EPIMERIZATION REACTION FOR THE PRODUCTION OF R-FLUOXETINE (R)-Fluoxetine, (R)-N-methyl-3- (4- trifluoromethylphenoxy)-3-phenylpropylamine, is useful for the treatment of depression and other indications. For example see US Patent Nos. 5,708,035 and 5,356,934. The (R)-isomer can be obtained by a number of methods, one of which is resolution of fluoxetine, racemic N-methyl-3- (4- trifluoromethylphenoxy)-3-phenylpropylamine. This method for obtaining (R)-fluoxetine produces significant quantities of material enriched in the (S)-isomer, which would have to be discarded without an efficient and inexpensive method of converting it to the racemate starting material. The present invention provides an efficient and inexpensive process for epimerizing the isomers of fluoxetine.

The present invention relates to a process for preparing racemic fluoxetine, comprising: reacting an mixture enriched in either fluoxetine isomer with a base having highly ionic counter-ion in an aprotic highly dipolar solvent. More particularly, the present invention relates to a process for preparing racemic fluoxetine, comprising: reacting a mixture enriched in (S)-fluoxetine with a base having highly ionic counter-ion in an aprotic highly dipolar solvent.

The term"fluoxetine"refers to racemic N-methyl-3- (4- trifluoromethylphenoxy)-3-phenylpropylamine, the compound of the formula

Herein, the Cahn-Prelog-Ingold designations of (R)-and (S)-are used to refer to specific isomers where designated.

It is understood that the present process is useful to change the isomeric ratio of mixtures enriched in fluoxetine isomers. The term"isomer enriched mixture"refers to a mixture of fluoxetine stereoisomers in which one isomer is present in an amount greater that the other isomer. Such mixtures can have amounts greater that range from slightly more of the enriched isomer to material that is substantally one isomer.

The usefulness of the present process is not significantly decreased when the mixture of isomers produced, while not racemic in the sense that the mixture of isomers is 1: 1, is made closer to racemic. Thus, as used herein the term"racemic"or"racemate"refers to mixtures of isomers that are 1: 1, to mixtures of isomers that are closer to 1: 1 than in the starting mixture of isomers.

We have discovered that the isomers of fluoxetine can be epimerized with a base having a highly ionic counter-ion in an aprotic highly dipolar solvent. The reaction can be carried out using a catalytic amount of base or may be carried out using a large molar excess. Typically from one to three molar equivalents of base are used. When the starting material is a salt an additional molar equivalent of base is used. Highly ionic counter-ions include potassium. Suitable bases are those that are able to provide equilibrium quantities of the intermediates shown in Reaction Scheme A, below. Examples of suitable bases include potassium hydroxide, potassium t-butoxide, potassium amide, and the like. Aprotic highly dipolar solvents are

well known in the art. See Solvents and Solvent Effects in Organic Chemistry (2nd Ed. 1990). Suitable solvents may also be highly polarizable. Examples of suitable aprotic highly dipolar solvents include dimethyl sulfoxide, dimethylformamide, dimethylacetamide, benzonitrile, nitrobenzene, pyridine, and N-methylpyrrolidinone, sulfolane, hexamethylphosphoramide, and the like. The aprotic highly dipolar solvent selected may be mixed, to a limited degree, with other aprotic solvents without detrimental effect. For example, the present process tolerates at least 20% toluene in admixture with the aprotic highly dipolar solvent. The reaction proceeds well at temperatures greater than about 25°C up to temperature in which starting materials or products are adversely affected.

Temperatures of from about 50°C to about 120°C are preferred, with temperatures of about 60°C to about 90°C being more preferred. Typically, the reaction requires from 3 hours to 3 days.

We theorize that the present process may proceed by the mechanism described in Reaction Scheme A. It is intended that the present invention not be limited by the depiction of the theoretical mechanism set forth in Reaction Scheme A.

Reaction Scheme A F3C FC OH O H step a (1) stepb FC F, C ° HN « OH---N stepc v \ \ cJ \ I/ (2) I/ (1) stepd r H _ C\ ^// Step e H ll I H step e ll | Hal" (3) fluoxetine

Reaction Scheme A depicts the theoretical mechanism for the present epimerization process for (S)-fluoxetine. It is understood that the mechanism is believed to be the same for each isomer. It is also understood that the steps depicted are believed to be in equilibrium with the steps before and/or after.

In Reaction Scheme A, step a, a base having a highly ionic counter-ion in an aprotic highly dipolar solvent abstracts the-NH-proton of (S)-fluoxetine to give compound (1). Any base capable of producing even a small amount of intermediate (1) is suitable for this reaction. It is understood that nature of the solvent affects the strength

of a given base. The importance of the ionic nature of the counter-ion and the polarizability of the solvent can be seen in step b.

In Reaction Scheme A, step b, compound (1) achieves a conformation allowing a five-membered transition state for abstraction of the benzylic proton. Because the benzylic proton is probably less labile than the-NH-hydrogen, the efficiency of this step is enhanced by highly ionic counter- ions and by the use of aprotic highly dipolar solvents which enhance the base strength of compound (1) and the dissociation of compound (1) and the counter-ion.

In Reaction Scheme A, step c, the benzylic proton is abstracted to give carbanion (2), which equilibrates in Reaction Scheme A, step d, to give the equilibrated carbanion (3). In Reaction Scheme A, step e, the equilibrated carbanion (3) is protonated to give fluoxetine.

The desired epimerized product is readily isolated by routine procedures that are well known and appreciated in the art, such as extraction, evaporation, filtration, trituration, and chromatography.

The present invention is further illustrated by the following examples and preparations. These examples and preparations are illustrative only and are not intended to limit the invention in any way.

The terms used in the examples and preparations have their normal meanings unless otherwise designated. For example"°C"refers to degrees Celsius;"N"refers to normal or normality;"M"refers to molar or molarity;"mol"refers to mole or moles;"mmol"refers to millimole or millimoles; "kg"refers to kilogram or kilograms;"g"refers to gram or grams;"mg"refers to milligram or milligrams;"mL"refers milliliter or milliliters;"L"refers to liter or liters; "brine"refers to a saturated aqueous sodium chloride solution;"h"refers to hour or hours;"min"refers to minute or minutes;"MTBE"refers to methyl t-butyl ether (also known as t-butyl methyl ether);"ee"refers to

enantiomeric excess;"HPLC"refers to high performance liquid chromatography, etc.

In the examples and preparations suitable HPLC conditions are as follows: Chiral AGPs (Crom Tech, 10 cm x 4 mm, 5 micron particle size), eluted with 20 mM potassium phosphate: methanol (pH adjusted to 4.8 with phosphoric acid and aqueous 2 N potassium hydroxide solution) (9: 1), at 1.0 mL/min, detection at 225 nM, in which (S)-fluoxetine and (R)-fluoxetine have retention times of 5.5 minutes and 7.5 minutes; respectively.

Example 1 (R)-N-Methyl-3- (4-trifluoromethylphenoxy)-3- phenylpropylamine hydrochloride ( (R)-fluoxetine hydrochloride, 1.0 g, 2.9 mmol, 100% R-isomer), dimethylsulfoxide (DMSO, 20 mL) and potassium t-butoxide (0.973 g, 8.7 mmol) were combined and heated at 90°C for 3 h. After cooling to room temperature, the reaction mixture was diluted with aqueous sodium hydroxide (2N, 40 mL) and extracted with ethyl ether (2X50 mL). The combined organic extracts were extracted with brine (50 mL), dried over magnesium sulfate, and concentrated to provide fluoxetine free base (0.802 g, 89%). Chiral HPLC analysis of the product indicated 22% ee (39: 61, S: R).

Example 2 (R)-N-Methyl-3- (4-trifluoromethylphenoxy)-3- phenylpropylamine hydrochloride ( (R)-fluoxetine hydrochloride, 1.0 g, 2.9 mmol, 100% R-isomer), dimethylsulfoxide (DMSO, 15 mL) and potassium hydroxide (powdered, 0.488 g, 8.7 mmol) were combined and heated at 90°C for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl ether (2X50 mL). The combined organic extracts were extracted with brine (50 mL), dried over magnesium sulfate, and concentrated to provide fluoxetine

free base (0.816 g, 91%). Chiral HPLC analysis of the product indicated 2.3% ee (47.7: 52.3, S: R).

Example 3 Enantiomerically enriched N-Methyl-3- (4- trifluoromethylphenoxy)-3-phenylpropylamine (enriched in (S)-fluoxetine, 1.0 g, 3.23 mmol, 79.5: 20.5, S: R-isomer), dimethylsulfoxide (DMSO, 15 mL), and potassium hydroxide (powdered, 0.544 g, 9.69 mmol) were combined and heated to 1109C for 1 h. The reaction mixture was diluted with water (40 mL) and extracted with ethyl ether (2X50 mL). The combined organic extracts were extracted with brine (50 mL), dried over magnesium sulfate, and concentrated to provide fluoxetine free base (0.962 g, 96.2%). Chiral HPLC analysis of the product indicated 2.2% ee (48.9: 51.10, S: R).

Example 4 Enantiomerically enriched N-Methyl-3- (4- trifluoromethylphenoxy)-3-phenylpropylamine (enriched in (S)-fluoxetine, 1.0 g, 3.23 mmol, 79.5: 20.5, S: R-isomer), dimethylsulfoxide (DMSO, 15 mL), and potassium hydroxide (powdered, 0.544 g, 9.69 mmol) were combined and heated to 80°C for 3 h. The reaction mixture was diluted with water (40 mL) and extracted with ethyl ether (2X50 mL). The combined organic extracts were extracted with brine (50 mL), dried over magnesium sulfate, and concentrated to provide fluoxetine free base (0.827 g, 82.7%). Chiral HPLC analysis of the product indicated 3.0% ee (51.5: 48.5, S: R).

Example 5 Enantiomerically enriched N-Methyl-3- (4- trifluoromethylphenoxy)-3-phenylpropylamine (enriched in (S)-fluoxetine, 1.0 g, 3.23 mmol, 79.5: 20.5, S: R-isomer), N, N-dimethylacetamide (DMAC, 15 mL), and potassium hydroxide (powdered, 0.544 g, 9.69 mmol) were combined and heated to 90°C for 6 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl ether (2X50 mL). The

combined organic extracts were extracted with brine (50 mL), dried over magnesium sulfate, and concentrated to provide fluoxetine free base (1.0 g, 100%). Chiral HPLC analysis of the product indicated 18.6% ee (59.4: 40.6, S: R).

Example 6 Enantiomerically enriched N-Methyl-3- (4- trifluoromethylphenoxy)-3-phenylpropylamine (enriched in (S)-fluoxetine, 25.0 g, 80.0 mmol, 79.5: 20.5, S: R-isomer), dimethylsulfoxide (DMSO, 110 mL), potassium hydroxide (pellets, 12 g, 213 mmol) and about 2.5 g mandelic acid as an impurity were combined and heated to 85°C for 12 h. The reaction mixture was diluted with sodium hydroxide (2 N, 80 mL) and extracted with ethyl ether (2X100 mL). The combined organic extracts were extracted with brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated to provide fluoxetine free base (19.8 g, 84.3%, corrected for the impurity). Chiral HPLC analysis of the product indicated 0.5% ee (49.8: 50.2, S: R).

Example 7 Enantiomerically enriched N-Methyl-3- (4- trifluoromethylphenoxy)-3-phenylpropylamine (enriched in (S)-fluoxetine, 21.6 g, 70 mmol, 79.1: 20.9, S: R-isomer) in toluene (about 400 mL) obtained from the resolution of fluoxetine to the (R)-isomer after extraction as described in Preparation 1.1. The filtrate was distilled to about 40 mL and 5 volumes of dimethylsulfoxide (DMSO, about 200 mL) along with potassium hydroxide (crushed, 18.6 g, 175 mmol) were added. The reaction mixture was heated to about 85 9C.

After about 7 hours, the reaction mixture was cooled and diluted with water (about 4 volumes) and methyl t-butyl ether (about 4 volumes). Chiral HPLC analysis of the organic layer indicated 0.2% ee (50.1: 49.9, S: R).