WO2008110357A1 - Procédé de préparation d'un maléate de flupirtine d'une modification cristalline b - Google Patents

Procédé de préparation d'un maléate de flupirtine d'une modification cristalline b Download PDF

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Publication number
WO2008110357A1
WO2008110357A1 PCT/EP2008/001976 EP2008001976W WO2008110357A1 WO 2008110357 A1 WO2008110357 A1 WO 2008110357A1 EP 2008001976 W EP2008001976 W EP 2008001976W WO 2008110357 A1 WO2008110357 A1 WO 2008110357A1
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WO
WIPO (PCT)
Prior art keywords
crystal modification
flupirtine
flupirtine maleate
maleate
solvent
Prior art date
Application number
PCT/EP2008/001976
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English (en)
Other versions
WO2008110357B1 (fr
Inventor
Han-Joachim Lankau
Norbert Höfgen
Helge Hartenhauer
Kristina Heinecke
Original Assignee
Elbion Gmbh
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Publication date
Application filed by Elbion Gmbh filed Critical Elbion Gmbh
Publication of WO2008110357A1 publication Critical patent/WO2008110357A1/fr
Publication of WO2008110357B1 publication Critical patent/WO2008110357B1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the present invention refers to a method for the production of a flupirtine maleate of the crystal modification B.
  • Flupirtine maleate is 2-amino-3-carbethoxyamino-6-(p-fluoro-benzyl amino)- pyridine-maleate.
  • the compound is available on the market as "KatadoloneTM” and is especially applied as an analgesic.
  • This substance is acylated with chloroformic acid ethyl ester and triethylamine under inert gas, which results in flupirtine base.
  • the catalyst is removed by filtration.
  • a solution of isopropanol and maleic acid is added to the filtrate, whereupon the flupirtine raw maleate precipitates under agitation.
  • the flupirtine raw maleate is converted to the free base.
  • the flupirtine raw base is crystallized from isopropanol and converted into pure flupirtine maleate after purification with charcoal/kieselguhr with an isopropanolic maleic acid solution.
  • pure crystal modification B is obtained when using seed crystals of modification B.
  • a product enriched in modification A ( ⁇ 80% modification A) is obtained without using seed crystals of modification B.
  • WO 98/47872 describes a method for the production of a flupirtine maleate of pure crystal modification A.
  • This product is obtained by processing a raw material which is a mixture of crystal modifications A and B with both crystal modification being present in different ratios. It is indicated that heating of the flupirtine maleate leads to the crystal modification B whereas cooling leads to a mixture of both crystal modification or the crystal modification A. Thus, the document does not describe the production of the pure crystal modification B.
  • the present invention refers to a method of preparing flupirtine maleate of crystal modification B, comprising the steps: (i) providing a flupirtine starting material;
  • step (ii) dissolving the starting material in a solvent or solvent mixture which supports formation of flupirtine maleate of crystal modification B, and (iii) if necessary, converting the dissolved starting material to flupirtine maleate, and (iv) obtaining flupirtine maleate of crystal modification B from the solution of step (ii) or (iii).
  • Flupirtine maleate of crystal modification B can be distinguished from other crystal modifications, e.g. crystal modification A, by X-ray diffraction analysis as described in the examples.
  • crystal modifications A and B may be distinguished by IR spectrometry as described in DE 31 33 519.
  • the method of the present invention refers to the production of pure flupirtine maleate of crystal modification B.
  • the flupirtine maleate of crystal modification B is substantially free from flupirtine maleate of crystal modification A, i.e. the amount of crystal modification A is less than 5% (w/w), more preferably less than 2% (w/w), and most preferably less than 1% (w/w).
  • the flupirtine maleate of crystal modification B is free from detectable amounts of crystal modification A and optionally other crystal modifications.
  • the starting material in step (i) may be any flupirtine maleate material, particularly a flupirtine maleate material, which is not a pure crystal modification B product.
  • the starting material may be flupirtine maleate of crystal modification A, e.g. a pure flupirtine maleate of crystal modification A, or flupirtine maleate in a mixture of crystal modifications A and B 1 particularly a mixture wherein the amount of crystal modification A is at least 10% or 20% (w/w).
  • the starting material may be any other crystal modification or solvate of flupirtine maleate or mixtures thereof.
  • the production of flupirtine maleate is known e.g. from DE 31 33 519 or WO 98/47872, which are herein incorporated by reference.
  • the starting material may be flupirtine base or a different flupirtine salt, preferably flupirtine base.
  • the starting material has to be converted to flupirtine maleate while dissolved.
  • the solvent in step (ii) is a solvent which supports formation of flupirtine maleate of crystal modification B.
  • organic aprotic solvents e.g. hydrocarbons, halogenated hydrocarbons, esters, ethers and ketones or mixtures thereof including mixtures with other solvents.
  • solvents are aromatic hydrocarbons such as toluene, xylene, mesitylene, ic, Qn ⁇ nuu ⁇ esters such as butyl acetate, pentyl acetate and hexyl acetate, or aliphatic ketones such as acetone or methyl ethyl ketone.
  • the solvent preferably comprises at least one organic aprotic solvent as described above in an amount of at least 50% (w/w), at least 70% (w/w), at least 80% (w/w), at least 90% (w/w) or at least 95% (w/w).
  • the remainder of the solvent mixture may be water and/or protic organic solvents such as alcohols, provided that they are not present in an amount which supports formation of flupirtine maleate in crystal modifications different from crystal modification B.
  • the solvent is water or a mixture thereof with other solvents.
  • the solvent comprises at least 50% (w/w), at least 70% (w/w), at least 80% (w/w), at least 90% (w/w) or at least 95%
  • (w/w) water The remainder may be selected from water-miscible organic solvents, e.g. alcohols, provided that they are not present in an amount which supports formation of flupirtine maleate in crystal modifications different from modification B.
  • water-miscible organic solvents e.g. alcohols
  • the amount of flupirtine and solvent may be varied in broad ranges.
  • water preferably 100-500 g flupirtine maleate, e.g. about 300 g flupirtine maleate, are used for 10 I water.
  • the starting material is not flupirtine maleate, it is necessary to convert the dissolved starting material to flupirtine maleate according to step (iii).
  • the starting material is preferably flupirtine base.
  • the conversion to flupirtine maleate preferably comprises adding maleic acid, more preferably a solution of maleic acid in a solvent or solvent mixture, preferably a solvent mixture as described above or a solvent or solvent mixture which together with the solvent or solvent of step (ii) supports formation of flupirtine maleate of crystal modification B.
  • Step (iv) preferably comprises crysiaiiisi ⁇ g ihe flupir'iine maieaie of crystal modification B from the solution.
  • the crystallisation step preferably does not involve the addition of seed crystals to the solution.
  • the crystallisation temperature is preferably from above 5-50 0 C, more preferably about 15-25°C.
  • the resulting crystallised flupirtine maleate may be separated from the solvent, e.g. by filtration, and subsequently dried. Preferably, the drying is carried out under reduced pressure, e.g. at 30-80 0 C.
  • the resulting pure flupirtine maleate of crystal modification B is stable, i.e. it is not converted to crystal modification A even after long storage time.
  • Pure flupirtine maleate of crystal modification B is particularly suitable in pharmaceutical applications.
  • Comparative example 2 5 g flupirtine maleate of the crystal modification A is heated in argon atmosphere in 150 ml butanol under reflux for 10 min. The mixture is then cooled to room temperature under agitation. The substance is filtrated after 2 hours and dried for 2 hours in a vacuum at a temperature of 60 0 C. 4.5 g flupirtine maleate (crystal modifications A and B) are obtained as shown by an X-ray diffractogram (Fig. 2).
  • Comparative example 3 3 g flupirtine raw base in 110 ml isopropanol is diluted with a solution of 1 ,3 g maleic acid in 10 ml isopropanol at 60 0 C, which contains seed crystals of the modification B. The substance is then cooled to 17°C and filtrated. The result is 2.8 g flupirtine maleate (8% crystal modification A and 92% crystal modification B).

Abstract

L'invention concerne un procédé de production d'un maléate de flupirtine de la modification cristalline B.
PCT/EP2008/001976 2007-03-12 2008-03-12 Procédé de préparation d'un maléate de flupirtine d'une modification cristalline b WO2008110357A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US90643007P 2007-03-12 2007-03-12
US60/906,430 2007-03-12

Publications (2)

Publication Number Publication Date
WO2008110357A1 true WO2008110357A1 (fr) 2008-09-18
WO2008110357B1 WO2008110357B1 (fr) 2008-11-13

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PCT/EP2008/001976 WO2008110357A1 (fr) 2007-03-12 2008-03-12 Procédé de préparation d'un maléate de flupirtine d'une modification cristalline b

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WO (1) WO2008110357A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102140077A (zh) * 2010-01-28 2011-08-03 范扶民 氟吡汀a晶型及其制备方法
WO2012004391A1 (fr) 2010-07-09 2012-01-12 K.H.S. Pharma Holding Gmbh Procédé de préparation de maléate de flupirtine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3133519A1 (de) * 1980-09-13 1982-06-09 Degussa Ag, 6000 Frankfurt "2-amino-3-carbethoxyamino-6-(p-fluor-benzylamino)-pyridin-maleat"
WO1998047872A1 (fr) * 1997-04-23 1998-10-29 Asta Medica Aktiengesellschaft Procede de preparation de maleate de flupirtine pur et de sa modification a
WO2008007117A1 (fr) * 2006-07-13 2008-01-17 Pliva Hrvatska D.O.O. Sel et formes polymorphes pharmaceutiquement acceptables du maléate de flupirtine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3133519A1 (de) * 1980-09-13 1982-06-09 Degussa Ag, 6000 Frankfurt "2-amino-3-carbethoxyamino-6-(p-fluor-benzylamino)-pyridin-maleat"
WO1998047872A1 (fr) * 1997-04-23 1998-10-29 Asta Medica Aktiengesellschaft Procede de preparation de maleate de flupirtine pur et de sa modification a
WO2008007117A1 (fr) * 2006-07-13 2008-01-17 Pliva Hrvatska D.O.O. Sel et formes polymorphes pharmaceutiquement acceptables du maléate de flupirtine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHOI, YONG M. ET AL: "A nine-step synthesis of [14C]flupirtine maleate labeled in the pyridine ring", JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS , 24(1), 1-14 CODEN: JLCRD4; ISSN: 0362-4803, 1987, XP002485789 *
SCHWOCH S ET AL: "2,3-DIHYDROSPIROÚ1H-4- AND 5-AZABENZIMIDAZOLE-2.1'-CYCLOHEXANE 3/4 (= SPIROÚCYCLOHEXANE-1,2'(3'H)-1'H-IMIDAZOÚ4,5-B 3/4 PYRIDINE 3/4 AND SPIROÚCYCLOHEXANE-1,2'(3'H)-1'H-IMIDAZOÚ4,5-C 3/4 PYRIDINE 3/4 ): REACTIONS WITH NUCLEOPHILES", HELVETICA CHIMICA ACTA, VERLAG HELVETICA CHIMICA ACTA. BASEL, CH, vol. 77, no. 8, 1 January 1994 (1994-01-01), pages 2175 - 2190, XP002073789, ISSN: 0018-019X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102140077A (zh) * 2010-01-28 2011-08-03 范扶民 氟吡汀a晶型及其制备方法
WO2012004391A1 (fr) 2010-07-09 2012-01-12 K.H.S. Pharma Holding Gmbh Procédé de préparation de maléate de flupirtine

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