4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: It is reported that venlafaxine of formula (II), 1-[2-dimethylamino-1-(4-methoxylphenyl)ethyl]cyclohexanol, is a reuptake inhibitor of 5-hydroxytryptamine (5-HT) and norepinephrine (NA), and is widely used for inhibiting reuptake of 5-hydroxytryptamine (5-HT) and norepinephrine (NA) and treating or adjuvantly treating central nervous system diseases such as depression. Venlafaxine is metabolized in liver to form a strongly active metabolite of formula (III), 1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]cyclohexanol, a weakly active metabolite of formula (IV), 1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol, and a metabolite of formula (V), 1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]cyclohexanol, in which the metabolite (III) and venlafaxine have the same therapeutic effects (see U.S. Pat. No. 4,535,186A, US20040176468A1, US20040147601A1, US20030191347A1). Moreover, the direct uptake of the metabolite (III) for treating central nervous system diseases, especially, depression, has the advantages of using a single active compound, facilitates the adjustment of dosage and therapeutic effects, alleviates side-effects, and reduces the risk of interaction with other drugs (see U.S. Pat. No. 6,673,838B2). However, because of the presence of more hydroxyl groups, the metabolite (III) has increased hydrophilicity, thus decreasing absorption rate via oral or transdermal routes of administration and possibly increasing pre-system side effects of unabsorbed drugs. In order to overcome the above defects of the metabolite (III), a series of derivatives represented by formula (VI) were synthesized. These compounds of formula (VI), which are prodrugs of the metabolite (III), were shown to have metabolized in vivo to produce the metabolite (III), thereby exhibiting therapeutic effects (see Chinese Patent No. CN1955159A, CN1706813A). Chinese Patent No. CN1955159A discloses a compound of formula (I), 4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenyl 4-methylbenzoate hydrochloride, and a method for preparing the same. The compound of formula (I), as described in CN1955159A, is a white crystalline solid with a melting point of 203.2° C.-206.5° C. treating adjuvantly treating central nervous system diseases such as depression

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1000 ml flask equipped with a mechanical stirrer and condenser, O-Desmethyl venlafaxine base (50 g), fumaric acid (24.24 g), and isopropyl alcohol (IPA) (1000 ml) were added at room temperature to form a mixture. The mixture was then heated to reflux. A clear solution was obtained after filtering the heated mixture through a 1-micron filter. The filtered solution was cooled to 50° C., and then gradually cooled to 5° C. over five hrs. The cooled solution was stirred at 5° C. overnight. The mixture was then heated back to 50° C., stirred at 50° C. for 2 hrs, and then cooled back to 5° C. and stirred at 5° C. for 3 hrs. A solid precipitate formed and was filtered under reduced pressure, washed with IPA, and dried in a vacuum oven, overnight, at 50° C. The obtained solid was kept in a closed container at 4° C. for five weeks, after which Form N was obtained. To a 1000 ml flask equipped with a mechanical stirrer and condenser to form a mixture The mixture was then heated to reflux A clear solution was obtained after filtering the heated mixture through a 1-micron filter gradually cooled to 5° C. over five hrs The mixture was then heated back to 50° C. stirred at 50° C. for 2 hrs cooled back to 5° C. stirred at 5° C. for 3 hrs A solid precipitate formed was filtered under reduced pressure washed with IPA dried in a vacuum oven, overnight, at 50° C The obtained solid was kept in a closed container at 4° C. for five weeks after which Form N was obtained

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mechanically stirred suspension of O-desmethylvenlafaxine (200.0 g, 0.759 mol in 2-propanol (1000 mL) at 70–75° C. under a nitrogen atmosphere was added dropwise a solution of 96% formic acid (40 ml, d=1.22, 46.85 g, 1.018 mol., 1.34 molar excess) over a period of 1 hour. The resulting, hazy solution was kept for a further 10 min. at 70–75° C. and then filtered through a pad of Celite filter aid (40 g, prewashed with hot 2-propanol). The filter pad was washed with hot (70–80° C.) 2-propanol (2×162 mL). The filtrate and washings (temperature 48–49° C.) were stirred slowly under a nitrogen atmosphere and allowed to cool to 45° C. The solution was seeded with crystals of O-desmethylvenlafaxine formate and allowed to cool at a rate of about 1° C. per 4 minutes. The solution became cloudy at 40.5° C. The stirred, cloudy solution was allowed to cool to 34–35° C., then maintained at that temperature for a period of 1.5 hours. Most of the product crystallized during this period. The stirred slurry of crystals was allowed to cool to 25° C. over a period of 1 hour and then cooled in an ice bath over a period of 1 hour to 5–10° C. The slurry was chilled to −10° C. in 40 min. and kept at that temperature for 30 min. The crystals were collected on a filter and washed with chilled (0 to −10° C.) acetone (3×400 mL). Drying in a vacuum oven at 47–48° C., for 36 hours at 80 mm Hg, under a nitrogen stream, (with intermediate crushing after 13 hours) furnished 203.1 g (86%) of the product, O-desmethylvenlafaxine formate. The product had a mp=145–147° C. and residue on ignition 0.1% (as sulfated ash). It was characterized by DSC (sharp endotherm at 151.8° C. filtered through a pad of Celite filter aid (40 g, prewashed with hot 2-propanol) The filter pad was washed with hot (70–80° C.) 2-propanol (2×162 mL) to cool at a rate of about 1° C. per 4 minutes at 40.5° C to cool to 34–35° C. maintained at that temperature for a period of 1.5 hours Most of the product crystallized during this period to cool to 25° C. over a period of 1 hour cooled in an ice bath over a period of 1 hour to 5–10° C The slurry was chilled to −10° C. in 40 min. kept at that temperature for 30 min The crystals were collected on a filter washed with chilled (0 to −10° C.) acetone (3×400 mL) Drying in a vacuum oven at 47–48° C., for 36 hours at 80 mm Hg, under a nitrogen stream, (with intermediate crushing after 13 hours)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mechanically stirred suspension of O-desmethylvenlafaxine (200.0 g, 0.759 mol in 2-propanol (1000 mL) at 70–75° C. under a nitrogen atmosphere was added dropwise a solution of 96% formic acid (40 ml, d=1.22, 46.85 g, 1.018 mol., 1.34 molar excess) over a period of 1 hour. The resulting, hazy solution was kept for a further 10 min. at 70–75° C. and then filtered through a pad of Celite filter aid (40 g, prewashed with hot 2-propanol). The filter pad was washed with hot (70–80° C.) 2-propanol (2×162 mL). The filtrate and washings (temperature 48–49° C.) were stirred slowly under a nitrogen atmosphere and allowed to cool to 45° C. The solution was seeded with crystals of O-desmethylvenlafaxine formate and allowed to cool at a rate of about 1° C. per 4 minutes. The solution became cloudy at 40.5° C. The stirred, cloudy solution was allowed to cool to 34–35° C., then maintained at that temperature for a period of 1.5 hours. Most of the product crystallized during this period. The stirred slurry of crystals was allowed to cool to 25° C. over a period of 1 hour and then cooled in an ice bath over a period of 1 hour to 5–10° C. The slurry was chilled to −10° C. in 40 min. and kept at that temperature for 30 min. The crystals were collected on a filter and washed with chilled (0 to −10° C.) acetone (3×400 mL). Drying in a vacuum oven at 47–48° C., for 36 hours at 80 mm Hg, under a nitrogen stream, (with intermediate crushing after 13 hours) furnished 203.1 g (86%) of the product, O-desmethylvenlafaxine formate. The product had a mp=145–147° C. and residue on ignition 0.1% (as sulfated ash). It was characterized by DSC (sharp endotherm at 151.8° C. filtered through a pad of Celite filter aid (40 g, prewashed with hot 2-propanol) The filter pad was washed with hot (70–80° C.) 2-propanol (2×162 mL) to cool at a rate of about 1° C. per 4 minutes at 40.5° C to cool to 34–35° C. maintained at that temperature for a period of 1.5 hours Most of the product crystallized during this period to cool to 25° C. over a period of 1 hour cooled in an ice bath over a period of 1 hour to 5–10° C The slurry was chilled to −10° C. in 40 min. kept at that temperature for 30 min The crystals were collected on a filter washed with chilled (0 to −10° C.) acetone (3×400 mL) Drying in a vacuum oven at 47–48° C., for 36 hours at 80 mm Hg, under a nitrogen stream, (with intermediate crushing after 13 hours)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mechanically stirred suspension of O-desmethylvenlafaxine (100.0 g, 0.380 mol) in 2-propanol (500 mL) at 70–75° C. under a nitrogen atmosphere was added dropwise a solution of 96% formic acid (20 ml, d=1.22, 23.42 g, 0.509 mol., 1.34 molar excess) over a period of 45 min. The resulting, hazy solution was kept for a further 10 min. at 70–75° C. and then filtered through a pad of Celite filter aid (20 g, prewashed with hot 2-propanol). The filter pad was washed with hot (70–75° C.) 2-propanol (2×81 mL). The filtrate and washings (temperature 44–45° C.) were warmed to 50° C., under a nitrogen atmosphere, using slow mechanical stirring. The solution was seeded with crystals of O-desmethylvenlafaxine formate and allowed to cool. After further seeding at 45° C. the solution was allowed to cool to 40–41° C. whereupon the solution became cloudy. The stirred, cloudy solution was maintained at 40–42° C. for 25 min. and then cooled quickly (using cold water) to 35° C. It was then maintained at 34–35° C. for 1.5 h. Copious crystallization occurred during this latter period. The stirred thick slurry of crystals was allowed to cool to 25° C. over a period of 50 min. and then cooled to 7° C. (using ice) over a period of 1 h. and 40 min. The slurry was chilled to −10° C. in 10 min. and kept at that temperature for 30 min. The crystals were collected on a filter and washed with chilled (−5 to −10° C.) acetone (3×200 mL). After drying in a vacuum oven at 46–47° C., for 47 h. at 80 mm Hg, under a nitrogen stream, the product, O-desmethylvenlafaxine formate, weighed 101.59 g (86% yield) and it had mp=146.5–148° C. It was characterized by DSC (sharp endotherm at 152.4° C.). filtered through a pad of Celite filter aid (20 g, prewashed with hot 2-propanol) The filter pad was washed with hot (70–75° C.) 2-propanol (2×81 mL) to cool After further seeding at 45° C. to cool to 40–41° C. whereupon the solution The stirred, cloudy solution was maintained at 40–42° C. for 25 min. cooled quickly (using cold water) to 35° C It was then maintained at 34–35° C. for 1.5 h Copious crystallization occurred during this latter period to cool to 25° C. over a period of 50 min. cooled to 7° C. (using ice) over a period of 1 h. 40 min The slurry was chilled to −10° C. in 10 min. kept at that temperature for 30 min The crystals were collected on a filter washed with chilled (−5 to −10° C.) acetone (3×200 mL) After drying in a vacuum oven at 46–47° C., for 47 h. at 80 mm Hg, under a nitrogen stream was characterized by DSC (sharp endotherm at 152.4° C.)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of O-desmethylvenlafaxine (39.51 g, 0.150 mol) in acetone (1500 mL) at 55–60° C., under a nitrogen atmosphere, was added a solution of 96% formic acid (13.5 mL, d=1.22, 2.29 molar excess) in acetone (150 mL) over a period of 10 min. The stirred mixture was kept at 55–60° C. for a further 5 min. to complete the dissolution. The warm solution was filtered through a pad of Celite filter aid (prewashed with warm acetone) and the filter pad was washed with warm acetone (150 mL). The filtrate and washings (temperature ˜35° C.) were warmed to 45° C. under a nitrogen atmosphere and seeded with crystals of O-desmethyl-venlafaxine formate. The stirred solution was allowed to cool. Crystallization ensued and was copious after 1 hour (when the temperature had fallen to 30° C.). The slurry of crystals at 27° C. was chilled to −10° C. over a period of half an hour and maintained at −5–−10° C. for 15 min. The crystals were then collected on a filter and washed with chilled (−5 to −10° C.) acetone (2×100 mL). After drying in a vacuum oven at room temperature under oil pump vacuum for 24 hours, the product, O-desmethyl-venlafaxine formate, weighed 38.5 g, (83% yield) and it had mp=148° C.–149.5° C. It was characterized by DSC (sharp endotherm at 152.4° C.). the dissolution The warm solution was filtered through a pad of Celite filter aid (prewashed with warm acetone) the filter pad was washed with warm acetone (150 mL) to cool Crystallization was copious after 1 hour had fallen to 30° C. The slurry of crystals at 27° C. was chilled to −10° C. over a period of half an hour maintained at −5–−10° C. for 15 min The crystals were then collected on a filter washed with chilled (−5 to −10° C.) acetone (2×100 mL) After drying in a vacuum oven at room temperature under oil pump vacuum for 24 hours was characterized by DSC (sharp endotherm at 152.4° C.)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of O-desmethylvenlafaxine (13.17 g, 0.050 mol.) in tetrahydrofuran (300 mL) at 62–65° C., under a nitrogen atmosphere, was added 96 wt % formic acid (2.20 mL, d=1.22, 0.056 mol., 1.2 molar excess) in tetrahydrofuran (30 mL) dropwise over a period of 2 minutes, while maintaining the temperature in the range 62° C.–64° C. The solution was filtered through a pad of Celite filter aid (prewashed with tetrahydrofuran) and the filter pad was washed with hot (60–65° C.) tetrahydrofuran (2×20 mL). The filtrate and washings (temperature ˜35° C.) were warmed to 50° C. under a nitrogen atmosphere and allowed to cool. At 48° C. the stirred solution was seeded with crystals of O-desmethylvenlafaxine formate. Crystallization ensued immediately. When the slurry of crystals had cooled to 22° C. it was chilled to −5° C. to −10° C. The crystals were collected on a filter and washed with chilled (−5 to −10° C.) tetrahydrofuran (2×30 mL). After drying in a vacuum oven at room temperature under oil pump vacuum for 23 hours the product, O-desmethylvenlafaxine formate, weighed 13.79 g, (89% yield) and it had mp=149–150° C. It was characterized by DSC (sharp endotherm at 151.5° C.). while maintaining the temperature in the range 62° C.–64° C The solution was filtered through a pad of Celite filter aid (prewashed with tetrahydrofuran) the filter pad was washed with hot (60–65° C.) tetrahydrofuran (2×20 mL) to cool At 48° C. Crystallization When the slurry of crystals had cooled to 22° C. it was chilled to −5° C. to −10° C The crystals were collected on a filter washed with chilled (−5 to −10° C.) tetrahydrofuran (2×30 mL) After drying in a vacuum oven at room temperature under oil pump vacuum for 23 hours the product, O-desmethylvenlafaxine formate was characterized by DSC (sharp endotherm at 151.5° C.)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of O-desmethylvenlafaxine (13.17 g, 0.050 mol.) in tetrahydrofuran (300 mL) at 62–65° C., under a nitrogen atmosphere, was added 96 wt % formic acid (2.20 mL, d=1.22, 0.056 mol., 1.2 molar excess) in tetrahydrofuran (30 mL) dropwise over a period of 2 minutes, while maintaining the temperature in the range 62° C.–64° C. The solution was filtered through a pad of Celite filter aid (prewashed with tetrahydrofuran) and the filter pad was washed with hot (60–65° C.) tetrahydrofuran (2×20 mL). The filtrate and washings (temperature ˜35° C.) were warmed to 50° C. under a nitrogen atmosphere and allowed to cool. At 48° C. the stirred solution was seeded with crystals of O-desmethylvenlafaxine formate. Crystallization ensued immediately. When the slurry of crystals had cooled to 22° C. it was chilled to −5° C. to −10° C. The crystals were collected on a filter and washed with chilled (−5 to −10° C.) tetrahydrofuran (2×30 mL). After drying in a vacuum oven at room temperature under oil pump vacuum for 23 hours the product, O-desmethylvenlafaxine formate, weighed 13.79 g, (89% yield) and it had mp=149–150° C. It was characterized by DSC (sharp endotherm at 151.5° C.). while maintaining the temperature in the range 62° C.–64° C The solution was filtered through a pad of Celite filter aid (prewashed with tetrahydrofuran) the filter pad was washed with hot (60–65° C.) tetrahydrofuran (2×20 mL) to cool At 48° C. Crystallization When the slurry of crystals had cooled to 22° C. it was chilled to −5° C. to −10° C The crystals were collected on a filter washed with chilled (−5 to −10° C.) tetrahydrofuran (2×30 mL) After drying in a vacuum oven at room temperature under oil pump vacuum for 23 hours the product, O-desmethylvenlafaxine formate was characterized by DSC (sharp endotherm at 151.5° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of O-desmethylvenlafaxine (23.9 g), 96 wt % formic acid (4.79 g) and 2B ethanol (100 mL) was evaporated to give a syrupy residue. This material was redissolved in 2 B ethanol (100 mL) and evaporated to give a solid, which upon trituration in ether (200 mL) followed by filtration and vacuum drying (18 h; 50° C.; 50 mmHg) gave 27 g of product. This material was recrystallized from a hot solution of methanol (30 mL) and acetone (400 mL), which upon cooling to room temperature followed by filtering and vacuum drying (18 h; 50° C.; 50 mmHg) gave 20 g (71.2% yield) of product. m.p. 151° C. was evaporated to give a syrupy residue evaporated to give a solid, which upon trituration in ether (200 mL) followed by filtration and vacuum drying (18 h; 50° C.; 50 mmHg)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dodecanethiol (69 g), venlafaxine (55 g), and an ethanolic solution of sodium ethanolate (21%, 82 g) are charged to a pressure vessel. The temperature is raised to 150° C. and the reaction mixture is stirred for 2 days. Then the temperature is lowered and the solution is filtered. The pH of the filtrate is adjusted to 9.5 with aqueous hydrogen chloride. The crystals are collected by suction filtration. The cake is washed with ethanol and dried in vacuo. the solution is filtered The crystals are collected by suction filtration The cake is washed with ethanol dried in vacuo

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dodecanethiol (69 g), venlafaxine (55 g), and an ethanolic solution of sodium ethanolate (21%, 82 g) are charged to a pressure vessel. The temperature is raised to 150° C. and the reaction mixture is stirred for 2 days. Then the temperature is lowered and the solution is filtered. The pH of the filtrate is adjusted to 9.5 with aqueous hydrogen chloride. The crystals are collected by suction filtration. The cake is washed with ethanol and dried in vacuo. the solution is filtered The crystals are collected by suction filtration The cake is washed with ethanol dried in vacuo

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Venlafaxine (5.6 g) and benzenethiol sodium salt (6.9 g) are charged to PEG 400 (25 g). The reaction mixture is heated to 160° C. for 5 hours. Then the temperature is lowered and water is added (60 g). The pH is adjusted to 3.5 with H3PO4. The organic by-products are removed by extraction with heptanes (25 g). The pH of the aqueous layer is then adjusted to 9.5 with aqueous ammonia. The precipitate is collected by suction filtration, re-slurried in water (100 g), isolated by suction filtration and dried in vacuo. The organic by-products are removed by extraction with heptanes (25 g) The precipitate is collected by suction filtration, re-slurried in water (100 g) isolated by suction filtration dried in vacuo