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WO2014114352A1 - Procédé de préparation d'étoricoxib - Google Patents

Procédé de préparation d'étoricoxib Download PDF

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Publication number
WO2014114352A1
WO2014114352A1 PCT/EP2013/051506 EP2013051506W WO2014114352A1 WO 2014114352 A1 WO2014114352 A1 WO 2014114352A1 EP 2013051506 W EP2013051506 W EP 2013051506W WO 2014114352 A1 WO2014114352 A1 WO 2014114352A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
etoricoxib
leaving group
process according
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.)
Ceased
Application number
PCT/EP2013/051506
Other languages
English (en)
Inventor
Jie Zhu
Pascal Renart VERKERK
Jordy Luten
Rolf Keltjens
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.)
Synthon BV
Original Assignee
Synthon BV
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 Synthon BV filed Critical Synthon BV
Priority to PCT/EP2013/051506 priority Critical patent/WO2014114352A1/fr
Publication of WO2014114352A1 publication Critical patent/WO2014114352A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention deals with a novel process and intermediates for making the
  • Etoricoxib i.e. 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine of formula (1),
  • COX-2-inhibitor which is currently approved, in the free base form, for the treatment of various inflammatory diseases, e.g. rheumatoid arthritis. It is marketed in the form of a film- coated tablet, e.g., under the brand name Arcoxia.
  • Etoricoxib was first disclosed in WO9803484. Etoricoxib may exist, in the solid state, in various polymorphic forms, which are disclosed, e.g. in WO0137833 and WO0192230.
  • WO9803484 discloses a process for making etoricoxib which comprises bromination of 2-amino pyridine derivatives, the coupling of the resulting bromide derivative with 4- (methylthio)phenyl-boronic acid in the presence of a suitable base, and the oxidation of the product to give the corresponding sulfone. Then the amino group of the sulfone is converted to the corresponding halide.
  • a palladium-catalyzed coupling of the sulfone halide derivative with an appropriately substituted metal-containing aromatic group gives etoricoxib of formula (1).
  • This method has several disadvantages as the costly catalyst palladium used for the coupling or the difficulties to purify the resulting product.
  • W09847871 discloses a method for the preparation of etoricoxib (see Scheme 1 below) which comprises reacting a compound of formula (2) with a ketosulfone of formula (3), which after heating in the presence of ammonium acetate yields etoricoxib of formula (1).
  • Impurity I Impurity II.
  • WO9955830 prepares etoricoxib by reacting a ketosulfone derivative with a special vinamidmium hexafiuoro hosphate salt (see Scheme 2 below).
  • the synthesis includes three steps, which has been optimized to a one-pot process.
  • the subject of the present invention is a novel synthetic route to intermediates involved in the synthesis of etoricoxib of formula (1).
  • the approach is based on a novel use of a reagent of formula (4) in a synthetic route leading to etoricoxib,
  • the invention provides a process for making the compound of formula
  • the above process leading to the compound of formula (5) further comprises reducing the compound of formula (5) to etoricoxib with a reducing agent, either by direct reduction of the OH group or by first converting the compound of formula (5) into a compound of formula (7),
  • L is a suitable leaving group, and then reducing the compound of formula (7) to etoricoxib with a reducing agent.
  • the leaving group (L) from compound (7) can be the same or different than the leaving group (L) from compound (4).
  • the present invention provides an alternative route for making etoricoxib of formula (1) based on employing a new reagent namely the compound of formula (8).
  • this reagent is stable enough to be stored and therefore be used on an industrial scale.
  • the process of the present invention is primarily drawn to make a compound of formula (5) or a salt thereof.
  • the process according to various aspects of the present invention is shown in the Scheme 3 below.
  • the starting material of the present invention is l-(6-methylpyridin-3-yl)-2-(4- (methylsulfonyl)phenyl)ethanone or ketosulphone (3).
  • This compound is known. It may be produced by a suitable process, e.g. the one described in WO9955830.
  • the second starting material is the reagent of general formula (4).
  • L is a suitable leaving group, for example a sulfonate group such as mesylate, tosylate, and besylate.
  • L is tosylate
  • it may be obtained by reaction of methyl 2-chloro-2-hydroxyacetate with tosyl chloride, advantageously using triethylamine as a base.
  • the first step of the process of the present invention includes providing the compound of formula (6).
  • This compound can be obtained by reaction of ketosulphone (3) with a compound of formula (4), wherein L is a suitable leaving group, in the presence of a base.
  • a suitable base is, without limitations, a strong base such as Lithium diisopropylamide (LDA), sodium hydride (NaH), or potassium tert butoxide (t-BuOK).
  • a suitable solvent for the condensation of compound (3) with compound (4) is an organic solvent and optionally preferably an aprotic solvent is used.
  • a more preferable solvent is an ether solvent, and a still more preferable solvent is THF. After the condensation, a mixture of water/organic solvent needs to be added in order to close the ring to form compound 6.
  • a suitable solvent could be, without limitations, water/ dichloromethane.
  • compound (6) may be obtained by reaction of the compound of formula (3) with methyl 2-chloro-3-(tosyloxy)acrylate (8) in the presence of t-BuOK in THF, isolation of the unstable open ring intermediate, followed by rapid addition of water/dichloromethane. If desired or advantageous, the compound of formula (6) may be isolated from the reaction mixture as such or in the form of a salt, and optionally purified.
  • the compound of formula (6) is converted to the compound of formula (5) by reaction with a nitrogen donor.
  • a suitable nitrogen donor is, without limitations, an ammonia-containing reagent, such as ammonium hydroxide, ammonium formate or ammonium acetate, or a mixture thereof.
  • a suitable solvent can optionally be added, preferred solvents are C1-C4 aliphatic alcohol such as 2-propanol.
  • the compound of formula (5) may be isolated from the reaction mixture as such as a mixture of two isomers or in a single enolate form or in the form of a salt, and optionally may be purified.
  • the compound of formula (6) is not purified after reaction of (3) with (4), and the nitrogen donor advantageously is added to the reaction mixture to give compound (5).
  • the OH group of the compound of formula (5) is converted into a leaving group in the presence of a base to form a compound of formula (7).
  • Suitable examples of leaving group include a sulfonate such as mesylate, tosylate, besylate, and imidazole sulfonate.
  • a useful leaving group is, without limitation, a sulfonate, preferably a tosylate.
  • the compound of formula (7) further is reduced to form etoricoxib.
  • a preferred reducing agent contains a metal such as palladium, nickel or zinc.
  • a homogenous palladium (Pd) catalyst, Ra/ Ni, or Zn/acid, more preferably zinc/formic acid or acetic acid is used.
  • acetic anhydride can be used in order to avoid the presence of water in the reaction mixture.
  • the compound of formula (5) can be directly reduced to etoricoxib.
  • the etoricoxib obtained can optionally be further recrystallized.
  • the present application provides a novel compound of formula (4) useful as an intermediate for making the compound of formula (5) and, subsequently, for preparing etoricoxib of formula (1).
  • the leaving group (L) in compound (7) can be the same or different than the leaving group (L) in compound (4).
  • Suitable examples of leaving group include halogens such as chlorine, bromine, or iodine, sulfonates such as mesylate, tosylate, besylate, and imidazole sulfonate.
  • the leaving group L in the compound of formula (4) is a tosylate.
  • the tosylate of formula (8) is stable enough to be stored and therefore can be used on an industrial scale.
  • the present application provides a novel compound of formula (5) useful for preparing etoricoxib of formula (1).
  • the present invention also includes the use of the compound of formula (5) for making etoricoxib of formula (1).
  • the present application also provides the novel compound of formula (6) useful as an intermediate in making the compound of formula (5) and, subsequently, for preparing etoricoxib of formula (1).
  • Etoricoxib produced according to any one of the processes in accordance with the present invention or otherwise obtainable by the use of any of the compounds of formula (4), (5), (6), or (7) as starting material in a process for making etoricoxib, may be advantageously provided in an isolated, typically solid and crystalline form, details of which procedures are known in the art. Accordingly, the obtained etoricoxib may be used in pharmaceutical compositions, e.g. for the treatment of inflammatory diseases.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé et des intermédiaires permettant de fabriquer un produit de formule (1), utile sur le plan pharmaceutique, appelé étoricoxib, ledit procédé étant basé, entre autres, sur l'utilisation d'un composé de formule (4) servant de réactif et d'un composé de formule (5) servant d'intermédiaire.
PCT/EP2013/051506 2013-01-25 2013-01-25 Procédé de préparation d'étoricoxib Ceased WO2014114352A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2013/051506 WO2014114352A1 (fr) 2013-01-25 2013-01-25 Procédé de préparation d'étoricoxib

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2013/051506 WO2014114352A1 (fr) 2013-01-25 2013-01-25 Procédé de préparation d'étoricoxib

Publications (1)

Publication Number Publication Date
WO2014114352A1 true WO2014114352A1 (fr) 2014-07-31

Family

ID=47605548

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/051506 Ceased WO2014114352A1 (fr) 2013-01-25 2013-01-25 Procédé de préparation d'étoricoxib

Country Status (1)

Country Link
WO (1) WO2014114352A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047871A1 (fr) * 1997-04-18 1998-10-29 Merck & Co., Inc. Procede de fabrication de 2-aryl-3-aryl-5-halopyridines utiles en tant qu'inhibiteurs de cox-2
WO1999055830A2 (fr) * 1998-04-24 1999-11-04 Merck & Co., Inc. Procede de synthese d'inhibiteurs de cox-2
WO2010097802A2 (fr) * 2009-02-27 2010-09-02 Cadila Healthcare Limited Procédé de préparation d'étoricoxib

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047871A1 (fr) * 1997-04-18 1998-10-29 Merck & Co., Inc. Procede de fabrication de 2-aryl-3-aryl-5-halopyridines utiles en tant qu'inhibiteurs de cox-2
WO1999055830A2 (fr) * 1998-04-24 1999-11-04 Merck & Co., Inc. Procede de synthese d'inhibiteurs de cox-2
WO2010097802A2 (fr) * 2009-02-27 2010-09-02 Cadila Healthcare Limited Procédé de préparation d'étoricoxib

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DAVIES I W ET AL: "A PRACTICAL SYNTHESIS OF A COX-2-SPECIFIC INHIBITOR", JOURNAL OF ORGANIC CHEMISTRY, ACS, US, vol. 65, no. 25, 1 January 2000 (2000-01-01), pages 8415 - 8420, XP002326845, ISSN: 0022-3263, DOI: 10.1021/JO000870Z *

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