MX2008003796A - Process for the stereoselective preparation of (-)-halofenate and intermediates thereof - Google Patents

Abstract

The present invention provides a compounds the formula (IV):and methods for producing anα-(phenoxy)phenylacetic acid compound of the formula:wherein R1is a member selected from the group consisting of:each R2is a member independently selected from the group consisting of (C1- C4)alkyl, halo, (C1-C4)haloalkyl, amino, (C1-C4aminoalkyl, amido, (C1- C4)amidoalkyl, (C1-C4)sulfonylalkyl, (C1-C4)sulfamylalkyl, (C1-C4)allcoxy, (C1- C4)heteroalkyl, carboxy and nitro;the subscript n is 1 when R1has the formula (a) or (b) and 2 when R1 has the formula (c) or (d);the subscript m is an integer of from O to 3;* indicates a carbon which is enriched in one stereoisomeric configuration;and the wavy line indicates the point of attachment of R1;and compounds .

Description

PROCESS FOR THE STEREOSELECTIVE PREPARATION OF (-) -HALOPHENATE AND ITS DERIVATIVES Cross-references with related applications This application claims the benefit of the US Patent Application. No. 60 / 720,300, filed on September 23, 2005; and the benefit of the U.S. Patent Application. with Serial No. yet to be assigned, submitted on September 20, 2006, and entitled PROCESS FOR THE PREPARATION OF (-) -HALOFENATE ESTEROSELECTIVA AND ITS DERIVATIVES (lawyer list No. 016325-020510US), content of which incorporated here as a reference.

Field of the Invention The present invention relates to the stereoselective process of preparation of (-) - halofenate (4-chloro-a- (3-trifluoromethylphenoxy) phenylacetic acid) and its intermediates.

BACKGROUND OF THE INVENTION Esters and amides derived from (-) - 4-chloro-α- (3-trifluoromethylphenoxy) (phenophenoic acid) phenylacetic acid are chiral compounds and are useful for improving a variety of physiological conditions, including conditions associated with the deposition of blood lipids, type II diabetes and hyperlipidemia (see, for example, U.S. Patent Application No. 10 / 656,567 and U.S. Patent No. 6,262,118, which are hereby incorporated in their entirety by way of reference in). Halofenic acid contains a unique chiral center with an alpha carbon atom substituted asymmetrically with the carbonyl carbon atom and, therefore, exists in two enantiomeric forms. It has been found that the (-) -enantiomer of halofenic acid is about twenty times less active in its ability to inhibit cytochrome P450 2C9, compared to the (+) - enantiomer. That is, the administration of a racemic halofenic acid or its derivatives can lead to a variety of drug interaction problems with other drugs, including anticoagulant, anti-inflammatory and other drugs, which are metabolized by this enzyme. That is, it is desirable to administer the (-) -enantiomer of halofenic acid or its derivatives that are substantially free of (+) - enantiomer to reduce the possibility of interactions with the drugs. Thus, the enantiomerically enriched forms of α- (phenoxy) phenylacetic acids or their derivatives are valuable chemical intermediates for the preparation of pharmaceutical compounds. As shown below, several synthetic routes to manufacture a- (phenoxy) phenylacetic acid derivatives have been reported in the literature. Unfortunately, these molecules are often difficult to produce with high enantiomeric purity and high yield by known synthetic methods.

Scheme 1. Synresis of feidlar acids. etic os a-lf noxíl ii, X = halo T il IX As shown in scheme 1, Devine et al. Were able to make a- (phenoxy) phenylacetic acids stereoselectively using a pyrrolidine derived from lactamide as a chiral auxiliary (see, U.S. Patent Nos. 5,708,186 and 5,856,519, the techniques of which are incorporated herein by reference). However, this method also has numerous drawbacks, including a) multiple isolation steps and b) low isolation performance. Therefore, there is a need for a more efficient process to produce a- (phenoxy) phenylacetic acid in a stereoselective manner, as well as derivatives thereof, for example, (-) -halophanate. Surprisingly, the present invention covers this and other needs.

Brief Description of the Invention The present invention provides methods that can be used to reliably convert phenylacetic acids substituted with a- (phenoxy) phenylacetic acid derivatives in high yield and with high enantiomeric purity. Thus, in one embodiment, the present invention provides a method for producing a compound of formula (I): (1) where; R1 is a member selected from the group consisting of: v Each R2 is a member selected independently from the group consisting of (C? -C) alkyl, halo, (C? -C) haloalkyl, amino, (C1-C4) aminoalkyl, amido, (C1-C4) amidoalkyl, (C 1 -C 4) sulfonylalkyl, (C 1 -C 4) sulfamylalkyl, (C 1 -C 4) alkoxy, (C 1 -C 4) heteroalkyl, carboxy and nitro; the subscript m is an integer from 0 to 3; * indicates a carbon that is enriched in a stereoisomeric configuration; and the wavy line indicates the point of attachment of R1; the method includes: a) contacting a compound of the formula (II): (II) with a carboxylic acid activating the reagent selected from the group consisting of a thionyl halide, an anhydride and a thioester that generates a reagent; in a compatible solvent; b) treating the product of step a) with bromine, with bromine in a compatible solvent; c) esterifying the product of step b), with chiral alcohol selected from the group consisting of: in a compatible solvent. In another embodiment, the present invention provides a- (substituted) phenylacetic acid compounds of the formula (IV): (IV) where: R1 is a member selected from the group consisting of in: the subscript n is 1 when R1 has the formula (a) or (b) and 2 when R1 has the formula (c) or (d); * indicates a carbon that is enriched in a stereoisomeric configuration; and the wavy line indicates the point of union of R1. Other features, objects and advantages of the invention and its preferred embodiments will be apparent from the detailed description below.

Detailed description of the invention I. Definitions "Alkyl" refers to branched or straight aliphatic hydrocarbon chain groups of one to ten carbon atoms, preferably one to six carbon atoms, and more preferably one to four carbon atoms. Exemplary algal groups include, but are not limited to, methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, and the like. "Aryl" refers to a portion of the bicyclic or monocyclic monovalent aromatic hydrocarbon having 6 or 10 ring carbon atoms. Unless stated or otherwise indicated, an aryl group may be substituted with one or more substituents, preferably one, two or three substituents, and more preferably one or more substituents selected from alkyl, haloalkyl, nitro and halo . More specifically, the term aryl includes, but is not limited to, phenyl, 1-naphthyl, and 2-naphthyl, and the like, each of which is optionally substituted by one or more substituents described above. "Chiral" or "chiral center" refers to a carbon atom with four different substituents. However, sufficient condition of chirality is the non-superposition of the mirror images. The terms "CPTA" and "halofenic acid" are used herein interchangeably and refer to (4-chlorophenyl) (3-trifluoromethylphenoxy) acetic acid. "Enantiomeric mixture" means a chiral compound with a mixture of enantiomers, including a racemic mixture. Preferably, the enantiomeric mixture refers to a chiral compound with substantially equal amounts of each enantiomer. More preferably, the enantiomeric mixture refers to a racemic mixture in which each enantiomer is present in the same amount. "Enantiomerically enriched" refers to a composition where an enantiomer is present in a greater amount than before to be subject to a separation process. "Enantiomeric excess" or "reads" refers to the amount of difference between the first enantiomer and the second enantiomer. The enantiomeric excess is defined by the equation:% ee = (% of the first enantiomer) - (% of the second enantiomer). Thus, if a composition comprises 98% of the first enantiomer and 2% of the second enantiomer, the enantiomeric excess of the first enantiomer is 98% -2% or 96%. The terms "halide" and "halo" are used herein interchangeably and refer to halogens including F, Cl, Br and I, as well as pseudohalides, such as -CN and -SCN. "Haloalkyl" refers to the alkyl group as defined herein, in which one or more hydrogen atoms have been replaced with halogens, including perhaloalkyl, such as trifluoromethyl. "Halofenate" refers to acetate 2-acetamidoethyl 4-chlorophenyl- (3-trifluoromethylphenoxy) (ie, acid 4-chloro-α- (3-trifluoromethylphenoxy) benzeneacetic, 2- (acetylamino) ethyl ester or (4-chlorophenyl) (3-trifluoromethylphenoxy) acetic acid, 2- (acetylamino) ethyl ester). "Heteroalkyl" means a branched or unbranched saturated acyclic alkyl moiety containing one or more heteroatoms or one or more heteroatom-containing substituents, wherein the heteroatom is O, N or S. Substituents containing exemplary heteroatoms include = 0, - 0Ra, -C (= 0) Ra, -NRaRb, -N (Ra) C (= 0) Rb, -C (= 0) NRaRb and -S (0) nRa (where n is an integer from 0 to 2 ). Each of Ra and Rb is a hydrogen, alkyl, haloalkyl, aryl or aralkyl independently. The term "metal" includes Group I, II and the transition metals, as well as the main group of metals, such as B and Si. "Optical purity" refers to the amount of a particular enantiomer present in the composition. By example, if a composition comprises 98% of the first enantiomer and 2% of the second enantiomer, the optical purity of the first enantiomer is 98%. Unless stated otherwise, the term "phenyl" refers to an optionally substituted phenyl group. Suitable phenyl substituents are the same as those described in the definition of "aryl". Similarly, the term "phenoxy" refers to a portion of the formula -OAra, wherein Ara is phenyl as defined herein. Thus, the term "α- (phenoxy) phenylacetic acid" refers to acetic acid which is substituted at the 2-position with an optionally substituted phenyl and optionally substituted phenoxy moieties. "Protection group" refers to a portion which, when bound to a reactive group in a molecule mask, reduces or prevents this reactivity. Examples of protection groups can be found in Protective Groups in the Organic Synthesis, by T. W. Greene and P. G. M. Wuts, 3rd edition, Compendium of Synthetic Organic Methods, by John Wiley & Sons, New York, 1999, and Harrison and Harrison et al., Vols. 1 to 8 (John Wiley and children, 1971-1996), which are incorporated here as a reference in their entirety. Representative hydroxy protecting groups include acyl groups, benzyl and trifyl ethers, tetrahydropyranyl ethers, trialkylsyl ethers and ethers of alilo. Amino protection groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trifly and substituted groups of trifly, allyloxycarbonyl , 9-fluoroenylmethyloxycarbonyl (FMOC), nitro-veratriloxycarbonyl (NVOC), and the like. The term "rate", when referring to a formation of a reaction product, refers to the kinetic and / or thermodynamic rates. As used herein, the term "treating", "making contact" or "reacting" refers to adding or mixing two or more reagents under the appropriate conditions to produce the indicated and / or desired product. It should be appreciated that the reaction that produces the indicated and / or desired product may not necessarily result directly from the combination of two reagents that were initially added, i.e., there may be one or more intermediates that are produced in the mixture that ultimately results in the formation of the indicated and / or desired product. As used herein, the terms "those defined above" and "those defined here", when referring to a variable, incorporate as a reference the broad definition of the variable, as well as the preferred definitions, more preferred and the most preferred of all, if they exist. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. In the description of an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule around its guiral center (s), the prefixes "d" and "1" or ( +) and (-) are used to designate the sign of rotation of plane-polarized light by the compound, with (-) or (1) meaning that the compound is "levorotatory" and with (+) or (d) meaning that the compound is "dextrorotatory". There is no correlation between the nomenclature of absolute stereochemistry and the rotation of an enantiomer. For a given chemical structure, these compounds, called "stereoisomers," are identical, except that they are mirror images. A specific stereoisomer can also be referred to as an "enantiomer", and a mixture of such isomers is often referred to as an "enantiomeric" or "racemic" mixture. See, for example, In troduction to Organic Chemistry, by Streitwiesser, A. & Heathcock, C. H., 2nd edition, Chapter 7 (MacMillan Publishing Co., E.U. 1981). The terms "substantially free of its (+) - stereoisomer", "substantially free of its (+) - enantiomer", are used interchangeably herein and mean that the compositions contain a proportion substantially greater than the (-) -isomer in relation to (+) -isomer. In a preferred embodiment, the term "substantially free of its (+) - stereoisomer" means that the composition has at least 90% of the weight of (-) - isomer and 10% or less of the weight of (+) - isomer. In a more preferred embodiment, the term "substantially free of its (+) - stereoisomer" means that the composition has at least 99% of the weight of (-) - isomer and 1% or less of the weight of (+) -isomer. In the most preferred embodiment, the term "substantially free of its (+) - stereoisomer" means that the composition contains more than 99% of the weight of (-) -isomer and 1% by weight of (-) -isomer. These percentages are based on the total amount of isomers in the composition.

II. Introduction Although the enantiomers of a chiral compound have exactly the same chemical properties, the spatial orientation of the atoms in the enantiomers is different. Thus, an enantiomer of a chiral drug often exerts the desired activity with a collateral effect (s) significantly lower (s) than the other enantiomer. While the resolution of racemates is often used in industrial processes for the preparation of optically active compounds, i.e., chiral; The chiral synthesis has made extensive progress in recent years.

The present invention provides a method for synthesizing a chiral ester - (halo) phenylacetic acid derivative. The chiral ester in the α- (halo) phenylacetic acid directs the alkylation of 3-trifluoromethylphenol to stereoselectively produce the α- (phenoxy) phenylacetic acid derivatives. Thus, the compounds produced using the methods of the present invention are useful in the production of the α- (phenoxy) phenylacetic acid derivatives in high yield, such as those described in the U.S. Patent Application. Do not. /656,567 and the US Patent. No. 6,262,118. In particular, the compounds and methods of the present invention are useful in the production of (-) -halophanate.

III. Stereoselective synthesis As noted above, the prior stereoselective process for producing (-) - halofenate requires several steps and results in a low yield composition or is of insufficient optical purity to be commercially viable. However, the present inventors have found that under certain conditions described herein, the α- (phenoxy) phenylacetic acid compound of sufficient optical purity can be produced in high yields and high optical purity with few isolation steps. These high yields are unusual since the treatment with bromine of similar compounds with bromine does not result in high yields (see Harpp et al., J. Org Chem. 40 (23): 3420 (1975)). Thus, in one aspect, the methods of the present invention are based on the surprising and unexpected discovery made by the present inventors that substituted phenylacetic acids can be activated, treated with bromine and esterified to result in an α-halophenyl ester. intermediate acetic acid with high performance. This intermediate can then be used to stereoselectively produce α- (phenoxy) phenylacetic acid derivatives. In particular, the methods for the present invention provide a desired enantiomer of an α- (phenoxy) phenylacetic acid derivative in yields of at least about 40%, preferably at least about 50%, more preferably at least less about 60%, and more preferably at least about 70%. In particular, the methods of the present invention provide a desired enantiomer of the α- (phenoxy) phenylacetic acid compound with optical purity of at least about 90%, preferably at least about 95%, more preferably at least less about 97%, and more preferably at least about 98%. A method for the stereoselective production of α- (phenoxy) phenylacetic acid derivatives, such as xiv, are generally shown in Scheme 2 below.

Scheme 2: General Rnrn In this way, phenylacetic acid x can be converted into an activated carboxylic acid derivative and subsequently halogenated with molecular bromine to obtain a halide-bromophenylacetyl xi in two steps. The phenylacetic acid is preferably a halophenylacetic acid, more preferably 4-halo-phenylacetic acid and more preferably 4-chloro-phenylacetic acid. Examples of carboxylic activation agents suitable for the present invention, which do not limit it, include thionyl halides such as thionyl chloride (S0C12); anhydrides such as trifluoroacetic anhydride (TFAA), and thioester that generates reagents. The agent of Activation of carboxylic acid is preferably a thionyl halide and more preferably a thionyl chloride. It is commercially available as a clear liquid and can be used pure or in a compatible solvent. The acid halide is then converted to chiral ester xiii, where R1 is a chiral alcohol auxiliary. A wide variety of chiral auxiliaries can be used, including those described in the examples in the following section. Preferably, the chiral auxiliary used results in the manufacture of only one diastereomer of phenyloacetic acid (phenoxy). It should be recognized that the chiral auxiliary alcohol compound must itself be of sufficient enantiomeric purity to yield an enantiomerically enriched α- (phenoxy) phenylacetic acid derivative. In this way, an enantiomer in position a is rapidly produced, for example, by removing the chiral auxiliary. In a particular embodiment, the chiral auxiliary is a co Preferably, the chiral alcohol has the formula: The displacement reaction of the ester xi with a compound xii of phenol substituted suitably in the presence of a base, such as a hydroxide, yields the α- (phenoxy) phenylacetic acid ester xiii. Examples of bases that can be used in the displacement reaction include, but are not limited to, hydroxide, such as lithium hydroxide, potassium hydroxide, sodium hydroxide and the like; alkoxide, such as lithium alkoxide, potassium alkoxide, sodium alkoxide and the like; and others like it; hydride, such as lithium hydride, potassium hydride, sodium hydride and the like; and others like it. Hydrolysis of the α- (phenoxy) phenylacetic acid ester xiii produces α- (phenoxy) phenylacetic acid xiv. Examples of hydrolyzing agents that can be used include, but are not limited to, hydroxide, such as lithium hydroxide, potassium hydroxide, sodium hydroxide and the like; hydroperoxide, such as lithium hydroperoxide, potassium hydroperoxide, sodium hydroperoxide and the like; and others like it. This synthetic route is shown more specifically in Scheme 3 below: Esqu ma 3; Synthesis this eoseleí tive of hydrophobic acid 2 6, (-) - (R > allophanic acid For example, 4-chlorophenylacetic acid 1 can be treated with thionyl chloride to activate the carboxylic acid. This can be treated with bromine to form 4-chlorophenylacetic chloride. The esterification is conveniently carried out with (S) -N, N-tetramethylenelactamide 2. This reaction sequence is particularly advantageous since the reactions are conveniently carried out in a reaction vessel with only one isolation step. The displacement reaction of ester 3 with 3-trifluoromethylphenol 4 in the presence of potassium hydroxide produces a- (phenoxy) phenylacetic acid ester 5. Hydrolysis of the ester a- (phenoxy) phenylacetic acid 5 with lithium hydroxide produced a- (phenoxy) phenylacetic acid 6. In this way, (4-chlorophenyl) - (3-trifluoromethylphenoxy) -acetic acid, ie CPTA, can be prepared in five steps with a yield of about 73%, after the crystallization of heptane. Thus, in one embodiment, the present invention provides a method for producing a compound of formula (I): (Or where; R is a member selected from the group consisting of: Each R2 is a member selected independently from the group consisting of (C? -C4) alkyl, halo, (C1-C4) haloalkyl, amino, (C3.-C4) aminoalkyl, α-ido, (C1-C4) amidoalkyl, (C?-C4) sulfonylalkyl, (C1-C4) sulfamylalkyl, (C?-C4) alkoxy, (C? -C4) heteroalkyl, carboxy and nitro; the subscript n is 1 when R1 has the formula (a) or (b) and 2 when R1 has the formula (c) or (d); the subscript m is an integer from 0 to 3; * indicates a carbon that is enriched in a stereoisomeric configuration; and the wavy line indicates the point of union of R1. The method generally includes: a) Activation of the carboxylic acid of a compound of formula (II): (II) with a carboxylic activation agent in a compatible solvent; b) Contacting a compound of formula (II): (II) with a carboxylic acid activation reagent selected from the group consisting of a thionyl halide generating reagent, an anhydride and a thioester; in a compatible solvent; b) Treat with bromine the product of step a) with bromine in a compatible solvent; c) Esterifying the product of step b) with a chiral alcohol selected from the group consisting of: in a compatible solvent. The present inventors have found that the agent for the treatment with bromine used in the preparation of a- (phenoxy) phenylacetic acid has a significant effect on the ease of isolation and on the total yield of the process. For example, when bromine is used in the manufacturing process of the α- (phenoxy) phenylacetic acid compound, higher total yields are obtained than when other halogenating agents are used. The amount of halogenating agent used is not particularly important. The amount used is typically greater than 1.00 molar equivalent, preferably about 1.5 molar equivalent or more, more preferably about 1.55 molar eguivalent.

The reactions are typically conducted in a compatible solvent. A compatible solvent is one that is inert under reaction conditions and can easily dissolve reagents. Suitable solvents for the above reactions are known to those skilled in the art. For example, suitable solvents for carboxylic acid activation, bromine treatment and esterification reactions include, but are not limited to, solvents that do not exchange protons with the dissolved substance, such as halogenated alkanes, tetrahydrofuran, aromatic hydrocarbons, dialkyl ethers, and mixtures of these. A particularly preferred solvent is a halogenated alkane, more preferably 1,2-dichloroethane. In one embodiment, the bromine treatment process involves heating the reaction mixture to a temperature in the range of about 70 ° C to the boiling point of the solution, preferably around 80 ° C to about 85 ° C. The heating is performed until the reaction is complete, which typically occurs within a range of 1 to about 24 hours, preferably about 2 to about 18 hours. At lower temperatures, longer reaction times are needed. It will be readily apparent to those skilled in the art that the progress of this and other reactions in the method of the present invention may be monitored by, for example, HPLC, and think of the complete reaction when the amount of unreacted initial reactants is less than about 1%. Bromine can be removed before adding the chiral alcohol auxiliary. This can be done by connecting the reaction vessel to a vacuum pump and removing the bromine with reduced pressure. The pressure, rate and degree of removal is not particularly important. The solution can be cooled before and / or after adding the chiral alcohol auxiliary. This allows the exothermic nature of the esterification reaction. The rate and amount of cooling of the reaction solution is not particularly important. In one embodiment, the esterification reaction involves cooling the reaction mixture to a temperature in the range of about 0 ° C to room temperature. The reaction is performed until complete, which is typically between a range of 5 to 60 minutes, typically around 30 minutes. In one embodiment, this method can be performed in a reaction vessel. In another embodiment, only the final product, the compound of formula (I), is isolated. In particular, the methods of the present invention are directed to intermediates in the synthesis of α- (phenoxy) phenylacetic acids of formula (V): (V) where R3 is haloalkyl and R2 is halide. In a particular embodiment, the methods of the present invention are directed to the synthesis of α- (phenoxy) phenylacetic acid of formula I, or preferably, of formula V, wherein R 2 is chloro. In another embodiment, the methods of the present invention are directed to the resolution of - (phenoxy) phenylacetic acid of formula I, or preferably, of formula V, wherein R 3 is preferably trifluoromethyl. In yet another embodiment of the present invention, the methods are directed to the stereoselective synthesis of the compounds of the formula V wherein R2 is Cl and R3 is CF3, for example, halofenic acid. In a particular embodiment, the compounds of α- (substituted) phenylacetic acid with the formula (IV): (IV) where: R1 is a member selected from the group consisting of: the subscript n is 1 when R1 has the formula (a) or (b) and 2 when R1 has the formula (c) or (d); * indicates a carbon that is enriched with a stereoisomeric configuration; and the wavy line indicates the point of attachment where R1 is synthesized using the chiral auxiliary. A particularly preferred compound of formula I and IV above is where R1 is: Unexpectedly, the O (substituted) phenylacetic acid compounds of the formula (IV): (IV) where: R1 is a member selected from the group consisting of: the subscript n is 1 when R1 has the formula (a) or (b) and 2 when R1 has the formula (c) or (d); * indicates a carbon that is enriched with a stereoisomeric configuration; and the wavy line indicates the point of attachment of R1; they are produced with high stereoselectivity and high performance. To be economically desirable, the methods of the present invention provide at least about 50% yield of the desired enantiomer, preferably about 60%, more preferably about 70% and more preferably about 75%. In one embodiment, the compound is selected from the group consisting of: where dotted and solid lines indicate the relative stereochemistry of the compound. In another embodiment, the compound is selected from the group consisting of: where the dotted and solid lines indicate the absolute stereochemistry of the compound. It should be noted that while the methods of the present invention are described in relation to the enrichment of the (-) - enantiomer of halofenic acid, the methods of the present invention are also applicable to enrich (+) - enantiomer. The method of the present invention essentially provides a compound enriched in the (-) -enantiomer based on the enantiomeric enrichment of the chiral auxiliary and the stereoselectivity of the reaction. He use of the (+) - enantiomer can be easily supplemented with the use of the opposite enantiomer of the chiral alcohol auxiliary. For example, the (+) - enantiomer can be manufactured using (R) -N, N-tetramethylenelactamide. The chiral auxiliary can be recovered from the conversion step described above and reused / recycled. Thus, the process of the present invention easily expands itself to a recycling type process.

IV. Synthesis of chiral alcohol auxiliaries A method for producing a chiral alcohol auxiliary 2 is shown in Scheme 4 below: Scheme 4: Synthesis of the chiral auxiliary Reaction of the lactic ester 7 with an excess of appropriate cyclic amine produces the chiral auxiliary 2. By using an excess of cyclic amine per ester equivalent the conversion is high and the amount of racemisation is minimized. For example, pyrrolidine 8 (ie, where R6 combines to form a five-membered ring) is particularly advantageous since pyrrolidine is a good solvent for the lactic ester and the reaction is conveniently carried out pure In this way, (S) -N, N-tetramethylenelactamide can be prepared in one step with about 95% yield.

V. Utility of enantiomerically enriched - (phenoxy) phenylacetic acid Enantiomerically pure α- (phenoxy) phenylacetic acid compounds are intermediates useful in the preparation of a variety of pharmaceutically active compounds, including the a- (phenoxy) phenylacetic acid compounds described in the U.S. Patent Application No. 10 / 656,567 t the U.S. Patent. No. 6,262,118. Thus, another aspect of the present invention provides a method for enantioselectively producing an α- (phenoxy) phenylacetic compound of the formula: SAW From the compound of α- (phenoxy) phenylacetic acid of formula V, where R 3 is alkyl or haloalkyl, R 2 is halo and R7 is heteroalkyl, preferably N-acetyl 2-aminoethyl (ie, a portion of the formula -CH2CH2NHC (= 0) (CH3) The method involves stereoselectively synthesizing an a- (phenoxy) phenylacetic acid compound of formula V as described above and reacting the enantiomerically enriched a- (phenoxy) phenylacetic acid with a carboxylic acid reactive agent. Suitable carboxylic acid reactive agents include thionyl halides, (e.g., thionyl chloride), anhydrides (e.g., TFAA), thioester generating reagents, and other carboxylic acid activation reagents known to those skilled in the art. . Activated α- (phenoxy) phenylacetic acid is then reacted with a compound of formula (R7-0) wM, for example, N-acetyl ethanolamine derivative, to produce the enantiomerically enriched phenylacetic compound a- (phenoxy) of formula VI, where R7 is as defined above, M is hydrogen or a metal, for example, Na, K, Li, Ca, Mg, Cs, etc. and the subscript w is the oxidation state of M. The present inventors have discovered that the reaction between the activated acid and the compound of the formula (R7-0) wM can be carried out without any major racemization. The additional objectives, advantages and new features of this invention will be readily apparent to those skilled in the art after examining the following examples of this, which are not intended to be limiting.

EXAMPLES Reagents and Experimental Material Unless otherwise indicated, reagents and solvents were purchased from Aldrich Chemical or Fisher Scientific. The operations were conducted under a positive nitrogen atmosphere. A Camile process control computer that was attached to a heating and cooling recirculation system was used to regulate the temperatures of the jacket in the lower drain glass reactors, straight walls, fitted with sleeves. Unless otherwise indicated, the solvents were removed using a Buchi rotary evaporator at 15 to 25 torr, with a bath temperature above 40 ° C. The solid samples were dried in a vacuum oven at 40 ° C, at 15 to 20 torr. A Cenco HYVAC vacuum pump was used to supply a vacuum of less than 1 torr for vacuum distillation. Water levels were determined by Karl Fisher analysis using a Metrohm 756 KF Voltmeter and an AG reagent Coulombs meter (Coulomat) HYDRANAL. The melting points were determined using a Mettler Toledo FP62 melting point apparatus. The pH was measured using a calibrated pH measurement Orion Model 190A. The protons and the 13C NMR spectrum were recorded on a Brunker Avance 300 MHz spectrometer.

The chiral HPLC analysis was performed at? = 240nm when injecting lOμL of sample dissolved in a mobile phase on a column of (R, R) WHELK-0 of 1.5μm and 250mm x 4.6mm (Regis Technologies) and released with a flow of l.OmL / min of acid 95/5 / 0.4 (v / v / v) hexanes / 2-propanol / acetic acid. The achiral HPLC analysis was performed at? = 220nm by injecting 5μL of sample dissolved in a mobile phase on a Phenomenex LUNA column at 5μm C18 (2) of 250mm x 4.6mm at 25 ° C. A flow of 1.5mL / min of the gradient was used starting at 66% vol of water / 34% vol of acetonitrile / 0.1% vol of trifluoroacetic acid and linearly increased up to 26% vol of water / 74% vol of acetonitrile / 0.1% vol of trifluoroacetic acid in 20 minutes. For the analysis of the acidifying solutions of esters, such as halofenate, acetonitrile was used as the injection solvent. When determined, the concentrations of the product by halofenate were evaluated by the HPLC assay, using the standard external method and the method of acute analysis at sample concentrations of less than 2.5mg / mL.

Example 2: Preparation of (-) - halofenate (6) Preparation of compound (3) In a neck flask 2-L 3 under air, immersed in an oil bath and fitted with a funnel and a condenser, 500mL of anhydrous 1,2-dichloroethane, 4-chlorophenylacetic acid (174.04g 98%, 1.Omol (Acros)) was added in one portion, DMF (0.40mL, approximately 0.5% mol) in a single portion and chloride Thionyl (95mL, 1.3mol, 1.3 eq.) for approx. 1 minute. The resulting mixture was heated to 70 ° C (oil bath temperature) for 15 minutes. Vigorous extraction of the gas started approximately after 5 minutes of heating (at 40-45 ° C approx.). The vigorous extraction of the gas was decreased to a regular flow and then gas extraction was stopped. After stirring at 70 ° C for 2 hours, bromine (80mL, ca. 249g, 1.55mol, 1.55 eq.) Was added to the resulting pale yellow solution (at 65 ° C) for ca. 1 minute to result in a brown solution. The reaction was stirred at 80 ° C to 85 ° C (hot bath temperature) overnight (about 18 hours) and then cooled to room temperature. This a-bromine acid chloride solution was stored at room temperature and used in the next ester formation step without further purification. The solution of crude acid chloride (138g, ca. 0.138mol) in 1,2-dichloroethane prepared above was diluted with 100mL of 1,2-dichloroethane. The excess bromine was removed by vacuum distillation until an approximate 100mL of solution remained. The chloride solution The acid was then added dropwise to a solution of (S) -N, N-tetramethylenelactamide (20.lg, 0.140mol) and triethylamide (14.78g, 0.147mol) in 100mL of 1,2-dichloroethane at 0 ° C. The resulting brown mixture was heated at room temperature for 1 hour. The reaction mixture was quenched with water (100mL), and the organic layer was separated and washed with 100mL of 10% Na2S203 and then with saturated NaHC03 (100mL). The organic layer was dried over Na2SO4 and then concentrated in vacuo to give 45.8g of crude product as a brown oil which was used in the next step without further purification.

Preparation of compound (6) To a solution of a, a, α-trifluoro-m-cresol (3.3g; 0.0204mol) in anhydrous THF (20mL) at room temperature was added dropwise lithium tert-butoxide (20mL of a 1.0 M solution in THF, 0.02 mol). The resulting solution of lithium phenoxide was added dropwise to a solution of bromine 3 (crude, 7.5g, 0.02mol) in 40mL of THF at -5 ° C. After stirring at -5 ° C for 1 hour, a pre-mixed solution of hydrogen peroxide (Fisher 50%; 105mL, 0.4mol) and LiOH-H20 (21g, 0.05mol) in water (50mL) was added at room temperature for 20 min. The reaction was stirred to between 0-4 C for 1 hour, quenched with saturated aqueous sodium bisulfate (150mL), then 1N HCl was added to adjust the pH of the solution in about 2. The THF was removed by vacuum distillation, and then the reaction mixture was diluted with EtOAc (100mL). The organic layer was washed with water and salt water, dried over Na 2 SO 4 and evaporated to yield 7 g of crude acid. The crude acid was crystallized from heptane to yield 4.6g of a white solid. Chiral HPLC analysis of 96.5: 3.5 enantiomers. The halofenic preparation can be carried out using similar conditions with other chiral auxiliaries listed above.

Example 3: Alternate Preparation of Haiofenate (6) To a solution of OI, OI, α-trifluoro-m-cresol (6.71g, 0.41mol) in anhydrous THF (20mL) and toluene (30mL) at room temperature was added hydrate. Lithium hydroxide (1.68g, 40mmol). The solvent was removed after 1 hour and the residue was dissolved in 30mL of anhydrous THF (30mL). The resulting solution of lithium phenoxide was added dropwise to a solution of bromine 3 (crude, 14.9g, 0.04mol) and Nal (0.3g) in 100mL of THF with stirring at room temperature for 1 hour at -5 ° C and for an additional 3 hours between -5 ° C and 0 ° C. - "" H NMR showed the disappearance of bromine 3. Hydrogen peroxide (Fisher 30%; 209mL, O.dmol) was added to a solution of lithium hydroxide (4.2g, 0. 09ml) in water (100mL), and the mixture was stirred at room temperature for 20 min. This solution was then added slowly to a cold solution of lactamide 4 in THF at 0 ° C. The reaction was stirred at 0-4 ° C for 1 hour, quenched with 1N HCl and adjusted to a pH of 2. The THF was removed by vacuum distillation and then the reaction mixture was diluted with EtOAc (150mL). The organic layer was washed with water, saturated with Na2S203 and with salt water, dried over Na2SO4 and evaporated to yield crude acid. The crude acid was crystallized from heptane to yield 8.4 g of a white solid. (99: 1 enantiomers, determined by chiral HPLC). It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in view thereof will be suggested to persons skilled in the art and are to be included within the spirit and scope of this application and approach. of the appended claims. All publications, patents and patent applications cited herein are incorporated by reference in their entirety for all purposes.

Claims (16)

1. Claims 1. A method for preparing a compound of formula (I ') (1) characterized in that; R1 is a member selected from the group consisting of: each R is a member selected independently from the group consisting of (C? -C4) alkyl, halo, (C1-C4) haloalkyl, amino, (C? -C4) aminoalkyl, amido, (C1-C4) amidoalkyl, (C 1 -C 4) sulfonylalkyl, (C 1 -C 4) sulfamylalkyl, (C 1 -C 4) alkoxy, (C 4 -C 4) heteroalkyl, carboxy and nitro; the subscript n is 1 when R1 has the formula (a) or (b) and 2 when R1 has the formula (c) or (d); the subscript m is an integer from 0 to 3; * indicates a carbon that is enriched in a stereoisomeric configuration; Y the wavy line indicates the junction point of R1; the method includes: a) contacting a compound of the formula (II): with a carboxylic acid that activates the reagent selected from the group consisting of a thionyl halide, anhydrides and thioester that generate reagents; in a compatible solvent; b) treating the product of step a) with bromine, with bromine in a compatible solvent; c) esterifying the product of step b), with chiral alcohol selected from the group consisting of: in a compatible solvent to stereoselectively produce a compound of formula (I).
2. 2. The method of claim 1, characterized because R1 is:
3. 3. The method of any of the preceding claims, characterized in that the compound of formula (II) is 4-chlorophenylacetic acid.
4. 4. The method of any of the preceding claims, characterized in that the carbonyl activating agent is thionyl halide. The method of any of the preceding claims, characterized in that the carbonyl activating agent is thionyl chloride. The method of any of the preceding claims, characterized in that the bromine is present in a concentration of at least about the molar equivalent of the amount of the compound of formula (II) -7. The method of any of the claims precedents, characterized in that the solvent is a halogenated alkane solvent. The method of any of the preceding claims, characterized in that the solvent is 1,2-dichloroethane. 9. The method of any of the claims precedents, characterized in that the conditions include carrying out the treatment with bromine at a temperature of at least about 70 ° C. The method of any of the preceding claims, characterized in that it additionally includes removing the excess bromine under a reduced pressure before step c). The method of any of the preceding claims, characterized in that the method is conducted in a reaction vessel. The method of any of the preceding claims, characterized in that only the compound of formula (I) is isolated. 13. A compound of formula (IV): (IV) characterized in that: R1 is a member selected from the group consisting of the subscript n is 1 when R1 has the formula (a) or (b) and 2 when R1 has the formula (c) or (d); * indicates a carbon that is enriched in a stereoisomeric configuration; and the wavy line indicates the point of union of R1. 14. A compound selected from the group with the formula: characterized in that the dotted and bold lines indicate the relative stereochemistry of the compound. 1
5. 5. A compound selected from the group with the formula: characterized in that the dotted and bold lines indicate the absolute stereochemistry of the compound. 1
6. 6. A composition characterized in that it comprises a compound of claims 14 or 15 in an enantiomeric excess of about 95%.