Water → (2S)-2-[4-(t-butoxycarbonylamino-methyl)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyric acid t-butyl ester

HRID 448505Notes

Reaction equation

HRID 448505 reaction equation
C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:27])[NH:14][CH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[C:18](=[O:26])O[C:20]2=[O:25])([CH3:11])([CH3:10])[CH3:9].Cl.[C:29]([O:33][C:34](=[O:42])[C@H:35]([CH2:37][CH2:38][C:39](=[O:41])[NH2:40])[NH2:36])([CH3:32])([CH3:31])[CH3:30].O>C1(C)C=CC=CC=1.C(Cl)Cl>[C:29]([O:33][C:34](=[O:42])[C@@H:35]([N:36]1[C:18](=[O:26])[C:17]2[C:21](=[CH:22][CH:23]=[CH:24][C:16]=2[CH2:15][NH:14][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:27])[C:20]1=[O:25])[CH2:37][CH2:38][C:39](=[O:41])[NH2:40])([CH3:32])([CH3:30])[CH3:31]

Participants

7

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 15602445H-Gln-OtBu hydrochlorideHCID 86611120(1,3-Dioxo-1,3-dihydro-isobenzofuran-4-ylmethyl)carbamic acid t-butyl ester

Product 1

HCID 67229532(2S)-2-[4-(t-butoxycarbonylamino-methyl)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyric acid t-butyl esterYield 30.2%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Procedure

Triethylamine (1.2 g, 11.8 mmol) was added to a stirred suspension of (1,3-dioxo-1,3-dihydro-isobenzofuran-4-ylmethyl)carbamic acid t-butyl ester (2.1 g, 7.9 mmol) and L-glutamine t-butyl ester hydrochloride (2.1 g, 8.6 mmol) in toluene (90 mL). The mixture was refluxed under Dean-Stark water separator overnight. The mixture was cooled to room temperature and diluted with CH2Cl2 (60 mL). The solution was washed with H2O (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (silica gel) to give (2S)-2-[4-(t-butoxycarbonylamino-methyl)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyric acid t-butylester (1.1 g, 29%): 1H NMR (CDCl3) δ 1.41 (s, 9H), 1.43 (s, 9H), 2.25-3.60 (m, 4H), 4.65 (d, J=6.5 Hz, 2H), 4.76-4.82 (dd, J=4.9 and 9.8 Hz, 1H), 5.47-5.61 (m, 3H), 7.67-7.79 (m, 3H); Chiral HPLC: Daicel ChiralPak AD, 46×250 mm, 20/80 IPA/hexane, 1 mL/min, 240 nm, 8.87 min (98% ee).

Workup

  1. washThe solution was washed with H2O (2×40 mL) and brine (40 mL)
  2. dry with materialdried (MgSO4)
  3. customSolvent was removed
  4. customthe residue was purified by chromatography (silica gel)

Sources & evidence

ORD record
ord-7524a7529ca047a0862d849ae7bb3be9
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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