WO2008138874A1 - Procédé de préparation de la (s)-prégabaline par résolution optique de prégabaline racémique - Google Patents

Procédé de préparation de la (s)-prégabaline par résolution optique de prégabaline racémique Download PDF

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Publication number
WO2008138874A1
WO2008138874A1 PCT/EP2008/055722 EP2008055722W WO2008138874A1 WO 2008138874 A1 WO2008138874 A1 WO 2008138874A1 EP 2008055722 W EP2008055722 W EP 2008055722W WO 2008138874 A1 WO2008138874 A1 WO 2008138874A1
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acid
pregabalin
process according
temperature
diastereomeric salt
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PCT/EP2008/055722
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English (en)
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Roberto Tufaro
Giovanni Marras
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Chemo Ibérica, S.A.
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Publication of WO2008138874A1 publication Critical patent/WO2008138874A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/34—Preparation of optical isomers by separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a novel process for preparing (S)-Pregabalin by optical resolution of racemic Pregabalin.
  • This invention also relates to two crystalline forms of (S)-Pregabalin-(-)-O,O'-dibenzoyl-L-tartrate (Vila).
  • GABA ⁇ - Amino butyric acid
  • GABA ⁇ - Amino butyric acid
  • GABA level appears to terminate seizures.
  • seizure means excessive unsynchronized neuronal activity that disrupts normal brain function.
  • Pregabalin which is also called ⁇ - isobutyl- ⁇ -amino butyric acid or isobutyl-GABA, increases the concentration of GABA by activating GAD and is a potent anticonvulsant: it has the ability to suppress seizure while avoiding the undesirable side effect of ataxia.
  • Pregabalin is useful as a therapeutic agent for the treatment of pain, epilepsy, convulsions, psychiatric disorders, attention deficit, hypersensitivity disorder, anxiety and mood disorders.
  • racemic Pregabalin is stereoselective.
  • the anticonvulsant effect of racemic Pregabalin is primarily attributable to the (S)-Pregabalin.
  • (S)-Pregabalin shows better anticonvulsant activity than the R-stereoisomer (see, for example, Yuen et al., Bioorganic & Medicinal
  • Pregabalin requires an efficient, cost effective and safe method for preparing the S-enantiomer substantially free of the R-enantiomer in a large scale.
  • (S)-Pregabalin Several methods have been used to prepare (S)-Pregabalin. Typically, the racemic mixture is synthesized and then subsequently resolved into its R- and S-enantiomers.
  • the racemic mixture is converted to a mixture of diastereomeric salts by reaction with a suitable chiral resolving agent, which is tipically a chiral acid or base, often selected from naturally occurring compounds, in a suitable solvent or solvent mixture.
  • a suitable chiral resolving agent which is tipically a chiral acid or base, often selected from naturally occurring compounds, in a suitable solvent or solvent mixture.
  • the diastereomers frequently have very different physical properties, including crystal formation and solubility.
  • one diastereomeric salt crystallizes and the other one stays in solution.
  • a further recrystallization from the same solvent or solvent mixture affords the diastereomeric salt with the desired enantiopurity.
  • the chiral resolving agent is then removed and recovered, giving the free desired enantiomer.
  • the unwanted enantiomer is tipically released, racemised and recycled through the process.
  • a 40% or better recovery of material with an enantiomeric purity above 95% must
  • a diasteroimeric salt of Pregabalin with (S)-(+)-mandelic acid of Formula (II) was obtained by heating to 50-65 0 C a solution of racemic Pregabalin (1 mol) and an excess of (S)-(+)-mandelic acid (1.5 mol) in isopropanol and water. Batch heating and temperature are kept to the minimum necessary to dissolve solids in order to minimize acid catalyzed decomposition of racemic Pregabalin to the corresponding lactam.
  • U.S. Patent No. 5,616,793 discloses a process for the preparation of (S)- Pregabalin, which involves resolution of the racemic key intermediate of Formula (III), with the chiral resolving agent (R)-(+)- ⁇ -phenylethylamine, in a solvent mixture of chloroform and ethanol to obtain the diastereomeric salt (IV) and then the desired R-enantiomer of Formula (V), according to Scheme 2.
  • racemic key intermediate of Formula (III) is only an intermediate of one synthetic route to prepare (S)-Pregabalin
  • racemic Pregabalin is the final key intermediate of many synthetic methods, such as the processes described in U.S. Patent No. 5,637,767; U.S. Patent No. 6,924,377 or U.S. Patent Application No.
  • An object of the present invention is to provide a novel, efficient, economic and commercially useful process for the optical resolution of racemic Pregabalin to obtain
  • (S)-Pregabalin that avoids the above-identified problems.
  • This invention also relates to two crystalline forms of the compound of (S)-Pregabalin-(-)-O,O'-dibenzoyl-L- tartrate (VII).
  • Processes are provided for preparing (S)-Pregabalin by optical resolution of racemic Pregabalin.
  • the invention provides a process for preparing (S)-Pregabalin, or a hydrate, a solvate, a polymorph thereof, by optical resolution of racemic Pregabalin comprising: a) dissolving racemic Pregabalin with a chiral acid resolving agent of Formula (VI)
  • Ri and R 2 are the same and each is hydrogen or methyl, and an acid, in at least a suitable solvent,; b) pouring the solution in water in order to precipitate the enriched diastereomeric salt; c) recovering the enriched diastereomeric salt; d) enriching the collected diastereomeric salt by recrystallizing it in at least a suitable solvent to obtain an optically pure diastereomeric salt; e) isolating free (S)-Pregabalin.
  • the invention provides a process for preparing (S)- Pregabalin, or a hydrate, a solvate, a polymorph thereof, by optical resolution of racemic Pregabalin comprising: a) dissolving racemic Pregabalin with a suitable acid in water; b) adding a chiral acid resolving agent of Formula (VI)
  • Ri and R 2 are the same and each is hydrogen or methyl; c) mixing the suspension at a suitable temperature in order to form the enriched diastereomeric salt; d) recovering the enriched diastereomeric salt; e) enriching the collected diastereomeric salt by recrystallizing it in at least a suitable solvent to obtain an optically pure diastereomeric salt; f) isolating free (S)-Pregabalin.
  • the invention provides a process for preparing (S)- Pregabalin, or a hydrate, a solvate, a polymorph thereof, by optical resolution of racemic Pregabalin, comprising: a) suspending racemic Pregabalin with a chiral acid resolving agent of Formula (VI)
  • Ri and R 2 are the same and each is hydrogen or methyl; and an acid, in at least a suitable solvent; b) heating the suspension; c) cooling the suspension obtained in step b); d) recovering an optically pure diastereomeric salt; e) isolating free (S)-Pregabalin.
  • the invention provides a process for isolating (S)- Pregabalin, or a hydrate, a solvate, a polymorph thereof from the optically pure diastereomeric salt of formula (VII)
  • the invention provides a pharmaceutical composition
  • (S)-Pregabalin made by optical resolution of racemic Pregabalin of the present invention optionally together with at least one pharmaceutically acceptable excipient.
  • the invention provides the use of (S)-Pregabalin made by optical resolution of racemic Pregabalin of the present invention for the preparation of a medicament.
  • the invention provides (S)-Pregabalin made by optical resolution of racemic Pregabalin of the present invention for use as a medicament.
  • the invention provides (S)-Pregabalin-(-)-O,O'- dibenzoyl-L-tartrate or a hydrate, a solvate, a polymorph thereof of Formula (Vila).
  • the invention provides a crystalline Form ⁇ of (S)-
  • Pregabalin-(-)-O,O'-dibenzoyl-L-tartrate (Vila), characterized by an X-ray powder diffraction pattern comprising peaks at about 9.7, 14.1, 16.3, 17.4, 19.4, 19.8, 21.6, 24.1° +/- 0.2° 2 ⁇ , and a differential scanning calorimetry endothermic maximum peak at about 164°C.
  • the invention provides a crystalline Form ⁇ of (S)-
  • Pregabalin-(-)-O,O'-dibenzoyl-L-tartrate (Vila), characterized by an X-ray powder diffraction pattern comprising peaks at about 7.1, 11.6, 13.4, 16.3, 17.3, 18.3, 22.8, 23.7° +/- 0.2° 2 ⁇ , and a differential scanning calorimetry endothermic maximum peak at about 160 0 C.
  • Figure 1 provides an XRPD pattern of crystalline Form ⁇ of (S)-Pregabalin-(-)- O,O'-dibenzoyl-L-tartrate (Vila).
  • Figure 2 provides a DSC thermogram of crystalline Form ⁇ of (S)-Pregabalin-(-)- O,O'-dibenzoyl-L-tartrate (Vila). It shows a peak at 163.73 0 C with an onset at 160.99 0 C.
  • Figure 3 provides an XRPD pattern of crystalline Form ⁇ of (S)-Pregabalin-(-)- 0,0 ' -dibenzoyl-L-tartrate (Vila) .
  • Figure 4 provides a DSC thermogram of crystalline Form ⁇ of (S)-Pregabalin-(-)- O,O'-dibenzoyl-L-tartrate (Vila). It shows a peak at 159.81 0 C with an onset at 157.37 0 C.
  • chiral acid resolving agent refers to an acidic compound that can lead to the precipitation of the diastereomer containing the desired enantiomer in high chemical and optical yields.
  • enriched diastereomeric refers to a compound that has more of one diastereomer than another.
  • optically pure refers to a sample containing greater than about 95% of the desired diastereoisomer or enantiomer by weight, preferably greater than about 98% of the desired diastereoisomer or enantiomer by weight, and more preferably greater than about 99.5% of the desired diastereoisomer or enantiomer by weight, based upon the total weight of the active ingredient.
  • the optically pure diastereomeric salt (S)-Pregabalin-(-)-O,O'-dibenzoyl-L-tartrate (Vila) is substantially free of (R)-Pregabalin-(-)-O,O'-dibenzoyl-L-tartrate.
  • substantially free means that a diastereoisomer contains less than about 5% weight percent, preferably less than 2% weight percent, and more preferably less than about 0.5% weight percent of the other diastereoisomer or enantiomer.
  • lower alcohol refers to straight chain or branched alkyl residues containing 1 to 4 carbon atoms with one hydroxy group, such as methanol, ethanol, n- propanol, isopropanol, n-butanol, tert-butanol and the like.
  • lower ketone refers to straight chain or branched alkyl residues containing 3 to 6 carbon atoms with one keto group, such as acetone, methylethylketone, diethylketone, isobutylmethylketone and the like.
  • hydrate refers to a solvate comprising a disclosed or claimed compound and a stoichiometric or non- stoichiometric amount of water.
  • solvate refers to a molecular complex comprising a disclosed or claimed compound and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g., EtOH).
  • solvent molecules e.g., EtOH.
  • polymorph refers to the property of some molecules and molecular complexes to assume more than one crystalline or amorphous form in the solid state.
  • excipient herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a tablet, capsule, pill, powder, granule, pellet, lozenge, pastille, elixir, syrup, solution, suspension, emulsion, drop, lotion, spray, tincture, cream, ointment, gel, unguent, suppository and transdermal devices for oral, enteral, parenteral or topical administrations .
  • a discrete article such as a tablet, capsule, pill, powder, granule, pellet, lozenge, pastille, elixir, syrup, solution, suspension, emulsion, drop, lotion, spray, tincture, cream, ointment, gel, unguent, suppository and transdermal devices for oral, enteral, parenteral
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the present invention provides a novel, efficient and economic method for the resolution of (S)-Pregabalin from racemic Pregabalin, particularly suited for large scale preparation. Optically pure (S)-Pregabalin was obtained by optical resolution of racemic Pregabalin.
  • the process of this invention is carried out with a chiral acid resolving agent and an acid, in accordance with the "Pope-Peachey" method known in the art (see, for example, Pope, W. J., Peachey, S. J., J. Chem. Soc, 75, 1066 (1899), and Sheldon, P. A., Chirotechnology, Marcel Dekker Inc., 1993).
  • the chiral acid resolving agent is a compound of Formula (VI)
  • Ri and R2 are the same and each is hydrogen or methyl; preferably Ri and R 2 are hydrogen.
  • the acid is selected from inorganic or organic acids, such as hydrochloric acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, citric acid, maleic acid, fumaric acid, lactic acid, malic acid, benzoic acid, L-tartaric acid, D- tartaric acid, S-camphor-10-sulfonic acid, methanesulfonic acid, p-toluensulfonic acid.
  • inorganic or organic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, citric acid, maleic acid, fumaric acid, lactic acid, malic acid, benzoic acid, L-tartaric acid, D- tartaric acid, S-camphor-10-sulfonic acid, methanesulfonic acid, p-toluensulfonic acid.
  • Preferred acids are hydrochloric acid, formic acid, L-tartaric acid.
  • the molar ratio of racemic Pregabalin/chiral acid resolving agent/acid is 1 :0.5:0.5 mole/mole or 1 :0.5:1 mole/mole.
  • This molar ratio of racemic Pregabalin/chiral acid resolving agent gave a diastereomeric salt of (S)-Pregabalin with an optical purity much higher than the obtained with other tried molar ratios.
  • An optically pure diastereomeric salt of an optically pure diastereomeric salt of (S)- Pregabalin may be obtained straight by suspending racemic Pregabalin with a chiral acid resolving agent and an acid, in at least a suitable solvent (Method C); or - when an enriched diastereomeric salt of (S)-Pregabalin (obtained from racemic Pregabalin, a chiral acid resolving agent and an acid in a suitable solvent or straight in water) is first precipitated in water, afterwards it may be further enriched by recrystallizing it in at least a suitable solvent to obtain an optically pure diastereomeric salt of (S)-Pregabalin (Methods A and B).
  • the dissolution and/or the suspension of racemic Pregabalin, a chiral acid resolving agent and an acid as well as the precipitation of the diastereomeric salt in a suitable solvent and/or in water may preferably and advantageously be carried out at the same temperature, for any convenient period of time.
  • a suitable temperature is from about 0 0 C to about 25°C; preferably the temperature is from about 10 0 C to about 20 0 C; more preferably the temperature is about 15 0 C.
  • the enriched diastereomeric salt was further enriched by mixing it with at least a suitable solvent to obtain an optically pure diastereomeric salt at any convenient temperature that provides the suspension of the diastereomeric salt for any convenient period of time.
  • a suitable temperature is comprised from about 4O 0 C to about reflux temperature of the solvent used; more preferably the temperature is the reflux temperature of the solvent used.
  • Suitable solvents include, but are not limited to, an alcohol, an ester, a ketone, a nitrile, water, or mixtures thereof.
  • Preferred solvents include an alcohol, preferably a lower alcohol, more preferably methanol or ethanol and still more preferably methanol; a ketone, preferably lower ketone, more preferably acetone; or water.
  • the isolated solids, diastereomeric salt or the pure enantiomer can be recovered with methods well known to those skilled in the art for the separation of the solid from the mother liquor, for example by filtration, with or without the assistance of pressure and/or vacuum, or by centrifugation, or by decantation.
  • the collected solids are washed with at least a suitable solvent and dried by conventional methods well known to those skilled in the art.
  • the isolated solids may be dried at each stage in the resolution or carried on the next step as solvent-wet solids with comparable results.
  • the invention provides a process for preparing (S)-Pregabalin, or a hydrate, a solvate, a polymorph thereof, by optical resolution of racemic Pregabalin comprising: a) dissolving racemic Pregabalin with a chiral acid resolving agent of Formula (VI)
  • Ri and R 2 are the same and each is hydrogen or methyl, and an acid, in at least a suitable solvent; b) pouring the solution in water in order to precipitate the enriched diastereomeric salt; c) recovering the enriched diastereomeric salt; d) enriching the collected diastereomeric salt by recrystallizing it in at least a suitable solvent to obtain an optically pure diastereomeric salt; e) isolating free (S)-Pregabalin.
  • the acid is selected from inorganic or organic acids, as defined above.
  • the acid is an organic acid, more preferably L-tartaric acid.
  • Ri and R 2 are hydrogen.
  • the molar ratio of racemic Pregabalin/chiral acid resolving agent/acid is 1 :0.5:0.5 mol/mol.
  • Any solvent capable of dissolving the mixture of racemic Pregabalin, chiral acid resolving agent and acid (step a)) is a suitable solvent of the invention.
  • suitable solvents include but are not limited to alcohols, preferably lower alcohols; preferably methanol or ethanol and still more preferably methanol.
  • racemic Pregabalin is in a ratio of about 1:5 to about 1:10 weight/volume to the solvent used (step a)).
  • the solvent used is in a ratio of about 1 :5 to about 1 :20 volume/volume to the water used (step b)).
  • a suitable temperature for dissolving the mixture of racemic Pregabalin, chiral acid resolving agent and acid is preferably from about 0 0 C to about 25°C; more preferably the temperature is from about 10 0 C to about 2O 0 C; yet more preferably the temperature is about 15°C.
  • a suitable temperature for precipitating the enriched diastereomeric salt from water (step b) is preferably from about 0 0 C to about 25°C; preferably the temperature is from about 10 0 C to about 20 0 C; more preferably the temperature is about 15°C.
  • the enriched diastereomeric salt (step c)) can be recovered with methods well known to those skilled in the art for the separation of the solid from the mother liquor, as described above.
  • the collected solid is washed with water and optionally dried by conventional methods well known to those skilled in the art.
  • Any solvent capable of suspending the diastereomeric salt and from which the enriched diastereomeric salt may be isolated (step d)) is a suitable solvent of the invention.
  • suitable solvents include but are not limited to ketones, preferably lower ketones, more preferably acetone.
  • the diastereomeric salt is preferably in a ratio of about 1 :5 to about 1 :10 weight/volume to the solvent used.
  • any convenient temperature that provides the suspension of the diastereomeric salt may be employed for any convenient period of time.
  • a suitable temperature for suspending the diastereomeric salt is from about 40 0 C to about reflux temperature of the solvent used; more preferably the temperature is the reflux temperature of the solvent used.
  • a suitable temperature for recovering the enriched diastereomeric salt is from about 0 0 C to about 25°C; preferably from about 10 0 C to about 20 0 C; more preferably the temperature is about 15 0 C.
  • optically pure diastereomeric salt was then recovered with methods well known to those skilled in the art for the separation of the solid from the mother liquor, as described above.
  • the collected solid is washed with the solvent used in step d), and optionally dried by conventional methods well known to those skilled in the art.
  • An optically pure diastereomeric salt was obtained.
  • an optically pure diastereomeric salt product with an enantiopurity of at least 99.5:0.5 (S/R) was obtained.
  • the invention provides a process for preparing (S)- Pregabalin, or a hydrate, a solvate, a polymorph thereof, by optical resolution of racemic Pregabalin comprising: a) dissolving racemic Pregabalin with a suitable acid in water; b) adding a chiral acid resolving agent of Formula (VI)
  • Ri and R 2 are the same and each is hydrogen or methyl; c) mixing the suspension at a suitable temperature in order to form the enriched diastereomeric salt; d) recovering the enriched diastereomeric salt; e) enriching the collected diastereomeric salt by recrystallizing it in at least a suitable solvent to obtain an optically pure diastereomeric salt; f) isolating free (S)-Pregabalin.
  • Ri and R 2 are hydrogen.
  • the acid is selected from inorganic or organic acids, as defined above.
  • the acid is an organic acid, more preferably L-tartaric acid.
  • the molar ratio of racemic Pregabalin/acid/chiral acid resolving agent is 1 : 1 :0.5 mol/mol.
  • Preferably racemic Pregabalin is in a ratio of about 1 :20 to about 1 :50 weight/volume to the water used.
  • a suitable temperature in order to dissolve or mix the reagents (steps a) and c)) is preferably from about 0 0 C to about 25°C; more preferably the temperature is from about 10 0 C to about 20 0 C; yet more preferably the temperature is about 15°C.
  • Mixing can be performed over any convenient period of time, preferably over a period between six hours to several hours; more preferably for about twelve hours.
  • the enriched diastereomeric salt (step d)) can be recovered with methods well known to those skilled in the art for the separation of the solid from the mother liquor, as described above.
  • the collected solid is washed with water and optionally dried by conventional methods well known to those skilled in the art.
  • any solvent capable of suspending the diastereomeric salt and from which the enriched diastereomeric salt may be isolated is a suitable solvent for step e).
  • suitable solvents include but are not limited to ketones, preferably lower ketones, more preferably acetone.
  • the diastereomeric salt is preferably in a ratio of about 1 :5 to about 1 : 10 weight/volume to the solvent used.
  • Any convenient temperature that provides the suspension of the diastereomeric salt may be employed for any convenient period of time.
  • a suitable temperature for suspending the diastereomeric salt is from about 40 0 C to about reflux temperature of the solvent used; more preferably the temperature is the reflux temperature of the solvent used.
  • a suitable temperature for recovering the enriched diastereomeric salt is from about 0 0 C to about 25°C; more preferably from about 10 0 C to about 20 0 C; yet more preferably the temperature is about 15 0 C.
  • optically pure diastereomeric salt was then recovered with methods well known to those skilled in the art for the separation of the solid from the mother liquor, as described above.
  • the collected solid is washed with the solvent used in step e), and optionally dried by conventional methods well known to those skilled in the art.
  • An optically pure diastereomeric salt was obtained.
  • an optically pure diastereomeric salt product with an enantiopurity of at least 99.5:0.5 (S/R) was obtained.
  • the invention provides a process for preparing (S)- Pregabalin, or a hydrate, a solvate, a polymorph thereof, by optical resolution of racemic Pregabalin, comprising: a. suspending racemic Pregabalin with a chiral acid resolving agent of Formula (VI)
  • Ri and R 2 are the same and each is hydrogen or methyl; and an acid, in at least a suitable solvent; b. heating the suspension; c. cooling the suspension obtained in step b); d. recovering an optically pure diastereomeric salt; e. isolating free (S)-Pregabalin.
  • the chiral acid resolving agent is a compound of Formula (VI) as defined above.
  • Ri and R 2 are hydrogen.
  • the acid is selected from inorganic or organic acids, as defined above.
  • the acid is an inorganic acid; more preferably hydrochloric acid (37%).
  • the acid is an organic acid, more preferably formic acid.
  • the molar ratio of racemic Pregabalin/chiral acid resolving agent/acid is 1 :0.5:0.5 mole/mole.
  • Any solvent capable of suspending the mixture of racemic Pregabalin, chiral acid resolving agent and acid (step a)) and capable of recovering the diastereomeric salt (step d)) is a suitable solvent of the invention.
  • suitable solvents include but are not limited to ketones, preferably lower ketones, more preferably acetone.
  • racemic Pregabalin is in a ratio of about 1 :5 to about 1 :20 weight/volume to the solvent used.
  • the suspension obtained in step a) is heated in step b) to a suitable temperature.
  • any convenient temperature that provides the suspension (step b)) of the diastereomeric salt may be employed for any convenient period of time.
  • the temperature is comprised from about 40 0 C to about reflux temperature of the solvent used; more preferably the temperature is the reflux temperature of the solvent used.
  • Heating (step b)) may be performed over any convenient period of time, preferably over a period between one hour to three hours; more preferably for about one hour.
  • step d) the suspension is cooled to recover the diastereomeric salt.
  • a suitable temperature is preferably from about 0 0 C to about 25°C; more preferably from about 10 0 C to about 20 0 C; yet more preferably the temperature is about 15°C.
  • the optically pure diastereomeric salt may be recovered with methods well known to those skilled in the art for the separation of the solid from the mother liquor, as described above.
  • the collected solid may be washed with the solvent used in step a), and optionally dried by conventional methods well known to those skilled in the art.
  • An optically pure diastereomeric salt was obtained.
  • an optically pure diastereomeric salt product with an enantiopurity of at least 99:1 (S/R) was obtained.
  • free (S)-Pregabalin is obtained from the diastereomeric salt of formula (VII), preferably from (S)-Pregabalin-(-)- O,O'-dibenzoyl-L-tartrate (Vila), with methods well known to those skilled in the art.
  • (S)-Pregabalin, or a hydrate, a solvate, a polymorph thereof can be performed, for example, by neutralising the diastereomeric salt formed with a base to separate (S)-Pregabalin and the salt of the chiral acid resolving agent used, wich can be recovered to use in other reaction cycles.
  • the invention provides a process for isolating (S)- Pregabalin, or a hydrate, a solvate, a polymorph thereof from the optically pure diastereomeric salt of formula (VII)
  • Ri and R 2 are the same and each is hydrogen or methyl, comprising: a) dissolving the optically pure diastereomeric salt in at least a suitable solvent; b) adding a base in order to precipitate free (S)-Pregabalin; c) recovering free (S)-Pregabalin.
  • Ri and R 2 are hydrogen.
  • any solvent capable of dissolving the optically pure diastereomeric salt (step a)) is a suitable solvent for step a).
  • suitable solvents include but are not limited to alcohols, preferably lower alcohols, preferably methanol or ethanol and still more preferably methanol.
  • diastereomeric salt of (S) Pregabalin is in a ratio of about 1 :1 to about 1 :5 weight/volume to the solvent used.
  • the solution of step a) is cooled to a temperature from about -5°C to about 5°C, preferably the temperature is about O 0 C.
  • a suitable temperature to recover the diastereomeric salt is from about - 5°C to about 5°C; preferably the temperature is about 0 0 C.
  • bases include, but are not limited to, aqueous ammonia (33%), sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate; preferably aqueous ammonia (33%).
  • optically pure diastereomeric salt is in a ratio of 1 :1 mole/mole to the base used.
  • (S)-Pregabalin was then recovered with methods well known to those skilled in the art for the separation of the solid from the mother liquor, as described above.
  • the collected solid is washed with the solvent used in the process and dried by conventional methods well known to those skilled in the art.
  • An optically pure (S)- Pregabalin was obtained.
  • Preferably an optically pure (S)-Pregabalin with an enantiopurity of at least 99.95:0.05 (S/R) was obtained.
  • the chiral acid resolving agent can be recovered from the mother liquors by means of neutralization with a suitable acid, in order to precipitate the chiral acid resolving agent.
  • Any acid is a suitable acid of the invention.
  • the acid is selected from inorganic or organic acids. Examples of acids include, but are not limited to, aqueous hydrochloric acid, sulphuric acid, formic acid, acetic acid.
  • the invention provides (S)-Pregabalin-(-)-O,O'-dibenzoyl- L-tartrate, or a hydrate, a solvate, a polymorph thereof of Formula (Vila):
  • the compounds of this invention may exist in different polymorphic forms, i.e., different crystalline forms.
  • polymorphs formed by the compound of formula (Vila), forming part of this invention may be prepared by crystallization of compound of formula (Vila) under different conditions. For example, using different solvents commonly used or their mixtures for crystallization; using different temperatures for crystallizations; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating the compound followed by gradual or fast cooling.
  • polymorphs may be determined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • the invention provides a crystalline Form ⁇ of (S)-
  • Pregabalin-(-)-O,O'-dibenzoyl-L-tartrate (Vila), characterized by an X-ray powder diffraction pattern as depicted in Figure 1, which comprises characteristic diffraction peaks at about 9.7, 14.1, 16.3, 17.4, 19.4, 19.8, 21.6, 24.1° +/- 0.2° 2 ⁇ .
  • a crystalline Form ⁇ of (S)-Pregabalin-(-)-O,O'-dibenzoyl-L-tartrate (Vila) has the characteristic DSC thermogram as depicted in Figure 2.
  • the DSC thermogram shows a characteristic endothermic maximum peak at about 164°C.
  • the invention provides a crystalline Form ⁇ of (S)- Pregabalin-(-)-O,O'-dibenzoyl-L-tartrate (Vila), characterized by an X-ray powder diffraction pattern as depicted in Figure 3, which comprises characteristic diffraction peaks at about 7.1, 11.6, 13.4, 16.3, 17.3, 18.3, 22.8, 23.7° +/- 0.2° 2 ⁇ .
  • a crystalline Form ⁇ of (S)-Pregabalin-(-)-O,O'-dibenzoyl-L-tartrate (Vila) has the characteristic DSC thermogram as depicted in Figure 4.
  • the DSC thermogram shows a characteristic endothermic maximum peak at about 160 0 C.
  • a crystalline form ⁇ of (S)-Pregabalin-(-)-O,O'-dibenzoyl-L-tartrate (Vila) can be also obtained by dissolving crude (S)-Pregabalin and (-)-O,O'-dibenzoyl-L-tartaric acid in at least a suitable polar solvent and distilling off the solvent.
  • Any solvent capable of dissolving (S)-Pregabalin and (-)-O,O'-dibenzoyl-L-tartaric acid is a suitable solvent.
  • Suitable solvents include but are not limited to alcohols, preferably lower alcohols, more preferably methanol.
  • the enriched diastereomeric salt of (S)-Pregabalin can be obtained without heating.
  • the present resolution method allow to obtain an optically pure (S)-Pregabalin in high yield and with an enantiomeric purity over 99.5%, with favourable energetic costs for the dissolution of diastereomeric mixture and favourable crystallization time of the enriched diastereomeric salt.
  • the chiral acid resolving agent can be easily recovered in a state of high purity, such that it can be re-used in one or more subsequent resolution processes.
  • (S)-Pregabalin may be administered per se or, preferably as a pharmaceutical composition.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (S)-Pregabalin made by optical resolution of racemic Pregabalin of the present invention optionally together with at least one pharmaceutically acceptable excipient.
  • Excipients include, by way of illustration and not limitation, diluents, fillers, agglutinants, disintegrants, disintegration inhibitors, absorption accelerators, binders, carriers, suspensing/dispersing agents, film formers/coatings, adhesives, antiadherents, wetting agents, lubricants, glidants, preservatives, sorbents, surface active agents, substances added to mask or counteract a disagreeable taste or odor, flavorings, colorants, fragrances, aromatising agents, sweeteners and substances added to improve appearance of the composition.
  • excipient compounds suitable to formulate a pharmaceutical composition.
  • the choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions and unit dosages thereof may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets, capsules, pills, powders, granules, pellets, lozenges, pastilles, or liquids, such as solutions, suspensions, emulsions, drops, lotions, sprays, tinctures, syrups, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous, intramuscular, and intravenous) use, or in the form of suppositories for rectal use, or in the form of creams, ointments, gels, unguents for topical use and other forms suitable for the inhalatory or transdermal administrations.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active
  • compositions containing (S)-Pregabalin can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the compounds of this invention are administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions of the present invention can be administered by a variety of routes including oral, rectal, parenteral (including subcutaneous, intravenous, intramuscular), topical, transdermal, ophtalmic and intranasal.
  • the compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. Typical unit dosage forms include pref ⁇ lled, premeasured ampoules or syringes of the liquid compositions or pills, tablets, capsules, powders, granules, pellets, lozenges, pastilles, suppositories or the like in the case of solid compositions.
  • (S)-Pregabalin is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder, such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfme cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses, gum tragacanth or gelatine; an excipient, such as starch or lactose, a disintegrating agent, such as alginic acid, primogel, or corn starch; a lubricant, such as magnesium stearate, hydrogenated castor oil, polyethylene glycol; a glidant, such as colloidal silicon dioxide; a sweetening agent, such as sorbitol, sucrose, aspartame or saccharin; or a flavoring agent, such as maltol, vanillin, menthol, citric acid,
  • Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors and the like.
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • (S)-Pregabalin in such compositions is typically a minor component, with the remainder being the injectable carrier and the like.
  • the invention provides the use of (S)-Pregabalin made by optical resolution of racemic Pregabalin of the present invention for the preparation of a medicament.
  • (S)-Pregabalin can be used, but not limited to, for the prophylaxis and/or treatment of condition or disorder related to diminished concentration of GABA; for the preparation of an anti-convulsant medicament, an anti-psychotic medicament, an anti-anxiety medicament, an anti-pain medicament.
  • Compositions of the present invention are useful for, but not limited to, the treatment of pain, epilepsy, convulsions, psychiatric disorders, attention deficit hypersensitivity disorder, anxiety and mood disorders.
  • the compound of the present invention for their therapeutic or preventive use in the above mentioned pathologies will be preferably used in a pharmaceutical composition suitable for the oral, rectal, parenteral (including subcutaneous, intravenous, intramuscular), topical, transdermal, ophtalmic and intranasal administration.
  • parenteral including subcutaneous, intravenous, intramuscular
  • topical including subcutaneous, intravenous, intramuscular
  • transdermal including asal
  • ophtalmic intranasal administration.
  • intranasal administration is oral.
  • the invention provides (S)-Pregabalin made by optical resolution of racemic Pregabalin of the present invention for use as a medicament. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.
  • Racemic Pregabalin can be prepared in accordance with well-known procedures.
  • Chiral HPLC analysis was performed on an Agilent 1100 with simple linear gradient of 0.05 M triethylamine (adjusted to pH 3 with phosphoric acid)/acetonitrile on a Spheri-5 RP- 18 cartridge column and a wavelength of 340 nm.
  • DSC thermal analysis was performed on a Mettler Toledo Star 822e differential scanning calorimeter. Approximately 2-5 mg samples were placed in aluminium pans and heated from 30 to 250 0 C in a dry nitrogen atmosphere at a heating rate of 10°C/minute.
  • Enantiomeric purity of the diastereomeric salts were determined by means of derivatization with FDAA (l-fluoro-2,4-dinitrophenyl-5-L-alanine amide, Marfey's reagent) in acetone and 1.0 M sodium bicarbonate at 40 0 C.
  • FDAA l-fluoro-2,4-dinitrophenyl-5-L-alanine amide, Marfey's reagent
  • the enriched diastereomeric salt (-)-O,O'-dibenzoyl-L-tartrate (VII) (21.5 g) was suspended in acetone (110 ml), and the mixture was refluxed for ten minutes. After cooling to 15°C, the solid was collected by filtration, washed with acetone and dried under vacuum at 50 0 C to afford the diastereomeric salt (S)-Pregabalin-(-)-O,O'- dibenzoyl-L-tartrate (VII) (17.2 g) as a white to off- white solid. Overall yield: 66%. Chiral Purity (HPLC): (S) > 99.5 %.
  • Step 2 The enriched diastereomeric salt (-)-O,O'-dibenzoyl-L-tartrate (VII) (23 g) was suspended in acetone (120 ml), and the mixture was refluxed for ten minutes. After cooling to 15°C, the solid was collected by filtration, washed with acetone and dried under vacuum at 50 0 C to afford the diastereomeric salt (S)-Pregabalin-(-)-O,O'- dibenzoyl-L-tartrate (VII) (18.4 g) as a white to off-white solid. Overall yield: 71%.

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Abstract

La présente invention porte sur un nouveau procédé de préparation de (S)-prégabaline par résolution optique de prégabaline racémique. Cette invention porte également sur le (S)-prégabaline-(-)-O,O'-dibenzoyl-L-tartrate ou un hydrate, un solvate, un polymorphe de celui-ci représenté par la Formule (VIIa) et sur deux formes cristallines de (S)-prégabaline-(-)-O,O'-dibenzoyl-L-tartrate.
PCT/EP2008/055722 2007-05-09 2008-05-08 Procédé de préparation de la (s)-prégabaline par résolution optique de prégabaline racémique WO2008138874A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009122215A1 (fr) * 2008-04-04 2009-10-08 Generics [Uk] Limited Nouveau procédé
WO2009087674A3 (fr) * 2007-12-18 2010-03-04 Watson Pharma Private Limited Procédé perfectionné pour la préparation de (s)-prégabaline
EP2527319A1 (fr) * 2011-05-24 2012-11-28 Laboratorios Del. Dr. Esteve, S.A. Formes cristallines de prégabaline et co-formateurs pour le traitement de la douleur
WO2014072785A2 (fr) 2012-11-07 2014-05-15 Hikal Limited Procédé de préparation de prégabaline

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5637767A (en) * 1995-06-07 1997-06-10 Warner-Lambert Company Method of making (S)-3-(aminomethyl)-5-methylhexanoic acid

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5637767A (en) * 1995-06-07 1997-06-10 Warner-Lambert Company Method of making (S)-3-(aminomethyl)-5-methylhexanoic acid

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009087674A3 (fr) * 2007-12-18 2010-03-04 Watson Pharma Private Limited Procédé perfectionné pour la préparation de (s)-prégabaline
WO2009122215A1 (fr) * 2008-04-04 2009-10-08 Generics [Uk] Limited Nouveau procédé
CN102089273A (zh) * 2008-04-04 2011-06-08 基因里克斯(英国)有限公司 新方法
EP2527319A1 (fr) * 2011-05-24 2012-11-28 Laboratorios Del. Dr. Esteve, S.A. Formes cristallines de prégabaline et co-formateurs pour le traitement de la douleur
ES2396663A1 (es) * 2011-05-24 2013-02-25 Laboratorios Del Dr. Esteve S.A. Forma cristalina de pregabalina y co-formadores en el tratamiento del dolor
WO2014072785A2 (fr) 2012-11-07 2014-05-15 Hikal Limited Procédé de préparation de prégabaline

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