N,N-Diethyl-3-formylbenzamide → HCID 10788230, compound

HRID 1795908Notes

Reaction equation

HRID 1795908 reaction equation
[NH:1]1[C:5]2C=CC=[CH:9][C:4]=2[N:3]=N1.[CH:10]([C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=O.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>[CH2:24]([N:3]1[C@H:4]([CH3:9])[CH2:5][N:1]([C@@H:10]([C:12]2[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=2)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:14]([CH3:15])[CH2:13]1)[CH:12]=[CH2:10]

Participants

7

Reactant 3

HCID 184481N,N-Diethyl-3-formylbenzamideHCID 178418255HCID 178418255, compoundHCID 178418385HCID 178418385, compound2×

Product 1

HCID 10788230HCID 10788230, compound

Reagents, catalysts & solvents 3

HCID 8471TriethylamineCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

2R,5S-1-allyl-2,5-dimethylpiperazine (6.99 g, 45.30 mmol, Chirotech Technology, Ltd., Cambridge, England), benzotriazole (5.45 g, 45.76 mmol, 1.01 eq.), and 3-formyl-N,N-diethylbenzamide (9.30 g, 45.30 mmol) were mixed in 300 mL of dry toluene with two drops of triethylamine. The mixture was placed in an oil bath maintained below 140° C. (bath temperature. The flask was attached to a Dean-Stark trap and reflux condenser to allow the azeotropic removal of water. The mixture was refluxed for 2–3 hours, under a nitrogen atmosphere, then the majority of the toluene was removed under reduced pressure. The crude adduct was used in the following procedure without isolation. The crude benzotriazole adduct was dissolved in 200 mL of tetrahydrofuran and phenylmagnesium bromide (1 M in THF, 1.75 equiv.) was added via a syringe. After stirring under nitrogen at room temperature for 2 hours, the reaction was quenched with 20 mL of saturated ammonium chloride solution. After stirring for 30 min, a generous amount of anhydrous magnesium sulfate was added. Filtering and concentrating the solution under reduced pressure gave the crude product contaminated with benzotriazole. This residue was dissolved in ethyl acetate and extracted with 10% aqueous NaOH solution three times to remove most of the benzotriazole. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate/magnesium sulfate, and the ethyl acetate was removed under reduced pressure. The crude material was chromatographed on silica gel (20–25 g of silica gel per gram of crude material) eluting first with methylene chloride, then with 20% ethyl acetate in methylene chloride to remove the less polar contaminant. Then, the column was eluted with a solution of ethyl acetate containing 2% ammonium hydroxide (solution A) in a gradient with methylene chloride (solution B), quickly increasing in polarity from 25% to 100% (solution A in B). The desired fractions were combined and the solvent was removed under reduced pressure to give 5.52 g of (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide was obtained as a golden oil. 1H NMR (300 MHz, CDCl3): δ 0.96–0.98 (d, J=6.1 Hz, 3H); 0.98–1.15(m, 6H); 1.17–1.19(d, J=6.1 Hz, 3H); 1.80–1.85(t, 1H); 2.01–2.18 (m, 2H); 2.40–2.62 (m, 3H); 2.76–2.81 (m, 2H); 3.11–3.60 (m, 4H); 5.05–5.11 (dd, J1=6.1 Hz, J2=16.6 Hz, 2H); 5.16 (s, 1H); 5.75–5.90 (m, 1H); 7.14–7.17 (d, J=7.3 Hz, 1H); 7.21–7.47 (m, 8H).

Workup

  1. customThe mixture was placed in an oil bath
  2. temperaturemaintained below 140° C. (bath temperature
  3. temperaturereflux condenser
  4. customthe azeotropic removal of water
  5. temperatureThe mixture was refluxed for 2–3 hours, under a nitrogen atmosphere
  6. customthe majority of the toluene was removed under reduced pressure
  7. dissolutionThe crude benzotriazole adduct was dissolved in 200 mL of tetrahydrofuran
  8. customthe reaction was quenched with 20 mL of saturated ammonium chloride solution
  9. stirringAfter stirring for 30 min
  10. additiona generous amount of anhydrous magnesium sulfate was added
  11. filtrationFiltering
  12. concentrationconcentrating the solution under reduced pressure
  13. customgave the crude product
  14. extractionextracted with 10% aqueous NaOH solution three times
  15. customto remove most of the benzotriazole
  16. washThe organic layer was washed with saturated sodium chloride solution
  17. dry with materialdried over sodium sulfate/magnesium sulfate
  18. customthe ethyl acetate was removed under reduced pressure
  19. customThe crude material was chromatographed on silica gel (20–25 g of silica gel per gram of crude material)
  20. washeluting first with methylene chloride
  21. customwith 20% ethyl acetate in methylene chloride to remove the less polar contaminant
  22. washThen, the column was eluted with a solution of ethyl acetate containing 2% ammonium hydroxide (solution A) in a gradient with methylene chloride (solution B)
  23. temperaturequickly increasing in polarity from 25% to 100% (solution A in B)
  24. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-edbba7f431604cbf8d6c71092a87c76d
Source dataset
uspto-grants-2006_04
Patent number
US07030124B2

Reaction notes

Loading…