EP1635809A4 - Resolution de derives d'acide alpha-(phenoxy)phenylacetique - Google Patents

Resolution de derives d'acide alpha-(phenoxy)phenylacetique

Info

Publication number
EP1635809A4
EP1635809A4 EP04755657A EP04755657A EP1635809A4 EP 1635809 A4 EP1635809 A4 EP 1635809A4 EP 04755657 A EP04755657 A EP 04755657A EP 04755657 A EP04755657 A EP 04755657A EP 1635809 A4 EP1635809 A4 EP 1635809A4
Authority
EP
European Patent Office
Prior art keywords
acid
cpta
phenoxy
enantiomer
phenylacetic acid
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Withdrawn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
EP04755657A
Other languages
German (de)
English (en)
Other versions
EP1635809A1 (fr
Inventor
Edward D Daugs
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.)
CymaBay Therapeutics Inc
Original Assignee
Metabolex 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
Priority claimed from US10/656,567 external-priority patent/US7199259B2/en
Application filed by Metabolex Inc filed Critical Metabolex Inc
Publication of EP1635809A1 publication Critical patent/EP1635809A1/fr
Publication of EP1635809A4 publication Critical patent/EP1635809A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

  • 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.
  • Figure 10B is a table showing experimental data and a solubility model calculation for entry 4 of Figure 2 at 28.3 °C.
  • 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.
  • 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.
  • rate when referring to a formation of a salt refers to kinetic and/or thermodynamic rates.
  • 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%.
  • 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
  • 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.
  • 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.
  • 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:
  • This example shows a method for separating (-)-CPTA from the CAF D-Base.
  • 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.
  • 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.
  • This example illustrates a process for recovering CAF D-Base from CPTA/CAF D- 15 Base salt.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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.
EP04755657A 2003-06-20 2004-06-18 Resolution de derives d'acide alpha-(phenoxy)phenylacetique Withdrawn EP1635809A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US60018903A 2003-06-20 2003-06-20
US10/656,567 US7199259B2 (en) 2003-06-20 2003-09-04 Resolution of α-(phenoxy)phenylacetic acid derivatives
PCT/US2004/019616 WO2004112774A1 (fr) 2003-06-20 2004-06-18 Resolution de derives d'acide ?lpha-(phenoxy)phenylacetique

Publications (2)

Publication Number Publication Date
EP1635809A1 EP1635809A1 (fr) 2006-03-22
EP1635809A4 true EP1635809A4 (fr) 2006-09-27

Family

ID=33544772

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04755657A Withdrawn EP1635809A4 (fr) 2003-06-20 2004-06-18 Resolution de derives d'acide alpha-(phenoxy)phenylacetique

Country Status (7)

Country Link
EP (1) EP1635809A4 (fr)
KR (1) KR101073742B1 (fr)
CA (1) CA2529774C (fr)
IL (1) IL172663A0 (fr)
MX (1) MXPA05013981A (fr)
RS (1) RS20050937A (fr)
WO (1) WO2004112774A1 (fr)

Families Citing this family (6)

* 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
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
US7199259B2 (en) 2003-06-20 2007-04-03 Metabolex, Inc. Resolution of α-(phenoxy)phenylacetic acid derivatives
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
KR100678287B1 (ko) * 2005-06-23 2007-02-02 한미약품 주식회사 클로피도그렐의 제조방법 및 이에 사용되는 중간체
US7714131B2 (en) 2005-09-23 2010-05-11 Metabolex, Inc. Process for the stereoselective preparation of (−)-halofenate and derivatives thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1182008A (en) * 1966-10-03 1970-02-25 Merck & Co Inc Resolution of d1-(3-Trifluoromethylphenoxy)-(4-Chlorophenyl)Acetic Acid
US3517050A (en) * 1966-10-03 1970-06-23 Merck & Co Inc Ester and amide derivative of (3-trifluoromethylphenoxy) (4 - halophenyl)acetic acid
WO2002044113A2 (fr) * 2000-11-28 2002-06-06 Metabolex, Inc. Utilisation de derives d'acide acetique(-)(3-halomethylphenoxy)(4-halophenyl) dans le traitement de la resistance a l'insuline, le diabete de type 2, l'hyperlipidemie et l'hyperuricemie

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1182008A (en) * 1966-10-03 1970-02-25 Merck & Co Inc Resolution of d1-(3-Trifluoromethylphenoxy)-(4-Chlorophenyl)Acetic Acid
US3517050A (en) * 1966-10-03 1970-06-23 Merck & Co Inc Ester and amide derivative of (3-trifluoromethylphenoxy) (4 - halophenyl)acetic acid
WO2002044113A2 (fr) * 2000-11-28 2002-06-06 Metabolex, Inc. Utilisation de derives d'acide acetique(-)(3-halomethylphenoxy)(4-halophenyl) dans le traitement de la resistance a l'insuline, le diabete de type 2, l'hyperlipidemie et l'hyperuricemie

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2004112774A1 *

Also Published As

Publication number Publication date
IL172663A0 (en) 2006-04-10
CA2529774A1 (fr) 2004-12-29
KR101073742B1 (ko) 2011-10-13
CA2529774C (fr) 2014-05-27
WO2004112774A1 (fr) 2004-12-29
RS20050937A (en) 2008-04-04
EP1635809A1 (fr) 2006-03-22
MXPA05013981A (es) 2006-03-02
KR20060030048A (ko) 2006-04-07

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