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WO2005062724A2 - Novel process for the preparation of aminoadamantane derivatives - Google Patents

Novel process for the preparation of aminoadamantane derivatives Download PDF

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WO2005062724A2
WO2005062724A2 PCT/IN2004/000440 IN2004000440W WO2005062724A2 WO 2005062724 A2 WO2005062724 A2 WO 2005062724A2 IN 2004000440 W IN2004000440 W IN 2004000440W WO 2005062724 A2 WO2005062724 A2 WO 2005062724A2
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formula
compound
linear
branched alkyl
preparation
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PCT/IN2004/000440
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WO2005062724A3 (en
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Nagarajan Periyandi
Srinivasu Kilaru
Rajamannar Thennati
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Sun Pharmaceutical Industries Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
    • 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
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
    • C07C29/12—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of mineral acids
    • C07C29/124—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of mineral acids of halides
    • 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 novel process for the preparation of aminoadamantane derivatives, compound of formula I, and their pharmaceutically acceptable salts.
  • the present invention relates to a process for the preparation of l-amino-3,5- di ethyladamantane, compound of formula I, wherein R ls R 2 are methyl & R 3 is hydrogen, commonly known as memantine (INN Name) used in the treatment of Alzheimer's & Parkinson's disease.
  • memantine INN Name
  • United States Patent No 3,391,142 (Assigned to: Eli Lilly and Company, referred to herein as '142 ) discloses a 4 step process for the preparation of memantine hydrochloride: (a) 1,3-dimethyladamantane, compound of formula Ha, wherein R h R 2 are methyl & R 3 is hydrogen; is brominated with bromine at reflux to give l-bromo-3,5- dimethyladamantane, compound of formula lib, as a liquid;
  • Formula II a Formula II b Formula II c (wherein Rj, R 2 are selected from C linear and branched alkyl & R is selected from hydrogen, C 1- linear and branched alkyl)
  • (b)l-bromo-3,5-dimethyladamantane is treated with acetonitrile in concentrated sulphuric acid at ambient temperature overnight to furnish l-acetamido-3,5-dimethyladamantane, compound of formula He;
  • l-acetamido-3,5-dimethyladamantane is deacetylated in diethyleneglycol with sodium hydroxide at reflux, to fo ⁇ n compound of formula I, wherein R1, R 2 are methyl & R is hydrogen, as an oil; and
  • compound of fonnula I wherein R ls R 2 are methyl & R 3 is hydrogen, is converted to the hydrochloride which is precipitated from ether and purified by crystallization from alcohol: ether mixture.
  • the object of the present invention is to prepare aminoadamantane derivatives, compound of formula I, using a novel process via a stable intermediate, compound of formula Lid.
  • Formula I Formula lid (wherein Ri, R 2 , are selected from C linear and branched alkyl & R is selected from hydrogen, CM linear and branched alkyl) SUMMARY OF THE INVENTION
  • the present invention describes a novel process for preparing compound of formula I.
  • Ri , R are selected from CM linear and branched alkyl & R 3 is selected from hydrogen, CM linear a d branched alkyl
  • compound of formula I maybe obtained via hydroxyadamantane derivative, compound of formula fid.
  • compound of formula Ed may be prepared by brominating , hydrolyzing and isolating compound of formula Ea wherein bromination is carried out under ambient conditions preferably 25 to
  • compound of formula Ed is reacted with acetonitrile to give compound of formula Ec in the presence of acid like sulphuric acid.
  • the reaction proceeds smoothly at 40 - 70°C, within 1 - 8 hours to yield acetamido derivative, compound of formula Ec, when compared to '142 wherein the reaction of 1- bromo-3,5-dimethyladamantane with acetonitrile and concentrated sulphuric acid is performed at ambient temperature overnight. Further, the process of the present invention avoids use of benzene, a carcinogenic solvent, reported for extraction.
  • the deacetylation of acetamido derivative, compound of formula Ec, to give compound of formula I maybe carried out by hydrolyzing the compound of formula Ec in presence of acidic or basic catalyst. Also the solvent selected for deacetylation reactions should be suitable as a medium and also assist in hydrolysis.
  • the acidic catalyst for deacetylation may be selected from hydrochloric acid , sulphuric acid and the like.
  • the basic catalyst for deacetylation may be selected from inorganic base(s) such as an alkoxide, wherein the alkyl residue is CI to C6 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 ethanola ine and the like; and mixtures of inorganic base(s) with organic base.
  • inorganic base(s) such as an alkoxide, wherein the alkyl residue is CI to C6 linear, branched or cyclic alky
  • the deacetylation of acetamido derivative, compound of formula Ec may be carried in a solvent selected from acyclic and cyclic polyether to yield aminoadamantane, compound 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)s such as poly(ethylene glycol)s (PEGs), 1,4-dioxane, crown ethers, mono alkylated or dialkylated poly(alkylene glycol)s wherein the alkyl group is selected from Ci 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) & the like and mixtures thereof.
  • poly(alkylene glycol)s and monoalkylated or dialkylated poly(alkylene glycol)s being mixtures are defined by an average molecular weight and do not have specific boiling point, for e.g. PEG 200, PEG 400, poly(ethylene glycol) dimethyl ether 250 and the like.
  • the deacetylation reaction of acetamido derivative, compound of formula Ec is carried out by basic hydrolysis in 3 to 10 parts by volume of acyclic or cyclic polyether solvent to give compound of formula I.
  • the deacetylation reaction of acetamido derivative, compound of formula Ec is carried out by heating one gram of compound of formula Ec with sodium hydroxide in 5-8 volumes of PEG 400 at 80-150°C temperature for 6 to 12 hours to give compound of formula I.
  • the compound of formula I may be converted to it pharmaceutically acceptable salts by addition of appropriate acid.
  • 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 hydrochloride salt formation of compound of formula 1 may be carried out with hydrochloric acid dissolved in alcoholic solvent like methanol, ethanol, isopropanol, n- propanol, n-butanol, t-butanol, isobutanol or by passing HC1 gas at a temperature ranging from about -10 to 100°C to get hydrochloride salt of aminoadamantane.
  • alcoholic solvent like methanol, ethanol, isopropanol, n- propanol, n-butanol, t-butanol, isobutanol or by passing HC1 gas at a temperature ranging from about -10 to 100°C to get hydrochloride salt of aminoadamantane.
  • the crystallisation to obtain pure product is carried out in environment friendly organic solvents like polar protic, aprotic and non polar solvents selected from methanol, isopropyl alcohol, ethyl acetate, ace
  • the obtained material is leached with 300 ml of n-hexane at room temperature for 0.5 hours and further cooled to 0-5°C and maintained for 1 hour. Filter and wash with 50 ml chilled n-hexane and dry at 40-45°C.
  • the obtained solid is leached with 138 ml of n-hexane at room temperature for 0.5hours and further cooled to 0-5°C and maintained for 1 hour. Filter and wash with chilled hexane and dry at 50-55°C.
  • 40 gm of l-acetamido-3,5-dimethyl adamantine, compound of formula Ec, is added to 200 ml of PEG 400 and 57.8 gm of sodium hydroxide is added and heated to 135-140°C, maintained for 10 hours, cooled to 80-85°C and 1.6 lit of water is added. Extracted with 800 ml of toluene and washed the toluene layer with 4.0 lit of water and toluene layer is distilled and degassed with vacuum to obtain memantine free base.
  • 160 ml of methanol is added to the above obtained memantine free base and stirred, added slowly methanolic hydrochloride to adjust the pH to -2.0 and charcoalised with 2.0 gm activated charcoal, methanol distilled & degassed with vacuum at below 50°C.
  • 160 ml acetone added to the degassed mass and stirred for 15 min at 50°C and gradually cooled to 0-5°C and stirred at 0-5°C for 30 min. Filter and wash with 40 ml chilled acetone. Dry the material at 50-55 C.

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

Abstract

A novel process for the preparation of aminoadamantane derivatives, compound of formula (I) (wherein R1, R2 are selected from C1-4 linear and branched alkyl & R3 is selected from hydrogen, C1-4 linear and branched alkyl) said process comprising a)brominating compound of formula (IIa), hydrolysing and isolating compound of formula (II d). b) converting compound of formula (II d) to compound of formula (II c), and c) deacetylating compound of formula (II c) to yield compound of formula (I).

Description

NOVEL PROCESS FOR THE PREPARATION OF AMINOADAMANTANE DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of aminoadamantane derivatives, compound of formula I, and their pharmaceutically acceptable salts.
Figure imgf000003_0001
Formula I (wherein R1; R2 are selected from C1-4 linear and branched alkyl & R3 is selected from hydrogen, C1-4 linear and branched alkyl)
Particularly, the present invention relates to a process for the preparation of l-amino-3,5- di ethyladamantane, compound of formula I, wherein Rls R2 are methyl & R3 is hydrogen, commonly known as memantine (INN Name) used in the treatment of Alzheimer's & Parkinson's disease.
BACKGROUND OF THE INVENTION
United States Patent No 3,391,142 (Assigned to: Eli Lilly and Company, referred to herein as '142 ) discloses a 4 step process for the preparation of memantine hydrochloride: (a) 1,3-dimethyladamantane, compound of formula Ha, wherein Rh R2 are methyl & R3 is hydrogen; is brominated with bromine at reflux to give l-bromo-3,5- dimethyladamantane, compound of formula lib, as a liquid;
Figure imgf000004_0001
Formula II a Formula II b Formula II c (wherein Rj, R2 are selected from C linear and branched alkyl & R is selected from hydrogen, C1- linear and branched alkyl) (b)l-bromo-3,5-dimethyladamantane is treated with acetonitrile in concentrated sulphuric acid at ambient temperature overnight to furnish l-acetamido-3,5-dimethyladamantane, compound of formula He; (c) l-acetamido-3,5-dimethyladamantane is deacetylated in diethyleneglycol with sodium hydroxide at reflux, to foπn compound of formula I, wherein R1, R2 are methyl & R is hydrogen, as an oil; and (d) compound of fonnula I , wherein Rls R2 are methyl & R3 is hydrogen, is converted to the hydrochloride which is precipitated from ether and purified by crystallization from alcohol: ether mixture. There are several disadvantages of this process. The bromination is carried out at reflux conditions which leads to generation of toxic bromine vapours. Being a tertiary bromide, one would be cautious to store the intermediate, compound of formula lib, for a longer duration. Diethylene glycol, used as a solvent is toxic and poisonous. When heated to 230°C with sodium hydroxide it decomposes exothermically to release explosive hydrogen gas and also emits acrid smoke and irritating fumes. Also use of ether in step (d) constitutes a hazard because of it's highly inflammable nature and tendency to form peroxides. Thus this process is unsafe and environmentally hazardous.
To overcome the disadvantages of prior art process we have developed a safe, environment friendly and commercially scalable process to prepare aminoadamantane derivatives, compound of formula I, via a stable intermediate.
OBJECT OF THE INVENTION
The object of the present invention is to prepare aminoadamantane derivatives, compound of formula I, using a novel process via a stable intermediate, compound of formula Lid.
Figure imgf000005_0001
Formula I Formula lid (wherein Ri, R2, are selected from C linear and branched alkyl & R is selected from hydrogen, CM linear and branched alkyl) SUMMARY OF THE INVENTION
A novel process for the preparation of compound of formula I,
Figure imgf000006_0001
Formula I (wherein R1( R2 are selected from C linear and branched alkyl & R3 is selected from hydrogen, C1-4 linear and branched alkyl) said process comprising;
a) brominating compound of formula Ha, hydrolysing and isolating compound of formula lid,
Figure imgf000006_0002
Formula II a Formula II d
(wherein Ri, R2) are selected from C linear and branched alkyl & R3 is selected from hydrogen, C linear and branched alkyl) b) converting compound of formula Lid to compound of formula Lie, and
Figure imgf000007_0001
formula He (wherein R1; R2j are selected from CM linear and branched alkyl & R3 is selected from hydrogen, CM linear and branched alkyl)
c) deacetylating compound of formula lie to yield compound of formula I.
More particularly, compound of formula I, wherein R1 } R2 are methyl & R is hydrogen, commonly known as memantine
Figure imgf000007_0002
Formula I DETAILED DESCRIPTION OF THE INVENTION
The present invention describes a novel process for preparing compound of formula I.
Figure imgf000008_0001
(wherein Ri,R , are selected from CM linear and branched alkyl & R3 is selected from hydrogen, CM linear a d branched alkyl)
According to one embodiment of the process of the present invention, compound of formula I maybe obtained via hydroxyadamantane derivative, compound of formula fid.
Figure imgf000008_0002
Formula Ed (wherein Rj, R2 and R are as defined above)
As a first step to introduce a functionality in compound of formula Ha, we resorted to using bromine as described in ' 142.
Figure imgf000009_0001
Formula LI a (wherein R1;R2 are selected from C linear and branched alkyl & R3 is selected from hydrogen, Cj- linear and branched alkyl) To our surprise the reaction occured at ambient conditions with bromine liquid to give bromoadamantane, compound of formula πb, making the process safe. However, the stability of the bromo compound on storage was a matter of concern. Hence, it was of particular interest for us to isolate an intermediate, which is stable, can be stored and can participate in the next reaction to furnish the desired acetamido intermediate, compound of formula He.
Figure imgf000009_0002
Formula lib Formula fie (wherein Ri, R2 are selected from CM linear and branched alkyl & R3 is selected from hydrogen, C linear and branched alkyl) In our attempt to use a storage stable intermediate we prepared compound of formula Ed, the hydroxyadamantane derivative which on reaction with acetonitrile in presence of sulphuric acid yields acetamido derivatives (Ritter reaction) which on deacetylation gives compound of formula I. Accordingly the compound of formula lid can thus be converted to desired compound of formula I.
Figure imgf000010_0001
Formula Ed (wherein Ri , R2 are selected from C1- linear and branched alkyl & R3 is selected from hydrogen, CM linear and branched alkyl)
We found that following the process of our invention, bromination of compound of formula LTa with bromine liquid under ambient conditions afforded directly the alcohol derivative, compound of formula Ed, as a solid instead of bromoadamantane, compound of formula Eb. The alcohol derivative, compound of formula Ed was confirmed by spectral analysis (13C, Mass, elemental analysis). Analytical Data for compounds of formula Ea and Ed is depicted in table I. For instance, compound of formula Ed may be prepared by treating compound of formula Ea with 2-3 volumes of bromine at room temperature for 5-20 hours. The reaction mixture is poured in ice followed by washing with reducing agent and stirring ibr 1-5 hours at room temperature. The reaction mixture is extracted with an organic solvent like methylene dichloride followed by washing with aqueous alkaline carbonate solution and aqueous wash. The organic layer is distilled out to give compound of formula Ed.
According to another embodiment of the process of the present invention compound of formula Ed may be prepared by brominating , hydrolyzing and isolating compound of formula Ea wherein bromination is carried out under ambient conditions preferably 25 to
40°C. The alcohol derivative, compound of formula Ed is stable, of reproducible quality
as compared to bromoadamantane and can be prepared in highly pure form. The alcohol derivative, compound of formula Ed, participated in Ritter reaction as expected.
According to yet another embodiment of the process of the present invention compound of formula Ed is reacted with acetonitrile to give compound of formula Ec in the presence of acid like sulphuric acid.
The reaction proceeds smoothly at 40 - 70°C, within 1 - 8 hours to yield acetamido derivative, compound of formula Ec, when compared to '142 wherein the reaction of 1- bromo-3,5-dimethyladamantane with acetonitrile and concentrated sulphuric acid is performed at ambient temperature overnight. Further, the process of the present invention avoids use of benzene, a carcinogenic solvent, reported for extraction. The deacetylation of acetamido derivative, compound of formula Ec, to give compound of formula I maybe carried out by hydrolyzing the compound of formula Ec in presence of acidic or basic catalyst. Also the solvent selected for deacetylation reactions should be suitable as a medium and also assist in hydrolysis.
The acidic catalyst for deacetylation may be selected from hydrochloric acid , sulphuric acid and the like.
The basic catalyst for deacetylation may be selected from inorganic base(s) such as an alkoxide, wherein the alkyl residue is CI to C6 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 ethanola ine and the like; and mixtures of inorganic base(s) with organic base.(s)
The deacetylation of acetamido derivative, compound of formula Ec, may be carried in a solvent selected from acyclic and cyclic polyether to yield aminoadamantane, compound 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)s such as poly(ethylene glycol)s (PEGs), 1,4-dioxane, crown ethers, mono alkylated or dialkylated poly(alkylene glycol)s wherein the alkyl group is selected from Ci to C6 linear or branched alkyl, diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl ether, triethylene glycol diethyl ether, tetraethylene glycol dimethyl ether (tetraglyme) & the like and mixtures thereof. The poly(alkylene glycol)s and monoalkylated or dialkylated poly(alkylene glycol)s being mixtures are defined by an average molecular weight and do not have specific boiling point, for e.g. PEG 200, PEG 400, poly(ethylene glycol) dimethyl ether 250 and the like.
hi the process of the present invention the deacetylation reaction of acetamido derivative, compound of formula Ec, is carried out by basic hydrolysis in 3 to 10 parts by volume of acyclic or cyclic polyether solvent to give compound of formula I.
For instance, the deacetylation reaction of acetamido derivative, compound of formula Ec, is carried out by heating one gram of compound of formula Ec with sodium hydroxide in 5-8 volumes of PEG 400 at 80-150°C temperature for 6 to 12 hours to give compound of formula I.
The compound of formula I may be converted to it pharmaceutically acceptable salts by addition of appropriate acid.
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.
The hydrochloride salt formation of compound of formula 1 may be carried out with hydrochloric acid dissolved in alcoholic solvent like methanol, ethanol, isopropanol, n- propanol, n-butanol, t-butanol, isobutanol or by passing HC1 gas at a temperature ranging from about -10 to 100°C to get hydrochloride salt of aminoadamantane. The crystallisation to obtain pure product is carried out in environment friendly organic solvents like polar protic, aprotic and non polar solvents selected from methanol, isopropyl alcohol, ethyl acetate, acetonitrile, acetone, toluene and the mixtures thereof.
The invention is further illustrated but not restricted by the description in the following examples.
Examples Example 1 Preparation of compound of formula E d (wherein Ri, R2 are CH3 & R3 is H) 500 ml of bromine liquid is added to 200 gm of 1,3 dimethyladamantane and stirred at room temperature for 12 hours and the reaction mixture is poured in 4.0 kg ice cold water The reaction mixture is decolorized with 950 gm sodium metabisulphite and stirred for 1.5 hours at room temperature. Extract with 2.0 lit MDC and the MDC layer is washed with 1.0 lit 10% sodium bicarbonate solution and subsequently with 2.0 lit water, MDC layer is dried over sodium sulphate, distilled and degassed with vacuum. The obtained material is leached with 300 ml of n-hexane at room temperature for 0.5 hours and further cooled to 0-5°C and maintained for 1 hour. Filter and wash with 50 ml chilled n-hexane and dry at 40-45°C.
Table 1 Analytical Data for -Bromo and -hydroxy compounds ( 13 C/ , Mass, elemental)
Figure imgf000015_0001
Example 2
Preparation of compound of formula Ec (wherein Ri, R2 are CH3 & R3 is H) 46 gm of l-Hydroxy-3,5-dimethyladamantane, compound of formula E d is added to a mixture of 184 ml acetonitrile and 386 ml sulphuric acid and heated to 45-50°C and maintained for 8 hours. The reaction mass is quenched in 1380 gm of ice water and extracted with 920 ml of MDC, MDC layer is washed with 230 ml of 10% sodium bicarbonate solution and subsequently with 460 ml of water, distilled and degassed with vacuum. The obtained solid is leached with 138 ml of n-hexane at room temperature for 0.5hours and further cooled to 0-5°C and maintained for 1 hour. Filter and wash with chilled hexane and dry at 50-55°C.
Example 3
Preparation ofhvdrochlori.de salt of compound of formula I (wherein Rls R2 are CH3 & R3 is H)
40 gm of l-acetamido-3,5-dimethyl adamantine, compound of formula Ec, is added to 200 ml of PEG 400 and 57.8 gm of sodium hydroxide is added and heated to 135-140°C, maintained for 10 hours, cooled to 80-85°C and 1.6 lit of water is added. Extracted with 800 ml of toluene and washed the toluene layer with 4.0 lit of water and toluene layer is distilled and degassed with vacuum to obtain memantine free base. 160 ml of methanol is added to the above obtained memantine free base and stirred, added slowly methanolic hydrochloride to adjust the pH to -2.0 and charcoalised with 2.0 gm activated charcoal, methanol distilled & degassed with vacuum at below 50°C. 160 ml acetone added to the degassed mass and stirred for 15 min at 50°C and gradually cooled to 0-5°C and stirred at 0-5°C for 30 min. Filter and wash with 40 ml chilled acetone. Dry the material at 50-55 C.

Claims

WE claim:
1) A novel process for the preparation of compound of formula I,
Figure imgf000018_0001
Formula I (wherein Ri, R2 are selected from C1-4 linear and branched alkyl & R is selected from hydrogen, CM linear and branched alkyl) said process comprising; a) brominating compound of formula Ea, hydrolysing and isolating compound of formula Ed,
Figure imgf000018_0002
Formula E a Formula II d (wherein R1; R2, are selected from C linear and branched alkyl & R3 is selected from hydrogen, CM linear and branched alkyl)
b) converting compound of formula Ed to compound of formula Ec, and
Figure imgf000019_0001
formula Ec (wherein R1; R2) are selected from Cι- linear and branched alkyl & R3 is selected from hydrogen, Cι-4 linear and branched alkyl)
c) deacetylating compound of formula Ec to yield compound of formula I.
2) A novel process as claimed in claim 1 step (a) wherein bromination is carried out at ambient temperature.
3) A novel process as claimed in claim 1 step (b) wherein conversion of Ed is carried out with acetonitrile in presence of acid.
4) A novel process as claimed in claim 1 wherein step (c) is carried out in solvent selected from acyclic or cyclic polyether.
5) A process for the preparation of compound of formula I,
Figure imgf000020_0001
said process comprising a) brominating compound of formula Ea, hydrolysing and isolating compound of formula Ed,
Figure imgf000020_0002
Formula E a Formula E d b) converting compound of formula Ed to compound of formula Ec, and
Figure imgf000020_0003
foπnula Ec c) deacetylating compound of formula Ec to yield compound of formula I.
6) A process as claimed in claim 5 step (a) wherein bromination is carried out at ambient temperature.
7) A process as claimed in claim 5 step (b) wherein conversion of Ed is carried out with acetonitrile in presence of acid.
8) A novel process as claimed in claim 5 wherein step (c) is carried out in solvent selected from acyclic or cyclic polyether.
9) A process for the preparation of compound of formula E d,
Figure imgf000021_0001
Formula E d (wherein Ri, R are selected from CM linear and branched alkyl & R3 is selected from hydrogen, CM linear and branched alkyl) said process comprising brominating compound of formula Ea, hydrolysing and isolating compound of formula Ed.
Figure imgf000021_0002
Formula Ea
10. A process as claimed in claim 9 wherein bromination is carried out at ambient temperature. 1) A process for the preparation of compound of formula I as claimed in claims 1 to 10 substantially as herein described and illustrated by examples lto 3
PCT/IN2004/000440 2003-12-31 2004-12-30 Novel process for the preparation of aminoadamantane derivatives WO2005062724A2 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006076560A1 (en) * 2005-01-11 2006-07-20 Teva Pharmaceutical Fine Chemicals S.R.L. Polymorphs of memantine hydrochloride
EP1721888A1 (en) * 2005-05-10 2006-11-15 A.M.S.A. ANONIMA MATERIE SINTETICHE E AFFINI S.p.A. Process for synthesising aminoadamantanes
JP2009527517A (en) * 2006-02-21 2009-07-30 ヘクサル アクチェンゲゼルシャフト Method for preparing adamantaneamines
WO2007132476A3 (en) * 2006-05-15 2009-10-22 Matrix Laboratories Limited A process for the preparation of memantine hydrochloride
JP2012513451A (en) * 2009-01-21 2012-06-14 メルツ・ファルマ・ゲゼルシヤフト・ミト・ベシュレンクテル・ハフツング・ウント・コンパニー・コマンデイトゲゼルシヤフト・アウフ・アクティーン Method for producing memantine
US20120245391A1 (en) * 2009-09-28 2012-09-27 MERZ PHARMA GmbH &CO. KGaA Method of preparing neramexane or a salt thereof
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Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3450761A (en) * 1967-03-30 1969-06-17 Sun Oil Co 1-aminoethyldimethyladamantane
SU1221866A1 (en) * 1984-03-27 1990-06-23 Институт Органической Химии Ан Усср Method of obtaining 1-oxyderivatives of adamantane, its methyl-substituted or bicyclo/3,3-1/ nonane

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WO2006076560A1 (en) * 2005-01-11 2006-07-20 Teva Pharmaceutical Fine Chemicals S.R.L. Polymorphs of memantine hydrochloride
US7462743B2 (en) 2005-01-11 2008-12-09 Teva Pharmaceutical Fine Chemicals S.R.L. Polymorphs of memantine hydrochloride
EP1721888A1 (en) * 2005-05-10 2006-11-15 A.M.S.A. ANONIMA MATERIE SINTETICHE E AFFINI S.p.A. Process for synthesising aminoadamantanes
US7405324B2 (en) 2005-05-10 2008-07-29 A.M.S.A. Anonima Materie Sintetiche E. Afini S.P.A. Process for synthesising aminoadamantanes
JP2009527517A (en) * 2006-02-21 2009-07-30 ヘクサル アクチェンゲゼルシャフト Method for preparing adamantaneamines
WO2007132476A3 (en) * 2006-05-15 2009-10-22 Matrix Laboratories Limited A process for the preparation of memantine hydrochloride
JP2012513451A (en) * 2009-01-21 2012-06-14 メルツ・ファルマ・ゲゼルシヤフト・ミト・ベシュレンクテル・ハフツング・ウント・コンパニー・コマンデイトゲゼルシヤフト・アウフ・アクティーン Method for producing memantine
US20120245391A1 (en) * 2009-09-28 2012-09-27 MERZ PHARMA GmbH &CO. KGaA Method of preparing neramexane or a salt thereof
US8692021B2 (en) * 2009-09-28 2014-04-08 Merz Pharma Gmbh & Co. Kgaa Method of preparing Neramexane or a salt thereof
RU2510962C2 (en) * 2012-06-19 2014-04-10 Федеральное государственное бюджетное учреждение науки Институт нефтехимии и катализа Российской академии наук Method of obtaining 1,3-dimethyladamantan-5-ol
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US9452971B2 (en) 2013-01-23 2016-09-27 Mitsubishi Gas Chemical Company, Inc. Manufacturing process for memantine
JPWO2014115638A1 (en) * 2013-01-23 2017-01-26 三菱瓦斯化学株式会社 Memantine manufacturing process

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