WO2011110219A1 - Procédé de préparation de prasugrel - Google Patents

Procédé de préparation de prasugrel Download PDF

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Publication number
WO2011110219A1
WO2011110219A1 PCT/EP2010/052971 EP2010052971W WO2011110219A1 WO 2011110219 A1 WO2011110219 A1 WO 2011110219A1 EP 2010052971 W EP2010052971 W EP 2010052971W WO 2011110219 A1 WO2011110219 A1 WO 2011110219A1
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WO
WIPO (PCT)
Prior art keywords
group
formula
compound
nitrogen
ring
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PCT/EP2010/052971
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English (en)
Inventor
Lambertus Thijs
Jie Zhu
Arjanne Overeem
Rolf Keltjens
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Synthon Bv
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Publication date
Application filed by Synthon Bv filed Critical Synthon Bv
Priority to PCT/EP2010/052971 priority Critical patent/WO2011110219A1/fr
Priority to EP10706686A priority patent/EP2545059A1/fr
Priority to CN2010800657297A priority patent/CN102869668A/zh
Publication of WO2011110219A1 publication Critical patent/WO2011110219A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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

  • Prasugrel has one asymmetric carbon (marked by the asterisk in the formula (I)), and is marketed in the registered medicinal products as a racemate. It may form acid addition salts, for instance prasugrel hydrochloride (see EP 2003136), which is the active ingredient in the medicinal products (sold, e.g., under brand name EFIENT or EFFIENT).
  • prasugrel Various processes are known for making prasugrel. Any of the processes comprise, as the key step, a step of N-alkylation on a tetrahydrothienopyridine nitrogen atom, by which two basic "fragments" of the final molecule are coupled together. The nature of the fragments is schematically shown using a dotted line in the following variant of the chemical formula of prasugrel:
  • the first process starts with 2-oxo- 2,4,5, 6,7, 7a-hexahydrothieno[3,2-c]pyridine (compound (B), prepared by a multistep process according to EP 192535), which is coupled with 2-fluoro-a-cyclopropylcarbonylbenzyl bromide (CI) to yield "2-ketoprasugrel" of formula (II), the 2-keto-group of which is finally subjected to a reductive acetylation to yield prasugrel of formula (I).
  • bromo functionality in (CI) may be replaced by a methane sulfonate group as taught by WO 2009/006859. No significant improvement has been obtained by this modification.
  • the second process which has been disclosed in EP 785205 (WO 96/11203), improves the low yields of the preceded process, which are apparently caused by instability of the keto- group of the thiolactone compound (B) at the reaction conditions (apparently, the thiolactone structure is susceptible to an easy ring opening).
  • the keto group of the compound (B) is protected by silylation, preferably by a tert.butyldimethylsilyl (TBDMS) group, to yield the corresponding silyl-enol ether (D).
  • TDMS tert.butyldimethylsilyl
  • This compound serves as reaction partner in the coupling with fragment (CI) to yield a "silyl-prasugrel" of formula (III).
  • Replacement of the silyl, e.g. TBDMS, group by an acetate group gives prasugrel in good yield.
  • WO2008-108291 suggests that a chlorinated analogue of the compound (CI) may be used in this process as well.
  • the present invention provides a new group of intermediates that are useful in making the compound prasugrel, processes of making them and processes for converting them into prasugrel.
  • the present invention provides 5-R-2-(amino-substituted) -4,5,6,7- tetrahydrothieno[3,2-c]pyridine compounds of general formula (A) and/or acid addition salts thereof,
  • R is a hydrogen atom or a nitrogen-protecting group or an alpha- cyclopropylcarbonyl-2-fluorobenzyl group
  • Ri,R2 is independently a CI -CIO alkyl group, optionally having one or more carbons substituted by a hydroxy group, or Ri,R 2 together with the bridging nitrogen may form a ring comprising from 3 to 10 carbon atoms, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring.
  • the invention provides processes for making compounds of the general formula (A).
  • the invented processes comprise reacting a compound of formula (V)
  • L is a leaving group, for instance a halo-group, most preferably a bromo-group, and R is defined as in the formula (A)
  • the process may be optionally followed by a step of isolation of the compound (A) from the reaction mixture and/or by converting group R into another group R within the definition above
  • the present invention provides a process for making the compounds of formula (V) comprising the step of reacting 5-R-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (VI),
  • the present invention provides a process for making prasugrel of formula (I) and/or pharmaceutically acceptable salts thereof comprising the step of converting a compound of formula (A) into the compound of formula (II)
  • the present invention provides novel intermediates and novel processes that may be used in making prasugrel (I) and/or pharmaceutically acceptable acid addition salts thereof.
  • each of the known syntheses of prasugrel is based on coupling of two basic fragments: the "thieno-pyrimidyl” fragment properly substituted in the position 2 (the above “Fragment 2" or its precursor) and the “fluorophenyl” fragment (the above “Fragment 1” or its precursor) followed by a subsequent step of conversion of a group in the position 2 of the so-formed condensation product into the desired acetoxy-group.
  • the choice of the group in the position 2 is apparently motivated by attempts to find a proper substituent, which would be stable enough under the reaction conditions of coupling the two basic fragments.
  • the compound (B) can be prepared only by a multistep process.
  • R is a hydrogen atom or a nitrogen-protecting group or a alpha-cyclopropylcarbonyl-2-fluorobenzyl group
  • Ri,R2 is independently a CI -CIO alkyl group, optionally having one or more carbons substituted by a hydroxy group, or Ri,R2 together with the bridging nitrogen may form a C3-C10 ring, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring.
  • the nitrogen protecting group R may be benzyl, trityl, benzyloxycarbonyl, tert-butyl, tert.butylcarbonyl, or tert.butyloxycarbonyl group.
  • the - R1R2 moiety may advantageously comprise an optionally substituted
  • dialkylamino group e.g. N-methyl-N-2-hydroxy ethyl group, or a 6 membered nitrogen- comprising ring, e.g. N- morpholinyl or N-piperazinyl group.
  • the compounds of formula (A) may form acid addition salts with various inorganic or organic acids; examples of these acids are, without limitation, hydrochloric, hydrobromic, sulfuric, methane sulfonic, benzene sulfonic, p-toluene sulfonic, formic, acetic, maleic, fumaric, oxalic, citric or succinic acid.
  • the compounds of formula (A) and/or its acid addition salts are preferably useful in its isolated form, which yet preferably is a solid state form such as any crystalline or an amorphous form; the solid state forms also embrace solvates and hydrates. Due to the intended industrial application, compounds (A) with more than 95% chemical purity, and particularly with more than 99% chemical purity are preferred.
  • the new compounds of formula (A) may be prepared by a process, in which a compound of formula (V) (V) reacts with an amine of formula (VII)
  • -NR R2 moiety may advantageously comprise an optionally substituted dialkylamino group, e.g. N-methyl-N- 2 -hydroxy ethyl group, or a 6 membered nitrogen-comprising ring, e.g. N- morpholinyl or N- piperazinyl group.
  • the leaving group L is typically a halo-group, most preferably a bromo-group.
  • the nitrogen-protecting group may be a benzyl,trityl, benzyloxycarbonyl, tert-butyl, tert.butylcarbonyl, or tert.butyloxycarbonyl group. (Compound V-2).
  • the R-group may also be the l-(2-fluorophenyl)-cyclopropylcarbonylmethyl group (compound V-l),
  • R-group in the starting compound (V) may also be hydrogen (compound
  • the reaction between the compound of formula (V) and the amine of formula (VII) typically proceeds under general conditions of so called Ullmann condensation reaction, which is a copper-mediated nucleophilic replacement of a halide by an amine.
  • Ullmann condensation reaction which is a copper-mediated nucleophilic replacement of a halide by an amine.
  • the reaction requires a copper catalyst/mediator, a solvent, e.g. a protic solvent, a base, and an enhanced temperature. A molar excess of the amine is preferred.
  • Any compound of the formula (A) defined above may be isolated from the reaction mixture by conventional isolation techniques such as extraction, chromatography and/or precipitation, and purified if desired. Preferably, it is isolated in a solid state form, which is advantageous from the aspects of storage and handling. Alternately, the compound of the formula (A) defined above may be used in the process of making prasugrel without isolation, e.g. as an extract in an inert solvent.
  • the amines of formula (A) may also be isolated in a form of an acid addition salt, e.g. a hydrochloride.
  • the R-group in the compound of formula (A) may be converted into another R- group.
  • the nitrogen-protective group in the compound of formula (A-2) may be removed and replaced by hydrogen yielding a compound of formula (A-3), and/or the hydrogen group in compound (A-3) may be replaced by the l-(2-fluorophenyl)- cyclopropylcarbonyl-methyl group yielding the compound (A-l).
  • the compound of formula (A-3) may react with 2-fluoro-a-cyclopropylcarbonylbenzylhalide of formula (C),
  • X is a halo-group, preferably with the corresponding bromide (compound CI), in an inert solvent and under presence of a base, e.g. an organic base.
  • a base e.g. an organic base.
  • the desired (A-l) may be isolated from the reaction mixture by precipitation or extraction/evaporation techniques.
  • the -NR R2 group in the compound (A-3) is N-morpholinyl group or N-(2- hydroxyethyl)-N-methylamino group.
  • the compound (CI) is obtainable according to processes known in the art (e.g.
  • the starting compounds of formula (V) can be made by a process, which comprises a step of reacting a 5-R-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (VI),
  • R is defined as in the formula (A), with a donor of leaving group L.
  • the "donor of leaving group L” is a compound, the reaction of which with the compound (VI) provides the compound of formula (V).
  • the leaving group L is a halo-, such as chloro- or bromo- group
  • the donor of the leaving group L may be the corresponding halogen, e.g. chlorine or bromine.
  • the compound of formula (VI) may be used for the reaction as a free base, or in a form of a salt, e.g. a hydrochloride.
  • reaction between the compound (VI) and the donor of the leaving group L proceeds in an inert solvent, generally at ambient or higher than ambient temperatures and the reaction product (V) may be isolated from the reaction mixture by conventional techniques.
  • a compound of formula (V) defined above may be used in the next step without isolation, e.g. as an extract in such inert solvent, which is suitable for the next reaction step.
  • the process of making the compound (V) may also comprise a step of converting a group R into another group R, whereby this converting step may precede or follow the step of reacting with the donor of leaving group L.
  • compound (VI) in which R is hydrogen (compound VI-3)
  • the compounds (VI-3) and (VI-2) may be converted into a compound of formula (VI- 1)
  • the compound of formula (VI-3) is the basic starting material of the overall process of the present invention. It is commercially available.
  • the R-converting step follows the step of reacting with the donor of leaving group L
  • the deprotection agent should be selected as such to avoid the simultaneous removal of the group in the position 2, e.g., by hydrolysis. Accordingly, the deprotection reaction preferably proceeds at anhydrous conditions.
  • a suitable deprotecting agent, particularly for removal of the trityl group, is, e.g., anhydrous HC1 or p-toluene sulfonic acid.
  • the compounds of formula (A) and preferably the compound (A-1) and/or any of its acid addition salts are useful as starting materials for making prasugrel (I).
  • the preferred starting material for the conversion step is the compound (A-1).
  • the product of the conversion of the amino-group into a keto-group is then compound (II),
  • the conversion of the compound (A-1) to the compound (II) may be executed by the reaction of the compound (A-1) with an aqueous acid.
  • aqueous acid For instance, diluted hydrochloric acid may be used as the reagent, as well as the solvent.
  • the reaction proceeds by heating the mixture, e.g. at a temperature from between 40°C to the reflux temperature, preferably at 50- 90 °C.
  • the course of the reaction may be monitored by a suitable analytical technique, e.g. by HPLC or TLC.
  • the reaction mixture is preferably neutralized and the product is isolated from the reaction mixture, e.g. by an extraction with a water immiscible organic solvent.
  • the compound (II) is converted into prasugrel by procedures known in the art (e.g. in EP 542411), i.e. by a reaction with acetic acid anhydride in a presence of a strong base, e.g. sodium hydride.
  • prasugrel is advantageously isolated from the reaction mixture by conventional techniques such as, for example, extraction, crystallization, trituration and chromatography, and purified, if desired or necessary. It may be isolated either as a free base or in a form of an acid addition salt, for instance as prasugrel hydrochloride.
  • the isolated forms also comprise hydrates and solvates.
  • Prasugrel prepared according to a process of the present invention may be used as a medicinal product, i.e. it may be formulated with suitable excipients into various medicinal dosage forms, e.g. tablets, capsules, injections, implants etc, for treatment or prevention of any disease treatable by prasugrel.
  • Example 10 1 -Cyclopropyl-2-(2-fluoro-phenyl)-2- ⁇ 2-[(2-hydroxy-ethyl)-methyl- amino]-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl ⁇ -ethanone

Abstract

Cette invention concerne un composé de Formule générale (A), et/ou des sels d'addition d'acide de celui-ci et leur procédé de préparation et d'utilisation pour obtenir du prasugrel. Dans la Formule (A), R est un atome d'hydrogène ou un groupe de protection de l'azote ou un groupe alpha- cyclopropylcarbonyl-2-fluorobenzyle et R1, R2 sont indépendamment un groupe alkyle C1-C10 ayant éventuellement un ou plusieurs atomes de carbone substitués par un groupe hydroxyle, ou R1,R2 avec l'azote de pontage peuvent former un cycle comprenant de 3 à 10 atomes de carbone, et éventuellement, comprenant également un autre atome d'azote, d'oxygène ou de soufre dans le cycle ou un substituant contenant un atome d'azote, d'oxygène, ou de soufre sur le cycle.
PCT/EP2010/052971 2010-03-09 2010-03-09 Procédé de préparation de prasugrel WO2011110219A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/EP2010/052971 WO2011110219A1 (fr) 2010-03-09 2010-03-09 Procédé de préparation de prasugrel
EP10706686A EP2545059A1 (fr) 2010-03-09 2010-03-09 Procédé de préparation de prasugrel
CN2010800657297A CN102869668A (zh) 2010-03-09 2010-03-09 制备普拉格雷的方法

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Application Number Priority Date Filing Date Title
PCT/EP2010/052971 WO2011110219A1 (fr) 2010-03-09 2010-03-09 Procédé de préparation de prasugrel

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WO2011110219A1 true WO2011110219A1 (fr) 2011-09-15

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EP (1) EP2545059A1 (fr)
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Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0192535A1 (fr) 1985-01-31 1986-08-27 Sanofi Nouveaux dérivés de l'acide alpha-[oxo-2-hexahydro-2,4,5,6,7a thiéno (3,2-c)pyridyl-5] phényl acétique, leur procédé de préparation et leur application thérapeutique
EP0421861A1 (fr) * 1989-10-02 1991-04-10 Elf Sanofi Dérivés d'hydroxy-2 thiophène et furanne condensés avec un cycle azoté, leur procédé de préparation et leur application en thérapeutique
EP0542411A2 (fr) 1991-09-09 1993-05-19 Sankyo Company Limited Dérivés de tétrahydrothieno-, und Pyrrolopyridinderivate, ihre Herstellung und Verwendung als Blutplättchen-Aggregation-Inhibitoren
WO1996011203A1 (fr) 1994-10-07 1996-04-18 Ube Industries, Ltd. 2-silyloxytetrahydrothienopyridine, son sel, et son procede de production
EP1104754A1 (fr) * 1998-08-11 2001-06-06 Daiichi Pharmaceutical Co., Ltd. Nouveaux derives sulfonyle
EP1298132A1 (fr) 2000-07-06 2003-04-02 Sankyo Company, Limited Sels d'addition acides de d riv s hydropyridine
WO2004098713A2 (fr) 2003-05-05 2004-11-18 Eli Lilly And Company Methode de traitement de maladies cardio-vasculaires
CN101245073A (zh) 2008-03-21 2008-08-20 上海医药工业研究院 一种医药中间体及其制备方法
CN101250193A (zh) 2008-03-28 2008-08-27 上海医药工业研究院 2-甲氧基-5-(α-环丙基羰基-2-氟苄基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶的制备方法
CN101250192A (zh) 2008-03-24 2008-08-27 上海医药工业研究院 5-(α-环丙基羰基-2-氟苄基)-2-氧-2,4,5,6,7,7a-六氢噻吩并[3,2-c]吡啶的制备方法
WO2008108291A1 (fr) 2007-03-02 2008-09-12 Daiichi Sankyo Company, Limited Procédé de production de chlorhydrate de prasugrel de grande pureté
EP2003136A1 (fr) 2006-04-06 2008-12-17 Daiichi Sankyo Company, Limited Procede de production de prasugrel de grande purete et sel d'addition d'acide de celui-ci
WO2009006859A2 (fr) 2007-07-09 2009-01-15 Zentiva A.S. Procédé de fabrication d'acétate de 5-[2-cyclopropyl-1-(2-fluorophényl)-2-oxoéthyl]-4,5,6,7-tétrahydrothiéno[3,2-c]pyridin-2-yle (prasugrel)

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EP0421861A1 (fr) * 1989-10-02 1991-04-10 Elf Sanofi Dérivés d'hydroxy-2 thiophène et furanne condensés avec un cycle azoté, leur procédé de préparation et leur application en thérapeutique
EP0542411A2 (fr) 1991-09-09 1993-05-19 Sankyo Company Limited Dérivés de tétrahydrothieno-, und Pyrrolopyridinderivate, ihre Herstellung und Verwendung als Blutplättchen-Aggregation-Inhibitoren
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EP1104754A1 (fr) * 1998-08-11 2001-06-06 Daiichi Pharmaceutical Co., Ltd. Nouveaux derives sulfonyle
EP1298132A1 (fr) 2000-07-06 2003-04-02 Sankyo Company, Limited Sels d'addition acides de d riv s hydropyridine
WO2004098713A2 (fr) 2003-05-05 2004-11-18 Eli Lilly And Company Methode de traitement de maladies cardio-vasculaires
EP2003136A1 (fr) 2006-04-06 2008-12-17 Daiichi Sankyo Company, Limited Procede de production de prasugrel de grande purete et sel d'addition d'acide de celui-ci
WO2008108291A1 (fr) 2007-03-02 2008-09-12 Daiichi Sankyo Company, Limited Procédé de production de chlorhydrate de prasugrel de grande pureté
WO2009006859A2 (fr) 2007-07-09 2009-01-15 Zentiva A.S. Procédé de fabrication d'acétate de 5-[2-cyclopropyl-1-(2-fluorophényl)-2-oxoéthyl]-4,5,6,7-tétrahydrothiéno[3,2-c]pyridin-2-yle (prasugrel)
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CN101250193A (zh) 2008-03-28 2008-08-27 上海医药工业研究院 2-甲氧基-5-(α-环丙基羰基-2-氟苄基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶的制备方法

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Title
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CN102869668A (zh) 2013-01-09

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