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WO2008062472A2 - Procédé pour la préparation de mémantine - Google Patents

Procédé pour la préparation de mémantine Download PDF

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Publication number
WO2008062472A2
WO2008062472A2 PCT/IN2007/000500 IN2007000500W WO2008062472A2 WO 2008062472 A2 WO2008062472 A2 WO 2008062472A2 IN 2007000500 W IN2007000500 W IN 2007000500W WO 2008062472 A2 WO2008062472 A2 WO 2008062472A2
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WO
WIPO (PCT)
Prior art keywords
formula
memantine
dimethyl
base
adamantine
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/IN2007/000500
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English (en)
Other versions
WO2008062472A3 (fr
Inventor
Rushikesh Udaykumar Roy
Prem Chand
Rajiv Kumar
Dwivedi Shriprakash Dhar
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Zydus Lifesciences Ltd
Original Assignee
Cadila Healthcare Ltd
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
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Publication of WO2008062472A2 publication Critical patent/WO2008062472A2/fr
Publication of WO2008062472A3 publication Critical patent/WO2008062472A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
    • 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 of formula (I) ' and its pharmaceutically acceptable salts. More particularly, the present invention provides the process for the preparation of Memantine hydrochloride. The present invention further provides an improved process for the preparation of 1- Acetamido-3 ,5 -dimethyl adamantine of formula (II), which is a key intermediate for the preparation of Memantine.
  • Memantine is chemically known as 3,5-Dimethyl-l- adamantylamine and represented by below mentioned formula (I), which is useful for the treatment of Alzheimer's and Parkinson's disease.
  • 1,3-Dimethyl adamantane is reacted with Br 2 to give 1-Bromo- 3,5-dimethyl adamantine.
  • l-bromo-3,5-dimethyladamantane reacts with 17 moles of acetonitrile and 35 moles of sulphuric acid at room temperature to give the crude intermediate product in 100 percent yield.
  • the intermediate product is subjected to alkaline hydrolysis with sodium hydroxide in diethylene glycol by refluxing at a temperature of greater than 19O 0 C. for six hours.
  • the hydrolyzed product is diluted with water, followed by several benzene extractions, and the memantine free base is recovered by solvent distillation. The free base is then diluted with ether, and the addition of hydrogen chloride gas provides crude memantine hydrochloride. Crystallization of the hydrochloride from an ethanol- ether mixture gives pure memantine hydrochloride in 69.8 %yield.
  • the said process may not be suitable for commercial production considering the bromination is carried out at reflux conditions, which leads to generation of toxic bromine vapors. Moreover, the use of ether in the process is hazardous because of its highly inflammable nature and tendency to form peroxides.
  • JP 2002 275142A2 discloses the synthesis of n- acetyl-memantine according to the following scheme with a yield of 45 percent.
  • U.S. Pat. No. 4,122,193 discloses pharmacological compositions and methods for treating living mammals suffering from hyperkinesias, as well as memantine hydrochloride, hydrobromide, and sulphate synthesis, where the hydrochloride is prepared according to the following scheme with a yield of 78 percent.
  • U.S. Pat. No. 5,599,998 discloses memantine synthesis with a yield of 48 percent according to the following scheme.
  • the disclosed method is cumbersome on an industrial scale, using metallic lithium and chloramine, which can b6 hazardous if not handled properly.
  • the deficiencies of the prior art processes described above include, but are not limited to the production of undesirable byproducts, such as Br 2 and SO 2 , very high reaction temperatures, the need for high pressures, and the use of dangerous reactants.
  • the undesirable byproducts are produced in the Ritter reaction of l-bromo-3,5- dimethyladamantane and acetonitrile in presence of 96 percent sulphuric acid.
  • the very high reaction temperatures typically from 19O 0 C to 225 0 C.
  • WO 2005/062724 discloses a novel process for the preparation of compound of below mentioned formula
  • Memantine is prepared as shown below:
  • a Group IA e.g., sodium hydroxide
  • HA hydroxide e.g., 1- methoxy-2-propanol
  • an alkoxy ale. solvent e.g., 1- methoxy-2-propanol
  • aminoadamantane e.g., l-amino-3,5- dimethyladamantane
  • acids e.g., HCl
  • an acid- addn. salts e.g., memantine hydrochloride
  • Patent WO 2006/122238 relates to process for preparing memantine or an acid addition salt of memantine comprises reaction of l-bromo-3 5 5-dimethyladamantane with formamide to form l-N-formylamino-3,5-dimethyladamantane.
  • 1-bromo- 3,5-dimethyladamantane prepn. given
  • H2NCHO H2NCHO
  • H2NCHO 1-bromo- 3,5-dimethyladamantane
  • H2NCHO 157° for 14 h
  • 76.4% pure l-N-forniylamino-3,5-dimethyladamantane was heated in cone.
  • HCl at 104° for 6.5 h to give 99.9% pure memantine hydrochloride.
  • the patent discloses gas chromatographic method for Memantine Hydrochloride and impurities. Further, patent provides bulk density and particle size distribution for Memantine Hydrochloride.
  • It is an object of the present invention is to prepare memantine of formula (I) and its pharmaceutically acceptable salts.
  • Yet another object of the present invention is to provide a one-pot process for the preparation of memantine of formula (I) and its pharmaceutically acceptable salts.
  • Still another object of the present invention is to provide a process for the preparation of l-Acetamido-3,5-dimethyl adamantine of formula (II) DESCRIPTION OF THE INVNETION:
  • Memantine of formula (I) or its pharmaceutically acceptable salts which comprises reacting halogenated-3,5-dimethyl adamantine of formula (III), wherein X is Cl or Br; with acetamide in presence of sulfuric acid to provide l-Acetamido-3,5-dimethyl adamantine of formula (II) and treating said l-Acetamido-3, 5 -dimethyl adamantine of. formula (II) with base in presence of solvent to obtain Memantine of formula (I), optionally converting Memantine of formula (I) in to pharmaceutically acceptable salts.
  • the process according to the present invention is carried out in a single pot.
  • the present invention further provides the improved process for the preparation of l-Acetamido-3, 5-dimethyl adamantine of formula (II) comprising reacting halogenated-3,5-dimethyl adamantine of formula (III), wherein X is Cl or Br; with acetamide in presence of sulfuric acid to provide l-Acetamido-3, 5-dimethyl adamantine of formula (II).
  • the deacetylation of acetamido compound may be carried in a solvent selected from acyclic and cyclic poly ether to yield Memantine of formula (I).
  • the acyclic or cyclic polyether used in the present invention may be selected from the group comprising 1,2-dimethoxyethane, 1,4-dimethoxybutane, poly (alkylene glycol) such as poly (ethylene glycol), (PEGs) 5 1, 4-dioxane, crown ethers, mono alkylated ordialkylated poly (alkylene glycol) wherein the alkyl group is selected from C 1 to C 6 linear or branched alkyl, diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl ether,triethylene glycol diethyl ether, tetraethylene glycol dimethyl ether(tetraglyme) and the like and mixtures thereof.
  • the poly (alkylene glycol) and monoalkylated or dialkylated poly (alkylene glycol) being mixtures are defined by an average molecular weight and do not have specific boiling point.
  • the base used in the reaction can be selected from selected from inorganic base (s) such as an alkoxide, wherein the alkyl residue is C 1 to C 6 linear, branched or cyclic alkyl and the counter ion is an alkali or alkaline earth metal, alkali or alkaline earth metal oxide, hydroxide, carbonate or bicarbonate preferably sodium hydroxide, potassium hydroxide, potassium tertiary butoxide and the like; an organic base (s) such as amine base selected from aliphatic or aromatic amines, cyclic or acyclic amines, for example isoquinolines, quinolines,dialkylarylamines, pyridine, substituted pyridines preferably alkanolamine bases like ethanolamine and the like; and mixtures of inorganic base (s) with organic base (s).
  • inorganic base s
  • inorganic base such as an alkoxide, wherein the alkyl residue is C 1 to C 6 linear, branched or
  • one pot process for preparing compounds of formula I or its pharmaceutically acceptable salts by reacting compound of formula lib with ammonium acetate without using solvent. It is then extracted with organic solvent preferably toluene. Then treated with alkali solution and diethylene glycol to obtain compound of formula I, which is free base of memantine, which can be optionally converted to its pharmaceutically acceptable salts.
  • Formula II b Formula I (where in Ri, R 2 are selected from Cj -4 linear and branched alkyl and R 3 is selected from hydrogen, C 1-4 linear and branched alkyl).
  • R 2 are selected from Cj -4 linear and branched alkyl
  • R 3 is selected from hydrogen, C 1-4 linear and branched alkyl.
  • the present invention describes a process for preparing memantine hydrochloride having formula :
  • deacetylation reaction of acetamido derivative is carried out by heating of compound of formula Hc with sodium hydroxide in 2-8 volumes of Diethylene glycol at 80-180 0 C temperature for 6 to 15 hours to give compound of formula I.
  • Formula I
  • R 1 , R 2 are selected from C 1-4 linear and branched alkyl and R 3 is selected from hydrogen, C 1-4 linear and branched alkyl
  • R 15 R 2 is CH 3 and R 3 is hydrogen.
  • Compound formula Hc can be obtain by converting compound of formula lib to compound of formula Hc by using acetamide without any solvent.
  • R 2 are selected from C 1-4 linear and branched alkyl and R 3 is selected from hydrogen, C 1-4 linear and branched alkyl.
  • R 15 R 2 is CH 3 and R 3 is hydrogen.
  • Compound of formula lib can be prepared by converting compound of formula Ha to compound of formula lib via bromination.
  • Formula II a (where in Rj, R 2 are selected from Cj -4 linear and branched alkyl and R 3 is selected from hydrogen, C 1-4 linear and branched alkyl).
  • Rj R 2 are selected from Cj -4 linear and branched alkyl
  • R 3 is selected from hydrogen, C 1-4 linear and branched alkyl.
  • R 15 R 2 is CH 3 and R 3 is hydrogen.
  • Compound of formula lib is prepared with about 4 to 8 mole ratio of Bromine , preferably 4.5 molar equivalent and obtained good yield. To our surprise the reaction occurred at ambient conditions with bromine liquid to give bromoadamantane, compound of formula lib, making the process safe.
  • Another aspect of the invention is the one pot process for preparing compound of formula I by reacting compound of formula lib with ammonium acetate without using solvent. It is then extracted with organic solvent preferably toluene. Then treated with alkali solution and diethylene glycol to obtain compound of formula I, which is optionally converted to its pharmaceutically acceptable salts.
  • R 2 are selected from Ci -4 linear and branched alkyl and R 3 is selected from hydrogen, C 1-4 linear and branched alkyl).
  • the pharmaceutically acceptable salts may be selected from mineral acid salts such as hydrochloride, hydrobromide, sulfate and the like; organic acid salts such as oxalate, citrate, succinate, maleate, fumarate, malate, tartrate, and the like ; and sulfonates such as methanesulfonate, benzenesulfonate, toluenesulfonate and the like ; preferably hydrochloride.
  • mineral acid salts such as hydrochloride, hydrobromide, sulfate and the like
  • organic acid salts such as oxalate, citrate, succinate, maleate, fumarate, malate, tartrate, and the like
  • sulfonates such as methanesulfonate, benzenesulfonate, toluenesulfonate and the like ; preferably hydrochloride.
  • the present invention further provides a process for purification of Memantine hydrochloride, which comprises treating memantine hydrochloride with aqueous solution of base selected from sodium hydroxide, potassium hydrochloride, sodium bicarbonate, in solvent selected from toluene, xylene, methylene dichloride, acetone or mixtures thereof to obtain memantine base, extracting memantine base in organic later, treating said memantine base with hydrochloride acid to obtain pure Memantine hydrochloride.
  • Example 1 (a): Preparation of l-Bromo-3,5-dimethyl adamantane with 4.5 equivalent of bromine
  • 1,3 -Dimethyl adamantane (48.0 g) was added to reaction vessel followed by addition of bromine (67.36 mL, 4.5 equivalent) at 25-30 0 C within 30 minutes.
  • the reaction mixture was heated at 48-51 C and maintained for 12 Hrs. After heating for 12 Hrs, the reaction mixture was cooled to 10-15 0 C and then methylene chloride (800 mL) was added at 5-10 0 C. Reaction mixture was stirred at 5-10 0 C for 30 minutes. To the reaction mixture water (1.5 L) was poured at 5-10 C within 1 Hr and stirred for 30 minutes. Sodium metabisulf ⁇ te (70.0 g) was added within 2-3 Hrs and stirred for 30 minutes at 5-10 0 C .
  • Example 1 (b) : Preparation of l-Bromo-3,5-dimethyl adamantane with 6.5 equivalent of bromine 1,3 -Dimethyl adamantane (48.0 g) was added to reaction vessel followed by addition of bromine (97.36 mL, 6.5 equivalent) at 25-30 0 C within 30 minutes. The reaction mixture was heated at 48-51 0 C and maintained for 12 Hrs.
  • reaction mixture was cooled to 20-25 0 C and then methylene chloride (800 mL) was added at 5-10 0 C. Reaction mixture was stirred at 5-10 0 C for 30 minutes. The reaction mixture was poured into water (1.5 L) at 5-10 0 C within 1 Hr and stirred for 30 minutes. Sodium metabisulfite (70.0 g) was added within 2-3 Hrs and stirred for 30 minutes at 5-10 0 C. After stirring the layers were settled for 30 minutes and then separated out. To the organic (MDC) layer solution of 1% sodium bicarbonate (500 mL) was added at 5-10 0 C and stirred for 30 minutes and after stirring layers were settled and separated out.
  • MDC organic
  • Example 2 (a): Preparation of l-Acetamido-3,5-dimethyl adamantane with 10.0 equivalent of acetamide l-Bromo-3,5-dimethyl adamantane (60.0 g) was added to reaction vessel followed by addition of acetamide (145.72 g) at 25-30 0 C. The reaction mixture was stirred and then heated at 130-140 0 C and heating was maintained for 3-4 Hrs. The reaction mixture was cooled to 20-25 0 C and toluene (300 mL) was added. Reaction mixture was stirred at 25-30 0 C for 1 Hr. Water (600 mL) was added at 25-30 0 C and stirred for 1 Hr.
  • Example 2 (b): Preparation of l-Acetamido-3,5-dimethyI adamantane with 5.0 equivalent of acetamide l-Bromo-3 ,5 -dimethyl adamantane (60.0 g) was added to reaction vessel followed by addition of acetamide (72.85 g) at 25-30 0 C. The reaction mixture was stirred and then heated at 130-140 0 C and heating was maintained for 3-5 Hrs. The reaction mixture was cooled to 80-85 0 C and toluene (300 mL) was added. Reaction mixture was stirred at 25-30 0 C for 1 Hr.
  • Example 3 (a): Preparation of Memantine Base l-Acetamido-3,5-dimethyl adamantane (40.0 g) was added to reaction vessel followed by addition of sodium hydroxide (57.80 g) and DEG (200 mL) at 25-30 0 C. The reaction mixture was stirred and then heated at 155-170 0 C and heating was maintained for 10 Hrs. The reaction mixture was cooled to 80-85 0 C and water (1600 mL) was added within 1 Hr. Reaction mixture was stirred for 30 minutes and toluene (500 mL) was added to the reaction mixture and further stirred for 1 Hr. After stirring the layers were settled for 30 minutes and then separated out.
  • Example 3 (b): Preparation of Memantine Base (One pot synthesis) l ⁇ Bromo-3,5-dimethyl adamantane (60.0 g) was added to reaction vessel followed addition of acetamide (87.42 g) the reaction mixture was stirred and heated at 130-140 0 C for 3 to 5 Hrs. The reaction mixture was cooled up to 80- 85 0 C and then toluene (300 mL) was added to reaction mixture and stirred for 1 Hr. The reaction mixture was treated with water (600 mL) and stirred for lhr. The reaction mixture was filtered and washed with toluene.
  • the organic layer was separated and toluene was distilled out at temperature range 105-130°C.Cool to 105-115 0 C and the reaction mass was again treated with DEG(270 mL) at 105-115 0 C maintaing 105-115 0 C for 2 hrs. Again distill out toluene at 130-140°C.Cool at 105-115 0 C and add sodium hydroxide (78 g) was added at 105-115 0 C. The reaction mixture was stirred and then heated at 155-170 0 C and heating was maintained for 10 Hrs. The reaction mixture was cooled to 80-85 0 C and water (200 mL) was added within 1 Hr.
  • Memantine Base (21.0 g) was added to reaction vessel followed by addition of methyl-tert-butyl ether (300 mL). The reaction mixture was stirred and then cooled at 10-15 0 C and this was maintained for 30 minutes. Then IPA/HC1 (20%) (23.40 g) was added within 1 Hr at 10-15 0 C and stirred for 1 Hr at 20-25 0 C. The reaction mixture was distilled under reduced pressure below 60 0 C. The crude solid (35-40 g) was obtained. Methanol (35-40 mL) was added and further stirred at 30-40 0 C for 30 minutes.
  • Memantine Base oil (21.0 g) was added to reaction vessel followed by addition of toluene (300 mL) at 25-30 0 C . The reaction mixture was stirred and then cooled at 10-15 0 C and maintained for 30 minutes. Then IPA/HC1 (20%) (23.40 g) was added within 1 Hr at 10-15 0 C and stirred for 1 Hr at 20-25 0 C. The reaction mixture was distilled under reduced pressure below 60 C. The crude solid (36-40 g) was obtained and methanol (35-40 mL) was added and further stirred at 30-40 0 C for 30 minutes.
  • reaction mixture was cooled up to 80- 85 0 C and then toluene (300 mL) was added to reaction mixture and stirred for 1 Hr.
  • the reaction mixture was treated with water (600 mL) and stirred for lhr.
  • the reaction mixture was filtered and washed with toluene.
  • the organic layer was separated and toluene was distilled out at temperature range 105-130 0 C and then cool to 105-115 0 C and the reaction mass was again treated with DEG(260 mL) at 105-115 0 C maintaining 105- 115 0 C for 2 hrs.
  • the toluene layer was cooled to 10-15 0 C and aqueous HCl (18-22 mL) was added drop wise with in 1 hr at 10-15 0 C and stirred for 30 minutes.
  • the reaction mixture was cooled 5-1O 0 C and maintain for lhr.
  • the product was filtered and washed with chilled acetone (5 x 50 mL), the product was dried under vacuum at 80-90 0 C for 15 hrs - 20 lirs. to obtain 25- 35g of the title compound i.e.
  • memantine hydrochloride with more than 99% purity and having individual known impurities like l-Bromo-3,5-dimethyladamantane, 1- Hydroxy-3,5-dimethyladamantane, l-(N)-Acetamido-3,5-dimethyl adamantane, 1- Amino-3,5-dimethyladamantane less than 0.10% and unknown impurities less than 0.10%. The total impurities is less than 0.5%.
  • Example 7 Preparation of Memantine Hydrochloride.
  • Memantine Base (5.0 g) was added to reaction vessel followed by addition of IPA (10 mL) at 25-30 0 C. The reaction mixture was stirred and then cooled at 10-15 0 C and this was maintained for 30 minutes. Then IPA/HC1 (5.1 g) was added within 1 Hr at 10-15 0 C and stirred for 1 Hr. The solid was filtered at 5-10 0 C and washed with chilled IPA (3 x 5.0 mL) and dried the solid to obtain (4.5 g) title compound memantine hydrochloride.
  • Example 8 Preparation of Memantine Hydrochloride.
  • Memantine Base (15.0 g) was added to reaction vessel followed by addition of cyclohexane (150 mL) at 10-15 0 C. The reaction mixture was stirred and then cooled at 10-15 0 C and this was maintained for 30 minutes. Then IPA/HC1 (15.25 g) was added within 1 Hr at 10-15 0 C and stirred for 1 Hr. The solid was filtered at 5-10 0 C and washed with chilled cyclohexane (3 x 15 mL) and dried the solid to afford title compound memantine hydrochloride (25 g).
  • Example 9 Purification of Memantine hydrochloride:
  • Memantine Hydrochloride 100 gm was added to 300ml of toluene. Aqueous solution of sodium hydroxide (35gm) was added to reaction mass and heated to 60- 65oC for about 90 minutes. Organic layer was isolated by extraction and hydrochloric acid was added to organic layer containing memantine base to form Memantine hydrochloride. The reaction mass is cooled to precipitate Memantine hydrochloride and isolated by filtration and dried.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur un procédé pour la préparation de Mémantine de formule (I) ou de ses sels pharmaceutiquement acceptables. Le procédé comprend les opérations consistant à (a) faire réagir une 3,5-diméthyl adamantine halogénée de formule (III) avec de l'acétamide en présence d'acide sulfurique pour fournir de la 1-acétamido-3,5-diméthyl adamantine de formule (II), dans laquelle X est Cl ou Br ; (b) traiter la 1-acétamido-3,5-diméthyl adamantine de formule (II) par une base en présence de solvant pour obtenir de la Mémantine de formule (I) et (c) facultativement convertir la Mémantine de formule (I) en sels pharmaceutiquement acceptables.
PCT/IN2007/000500 2006-10-24 2007-10-22 Procédé pour la préparation de mémantine Ceased WO2008062472A2 (fr)

Applications Claiming Priority (2)

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IN1761MU2006 2006-10-24
IN1761/MUM/2006 2006-10-24

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WO2008062472A3 WO2008062472A3 (fr) 2008-07-10

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010007351A1 (fr) * 2008-07-14 2010-01-21 Cipla Limited Procédé de préparation de la mémantine et de ses sels et intermédiaire destiné à être utilisé dans ce procédé
WO2010015415A1 (fr) 2008-08-08 2010-02-11 Merz Pharma Gmbh & Co. Kgaa Procédé pour la fabrication de dérivés d'adamantane avec un rendement élevé
WO2010067252A1 (fr) * 2008-12-12 2010-06-17 Alembic Limited Procédé amélioré de synthèse du 1-bromo-3,5-diméthyladamantane
CN102093228A (zh) * 2011-01-18 2011-06-15 广东工业大学 一种1,3-金刚烷二胺的合成方法
CN102617277A (zh) * 2012-03-12 2012-08-01 浙江洪波化工有限公司 一种1-溴-3,5-二甲基金刚烷的合成方法
EP2555616A4 (fr) * 2010-04-08 2014-04-02 Hetero Research Foundation Procédé de préparation d'hydrochlorure de mémantine
WO2014115638A1 (fr) 2013-01-23 2014-07-31 三菱瓦斯化学株式会社 Procédé de préparation de mémantine
CN104529791A (zh) * 2014-12-10 2015-04-22 哈药集团技术中心 一种盐酸美金刚的制备方法
CN105503718A (zh) * 2015-12-18 2016-04-20 重庆康乐制药有限公司 一种盐酸阿莫地喹的连续制备方法
JP2017114820A (ja) * 2015-12-25 2017-06-29 宇部興産株式会社 １−アミノ−３，５−ジメチルアダマンタン塩酸塩の製造方法
CN113387815A (zh) * 2021-07-23 2021-09-14 刘振洋 一种美金刚的绿色制备方法

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ES2059602T3 (es) * 1989-04-14 1994-11-16 Merz & Co Gmbh & Co Uso de derivados de adamantano para la prevencion y tratamiento de isquemia cerebral.
CZ288445B6 (en) * 1996-06-20 2001-06-13 Lachema Np Process for preparing hydrochloride of 5-amino-1,3-dimethyltricyclo(3,3,1,1 3,7 )decane
EP1879849A1 (fr) * 2005-05-11 2008-01-23 Dr. Reddy's Laboratories, Inc. Procede de preparation de memantine

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010007351A1 (fr) * 2008-07-14 2010-01-21 Cipla Limited Procédé de préparation de la mémantine et de ses sels et intermédiaire destiné à être utilisé dans ce procédé
WO2010015415A1 (fr) 2008-08-08 2010-02-11 Merz Pharma Gmbh & Co. Kgaa Procédé pour la fabrication de dérivés d'adamantane avec un rendement élevé
US8796491B2 (en) 2008-08-08 2014-08-05 Merz Pharma Gmbh & Co. Kgaa Process for manufacturing adamantane derivatives with high yield
WO2010067252A1 (fr) * 2008-12-12 2010-06-17 Alembic Limited Procédé amélioré de synthèse du 1-bromo-3,5-diméthyladamantane
EP2555616A4 (fr) * 2010-04-08 2014-04-02 Hetero Research Foundation Procédé de préparation d'hydrochlorure de mémantine
CN102093228A (zh) * 2011-01-18 2011-06-15 广东工业大学 一种1,3-金刚烷二胺的合成方法
CN102093228B (zh) * 2011-01-18 2013-12-11 广东工业大学 一种1,3-金刚烷二胺的合成方法
CN102617277A (zh) * 2012-03-12 2012-08-01 浙江洪波化工有限公司 一种1-溴-3,5-二甲基金刚烷的合成方法
WO2014115638A1 (fr) 2013-01-23 2014-07-31 三菱瓦斯化学株式会社 Procédé de préparation de mémantine
US9452971B2 (en) 2013-01-23 2016-09-27 Mitsubishi Gas Chemical Company, Inc. Manufacturing process for memantine
CN104529791A (zh) * 2014-12-10 2015-04-22 哈药集团技术中心 一种盐酸美金刚的制备方法
CN105503718A (zh) * 2015-12-18 2016-04-20 重庆康乐制药有限公司 一种盐酸阿莫地喹的连续制备方法
JP2017114820A (ja) * 2015-12-25 2017-06-29 宇部興産株式会社 １−アミノ−３，５−ジメチルアダマンタン塩酸塩の製造方法
CN113387815A (zh) * 2021-07-23 2021-09-14 刘振洋 一种美金刚的绿色制备方法

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