Triethylamine → 3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester

HRID 1367069Notes

Reaction equation

HRID 1367069 reaction equation
[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([NH2:21])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:7]=1.C(N(CC)CC)C.C([O:32][C:33](=O)[C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:43]Br)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH:18]2[CH2:19][CH2:20]2)[CH:7]=1)[N:21]1[CH2:43][C:35]2[C:34](=[C:39]([N+:40]([O-:42])=[O:41])[CH:38]=[CH:37][CH:36]=2)[C:33]1=[O:32]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 13000593Ethyl 2-(bromomethyl)-6-nitrobenzoateHCID 588000783-Amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid methyl ester

Product 1

HCID 103902253-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl esterYield 77%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid methyl ester (490 mg, 1.5 mmol) and triethyl amine (0.43 ml, 3.1 mmol) in DMF (10 ml) was added 2-bromomethyl-6-nitro-benzoic acid ethyl ester (460 mg, 1.6 mmol). The mixture was heated at 90° C. under nitrogen atmosphere overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml). The organic layer was washed with water (30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester as a yellowish solid (550 mg, 75%). 1HNMR (CDCl3): δ0.31-0.37 (m, 2H), 0.59-0.67 (m, 2H), 1.22-1.28 (m, 1H), 3.09 (dd, J=7, 15 Hz, 1H), 3.28 (dd, J=9, 15 Hz, 1H), 3.65 (s, 3H), 3.79-3.91 (m, 2H), 4.18 (d, J=17 Hz, 1H), 4.46 (d, J=17 Hz, 1H), 5.83 (dd, J=7, 9 Hz, 1H), 6.61 (t, JH-F=75 Hz, 1H), 7.04-7.05 (m, 3H), 7.58-7.76 (m, 3H).

Workup

  1. customThe solvent was removed in vacuo
  2. extractionThe resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml)
  3. washThe organic layer was washed with water (30 ml), brine (30 ml)
  4. dry with materialdried over magnesium sulfate
  5. customThe solvent was removed in vacuo
  6. customthe resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1)

Sources & evidence

ORD record
ord-ed13dc4fe979497b808a67eb19bbdee2
Source dataset
uspto-grants-2011_02
Patent number
US07893102B2

Reaction notes

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