WO2009057140A2 - Improved process for memantine hydrochloride - Google Patents
Improved process for memantine hydrochloride Download PDFInfo
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- WO2009057140A2 WO2009057140A2 PCT/IN2008/000709 IN2008000709W WO2009057140A2 WO 2009057140 A2 WO2009057140 A2 WO 2009057140A2 IN 2008000709 W IN2008000709 W IN 2008000709W WO 2009057140 A2 WO2009057140 A2 WO 2009057140A2
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- Prior art keywords
- formula
- compound
- memantine
- solvent
- acid
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- 0 C*(C1)CC(C2)=CC(C)(C)CC12N Chemical compound C*(C1)CC(C2)=CC(C)(C)CC12N 0.000 description 2
Classifications
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- 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
Definitions
- the present invention relates to an improved eco-friendly process for the preparation of memantine hydrochloride.
- Memantine hydrochloride is chemically known as l-amino-3,5-diniethyl adamantane hydrochloride, which is represented by the compound of 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.
- Memantine is commercially available in the form of hydrochloride salt under the brand name NAMENDA, which is available for oral administration as capsule shaped film-coated tablets containing 5 mg and 10 mg of memantine hydrochloride.
- Memantine, its pharmaceutically acceptable salts thereof and process for their preparation were first disclosed in US patent 3391142.
- the disclosed process comprises of reacting l-bromo-3,5-dimethyladamantane with sulphuric acid in acetonitrile gives l-acetamido-3,5-dimethyl adamantine, followed by deacetylation in diethylene glycol with sodium hydroxide at reflux temperature which gives memantine.
- the obtained memantine is converted into its hydrochloride salt by treating with anhydrous hydrogen chloride and recrystallized from a mixture of alcohol and ether.
- This process involves the addition of bromine at reflux condition for the preparation of starting compound l-bromo-3,5-dimethyladamantane, which leads to the generation of toxic bromine vapours and also producing excess of effluent. Hence this process is not suitable for the commercial purpose as well as it is not eco-friendly.
- Tetrahedron letters 56, page number. 5833-5835, 1968 discloses a process for the preparation of l-amino-3 ,5 -dimethyl adamantane without bromination reaction.
- the disclosed process comprises of amination of 1,3-dimethyl adamantane with trichloroamine and aluminium chloride give l-amino-3,5-dimethyl adamantane with 40% yield.
- JP 2002/275142 discloses a alternate process for the preparation of l-acetarnido-3,5-dimethyl adamantane directly from 1,3-dimethyl adamantane without converting into l-halo-3, 5 -dimethyl adamantane as shown by the following scheme with a yield of 45%.
- the main aim of the present invention is to provide an eco-friendly process over the prior art processes.
- the aim of the present invention is attained by two ways, one is by providing an improved eco-friendly process for the preparation of l-acetamido-3,5- dimethyl adamantane from 1,3 -dimethyl adamantane without using any solvents in the reaction and without converting it into l-brorno-3,5-dimethyl adamantane, there by avoiding the toxic vapours and effluents caused by the usage of bromine.
- the non-usage of solvent leads to the reduction of production cost and effluent formation and make the process eco-friendly as well as economic.
- the present invention relates to an improved eco-friendly process for the preparation of memantine and its pharmaceutically acceptable salts thereof, especially hydrochloride salt.
- Memantine hydrochloride is chemically known as l-amino-3,5- dimethyl adamantane hydrochloride, which is represented by the compound of formula- 1.
- the first aspect of the present invention is to provide an improved eco-friendly process for the preparation of memantine hydrochloride compound of formula- 1, which comprises of reacting the 1,3 -dimethyl adamantane compound of formula- 2 with suitable nitrile in presence of a suitable strong acid at a temperature of about 50-85 0 C and for a period of time sufficient to produce l-acetamido-3,5-dimethyl adamantane compound of formula-3 followed by isolation of l-acetamido-3,5-dimethyladarnantane compound of formula-3.
- the second aspect of the present invention is to provide an eco-friendly one-pot process for the preparation of memantine hydrochloride compound of formula- 1 from 1,3-dimethyl adamantane compound of formula-2 without isolating any intermediates, which comprises of reacting 1,3-dimethyl adamantane compound of formula-2 with suitable nitrile in presence of a suitable strong acid at a temperature of about 50-85°C and for a period of time sufficient to produce l-acetamido-3,5-dirnethyl adamantane compound of formula-3 and hydrolyzing it with suitable alkali metal hydroxide in a suitable alcoholic solvent or an aqueous alcoholic solvent or mixtures thereof provide memantine compound of formula-4, which on subsequent treatment with hydrochloric acid in a suitable solvent and addition of suitable anti-solvent such as ester solvents gives memantine hydrochloride compound of formula- 1.
- Figure-1 Illustrates the X-ray powder diffraction pattern of memantine hydrochloride compound of formula- 1.
- Memantine hydrochloride is chemically known as l-amino-3,5- dimethyl adamantane hydrochloride, which is represented by the compound of formula- 1.
- the first aspect of the present invention provides an improved eco-friendly process for the preparation of memantine hydrochloride compound of formula- 1, which comprises of reacting 1,3-dimethyladamantane compound of formula-2
- Suitable alkali metal hydroxide like sodium hydroxide or potassium hydroxide, preferably sodium hydroxide in a suitable alcoholic solvent selected from polyethylene glycol or diethylene glycol or aqueous alcoholic solvents or mixtures thereof preferably polyethylene glycol or aqueous polyethylene glycol at a temperature of about 110-200°C preferably 120-160°C for a sufficient period of time preferably about 2 to 25 hours, most preferably 2 to 20 hours to provide l-amino-3,5-dimethyladamantane compound of formula-4,
- suitable alkali metal hydroxide like sodium hydroxide or potassium hydroxide, preferably sodium hydroxide in a suitable alcoholic solvent selected from polyethylene glycol or diethylene glycol or aqueous alcoholic solvents or mixtures thereof preferably polyethylene glycol or aqueous polyethylene glycol at a temperature of about 110-200°C preferably 120-160°C for a sufficient period of time preferably about 2 to 25 hours, most preferably 2 to 20 hours to provide l
- Formula-4 which on in-situ treating with hydrochloric acid in a suitable alcoholic solvent like isopropyl alcohol, methanol and the like preferably isopropyl alcohol followed by the addition of suitable ester solvents like ethyl acetate provides memantine hydrochloride compound of formula- 1.
- the second aspect of the present invention is to provide an eco-friendly and cost effective one pot process for the preparation of memantine hydrochloride compound of formula- 1 from 1,3-dimethyladmantane compound of formula-2 without isolating any intermediate, which comprises of reacting 1,3-dimethyladamantane compound of formula-2,
- Formula-3 which on in-situ hydrolysis with a suitable alkali metal hydroxide like sodium hydroxide or potassium hydroxide preferably sodium hydroxide in a suitable alcoholic solvents selected from diethylene glycol, polyethylene glycol or aqueous alcoholic solvent or mixtures thereof at a temperature of about 110-200 0 C preferably 120-160°C, with or without employing pressure for a sufficient period of time preferably 2 to 25 hours, most preferably 2 to 20 hours provides the l-amino-3,5-dimethyl adamantane compound of formula-4,
- Formula-4 which on subsequent treatment with hydrochloric acid in a suitable alcoholic solvents like isopropyl alcohol, methanol and the like preferably isopropyl alcohol followed by the addition of suitable ester solvents like ethyl acetate provides memantine hydrochloride compound of formula- 1.
- the aqueous alcoholic solvent refers to the mixture of particular alcoholic solvent with water for example a mixture of polyethylene glycol and water or diethylene glycol and water.
- water content of the aqueous alcoholic solvent according to the present invention is 0.2 to 5% v/v.
- the memantine hydrochloride compound of formula- 1 prepared according to the present invention is characterized by the X-ray powder diffraction (as shown in figure- 1) is similar to the prior art crystalline form i.e., Crystalline form-I of memantine hydrochloride.
- XRD analysis of memantine hydrochloride was carried out using SIEMENS/D- 5000 X-Ray Diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min.
- Example-1 Preparation of l-acetamido-3,5-dimethyI adamantane :
- Example-2 Preparation of l-acetamido-3,5-dimethyl adamantane : A mixture of 1,3-dimethyl adamantane (10 grams) and acetonitrile (36.8 ml) was heated to 60-65°C. Sulphuric acid (75 ml) was slowly added to the above reaction mixture at below 8O 0 C. The reaction mixture was stirred for 10 hours at 65-70°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with toluene. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene and the organic layer was washed with water. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 70 0 C to get the title compound. Yield: 12.3 grams
- Example-4 Preparation of memantine hydrochloride from l-acetamido-3,5- dimethyl adamantane:
- D(0.5) is 8 ⁇ m and D(0.9) is 30 ⁇ m
- the reaction mixture was quenched with ice water. Added toluene to the reaction mixture and stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 70 0 C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-5 0 C.
- the methylene chloride from the organic layer was distilled off under reduced pressure at below 40°C and added polyethylene glycol (60 ml) and sodium hydroxide (14.5 grams).
- the reaction mixture was heated to 120 0 C.
- the reaction mixture was stirred for 20 hours at 120°C. Cooled the reaction mixture to 25-35°C.
- the reaction mixture was quenched with ice water.
- the organic and aqueous layers were separated.
- the aqueous layer was extracted with toluene.
- the organic layer was dried with sodium sulphate.
- the toluene from the organic layer was distilled off under reduced pressure at below 7O 0 C.
- Residual solvents by GC Ethanol- 366 ppm; 2-propanol - 809 ppm; Acetonitrile -357 ppm; Ethyl acetate- not detected; toluene- 118 ppm and acetic acid- not detected.
- Bulk density Untapped: 0.23 g/ml ; Tapped : 0.35 g/ml
- D(0.5) is 9 ⁇ m and D(0.9) is 34 ⁇ m
- Example-7 One-pot preparation of memantine hydrochloride:
- Example-8 One-pot preparation of memantine hydrochloride:
- the methylene chloride from the organic layer was distilled off under reduced pressure at below 40°C and added polyethylene glycol (60 ml), water (2.8 ml) and sodium hydroxide (14.5 grams).
- the reaction mixture was heated to 120 0 C.
- the reaction mixture was stirred for 20 hours at 120°C. Cooled the reaction mixture to 25-35 0 C.
- the reaction mixture was quenched with ice water.
- the organic and aqueous layers were separated.
- the aqueous layer was extracted with toluene.
- the organic layer was dried with sodium sulphate.
- the toluene from the organic layer was distilled off under reduced pressure at below 7Q°C.
- Polyethylene glycol (58 ml), sodium hydroxide (17 grams) was added and stirred for 30 minutes. Apply nitrogen pressure of 1.5 kg to the reaction mixture and heated to 12O 0 C. The reaction mixture was stirred for 12 hours at 120-130 0 C under nitrogen pressure and then cooled to 45°C. Toluene (50 ml) was added to the reaction mixture and stirred for 15 minutes. Then water (140 ml) was added, stirred and the layers were separated. The aqueous layer was extracted with toluene and then washed the toluene layer with water. The toluene layer was distilled off under reduced pressure at below 70°C.
- Residual solvents by GC Ethanol- 121 ppm; 2-propanol - 765 ppm; Acetonitrile-not detected; Ethyl acetate- not detected; toluene- not detected and acetic acid- 778 ppm.
- D(0.5) is 7 ⁇ m and D(0.9) is 24 ⁇ m
Abstract
The present invention provides an improved eco-friendly process for the preparation of memantine hydrochloride compound of formula (1). The present invention also provides one-pot process for the preparation of memantine hydrochloride compound of fomula (1) from 1,3 -dimethyl adamantane without isolating any intermediates.
Description
IMPROVED PROCESS FOR MEMANTINE HYDROCHLORIDE
Related Applications:
This application claims the benefit of priority of our Indian patent application number 2463/CHE/2007 filed on October 30, 2007, which is incorporated herein by reference.
Field of the Invention:
The present invention relates to an improved eco-friendly process for the preparation of memantine hydrochloride. Memantine hydrochloride is chemically known as l-amino-3,5-diniethyl adamantane hydrochloride, which is represented by the compound of 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. Memantine is commercially available in the form of hydrochloride salt under the brand name NAMENDA, which is available for oral administration as capsule shaped film-coated tablets containing 5 mg and 10 mg of memantine hydrochloride.
Background of the Invention:
Memantine, its pharmaceutically acceptable salts thereof and process for their preparation were first disclosed in US patent 3391142. The disclosed process comprises of reacting l-bromo-3,5-dimethyladamantane with sulphuric acid in acetonitrile gives
l-acetamido-3,5-dimethyl adamantine, followed by deacetylation in diethylene glycol with sodium hydroxide at reflux temperature which gives memantine. The obtained memantine is converted into its hydrochloride salt by treating with anhydrous hydrogen chloride and recrystallized from a mixture of alcohol and ether. This process involves the addition of bromine at reflux condition for the preparation of starting compound l-bromo-3,5-dimethyladamantane, which leads to the generation of toxic bromine vapours and also producing excess of effluent. Hence this process is not suitable for the commercial purpose as well as it is not eco-friendly.
Tetrahedron letters 56, page number. 5833-5835, 1968 discloses a process for the preparation of l-amino-3 ,5 -dimethyl adamantane without bromination reaction. The disclosed process comprises of amination of 1,3-dimethyl adamantane with trichloroamine and aluminium chloride give l-amino-3,5-dimethyl adamantane with 40% yield.
The Japanese patent publication number JP 2002/275142 discloses a alternate process for the preparation of l-acetarnido-3,5-dimethyl adamantane directly from 1,3-dimethyl adamantane without converting into l-halo-3, 5 -dimethyl adamantane as shown by the following scheme with a yield of 45%.
CCHH3s NN--hhyyddroxypthalimide
Even though the above two references disclosed a process for the preparation of memantine hydrochloride without involving the usage of bromine, but the overall yield is less than 45% and also involves the usage of expensive and dangerous reagents. Hence the above said processes are commercially not suitable. Still there is a need in the art for the eco-friendly and commercially viable process for the preparation of memantine and its pharmaceutically acceptable salts.
It will be appreciable to have an eco-friendly process which avoids/ eliminates/reduces the usage of solvent or toxic reagents which affects the environment
or reduces number of stages thereby saving the production cost, time and effluent formation to safeguard the environment.
The main aim of the present invention is to provide an eco-friendly process over the prior art processes. The aim of the present invention is attained by two ways, one is by providing an improved eco-friendly process for the preparation of l-acetamido-3,5- dimethyl adamantane from 1,3 -dimethyl adamantane without using any solvents in the reaction and without converting it into l-brorno-3,5-dimethyl adamantane, there by avoiding the toxic vapours and effluents caused by the usage of bromine. The non-usage of solvent leads to the reduction of production cost and effluent formation and make the process eco-friendly as well as economic.
The second way attained by providing commercial viable and economic one-pot process for the preparation of memantine hydrochloride without isolating any intermediates and there by reducing the solvent usage, material wastage and excess time of production.
Brief Description of the Invention:
The present invention relates to an improved eco-friendly process for the preparation of memantine and its pharmaceutically acceptable salts thereof, especially hydrochloride salt. Memantine hydrochloride is chemically known as l-amino-3,5- dimethyl adamantane hydrochloride, which is represented by the compound of formula- 1.
Formula- 1
The first aspect of the present invention is to provide an improved eco-friendly process for the preparation of memantine hydrochloride compound of formula- 1, which comprises of reacting the 1,3 -dimethyl adamantane compound of formula- 2 with suitable
nitrile in presence of a suitable strong acid at a temperature of about 50-850C and for a period of time sufficient to produce l-acetamido-3,5-dimethyl adamantane compound of formula-3 followed by isolation of l-acetamido-3,5-dimethyladarnantane compound of formula-3.
Hydrolyzing the l-acetamido-3,5-dimethyladarnantane with a suitable alkali metal hydroxide in a suitable alcoholic solvents or aqueous alcoholic solvent or mixtures thereof for a sufficient period of time to obtain l-amino-3,5-dimethyladamantane compound of formula-4 with or without employing pressure, which on in-situ treatment with hydrochloric acid in a suitable alcoholic solvents followed by the addition of suitable anti-solvents like ester solvents to provide memantine hydrochloride compound of formula- 1.
The second aspect of the present invention is to provide an eco-friendly one-pot process for the preparation of memantine hydrochloride compound of formula- 1 from 1,3-dimethyl adamantane compound of formula-2 without isolating any intermediates, which comprises of reacting 1,3-dimethyl adamantane compound of formula-2 with suitable nitrile in presence of a suitable strong acid at a temperature of about 50-85°C and for a period of time sufficient to produce l-acetamido-3,5-dirnethyl adamantane compound of formula-3 and hydrolyzing it with suitable alkali metal hydroxide in a suitable alcoholic solvent or an aqueous alcoholic solvent or mixtures thereof provide memantine compound of formula-4, which on subsequent treatment with hydrochloric acid in a suitable solvent and addition of suitable anti-solvent such as ester solvents gives memantine hydrochloride compound of formula- 1.
Advantages of the present Invention:
• Provides an eco-friendly and industrially feasible process for the preparation of memantine hydrochloride which avoids the usage of bromine.
• Provides the cost effective and eco-friendly process for the preparation of l-acetamido-3,5-dimethyl adamantane from 1,3-dimethyl adamantane compound of formula-2 without using a solvent thereby reducing the solvent consumption and reduces the formation of effluent as well as the cost of production.
• Provides eco-friendly and economic one-pot process for the preparation of memantine hydrochloride which avoids unnecessary isolation and excess solvent usage and minimizes time cycle and the wastage of material by transformation.
• Provides commercially viable process which gives high yield and high purity without any further purification.
Brief Description of Drawing:
Figure-1: Illustrates the X-ray powder diffraction pattern of memantine hydrochloride compound of formula- 1.
Detailed Description of the Invention:
Accordingly the present invention provides an improved eco-friendly process for the preparation of memantine and its pharmaceutically acceptable salts thereof especially hydrochloride salt. Memantine hydrochloride is chemically known as l-amino-3,5- dimethyl adamantane hydrochloride, which is represented by the compound of formula- 1.
Formula- 1
The first aspect of the present invention provides an improved eco-friendly process for the preparation of memantine hydrochloride compound of formula- 1, which comprises of reacting 1,3-dimethyladamantane compound of formula-2
Formula-2
with acetonitrile in presence of a suitable acid selected from sulphuric acid, phosphoric acid and acetic acid or mixtures thereof, preferably sulphuric acid at a temperature of about 50-70°C preferably 60-65°C for a period of time sufficient to produce 1-acetamido- 3,5-dimethyl adamantane compound of formula-3 preferably 2 to 15 hours, most preferably 2 to 10 hours in the absence of any solvent and recovering l-acetamido-3,5- dimethyl adamantane compound of formula-3 or by extracting the l-acetamido-3,5- dimethyladamantane compound using methylene chloride or toluene and concentrating the organic layer to provide the l-acetamido-3,5-dimethyladamantane compound of formula-3, other nitriles like propionitrile, butyronitrile and valeronitrile can also be used in place of acetonitrile. If other nitrile is used, the compound of formula-2 is converted into the corresponding alkylamido derivative compounds which is hydrolyzed to provide the l-amino-3,5-dimethyl adamantane compound of formula-4,
Formula-3
Hydrolyzing the l-acetamido-3,5-dimethyl adamantane compound of formula-3 with suitable alkali metal hydroxide like sodium hydroxide or potassium hydroxide, preferably sodium hydroxide in a suitable alcoholic solvent selected from polyethylene glycol or diethylene glycol or aqueous alcoholic solvents or mixtures thereof preferably polyethylene glycol or aqueous polyethylene glycol at a temperature of about 110-200°C preferably 120-160°C for a sufficient period of time preferably about 2 to 25 hours, most preferably 2 to 20 hours to provide l-amino-3,5-dimethyladamantane compound of formula-4,
Formula-4
which on in-situ treating with hydrochloric acid in a suitable alcoholic solvent like isopropyl alcohol, methanol and the like preferably isopropyl alcohol followed by the addition of suitable ester solvents like ethyl acetate provides memantine hydrochloride compound of formula- 1.
Formula- 1
The second aspect of the present invention is to provide an eco-friendly and cost effective one pot process for the preparation of memantine hydrochloride compound of formula- 1 from 1,3-dimethyladmantane compound of formula-2 without isolating any intermediate, which comprises of reacting 1,3-dimethyladamantane compound of formula-2,
Formula-2 with acetonitrile in presence of a suitable acid selected from sulphuric acid, phosphoric acid and acetic acid or mixtures thereof, preferably sulphuric acid at about 50-70°C preferably 60-700C and for a period of time sufficient preferably is about 2 to 15 hours, most preferably 2 to 10 hours to produce l-acetamido-3,5-dimethyladamantane compound of formula-3, in absence of any solvent, other nitriles like propionitrile, butyronitrile and valeronitrile can also be used in place of acetonitrile. If other nitrile is used, the compound of formula-2 is converted into the corresponding alkylamido derivative compounds which is hydrolyzed to provide the l-amino-3,5-dimethyl adamantane compound of formula-4,
Formula-3 which on in-situ hydrolysis with a suitable alkali metal hydroxide like sodium hydroxide or potassium hydroxide preferably sodium hydroxide in a suitable alcoholic solvents selected from diethylene glycol, polyethylene glycol or aqueous alcoholic solvent or mixtures thereof at a temperature of about 110-2000C preferably 120-160°C, with or without employing pressure for a sufficient period of time preferably 2 to 25 hours, most preferably 2 to 20 hours provides the l-amino-3,5-dimethyl adamantane compound of formula-4,
Formula-4 which on subsequent treatment with hydrochloric acid in a suitable alcoholic solvents like isopropyl alcohol, methanol and the like preferably isopropyl alcohol followed by the addition of suitable ester solvents like ethyl acetate provides memantine hydrochloride compound of formula- 1.
Preferably the aqueous alcoholic solvent refers to the mixture of particular alcoholic solvent with water for example a mixture of polyethylene glycol and water or diethylene glycol and water. Preferably water content of the aqueous alcoholic solvent according to the present invention is 0.2 to 5% v/v.
The memantine hydrochloride compound of formula- 1 prepared according to the present invention is characterized by the X-ray powder diffraction (as shown in figure- 1) is similar to the prior art crystalline form i.e., Crystalline form-I of memantine hydrochloride.
XRD analysis of memantine hydrochloride was carried out using SIEMENS/D- 5000 X-Ray Diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min.
The related substances of memantine hydrochloride was analyzed by GC using the following conditions:
Column:AT-5; Length:30mts; Film thickness:5.0μm; Injector temperature:230°C; Split: 1:5; Detector temperature:280°C; Carriergas:Helium; Column flow:3.0PSI; Load: 1.0 μl; Diluent: toluene
The RS/OVI of memantine hydrochloride was analyzed by GC using the following conditions:
Column: AT-624; Length:30mts; Film thickness: 3. Oμm; Injector temperature:140°C; split: 1:5; Detector temperature:260°C; Carriergas: Helium; Column flow:2.8 PSI; Load: 1.0 μl
The present invention schematically represented by the following schemes:
Scheme-1:
Formula-3
NaOH or KOH Polyethyleneglycol or Aq.polyethyleneglycol
Formula- 1
Formula-4
Scheme-2:
Fommla-2
NaOH or KOH Polyethyleneglycol or Aq.polyethyleneglycol
Formula- 1
Formula-4
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:
Example-1: Preparation of l-acetamido-3,5-dimethyI adamantane :
A mixture of 1,3 -dimethyl adamantane (10 grams) and acetonitrile (36.8 ml) was heated to 60-65°C. Sulphuric acid (75 ml) was slowly added to the above reaction mixture at below 80°C. The reaction mixture was stirred for 10 hours at 65-70°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with methylene chloride. The organic and aqueous layers were separated. The aqueous layer was extracted with methylene chloride and the organic layer was washed with water. The organic layer was dried with sodium sulphate. The methylene chloride from the organic layer was distilled off under reduced pressure at below 40°C to get the title compound. Yield: 12.5 grams.
Purity by GC: 99.47%
Example-2: Preparation of l-acetamido-3,5-dimethyl adamantane : A mixture of 1,3-dimethyl adamantane (10 grams) and acetonitrile (36.8 ml) was heated to 60-65°C. Sulphuric acid (75 ml) was slowly added to the above reaction mixture at below 8O0C. The reaction mixture was stirred for 10 hours at 65-70°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with toluene. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene and the organic layer was washed with water. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 700C to get the title compound. Yield: 12.3 grams
ExampIe-3: Preparation of memantine hydrochloride from l-acetamido-3,5- dimethyl adamantane:
A mixture of l-acetamido-3,5-dimethyl adamantane (10 grams), polyethylene glycol (60 ml) and sodium hydroxide (14.5 grams) was heated to 1200C. The reaction
mixture was stirred for 20 hours at 120°C. Cooled the reaction mixture to 25-35°C. The reaction mixture was quenched with ice water. Added toluene to the reaction mixture and stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 70°C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-5°C. Isopropyl alcoholic hydrochloric acid (10 ml) was added to the above mixture at 0-5°C. The reaction mixture was heated to 80-85°C and stirred for 30 minutes. Ethyl acetate (20 ml) was added to the above reaction mixture at 75-80°C. The reaction mixture was cooled to 0-5°C. The separated solid was filtered and dried at 5O0C for 5 hours to get the title compound. Yield: 7.5 grams; Purity by GC: 99.90%
Example-4: Preparation of memantine hydrochloride from l-acetamido-3,5- dimethyl adamantane:
A mixture of l-acetamido-3,5-dimethyl adamantane (10 grams), polyethylene glycol (60 ml) and sodium hydroxide (14.5 grams) was heated to 12O0C. The reaction mixture was stirred for 20 hours at 1200C. Cooled the reaction mixture to 25-35°C. The reaction mixture was quenched with ice water. Added methylene chloride to the reaction mixture and stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with methylene chloride. The organic layer was dried with sodium sulphate. Methylene chloride from the organic layer was distilled off under reduced pressure at below 400C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-50C. Isopropyl alcoholic hydrochloric acid (10 ml) was added to the above reaction mixture at 0-50C. The reaction mixture was heated to 80-850C and stirred for 30 minutes. Ethyl acetate (20 ml) was added to the above reaction mixture at 75-800C. The reaction mixture was cooled to 0-50C. The separated solid was filtered dried at 500C for 5 hours to get the title compound. Yield: 7.3 grams; Purity by GC: 99.92 %
Residual solvents by GC: Ethanol- not detected; 2-propanol - 774 ppm; Acetonitrile - not detected; Ethyl acetate-not detected; toluene-not detected and aceticacid-not detected. Bulk density: Untapped: 0.20 g/ml; Tapped: 0.43 g/ml
Particle size: D(0.5) is 8 μm and D(0.9) is 30 μm
Example-5: Preparation of memantine hydrochloride from l-acetamido-3,5- dimethyl adamantane:
A mixture of l-acetamido-3, 5 -dimethyl adamantane (10 grams), polyethylene glycol (60 ml) and water (3 ml) and sodium hydroxide (14.5 grams) was heated to 1200C. The reaction mixture was stirred for 20 hours at 120°C. Cooled the reaction mixture to 25-
35°C. The reaction mixture was quenched with ice water. Added toluene to the reaction mixture and stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 700C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-50C.
Isopropyl alcoholic hydrochloric acid (10 ml) was added to the above mixture at 0-50C.
The reaction mixture was heated to 80-850C and stirred for 30 minutes. Ethyl acetate
(20 ml) was added to the above reaction mixture at 75-800C. The reaction mixture was cooled to 0-50C. The separated solid was filtered dried at 500C for 5 hours to get the title compound.
Yield: 7 grams
ExampIe-6: One-pot preparation of memantine hydrochloride:
A mixture of 1,3-dimethyl adamantane (10 grams) and acetonitrile (36.8 ml) was heated to 60-650C. Sulphuric acid (75 ml) was slowly added to the above reaction mixture at below 800C. The reaction mixture was stirred for 10 hours at 65-700C. Cooled the reaction mixture to 25-35°C. The reaction mixture was quenched with ice water. Added methylene chloride to the reaction mixture and stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with methylene chloride and the organic layer was washed with water. The organic layer was dried with sodium sulphate. The methylene chloride from the organic layer was distilled off under
reduced pressure at below 40°C and added polyethylene glycol (60 ml) and sodium hydroxide (14.5 grams). The reaction mixture was heated to 1200C. The reaction mixture was stirred for 20 hours at 120°C. Cooled the reaction mixture to 25-35°C. The reaction mixture was quenched with ice water. Added toluene to the reaction mixture and stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 7O0C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-50C. Isopropyl alcoholic hydrochloric acid (10 ml) was added to the above mixture at 0-50C. The reaction mixture was heated to 80-850C and stirred for 30 minutes. Ethyl acetate (20 ml) was added to the above reaction mixture at 75-8O0C. The reaction mixture was cooled to 0-50C. The separated solid was filtered dried at 5O0C for 5 hours to get the title compound. Yield: 9.5 grams; Purity by GC: 99.90%
Residual solvents by GC: Ethanol- 366 ppm; 2-propanol - 809 ppm; Acetonitrile -357 ppm; Ethyl acetate- not detected; toluene- 118 ppm and acetic acid- not detected. Bulk density: Untapped: 0.23 g/ml ; Tapped : 0.35 g/ml
Particle size: D(0.5) is 9 μm and D(0.9) is 34 μm
Example-7: One-pot preparation of memantine hydrochloride:
The title compound is prepared in analogues manner of example-6, wherein toluene was used as a solvent in place of methylene chloride. Yield: 9.6 grams.
Example-8: One-pot preparation of memantine hydrochloride:
A mixture of 1,3-dimethyl adamantane (10 grams) and acetonitrile (36.8 ml) was heated to 60-650C. Sulphuric acid (75 ml) was slowly added to the above reaction mixture at below 8O0C. The reaction mixture was stirred for 10 hours at 65-700C. Cooled the reaction mixture to 25-350C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with methylene chloride. The organic and aqueous layers
were separated. The aqueous layer was extracted with methylene chloride and the organic layer was washed with water. The organic layer was dried with sodium sulphate. The methylene chloride from the organic layer was distilled off under reduced pressure at below 40°C and added polyethylene glycol (60 ml), water (2.8 ml) and sodium hydroxide (14.5 grams). The reaction mixture was heated to 1200C. The reaction mixture was stirred for 20 hours at 120°C. Cooled the reaction mixture to 25-350C. The reaction mixture was quenched with ice water. Added toluene to the reaction mixture and stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 7Q°C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-50C. Isopropyl alcoholic hydrochloric acid (10 ml) was added to the above mixture at 0-50C. The reaction mixture was heated to 80-850C and stirred for 30 minutes. Ethyl acetate (20 ml) was added to the above reaction mixture at 75-800C. The reaction mixture was cooled to 0-50C. The separated solid was filtered dried at 500C for 5 hours to get the title compound. Yield: 7.8 grams
Example-9: Preparation of memantine hydrochloride compound of formula-1:
A mixture of 1,3 -dimethyl adamantane (10 grams) and acetonitrile (37 ml) was heated to 60-650C. Sulphuric acid (65 ml) was slowly added to the above reaction mixture at below 700C and stirred for 8 hours. The reaction mixture was cooled to 25-35°C and quenched with ice water. Extracted the reaction mixture with methylene chloride. The organic layer was washed with water. The methylene chloride from the organic layer was distilled off under atmospheric pressure at below 400C. The reaction mixture cooled and toluene (10 ml) was added and distilled off the solvent completely under reduced pressure. Polyethylene glycol (58 ml), sodium hydroxide (17 grams) was added and stirred for 30 minutes. Apply nitrogen pressure of 1.5 kg to the reaction mixture and heated to 12O0C. The reaction mixture was stirred for 12 hours at 120-1300C under nitrogen pressure and then cooled to 45°C. Toluene (50 ml) was added to the reaction mixture and stirred for 15 minutes. Then water (140 ml) was added, stirred and
the layers were separated. The aqueous layer was extracted with toluene and then washed the toluene layer with water. The toluene layer was distilled off under reduced pressure at below 70°C. The residue obtained is cooled and dissolved it in isopropyl alcohol (23 ml) and filtered to obtain the reaction mixture free of extraneous matter. The filtrate was cooled to 0-50C and isopropyl alcoholic hydrochloric acid (11 ml) was added then stirred for 40 minutes. The solid obtained is filtered, washed and then dried at 50-60°C to get the title compound. Yield: 7.7 grams
Purity by GC: > 99.5%
Example-10: Purification of memantine hydrochloride compound of formula-l:
A mixture of isopropyl alcohol (30 ml), ethyl acetate (20 ml) and memantine hydrochloride (10 grams) was heated to reflux temperature for 90 minutes. The reaction mixture was then cooled to 0-50C and stirred for 2 hours. The solid formed is filtered, washed with mixture of ethyl acetate and isopropyl alcohol then dried at 70-750C to get high pure memantine hydrochloride.
Yield: 8.5 grams
Residual solvents by GC: Ethanol- 121 ppm; 2-propanol - 765 ppm; Acetonitrile-not detected; Ethyl acetate- not detected; toluene- not detected and acetic acid- 778 ppm.
Bulk density: Untapped 0.20 g/ml ; Tapped : 0.34 g/ml
Particle size: D(0.5) is 7 μm and D(0.9) is 24 μm
Claims
1. An improved process for the preparation of memantine hydrochloride compound of formula- 1,
5 Formula- 1 which comprises: a) reacting a 1,3 -dimethyl adamantane compound of formula-2
Formula-2
10 with acetonitrile in presence of an acid at a temperature of about 50-70°C for a sufficient period of time about 2 to 15 hours to provide l-acetamido-3,5- dimethyladamantane compound of formula-3, in absence of any solvent,
Formula-3 5 b) hydrolyzing the l-acetamido-3,5-dimethyl adamantane compound of formula-3 with a suitable base in an alcoholic solvent at a temperature of about 12O0C to 180°C for a sufficient period of time about 2-25 hours to provide memantine compound of formula-4,
>0 Formula-4 c) treating the memantine compound of formula-4 in-situ with hydrochloric acid in an alcoholic solvent, d) isolating memantine hydrochloride compound of formula- 1 by adding ester solvent.
2. The process of claim I5 comprises at least one of the following: i) a step a) wherein the acid is sulphuric acid; ii) a step b) wherein the base is alkali metal hydroxide selected from sodium hydroxide or potassium hydroxide; alcoholic solvent is polyethylene glycol; iii) a step c) wherein the alcoholic solvent is isopropyl alcohol; iv) a step d) wherein the ester solvent is ethyl acetate.
3. An improved process for the preparation of memantine hydrochloride compound of formula- 1 , which comprises : a) reacting the 1 ,3 -dimethyl adamantane compound of formula-2
Formula-2 with acetonitrile in presence of a suitable acid at a temperature of about 50-700C for a sufficient period of time about 2 to 15 hours to provide l-acetamido-3,5- dimethyladamantane compound of formula-3, in absence of any solvent,
Formula-3 b) hydrolyzing the l-acetamido-3,5-dimethyl adamantane compound of formula-3 with a alkali metal base in a aqueous alcoholic solvent at a temperature of about 120°C to 180°C for a sufficient period of time about 2-25 hours to provide memantine compound of formula-4,
Formula-4 c) treating the memantine compound of formula-4 with hydrochloric acid in a alcoholic solvent, d) isolating memantine hydrochloride compound of formula- 1 by adding ester solvent.
4. The process of claim 3, comprises at least one of the following: i) a step a) wherein the acid is sulphuric acid; ii) a step b) wherein the base is alkali metal hydroxide selected from sodium hydroxide or potassium hydroxide; alcoholic solvent is aqueous polyethylene glycol; iii) a step c) wherein the alcoholic solvent is isopropyl alcohol; iv) a step d) wherein the ester solvent is ethyl acetate.
5. The process according to step b) of claim 3, wherein the aqueous alcoholic solvent contains 0.2 to 5% v/v of water.
6. One-pot process for the preparation of memantine hydrochloride compound of formula-1 from 1,3-dimethyl adamantane without isolating any intermediates,
Formula- 1 which comprises of reacting the 1,3 -dimethyl adamantane compound of formula-2,
Formula-2 with acetonitrile in presence of a suitable acid at a temperature of about 50-700C for a sufficient period of time about 2-15 hours to obtain l-acetamido-3,5- dimethyladamantane compound of formula-3, in absence of any solvent,
Formula-3 which on in-situ hydrolysis with a suitable base in a suitable alcoholic solvent such as polyethylene glycol at a temperature of about 120-1800C for a sufficient period of time about 2 to 25 hours provides memantine compound of formula-4,
Formuia-4 which on subsequent treatment with hydrochloric acid in a suitable alcoholic solvent such as isopropyl alcohol followed by adding suitable ester solvents provides mementine hydrochloride compound of formula- 1.
7. The process of claim 6, wherein the suitable acid is sulfuric acid; base is alkali metal hydroxide selected from sodium hydroxide or potassium hydroxide and ester solvent is ethyl acetate.
8. One-pot process for the preparation of memantine hydrochloride compound of formula-1 from 1,3 -dimethyl adamantane without isolating any intermediates,
Formula- 1 which comprise of reacting the 1,3 -dimethyl adamantane compound of formula-2
Formula-2 with acetonitrile in presence of a suitable acid at a temperature of about 50-700C for a sufficient period of time about 2-15 hours to obtain l-acetamido-3,5- dimethyladamantane compound of formula-3, in the absence of any solvent,
Formula-3 which on in-situ hydrolysis with a suitable base in a suitable aqueous alcoholic solvent such as aqueous polyethylene glycol at a temperature of about 120-180°C for a sufficient period of time about 2 to 25 hours provides memantine compound of formula-4,
Formula-4 which on subsequent treatment with hydrochloric acid in a suitable alcoholic solvent such as isopropyl alcohol followed by adding suitable ester solvents provides memantine hydrochloride compound of formula- 1.
9. The process of claim 8, wherein the suitable acid is sulfuric acid; base is alkali metal hydroxide selected from sodium hydroxide or potassium hydroxide and ester solvent is ethyl acetate.
10. The process according to claim 8, wherein the aqueous alcoholic solvent contains 0.2 to 5 % v/v of water.
11. The process according to claims 6 and 8, wherein the intermediates l-acetamide-3,5- dimethyladamantane compound of formula-3 and memantine compound of formula-4 are not isolated.
12. Memantine hydrochloride having bulk density in the range of 0.1 to 0.7 g/ml.
13. Memantine hydrochloride having Dg0 particle size less thanlOO microns.
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| WO2009153806A2 (en) * | 2008-05-09 | 2009-12-23 | Sairam Organics Pvt. Ltd. | Process for preparing memantine hydrochloride substantially free of !mpurities |
| CN102875387A (en) * | 2012-10-23 | 2013-01-16 | 滨州泓瑞医药科技有限公司 | Amantadine hydrochloride preparation method |
| WO2014024202A1 (en) * | 2012-08-07 | 2014-02-13 | Zcl Chemicals Limited | An improved process for the preparation of memantine hydrochloride |
| WO2014115638A1 (en) | 2013-01-23 | 2014-07-31 | 三菱瓦斯化学株式会社 | Manufacturing process for memantine |
| CN106946713A (en) * | 2017-03-13 | 2017-07-14 | 张家港九力新材料科技有限公司 | A kind of preparation method of memantine |
| CN107365255A (en) * | 2016-05-11 | 2017-11-21 | 常州制药厂有限公司 | A kind of industrialized memantine production method |
| CN109206317A (en) * | 2018-09-12 | 2019-01-15 | 青岛海蓝医药有限公司 | A kind of preparation process of adamantane amine nitrate derivatives |
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| WO2009153806A3 (en) * | 2008-05-09 | 2010-12-23 | Sairam Organics Pvt. Ltd. | Process for preparing memantine hydrochloride substantially free of impurities |
| WO2009153806A2 (en) * | 2008-05-09 | 2009-12-23 | Sairam Organics Pvt. Ltd. | Process for preparing memantine hydrochloride substantially free of !mpurities |
| EP2882291A4 (en) * | 2012-08-07 | 2016-04-27 | Zcl Chemicals Ltd | An improved process for the preparation of memantine hydrochloride |
| WO2014024202A1 (en) * | 2012-08-07 | 2014-02-13 | Zcl Chemicals Limited | An improved process for the preparation of memantine hydrochloride |
| CN102875387A (en) * | 2012-10-23 | 2013-01-16 | 滨州泓瑞医药科技有限公司 | Amantadine hydrochloride preparation method |
| US9452971B2 (en) | 2013-01-23 | 2016-09-27 | Mitsubishi Gas Chemical Company, Inc. | Manufacturing process for memantine |
| WO2014115638A1 (en) | 2013-01-23 | 2014-07-31 | 三菱瓦斯化学株式会社 | Manufacturing process for memantine |
| CN107365255A (en) * | 2016-05-11 | 2017-11-21 | 常州制药厂有限公司 | A kind of industrialized memantine production method |
| CN106946713A (en) * | 2017-03-13 | 2017-07-14 | 张家港九力新材料科技有限公司 | A kind of preparation method of memantine |
| CN109206317A (en) * | 2018-09-12 | 2019-01-15 | 青岛海蓝医药有限公司 | A kind of preparation process of adamantane amine nitrate derivatives |
| WO2020052179A1 (en) * | 2018-09-12 | 2020-03-19 | 青岛海蓝医药有限公司 | Preparation process for amantadine nitrate derivative |
| JP2021536497A (en) * | 2018-09-12 | 2021-12-27 | チンタオ ハイラン ファーマシューティカルズ カンパニー リミテッド | Manufacturing process of amantadine nitrate ester derivative |
| US20220371987A1 (en) * | 2018-09-12 | 2022-11-24 | Qingdao Hailan Pharmaceuticals Co., Ltd. | Process for manufacture of amantadine nitrate derivatives |
| JP7268280B2 (en) | 2018-09-12 | 2023-05-08 | チンタオ ハイラン ファーマシューティカルズ カンパニー リミテッド | Manufacturing process of amantadine-based nitrate derivatives |
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