BACKGROUND OF THE INVENTION Stereospecific synthesis of 3-aryloxy-3- phenylpropylamines are known in the art. In many of these methods asymmetry is introduced by utilizing enantiomers of 3-hydroxy-3-phenylpropylamines, prepared by either stereospecific reduction of a ketone or by resolution of the alcohol. J. Org. Chem., 53,2916-2920 (1988); Tet. Let., 30,5207-5210 (1989); US Patents No. 4,868,344; J. Org.

Chem., 53,4081-4084 (1988); and Tet. Let., 31,7101 (1990).

In general, the 3-aryloxy substituent is introduced utilizing a specific enantiomer of the alcohol by either the Mitsunobu reaction using a phenol or by nucleophilic aromatic displacement of the alkoxide on an arylhalide.

Because of the expense and difficulty of the Mitsunobu reaction at large scale, a commercial process which uses the nucleophilic aromatic displacement route is preferred.

For suitably active aryl halides stereospecific nucleophilic aromatic displacement proceeds in a facile manner. For example, 4-chlorobenzotrifluoride reacts readily with alkoxides without racemization. Tet. Let., 30, 5207-5210 (1989); J. Org. Chem., 53,4081-4084 (1988); and Tet. Let., 35,1339-1342 (1994). However, the reaction of 2-fluorotoluene with the alkoxide of (S)-N-methyl-3-phenyl- 3-hydroxypropylamine gives modest chemical yields of tomoxetine and epimerization of the chiral center was observed. Tet. Let., 35,1339-1342 (1994). Thus, nucleophilic aromatic displacement methodology does not appear to be amenable to directly introducing the 2- methylphenoxy substituent of tomoxetine in a high yield, stereospecific manner.

The present processes provide the tomoxetine 2- methylphenoxy substituent by reduction of a formyl group to a methyl group.

As can be readily envisioned by those skilled in the art, the formyl can be directly prepared from a 2- halobenzaldehyde. However, reaction with both 2- chlorobenzaldehyde and 2-fluorobenzaldehyde with the sodium alkoxide of N, N-dimethyl-3-phenyl-3-hydroxypropylamine in dimethylsulfoxide at about 10-15°C did not provide the desired formyl compound in good yield. Rather, the reaction lead to Cannizzaro-type products and complex mixtures of products. To ultimately provide the desired formyl intermediate the present processes utilize nucleophilic aromatic displacement on a halobenzene substituted in the 2- position by an acetal, imine, or cyano group.

The present processes provide a high yield preparation of tomoxetine using a nucleophilic aromatic displacement without significant racemization.

SUMMARY OF THE INVENTION The present invention relates to processes for preparing tomoxetine and the pharmaceutically-acceptable addition salts thereof comprising the steps of: (a) reacting an alkoxide of an alcohol of the formula wherein G is selected from the group consisting of hydrogen ((R)-N- methyl-3-phenyl-3-hydroxypropylamine) and methyl ( (R)-N, N- dimethyl-3-phenyl-3-hydroxypropylamine) with an arylhalide of the formula wherein X is selected from the group consisting of fluoro, chloro, bromo, and iodo; Z is a radical selected from the group consisting of wherein Ri and R1, are selected from the group consisting of C1-C6 alkyl and benzyl or R1 and Rl, are taken together form a C2- C8 alkylene,

R2 is selected from the group consisting of C1-C6 alkyl, phenyl, substituted phenyl, and benzyl to give a 3-aryloxy compound of the formula (b) hydrolysis of the 3-aryloxy compound wherein Z is either (RlO) (Rl, O) CH-or R2N=CH-, (Z1), to give a formyl compound of the formula ((R)-N-methyl-3-(2-formylphenoxy)-3-phenylpropylamine where G is hydrogen and (R)-N, N-dimethyl-3- (2-formylphenoxy)-3- phenylpropylamine where G is methyl) or alternately, (bl) reduction of the 3-aryloxy compound wherein Z is cyano, (Z2), using a suitable cyano reducing conditions to give an imine of the formula

( (R)-N-methyl-3-(2-iminophenoxy)-3-phenylpropylamine where G is hydrogen and (R)-N, N-dimethyl-3- (2-iminophenoxy)-3- phenylpropylamine where G is methyl), followed by (b2) hydrolysis of the imine to give a formyl compound of the formula ( (R)-N-methyl-3- (2-formylphenoxy)-3-phenylpropylamine where<BR> G is hydrogen and (R)-N, N-dimethyl-3- (2-formylphenoxy)-3- phenylpropylamine where G is methyl); (c) reduction of the formyl compound using a suitable aldehyde reducing agent to give a 2-hydroxymethylphenyl compound of the formula

( (R)-N-methyl-3- (2-hydroxymethylphenoxy)-3-phenylpropylamine<BR> where G is hydrogen and (R)-N, N-dimethyl-3- (2- hydroxymethylphenoxy)-3-phenylpropylamine where G is methyl); (d) conversion of the 2-hydroxymethylphenoxy compound to an activated compound of the formula wherein Y is selected from the group consisting of halogen and ester; (e) reduction of the activated compound using suitable reducing conditions to give a compound of the formula ( (R)-N-methyl-3- (2-methylphenoxy)-3-phenylpropylamine<BR> (tomoxetine) where G is hydrogen and (R)-N, N-dimethyl-3- (2- methylphenoxy)-3-phenylpropylamine where G is methyl); (f) N-demethylation of (R)-N, N-dimethyl-3- (2-methylphenoxy)- 3-phenylpropylamine to give tomoxetine; and

(g) optional formation of an acid addition salt using a pharmaceutically-acceptable acid.

The present invention also relates to the following compounds which are useful intermediates of the processes described above.

In a further embodiment the present invention provides compounds of the formula: wherein G is selected from the group consisting of hydrogen and methyl; Z is a radical selected from the group consisting of wherein R1 and R1, are selected from the group consisting of C1-C6 alkyl and benzyl or R1 and Ri. are taken together form a C2- C8 alkylene; and R2 is selected from the group consisting of Ci-Ce alkyl, phenyl, substituted phenyl, and benzyl;

wherein G is selected from the group consisting of hydrogen and methyl; wherein G is selected from the group consisting of hydrogen and methyl; and wherein G is selected from the group consisting of hydrogen and methyl; and

Y is selected from the group consisting of halogen and ester.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms have the meanings indicated: (a) the term"C1-C6 alkyl"refers to a straight or branched chain alkyl having from one to six carbon atoms and includes, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, iso-butyl, t-butyl, pentyl, hexyl, and the like; (b) the term"C2-C8 alkylene"refers to a straight or branched chain alkylene having from two to eight carbon atoms and includes, ethylene, propylene, 1,2- dimethylethylene, 2,2-dimethylpropylene, and the like; (c) the term"halogen"refers to a chlorine atom, bromine atom, or an iodide atom; (d) the term"substituted phenyl"refer to a radical of the formula wherein R is from 1 to 2 substituents independently selected from the group consisting of hydrogen and C1-C6 alkyl; (e) the term"ee"or"enantomeric excess"refers to the percent by which one enantiomer, E1, is in excess in a mixture of both enantiomers (E1 + E2), as calculated by the equation {(E1-E2) (E1 + E2)} x 100% = ee; (f) the term"pharmaceutically-acceptable addition salt" refers to an acid addition salt.

Tomoxetine and the intermediates described herein form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. A pharmaceutically-acceptable

addition salt is formed from a pharmaceutically-acceptable acid as is well known in the art. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, P-hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, benzene-sulfonate, p- bromobenzenesulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p- toluenesulfonate, xylenesulfonate, tartarate, and the like.

The present invention relates to processes for the stereospecific preparation of tomoxetine, (R)-N-methyl-3- (2- methylphenoxy)-3-phenylpropylamine. Herein, the Cahn- Prelog-Ingold designations of (R)-and (S)-are used to refer to specific isomers where designated.

As will be appreciated by the skilled artisan, the present processes are not necessarily limited to the

preparation of a specific isomer. Rather the present processes are capable of preparing either of the specific enantiomers or racemic mixtures depending on the enantomeric purity of the starting materials used. The present invention is most useful as a preparation of a substantially pure tomoxetine, (R)-N-methyl-3- (2-methylphenoxy)-3- phenylpropylamine, utilizing a starting alcohol of substantially isomeric purity. As used herein the term "substantially pure"refers to enantomeric purity of tomoxetine or intermediates thereof. Accordingly to the present invention substantially pure tomoxetine can be prepared comprising the (R)-enantiomer which is greater than 90%, preferably greater than 95%, and more preferably greater than 98% of the material prepared.

The substantially pure isomers of the starting alcohols can be obtained by stereospecific reduction or resolved and recovered by techniques known in the art, such as, chromatography on chiral stationary phases and fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers are known in the art and described in Stereochemistry of Organic Compounds, E. L.

Eliel and S. H. Wilen (Wiley-Interscience 1994) and Enantiomers, Racemates, and Resolutions, J. Jacques, A.

Collet, and S. H. Wilen (Wiley-Interscience 1981).

The present preparations of tomoxetine are carried out according to Reaction Scheme A below. In Reaction Scheme A, all substituents, unless otherwise indicated, are as previously defined. In Reaction Scheme A all reagents are well known and appreciated in the art.

Reaction Scheme A OH Z Z) o I c>> I stepa z 0 N"CH3 N/ (3) G stepb step b1 H H C C O HN . CH3/CH3 N E N (5) I step b2 G (4) Li step c Ho y step d O O /CH3CH3 u (6) G (7) G H C step e H C _ 0 %//CH3 step f t NzCH3 . to tomoxet ! né.. H (when G s Hne G (tomoxetine)

In Reaction Scheme A, step a, a nucleophilic aromatic displacement, the alkoxide of an alcohol of formula (1), (R)-N-methyl-3-phenyl-3-hydroxypropylamine where G is hydrogen and (R)-N, N-dimethyl-3-phenyl-3-hydroxypropylamine where G is methyl, is contacted with a arylhalide of formula (2) to give a 3-aryloxy compound of formula (3).

In general, arylhalides in which X is fluoro and chloro, bromo, and iodo are suitable with fluoro, chloro, and bromo being preferred, and fluoro and chloro being more preferred. For the arylhalide in which Z is R2N=CH- compounds in which X is fluoro are most preferred. Also, for the arylhalide in which Z is R2N=CH-compounds in which R2 is sterically large are preferred with t-butyl, phenyl, and 2,6-dimethylphenyl being preferred, and t-butyl being more preferred.

For example, the reaction is carried out using an alkoxide of an alcohol of formula (1). While many metals are suitable for this reaction, generally, an alkali metal alkoxide is used, with the lithium, sodium, and potassium alkoxide being preferred and with the sodium alkoxide being more preferred. The alkoxide is formed by contacting of an alcohol of formula (1) with a suitable base, such as lithium hydride, lithium N, N-diisopropylamide, sodium hydride, potassium hydride, and potassium t-butoxide. When a sodium alkoxide is used a catalytic amount of potassium ion may be advantageous. Such a catalytic amount of potassium ion can be added, for example, in the form of potassium benzoate.

Typically, the reaction is carried out in a substantially anhydrous, aprotic solvent, such as tetrahydrofuran, dioxane, acetonitrile, N-methylpyrrolidinone, N, N- dimethylformamide, N, N-dimethylacetamide, or

dimethylsulfoxide. In general, the reaction is carried out at temperatures of from about -50°C to about 70°C. For reactions using arylhalides in which Z is either (RlO) (Rl, O) CH-or R2N=CH-the reaction is typically carried out at about 20°C to about 70°C with about 25°C to about 50°C being preferred. For the reactions using arylhalides in which Z is cyano the reaction is typically carried out at about-50°C to about 70°C with about-10°C to about 25°C being preferred. The reaction typically requires from about 30 minutes to about 24 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization. Alternately, the product can be taken directly to the next step without isolation or without purification.

In Reaction Scheme A, step b, hydrolysis of a 3-aryloxy compound of formula (3) in which Z is either (R10) (R1, 0) CH- or R2N=CH-, (Z1), to give a formyl compound of the formula (5), (R)-N-methyl-3- (2-formylphenoxy)-3-phenylpropylamine where G is hydrogen and (R)-N, N-dimethyl-3- (2- formylphenoxy)-3-phenylpropylamine where G is methyl.

Generally, the reaction is carried out with water in a suitable solvent, such as water, ethanol, methanol, or the solvent used in the nucleophilic aromatic displacement.

Acidic conditions may be required. The hydrolysis of acetals and imines is well known and appreciated in the art.

Protecting Groups in Organic Synthesis, Theodora W. Greene.

The reaction typically requires from about 30 minutes to about 24 hours. The product can be isolated and purified by techniques well known in the art, such as evaporation, extraction, trituration, chromatography, and crystallization. The product can also be taken directly to the next step without isolation or without purification.

Alternately in Reaction Scheme A, steps bl and b2, a formyl compound of formula (5) is prepared from a 3-aryloxy compound of formula (3) in which Z is cyano, (R)-N-methyl-3- (2-cyanophenoxy)-3-phenylpropylamine where G is hydrogen and (R)-N,N-dimethyl-3- (2-cyanophenoxy)-3-phenylpropylamine where G is methyl.

In Reaction Scheme A, step bl, a 3-aryloxy compound of formula (3) in which Z is cyano undergoes suitable cyano reducing conditions to give the imine of formula (4), (R)-N- methyl-3- (2-iminophenoxy)-3-phenylpropylamine where G is hydrogen and (R)-N, N-dimethyl-3- (2-iminophenoxy)-3- phenylpropylamine where G is methyl.

Suitable cyano reducing conditions are ones which do not readily give over-reduction of the cyano group to the amine. Suitable cyano reducing conditions include, the use of hydride transfer reagents and hydrogenation using a catalyst.

For example, a compound of formula (3) in which where Z is cyano is contacted with Raney nickel and sodium hypophosphite in aqueous acetic acid-pyridine or formic acid. The reaction is typically carried out at temperatures of from about 20° to about 90°C with temperatures of about 50°C to about 80°C being preferred. The reaction typically requires from about 2 to 8 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization. Preferably, the product can be taken directly to the next step without isolation.

In Reaction Scheme A, step b2, an imine of formula (4) is hydrolyzed to give a formyl compound of the formula (5), (R)-N-methyl-3- (2-formylphenoxy)-3-phenylpropylamine where G

is hydrogen and (R)-N, N-dimethyl-3- (2-formylphenoxy)-3- phenylpropylamine where G is methyl.

For example, the hydrolysis of the imine of formula (4) can be carried out as described in Reaction Scheme A, step b, above. As will be appreciated to one skilled in the art, when water is present in the reaction conditions employed in step bl, the hydrolysis may take place spontaneously during step bl. The product can be isolated and purified by techniques well known in the art, such as filtration, quenching, evaporation, extraction, trituration, chromatography, and crystallization. Alternately, the product can be directly taken on the next step without isolation or without purification.

In Reaction Scheme A, step c, the formyl compound of formula (5) is contacted with a suitable aldehyde reducing agent to give the 2-hydroxymethylphenoxy compound of the formula (6), (R)-N-methyl-3- (2-hydroxymethylphenoxy)-3- phenylpropylamine where G is hydrogen and (R)-N, N-dimethyl- 3- (2-hydroxymethylphenoxy)-3-phenylpropylamine where G is methyl.

A suitable aldehyde reducing group is one which reduces the formyl group of the compound of formula (5) to the hydroxymethyl group of formula (6). Such reducing agents are well known in the art and include hydride transferring reagents, such as borohydride reagents, including lithium borohydride, sodium borohydride, potassium borohydride, aluminum hydride reagents, including lithium aluminum hydride and diisobutylaluminum hydride, borane and its complexes, triisopropoxyaluminum, hydrogenation using a catalyst, and the like.

For example, the reaction is carried out by contacting the formyl compound of formula (5) and a molar excess of a

suitable aldehyde reducing agent in a suitable solvent.

Depending on the reducing agent selected suitable solvents include, water, ethanol, methanol, isopropanol, ethanol/water mixtures, methanol/water mixtures, isopropanol/water mixtures, dioxane, tetrahydrofuran, diethyl ether, and methyl t-butyl ether. In general, the reaction is carried out at temperatures of from about 0°C to the refluxing temperature of the solvent. The reaction requires from about 1 hour to about 24 hours. The product can be isolated and purified by techniques well known in the art, such as quenching, filtration, evaporation, extraction, trituration, chromatography, and crystallization.

In Reaction Scheme A, step d, the 2- hydroxymethylphenoxy compound of the formula (6) is activated to give an activated compound of the formula (7).

Suitable activating groups are ones which can be reduced to a methyl group and include halogens and esters.

When halogen, the activating group is preferably chloro and bromo, and more preferably chloro. When ester, the activating group is preferably, but not necessarily, an ester having an electron withdrawing character. Suitable esters include, acetyl, trifluoroacetyl, benzoyl, 4- fluorobenzoyl, pentafluorobenzoyl, and the like. The formation of an activating groups from alcohols is well known and appreciated in the art.

Compound of formula (7) in which Y is halogen are readily prepared using halogenation reagents such as thionyl chloride, carbon tetrachloride/triphenylphosphine, phosphorous trichloride, thionyl bromide, triphenylphosphine/bromine, and the like.

For example, a 2-hydroxymethylphenoxy compound of the formula (6) is contacted with a slight molar excess of

thionyl chloride to give an activated compound of the formula (7). The reaction is carried out in a suitable solvent, such as dichloromethane, chloroform, benzene, toluene, and the like. In general, the reaction is carried out at temperatures of from about-20°C to the refluxing temperature of the solvent. The reaction requires from about 1 hour to about 18 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.

Compound of formula (7) in which Y is ester are readily prepared using acid halides, activated esters, and anhydrides are is well known and appreciate in the art.

For example, a 2-hydroxymethylphenoxy compound of the formula (6) is contacted with a slight molar excess of an acid halide, activated ester, or anhydride to give an activated compound of the formula (7). Suitable acid halides include acetyl chloride, acetyl bromide, benzoyl chloride, 4-fluorobenzoyl chloride, pentafluorobenzoyl chloride and the like; suitable activated esters include 1- acetylimidizole and the like; suitable anhydrides include acetyl anhydride, trifluoroacetyl anhydride, benzoyl anhydride and the like. The reaction is carried out in a suitable solvent, such as dichloromethane, chloroform, benzene, toluene, and the like. The reaction is carried out using a suitable base such as the compound of formula (6), triethylamine, pyridine and the like. In general, the reaction is carried out at temperatures of from about-20°C to about 50°C. The reaction requires from about 1 hour to about 6 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.

In Reaction Scheme A, step e, the activated compound of the formula (7) undergoes suitable reducing conditions to give the compound of the formula (8), (R)-N-methyl-3- (2- methylphenoxy)-3-phenylpropylamine (tomoxetine) where G is hydrogen and (R)-N, N-dimethyl-3- (2-methylphenoxy)-3- phenylpropylamine where G is methyl.

Suitable reducing conditions are those that reduce the activating group to give a methyl group. Suitable reducing conditions depend on the activating group used and include, dissolving metal reductions and single electron transfer reactions, such as those using magnesium metal, magnesium almagams, zinc metal, and cadmium metal; hydride reductions, such as those using lithium aluminum hydrides, tin hydrides, and super hydrides, such as lithium triethylborohydride; and hydrogenation using a catalyst.

For example, an the activated compound of formula (7) in which the activating group is a halogen, is contacted with an excess of zinc metal in a suitable solvent, such as acetic acid or acetic acid/water mixtures. In general, the reaction is carried out at temperatures of from about 0°C to about 50°C. The reaction requires from about 1 hour to about 24 hours. The product can be isolated and purified by techniques well known in the art, such as quenching, filtration, evaporation, extraction, trituration, chromatography, and crystallization.

Alternately, for example, the activated compound of formula (7) in which the activating group is a halogen is contacted with an excess of magnesium metal or a magnesium/cadmium amalgam in a suitable solvent, such as methanol or ethanol. In general, the reaction is carried out at temperatures of from about 0°C to about 50°C. The reaction requires from about 1 hour to about 24 hours. The product can be isolated and purified by techniques well

known in the art, such as quenching, filtration, evaporation, extraction, trituration, chromatography, and crystallization.

For example, the activated compound of formula (7) in which the activating group is an ester, such as acetyl or trifluoroacetyl, is contacted with hydrogen, in the presence of a catalyst, such as palladium-on-carbon, in a suitable solvent, such as water, ethanol, isopropanol, ethyl acetate, and the like. The reaction typically requires from about 2 to 48 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.

In Reaction Scheme A, step f, the compound of the formula (8) where G is methyl, (R)-N, N-dimethyl-3- (2- methylphenoxy)-3-phenylpropylamine, is N-demethylated to give tomoxetine. Such N-demethylation reactions are well known and appreciated in the art and include demethylations which proceed through a N-cyano and carbamate intermediates followed by hydrolysis. See for example, U. S. Patent Nos.

4,956,388; 4,314,081; and 5,362,886.

For example, (R)-N, N-dimethyl-3- (2-methylphenoxy)-3- phenylpropylamine is contacted with a slight molar excess of chloro formate, such as phenyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, and the like.

The reaction is carried out in the presence of a suitable base, such as triethylamine, pyridine, N, N- diisopropylethylamine, and the like. The reaction is carried out in a suitable solvent, such as toluene, dichloromethane, tetrahydrofuran, and the like. Typically the reaction is carried out at temperatures of from about 0°C to the refluxing temperature of the solvent and require about 1 hour to 48 hours. The carbamate intermediate can be

isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization. The carbamate intermediate is then hydrolyzed to give product. For example, the carbamate intermediate is contacted with an excess of sodium hydroxide or potassium hydroxide. The reaction is carried out in a suitable solvent, such as water, dimethyl sulfoxide, ethanol, dimethyl sulfoxide/water mixtures, and the like. Typically the reaction is carried out at temperatures of from about 20°C to about 100°C and require about 1 hour to 48 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.

In Reaction Scheme A, optional step g, not shown, an acid addition salt is formed using a pharmaceutically- acceptable acid. The formation of acid addition salts is well known and appreciated in the art.

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; "bp"refers to boiling point;"mp"refers to melting point; "brine"refers to a saturated aqueous sodium chloride solution;"MS"refers to mass spectrometry;"IR"refers to

infrared spectroscopy;"UV"refers to ultraviolet spectroscopy;"NMR"refers to nuclear magnetic resonance spectroscopy;" [CCID"refers to specific rotation of the sodium D line in a 1 decimeter cell;" [a] 365"refers to specific rotation at 365 nanometers in a 1 decimeter cell, "c"refers to concentration in g/mL;"TLC refers to thin layer chromatography on silica gel;"Rf"refers to retention factor;"tr"refers to retention time,"min"refers to minute;"TFA"refers to trifluoroacetic acid;"CH2C12" refers to dichloromethane;"MeOH"refers to methanol; "NH40H"refers to a concentrated aqueous ammonia solution; "PMA"refers to phosphomolybdic acid, etc.

PREPARATION 1.1 1-Fluoro-2- (t-butylimino) benzene Combine 2-fluorobenzaldehyde (50 g, 400 mmol), t- butylamine (44 mL, 410 mmol), and dichloromethane (500 mL).

Add 4A molecular sieves (about 200 g). After 18 hours, filter, evaporate in vacuo, to give a residue. Distill the residue to give the title compound: bp 88-90°C at 8 mm; 1H NMR (CDC13) characteristic resonances 8 8.58 (s, 1 H), 1.31 (s, 9 H).

PREPARATION 1.2 1-Fluoro-2- (t-butylimino) benzene Combine 2-fluorobenzaldehyde (100 g, 800 mmol), t- butylamine (106 mL), and dichloromethane (2 L). Add 4A molecular sieves (about 175 g). After 18 hours, filter, evaporate in vacuo to give the title compound (138.6 g which contained approximately 1% of 2-fluorobenzaldehyde): 1H NMR (CDC13) characteristic resonances 8 8.58 (s, 1 H), 1.31 (s, 9 H); 13C NMR (CDC13) 8 164.2,160.2,148.5,148.4,137.6, 131.6,131.4,127.4,127.4,124.7,124.6,124.2,124.1, 115.6,115.3,29.6; IR (CHC13) 2972,1637,1614,1584,1486 cm

PREPARATION 2 1-Chloro-2- (t-butylimino) benzene Combine 2-chlorobenzaldehyde (57.8 g, 410 mmol), t- butylamine (34.5 mL, 470 mmol), and p-toluenesulfonic acid hydrate (about 50 mg), and dichloromethane (500 mL). Heat to reflux using a water separator charged with 4A molecular sieves (about 20 g). After 14 hours, cool, filter, evaporate in vacuo to give the a residue. Distill the residue tom give the title compound: bp 75 °C at 1 mm; 1H <BR> <BR> <BR> NMR (CDC13) 6 8.64 (s, 1 H), 8.00 (m, 1 H), 7.2-7.4 (m, 3H), 1.29 (s, 9 H).

PREPARATION 3.1 (R)-N, N-Dimethyl-3-hydroxy-3-phenylpropylamine mandelic acid salt Combine (R, S)-N, N-dimethyl-3-hydroxy-3- phenylpropylamine (150.0 g, 837.5 mmol), acetone (1125 mL), and methyl t-butyl ether (1125 mL). Add (-)-mandelic acid (57.34 g, 376.9 mmol). Heat to reflux. After 2.5 hours, slowly cool to ambient temperature over about 2 hours to give a solid. Collect the solid by filtration and rinse with acetone/methyl t-butyl ether (1/1,600 mL) to give, after drying, the title compound (100.5 g): HPLC, Chiralcel OD-H column (150 mm x 4.6 mm) at 35 °C, detection at 258 nm, eluting with hexane-isopropanol-diethyl amine 96.8: 3: 0.2 at 1 mL/min, tR = 9.0 min (R) enantiomer; tR (S) enantiomer = 15 min, 93% ee.

PREPARATION 3.2 (R)-N, N-Dimethyl-3-hydroxy-3-phenylpropylamine mandelic acid salt Combine (R)-N, N-dimethyl-3-hydroxy-3-phenylpropylamine (97.5 g) mandelic acid salt and ethanol (1.0 L). Heat to about 55°C. Add methyl t-butyl ether (400 mL). Cool in an ice-bath with stirring to give a solid. Collect the solid by filtration to give, after drying, the title compound.

HPLC; Chiralcel OD-H column (150 mm x 4.6 mm) at 35 °C, detection at 258 nm, eluting with hexane-isopropanol-diethyl amine 96.8: 3: 0.2 at 1 mL/min, tR (R) enantiomer = 9.0 min, tR (S) enantiomer = 15 min, 99% ee.

PREPARATION 4.1 (R)-N, N-Dimethyl-3-hydroxy-3-phenylpropylamine Combine (R)-N, N-dimethyl-3-hydroxy-3-phenylpropylamine mandelic acid salt (39.0 g) and dichloromethane (390 mL).

Add an aqueous 0.3 M sodium hydroxide solution (500 mL).

After 10 minutes, separate the layers, extract the organic layer with an aqueous 0.05 M sodium hydroxide solution (500 mL) and stir. Separate the layers, dry the organic layer over 4A molecular sieves, filter, and evaporate to give the title compound (19.83 g): HPLC, Zorbax C18, detection at 220 nm, eluting with acetonitrile-water 2: 1 containing 0.1% TFA at 2 mL/min, tR = 1.2 min (R) enantiomer 99.9% ee. 1H NMR (CDC13) characteristic resonances at 8 4.83 (dd, l H), 2.27 (s, 6 H).

PREPARATION 4.2 (R)-N, N-Dimethyl-3-hydroxy-3-phenylpropylamine Combine (R)-N, N-dimethyl-3-hydroxy-3-phenylpropylamine mandelic acid salt (78.0 g), water (500 mL), and dichloromethane (500 mL). Add an aqueous 5M sodium hydroxide solution (60 mL) and a concentrated aqueous ammonia solution (10 mL) and stir. After 1 hour, separate the layers, extract the aqueous layer twice with dichloromethane. Combine the organic layers, extract with water, dry the organic layer over 4A molecular sieves, filter, and evaporate to give the title compound (40.1 g).

HPLC, Chiralcel OD-H column (150 mm x 4.6 mm) at 35 °C, detection at 258 nm, eluting with hexane-isopropanol-diethyl amine 96.8: 3: 0.2 at 1 mL/min, tR (R) enantiomer = 9.1 min, tR (S) enantiomer = 15 min, >99% ee.

EXAMPLE 1 Tomoxetine, (R)-N-methyl-3- (2-methylphenoxy)-3- phenylpropylmaine 1.1.1 Synthesis of (R)-N, N-dimethyl-3- (2- (t- butylimino) phenoxy)-3-phenylpropylamine Combine (R)-N, N-dimethyl-3-hydroxy-3-phenylpropylamine (33.2 g, 196 mmol), 1-fluoro-2- (t-butylimino) benzene (32.5 g, 197 mmol), sodium hydride (7.7 g, 60% in oil, 193 mmol), and dimethylsulfoxide (66 mL) with cooling in a water bath to about 15°C. After 1.5 hours, warm the reaction mixture to about 30°C. After 16 hours, add an additional amount of sodium hydride (0.31 g, 60% in oil) to give, after 7 hours, a solution containing the title compound (98% conversion based on the starting alcohol): 1H NMR (aliquot assayed <BR> <BR> <BR> directly in CDC13) characteristic resonances at 8 8.72 (s, 1 H), 5.18 (dd 1 H), 1.25 (s 9H).

1.1.2 Synthesis of (R)-N, N-dimethyl-3- (2- (t- butylimino) phenoxy)-3-phenylpropylamine Combine (R)-N, N-dimethyl-3-hydroxy-3-phenylpropylamine (1.62 g, 9.0 mmol), 1-chloro-2- (t-butylimino) benzene (2.03 g, 11.3 mmol), and dimethylsulfoxide (4 mL). Cool to about 15°C using an ice bath. Add sodium hydride (0.40 g, 60% in oil, 10 mmol). After 6 hours, add potassium benzoate (0.16 g). After 10 hours, heat to about 60°C. Stir for 48 hours and cool to ambient temperature to obtain a solution containing the title compound: TLC, Rf=0.56 eluting with CH2Cl2-MeOH-NH40H 800: 40: 4.

1.1.3 Synthesis of (R)-N, N-dimethyl-3- (2- (t- butylimino) phenoxy)-3-phenylpropylamine Combine (R)-N, N-dimethyl-3-hydroxy-3-phenylpropylamine (6.47 g, 36.1 mmol), 1-fluoro-2- (t-butylimino) benzene (6.5 g, 36.3 mmol), sodium hydride (1.36 g, 60% in oil, 34 mmol), and dimethylsulfoxide (about 25 mL) with cooling in a water bath and adding ice to maintain the temperature at about 10°

to 20°C. After 1.5 hours, warm the reaction mixture to about 30°C and stir for 16 hours to give a solution containing the title compound: TLC, Rf=0.79 eluting with CH2Cl2-MeOH-NHOH 800: 50: 5, visualized with PMA.

1.2.1 Synthesis of (R)-N, N-dimethyl-3- (2-formylphenoxy)-3- phenylpropylamine Combine the solution (R)-N, N-dimethyl-3- (2- (t- butylimino) phenoxy)-3-phenylpropylamine obtained in Example 1.1.1, acetic acid (60 mL), and water (2400 mL) and stir.

After 1 hour, cool to about 0°C. After 18 hour, add hexane/methyl t-butyl ether (1/1,1 L). Neutralize the aqueous layer using sodium bicarbonate (about 150 g) and place under vacuum to remove most of the t-butylamine.

Separate the layers, extract aqueous layers three times with methyl t-butyl ether (500 mL), combine the organic layers, dry over 4A molecular sieves, and evaporate in vacuo to give the title compound (51 g): 96.5% by HPLC, Zorbax C18, detection at 220 nm, eluting with acetonitrile-water 2: 1 containing 0.1% TFA at 2 mL/min; TLC, Rf=0.79 eluting with CH2Cl2-MeOH-NH40H 800: 50: 5, visualized with PMA; 1H NMR (CDC13) 6 10.64 (s, 1 H), 7.79 (dd 1 H), 6.8-7.4 (multiplets, 8 H), 5.37 (dd, 1 H), 2.22 (s, 6 H) 1.95-2.3 (multiplets, 4 H).

1.2.2 Synthesis of (R)-N, N-dimethyl-3- (2-formylphenoxy)-3- phenylpropylamine Combine the solution (R)-N, N-dimethyl-3- (2- (t- butylimino) phenoxy)-3-phenylpropylamine obtained in Example 1.1.2, acetic acid (10 mL), and water (100 mL) and stir.

After 1 hour, add methyl t-butyl ether (50 mL). Neutralize the aqueous layer using sodium bicarbonate and extract the aqueous layer with dichloromethane (250 mL). Separate the layers, dry the organic layer over 4A molecular sieves and evaporated in vacuo to give the title compound: TLC, Rf=0.48 eluting with CH2Cl2-MeOH-NH40H 800: 40: 4, visualized with PMA.

1.2.3 Synthesis of (R)-N, N-dimethyl-3- (2-formylphenoxy)-3- phenylpropylamine Combine the solution (R)-N, N-dimethyl-3- (2- (t- butylimino) phenoxy)-3-phenylpropylamine obtained in Example 1.1.3, acetic acid (21 mL), and water (100 mL) and stir.

After 20 minutes, add heptane. After 1 hour, separate the layers, neutralized the aqueous layer with sodium bicarbonate, and extract with dichloromethane. Evaporate the dichloromethane extract in vacuo to give the title compound: HPLC, Zorbax C, 8, detection at 220 nm, eluting with acetonitrile-water 2: 1 containing 0.1% TFA at 2 mL/min, tr=3.40 min.

1.3 Synthesis of (R)-N, N-dimethyl-3- (2- hydroxymethylphenoxy)-3-phenylpropylamine Combine (R)-N, N-dimethyl-3- (2-formylphenoxy)-3- phenylpropylamine (51 g) and cold (ice-bath) methanol (1 L).

Add sodium borohydride (7.1 g) portionwise over about 2 hours. After the addition is complete, quench by the addition of acetone (20 mL). Add acetic acid (57 mL).

Adjust the pH to about 9-10 using a concentrated aqueous ammonia solution (about 50 mL) and partition the pH adjusted reaction mixture between water (1 L) and dichloromethane (500 mL) before concentrating under a stream of nitrogen to remove most to the methanol. Adjust the pH of the aqueous phase to about 10 using an aqueous 5 M sodium hydroxide solution, mix, and separate the layers. Extract the aqueous layer three times with dichloromethane, adjust the pH of the aqueous phase to about 11 using an aqueous 5 M sodium hydroxide solution, and extract two times with dichloromethane. Combine the organic layers and concentrate in vacuo to give the title compound (57.7 g): HPLC, Zorbax C18, detection at 220 nm, eluting with acetonitrile-water 2: 1 containing 0.1% TFA at 2 mL/min, tr=3.07 min; 1H NMR

(CDC13) characteristic resonances at 8 5.30 (dd, 1 H), 4.72 (dd, 2 H), 2.29 (s, 6H).

1.4.1.1 Synthesis of (R)-N, N-dimethyl-3- (2- chloromethylphenoxy)-3-phenylpropylamine hydrochloric acid salt Combine (R)-N, N-dimethyl-3- (2-hyrdoxymethylphenoxy)-3- phenylpropylamine (6.0 g, 21.1 mmol), and dichloromethane (60 mL). Cool in an ice-bath. Add dropwise thionyl chloride (2.7 g, 1.66 mL) and then warm to ambient temperature. After 1.5 hours, evaporate to give the title compound: HPLC, Zorbax C18, detection at 220 nm, eluting with acetonitrile-water 2: 1 containing 0.1% TFA at 2 mL/min, tr=8.58 min; TLC, Rf=0.6 eluting with CH2Cl2-MeOH-NH4OH 400: 40: 4.

1.4.1.2 Synthesis of N, N-dimethyl-3- (2-chloromethylphenoxy)- 3-phenylpropylamine hydrochloric acid salt Combine N, N-dimethyl-3- (2-hyrdoxymethylphenoxy)-3- phenylpropylamine (0.84 g, 2.94 mmol) and dichloromethane (10 mL). Cool in an ice-bath. Add dropwise freshly distilled thionyl chloride (0.4 mL). After 1 hour, evaporate in vacuo to give the title compound.

1.4.2 Synthesis of N, N-dimethyl-3- (2- trifluoroacetoxymethylphenoxy)-3-phenylpropylamine trifluoroacetic acid salt Combine N, N-dimethyl-3- (2-hyrdoxymethylphenoxy)-3- phenylpropylamine (1.10 g, 3.86 mmol) and dichloromethane (60 mL). Cool in an ice-bath. Add trifluoroacetic anhydride (0.58 mL). After 2 hours, evaporate in vacuo to give the title compound: HPLC, Zorbax C18, detection at 220 nm, eluting with acetonitrile-water 2: 1 containing 0.1% TFA at 2 mL/min, tr=27 min.

1.4.3 Synthesis of N, N-dimethyl-3- (2-acetoxymethylphenoxy)- 3-phenylpropylamine hydrochloric acid salt Combine N, N-dimethyl-3- (2-hydroxymethylphenoxy)-3- phenylpropylamine (0.27 g, 0.96 mmol) and dichloromethane (2 mL). Add acetyl chloride (0.07 mL). After 30 minutes, evaporate in vacuo to give the title compound: HPLC, Zorbax C18, detection at 220 nm, eluting with acetonitrile-water 2: 1 containing 0.1% TFA at 2 mL/min, tr=5. 90 min; TLC, Rf=0.69 eluting with CH2Cl2-MeOH-NH40H 400: 40: 4.

1.5.1.1 Synthesis of (R)-N, N-dimethyl-3- (2-methylphenoxy)-3- phenylpropylamine Combine (R)-N, N-dimethyl-3- (2-chlorormethylphenoxy)-3- phenylpropylamine hydrochloric acid from Example 1.4.1.1, zinc metal (15.9 g, 243 mmol), acetic acid (43 mL), and water (0.2.5 mL) and stir vigorously. After 1.5 hours, filter through celite, rinse with two portions of methanol, and evaporate in vacuo to give a residue. Combine the residue and dichloromethane (230 mL) and extract with a saturated aqueous ammonium chloride solution (115 mL).

Extract the aqueous layer with dichloromethane, combine the organic layers, and extract with water/saturated aqueous sodium bicarbonate solution (1/2). Dry the organic layer over 4A molecular sieves and evaporate using a stream of nitrogen to give the title compound: 95% by GLC, DBI column (J&W Scintific) at 60°C for 1 min then 20°C/min to 300°C and 12 min at 300 °C; HPLC, Chiralcel OD column at 35°C, detection at 258 nm, eluting with hexane-isopropanol-diethyl amine 96.8: 3: 0.2 at 1 mL/min, tR (R) enantiomer 8.6 min, 94% ee; 1H NMR (CDC13) characteristic peaks 8 5.22 (dd, 1 H); 3C NMR (CDC13) characteristic peaks b (aliphatic) 78.1, 56.1,45.1,36.9,16.5; [a] 365 =-136.9 (c = 1, MeOH); W X 7 277 (1360), 270 (1500); IR (CHC13) 2973,1601,1492, 1240,1120 cm-1; MS m/z (field desorption) 269 M); Anal.

Calcd for C18H23NO: C, 80.26; H, 8.61; N, 5.20. Found: C, 80.19; H, 8.51; N, 5.28.

1.5.1.2 Synthesis of (N, N-dimethyl-3- (2-methylphenoxy)-3- phenylpropylamine Combine N, N-dimethyl-3- (2-chloromethylphenoxy)-3- phenylpropylamine hydrochloric acid salt obtained from Example 1.4.1.2 and methanol (75 mL). Cool in an ice-bath.

Add magnesium metal (3 g). After about 1 hour, remove the ice-bath and allow reaction to exotherm. After 1.5 hour, evaporate in vacuo to give a residue. Dilute the residue with water (70 mL), a saturated aqueous ammonium chloride solution (10 mL), and acetic acid (10 mL). Extract three times with dichloromethane, combine the organic layers, dry over sodium sulfate, filter, and evaporate in vacuo to give the title compound: 96% by HPLC, Zorbax C18, detection at 220 nm, eluting with acetonitrile-water 2: 1 containing 0.1% TFA at 2 mL/min, tr=15.5 min; 1H NMR (CDC13) characteristic resonances at 8 5.22 (dd, 1 H), 2.32 (s, 6H).

1.5.2 Synthesis of N, N-dimethyl-3- (2-methylphenoxy)-3- phenylpropylamine Dissolve N, N-dimethyl-3- (2- trifluoroacetoxymethylphenoxy)-3-phenylpropylamine trifluoroacetic acid salt from the Example 1.4.2 in ethanol (20 mL). Add 5% palladium-on-carbon (0.75 g). Cool in an ice-bath and create a hydrogen atmosphere above the reaction mixture at atmospheric pressure. After 1 hours, add a concentrated aqueous ammonia solution (about 1 mL), filter the reaction mixture through celite, and evaporatre the filtrate to give a residue. Partition the residue between methyl t-butyl ether and an aqueous sodium bicarbonate solution. Separate the organic layer, dry over 4A molecular sieves, and evaporate using a stream of nitrogen to give the title compound: TLC, Rf=0.78 eluting with CH2Cl2: MeOH: NH40H, 400: 40: 4; 1H NMR characteristic resonances at 8 6.66 (d, 1 H), 5.26 (dd, 1 H), 13C NMR (CDC13) characteristic resonances at 8 (aliphatic): 78.0,56.0,45.5,36.9,16.5; IR (CHC13):

2930,1601,1492 cml ; W (MeOH) (£): 271 (900); MS m/z (field desorption) 269 (M+).

1.5.3 Synthesis of N, N-dimethyl-3- (2-methylphenoxy)-3- phenylpropylamine Combine N, N-dimethyl-3- (2-acetoxymethylphenoxy)-3- phenylpropylamine hydrochloric acid salt from Example 1.4.3 and ethanol (2 mL). Add 5% palladium-on-carbon (about 0.1 g). Cool in an ice-bath and create a hydrogen atmosphere above the reaction mixture at atmospheric pressure. After 2 hour, warm to ambient temperature. After 6 hours, filter the reaction mixture through celite and evaporatre the filtrate to give a residue. Partition the residue between dichloromethane and an aqueous sodium bicarbonate solution.

Separate the organic layer, dry the organic layer over 4A molecular sieves, and evaporate using a stream of nitrogen to give the title compound: HPLC, Zorbax C18, detection at 230 nm, eluting with acetonitrile-water 2: 1 containing 0.1% TFA at 2 mL/min, tr=8 min.

1.6 Synthesis of Tomoxetine hydrochloric acid salt, (R)-N- methyl-3- (2-hydroxymethylphenoxy)-3-phenylpropylamine hydrochloric acid salt Combine (R)-N, N-dimethyl-3- (2-hydroxymethylphenoxy)-3- phenylpropylamine (1.75 g, 6.5 mmol) and toluene (50 mL).

Dry by azeotropic distillation to leave about 25 mL of solution. Cool to about 65°C, add triethylamine (0.14 mL), and phenyl chloroformate (1.25 g, 8.45 mmol). After about 2 hours at 60-65°C, add triethylamine (0.14 mL). After an additional hour, cool to ambient temperature, add a saturated aqueous sodium bicarbonate solution (about 10 mL), and stir. After 2 hours, separate the layers and evaporate the organic layer to give a residue. Combine the residue, dimethyl sulfoxide (25 mL), and an aqueous 5 M sodium hydroxide solution. Heat to about 60°C. After 4 hours, cool to ambient temperature, add water (40 mL) containing

acetic acid (5.6 g) and extract three times with methyl t- butyl ether/hexane (1/1, about 30 mL). Dilute the aqueous 'layer with water, add an aqueous sodium hydroxide solution (about 10 mL), and extract three times with ethyl acetate (50 mL). Combine the ethyl acetate extracts, extract three times with water (25 mL), dry over 4A molecular sieves, filter, evaporate in vacuo to about 20 mL, and add an aqueous 12 M hydrochloric acid solution (0.43 mL). Four times, concentrate to about 5 mL and add ethyl acetate (20 mL) and then heat to reflux to give a solid. Cool and collect the solid by filtration to give the title compound (1.41 g): 1H NMR (CDC13) characteristic resonances 8 9.63 (broad s, 2H) 5.38 (dd, 1 H), 2.28 (s, 3 H); IR (CHC13), 2979, 2729 (broad), 1492,1238 cul. 13C NMR (CDC13), 155.2, 140.1,130.8,128.9,128.6,128.1,126.7,125.8,125.4, 120.8,112.8,76.5,46.2,34.6,32.9,16.6; MS (FD) m/z 255 (M 100%); [a] D =-43.2° (c = 1, MeOH); [a] 365 =-193.6 (c = 1, MeOH); HPLC, Chiralcel OD-H detection at 271 nm, eluting with 15% isopropanol/85% hexane containing 0.2% diethylamine at 1 mL/min, >99% ee; Elem. Anal. Calcd for: C17H2, NO-HC1: C, 69.97; H, 7.60; N, 4.80; Cl, 12.15. Found: C, 69.78; H, 7.66; N, 4.60; Cl, 12.22.

PREPARATION 5 1-Fluoro-2- (diethoxymethyl) benzene Combine 2-fluorobenzaldehyde (22 g, 176 mmol), ethanol (500 mL), p-toluenesulfonic acid, and hexane. Heat to reflux using a water separator charged with 4A molecular sieves (about 20 g). After 3 hours, evaporate in vacuo to give a residue. Distill the residue to give the title compound: bp 105°C, 1H NMR (CDC13) characteristic resonance 6 5.73 (s, 1 H).

EXAMPLE 2 N-methyl-3- (2-methylphenoxy)-3-phenylpropylmaine 2.1 Synthesis of N, N-dimethyl-3- (2- (diethoxymethyl) phenoxy)- 3-phenylpropylamine Combine (R)-N, N-dimethyl-3-hydroxy-3-phenylpropylamine (3.25 g, 18.2 mmol), 1-fluoro-2- (diethoxymethyl) benzene (5.38 g, 27.3 mmol), potassium benzoate (0.3 g), and dimethylsulfoxide (8 mL). Add sodium hydride (0.85 g, 60% in oil, 21 mmol). Cool using a water bath. After 2 hours, allow the reaction mixture to warm to ambient temperature.

After 1 hour, warm to about 50°C and then to about 75-80°C.

After 18 hours, cool to obtain a solution containing the title compound: TLC, Rf=0.48 eluting with CH2Cl2-MeOH-NH40H, <BR> <BR> <BR> 800: 40: 4; 1H NMR (CDC13) characteristic resonances at 8 5.93 (s, 1 H), 5.28 (dd. 1 H).

2.2.1 Synthesis of N, N-dimethyl-3- (2-formylphenoxy)-3- phenylpropylamine Cool the solution of N, N-dimethyl-3- (2- (diethoxymethyl) phenoxy)-3-phenylpropylamine obtained in Example 2.1 to ambient temperature and partition the reaction mixture between methyl t-butyl ether (20 mL) and an aqueous 1 M hydrochloric acid solution (30 mL) and stir.

After 20 minutes, separate the layers, extract the aqueous layer twice with methyl t-butyl ether to give an aqueous solution of the title compound as the hydrochloride salt: TLC, Rf=0.45 eluting with CH2Cl2-MeOH-NH40H 800: 40: 4.

2.2.2 Synthesis of N, N-dimethyl-3- (2-formylphenoxy)-3- phenylpropylamine Combine an aliquot of the solution of N, N-dimethyl-3- (2- (diethoxymethyl) phenoxy)-3-phenylpropylamine obtained in Example 2.1 (0.10 g) and acetonitrile/water/1 M aqueous hydrochloric acid solution (about 3 mL). After 20 minutes, basify using sodium bicarbonate and partition the reaction mixture between water and dichloromethane. Separate the

organic layer and evaporate to give the title compound: TLC, Rf=0.45 eluting with CH2Cl2-MeOH-NH40H 800: 40: 4.

2.3 Synthesis of N, N-dimethyl-3- (2-hydroxymethylphenoxy)-3- phenylpropylamine Cool using an ice bath and basify the solution of N, N- dimethyl-3- (2-formylphenoxy)-3-phenylpropylamine obtained in Example 2.2.1 using an aqueous 5 M sodium hydroxide solution. Add sodium borohydride (1.37 g) and methanol (50 mL). After about 45 minutes, quench the reaction mixture with acetone (about 3 mL). Acidify to a pH of about 1 using a concentrated aqueous hydrochloric acid solution and stir.

After 5 minutes, adjust the pH to about 10 using an aqueous 5 M sodium hydroxide solution and evaporate in vacuo to remove most of the methanol before extracting twice with dichloromethane (50 mL). Dry the combined organic layers over 4A molecular sieves, filter, and evaporate in vacuo to give the title compound (2.1 g): TLC, Rf=0.45 eluting with CH2Cl2-MeOH-NH40H 800: 40: 4; 1H NMR (CDC13) characteristic resonance at 8 5.24 (dd, 1H).

2.4 Synthesis of N-methyl-3- (2-methylphenoxy)-3- phenylpropylamine Prepare N-methyl-3- (2-methylphenoxy)-3- phenylpropylamine from the product obtained in Example 2.3 by demethylation as described above in Example 1.6.

EXAMPLE 3 Tomoxetine, (R)-N-methyl-3- (2-methylphenoxy)-3- phenylpropylamine 3.1 Synthesis of (R)-N, N-dimethyl-3- (2-cyanophenoxy)-3- phenylpropylamine Combine (R)-N, N-dimethyl-3-hydroxy-3-phenylpropylamine (8.9 g, 49.6 mmol, dried in vacuo at about 40°C for 18 hours) and dimethylsulfoxide (18 mL). Add sodium hydride (about 100 mg). After about 5 minutes, add 2-

chlorobenzonitrile (7.5 g, 54.6 mmol). Cool in an water bath and add sodium hydride (2.05 g, 60% on oil, 51.3 mmol) in five portions over about 2 hours. After 48 hours, add an additional amount of sodium hydride (100 mg). After 24 hours, dilute the reaction mixture with water (50 mL), adjust the pH with acetic acid (about 5 mL), and extract with hexane. Basify the aqueous layer to a pH of about 11 using an aqueous 50% sodium hydroxide solution and extract with ethyl acetate. Extract the ethyl acetate layer three times with water, dry over sodium sulfate, filter, and evaporate in vacuo to give a residue. Combine the residue and methanol (150 mL). Add a solution of oxalic acid (4.48 g) in methanol (50 mL). Concentrate the solution to about 60 mL and add methyl t-butyl ether (about 60 mL) and continue to concentrate while inducing crystallization by scratching. Add an additional portion of methyl t-butyl ether (about 100 mL) and cool to about 0°C. When crystallization is complete, collect the solid by filtration, rinse with cold methyl t-butyl ether (about 50 mL), and dry to give (R)-N, N-dimethyl-3- (2-cyanophenoxy)-3- phenylpropylamine oxalic acid salt (16.4 g). HPLC using a Chiracel-OD column, eluting with 5% isopropanol/heptane/ 1% diethethylamine at 2 mL/minute gives retention time of 5.3 minutes for the (R)-isomer and 3.6 minutes for the (S)- isomer with ee= 88%. Combine (R)-N, N-dimethyl-3- (2- cyanophenoxy)-3-phenylpropylamine oxalic acid salt (6.79 g), dichloromethane (130 mL), water (200 mL), concentrated aqueous ammonia (25 mL), and an aqueous 5 M sodium hydroxide solution (7 mL). After mixing thoroughly, separate the layers, extract the aqueous layer with dichloromethane.

Combine the organic layers, extract with water/concentrated aqueous ammonia/aqueous 5 M sodium hydroxide solution (200/25/7), dry over sodium sulfate, filter, and evaporate in vacuo to give the title compound.

3.2 Synthesis of (R)-N, N-dimethyl-3- (2-formylphenoxy)-3- phenylpropylamine Combine, in a nitrogen-purged vessel, (R)-N, N-dimethyl- 3- (2-cyanophenoxy)-3-phenylpropylamine (5.0 g, 17.83 mmol), Raney nickel (3 g), pyridine (37 mL), acetic acid (20 mL), and a solution of sodium hypophosphate (5 g) in water (20 mL). Heat to about 70°C and stir vigorously. After 2 hours, add Raney nickel (1 g). Af-ter 3 additional hours, filter to remove the catalyst, rinse with water and four portions of ethyl acetate, cool the filtrate to about 0°C, and slowly add a cooled solution of sodium bicarbonate (24.5 g) in water (75 mL). Separate the layers, extract the aqueous layer twice with ethyl acetate. Combine the organic layers extract with a saturated aqueous sodium bicarbonate solution and then brine, dry over sodium sulfate, filter, and evaporate in vacuo to give a residue. Combine the residue and methanol and evaporate in vacuo to give the title compound.

3.3 Synthesis of (R)-N, N-dimethyl-3- (2- hyrdoxymethylphenoxy)-3-phenylpropylamine Combine (R)-N, N-dimethyl-3- (2-formylphenoxy)-3- phenylpropylamine obtained in Example 3.2 and methanol (50 mL). Cool to about-10°C and add portionwise sodium borohydride (0.67 g) over about 1 hour. After 5 hours, quench by the addition of acetone and evaporate the reaction mixture in vacuo to give a residue. Partition the residue between dichloromethane (20 mL containing methanol 1 mL) and water. Add a saturated aqueous sodium bicarbonate solution (30 mL) and separate the layers. Extract the aqueous layer with dichloromethane. Combine the organic layers, dry over sodium sulfate, filter and evaporate in vacuo to give a residue (4.71 g). Combine the residue (4.5 g) and oxalic acid in (1.42 g, 15.8 mmol) in methanol (4 mL). Add methyl t-butyl ether (18 mL), induce crystallization by scratching, and cool to about 0°C to give a solid. Collect the solid by

filtration, rinse with cold methyl t-butyl ether, and dry in vacuo to give (R)-N, N-dimethyl-3- (2-hyrdoxymethylphenoxy)-3- phenylpropylamine oxalic acid salt (5.0 g): Elem. Anal.

Calcd. for C18H23NO2 C2H204 : C, 63.99; H, 6.71; N, 3.73.

Found: C, 63.98; H, 6.71; N, 3.64. Combine (R)-N, N- dimethyl-3- (2-hyrdoxymethylphenoxy)-3-phenylpropylamine oxalic acid salt (4.0 g), dichloromethane (80 mL), water (120 mL), concentrated aqueous ammonia (16 mL), and an aqueous 5 M sodium hydroxide solution (5 mL). After mixing thoroughly, separate the layers, extract the aqueous layer with dichloromethane. Combine the organic layers, extract with water/concentrated aqueous ammonia/aqueous 5 M sodium hydroxide solution (120/16/5), dry over sodium sulfate, filter, and evaporate in vacuo to give the title compound.

3.4 Synthesis of (R)-N, N-dimethyl-3- (2-chloromethylphenoxy)- 3-phenylpropylamine hydrochloric acid salt Combine (R)-N, N-dimethyl-3- (2-hyrdoxymethylphenoxy)-3- phenylpropylamine (1.54 g, 5.32 mmol), and dichloromethane (15 mL). Cool in an ice-bath. Add dropwise thionyl chloride (0.4 mL) and then warm to ambient temperature.

After 1.5 hours, evaporate to give the title compound (1.81 g).<BR> <BR> <P>3.5 Synthesis of (R)-N, N-dimethyl-3- (2-methylphenoxy)-3- phenylpropylamine hydrochloric acid salt Combine (R)-N, N-dimethyl-3- (2-chloromethylphenoxy)-3- phenylpropylamine hydrochloric acid salt_ (1.56 g, 4.58 mmol), zinc metal (3.46 g, 53.2 mmol), acetic acid (9.3 mL), and water (0.76 mL) and stir vigorously. After 5 hours, filter, rinse with two portions of methanol, and evaporate in vacuo to give a residue. Combine the residue and dichloromethane (50 mL) and extract with an aqueous 1 M hydrochloric acid solution (50 mL). Extract the aqueous layer with dichloromethane, combine the organic layers, and extract with a saturated aqueous sodium bicarbonate

solution. Evaporate the organic layer to give a residue.

Combine the residue and ethyl acetate (about 10 mL) and add a solution 1 M solution of hydrochloric acid in ethyl acetate (5 mL) Evaporate in vacuo to give a residue.

Triturate the residue with ethyl acetate (about 1 mL) to give a solid. Dissolve the gummy solid in dichloromethane and treat with decolorizing carbon. Filter and evaporate in vacuo to give a residue. Recrystallize the residue from dichloromethane and diethyl ether to give after cooling a solid. Collect the solid by filtration to give, after drying, the title compound (0.87 g): MS (FIA) m/z = 270; HPLC, Chiralcel OD column at 35°C, detection at 258 nm, eluting with hexane-isopropanol-diethyl amine 97.5: 3: 0.5 at 1 mL/min, tR (R) enantiomer 2.7 min, 94% ee.<BR> <BR> <P>3.6 Synthesis of Tomoxetine, (R)-N-methyl-3- (2- methylphenoxy)-3-phenylpropylamine hydrochloric acid salt Prepare tomoxetine from the product obtained in Example 3.5 by demethylation as described above in Example 1.6.

EXAMPLE 4 Tomoxetine, (R)-N-methyl-3-(2-methylphenoxy)-3- phenylpropylmaine 4.1.1 Synthesis of (R)-N-methyl-3- (2-cyanophenoxy)-3- phenylpropylamine Combine (R)-N-methyl-3-hydroxy-3-phenylpropylamine (6.29 g, 38 mmol), 2-chlorobenzonitrile (5.76 g, 41.8 mmol), and dimethylsulfoxide (14 mL). Cool in a water bath and add sodium hydride (1.67 g, 60% in oil, 41.7 mmol) in three portions over about 1 hour. After the addition of sodium hydride is complete, allow to warm to ambient temperature while not allowing the reaction to heat to above about 28°C.

After 5 hours, cool the reaction mixture, dilute with water (50 mL), adjust the pH to about 5 with acetic acid, and extract with hexane. Basify the aqueous layer to a pH of about 11 using an aqueous 50% sodium hydroxide solution and

extract three times with dichloromethane. Combine the organic layers and evaporate in vacuo to give a residue.

Combine the residue and a solution of oxalic acid (3.42 g, 38 mmol) in warm methanol (10 mL). Stir while slowly adding methyl t-butyl ether (90 mL) to give a solid. Cool to about 0°C, collect the solid by filtration, rinse with cold (about 0°C) methyl t-butyl ether/methanol (10/1,100 mL) and dry to give (R)-N-methyl-3- (2-cyanophenoxy)-3-phenylpropylamine oxalic acid salt. Combine (R)-N-methyl-3- (2-cyanophenoxy)- 3-phenylpropylamine oxalic acid salt (9.0 g, 25.2 mmol), dichloromethane (200 mL), water (200 mL), concentrated aqueous ammonia solution (25 mL), and an aqueous 5 M sodium hydroxide solution (12 mL) and mix. Separate the layers and extract the aqueous layer with dichloromethane. Combine the organic layers and extract with water (200 mL) containing concentrated aqueous ammonia solution (25 mL) and an aqueous 5 M sodium hydroxide solution (12 mL). Dry the organic layer over sodium sulfate, filter, and evaporate in vacuo to give the title compound.

4.1.2 Synthesis of (R)-N-methyl-3- (2-cyanophenoxy)-3- phenylpropylamine Combine sodium hydride (0.285 g, 60%, 11.88 mmol) and dimethylsulfoxide (2.0 mL). Add via cannula a solution of (R)-N-methyl-3-hydroxy-3-phenylpropylamine (2.0 g, 12.12 mmol) in dimethylsulfoxide (2.5 mL). Cool in an ice bath and add 2-fluorobenzonitrile (1.54 g, 12.73 mmol). After 40 minutes, allow to warm to ambient temperature. After 1 hour, partition the reaction mixture between water and ethyl acetate, extract the aqueous layer with ethyl acetate, combine the organic layers, extract with water/brine (1/1), dry over sodium sulfate, filter, and evaporate in vacuo to give the title compound.

4.2 Synthesis of (R)-N-methyl-3- (2-formylphenoxy)-3- phenylpropylamine

Combine, in a nitrogen-purged vessel, (R)-N-methyl-3- (2-cyanophenoxy)-3-phenylpropylamine (4.75 g, 17.8), Raney nickel (3 g), pyridine (37 mL), acetic acid (20 mL), and a solution of sodium hypophosphate (5 g) in water (20 mL).

Heat to about 70°C and stir vigorously. After 2.5 hours, add Raney nickel (2 g). After 3 additional hours, cool to ambient temperature, filter to remove the catalyst, rinse with water, cool the filtrate to about 5°C, and slowly add a cooled solution of potassium carbonate (13.55 g) in water (30 mL) to give a solution of the title compound.

4.3 Synthesis of (R)-N-methyl-3- (2-hyrdoxymethylphenoxy)-3- phenylpropylamine Slowly, add portionwise sodium borohydride (1.5 g, 39.5 mmol) to the solution of (R)-N-methyl-3- (2- formylphenoxy)-3-phenylpropylamine obtained in Example 4.2.

After 18 hours, add a solution of potassium carbonate (13.55 g) in water (40 mL) and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate, filter and evaporate in vacuo to give a residue. Combine the residue and dichloromethane. Extract with a saturated aqueous sodium bicarbonate solution, dry the organic layer over sodium sulfate, filter, and evaporate in vacuo to give the title compound (4.3 g).

4.4 Synthesis of (R)-N-methyl-3- (2-chloromethylphenoxy)-3- phenylpropylamine hydrochloric acid salt Combine (R)-N-methyl-3- (2-hyrdoxymethylphenoxy)-3- phenylpropylamine (2.15 g, 7.92 mmol) and dichloromethane (20 mL). Cool to about 0°C and purge with hydrogen chloride (gas). After about 1 minute, add thionyl chloride (0.6 0 mL, 8.32 mmol). After 1.5 hours, evaporate in vacuo to give the title compound (2.45 g).

4.5 Synthesis of Tomoxetine, (R)-N-methyl-3- (2- methylphenoxy)-3-phenylpropylamine hydrochloric acid salt

Combine (R)-N-methyl-3- (2-chloromethylphenoxy)-3- phenylpropylamine hydrochloric acid salt (2.45 g, 7.51 mmol), zinc metal (2.94 g, 45 mmol), acetic acid (20 mL) and water (1.2 mL). After 4 hours, filter, rinse the solids with methanol and evaporate the filtrate to give a residue.

Combine the residue and dichloromethane and extract with an aqueous 1 M hydrochloric acid solution. Extract the aqueous layers twice with dichloromethane, combine the organic layers, and extract with a saturated aqueous sodium bicarbonate solution. Dry the organic layer over sodium sulfate, filter and evaporate in vacuo to give a residue.

Combine the residue, ethyl acetate (about 250 mL), and an aqueous 1 M hydrochloric acid solution (about 7.5 mL) and evaporate in vacuo to give a residue. Recrystallize the residue from dichloromethane/diethyl ether to give a solid.

Collect the solid by filtration and recrystallize from ethyl acetate to give, after collection and drying, the title compound: 1H NMR (CDC13) 8 9.63 (broad s, 2H), 6.55-7.4 (m, 9H), 5.38 (dd, 1 H), 3.12 (t, 2H), 2.6 (s, 3H), 2.4-2.6 (m, 2H), 2.28 (s, 3 H).