EP2945926A1 - Couplage médié par dcc pour la fabrication d'halofénate - Google Patents

Couplage médié par dcc pour la fabrication d'halofénate

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Publication number
EP2945926A1
EP2945926A1 EP13871679.0A EP13871679A EP2945926A1 EP 2945926 A1 EP2945926 A1 EP 2945926A1 EP 13871679 A EP13871679 A EP 13871679A EP 2945926 A1 EP2945926 A1 EP 2945926A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
solution
alkyl
toluene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13871679.0A
Other languages
German (de)
English (en)
Other versions
EP2945926A4 (fr
Inventor
Jiangao Song
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Diatex Inc
CymaBay Therapeutics Inc
Original Assignee
CymaBay Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by CymaBay Therapeutics Inc filed Critical CymaBay Therapeutics Inc
Publication of EP2945926A1 publication Critical patent/EP2945926A1/fr
Publication of EP2945926A4 publication Critical patent/EP2945926A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

  • Ester and amide derivatives of (-)-4-chloro-a-(3-trifluoromethylphenoxy)phenylacetic acid (I) ((-)-halofenic acid), including (-)-halofenate (II), are chiral compounds and are useful in ameliorating a variety of physiological conditions, including conditions associated with blood lipid deposition, Type II diabetes, hyperlipidema and hyperuricemia (see, e.g., U.S. Pat. Nos. 7,199,259 and 6,262,118 which are incorporated herein by reference in their entireties).
  • Halofenic acid and its ester and amide derivatives contain a single chiral center alpha to the carbonyl carbon atom, and therefore exist in two enantiomeric forms.
  • the administration of halofenate i.e., a racemic mixture of the two enantiomers of 2-acetamidoethyl (4- chlorophenyl) (3-trifluoromethylphenoxy) acetate
  • this racemic mixture also results in various adverse effects including nausea, gastrointestinal ulcers, and gastrointestinal bleeding.
  • Other side effects that have been reported with racemic halofenate include potential adverse drug-drug interactions, including difficulties controlling anticoagulation with CoumadinTM.
  • R is selected from the group consisting of arylCi_ 6 alkyl-, (Ci_ 6 alkyl) 2 NCi_ 6 alkyl-, Ci_ 6 alkyl-NHCi_ 6 alkyl- ,Ci_ 6 alkylC(0)NHCi_ 6 alkyl-, arylC(0)NHCi_ 6 alkyl-, Ci_ 6 alkyl- NHC(0)NHCi_ 6 alkyl-, aryloxyCi_ 6 alkyl- and Ci_ 6 alkylNHC(0)NHphenyl-; and
  • X and X' are each independently a halogen
  • X and X' are each independently a halogen
  • the compound of formula (III) obtained from the crude reaction mixture may be allowed to remain in the crude reaction mixture without requiring workup for an extended period of time, wherein the compound of the formula (III) does not undergo epimerization or racemization.
  • the compound of the formula (III) may remain in the crude reaction mixture for at least 1.5 hours, 2 hours, 5 hours, 10 hours, 15 hours, 17 hours or more than 24 hours without any measurable racemization.
  • the compound of the formula (III) may remain in the crude reaction mixture at about 0 °C, 10 °C, 15 °C, 20 °C or at about room temperature for the above cited period of time without any measurable racemization.
  • R is Ci_ 6 alkylC(0)NHCi_ 6 alkyl or arylC(0)NHC 1-6 alkyl
  • X is F and X' is CI
  • the coupling agent is N,N'-dicyclohexylcarbodiimide.
  • R is CH 3 CONHCH 2 CH 2 - and X is F and X' is CI.
  • the compound of the formula (lb) is N-acetylethanolamine.
  • no base is used.
  • the compound of formula (III) is the compound of formula (II):
  • the aprotic solvent is selected from the group consisting of toluene, xylenes, cyclohexane, diisopropylether, isopropyl acetate, THF, hexanes, MTBE, and combinations thereof.
  • the aprotic solvent is toluene.
  • the mole ratio of ⁇ , ⁇ '-dicyclohexylcarbodiimide to the compound of formula (la) is 1.05: 1 to 1.15: 1, and the mole ratio of the compound of formula (lb) to the compound of formula (la) is 1.02: 1 to 1.7: 1.
  • the mole ratio of ⁇ , ⁇ '- dicyclohexylcarbodiimide to the compound of formula (la) is 1.1 : 1
  • the mole ratio of the compound of formula (lb) to the compound of formula (la) is 1.5: 1.
  • the process is performed using 4-(N,N-dimethylammo)pyridine (DMAP). In another embodiment, no DMAP is used.
  • the process is performed with no N-hydroxy based agent typically used in DCC coupling reactions to avoid racemization (such as, e.g., 1- hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or N-hydroxy-5-norbornene- e «Jo-2,3-dicarboximide (BONB)).
  • N-hydroxy based agent typically used in DCC coupling reactions to avoid racemization
  • the process further comprises: contacting a compound of formula (la) with a compound of formula (lb); cooling the resulting solution at about 0 °C; and contacting a solution of N,N'-dicyclohexylcarbodiimide with the solution comprising the compounds of formulae (la) and (lb) for a sufficient period of time to form the compound of formula (III).
  • one process comprises contacting a solution comprising N-acetylethanolamine in toluene with a solution of the compound of formula (la) in toluene; cooling the resulting solution at about 0 °C; and contacting a solution of ⁇ , ⁇ '-dicyclohexylcarbodiimide in toluene with the solution comprising N-acetylethanolamine and the compound of formula (la) for a sufficient period of time to form the compound of formula (III).
  • the process further comprises isolating dicyclohexylurea (DCU) precipitate as a by-product from the filtrate and washing the precipitate with an aprotic solvent such as toluene.
  • DCU dicyclohexylurea
  • the process further comprises adding an aprotic solvent, such as cyclohexane, to the filtrate, washing the filtrate with water and azeotropically distilling water from the filtrate, and isolating the compound of the formula (III) by crystallization.
  • the compound of formula (III) is obtained with a yield of about 80% or greater before recrystalhzation. In certain embodiments, the compound of formula (III) is obtained with an enantiomeric excess of about 98% or greater before
  • the compound of formula (III) has an enantiomeric excess of about 98%, about 99%, about 99.5%, about 99.9%, or greater before recrystalhzation. In certain embodiments, the compound of formula (III) is obtained with a chemical purity of about 98% or greater before recrystalhzation. In some embodiments, the compound of formula (III) has a DCU level of less than 1.0% before recrystalhzation, less than about 0.9%, less than about 0.7%, less than about 0.5%, less than about 0.3% or less than about 0.1%.
  • the process provides for the preparation of (-)-halofenate (II) or a salt thereof:
  • the process comprising: contacting a solution of (-)-4-chloro-phenyl-(3-trifluoromethyl- phenoxy)-acetic acid in an aprotic solvent with N-acetylethanolamine; contacting the resulting solution mixture with a solution of N,N'-dicyclohexylcarbodiimide in an aprotic solvent to form (-)-halofenate.
  • the aprotic solvent is selected from the group consisting of toluene, xylenes, cyclohexane, di-isopropyl ether, isopropyl acetate, THF, hexanes and MTBE or combinations thereof.
  • the aprotic solvent is toluene.
  • the contacting the resulting solution mixture with a solution of ⁇ , ⁇ '- dicyclohexylcarbodiimide in an aprotic solvent s performed at about 0 °C.
  • the process further comprises filtering the DCU by-product from the solution.
  • the (-)-halofenate is obtained with a yield of about 80% or greater. In certain embodiments of the process, the (-)-halofenate is obtained with an
  • the (-)-halofenate has an enantiomeric excess of about 98%, about 99%, about 99.5%, about 99.9%, or greater before purification.
  • the (-)-halofenate is obtained with a chemical purity of about 98% or greater before purification.
  • the (-)-halofenate has a DCU level of less than 1.0%, about 0.5% about 0.3% or about 0.1% before purification.
  • the process further comprises purifying (e.g. recrystallizing) the compound of formula (III) (e.g. the compound of formula (II), (-)-halofenate).
  • Recrystallization may be performed in a variety of solvents, for example using diisopropylether, cyclohexane, or a mixture of toluene and cyclohexane. Recrystallization may be used to improve the enantiomeric excess or chemical purity of the desired product.
  • the compound of formula (III) has an enantiomeric excess of about 99.9% or greater after recrystallization.
  • the compound of formula (III) has a chemical purity of about 99% or greater after recrystallization. In some embodiments, the compound of formula (III) has a DCU level of less than about 0.5%, less than about 0.3%, or less than about 0.1%. Other aspects of the current disclosure are described below.
  • Alkyl refers to straight, branched, or cyclic aliphatic hydrocarbons chain groups of one to ten carbon atoms (Ci_io alkyl), one to six carbon atoms (Ci_ 6 alkyl) or one to four carbon atoms (Ci_4 alkyl).
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, n- 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 indicated otherwise, an aryl group can be substituted with one or more substituents, such as one, two or three substituents; or 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) noted above.
  • 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 or 4-chloro-a-(3- trifluoromethylphenoxy)phenylacetic acid.
  • the (-) optical isomer of CPTA has an R
  • Enantiomeric mixture refers to a chiral compound having a mixture of enantiomers, including a racemic mixture.
  • Enantiomerically enriched refers to a composition where one enantiomer is present in a higher amount than the other enantiomer.
  • halogen refers to F, CI, Br and I. In one aspect, halogen refers to F and CI.
  • Haloalkyl refers to alkyl group as defined herein in which one or more hydrogen atoms have been replaced with halogen(s), including perhaloalkyls, such as trifluoromethyl.
  • Halofenate refers to 2-acetamidoethyl 4-chlorophenyl-(3-trifluoromethyl- phenoxy)acetate (i.e., 4-chloro-a-(3-(trifluoromethyl)phenoxy)benzeneacetic acid, 2- (acetylamino)ethyl ester or (4-chlorophenyl)(3-trifluoromethylphenoxy)acetic acid), 2- (acetylamino)ethyl ester).
  • 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 group of the formula -OAr a , wherein Ar a is phenyl as defined herein.
  • a-(phenoxy)phenylacetic acid refers to acetic acid that is substituted on the 2-position with an optionally substituted phenyl and optionally substituted phenoxy moieties.
  • 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.
  • 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. In another embodiment, 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 another embodiment, the term “substantially free of its (+)-stereoisomer” means that the composition contains greater than 99%, 99.5%, 99.8% or 99.9% by weight of the (-)-isomer. These percentages are based upon the total amount of isomers in the composition.
  • the present application discloses a condensation reaction of (-)- CPTA with N-acetylethanolamine to provide (-)-halofenate in high chemical yields, high chiral purity and provides a favorable by-product profile.
  • the condensation reaction to provide (-)-halofenate may be performed in a single step.
  • DCC may be used in the absence of a base in the ester formation step for the synthesis of (-)-halofenate.
  • Scheme 1 illustrates a general method of preparing compounds of formula (III).
  • the process for the preparation of the compound of the formula (III), such as (R)-2-acetamidoethyl 2-(4-chlorophenyl)-2-(3-(trifluoromethyl)phenoxy)acetate may be performed by initially dissolving DCC in an aprotic solvent, such as toluene.
  • a solution of ROH such as N-acetylethanolamine
  • an aprotic solvent such as toluene
  • the N-acetylethanolamine solution is mixed with a solution of a compound of the formula (la) wherein X and X' are as defined herein, such as (-)-CPTA, in an aprotic solvent, such as toluene.
  • a solution of a compound of the formula la such as (-)-4-chloro- phenyl-(3-trifluoromethyl-phenoxy)-acetic acid is prepared in an aprotic solvent, such as toluene, and the compound of the formula ROH, wherein R is as defined herein, is then added to the mixture.
  • the solution of DCC is then added to the solution comprising the compound of the formula (la) with the compound of the formula ROH.
  • the addition of the solution of DCC to the solution comprising the compound of formula (la) with ROH is performed below room temperature, such as below about 15 °C, below 10 °C, below 5 °C or about 0 °C for about 1 hour, 2 hours, 3 hours, 5 hours or more. In one variation, the addition of the DCC solution is performed at about 0 °C for about 1.5 hours or until all of the DCC solution is added.
  • the resulting solution or suspension is stirred at below room temperature, such as about 10 °C or 0 °C, for at least about 3 hours, 5 hours, 7 hours, about 12 hours or more, until the reaction is determined to be complete. Reaction completion may be monitored by chromatographic methods, such as by TLC, HPLC or other spectroscopic methods.
  • the precipitated DCU by-product may be removed from the solution using standard methods, such as filtration over Whatman paper, filtration on a Buchner funnel, optionally with silica gel and/or celite to remove the DCU. Depending on the solvent or solvent mixtures that are used in the process, more than one filtration steps to remove DCU may require as the DCU precipitates out over time.
  • the DCU cake is washed with a solvent, such as toluene.
  • a solvent such as toluene.
  • an organic solvent such as cyclohexane
  • the resulting solution is washed with water, and water is separated from the organic solution. Residual water is then removed from the organic solution by drying, such as the use of drying agent (sodium sulfate, magnesium sulfate etc.) and or by azeotropic distillation of the cyclohexane-toluene solution.
  • a solid compound of formula (III), such as (R)-2-acetamidoethyl 2-(4-chlorophenyl)- 2-(3-(trifluoromethyl)phenoxy)acetate, may be obtained from solution.
  • an organic solvent such as cyclohexane
  • the resulting mixture is heated to above room temperature, such as about 35 °C, 37 °C or about 40 °C.
  • the resulting solution is seeded with crystals of the desired product, such as crystals of (R)-2- acetamidoethyl 2-(4-chlorophenyl)-2-(3-(trifluoromethyl)phenoxy)acetate, and mixed at the same temperature for at least about 1 hour, 2 hours, 3 hours or about 4 hours or more, and the mixture is allowed to cool slowly to room temperature or below room temperature, such for at least about 1 hour, 2 hours, 3 hours or about 4 hours or more, and the resulting crystals are filtered and washed with a cold (about 10 °C or colder) solvent such as cyclohexane.
  • the crystalline product may be dried to afford the desired product.
  • the above described processes allow the isolated (-)-halofenate to have a DCU level of about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05% or about 0.01% or less.
  • these e.e. and chemical purity levels are obtained before further purification (e.g.
  • the product obtained, (-)-halofenate is substantially free of its (+)-stereoisomer.
  • DCU may be precipitated out of the solution at different rates over time, and upon precipitation, DCU may be isolated from the desired solution containing the product by a filtration process.
  • DCC (22.7 g, 110 mmol) was dissolved in toluene (50 mL) at 20 °C.
  • N-acetylethanolamine (15.5 g, 150 mml)
  • toluene 150 mL
  • (-)-4-chloro-phenyl)-(3-trifluoromethyl-phenoxy)-acetic acid 33.1 g, 100 mmol.
  • the mixture was stirred at 20 °C until a clear solution was formed.
  • the solution was cooled with an ice-water bath.
  • DCC in toluene solution dropwise at 0 °C in 90 min.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé pour la préparation d'un composé d'halofénate de formule (III) ou un sel de celui-ci : dans laquelle R, X et X' sont tels que présentement définis, le procédé comprenant la mise en contact d'un composé de formule (Ia) avec un composé de formule (Ib) et du Ν,Ν'-dicyclohexylcarbodiimide dans des conditions suffisantes pour former le composé de formule (III).
EP13871679.0A 2013-01-18 2013-01-18 Couplage médié par dcc pour la fabrication d'halofénate Withdrawn EP2945926A4 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2013/022213 WO2014113022A1 (fr) 2013-01-18 2013-01-18 Couplage médié par dcc pour la fabrication d'halofénate

Publications (2)

Publication Number Publication Date
EP2945926A1 true EP2945926A1 (fr) 2015-11-25
EP2945926A4 EP2945926A4 (fr) 2016-09-14

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP13871679.0A Withdrawn EP2945926A4 (fr) 2013-01-18 2013-01-18 Couplage médié par dcc pour la fabrication d'halofénate

Country Status (9)

Country Link
EP (1) EP2945926A4 (fr)
CN (1) CN105143172B (fr)
AU (1) AU2013374358B2 (fr)
CA (1) CA2901353A1 (fr)
EA (1) EA028385B1 (fr)
HK (1) HK1211020A1 (fr)
NZ (1) NZ711096A (fr)
WO (1) WO2014113022A1 (fr)
ZA (1) ZA201505919B (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3517050A (en) * 1966-10-03 1970-06-23 Merck & Co Inc Ester and amide derivative of (3-trifluoromethylphenoxy) (4 - halophenyl)acetic acid
US7432394B2 (en) * 2005-09-23 2008-10-07 Metabolex, Inc. Resolution of α-(phenoxy) phenylacetic acid derivatives with naphthyl-alkylamines
WO2009121940A1 (fr) * 2008-04-03 2009-10-08 Janssen Pharmaceutica Nv Procédé de préparation de l'ester 2-acétylamino-éthylique de l'acide (-)-(4-chlorophényl)-(3-trifluorométhylphénoxy)-acétique

Also Published As

Publication number Publication date
AU2013374358A1 (en) 2015-09-03
CA2901353A1 (fr) 2014-07-24
ZA201505919B (en) 2017-05-31
EA201591348A1 (ru) 2016-01-29
HK1211020A1 (en) 2016-05-13
EA028385B1 (ru) 2017-11-30
NZ711096A (en) 2016-10-28
AU2013374358B2 (en) 2017-06-08
CN105143172B (zh) 2016-12-14
EP2945926A4 (fr) 2016-09-14
CN105143172A (zh) 2015-12-09
WO2014113022A1 (fr) 2014-07-24

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