proline dl-form → Ethyl 3-(4-chloro-2-methylphenyl)-3-{7-[(ethylsulfanyl)methyl]-1H-indol-3-yl}propanoate

HRID 561402Notes

Reaction equation

HRID 561402 reaction equation
[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C[C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16]C(=O)O1.N1CCCC1C(O)=O.[CH2:29]([S:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[CH:38]2)[CH3:30]>C(#N)C.[Cu].C(O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:38]2[C:37]3[C:41](=[C:33]([CH2:32][S:31][CH2:29][CH3:30])[CH:34]=[CH:35][CH:36]=3)[NH:40][CH:39]=2)[CH2:16][C:17]([O:19][CH2:12][CH3:20])=[O:18])=[C:4]([CH3:10])[CH:3]=1

Participants

9

Reactant 4

HCID 614proline dl-formHCID 162492,2-Dimethyl-1,3-dioxane-4,6-dioneHCID 27576584-Chloro-2-methylbenzaldehydeHCID 583922897-[(Ethylsulfanyl)methyl]-1H-indole

Product 1

HCID 58392526Ethyl 3-(4-chloro-2-methylphenyl)-3-{7-[(ethylsulfanyl)methyl]-1H-indol-3-yl}propanoateYield 28.5%

Reagents, catalysts & solvents 4

HCID 23978CopperCatalyst2×HCID 702EthanolSolvent2×HCID 1049PyridineSolvent2×HCID 6342AcetonitrileSolvent

Procedure

849 mg (5.49 mmol) of 4-chloro-2-methylbenzaldehyde, 791 mg (5.49 mmol) of Meldrum's acid and 30.1 mg (0.26 mmol) of D,L-proline were added to a solution of 1.00 g (5.23 mmol) of the compound from Example 10A in 44 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, the residue was taken up in diethyl ether, and a precipitate was separated off and discarded. Concentration resulted in 2.70 g of a crude product, of which 2.40 g were introduced into 9.5 ml of pyridine and 2.5 ml of ethanol, and 0.9 mg (14 μmol) of copper powder was added. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. 950 mg of a crude product were obtained and were introduced into 14.2 ml of pyridine and 3.7 ml of ethanol, and 1.3 mg (21 μmol) of copper powder were added. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 620 mg of the title compound.

Workup

  1. concentrationIt was concentrated
  2. customa precipitate was separated off
  3. concentrationConcentration
  4. customresulted in 2.70 g of a crude product, of which 2.40 g
  5. additionwas added
  6. temperatureThe reaction mixture was heated
  7. temperatureunder reflux for 1 h
  8. concentrationIt was concentrated
  9. washwashed with 1N hydrochloric acid
  10. dry with materialdried over magnesium sulfate
  11. filtrationfiltered through silica gel
  12. concentrationconcentrated
  13. custom950 mg of a crude product were obtained
  14. additionwere added
  15. temperatureThe reaction mixture was heated
  16. temperatureunder reflux for 1 h
  17. concentrationIt was concentrated
  18. washwashed with 1N hydrochloric acid
  19. dry with materialdried over magnesium sulfate
  20. filtrationfiltered through silica gel
  21. concentrationconcentrated
  22. customThe crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient)

Sources & evidence

ORD record
ord-051c2c569bfa4b20a18b3b1bcc1e3fa9
Source dataset
uspto-grants-2011_11
Patent number
US08063234B2

Reaction notes

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