News Column

Patent Issued for Process for Manufacturing Adamantane Derivatives with High Yield

August 20, 2014



By a News Reporter-Staff News Editor at Biotech Week -- Merz Pharma GmbH & Co. KGaA (Frankfurt am Main, DE) has been issued patent number 8796491, according to news reporting originating out of Alexandria, Virginia, by NewsRx editors (see also Merz Pharma GmbH & Co. KGaA).

The patent's inventors are Gold, Markus-Rene (Karlstadt, DE); Koller, Herbert (Vienna, AT); Pyerin, Michael (Brunn Am Gebirge, AT).

This patent was filed on August 7, 2009 and was published online on August 5, 2014.

From the background information supplied by the inventors, news correspondents obtained the following quote: "Memantine (1-amino-3,5-dimethyl adamantane), its therapeutic use and methods for its preparation are known in the art. For a summary of the prior art in this respect reference is made to U.S. provisional application 61/062,602 and EP 08001545.6.

"International Publication No. WO 2006/122238 discloses processes for preparing memantine or an acid addition salt of memantine, which involve either reaction of 1-bromo-3,5-dimethyladamantane with formamide to form N-formyl-1-amino-3,5-dimethyladamantane or reaction of 1-hydroxy-3,5-dimethyladamantane with a hydrogen halide to obtain 1-halo-3,5-dimethyl adamantane which is then reacted with formamide to yield N-formyl-1-amino-3,5-dimethyladamantane. The N-formyl-1-amino-3,5-dimethyladamantane intermediate is deformylated under acidic conditions to yield memantine hydrochloride. Excess of bromine is distilled off from the reaction mass, after the reaction is completed. The reactions disclosed therein are summarized in the following scheme 1:

"##STR00001##

"LV 1318613 B relates to a method of preparation of 1-amino-3,5-dimethyladamantane hydrochloride (memantine HCl) wherein 1,3-dimethyladamantane is reacted with nitric acid followed by addition of urea and heating of the reaction mixture. Nitric acid is added at 10-30.degree. C. to the pre-formed emulsion of the hydrocarbon in acetic acid and subsequently, 30-55% of aqueous urea solution is added in the molar ratio 1,3-dimethyladamantane-acetic acid-urea 1:3-4:9-12:2.5-5-0 accordingly.

"Kisilenko et al. ('Bromine complexes of 1-bromoadamantanes', Translation from Zhurnal Obshchei Khimii, vol. 57, No. 12, pg. 2659-2662, Plenum publishing corporation, pages 2370-2372, 1988) have shown that 1-bromoadamantanes form fairly stable complexes with bromine.

"The Russian patent application RU 2 309 940 discloses a method for the preparation of 3,5-dimethyladamantyl-1-amine or its salts. The method includes a stage of bromination of 1,3-dimethyladamantane with liquid bromine while boiling. Bromination is carried out with a molar ratio of 1,3-dimethyladamantane to bromine of 1 to 2 to 8, or 1 to 3 to 6, and the bromine is separated off by distillation. When using the claimed method, the yield of the target product is 63 to 75%. DIKTAT MR

"WO 2008/062472 also relates to a process for preparing memantine or an acid addition salt of memantine comprising the reaction of 1-bromo-3,5-dimethyladamantane with formamide to form 1-N-formyl-3,5-dimethyl adamantane."

Supplementing the background information on this patent, NewsRx reporters also obtained the inventors' summary information for this patent: "These and other objects are solved by a process comprises the amidation of a substituted 1-bromo-adamantane, e.g. 1-bromo-3,5-dimethyladamantane comprising a step (i) of reacting said substituted 1-bromo-adamantane, e.g. 1-bromo-3,5-dimethyladamantane, with an amide, wherein the substituted 1-bromo-adamantane, e.g. 1-bromo-3,5-dimethyladamantane is used in the form of a mixture comprising bromine.

"In one embodiment the method of the present invention comprises a step (0) wherein an excess of bromine is reacted with a substituted adamantane, e.g. 1,3-dimethyladamantane resulting in a mixture of a substituted 1-bromo-adamantane, e.g. 1-bromo-3,5-dimethyladamantane and bromine.

"In particular the invention relates to a process for the amidation of a substituted 1-bromo-adamantane comprising a step (0) of reacting a substituted adamantane with an excess of bromine to obtain a substituted 1-bromo-adamantane and a step (i) of reacting said substituted 1-bromo-adamantane with an amide, wherein the substituted 1-bromo-adamantane is used in the form of a mixture comprising bromine as obtained in step (0), wherein in step (0) a bromine:substituted adamantane molar ratio of from [2.5:1] to less than [5:1] is employed.

"In one embodiment of the present invention the amidation product of step (i) is further processed in a step (ii) to a 1-aminoadamantane derivative or a pharmaceutically acceptable salt thereof.

"In a further embodiment a bromine:substituted adamantane molar ratio from [2.8:1] to [3.5:1] is employed in step (0).

"In one embodiment of the instant invention in step (0) the bromine:substituted adamantine molar ratio is [3:1].

"In one embodiment the reaction temperature in step (0) is between 50 to 100.degree. C.

"The substituted 1-bromo-adamantane in said mixture of step (0) is present as a complex with bromine.

"In one embodiment the substituted 1-bromo-adamantane is 1-bromo-3,5-dimethyladamantane or 1-bromo-3,5-diphenyladamantane.

"In one embodiment the amide in step (i) is either acetamide or formamide.

"In one embodiment the molar ratio between the substituted adamantane and formamide ranges from [1:3] to [1:10].

"In one embodiment the substituted 1-bromo-adamantane and bromine are transferred to the formamide solution over a time period of 4 hours at a temperature ranging from 65.degree. C. to 85.degree. C. under constant agitation at 90 rpm to 100 rpm.

"In one embodiment step (ii) comprises acid hydrolysis of the amidation product of step (i) by employing an organic acid or an inorganic acid or a mixture of two or more organic acids, or a mixture of two or more inorganic acids or a mixture of at least one organic acid and at least one inorganic acid.

"In one embodiment the organic acid is selected from the group of para-toluenesulphonic acid, methanesulfonic acid, para-bromophenylsulphonic acid, carbonic acid, succinic acid, benzoic acid, maleic acid, tartaric acid, fumaric acid, methylsulfonic acid, formic acid, citric acid, acetic acid, oxalic acid and mixtures thereof and wherein the inorganic acid is selected from the group of hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, hydroiodic acid and mixtures thereof.

"In one embodiment the 1-aminoadamanatane derivative is selected from the group of memantine, amantadine, 1-Amino-methyladamantane, 1-Amino-3,5,7-trimethyladamantane, 1-Amino-3-ethyl-5-methyladamantane and 1-Amino-3-phenyladamantane, 1-Amino-3,5-dimethyladamantane, 1-Amino-3-ethyladamantane, 1-Amino-3-isopropyladamantane, 1-Amino-3-n-butyladamantane, 1-Amino-3,5-diethyladamantane, 1-Amino-3,5-diisopropyladamantane, 1-Amino-3-methyl-5-ethyladamantane, 1-Amino-3-butyl-5-phenyladamantane, 1-Amino-3-pentyladamantane, 1-Amino-3-dipentyladamantane, 1-Amino-3-pentyl-5-hexyladamantane, 1-Amino-3-pentyl-5-cyclohexyladamantane, 1-Amino-3-methyl-5-propyladamantane, 1-Amino-3-methyl-5-butyladamantane, 1-Amino-3-methyl-5-pentyladamantane, 1-Amino-3-methyl-5-hexyladamantane, 1-Amino-3-methyl-5-cyclohexyladamantane, 1-Amino-3-methyl-5-phenyladamantane, 1-Amino-3-ethyl-5-propyladamantane, 1-Amino-3-ethyl-5-butyladamantane, 1-Amino-3-ethyl-5-pentyladamantane, 1-Amino-3,5-dicyclohexyladamantane, 1-Amino-3-cyclohexyl-5-phenyladamantane, 1-Amino-3,5-diphenyladamantane, 1-Amino-3,5,7-trimethyladamantane, 1-Amino-3,5-dimethyl-7-ethyladamantane, 1-Amino-3-ethyl-5-hexyladamantane, 1-Amino-3-ethyl-5-cyclohexyladamantane, 1-Amino-3-ethyl-5-phenyladarnantane, 1-Amino-3-propyl-5-butyladamantane, 1-Amino-3-propyl-5-pentyladamantane, 1-Amino-3-propyl-5-hexyladamantane, 1-Amino-3-propyl-5-cyclohexyladamantane, 1-Amino-3-propyl-5-phenyladamantane, 1-Amino-3-butyl-5-pentyladamantane, 1-Amino-3-butyl-5-hexyladamantane, 1-Amino-3-butyl-5-cyclohexyladamantane or a pharmaceutically acceptable salt thereof.

"In one embodiment the pharmaceutically acceptable salt of 1-aminoadamantane derivative is selected from the group of hydrochloric, hydrobromic, methylsulfonic, perchloric, sulfuric, phosphoric, acetic, nitric, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, tartaric, citric, benzoic, carbonic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic, cyclohecanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, hydrobromic, hydroiodic, mesylate, phosphate, sulfate."

For the URL and additional information on this patent, see: Gold, Markus-Rene; Koller, Herbert; Pyerin, Michael. Process for Manufacturing Adamantane Derivatives with High Yield. U.S. Patent Number 8796491, filed August 7, 2009, and published online on August 5, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8796491.PN.&OS=PN/8796491RS=PN/8796491

Keywords for this news article include: Antidyskinetic, Antiparkinson Agents, Drugs, Bromine, Therapy, Halogens, Chemistry, Memantine, Adamantane, Amantadine, Formamides, Acetic Acid, Nitric Acid, Formic Acids, Hydrocarbons, Cycloparaffins, Dopamine Agent, Topical Agents, Bridged Compounds, Organic Chemicals, Otic Preparations, Nitrogen Compounds.

Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC


For more stories on investments and markets, please see HispanicBusiness' Finance Channel



Source: Biotech Week


Story Tools






HispanicBusiness.com Facebook Linkedin Twitter RSS Feed Email Alerts & Newsletters