Diethyl Ether → (S)-[2-chloro-6-(2,6-diethyl-phenyl)-4-ethyl-pyridin-3-ylmethyl]-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine

HRID 251600Notes

Reaction equation

HRID 251600 reaction equation
[H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].CO[C:13](=O)[C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][C:17]([C:22]2[C:27]([CH2:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:30][CH3:31])=[N:16][C:15]=1[Cl:32].CCO[CH2:37][CH3:38]>>[Cl:32][C:15]1[C:14]([CH2:13][N:16]([CH3:17])[C@@H:15]2[C:37]3[C:38](=[CH:27][CH:22]=[CH:23][CH:24]=3)[CH2:18][CH2:19][CH2:14]2)=[C:19]([CH2:20][CH3:21])[CH:18]=[C:17]([C:22]2[C:27]([CH2:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:30][CH3:31])[N:16]=1

Participants

5

Reactant 4

HCID 3283Diethyl Ether2×HCID 6451240Aluminum(III) ChlorideHCID 21226445Aluminium lithium hydrideHCID 596782342-Chloro-6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester

Product 1

HCID 59678252(S)-[2-chloro-6-(2,6-diethyl-phenyl)-4-ethyl-pyridin-3-ylmethyl]-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine

Procedure

A stirred solution of LiAlH4 (1M in TI-RF, 3 mL) in ether (10 mL) is treated with AlCl3 (133 mg) under nitrogen. After 30 minutes, 2-chloro-6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester (250 mg) in 5 mL of ether is added. The resulting mixture is heated at reflux for 2 hours. On cooling, Na2SO4.10H2O (1.0 g) is added. The mixture is stirred at room temperature for one hour and filtered through Celite. The filtrate is concentrated in vacuo. CH2Cl2 (5 mL) and SOCl2 (0.5 mL) are added to the residue. The resulting mixture is stirred at room temperature for one hour. The volatile material is removed in vacuo. K2CO3 (500 mg) and (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (200 mg) in DMF (5 ml) are added to the residue and the reaction mixture is stirred at room temperature overnight. Hexane (20 mL) and water (5 mL) are added to the mixture. The organic layer is separated, washed once with brine, dried (Na2SO4) and concentrated. The crude product is purified by PTLC (4:1 hexane/EtOAc) to give (S)-[2-chloro-6-(2,6-diethyl-phenyl)-4-ethyl-pyridin-3-ylmethyl]-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine. 1H NMR (CDCl3) 7.62 (d, 1H), 7.11-7.30 (m, 7H), 4.02 (m, 3H), 3.01 (m, 2H), 2.80 (m, 2H), 2.39 (m, 4H), 2.15 (m, 5H), 1.85-2.00 (m, 2H), 1.33 (t, 3H), 1.09 (t, 6H).

Workup

  1. temperatureThe resulting mixture is heated
  2. temperatureat reflux for 2 hours
  3. temperatureOn cooling
  4. filtrationfiltered through Celite
  5. concentrationThe filtrate is concentrated in vacuo
  6. additionCH2Cl2 (5 mL) and SOCl2 (0.5 mL) are added to the residue
  7. stirringThe resulting mixture is stirred at room temperature for one hour
  8. customThe volatile material is removed in vacuo
  9. additionK2CO3 (500 mg) and (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (200 mg) in DMF (5 ml) are added to the residue
  10. stirringthe reaction mixture is stirred at room temperature overnight
  11. additionHexane (20 mL) and water (5 mL) are added to the mixture
  12. customThe organic layer is separated
  13. washwashed once with brine
  14. dry with materialdried (Na2SO4)
  15. concentrationconcentrated
  16. customThe crude product is purified by PTLC (4:1 hexane/EtOAc)

Sources & evidence

ORD record
ord-e1dbbd33bdca46429e212ea3e634187f
Source dataset
uspto-grants-2011_01
Patent number
US07863454B2

Reaction notes

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