WO2007069265A1 - Nouveau procede de synthese de lamotrigine et de son intermediaire - Google Patents

Nouveau procede de synthese de lamotrigine et de son intermediaire Download PDF

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Publication number
WO2007069265A1
WO2007069265A1 PCT/IN2006/000357 IN2006000357W WO2007069265A1 WO 2007069265 A1 WO2007069265 A1 WO 2007069265A1 IN 2006000357 W IN2006000357 W IN 2006000357W WO 2007069265 A1 WO2007069265 A1 WO 2007069265A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
lamotrigine
dichlorophenyl
aminoguanidine
acetonitrile
Prior art date
Application number
PCT/IN2006/000357
Other languages
English (en)
Inventor
Arul Ramakrishnan
Vasant Dabholkar Bhushan
B. Deore Dinesh
Original Assignee
Unichem Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Unichem Laboratories Limited filed Critical Unichem Laboratories Limited
Publication of WO2007069265A1 publication Critical patent/WO2007069265A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members 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
    • C07D253/075—Two hetero atoms, in positions 3 and 5

Definitions

  • This invention relates to a new method for preparing a pharmaceutically active compound with antiepileptic properties.
  • Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder.
  • epilepsy it is used to treat partial seizures, primary and secondary tonic- clonic seizures, and seizures associated with Lennox-Gastaut syndrome. It also acts as a mood stabilizer. It is the only anticonvulsant mood stabilizer that treats the
  • the European patent 247892 describes a process in which 8 M solution of Sulphuric acid is used instead of 8 N Nitric acid in the condensation reaction and the reaction
  • S time is 41 hrs.
  • the cyclisation is carried out in n-propanol at reflux temperature to yield 41% of the product.
  • a similar process is disclosed in WO 2000/35888, in which condensation is carried out in a mixture of dilute Sulphuric acid and acetonitrile for 60 hrs. and then cyclisation is carried out with 1% aqueous potassium hydroxide.
  • the crude product is purified by recrystalisation in methanol with the help of clarifier to
  • US633198 also describes a process, which is modification of the above process, where cyclisation is carried out in n-propanol to get 60% yield of product with reaction time of 4,4 to 48 hrs. This has also a disadvantage of long reaction time and aggressive reaction medium.
  • US6639072 also 'describes the similar process for preparing Schiff base using 2,3- dichlorobenzoyl cyanide, aminoguanidine bicarbonate, and concentrated Sulphuric acid. Using p-toluene sulphonic acid as a catalyst and toluene as a solvent at 110° C. Although under such condition a reduced reaction time is achieved but the overall yield (50%) and quality suffer.
  • PCT publication WO96/20935 describes a six-steps process, which is difficult to carry out, and hardly realizable on industrial scale, as well as the yield of the final product is very low.
  • the disadvantages of this process are complicated synthesis and applied hazardous reagents.
  • PCT application WO03/078407 describes a process in which aminoguanidine is condensed with 2,3-dichlorobenzoyl cyanide in presence of methane sulphonic acid in a polar solvent e.g. DMSO, DMF or NMP, subsequently the dehydrating agents are used such as thionyl chloride, phosphorous oxychloride, phosphorous trichloride or
  • an object of the invention is to provide a process for the preparation of
  • Another object of the invention is to provide a process for the preparation of 3,5- Diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine of a formula (I), commonly known as S Lamotrigine, which is safe and convenient.
  • a formula (I) commonly known as S Lamotrigine
  • Another object of the invention is to provide a process for the preparation of 3,5- Diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine of a formula (I), commonly known as Lamotrigine, which is less time consuming as well as involves less number of reaction steps.
  • a formula (I) commonly known as Lamotrigine
  • Another object of the invention is to provide a process for the preparation of 3,5- -" ' Diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine of a formula (I), commonly known as Lamotrigine, which is efficient and economical.
  • Another object of the invention is to provide a process for the preparation of 3,5- Diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine of a formula (I), commonly known as ⁇ ⁇ 5 Lamotrigine, which is suitable for industrial scale manufacture
  • the present invention provides a novel process for the preparation of lamotrigine and its intermediate having formula (II), which comprises: ' a) preparation of reagent by dissolving phosphorous penta oxide in methane sulfonic acid. b) treatment of aminoguanidine bicarbonate and 2,3- dichlorobenzoylcyanide with the reagent formed in (a) under anhydrous condition to form an intermediate of formula (II)
  • the reagent is prepared by dissolving phosphorus pentaoxide in methane sulfonic acid and stirring for two hours at room temperature. Methane sulfonic acid and phosphorus pentaoxide may be taken in molar ratio of 9:1. Aminoguanidine bicarbonate is added to the prepared reagent. Subsequently, 2,3- s dichlorobenzoylcyanide is added. The reaction mass is stirred for 15-30 hrs. preferably for 20-24 hrs.
  • 2-(2,3-Dichlorophenyl)-2-(aminoguanidine)-acetonitrile monomesylate having formula (II) is isolated by addition of reaction mass into water while maintaining the temperature in the range of 20-40° C. preferably in the range of 20-25X.
  • lower alkyl alcohol to obtain crude lamotrigine.
  • the lower alkyl alcohol may be straight chain C 1 -C3 aliphatic alcohol such as methanol, Isopropanol, or ethanol and preferably methanol.
  • the isolated crude Lamotrigine can be recrystalized by dissolving it in a solution of Isopropanol - water in a ratio 9:1 at reflux temperature and by treating with activated carbon.
  • the hot solution is filtered through hyflow and water is removed by azeotropic distillation of isopropanol till water content reaches to less than 1%.
  • the obtained solid is filtered and dried under vacuum at 65° C. for 15-20 hrs, to get anhydrous lamotrigine.
  • phosphorus pentaoxide used to prepare a reagent is solid in nature and the quantity required for the reaction is low i.e. in the ratio 1:1.5 molar 5 ratio. It is relatively less hazardous as compared to the drying agents used in all state of the art process. No toxic solvent has been used hence the process is green.
  • the reaction for the preparation of intermediate is carried out at room temperature. It makes the process, economical and the product purer since the formation of undesired impurity suppressed at this temperature.
  • the present process avoids the basification of the intermediate 2-(2,3- dichlorophenyl)-2-(aminoguanidine)-acetonitrile monomesylate of formula (II) to Schiff base. It significantly reduces the production cost at industrial scale.
  • 2-(2,3-dichlorophenyl)-2-(aminoguanidine)-acetonitrile monomesylate mild base is used which further improves the quality.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de 3,5-diamino-6-(2,3-dichlorophényl)-1,2,4-triazine de formule (I), connu sous le nom de Lamotrigine qui comprend les étapes consistant à mettre en réaction du bicarbonate d'aminoguanidine et 2,3-dichlorobenzocynide avec un réactif préparé par dissolution de pentoxyde de phosphore et d'acide sulfonique de méthane, afin de produire un nouvel intermédiaire de monomésylate de 2-(2,3-dichlorophényl)-2-(aminoguanidine)-acétonitrile qui est en outre cyclisé en lamotrigine sans alcalinisation.
PCT/IN2006/000357 2005-12-12 2006-09-12 Nouveau procede de synthese de lamotrigine et de son intermediaire WO2007069265A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1532/MUM/2005 2005-12-12
IN1532MU2005 2005-12-12

Publications (1)

Publication Number Publication Date
WO2007069265A1 true WO2007069265A1 (fr) 2007-06-21

Family

ID=38162610

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000357 WO2007069265A1 (fr) 2005-12-12 2006-09-12 Nouveau procede de synthese de lamotrigine et de son intermediaire

Country Status (1)

Country Link
WO (1) WO2007069265A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008019798A1 (fr) * 2006-08-14 2008-02-21 Lonza Ag Procédé de préparation de lamotrigine
WO2009069073A1 (fr) * 2007-11-28 2009-06-04 Alembic Limited Procédé amélioré de préparation de lamotrigine
CN102070545A (zh) * 2010-10-22 2011-05-25 蒋勇 制备拉莫三嗪的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035888A1 (fr) * 1998-12-14 2000-06-22 Sharad Kumar Vyas Procede et appareil ameliore de preparation de 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine
WO2004039767A1 (fr) * 2002-10-31 2004-05-13 Vita Cientifica, S.L. Procede de preparation d'un compose actif d'un point de vue pharmaceutique et sur un procede de preparation de son intermediaire

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035888A1 (fr) * 1998-12-14 2000-06-22 Sharad Kumar Vyas Procede et appareil ameliore de preparation de 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine
WO2004039767A1 (fr) * 2002-10-31 2004-05-13 Vita Cientifica, S.L. Procede de preparation d'un compose actif d'un point de vue pharmaceutique et sur un procede de preparation de son intermediaire

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008019798A1 (fr) * 2006-08-14 2008-02-21 Lonza Ag Procédé de préparation de lamotrigine
WO2009069073A1 (fr) * 2007-11-28 2009-06-04 Alembic Limited Procédé amélioré de préparation de lamotrigine
CN102070545A (zh) * 2010-10-22 2011-05-25 蒋勇 制备拉莫三嗪的方法

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