Ethyl Acetate → (4-Chloro-indan-1-yl)-acetic acid ethyl ester

HRID 2252941Notes

Reaction equation

HRID 2252941 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=O.[CH3:14][CH2:15][O:16][C:17]([CH3:19])=[O:18]>C1COCC1.[Rh]>[CH2:15]([O:16][C:17](=[O:18])[CH2:19][CH:8]1[C:9]2[C:5](=[C:4]([Cl:3])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[CH3:14]

Participants

6

Reactant 3

HCID 8857Ethyl AcetateHCID 24758Sodium hydrideHCID 113326814-chloro-2,3-dihydro-1H-inden-1-one

Product 1

HCID 23549532(4-Chloro-indan-1-yl)-acetic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 23948RhodiumCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

Use of 2-chlorocinnamic acid (Intermediate TWENTYTHREE-1) (commercially available from Aldrich) in the applicable process steps described in Method TWENTY produced 4-chloro-indan-1-one (Intermediate TWENTYFOUR-1). Triethylphosphonoacetate (3.5 mL, 17.2 mmol) was added to a mixture of NaH (0.69 g, 12.2 mmol) in THF (25 mL). After 30 m, a solution of 4-chloro-indan-1-one (Intermediate TWENTYFOUR-1) (1.46 g, 8.8 mmol) in THF (20 mL) was added to the mixture. The reaction mixture was allowed to stir for 16 h at rt. The solution was quenched with water and diluted with EtOAc. The layers were separated and the organic phase was dried over MgSO4, filtered and evaporated under reduced pressure. The residue was subjected to chromatography on silica gel with 3% EtOAc:hexane. The fractions that contained the unsaturated esters were collected and evaporated to give the product, 1.67 g. The mixture of esters (1.67 g, 7.06 mmol) in EtOAc was hydrogenated in the presence of 5% Rh on Alumina (0.14 g) at 40-50 psi H2 at rt for 2 d. The mixture was filtered through a plug of Celite® and concentrated in vacuo to produce (4-chloro-indan-1-yl)-acetic acid ethyl ester (Intermediate TWENTYFOUR-2). Use of (4-chloro-indan-1-yl)-acetic acid ethyl ester (Intermediate TWENTYFOUR-2) in the applicable process steps described in Method SEVENTEEN and Method A produced 4-(4-chloro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 166).

Workup

  1. customThe solution was quenched with water
  2. additiondiluted with EtOAc
  3. customThe layers were separated
  4. dry with materialthe organic phase was dried over MgSO4
  5. filtrationfiltered
  6. customevaporated under reduced pressure
  7. customwere collected
  8. customevaporated
  9. customto give the product, 1.67 g
  10. filtrationThe mixture was filtered through a plug of Celite®
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-a62a9b69fca24a85babe94418dc8a429
Source dataset
uspto-grants-2008_01
Patent number
US07323485B2

Reaction notes

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