- Improved method for synthetizing lamotrigine
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The invention discloses an improved method for synthetizing lamotrigine. The method comprises the following steps: step I, carrying out helogenating reaction through 3-amino-1,2,4-triazine (I) and a halogenating reagent in the presence of an organic solvent to obtain 3-amino 6-halogeno-1,2,4-triazine (II); step II, carrying out amination reaction of a compound II to prepare 3,5-diamino 6-halogeno-1,2,4-triazine (compound III); and step III, carrying out suzuki coupling reaction through the compound III and 2,3-dichlorobenzene boric acid derivative in the solvent under catalysis of palladium/[N,N] pyridine amidino ligand/alkali to prepare lamotrigine (IV). Through the method, metal cyanide is not used; meanwhile, the method is high in reaction selectivity and high in reaction yield.
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Paragraph 0049-0061
(2018/07/06)
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- Improved synthesis process for lamotrigine
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The invention discloses an improved synthesis process for lamotrigine. The process comprises the following steps: (1) synthesizing 2,3-dichlorobenzoyl cyanide: adding 2,3-dichlorobenzoic acid and thionyl chloride into a reactor, carrying out depressurized evaporating to remove thionyl chloride after a reaction is completed, adding cuprous cyanide into the reactor, and filtering out solids after a reaction is completed, so as to obtain a 2,3-dichlorobenzoyl cyanide solution; (2) preparing a condensate: adding aminoguanidine carbonate and an entrainer into a reactor, dropwise adding concentrated sulfuric acid, distilling off the entrainer and water, carrying out suction filtration, enabling solids to enter a reaction bottle, carrying out depressurized pumping, then, adding the 2,3-dichlorobenzoyl cyanide solution obtained in the step (1) into the reaction bottle, cooling the reaction bottle to room temperature after a reaction is completed, and carrying out suction filtration, so as to obtain the condensate; and (3) preparing cyclics: adding liquid alkali into the condensate obtained in the step (2), and carrying out crystallizing, filtering, washing and baking after a reaction, thereby obtaining the lamotrigine. According to the improved synthesis process for the lamotrigine, the quality and yield of the product, i.e., the lamotrigine can be remarkably increased, and the yield reaches 90% or more.
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Paragraph 0033
(2017/07/21)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF LAMOTRIGINE
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The present invention relates to an improved process for the preparation of Lamotrigine (I) comprising a step of cyclizing 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile(III) in the presence of an alcohol and an acid.
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Page/Page column 3; 5
(2009/07/03)
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- Improved method for synthesizing lamotrigine
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The invention relates, in general, to an improved process for preparing lamotrigine and related compounds. Processes for preparing and purifying lamotrigine, including lamotrigine hydrate, lamotrigine monohydrate and anhydrous lamotrigine, are described.
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Page/Page column 7
(2009/12/23)
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- A PROCESS FOR THE PREPARATION OF LAMOTRIGINE
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A novel process for the preparation of lamotrigine and its intermediates is devised.
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Page/Page column 13
(2008/06/13)
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- A NOVEL PROCESS FOR THE SYNTHESIS OF LAMOTRIGINE AND ITS INTERMEDIATE
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This invention discloses a process for the preparation of 3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine of a formula (I), commonly known as Lamotrigine which comprises the step of reacting aminoguanidine bicarbonarte and 2,3- dichlorobenzocynide with a reagent prepared by dissolving phosphorus pentoxide and methane sulfonic acid, to produce a novel intermediate 2-(2,3-dichlorophenyl)-2-(aminoguanidine)-acetonitrile monomesylate which is further cyclized to lamotrigine without basification.
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Example 2; 3
(2010/11/27)
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- METHOD FOR PREPARING LAMOTRIGINE AND ITS INTERMEDIATE 2,3-DICHLOROBENZOYL CHLORIDE
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The invention relates to an improved method for preparing 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, also commonly known as lamotrigine. The present invention also relates to a method for preparing the intermediate 2,3-dichlorobenzoyl chloride, which comprises the synthesis by photochlorination of 2,3-dichlorobenzotrichloride followed by hydrolysis thereof. Said 2,3-dichlorobenzoyl chloride intermediate is useful for preparing lamotrigine.
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Page/Page column 16-17
(2010/11/29)
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- LAMOTRIGINE MONOHYDRATE
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The invention relates to lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) monohydrate (Ia) and anhydrous lamotrigine, and a process for preparing the same. An improved process is provided for manufacturing the lamotrigine (I). The process comprises of reacting 2,3-dichlorobenzoyl cyanide (II) with aminoguanidine bicarbonate in aqueous mineral acid, optionally together with a water miscible organic solvent, at 30 - 80 °C to produce the 2-(2,3-dichlorophenyl)-2-(guanidinylamino)acetonitrile (Schiff base). The Schiff base is further cyclised in aqueous alcohol to produce pure lamotrigine of a pharmaceutically acceptable quality which on further drying at 45 - 50 °C under vacuum yields lamotrigine monohydrate, and/or on further drying at 100 - 110 °C yields anhydrous lamotrigine. The lamotrigine monohydrate or anhydrous lamotrigine thereby produced may then be brought into association with a pharmaceutically acceptable carrier for administration to a patient in need thereof.
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- A new approach to the synthesis of lamotrigine and other 3,5-diamino-1,2,4-triazine derivatives
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A new in principle method for the synthesis of 6-aryl(hetaryl)-3,5-diamino- 1,2,4-triazines by decomposition of pre-synthesized tetrazolo[1,5-b][1,2,4] triazines was developed. The advantages of this method over traditional methods were demonstrated using the synthesis of a modern antiepileptic preparation lamotrigine, as an example.
- Ulomskii,Shestakova,Deev,Rusinov,Chupakhin
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p. 726 - 732
(2007/10/03)
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- NEW PROCESS FOR THE SYNTHESIS OF HIGH PURITY 3,5-DIAMINO-6-(2, 3-DICHLOROPHENYL)-1,2,4-TRIAZINE
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The present invention relates to a new process for the synthesis of high purity 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine of formula (I) using 2,3-dichlorobenzoyl cyanide and an aminoguanidine salt as starting materials. 2,3-dichlorobenzoyl cyanide is reacted with 1-2 mol equivalent of aminoguanidine salt in 3-6 mol equivalent of methanesulfonic acid, then the obtained adduct of formula (IV) is transformed without isolation into the product with magnesium oxide. In given case the obtained crude product can be recrystallized from a proper organic solvent.
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- PROCESS FOR PREPARING A PHARMACEUTICALLY ACTIVE COMPOUND AND FOR PREPARING ITS INTERMEDIATE
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The invention discloses a method for preparing the intermediate 2-(2,3-dichlorophenyl)-2-(aminoguanidine) acetonitrile of formula (II), which comprises the reaction of 2,3-dichlorobenzoyl cyanide with aminoguanidine bicarbonate in non-aqueous medium in the presence of methanesulphonic acid, which produces good yields and short reaction times. Said intermediate is useful for preparing 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine of formula (I). The invention also relates to a method for preparing (I) with high purity.
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- Compositions of a cyclooxygenase-2 selective inhibitor and a sodium ion channel blocker for the treatment of pain, inflammation or inflammation mediated disorders
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The present invention provides compositions and methods for the treatment of pain, inflammation or inflammation-mediated disorders in a subject. More particularly, the invention provides a combination therapy for the treatment of pain, inflammation or inflammation mediated disorders comprising the administration to a subject of a sodium ion channel blocker in combination with a cyclooxygenase-2 selective inhibitor.
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- Method for producing lamotrigine from alpha-oxo-2,3-dichlorophenyl acetamidino-aminoguanidino hydrazone by ring closure reaction
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The present invention relates to a method for producing 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (lamotrigine) by cyclization reaction from α-oxo-2,3-dichlorophenylacetamidino-aminoguanidino-hydrazone.
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Page/Page column 4
(2008/06/13)
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- Process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine
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A process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3-5-diamine (lamotrigine) of the formula I: 2,3-Dichloronitrobenzene in C1-C6aliphatic alkanol is hydrogenated at 55-90 psi gas pressure using metal catalyst at 27-35° C. 2,3-Dichloroaniline is diazotised and cyano-de-diazonised with metal cyanide at 65-80° C. 2,3-Dichlorobenzonitrile is hydrolysed and 2,3-dichlorobenzoic acid is chlorinated at 55-130° C. Cyano-de-halogenation of 2,3-dichlorobenzoyl chloride is carried out with a metal cyanide and alkali metal iodide by refluxing in an aprotic solvent under an inert atmosphere. 2,3-Dichlorobenzoyl cyanide is condensed with aminoguanidine bicarbonate in an organic solvent in acidic conditions using catalyst at 90-125° C. followed by insitu cyclisation of the Schiff's base by refluxing in an aliphatic alkanol with base. Crude lamotrigine is purified.
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Page/Page column 8-9
(2010/01/31)
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- Crystal forms of lamotrigine and processes for their preparations
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The present invention relates to lamotrigine, a useful agent for anti-epilepsia. New crystal forms of lamotrigine containing molecules of the solvent in stoichiometric ratios are disclosed. The present invention also provides processes for preparing the new crystal forms of lamotrigine.
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- Efficient process for the preparation of lamotrigine and related 3,5-diamino-6-substituted-1,2,4-triazines
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A process for the manufacture of 3,5-diamino-6-substituted-1,2,4-triazines is disclosed which comprises the steps of: (a) reacting a compound of formula (II): ?with aminoguanidine salts, (b) dehydrating the compound obtained to form a compound of formula IV, ?and (c) cyclization of the compound of formula IV into a 3,5-diamino-6-substituted-1,2,4-triazine compound of formula I or into a hydrated form thereof.
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- Process for preparing substituted benzoyl cyanide amidinohydrazones
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The present invention provides a process for preparing a compound of the general formula (I): wherein R1 to R5 are independently selected from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or C1-6 alkoxy, all optionally substituted by one or more of halogen, hydroxy and aryl groups, as well as being independently selected from amino, mono- or disubstituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and alkylthio groups, which process comprises reacting a compound of the general formula (II): wherein R1 to R5 are as defined in formula (I), with aminoguanidine bicarbonate in a mixture of a water-soluble solvent and polyphosphoric acid.
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- Process for preparing substituted Benzoyl Cyanide Amidinohydrazones
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The present invention provides a process for preparing a compound of the general formula (I):wherein R1to R5are independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl or C1-6alkoxy, all optionally substituted by one or more of halogen, hydroxy and aryl groups, as well as being independently selected from amino, mono- or disubstituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and alkylthio groups, which process comprises reacting a compound of the general formula (II):wherein R1to R5are as defined in formula (I), with aminoguanidine bicarbonate in a mixture of a water-soluble solvent and polyphosphoric acid.
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- Process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine
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There is disclosed an improved process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine which process comprises the step of reacting 2,3-dichlorobenzoylchloride with cuprous cyanide in presence of acetonitrile and a cosolvent to produce dichlorobenzoyl cyanide, said dichlorobenzoyl cyanide is reacted with aminoguanidine bicarbonate to produce an intermediate product, which is cyclized in presence of aqueous potassium hydroxide to produce 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine.
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- 1,2,4-Triazine derivative, its preparation and its use as reference marker for testing purity and stability of "lamotrigine"
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A method of testing the purity or stability to degradation of a sample of lamotrigine or a pharmaceutical dosage form comprising lamotrigine comprises assaying the said sample for the presence of a compound selected from 3-amino-6-(2,3-dichlorophenyl)-1,2,4-triazine-5-(4H)-one (compound A) and N-[5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazine-3-yl]-2,3-dichlorobenzamide (compound B). A process for producing compound B, which is novel, is also disclosed.
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- Process for the preparation of lamotrigine
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The invention provides a process for producing lamotrigine of formula (I): STR1 which process comprises subjecting a compound of formula (II): STR2 wherein R is CN or CONH2, in an organic solvent, to ultra violet or visible radiation and, when R is CN, to heat.
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- Process for the preparation of lamotrigine
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Lamotrigine, 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, may be prepared by treating 6-(2,3-dichlorophenyl)-5-chloro-3-thiomethyl-1,2,4-triazine of formula (II) STR1 with ammonia. Precursors to the compound of formula (II), and their preparation, are also described.
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- Triazine salt
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3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine isethionate is provided. This salt has high water solubility and thus advantageously allows parenteral administration in the form of a sterile aqueous solution suitable for injection.
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- 1,2,4-triazines
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Compounds of Formula I are novel and useful as cardiovascular agents, particularly anti-arrhythmic agents: STR1 or the 5-imino-tautomer thereof or a salt of either, wherein R1 is C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C3-10 cycloalkyl, any of which is optionally substituted, and R2 to R6 are independently selected from hydrogen, halogen atom, C1-6 alkyl, alkenyl or alkynyl (all optionally substituted by one or more of halogen, hydroxy and aryl, amino, mono- or di-substituted amino, alkoxy (optionally substituted by one or more of halogen, hydroxy and aryl), alkenyloxy, aryl, acyloxy, cyano, nitro, aryl and alkylthio groups or any adjacent two of R2 to R6 are linked to form a (--CH=CH--CH=CH--) group.
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