WO2016095879A1 - Préparation d'un intermédiaire haute pur pour la synthèse d'odanacatib - Google Patents

Préparation d'un intermédiaire haute pur pour la synthèse d'odanacatib Download PDF

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Publication number
WO2016095879A1
WO2016095879A1 PCT/CZ2015/000151 CZ2015000151W WO2016095879A1 WO 2016095879 A1 WO2016095879 A1 WO 2016095879A1 CZ 2015000151 W CZ2015000151 W CZ 2015000151W WO 2016095879 A1 WO2016095879 A1 WO 2016095879A1
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
mmol
formula
odanacatib
synthesis
Prior art date
Application number
PCT/CZ2015/000151
Other languages
English (en)
Inventor
Peter BABIAK
Josef Zezula
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.
Publication of WO2016095879A1 publication Critical patent/WO2016095879A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the invention relates to an improved process for the preparation and purification of
  • This compound is an advanced intermediate for the synthesis of Odanacatib - an inhibitor of cathepsin of the K structure, which has been developed by Merck for the treatment of osteoporosis (
  • the amide coupling reaction used to prepare the derivatives of type 1 in the basic patent (WO2003/075836), was carried out with the following activation agents: PyBOP (benzotriazol-1 -yloxytris(pyrrolidino)phosphonium hexafluorophosphate), HATU (o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) or EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride).
  • PyBOP benzotriazol-1 -yloxytris(pyrrolidino)phosphonium hexafluorophosphate
  • HATU o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • EDCI 1-(3-di
  • the present invention relates to a process for producing (S)-2-(((S)-1-(4- bromophenyl)-2,2,2-trifluoroethyl)amino)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl- pentanamide of formula 1 by reaction of the acid, or its sal
  • ⁇ , ⁇ -dimethylaminopyridine is present in the reaction mixture.
  • a preferred solvent for this reaction is dimethylformamide (DMF) and the base is preferably diisopropylethylamine (DIEA).
  • the optimized procedure makes use of the above mentioned advantages of T3P, the addition of ⁇ , ⁇ -dimethylaminopyridine (DMPA) is used to accelerate the reaction.
  • DMPA ⁇ , ⁇ -dimethylaminopyridine
  • the reaction is preferably conducted in WjW-dimethylformarnide (DMF), wherein after completion of the reaction a highly pure product is obtained in a high yield by slow addition of water to the reaction mixture.
  • Example 2 HATU in DMF.
  • Example 3 T3P in EA.

Landscapes

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

Abstract

La présente invention concerne un procédé de production de (S)-2-(((S)-1-(4-bromophényl)-2,2,2-trifluoroéthyl)amino)-N-(1-cyanocyclopropyl)-4-fluoro-4-méthylpentanamide de formule 1 par réaction de l'acide ou ses sels de formule 3 avec le composé de formule 4, la réaction étant effectuée dans un solvant en présence de l'anhydride de l'acide n-propanephosphonique de formule 5 et d'une base.
PCT/CZ2015/000151 2014-12-19 2015-12-14 Préparation d'un intermédiaire haute pur pour la synthèse d'odanacatib WO2016095879A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2014-941 2014-12-19
CZ2014-941A CZ2014941A3 (cs) 2014-12-19 2014-12-19 Příprava vysoce čistého intermediátu pro syntézu Odanacatibu

Publications (1)

Publication Number Publication Date
WO2016095879A1 true WO2016095879A1 (fr) 2016-06-23

Family

ID=55168075

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2015/000151 WO2016095879A1 (fr) 2014-12-19 2015-12-14 Préparation d'un intermédiaire haute pur pour la synthèse d'odanacatib

Country Status (2)

Country Link
CZ (1) CZ2014941A3 (fr)
WO (1) WO2016095879A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003075836A2 (fr) 2002-03-05 2003-09-18 Merck Frosst Canada & Co. Inhibiteurs de cathepsine cysteine protease
WO2005021487A1 (fr) * 2003-08-27 2005-03-10 Merck Frosst Canada Ltd. Inhibiteurs de la cathepsine
WO2008119176A1 (fr) 2007-04-02 2008-10-09 Merck Frosst Canada Ltd. Procédé d'amidation pour la préparation d'inhibiteurs de la cathepsine k
WO2012148555A1 (fr) 2011-03-02 2012-11-01 Merck Sharp & Dohme Corp. Procédé d'amidation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003075836A2 (fr) 2002-03-05 2003-09-18 Merck Frosst Canada & Co. Inhibiteurs de cathepsine cysteine protease
WO2005021487A1 (fr) * 2003-08-27 2005-03-10 Merck Frosst Canada Ltd. Inhibiteurs de la cathepsine
WO2008119176A1 (fr) 2007-04-02 2008-10-09 Merck Frosst Canada Ltd. Procédé d'amidation pour la préparation d'inhibiteurs de la cathepsine k
WO2012148555A1 (fr) 2011-03-02 2012-11-01 Merck Sharp & Dohme Corp. Procédé d'amidation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
-: "T3P - Propane Phosphonic Acid Anhydride The coupling agent of the future", EUTICALS - THE PHARMACEUTICAL & FINE CHEMICAL COMPANY, 1 January 2012 (2012-01-01), pages 1 - 6, XP055264571, Retrieved from the Internet <URL:http://www.euticals.com/attachments/article/11/EUTICALS_T3P-Coupling-Agents_2012_final_web.pdf> [retrieved on 20160412] *
K.D. WEHRSTEDT ET AL., J HAZARDOUS MATERIALS, vol. A126, 2005, pages 1 - 7
WAGHMARE ANIRUDHA A ET AL: "Propylphosphonic anhydride (T3P TM ): An expedient reagent for organic synthesis", REVIEW JOURNAL OF CHEMISTRY, PLEIADES PUBLISHING, MOSCOW, vol. 4, no. 2, 17 May 2014 (2014-05-17), pages 53 - 131, XP035316187, ISSN: 2079-9780, [retrieved on 20140517], DOI: 10.1134/S2079978014020034 *

Also Published As

Publication number Publication date
CZ2014941A3 (cs) 2016-06-29

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