Hydrochloric Acid → 3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid

HRID 346887Notes

Reaction equation

HRID 346887 reaction equation
[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(ON1[C:29](=[O:30])[CH:28]2[C:31](=C=O)[CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:37])C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C(#N)C>[CH:19]1([CH2:18][O:17][C:9]2[CH:8]=[C:7]([CH:2]([N:1]3[C:29](=[O:30])[C:28]4[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]3=[O:37])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=2[O:13][CH:14]([F:16])[F:15])[CH2:21][CH2:20]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 210823383-Amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acidHCID 86594617N-ethoxy-carbonyl-phthalimide

Product 1

HCID 103654413-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acidYield 91%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (0.78 g, 2.9 mmol) and N-ethoxy-carbonyl-phthalimide (0.64 g, 2.9 mmol) in 30 ml of water and acetonitrile (1:1) was added sodium carbonate (0.33 g, 31 mmol). The mixture was stirred at room temperature for 5 hours. 1N HCl was added dropwise until pH=2. The mixture was extracted with ether (2×25 ml). The organic layer was washed with water (2×20 ml), brine (20 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a colorless oil (1.1 g, 91%). 1HNMR (CDCl3): δ 0.32–0.38 (m, 2H), 0.60–0.67 (m, 2H), 1.17–1.28 (m, 1H), 3.33(dd,J=6, 17Hz, 1H), 3.79 (dd, J=10, 17 Hz, 1H), 3.86 (d, J=8 Hz, 2H), 4.92 (broad, 1H), 5.74 (dd, J=6, 10 Hz, 1H), 6.58 (t, JH-F=75 Hz, 1H), 7.10 (s, 2H), 7.16 (s, 1H), 7.69–7.74 (m, 2H), 7.78–7.83 (m, 2H).

Workup

  1. extractionThe mixture was extracted with ether (2×25 ml)
  2. washThe organic layer was washed with water (2×20 ml), brine (20 ml)
  3. dry with materialwas dried over magnesium sulfate
  4. customThe solvent was removed in vacuo

Sources & evidence

ORD record
ord-043e4b12042d4ad886d6c06b2290971b
Source dataset
uspto-grants-2007_02
Patent number
US07173058B2

Reaction notes

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