EP1879849A1 - Process for preparing memantine - Google Patents

Process for preparing memantine

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Publication number
EP1879849A1
EP1879849A1 EP06752504A EP06752504A EP1879849A1 EP 1879849 A1 EP1879849 A1 EP 1879849A1 EP 06752504 A EP06752504 A EP 06752504A EP 06752504 A EP06752504 A EP 06752504A EP 1879849 A1 EP1879849 A1 EP 1879849A1
Authority
EP
European Patent Office
Prior art keywords
dimethyl adamantane
less
memantine
formyl
adamantane
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.)
Withdrawn
Application number
EP06752504A
Other languages
German (de)
French (fr)
Inventor
Venkata Ramakrishna Mallemula
Ravi Kumar Mylavarapu
Mukunda Reddy Jambula
Sanjay Shukla
Sumathi Konari
Raju Veeramalla
Madhu Raju Veera Boina
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.)
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Original Assignee
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
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 Dr Reddys Laboratories Ltd, Dr Reddys Laboratories Inc filed Critical Dr Reddys Laboratories Ltd
Publication of EP1879849A1 publication Critical patent/EP1879849A1/en
Withdrawn legal-status Critical Current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
    • C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
    • 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
    • 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 a process for the preparation of memantine and its acid addition salts.
  • the present invention also relates to a process for preparing memantine hydrochloride.
  • Memantine has the chemical name 1-amino-3,5-dimethyl adamantane (hereinafter referred to by the officially adopted name “memantine”), and can be represented by the structural Formula 1.
  • Memantine is an orally active NMDA (N-methyl-D-aspartate) receptor antagonist which works by blocking the NMDA receptors in the brain. It blocks the excessive activity of glutamate, but still allows the normal activation of these receptors that occurs when the brain forms a memory. Therefore it improves the brain functioning in Alzheimer's disease, and may also block the glutamate activity that could cause further damage to the brain cells.
  • NMDA N-methyl-D-aspartate
  • Memantine hydrochloride is commercially available in the market in products sold under the trademark NAMENDA. It is available for oral administration as capsule shaped film-coated tablets containing 5 mg and 10 mg of memantine hydrochloride.
  • U.S. Patent No. 3,391 ,142 discloses memantine and its related compounds, and their pharmaceutically acceptable salts. This patent also describes a process for the preparation of memantine as depicted in Scheme 1.
  • a process with a reduced number of stages, and which does not require isolation of unstable or hazardous intermediates, will be helpful. Also a process which is easily scalable and is industrially feasible will be helpful.
  • the present invention provides a process for the preparation of memantine and its acid addition salts which involves a reduced number of stages, is cost effective and easily scaleable.
  • An aspect of the invention includes a process for preparing memantine or an acid addition salt of memantine, comprising reacting 1-bromo-3,5-dimethyl adamantane with formamide to form 1-N-formyl-3,5-dimethyl adamantane. Excess bromine can be removed by distillation, after the reaction. The reaction can occur using bromine as a solvent.
  • Another aspect of the invention includes a process for preparing 1-N- formyl-3,5-dimethyl adamantane, comprising reacting 1-hydroxy-3,5-dimethyl adamantane with a hydrogen halide to obtain 1-halo-3,5-dimethyl adamantane, and reacting a 1-halo-3,5-dimethyl adamantane with formamide to obtain 1-N- formyl-3,5-dimethyl adamantane.
  • the reaction can occur using formamide as a solvent.
  • Memantine or an acid addition salt of memantine can be prepared from the 1-N-formyl-3,5-dimethyl adamantane.
  • memantine hydrochloride can be prepared by reacting 1-N-formyl-3,5-dimethyl adamantane with hydrochloric acid.
  • Fig. 1 is a schematic representation of a process for the preparation of memantine hydrochloride.
  • Fig. 2 is an X-ray powder diffraction pattern of memantine hydrochloride prepared in Example 8.
  • the invention provides a process for the preparation of memantine of Formula I and pharmaceutically acceptable acid addition salts thereof.
  • the invention also provides pharmaceutically acceptable acid addition salts of memantine. Since memantine is an amine, it is basic in nature and accordingly reacts with a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since the free amine is typically an oil at room temperature, it is usually useful to convert the free amine to a corresponding pharmaceutically acceptable acid addition salt, which salt is routinely solid at room temperature, for ease of handling.
  • Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric, and phosphoric as well as organic acids such as para-toluenesulphonic, methanesulphonic, oxalic, carbonic, succinic, citric, benzoic, and acetic acid and related inorganic and organic acids.
  • inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric, and phosphoric
  • organic acids such as para-toluenesulphonic, methanesulphonic, oxalic, carbonic, succinic, citric, benzoic, and acetic acid and related inorganic and organic acids.
  • a process for preparing memantine of Formula I and its acid addition salts comprises the steps of: a) reacting 1 ,3-dimethyl adamantane of Formula Il with bromine to form 1-bromo-3,5-dimethyl adamantane of Formula III; b) converting 1-bromo-3,5-dimethyl adamantane of Formula III to 1 -N- formyl 3, 5-dimethyl adamantane of Formula Vl; and c) converting 1-N-formyl-3,5-dimethyl adamantane of Formula Vl to memantine of Formula I or optionally to any of its acid addition salts.
  • one or more of sequential steps a) and b) are carried out without isolating intermediate compounds.
  • step a) is carried out without isolating the intermediate, followed by isolation of the compound of Formula Vl.
  • Step a) involves the reaction of 1 ,3-dimethyl adamantane of Formula Il with bromine to form 1-bromo-3 ( 5-dimethyl adamantane of Formula III.
  • Suitable solvents that can be used for the reaction include, but are not limited to: alcohols such as methanol, ethanol, propane, butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, propyl acetate, and the like; and mixtures thereof.
  • alcohols such as methanol, ethanol, propane, butanol, and the like
  • ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like
  • esters such as ethyl acetate, propyl acetate, and the like; and mixtures thereof.
  • Bromine itself can also act as a medium for the reaction, and hence the reaction can be carried out in the absence of any additional solvent.
  • the reaction is usually carried out at lower temperatures of about 20 to 40° C, or 20 to 30° C.
  • the addition of bromine to the reaction mass is carried out slowly. Fast addition of the bromine leads to the formation of impurities due to exothermicity of the reaction.
  • the rate of addition of bromine typically is maintained slow enough so that the temperature of the reaction does not exceed about 40° C.
  • An additional embodiment involves the distillation of the excess bromine from the reaction mass after completion of the reaction.
  • Distillation of the bromine may be conducted under vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20° C to about 70° C. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product.
  • the 1-bromo-3, 5-dimethyl adamantane of Formula III is difficult to handle because of its irritant nature, hence an in-situ process which proceeds without isolating the bromo intermediate of Formula III is advantageous.
  • This provides an in-situ process to prepare the N-formyl intermediate of Formula Vl starting from 1 ,3-dimethyl adamantane of Formula II.
  • Step b) involves converting 1-bromo-3,5-dimethyl adamantane of Formula III to 1-N-formyl-3,5-dimethyl adamantane of Formula Vl using formamide.
  • Suitable solvents which can be used for the reaction include, but are not limited to: alcohols such as methanol, ethanol, propanol, butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl lsobutyl ketone, and the like; esters such as ethyl acetate, propyl acetate, and the like; and mixtures thereof.
  • the reaction can also be conducted using formamide itself acting as the solvent medium.
  • Suitable temperatures for conducting the reaction can range from about 100-160° C, or about 120-160° C.
  • Suitable protic solvents which can be used include, but are not limited to, water, alcohols such as n-butanol, methanol, propanol, and the like, acetic acid, formic acid and the like, or mixtures thereof.
  • protic solvent is suitably carried out at lower temperatures such as below 30° C.
  • the protic solvent used can be cooled to lower temperatures of below 10° C to allow the solvent addition below 30° C.
  • Step c) involves converting 1-N-formyl-3,5-dimethyl adamantane of Formula Vl to memantine of Formula I, or to one of its acid addition salts by reacting with an organic or inorganic acid.
  • reaction mass For isolating memantine from the above reaction mass, after the completion of the reaction the reaction mass will be adjusted with a suitable base to a pH of 13 to 14 and then extracted with an organic solvent.
  • Suitable solvents which can be used for the reaction include water or water-miscible solvents such as: alcohols like methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones such as acetone, ethylmethyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N, N- dimethylacetamide and the like; and mixtures thereof, or their combinations with water in various proportions without limitation.
  • water or water-miscible solvents such as: alcohols like methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones such as acetone, ethylmethyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionit
  • Suitable acids which can be used include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, and organic acids such as para-toluenesulphonic acid, methanesulphonic acid, para-bromophenylsulphonic acid, carbonic acid, succinic acid, benzoic acid, acetic acid, maleic acid, tartaric acid, fumaric acid, citric acid, and the like or mixtures thereof.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid
  • organic acids such as para-toluenesulphonic acid, methanesulphonic acid, para-bromophenylsulphonic acid, carbonic acid, succinic acid, benzoic acid, acetic acid, maleic acid, tartaric acid, fumaric acid, citric acid, and the like or mixtures thereof.
  • Suitable temperatures for conducting the reaction can range from about 0- 15O 0 C, or about 100-110° C.
  • the quantity of organic or inorganic acid used frequently ranges from a 10- to 100-fold molar excess of the acid per molar equivalent of 1 -N-formyl-3,5- dimethyl adamantane.
  • the intermediate compounds of Formula III or Vl may or may not be isolated. The same can be converted in-situ, if desired, to the compound of Formula Vl in step b), or the compound of Formula I in step c) respectively.
  • the present invention provides an alternate process for the preparation of the intermediate 1-N-formyl-3,5-dimethyl adamantane of Formula Vl.
  • a process for preparing the intermediate 1-N-formyl-3,5- dimethyl adamantane of Formula Vl comprises the steps of: a) reacting 1-hydroxy-3,5-dimethyl adamantane of Formula V with a hydrogen halide to obtain 1-halo-3,5-dimethyl adamantane of Formula VII; and b) reacting the 1-halo-3,5-dimethyl adamantane of Formula VII with formamide to get 1-N-formyl-3,5-dimethyl adamantane of Formula Vl.
  • Step a) involves reacting 1-hydroxy-3,5-dimethyl adamantane of Formula V with a hydrogen halide to obtain 1-halo-3,5-dimethyl adamantane of Formula VII.
  • 1-hydroxy-3,5-dimethyl adamantane of Formula V can be prepared by a process similar to that given in International Application Publication No. WO 2005/062724 A2.
  • Suitable solvents include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters or ethers; hydrocarbons such as toluene; nitriles such as acetonitrile; dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N 1 N- dimethylacetamide, and the like; or mixtures thereof, or their combinations with water in various proportions without limitation.
  • alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, and the like
  • ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like
  • esters or ethers hydrocarbons such as toluene
  • nitriles such as
  • Hydrogen halides which can be used include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like, or mixtures thereof, including aqueous solutions of the hydrogen halides.
  • the hydrogen halide or aqueous solutions thereof can also act as the solvent medium.
  • the pH of the reaction mass can range from about 0.1 to 7, or about 0.1 to 2.
  • Suitable temperatures for conducting the reaction can range from about 0- 100 0 C, or about 20 to 40° C.
  • Step b) involves reacting 1-halo-3,5-dimethyl adamantane of Formula VII with formamide to get 1-N-formyl-3,5-dimethyl adamantane of Formula Vl.
  • Suitable solvents which can be used include but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters or ethers; hydrocarbons such as toluene; nitriles such as acetonitrile; dimethylsulfoxide (DMSO), N.N-dimethylformamide (DMF), N, N- dimethylacetamide and the like; or mixtures thereof, or their combinations with water in various proportions without limitation.
  • the reaction can also be conducted using formamide itself acting as the solvent medium.
  • Suitable temperatures for conducting the reaction can range from about 100 to 160° C, or about 130-160° C.
  • Suitable protic solvents which can be used include, but are not limited to, water, alcohols such as n-butanol, methanol, propanol, and the like, acetic acid, formic acid and the like, or mixtures thereof.
  • protic solvent is suitably carried out at lower temperatures such as below 30° C.
  • the protic solvent used can be cooled to lower temperatures of below 10° C to allow the solvent addition below 30° C.
  • the intermediate compounds of Formula VII may or may not be isolated. The same can be converted in-situ, if desired, to the compound of Formula Vl in step b).
  • the present invention provides pure memantine of Formula I and its acid addition salts substantially free of process related impurities and residual organic solvents, and a process for preparation thereof.
  • Memantine and its acid addition salts prepared according to this embodiment have a low level of impurities, as determined by gas chromatography ("GC"). For example, it contains about 0.15 area-%, or 0.05 area-%, or less, of each of the following impurities: a) 1-bromo-3,5-dimethyl adamantane of Formula III; b) 1-N-formyl-3,5-dimethyl adamantane of Formula Vl; and c) 1-hydroxy-3,5-dimethyl adamantane of Formula V.
  • GC gas chromatography
  • Memantine or its acid addition salts contaminated by impurities can be purified by recrystallization, slurrying or a combination thereof in an organic solvent to obtain substantially pure memantine and its salts.
  • Suitable solvents in which memantine or its acid addition salts can be dissolved or slurried for purification include but are not limited to: ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols like methanol, ethanol, isopropyl alcohol, n-propanol, halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like, esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbons such as tol
  • the concentration of memantine or its acid addition salts in the solvent can range from 40 to 80% or more.
  • the solution can be prepared at an elevated temperature if desired to achieve the desired concentration. Any temperature is acceptable for the dissolution as long as a clear solution of the memantine or its acid addition salts is obtained and is not detrimental to the drug substance chemically or physically.
  • the solution may be brought down to a lower temperature for further processing if required or an elevated temperature may be used. A higher temperature will allow the precipitation of solutions with higher concentrations of memantine or its acid addition salts resulting in better economies of manufacture.
  • the recrystallization can optionally proceed with the wet compound obtained in step c). Proceeding with the wet compound for crystallization avoids the additional step of drying the crude compound.
  • the recrystallization or slurrying process can be repeated multiple times until the product meets the required specification for purity.
  • Memantine or its acid addition salts obtained in this invention typically contains less than about 5000 ppm, or less than about 3000 ppm, or less than about 1000 ppm of any organic solvent, and less than about 200 ppm, or less than about 100 ppm of individual residual organic solvents.
  • the residual solvent contents are brought within the above limits by drying the memantine or its acid addition salts obtained after recrystallization from an organic solvent to obtain memantine and its acid addition salts substantially free of residual solvents.
  • Drying can be carried out under reduced pressure until the residual solvent content reduces to an amount that is within the limits given by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH”) guidelines.
  • the guideline solvent level depends on the type of solvent but is not more than about 5000 ppm, or about 4000 ppm, or about 3000 ppm.
  • the drying can be carried out at reduced pressures, such as below about 200 mm Hg or below about 50 mm Hg, at temperatures such as about 35° C to about 70° C.
  • the drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications.
  • Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like.
  • the dried product can optionally be milled to get the desired particle sizes.
  • Milling or micronization can be performed prior to drying, or after the completion of drying of the product.
  • the milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high velocities.
  • Drying is more efficient when the particle size of the material is smaller and the surface area is higher, hence milling can be performed prior to the drying operation.
  • Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.
  • the present invention provides memantine or its acid addition salts having particle sizes of less than about 200 ⁇ m and a bulk density less than about 0.5 g/ml.
  • D-io, D 50 and Dg 0 values are useful ways for indicating a particle size distribution.
  • Dgo refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value.
  • D 5 o and Dio refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value.
  • Methods for determining Di 0 , D 50 and Dgo include laser diffraction, such as using Malvern Instruments Ltd. (of Malvern, Worcestershire, United Kingdom) equipment.
  • memantine and its acid addition salts according to the invention have a Di 0 less than about 15 ⁇ m or less than about 10 ⁇ m, D 50 less than about 40 ⁇ m or less than about 20 ⁇ m, and D 90 less than about 200 ⁇ m or less than about 50 ⁇ m. There is no specific lower limit for any of the D values.
  • Memantine and its acid addition salts obtained according to the invention have a bulk density less than about 0.3 g/ml, or less than about 0.5 g/ml, before tapping, and a bulk density of less than about 0.5 g/ml, or less than about 1 g/ml, after tapping.
  • the bulk densities are determined using Test 616 "Bulk Density and Tapped Density," United States Pharmacopeia 24, pages 1913-4 (United States Pharmacopeial Convention, Inc., Rockville, Maryland, 1999).
  • the reaction mass was filtered over a celite bed and the bed was washed with 12.5 liters of dichloromethane.
  • the filtrate was taken into another reactor and stirred at 25° C for 10 minutes.
  • the layers were separated and the aqueous layer was extracted with 15 liters of dichloromethane in 2 equal lots.
  • the combined dichloromethane layer was washed with 51 liters of 10% sodium bicarbonate solution in 2 equal lots.
  • the dichloromethane layer was dried over sodium sulphate and distilled under vacuum at a temperature of 40° C to yield 2.3 kg of the title compound in the form of a residue.
  • the reaction mass was cooled to 4° C and maintained for 3.5 hours.
  • the reaction mass was then filtered and the filtered cake was washed with 2.1 liters of chilled acetone (chilled to a temperature of 5° C).
  • the wet compound was dried at 73° C for 7 hours to yield 1.05 kg of the title compound.
  • the dried compound was then milled in a micronizer (Manufacturer: Microtech Engineering company, Model: M- 50).
  • dichloromethane 125 liters of dichloromethane was added to the reaction mass and the temperature was raised to 25° C. The reaction mass was then filtered over a celite bed and the bed was washed with 42 liters of dichloromethane. The filtrate was allowed to settle and the organic layer was separated. The aqueous layer was extracted with 124.5 liters of dichloromethane in two equal lots. The combined dichloromethane layer was washed with 166 liters of 10% aqueous solution of sodium bicarbonate in two equal lots. The dichloromethane layer was dried over sodium sulfate and distilled atmospherically to dryness at 40° C to yield 18.2 kg of the title compound.
  • the solid was washed with 10 liters of chilled water.
  • the wet solid was then taken into another reactor and 20 liters of isopropanol was added to it.
  • the reaction mass was stirred at 28° C for 45 minutes. Then the reaction mass was cooled to 5° C and maintained for 2.5 hours.
  • the reaction mass was then filtered and the filtered solid was washed with 10 liters of chilled isopropanol.
  • the wet cake was dried in an oven at 92° C for 11 hours to yield 4.6 kg of the title compound.
  • Fig. 2 shows the X-ray powder diffraction pattern for the product, obtained using Cu Ka- 1 radiation (1.541 A wavelength).
  • Length 50 meters.
  • Injection volume 1 ⁇ l.
  • Film thickness 3.0 ⁇ m of 6% cyanopropylphenyl-94% methylpolysiloxane.
  • Injector temperature 140° C.
  • Carrier gas Helium
  • Diluent N,N-dimethylacetamide.
  • Temperature column temperature is programmed according to the following steps: it is held at 40° C for 8 minutes then increased to 165° C at a rate of 10° C per minute and held at 165° C for 5 minutes. Again increased to 250° C at a rate of 35° C and held at 250° C for 20 minutes.

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Abstract

A process for preparing memantine or an acid addition salt of memantine comprises reacting 1-bromo-3,5-dimethyl adamantane with formamide to form 1-N-formyl-3,5-dimethyl adamantane.

Description

PROCESS FOR PREPARING MEMANTINE
INTRODUCTION TO INVENTION
The present invention relates to a process for the preparation of memantine and its acid addition salts. The present invention also relates to a process for preparing memantine hydrochloride.
Memantine has the chemical name 1-amino-3,5-dimethyl adamantane (hereinafter referred to by the officially adopted name "memantine"), and can be represented by the structural Formula 1.
Formula I
Memantine is an orally active NMDA (N-methyl-D-aspartate) receptor antagonist which works by blocking the NMDA receptors in the brain. It blocks the excessive activity of glutamate, but still allows the normal activation of these receptors that occurs when the brain forms a memory. Therefore it improves the brain functioning in Alzheimer's disease, and may also block the glutamate activity that could cause further damage to the brain cells.
Memantine hydrochloride is commercially available in the market in products sold under the trademark NAMENDA. It is available for oral administration as capsule shaped film-coated tablets containing 5 mg and 10 mg of memantine hydrochloride. U.S. Patent No. 3,391 ,142 discloses memantine and its related compounds, and their pharmaceutically acceptable salts. This patent also describes a process for the preparation of memantine as depicted in Scheme 1.
International Application Publication No. WO 2005/062724 A2 describes an alternate process for the preparation of memantine as depicted in Scheme 2, and U.S. Patent No. 5,061 ,703 discloses a process for the preparation of derivatives of memantine.
Scheme 2
A process with a reduced number of stages, and which does not require isolation of unstable or hazardous intermediates, will be helpful. Also a process which is easily scalable and is industrially feasible will be helpful.
The present invention provides a process for the preparation of memantine and its acid addition salts which involves a reduced number of stages, is cost effective and easily scaleable.
SUMMARY OF THE INVENTION
An aspect of the invention includes a process for preparing memantine or an acid addition salt of memantine, comprising reacting 1-bromo-3,5-dimethyl adamantane with formamide to form 1-N-formyl-3,5-dimethyl adamantane. Excess bromine can be removed by distillation, after the reaction. The reaction can occur using bromine as a solvent.
Another aspect of the invention includes a process for preparing 1-N- formyl-3,5-dimethyl adamantane, comprising reacting 1-hydroxy-3,5-dimethyl adamantane with a hydrogen halide to obtain 1-halo-3,5-dimethyl adamantane, and reacting a 1-halo-3,5-dimethyl adamantane with formamide to obtain 1-N- formyl-3,5-dimethyl adamantane. The reaction can occur using formamide as a solvent.
Memantine or an acid addition salt of memantine can be prepared from the 1-N-formyl-3,5-dimethyl adamantane. For example, memantine hydrochloride can be prepared by reacting 1-N-formyl-3,5-dimethyl adamantane with hydrochloric acid.
BREIF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a schematic representation of a process for the preparation of memantine hydrochloride.
Fig. 2 is an X-ray powder diffraction pattern of memantine hydrochloride prepared in Example 8.
DETAILED DESCRIPTION OF THE INVENTION
In an aspect, the invention provides a process for the preparation of memantine of Formula I and pharmaceutically acceptable acid addition salts thereof. As pointed out above, the invention also provides pharmaceutically acceptable acid addition salts of memantine. Since memantine is an amine, it is basic in nature and accordingly reacts with a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since the free amine is typically an oil at room temperature, it is usually useful to convert the free amine to a corresponding pharmaceutically acceptable acid addition salt, which salt is routinely solid at room temperature, for ease of handling. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric, and phosphoric as well as organic acids such as para-toluenesulphonic, methanesulphonic, oxalic, carbonic, succinic, citric, benzoic, and acetic acid and related inorganic and organic acids.
In an embodiment, a process for preparing memantine of Formula I and its acid addition salts comprises the steps of: a) reacting 1 ,3-dimethyl adamantane of Formula Il with bromine to form 1-bromo-3,5-dimethyl adamantane of Formula III; b) converting 1-bromo-3,5-dimethyl adamantane of Formula III to 1 -N- formyl 3, 5-dimethyl adamantane of Formula Vl; and c) converting 1-N-formyl-3,5-dimethyl adamantane of Formula Vl to memantine of Formula I or optionally to any of its acid addition salts. Suitably, one or more of sequential steps a) and b) are carried out without isolating intermediate compounds. In one embodiment of the invention, step a) is carried out without isolating the intermediate, followed by isolation of the compound of Formula Vl.
Step a) involves the reaction of 1 ,3-dimethyl adamantane of Formula Il with bromine to form 1-bromo-3(5-dimethyl adamantane of Formula III.
Suitable solvents that can be used for the reaction include, but are not limited to: alcohols such as methanol, ethanol, propane, butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, propyl acetate, and the like; and mixtures thereof.
Bromine itself can also act as a medium for the reaction, and hence the reaction can be carried out in the absence of any additional solvent.
The reaction is usually carried out at lower temperatures of about 20 to 40° C, or 20 to 30° C.
The addition of bromine to the reaction mass is carried out slowly. Fast addition of the bromine leads to the formation of impurities due to exothermicity of the reaction. The rate of addition of bromine typically is maintained slow enough so that the temperature of the reaction does not exceed about 40° C. An additional embodiment involves the distillation of the excess bromine from the reaction mass after completion of the reaction.
Distillation of the bromine may be conducted under vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20° C to about 70° C. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product.
Also, the 1-bromo-3, 5-dimethyl adamantane of Formula III is difficult to handle because of its irritant nature, hence an in-situ process which proceeds without isolating the bromo intermediate of Formula III is advantageous. This provides an in-situ process to prepare the N-formyl intermediate of Formula Vl starting from 1 ,3-dimethyl adamantane of Formula II.
Step b) involves converting 1-bromo-3,5-dimethyl adamantane of Formula III to 1-N-formyl-3,5-dimethyl adamantane of Formula Vl using formamide. Suitable solvents which can be used for the reaction include, but are not limited to: alcohols such as methanol, ethanol, propanol, butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl lsobutyl ketone, and the like; esters such as ethyl acetate, propyl acetate, and the like; and mixtures thereof. The reaction can also be conducted using formamide itself acting as the solvent medium.
Suitable temperatures for conducting the reaction can range from about 100-160° C, or about 120-160° C.
After the completion of the reaction, the reaction mass is quenched with a protic solvent. Suitable protic solvents which can be used include, but are not limited to, water, alcohols such as n-butanol, methanol, propanol, and the like, acetic acid, formic acid and the like, or mixtures thereof.
The addition of protic solvent is suitably carried out at lower temperatures such as below 30° C. The protic solvent used can be cooled to lower temperatures of below 10° C to allow the solvent addition below 30° C.
Step c) involves converting 1-N-formyl-3,5-dimethyl adamantane of Formula Vl to memantine of Formula I, or to one of its acid addition salts by reacting with an organic or inorganic acid.
For isolating memantine from the above reaction mass, after the completion of the reaction the reaction mass will be adjusted with a suitable base to a pH of 13 to 14 and then extracted with an organic solvent.
Suitable solvents which can be used for the reaction include water or water-miscible solvents such as: alcohols like methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones such as acetone, ethylmethyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N, N- dimethylacetamide and the like; and mixtures thereof, or their combinations with water in various proportions without limitation. Suitable acids which can be used include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, and organic acids such as para-toluenesulphonic acid, methanesulphonic acid, para-bromophenylsulphonic acid, carbonic acid, succinic acid, benzoic acid, acetic acid, maleic acid, tartaric acid, fumaric acid, citric acid, and the like or mixtures thereof.
Suitable temperatures for conducting the reaction can range from about 0- 15O0 C, or about 100-110° C.
The quantity of organic or inorganic acid used frequently ranges from a 10- to 100-fold molar excess of the acid per molar equivalent of 1 -N-formyl-3,5- dimethyl adamantane.
The intermediate compounds of Formula III or Vl may or may not be isolated. The same can be converted in-situ, if desired, to the compound of Formula Vl in step b), or the compound of Formula I in step c) respectively. In another aspect, the present invention provides an alternate process for the preparation of the intermediate 1-N-formyl-3,5-dimethyl adamantane of Formula Vl.
In an embodiment, a process for preparing the intermediate 1-N-formyl-3,5- dimethyl adamantane of Formula Vl comprises the steps of: a) reacting 1-hydroxy-3,5-dimethyl adamantane of Formula V with a hydrogen halide to obtain 1-halo-3,5-dimethyl adamantane of Formula VII; and b) reacting the 1-halo-3,5-dimethyl adamantane of Formula VII with formamide to get 1-N-formyl-3,5-dimethyl adamantane of Formula Vl.
Step a) involves reacting 1-hydroxy-3,5-dimethyl adamantane of Formula V with a hydrogen halide to obtain 1-halo-3,5-dimethyl adamantane of Formula VII.
1-hydroxy-3,5-dimethyl adamantane of Formula V can be prepared by a process similar to that given in International Application Publication No. WO 2005/062724 A2.
Suitable solvents that can be used include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters or ethers; hydrocarbons such as toluene; nitriles such as acetonitrile; dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N1N- dimethylacetamide, and the like; or mixtures thereof, or their combinations with water in various proportions without limitation.
Hydrogen halides which can be used include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like, or mixtures thereof, including aqueous solutions of the hydrogen halides. The hydrogen halide or aqueous solutions thereof can also act as the solvent medium.
The pH of the reaction mass can range from about 0.1 to 7, or about 0.1 to 2.
Suitable temperatures for conducting the reaction can range from about 0- 1000 C, or about 20 to 40° C.
Step b) involves reacting 1-halo-3,5-dimethyl adamantane of Formula VII with formamide to get 1-N-formyl-3,5-dimethyl adamantane of Formula Vl.
Suitable solvents which can be used include but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters or ethers; hydrocarbons such as toluene; nitriles such as acetonitrile; dimethylsulfoxide (DMSO), N.N-dimethylformamide (DMF), N, N- dimethylacetamide and the like; or mixtures thereof, or their combinations with water in various proportions without limitation. The reaction can also be conducted using formamide itself acting as the solvent medium.
Suitable temperatures for conducting the reaction can range from about 100 to 160° C, or about 130-160° C.
After the completion of the reaction, the reaction mass is quenched with a protic solvent. Suitable protic solvents which can be used include, but are not limited to, water, alcohols such as n-butanol, methanol, propanol, and the like, acetic acid, formic acid and the like, or mixtures thereof.
The addition of protic solvent is suitably carried out at lower temperatures such as below 30° C. The protic solvent used can be cooled to lower temperatures of below 10° C to allow the solvent addition below 30° C.
The intermediate compounds of Formula VII may or may not be isolated. The same can be converted in-situ, if desired, to the compound of Formula Vl in step b). In yet another aspect, the present invention provides pure memantine of Formula I and its acid addition salts substantially free of process related impurities and residual organic solvents, and a process for preparation thereof.
Memantine and its acid addition salts prepared according to this embodiment have a low level of impurities, as determined by gas chromatography ("GC"). For example, it contains about 0.15 area-%, or 0.05 area-%, or less, of each of the following impurities: a) 1-bromo-3,5-dimethyl adamantane of Formula III; b) 1-N-formyl-3,5-dimethyl adamantane of Formula Vl; and c) 1-hydroxy-3,5-dimethyl adamantane of Formula V.
Memantine or its acid addition salts contaminated by impurities can be purified by recrystallization, slurrying or a combination thereof in an organic solvent to obtain substantially pure memantine and its salts.
Suitable solvents in which memantine or its acid addition salts can be dissolved or slurried for purification include but are not limited to: ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols like methanol, ethanol, isopropyl alcohol, n-propanol, halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like, esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, n-hexane and the like; nitriles such as acetonitrile, propionitrile and the like; dimethylsulfoxide (DMSO), N1N- dimethylformamide (DMF), N,N-dimethylacetamide and the like; or mixtures thereof, or their combinations with water in various proportions without limitation.
For recrystallization of memantine or its salts in a solvent, the concentration of memantine or its acid addition salts in the solvent can range from 40 to 80% or more. The solution can be prepared at an elevated temperature if desired to achieve the desired concentration. Any temperature is acceptable for the dissolution as long as a clear solution of the memantine or its acid addition salts is obtained and is not detrimental to the drug substance chemically or physically. The solution may be brought down to a lower temperature for further processing if required or an elevated temperature may be used. A higher temperature will allow the precipitation of solutions with higher concentrations of memantine or its acid addition salts resulting in better economies of manufacture.
The recrystallization can optionally proceed with the wet compound obtained in step c). Proceeding with the wet compound for crystallization avoids the additional step of drying the crude compound.
The recrystallization or slurrying process can be repeated multiple times until the product meets the required specification for purity.
Memantine or its acid addition salts obtained in this invention typically contains less than about 5000 ppm, or less than about 3000 ppm, or less than about 1000 ppm of any organic solvent, and less than about 200 ppm, or less than about 100 ppm of individual residual organic solvents.
The residual solvent contents are brought within the above limits by drying the memantine or its acid addition salts obtained after recrystallization from an organic solvent to obtain memantine and its acid addition salts substantially free of residual solvents.
Drying can be carried out under reduced pressure until the residual solvent content reduces to an amount that is within the limits given by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The guideline solvent level depends on the type of solvent but is not more than about 5000 ppm, or about 4000 ppm, or about 3000 ppm.
The drying can be carried out at reduced pressures, such as below about 200 mm Hg or below about 50 mm Hg, at temperatures such as about 35° C to about 70° C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications.
Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like. The dried product can optionally be milled to get the desired particle sizes.
Milling or micronization can be performed prior to drying, or after the completion of drying of the product. The milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high velocities.
Drying is more efficient when the particle size of the material is smaller and the surface area is higher, hence milling can be performed prior to the drying operation.
Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.
In still another aspect, the present invention provides memantine or its acid addition salts having particle sizes of less than about 200 μm and a bulk density less than about 0.5 g/ml.
The D-io, D50 and Dg0 values are useful ways for indicating a particle size distribution. Dgo refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value. Likewise D5o and Dio refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value. Methods for determining Di0, D50 and Dgo include laser diffraction, such as using Malvern Instruments Ltd. (of Malvern, Worcestershire, United Kingdom) equipment.
In an embodiment, memantine and its acid addition salts according to the invention have a Di0 less than about 15 μm or less than about 10 μm, D50 less than about 40 μm or less than about 20 μm, and D90 less than about 200 μm or less than about 50 μm. There is no specific lower limit for any of the D values.
Memantine and its acid addition salts obtained according to the invention have a bulk density less than about 0.3 g/ml, or less than about 0.5 g/ml, before tapping, and a bulk density of less than about 0.5 g/ml, or less than about 1 g/ml, after tapping. The bulk densities are determined using Test 616 "Bulk Density and Tapped Density," United States Pharmacopeia 24, pages 1913-4 (United States Pharmacopeial Convention, Inc., Rockville, Maryland, 1999).
Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which examples are not intended to limit the scope of the appended claims in any manner. In the examples, reaction completion, purities of products and residual solvent contents were determined by a gas chromatographic method. EXAMPLE 1
PREPARATION OF 1-BROMO-3.5-DIMETHYL ADAMANTANE (FORMULA III)
8.0 liters of bromine was taken into a reactor and 5.1 kg of 1 ,3-dimethyl adamantane was added into the reactor slowly at 28° C in 2.5 hours. The reaction mass was maintained at 28° C for 24 hours. Reaction completion was checked using a gas chromatographic technique. After the reaction was completed, the bromine was distilled off from the reaction mass at a temperature of below 40° C. After the completion of distillation, 13.4 kg of the title compound in the form of a residue was recovered from the reactor.
Purity by GC: 98.35%,
1 ,3-dimethyl adamantane: 0.53%.
1-hydroxy-3,5-di methyl adamantane: 0.66%.
EXAMPLE 2
PREPARATION OF 1-N-FORMYL-3,5-DIMETHYL ADAMANTANE (FORMULA Vl)
64 liters of formamide was taken into a reactor and 2.55 kg of the 1-bromo- 3,5-dimethyl adamantane of Formula III obtained above was added to it. The reaction mass was heated to a temperature of 157° C and maintained for 14 hours. Reaction completion was checked using gas chromatography. After the reaction is completed, the reaction mass was cooled to 28° C. The reaction mass was then further cooled to 4° C and maintained for 4.25 hours. 37.5 liters of chilled water was added to the reaction mass slowly below 5° C. Then 37.5 liters of dichloromethane was added to the reaction mass. The temperature of the reaction mass was raised to 25° C. The reaction mass was filtered over a celite bed and the bed was washed with 12.5 liters of dichloromethane. The filtrate was taken into another reactor and stirred at 25° C for 10 minutes. The layers were separated and the aqueous layer was extracted with 15 liters of dichloromethane in 2 equal lots. The combined dichloromethane layer was washed with 51 liters of 10% sodium bicarbonate solution in 2 equal lots. The dichloromethane layer was dried over sodium sulphate and distilled under vacuum at a temperature of 40° C to yield 2.3 kg of the title compound in the form of a residue.
Purity by GC: 76.4 %,
1 ,3-dimethyl adamantane: 0.11 %, 1-hydroxy-3,5-dimethyl adamantane: 21.28%.
EXAMPLE 3
PREPARATION OF MEMANTINE HYDROCHLORIDE (FORMULA VIII): 21 liters of 36% aqueous hydrochloric acid was taken into a reactor and 2.1 kg of 1-N-formyl-3,5-dimethyl adamantane of Formula Vl obtained above was added to it. The reaction mass was heated to a temperature of 104° C and maintained for 6.5 hours. Reaction completion was checked using gas chromatographic technique. After the reaction was completed, the reaction mass was cooled to 4° C and maintained for 3 hours. The reaction mass was filtered in a centrifuge and the filtered solid was washed with 2.1 liters of chilled water. The wet cake was taken into another reactor and 8.5 liters of acetone was added to it. The reaction mass was cooled to 4° C and maintained for 3.5 hours. The reaction mass was then filtered and the filtered cake was washed with 2.1 liters of chilled acetone (chilled to a temperature of 5° C). The wet compound was dried at 73° C for 7 hours to yield 1.05 kg of the title compound. The dried compound was then milled in a micronizer (Manufacturer: Microtech Engineering company, Model: M- 50).
Purity by GC: 99.9%, 1-hydroxy-3,5-dimethyl adamantane: Less than 0.004%,
1-bromo-3,5-dimethyl adamantane: 0.01 %, 1-formamido-3,5-dimethyl adamantane: 0.03%. Residual Solvents: methanol = 231 ppm, dichloromethane = 249 ppm, cyclohexane = 43 ppm, toluene = 122 ppm. Particle size distribution: Before milling: Di0 = 3.2 μm; D50 = 18.4 μm; D90
= 96.6 μm. After milling: D10 = 1.7 μm; D50 = 9.6 μm; Dg0 = 48.3 μm.
Bulk Density: Before milling: Before tapping: 0.20 g/ml ; After tapping: 0.38 g/ml. After milling: Before tapping: 0.20 g/ml; After tapping: 0.39 g/ml. EXAMPLE 4
PREPARATION OF I-CHLORO-S.δ-DIMETHYL ADAMANTANE (FORMULA VII) 15 g of 1-hydroxy-3,5-dimethyl adamantane was taken into a round bottom flask and 300 ml of 36% aqueous hydrochloric acid was added to it. The reaction mass was stirred at 28° C for 21 hours. The reaction mass was kept for layer separation. The upper layer was separated to yield 13.0 g of the title compound in the form of crude. Purity by GC: 99.88%.
EXAMPLE 5
PREPARATION OF 1-N-FORMYL-3.5-DIMETHYL ADAMANTANE (FORMULA Vl)
10 g of 1-chloro-3,5-dimethyl adamantane of Formula VII prepared above was taken into a round bottom flask and 250 ml of formamide was added to it. The reaction mass was heated to 152° C and maintained at that temperature for 10 hours. The reaction mass was then cooled to 10 ° C, and 150 ml of water chilled to a temperature of 5° C was added to it slowly. Then 150 ml of dichloromethane was added to it and the temperature of the reaction mass was brought up to 28° C. The reaction mass was filtered through a celite bed and the celite bed was washed with 50 ml of dichloromethane. The filtrate was transferred into a separating funnel and the organic layer was separated. The aqueous layer was extracted with 150 ml of dichloromethane in two equal lots. The combined organic layer was washed with 200 ml of 10% sodium bicarbonate solution in two equal lots. The organic layer was dried over sodium sulphate and distilled under vacuum at 38° C to yield 9.6 g of the title compound. Purity by GC: 77.35%. EXAMPLE 6
PREPARATION OF 1-AMINO-3.5-DIMETHYL ADAMANTANE HYDROCHLORIDE (FORMULA VIII) 9.0 g of 1-N-formyl-3,5-dimethyl adamantane of Formula Vl and 90 ml of
36% aqueous hydrochloric acid were taken into a round bottom flask and heated to 102° C. The reaction mass was maintained at 102° C for 6 hours. The reaction mass was then allowed to cool to 2° C and maintained for 2 hours. The reaction mass was then filtered and the solid was washed with 20 ml of water chilled to a temperature of 5° C. The wet compound was taken into another round bottom flask and 54 ml of acetone was added to it. The reaction mass was stirred at 28° C for one hour, and then the reaction mass was cooled to 2° C. The reaction mass was maintained at 2° C for 2 hours. The reaction mass was then filtered and the solid was washed with 18 ml of acetone. The solid was suction dried under vacuum of 400 mm Hg and then dried in a vacuum oven at a temperature of 60° C and vacuum of 400 mm Hg for 6 hours to yield 5.0 g of the title compound. Purity by GC: 99.59%
EXAMPLE 7
PREPARATION OF 1-N-FORMYL-3.5-DIMETHYL ADAMANTANE (FORMULA VI)
13 liters of bromine was taken into a reactor and 8.3 kg of 1,3-dimethyl adamantane was added to it at 30° C. The reaction mass was maintained at 30° C for 24 hours. Reaction completion was checked using a gas chromatographic technique. 200 liters of formamide was taken in another reactor and the reaction mass from the previous reactor was added to it. The previous reactor was rinsed with 8 liters of formamide and added to the reaction mass. The temperature of the reaction mass was raised to 155° C. The reaction mass was maintained at 155° C for 8 hours. Reaction completion was checked using gas chromatography. After the reaction was completed, the reaction mass was cooled to 4° C and maintained for 1.5 hours. 125 liters of chilled water was added to the reaction mass at 4° C. 125 liters of dichloromethane was added to the reaction mass and the temperature was raised to 25° C. The reaction mass was then filtered over a celite bed and the bed was washed with 42 liters of dichloromethane. The filtrate was allowed to settle and the organic layer was separated. The aqueous layer was extracted with 124.5 liters of dichloromethane in two equal lots. The combined dichloromethane layer was washed with 166 liters of 10% aqueous solution of sodium bicarbonate in two equal lots. The dichloromethane layer was dried over sodium sulfate and distilled atmospherically to dryness at 40° C to yield 18.2 kg of the title compound.
Purity by GC: 96.29% 1 ,3-dimethyl adamantane: less than 0.004%.
1-hydroxy-3,5-dimethyl adamantane: 2.81 %.
1-bromo-3,5-dimethyl adamantane: 0.05%.
EXAMPLE 8
PREPARATION OF MEMANTINE HYDROCHLORIDE (FORMULA VIII)
24 liters of water was taken into a reactor and 24 liters of 36% aqueous hydrochloric acid was added to it. 10 kg of 1-N-formyl-3,5-dimethyl adamantane of Formula Vl was added to the reaction mass. The reaction mass was heated to a temperature of 102° C. The reaction mass was maintained at 102° C for 24 hours. Reaction completion was checked using gas chromatographic technique. After the reaction was completed the reaction mass was cooled to 5° C. The reaction mass was maintained at 5° C for 2 hours and 30 minutes and then s olids were separated using a centrifuge (Manufacturer: Nima Engineering Pvt. Ltd. Model: 14" x 7" - LAD CANT). The solid was washed with 10 liters of chilled water. The wet solid was then taken into another reactor and 20 liters of isopropanol was added to it. The reaction mass was stirred at 28° C for 45 minutes. Then the reaction mass was cooled to 5° C and maintained for 2.5 hours. The reaction mass was then filtered and the filtered solid was washed with 10 liters of chilled isopropanol. The wet cake was dried in an oven at 92° C for 11 hours to yield 4.6 kg of the title compound.
Purity by GC: 99.98%
1-chloro-3,5-dimethyl adamantane: less than 0.005%. 1-hydroxy-3,5-dimethyl adamantane: 0.003%.
1-N-formyl-3,5-dimethyl adamantane: 0.01%.
Residual Solvents: methanol = 33 ppm, dichloromethane = 14 ppm, acetone= 2 ppm, isopropanol = 383 ppm. Fig. 2 shows the X-ray powder diffraction pattern for the product, obtained using Cu Ka- 1 radiation (1.541 A wavelength).
EXAMPLE 9
Gas Chromatography method for memantine hydrochloride and impurities.
Chromatographic conditions:
Column: Agilent Ultra 2, or equivalent (crosslinked 5% phenylmethylsiloxane).
Length: 50 meters.
ID: 0.32 mm. Film thickness: 0.52 microns.
Column Temperature: Initial temperature: 50° C, Hold time-1: 0 minutes, Heating rate-1 : 5° C; Final temperature: 145° C, Hold time-2: 0 minutes, Heating rate-2:
10° C; Final temperature: 250° C, Final hold time: 20 minutes, Injection port temperature: 220° C, Detector temperature: 300° C. Carrier gas: Helium
Flow rate: 4.0 ml/minute
Injection mode (Split): 1 : 50
Injection volume: 1 μl.
Solvent: Hexane.
PEAK LOCATIONS:
Gas Chromatography method for residual organic solvents.
Chromatographic Conditions:
Column: Alltech AT-624 capillary, or equivalent. Length: 30 meters.
ID: 0.53 mm.
Film thickness: 3.0 μm of 6% cyanopropylphenyl-94% methylpolysiloxane.
Injector temperature: 140° C.
Detector temperature: 260° C. Mode of injection [split]: 1 :5
Carrier gas: Helium
Flow rate: 4.0 ml/minute.
Sample: 1 μl.
Diluent: N,N-dimethylacetamide. Temperature: column temperature is programmed according to the following steps: it is held at 40° C for 8 minutes then increased to 165° C at a rate of 10° C per minute and held at 165° C for 5 minutes. Again increased to 250° C at a rate of 35° C and held at 250° C for 20 minutes.

Claims

CLAIMS:
1. A process for preparing memantine or an acid addition salt of memantine, comprising reacting 1-bromo-3,5-dimethyl adamantane with formamide to form 1- N-formyl-3,5-dimethyl adamantane.
2. The process of claim 1 , wherein formamide comprises a solvent for reaction.
3. The process of claim 1 , wherein 1-bromo-3,5-dimethyl adamantane is formed by reacting 1 ,3-dimethyl adamantane with bromine, and removing residual bromine by distillation.
4. The process of claim 3, wherein 1-bromo-3,5-dimethyl adamantane is not isolated after residual bromine removal and before further reaction.
5. The process of claim 3, wherein bromine comprises a solvent for reaction.
6. The process of claim 1 , wherein 1-N-formyl-3,5-dimethyl adamantane is not isolated before further reaction.
7. The process of claim 1 , further- comprising reacting 1-N-formyl-3,5-dimethyl adamantane with an acid to form an acid addition salt of memantine.
8. The process of claim 1 , further comprising reacting 1-N-formyl-3,5-dimethyl adamantane with hydrochloric acid to form memantine hydrochloride.
9. The process of claim 8, wherein solid memantine hydrochloride is recovered and subjected to particle size reduction, to produce a particle size distribution of Dg0 less than about 200 μm, D50 less than about 40 μm, and D-io less than about 15 μm.
10. The process of claim 8, wherein solid memantine hydrochloride is recovered and subjected to particle size reduction, to produce a particle size distribution of D90 less than about 50 μm, D5o less than about 20 μm, and D10 less than about 10 μm.
11. The process of claim 9, wherein solid memantine hydrochloride has a bulk density less than about 0.5 g/ml before tapping, and a bulk density less than about 1 g/ml after tapping.
12. The process of claim 9, wherein solid memantine hydrochloride has a bulk density less than about 0.3 g/ml before tapping, and a bulk density less than about 0.5 g/ml after tapping.
13. The process of claim 8, wherein memantine hydrochloride contains less than about 0.15 area-percent of each of the impurities 1-bromo-3,5-dimethyl adamantane, 1-N-formyl-3,5~dimethyl adamantane, and 1-hydroxy-3,5-dimethyl adamantane, as determined by gas chromatography.
14. The process of claim 8, wherein memantine hydrochloride contains less than about 0.05 area-percent of each of the impurities 1-bromo-3,5-dimethyl adamantane,
1-N-formyl-3,5-dimethyl adamantane, and 1-hydroxy-3,5-dimethyl adamantane, as determined by gas chromatography.
15. A process for preparing 1-N-formyl-3,5-dimethyl adamantane, comprising reacting 1-hydroxy-3,5-dimethyl adamantane with a hydrogen halide to obtain 1- halo-3,5-dimethyl adamantane, and reacting a 1-halo-3,5-dimethyl adamantane with formamide to obtain 1-N-formyl-3,5-dimethyl adamantane.
16. The process of claim 15, wherein 1-N-formyl-3,5-dimethyI adamantane is not isolated before further reaction.
17. The process of claim 15, further comprising reacting 1-N-formyl-3,5- dimethyl adamantane with an acid to form an acid addition salt of memantine.
18. The process of claim 15, further comprising reacting 1-N-formyl-3,5- dimethyl adamantane with hydrochloric acid to form memantine hydrochloride.
19. The process of claim 18, wherein solid memantine hydrochloride is recovered and subjected to particle size reduction, to produce a particle size distribution of Dg0 less than about 200 μm, D50 less than about 40 μm, and D10 less than about 15 μm.
20. The process of claim 18, wherein solid memantine hydrochloride is recovered and subjected to particle size reduction, to produce a particle size distribution of D90 less than about 50 μm, D5o less than about 20 μm, and D10 less than about 10 μm.
21. The process of claim 19, wherein solid memantine hydrochloride has a bulk density less than about 0.5 g/ml before tapping, and a bulk density less than about 1 g/ml after tapping.
22. The process of claim 19, wherein solid memantine hydrochloride has a bulk density less than about 0.3 g/ml before tapping, and a bulk density less than about 0.5 g/ml after tapping.
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ATE541827T1 (en) * 2006-02-21 2012-02-15 Hexal Ag METHOD FOR PRODUCING ADAMANTANAMINES
WO2008062472A2 (en) * 2006-10-24 2008-05-29 Cadila Healthcare Limited Process for the preparation of memantine
GB0713930D0 (en) * 2007-07-18 2007-08-29 Generics Uk Ltd Novel assay methods
EP2331495B1 (en) * 2008-08-08 2016-01-27 Merz Pharma GmbH & Co. KGaA Process for manufacturing adamantane derivatives with high yield
EP2373612B1 (en) 2008-12-17 2013-04-17 Merz Pharma GmbH & Co. KGaA Method for producing memantine
EP2389351A1 (en) * 2009-01-21 2011-11-30 Merz Pharma GmbH & Co. KGaA A process for preparing memantine
WO2011125062A1 (en) * 2010-04-08 2011-10-13 Hetero Research Foundation Process for the preparation of memantine hydrochloride
JP2017114820A (en) * 2015-12-25 2017-06-29 宇部興産株式会社 Process for producing 1-amino-3,5-dimethyladamantane hydrochloride
WO2020075024A1 (en) * 2018-10-12 2020-04-16 Dr. Reddy’S Laboratories Limited Process for preparation of memantine
CN116046926B (en) * 2022-12-07 2024-11-05 合肥久诺医药科技有限公司 Detection method of 1-bromo-3, 5-dimethyl adamantane related substances

Family Cites Families (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
ES2059602T3 (en) * 1989-04-14 1994-11-16 Merz & Co Gmbh & Co USE OF ADAMANTANE DERIVATIVES FOR THE PREVENTION AND TREATMENT OF BRAIN ISCHEMIA.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006122238A1 *

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