Water → ethyl (6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate

HRID 1792917Notes

Reaction equation

HRID 1792917 reaction equation
[H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:10]2O)([CH3:6])([CH3:5])[CH3:4].[C:22]([C:26]1[CH:34]=[C:33]2[C:29]([CH:30](O)[N:31]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:32]2=[O:35])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].O.C[O:43][CH2:44][CH2:45]OC>C(OCC)(=O)C>[C:3]([C:7]1[CH:8]=[C:9]2[C:13]([C:12](=[O:16])[N:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:10]2[CH2:45][C:44]([O:35][CH2:32][CH3:33])=[O:43])=[CH:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4].[C:22]([C:26]1[CH:34]=[C:33]2[C:29](=[CH:28][CH:27]=1)[CH:30]([CH2:45][C:44]([O:16][CH2:12][CH3:13])=[O:43])[N:31]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:32]2=[O:35])([CH3:25])([CH3:24])[CH3:23]

Participants

8

Reactant 5

HCID 962WaterHCID 80711,2-DimethoxyethaneHCID 24758Sodium hydrideHCID 220254325-Tert-butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-oneHCID 220254776-Tert-butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one

Product 2

HCID 69714217ethyl (6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetateHCID 86591362ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
20 °C

Procedure

Ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate and ethyl (6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are prepared as described in Example 2, starting with 2.9 g of 60% sodium hydride in 200 cm3 of 1,2-dimethoxyethane, 15.2 cm3 of triethyl phosphonoacetate and 9.6 g of a mixture of 5-tert-butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-tert-butyl-3-hydoxy-2-isobutyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 18 hours and then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 110 cm3 of water and then 100 cm3 of ethyl acetate. After separation of the phases by settling, the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 100 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is separated out by HPLC chromatography on a 10 μm WHELK-01SS chiral column, eluting successively with heptane/isopropanol mixtures (90/10 and then 50/50 by volume). The fractions comprising the first regioisomer are combined and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is dried under reduced pressure (3 kPa) at a temperature in the region of 40° C. 1.81 g of ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a viscous gray oil (Rf=0.43, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)). The fractions comprising the second regioisomer are combined and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is dried under reduced pressure (3 kPa) at a temperature in the region of 40° C. 3.53 g of ethyl (6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a viscous gray oil. (Rf=0.38, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).

Workup

  1. temperatureThe mixture is refluxed for 18 hours
  2. customAfter separation of the phases
  3. extractionthe aqueous phase is extracted twice with 100 cm3 of ethyl acetate
  4. washwashed with 100 cm3 of brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C
  8. customThe residue is separated out by HPLC chromatography on a 10 μm WHELK-01SS chiral column
  9. washeluting successively with heptane/isopropanol mixtures (90/10
  10. concentrationconcentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C
  11. customThe residue is dried under reduced pressure (3 kPa) at a temperature in the region of 40° C

Sources & evidence

ORD record
ord-892763597df54b7aa3735c07130c2bb0
Source dataset
uspto-grants-2006_07
Patent number
US07078428B2

Reaction notes

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