WO2013050873A1 - Procédé de préparation de lersivirine - Google Patents

Procédé de préparation de lersivirine Download PDF

Info

Publication number
WO2013050873A1
WO2013050873A1 PCT/IB2012/002449 IB2012002449W WO2013050873A1 WO 2013050873 A1 WO2013050873 A1 WO 2013050873A1 IB 2012002449 W IB2012002449 W IB 2012002449W WO 2013050873 A1 WO2013050873 A1 WO 2013050873A1
Authority
WO
WIPO (PCT)
Prior art keywords
isophthalonitrile
reaction
stage
pyrazol
diethyl
Prior art date
Application number
PCT/IB2012/002449
Other languages
English (en)
Inventor
Anna CODINA
Andrew DERRICK
Richard Joyce
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 WO2013050873A1 publication Critical patent/WO2013050873A1/fr

Links

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

Definitions

  • the present invention is directed to a process for the preparation of lersivirine (a non- nucleoside reverse transcriptase inhibitor (NNRTi) useful for the treatment of HIV infection).
  • lersivirine a non- nucleoside reverse transcriptase inhibitor (NNRTi) useful for the treatment of HIV infection.
  • NRTi non- nucleoside reverse transcriptase inhibitor
  • WO02/085860 discloses a process for the synthesis of lersivirine consisting of the two steps shown 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 1 19 (with reference to Example 1 14) 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) comprises a first stage wherein the reaction is controlled so as to maintain a reaction temperature between 15-30 °C and a second stage wherein the reaction is controlled so as to maintain a reaction temperature between 40-70 °C.
  • the first stage is controlled so as to maintain a reaction temperature between 20-25 °C.
  • the second stage is controlled so as to maintain a reaction temperature of about 60 °C.
  • This stage preferably takes place at a temperature between 15-30 °C, more preferably 20-25 °C.
  • the reaction temperature may be controlled by (i) adjusting the rate of addition of one reagent to the other; and/or (ii) adjusting the rate of agitation (e.g. stirring) of the reaction mixture; and/or (iii) cooling the reaction mixture.
  • the intermediate compound shown above converts relatively slowly to form 5- ⁇ [3,5-diethyl-1 -(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy ⁇ isophthalonitrile.
  • This stage preferably takes place at a temperature between 40-70 °C, more preferably about 60 °C.
  • the reaction temperature may be controlled by heating the reaction mixture.
  • the principal advantage of maintaining a reaction temperature between 15-30 °C for the first stage of step (a) is that the reaction proceeds without excessive formation of unwanted byproducts (in particular 5-hydroxyisophthalonitrile).
  • the principal advantage of maintaining a reaction temperature between 40-70 °C for the second stage of step (a) is that the reaction proceeds without excessive formation of unwanted by-products (in particular the organic ester of 5- ⁇ [3,5- diethyl-1 -(2-hydroxyethyl)-1 H-pyrazol-4-yl]oxy ⁇ isophthalonitrile where an organic acid is used in step (a)).
  • the present invention provides a process for the synthesis of lersivirine of high purity (>99.5wt%) in good overall yield (87% isolated yield) with manageable levels of undesirable by-products ( ⁇ 0.22% in total), in particular very low levels of the acetate ester of lersivirine
  • Step (a) 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
  • step (a) A further advantage of maintaining specified reaction temperatures for step (a) is that the reaction may be performed using acetic acid as the acid for step (a) which is preferred from an environmental standpoint.
  • the crystallised solid is granulated, filtered, washed with n-heptane and dried under vacuum to afford 5- ⁇ [3,5-diethyl-1 -(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy ⁇ isophthalonitrile.
  • the 5- ⁇ [3,5-diethyl-1-(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy ⁇ isophthalonitrile may be further purified by recrystallisation from isopropyl acetate/n-heptane.

Landscapes

  • 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

Cette invention concerne un procédé de préparation de lersivirine ou d'un sel pharmaceutiquement acceptable de celle-ci, ledit procédé comprenant : (a) la réaction d'un 5-(2-oxo-1-propanoylbutoxy)isophtalonitrile et d'un 2- hydrazino-éthanol, en présence d'un acide, pour former un 5-{[3,5-diéthyl- 1-(2-hydroxyéthyl)-1H-pyrazol-4-yl]oxy}isophtalonitrile, et éventuellement, (b) la réaction du 5-{[3,5-diéthyl-1-(2-hydroxyéthyl)- 1H-pyrazol-4-yl]oxy}isophtalonitrile avec un réactif convenable pour former un sel pharmaceutiquement acceptable de 5-{[3,5-diéthyl- 1-(2-hydroxyéthyl)-1H-pyrazol-4-yl]oxy}isophtalonitrile. Le procédé selon l'invention est caractérisé en ce que l'étape (a) comprend un premier stade qui consiste à contrôler la réaction pour maintenir la température réactionnelle entre 15 et 30°C et un second stade qui consiste à contrôler la réaction pour maintenir la température réactionnelle entre 40 et 70°C.
PCT/IB2012/002449 2011-10-07 2012-10-04 Procédé de préparation de lersivirine WO2013050873A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161544393P 2011-10-07 2011-10-07
US61/544,393 2011-10-07

Publications (1)

Publication Number Publication Date
WO2013050873A1 true WO2013050873A1 (fr) 2013-04-11

Family

ID=47436122

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2012/002449 WO2013050873A1 (fr) 2011-10-07 2012-10-04 Procédé de préparation de lersivirine

Country Status (1)

Country Link
WO (1) WO2013050873A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085860A1 (fr) 2001-04-10 2002-10-31 Pfizer Limited Derives de pyrazole pour le traitement de vih

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085860A1 (fr) 2001-04-10 2002-10-31 Pfizer Limited Derives de pyrazole pour le traitement de vih

Similar Documents

Publication Publication Date Title
EA012163B1 (ru) Способ получения хиральных 8-(3-аминопиперидин-1-ил)ксантинов
US8884046B2 (en) Compounds useful in the synthesis of benzamide compounds
US10040771B2 (en) Method for preparing prostacyclin receptor agonist 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol
CN110627736A (zh) 一种1-苯基-5-羟基四氮唑的回收利用方法
WO2011021218A2 (fr) Procédé amélioré pour la préparation d'un composé acide 4-[3,5-bis(2-hydroxyphényl)- 1 h- 1,2,4-triazol- 1 -yl]benzoïque et de ses sels d'amine
CN103724288B (zh) 原甲酸三乙酯法制备1h-四氮唑乙酸的后处理方法
CN104829590A (zh) 一种纯化曲格列汀的方法
WO2011031409A1 (fr) Procédés de préparation du fébuxostat
US20100197930A1 (en) Process for producing toluidine compound
CN105315256A (zh) 一种适合工业化的高纯度琥珀酸曲格列汀的制备方法
CN111004121A (zh) 一种4-烷氧基乙酰乙酸酯类化合物的制备方法
JP2008260725A (ja) ２−イミノ−４−チアゾリジノンの製造方法
WO2015087343A2 (fr) Procédé amélioré pour la préparation de nilotinib et de sels pharmaceutiquement acceptables de celui-ci
WO2013050873A1 (fr) Procédé de préparation de lersivirine
CA2722818C (fr) Procede de fabrication de 1,7'-dimethyl-2'-propyl-2,5'-bis-1h-benzimidazole
WO2012011129A2 (fr) Nouveau polymorphe de sel de calcium d'acide bis[(e)-7-[4-(4-fluorophényl)-6-iso-propyl-2-[méthyl (méthylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-énoïque]
US10253021B2 (en) Method for producing benzoxazole compound
EP3312174B1 (fr) Procédé de préparation de trityl candésartan
CN115572747B (zh) 托匹司他的制备方法
TWI570114B (zh) 製備４－羥基－２－酮基－２，５－二氫呋喃－３－羧酸酯之鈉鹽或鉀鹽之方法
JP2010189293A (ja) １，４―ジヒドロピリジン誘導体の製造法
CA3036936A1 (fr) Methode de production optimisee pour un agent de lutte antiparasitaire a 2-acyliminopyridine
WO2016034150A1 (fr) Sunitinib et son procédé de préparation cristalline
WO2013057593A1 (fr) Procédé de préparation de dérivés de lersivirine
CZ2004218A3 (en) Process for preparing 4-chloro-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12806662

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12806662

Country of ref document: EP

Kind code of ref document: A1