| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | October 11, 1988 |
| PATENT TITLE |
Racemization process |
| PATENT ABSTRACT | The present invention provides a process for the epimerization of (+)-N-methyl-3-(2-methylphenoxy)- 3-phenylpropylamine to its racemic form with an anion forming compound in a suitable solvent |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 27, 1985 |
| PATENT CLAIMS |
I claim: 1. A process for preparing (+-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine of the formula ##STR2## comprising reacting (+)-N-methyl-3-(2-methylphenoxy) -3-phenylpropylamine with an anion forming compound selected from the group consisting of a C.sub.1 -C.sub.6 alkyl alkali metal and C.sub.1 -C.sub.6 alkyl amide in a suitable solvent selected from the group consisting of 1,2-dimethoxyethane and tetrahydrofuran under inert conditions wherein from about 0.5 molar equivalents to about 1.5 molar equivalents of an anion forming compound are employed for each 1.0 molar equivalent of (+-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine. 2. A process of claim 1 wherein the suitable solvent is tetrahydrofuran. 3. A process of claim 2 wherein the anion forming compound is a C.sub.1 -C.sub.6 alkyl alkali metal. 4. A process of claim 3 wherein the C.sub.1 -C.sub.6 alkyl alkali metal is a C.sub.1 -C.sub.6 alkyllithium. 5. A process of claim 4 wherein the C.sub.1 -C.sub.6 alkyllithium compound is n-butyllithium. 6. A process of claim 4 wherein the C.sub.1 -C.sub.6 alkyllithium compound is sec-butyllithium. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
-------------------------------------------------------------------------------- BACKGROUND OF THE INVENTION Tomoxetine, (-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, is a valuable compound capable of treating humans suffering from depression. The synthesis currently employed to manufacture tomoxetine produces a racemic mixture which must be resolved to the appropriate (-) isomer. The resolution of racemic (+-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine produces significant quantities of the undesired (+) isomer. The (+) isomer generally has been discarded because there has been no inexpensive and efficient method of converting it to the desired (-) isomer. The present invention provides a process for epimerizing the (+) isomer to its racemic form, which can then be quickly and economically converted to the desired (-) isomer, tomoxetine. SUMMARY OF THE INVENTION The present invention relates to a process for preparing (+-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine of the formula ##STR1## comprising reacting (+)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine with an anion forming compound selected from the group consisting of a C.sub.1 -C.sub.6 alkyl alkali metal, C.sub.1 -C.sub.6 alkylamide, alkali metal naphthalene and alkali metal isoprene in a suitable solvent selected from the group consisting of 1,2-dimethoxyethane and tetrahydrofuran under inert conditions. DETAILED DESCRIPTION OF THE INVENTION The term "C.sub.1 -C.sub.6 alkyl", as used herein, represents a straight or branched alkyl chain having from one to six carbon atoms. Typical C.sub.1 -C.sub.6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, and the like. The term "alkali metal", as used herein, represents lithium and sodium. The anion forming compound employed in the process of the present invention is selected from the group consisting of a C.sub.1 -C.sub.6 alkyl alkali metal, C.sub.1 -C.sub.6 alkylamide, alkali metal naphthalene and alkali metal isoprene. The anion forming compound should be sufficiently basic so as to remove the amine hydrogen atom from (+)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine to provide the corresponding anion, and be soluble in the reaction medium. The anion forming compound should not be so strong that it decomposes or degrades the enantiomeric and racemic compounds themselves. A variety of compounds are suitable anion forming compounds for use in the present process. Preferably, C.sub.1 -C.sub.6 alkylamide and particularly C.sub.1 -C.sub.6 alkyl alkali metal reagents may be employed. Exemplary C.sub.1 -C.sub.6 alkylamides include lithium diethylamide and the like. Typical C.sub.1 -C.sub.6 alkyl alkali metal derivatives include the alkyllithium reagents such as methyllithium, sec-butyllithium and n-butyllithium. Primarily for economic reasons, n-butyllithium is the preferred anion forming compound. Other suitable but less preferred anion forming compounds include alkali metal naphthalenes such as sodium and lithium naphthalenes, as well as alkali metal isoprenes such as sodium and lithium isoprenes. The quantity of anion forming compound employed in the present process varies depending on the purity of the starting (+) enantiomer. Impurities generally are present with the (+) isomer since the compound is isolated from the mother liquor following resolution of the racemic mixture. Isolation is accomplished by simply evaporating the volatile constituents of the mother liquor following isolation of the desired (-) isomer, typically under reduced pressure. Generally, from about 0.5 molar equivalents to about 1.5 molar equivalents of anion forming compound are employed in the present process for each 1.0 molar equivalent of starting material, with increasing impurities requiring greater amounts of anion forming compound. However, excess anion forming compound may be employed to ensure complete anion formation and is not harmful to the reaction process. As is typical when forming the anion of a compound, the reaction mixture develops a color, for example a pink or reddish hue, and this is generally apparent in the present process as well. The process of the invention is conducted in a suitable solvent selected from the group consisting of 1,2-dimethoxyethane and especially tetrahydrofuran (THF), which is preferred. When employing THF, the reaction is substantially complete after about 1 to about 5 hours, more typically from about 2 to about 4 hours, when conducted at a temperature in the range of about 15.degree. C. to about 30.degree. C., more typically from about 20.degree. C. to about 25.degree. C. Of course, longer reaction times may be employed if desired, for example when using less preferred anion forming compounds in the process. More generally, longer reaction times may be required for 1,2-dimethoxyethane. For example, the process is typically complete after about 1 to about 40 hours when conducted at a temperature in the range of about -50.degree. C. to about the reflux temperature of the reaction mixture when the reaction is conducted in the presence of 1,2-dimethoxyethane. The term "inert conditions," as defined herein, refers to the use of a reaction medium exhibiting no chemical activity or that is totally unreactive. Since the anion forming compound is sensitive to both moisture and air, all apparatus may be dried prior to use. Further, the reaction must be conducted under an inert atmosphere, for example, in the presence of argon or especially nitrogen. Finally, all solvents should be thoroughly dried prior to use. The desired racemic product is readily isolated by routine procedures well known to one of ordinary skill in the art. Water is typically added to the reaction mixture in order to quench any excess anion forming compound which is present. The aqueous solution is extracted with a suitable water immiscible organic solvent such as methylene chloride or chloroform. The organic phase is then concentrated, typically under vacuum, to provide a residue of the racemic product which is suitable for resolution to the desired (-) enantiomer. The residue may be further purified if desired by common techniques such as chromatography over solid supports such as silica gel or alumina or crystallization from common solvents. Racemic (+-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine thus prepared may be converted to the desired (-) enantiomer by well known procedures used to produce optical isomers. Preferably, the racemate is reacted with L-(+)-mandelic acid to produce the salt of the (-) isomer, which readily crystallizes. Typically, 0.5 molar equivalents of L-(+)-mandelic acid is combined with 1.0 molar equivalent of the racemic compound in a mutual solvent. Exemplary mutual solvents include the ethers such as diethyl ether or tetrahydrofuran; the aliphatic hydrocarbons such as hexane, pentane and the like; aromatic hydrocarbons such as benzene, toluene and xylene; the alcohols such as methanol or ethanol; esters such as ethyl acetate; halogenated hydrocarbons such as methylene chloride or chloroform; and other like protic and aprotic solvents. The reaction is substantially complete after about 1 to about 24 hours when conducted at a temperature in the range of about 0.degree. C. to about the reflux temperature of the reaction mixture. The product thus prepared may be isolated by standard procedures. The compound thus prepared is preferably converted to the hydrochloride salt prior to its use as a pharmaceutical agent. This compound is prepared by well known procedures. Typically, the mandelic acid salt is converted to the free amine by reaction with a suitable base such as sodium hydroxide. The free amine is then dissolved in a suitable solvent and combined with hydrochloric acid, either in gaseous form, or preferably an aqueous solution. Tomoxetine hydrochloride thus prepared may be isolated according to standard procedures such as crystallization from common solvents. The present process permits the use of previously discarded (+) isomer generated in the resolution of racemic (+-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine. As such, the present process would be particularly useful in a production setting in the form of a continuous process whereby the (+) isomer generated in the resolution process may be converted to the racemic mixture which is then combined with the racemic mixture material prepared by the currently employed manufacturing procedure for that compound. Further, the present process does not require complete conversion of the (+) isomer to the racemic mixture since subsequent resolution of the racemic mixture would merely generate additional (+) isomer which can be racemized to the racemic mixture in continuous fashion by the present process. Tomoxetine and salts thereof are known pharmaceuticals useful for the treatment of a variety of human disorders. See, e.g., U.S. Patent Nos. 4,314,081, 4,018,895, and 4,194,009, all incorporated herein by reference, for a discussion of the use of the compounds disclosed therein as psychotropic agents, and in particular their use as antidepressants. The following Examples illustrate the synthesis of (+-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine according to the process of the present invention. The Examples are not intended to be limiting in any respect and should not be so construed. As is known, a mixture of equal parts of enantiomers is a racemic mixture. A racemic mixture is optically inactive since the rotation caused by a molecule of one isomer is exactly canceled by an equal and opposite rotation caused by a molecule of its enantiomer. As such, the formation of the racemic mixture prepared by the present process is measured by its specific rotation. Specific rotations approaching zero degrees are indicative of a racemic mixture. |
| PATENT EXAMPLES | Available on request |
| PATENT PHOTOCOPY | Available on request |
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