WO2010007351A1 - Procédé de préparation de la mémantine et de ses sels et intermédiaire destiné à être utilisé dans ce procédé - Google Patents

Procédé de préparation de la mémantine et de ses sels et intermédiaire destiné à être utilisé dans ce procédé Download PDF

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Publication number
WO2010007351A1
WO2010007351A1 PCT/GB2009/001717 GB2009001717W WO2010007351A1 WO 2010007351 A1 WO2010007351 A1 WO 2010007351A1 GB 2009001717 W GB2009001717 W GB 2009001717W WO 2010007351 A1 WO2010007351 A1 WO 2010007351A1
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WO
WIPO (PCT)
Prior art keywords
memantine
process according
formula
alkali metal
compound
Prior art date
Application number
PCT/GB2009/001717
Other languages
English (en)
Inventor
Srinivas Laxminarayan Pathi
Rajendra Narayanrao Kankan
Original Assignee
Cipla Limited
Curtis, Philip, Anthony
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 Cipla Limited, Curtis, Philip, Anthony filed Critical Cipla Limited
Publication of WO2010007351A1 publication Critical patent/WO2010007351A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to an improved process for the preparation of memantine and its pharmaceutically acceptable salts. More particularly, the present invention provides an improved process for the preparation of memantine hydrochloride. The present invention further provides a process for the preparation of a novel key intermediate, 2-(3,5- dimethyl-adamantan-1-yl)-isoindole-1 ,3-dione, which is useful in the synthesis of memantine.
  • Memantine is chemically known as 3,5-dimethyl-1-adamantylamine and is represented by formula (I).
  • Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking N-methyl-D-asparate (NMDA) glutamate receptors.
  • NMDA N-methyl-D-asparate
  • the interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement the drug produces in Alzheimer's disease.
  • Memantine was first synthesized and patented by EIi Lilly and Company in US patent 3,391 ,142 as shown in Scheme 1 below.
  • the process involves bromination of 1 ,3-dimethyladamantane at reflux temperature to yield 1-bromo-3,5-dimethyladamantane; which in turn is reacted with 17 moles of acetonitrile and 35 moles of sulfuric acid at ambient temperature followed by isolation in benzene to yield 1-acetamido-3,5-dimethyl adamantane.
  • the intermediate is subjected to alkaline hydrolysis with NaOH in diethylene glycol at reflux temperature to yield crude memantine.
  • the crude product is then subjected to several extractions in benzene, followed by evaporation & isolation of memantine hydrochloride in ethereal HCI solution, which is further crystallized in a mixture of alcohol and ether.
  • EP1674446 discloses another method of synthesizing memantine as shown in Scheme 2 below.
  • 1-bromo-3,5-dimethyladamantane is reacted with urea in 80% formic acid at 80 0 C followed by acid hydrolysis to yield crude memantine which is further converted to memantine hydrochloride in ethanolic HCI.
  • the crude product is further crystallized in alcohol, ketone, water or a mixture thereof to yield pure memantine HCI.
  • US 4,122,193 discloses another method of preparing memantine hydrochloride in which 1- chloro-3,5-dimethyladamantane is reacted with urea at 22O 0 C in a closed vessel; followed by pulverization; acidifying with HCI; basifying with NaOH; extracting in ether and finally isolating memantine HCI by passing dry HCI gas.
  • US 5,599,998 discloses a synthesis of memantine comprising reacting 1-bromo-3,5- dimethyladamantane with lithium metal at O 0 C in ether by sonication followed by amination with ammonium chloride to yield memantine.
  • the disclosed method is cumbersome on an industrial scale due to the use of metallic lithium and chloramines, which can be hazardous on a large scale.
  • WO 2005/062724 discloses a process for preparing memantine wherein 1 ,3- dimethyladamantane is brominated and hydrolyzed to 1-hydroxy-3,5-dimethyladamantane, which is further converted to 1-acetamido-3,5-dimethyladamantane and further to memantine.
  • the preparation of memantine is also disclosed in other patents such as WO 2005/023753, CN 1400205, CN 1335299, WO 2006/122238, US2006/258885, WO 2007/096124, WO 2008/040560 and WO 2008/062472.
  • the object of the present invention is to provide an improved process for preparing memantine and its salts.
  • Another object of the present invention is to provide a novel intermediate which is useful in the synthesis of memantine.
  • Yet another object of the present invention is to provide an improved process for preparing the novel intermediate.
  • Yet another object of the present invention is to provide processes which are simple, economical and suitable for industrial scale up.
  • X is chloro or bromo, most preferably bromo.
  • the alkali metal phthalimide may be lithium phthalimide, sodium phthalimide or potassium phthalimide, preferably potassium phthalimide.
  • the advantages of the novel phthalimide intermediate Il include that it is easy to prepare and to hydrolyze. This is to be compared with the process disclosed in US 3,391 ,142, (see Scheme 1 above) which involves conversion of 1-bromo-3,5-dimethyladamantane to 1-acetamido-3,5-dimethyladamantane in the presence of acetonitrile and sulfuric acid. The 1-acetamido-3,5-dimethyladamantane is then purified in benzene which is a highly carcinogenic solvent.
  • the 1-acetamido-3,5-dimethyladamantane is converted to memantine by refluxing in a high boiling point solvent of diethylene glycol (boiling point 244-245°C) and sodium hydroxide. The compound is extracted several times with benzene. The free base is then converted to memantine hydrochloride in ether by adding hydrogen chloride gas.
  • ether is hazardous because of its highly flammable nature and its tendency to form peroxides.
  • undesirable by-products are produced in the Ritter reaction of the 1-bromo-3,5-dimethyladamantane product and acetonitrile in the presence of 96% sulfuric acid. The overall efficiency is 19.8% compared to that of the process of the present invention (23.9%).
  • the condensation step is carried out at a temperature below 140 0 C, suitably below 130 0 C.
  • the condensation step is carried out in the presence of a solvent.
  • the solvent may be an organic solvent, for example the organic solvent may be selected from the group consisting of methanol, ethanol, isopropyl alcohol (IPA), t-butanol, methyl isobutylketone, toluene, t-amylalcohol, acetonitrile, diglyme, N,N-dimethylformamide (DMF), dimethylsulphoxide (DMSO) xylene and hexamethyl phosphoramide (HMPA).
  • the compound of formula III may be synthesized by the methods known in the prior art, for example as disclosed in US 3,391 ,142. Suitably, compound III is synthesized by halogenation of 1 ,3-dimethyladamantane of formula IV.
  • the halogenating agent may be selected from fluorine, chlorine, bromine or iodine.
  • the halogenating agent is chlorine or bromine, most preferably bromine.
  • a process for the preparation of memantine of formula I or a salt thereof comprising hydrolyzing 2-(3,5-dimethyl-adamantan-1-yl)-isoindole-1 ,3-dione of formula Il to produce memantine of formula I.
  • the hydrolysis step is carried out in the presence of a base.
  • the base may be an organic base or an inorganic base.
  • the base may be selected from monomethylamine, dimethylamine, triethylamine, potassium carbonate, sodium carbonate and diisopropylethylamine.
  • the base may be used alone or as a mixture with water.
  • monomethylamine is used in a solution with water.
  • the hydrolysis step is carried out at a temperature below 50 0 C, preferably below 40 0 C 1 most preferably below 30 0 C.
  • the hydrolysis step is carried out at a temperature ranging from about 20 0 C to about 30 0 C, preferably from about 25°C to about 30°C.
  • memantine or a salt thereof prepared according to a process defined above.
  • the memantine prepared according to the process described above may be in any polymorphic form, including amorphous and crystalline form. It may also be in the form of a hydrate or solvate.
  • the salt of memantine 1 is the hydrochloride salt.
  • the conversion to memantine hydrochloride is carried out by reacting memantine with hydrochloric acid in an organic solvent.
  • the organic solvent may be a polar protic or aprotic solvent.
  • the solvent may be selected from acetone, tetrahydrofuran (THF), methanol, ethanol, isopropanol or a mixture thereof. In an embodiment, the solvent is not ether.
  • the hydrochloric acid may be added as a gas or in a solution.
  • the hydrochloride acid is used in a solution, where the solvent is a polar protic or aprotic solvent that is described above.
  • the mixture is maintained at a temperature ranging from about 10 0 C to about 30 0 C.
  • the mixture is maintained at a temperature ranging from about 1O 0 C to about 15°C.
  • the mixture is maintained at the temperature for a sufficient amount of time to allow the formation of memantine hydrochloride.
  • the mixture is maintained for a period of time ranging from about 1 to about 5 hours.
  • Memantine hydrochloride may then be isolated by any method known in the art, such as filtration and drying. Memantine hydrochloride may then optionally be purified by crystallization from suitable solvent.
  • memantine or a salt thereof prepared according to a process defined above, in medicine.
  • memantine or a salt thereof prepared according to a process defined above for treatment of Alzheimer's and Parkinson's disease.
  • the present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of a NMDA receptor antagonist in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of memantine, or a pharmaceutically acceptable salt thereof, prepared according to the present invention, substantially as hereinbefore described.
  • the present invention provides a novel compound, 2-(3,5- dimethyl-adamantan-1-yl)-isoindole-1 ,3-dione of formula Il
  • the invention provides a process for the preparation of the novel of compound of formula II, which process comprises reacting a 1-halo-3,5- dimethyladamantane of formula III (wherein X is selected from fluoro, chloro, bromo or iodo)
  • X is selected from chloro or bromo, most preferably bromo.
  • the solvent used may be selected from the group consisting of polar protic or aprotic solvents such as water, methanol, ethanol, propanol, isopropanol, tert-butanol, 1 ,4-dioxane, acetone, acetonitrile, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), dimethylformamide (DMF), or mixtures thereof; more preferably DMF.
  • polar protic or aprotic solvents such as water, methanol, ethanol, propanol, isopropanol, tert-butanol, 1 ,4-dioxane, acetone, acetonitrile, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), dimethylformamide (DMF), or mixtures thereof; more preferably DMF.
  • the present invention provides a novel synthesis of memantine of formula I from 1-halo-3,5-dimethyladamantane of formula III, via the novel intermediate compound of formula Il as depicted below in Scheme 3.
  • the base used in the hydrolysis step may be selected from inorganic bases such as alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides or organic bases such as primary, secondary or tertiary amines.
  • inorganic bases such as alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides or organic bases such as primary, secondary or tertiary amines.
  • reaction time and temperature may vary depending upon the solvent and base used.
  • Memantine obtained according to the process of the present invention may be further purified by acid/base treatment or by crystallization from solvents to obtain pharmaceutically acceptable grade memantine of formula I.
  • the invention provides the use of memantine or a salt thereof prepared according to a process defined above useful in treating Alzheimer's and Parkinson's disease.
  • the invention further describes a method of treating a disease state prevented, ameliorated or eliminated by the administration of a NMDA receptor antagonist in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of memantine, or a pharmaceutically acceptable salt thereof, prepared according to the present invention, substantially as hereinbefore described.
  • Memantine (10 gms, 0.0558 moles) was dissolved in ethanol (20 ml) at .25-35 0 C. Acetone (35 ml) was added and the reaction mass was cooled to 10-15 0 C. The reaction mass was acidified with IPA-HCI (16 ml) slowly over a period of 1 hour maintaining temperature at 10-15 0 C. The reaction mass was further stirred for 1 hour at 10-15 0 C. The solid obtained was isolated by filtration, washed with chilled isopropyl ether (40 ml) and dried under vacuum below 45-55 0 C to yield memantine hydrochloride (8.8 gm, 73.15%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur la 2-(3,5-diméthyl-adamantan-1-yl)-isoindole-1,3-dione de formule II, qui est utile comme intermédiaire dans la préparation de la mémantine et de ses sels. La présente invention porte également sur un procédé de préparation de la 2-(3,5-diméthyl-adamantan-1-yl)-isoindole-1,3-dione et sur un procédé de préparation de la mémantine ou d'un sel de celle-ci à l'aide de la 2-(3,5-diméthyl-adamantan-1-yl)-isoindole-1,3-dione.
PCT/GB2009/001717 2008-07-14 2009-07-10 Procédé de préparation de la mémantine et de ses sels et intermédiaire destiné à être utilisé dans ce procédé WO2010007351A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1474/MUM/2008 2008-07-14
IN1474MU2008 2008-07-14

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WO2010007351A1 true WO2010007351A1 (fr) 2010-01-21

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007096124A1 (fr) * 2006-02-21 2007-08-30 Hexal Ag Procédé de synthèse d'adamantanamines
WO2008062472A2 (fr) * 2006-10-24 2008-05-29 Cadila Healthcare Limited Procédé pour la préparation de mémantine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007096124A1 (fr) * 2006-02-21 2007-08-30 Hexal Ag Procédé de synthèse d'adamantanamines
WO2008062472A2 (fr) * 2006-10-24 2008-05-29 Cadila Healthcare Limited Procédé pour la préparation de mémantine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANTHONY A. ALLEN AND FREDERICK KURZER: "Di-isophorone and Related Compounds. Part 8 1-Aminodi-isophorane Derivatives", MONATSHEFTE FÜR CHEMIE, vol. 112, 1981, pages 617 - 626, XP002549250 *
T. LAUE AND A. PLAGENS: "Named Organic Reactions", 2005, JOHN WILEY & SONS, LTD, ISBN: 0-470-01040-1, XP002549251 *

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