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WO2011125062A1 - Procédé de préparation d'hydrochlorure de mémantine - Google Patents

Procédé de préparation d'hydrochlorure de mémantine Download PDF

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Publication number
WO2011125062A1
WO2011125062A1 PCT/IN2010/000230 IN2010000230W WO2011125062A1 WO 2011125062 A1 WO2011125062 A1 WO 2011125062A1 IN 2010000230 W IN2010000230 W IN 2010000230W WO 2011125062 A1 WO2011125062 A1 WO 2011125062A1
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WO
WIPO (PCT)
Prior art keywords
hydrochloride
amino
dimethyladamantane
memantine
process according
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IN2010/000230
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Rapolu Raji Reddy
Matta Ramakrishna Reddy
Bandi Vamsi Krishna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hetero Research Foundation
Original Assignee
Hetero Research Foundation
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 Hetero Research Foundation filed Critical Hetero Research Foundation
Priority to EP10849334.7A priority Critical patent/EP2555616A4/fr
Priority to PCT/IN2010/000230 priority patent/WO2011125062A1/fr
Publication of WO2011125062A1 publication Critical patent/WO2011125062A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/013—Preparation of halogenated hydrocarbons by addition of halogens
    • C07C17/06—Preparation of halogenated hydrocarbons by addition of halogens combined with replacement of hydrogen atoms by halogens
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/84—Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • 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 provides an improved process for the preparation of 1- bromo-3,5-dimethyladamantane.
  • the present invention also provides a process for preparing free flowing solid of l-acetamido-3,5-dimethyladamantane.
  • the present invention further provides a process for the preparation of memantine hydrochloride substantially free of l-amino-3,5,7-trimethyladamantane hydrochloride and/or 1- amino-3-methyladamantane hydrochloride impurity.
  • Memantine hydrochloride is chemically, 3,5-dimethyltricyclo-[3.3.1.1 3 ' 7 ]decan-l-amine hydrochloride and has the structural formula:
  • Memantine hydrochloride is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA glutamate receptors.
  • the interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement the drug produces in Alzheimer's disease.
  • Memantine hydrochloride is marketed under the brand name Namenda ® by Forest Labs.
  • U.S. Patent No. 3,391,142 disclosed process comprises of reacting 1-bromo- 3,5-dimethyladamantane with sulphuric acid in acetonitrile gives l-acetamido-3,5- dimethyl adamantine, followed by deacetylation in diethylene glycol with sodium hydroxide at reflux temperature which gives memantine.
  • the obtained memantine is converted into its hydrochloride salt by treating with anhydrous hydrogen chloride and recrystallized from a mixture of alcohol and ether.
  • This process involves the addition of bromine at reflux condition for the preparation of starting compound l-bromo-3,5- dimethy ladamantane .
  • PCT Publication no. WO 2006/122238 disclosed a process for the preparation of memantine hydrochloride, which comprises reacting l-bromo-3,5-dimethyl adamantane with formamide to form l-N-formyl-3, 5 -dimethyl adamantine, converting
  • U.S. Patent application no. 2006/0173215 disclosed a process for the preparation of n-acetamido-3,5-dimethyladamantane by reacting l-bromo-3,5- dimethyladamantane and a nitrile, the presence of phosphoric acid at about 50 to 100°C and for a period of time sufficient to produce n-acetamido-3,5- dimethy ladamantane.
  • a process for the preparation of memantine hydrochloride by dissolving n-acetamido-3,5- dimethyladamantane in a solvent selected from the group consisting of C 3- 6 alcohols such as n-butanol in the presence of a strong inorganic base such as potassium hydroxide or sodium hydroxide for a sufficient period of time to obtain memantine and reacting the memantine with hydrogen chloride or hydrochloric acid to obtain memantine hydrochloride.
  • a solvent selected from the group consisting of C 3- 6 alcohols such as n-butanol
  • a strong inorganic base such as potassium hydroxide or sodium hydroxide
  • U.S. Patent application no. 2006/0258885 disclosed a process for the preparation of l -acetamido-3,5-dimethyl-adamantane, which comprising the 1-chloro- 3, 5 -dimethy ladamantane, 5-10 equivalents of acetonitrile and 5-20 equivalents of glacial acetic acid, to provide a reaction mixture, the reaction mixture 3-10 equivalents of concentrated sulfuric acid, to provide l-acetamido-3,5-dimethyl-adamantane.
  • memantine hydrochloride which comprising the l-acetamido-3,5-dimethyl-adamantane, 5-20 equivalents of an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide and a solvent chosen from the group consisting of l-methoxy-2-propanol,
  • PCT Publication no. WO 2007/132476 disclosed a process for the preparation of memantine hydrochloride, which comprises 3,5-Dimethyladamantane is reacted with bromine to form l-bromo-3,5,- dimethyladamantane at reflux, it is reacted with acetonitrile in the presence of sulphuric acid to form l-acetamido-3,5- dimethyladamantane.
  • l-acetamido-3,5-dimethyladamantane is treated with an organic acid such as p-toulene sulfonic acid or benzene sulfonic acid to form 1- acetamido-3,5-dimethyladamantane p-toluene sulfonate, which is setting free of salt in the presence of base such as ammonia to get the pure l-acetamido-3,5- dimethyladamantane.
  • l-acetamido-3,5-dimethyladamantane is subjected to hydrolysis followed by in-situ reaction with hydrochloric acid to form memantine hydrochloride.
  • PCT Publication no. WO 2008/040560 disclosed a process for the preparation of memantine, which comprises reacting N-chloro-acetyamino-3,5- dimethyladamantane with thiourea in the presence of an organic solvent such as isopropanol, and optionally recovering memantine and its hydrochloride acid salt form from reaction mixture.
  • an organic solvent such as isopropanol
  • U.S. Patent application no. 2008/0033054 disclosed a process for preparing memantine hydrochloride containing less than about 0.15% of at least one of 1-amino- 3-methyladamantane hydrochloride or l-amino-3,5,7-trimethyladamantane hydrochloride.
  • PCT Publication no. WO 2008/062472 disclosed a process for the preparation of memantine hydrochloride, which comprises reacting 1,3 -dimethyl adamantane with bromine in methylene chloride to provide l-bromo-3,5-dimethyl adamantine which is reacted with acetamide in presence of anhydrous sodium sulfate to provide 1- acetamido-3,5-dimethyl adamantine and treated with sodium hydroxide in presence of toluene to obtain memantine.
  • acetamide in presence of anhydrous sodium sulfate
  • 1- acetamido-3,5-dimethyl adamantine optionally converting memantine to memantine hydrochloride by treating memantine with hydrochloride in isopropyl alcohol.
  • WO 2009/057140 disclosed a process for the preparation of memantine hydrochloride which comprises reacting a 1,3 -dimethyl adamantane with acetonitrile in presence of sulphuric acid at a temperature of about 50 to 70°C for a sufficient period of time about 2 to 15 hours to provide l-acetamido-3,5- dimethyladamantane in absence of any solvent, hydrolysis with a sodium hydroxide in polyethylene glycol at a temperature of about 120 to 180°C for a sufficient period of time about 2 to 25 hours provides mantine which on subsequent treatment with hydrochloric acid in isopropyl alcohol followed by adding ethyl acetate to obtain memantine hydrchloride.
  • the common impurities of the memantine hydrochloride are l-amino-3,5,7- trimethyladamantane hydrochloride and l-amino-3-methyladamantane hydrochloride.
  • one object of the present invention is to provide an improved process for the preparation of l-bromo-3,5-dimethyladamantane.
  • Another object of the present invention is to provide a process for preparing free flowing solid of l-acetamido-3,5-dimethyladamantane.
  • Yet another object of the present invention is to provide a process for the preparation of memantine hydrochloride substantially free of l-amino-3,5,7- trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity.
  • an improved process for the preparation of l-bromo-3,5-dimethyladamantane which comprises reacting dimethyladamantane with bromine at 15 to 35°C to obtain 1- bromo-3 ,5-dimethyladamantane.
  • the reaction may preferably be carried out in the presence or absence of a solvent.
  • a process for preparing free flowing solid of l -acetamido-3,5-dimethyladamantane which comprises stirring l-acetamido-3,5-dimethyladamantane with water at above 35°C and isolating the free flowing solid of l-acetamido-3,5-dimethyladamantane.
  • the l-acetamido-3, 5 -dimethyladamantane used in the process can be obtained by previously known methods.
  • the stirring may be carried out at 40 to 80°C and more preferably at 45 to 60°C.
  • Isolation of free flowing solid of l-acetamido-3, 5 -dimethyladamantane may preferably be carried out by the methods known such as filtration or centrifugation.
  • a process for the preparation of memantine hydrochloride substantially free of 1-amino- 3,5,7-trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity which comprises: a) dissolving memantine hydrochloride containing l-amino-3, 5,7- trimethyladamantane hydrochloride and l-amino-3 -methyladamantane hydrochloride impurity in an alcohol solvent;
  • step (b) heating the solution obtained in step (a) at reflux;
  • step (b) adding ketonic solvent to the solution obtained in step (b);
  • step (c) maintaining the solution obtained in step (c) at below 50°C;
  • memantine hydrochloride substantially free of l-amino-3, 5,7- trimethyladamantane hydrochloride and/or l-amino-3 -methyladamantane hydrochloride impurity refers to memantine hydrochloride having the content of either or both of l-amino-3, 5,7-trimethyladamantane hydrochloride and l-amino-3- methyladamantane hydrochloride impurity in equal to or less than about 0.2% by weight, preferably equal to or less than about 0.1% by weight, more preferably equal to or less than about 0.05% by weight and still more preferably not detected.
  • the contents of memantine hydrochloride and the impurities are determined by Gas chromatography (GC).
  • Preferable alcohol solvent used in step (a) may be selected from methanol, ethanol or isopropyl alcohol and more preferable alcohol solvent is methanol.
  • ketonic solvent used in step (c) may be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone and more preferable ketonic solvent is acetone.
  • step (d) may preferably be carried out at 0 to 35°C and more preferably at 0 to 5°C.
  • Isolation of memantine hydrochloride substantially free of l-amino-3,5,7- trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity in step (e) may preferably be carried out by the methods known such as filtration or centrifugation.
  • the solution was cooled to 0 to 5°C and then added concentrated sulfuric acid (300 ml) drop wise for 2 hours at 0 to 5°C. Then, the contents were maintained for 14 hours at 25 to 30°C and the reaction mass was poured into a mixture of water and methylene chloride under stirring at 0 to 5°C. The layers were separated and the organic layer was distilled off completely under vacuum at below 45°C to obtain a residue. To the residue was added water (500 ml) at 35 to 40°C and stirred for 30 minutes at 50°C. The reaction mass was cooled to 25 to 30°C and maintained for 2 hours at 25 to 30°C, filtered. The solid obtained was dried at 45°C for 6 hours to obtain 130 gm of l-acetamido-3, 5 -dimethyl adamantane.
  • the reaction mass was cooled to 0 to 5°C and stirred for 1 hour at 0 to 5 °C.
  • the separated solid was filtered and dried at 50°C for 2 hours to obtain 87 gm of memantine hydrochloride containing l-amino-3,5,7-trimethyladamantane hydrochloride and l-amino-3-methyladamantane hydrochloride impurity.
  • Memantine hydrochloride containing l -amino-3,5,7-trimethyladamantane hydrochloride and l-amino-3-methyladamantane hydrochloride impurity (87 gm) as obtained in example 2 was dissolved in methanol (175 ml) at 25 to 30°C and stirred to obtain a solution. The solution was heated to reflux and maintained for 20 minutes. The reaction mass was cooled to 50 to 55°C and then added acetone (525 ml), and stirred for 1 hour at 50 to 55°C. The reaction mass was cooled to 0 to 5°C and stirred for 1 hour at 0 to 5°C.
  • the separated solid was filtered and dried at 50 to 55°C for 4 hours to obtain 74 gm of memantine hydrochloride substantially free of 1-amino- 3,5,7-trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity.
  • Memantine hydrochloride containing l-amino-3,5,7-trimethyladamantane hydrochloride and l-amino-3-methyladamantane hydrochloride impurity (87 gm) was dissolved in methanol (350 ml) and stirred to obtain a solution. The solution was heated to reflux and maintained for 20 minutes. The reaction mass was cooled to 50 to 55°C and then added acetone (1000 ml), and stirred for 1 hour at 50 to 55°C. The reaction mass was cooled to 0 to 5°C and stirred for 1 hour at 0 to 5°C, filtered.
  • the solid obtained was dried at 50 to 55°C for 4 hours to obtain 78 gm of memantine hydrochloride substantially free of l-amino-3,5,7-trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity.
  • Memantine hydrochloride containing l-amino-3,5,7-trimethyladamantane hydrochloride and l-amino-3-methyladamantane hydrochloride impurity (44 gm) was dissolved in ethanol (90 ml) and stirred to obtain a solution. The solution was heated to reflux and maintained for 20 minutes. The reaction mass was cooled to 50 to 55°C and then added acetone (260 ml), and stirred for 1 hour at 50 to 55°C. The reaction mass was cooled to 0 to 5°C and stirred for 1 hour 0 to 5°C.
  • the separated solid was filtered and dried at 50 to 55°C for 4 hours to obtain 35 gm of memantine hydrochloride substantially free of l-amino-3,5,7-trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity.
  • Memantine hydrochloride 99.85%;

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

Abstract

La présente invention concerne un procédé amélioré pour la préparation de 1-bromo-3,5-diméthyladamantane. La présente invention concerne également un procédé de préparation de solide non agglomérant de 1-acétamido-3,5-diméthyladamantane. La présente invention concerne en outre un procédé de préparation d'hydrochlorure de mémantine sensiblement dépourvu d'impureté 1-amino-3,5,7-triméthyladamantane hydrochlorure et/ou 1-amino-3-méthyladamantane hydrochlorure.
PCT/IN2010/000230 2010-04-08 2010-04-08 Procédé de préparation d'hydrochlorure de mémantine Ceased WO2011125062A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP10849334.7A EP2555616A4 (fr) 2010-04-08 2010-04-08 Procédé de préparation d'hydrochlorure de mémantine
PCT/IN2010/000230 WO2011125062A1 (fr) 2010-04-08 2010-04-08 Procédé de préparation d'hydrochlorure de mémantine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2010/000230 WO2011125062A1 (fr) 2010-04-08 2010-04-08 Procédé de préparation d'hydrochlorure de mémantine

Publications (1)

Publication Number Publication Date
WO2011125062A1 true WO2011125062A1 (fr) 2011-10-13

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PCT/IN2010/000230 Ceased WO2011125062A1 (fr) 2010-04-08 2010-04-08 Procédé de préparation d'hydrochlorure de mémantine

Country Status (2)

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EP (1) EP2555616A4 (fr)
WO (1) WO2011125062A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106966909A (zh) * 2016-09-06 2017-07-21 南京优科制药有限公司 一种盐酸美金刚的纯化方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110845339A (zh) * 2019-11-08 2020-02-28 湖南洞庭药业股份有限公司 一种盐酸美金刚的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3391142A (en) * 1966-02-09 1968-07-02 Lilly Co Eli Adamantyl secondary amines
US20080033054A1 (en) * 2006-03-27 2008-02-07 Valeriano Merli Process for preparing memantine hydrochloride substantially free of impurities

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2591487A1 (fr) * 2005-01-11 2006-07-20 Teva Pharmaceutical Fine Chemicals S.R.L. Polymorphes du chlorhydrate de memantine
EP1879849A1 (fr) * 2005-05-11 2008-01-23 Dr. Reddy's Laboratories, Inc. Procede de preparation de memantine
EP1908748A1 (fr) * 2006-10-05 2008-04-09 Krka Procédé de préparation de memantine et du chlorohydrate de memantine
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
US3391142A (en) * 1966-02-09 1968-07-02 Lilly Co Eli Adamantyl secondary amines
US20080033054A1 (en) * 2006-03-27 2008-02-07 Valeriano Merli Process for preparing memantine hydrochloride substantially free of impurities

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2555616A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106966909A (zh) * 2016-09-06 2017-07-21 南京优科制药有限公司 一种盐酸美金刚的纯化方法

Also Published As

Publication number Publication date
EP2555616A4 (fr) 2014-04-02
EP2555616A1 (fr) 2013-02-13

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