- An Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of Lamotrigine
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2,3-Dichlorobenzoyl cyanide is a key intermediate in the synthesis of Lamotrigine. An assessment of various catalytic systems for the cyanation of 2,3-dichlorobenzoyl chloride with cyanide salts is described. High-throughput experimentation identified many conditions for effecting the requisite chemistry, including amine bases and phase-transfer catalysts, as well as catalyst-free conditions utilizing acetonitrile as a polar cosolvent. A novel catalyst, CuBr2, was identified by consideration of the possible oxidation of Cu(I) during high-throughput screening experimentation. CuCN was found to be the best cyanide source for achieving clean conversion; however, the solubility of CuCN was the major factor limiting reaction rate under many conditions. Improving CuCN solubility by using acetonitrile as solvent enhanced the reaction rate even in the absence of the catalysts tested but significantly complicated isolation of the product. With no acetonitrile cosolvent, phase-transfer catalysts such as tetrabutylammonium bromide (TBABr) are effective; however, use of TBABr led to inconsistent reaction profiles from run-to-run, due to an unexpected clumping of the CuCN solid. Switching to cetyltrimethylammonium bromide (CTAB) alleviated this clumping behavior, leading to consistent reactivity. This CTAB-catalyzed process was scaled up, giving 560 kg of 2,3-dichlorobenzoyl cyanide in 77% isolated yield.
- Leitch, David C.,John, Matthew P.,Slavin, Paul A.,Searle, Andrew D.
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p. 1815 - 1821
(2017/11/24)
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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 0031
(2017/07/21)
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- Regioselective synthesis of 1-substituted indazole-3-carboxylic acids
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In this article, we study the synthesis of 1-substituted indazole-3-carboxylic acids from 2-halobenzoic acids.
- Veerareddy, Arava,Gogireddy, Surendrareddy,Dubey
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p. 1311 - 1321
(2015/04/27)
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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 12
(2008/06/13)
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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 14
(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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- 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
(2010/01/31)
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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-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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