3-(4-Methoxy-phenyl)-N-propyl-propionamide → 4-(3-n-Propylamino)propylanisole

HRID 890599Notes

Reaction equation

HRID 890599 reaction equation
[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:10][C:11](=O)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:8][CH3:9]>O1CCCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][NH:10][CH2:7][CH2:8][CH3:9])=[CH:15][CH:16]=1

Participants

4

Reactant 2

HCID 51850723-(4-Methoxy-phenyl)-N-propyl-propionamideHCID 21226445Aluminium lithium hydride

Product 1

HCID 136504204-(3-n-Propylamino)propylanisole

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

To a stirred mixture of LiAlH4 (8.0 g, 200 mmol) in tetrahydrofuran (100 mL) was added dropwise a solution of 3-(4-methoxyphenyl)-propionic acid n-propyl amid (10.7 g, 49 mmol) (from a) above) in tetrahydrofuran (100 mL). After refluxing for 12 h the mixture was cooled to 50° C. and excess hydride was destroyed by careful addition of water (10 mL), 5% aqueous NaOH (40 mL) and water (20 mL) allowing reflux conditions. The hot slurry was filtered and the white precipitate was washed thoroughly with ethanol. Volatiles were evaporated and the resulting oil dissolved in ethyl acetate (50 mL) what was extracted with 0.5 N aqueous HCl (4×50 mL). The acidic phase was made alkaline (pH=9) by addition of 30% aqueous NaOH and extracted with ethyl acetate (4×50 mL). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to dryness to give an oil that partially crystallized in diethyl ether as the hydrochloride salt. Recrystallization from acetone/diethyl ether gave white flacky crystalline material. Total yield (as free base): 9.9 g, 48 mmol, 98%, mp 176–177° C. IR (neat) cm−1 2960, 2772, 1611, 1514; 1H-NMR (CDCl3) δ 9.46 (br s, 1H), 7.16 (d, 2H), 6.90 (d, 2H), 3.72 (s, 3H), 2.82 (br s, 4H), 2.59 (t, 2H), 2.15 (p, 2H), 1.83 (h, 2H), 0.89 (t, 3H) ppm; 13C-NMR (CDCl3) δ 156.6, 130.3, 127.7, 112.4, 53.7, 47.9, 45.66, 30.3, 25.9, 17.8, 9.7 ppm; MS (EI) m/z 207 (M+).

Workup

  1. temperatureAfter refluxing for 12 h the mixture
  2. customexcess hydride was destroyed by careful addition of water (10 mL), 5% aqueous NaOH (40 mL) and water (20 mL)
  3. temperatureallowing reflux conditions
  4. filtrationThe hot slurry was filtered
  5. washthe white precipitate was washed thoroughly with ethanol
  6. customVolatiles were evaporated
  7. dissolutionthe resulting oil dissolved in ethyl acetate (50 mL) what
  8. extractionwas extracted with 0.5 N aqueous HCl (4×50 mL)
  9. additionby addition of 30% aqueous NaOH
  10. extractionextracted with ethyl acetate (4×50 mL)
  11. washwashed with brine
  12. dry with materialdried (MgSO4)
  13. customevaporated to dryness
  14. customto give an oil that
  15. custompartially crystallized in diethyl ether as the hydrochloride salt
  16. customRecrystallization from acetone/diethyl ether
  17. customgave white flacky crystalline material
  18. customTotal yield (as free base)

Sources & evidence

ORD record
ord-2a265bc3df854d74b3b47edfbd714330
Source dataset
uspto-grants-2006_02
Patent number
US06998405B2

Reaction notes

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