WO2015003670A1 - A new process for the preparation of elvitegravir - Google Patents

A new process for the preparation of elvitegravir Download PDF

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Publication number
WO2015003670A1
WO2015003670A1 PCT/CZ2014/000076 CZ2014000076W WO2015003670A1 WO 2015003670 A1 WO2015003670 A1 WO 2015003670A1 CZ 2014000076 W CZ2014000076 W CZ 2014000076W WO 2015003670 A1 WO2015003670 A1 WO 2015003670A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
elvitegravir
reaction
converted
production
Prior art date
Application number
PCT/CZ2014/000076
Other languages
English (en)
French (fr)
Inventor
Stanislav Radl
Jan Stach
Original Assignee
Zentiva, K.S.
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 Zentiva, K.S. filed Critical Zentiva, K.S.
Priority to HU1600128A priority Critical patent/HUP1600128A2/hu
Priority to CN201480038026.3A priority patent/CN105377818B/zh
Publication of WO2015003670A1 publication Critical patent/WO2015003670A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to an improved process for the production of elvitegravir
  • the carbonate reacts, in the presence of an organopalladium catalyst, with 3-chloro-2- fluorobenzyl zinc bromide (11) (prepared from 3-chloro-2-fluorobenzyl bromide (10) in the conditions of Negishi coupling) producing the protected benzyl quinolone derivative 12a.
  • 3-chloro-2- fluorobenzyl zinc bromide (11) prepared from 3-chloro-2-fluorobenzyl bromide (10) in the conditions of Negishi coupling
  • This is, in the next step, subjected to alkaline deprotection to the intermediate 13, which is, in the final step, subjected to reaction with sodium methoxide providing the end product elvitegravir (Scheme 1).
  • Patent application WO 2011/004389 of Matrix Laboratories describes a synthetic procedure analogous to the method of the basic patent, using protection of the hydroxyl with the tetrahydropyranyl group (Scheme 3).
  • the hydroxyl group of the enamine 22 is, in the next step, protected by a reaction with tert-butyldimethylsilyl chloride and the resulting 23 is subsequently cycled to the protected quinolone derivative 24.
  • both hydrolysis of the ethyl ester and removal of the protecting TBDMS group are performed (Scheme 4).
  • This invention provides an improved process for the production of elvitegravir of formula I,
  • a suitable catalyst e.g. a palladium catalyst.
  • the purity of the intermediate Ila according to HPLC generally exceeds 99%.
  • the general protecting group PG may be, e.g., the trimethylsilyl group or other protecting groups suitable for protection of an oxygen atom, e.g., di-t-butyldimethylsilyl, benzyl, tetrahydropyranyl, tetrahydrofuranyl, others being mentioned, e.g,. in Protective Groups in Organic Synthesis, Third Edition. Theodora W. Greene, Peter G.M. Wuts, John Wiley, 1999. The compounds V and VII conveniently need not be isolated.
  • elvitegravir is obtained by easy removal of the protecting groups - the protecting group on the carbonyl function is removed with water, alcohol; the protecting group on the hydroxyl is removed by reaction with a diluted aqueous acid or water at an elevated temperature. Alternatively, the deprotection can be carried out at the room temperature.
  • PdCl 2 (PPh 3 ) 2 39 mg was added as a catalyst and 10 ml of a solution of 3-chloro-2- fluorobenzyl zinc bromide in tetrahydrofuran (0.5 M) was added at 60°C during 1 h; the mixture was further heated up at 60°C for 1.5 h.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
PCT/CZ2014/000076 2013-07-11 2014-07-03 A new process for the preparation of elvitegravir WO2015003670A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
HU1600128A HUP1600128A2 (en) 2013-07-11 2014-07-03 A new process for the preparation of elvitegravir
CN201480038026.3A CN105377818B (zh) 2013-07-11 2014-07-03 用于制备埃替拉韦的新方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2013-544A CZ307255B6 (cs) 2013-07-11 2013-07-11 Nový způsob přípravy elvitegraviru
CZPV2013-544 2013-07-11

Publications (1)

Publication Number Publication Date
WO2015003670A1 true WO2015003670A1 (en) 2015-01-15

Family

ID=51229772

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2014/000076 WO2015003670A1 (en) 2013-07-11 2014-07-03 A new process for the preparation of elvitegravir

Country Status (4)

Country Link
CN (1) CN105377818B (cs)
CZ (1) CZ307255B6 (cs)
HU (1) HUP1600128A2 (cs)
WO (1) WO2015003670A1 (cs)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105315203A (zh) * 2014-06-06 2016-02-10 上海迪赛诺化学制药有限公司 一种v型埃替拉韦晶体及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004046115A1 (ja) 2002-11-20 2004-06-03 Japan Tobacco Inc. ４−オキソキノリン化合物及びそのｈｉｖインテグラーゼ阻害剤としての利用
WO2005113509A1 (en) * 2004-05-20 2005-12-01 Japan Tobacco Inc. Novel 4-oxoquinoline compound and use thereof as hiv integrase inhibitor
US20090318702A1 (en) * 2006-03-06 2009-12-24 Koji Matsuda Process for production of 4-oxoquinoline compound
US7825252B2 (en) 2006-09-12 2010-11-02 Gilead Sciences, Inc. Process and intermediates for preparing integrase inhibitors
WO2011004389A2 (en) 2009-06-18 2011-01-13 Matrix Laboratories Ltd An improved process for the preparation of elvitegravir

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ304983B6 (cs) * 2012-10-12 2015-03-11 Zentiva, K.S. Způsob výroby a nové intermediáty syntézy elvitegraviru
CZ304984B6 (cs) * 2012-10-12 2015-03-11 Zentiva, K.S. Zlepšený způsob výroby a nové intermediáty syntézy elvitegraviru

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004046115A1 (ja) 2002-11-20 2004-06-03 Japan Tobacco Inc. ４−オキソキノリン化合物及びそのｈｉｖインテグラーゼ阻害剤としての利用
EP1564210A1 (en) 2002-11-20 2005-08-17 Japan Tobacco Inc. 4-oxoquinoline compounds and utilization thereof as hiv integrase inhibitors
US7176220B2 (en) 2002-11-20 2007-02-13 Japan Tobacco Inc. 4-oxoquinoline compound and use thereof as pharmaceutical agent
WO2005113509A1 (en) * 2004-05-20 2005-12-01 Japan Tobacco Inc. Novel 4-oxoquinoline compound and use thereof as hiv integrase inhibitor
US20090318702A1 (en) * 2006-03-06 2009-12-24 Koji Matsuda Process for production of 4-oxoquinoline compound
US7825252B2 (en) 2006-09-12 2010-11-02 Gilead Sciences, Inc. Process and intermediates for preparing integrase inhibitors
WO2011004389A2 (en) 2009-06-18 2011-01-13 Matrix Laboratories Ltd An improved process for the preparation of elvitegravir

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THEODORA W. GREENE; PETER G.M WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY

Also Published As

Publication number Publication date
CN105377818A (zh) 2016-03-02
CZ307255B6 (cs) 2018-05-02
CZ2013544A3 (cs) 2015-01-21
CN105377818B (zh) 2018-03-30
HUP1600128A2 (en) 2016-07-28

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