Sodium hydride → 4-[5-(3-Ethoxycarbonyl-2-oxo-propoxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-3-oxo-butyric acid ethyl ester

HRID 1248

Reaction equation

HRID 1248 reaction equation
[H-].[Na+].[CH3:3][C:4]1([CH3:13])[O:8][CH:7]([CH2:9][OH:10])[CH:6]([CH2:11][OH:12])[O:5]1.Cl[CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:16](=[O:23])[CH2:15][O:10][CH2:9][CH:7]1[CH:6]([CH2:11][O:12][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:5][C:4]([CH3:13])([CH3:3])[O:8]1)[CH3:22]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 69484Ethyl 4-chloroacetoacetateHCID 318275[5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol

Product 1

HCID 867521794-[5-(3-Ethoxycarbonyl-2-oxo-propoxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-3-oxo-butyric acid ethyl esterYield 43.7%

Reagents, catalysts & solvents 2

HCID 94433Tetrabutylammonium hydrogen sulfateCatalystHCID 8028TetrahydrofuranSolvent3×

Procedure

To a suspension of sodium hydride (4.0 g, 60% dispersion in oil) in tetrahydrofuran (150 mL) under a nitrogen atmosphere was added a solution of 2,2-dimethyl-[1,3]dioxolane-4,5-dimethanol (VII, 4.05 g) in tetrahydrofuran (25 mL) over 2 min at room temperature, followed by solid tetrabutylammonium hydrogen sulfate (0.4 g). The resulting mixture was cooled in an ice bath and a solution of ethyl 4-chloroacetoacetate (VIII, 8.1 g) in tetrahydrofuran (25 mL) was added dropwise over a period of 15 min. The reaction mixture was warmed to room temperature over 1 h then refluxed for 6 h. On cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid (20 mL) and volatile materials were removed under reduced pressure. The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic fractions was washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (grade 9385, Merck, 230-400 mesh, 60 Å) using a mixture of hexane and ethyl acetate (8:2, 7:3 and 6:4; 500 mL each) as eluent, thereby affording the title compound (IX 4.5 g) as an oil and the mono O-alkylated compound, 4-(2-chlorophenyl)-2-(5-hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy-methyl-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester (X, 1.95 g). Compound IX. IR (neat, cm-1): 1723, 1636; MS (CI): 436 (100%, [M+NH4 ]+). Compound X. IR (neat, cm-1): 3455, 1734;

Workup

  1. temperatureThe resulting mixture was cooled in an ice bath
  2. temperaturethen refluxed for 6 h
  3. temperatureOn cooling to room temperature
  4. customthe reaction mixture was quenched with 1N hydrochloric acid (20 mL) and volatile materials
  5. customwere removed under reduced pressure
  6. extractionThe aqueous phase was extracted with ethyl acetate (3×30 mL)
  7. washThe combined organic fractions was washed with brine
  8. dry with materialdried (sodium sulfate)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by flash chromatography on silica gel (grade 9385, Merck, 230-400 mesh, 60 Å)
  12. additiona mixture of hexane and ethyl acetate (8:2, 7:3 and 6:4; 500 mL each) as eluent

Sources & evidence

ORD record
ord-70ae7882edfe4b59882bded66d4f531c
Source dataset
uspto-grants-1998_03
Patent number
US05723618

Linked notes

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