Venlafaxine N-Dimer synthesis

Yield:-

Reaction Conditions:

in methanol at 75; for 72 h;

Steps:

6

Example 6Preparation of ODV-N-DimerTo a 0.5 liter reactor equipped with mechanical stirrer, condenser and thermometer were added, at room temperature, TDMV (62.2 g, 0.264 mol.), formaldehyde 24% (100 g, 0.8 mol) and MeOH (100 ml). The reaction mixture was heated to 75° C. and kept at this temperature for 3 days, the suspension was then cooled to 25° C. pH was adjusted to 8.5 with 47% NaOH. The solid was filtered under reduced pressure and washed with H₂O (3×60 ml).The filtrate with 24.8% ODV-N-dimer was basified to pH 12 and extracted with EtOAc. After evaporation of the solvent, the reaction crude 13.6 g was purified by column chromatography (500 g silica gel, diameter 7 cm, eluent CH₂Cl₂/MeOH/H₂O 65/35/8). Elution of 1.5 L in erlemeyer and then the fractions were collected in tubes of 50 ml. In the fraction 10, after evaporation was collected 2 g of a mixture containing 27.3% ODV-N-dimer.This fraction was again purified by chromatography on a combiflash (120 g column CH₂Cl₂/MeOH 95/5) to get 0.26 g ODV N-dimer with a purity of 80% (HPLC area). A new column chromatography was performed (eluent CH₂Cl₂/MeOH/H₂O 65/35/8) in order to get 70 mg of ODV N-dimer having an HPLC purity of 94.3%. N-O-ODV Dimer (in CD₃OD) C H Chem. Shift, Chem. Shift, No ppm ppm Multiplicity J, Hz 1a 61.68 3.16 dd 13, 9 1b 2.5 dd 13, 6 2 53.58 2.79 dd 9, 6 3 132.21 - - - 4 131.48 6.59 dd 8.5, 2 5 116.12 6.58 d 8.5 6 157.17 - - - 7 123.6 - - - 8 131.48 6.85 d 2 9a 61.48 3.57 d 13 9b 3.64 d 13 10 45.75 2.25 s - 11 41.78 2.18 s - 12a 58.75 3.04 dd 12, 6 12b 2.98 dd 12, 9.5 13 54.02 2.85 dd 9.5, 6 14 132.25 - - - 15 161.48 7.02 16 115.9 6.72 17 157.17 - - - 1' 75.61 - - - 2' 37.81 0.9-1.7 m - 3' 22.6-22.79 4' 26.94 5' 33.2 6' 74.64 - - - 7' 34.39 0.9-1.7 m - 8' 26.99 9' 38.35

References:

US2009/234020,2009,A1 Location in patent:Page/Page column 7