WO2004112774A1 - Resolution de derives d'acide ?lpha-(phenoxy)phenylacetique - Google Patents

Resolution de derives d'acide ?lpha-(phenoxy)phenylacetique Download PDF

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Publication number
WO2004112774A1
WO2004112774A1 PCT/US2004/019616 US2004019616W WO2004112774A1 WO 2004112774 A1 WO2004112774 A1 WO 2004112774A1 US 2004019616 W US2004019616 W US 2004019616W WO 2004112774 A1 WO2004112774 A1 WO 2004112774A1
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Prior art keywords
acid
cpta
phenoxy
enantiomer
phenylacetic acid
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PCT/US2004/019616
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English (en)
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Edward D. Daugs
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Metabolex, Inc.
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Priority claimed from US10/656,567 external-priority patent/US7199259B2/en
Application filed by Metabolex, Inc. filed Critical Metabolex, Inc.
Priority to JP2006517439A priority Critical patent/JP2007524614A/ja
Priority to CA2529774A priority patent/CA2529774C/fr
Priority to MXPA05013981A priority patent/MXPA05013981A/es
Priority to EP04755657A priority patent/EP1635809A4/fr
Priority to YUP-2005/0937A priority patent/RS20050937A/sr
Publication of WO2004112774A1 publication Critical patent/WO2004112774A1/fr
Priority to IL172663A priority patent/IL172663A0/en
Priority to KR1020057024492A priority patent/KR101073742B1/ko

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings

Definitions

  • the present invention relates to an enantioselective resolution process for the separation of ⁇ -(phenoxy)phenylacetic acids from its enantiomeric mixture.
  • Esters and amides derivatives of ⁇ -(phenoxy)phenylacetic acids are chiral compounds and are useful in ameliorating a variety of physiological conditions, including conditions associated with blood lipid deposition, e.g., Type II diabetes and hyperlipidema. See, for example, U.S. Patent Nos. 3,517,050 and 6,262,118.
  • ⁇ - (phenoxy)phenylacetic acids contain a single chiral center at an asymmetrically substituted carbon atom alpha to the carbonyl carbon atom, and therefore exist in two enantiomeric forms.
  • Cytochrome P450 2C9 is an enzyme known to play a significant role in the metabolism of specific drugs. It is known to one skilled in the art that changes in drug metabolism mediated by inhibition of cytochrome P450 enzymes has a high potential to precipitate significant adverse effects in patients. It is also known that a racemic ⁇ - (phenoxy)phenylacetic acid, e.g., halofenic acid, inhibits cytochrome P450 2C9. See, for example, U.S. patent No. 6,262,118.
  • a racemic ⁇ -(phenoxy)phenyl- acetic acid such as halofenic acid or its derivatives
  • administration of a racemic ⁇ -(phenoxy)phenyl- acetic acid can lead to a variety of drug interaction problems with other drugs, including anticoagulants, anti-inflammatory agents and other drugs that are metabolized by this enzyme.
  • the (-)-enantiomer of halofenic acid is about twenty-fold less active in its ability to inhibit cytochrome P450 2C9 compared to the (+)-enantiomer. Id.
  • One aspect of the present invention provides a method for producing an enantiomerically enriched ⁇ -(phenoxy)phenylacetic acid compound of the formula: wherein
  • R 1 is alkyl or haloalkyl
  • X is halide; from an enantiomeric mixture of the ⁇ -(phenoxy)phenylacetic acid compound comprising a first and a second enantiomers.
  • the enantiomeric mixture is a racemic mixture.
  • Methods of the present invention includes:
  • At least a portion of the second enantiomer can be converted to the first enantiomer, e.g., racemized, by contacting the second enantiomer with a base.
  • the resulting enatiomeric mixture can then be recycled and subjected to a similar enantiomeric enrichment process to increase the yield of the first enantiomer acid-base salt.
  • the chiral amine compound is of the formula:
  • each of R 2 and R 3 is independently hydrogen or alkyl; or R 2 and R 3 together with atoms to which they are attached to form a heterocyclic ring moiety;
  • R 4 is hydrogen or alkyl;
  • each of R 5 and R 6 is independently hydrogen or alkyl, or one of R 5 or R 6 is an amine protecting group; and
  • Ar is aryl.
  • Figure 1 is a graph showing the solubility profiles of (-)- and (+)-CPTA/CAF D- Base salts in 2-propanol.
  • Figure 2 shows results of a process for resolving a racemic mixture of CPTA using CAF D-Base under a variety of crystallization conditions.
  • Figure 3 is a graph showing the solubility of (-)- and (+)-CPTA/CAF D-Base salts in pure isopropanol and a solution comprising a mixture of isopropanol and CPTA (11 %).
  • Figure 4 is a graph showing the composition of a mixture with a various amount of each components.
  • Figure 5 is a graph showing a (-/+)-salt saturation profile for crystallization and heating.
  • Figure 6 is a table showing comparison of the model prediction to experimental results for entry 4 of Figure 2.
  • Figure 7 is a graph showing the amount of (+)-salt formation as a function of the amount of CAF D-Base added.
  • Figure 8 is a graphic representation of experimental data for the resolution shown in entry 11 of Figure 2.
  • Figure 9 shows the actual and calculated amount of CPTA in mother liquor and a graphic comparison of a calculated percentage of (+)-CPTA salt with the experimental data.
  • Figure 10A shows tables showing experimental data and a solubility model calculation for Figure 7 (i.e., entry 13 of Figure 2).
  • Figure 10B is a table showing experimental data and a solubility model calculation for entry 4 of Figure 2 at 28.3 °C.
  • Figure 11 is a graph showing solubility of racemic CPTA at various temperatures in 1 ,2-dichloroethane.
  • Figure 12 is a graph showing solubility of racemic CPTA at various temperatures in heptane.
  • Figure 13 is a table of results in Example 24 showing yield of CPTA resolution using CAF D-Base under variety of crystallization conditions.
  • Figure 14 shows a cooling profiles for the resolution crystallization of various entries in Figure 2.
  • Figure 15 is a table showing the amount of (-)-halofenate yield from (-)-CPTA salt in Example 26.
  • Figure 16 is a graph showing solubility of racemic CPTA sodium salt at various temperatures in water.
  • Figure 17 is a graph showing CPTA racemization profile at various pH during hydrolysis of (-)-halofenate.
  • Figure 18 is a table showing the results of CAF D-Base recovery at various pH as described in Example 30.
  • Figure 19 is experimental results of solubility determination of racemic CPTA in 1 ,2-dichloroethane and heptane as determined in Example 33.
  • Figure 20 is experimental results of solubility determination of racemic CPTA sodium salt in water as determined in Example 41.
  • Figure 21 is experimental results of basic hydrolysis of (+)-halofenate as determined in Example 42.
  • Alkyl refers to straight or branched aliphatic hydrocarbons chain groups of one to ten carbon atoms, preferably one to six carbon atoms, and more preferably one to four carbon atoms.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, «-propyl, 2-propyl, tert-butyl, pentyl, and the like.
  • Aryl refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon moiety of 6 to 10 carbon ring atoms. Unless stated or indicated otherwise, an aryl group can be substituted with one or more substituents, preferably one, two, or three substituents, and more preferably one or two 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 with one or more substituent(s) discussed above.
  • CAF D base refers to chloramphenicol D base, i.e., D-threo-(-)-2-amino-l- (nitrophenyl)- 1 ,3-propanediol.
  • Chiral or “chiral center” refers to a carbon atom having four different substituents. However, the ultimate criterion of chirality is non-superimposability of mirror images.
  • CPTA and halofenic acid are used interchangeably herein and refer to (4-chlorophenyl)(3-trifluoromethylphenoxy)acetic acid.
  • Enantiomeric mixture means a chiral compound having a mixture of enantiomers, including a racemic mixture.
  • enantiomeric mixture refers to a chiral compound having a substantially equal amounts of each enantiomers. More preferably, enantiomeric mixture refers to a racemic mixture where each enantiomer is present in an equal amount.
  • Enantiomerically enriched refers to a composition where one enantiomer is present in a higher amount than prior to being subjected to a separation process.
  • halide and “halo” are used interchangeably herein and refer to halogen, which includes F, Cl, Br, and I, as well as pseudohalides, such as -CN and -SCN.
  • Haloalkyl refers to alkyl group as defined herein in which one or more hydrogen atoms have been replaced with halogens, including perhaloalkyls, such as trifluoromethyl.
  • Halofenate refers to 2-acetamidoethyl 4-chlorophenyI-(3-trifiuoromethyl- phenoxy)acetate (i.e., 4-chloro- ⁇ -(3-(trifluoromethyl)phenoxy)benzeneacetic acid, 2- (acetylamino)ethyl ester or (4-chlorophenyl)(3-trifluoromethylphenoxy)acetic acid), 2- (acetylamino)ethyl ester).
  • Heteroalkyl means a branched or unbranched acyclic saturated alkyl moiety containing one or more heteroatoms or one or more heteroatom-containing substituents, where the heteroatom is O, N, or S.
  • Each of R a and R b is independently hydrogen, alkyl, haloalkyl, aryl, or aralkyl.
  • heterocyclyl and “heterocyclic ring” are used interchangeably and refer to a non-aromatic cyclic moiety of 3 to 8 ring atoms in which one, two, or three ring atoms are heteroatoms selected from N, O, or S(O) n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group.
  • the heterocyclyl ring can be optionally substituted independently with one, two, or three substituents selected from halogen, alkyl, aryl, hydroxy, amino, or alkoxy. More specifically the term heterocyclyl includes, but is not limited to, 1,3-dioxane and its derivatives, and the like.
  • leaving group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or a group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, N,O- dimethylhydroxylamino, and the like.
  • halo such as chloro, bromo, and iodo
  • alkanesulfonyloxy arenesulfonyloxy
  • alkylcarbonyloxy e.g., acetoxy
  • arylcarbonyloxy mesyloxy, tosyloxy, tri
  • metal includes Group I, II, and transition metals as well as main grouop metals, such as B and Si.
  • Optical purity refers to the amount of a particular enantiomer present in the composition. For 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%.
  • phenyl refers to an optionally substituted phenyl group. Suitable phenyl substituents are same as those described in the definition of "aryl.”
  • phenoxy refers to a moiety of the formula -OAr a , wherein Ar is phenyl as defined herein.
  • ⁇ -(phenoxy)phenylacetic acid refers to acetic acid that is substituted on the 2-position with an optionally substituted phenyl and optionally substituted phenoxy moieties.
  • Protecting group refers to a moiety that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity.
  • hydroxy protecting groups include acyl groups, benzyl and trityl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
  • Representative amino protecting groups include, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2- trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9- fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), and the like.
  • rate when referring to a formation of a salt refers to kinetic and/or thermodynamic rates.
  • the term "treating”, “contacting” or “reacting” refers to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
  • stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer can also be referred to as an "enantiomer,” and a mixture of such isomers is often called an “enantiomeric” or “racemic” mixture.
  • enantiomeric or “racemic” mixture.
  • compositions contain a substantially greater proportion of the (-)-isomer in relation to the (+)-isomer.
  • the term “substantially free of its (+) stereoisomer” means that the composition is at least 90% by weight of the (-)-isomer and 10% by weight or less of the (+)-isomer.
  • the term "substantially free of its (+)-stereoisomer” means that the composition contains at least 99% by weight of the (-)-isomer and 1% by weight or less of the (+)-isomer. In the most preferred embodiment, the term “substantially free of its (+)- stereoisomer” means that the composition contains greater than 99% by weight of the (-)- isomer. These percentages are based upon the total amount of isomers in the composition.
  • This process of resolving the final product is particularly useful in a large scale preparation of pharmaceutically active chiral compounds.
  • enantiomers of a chiral compound have exact same chemical bonds, the spatial orientation of atoms in enantiomers is different.
  • one enantiomer of a chiral drug often exerts desired activity with a significantly less side-effect(s) than the other enantiomer. While such relationship between chirality of an optically active drug and its side-effect(s) has been known for sometime, many chiral drugs are still administered in a racemic form.
  • Diastereomeric crystallization is widely used on industrial scale. The theoretical once-through yield of a resolution via diastereomer crystallization is 50 percent. Typically, however, more than one re-crystallization process is necessary in order to produce a composition that is of a sufficient optical purity.
  • the present invention provides a method for enantiomerically enriching an enantiomeric mixture, preferably a racemic mixture, of ⁇ -(phenoxy)phenylacetic acid compound, e.g., halofenic acid.
  • methods of the present invention provides a solid acid-base salt of the (-)-enantiomer of ⁇ -(phenoxy)phenylacetic acid compound. In this manner, the (-)-enantiomer can be readily separated from the solution.
  • the carboxylic acid group of the enantiomerically enriched ⁇ - (phenoxy)phenylacetic acid can then be activated by a carboxylic acid activation group to produce an activated ⁇ -(phenoxy)phenylacetic acid, which can be reacted with an alcohol, an amine, a thiol, or other nucleophilic compounds to produce an enantiomerically enriched ⁇ - (phenoxy)phenylacetic acid esters, amides, thioesters, or other derivatives, respectively.
  • enantiomerically enriched ⁇ -(phenoxy)phenylacetic acid compounds produced using methods of the present invention are useful in producing ⁇ -(phenoxy)phenylacetic acid derivatives such as those disclosed in U.S. Patent No. 3,517,050.
  • methods of the present invention are useful in producing (-)-halofenate.
  • ⁇ -(phenoxy)phenylacetic acid compound of a sufficient optical purity can be produced by a single crystallization process.
  • methods of the present invention are based on the surprising and unexpected discovery by the present inventors that an enantiomeric mixture of a ⁇ -(phenoxy)phenylacetic acid compound can be enantiomerically enriched using a chiral amine compound.
  • methods of the present invention provide a desired enantiomer of the ⁇ -(phenoxy)phenylacetic acid compound in optical purity of at least about 90%, preferably at least about 95%, more preferably at least about 97%, and most preferably at least about 98%.
  • methods of the present invention provide enantiomeric enrichment of an enantiomeric mixture, preferably a racemic mixture, of a ⁇ - (phenoxy)phenylacetic acid compound of the formula:
  • R 1 is alkyl or haloalkyl
  • X is halide.
  • the process generally involves forming a solid enantiomerically enriched acid-base salt of the ⁇ -(phenoxy)phenylacetic acid compound uing a chiral amine compound.
  • methods of the present invention are directed to the resolution of ⁇ -
  • R 1 is alkyl or haloalkyl
  • X is halide
  • methods of the present invention are directed to the resolution of ⁇ -(phenoxy)phenylacetate acid of Formula I or, preferably of Formula II, where X is chloro.
  • methods of the present invention are directed to the resolution of ⁇ -(phenoxy)phenylacetic acid of Formula I or, preferably, Formula II, where R 1 is haloalkyl, preferably trifluoromethyl.
  • ⁇ -(phenoxy)phenylacetic acid is crystallized using a chiral base.
  • chiral bases can be used, including those disclosed in the Examples section below.
  • the chiral base used results in a solid acid-base salt of the (-)-enantiomer of ⁇ -(phenoxy)phenylacetic acid. In this manner, the (-)-enantiomer is readily separated from the solution, for example, by filtration.
  • the chiral base is an amine compound of the formula:
  • each of R 2 and R 3 is independently hydrogen, alkyl or a hydroxy protecting group; or R and R together with atoms to which they are attached to form a heterocyclic ring moiety;
  • R 4 is hydrogen or alkyl;
  • each of R 5 and R 6 is independently hydrogen or alkyl, or one of R 5 or R 6 is an amine protecting group; and
  • Ar is aryl.
  • R 2 and R 3 together along with oxygen atoms to which they are attached to form 1,3-dioxane, a substituted 1,3-dioxane (e.g., dialkyl substistuted 1,3-dioxane, such as 5,5-dimethyl- 1,3-dioxane), or a derivative thereof.
  • 1,3-dioxane e.g., dialkyl substistuted 1,3-dioxane, such as 5,5-dimethyl- 1,3-dioxane
  • R 2 and R 3 are hydrogen.
  • R 4 is hydrogen
  • Ar is a substituted aryl.
  • a particularly preferred Ar moiety is optionally substituted phenyl.
  • An especially preferred Ar moiety is 4-nitrophenyl.
  • one particularly preferred chiral base is an amine compound of Formula III above, wherein R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen; and Ar is 4- nitrophenyl.
  • a particularly preferred ⁇ -(phenoxy)phenylacetic acid compound is of Formula II above, wherein R 1 is trifluoromethyl and X is chloro.
  • R 2 , R 3 , R 4 and Ar are those defined herein
  • the chiral amine compound is used in crystallization of the ⁇ - (phenoxy)phenylacetic acid compound, higher %ee obtained by using the chiral amine compound in an amount less than 0.5 molar equivalent, preferably about 0.48 molar equivalent or less, more preferably about 0.47 molar equivalent or less, and most preferably about 0.45 molar equivalent or less.
  • the chiral amine compound itself should be of a sufficient enantiomeric purity in order to yield a highly enantiomerically enriched ⁇ -(phenoxy)phenylacetic acid derivatives.
  • the crystallization is typically conducted in a solvent that allows a different solubility of salts that are formed between two enantiomers of the -(phenoxy)phenylacetic acid and the chiral amine. In this manner, one of the diastereomeric salt precipitates out of the solution preferentially.
  • Suitable crystallization solvents include protic solvents, such as alcohols.
  • a particularly preferred crystallization solvent is isopropyl alcohol.
  • the yield of enantiomerically enriched ⁇ -(phenoxy)phenylacetic acid also depends on, among others, the amount of crystallization solvent used. For example, if a large quantity of crystallization solvent is used, the mixture becomes too dilute and the solid formation is reduced. If the amount of crystallization solvent used is too small, the solution will be supersaturated with the undesired diastereomeric salt which may lead to crystallization of the undesired diastereomeric salt, thereby reducing the optical purity of a desired enantiomer.
  • the amount of crystallization solvent used is preferably from about 2 grams to about 6 grams per one gram of the ⁇ - (phenoxy)phenylacetic acid compound, more preferably from about 3 grams to about 5 grams, still more preferably from about 3.5 grams to about 4.5 grams, and most preferably about 4 grams.
  • the crystallization process involves heating the crystallization solution mixture to a temperature above the nucleation temperature of both enantiomers to dissolve substantially all of both enantiomers.
  • the crystallization solution is heated to a temperature in the range of from about 60 °C to the boiling point of the solution, preferably from about 70 °C to about 80 °C. More preferably, the crystallization solution is heated to about 75 °C.
  • the solution can be heated prior to and/or after the chiral amine compound is added. Heating is carried out until the solid materials are substantially completely dissolved, which typically ranges from about 0.5 to about 16 hours, preferably from about 1 to about 8 hours.
  • the crystallization solution is then cooled until it is at or below the nucleation temperature of the first diastereomeric salt, e.g., salt of (-)-enantiomer of the ⁇ -(phenoxy)- phenylacetic acid, but preferably above the nucleation temperature of the second diastereomeric salt, e.g., salt of (+)-enantiomer of the ⁇ -(phenoxy)phenylacetic acid.
  • the first diastereomeric salt e.g., salt of (-)-enantiomer of the ⁇ -(phenoxy)- phenylacetic acid
  • the second diastereomeric salt e.g., salt of (+)-enantiomer of the ⁇ -(phenoxy)phenylacetic acid.
  • the use of a chiral amine compound results in formation of an acid-base salt with one of the enantiomer at a significantly faster rate than formation of an acid-base salt of the other enantiomer. This rate may be due to kinetic and/or thermodynamic rate difference between the two enantiomers.
  • the solubility profile of the ⁇ -(phenoxy)phenylacetic acid compound of the present invention has a higher solubility at a higher temperature. Therefore, by cooling the crystallization solution to just above the nucleation temperature of the second diastereomeric salt affords a higher recovery yield of the solid first diastereomeric salt.
  • the crystallization solution can be further cooled until the temperature of the solution is near or above the saturation point of the second diastereomeric salt. This prevents formation of a diastereomeric solid acid-base salt from the second enantiomer while increasing the formation of the diastereomeric solid acid-base salt of the first enantiomer.
  • the rate of cooling the crystallization solution may affect the optical purity of the solid acid-base salt that is formed. For example, if the crystallization solution is cooled too fast, the undesirable enantiomer may get trapped within the lattice of the solid acid-base salt of the desired enantiomer. However, a too slow cooling rate increases the production time and cost. Therefore, the crystallization solution should be cooled at a rate which minimizes the loss of optical impurity but at a rate sufficient to be economical.
  • the crystallization solution cooling rate is from about 0.05 °C/min to about 1 °C/min, preferably from about 0.1 °C/min to about 0.7 °C/min, and more preferably from about 0.25 °C/min to about 0.4 °C.
  • the crystallization solution is then maintained at above the saturation point of the solid acid-base salt of the second, i.e., undesired, enantiomer.
  • the crystallization solution is maintained at this temperature for about 1 to about 72 hours, preferably from about 2 to about 48 hours, and more preferably from about 3 to about 30 hours.
  • the present invention essentially provides a solid precipitate enriched in the (-)-enantiomer and a liquid filtrate, i.e., mother liquor, enriched in the (+)- enantiomer.
  • a liquid filtrate i.e., mother liquor
  • Liberation of the desired (-)-enantiomer and recovery of the chiral amine compound from the precipitated salt can be readily accomplished by acidification of the salt with, for example, a dilute mineral acid or any other inorganic or organic acid conventionally known to hydro lyze salts of this
  • the filtrate can be further treated with acid or, preferably, base to convert the (+)-enantiomer enriched filtrate to the racemic mixture.
  • the (+)-enantiomer can be racemized using aqueous sodium hydroxide solution. This racemic mixture can then be reused, i.e., recycled.
  • isopropyl ester 2 i.e., where R is isopropyl
  • is particularly advantages as the subsequent reaction is conveniently carried out in isopropanol solvent.
  • Hydrolysis of -(phenoxy)phenylacetic acid ester 4 afforded ⁇ -(phenoxy)phenylacetic acid I.
  • (4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetic acid i.e., CPTA
  • CPTA (4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetic acid
  • Enantiomerically enriched ⁇ -(phenoxy)phenylacetic acid compounds are useful intermediates in preparing a variety of pharmaceutically active compounds, including ⁇ - (phenoxy)phenylacetic acid compounds disclosed in U.S. Patent No. 3,517,050.
  • anther aspect of the present invention provides a method for enantioselectively producing a ⁇ - (phenoxy)phenylacetate compound of the formula:
  • the method involves resolving the racemic mixture of the ⁇ -(phenoxy)phenylacetic acid compound of Formula I as described above and producing an enantiomerically enriched activated ⁇ -(phenoxy)phenylacetic acid by reacting the enantiomerically enriched ⁇ -(phenoxy)phenylacetic acid with a carboxylic acid activating reagent.
  • carboxylic acid activating reagents include thionyl halides (e.g., thionyl chloride), anhydrides, thioester generating reagents, and other carboxylic acid activating reagents known to one skilled in the art.
  • the activated ⁇ -(phenoxy)phenylacetic acid is than reacted with a compound of the formula (R 7 -O) w M, e.g., N-acetyl ethanolamine derivative, to produce enantiomerically enriched ⁇ -(phenoxy)phenylacetate compound of Formula III, where R 7 is as defined above, M is hydrogen or a metal, e.g., Na, K, Li, Ca, Mg, Cs, etc. and the superscript w is the oxidation state of M.
  • R 7 is as defined above
  • M is hydrogen or a metal, e.g., Na, K, Li, Ca, Mg, Cs, etc. and the superscript w is the oxidation state of M.
  • the present inventors have discovered that the reaction between the activated acid and the compound of formula (R 7 -O) w M can be carried out without any significant racemization.
  • esters such as halofenate
  • acetonitrile was used as the injection solvent.
  • product concentrations for CPTA and halofenate were evaluated by HPLC assay using the external standard method and the achiral analysis procedure at sample concentrations of less than 2.5 mg/mL.
  • This example shows the results of resolving a racemic mixture of CPTA using a variety of different chiral bases to obtain a solid enantiomerically enriched (-)-isomer. Unlike the previous method, methods of the present invention allow the solid enantiomerically enriched (-)-CPTA to be readily isolated from the solution.
  • Racemic CPTA was prepared by the potassium hydroxide hydrolysis of racemic halofenate.
  • chiral base screening equal molar mixtures of CPTA and the chiral base were mixed in ethanol, methanol and acetone in glass vials, and the solutions were allowed to stand undisturbed. After holding overnight at ambient temperature, the samples that remained in solution were placed in a refrigerator at 5 °C. After holding overnight in the refrigerator, a small amount of water was added to the samples that remained a solution in ethanol. After four days at ambient temperature, the aqueous ethanol solutions were placed back in the refrigerator. All of the samples remained in the refrigerator, and were periodically checked for precipitate formation over the course of a month. A list of the bases and solvent conditions examined, and temperatures at which crystalline salts were found is shown in Table 1.
  • Recrystallization of the CPTA CAF D Base salt from 2-propanol increased the optical purity from approximately 87 %ee to 98 %ee with 87% mass recovery, or 93% recovery based on the (-)-CPTA content of the feed (Table 4).
  • Racemization of the undesired CPTA enantiomer could be recycled back into the process.
  • heating an enantiomerically enriched undesired isomer of CPTA in 1 N aqueous sodium hydroxide at reflux resulted in racemization in less than one hour. No other by-products were detected by HPLC analysis of the isolated CPTA.
  • This example illustrates a method for obtaining (+)-CPTA.
  • This example illustrates a method for synthesizing (+)-halofenate from (+)-CPTA.
  • This example illustrates a method for preparing racemic CPTA.
  • a 2-L round-bottom flask with an overhead stirrer was charged with 102.7 g of halofenate, 500 mL of water, and 16.3 g of 2-propanol. The slurry was stirred, and 32.3 g of aqueous 45% potassium hydroxide was added. After heating to reflux for 1 hour, the solution was cooled to ambient temperature and charged with 380 mL of hexanes. The pH was adjusted from 12.5 to 2 with 24.57 g of 37% hydrochloric acid. The three phase mixture was heated to 60 °C to give two phases. The lower aqueous phase was removed and extracted with 50 mL of hexanes.
  • This example shows representative results of chiral resolution screening in ethanol using a variety of chiral bases.
  • This example shows representative results of chiral resolution screening in acetone using a variety of chiral bases.
  • This example shows representative results of chiral resolution screening in methanol using a variety of chiral bases.
  • the slurry was heated to 60 °C, then cooled to 30 °C at a rate of 0.04 °C/min and held overnight to give a slurry.
  • Chiral HPLC analysis showed 29.94 and 44.19 area% of (+) and (-)-CPTA, respectively, in the solid phase, and 77.54 and 20.88 area% of (+) and (-)-CPTA, respectively, in the solution.
  • the slurry was diluted with 50 mL of 2- propanol and heated to 57 °C to give a solution, then cooled to 30 °C at a rate of 0.2 °C/min. A slurry started to form after 1 hour at 30 °C.
  • Example 11 shows the result of resolving CPTA with CAF D base.
  • a 150-mL bottom-drain flask was charged with 19.54 g of CPTA, 6.82 g of CAF D Base (i.e., D-threo-(-)-2-amino-l-(nitrophenyl)-l,3-propandiol), and 80.2 g of 2-propanol.
  • the mixture was warmed to 70 °C to give a solution, then cooled to a jacket temperature of 5 °C at a rate of 0.1 °C/min.
  • the mixture was hazy at 62 °C.
  • the solid contained 0.995 area% of (+)- CPTA and 99.01 area% of (-)-CPTA; the mother liquor contained 44.53 area% of (+)-CPTA and 54.47 area% of (-)-CPTA.
  • the reactor was cleaned out with acetone. The acetone was evaporated to a residue of 0.27 g (3.4 wt%).
  • This example illustrates a method for preparing (+)-CPTA CAF D Base salt.
  • Example 14 shows solubility of diastereomeric CPTA-CAF D base salts in 2- propanol.
  • This example illustrates a method for racemizing enantiomerically enriched CPTA.
  • This example illustrates a process for resolving a racemic mixture of CPTA using CAF D-Base under a variety of crystallization conditions.
  • the general crystallization procedure was to charge CPTA, CAF D-Base, and 2- propanol at room temperature and heat to a solution at about 75 °C. The solution was cooled to about 60 °C and held until nucleation occurred. Several batches were seeded with (-)-Salt (i.e., salt of (-)-CPTA and CAF D-Base) to induce nucleation. After the slurry had developed over about an hour, the vessel was cooled to the isolation temperature. The first 5 entries in Figure 2 used a slow cooling rate of about 0.05-0.10 °C / minute to reach the isolation temperature. The other experiments used a faster cooling rate of 0.25-0.40 °C / minute. A fiber optic probe is inserted directly into the crystallizer to determine the slurry density.
  • Entry 9 of Figure 2 (at 0.45 eq. base) maintained 99.5% (-)-Salt purity after 16 hours at 22 °C. Calculated yields of (-)-CPTA from the three batches under these conditions were 70.7- 71.6%. Calculated yields are derived from a forced mass balance from the racemic CPTA feed, by knowing the crystal and mother liquor composition of (-)-CPTA and (+)-CPTA.
  • This example provides a model to describe the resolution/crystallization of CPTA salt.
  • the concentration of free CPTA depends on the amount of base charged and the solvent loading. For example, a resolution of CPTA by charging 4.0 grams of 2-propanol and 0.50 equivalent of CAF D-Base, results in formation of the salt in 2-propanol which contains 11% free CPTA.
  • This solvent possesses greater solubility for both the (-)-Salt and the (+)- Salt, and was determined as shown in Figure 3.
  • Figure 3 also includes the solubility data in pure 2-propanol, expressed in gram of component per gram of 2-propanol. As Figure 3 shows the curves for the respective salts are of similar shape.
  • the solubility model allows calculation of the complete mass balance for the isolation: the amount of (-)-Salt and (+)-Salt in the crystal, the amount of (-)- Salt and (+)-Salt in the mother liquor, and also the amount of (-)-free CPTA and (+)-free CPTA in the mother liquor.
  • One procedure for quantifying (- / +)-Salt and (- / +)-free CPTA in mother liquor by an extractive work-up, using solubility differences, is provide in Example 19 below.
  • the CAF D-Base will coordinate substantially only with (-)-CPTA, forming almost exclusively (-)-Salt. Additionally, by aid of the curve in Figure 7, the amount of (-)-CPTA and (+)-CPTA (free acid) can be calculated. Between 0.35-0.75 equivalent of base charged, the % ratio of ⁇ (-)- CPTA / total CPTA free acid ⁇ is around 25% (23.3-27.1%).
  • This example illustrates resolution of a racemic mixture of CPTA.
  • a 200-mL vessel was charged with 17.0 g of CPTA (51.4 mmol), 4.91 g of CAF D- Base (23.1 mmol, 0.450 eq.), and 85 L of 2-propanol. The mixture was heated to a solution at 78 °C, and then cooled at 0.5 °C / min to 54 °C. About Vz hour later, the solution was seeded with (-)-Salt to induce nucleation. After holding at 54 °C for about 1-1/2 hours, the slurry was cooled to 22 °C at 0.25 °C / minute.
  • Figure 8 shows the analytical and mass balance results in the rectangular boxes.
  • the calculated yield (from CPTA) based on feed/mother liquor/crystal composition is given inside the circles.
  • the vessel was seeded several times with crystal containing (+)-Salt, and about 2 hours later, 0.31 g of CAF D-Base (1.46 mmoi, -0.03 eq.) was added.
  • the vessel was sampled two times (see Figure 8) before the final isolation on a 60-mL medium-fritted funnel.
  • the mother liquor was clear, pale yellow-gold, 59.1 g.
  • the solid was washed with 19.2 g of 2-propanol, with recovery of 18.8 g of wash solution.
  • the washed solid (10.07 g) was further dried by suction on the funnel for an hour to 8.36 g (15.4 mmol salt).
  • Example 19 This example illustrates an extractive work-up process to quantify (-/+)-Salt and (- /+)-CPTA in Mother Liquor.
  • the final mother liquor from separation of entry 4 of Figure 2 at 55.3 °C (see Figures 2 and 5) was analyzed by evaporating 0.1286 g to a glassy residue of 0.0242 g.
  • This example shows solubility of (-)- and (+)-CPTA # CAF D-Base salts in alcohols containing CPTA.
  • Solvent was prepared by dissolving 2.40 g of racemic CPTA in 19.42 g of 2- propanol (Fisher HPLC Grade) or 4.90 g of racemic CPTA in 31.4 g of ethanol. The respective concentrations of CPTA in solution were 11.0% and 13.5%. Solubility of the (-)- CPTA • CAF D-Base Salt (i.e., (-)-Salt) or (+)-CPTA • CAF D-Base Salt (i.e., (+)-Salt) was determined by a gravimetric method. At a given temperature, a portion of the supernatant liquid from a saturated solution was remove to a vial of known weight.
  • This example illustrates a method for preparing enantiomerically enriched (-)- halofenate.
  • CPTA was prepared in five steps, as discussed above, without intermediate isolation in about 85% yield following crystallization from heptane. Resolution gave an average of 32% yield (max 50%) of >98% optically pure (-)-CPTA diastereomeric salt.
  • the (-)-CPTA was esterified to give (-)-halofenate in about 55% yield using thionyl chloride and N-acetylethanolamine.
  • (-)-CPTA can be recovered from the final product mother liquor and cycled back through the process.
  • the resolving agent was isolated from water in about 90% recovery by a pH adjustment.
  • This example illustrates a method for preparing CPTA.
  • the sodium salt of CPTA can be isolated as a solid by simply cooling the reaction mixture. Better isolated yields were obtained, however, by isolation of the carboxylic acid.
  • the basic aqueous CPTA reaction mixture was acidified with hydrochloric acid, and the CPTA was extracted into 1,2-dichloroethane. Solvent exchange of the separated organic phase from 1 ,2-dichloroethane to heptane afforded CPTA as a white solid in approximately 85% yield from 4-chlorophenylacetic acid.
  • CPTA crystallization from heptane was exothermic. Seeding of a solution of approximately 170 g of CPTA in 500 mL of heptane at 46 °C resulted in a temperature increase to 54 °C as the crystallization progressed. Crystallization increased the CPTA purity as determined by HPLC analysis from 93-95 to >99 area %. HPLC assay of a crystallization mother liquor, which contained 15 area % of CPTA, found less than 3% yield loss to the mother liquor. As the purity was improved by crystallization, isolated yields were high, and the loss to the mother liquor was minor.
  • Results of CPTA resolution using CAF D-Base under various crystallization conditions are shown in Figure 13.
  • the molar ratio of the CAF D-Base was varied from 0.5 to 0.56.
  • the amount of 2-propanol solvent listed for the crystallizations and recrystallizations are both based on the initial charge of racemic CPTA.
  • Chiral HPLC results for both the isolated solids and mother liquors are normalized to 100%.
  • the calculated yield and overall yield are calculated from the ratio of the (+)-enantiomer and (-)-enantiomer forms in the isolated solids and mother liquors.
  • the actual percent yield in the last column is of weighed, dried material, and is based on a maximum yield of 50%.
  • Figure 14 shows the cooling profiles for the resolution crystallizations listed in order of decreasing yield of (-)-CPTA.
  • Experiment number in Figure 14 corresponds to the experiment number in Figure 13.
  • the isolated yield of (-)-CPTA was determined using the calculated yield of Figure 13 and the percent of (-)-CPTA in the isolated material. In general, longer hold times at low temperatures led to an increase in yield.
  • This example shows a method for separating (-)-CPTA from the CAF D-Base.
  • This example shows a method for esterifying (-)-CPTA without any significant racemization.
  • First crop isolated yields ranged from 47 to 59% and averaged 55%. This isolated yield represents a reaction yield of 75 to 80% for this step. A second crop afforded a higher overall yield; however, the product quality was poorer with the second crop material.
  • Example 27 shows a method for recovering and recycling (+)-CPTA.
  • This example shows a method for producing CPTA from (+)-halofenate.
  • Example 29 This example illustrates a method for recovering (-)-CPTA from (-)-halofenate crystallization mother liquor.
  • the (-)-halofenate crystallization mother liquor contains a large amount of (-)-halofenate and (-)-CPTA.
  • additional (-)-CPTA can be generated as feed for the resolution step.
  • This example illustrates a method for recovering CAF D-Base.
  • the CAF D-Base is found in the acidic phase from separation of (-)-CPTA from the diastereomeric salt, and from the acidic wash step of the CPTA recovery from the resolution mother liquors. Basification with aqueous sodium hydroxide to a pH greater than about 12 resulted in precipitation with good recovery in a form that was easily filtered. Results are shown in Figure 18. Recovery from the diastereomeric salt was generally greater than 90%; recovery from the resolution mother liquor was lower. Concentrations in the aqueous solution ranged from about 5 to 20%.
  • the enantiomeric purity of the CAF D-Base can be determined by careful analysis of the melting point by DSC (D. Pitre, M. Nebuloni, and V. Ferri; Arch. Pharm. (Weinheim) 324, 525 (1991)). As the conglomerate of the (+)- and (-)-forms, e.g., racemate, melts more than 20 °C lower than the pure enantiomer, melting point was found to be a sensitive method for assessing enantiomeric purity. However, measurement of the enantiomeric purity of two of the samples by chromatographic separation of a derivative showed no loss of chiral purity. The enantiomeric purity of the recovered CAF D-Base, near the detection limit of the HPLC analysis method, was indistinguishable from the source material.
  • This example illustrates another method for preparing racemic CPTA.
  • Example 33 This example illustrates a method for determining solubility of racemic CPTA.
  • Example 34 This example illustrates a method for resolving a racemic mixture of CPTA.
  • a 1-L bottom-drain reactor was charged with 48.2 g (146 mmol) of CPTA, 16.4 g (77.3 mmol) of (lR,2R)-(-)-2-amino-l-(4-nitrophenyl)-l,3-propanediol (CAF D- Base), and 193 g of 2-propanol.
  • the slurry was heated to 70 °C to give a solution, then cooled to 60 °C and held for 1 h.
  • the resulting slurry was cooled at 0.25 °C/min to a jacket temperature of 2 °C and held for 14 h; the internal temperature was 4 °C.
  • the solid was isolated by vacuum filtration and rinsed with 27 g of 2-propanol.
  • the mother liquor and wash solution was sampled for HPLC analysis, and the results are shown in Figure 13.
  • the 50.48-g wetcake was reloaded to the 1-L reactor with 193 g of 2-propanol, and the slurry warmed to a gentle reflux with a jacket temperature of 85 °C to give a solution.
  • the solution was, sampled for HPLC analysis; the results are listed in Figure 13. A slurry formed upon cooling to 65 ° C.
  • This example illustrates a method for racemizing (+)-CPTA and recovering racemic
  • Example 37 This example illustrates a method for isolating (-)-CPTA from the diastereomeric salt.
  • a 500-mL flask with a magnetic stirrer was charged with 40.0 g (73.7 mmol) of (-)- CPTA / CAF D-Base, 100 g of 1,2-dichloroethane, 40 g of water and 7.6 g (77 mmol) of 37% hydrochloric acid. After complete dissolution of the solid, the lower organic phase was removed and washed with 10 mL of water. The pH of the combined aqueous phase was 0.9. 5 HPLC assay of 128.2 g of the organic phase found 24.32 g (73.6 mmol, 99.8% of theory) of (-)-CPTA as a solution in 1 ,2-dichloroethane.
  • a 50-mL round-bottom flask equipped with a magnetic stirrer, heating mantel and a 10 short path distillation head was charged with 29.09 g of N-acetylethanolamine and placed under a vacuum of approximately 0.8 torr. Bubbles formed as the liquid was heated, although no condensate was collected. Distillate was collected at a head temperature of approximately 130 °C to afford 26.71 g (92% recovery) of N-acetylethanolamine as a clear liquid.
  • This example illustrates a method for producing (-)-halofenate.
  • HPLC assay of 294.1 g of the mother liquor and wash found 11.2 g of halofenate and 1.26 g of CPTA. The solvent was evaporated, and 12.47 g of the residue was dissolved in 14 mL of 2-propanol. Addition of 84 mL of heptane gave a slurry after stirring overnight at ambient temperature. The slurry was chilled in an ice bath and the solid was collected, rinsed with 9 g of heptane, and dried to give 5.64 g (13.6 mmol, 20.7% yield, 89.9% halofenate and 3.9% CPTA by HPLC analysis, 99.6 %ee) of (-)-halofenate. HPLC assay of 81.74 g of the mother liquor and wash found 3.66 g (8.8 mmol, 13.5%) of halofenate and 0.93 g (2.8 mmol, 4.8%) of CPTA.
  • This example illustrates a method for isolating racemic CPTA sodium salt.
  • This example illustrates a method for determining the solubility of racemic CPTA sodium salt.
  • a 100-mL water jacketed resin pot with a magnetic stirrer was connected to a recirculating water bath and charged with 3.48 g of the racemic CPTA sodium salt and 20.0 g of water.
  • the bath temperature was warmed to 35 °C, and the slurry was stirred for one hour.
  • the agitator was shut off, and the solid was allowed to settle for 30 min.
  • the pH was 9.4.
  • a 0.3036 g-sample of the supernate was removed and diluted to 25.00 mL with acetonitrile, and the solution was assayed by HPLC analysis. Analysis was repeated at 47 °C and at 19 °C.
  • the solution was diluted with 25 mL of 1 ,2-dichloroethane, and 11 mL (150 mmol) of thionyl chloride was added. After heating at reflux for 2 hours and removing 22.6 g of distillate, the solution was cooled in an ice bath for the dropwise addition of 38.6 g (374 mmol) of distilled N-acetylethanolamine. The reaction temperature rose from 7 to 18 °C during the addition. After stirring overnight at ambient temperature, the solution was added with stirring to 12.7 g of potassium carbonate in 51 mL of water chilled in an ice bath. The organic phase was removed and washed with 51 g of water.
  • the organic phase (85.2% of halofenate and 6.1% CPTA by HPLC analysis) was evaporated to an oil of 44.3 g, treated with 133 g of heptane, then evaporated to a solid of 43.3 g.
  • the solid residue was dissolved in 61.5 g of 2-propanol and charged to the 1-L bottom-drain reactor along with 320 g of heptane, warmed to 50 °C, and cooled at 3 °C/min to 20 °C, then at 1 °C/min to -3 °C.
  • the solution became hazy at 27 °C, and a thick slurry formed at 15 °C.
  • This example illustrates a process for recovering CAF D-Base from CPTA/CAF D- 15 Base salt.
  • Example 45 25 This example illustrates a process for recovering CAF D-Base from the resolution mother liquor.

Abstract

L'invention concerne un procédé de production de composé d'acide alpha-(phénoxy)phénylacétique à enrichissement énantiomère, de formule (I), à partir de son mélange énantiomère, sachant que R1 est alkyle ou haloalkyle et que X est halogénure.
PCT/US2004/019616 2003-06-20 2004-06-18 Resolution de derives d'acide ?lpha-(phenoxy)phenylacetique WO2004112774A1 (fr)

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JP2006517439A JP2007524614A (ja) 2003-06-20 2004-06-18 α−（フェノキシ）フェニル酢酸誘導体の分割
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MXPA05013981A MXPA05013981A (es) 2003-06-20 2004-06-18 Resolucion de derivados de acido a- (fenoxi) fenilacetico.
EP04755657A EP1635809A4 (fr) 2003-06-20 2004-06-18 Resolution de derives d'acide alpha-(phenoxy)phenylacetique
YUP-2005/0937A RS20050937A (en) 2003-06-20 2004-06-18 Resolution of alpha- (phenoxy)phenylacetic acid derivatives
IL172663A IL172663A0 (en) 2003-06-20 2005-12-18 A process for the preparation of ??-(phenoxy)phenylacetic acid derivatives
KR1020057024492A KR101073742B1 (ko) 2003-06-20 2005-12-20 α-(페녹시)페닐아세트산 유도체의 분리

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Publication number Priority date Publication date Assignee Title
US7199259B2 (en) 2003-06-20 2007-04-03 Metabolex, Inc. Resolution of α-(phenoxy)phenylacetic acid derivatives
EP1940387A1 (fr) * 2005-09-23 2008-07-09 Metabolex, Inc. Procede de preparation stereoselective de (-)-halofenates et d'intermediaires de ces derniers
JP2008546761A (ja) * 2005-06-23 2008-12-25 ハンミ ファーム． シーオー．， エルティーディー． クロピドグレルの製造方法及びこの方法に用いられる中間体
WO2006102375A3 (fr) * 2005-03-21 2009-04-02 Metabolex Inc Methodes pour eviter un oedeme dans le traitement ou la prevention de maladies sensibles a ppar$g(g), telles que le cancer
US7576131B2 (en) 1999-06-04 2009-08-18 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia
US8354448B2 (en) 1999-06-04 2013-01-15 Metabolex, Inc. Use of (−)(3-trihalomethylphenoxy)(4-halophenyl) acetic acid derivatives for treatment of type 2 diabetes

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US6262118B1 (en) * 1999-06-04 2001-07-17 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes and hyperlipidemia

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NL6712585A (fr) * 1966-10-03 1968-04-04
US3517050A (en) * 1966-10-03 1970-06-23 Merck & Co Inc Ester and amide derivative of (3-trifluoromethylphenoxy) (4 - halophenyl)acetic acid
US6624194B1 (en) * 1999-06-04 2003-09-23 Metabolex, Inc. Use of (−) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia

Patent Citations (1)

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US6262118B1 (en) * 1999-06-04 2001-07-17 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes and hyperlipidemia

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7576131B2 (en) 1999-06-04 2009-08-18 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia
US8329749B2 (en) 1999-06-04 2012-12-11 Metabolex, Inc. Use of (−) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of hyperuricemia
US8354448B2 (en) 1999-06-04 2013-01-15 Metabolex, Inc. Use of (−)(3-trihalomethylphenoxy)(4-halophenyl) acetic acid derivatives for treatment of type 2 diabetes
US8481597B2 (en) 1999-06-04 2013-07-09 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia
US7199259B2 (en) 2003-06-20 2007-04-03 Metabolex, Inc. Resolution of α-(phenoxy)phenylacetic acid derivatives
WO2006102375A3 (fr) * 2005-03-21 2009-04-02 Metabolex Inc Methodes pour eviter un oedeme dans le traitement ou la prevention de maladies sensibles a ppar$g(g), telles que le cancer
US8288438B2 (en) 2005-03-21 2012-10-16 Metabolex, Inc. Methods for avoiding edema in the treatment or prevention of PPARγ-responsive diseases, including cancer
JP2008546761A (ja) * 2005-06-23 2008-12-25 ハンミ ファーム． シーオー．， エルティーディー． クロピドグレルの製造方法及びこの方法に用いられる中間体
EP1940387A1 (fr) * 2005-09-23 2008-07-09 Metabolex, Inc. Procede de preparation stereoselective de (-)-halofenates et d'intermediaires de ces derniers
US7714131B2 (en) 2005-09-23 2010-05-11 Metabolex, Inc. Process for the stereoselective preparation of (−)-halofenate and derivatives thereof
EP1940387A4 (fr) * 2005-09-23 2010-11-03 Metabolex Inc Procede de preparation stereoselective de (-)-halofenates et d'intermediaires de ces derniers

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