WO2012004391A1 - Procédé de préparation de maléate de flupirtine - Google Patents

Procédé de préparation de maléate de flupirtine Download PDF

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Publication number
WO2012004391A1
WO2012004391A1 PCT/EP2011/061650 EP2011061650W WO2012004391A1 WO 2012004391 A1 WO2012004391 A1 WO 2012004391A1 EP 2011061650 W EP2011061650 W EP 2011061650W WO 2012004391 A1 WO2012004391 A1 WO 2012004391A1
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water
solvent
temperature
flupirtine
polymorph
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PCT/EP2011/061650
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English (en)
Inventor
Stephen John Martin
Alasdair Garnett
Janis Jaunbergs
Olga Vasiluka
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K.H.S. Pharma Holding Gmbh
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Publication of WO2012004391A1 publication Critical patent/WO2012004391A1/fr

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    • 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 relates to a process for the preparation of flupirtine maleate.
  • Flupirtine i.e., ethyl ⁇ 2-amino-6-[(4-fluorobenzyl)amino]pyridin-3-yl ⁇ carbamate of the following formula, is a centrally acting, non-opioid, nonsteroidal anti-inflammatory analgesic.
  • Flupirtine especially in the form of its maleic acid salt (mainly sold under the trade names Katadolon® and Trancolong®), has been used for many years in the therapy of pain, such as neuralgias, pain associated with degenerative joint diseases, headaches and postoperative pain. Furthermore, there are reports of the usefulness of flupirtine in the treatment of diseases not related to pain, such as batten disease, tinnitus, diseases which are associated with damage to the hematopoietic cell system, dysfunction of the lower urinary tract, and dystonia.
  • diseases not related to pain such as batten disease, tinnitus, diseases which are associated with damage to the hematopoietic cell system, dysfunction of the lower urinary tract, and dystonia.
  • flupirtine maleate shows polymorphism, i.e., it exists in different polymorphic forms (cf, e.g., DE 31 33 519 C2, WO 2008/007117, WO 2008/110357, and K.-F. Landgraf et al., Eur. J. Pharm. Biopharm. 1998, 46(3):329-337), such as polymorph A or polymorph B (as described and characterized in DE 31 33 519 C2), or polymorph V, polymorph W, polymorph X, polymorph Y, or polymorph Z (as described and characterized in WO 2008/007117).
  • DE 31 33 519 C2 teaches a sequence of purification steps including converting the crude flupirtine maleate to the free flupirtine base using concentrated NH 3 ; isolating the free flupirtine base; treating with and/or recrystallization in the presence of charcoal to yield purified flupirtine; and adding maleic acid to yield purified flupirtine maleate.
  • EP 0 977 736 suggests a process, wherein the steps of hydrogenation of ANFP to DAFP in the presence of Raney-Ni, acylation with ethyl chloroformate and precipitation of flupirtine with maleic acid are carried out in water-soluble alcohols, in particular isopropanol.
  • pure polymorph A of flupirtine maleate can be obtained by stirring mixtures of polymorphs A and B in isopropanol (the ratio of flupirtine maleate to isopropanol being 1 : 1 to 1 :0.8) at a temperature in the range of -10°C to 60°C for about 2 h to 5 h.
  • the present invention provides a process for the preparation of flupirtine maleate comprising the steps of (i) reacting 2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine (ANFP) with one or more reducing agents to yield 2,3-diamino-6-(4-fluorobenzylamino) pyridine (DAFP); (ii) reacting DAFP with X-C(0)OCH 2 CH 3 , wherein X is a leaving group, to yield ethyl ⁇ 2-amino-6-[(4- fluorobenzyl)amino]pyridin-3-yl ⁇ carbamate (flupirtine); and (iii) reacting flupirtine with maleic acid to yield flupirtine maleate, wherein at least one of steps (i) and (ii) is carried out in an ester solvent and/or an aprotic amide solvent.
  • the ester solvent is selected from the group consisting of acetate esters and carbonate esters. More preferably, the ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, ethyl acetoacetate, triacetin, and propylene carbonate. Most preferably, the ester solvent is ethyl acetate.
  • step (i) may be performed in a solvent selected from the group consisting of an ester solvent, an aprotic amide solvent, and a water- soluble solvent (such water-soluble alcohol (e.g., ethanol) or a water-soluble nitrogen-containing solvent (such as acetonitrile)).
  • the amount of solvent used in step (i) may be 2 to 20 parts by volume (such as 3 to 7 parts by volume, 4 to 6 parts by volume, 4.5 to 5 parts by volume, 7 to 15 parts by volume, 8 to 12 parts by volume, 9 to 10 parts by volume) relative to 1 part by weight of ANFP.
  • the solvent used in step (i) may be (substantially) anhydrous or may contain water (the amount of water present in step (i) may be 2 to 40% by volume, preferably 2 to 20% by volume, more preferably 5 to 15%) by volume, more preferably 8 to 10%> by volume, based on the total volume of the ester solvent, aprotic amide solvent and water-soluble solvent used in step (i)).
  • step (i) may be performed by using a redox catalyst.
  • the redox catalyst comprises a metal selected from the group consisting of the transition metals of the 8 th to 10 th groups of the periodic table of the elements. More preferably, the redox catalyst comprises a metal selected from the group consisting of Pt, Pd, Ni, Ir, Rh, and Ru. Even more preferably, the redox catalyst is selected from the group consisting of Pd/C, Pearlman's catalyst, Adam's catalyst, Pt/C, and Raney-Ni. Most preferably, the redox catalyst is Pd/C.
  • the redox catalyst may be used in an amount of 0.1 to 20% by weight, preferably 0.5 to 15%> by weight, more preferably, 1.0 to 10%) by weight, more preferably 1.5 to 7% by weight, more preferably 2.0 to 6% by weight, more preferably 2.5 to 5%> by weight, more preferably 3.0 to 4.5% by weight, based on the amount of ANFP.
  • step (i) may be performed in absence of one (two, three, four) or more of the redox catalysts specified above.
  • step (i) is performed in absence of one (two, three, four) or more of the redox catalysts selected from group consisting Raney-Ni, Pd/C, Pearlman's catalyst, Adam's catalyst, and Pt/C, such as in the absence of Raney-Ni and/or Pd/C.
  • step (i) is performed in absence of any redox catalyst.
  • the one or more reducing agents may be selected from the group consisting of hydrogen; metals, preferably base metals (such as Fe, Zn, Sn, or Sm); metal hydrides (such as lithium aluminum hydride (LiAlH 4 ) or diisobutylaluminum); reducing metal compounds (such as SnC3 ⁇ 4 or FeC3 ⁇ 4); reducing boron compounds (such as diborane, decaborane, 9-borabicyclononane or sodium borohydride (NaBH 4 )); reducing carbon compounds (such as formic acids and salts thereof); reducing silicon compounds (such as polymethylhydrosiloxane or triethylsilane); reducing sulfur compounds (such as dithionite); and reducing nitrogen compounds (such as hydrazine).
  • metals preferably base metals (such as Fe, Zn, Sn, or Sm); metal hydrides (such as lithium aluminum hydride (LiAlH 4 ) or diisobuty
  • the one or more reducing agents comprise hydrogen or dithionite.
  • the one or more reducing agents comprise hydrogen, in particular if step (i) is performed by using a redox catalyst.
  • the solvent used in step (i) is preferably an ester solvent or an aprotic amide solvent.
  • the one or more reducing agents comprise dithionite, in particular if step (i) is performed in absence of one or more of the redox catalysts specified above or in absence of any redox catalyst.
  • the solvent used in step (i) is preferably a water-soluble solvent, such as a water-soluble alcohol (e.g., ethanol) or a water-soluble nitrogen-containing solvent (e.g., acetonitrile).
  • step (i) may be performed by using a phase transfer catalyst.
  • step (i) may be performed at a temperature of from 20°C to 80°C.
  • the lower limit of the temperature range for performing step (i) may be 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 3 PC, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, or 39°C.
  • the upper limit of the temperature range for performing step (i) may be 70°C, preferably 60°C, more preferably 50°C, even more preferably 45°C, 44°C, 43°C, 42°C, 41°C, or 40°C.
  • a preferred temperature range for performing step (i) is 20°C to 30°C, in particular if in step (i) a redox catalyst is present. Another preferred temperature range is 30°C to 50°C, in particular if step (i) is performed in absence of one or more of the redox catalysts specified above or in absence of any redox catalyst.
  • step (i) may be performed for a period of time in the range of 0.5 to 36 h, preferably 1 to 24 h, more preferably 1.5 to 12 h, more preferably 2 to 6 h, more preferably 3 to 5 h.
  • step (i) may be performed until the reaction is substantially complete, i.e., until substantially the entire initial amount of ANFP is consumed.
  • the temperature can be raised continuously to the desired value or it can be raised gradually (i.e., in two or more steps).
  • the reaction mixture of step (i) may be continuously heated to any one of the above temperatures or temperature ranges (e.g., 30°C to 40°C, such as 34°C to 37°C (preferably 34°C to 36°C or 36°C to 37°C) or 40°C to 50°C, such as 44°C to 47°C) over a period of time (e.g., 30 min to 2 h, such as 50 min to 70 min, preferably 55 min to 60 min) and then the temperature or temperature range may be maintained for a period of time (e.g., 5 min to 1 h, such as 10 min to 45 min, preferably 15 min to 30 min).
  • a period of time e.g., 30 min to 40°C, such as 34°C to 37°C (preferably 34°C to 36°C or 36°C to 37°C) or 40°C to 50°C, such as 44°C to 47°C
  • a period of time e.g., 30 min to 2 h, such as 50 min to 70
  • the reaction mixture of step (i) may be incubated at any one of the above temperatures or temperature ranges (e.g., 30°C to 40°C, such as 34°C to 37°C, preferably 34°C to 36°C or 36°C to 37°C) for a period of time (e.g., 30 min to 2 h, such as 50 min to 70 min, preferably 55 min to 60 min), and then the reaction mixture of step (i) is heated to a higher temperature or temperature range (e.g., 40°C to 50°C, such as 44°C to 48°C) over a period of time (e.g., 10 min to 1 h, such as 20 min to 45 min, preferably 30 min to 35 min).
  • a higher temperature or temperature range e.g., 40°C to 50°C, such as 44°C to 48°C
  • the reaction mixture is maintained at the higher temperature or temperature range for a period of time (for example, 5 min to 2 h, such as 10 min to 1.5 h, preferably 30 min to 1 h, more preferably 40 min to 50 min).
  • This procedure i.e., heating at a particular temperature or temperature range for a period of time and then raising the temperature or temperature range to a higher temperature or temperature range over a period of time, optionally maintaining the higher temperature or temperature range
  • This procedure i.e., heating at a particular temperature or temperature range for a period of time and then raising the temperature or temperature range to a higher temperature or temperature range over a period of time, optionally maintaining the higher temperature or temperature range
  • step (i) may be cooled to any temperature lower than the highest temperature or temperature range, preferably to the temperature or temperature range at which the next step (e.g., step (a) (see below) or step (ii)) is to be performed.
  • step (i) and before step (ii) may further comprise the step of (a) performing a solvent exchange.
  • the performance of a solvent exchange before step (ii) is particularly preferable for the embodiment of the process of the present invention wherein the solvent used in step (ii) differs from the solvent used in step (i).
  • the solvent exchange may comprise the steps of (al) removing the volatile components (such as the solvent used in step (i) (e.g., ester solvent, aprotic amide solvent, water-soluble solvent), volatile chemical base (e.g., ammonia), etc.) from the reaction mixture of step (i) and (a2) adding to the remaining residue one or more solvents other than the solvent(s) used in step (i).
  • the volatile components to be removed in step (al) may comprise water which may be removed as water or as azeotrope with one or more of the solvents used in step (i).
  • the volatile components comprise only compounds and/or azeotropes having a boiling point (at standard atmospheric pressure) lower than the boiling point of water (at standard atmospheric pressure).
  • the volatile components may be removed by any means known to the skilled person, for example, by distillation, preferably under reduced pressure (such as below standard atmospheric pressure, e.g., below about 100 kPa), preferably below 10 kPa, more preferably below 100 Pa, more preferably below 1 Pa), optionally at elevated temperature (i.e., above 20°C, such as 25°C to 80°C, 30°C to 70°C, 35°C to 65°C, 40°C to 50°C or 60°C to 62°C).
  • reduced pressure such as below standard atmospheric pressure, e.g., below about 100 kPa
  • 10 kPa preferably below 100 Pa
  • elevated temperature i.e., above 20°C, such as 25°C to 80°C, 30°C to 70°C, 35°C to 65°C, 40°C to 50
  • the one or more solvents to be added in step (a2) comprise one or more of the solvents in which step (ii) is to be carried out. More preferably, the one or more solvents to be added in step (a2) are the solvent or mixture of solvents in which step (ii) is to be carried out.
  • the amount of the one or more solvents to be added in step (a2) is not limited and may be adjusted in such a way that the mixture of the one or more solvents to be added in step (a2) and the DAFP obtained in step (i) form one phase.
  • the amount of the one or more solvents to be added in step (a2) is equal to the amount of solvent used in step (ii).
  • step (i) is performed in a water-soluble solvent (such as a water-soluble alcohol (e.g., ethanol) or a water-soluble nitrogen-containing solvent (e.g., acetonitrile)), optionally in the presence of water and/or a chemical base (preferably a volatile chemical base, such as aqueous ammonia), the solvent exchange may comprise the steps of removing the volatile components (such as the water-soluble solvent and, if present, the volatile chemical base) from the reaction mixture and adding to the remaining residue an ester solvent and/or aprotic amide solvent.
  • a water-soluble solvent such as a water-soluble alcohol (e.g., ethanol) or a water-soluble nitrogen-containing solvent (e.g., acetonitrile)
  • a chemical base preferably a volatile chemical base, such as aqueous ammonia
  • Step (a2) may be performed at any suitable conditions, e.g., at standard conditions or at elevated temperature (e.g., 25°C to the reflux temperature of the remaining residue) or reduced temperature (e.g., below 20°C, such as 5°C to 19°C).
  • elevated temperature e.g., 25°C to the reflux temperature of the remaining residue
  • reduced temperature e.g., below 20°C, such as 5°C to 19°C.
  • water can be added to the remaining residue obtained from step (al), in particular if the step of removing the volatile components is performed under stirring.
  • the water can be added before, after or simultaneously with step (a2).
  • the amount of water may be 3 to 7 parts by volume, preferably 4 to 6 parts by volume, more preferably 4.5 to 5 parts by volume, relative to 1 part by weight of ANFP.
  • step (a2) e.g., an ester solvent and/or an aprotic amide solvent, preferably and ester solvent
  • the process of the invention preferably comprises, after step (a2) and before step (ii), the step of (b) separating the water layer from the layer formed by the one or more solvents added in step (a2).
  • step (ii) is performed with the layer formed by the one or more solvents added in step (a2) after the water layer has been removed.
  • step (b) is performed after the temperature of the mixture obtained from step (a2) has been adjusted to the temperature at which step (ii) is to be performed.
  • the leaving group X may be selected from the group consisting of -CI, -Br, -I, and a sulfonyl moiety.
  • the sulfonyl moiety is selected from the group consisting of 4-toluenesulfonyl, 4-bromobenzenesulfonyl, 4- nitrobenzenesulfonyl, 2-nitrobenzenesulfonyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, methylsulfonyl, and fluorosulfonyl.
  • step (ii) the molar ratio between DAFP and X-C(0)OCH 2 CH 3 may be 1 : 1 to 1 :2.1, such as 1 : 1 to 1 :2, preferably 1 : 1 to 1 : 1.8, more preferably, 1 :1.1 to 1 :1.5, more preferably 1 : 1.2 to 1 :1.4.
  • step (ii) may be performed in a solvent selected from the group consisting of an ester solvent, an aprotic amide solvent, and a water- soluble alcohol.
  • the solvent in which step (ii) is to be performed may also be a mixture of any two or more of these solvents (e.g., a mixture of an ester solvent (such as ethyl acetate) and a water-soluble alcohol (such as isopropanol).
  • the amount of solvent used in step (ii) may be 5 to 20 parts by volume, such as 7 to 15 parts per volume, preferably 8 to 12 parts by volume, more preferably 9 to 11 parts by volume, more preferably 10 parts by volume, relative to 1 part by weight of DAFP or ANFP.
  • the solvent used in step (ii) may be (substantially) anhydrous or may contain water (the amount of water present in step (ii) may be 2 to 20% by volume, preferably 5 to 15% by volume, more preferably 8 to 10%) by volume, based on the total volume of the ester solvent, aprotic amide solvent and water- soluble alcohol used in step (ii)).
  • a chemical base may be added in step (ii).
  • the reactants present in step (ii) may be mixed in any possible sequence.
  • DAFP, X-C(0)OCH 2 CH 3 , and a chemical base are mixed simultaneously.
  • a reaction mixture is prepared containing DAFP and X-C(0)OCH 2 CH 3 and after incubation for 5 min to 1 h, preferably 10 to 50 min, more preferably 15 to 45 min, more preferably 30 to 40 min, a chemical base is added to the reaction mixture and then the reaction mixture is preferably incubated for 5 min to 1 h, preferably 10 to 50 min, more preferably 15 to 45 min, more preferably 30 to 40 min.
  • the amount of chemical base added may be 1 :1 to 1 :2.5 molar equivalents, such as 1 :1 to 1 :2.4 or 1 :2.1 molar equivalents, preferably 1 :1 to 1 :2 molar equivalents, more preferably 1 : 1.1 to 1 :1.5 molar equivalents, more preferably 1 : 1.2 to 1 : 1.4 molar equivalents, relative to DAFP.
  • step (ii) may be performed at a temperature of 20°C to 80°C.
  • the lower limit of the temperature range for performing step (ii) may be 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, or 39°C.
  • the upper limit of the temperature range for performing step (i) may be 70°C, preferably 60°C, more preferably 50°C, even more preferably 45°C, 44°C, 43°C, 42°C, 41°C, or 40°C.
  • a preferred temperature range for performing step (ii) is 20°C to 55°C.
  • step (ii) may be performed for a period of time in the range of 5 min to 2 h, preferably 10 min to 1.5 h, more preferably 15 min to 1 h, more preferably 30 to 45 min.
  • the temperature at which step (ii) is performed is maintained over the above mentioned period of time and can be selected from any one of the above temperatures or temperature ranges (e.g., 35°C to 55°C).
  • the temperature at which step (ii) is performed can be varied.
  • step (ii) first DAFP and X-C(0)OCH 2 CH 3 are incubated and then a chemical base is added.
  • DAFP and X-C(0)OCH 2 CH 3 may be first incubated at a first temperature (which may be any one of the above temperatures or temperature ranges, e.g., 20°C to 50°C, such as 45°C to 50°C) for a period of time (e.g., 5 min to 1 h, preferably 10 to 50 min, more preferably 15 to 45 min, more preferably 30 to 40 min), then a chemical base is added and the resulting reaction mixture is incubated at a second temperature, i.e., a temperature or temperature range which is either higher (e.g., 50°C to 55°C) or lower (e.g., 38°C to 45°C) than the first temperature, for a period of time (e.g., 5 min to 1 h, preferably 10 min to 50 min, more preferably 15 min
  • the molar ratio between flupirtine and maleic acid in step (iii) may be 1 :1 to 1 :2, preferably 1 : 1.1 to 1 : 1.9, more preferably 1 : 1.2 to 1.8, even more preferably 1 : 1.5 to 1 : 1.7.
  • maleic acid in step (iii) may be added as solution in water or a water-soluble alcohol.
  • the amount of water or water-soluble alcohol for preparing the maleic acid solution may be 4 to 15 parts by volume (such as 5 to 15 parts by volume, preferably 5.5 to 11.5 parts by volume) relative to 1 part by weight of maleic acid.
  • step (iii) may be performed at a temperature of -10°C to 80°C, preferably -5°C to 70°C, more preferably 0°C to 60°C, more preferably 10°C to 50°C, more preferably 20°C to 40°C, more preferably 25°C to 30°C.
  • a preferred temperature range for performing step (iii) is 35°C to 45°C.
  • step (iii) may be performed for a period of time in the range of 5 to 50 min, preferably 10 to 30 min, more preferably 15 to 20 min.
  • the temperature at which step (iii) is performed is maintained over the above mentioned period of time and can be selected from any one of the above temperatures or temperature ranges (e.g., 15°C to 55°C, such as 50°C to 55°C or 35°C to 45°C). In another embodiment, the temperature at which step (iii) is performed can be varied.
  • flupirtine and maleic acid may be first incubated at a first temperature (which may be any one of the above temperatures or temperature ranges, e.g., 15°C to 55°C, such as 50°C to 55°C or 35°C to 45°C) for a period of time (e.g., 5 min to 1.5 h, preferably 10 min to 70 min, more preferably 15 min to 65 min, more preferably 30 min to 60 min) and then the reaction mixture is cooled (e.g., to a temperature of 15°C to 30°C, such as 15°C to 20°C or 30°C to 40°C) over a period of time (e.g., 10 min to 1.5 h, such as 20 min to 70 min, preferably 30 min to 60 min, more preferably 40 min to 50 min).
  • a first temperature which may be any one of the above temperatures or temperature ranges, e.g., 15°C to 55°C, such as 50°C to 55°C or 35°C to 45°C
  • the process of the present invention may further comprise the step of adding an oxygen scavenger agent in step (ii) and/or step (iii).
  • the amount of oxygen scavenger agent added in step (ii) may be 0.01 to 2.5% by weight, such as 0.01 to 2.1% by weight, preferably 0.01 to 2% by weight, more preferably 0.05 to 1.5% by weight, more preferably 0.1 to 1% by weight, based on the amount of DAFP used in step (ii).
  • the amount of oxygen scavenger agent added in step (iii) may be 0.01 to 2.5% by weight, such as 0.01 to 2.1% by weight, preferably 0.01 to 2% by weight, more preferably 0.05 to 1.5% by weight, more preferably 0.1 to 1% by weight, based on the amount of flupirtine used in step (iii).
  • the process of the present invention may further comprise the step of filtering the reaction mixture after step (i) and before step (ii) and/or after step (ii) and before step (iii).
  • the filtration step is performed at the same temperature at which the following step is performed.
  • a filtration step is performed after step (i) and before step (ii) said filtration step is preferably performed at the temperature at which step (ii) is performed.
  • a filtration step is performed after step (ii) and before step (iii) said filtration step is preferably performed at the temperature at which step (iii) is performed.
  • a redox catalyst is used in step (i) it is preferred to perform a filtration step after step (i) and before step (ii) and/or after step (ii) and before step (iii).
  • degassed solvents in at least step (ii), preferably in at least steps (i) and (ii), more preferably in each of steps (i) to (iii), only degassed solvents may be used.
  • every solvent used in the process of the present invention is a degassed solvent.
  • steps (i) and (ii) may be performed under an atmosphere of an inert gas.
  • each of steps (i) to (iii), more preferably the whole process of the present invention is performed under an inert gas.
  • the inert gas is oxygen-free.
  • the process of the present invention may further comprise the step of isolating the flupirtine maleate.
  • a solvent is used in which flupirtine maleate precipitates under standard conditions.
  • the solvent used in step (iii) is selected from the group consisting of an ester solvent, an aprotic amide solvent, and a water-soluble alcohol.
  • the solvent used in step (iii) may also be a mixture of two or more solvents selected from the group consisting of ester solvents, aprotic amide solvents, and water-soluble alcohols.
  • the solvent used in step (iii) may be (substantially) anhydrous or may contain water.
  • the solvent used in step (iii) is a (substantially) anhydrous mixture of an ester solvent (such as ethyl acetate) and a water-soluble alcohol (such as isopropanol), or a mixture of an ester solvent and water, or a mixture of an ester solvent, a water-soluble alcohol, and water.
  • an ester solvent such as ethyl acetate
  • a water-soluble alcohol such as isopropanol
  • the precipitated flupirtine maleate may be isolated from the reaction mixture by any conventional means, such as filtration, decantation, and/or centrifugation.
  • two or more steps may be performed without isolating and/or purifying the intermediates.
  • the reaction mixture which is obtained from step (i) of the process of the present invention and which preferably comprises (1) the intermediate DAFP, (2) an ester solvent and/or an aprotic amide solvent, and (3) optionally, a redox catalyst may be used directly, i.e., without further isolation and/or purification of the intermediate DAFP, in step (ii).
  • the reaction mixture obtained from step (i) is mixed with X-C(0)OCH 2 CH 3 and optionally, a chemical base.
  • reaction mixture which is obtained from step (ii) and which preferably comprises (1) the intermediate flupirtine, (2) an ester solvent and/or an aprotic amide solvent, and (3) optionally, a water-soluble alcohol and/or water is used directly, i.e., without further isolation and/or purification of the intermediate flupirtine, in step (iii).
  • the process of the present invention comprises the steps of (i) suspending ANFP and a redox catalyst in an ester solvent (the amount of ester solvent may be 8 to 12 parts by volume, preferably 9 to 1 1 parts by volume, more preferably 10 parts by volume, relative to 1 part by weight of ANFP) and reacting ANFP with hydrogen; (ii) adding X-C(0)OCH 2 CH 3 and incubating the resulting reaction mixture, preferably at a temperature as defined above, preferably for a period of time in the range of 5 min to 2 h (more preferably 20 to 40 min); optionally, adding a chemical base to the reaction mixture and incubating the reaction mixture, preferably at a temperature as defined above, preferably for a period of time in the range of 5 min to 2 h (more preferably 20 to 40 min); optionally, adding an oxygen scavenger agent; optionally, adding a water-soluble alcohol (the amount of water-soluble alcohol may be 8 to 12 parts by volume,
  • the process of the present invention comprises the steps of (i) reacting ANFP, a reducing agent (such as a dithionite salt), and a chemical base (such as aqueous ammonia) in an ester solvent
  • the amount of ester solvent may be any of the above-mentioned amounts, such as 8 to 12 parts by volume, preferably 9 to 11 parts by volume, more preferably 10 parts by volume, relative to 1 part by weight of ANFP
  • the total amount of water present in step (i) may be any of the above-mentioned amounts, such as 2 to 20% by volume, preferably 5 to 15% by volume, more preferably 8 to 10% by volume, based on the volume of the ester solvent
  • a phase transfer catalyst optionally, heating the reaction mixture, preferably to a temperature of up to 80°C (such as 40°C to 50°C);
  • adding X- C(0)OCH 2 CH 3 incubating the reaction mixture
  • the process of the present invention comprises the steps of (i) reacting ANFP, a reducing agent (such as a dithionite salt), and a chemical base (preferably a volatile chemical base, such as aqueous ammonia) in a water-soluble solvent (such as a water-soluble alcohol or a water-soluble nitrogen-containing solvent) (the amount of water- soluble alcohol may be 8 to 12 parts by volume, preferably 9 to 11 parts by volume, more preferably 10 parts by volume, relative to 1 part by weight of ANFP), optionally, in the presence of water (the total amount of water present in step (i) may be 2 to 40% by volume, preferably 2 to 20%> by volume, more preferably 5 to 15%> by volume, more preferably 8 to 10%> by volume, based on the volume of the water-soluble alcohol) and/or a phase transfer catalyst; optionally, heating the reaction mixture, preferably to a temperature of up to 80°C (such as 40°C to 50°C); performing a chemical base (preferably a volatile chemical base, such
  • the process of the present invention may further comprise the step of washing flupirtine maleate one or more times with water, a water-soluble ketone (such as acetone), and/or an aqueous solution of a water-soluble alcohol (such as 10% to 50% water in a water-soluble alcohol (preferably isopropanol)), preferably at a temperature of -10°C to 20°C, more preferably 0°C to 10°C.
  • a water-soluble ketone such as acetone
  • an aqueous solution of a water-soluble alcohol such as 10% to 50% water in a water-soluble alcohol (preferably isopropanol)
  • the process of the present invention may further comprise the step of drying the flupirtine maleate, e.g., at a temperature in the range of 20°C to 60°C, preferably, 25°C to 50°C, more preferably, 30°C to 40°C.
  • the drying may be performed under reduced pressure, such as below atmospheric pressure (about 100 kPa), preferably below 10 kPa, more preferably below 100 Pa, more preferably below 1 Pa.
  • the process of the present invention may further comprise the step of converting the flupirtine maleate, either partially or (substantially) completely, into a particular polymorphic form (such as polymorph A, polymorph B, etc.).
  • This conversion step may be performed prior to and/or after the isolation of the flupirtine maleate.
  • this conversion step it is possible to obtain a flupirtine maleate preparation which is either (substantially) pure or enriched with respect to one particular polymorphic form.
  • a flupirtine maleate preparation which is either (substantially) pure or enriched with respect to polymorph B, may be obtained by the following steps (after step (iii) of the process of the present invention): heating the reaction mixture obtained from step (iii) to a temperature of 55°C to 75°C, preferably 60°C to 70°C, most preferably 61°C to 65°C, to dissolve the flupirtine maleate; cooling the reaction mixture to a temperature of -10°C to 20°C, more preferably -5°C to 15°C, most preferably 0°C to 5°C (e.g., over a period of time of 5 min to 30 min, preferably 10 min to 15 min); filtering off the crystals; optionally, washing the crystals one or more times with a water-soluble ketone (such as acetone) or an aqueous solution of a water-soluble alcohol (such as 10% to 50% water in a water-soluble alcohol
  • a flupirtine maleate preparation which is either (substantially) pure or enriched with respect to polymorph B, may be obtained by the following steps: mixing flupirtine maleate with a water-soluble alcohol (such as isopropanol) and water (the ratio of water-soluble alcohol to water may be 50:50 to 90:10, preferably 60:40 to 80:20, more preferably 65:35 to 75:25, more preferably 70:30 (vol/vol or wt/wt); the total amount of water-soluble alcohol and water may be 10 to 20 parts per weight, preferably 12 to 18 parts per weight, more preferably 15 parts per weight, based on 1 part by weight of flupirtine maleate); heating the reaction mixture to a temperature of 55°C to 75°C, preferably 60°C to 70°C, most preferably 61°C to 65°C, to dissolve the flupirtine maleate; cooling the reaction mixture to a temperature of -10°C to 20°C, more preferably
  • flupirtine maleate may be heated without solvent to a temperature of 40°C to 180°C, preferably 80°C to 150°C, more preferably 80°C to 130°C.
  • the heating step is repeated one or more times.
  • step (i), step (ii), and/or step (iii) may be performed under stirring.
  • ANFP may be prepared by reacting 2-amino-6-chloro-3-nitropyridine (ACNP) with 4-fluorobenzylamine.
  • the reaction of ACNP with 4-fluorobenzylamine may be carried out in an ester solvent, an aprotic amide solvent, a water soluble-alcohol, or a mixture of two or more of these liquids.
  • a chemical base such as an organic amine
  • flupirtine maleate refers to any polymorphic form of said compound (such as polymorph A or polymorph B, as described and characterized in DE 31 33 519 C2, or polymorph V, polymorph W, polymorph X, polymorph Y, or polymorph Z, as described and characterized in WO 2008/007117) and any polymorphic form of its tautomers and isomers (i.e., the fumarate).
  • flupirtine maleate may be prepared as (substantially) pure polymorphic form (such as (substantially) pure polymorph A, B, V, W, X, Y, or Z), preferably as (substantially) pure polymorph B.
  • flupirtine maleate may be prepared as any mixture of two or more (such as 3, 4, 5, 6, 7, 8, 9, or 10 or more) of the above polymorphic forms (such as a mixture of polymorph B with one or more polymorphs other than polymorph B), wherein the proportion of any of the two or more polymorphic forms present in said mixture relative to the total amount of flupirtine maleate present in said mixture may have any value as long as the sum of all proportions of said two or more polymorphic forms present in said mixture is 100%.
  • the proportion x ; for each of the two polymorphic forms may be between 0.001 to 99.999% (e.g., 0.01 to 99.99%, such as 0.1 to 99.9%, 1 to 99%, 5 to 95%, 10 to 90%, 15 to 85%, 20 to 80%, 25 to 75%, 30 to 70%), 35 to 65%), 40 to 60%, 45 to 55%, or 50%) as long as the sum of the proportions x A and x B is 100%).
  • the process of the present invention may comprise the step of converting the flupirtine maleate, either partially or (substantially) completely, into a particular polymorphic form (such as polymorph A, polymorph B, etc.), wherein said conversion step may be performed prior to and/or after the isolation of flupirtine maleate.
  • a particular polymorphic form such as polymorph A, polymorph B, etc.
  • a particular polymorphic form of flupirtine maleate e.g., a polymorphic form which can be easily separated from the reaction mixture obtained in step (iii) and/or which can be obtained in higher yield and/or purity from the reaction mixture obtained in step (iii) (such as polymorph B) compared to other polymorphic forms of flupirtine maleate
  • a flupirtine maleate preparation which is either (substantially) pure or enriched with respect to the desired polymorphic form.
  • stirring mixtures of polymorphs A and B (the amount of polymorph A being at most 40%) in an organic solvent (such as isopropanol) at a temperature in the range of -10°C to 70°C for about 20 min to 5 h is sufficient to obtain flupirtine maleate preparations containing polymorph A in an amount of 60% to 90% (cf. DE 31 33 519 C2) or even 100%) (pure polymorph A; cf. EP 0 977 736).
  • polymorph A may also be obtained by reacting flupirtine with maleic acid in presence of crystals of pure flupirtine maleate polymorph A.
  • a solution of flupirtine maleate is obtained as taught in EP 0 977 736 and DE 31 33 519 C2 (i.e., by hydrogenating ANFP in the presence of a redox catalyst to yield DAFP; reacting DAFP with ethyl chloroformate to yield flupirtine; and reacting flupirtine with maleic acid in presence of crystals of pure flupirtine maleate polymorph A)
  • the resulting flupirtine maleate crystals mainly consist of polymorph A but also contain an impurity (ethyl (2,6-diaminopyridin-3-yl) carbamate maleate) which may be present in significant amounts (up to 28%) depending on the particular reaction conditions used to prepare flupirtine) and which cannot be removed from the flupirtine maleate crystals by washing or stirring a slurry of the flupir
  • a flupirtine maleate preparation which is (substantially) pure with respect to polymorph A, i.e., whose total amount of impurities (in particular, ethyl (2,6-diaminopyridin-3-yl) carbamate maleate and/or polymorphic forms other than polymorphic form B) is less than 1%, may be prepared by crystallizing flupirtine maleate as polymorph B; converting polymorph B into polymorph A; and optionally, washing polymorph A.
  • a flupirtine maleate preparation which is either (substantially) pure or enriched with respect to polymorph A, may be obtained by the following steps: providing flupirtine maleate as polymorph B (such as specified above); mixing the flupirtine maleate with a water-soluble alcohol (such as isopropanol) and water (the ratio of water-soluble alcohol to water may be 50:50 to 90: 10, preferably 60:40 to 80:20, more preferably 65:35 to 75:25, more preferably 70:30 (vol/vol or wt/wt); the total amount of water-soluble alcohol and water may be 10 to 20 parts per weight, preferably 12 to 18 parts per weight, more preferably 15 parts per weight, based on 1 part by weight of flupirtine maleate); heating the reaction mixture to a temperature of 55°C to 75°C, preferably 60°C to 70°C, most preferably 61°C to 65°C, to dissolve the flupirtine maleate; cooling the reaction mixture to a temperature of -10°C to 20°C, more
  • the above steps starting from the step of mixing flupirtine maleate with a water-soluble alcohol and water to the step of drying the crystals are repeated one or more times.
  • the flupirtine maleate to be provided may be prepared by any of the modes and embodiments described above for the process of the present invention.
  • One embodiment of the process of the present invention is illustrated in Figure 2.
  • Polymorphism as referred to herein means that a solid material (such as a compound) is able to exist in more than one form or crystalline structure, i.e., "polymorphic modifications” or “polymorphic forms".
  • polymorphic modifications or “polymorphic forms”.
  • polymorphic forms are used interchangeable in the present invention. According to the present invention, these "polymorphic modifications” include crystalline forms, amorphous forms, solvates, and hydrates.
  • solvent effects the packing of crystal may be different in polar and nonpolar solvents
  • Polymorphic forms may have different chemical, physical, and/or pharmacological properties, including but not limited to, melting point, X-ray crystal and diffraction pattern, chemical reactivity, solubility, dissolution rate, vapor pressure, density, hygroscopicity, flowability, stability, compactability, and bioavailability. Polymorphic forms may spontaneously convert from a metastable form (unstable form) to the stable form at a particular temperature. According to Ostwald's rule, in general it is not the most stable but the least stable polymorph that crystallizes first. Thus, quality, efficacy, safety, processability and/or manufacture of a chemical compound, such as flupirtine maleate, can be affected by polymorphism.
  • a chemical compound such as flupirtine maleate
  • the most stable polymorph of a compound (such as flupirtine maleate) is chosen due to the minimal potential for conversion to another polymorph.
  • a polymorphic form which is not the most stable polymorphic form may be chosen due to reasons other than stability, e.g. solubility, dissolution rate, and/or bioavailability.
  • crystal form of a material as used herein means that the smallest components (i.e., atoms, molecule or ions) of said material form crystal structures.
  • a "crystal structure” as referred to herein means a unique three-dimensional arrangement of atoms or molecules in a crystalline liquid or solid and is characterized by a pattern, a set of atoms arranged in a particular manner, and a lattice exhibiting long-range order and symmetry.
  • a lattice is an array of points repeating periodically in three dimensions and patterns are located upon the points of a lattice. The subunit of the lattice is the unit cell.
  • the lattice parameters are the lengths of the edges of a unit cell and the angles between them.
  • the symmetry properties of the crystal are embodied in its space group. In order to describe a crystal structure the following parameters are required: chemical formula, lattice parameters, space group, the coordinates of the atoms and occupation number of the point positions.
  • amorphous form of a material as used herein means that the smallest components (i.e., atoms, molecule or ions) of said material are not arranged in a lattice but are arranged randomly. Thus, unlike crystals in which a short-range order (constant distances to the next neighbor atoms) and a long- range order (periodical repetition of a basic lattice) exist, only a short-range order exists in an amorphous form.
  • solvate refers to an addition complex of a dissolved material in a solvent (such as an ester solvent, an aprotic amide solvent, a water-soluble alcohol, water or a mixture of two or more of these liquids), wherein the addition complex exists in the form of a crystal or mixed crystal.
  • a solvent such as an ester solvent, an aprotic amide solvent, a water-soluble alcohol, water or a mixture of two or more of these liquids
  • the amount of solvent contained in the addition complex may be stoichiometric or non-stoichiometric.
  • a “hydrate” is a solvate wherein the solvent is water.
  • Methods for the characterization of polymorphs of a material are known to the skilled person (cf, e.g., DE 31 33 519 C2, WO 2008/007117, and K.-F. Landgraf et al., Eur. J. Pharm. Biopharm. 1998, 46(3):329-37) and include, but are not limited to, X-ray diffraction, in particular single crystal X-ray diffraction, powder X-ray diffraction, thermal analysis (such as differential scanning calorimetry (DSC), hot-stage microscopy, and thermal gravimetric analysis), and several spectrometry methods (such as solid state nuclear magnetic resonance (ssNMR), infrared and near red, and Raman).
  • X-ray diffraction in particular single crystal X-ray diffraction
  • powder X-ray diffraction such as differential scanning calorimetry (DSC), hot-stage microscopy, and thermal gravimetric analysis
  • spectrometry methods such as solid state nuclear
  • ester solvent refers to any solvent containing at least one ester group.
  • ester solvent does not include ester solvents which are miscible with water in any ratio at a temperature of about 20°C.
  • the ester solvent is one which is miscible with water in a ratio of 1 to 32 parts by weight of ester solvent relative to 100 parts by weight of water at a temperature of about 20°C.
  • the ester solvent is one which is miscible with water in a ratio of 2 to 24 parts by weight of ester solvent relative to 100 parts by weight of water at a temperature of about 20°C.
  • the ester solvent is one which is miscible with water in a ratio of 3 to 12 parts by weight of ester solvent relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the ester solvent is one which is miscible with water in a ratio of 4 to 9 parts by weight of ester solvent relative to 100 parts by weight of water at a temperature of about 20°C.
  • the ester solvent is an ester which can be considered as derived from the reaction of an aliphatic carboxylic acid with an aliphatic alcohol (although the actual preparation of said ester solvent may require compounds which are not an aliphatic carboxylic acid and/or an aliphatic alcohol).
  • the aliphatic carboxylic acid is a linear, branched or cyclic carboxylic acid.
  • the aliphatic carboxylic acid has a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms and has at least one carboxylic acid group, preferably at least 2 carboxylic acid groups, wherein the maximum number of carboxylic acid groups may be the half of the total number of carbon atoms in the aliphatic carboxylic acid, rounded down to the next integer if the half is not an integer (for example, 4 carbon atoms 2 carboxylic acid groups; 5 or 6 carbon atoms 3 carboxylic acid groups; 7 or 8 carbon atoms -> 4 carboxylic acid groups; etc).
  • the aliphatic carboxylic acid may contain one or more additional functional groups (such as CN, keto, amide groups) in addition to the one or more carboxylic acid groups as long as said one or more additional functional groups are (substantially) inert with respect to the reactants used in the process of the present invention (i.e., said one or more additional functional groups do not chemically react / do not form covalent bonds with the reactants used in the process of the present invention).
  • the aliphatic carboxylic acid does not contain carbon-carbon double or triple bounds.
  • the aliphatic carboxylic acid contains only hydrogen and carbon atoms.
  • Preferred aliphatic carboxylic acids are those having 1, 2, 3, 4, 5, or 6 carbons atoms and 1, 2, or 3 carboxylic acid groups, such as formic acid, acetic acid, acetoacetic acid, propionic acid (or its 2- isomer), butanoic acid (or its 2-isomer), oxalic acid, malonic acid, cyanoacetic acid, succinic acid, succinamic acid, and propane-l,2,3-tricarboxylic acid.
  • a particularly preferred aliphatic carboxylic acid is acetic acid.
  • ester solvents are acetate ester solvents.
  • the aliphatic alcohol is a linear, branched or cyclic alcohol, which may have 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms and which has at least one OH group, preferably at least 2 OH groups, wherein the maximum number of OH groups may be the half of the total number of carbon atoms in the aliphatic alcohol, rounded down to the next integer if the half is not an integer (for example, 4 carbon atoms -> 2 OH groups; 5 or 6 carbon atoms -> 3 OH groups; 7 or 8 carbon atoms 4 OH groups; etc).
  • the aliphatic alcohol may contain one or more additional functional groups (such as CN, keto, amide groups) in addition to the one or more alcohol groups as long as said one or more additional functional groups are (substantially) inert with respect to the reactants used in the process of the present invention (i.e., said one or more additional functional groups do not chemically react / do not form covalent bonds with the reactants used in the process of the present invention).
  • the aliphatic alcohol does not contain carbon-carbon double or triple bounds.
  • the aliphatic alcohol contains only hydrogen and carbon atoms.
  • Preferred aliphatic alcohols are those having 1, 2, 3, 4, 5, or 6 carbons atoms and 1, 2, or 3 OH groups, such as methanol, ethanol, n-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, glycol, 1,2- propanediol, 1,3 -propanediol, and glycerol.
  • the ester solvent is a carbonate ester.
  • carbonate ester as used herein can be considered as derived from the reaction of carbonic acid with an aliphatic alcohol (although the actual preparation of said carbonate ester solvent may require compounds which are not carbonic acid and/or an aliphatic alcohol).
  • the aliphatic alcohol is as defined above.
  • Preferred aliphatic alcohols are those having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 carbon atoms and at least 2 OH groups. Specific examples include glycol, 1 ,2-propanediol, 1,3 -propanediol, and glycerol.
  • Preferred ester solvents include acetate esters and carbonate esters.
  • ester solvents include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl acetoacetate, triacetin, and propylene carbonate.
  • an aprotic amide solvent may be used in the process of the present invention.
  • the term "amide solvent” as used herein refers to any solvent containing at least one amide group.
  • the term "amide solvent” does not include amide solvents which are miscible with water in any ratio at a temperature of about 20°C.
  • the amide solvent is one which is miscible with water in a ratio of 1 to 32 parts by weight of amide solvent relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the amide solvent is one which is miscible with water in a ratio of 2 to 24 parts by weight of amide solvent relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the amide solvent is one which is miscible with water in a ratio of 3 to 12 parts by weight of amide solvent relative to 100 parts by weight of water at a temperature of about 20°C.
  • the amide solvent is one which is miscible with water in a ratio of 4 to 9 parts by weight of amide solvent relative to 100 parts by weight of water at a temperature of about 20°C.
  • the aprotic amide solvent is an amide which can be considered as derived from the reaction of an aliphatic carboxylic acid with an aliphatic amine (although the actual preparation of said amide solvent may require compounds which are not an aliphatic carboxylic acid and/or an aliphatic amine).
  • the aliphatic carboxylic acid may be as defined above for the ester solvent.
  • the aliphatic amine is a linear, branched or cyclic amine which may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms and which has at least one primary or secondary amine group, preferably at least 2 primary or secondary amine groups, wherein the maximum number of primary or secondary amine groups may be the half of the total number of carbon atoms in the aliphatic amine, rounded down to the next integer if the half is not an integer (for example, 4 carbon atoms 2 primary or secondary amine groups; 5 or 6 carbon atoms 3 primary or secondary amine groups; 7 or 8 carbon atoms 4 primary or secondary amine groups; etc).
  • the aliphatic amine may contain one or more additional functional groups (such as CN, keto, ester, tertiary amine groups) in addition to the one or more primary or secondary amine groups as long as said one or more additional functional groups are (substantially) inert with respect to the reactants used in the process of the present invention (i.e., said one or more additional functional groups do not chemically react / do not form covalent bonds with the reactants used in the process of the present invention).
  • the aliphatic amine does not contain carbon-carbon double or triple bounds.
  • the aliphatic amine contains only hydrogen and carbon atoms.
  • Preferred aliphatic amines are those having 1, 2, 3, 4, 5, or 6 carbons atoms and 1, 2, or 3 primary or secondary groups, such as methylamine, ethylamine, n-propylamine, 2-propylamine, 1 -butylamine, 2-butylamine, tert-butylamine, 1 ,2-diaminopropane, 1,3- diaminopropane, and 1,2,3-triaminopropane.
  • the aprotic amide solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, and N-methyl-2-pyrrolidone.
  • water-soluble solvent refers to any solvent which is a liquid under standard conditions and is miscible with water at a temperature of about 20°C.
  • water- soluble solvent does not include solvents which are only slightly miscible with water at a temperature of about 20°C, i.e., which are miscible with water in a ratio of not more 32 parts by weight of solvent relative to 100 parts by weight of water at a temperature of about 20°C.
  • the water- soluble solvent is one which is miscible with water in a ratio of at least about 50 parts by weight of water-soluble solvent relative to 100 parts by weight of water at a temperature of about 20°C.
  • the water-soluble solvent is one which is miscible with water in a ratio of at least about 75 parts by weight of water-soluble solvent relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the water-soluble solvent is one which is miscible with water in a ratio of at least about 100 parts by weight of water-soluble solvent relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the water-soluble solvent is one which is miscible with water in any ratio at a temperature of about 20°C.
  • Preferred water-soluble solvents include water-soluble alcohols and water-soluble nitrogen-containing solvents.
  • water-soluble alcohol refers to any alcohol which has at least one OH group, is a liquid under standard conditions and is miscible with water at a temperature of about 20°C.
  • water-soluble alcohol does not include alcohols which are only slightly miscible with water at a temperature of about 20°C, i.e., which are miscible with water in a ratio of not more 32 parts by weight of alcohol relative to 100 parts by weight of water at a temperature of about 20°C.
  • the water-soluble alcohol is one which is miscible with water in a ratio of at least about 50 parts by weight of water-soluble alcohol relative to 100 parts by weight of water at a temperature of about 20°C.
  • the water-soluble alcohol is one which is miscible with water in a ratio of at least about 75 parts by weight of water-soluble alcohol relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the water-soluble alcohol is one which is miscible with water in a ratio of at least about 100 parts by weight of water-soluble alcohol relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the water-soluble alcohol is one which is miscible with water in any ratio at a temperature of about 20°C.
  • Particularly preferred water-soluble alcohols include methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, glycol, 1 ,2-propanediol, 1,3-propanediol 1 ,2-butanediol, 1,3-butanediol, and glycerol.
  • water-soluble nitrogen-containing solvent refers to any solvent which contains at least one nitrogen atom, is a liquid under standard conditions and is miscible with water at a temperature of about 20°C.
  • water-soluble nitrogen-containing solvent does not include nitrogen-containing solvents which are only slightly miscible with water at a temperature of about 20°C, i.e., which are miscible with water in a ratio of not more 32 parts by weight of nitrogen-containing solvent relative to 100 parts by weight of water at a temperature of about 20°C.
  • the water-soluble nitrogen-containing solvent is one which is miscible with water in a ratio of at least about 50 parts by weight of water-soluble nitrogen-containing solvent relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the water-soluble nitrogen-containing solvent is one which is miscible with water in a ratio of at least about 75 parts by weight of water-soluble nitrogen-containing solvent relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the water-soluble nitrogen-containing solvent is one which is miscible with water in a ratio of at least about 100 parts by weight of water-soluble nitrogen- containing solvent relative to 100 parts by weight of water at a temperature of about 20°C.
  • the water-soluble nitrogen-containing solvent is one which is miscible with water in any ratio at a temperature of about 20°C.
  • Particularly preferred water-soluble nitrogen-containing solvent include acetonitrile, dimethylformamide, dimethylacetamide, pyridine, piperidine, and N-methyl-2- pyrrolidone.
  • water-soluble ketone refers to any compound which contains a keto group, is a liquid under standard conditions and is miscible with water at a temperature of about 20°C.
  • water-soluble ketone does not include liquid ketones which are only slightly miscible with water at a temperature of about 20°C, i.e., which are miscible with water in a ratio of not more 32 parts by weight of liquid ketone relative to 100 parts by weight of water at a temperature of about 20°C.
  • the water-soluble ketone is one which is miscible with water in a ratio of at least about 50 parts by weight of water-soluble ketone relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the water-soluble ketone is one which is miscible with water in a ratio of at least about 75 parts by weight of water-soluble ketone relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the water-soluble ketone is one which is miscible with water in a ratio of at least about 100 parts by weight of water- soluble ketone relative to 100 parts by weight of water at a temperature of about 20°C. In one embodiment, the water-soluble ketone is one which is miscible with water in any ratio at a temperature of about 20°C. A particularly preferred water-soluble ketone is acetone.
  • reaction refers to a substance or compound that is added to a system in order to bring about a chemical reaction (i.e., a "reactant") or is added to see if a reaction occurs.
  • a "reactant” is a substance that is consumed in the course of a chemical reaction.
  • solvents and catalysts although they are involved in the reaction, are not referred to as reactants in the present invention.
  • leaving group refers to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
  • the ability of a leaving group to depart is generally correlated with the pKa of the conjugate acid, with lower pKa being associated with better leaving group ability. Since leaving group ability is a kinetic phenomenon, relating to a reaction's rate, whereas pKa is a thermodynamic phenomenon, describing the position of an equilibrium, the correlation is not perfect. However, it is a general rule that more highly stabilized anions act as better leaving groups.
  • Preferred leaving groups are halogens (i.e., -CI, -Br, or -I) and sulfonyl moieties.
  • Preferred sulfonyl moieties have the formula -OS(0)2R, wherein R is F, CI, alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, perfluorinated alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms (such as CF 3 or nonafluorobutyl), or aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of halogens (F, CI, Br, I), alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, and nitro.
  • R is F, CI, alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, perfluorinated alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms (such as CF 3 or nonafluorobutyl), or aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of halogens (F, CI, Br, I), alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms,
  • Exemplary leaving groups include -CI, -Br, -I, 4-toluenesulfonyl, 4-bromobenzenesulfonyl, 4-nitrobenzenesulfonyl, 2-nitrobenzenesulfonyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, methylsulfonyl, and fluorosulfonyl.
  • a "catalyst” as used herein refers to a substance which catalyzes a chemical reaction, e.g., increases the rate of a chemical reaction by lowering the activation energy, but which, unlike other reactants that participate in the chemical reaction, is not consumed by the reaction itself.
  • a catalyst may participate in multiple chemical reactions, such as a redox reaction.
  • the catalyst does not comprise a carrier material, e.g., each component of the catalyst is catalytically active (such as bare metal).
  • the catalyst comprises one or more catalytically active components and a carrier material.
  • a "carrier material" as used in the context of catalysts refers to neutral material used to support a catalyst.
  • Exemplary carrier materials include carbon, activated carbon, charcoal, aluminum oxides (such as alumina and activated alumina), pumice, magnesia, zirconia, kieselguhr or diatomaceous earth, fuller's earth, silicon carbide, or a mixture of two or more of carrier materials.
  • the content of catalytically active component(s) in the catalyst may be 0.1 to 20% by weight, preferably 0.5 to 15%> by weight, more preferably, 1.0 to 10%> by weight, more preferably 1.5 to 7%> by weight, more preferably 2.0 to 6%> by weight, more preferably 2.5 to 5%> by weight, more preferably 3.0 to 4.5%) by weight.
  • the catalyst may comprise an enzyme.
  • the enzyme may be a variant of a naturally occurring enzyme, wherein said variant has been prepared by recombinant means and has one or more improved properties compared to the naturally occurring enzyme, such as higher stability in an organic solvent (e.g., ester solvent, aprotic amide solvent, or water-soluble alcohol), higher catalytic activity in said organic solvent, and/or higher substrate specificity.
  • an organic solvent e.g., ester solvent, aprotic amide solvent, or water-soluble alcohol
  • the amount of catalyst in a chemical reaction may depend from various parameters, such as the type of the chemical reaction, the reactants participating in said chemical reaction, the type of catalysis (homogeneous vs. heterogeneous), and the catalyst used (without or with carrier material).
  • the amount of catalyst used in a chemical reaction may be 0.1 to 20%> by weight, preferably 0.5 to 15%> by weight, more preferably, 1.0 to 10% by weight, more preferably 1.5 to 7% by weight, more preferably 2.0 to 6% by weight, more preferably 2.5 to 5% by weight, more preferably 3.0 to 4.5% by weight, relative to the amount by weight of the starting material used (e.g., the amount of a compound to be reduced, such as ANFP).
  • the amount of catalyst used in a chemical reaction may be the same as defined above or lower, e.g., only 1/10, 1/20, 1/50, or 1/100 of the above ranges (e.g., 0.1 to 1% by weight or 0.01 to 0.1% by weight).
  • the amount of catalyst used in a chemical reaction may be 0.01 to 10 mol-%, preferably 0.1 to 5 mol-%, more preferably, 0.5 to 4 mol-%, more preferably 1 to 3 mol-%, more preferably 1.5 to 2 mol-%, relative to the molecular amount of the starting material used (e.g., the amount of a compound to be reduced, such as ANFP).
  • a "redox reaction” or “reduction- oxidation reaction” as used herein means a reaction in which electrons are transferred between species or in which atoms change oxidation number.
  • the species or atom which donates one or more electrons is the “reducing agent” or “reductant”; and the species or atom which accepts the one or more electrons is the “oxidizing agent” or “oxidant”.
  • Reducing and oxidizing agents function as conjugate reductant- oxidant pairs or redox pairs; thus, the reductant undergoes the reaction: reductant conjugate oxidant + n e " ; and the oxidant undergoes the reaction: oxidant + n e conjugate reductant.
  • Exemplary reducing agents for the process of the present invention include the following:
  • reaction conditions may be selected from the following: H 2 pressure: 100 to 4000 kPa, preferably, 200 to 3000 kPa, more preferably 400 to 2000 kPa, more preferably, 500 to 1000 kPa; reaction temperature and time: as defined for step (i));
  • metals preferably base metals, more preferably Fe, Zn, Sn, or Sm, or alloys of these metals (such as Zn-Hg amalgam); the metal or alloy is preferably used in combination with an acid (such as mineral acids, e.g., HC1, HBr, HN0 3 , H 3 P0 4 , H 2 S0 4 , NH 4 C1), optionally, in the presence of water;
  • an acid such as mineral acids, e.g., HC1, HBr, HN0 3 , H 3 P0 4 , H 2 S0 4 , NH 4 C1
  • metal hydrides such as lithium aluminum hydride (LiAlH 4 ) and diisobutylaluminum hydride (DIB AH);
  • reducing metal compounds i.e., compounds comprising a metal ion which has the ability to donate one or more electrons
  • exemplary reducing metal compounds are Sn(II) salts (such as SnC3 ⁇ 4) and Fe(II) salts (such as FeC ⁇ );
  • boron compounds such as diborane (B 2 H 6 ), decaborane (Bi 0 Hi 4 ), 9- borabicyclononane (9-BBN) and sodium borohydride (NaBH );
  • reducing carbon compounds such as formic acids and salts thereof (in particular triethylammonium formate), ascorbic acid and salts thereof, and oxalic acid and salts thereof;
  • reducing silicon compounds such as polymethylhydrosiloxane (PMHS) and triethylsilane
  • reducing sulfur compounds such as sulfites and dithionites
  • the amount of reducing agent used in step (i) of the process of the present invention may be 1.5 to 3, preferably 2.0 to 2.5 times of the theoretical amount required for reducing ANFP to DAFP.
  • Preferred reducing agents include hydrogen, Fe (particularly in combination with HC1), Zn (particularly in combination with NH 4 C1), Sm, decaborane, formic acid and its salts, PMHS, triethylsilane, and dithionites (such as sodium dithionite).
  • base metals refers to metals whose conjugate oxidation-reduction pairs have more negative standard potentials than the standard hydrogen electrode.
  • base metals include the following metals: Li, Be, Na, Mg, Al, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Zn, Ga, Ge, Rb, Sr, Y, Zr, Nb, Mo, Cd, In, Sn, Sb, Cs, Ba, Hf, Ta, W, Tl, Pb, Bi, La, Ce, Nd, Sm, and Yb.
  • a "redox catalyst” as used herein refers to a catalyst as defined herein which catalyzes a redox reaction.
  • the redox catalyst may comprise a metal selected from the group consisting of the transition metals of the 8 th to 10 th groups of the periodic table of the elements. More preferably, the redox catalyst comprises a metal selected from the group consisting of Pt, Pd, Ni, Ir, Rh, and Ru. Even more preferably, the redox catalyst is selected from the group consisting of Pd/C, Pd(OH) 2 /C (Pearlman's catalyst), platinum dioxide (such as platinum(IV) oxide hydrate, Pt0 2 -H 2 0 (Adam's catalyst)), Pt/C, and Raney-Ni.
  • the redox catalyst is Pd/C or Pt/C.
  • Preferred contents of the catalytically active components (such as Pd in Pd/C) in the redox catalysts as well as preferred amounts of redox catalysts used in a redox reaction are as defined above for "catalyst”.
  • phase transfer catalyst refers to a catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs.
  • phase transfer catalysts are selected from the group consisting of quaternary ammonium compounds (such as ⁇ (R ⁇ R 2 X " , wherein R 1 is CM alkyl, R 2 is Cg.ig alkyl or benzyl, and X is CI, Br, or I; e.g., benzyltrimethylammonium chloride), quaternary phosphonium compounds (such as [P(R 1 )sR 2 ] + X " , wherein R 1 is CM alkyl, R 2 is Cg.ig alkyl or benzyl, and X is CI, Br, or I; e.g., hexadecyltributylphosphonium bromide), crown ethers (such as 12-crown-4 (facilitating the dissolving of lithium salts in organic solvents
  • phase transfer catalysts used in the process of the present invention are as defined above for "catalyst".
  • An "oxygen scavenger agent” as used herein refers to a chemical substance added to a mixture in order to remove or inactivate oxygen in said mixture.
  • the oxygen scavenger agent is a sulfite salt, more preferably sodium sulfite.
  • a “chemical base” as used herein is any compound which is capable of receiving one or more protons (Bronsted-Lowry acid-base theory).
  • the chemical base is non-nucleophilic.
  • the chemical base may be NH 3 , a carbonate salt (such as K 2 CO 3 or CS 2 CO 3 ), an organic amine (such as a cyclic amine (e.g., l,8-diazabicycloundec-7-ene (DBU)) or an aliphatic amine as defined above), an alkoxide (such sodium tert-butoxide or potassium tert-butoxide), an amine salt (such as lithium diisopropylamide (LDA) or lithium tetramethylpiperidide (LiTMP)), or a silicon-based amide (such as sodium bis(trimethylsilyl)amide (NaHMDS) or potassium bis(trimethylsilyl)amide (KHMDS)).
  • a carbonate salt such as K 2 CO 3
  • Preferred organic amines include trialkylamines, wherein the alkyl groups have independently 1 , 2, 3, 4, 5, or 6 carbon atoms, such as triethylamine (TEA), ⁇ , ⁇ -diisopropylethylamine (DIPEA), or trimethylamine.
  • TAA triethylamine
  • DIPEA ⁇ , ⁇ -diisopropylethylamine
  • a "degassed solvent” as used herein refers to a solvent (including ester solvents as defined herein, aprotic amide solvents as defined herein, water-soluble alcohols as defined herein, water-soluble ketones as defined herein, and water, as well as mixtures of any two or more of these liquids) from which dissolved gases have been removed.
  • the removal of the dissolved gases (in particular dissolved oxygen) from a solvent may be performed by one or more of the following procedures: (i) subjecting the solvent to be degassed to reduced pressure (often referred to as vacuum degasification), optionally, with sonication and/or stirring; (ii) heating the solvent to be degassed just below the boiling temperature of said solvent, optionally, with sonication (preferably ultrasonication) and/or stirring; (iii) flowing the solvent to be degassed inside a gas-liquid separation membrane and evacuating outside (membrane degasification); (iv) bubbling the solvent to be degassed with an inert gas, optionally, with sonication, stirring and/or heating; (v) adding an oxygen scavenger agent to the solvent to be degassed; (vi) placing the solvent to be degassed into a flask, flash-freezing the solvent, preferably with liquid nitrogen, applying reduced pressure, sealing the flask, thawing the solvent, preferably by
  • the removal of dissolved gases (in particular dissolved oxygen) from a solvent is performed by boiling the solvent to be degassed under an inert gas (such as nitrogen), optionally, with stirring, at atmospheric pressure for one hour.
  • an inert gas such as nitrogen
  • the inert gas may be selected from the group consisting of nitrogen and noble gases. More preferably, the inert gas is nitrogen.
  • inert gas refers to a non-reactive gas.
  • Inert gases include nitrogen, carbon dioxide, sulfur hexafluoride, and noble gases.
  • Preferred inert gases are nitrogen, sulfur hexafluoride, helium, argon, and neon.
  • ble gas refers to any of the group consisting of helium, neon, argon, krypton, and xenon.
  • Methods which may be used for monitoring the progress of one or more reaction steps of the process of the present invention include the methods for characterization of polymorphs of a material as described above as well as HPLC, liquid chromatography (LC), thin layer chromatography (TLC), gas chromatography (GC), mass spectrometry (MS), GC-MS, nuclear magnetic resonance (NMR) spectroscopy (preferably for 3 ⁇ 4 13 C, 10 B, U B, 14 N, 15 N, 17 0, 19 F, 23 Na, 29 Si, 31 P, 35 C1), infrared (IR) spectroscopy, Raman spectroscopy, and elemental analysis.
  • HPLC liquid chromatography
  • TLC thin layer chromatography
  • GC gas chromatography
  • MS mass spectrometry
  • GC-MS nuclear magnetic resonance (NMR) spectroscopy (preferably for 3 ⁇ 4 13 C, 10 B, U B, 14 N, 15 N, 17 0, 19 F, 23 Na, 29 Si, 31 P, 35 C1), infrared (IR) spect
  • substantially pure means that a compound or preparation has a purity of at least 99%, preferably at least 99.9%>, more preferably at least 99.99%>, more preferably at least 99.999%).
  • the amount of impurities are below the detection limit of the analysis method used.
  • the analysis method may be chosen from those methods which are used for monitoring the progress of one or more reaction steps of the process of the present invention.
  • a flupirtine maleate preparation which is substantially pure with respect to polymorphic form B means that at least 99% of the flupirtine maleate preparation is polymorphic form B, preferably that the total amount of impurities (in particular, ethyl (2,6- diaminopyridin-3-yl) carbamate maleate and/or polymorphic forms other than polymorphic form B) in said flupirtine maleate preparation is below the detection limit of the analysis method used.
  • substantially complete means that in a reaction substantially the entire initial amount of the starting material is consumed.
  • substantially the entire initial amount means at least 95%, preferably at least 98%, more preferably at least 99%, more preferably at least 99.9%, more preferably at least 99.99%, more preferably at least 99.999%) of the initial amount.
  • the amount of starting material is below the detection limit of the analysis method used.
  • the analysis method may be chosen from those methods which are used for monitoring the progress of one or more reaction steps of the process of the present invention.
  • substantially completely converted means that after conversion, the amount of converted compound in the preparation is at least 95%, preferably at least 98%, more preferably at least 99%, more preferably at least 99.9%, more preferably at least 99.99%, more preferably at least 99.999%), while the amount of unconverted compound is less than 5%, preferably, less than 2%>, more preferably less than 1%, more preferably less than 0.1%, more preferably less than 0.01%, more preferably less than 0.001%).
  • the amount of unconverted compound is below the detection limit of the analysis method used.
  • the analysis method may be chosen from those methods which are used for monitoring the progress of one or more reaction steps of the process of the present invention.
  • "converting flupirtine maleate substantially completely into polymorphic form B” means that after conversion, at least 95% of the flupirtine maleate in the preparation are polymorphic form B, preferably that the total amount of polymorphic forms other than polymorphic form B is below the detection limit of the analysis method used.
  • substantially anhydrous as used herein in conjunction with a solvent or mixture means that the solvent or mixture contains water in an amount of not more than 5% by weight, preferably, not more than 1% by weight, more preferably not more than 0.1%) by weight, more preferably not more than 0.01%) by weight, more preferably not more than 0.001%) by weight, based on the total weight of the solvent or mixture.
  • partially converted as used herein in conjunction with a compound means that the compound has not been completely converted.
  • partially converted means that 1 to 95%, preferably less than 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%), 15%, 10%), or less than 5% have been converted.
  • enriched as used herein in conjunction with a preparation of a polymorphic form means that the preparation includes a higher ratio of designated polymorphic form to non- designated polymorphic form as compared to the original preparation from which it was obtained.
  • standard conditions refers to a temperature of 20°C and an absolute pressure of 101.325 kPa.
  • one or more times means at least once, preferably once, twice, 3, 4, 5, or 6 times.
  • a “solvent” as used herein refers to any chemical compound which is a liquid under standard conditions, which dissolves a solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume (e.g., 100 mL) of solvent at a specified temperature (preferably about 20°C), and which is inert with respect to said solute, preferably with respect to the reactants used in the process of the present invention.
  • a certain volume e.g., 100 mL
  • a specified temperature preferably about 20°C
  • solvent exchange means that one or more solvents contained in a mixture are removed from the mixture and to the remaining residue one or more solvents are added, wherein the one or more solvents which are added to the remaining residue differ from the one or more solvents initially present in the mixture. For example, if a mixture comprising solvents A and B is subjected to a solvent exchange both solvents A and B may be removed from the mixture and to the remaining residue either solvent A or solvent B or one or more solvents other than A and B is/are added. Alternatively, if only solvent A is removed from the mixture, either solvent B or one or more solvents other than A and B may be added to the remaining residue.
  • the solvent exchange may be performed by any means known to the skilled person and includes thermal solvent exchange (such as by vaporization using, for example, a rotary evaporator) and non-thermal solvent exchange (such as by molecular separation processes, e,g Berry nanofiltration, pervaporation, membrane technology, or a combination thereof; cf. the products sold by Sulzer and Evonik Industries.
  • the remaining residue may be in the form of a liquid (such as a solution, emulsion, or dispersion/suspension) or a solid.
  • the expression "reflux temperature" used herein in conjunction with a remaining residue refers to the boiling point of the liquid contained in the remaining residue which has the lowest boiling point of all liquids contained in the remaining residue.
  • a reaction is to be carried out in solvent A (or a mixture of solvents A and B, respectively)
  • at least 30% such as at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or 100%
  • at least 30% such as at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or 100%
  • the total amount of liquid(s) other than solvent A (or the mixture of solvents A and B, respectively) in the liquid part of the reaction mixture may be at most 50%> (such as at most 45%), at most 40%, at most 35%, at most 30%, at most 25%, at most 20%, at most 15%, at most 10%), at most 9%, at most 8%, at most 7%, at most 6%, at most 5%, at most 4%, at most 3%, at most 2%, at most 1%) by weight or volume.
  • solvent which is not completely miscible with water means that a mixture of the solvent with water does not form a single phase but forms two liquid phases (e.g., at standard conditions of temperature and pressure; and/or particular amounts used for the solvent and water).
  • volatile as used herein in conjunction of a component of a mixture refers to a compound which can be separated from the mixture by vaporization, e.g., by gradually increasing the temperature (starting from, e.g., about 20°C) and/or reducing the pressure (starting from, e.g., standard atmospheric pressure).
  • the volatile components also include azeotropes.
  • volatile components comprise all compounds and/or azeotropes having a boiling point (at standard atmospheric pressure) lower than the boiling point of water (at standard atmospheric pressure).
  • the expression "1 part by volume of A relative to 1 part by weight of B" as used herein in conjunction with a mixture of A and B means that for each unit amount of B (measured in gram) one unit amount of A (measured in milliliter [mL]) is present in the mixture.
  • a mixture comprising 3 parts by volume of A relative to 1 part by weight of B means that the mixture comprises 3 mL of A for each g of B, or 3 L of A for each kg of B.
  • a water-soluble ketone preferably acetone
  • a water-soluble alcohol such as 10% to 50% water in a water-soluble alcohol (preferably isopropanol)
  • the process of the present invention prevents the generation of precursors of the colored impurities (e.g., ethyl (2,6-diaminopyridin-3-yl) carbamate maleate), thereby allowing the preparation of substantially pure flupirtine maleate which is not colored.
  • a KBr disc of a sample of flupirtine maleate was prepared according to standard procedures in the art and the infrared spectrum is recorded over the range of from 4000 to 600 cm "1 on a Perkin Elmer Spectrum One Instrument. The following peaks obtained for flupirtine maleate were identified:
  • HPLC was used to determine the purity of flupirtine maleate preparations and the maleic acid content.
  • flupirtine maleate reference standard Approximately 40 mg ( ⁇ 1 mg) of flupirtine maleate reference standard were weighed, dissolved in 2 mL MeCN, and diluted with diluent.
  • RT retention time
  • RRT relative RT
  • RF response factor
  • DSC Differential scanning calorimetry
  • Samples were analysed in duplicate using 4.00 to 6.00 mg weighed into a crucible with a sealed lid. Prior to analysis a blank (i.e., an empty sealed crucible) was run. A temperature of from 40°C to 200°C was scanned at 20°C/minute.
  • Polymorph A of flupirtine maleate shows peaks between 160 to 170°C, and 180 to 190°C, while polymorph B shows a peak at 185°C only. Representative scans of polymorphs A and B obtained by the process of the present invention are shown in Figures 4 and 5.
  • the DSC results for the samples show the expected profile for polymorph A with two peaks, one at approximately 169°C and the other at approximately 185°C. This can be explained as follows. Although polymorph A is more stable at ambient temperature, flupirtine maleate is an enantiotropic system showing a transition temperature above which polymorph B is more stable. In the DSC measurement, the lower temperature endotherm shows the melting of polymorph A, but a second, higher temperature endotherm corresponding to the melting of polymorph B is also seen since polymorph B is formed during the heating process. The presence of both endotherms in the DSC is normal even when the original sample contained only polymorph A. A sample of pure polymorph B gives a single endotherm at approximately 185°C. DSC cannot therefore be used to conclusively show the absence of polymorph B in a sample, although the absence of the lower temperature endotherm could be used to indicate a sample of pure polymorph B.
  • Gas chromatography chromatography
  • Carrier gas nitrogen
  • the diffractograms were recorded with a powder diffractometer D5000 (Siemens, Germany).
  • the analysis conditions were as follows: PSD fast-scan; start: 4.008°; end: 30.024°; step: 0.014°; step time:
  • ANFP 7.0 kg
  • Pd/C 5% Pd on carbon; 1.0 kg
  • degassed ethyl acetate 70 L
  • the pressure hydrogenator was purged three times with nitrogen and then three times with hydrogen (200 kPa per purge).
  • the reaction mixture was stirred for 34 h at a temperature of 25°C and a hydrogen pressure of 200 kPa.
  • the pressure was released, the pressure hydrogenator was purged three times with nitrogen (200 kPa per purge) and the reaction was monitored for completion by LC (amount of residual ANFP: 0.7%).
  • Ethyl chloroformate (3.15 kg together with 0.5 L degassed ethyl acetate), triethylamine (3.15 kg together with 0.5 L degassed ethyl acetate), and sodium sulfite (70 g together with 250 mL degassed ethyl acetate) were added to the pressure hydrogenator (in intervals of 30 min), wherein the reaction mixture was stirred and the temperature was maintained at 40°C.
  • Degassed isopropanol (51 kg) was added, the reaction mixture was filtered at 40°C to remove the redox catalyst, and the catalyst was washed with isopropanol (28 kg).
  • the filtrates were passed directly into a solution of maleic acid (5.0 kg) and sodium sulfite (70 g) in degassed isopropanol (39 kg) at 40°C under stirring.
  • the slurry was heated to 65°C, then cooled to 3°C and stirred at 3°C for 15 min.
  • the crude flupirtine maleate was filtered off at 5°C, washed twice with degassed isopropanol (25 kg and 18 kg, respectively) at 5°C and dried at about 30°C under reduced pressure. Yield of crude flupirtine maleate: 9.85 kg (88% of theory).
  • Flupirtine maleate (12.0 kg) was mixed with isopropanol (127.4 L) and deionized water (54.6 L) and the reaction mixture was stirred and heated to 65°C to dissolve the flupirtine maleate. The solution was cooled to 47°C to 48°C, a slurry of pure polymorph A of flupirtine maleate (240 g in 1 L 50/50 isopropanol/water) was added, and the reaction mixture was cooled to 0°C over 1 h. The crystals were filtered off, washed with an aqueous isopropanol solution (21.6 L isopropanol and 2.4 L water), and dried at about 32°C under reduced pressure. Purity of flupirtine maleate polymorph A: 99.9% (polymorph B: 0.05%).
  • a jacketed glass vessel (2 L) was fitted with an overhead stirrer, a reflux condenser and a nitrogen supply tube.
  • Ethyl alcohol (96%, 500 mL) was charged, followed by ANFP (50.0 g), sodium dithionite (145 g) and aqueous ammonia (600 mL; ammonia content by titration: 28.7%).
  • the reaction mixture was heated with stirring to 44-47°C over 55 min and maintained at that temperature for further 15 min.
  • Ethyl alcohol and ammonia were removed by distillation at reduced pressure (70-80 kPa), while gradually increasing the temperature in the vessel to 60-62°C over 4 h. Water (250 mL) was added as necessary to maintain the stirring.
  • Ethyl acetate (750 mL) was added and the mixture was extracted, then the layers were separated. The ethyl acetate layer was treated with ethyl chloroformate (32 mL) at 47°C and 5 min later with triethylamine (55 mL) at 53°C. After 30 min additional ethyl acetate (200 mL) was added to allow for easier stirring, then maleic acid aqueous solution (35 g maleic acid in 200 mL water) was added over 5 min.
  • a glass vessel (2 L) was fitted with air cooled condenser, overhead stirrer and thermometer.
  • the crude flupirtine maleate was charged (73.6 g) and suspended in isopropanol/water (10:4 mixture, total of 1.03 L). The mixture was heated to 61°C over 30 min to dissolve the solids. Then the solution was gradually cooled with stirring to 0-5°C over 3 h and 20 min.
  • Purified flupirtine maleate was collected by filtration on a Buchner funnel and washed with cold isopropanol/water 9:1 mixture (75 mL), dried at reduced pressure (-80 kPa, 35°C). Yield: 61.86 g (86.3% of theory); purity: 98.7%.
  • a glass vessel (2 L) was fitted with an air cooled condenser, an overhead stirrer and a thermometer.
  • Purified flupirtine maleate (123.65 g) was charged and suspended in isopropanol/water (10:4 (vol/vol), total of 1.30 L). The mixture was heated to 65°C over 30 min to dissolve the solids. Then the solution was gradually cooled with stirring. At 48°C 10 mg of flupirtine maleate polymorph A seed crystals were added. Cooling was continued to 0-5°C over 4 h.
  • flupirtine maleate preparations containing polymorph A in an amount of at most 40%
  • an organic solvent such as isopropanol
  • flupirtine maleate preparations containing polymorph A in an amount of 60% to 100% we stirred the flupirtine maleate obtained from Examples 2 and 3, above, in isopropanol at ambient temperature and determined the ratio of polymorph B to polymorph A by XRD.
  • This impurity was present in significant amounts (up to 28% if the hydrogenation of ANFP was performed over night) and could not be removed from the precipitated crystals by washing or stirring a slurry of the precipitated crystals in an appropriate solvent without dissolving the flupirtine maleate crystals completely.
  • a flupirtine maleate preparation can be obtained which is (substantially) pure with respect to polymorph A, i.e., whose total amount of impurities (in particular, ethyl (2,6- diaminopyridin-3-yl) carbamate maleate and/or polymorphic forms other than polymorphic form B) is less than 1%.
  • the water layer was separated and discarded.
  • the air sensitive ethyl acetate layer was treated with ethyl chloroformate (14.5 mL, 151 mmol), while stirring and slowly flushing with nitrogen for 30 min.
  • Triethylamine 25 mL, 179 mmol was added and stirred for 30 min.
  • An aqueous solution of maleic acid prepared from maleic acid (14.0 g, 120 mmol) and water (160 mL) was added to the reaction mixture. The mixture was maintained at 40°C for 1 h, then cooled to 20°C. The precipitate was collected by filtration, the vessel and the precipitate were washed with an additional portion of ethyl acetate (55 mL).
  • the purity of the flupirtine maleate obtained is not satisfactory. It was found that the best way to remove dissolved gases (in particular dissolved oxygen) from a solvent is by boiling the solvent to be degassed under an inert gas (such as nitrogen), optionally, with stirring, at atmospheric pressure for one hour. In addition, it has been found that instead of degassing a solution of, e.g., maleic acid in a water-soluble alcohol, the solvent should be degassed alone in order to avoid possible side products during the degasification, and the addition of compounds to a reaction mixture should be performed under a blanket of inert gas.
  • an inert gas such as nitrogen
  • the amount of impurities (especially the amount of ethyl (2,6- diaminopyridin-3-yl) carbamate maleate or of its precursors) in a flupirtine maleate preparation may be decreased and thus, the purity and color of the flupirtine maleate preparation improved by one or more of the following measures: (1) reducing the amount of redox catalyst; (2) lowering the reaction temperature in the catalytic hydration of ANFP to below 40°C; (3) adding an oxygen scavenger agent in step (ii) and/or step (iii); (4) performing a "two-step crystallization", i.e., crystallizing flupirtine maleate obtained from step (iii) as polymorph B; isolating polymorph B; and converting polymorph B into polymorph A; and (5) washing flupirtine maleate with a water-soluble ketone (preferably acetone) or an aqueous solution of a water-soluble alcohol (such as 10% to 50% water in a water-

Abstract

La présente invention concerne un procédé de préparation de maléate de flupirtine, Flupirtine.
PCT/EP2011/061650 2010-07-09 2011-07-08 Procédé de préparation de maléate de flupirtine WO2012004391A1 (fr)

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CN105541705A (zh) * 2015-12-31 2016-05-04 山东罗欣药业集团股份有限公司 一种马来酸氟吡汀化合物的合成方法
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CN110317167A (zh) * 2019-08-17 2019-10-11 西安都创医药科技有限公司 一种氟吡汀衍生物及其无机酸盐的制备方法

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CN103333103A (zh) * 2013-07-12 2013-10-02 南京正大天晴制药有限公司 一锅法制备马来酸氟吡汀的方法
CN103333103B (zh) * 2013-07-12 2015-07-22 南京正大天晴制药有限公司 一锅法制备马来酸氟吡汀的方法
CN103910674A (zh) * 2013-12-19 2014-07-09 天津红日药业股份有限公司 用于马来酸氟吡汀分析中的参比化合物
CN103910674B (zh) * 2013-12-19 2015-12-02 天津红日药业股份有限公司 用于马来酸氟吡汀分析中的参比化合物
CN105541705A (zh) * 2015-12-31 2016-05-04 山东罗欣药业集团股份有限公司 一种马来酸氟吡汀化合物的合成方法
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CN109053562B (zh) * 2018-07-20 2022-05-27 四川青木制药有限公司 一种制备a晶型高堆密度的马来酸氟吡汀的方法
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