Venlafaxine

White Solid

P-Methoxybenzeneacetonitrile (100g, 0.66mol) was dissolved in 250ml of tetrahydrofuran. Under nitrogen protection and -700°C, a butyl lithium hexane solution (410ml, 0.66mol) was added. After the addition was complete, after stirring for 30 min, cyclohexanone (70 ml, 0.7 mol) was added. It was then stirred at -65°C for 2h. The reaction solution was poured into 200 ml of saturated aqueous ammonium chloride solution containing 300 g of ice, and then 500 ml of water was added. The deposited precipitate was collected by filtration, and washed with water and ether. The product of the second component can also be obtained from the filtrate: a total of 135 g of 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (I) is obtained, the yield is 82.9%, and the melting point is 123-126°C. Compound (I) (12g, 0.05mol) was dissolved in an ammonia-ethanol mixture (250ml, 2:8 volume ratio), and 5% rhodium-alumina (2.8g) was added for catalytic hydrogenation. When the reaction was completed, the catalyst was removed by filtration and washed with ethanol. The washing liquid and the filtrate are combined and concentrated to the remaining oil (12g), which is 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (Ⅱ), which can be directly Used for the next reaction. The purification of compound (II) can be carried out as follows: the above oil is dissolved in 100rnl toluene, acidified with a hydrogen chloride isopropanol solution to Ph value 2, and diluted with 400ml of ether to make the hydrochloride of compound (II) as crystalline The solid precipitated and collected 9g, yield 57%, melting point 168 ~ 172 ℃. Compound (II) (12 g), 33% aqueous formaldehyde solution (12.5 ml), 88% formic acid (16.5 ml) and water (115 ml) were stirred together overnight. The reaction solution was concentrated to 30 ml, then 200 ml of water was added, adjusted to Ph value 2 with concentrated hydrochloric acid, and extracted with ethyl acetate to remove pink impurities. The aqueous solution after extraction was basified with 50% sodium hydroxide solution, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dissolved in 700ml of ethyl acetate, and a solution of hydrogen chloride in isopropanol was added to collect 10.8g of venlafaxine hydrochloride, yield 80%, melting point 207～208℃, TLC Rf=0.83 (cyclohexane-ethyl acetate -Ethanol-concentrated ammonia water 1:1:0.5:0.05 volume ratio). Recrystallized from methanol-ethyl acetate to obtain a very pure sample, melting point 215 ~ 217 ℃. The overall yield is 24%. Separation of optical isomers. (+)- Configuration separation. Dissolve racemic venlafaxine (61.8g, 0.223mo1) in 450ml ethyl acetate, add di(p-tolyl)-L-tartaric acid monohydrate (43g, 0.11mo1) in 320ml ethyl acetate The solution was then left at room temperature overnight. The precipitated bis(p-tolyl)-L-tartrate salt was filtered, dried, and recrystallized 3 times with a mixture of ethyl acetate and methanol (6:5 volume ratio) to obtain 44.3g of white crystals, melting point 126-128°C , [Α]D23-56.1° (C=0.99, ethanol). The salt was added to 2mol/L sodium hydroxide solution, and the free base was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated until crystals precipitated to obtain 25.6 g (+)-venlafaxine, melting point 102-104°C. [α]D20+27.6° (C=1.07, 95% ethanol). 23.2g (+)-venlafaxine was dissolved in 500ml of ether, and 25ml of 4.5mol/L hydrogen chloride in isopropanol was added. The precipitate deposited by filtration was recrystallized with 100 ml of methanol and 500 ml of ether to obtain 23.7 g (+)-venlafaxine hydrochloride with a yield of 68%, a melting point of 240-240.5°C, and [α]D23-4.7. (C=0.945, ethanol). (-)-Configuration separation. The filtrate in the (+)-configuration separation, containing (-)-venlafaxine, was treated with 1 mol/L sodium hydroxide, washed with brine, dried over anhydrous magnesium sulfate, and concentrated to dryness (30.4 g, 0.11mo1). This solid was dissolved in 225 ml of ethyl acetate, bis(p-tolyl)-D-tartaric acid monohydrate (22.24 g, 55 mmol) was added, and it was left at room temperature for 3 h. The precipitated crystalline precipitate was collected by filtration and recrystallized twice with methanol-ethyl acetate to obtain 44.4g (-)-venlafaxine bis(p-tolyl)-D-tartrate salt, melting point 124-126°C, [α]D23+55.70° (C=0.97, ethanol). The salt was treated with 2mol/L sodium hydroxide to obtain (-)-venlafaxine, melting point 102～104℃, [α] D23-27.1°(C=1.04, 95% ethanol). (-)-Venlafaxine is dissolved in ether and treated with 4.5mol/L hydrogen chloride in isopropanol to obtain 19.4g(-)-venlafaxine hydrochloride, melting point 240-240.5℃, [α] D23+4.6 °(C=1.0, ethanol).

antidepressant;serotonin-norepinephrine reuptake inhibitor

Molecular Weight:277.4
XLogP3:2.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:277.204179104
Monoisotopic Mass:277.204179104
Topological Polar Surface Area:32.7
Heavy Atom Count:20
Complexity:279
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes