Definitions

• the present invention relates to a process for preparing atomoxetine hydrochloride.
• Atomoxetine HCl is a selective norepinephrine reuptake inhibitor. It is marketed under the name STRATTERA® for the treatment of Attention- Deficit/Hyperactivity Disorder (ADHD) and is available in 10 mg, 18 mg, 25 mg, 40 mg, and 60 mg dosage forms.
• ADHD Attention- Deficit/Hyperactivity Disorder
• Atomoxetine chemically known as (R)-(-)-N-methyl-3-(2-methylphenoxy)-3- phenylpropylamine; has the following structure:
• Atomoxetine the (R)-(-) enantiomer of tomoxetine, is a aryloxyphenylpropylamine. It is about twice as effective as the racemic mixture and about nine times more effective than the (+)-enantiomer, as disclosed in U.S. Patent No. 4,018,895 (assigned to Eli Lilly and Co.), EP 0 052 492 (Eli Lilly and Co.), and EP 0 721 777 (Eli Lilly and Co.).
• Patent No. 6,541,668 and WO 00/58262 (assigned to Eli Lilly and Co.) and WO 94/00416 (by Richter Gedeon Vegyeszeti Gyar RT). These documents disclose an aromatic nucleophilic displacement of an aryl halide by 3- hydroxy-3-phenylpropylamines under strongly basic conditions.
• the nucleophilic aromatic displacement process disclosed in WO 00/58262 includes reacting N- methyl-3-hydroxy-3-phenylpropylamine with a protected 2-fluorobenzaldehyde to produce tomoxetine after several functional group interconversion steps.
• EP Patent No. 0 052 492 discloses a process for the preparation of atomoxetine HCl. hi this process, (R)-(— )-tomoxetine (S)-(+)-mandelate is first basified in water to eliminate the mandelate, then extracted in diethyl ether. HCl gas is bubbled into the solution to obtain (R)-(-)-tomoxetme (atomoxetime) hydrochloride. Yields are reported as approximately 77%-90%.
• U.S. Patent No. 6,541,668 assigned to Eli Lilly and Co., discloses a process for the preparation of atomoxetine HCl involving basifying the mandelate salt, followed by extracting with t-butyl methyl ether, removing water by azeotropic distillation, and adding hydrogen chloride. This process is inefficient due to long process time, low product yields, and the use of hazardous solvents that are incompatible with large-scale industrial synthesis.
• the present invention provides improved processes for the preparation of atomoxetine hydrochloride under reaction conditions that improve reaction yields and facilitate commercial synthesis.
• the invention is directed to the synthesis of atomoxetine HCl comprising: a) combining a mixture of (R)-(-)-tomoxetine (S)-(+)-mandelate with an organic solvent to obtain a reaction mixture; b) combining the reaction mixture with HCl to obtain atomoxetine HCl; and c) recovering atomoxetine HCl.
• the present invention provides a process for preparing atomoxetine HCl comprising: a) combining a mixture of (R)-(-)-tomoxetine (S)-(+)-mandelate and an organic solvent in the presence of water and a base to obtain a reaction mixture; b) combining the reaction mixture with HCl to obtain atomoxetine HCl; and c) recovering the atomoxetine HCl.
• the amount of water is about 3 to about 7 ml per 1 gram of the starting material. Most preferably, the amount of water is about 5 ml per 1 gram of the starting material.
• the present invention provides a process for preparing atomoxetine HCl comprising combining N-methyl-3-hydroxy-3-phenylpropylamine with 2-fluorotoluene in the presence of about 0.1 to about 20 moles DMSO and an alkali metal hydroxide to obtain a tomoxetine racemate, separating the desired (R)-(- )-tomoxetine from the (S)-(+)-tomoxetine in a (S)-(+)-mandelate form; and reacting the mandelate with HCl to obtain atomoxetine HCl.
• aromatic solvent refers to a C 6-1O aromatic hydrocarbon such as but not limited to benzene, xylene, or toluene.
• room temperature is meant to indicate a temperature of about 18-25°C, preferably about 20-22°C.
• the present invention provides improved processes for the preparation of atomoxetine under reaction conditions that improve reaction yields and facilitate the process.
• the present invention is directed to the synthesis of atomoxetine hydrochloride by combining a mixture of (R)-(-)-tomoxetine (S)-(+)-mandelate and an organic solvent with HCl.
• the processes of the present invention preferably avoid the use of solvents that may be harmful to the environment, such as ethers and dichloromethane, which are required in some prior art processes for the preparation of atomoxetine HCl, such as the processes disclosed in EP Patent No. 0 052 492.
• a process for the synthesis of atomoxetine HCl comprising combining (R)-(-)-tomoxetine (S)-(+)-mandelate and an organic solvent to obtain a reaction mixture, followed by combining the reaction mixture with HCl, either as a gas or an aqueous solution, to obtain a slurry.
• the temperature is maintained at about 15°C to about 2O 0 C when HCl is added.
• the slurry is maintained, preferably by stirring, for a sufficient time to obtain atomoxetine HCl, which is then recovered.
• Another embodiment of the present invention provides a process for preparing atomoxetine hydrochloride, comprising providing a mixture containing (R)-(-)- tomoxetine (S)-(+)-mandelate, an organic solvent and water, and combining the mixture with a base to obtain a biphasic system.
• the amount of water is about 3 to about 7 ml per 1 gram of the starting material. Most preferably, the amount of water is about 5 ml per 1 gram of the starting material.
• the base is selected from the group consisting of NaOH, KOH, Na 2 CO 3 and K 2 CO 3 . Most preferably, the base is NaOH.
• HCl is added, either as gas or as an aqueous solution.
• the water content of the organic phase is less than about 1%. It is also preferred that the temperature is maintained at about 15 0 C to about 20 0 C when HCl is added.
• the organic solvent used in the processes described above for preparing atomoxetine hydrochloride is selected from the group consisting of aliphatic or aromatic hydrocarbons such as C 5-8 alkanes, toluene and xylene, Ci -4 alkyl esters such as methyl acetate, ethyl acetate, n-butyl acetate and iso-butyl acetate, ketones such as acetone, methyl-ethyl ketone, linear or branched C 1-4 alcohols such as methanol, ethanol and isopropanol and mixtures thereof.
• the organic solvent is selected from the group consisting of ethyl acetate, n-butyl acetate, and iso- butyl acetate.
• the present invention includes a process for the preparation of atomoxetine hydrochloride comprising the following steps: a) combining N-methyl-3 -hydroxy-3 -phenylpropylamine with dimethylsulfoxide .
• the resultant mixture in step c) is heated to a temperature of about 80 0 C to about 145 0 C.
• the amount of the alkali metal hydroxide added in step a) is about 3 mole equivalents per mole equivalent of N-methyl-3 -hydroxy-3 -phenylpropylamine
• the resultant mixture is heated to a temperature from about 135 0 C to about 145 0 C.
• the amount of the alkali metal hydroxide added in step a) is about 5 mole equivalents per mole equivalent of N-methyl-3 -hydroxy-3 -phenylpropylamine
• the resultant mixture is heated to a temperature of about 8O 0 C to about 100 0 C.
• the amount of DMSO is about 0.1 to about 20 moles per moles of N-methyl-3 -hydroxy-3 -phenylpropylamine, and the preferred base is KOH.
• the mixture obtained in step (a) is maintained preferably by heating mixture to a temperature from about 80°C to about 150°C, to obtain racemic tomoxetine.
• step g) may be performed in the presence of an organic solvent only.
• the obtained (R)-(-)-tomoxetine (S)-(+)-mandelate may be recrystallized from a solution comprising an aromatic solvent and a C 1-4 alcohol.
• the reaction mixture obtained in step (f) may be a biphasic system, hi this case, the two phases may be separated, and the HCl in step h) may be added to the organic phase.
• Atomoxetine HCl maybe separated from the reaction mixture by techniques known in the art, such as filtration.
• the product may be washed with an organic solvent.
• the product may then be dried, preferably under reduced pressure.
• a preferred C 1-4 alcohol is methanol.
• the aromatic solvent is toluene.
• the (S)-(+)-tomoxetine in the solvent mixture (“mother liquor,” from which (R)-(-)-tomoxetine (S)-(+)-mandelate was obtained) may be racemized by combining an aprotic dipolar solvent and a base having a highly ionic counter ion. Preferably, the mixture is heated. Step (d) is repeated to further resolve the (R)-(-) -tomoxetine (S)-(+)-mandelate.
• the present invention provides a process for preparing a pharmaceutical composition comprising R(-)-tomoxetine (atomoxetine) or a pharmaceutically acceptable salt thereof, which comprises bringing R(-)-tomoxetine (atomoxetine) or a pharmaceutically acceptable salt thereof into contact with one or more pharmaceutically acceptable carriers or excipients.
• the mixture was allowed to cool to 80°C, then 400 g (3.63 mol) of 2-fluorotoluene were added.
• the mixture was heated to reflux (145°C-147°C) for one hour, and allowed to cool to about 9O 0 C. 1000 ml of water and 1000 ml of toluene were added.
• the mixture was stirred for some minutes, at which time the phases were separated.
• the aqueous phase was extracted with 2 x 200 ml of toluene.
• the organic phases were collected and washed with 3 x 200 ml of water. Final organic phase weight: 1700 g.
• HPLC assay prepared as described in Example 1 was concentration in vacuum to remove water. The residue was taken up with 2025 ml of toluene and 26 ml of methanol. To the obtained solution 94 g (0.618 mol) of (S)-(+)-mandelic acid were added at 25°C. All solids were solubilized by heating to 65°-70°C. The crude mandelate salt was crystallized on cooling. The solid was isolated by filtration at 5°- 10°C, washed with about 300 ml of toluene and dried in vacuo. Weight: 178 g. Tomoxetine content: 63.2% by weight (HPLC assay). Yield: 43.15%.Crude mandelate salt (R)-(-)-Tomoxetine enantiomeric ratio: R/S is about 95/5 (by chiral HPLC).

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• 2005
  • 2005-06-28 EP EP05763911A patent/EP1673335A2/de not_active Withdrawn

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