, 54.02; H, 4.14; N, 8.22. Found: C, 53.89; H, 3.96; N, 8.22.

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 materialdried 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-b393e3d07d16412584ec853119a38040
Source dataset
uspto-grants-2007_02
Patent number
US07173058B2

Reaction notes

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