WO2008046792A1 - FORME CRISTALLINE DE L'ACÉTATE RACÉMIQUE DE MÉTHYL-α-(2-CHLOROPHÉNYL)-2-(6,7-DIHYDROTHIÉNO[3,2-C]PYRIDIN-5(4H)), SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION - Google Patents

FORME CRISTALLINE DE L'ACÉTATE RACÉMIQUE DE MÉTHYL-α-(2-CHLOROPHÉNYL)-2-(6,7-DIHYDROTHIÉNO[3,2-C]PYRIDIN-5(4H)), SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION Download PDF

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Publication number
WO2008046792A1
WO2008046792A1 PCT/EP2007/060905 EP2007060905W WO2008046792A1 WO 2008046792 A1 WO2008046792 A1 WO 2008046792A1 EP 2007060905 W EP2007060905 W EP 2007060905W WO 2008046792 A1 WO2008046792 A1 WO 2008046792A1
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WO
WIPO (PCT)
Prior art keywords
pyridine
acetate
methyl
chlorophenyl
dihydrothieno
Prior art date
Application number
PCT/EP2007/060905
Other languages
German (de)
English (en)
Inventor
Zbigniew Majka
Andrzej Wojciech Sawicki
Andrzej Trzepalka
Original Assignee
Adamed Sp. Z O.O.
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 Adamed Sp. Z O.O. filed Critical Adamed Sp. Z O.O.
Publication of WO2008046792A1 publication Critical patent/WO2008046792A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a crystalline form of the racemic methyl- ⁇ - (2-chlorophenyl) -2 - (6, 7-dihydrothieno [3, 2-c] pyridine-5 (4H)) acetate, a process for their preparation and their use.
  • Racemic methyl ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate is the most important intermediate in the preparation of clopidogrel.
  • Clopidogrel is a generic name of the (+) - (S) -methyl- ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate, a Substance known as an antithrombotic drug.
  • Camphorsulfonic acid contained 35% clopidogrel and 65% of its levorotatory isomers. This mixture was used for the secretion of this left-handed isomer.
  • the left-rotating isomer of clopidogrel has a toxic effect on the central nervous system. Therefore, it is useless for the therapy and represents after the secretion stage of clopidogrel from Razemate a waste product.
  • the publication WO 2004/013147 describes the racemization of the left-rotating isomer of clopidogrel or of a mixture containing this enantiomer in excess in the presence of a catalytic amount of an organic or inorganic base.
  • the process is carried out in a solvent.
  • the base used for the racemization is neutralized with acid, the reaction mixture is rinsed for the purpose of leaching the neutralization products, the organic layer is dried and concentrated, and then the recovered Methyl ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate as an oily racemate.
  • This racemate is subjected to further work-up for the purpose of isolating the clopidogrel.
  • clopidogrel both in the form of individual enantiomers and in racemic form, despite its basic character, does not form any crystalline precipitating addition salts with some acid.
  • These acids include carboxylic acids.
  • carboxylic acids Some of those added to the solution of clopidogrel in the organic solvent to convert it to salt crystallize from this system in an unchanged form.
  • the pharmaceutically acceptable acids such as: ascorbic acid, malic acid, tartaric acid and mandelic acid do not form clopidogrel salts leaving the solutions, nor do they cause changes in the configuration of the clopidogrel.
  • the racemization process according to the invention achieves special effects which confirm the unobviousness of both the process of preparation and of the new product to be produced.
  • the inventive method is very simple to implement and much more economical, because it ensures time and energy savings, lower device requirements compared to the prior art.
  • the crystalline racemate of the present invention is more advantageous in handling operations associated with separation of the enantiomers for clopidogrel secretion.
  • the new crystalline form racemic methyl- ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate is characterized by the melting temperature in the range of 56- 60 0 C.
  • the Crystalline racemate also has the characteristic peaks in the powder diffractogram Röentgen-(XRPD) in degrees 2 ⁇ ( ⁇ 0.2 ° ⁇ ): 14.1, 16.2, 17.0, 18.6, 19.4, 19.8, 21.0, 25.2, 25.5, 27.3, 32.0.
  • the powder diffractogram is shown in attached Figure 1 and a detailed list of peaks is presented in Table 1.
  • Table 1 Characteristic XRPD peaks, the lattice spacings d and relative intensities 1/1 ° of the interference lines for the crystalline racemate of methyl ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3, 2-c] pyridine-5 (4H)) -acetate
  • the present invention also relates to the process for preparing the crystalline racemate of methyl ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate.
  • the process for preparing the crystalline racemate of methyl ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate is advantageously characterized in that the (- ) - (R) -methyl- ⁇ - (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) -acetate or the mixture of the enantiomers of the methyl- ⁇ - (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) - acetate with excess of the left-handed enantiomer until the consistency which allows stirring is heated, formic acid or acetic acid added with stirring and the mixture is heated to the temperature of about 70 0 C to about 1 10 0 C, then it is cooled to the temperature of about 40 0 C to about 80 0 C, the
  • organic solvent is a solvent selected from the group of alcohols, ketones, ethers, and most advantageously methanol or ethanol.
  • the subject of the invention is also the crystalline form of the racemic methyl- ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate obtained by any one of was prepared as described above.
  • the invention further relates to the process for the preparation of
  • the invention further provides the use of the inventive crystalline racemate of methyl ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate as defined above, for the preparation of the (+) - (S) -methyl- ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate (clopidogrel) and / or its salts.
  • link rotatory enantiomer of clopidogrel or the mixture of enantiomers with excess of the link rotating enantiomer to the temperature of at least 50 0 C for the purpose of reducing the viscosity and facilitating the stirring is heated, because the substrates oily forms of liquids are.
  • formic acid or acetic acid is added thereto with stirring in an amount of 0.05 to 3 times, preferably 0.1 to 1 times, per mole of racemized substrate.
  • the whole is stirred at the temperature of 70 to 110 ° C., preferably at 110 ° C., for 1.5 to 3 hours, preferably for 2 hours.
  • the mixture is cooled to 40-80 0 C, advantageously to 70 0 C, the organic solvent is added and with stirring to 0-20 0 C, advantageously on 4- 10 0 C cooled.
  • the product is filtered off, washed with a small amount of the solvent and dried. The drying can be carried out on the air as well as in the usual dryer or vacuum dryer at the temperature up to 35 ° C, advantageously at room temperature.
  • Second variant of the method according to the invention consists in dissolving the substrate: the left-rotating enantiomer of clopidogrel or the mixture of enantiomers with excess of the left-rotating isomer in the organic solvent and the addition of formic acid or acetic acid in the amount of 0.05 to 3 (advantageously 0, 1 to 1-fold of one mole) based on racemized substrate.
  • the mixture is then heated to the boiling point and kept under these conditions for 10-24 hours, preferably 12 hours. After this time, the whole is cooled to the temperature of 0- 15 0 C, 1-10 hours, advantageously mixed for 1-2 hours at this temperature and the precipitate formed is filtered off.
  • the thus prepared crystalline racemate of methyl ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate is dried under conditions as in the first variant.
  • the process uses concentrated formic acid (99.9%) and concentrated acetic acid (glacial acetic acid) (at least 99%).
  • organic solvent selected from the group of alcohols, for example, methanol, ethanol, n-propanol, isopropanol, butanol; from the group of ketones, for example acetone, isobutyl methyl ketone; from the group of ethers, for example diethyl ether, diisopropyl ether, isobutyl methyl ether, tetrahydrofuran.
  • alcohols for example, methanol, ethanol, n-propanol, isopropanol, butanol
  • ketones for example acetone, isobutyl methyl ketone
  • ethers for example diethyl ether, diisopropyl ether, isobutyl methyl ether, tetrahydrofuran.
  • ethers for example diethyl ether, diisopropyl ether, isobutyl methyl ether, tetrahydrofuran.
  • the most advantageous group are alcohol
  • Crystalline racemate of methyl ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate can be used to prepare the clopidogrel, according to methods known from the prior art Known in the art, for example from EP 281459. Conditions of the analyzes
  • the powder diffractogram was carried out using Rigaku's X-ray powder diffractometer MiniFlex, Cu-Ka radiation and K ⁇ filter.
  • the lamp parameters were determined to be 30 kV and 15 mA.
  • the divergence aperture and the grit shutter were set at 4.2 ° and the reception slit at 0.3 mm.
  • the diffraction radiation was detected by NaI scintillation counter. Scanning ⁇ / 2 ⁇ was performed continuously: 1 ° / min with the step 0.02 ° in the range of 2.0 to 40 ° for 2 ⁇ -angle.
  • the sample was prepared by injecting the preparation into the quartz sample holder.
  • the acidity in the product was determined by titration with the aid of the titration machine 736 GP Titrino from Metrohm.
  • Example 3 160 g (0.5 mol) of the mixture of enantiomers: (-) - (R) -methyl- ⁇ - (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine -5 (4H)) - acetate 70% and the
  • (+) - (S) -methyl- ⁇ - (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) -acetate 30% is added until the consistency, the allows stirring, preheated.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne la forme cristalline de l'acétate racémique de méthyl-α-(2-chlorophényl)-2-(6,7-dihydrothiéno [3,2-c] pyridin-5(4H)), qui présente des pics caractéristiques de diffractogramme X sur poudre (XRPD), indiqués en degrés 2ϑ (± 0,2°ϑ) : 14,1, 16,2, 17,0, 18,6, 19,4, 19,8, 21,0, 25,2, 25,5, 27,3, 32,0. L'invention concerne en outre un procédé de préparation de sa forme. L'invention concerne aussi l'utilisation du racémique cristallin de l'acétate de méthyl-α-(2-chlorophényl)-2-(6, 7-dihydrothiéno[3,2-c]pyridin-5(4H))pour la préparation de l'acétate de (+)-(S)-méthyl-α-(2-chlorophényl)-2-(6,7-dihydrothiéno[3,2-c]pyridin-5(4H)) (clopidogrel) et/ou de ses sels.
PCT/EP2007/060905 2006-10-17 2007-10-12 FORME CRISTALLINE DE L'ACÉTATE RACÉMIQUE DE MÉTHYL-α-(2-CHLOROPHÉNYL)-2-(6,7-DIHYDROTHIÉNO[3,2-C]PYRIDIN-5(4H)), SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION WO2008046792A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP-380849 2006-10-17
PL380849A PL380849A1 (pl) 2006-10-17 2006-10-17 Krystaliczna postać racemicznego -(2-chlorofenylo)-6,7-dihydrotieno[3,2-c]pirydylo-5(4H)-octanu metylu, sposób jej wytwarzania i zastosowanie

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WO2008046792A1 true WO2008046792A1 (fr) 2008-04-24

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059128A2 (fr) * 2001-01-24 2002-08-01 Cadila Healthcare Ltd. Procede de preparation de clopidogrel
WO2003004502A1 (fr) * 2001-07-06 2003-01-16 Brantford Chemicals Inc. Procede de preparation de derives de tetrahydrothieno[3,2-c]pyridine
WO2004013147A1 (fr) * 2002-08-02 2004-02-12 Teva Pharmaceutical Industries Ltd. Racemisation et separation d'enatiomeres de clopidogrel
WO2005104663A2 (fr) * 2004-03-05 2005-11-10 Ipca Laboratories Limited Procede industriel de fabrication de sulfate d'hydrogene de clopidrogrel
WO2006042481A1 (fr) * 2004-10-18 2006-04-27 Zentiva A.S. Procede de fabrication de clopidogrel
WO2006094468A1 (fr) * 2005-03-08 2006-09-14 Zentiva, A.S. PROCEDE DE RACEMISATION DE L’ISOMERE R(-) DE L’ESTER DE METHYLE DE L’ACIDE (2-CHLOROPHENYL)-6,7-DIHYDROTHIENO[3,2-c]PYRIDINE-5(4H)-ACETIQUE

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059128A2 (fr) * 2001-01-24 2002-08-01 Cadila Healthcare Ltd. Procede de preparation de clopidogrel
WO2003004502A1 (fr) * 2001-07-06 2003-01-16 Brantford Chemicals Inc. Procede de preparation de derives de tetrahydrothieno[3,2-c]pyridine
WO2004013147A1 (fr) * 2002-08-02 2004-02-12 Teva Pharmaceutical Industries Ltd. Racemisation et separation d'enatiomeres de clopidogrel
WO2005104663A2 (fr) * 2004-03-05 2005-11-10 Ipca Laboratories Limited Procede industriel de fabrication de sulfate d'hydrogene de clopidrogrel
WO2006042481A1 (fr) * 2004-10-18 2006-04-27 Zentiva A.S. Procede de fabrication de clopidogrel
WO2006094468A1 (fr) * 2005-03-08 2006-09-14 Zentiva, A.S. PROCEDE DE RACEMISATION DE L’ISOMERE R(-) DE L’ESTER DE METHYLE DE L’ACIDE (2-CHLOROPHENYL)-6,7-DIHYDROTHIENO[3,2-c]PYRIDINE-5(4H)-ACETIQUE

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