WO2017109524A1 - Procédé et intermédiaire pour la production de baricitinib - Google Patents

Procédé et intermédiaire pour la production de baricitinib Download PDF

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Publication number
WO2017109524A1
WO2017109524A1 PCT/HU2016/050066 HU2016050066W WO2017109524A1 WO 2017109524 A1 WO2017109524 A1 WO 2017109524A1 HU 2016050066 W HU2016050066 W HU 2016050066W WO 2017109524 A1 WO2017109524 A1 WO 2017109524A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
production
baricitinib
hydrochloric acid
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/HU2016/050066
Other languages
English (en)
Inventor
Gyula Simig
Balázs VOLK
Katalin KÁTAINÉ FADGYAS
Tamás Nagy
Mária TÓTHNÉ LAURITZ
Éva SIPOS
András DANCSÓ
Éva SZABÓ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Egis Pharmaceuticals PLC
Original Assignee
Egis Pharmaceuticals PLC
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 Egis Pharmaceuticals PLC filed Critical Egis Pharmaceuticals PLC
Publication of WO2017109524A1 publication Critical patent/WO2017109524A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Our invention falls in the technical field of synthetic pharmacologically active substance production. Specifically it relates to novel pharmaceutical intermediate products and to their production methods.
  • Baricitinib is a pharmacologically active substance developed for the treatment of rheumatoid arthritis belonging to the family of Janus kinase inhibitors. Baricitinib was first disclosed in international patent application number WO2009114512. According to one of the methods disclosed in the application for the production of baricitinib (see reaction scheme 1), the formula (IV) compound is reacted with the formula (V) compound in the presence of 1,8- diazabicyclo[5.4.0]-undec-7-ene (DBU) in acetonitrile.
  • DBU 1,8- diazabicyclo[5.4.0]-undec-7-ene
  • Reaction scheme 1 The synthesis pathway of baricitinib according to international patent application number WO2009114512 with the use of the SEM protecting group
  • the use of the SEM protecting group in the method presented above is exceptionally disadvantageous from the aspect of technology, as two chemical steps are required in order to remove it. First of all, in a long reaction (10-20 hours) catalysed with acid (optionally a Lewis acid, e.g. LiBF 4 ) the SEM protecting group is transformed into a hydroxymethyl group, which needs to be removed with further alkaline treatment (e.g. aqueous ammonium-hydroxide).
  • acid optionally a Lewis acid, e.g. LiBF 4
  • alkaline treatment e.g. aqueous ammonium-hydroxide
  • compound (III) was obtained by reacting the compounds (IX) and (X) in the presence of DBU in dimethylformamide (DMF), from which the pivaloyloxymethyl (POM) protecting group was removed in one step, by treatment with an alkali.
  • DMF dimethylformamide
  • Reaction scheme 2 The synthesis pathway of baricitinib according to international patent application number WO2009114512 with the use of the POM protecting group
  • the subject of our invention relates to the compound of formula (I) and compound of formula (II), and also to the salts of the latter compound formed with organic and inorganic acids, preferably hydrochloric acid.
  • the subject of our invention also relates to a method for the production of the compound of formula (I), characterised by that
  • the compound of formula (IV) is reacted with the compound of formula (X) in an organic solvent, preferably acetonitrile, in the presence of a base, preferably l,8-diazabicyclo[5.4.0]- undec-7-ene (DBU).
  • organic solvent preferably acetonitrile
  • a base preferably l,8-diazabicyclo[5.4.0]- undec-7-ene (DBU).
  • the subject of our invention also relates to a method for the production of the formula (II) compound, characterised by that the Boc protecting group of the compound of formula (I) is removed using aqueous hydrochloric acid treatment.
  • the protecting group may also be removed in an organic solvent, the organic solvent used is preferably ethyl acetate or toluene.
  • the subject of our invention also relates to a method for the production of the compound of formula (III), characterised by that the compound of formula (II) or its salt is reacted with ethanesulfonic acid chloride in an organic solvent in the presence of a base.
  • N,N- diisopropylethylamine is preferably used in the method as the base, while the solvent, according to a preferable embodiment, may be ethyl acetate, tetrahydrofuran or toluene.
  • the subject of our invention also relates to a method for the production of baricitinib, characterised by that the compound of formula (II) is sulphonated, then baricitinib is produced by performing alkaline hydrolysis on the created compound of formula (III).
  • the compound of formula (II) is preferably produced via the acidic removal of the Boc protecting group from the compound of formula (I).
  • the compound of formula (I) is preferably produced in the way presented above.
  • the subject of our invention also relates to the use of the compounds of formula (I) or (II) for the production of the baricitinib active substance, or its salts.
  • the compound of formula (I) according to the invention may be preferably produced by reacting tert-butyl 3-(cyanomethylidene)azetidine-l-carboxylate of formula (IV) with 4-(lH- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pirimidin-7-yl]methyl 2,2-dimethylpropanoate of formula (X) at room temperature for 2 hours in an organic solvent, in the presence of DBU, then the tert- butyl-3-(cyanomethyl)-3-[4-(7- ⁇ [(2,2-dimethylpropanoyl)oxy]methyl ⁇ -7H-pyrrolo[2,3-
  • the compound of formula (I) is a compound with a high melting point and that crystalizes well, and which is very suitable for use as an intermediate product in a pharmaceutical industry production process. Furthermore, after being produced with the method according to the invention, it may be taken into the next step without any further purification steps as it may be produced with chemical purity in excess of 99.5% .
  • reaction scheme 1 in the process using the SEM protecting group (reaction scheme 1) the reaction of the compound of formula (IV) with the compound of formula (V) takes place at room temperature for 16 hours, then the desired product is obtained at a yield of 72% by using flash chromatography purification.
  • the subject of the invention also relates to 4- ⁇ l-[3-(cyanomethyl)azetidin-3-yl]- lH-pyrazol- 4-yl ⁇ -7H-pyrrolo[2,3- ⁇ i]pirimidin-7-yl)methyl 2,2-dimethylpropanoate of formula (II) and its salts as well as to the production of the compound of formula (II) and of the salts of the compound of formula (II), and furthermore to the use of these compounds for the synthesis the active substance baricitinib or its salts.
  • a further disadvantage of the method according to reaction scheme 1 according to patent application number WO2009114512 is that the removal of the Boc protecting group from the compound of formula (VI) is carried out for 16 hours.
  • the reaction is completed in 1 to 3 hours, preferably under 1 hour at room temperature or at 50 °C, preferably at room temperature.
  • the compound of formula (II) may be produced with 75-90%-yield and at a chemical purity level higher than 96%. It was also surprising to find that, similarly to the compound of formula (I), the compound of formula (II) and its salts have high melting points and crystalize well, and are also very suitable as intermediates in pharmaceutical industry production processes. After being produced with the method according to the invention they may be taken into the next step without any further purification steps as they may be produced with chemical purity in excess of 96%.
  • the subject of the invention also relates to a production method for (4- ⁇ l-[3-(cyanomethyl)- l-(ethylsulphonyl)azetidin-3-yl]- lH-pyrazol-4-yl ⁇ -7H-pyrrolo[2,3- ⁇ i]pirimidin-7-yl)methyl 2,2-dimethylpropanoate of formula (III) from the compound of formula (II) or from its hydrochloric acid salts.
  • the reaction mixture is stirred for 2 hours at room temperature, then for a further 2 hours at 0-5 °C.
  • the precipitated solid material is filtered, then washed on the filter with 2x25 ml of 5 °C acetonitrile, then dried at room temperature and atmospheric pressure until constant weight is achieved. In this way 38.8 g (90.0%) of a white solid product is obtained, the purity of which measured with LC MS at 254 nm is 99.8%.
  • the sample is spectroscopically identical to the substance produced using method A.
  • reaction mixture is stirred at room temperature for 1.5 hours.
  • 300 ml of ethyl acetate is added to the reaction mixture, then 100 ml of saturated sodium carbonate aqueous solution is added to it drop by drop.
  • Solvent is evaporated from the reaction mixture until a thick suspension is obtained.
  • 60 ml of water is then added to it, then the suspension is filtered. In this way 10 g of raw product is obtained, which is dissolved in 100 ml of hot methanol.
  • the hot solution is filtered through a glass filter.
  • the filtrate is stirred and cooled to 20-23 °C, and then stirred at this temperature for 1 hour.
  • the sample is spectroscopically identical to the substance produced using method A.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des procédés et des intermédiaires pour la production de baricitinib. Selon le nouveau procédé, du baricitinib peut être produit de préférence par le biais des intermédiaires tert-butyl-3-(cyanométhyl)-3-[4-(7-{[(2,2-diméthylpropanoyl)oxy]méthyl}-7H-pyrrolo[2,3-d]pirimidine-4-yl)- lH-pyrazol-l-yl]azétidine-l-carboxylate et 4-{1-[3-(cyanométhyl)azétidine-3-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pirimidine-7-yl)méthyl 2,2-diméthylpropanoate.
PCT/HU2016/050066 2015-12-23 2016-12-21 Procédé et intermédiaire pour la production de baricitinib Ceased WO2017109524A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP1500647 2015-12-23
HU1500647A HU230805B1 (hu) 2015-12-23 2015-12-23 Eljárás és köztitermék baricitinib előállítására

Publications (1)

Publication Number Publication Date
WO2017109524A1 true WO2017109524A1 (fr) 2017-06-29

Family

ID=89992039

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2016/050066 Ceased WO2017109524A1 (fr) 2015-12-23 2016-12-21 Procédé et intermédiaire pour la production de baricitinib

Country Status (2)

Country Link
HU (1) HU230805B1 (fr)
WO (1) WO2017109524A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109651424A (zh) * 2017-10-11 2019-04-19 新发药业有限公司 一种7-保护基-4-(1-氢-吡唑-4-基)吡咯[2,3-d]嘧啶的简便合成方法
WO2020072870A1 (fr) 2018-10-05 2020-04-09 Johnson Matthey Public Limited Company Formes co-cristallines du baricitinib
RU2835445C1 (ru) * 2024-05-02 2025-02-25 Акционерное Общество "Биохимик" Способ получения 2-[1-этилсульфонил-3-[4-(7h-пирроло[2,3-d]пиримидин-4-ил)пиразол-1-ил]азетидин-3-ил]ацетонитрила

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009114512A1 (fr) * 2008-03-11 2009-09-17 Incyte Corporation Dérivés d'azétidine et de cyclobutane en tant qu'inhibiteurs de janus kinase (jak)
WO2010083283A2 (fr) * 2009-01-15 2010-07-22 Incyte Corporation Procédés de préparation d'inhibiteurs des jak et composés intermédiaires apparentés
WO2011031554A2 (fr) * 2009-08-27 2011-03-17 Biocryst Pharmaceuticals, Inc. Composés hétérocycliques en tant qu'inhibiteurs de janus kinase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009114512A1 (fr) * 2008-03-11 2009-09-17 Incyte Corporation Dérivés d'azétidine et de cyclobutane en tant qu'inhibiteurs de janus kinase (jak)
WO2010083283A2 (fr) * 2009-01-15 2010-07-22 Incyte Corporation Procédés de préparation d'inhibiteurs des jak et composés intermédiaires apparentés
WO2011031554A2 (fr) * 2009-08-27 2011-03-17 Biocryst Pharmaceuticals, Inc. Composés hétérocycliques en tant qu'inhibiteurs de janus kinase

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109651424A (zh) * 2017-10-11 2019-04-19 新发药业有限公司 一种7-保护基-4-(1-氢-吡唑-4-基)吡咯[2,3-d]嘧啶的简便合成方法
CN109651424B (zh) * 2017-10-11 2021-01-22 新发药业有限公司 一种7-保护基-4-(1-氢-吡唑-4-基)吡咯[2,3-d]嘧啶的合成方法
WO2020072870A1 (fr) 2018-10-05 2020-04-09 Johnson Matthey Public Limited Company Formes co-cristallines du baricitinib
RU2835445C1 (ru) * 2024-05-02 2025-02-25 Акционерное Общество "Биохимик" Способ получения 2-[1-этилсульфонил-3-[4-(7h-пирроло[2,3-d]пиримидин-4-ил)пиразол-1-ил]азетидин-3-ил]ацетонитрила

Also Published As

Publication number Publication date
HUP1500647A2 (en) 2017-08-28
HU230805B1 (hu) 2018-06-28

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