+

WO2006030299A1 - Processus de preparation de polymorphes d'efavirenz - Google Patents

Processus de preparation de polymorphes d'efavirenz Download PDF

Info

Publication number
WO2006030299A1
WO2006030299A1 PCT/IB2005/002746 IB2005002746W WO2006030299A1 WO 2006030299 A1 WO2006030299 A1 WO 2006030299A1 IB 2005002746 W IB2005002746 W IB 2005002746W WO 2006030299 A1 WO2006030299 A1 WO 2006030299A1
Authority
WO
WIPO (PCT)
Prior art keywords
efavirenz
solvents
solvent
preparation
under vacuum
Prior art date
Application number
PCT/IB2005/002746
Other languages
English (en)
Inventor
Chandra Has Khanduri
Atulya Kumar Panda
Yatendra Kumar
Original Assignee
Ranbaxy Laboratories Limited
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 Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2006030299A1 publication Critical patent/WO2006030299A1/fr

Links

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the field of the invention relates to processes for the preparation of polymorphic forms of efavirenz. More particularly, it relates to the preparation of Form I and Form II of efavirenz.
  • the invention also relates to pharmaceutical compositions that include the Form I of efavirenz and use of said compositions for treatment of HTV-I infections in combination with other antiretro viral agents.
  • Efavirenz of Formula I is an HIV-I specific, non-nucleoside, reverse transcriptase inhibitor. Chemically, efavirenz is (4iS)-6-chloro-4-(cyclopropylethynyl)-4- (trifluoromethyl)-l,4-dihydro-2H-3,l-benzoxazin-2-one. It is indicated for the treatment of ⁇ IV-1 infection in combination with other antiretro viral agents.
  • U.S. Patent Nos. 6,639,071 and 5,965,729 disclose crystalline polymorphic forms of efavirenz designated as Form I, II and III having specific X-Ray diffraction patterns.
  • U.S. Patent No. 6,639,071 discloses that efavirenz was previously crystallized from a heptane-tetrahydrofuran (TFfF) solvent system by the crystallization procedure which required the use of high temperatures (about 9O 0 C) to dissolve the final product. Crystals were formed by nucleation during the cooling process. This crystallization provides minimal purification. The final product slurry was extremely difficult to mix and handle due to its high viscosity and heterogeneous nature. The problem was solved by the addition of an anti-solvent to initiate the crystallization.
  • TfF heptane-tetrahydrofuran
  • U.S. Patent No. 6,673,372 discloses polymorphic forms of efavirenz designated as Form 2 and Form 5.
  • Figure 2 is an X-ray powder diffraction pattern of Form I of efavirenz.
  • the form II of efavirenz when made by the process of the present invention is easy to isolate and handle, thus making the process amenable for commercial scale use.
  • a process for the preparation of Form II of efavirenz includes obtaining a solution of efavirenz in one or more organic solvents; adding an anti-solvent to the solution; and isolating the Form II of efavirenz by the removal of the solvents.
  • Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, decantation and centrifugation.
  • the process may include further forming of the product so obtained into a finished dosage form.
  • the process may include further drying of the product obtained.
  • a process for the preparation of Form I of efavirenz includes drying Form II of efavirenz under vacuum at a temperature from about 5O 0 C or more for about 6 hours or more.
  • a pharmaceutical composition that includes a therapeutically effective amount of the Form I of efavirenz; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • a method for treating HTV-I infections in a warm-blooded animal includes providing a pharmaceutical composition to the warm-blooded animal, the pharmaceutical composition comprising Form I of efavirenz.
  • the inventors have developed a process for the preparation of polymorphic forms of efavirenz. More particularly, the inventors have developed a process for the preparation of Form II and conversion of Form II to Form I of efavirenz.
  • the term "Form II" of efavirenz refers to a polymorph of efavirenz having, for example, an X-Ray Powder Diffraction (XRPD) pattern substantially as depicted in Figure 1.
  • XRPD X-Ray Powder Diffraction
  • Form I X-Ray Powder Diffraction
  • a process for the preparation of Form II of efavirenz includes the steps of: a) obtaining a solution of efavirenz in one or more organic solvents; b) adding an anti-solvent to the solution; and c) isolating the Form II of efavirenz by the removal of the solvents.
  • the solution of efavirenz may be obtained by dissolving efavirenz in a suitable solvent. Alternatively, such a solution may be obtained directly from a reaction in which efavirenz is formed. If a suspension is obtained in a solvent, the suspension containing efavirenz may be heated to obtain a solution. It may be heated from about 30 0 C to about 150 0 C, for example from about 50 0 C to about 100 0 C. It may be heated from about 10 minutes to about 24 hours. More particularly, it may be heated for about 2-3 hours.
  • the efavirenz can be prepared by any of the methods known in the art including those described in U.S. Patent Nos. 5,519,021; 5,698,741; 5,663,467; and WO 94/03440; 95/20389; and 96/22955.
  • efavirenz includes all polymorphic forms, amorphous form, solvates, hydrates, and mixtures thereof.
  • suitable solvents includes any solvent or solvent mixture in which efavirenz can be solubilized, including, for example, aromatic hydrocarbons; lower alkanols; chlorinated hydrocarbons; polar aprotic solvents, or mixtures thereof.
  • the aromatic hydrocarbon may include one or more of benzene, toluene, and xylene.
  • alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable lower alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol.
  • chlorinated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone. Mixtures of all of these solvents are also contemplated.
  • a suitable anti-solvent that may be added to precipitate out Form II of efavirenz includes C 6-8 straight or branched chain alkanes, petroleum ether, C 5-7 cycloalkanes, C 4-12 ethers, and mixtures thereof.
  • the reaction mass can be stirred for some time for example, from about 10 minutes to about 6 hours to get Form II of efavirenz.
  • the solvent may be removed from the solution by a technique which includes, for example, filtration, filtration under vacuum, decantation and centrifugation.
  • the product may be washed and dried by conventional methods.
  • the solution may be cooled before filtration to obtain better yields of the Form II of efavirenz. It may be cooled from about 100 0 C to about O 0 C, for example from about 5O 0 C to about 1O 0 C.
  • a process for the preparation of Form I of efavirenz includes the steps of: a) obtaining a solution of efavirenz in one or more organic solvents; b) adding an anti-solvent to the solution; c) isolating Form II of efavirenz by the removal of the solvents; and d) drying the isolated Form II under vacuum at a temperature from about 5O 0 C or more, and obtaining the Form I of efavirenz.
  • a process for the preparation of Form I of efavirenz includes the step of: a) drying Form II under vacuum at a temperature from about 5O 0 C or more, and obtaining the Form I of efavirenz.
  • Form II of efavirenz can be converted into Form I of efavirenz by drying under vacuum at a temperature from about 5O 0 C or more for example, at a temperature from about 6O 0 C to about 100 0 C.
  • the resulting Form I of efavirenz may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. hi these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
  • compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration.
  • the oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs.
  • Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.
  • the Form I of efavirenz can be administered for the treatment of HIV-I infections in combination with other antiretroviral agents, in a warm-blooded animal.
  • a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
  • Example 1 Preparation of Form II of efavirenz Efavirenz (5 gm) was dissolved in toluene (5 ml) by heating to 70 0 C. Hexane (75 ml) was added to this solution and the resultant mass was cooled to ambient temperature and further stirred for 30 minutes. The product obtained was filtered, washed with a mixture of toluene and hexane (1:15) and finally dried at 35-4O 0 C under vacuum.
  • Form II of efavirenz (4.15 g) prepared by example 1 was dried under vacuum at 50-60 0 C for 12 hours. The solid obtained was subsequently dried at 75-80 0 C for about 6- 12 hours to obtain the title compound.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des processus de préparation de formes polymorphes d'efavirenz. Plus spécifiquement, cette invention a pour objet la préparation de forme I et de forme II d'efavirenz, des compositions pharmaceutiques contenant la forme I d'efavirenz, et l'utilisation desdites compositions dans le traitement d'infections par le VIH-1 en combinaison avec d'autres agents antirétroviraux.
PCT/IB2005/002746 2004-09-17 2005-09-16 Processus de preparation de polymorphes d'efavirenz WO2006030299A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1767/DEL/2004 2004-09-17
IN1767DE2004 2004-09-17

Publications (1)

Publication Number Publication Date
WO2006030299A1 true WO2006030299A1 (fr) 2006-03-23

Family

ID=35432696

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/002746 WO2006030299A1 (fr) 2004-09-17 2005-09-16 Processus de preparation de polymorphes d'efavirenz

Country Status (1)

Country Link
WO (1) WO2006030299A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008108630A1 (fr) * 2007-03-02 2008-09-12 Ultimorphix Technologies B.V. Formes polymorphes de l'efavirenz
WO2011032634A1 (fr) 2009-09-16 2011-03-24 Archimica Gmbh Sels d'éfavirenz, leur procédé de préparation et de libération du sel
EP2471783A1 (fr) 2010-12-23 2012-07-04 Esteve Química, S.A. Nouvelle forme polymorphe de l'éfavirenz
WO2014000555A1 (fr) * 2012-06-25 2014-01-03 上海迪赛诺药业有限公司 Procédé de préparation de la forme cristalline i de l'éfavirenz

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020115664A1 (en) * 1997-02-05 2002-08-22 Crocker Louis S. Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020115664A1 (en) * 1997-02-05 2002-08-22 Crocker Louis S. Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008108630A1 (fr) * 2007-03-02 2008-09-12 Ultimorphix Technologies B.V. Formes polymorphes de l'efavirenz
WO2011032634A1 (fr) 2009-09-16 2011-03-24 Archimica Gmbh Sels d'éfavirenz, leur procédé de préparation et de libération du sel
DE102009041443A1 (de) 2009-09-16 2011-03-31 Archimica Gmbh 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
EP2471783A1 (fr) 2010-12-23 2012-07-04 Esteve Química, S.A. Nouvelle forme polymorphe de l'éfavirenz
WO2014000555A1 (fr) * 2012-06-25 2014-01-03 上海迪赛诺药业有限公司 Procédé de préparation de la forme cristalline i de l'éfavirenz
CN103508973A (zh) * 2012-06-25 2014-01-15 上海迪赛诺药业有限公司 制备依非韦伦i型结晶的方法
CN103508973B (zh) * 2012-06-25 2016-04-27 上海迪赛诺药业有限公司 制备依非韦伦i型结晶的方法

Similar Documents

Publication Publication Date Title
JP5757860B2 (ja) 結晶形態のテノホビルジソプロキシル及びその製造方法
JP4700813B2 (ja) テルミサルタンの多形体、その調製方法及び医薬組成物の調製のためのその使用
US6600073B1 (en) Methods for preparation of sertraline hydrochloride polymorphs
US20080287550A1 (en) Sertraline hydrochloride form II and methods for the preparation thereof
EP3953339B1 (fr) Procédé de préparation de 1-désoxy-1-méthylamino-d-glucitol 2-(3,5-dichlorophényl)-6-benzoxazolecarboxylate
US7071331B2 (en) Synthesis of quetiapine and pharmaceutically acceptable salts thereof
CZ13392U1 (cs) Volná báze racemického tamsulosinu
WO2006030299A1 (fr) Processus de preparation de polymorphes d'efavirenz
JP2020502077A (ja) Ｒ−６−ヒドロキシ−８−［１−ヒドロキシ−２−［２−（４−メトキシフェニル）−１，１−ジメチルエチルアミノエチル］−２ｈ−１，４−ベンゾオキサジン−３（４ｈ）−オン塩酸塩の改良された製造法
WO2000032551A9 (fr) Polymorphes de chlorhydrate de sertraline
JP2005511668A (ja) 結晶性ベンラファキシン塩基及びベンラファキシン塩酸塩の新規多形、並びにそれらの製法
WO2014096214A1 (fr) Procédé de préparation de rivaroxaban
JP2024069193A (ja) ブロモドメイン阻害剤の合成方法
KR20090084950A (ko) 결정형 칸데사르탄 실렉세틸 제조 방법
TW201736392A (zh) 一種奧貝膽酸的新結晶形式及其製備方法
JP2018528233A (ja) インドリン化合物および新規インドリン塩を製造するプロセス
EP3242876A1 (fr) Procédé amélioré de préparation de lurasidone et de ses intermédiaires
TWI826724B (zh) 用以製造1,5-苯并噻氮呯化合物之方法
EP1984356A1 (fr) Procédé amélioré pour la préparation de candésartan cilexetil
EP1720867B1 (fr) Procede de preparation de ziprasidone
US20240309017A1 (en) Processes for purification of bictegravir intermediates
US20050143432A1 (en) Novel crystalline forms of valdecoxib
EP3617193B1 (fr) Procédé de fabrication d'inhibiteurs de la transcriptase inverse
TW202112781A (zh) 製備4-苯基-5-烷氧基羰基-2-噻唑-2-基-1,4-二氫嘧啶-6-基]甲基]-3-側氧-5,6,8,8a-四氫-1H-咪唑并[1,5-a]吡-2-基]-羧酸之替代方法
JP2010100562A (ja) アムロジピン製造中間体の精製方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载