MXPA01006680A - Method for the preparation of aryl ethers - Google Patents

Abstract

A method for preparing a compound of formula (IXa) from a compound of formula (VIIa), and preparation of intermediates useful in the method.

Description

METHOD FOR PREPARING ARIL ETHERIES FIELD OF THE INVENTION The present invention relates to an improved method for preparing certain aryl ethers that are useful as antidepressants. The invention also relates to intermediates useful in the method, and to the methods for preparing these intermediates.

BACKGROUND OF THE INVENTION U.S. Patent 4,229,449, issued October 21, 1980, discloses compounds of the formula (A) (A) where n and ni are, independently, 1, 2 or 3; each of the groups R and Ri, which may be the same or different, is hydrogen; halogen; haloalkyl of d-C6; hydroxy; C6-C6 alkoxy; optionally substituted Ci-Cc alkyl; C 1 -C 6 aryl-alkyl optionally substituted; C 1 -C 6 aryl-alkoxy optionally substituted; -N02; NR5R6 wherein R5 and R6 are, independently, hydrogen or Ci-Cß alkyl or two adjacent R groups or two adjacent Ri groups, taken together, form a -0-CH2-0- radical; R2 is hydrogen; optionally substituted C 1 -C 2 alkyl or arylCi-Ce alkyl; each of the groups R3 and R, which may be identical or different, is hydrogen, optionally substituted Ci-C alquilo alkyl, C2-C alkenyl, C2-C4 alkynyl, optionally substituted C ar-C aryl alkyl, Optionally substituted C3-C cycloalkyl or R3 and R with the nitrogen atom to which they are attached form an optionally substituted, saturated or unsaturated, hexatomic or pentatomic heteromonocyclic radical optionally containing other heteroatoms belonging to the class of O, S and N; or R2 and R, taken together, form a radical -CH2-CH2-; or a pharmaceutically acceptable salt thereof; The compounds are exposed to possess antidepressant activity.

In particular, U.S. Patent 4,229,449 discloses. the compound: 2- [a- (2-ethoxy phenoxy) benzyl] morpholine: and their pharmaceutically acceptable salts, which possess useful antidepressant properties. This compound is also known as Reboxetine. As illustrated in Figure 4, United States Patent 5,068,433 (issued November 26, 1991) and related United States Patent 5,391,735 (issued February 21, 1995) disclose the processes and intermediates useful for preparing diastomers Individuals of compounds of the formula VIb: wherein R is C6-C6 alkoxy or t-ri-halometyl. These diastomers are thought to be useful intermediates for preparing compounds of the formula A, including Reboxetine. However, the processes set forth in these patents and in US Pat. No. 4,229,449 are not efficient and provide a low overall yield of the 5 compounds of formula A when carried out on a commercial scale. In addition, the processes require the use of expensive reagents and also require significant production times. In this way, it is not economical to prepare the compounds of the formula A on a commercial scale using the processes outlined in these patents. Accordingly, there is currently a need for improved processes for preparing the compounds of the formula (A) and for preparing intermediates useful for providing the compounds of the formula (A). Ideally, the improved processes should use inexpensive reagents, which are carried out more quickly or which provide improved or improved intermediates. global returns compared to existing processes. These improvements could facilitate the commercial scale production of the compounds of the formula (A).

BRIEF DESCRIPTION OF THE INVENTION As illustrated in Figure 2, the invention provides a method for preparing an amine of the formula Vlla: Vlla comprising: a) oxidizing a trans-cinnamyl alcohol optionally substituted to provide an intermediate epoxide of the formula la: b) reacting the epoxide with a phenol optionally substituted to provide a diol of the formula lia: c) reacting the diol with a solid reagent to provide an alcohol of the formula Illa: Ula wherein P is a radical linked by silyl; d) reacting the alcohol of the formula Illa with the reactive derivative of a sulfonic acid to provide a compound of the formula IVa: IVa wherein Ra is a residue of a sulfonic acid; e) removing P from the compound of the formula IVa to provide an alcohol of the formula Va: It goes f) to displace the sulfonyloxy group to provide an epoxide of the formula Via: Via g) reacting the epoxide with ammonia to provide the compound of the formula Vlla. As illustrated in Figure 3, the invention also provides a method further comprising: h) reacting a compound of the formula Vlla: ? Vlla with a carboxylic acid of the formula HOOCCH2L or a reactive derivative thereof, wherein L is a leaving group, to provide an amide of the formula Villa: i) reacting the compound of the formula Villa to provide a compound of the formula IXa: IXa and j) reducing the compound of the formula IXa to prroopporcionar a corresponding compound of the following pair formula The invention also provides novel intermediates set forth herein (for example, the compounds of formulas III-V and Illa-Va) as well as the methods for their synthesis.

DETAILED DESCRIPTION The following definitions are used, unless otherwise described: halo is fluorine, chlorine, bromine or iodine. Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; although the reference to an individual radical as "propyl" embraces only the straight chain radical, a branched chain isomer as "isopropyl" to which it specifically refers. The aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having between about nine and ten ring atoms in which at least one ring is aromatic. "Commercial scale" means an ultimogram quantity that is sufficient to be distributed to a large number of consumers, for example, at least about 10 kg, about 100 kg or about 1000 kg of material. It will be appreciated by those skilled in the art that the compounds of the formula (A) and the intermediates described herein having a chiral center can exist in optically active and racemic forms and can be isolated from them. Some compounds may exhibit polymorphism. It should be understood that the present invention encompasses any racemic, optically active, polymorphic or stereoisomeric form or mixtures thereof, it is well known in the art how to prepare optically active forms (e.g., by resolution of the racemic form by techniques of recrystallization, by synthesis of optically active starting materials, by chiral synthesis or by chromatographic separation using a chiral stationary phase). The methods of the invention allow the preparation of individual diastomer mixtures of the compounds of the formula A and the intermediates disclosed herein. It should be understood that these mixtures can be separated into the corresponding enantiomers using techniques that are known in the art. Accordingly, the invention also provides for the preparation of individual enantiomers of the compounds of the formula (A) as well as the individual enantiomers of any of the intermediates disclosed herein. The preferred compounds have the stereochemistry corresponding to the stereochemistry of Reboxetine. The specific and preferred values listed below for the radicals, substituents and variations are provided for illustration only; they do not exclude other defined values or other values within the ranges defined for the radicals and substituents. Specifically, n is 1. Specifically, it is not 1. Specifically, R is hydrogen, halo, trifluoromethyl, hydroxy, Ci-Cβ alkoxy, C?-C6 alkyl, aryl-C?-C6 alkyl, aryl-C alco-alkoxy -Cß, nitro or NR5R6. Specifically, n is 2 and two adjacent R groups form a methylenedioxy radical. Specifically, Rf is hydrogen, halo, trifluoromethyl, hydroxy, C?-C6 alkoxy, Ci-Cg alkyl, C?-C6 aryl-alkyl, Ci-Ce aryl-alkoxy, nitro or NR5R6. Specifically, neither is 2 and two adjacent Ri groups form a methylenedioxy radical. Specifically, R5 and Re are each hydrogen.

Specifically, R 2 is hydrogen, methyl, ethyl, phenyl, benzyl or phenethyl. Specifically, each R3 and R is hydrogen. Specifically, at least one R 3 and R 4 is optionally substituted C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, optionally substituted C 1 -C 4 aryl alkyl, optionally substituted C 3 -C 7 cycloalkyl or R 3 and R together with the nitrogen atom to which they are attached are morpholino, piperidino, N-pyrrolidinyl, N-methyl-piperazinyl or N-phenyl-piperazinyl. Specifically R2 and R4, taken together form a radical -CH2-CH2-; and R3 is hydrogen. Specifically, as soon as a group can be replaced by "one or more" radicals, the group can be replaced by at least 1, 2 or 3 radicals. A preferred group of compounds are compounds wherein n is 1 and R is 2-methoxy or 2-ethoxy. Another preferred group of compounds are compounds wherein ni is 1 and Ri is hydrogen or halo. The Patents of the United States numbers 4,229,449, 5,068,433 and 5,391,735 provide examples of certain specific and preferred values for the substituents and groups described herein. It should be understood that these specific and preferred values are also specific and preferred values for the substituents and specific groups described herein. For example, U.S. Patent No. 4,229,449 includes the following description for the substituents and groups herein: a) the alkyl, alkenyl, alkynyl and alkoxy groups can be straight or branched chains; b) when one or more of the R and Ri groups is a substituted C? -C6 alkyl group, preferably substituted C? -C6 alkyl by one or more substituents selected from hydroxy, Cj.-C6 alkoxy, -NR5R6 or -C (= 0) NR5R6; c) preferably aryl is phenyl; d) when one or more of the groups R3 and R4 is a C6-6 alkyl group substituted, preferably it is Ci-C3 alkyl substituted by one or more substituents selected from halogen, hydroxy, alkoxy or C6C6, -NR5R6, or -C (= 0) NR5R6; the same substituents can be present in a substituted C? -C? 2 alkyl group; e) substituted C 1 -C 6 alkyl aryl, aryl C 1 -C 4 alkyl and C 1 -C 6 aryl alkoxy groups are preferably aryl C 1 -C 6 alkyl, aryl C 1 alkyl C4 and C6-C6-alkoxy in which the aryl group is substituted by one or more C6-C6 alkyl, halogen, C6-C6 haloalkyl, hydroxy, Ci-Ce alkoxy and -NR5R6 , "f) a substituted C3-C7 cycloalkyl group is a C3-C cycloalkyl substituted by one or more substituents preferably selected from C? -C6 alkyl, halogen, C? -C6 haloalkyl, hydroxy, alkoxy of C? -C6 and -NR5R6; g) a C? -C6 alkyl group is preferably methyl, ethyl or isopropyl; h) a C? -C? 2 alkyl group is preferably methyl, ethyl, isopropyl or octyl i) a C2-C4 alkenyl group is preferably vinyl or allyl, a C2-C4 alkynyl group is preferably propargyl, j) a haloalkyl group of Ci-Ce is preferably trihaloC1 alkyl; C6, in particular trifluoromethyl; k) a Ci-Cβ alkoxy group of pref Erencia is methoxy or ethoxy; 1) an aryl C 1 -C 6 alkyl or a C 1 -C 4 arylalkyl group is preferably benzyl or phenethyl; m) an aryl-Cxi-C6 alkoxy group is preferably benzyloxy; n) in a group -NR5Re, R5 and Re are preferably, independently, hydrogen or C? -C3 alkyl; in particular methyl, ethyl or isopropyl; o) a C3-C cycloalkyl group is preferably cyclopropyl, cyclopentyl or cyclohexyl; p) when R3 and R4, with the nitrogen atom to which they are attached, form a substituted heteromonocyclic radical, the substituents are preferably C6-C6 alkyl or aryl, in particular methyl or phenyl; the preferred heteromonocyclic radicals are morpholino, piperidino, N-pyrrolidinyl, N-methyl-piperazinyl and N-phenyl-piperazinyl; and q) when two adjacent R groups or two adjacent Ri groups form the radical -0-CH2-0-, this is preferably a 3,4-methylenedioxy radical; The United States patent number 4,229,449 also teaches that the compounds of the formula (A) can be administered as pharmaceutically acceptable salts, including salts with inorganic acids, for example hydrochloric acid, hydrobromic acid and sulfuric acid; and including salts with organic acids, for example, citric acid, tartaric acid, methanesulfonic acid, fumaric acid, malic acid, maleic acid and mandelic acid. Preferred salts are exposed to be acid salts (eg, hydrochloric acid or methanesulfonic acid salt) formed with the amine group -NR3R4 group. Accordingly, the methods of the invention that provide a compound of the formula (A) may also optionally comprise the preparation of a salt of the compound of the formula (TO) . Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art. The epoxidation of a trans-cinnamic alcohol of the formula: to provide an epoxide of the formula. it can be conveniently carried out by using an epoxidation agent, for example, vanadic anhydride and hydrogen peroxide, vanadium (acetylacetonate) 2 and tert-butyl hydroperoxide, or a peroxy acid such as perbenzoic acid, peracetic acid m-chloroperbenzoic acid or mono- or di-peroxy phthalic. The reaction can be carried out in any suitable solvent or combination of solvents, for example, in a hydrocarbon, a halogenated hydrocarbon, a linear or branched ether, a carboxylic acid or an ester. Specific solvents include benzene, toluene, chloroform, methylene chloride, diethyl ether, dioxane, acetic acid, and ethyl acetate. Preferably, the reaction is carried out in methylene chloride or ethyl acetate. Most preferred in methylene chloride. The reaction can be performed at any Freezing point temperature at the reflux temperature of the reaction mixture. Preferably, the reaction is carried out at a temperature in the range of between about 0 ° C and 50 ° C. More preferably, at a temperature in the range ID between approximately 5 ° C and 25 ° C. U.S. Patent 5,068,433 and related U.S. Patent 5,391,735 disclose that an epoxide of formula Ib can be prepared from trans-cinnamic alcohol using a suitable oxidizing agent, for example, vanadic anhydride and hydrogen peroxide or a peroxy acid such as, for example, perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, mono- or di-peroxyphtalic or peroxytrifluoroacetic acid. At In Example 1, these patents specifically exemplify the preparation of an epoxide of the formula Ib by the oxidation of the trans-cinnamic alcohol with m-chloroperbenzoic acid. Oxidation of trans-cinnamic alcohol with m-chloroperbenzoic acid was also reported by P. Melloni et al. Tetra edron, 1985, 41, no. 7, 1393-1399. M-chloroperbenzoic acid is expensive to be used on a commercial scale. In this way, a different epoxidation reagent could be preferred for the commercial scale production of a compound of the formula (A). Studies with mono-peroxy phthalic acid have shown that this reagent can be used to prepare the epoxide Ib on a commercial scale. However, preparation of mono-peroxy phthalic acid from phthalic anhydride and hydrogen peroxide takes time. In addition, the epoxidation reaction with mono-peroxy phthalic acid generates a large amount of a by-product of solid phthalic acid which must be filtered out of the product mixture. This filtration step takes time and generates a large amount of aqueous and solid waste. Thus, m-chloroperbenzoic acid and mono-peroxy phthalic acid are not ideally suited for the commercial scale epoxidation of trans-cinnamic alcohol. It has been found that the epoxidation of cinnamyl alcohol can be carried out on a commercial scale using peracetic acid. Peracetic acid is less expensive and, like a liquid, it is easier to handle on a large scale than m-chloroperbenzoic acid, which is a solid. Additionally, the use of peracetic acid reduces the time required to prepare epoxide Ib, by eliminating the need to prepare mono-peroxy phthalic acid; the peracetic acid also substantially reduces the amount of aqueous and solid waste generated by the epoxidation reaction compared to the reaction with mono-peroxy phthalic acid. Accordingly, the invention provides a method for preparing an epoxide of the formula la: which comprises oxidizing a correspondingly substituted trans-cinnamic alcohol with peracetic acid. The epoxide is quite sensitive to decomposition by strong acids. Commercial peracetic acid is stabilized with sulfuric acid. Therefore, peracetic acid should be treated with a suitable base (eg, sodium or potassium acetate) before use; or the reaction can be conveniently carried out in the presence of a suitable solid base (for example, sodium or potassium carbonate). Preferably, the reaction is carried out on a commercial scale. Preferably, the reaction is carried out in methylene chloride and at a temperature of less than about 30 ° C. The reaction of an epoxide of the formula la with a phenol optionally substituted to provide a diol of the formula Ia can conveniently be carried out using a suitable base, for example, aqueous sodium or potassium hydroxide, sodium hydride or potassium hydride. . The reaction can be carried out in any suitable solvent or combination of solvents, for example, in a hydrocarbon, a halogenated hydrocarbon or a linear or branched ether, such as benzene, toluene, tetrahydrofuran, methylene chloride, diethyl ether or dioxane. The reaction can be carried out at any suitable temperature from the point of conqelation to the reflux temperature of the reaction mixture. Preferably, the reaction is carried out at a temperature in the range between about 0 ° C and 100 ° C. More preferably, at a temperature in the range of between about 20 ° C and 50 ° C. Preferably, the reaction can be carried out under phase transfer conditions using a suitable phase transfer catalyst (e.g., tributylmethylammonium chloride) as illustrated in Example 2. P. Melloni et al. Tetrahedron, 1985, 41, no. 7, 1393-1399 discloses the isolation of the compound of formula II (Figure 1) by recrystallization from isopropyl ether. It has been found that the compound of formula II can be conveniently isolated by recrystallization from methyl tert-butyl ether (MTBE). MTBE is less expensive and is less prone to the formation of explosive peroxides than the isobutyl ether. In this way, the compound of formula II can preferably be isolated by recrystallization from MTBE. Protecting the primary hydroxyl group in a diol of the formula lia to form a mono-protenido compound of the formula Illa wherein P is a silylating protective group can be carried out using any suitable silylating reagent (e.g., tert-butyldimethylsilyl chloride, trimethylsilyl chloride, tert-butyldiphenylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride, hexamethyldisilazane with or without trimethylsilyl chloride or triphenylsilyl chloride). The reaction can be carried out in any suitable solvent or combination of solvents, for example, in a hydrocarbon, an ester, a halogenated hydrocarbon or a linear or branched ether, such as benzene, toluene, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, ethyl acetate or dioxane. The reaction can be carried out at any suitable temperature which allows the selective protection of the primary alcohol with respect to the secondary alcohol, provided that the temperature is above the freezing point of the reaction mixture. Preferably, the reaction is carried out at a temperature below -5 ° C. More preferably, the reaction is carried out at a temperature below -10 ° C or lower at -15 ° C. Most preferably, the reaction is carried out at a temperature in the range of between about -15 ° C and -25 ° C. Other suitable silylating reagents and reaction conditions are known in the art, for example, see Greene, T.W .; utz, P.G.M. "Protecting Groups In Organic Synthesis" second edition, 1991, New York, John Wiley & amp;; Sons, Inc. As illustrated in Figure 4, U.S. Patents 5,068,433 and 5,391,735 state that a diol of formula Ilb can be esterified to provide a compound of formula Illb wherein R 2 is a residue of a carboxylic acid . Unfortunately, the primary alcohol protection of the diol, under the conditions described in these patents, proceeds with low selectivity; also up to 13% of the ester is formed in the secondary alcohol. The formation of the mono p-nit robenzoate in the secondary alcohol results in a direct decrease in the production of the amine of the formula VIb. The formation of the mono p-nit robenzoate in the secondary alcohol also provides the unwanted diastomer of the amine of the formula VIb as a contaminant in the amine product. In addition, the formation of the bis p-nitrobenzoate causes a reduced production of the amine of the formula VIb, and provides the bis p-nitrobenzoate as a contaminant in the amine product. Due to the presence of these unwanted contaminants, there is a need for extensive purification of the amine product, which consumes time and causes an additional reduction in yield. Thus, the processes described in U.S. Patent Nos. 5,068,433 and 5,391,735 are not ideally suited for the commercial scale production of the amine of the formula Via. It has unexpectedly been found that the primary alcohol in the diol of the formula Ilb it can be selectively protected in high yield using a silyl protecting group. In particular, it has been found that the primary alcohol can be selectively protected with a gruop t rimet ilsilyl. The reaction with t-rimethylsilyl chloride is almost completely selective, both in the reaction with the primary versus the secondary alcohol, and in the absence of formation of the bis-rimet-ylsilyl ether. As a result, the yield of the amine Vllb obtained from the process of the invention is significantly increased with respect to the yield obtained using the previously known processes. In addition, tritium chloride is less expensive than p-nitrobenzoyl chloride, is more readily available, and is easier to handle on a large scale, since trimethylsilyl chloride is a liquid and chloride of p-nitrobenzoyl is a solid. There is some precedence for the selectivity seen for the reaction of Ilb with trimethylsilyl chloride. The trimethylsilyl groups have been used extensively for the derivatization of alcohols, mainly in analytical applications where the desired result is exhaustive silylation. Significant selectivity has been observed for reactions of secondary alcohols in different environments (for example, see HJ Schneider, R. Homing, Leibi gs Ann. Ch em., 1974, 1864-1871 and EW Yankee et al., J Am. Chem. Soc., 1974, 5865). However, the relative proportion information for the reactions of the primary and secondary alcohols is not available and the literature lacks examples of selective protection of a primary alcohol with trimethylsilyl chloride in the presence of a secondary alcohol. Examples for the reaction of a primary alcohol in the presence of a secondary alcohol are reported with hexamat ildis ila zano catalyzed by the trimethyl chloride ilium (J.

Cossy, P. Palé, Te t. Le t t. 1987, 6039-6040), and by the reaction with hexamethyldisilazane catalyzed by metal chlorides (H. Firouzabadi et al., Syn.Comm., 1997, 2709-2719) where the best selectivity was 85: 3: 12, primary: secondary: bis-ether). The selective protection of the primary alcohol can be carried out using a silyl protecting group (preferably, trimethylsilyl chloride) at a low temperature. It has also been determined that the migration of the silyl protecting group can be prevented by 1) keeping the protected compound of the formula Illa at a low temperature through conversion from a compound of the formula Ia to a compound of the formula Va and 2) by carrying out the sequence of reactions required for a short period of time (for example, less than about 5 hours, and preferably, less than about 4, about 3 or about 2 hours). As illustrated in Example 6, this can be conveniently carried out by carrying out the conversion of the diol of the formula Ia to the compound of the formula IIIa, IVa and Va in a reactor, without isolating the intermediates of the formula IIIa, IVa.

Accordingly, the invention provides a method for preparing a compound of the formula Illa: Ula where P is a radical attached to silyl; which comprises reacting a diol of the formula lia: with a suitable silylating reagent. Preferably, P is a trimethylsilyl group and the silylating reagent is trimethylsilyl chloride. Preferred solvents include ethyl acetate and methylene chloride. The reaction of an alcohol of the formula Illa with a reactive derivative of a sulfonic acid to provide a compound of the formula IVa wherein Ra is the residue of a sulfonic acid can be carried out by using any suitable sulfonating reagent, for example, a sulphonic acid halide, in particular a sulfonic acid chloride (for example, p-toluenesulfonyl chloride, benzenesulfonyl chloride, (Ci-C6) alkylsulfonyl chloride or trifluoromethylsulfonyl chloride). A preferred reactive derivative of a sulfonic acid is methanesulfonyl chloride. The reaction can be conveniently carried out in the presence of a suitable base (for example, triethylamine or pyridine). The reaction can be carried out in any suitable solvent or combination of solvents, for example, in a hydrocarbon, a halogenated hydrocarbon, an organic ester or a linear or branched ether, such as benzene, toluene, tetrahydrofuran, methylene chloride, acetate of ethyl, diethyl ether or dioxane. Preferably, the reaction is carried out in ethyl acetate. The reaction can be carried out at any temperature above the freezing point of the reaction mixture. Preferably, the reaction is carried out at a temperature below -5 ° C. More preferably, the reaction is carried out at a temperature lower than -10 ° C or lower than -15 ° C. Most preferably, the reaction is carried out at a temperature in the range of between about -15 ° C and -25 ° C. Other derivatives of suitable sulfonic acid reagents and reaction conditions are known in the art, for example see Jerry March "Advanced Organic Chemistry" fourth edition, 1992, New York, John Wiley & sons, Inc., 352-356. Removal of the P-silyl group from a compound of the formula IVa to provide an alcohol of the formula Va can be carried out using any suitable catalyst, for example, an acid (for example, HCl) or a fluoride ion source (for example, HCl). example, tetrabutylammonium fluoride). The reaction can be carried out in any suitable solvent or combination of solvents, for example, in a hydrocarbon, a halogenated hydrocarbon, an organic ester or a linear or branched ether, such as benzene, toluene, chloroform, methylene chloride, acetate of ethyl, diethyl ether, tetrahydrofuran or dioxane. Preferably, the reaction is carried out in ethyl acetate. The reaction can be carried out at any temperature above the freezing point of the reaction mixture. Preferably, the reaction is carried out at a temperature in the range of between about -78 ° C and 100 ° C. More preferably, the reaction is carried out at a temperature in the range of between about -50 ° C and 50 ° C. More preferably, the reaction is carried out at a temperature in the range between about -25 ° C and 25 ° C. The reaction of an alcohol of the formula Va to provide an epoxide of the formula Via can be carried out in the presence of any suitable base, for example, an alkali metal or an alkaline earth metal hydroxide similar to sodium or potassium hydroxide. The reaction can be carried out in any suitable solvent or combination of solvents, for example, in a hydrocarbon, a halogenated hydrocarbon or a linear or branched ether, such as benzene, toluene, chloroform, methylene chloride, diethyl ether, tetrahydrofuran or dioxane . Preferably, the reaction is carried out under phase transfer conditions in a mixture of toluene and water in the presence of a phase transfer catalyst (eg, tributylmethyl ammonium chloride). The reaction can be carried out at any temperature above the freezing point and below the reflux temperature of the reaction mixture. Preferably, the reaction is carried out at a temperature in the range of between about -78 ° C and 100 ° C. More preferably, the reaction is carried out at a temperature in the range of between about -50 ° C and 50 ° C. More preferably, the reaction is carried out at a temperature in the range of about 15 ° C and 30 ° C. As illustrated in Figure 4, U.S. Patents 5,068,433 and 5,391,735 state that a compound of formula IVb can be converted to an epoxide of formula Vb by treatment with a suitable base in an aqueous organic solvent solvent such as , for example, dioxane or dimethylformamide (see column 4, lines 19-27 and Example 5 hereof). P. Melloni et al. Tetrahedron, 1985, 41, no. 7, 1393-1399 also disclose the conversion of a specific compound of formula IVb to the corresponding epoxide of formula Vb by treatment with sodium hydroxide in dioxane (see page 1397). When carried out on a large scale (approximately 165 kg), this reaction is slow (18 hours), and the removal of dioxane is difficult due to its high boiling point and its high freezing point (p.p. 11.8 ° C). In this way, the distillation may require one or two days, and there is a risk that the dioxane will freeze in the apparatus during distillation, causing damage to the condensers. In addition, dioxane is a carcinogen and is toxic. As illustrated in Figure 2, and as shown in Example 6 below, it has been discovered that a compound of the formula Va can be converted to an epoxide of the formula Via in a mixture of toluene and water under transfer conditions of phase. The reaction can be carried out on a large scale in about 45 minutes, and toluene can be easily removed from the product mixture. Accordingly, the invention provides a method for preparing a compound of the formula Via: )neither Route where R, Ri n and ni have any of the values defined herein; which comprises treating a corresponding compound of the formula Va: It goes where Ra is the residue of a sulfonic acid, with a suitable base, under phase transfer conditions. Preferably, the reaction is carried out at a temperature in the range of about 0 ° C and the reflux temperature of the reaction mixture. Most preferably, the reaction is carried out at a temperature in the range of about 15 ° C and 35 ° C. The reaction of an epoxide of the formula Via with ammonia to provide an amine of the formula Vlla can be carried out in the presence of any suitable ammonia source, for example, ammonia hydroxide or aqueous ammonium. The reaction can be carried out in any suitable solvent or combination of solvents, for example, a hydrocarbon, a halogenated hydrocarbon, an aliphatic alcohol or a linear or branched ether, such as benzene, toluene, chloroform, methylene chloride, diethyl ether, methanol, ethanol, isopropanol, dioxane, tetrahydrofuran or dimethylformamide. Preferably, the reaction is carried out in methanol using ammonium hydroxide as a source of ammonia, as described in Example 7. The reaction can be carried out at or below any reflux temperature of the mixture. reaction. Preferably, the reaction is carried out at a temperature in the range of between about -50 ° C and 1 00 ° C. Most preferably, the reaction is carried out at a temperature in the range of between about 0 ° C and 80 ° C. Most preferably, the reaction is carried out at a temperature in the range of about 20 ° C and 50 ° C. The reaction of an amine of the formula Vlla to provide a corresponding amide of the formula Villa can be conveniently carried out with a reactive derivative of a carboxylic acid of the formula HOOCCH 2 L wherein L is a suitable leaving group. Suitable leaving groups are known in the art, and include halides (for example, bromine, chlorine or iodine), sulfonyl esters (for example, 4-toluenesulfonyloxy, methylsulfonyloxy, trifluoromethyl-sulfonyloxy, (C6-6) alkylsulfonyloxy or phenylsulfonyloxy). , wherein the phenyl may be optionally substituted with one or more substituents independently selected from halo, (Ci-C6) alkyl, nitro, (C? -C6) alkoxy, trifluoromethyl and cyano). A preferred carboxylic acid is chloroacetyl chloride. The reaction can be conveniently carried out in the presence of a suitable base (i.e., triethylamine or pyridine). The reaction can be carried out in any suitable solvent or combination of solvents, for example, in a hydrocarbon, a halogenated hydrocarbon, an organic ester or a linear or branched ether, such as benzene, toluene, chloroform, methylene chloride, acetate of ethyl, dimethyl carbonate, diethyl ether, tetrahydrofuran or dioxane. Preferably, the reaction is carried out in dimethyl carbonate or methylene chloride. The reaction can be carried out at any temperature above the freezing point of the reaction mixture. Preferably, the reaction is carried out at a temperature below 50 ° C. More preferably, the reaction is carried out at a temperature below 25 ° C or below 15 ° C. Most preferably, the reaction is carried out at a temperature in the range of about 0 ° C to 10 ° C.

The reaction of a compound of the formula VIIIA to form a morpholinone of the formula IXa can be conveniently carried out in the presence of a suitable base (for example, sodium hydride, potassium hydride or potassium tert-butoxide). The reaction can be carried out in any suitable solvent or combination of solvents, for example, in a hydrocarbon, a halogenated hydrocarbon, an aliphatic alcohol or a linear or branched ether, such as benzene, toluene, methylene chloride, diethyl ether, isopropanol, tetrahydrofuran or dioxane. Preferably, the reaction is carried out in isopropanol with potassium tert-butoxide as a base as described in Example 9. The reaction can be carried out at any temperature above the freezing point and at the reflux temperature or lower at this temperature of the mixture. Preferably, the reaction is carried out at a temperature in the range of between about -78 ° C and 100 ° C. Most preferably, the reaction is carried out at a temperature in the range of between about -25 ° C and 50 ° C. More preferably, the reaction is carried out at a temperature in the range of about 0 ° C and 30 ° C.

The reduction of a morpholinone of the formula IXa to form a compound of the formula (A) wherein R 2 and R 4 are ethylene, can be conveniently carried out in the presence of a suitable reducing agent (for example, borane, lithium hydride- aluminum, diisobutyl aluminum hydride, diisopropylaluminum hydride or bis (2-methoxyethoxy) aluminum hydride). The reaction can be carried out in any suitable solvent or combination of solvents, for example, in a hydrocarbon or in a linear or branched ether, such as benzene, toluene, diethyl ether or tetrahydrofuran. The reaction can be carried out at any temperature above the freezing point and at the reflux temperature or below that temperature of the mixture. Preferably, the reaction is carried out at a temperature in the range of between about -78 ° C and 100 ° C. More preferably, the reaction is carried out at a temperature below 50 ° C or at a temperature below 10 ° C. More preferably, the reaction is carried out at a temperature in the range between about -20 ° C and 5 ° C. P. Melloni et al. Te t ra h edron, 1985, 41, no. 7, 1393-1399, on page 1399, state that a morpholinone of formula IX (Figure 1) can be reduced to morpholine (Reboxetine) by the addition of a toluene solution containing 2.96 equivalents of R-EDAL (hydride of sodium bis (2-methoxyethoxy) aluminum) to a solution of morpholinone. When this reaction is carried out on a large scale (approximately 25 kg of morpholinone), the reaction product is typically contaminated with 0.6 to 1% of the following impurity: For the final drug product of formula (A) to comply with regulatory standards in some countries, the concentration of this impurity in the final product must be less than 0.1%. The removal of this impurity is difficult but can be done using a controlled pH extraction of approximately pH 5.2. During this extraction, however, 20-30% of the compound of the formula (A) is typically lost and can not be easily recovered. It has been determined that the amount of impurity resulting from the reduction can be significantly reduced by the addition of a solution of the morpholinone IXa to a solution containing an excess (eg, about 5 equivalents) of the bis (2-) sodium hydride. methoxyethoxy) aluminum. Using this procedure, it has been found that the reaction produces directly Reboxetine-free base containing less than 0.1% of the impurity. This material can be used directly, without carrying out an extraction with controlled pH. This reduces the processing time and eliminates the loss of 20-30% of the product. It has been found that using less than 5 equivalents of the reducing agent reduces the yield of the reaction. In this way, the preference reduction is carried out using at least about 4 equivalents of sodium bis (2-methoxyethoxy) aluminum hydride or other suitable reducing agent. More preferably, the reduction is carried out using at least about 5 equivalents of a suitable reducing agent (eg, at least between about 5 and 10 equivalents of sodium bis (2-methoxyethoxy) aluminum hydride). Preferably, the reducing agent is not lithium aluminum hydride. Accordingly, the invention provides a method for preparing a compound of the following formula: wherein R, R n and ni have any of the values defined herein; which comprise adding a corresponding compound of the formula Xla: IXa to a solution comprising at least 4 equivalents of a suitable reducing agent. This invention also provides a compound of the formula Illa: nia wherein R, R n and ni have any of the values, specific values or preferred values described herein for a corresponding radical in a compound of the formula (A), and P is a suitable silyl protecting group (for example, tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, triphenylsilyl). Preferably, the compound of the formula Illa is a compound of the formula III. The invention also provides a compound of formula IVa: IVa wherein R, R n and ni have any of the values, specific values or preferred values described hereinbefore for a corresponding radical in a compound of the formula (A); P is a silyl protecting group (eg, tert-1-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, triphenylsilyl); and Ra is a residue of a sulphonic acid (eg, p-toluenesulfonyl, phenylsulfonyl, methylsulfonyl, ethylsulphonyl or trifluoromethylsulfonyl) Preferably, the compound of the formula IVa is a compound of the formula IV. the formula Va: It goes where R, R n and ni have any of the values, specific values or preferred values described hereinbefore for a corresponding radical in a compound of the formula (A); and Ra is a residue of a sulphonic acid (for example, p-toluenesulfonyl, phenylsulfonyl, methylsulfonyl, and ilsulphonyl or trifluoromet ilsulfoni, etc. Preferably, the compound of the formula Va is a compound of the formula V. As illustrated in Figure 1, the invention preferably also provides a method to prepare a compound of formula VII: comprising: a) oxidizing a trans-cinnamyl alcohol optionally substituted to provide an intermediate epoxide of formula I: b) reacting the epoxide with a phenol optionally substituted to provide a diol of the formula I I: c) reacting the diol with a silylating reagent to provide an alcohol of the formula III: d) reacting the alcohol of formula III with the reactive derivative of methanesulfonic acid to provide a compound of formula IV: e) removing the trimethylsilyl group of the compound of the formula IV to provide an alcohol of the formula V: f) displacing the sulfonyloxy group to provide an epoxide of formula VI: g) reacting the epoxide with ammonia to provide the compound of the formula VII. The resulting compound of formula VII can be conveniently isolated by conversion to the methane sulphonate salt, for example, as described in Example 7. The above method for preparing a compound of formula VII can optionally comprise: h) making reacting the compound of formula VII with chloroacetyl chloride to provide an amide of formula VIII: i) reacting the compound of formula VIII to provide a compound of formula IX: j) reducing the compound of formula IX to provide a corresponding morpholine compound of the following formula: The invention will now be illustrated by the following non-limiting examples, wherein unless stated otherwise: a) the melting points were determined in open capillary tubes in a Buchi melting point apparatus and are uncorrected; b) NMR spectrum data were recorded in a Bruker AMX400 operating at 400.13 MHz for 1H observation and 100.62 for 13C observation; the samples were dissolved in (1H d = 7.26; 13C, d = 77.0) and internally designated as CDC13; c) mass spectral data were acquired in a Fisons individual quad spectrometer Trio 2000 operating in electronic impact mode (El) or by chemical ionization (Cl); the exploration interval was 110-600 uma for Cl and 45-600 uma for El; the initial temperature was 150 ° C, the electronic multiplier 400 V, and the electronic energy -70 eV; chemical ionization was carried out with ammonium as reactive gas and adjusted to an initial pressure of 1.4 x 10-4 mTorr; d) reactions were routinely monitored using a Perquin Elmer HPLC (Series 200 pump and 235C diode array detector) using Nucleosil-100 C-18 columns and mixtures of water and acetonitrile as the eluent, with or without added CF3COOH; the conversion of cinnamyl alcohols to epoxides was monitored at 215 nm, the others at 275 nm; e) reagents and solvents, were commercial products and were used without purification; f) the reactions were carried out under itrogen; and g) thin-layer chromoatography (TLC) was performed using Analytech uniplaca silica gel plates (250 μ, Cat. No. 02521).

EXAMPLES Example 1. (2RS, 3RS) -2, 3-Epoxy-3-phenylpropanol (1) Sodium carbonate (224 g) and trans-cinnamyl alcohol (200.0 g) were mixed with 2L of methylene chloride. A slow purification with nitrogen was maintained through the vapor space of the flask and the mixture was cooled to 15-20 ° C with a bath of ice water. The peracetic acid solution (35%, 381.2mL) was added for a period of 3 hours, keeping the internal temperature below 25 ° C. After finishing the addition of the peracetic acid, the mixture was stirred for 2-3 hours until the end, as shown by HPLC analysis. The mixture was cooled to 10 ° C with an ice bath and a solution of sodium sulfite (160g) in 1200 ml of water was added slowly over 90 minutes, keeping the temperature at less than 30 ° C. The phases were separated and the aqueous phase was extracted with methylene chloride (200 mL) to provide a solution of the title compound.

Example 2. (2RS, 3SR) -3- (2-Etboxyphenoxy) -2-hydroxy-3-phenylpropanol (II) Water (800 mL), sodium hydroxide (50%, 83.1 mL), tributylmethylammonium chloride ( 75%, 27.5 ml), and 2-ethoxyphenol (306.72 g) and stirred at 20-25 ° C. The 2,3-epoxy-3-phenylpropanol methylene chloride solution of Example 1 was added, and the two-phase mixture was stirred and heated to 40 ° C internal temperature. The methylene chloride was distilled at atmospheric pressure for a period of 3-4 hours. When the methylene chloride was removed, the internal temperature was increased to 60 ° C for 2 hours. The mixture was cooled to less than 30 ° C, toluene (1200 ml) was added, and the mixture was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with toluene (800 mL). The toluene solutions were combined and washed with 1 N NAOH (2 x 400 ml) and with water (400 ml) at about 25 ° C. The toluene solution was concentrated under partial vacuum maintaining an internal temperature of 40-50 ° C. The residual oil was dissolved in methyl t-butyl ether (760 ml) and the water content was verified to be less than 0.1% by the potassium fluoride test. The solution was seeded with crystals of the title compound at 20-25 ° C, stirred for 1 hour, and cooled to 0 ° C for 2 hours. The resulting solids were filtered, washed with methyl t-butyl ether (2 x 200 mL, cooled to 15 ° C), and dried under vacuum to provide 256.1 g of the title compound (60.5% from cinnamyl alcohol).

Example 3. (2RS, 3SR) -3- (2-Ethoxy-enoxi) -2-hydroxy-3-phenyl-1- (rimethylsilyloxy) propane (III) 3- (2-Ethoxyphenoxy) -2-hydroxy-3 was dissolved phenylpropanol from Example 2 (1.44 g, 5 mmol) and triethylamine (0.77 mL, 5.5 mmol) in ethyl acetate (15 mL) and cooled to -17 ° C. Dissolved trimethylsilyl chloride (0.64 mL, 5.0 mmol) in 5 mL of ethyl acetate was added for 10 minutes keeping the temperature below 15 ° C. A white precipitate formed during this addition. The mixture was stirred below -15 ° C for 15 minutes, and 20 mL of pentane was added. The solids were removed by filtration and the filtrate was concentrated under vacuum to a cloudy oil. The oil was chromatographed on silica (230-400 mesh) eluting with 4: 1 heptane-acetic acid or ethyl. Fractions containing product were concentrated to provide 1.80 g (88.5%) of the title compound as a clear, colorless oil; H NMR (400.13 MHZ, CDC13) d 0.09 (s, 9H), 1.47 (t, J = 6.8 Hz, 3H), 2.82 (d, J = 5.2, ÍH), 3.80 (m, 3H), 4.0-4.11 ( m, 4H), 5.08 (d, J = 6.0, ÍH), 6.76 (m, 2H), 6.85 (m, 2H), 7.2-7.45 (m, 5H); 13C NMR (100.62 MHZ, CDC13) d 0.0, 15.54, 63.34, 65.06, 75.22, 83.71, 114.28, 118.60, 121.51, 122.95, 127.84, 128.49, 128.84, 138.93, 148.34, 150.40; MS (ei) m / e 360; Example 4. (2RS, 3SR) -3- (2-Ethoxyphenoxy) -2-mesyloxy-3-phenyl-1- (trimethylsilyloxy) propane (IV) 3- (2-Ethoxyphenoxy) -2-hydroxy-3- was dissolved phenylpropanol from Example 2 (1.44 g, 5 mmol) and triethylamine (0.77 mL, 5.5 mmol) in ethyl acetate (15 mL) and cooled to -17 ° C. Dissolved trimethylsilyl chloride (0.64 mL, 5.0 mmol) in ethyl acetate (5 mL) was added over 10 minutes keeping the temperature below -15 ° C. A white precipitate formed during this addition. The mixture was stirred below -15 ° C for 15 minutes. Triethylamine (0.8 mL, 5.7 mmol) was added, followed by methanesulfonyl chloride (0.46 mL, 6.0 mmol) dissolved in 5 mL of ethyl acetate, maintaining the temperature below -15 ° C. The mixture was stirred below -15 ° C for 15 minutes. Pentane (20 mL) was added and the solids were removed by filtration. The filtrate was concentrated under vacuum to a cloudy oil. The oil was subjected to silica chromatography (230-400 mesh) eluting with 4: 1 heptane-ethyl acetate. The fractions containing the product were concentrated to provide 2.00 g (91.2%) of the title compound as an oil that solidified on standing; p.f. 80-82.5 ° C; 1 NMR (400.13 MHZ, CDC13) d 0.17 (s, 9H), 1.50 (t, J = 6.8 Hz, 3H), 3.06 (s, 3H), 3.77 (dd, J = ll, 6, ÍH), 4.00 ( dd, J = ll, 6, 1H), 4.10, (q, J = 6.8, 2H), 5.07, (m, ÍH), 5.51 (d, J = 4.4, ÍH), 6.75 (m, 2H), 6.91 (m, 2H), 7.2-7.49 (m, 5H); 13C NMR (100.62 MHZ, CDC13) d 0.0, 15.66, 38.87, 61.57, 64.88, 79.90, 85.20, 113.97, 116.99, 121.32, 122.79, 128.26, 129.09, 129.14, 136.75, 147.72, 149.95; MS (ei) m / e 438.

Example 5. (2RS, 3SR) -3- (2-Ethoxyphenoxy) -2-mesyloxy-3-f nyl-1-propanol (V) 3- (2-Ethoxyphenoxy) -2-hydroxy-3-phenylpropanol was dissolved Example 2 (0.288 g, 1 mmol) and triethylamine (0.15 mL, 1.1 mmol) in ethyl acetate (5 mL) and cooled to -17 ° C. Trimethylsilyl chloride (0.13 mL, 1.0 mmol) dissolved in ethyl acetate (2 mL) was added for 10 minutes keeping the temperature below 15 ° C. A precipitate formed during this addition. The mixture was stirred below -15 ° C for 15 minutes. Triethylamine (0.15 mL, 1.1 mmol) was added, followed by methanesulfonyl chloride (0.085 mL, 1.1 mmol) dissolved in ethyl acetate (2 mL) keeping the temperature below -15 ° C. The mixture was stirred below -15 ° C for 15 minutes. Hydrochloric acid (2N, 2 mL) was added and the mixture was allowed to warm to 20-25 ° C and stirred for 30 minutes. The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution (5 mL) and dried over sodium sulfate. The solution was evaporated to provide 0.377 g of an oil. The oil was subjected to silica chromatography (230-400 mesh) eluting with 1: 1 hexane-ethyl acetate. The fractions containing the product were concentrated to give 0.33 g (91%) of the title compound as an oil that solidified at rest; p.f. 83-86 ° C; H NMR (400.13 MHZ, CDC13) d 1.66 (t, J = 8.2 Hz, 3H), 2.85 (s, 3H), 4. 14-4.35 (m, 4H), 5.12 (m, ÍH), 5.52 (d, J = 6.1 Hz), 6.8-7.15 (m, 4H), 7.5-7.7 (m, 5H); 13C NMR (100.62 MHZ, CDC13) d 14.73, 37.80, 62.19, 64.27, 81.40, 84, 04, 112.88, 117.19, 120.67, 122.86, 127.40, 128. 77, 128.86, 137.02, 146.40, 149.30; MS (ei) m / e 366.

Example 6. (2RS, 3RS) -1, 2-Epoxy-3- (2-ethoxyphenoxy) -3-phenylpropane (VI) 3- (2-Ethoxyphenoxy) -2-hydroxy-3-phenyl-1-propanol was dissolved of Example 2 (28.8g) and triethylamine (1 6.7 mL) in ethyl acetate (1 70 mL) and cooled to a temperature between 20 to -15 ° C. A solution of trimethylsilyl chloride was squeezed (13.2 ml) in ethyl acetate (20 ml) maintaining the reaction temperature between -20 and -15 ° C. After finishing the addition, the mixture was stirred for 5 minutes at a temperature between -20 and -15 ° C. Methanesulfonyl chloride (9.3 ml) was added to the solution maintaining the temperature between -20 and -15 ° C. Triethylamine (16.7 ml) was then added, again maintaining a temperature between -20 and -15 ° C. The mixture was stirred for 15 minutes after finishing the addition of triethylamine. A solution of concentrated hydrochloric acid (8.3 ml) and water (92 ml) was added to the reaction mixture. The mixture was allowed to warm to 15-25 ° C and was stirred for 45 minutes. The reaction was monitored by TLC. The phases were separated and the organic phase was washed with a solution of sodium bicarbonate (5 g) in 45 ml of water and then with a solution of 12.5 grams of sodium chloride and 37.5 ml of water. The organic phase was concentrated under vacuum to an oil. Toluene (200 ml) was added and the solution was concentrated to an oil, which was redissolved in 200 ml of toluene. Sodium hydroxide solution added (50%, 36 g) water (60 mL) and tributylmethylammonium chloride (70%, 2.5 g) to the toluene solution. The mixture was purged with nitrogen, stirred at high speed at 20-25 ° C for 45 minutes, and analyzed by HPLC. The phases were separated and the oily yellow interface was maintained with the organic phase. The aqueous phase was extracted with toluene (50 mL) and the toluene solutions were combined. The toluene solutions were washed with saturated sodium chloride solution (50 mL, 12.5 grams of NACI and 37.5 mL of water). The toluene solution was concentrated under vacuum at 60 ml (bath temperature 40 ° C). Methanol (300 ml) was added, the solution was concentrated to a volume of 60 ml. Methanol (300 ml) was added and the mixture was again concentrated to a volume of 60 ml to provide a solution of the title compound.

Example 7. (2RS, 3RS) -3- (2-Ethoxyphenoxy) 2-Idroxy-3-phenylpropyl ananine (VII) To the methanol solution of Example 6 were added 270 ml of methanol and 300 ml of ammonium hydroxide. The mixture was stirred in a sealed container and heated at 40 ° C for three hours. After three hours the reaction was cooled and analyzed by HPLC. Methylene chloride (223 ml) was added and the mixture was stirred and then allowed to settle. The phases were separated and the aqueous phase was extracted with methylene chloride (2 X 100 ml). The organic layers were combined and distilled under vacuum to a volume of 300 ml. Methylene chloride (180 ml) was added again to the solution. The methylene chloride solution was washed with 250 ml of water. The water was extracted with 100 ml of methylene chloride and the methylene chloride solutions were combined. A solution of 250 ml of water and 10 ml of concentrated hydrochloric acid was added to the combined methylene chloride solutions. The pH was adjusted to below 2 by the addition of more HCl. The mixture was stirred and then allowed to settle. The phases were separated and the organic phase was extracted with 250 ml of water. The aqueous phases were combined and washed with 46 ml of methylene chloride.

Methylene chloride (144 ml) was added to the aqueous phase and the pH was adjusted to more than 12 with 50% aqueous NAOH (approximately 10 g). The phases were separated and the aqueous phase was extracted with 72 ml of methylene chloride. The organic phases were combined and distilled at a volume of 200 ml. Isopropyl alcohol (200 ml) was added and the mixture was distilled to a volume of 200 ml. Isopropyl alcohol (200 ml) was added and the solution was distilled again to a volume of 200 ml. Methanesulfonic acid (7.9 g) was added and the mixture was stirred at 20-25 ° C for 2 hours. The resulting paste was cooled to 0-5 ° C and stirred for 60 minutes. The solids were filtered and washed with 100 ml of isopropyl alcohol. The resulting solid was dried in a vacuum oven at 60 ° C to provide 24.5 g of the title compound as the methane sulphonate salt (64% total of 3- (2-ethoxyphenoxy) -2-hydroxy-3-phenol 1 - 1-propanol).

Example 8. (2RS, 3SR) -N-Chloroacetyl-3- (2-ethoxyphenoxy) -2-hydroxy-3-phenylpropylamine (VIII) were stirred (2RS, 3RS) -1, 2-Epoxy-3- (2- ethoxy phenoxy) -3-phenylpropane (47.7 g) and dimethyl carbonate (700 mL) to form a white suspension.

Triethylamine (52 mL) was added and the mixture was cooled to 6-10 ° C using an ice / H20 bath. A solution of chloroacetyl chloride (13.8 mL) in dimethyl carbonate (50 mL) was added over a period of 30 minutes maintaining the temperature between 4-10 ° C. The mixture was stirred for 1 hour. The mixture was washed with 500 mL of H20 and then with 500 mL of 3% aqueous NaCl solution. The organic layer was concentrated under vacuum at 40 ° C to provide a dark oil. Isopropanol (500 mL) was added and the mixture was again concentrated to remove any residual dimethyl carbonate to provide the title compound.

Example 9. (2RS, 3RS) -2- [a- (2-E-oxyphenoxy) benzyl] morpholine-5-one (IX) The product of Example 8 was stirred with 200 mL of isopropanol to form a suspension. A solution of isopropanol (305 mL) and potassium t-butoxide (30.6 g) was prepared. This was added to the isopropanol suspension maintaining the reaction temperature between 20-23 ° C with an ice bath. The mixture was stirred at 20-25 ° C for 1 hour. The pH of the mixture was adjusted 6.4 by the addition of 1N HCl (ca 210 mL). The mixture was evaporated under vacuum to an oil. Water (170 mL) toluene (150 mL) was added to the residue and the mixture was stirred for 5 minutes. The aqueous layer was extracted with 100 mL of toluene. The toluene extracts were combined and washed with 100 mL of IN HCl and 100 mL of 10% NACI solution. The toluene solution was evaporated to an oil and the residue redissolved in 240 mL of toluene to provide a solution of the title compound.

Example 10. (2RS, 3RS) -2- [a- (2-Ethoxyphenoxy) benzyl] morpholine (Reboxe ina) A vitrified solution in toluene (65%, 187 mL) was diluted with 187 mL of toluene and the solution was cooled at less than 5 ° C. The toluene solution of Example 9 was added for 1 hour keeping the temperature below 5 ° C. The mixture was stirred for 15 minutes after the end of the addition. A solution of 60 g of 50% NaOH in sufficient water was added to constitute a volume of 350 mL, keeping the temperature below 55 ° C. The two-phase mixture was stirred at 55 ° C for 15 minutes after the addition was complete. The toluene phase was washed with 5% sodium carbonate solution (3 X 170 mL). Water was added to the toluene solution and IN HCl was added to provide a pH of 3.11. The aqueous phase was extracted with 480 mL of toluene. Toluene (480 mL) was added to the aqueous solution and the pH adjusted to more than 12 with 50% NAOH. The aqueous phase was extracted with 240 mL of toluene. The two toluene solutions were combined and washed with sodium carbonate solution (5%, 175 mL) and water (175 mL). The toluene was evaporated to provide 32 g of the title compound as the free base.

Example 11. Methanesulfonate salt of (2RS, 3RS) -2- [a- (2-Ethoxyphenoxy) benzyl] morpholine The oil of Example 10 was dissolved in 122 mL of acetone and stirred with 2 g of activated charcoal. (eg, Darco G-60, Calgon Carbon Corporation, or Norit, American Norit Corporation) and 2 g of celite at 20-25 ° C for 1 hour. The mixture was filtered and the volume of the filtrate was adjusted to 320 mL. The solution was cooled to 0 ° C and methanesulfonic acid (5.1 mL) was added. The mixture was stirred at 0 ° C for 70 minutes, then filtered. The solids were washed with 100 mL of acetone and dried under nitrogen to provide 30.08 g of white solids. The solids were suspended in 200 mL of acetone and stirred at 50 ° C for 2 hours. The suspension was cooled to 0 ° C for 30 minutes and filtered. The solids were dried under nitrogen to provide 27.72 g of the title compound (54.3% total 3- (2-ethoxyphenoxy) -2-hydroxy-3-phenylpropyl amine). All publications, patents, and patent documents referred to herein, as well as the full disclosure of U.S. Provisional Application No. 60 / 114,092, are hereby incorporated by reference, even if incorporated individually as a reference. . The invention has been described with reference to various specific and preferred modalities and techniques. However, it should be understood that many variations and modifications may be made as long as they remain within the spirit and scope of the invention.

Claims (20)

1. A method for preparing an amine of the formula Vlla: VIIa where n and ni are, independently, 1, 2 or 3; each of the groups R and Rx, which may be the same or different, is hydrogen; halogen; halo C -C6 alkyl; hydroxy; C6-C6 alkoxy; alkyl of C6-C6 optionally substituted; C 1 -C 6 aryl-alkyl optionally substituted; C 1 -C 6 aryl-alkoxy optionally substituted; -N02; NR5R6 wherein R5 and Re are, independently, hydrogen or C? -Cd alkyl or two adjacent R groups or two adjacent Rx groups, taken together, form a -0-CH2-0- radical; comprising: a) oxidizing an optionally substituted trans-cinnamate alcohol to provide an intermediate epoxide of the formula la: b) reacting the epoxide with a phenol optionally substituted to provide a diol of the formula lia: c) reacting the diol with a reactive solvent to provide an alcohol of the formula Illa: Ula wherein P is a radical linked by silyl; d) reacting the alcohol of the formula Illa with the reactive derivative of a sulfonic acid to provide a compound of the formula IVa: IVa wherein Ra is a residue of a sulfonic acid; e) removing P from the compound of formula IVa to provide an alcohol of formula Va: It goes f) to displace the sulfonyloxy group to provide an epoxide of the formula Via: Via and g) reacting the epoxide with ammonia to provide the compound of the formula Vlla.

2. The method according to claim 1 further comprising: h) reacting a compound of the formula Vlla: Vlla with a carboxylic acid of the formula HOOCCH2L or a reactive derivative thereof, wherein L is a leaving group, to provide an amide of the formula Villa: i) reacting the compound of the formula Villa to provide a compound of the formula IXa: IXa j) reducing the compound of formula IXa to provide a corresponding compound of the following formula:

3. The method according to claim 2 further comprising forming a pharmaceutically acceptable salt of the morpholine compound.

4. A method for preparing a compound of the formula VI I: comprising: a) oxidizing a trans-cinnamyl alcohol optionally substituted to provide an intermediate epoxide of formula I: b) reacting the epoxide with a phenol optionally substituted to provide a diol of the formula I I: c) reacting the diol with a silylating reagent to provide an alcohol of formula III: d) reacting the alcohol of formula III with the reactive derivative of methansulonic acid to provide a compound of formula IV: e) removing the trimethylsilyl group of the compound of formula IV to provide an alcohol of formula V: f) displacing the sulfonyloxy group to provide an epoxide of formula VI: SAW g) reacting the epoxide with ammonia to provide the compound of the formula VII.

5. The method according to claim 4 further comprising preparing the methane sulphonate salt of the compound of the formula VII.

6. The method according to claim 4 further comprising: h) reacting the compound of the formula VII with chloroacetyl chloride to provide an amide of the formula VIII: i) reacting the compound of formula VIII to provide a compound of formula IX: and j) reducing the compound of formula IX to provide a corresponding morpholine compound of the following formula:

7. The method according to claim 5 further comprising: h) reacting the methane sulfonate salt with chloroacetyl chloride to provide an amide of the formula VIII: i) reacting the compound of formula VIII to provide a compound of formula IX: and j) reducing the compound of formula IX to provide a corresponding morpholine compound of the following formula:

8. The method according to claim 6 or 7 further comprising forming a pharmaceutically acceptable salt of the morpholine compound.

9. The method according to claim 8 wherein the salt is a methane sulfonate salt.

10. A method for preparing an epoxide of the formula which comprises oxidizing a corresponding alkene with peracetic acid

11. A method for preparing a compound of the formula Illa: i nía where n and ni are, independently, 1, 2 or- 3; each of the groups R and Rx, which may be the same or different, is hydrogen; halogen; halo C -C6 alkyl; hydroxy; C6-C6 alkoxy; optionally substituted C? -C6 alkyl; C 1 -C 6 aryl-alkyl optionally substituted; C 1 -C 6 aryl-alkoxy optionally substituted; -N02; NR5R6 wherein R5 and Re are, independently, hydrogen or C? -C6 alkyl or two adjacent R groups or two adjacent R groups, taken together, form a -0-CH2-0- radical; and P is a silyl-linked radical; which comprises reacting a diol of the formula lia: i with a suitable silylating reagent

12. A method for preparing a compound of the formula Via Path where n and ni are, independently, 1, 2 or 3; and each of the groups R and Rx, which may be the same or different, is hydrogen; halogen; haloalkyl of C? -Cd; hydroxy; C6-C6 alkoxy, optionally substituted C6-alkyl, optionally substituted C6-C6-alkyl, optionally substituted C6-C6-alkoxy, -N02, NR5R6 wherein R5 and R are, independently , hydrogen or C? -C6 alkyl or two adjacent R groups or two adjacent Rx groups, taken together, form a radical -0-CH2-0-, which comprises treating a corresponding compound of the formula Va: Va wherein Ra is the residue of a sulfonic acid, with a suitable base, under phase transfer conditions.

13. A method for preparing a compound of the following formula: where n and ni are, independently, 1, 2 or 3; and each of the groups R and Rx, which may be the same or different, is hydrogen; halogen; haloalkyl of C? -Cβ; hydroxy; C6-C6 alkoxy, optionally substituted C6-C6 alkyl, optionally substituted C6-C6-alkyl, optionally substituted C6-C6-alkoxy, -N02, NR5R6 wherein R5 and R are, independently, hydrogen or C? -C6 alkyl or two adjacent R groups or two adjacent R groups, taken together, form a -0-CH2-0- radical, which comprises adding a corresponding compound of the formula IXa: l IXa to a solution comprising at least 4 equivalents of a suitable reducing agent.

14. The method according to claim 13 wherein the reducing agent is borane, diisobutylaluminum hydride, diisopropylaluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride.

15. A compound of the formula Illa Ula where n and ni are, independently, 1, 2 or 3; each of the groups R and Rx, which may be the same or different, is hydrogen; halogen; halo C -C6 alkyl; hydroxy; C6-C6 alkoxy; optionally substituted C? -C6 alkyl; C 1 -C 6 aryl-alkyl optionally substituted; C 1 -C 6 aryl-alkoxy optionally substituted; -N02; NR5Rd wherein R5 and Re are, independently, hydrogen or C? -C6 alkyl or two adjacent R groups or two adjacent Rx groups, taken together, form a -0-CH2-0- radical; and P is a suitable silyl protecting group.

16. The compound according to claim 15 which is a compound of the formula III:

17. A compound of the formula IVa IVa where n and ni are, independently, 1, 2 or 3; each of the groups R and Rx, which may be the same or different, is hydrogen; halogen; halo C -C6 alkyl; hydroxy; C6-C6 alkoxy; optionally substituted C? -C6 alkyl; C 1 -C 6 aryl-alkyl optionally substituted; C 1 -C 6 aryl-alkoxy optionally substituted; -N02; NR5R6 wherein R5 and Re are, independently, hydrogen or C-C6 alkyl or two adjacent R groups or two adjacent Rx groups, taken together, form a -0-CH2-0- radical; P is a suitable silyl protecting group; Y Ra is a residue of a sulfonic acid.

18. The compound according to claim 17 which is a compound of formula IV:

19. A compound of the formula Va? It goes where n and are not, independently, 1, 2 or 3; each of the groups R and Rx, which may be the same or different, is hydrogen; halogen; halo C -C6 alkyl, hydroxy; C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 -alkoxy, -N02, NR 5 R 6 wherein R 5 and R are, independently , hydrogen or C? -C6 alkyl or two adjacent R groups or two adjacent Rx groups, taken together, form a radical -0-CH2-0-; and Ra is a residue of a sulfonic acid.

20. The compound according to claim 19 which is a compound of the formula V: RE SUMMARY OF THE INVENTION A method for preparing a compound of the formula (IXa) from a compound of the formula (Vlla) and the preparation of the intermediates useful in the method is set forth.