WO2011032634A1 - Sels d'éfavirenz, leur procédé de préparation et de libération du sel - Google Patents

Sels d'éfavirenz, leur procédé de préparation et de libération du sel Download PDF

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Publication number
WO2011032634A1
WO2011032634A1 PCT/EP2010/005230 EP2010005230W WO2011032634A1 WO 2011032634 A1 WO2011032634 A1 WO 2011032634A1 EP 2010005230 W EP2010005230 W EP 2010005230W WO 2011032634 A1 WO2011032634 A1 WO 2011032634A1
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WO
WIPO (PCT)
Prior art keywords
compound
iodide
bromide
alkaline earth
atom
Prior art date
Application number
PCT/EP2010/005230
Other languages
German (de)
English (en)
Other versions
WO2011032634A8 (fr
Inventor
Andreas Meudt
Michael Nonnenmacher
Original Assignee
Archimica Gmbh
Jung, Jörg
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 Archimica Gmbh, Jung, Jörg filed Critical Archimica Gmbh
Publication of WO2011032634A1 publication Critical patent/WO2011032634A1/fr
Publication of WO2011032634A8 publication Critical patent/WO2011032634A8/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2

Definitions

  • the present invention relates to salts of efavirenz, which can be used as an inhibitor for the reverse transcriptase of the human immunodeficiency virus.
  • the salts described are compounds in which the nitrogen atom bound to hydrogen is replaced by a metal atom.
  • this invention relates to the synthesis of the derivatives of efavirenz as well as their purification and crystallization and the use for the preparation of a solution of efavirenz in organic solvents.
  • Efavirenz (Ia) is used as a potent inhibitor of human immunodeficiency virus (HIV) reverse transcriptase.
  • HIV human immunodeficiency virus
  • high levels of purity, both in terms of organic and inorganic impurities, are required.
  • Many efforts have been made to purify the crude products obtained from various synthetic approaches. Accordingly, crystal structure data of many different modifications have been published (see, for example, WO98 / 33782, WO99 / 64405, WO2006018853, WO2006030299, WO2006040643, WO2006029079, WO2008108630).
  • a salt of efavirenz is formed by the hydrogen atom on the nitrogen by a metal atom from the series Alkali or alkaline earth metals is replaced or obtained by an aluminum atom or a tetraalkylammonium cation and as a solution, suspension, solid mixture or solid and from which the pure derivative is obtained by crystallization, recrystallization or washing with one or more solvents.
  • the claim to release efavirenz is also met, since by reacting the salt in a suitable solvent with a suitable acid, a solution of efavirenz is formed in this solvent.
  • the invention relates to derivatives of 6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (I) and (S) -6-chloro -4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (Ia) in which the hydrogen atom bound to the nitrogen atom is represented by a metal atom the series of alkali or alkaline earth metals is replaced or by an aluminum atom or a tetraalkylammonium cation.
  • the alkaline earth metal salts or the aluminum salts of efavirenz may also contain other anions such as fluoride, chloride, bromide, iodide, or sulfate.
  • the invention relates to the synthesis of derivatives of 6-chloro-4- (cyclopropylethinyl) -1, 4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (I, Ia), in in which the hydrogen atom bound to the nitrogen atom is replaced by a metal atom from the series of alkali or alkaline earth metals or by an aluminum atom or a tetraalkylammonium cation.
  • the alkaline earth metal salts or the aluminum salts of efavirenz may also contain other anions such as fluoride, chloride, bromide, iodide, or sulfate.
  • the starting point is 6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (I) or (S) -6-chloro-4 - (cyclopropylethynyl) -1, 4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (Ia) in pure form or as a mixture with one or more minor components and or other impurities or from a solution of (S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one or (S) -6-chloro-4- (cyclopropylethynyl ) -1, 4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxa
  • This raw material is added either directly or after dilution in an organic solvent or solvent mixture with a basic metal salt or other basic compound of the metals lithium, sodium, potassium, magnesium or calcium, forming one of the above-defined derivatives of I or Ia.
  • the invention further relates to the isolation and purification of the derivatives of efavirenz as defined above, wherein the other constituents of the mixture are removed or substantially removed by distillation and / or washing with a suitable solvent and / or recrystallization and / or drying of the crude product mixture.
  • the invention relates to the reaction of the above-defined derivatives of efavirenz to a solution of efavirenz in an organic solvent or solvent mixture.
  • the inventive derivative of efavirenz is suspended or dissolved in the solvent or solvent mixture and mixed at a suitable temperature with a pure or dissolved in a solvent or solvent mixture organic or inorganic Brönstedt acid, wherein Efavirenz and the corresponding metal salt of the acid.
  • the metal atom of the salt of the invention is 6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (I) or S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (Ia) to an alkali or alkaline earth metal, in one especially preferred embodiment to lithium, sodium, potassium, magnesium or calcium and in a most preferred embodiment to sodium or potassium.
  • the reagent with which the compound of type I or la is reacted to a basic metal salt or a basic metal compound in a particularly preferred embodiment to an alkali or alkaline earth metal compound, in a most preferred embodiment an alkali or alkaline earth metal hydride.
  • it is an alkali metal hydride, in a very particularly preferred embodiment, sodium or potassium hydride.
  • it is an alkali metal amide.
  • it is a C 1 to C 10 alkyl or C 6 to C 10 aryllithium compound.
  • the compound of type I or la is present before the reaction to the salt according to the invention in a mixture with other substances, wherein the main component or single further component of this mixture is an organic solvent or solvent mixture, in a particularly preferred embodiment, an ether or hydrocarbon and in a most preferred embodiment tetrahydrofuran, methyltetrahydrofuran or toluene.
  • the mixture may contain other organic substances as well as inorganic impurities, in a preferred embodiment these are by-products from the synthesis of efavirenz.
  • the salt of the invention is isolated by replacing the organic solvent or solvent mixture in which the salt is soluble with a solvent or solvent mixture in which said salt is sparingly soluble or insoluble.
  • the solvent is hexane, heptane, methylcyclohexane or toluene or mixtures of two or more of these solvents.
  • the salt according to the invention is isolated by filtration after it has been produced in an organic solvent or solvent mixture in which it is insoluble, in a particularly preferred embodiment the solvent is toluene.
  • the contaminated salt of the invention is purified from Efavirenz by washing with a solvent
  • the solvent is C 1 -C 8 alkanes or C 5 -C 8 cycloalkanes, C 6 -C 8 aromatic hydrocarbons, C 6 -C 8 halogenated aromatic hydrocarbons, C1-C3 halogenated hydrocarbons, C1-C4 alkylnitriles, symmetrical or asymmetrical C1-C8 dialkyl ethers, C4-C8 cyclic alkyl ethers or C2-C8 dialkyl ketones, in a very particularly preferred embodiment, hexane, cyclohexane, methylcyclohexane, heptane, dichloromethane, Acetonitrile or toluene.
  • the contaminated salt of efavirenz of the invention is purified by recrystallization from a solvent or solvent mixture, in a particularly preferred embodiment the solvent is acetonitrile or dichloromethane.
  • the solvent in which the derivative of the invention is suspended or dissolved to protonate by addition of a Bronsted acid is C1-C8 alcohols, symmetrical or asymmetrical C2-C8 dialkyl ethers, C4-C8 cyclic alkyl ethers , C6-C8 aromatic hydrocarbons or C1-C8 halogenated hydrocarbons and in a particularly preferred embodiment to ethanol or methyl tert-butyl ether, in a very particularly preferred embodiment to methyl tert-butyl ether
  • the Bronsted acid is hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfuric acid, salts of bisulfate, ammonium chloride, ammonium bromide, ammonium iodide, C1-C8 Monoalkylammonium chloride, bromide, iodide, C1-C8 di- or Trialkylammpniumchlorid, bromide or iodide with the same or mixed alkyl radicals, and in a particularly preferred embodiment to hydrochloric acid or ammonium chloride.
  • a solution of 4.0 g of efavirenz in 32 g of absolute tetrahydrofuran is mixed in four portions with 1.46 g of a 35% suspension of potassium hydride in mineral oil. After the mixture has been stirred for 1 h, 25 g of the solvent are distilled off and 32 g of n-hexane are added. It is distilled again 25g of the solvent and mixed again with 32 g of n-hexane. The resulting solid is filtered off with suction and washed with 16 g of methylcyclohexane. It is then dried to constant weight and receives 3.27 g (72%) of the desired potassium compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de composés de formule (I), dans laquelle l'atome d'hydrogène lié à l'atome d'azote est remplacé par un atome métallique de la série des métaux alcalins ou alcalino-terreux ou par un atome d'aluminium ou un cation tétraalkylammonium, les sels de métal alcalino-terreux ou les sels d'aluminium du composé (I), pouvant contenir, en plus du composé (I) déprotoné, également d'autres anions comme un fluorure, un chlorure, un bromure, un iodure, ou un sulfate.
PCT/EP2010/005230 2009-09-16 2010-08-26 Sels d'éfavirenz, leur procédé de préparation et de libération du sel WO2011032634A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102009041443.6 2009-09-16
DE200910041443 DE102009041443A1 (de) 2009-09-16 2009-09-16 Salze des 6-Chlor-4-(cyclopropylethinyl)-1,4-dihydro-4-(trifluormethyl)-2H-3,1-benzoxazin-2-ons und deren Synthese, Aufreinigung und Anwendung als Vorstufen für Efavirenz

Publications (2)

Publication Number Publication Date
WO2011032634A1 true WO2011032634A1 (fr) 2011-03-24
WO2011032634A8 WO2011032634A8 (fr) 2011-05-12

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PCT/EP2010/005230 WO2011032634A1 (fr) 2009-09-16 2010-08-26 Sels d'éfavirenz, leur procédé de préparation et de libération du sel

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DE (1) DE102009041443A1 (fr)
WO (1) WO2011032634A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102924398A (zh) * 2012-11-22 2013-02-13 安徽贝克生物制药有限公司 用于除去依非韦伦对应异构体的方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998033782A1 (fr) 1997-02-05 1998-08-06 Merck & Co., Inc. Procede de cristallisation d'un inhibiteur de transcriptase inverse utilisant un antisolvant
WO1999064405A1 (fr) 1998-06-11 1999-12-16 Du Pont Pharmaceuticals Company Efavirenz sous forme cristalline
WO2003090691A2 (fr) * 2002-04-26 2003-11-06 Gilead Sciences, Inc. Technique et compositions permettant d'identifier des composes therapeutiques anti-vih
WO2006018853A2 (fr) 2004-08-19 2006-02-23 Hetero Drugs Limited Nouveaux polymorphes d'efavirenz
WO2006029079A2 (fr) 2004-09-02 2006-03-16 Bristol-Myers Squibb Company Synthese de benzoxazinone
WO2006030299A1 (fr) 2004-09-17 2006-03-23 Ranbaxy Laboratories Limited Processus de preparation de polymorphes d'efavirenz
WO2006040643A2 (fr) 2004-10-11 2006-04-20 Ranbaxy Laboratories Limited Formes polymorphes d'efavirenz et processus de leur fabrication
WO2008052737A2 (fr) * 2006-10-30 2008-05-08 Roche Diagnostics Gmbh Analogues de médicaments contre le vih immunochimiquement équivalents
WO2008108630A1 (fr) 2007-03-02 2008-09-12 Ultimorphix Technologies B.V. Formes polymorphes de l'efavirenz

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998033782A1 (fr) 1997-02-05 1998-08-06 Merck & Co., Inc. Procede de cristallisation d'un inhibiteur de transcriptase inverse utilisant un antisolvant
WO1999064405A1 (fr) 1998-06-11 1999-12-16 Du Pont Pharmaceuticals Company Efavirenz sous forme cristalline
WO2003090691A2 (fr) * 2002-04-26 2003-11-06 Gilead Sciences, Inc. Technique et compositions permettant d'identifier des composes therapeutiques anti-vih
WO2006018853A2 (fr) 2004-08-19 2006-02-23 Hetero Drugs Limited Nouveaux polymorphes d'efavirenz
WO2006029079A2 (fr) 2004-09-02 2006-03-16 Bristol-Myers Squibb Company Synthese de benzoxazinone
WO2006030299A1 (fr) 2004-09-17 2006-03-23 Ranbaxy Laboratories Limited Processus de preparation de polymorphes d'efavirenz
WO2006040643A2 (fr) 2004-10-11 2006-04-20 Ranbaxy Laboratories Limited Formes polymorphes d'efavirenz et processus de leur fabrication
WO2008052737A2 (fr) * 2006-10-30 2008-05-08 Roche Diagnostics Gmbh Analogues de médicaments contre le vih immunochimiquement équivalents
WO2008108630A1 (fr) 2007-03-02 2008-09-12 Ultimorphix Technologies B.V. Formes polymorphes de l'efavirenz

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102924398A (zh) * 2012-11-22 2013-02-13 安徽贝克生物制药有限公司 用于除去依非韦伦对应异构体的方法
CN102924398B (zh) * 2012-11-22 2015-11-18 安徽贝克生物制药有限公司 用于除去依非韦伦对应异构体的方法

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DE102009041443A1 (de) 2011-03-31
WO2011032634A8 (fr) 2011-05-12

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