WO2013050884A1 - Procédé pour la préparation de lersivirine - Google Patents

Procédé pour la préparation de lersivirine Download PDF

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Publication number
WO2013050884A1
WO2013050884A1 PCT/IB2012/002903 IB2012002903W WO2013050884A1 WO 2013050884 A1 WO2013050884 A1 WO 2013050884A1 IB 2012002903 W IB2012002903 W IB 2012002903W WO 2013050884 A1 WO2013050884 A1 WO 2013050884A1
Authority
WO
WIPO (PCT)
Prior art keywords
lersivirine
dione
preparation
acid
reacting
Prior art date
Application number
PCT/IB2012/002903
Other languages
English (en)
Inventor
Flavien SUSANNE
Original Assignee
Phivco Uk 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 Phivco Uk Limited filed Critical Phivco Uk Limited
Publication of WO2013050884A1 publication Critical patent/WO2013050884A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/18—One oxygen or sulfur atom
    • 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 present invention is directed to a process for the preparation of the chemical compound lersivirine which is a non-nucleoside reverse transcriptase inhibitor (NNRTi) useful for the treatment of HIV infection.
  • NRTi non-nucleoside reverse transcriptase inhibitor
  • the structure of lersivirine is shown below. Its chemical name is 5- ⁇ [3,5-diethyl-1- (2-hydroxyethyl)-1 /-/-pyrazol-4-yl]oxy ⁇ i
  • WO02/085860 discloses a process for the synthesis of lersivirine in two steps as shown in Scheme 1 below.
  • Step A is specifically described in Preparation 45 (with reference to Preparation 9) and generically described on page 14.
  • Step B is specifically described in Example 119 (with reference to Example 114) and Example 282 and generically described on pages 1 1 and 12.
  • the present invention provides a process for the preparation of lersivirine or a
  • step A characterised in that the base for step A comprises 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the solvent for steps A and B comprises acetonitrile.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DBU as the base for step A and acetonitrile as the solvent for steps A and B
  • acetonitrile as the solvent for steps A and B
  • DBU accelerates the rate of reaction for step A such that it approaches the rate of reaction for step B.
  • Acetonitrile effectively solubilises all starting materials, intermediates and by-products (e.g. DBU.HCI) so as to provide a homogenous solution which flows efficiently throughout a continuous reaction system.
  • the present invention provides a
  • step A is conducted at elevated temperature. Preferably, at a temperature from 70 - 80 °C, most preferably at about 74 °C.
  • Step B is conducted in the presence of an acid.
  • Suitable acids include any straight chain or branched chain aliphatic acid, any mineral acid or any straight chain or branched chain
  • halogenated aliphatic acid Preferred acids are hydrochloric acid and acetic acid.
  • step B is conducted at elevated temperature.
  • a temperature from 80 - 90 °C, most preferably at about 85 °C.
  • the 4-haloheptane-3,5-dione may be 4-chloroheptane-3,5-dione, 4-bromoheptane-3,5- dione or 4-iodoheptane-3,5-dione. 4-chloroheptane-3,5-dione is preferred.
  • the process may be performed using commercially available hardware designed for performing continuous reactions.
  • references is made to Anderson, Neal G; Organic Pocess Research & Development 2001, 5, 613-621 and the references cited therein.
  • the product of step B or optional step C may be collected and then further processed (i.e. separated and purified) in a batch fashion.
  • the separation and purification (e.g. crystallisation) steps are also conducted in a continuous manner. This may be achieved by the use of continuous separation and purification techniques known in the art.
  • centrifugal separators such as those manufactured by CINC industries (http://www.cincmfg.com/) and disclosed in United States Patents 4,175,040, 4,959,158 and 5,591 ,340, and (ii) rotating disk and baffle tray columns such as those manufactured by Koch Modular Process Systems, LLC (http://www.liquid-extraction.com/karr- column.htm).
  • FIG. 1 schematically illustrates a suitable plug flow reactor system which may be used for the present invention.
  • Tank 1 contains 5-hydroxyisophthalonitrile and DBU in acetonitrile and tank 2 contains 4-haloheptane-3,5-dione in acetonitrile.
  • These reagents are mixed and pumped through the first plug flow reactor (PFR - Step A) where they react to form to form 5-(2-oxo-1- propanoylbutoxy)isophthalonitrile.
  • the outflow is mixed with HCI and 2-hydrazinoethanol from tanks 3 and 4 respectively and pumped through the second plug flow reactor (PFR - Step B) where they react to form to form lersivirine.
  • the outflow is passed to a continuous extraction apparatus 8 which is fed with water and isopropyl acetate from tanks 5 and 6 respectively.
  • the organic extract is switched between two batch crystallisation tanks 9 which are fed with heptanes from tank 7 to assist recrystallisation.
  • the crystalline batches are then filtered (10) and dried (1 1 ) in batch mode.
  • Step B Preparation of 5-fr3,5-diethyl-1-(2-hvdroxyethyl)-1 /-/-pyrazol-4-ylloxy ⁇ isophthalonitrile (lersivirine)
  • aqueous hydrochloric acid solution is prepared in a head tank and the resulting solution is pumped in to a mixing chamber where meets the flow from step A. Cooling is applied to remove the heat of reaction. After a short path the reaction flow is combined with an aqueous solution of 2-hydrazinoethanol which is also pumped. The combined flow is then rapidly heated and flowed along a tube reactor to effect the desired reaction. After the determined aging time the flow is combined with pumped solution of aqueous sodium hydroxide and collected in a receiving tank. In batch mode, isopropyl acetate and aqueous sodium carbonate are added to the receiving tank and the phases are mixed. After allowing the mixture to settle the organic phase is separated.
  • the organic phase is washed several times with water and filtered. The solution is then concentrated by distillation to remove water. Further isopropyl acetate is added and the solution is then concentrated by distillation to remove further water. n-Heptane is added and the reaction is seeded and cooled. After cooling, the crystallised solid is granulated, filtered, washed with n-heptane and dried under vacuum to afford lersivirine. If necessary, the lersivirine may be further purified by recrystallisation from isopropyl acetate/n-heptane.

Landscapes

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

Abstract

La présente invention porte sur un procédé pour la préparation de lersivirine ou d'un sel pharmaceutiquement acceptable de celle-ci caractérisé en ce qu'il utilise la base 1,8-diazabicyclo[5.4.0]undéc-7-ène (DBU) et le solvant acétonitrile.
PCT/IB2012/002903 2011-10-07 2012-10-04 Procédé pour la préparation de lersivirine WO2013050884A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161544397P 2011-10-07 2011-10-07
US61/544,397 2011-10-07

Publications (1)

Publication Number Publication Date
WO2013050884A1 true WO2013050884A1 (fr) 2013-04-11

Family

ID=47720539

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2012/002903 WO2013050884A1 (fr) 2011-10-07 2012-10-04 Procédé pour la préparation de lersivirine

Country Status (1)

Country Link
WO (1) WO2013050884A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4175040A (en) 1978-08-28 1979-11-20 Continental Oil Company Centrifugal water oil separator
US4959158A (en) 1989-03-30 1990-09-25 The United States Of America As Represented By The Unitd States Department Of Energy Method for separating disparate components in a fluid stream
US5591340A (en) 1995-09-01 1997-01-07 Costner Industries Nevada, Inc. Centrifugal separator
WO2002085860A1 (fr) 2001-04-10 2002-10-31 Pfizer Limited Derives de pyrazole pour le traitement de vih

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4175040A (en) 1978-08-28 1979-11-20 Continental Oil Company Centrifugal water oil separator
US4959158A (en) 1989-03-30 1990-09-25 The United States Of America As Represented By The Unitd States Department Of Energy Method for separating disparate components in a fluid stream
US5591340A (en) 1995-09-01 1997-01-07 Costner Industries Nevada, Inc. Centrifugal separator
WO2002085860A1 (fr) 2001-04-10 2002-10-31 Pfizer Limited Derives de pyrazole pour le traitement de vih

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANDERSON; NEAL G, ORGANIC POCESS RESEARCH & DEVELOPMENT, vol. 5, 2001, pages 613 - 621
C. E. MOWBRAY ET. AL.: "Pyrazole NNRTIs 4. Selection of UK-453,061 (Lersivirine) as a Development Candidate.", BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 19, 27 August 2009 (2009-08-27), pages 5857 - 5860, XP026640586 *

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