WO2006076562A1 - Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride - Google Patents

Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride Download PDF

Info

Publication number
WO2006076562A1
WO2006076562A1 PCT/US2006/001204 US2006001204W WO2006076562A1 WO 2006076562 A1 WO2006076562 A1 WO 2006076562A1 US 2006001204 W US2006001204 W US 2006001204W WO 2006076562 A1 WO2006076562 A1 WO 2006076562A1
Authority
WO
WIPO (PCT)
Prior art keywords
dimethyladamantane
acetamido
memantine
amino
sufficient period
Prior art date
Application number
PCT/US2006/001204
Other languages
French (fr)
Inventor
Valeriano Merli
Silvia Mantovani
Paola Daverio
Stefano Bianchi
Alessandro Spreafico
Original Assignee
Teva Pharmaceutical Fine Chemicals S.R.L.
Teva Pharmaceuticals Usa, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teva Pharmaceutical Fine Chemicals S.R.L., Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceutical Fine Chemicals S.R.L.
Priority to MX2007007302A priority Critical patent/MX2007007302A/en
Priority to EP06718295A priority patent/EP1836157B1/en
Priority to DE602006009619T priority patent/DE602006009619D1/en
Priority to AT06718295T priority patent/ATE444950T1/en
Priority to CA002591666A priority patent/CA2591666A1/en
Publication of WO2006076562A1 publication Critical patent/WO2006076562A1/en
Priority to IL183244A priority patent/IL183244A0/en
Priority to HR20090676T priority patent/HRP20090676T1/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • 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 is directed to processes for the preparation of l-amino-3,5-dimethyladamantane hydrochloride, ("memantine hydrochloride”) and its intermediates.
  • Memantine hydrochloride is one of a small group of drugs known as Tricyclic
  • TAVs Antivirals
  • NMDA central nervous system N-methyl-d-aspartate
  • U.S. Patent No. 3,391,142 discloses the synthesis of memantine hydrochloride and its precursor, n-acetyl-memantine, according to following scheme, where the reported yield of the first step is 100 percent, the reported yield of the second step is 69.8 percent, and the reported overall yield is 69.8 percent.
  • JP 2002275142A2 discloses the synthesis of n-acetyl-memantine according to the following scheme with a yield of 45 percent.
  • U.S. Patent 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.
  • Chinese Patent Publication No. CN1400205A discloses memantine hydrochloride synthesis according to the following scheme.
  • U.S. Patent 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 be 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 190° to 225°C are required in the alkaline hydrolysis of n-acetyl-memantine in diethylene glycol or ethylene glycol and in the reaction between l-halo-3,5-dimethyladamantane and urea.
  • the present invention is directed to a process for the synthesis of n-acetamido-3,5-dimethyladamantane by reacting l-halo-3,5- dimethyladamantane and a nitrile, in the presence of phosphoric acid, at a temperature of about 55° to about 9O 0 C and for a period of time sufficient to produce n-acetamido-3,5- dimethyladamantane, and recovering n-acetamido-3,5-dimethyladarnantane.
  • the present invention is directed to a crystalline of n-acetamido-3,5- dimethyladamantane, designated herein as Form II, characterized by at least one of an x-ray powder diffraction pattern, having peaks at about 6.1, 12.2, and 15.5 ⁇ 0.2 degrees 20, and an x-ray powder diffraction pattern substantially as depicted in Fig. 1.
  • the present invention is also directed to a crystalline of n-acetamido-3,5- dimethyladamantane, designated herein as Form I, characterized by an x-ray powder diffraction pattern, having peaks at about 6.1, 12.2, 12.9, 13.9, 15.5, 16.8, 18.3, 19.0, 20.4, and 24.5 degrees 2 ⁇ ⁇ 0.2 degrees 2 ⁇ , or as depicted in Fig. 2.
  • the invention is directed to a process for the synthesis of memantine, comprising: solvolysis of n-acetamido-3,5-dimethyladarnantane in a solvent selected from the group consisting of C 4-6 alcohols in the presence of a strong inorganic base for a adequate period of time to obtain l-amino-3,5-dimethyladarnantane; and recovering an anhydrous alcoholic solution of l-ammo-3,5-dimethyladamantane.
  • the invention is directed to a "one pot" process for the synthesis of memantine from l-halo-3,5-dimethyladamantane without the isolation of n-acetyl-3 ,5-dimethyladamantane.
  • the memantine prepared by the above processes is subsequently converted into a memantine hydrochloride.
  • the memantine prepared by the above processes has a yield which is not less than 80%.
  • Fig. 1 illustrates a characteristic X-ray powder diffraction pattern of n-acetamido-3,5-dimethyladamantane Form I.
  • halo- refers to chloro, bromo, iodo, and fluoro.
  • the present invention is directed to processes for preparation of memantine, its intermediates thereof, and its hydrochloric acid salt form that overcome one or more of the problems of the prior art processes. Particularly, the processes may be used to produce the desired product in higher yield than the prior art processes.
  • the present invention is directed to a process for the synthesis of n-acetamido-3,5-dimethyladamantane by providing l-halo-3,5- dimethyladamantane, as shown below in Scheme 1 and labelled as the 1 st step. This process is performed by reacting
  • the reaction temperature is about 65° to about 90°C.
  • An adequate period of time sufficient to produce n-acetamido-3,5-dimethyladamantane is about 1 to about 20 hours, although most preferably about 1 to about 10 hours.
  • the nitrile may be selected from a group consisting of propionitrile, butyronitrile, valeronitrile, phenylacetonitrile, and acetonitrile.
  • acetonitrile is used, preferably in an amount of about 2 to about 15 moles/mole of l-halo-3,5- dimethyladamantane, most preferably, about 3 to about 6 moles/mole of l-halo-3,5- dimethyladamantane.
  • the phosphoric acid is added drop- wise at a temperature below 40°C for a period of about 15 minutes.
  • the amount of phosphoric acid is in a phosphoric acid:l-halo-3,5-dimethyladamantane mole ratio within a range of 2:1 to 4:1.
  • the desired product may be recovered by a variety of methods well known in the art.
  • recovery is preformed by extracting the n-acetamido-3,5- dimethyladamantane using water and n-butyl alcohol, adjusting the pH using a strong base, washing, and then concentrating the organic phase by distillation, suspending the resulting residue in acetone and water, cooling, and isolating the crystals.
  • n-acetamido-3,5-dimethyladamantane prepared as described above may be converted to memantine acid addition salt form, preferably memantine hydrochloride by any method known in the art.
  • the use of phosphoric acid instead of sulphuric acid avoids the undesirable byproducts, while providing results that are at least as good as those obtained with processes using sulphuric acid in terms of yield, quality, and reaction time.
  • the present invention reduces the quantity of undesirable byproducts, such that less phosphoric acid is used compared to the large amount of sulphuric acid used in the U.S. Patent No. 3,391,142, easing large scale industrial production.
  • the present invention is also directed to a crystalline form of a memantine intermediate n-acetamido-3,5-dimethyladamantane, designated herein as Form I, characterized by at least one of an x-ray powder diffraction pattern, having peaks at about 6.1, 12.2, and 15.5 degrees 20, and an x-ray powder diffraction pattern substantially as depicted in Figure 1.
  • Form I can be further characterised by x-ray powder diffraction peaks at about 12.9, 13.9, 16.8, 18.3, 19.0, 20.4, and 24.5 degrees 20.
  • the invention is directed to a process for the synthesis of memantine using n-acetamido-3,5-dimethyladamantane, and is summarized in Scheme 2.
  • the process of the invention comprises: dissolving n-acetamido-3,5- dimethyladamantane in a solvent selected from the group consisting of C 3-6 alcohols in the presence of a strong inorganic base for a sufficient period of time to obtain l-amino-3,5-dimethyladamantane; and recovering an anhydrous alcoholic solution of 1 -amino-3 ,5-dimethyladarnantane.
  • dissolving n-acetamido-3,5-dimethyladamantane is by heating at about 90°C to reflux, and, more preferably, to a temperature in the range of about 125° to about 135 0 C.
  • the solvent is n-butanol.
  • the solvent is preferably in a volume/weight ratio of between about 2:1 and about 5:1 with respect to the n-acetamido-3,5- dimethyladamantane, most preferably about 4:1.
  • the strong inorganic base is an alkali metal hydroxide, most preferably KOH or NaOH.
  • the strong inorganic base is in an amount of about 4 to about 12 moles/mole of n-acetamido-3,5-dimethyladamantane, most preferably about 5 to about 6 moles/mole of n-acetamido-3,5-dimethyladamantane.
  • a sufficient period of time is preferably about 5 to 15 hours, more preferably about 9 to about 12 hours, and most preferaby about 10 to about 11 hours.
  • the desired product, l-amino-3,5-dimethyladamantane may be recovered by a variety of methods known in the art.
  • the solution of l-amino-3,5-dimethyladamantane is cooled, preferably to about 50° to about 80°C, the reaction mixture is washed with water, distilling n-butanol and water until a semisolid residue of l-amino-3,5-dimethyladamantane (memantine free base) is obtained.
  • the solution of 1 -amino-3 ,5 -dimethyladamantane is then converted into a memantine acid addition salt form, preferably memantine hydrochloride, as summarized in Scheme 3.
  • HCl is combined with l-amino-3,5-dimethyladamantane to obtain memantine HCl, and memantine HCl is recovered.
  • the solution of l-amino-3,5-dimethyladamantane is first concentrated under 50mm Hg vacuum at a temperature of about 55°C, to obtain a residue which is suspended in an organic solvent, such as ethyl acetate, while maintaining the temperature at about 5O 0 C. The suspension is then cooled to about 20 0 C for about one hour, washed with water, and dried to obtain memantine HCl.
  • the invention is directed to a "one pot" process for the synthesis of memantine hydrochloride from l-halo-3,5-dimethyladamantane without the isolation of n-acetamido-3,5-dimethyladamantane.
  • the process of the invention comprises: a. reacting l-halo-3,5-dimethyladamantane and a nitrile, in the presence of phosphoric acid at about 50° to about 100°C and for a period of time sufficient to produce n-acetamido-3,5-dimethyladamantane, b.
  • n-acetamido-3,5-dimethyladamantane in a solvent selected from the group consisting OfC 3-6 alcohols in the presence of a strong inorganic base for a sufficient period of time to obtain l-amino-3,5-dimethyladamantane; and c. recovering an alcoholic solution of l-amino-3,5-dimethyladamantane.
  • the solution of l-amino-3,5-dimethyladamantane is then converted into memantine's acid addition salt form, most preferably memantine hydrochloride.
  • Example 3 Synthesis of memantine free base from n-acetyl-memantine
  • Ten grams (0.045 mol) of n-acetyl-memantine, 75 ml of n-butanol, and 10.5g sodium hydroxide flakes (0.263mol) is introduced into a three necked round bottom flask equipped with a thermometer, condenser, and mechanical stirrer at room temperature.
  • the resulting suspension is heated to 120 0 C, and maintained at 120°C for 10 hours.
  • the reaction mixture is cooled to 80 0 C, and 25 ml of water were added.
  • the phases are separated, 25 ml of water were added to the rich organic phase, and the pH was brought to 10.5-11 with 37% HCl.
  • the resulting solution was filtered, and 23.1 g of 37 percent HCl were added to the filtrate.
  • the solution was concentrated under a 50 mm Hg vacuum to a residual volume of 90ml at a temperature of 55 0 C. Following the vacuum concentration, 250 ml of ethyl acetate were added to the residue, while maintaining the temperature at 5O 0 C.
  • the suspension was cooled to 20 0 C, stirred at 2O 0 C for one hour, and filtered and washed three times with 30 ml of ethyl acetate.
  • the product was dried at 50° to 55°C for 20 hours, providing 44.2 g of product at a yield of 90.8 percent.
  • memantine hydrochloride may be produced in a "one pot” process.
  • the phases were separated, and 22 ml of water were added to the organic phase. [00056] After stirring, the phases were separated, and water was removed by azeotropic distillation through a plates column. Prior to distillation, the KF was 14 percent; after distillation, the Karl Fisher titration value was 0.08 percent.

Abstract

A process for the preparation of memantine hydrochloride, intermediates thereof and its hydrochloric acid form are provided.

Description

PROCESS FOR THE PREPARATION OF 1-AMINO-S5S-DIMETHYLADAMANTANE HYDROCHLORIDE
RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional Patent Application No.
60/642,957, filed January 11, 2005, and U.S. Provisional Patent Application No. 60/677,599, filed May 3, 2005, the teaching of which are incorporated herein.
FIELD OF THE INVENTION
[0002] The present invention is directed to processes for the preparation of l-amino-3,5-dimethyladamantane hydrochloride, ("memantine hydrochloride") and its intermediates.
BACKGROUND OF THE INVENTION
[0003] Memantine hydrochloride is one of a small group of drugs known as Tricyclic
Antivirals (TAVs), and provides good and persistent activation of central nervous system N-methyl-d-aspartate (NMDA) receptors, such that it can be used in the treatment of Parkinson's and Alzheimer's diseases. The chemical structure of memantine hydrochloride is as illustrated in the following scheme.
Figure imgf000002_0001
[0004] Three strategies for the synthesis of memantine hydrochloride are disclosed in the prior art:
A) N-acetyl-memantine alkaline hydrolysis, disclosed in U.S. Patent No. 3,391,142, Czech Patent Publication No. CZ282398B6, Japanese Patent Publication No. JP 2002 275142A2, and Chinese Patent Publication No. CN 1335299;
B) Reaction of l-halo-3,5-dimethyladamantane and urea at high temperature, and alkaline hydrolysis of the resulting adamantyl urea intermediate, disclosed in U.S. Patent No. 4,122,193 and Chinese Patent Publication No. CN1400205A; and
C) Electrophylic substitution on metallated 3,5-dimethyladamantane by chloramine, disclosed in U.S. Patent No. 5,599,998. [0005] U.S. Patent No. 3,391,142 discloses the synthesis of memantine hydrochloride and its precursor, n-acetyl-memantine, according to following scheme, where the reported yield of the first step is 100 percent, the reported yield of the second step is 69.8 percent, and the reported overall yield is 69.8 percent.
Figure imgf000003_0001
NaOH-DEG Ether- HCI gas
Figure imgf000003_0004
cryst EtOH-Ether
Figure imgf000003_0003
Figure imgf000003_0002
[0006] In the first reaction, 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 190°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 a 69.8 percent yield. [0007] Czech Patent Publication No. CZ282398B6 discloses the synthesis of memantine according to the following scheme, which is carried out under pressure.
Figure imgf000003_0005
[0008] Japanese Patent Publication No. JP 2002275142A2 discloses the synthesis of n-acetyl-memantine according to the following scheme with a yield of 45 percent.
Figure imgf000004_0001
[0009] Chinese Patent Publication No. CN 1335299 discloses memantine hydrochloride synthesis according to the scheme.
Figure imgf000004_0002
[00010] U.S. Patent 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.
Figure imgf000004_0003
[00011] Chinese Patent Publication No. CN1400205A discloses memantine hydrochloride synthesis according to the following scheme.
Figure imgf000005_0001
[00012] U.S. Patent No. 5,599,998 discloses memantine synthesis with a yield of 48 percent according to the following scheme.
Lithium metal NH2Cl
Figure imgf000005_0002
00C, Ether, sonication
Figure imgf000005_0003
Sonication
Figure imgf000005_0004
[00013] In addition to the low yield, the disclosed method is cumbersome on an industrial scale, using metallic lithium and chloramine, which can be hazardous if not handled properly.
[00014] The deficiencies of the prior art processes described above include, but are not limited to the production of undesirable byproducts, such as Br2 and SO2, 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 190° to 225°C are required in the alkaline hydrolysis of n-acetyl-memantine in diethylene glycol or ethylene glycol and in the reaction between l-halo-3,5-dimethyladamantane and urea. Where the alkaline hydrolysis is performed in low boiling alcohols, elevated pressure is required to attain the reaction temperatures required for an acceptable reaction time. Moreover, as discussed above, the dangerous reactants lithium and chloramine are required in the electrophilic amination reaction. Therefore, there is a need in the art to provide improved processes for preparing memantine hydrochloride.
SUMMARY OF THE INVENTION
[00015] It is an objective of this invention to provide processes for the preparation of memantine, intermediates thereof, and its hydrochloric acid addition salt form without the deficiencies of prior art processes. [00016] In a first embodiment, the present invention is directed to a process for the synthesis of n-acetamido-3,5-dimethyladamantane by reacting l-halo-3,5- dimethyladamantane and a nitrile, in the presence of phosphoric acid, at a temperature of about 55° to about 9O0C and for a period of time sufficient to produce n-acetamido-3,5- dimethyladamantane, and recovering n-acetamido-3,5-dimethyladarnantane. [00017] The present invention is directed to a crystalline of n-acetamido-3,5- dimethyladamantane, designated herein as Form II, characterized by at least one of an x-ray powder diffraction pattern, having peaks at about 6.1, 12.2, and 15.5 ± 0.2 degrees 20, and an x-ray powder diffraction pattern substantially as depicted in Fig. 1. [00018] The present invention is also directed to a crystalline of n-acetamido-3,5- dimethyladamantane, designated herein as Form I, characterized by an x-ray powder diffraction pattern, having peaks at about 6.1, 12.2, 12.9, 13.9, 15.5, 16.8, 18.3, 19.0, 20.4, and 24.5 degrees 2θ ± 0.2 degrees 2Θ, or as depicted in Fig. 2. [00019] In a another embodiment, the invention is directed to a process for the synthesis of memantine, comprising: solvolysis of n-acetamido-3,5-dimethyladarnantane in a solvent selected from the group consisting of C4-6 alcohols in the presence of a strong inorganic base for a adequate period of time to obtain l-amino-3,5-dimethyladarnantane; and recovering an anhydrous alcoholic solution of l-ammo-3,5-dimethyladamantane. [00020] In a further embodiment, the invention is directed to a "one pot" process for the synthesis of memantine from l-halo-3,5-dimethyladamantane without the isolation of n-acetyl-3 ,5-dimethyladamantane.
[00021] Preferably, the memantine prepared by the above processes is subsequently converted into a memantine hydrochloride.
[00022] Preferably, the memantine prepared by the above processes has a yield which is not less than 80%.
BRIEF DESCRIPTION QF THE DRAWINGS Fig. 1 illustrates a characteristic X-ray powder diffraction pattern of n-acetamido-3,5-dimethyladamantane Form I.
DESCRIPTION OF THE INVENTION
[00023] As used herein, the preface "halo-" refers to chloro, bromo, iodo, and fluoro. [00024] The present invention is directed to processes for preparation of memantine, its intermediates thereof, and its hydrochloric acid salt form that overcome one or more of the problems of the prior art processes. Particularly, the processes may be used to produce the desired product in higher yield than the prior art processes.
[00025] In a first embodiment, the present invention is directed to a process for the synthesis of n-acetamido-3,5-dimethyladamantane by providing l-halo-3,5- dimethyladamantane, as shown below in Scheme 1 and labelled as the 1st step. This process is performed by reacting
Figure imgf000007_0001
Scheme 1 l-halo-3,5-dimethyladamantane and a nitrile, in the presence of phosphoric acid at about 50° to about 100°C and for a period of time sufficient to produce n-acetamido-3,5- dimethyladamantane, and then recovering n-acetamido-3,5-dimethyladamantane. [00026] Preferably the l-halo-3,5-dimethyladamantane used is l-bromo-3,5- dimethyladamantane
[00027] Preferably, the reaction temperature is about 65° to about 90°C. An adequate period of time sufficient to produce n-acetamido-3,5-dimethyladamantane is about 1 to about 20 hours, although most preferably about 1 to about 10 hours. [00028] The nitrile may be selected from a group consisting of propionitrile, butyronitrile, valeronitrile, phenylacetonitrile, and acetonitrile. Most preferably, acetonitrile is used, preferably in an amount of about 2 to about 15 moles/mole of l-halo-3,5- dimethyladamantane, most preferably, about 3 to about 6 moles/mole of l-halo-3,5- dimethyladamantane.
[00029] Preferably, before the start of the reaction, the phosphoric acid is added drop- wise at a temperature below 40°C for a period of about 15 minutes. The amount of phosphoric acid is in a phosphoric acid:l-halo-3,5-dimethyladamantane mole ratio within a range of 2:1 to 4:1.
[00030] The desired product may be recovered by a variety of methods well known in the art. In one convenient method, recovery is preformed by extracting the n-acetamido-3,5- dimethyladamantane using water and n-butyl alcohol, adjusting the pH using a strong base, washing, and then concentrating the organic phase by distillation, suspending the resulting residue in acetone and water, cooling, and isolating the crystals.
[00031] The n-acetamido-3,5-dimethyladamantane prepared as described above may be converted to memantine acid addition salt form, preferably memantine hydrochloride by any method known in the art.
[00032] As discussed above, the process disclosed in U.S. Patent No. 3,391,142 involves a Ritter reaction between l-bromo-3,5-dimethyladamantane and acetonitrile in a large amount of concentrated sulphuric acid. Due to the oxidizing power of sulphuric acid, bromine and SO2 are by products of the reaction according to following scheme.
H2SO4 + 2HBr >- Br2 + SO2 + 2H2O
[00033] In contrast, in the present invention, the use of phosphoric acid instead of sulphuric acid avoids the undesirable byproducts, while providing results that are at least as good as those obtained with processes using sulphuric acid in terms of yield, quality, and reaction time. In addition, the present invention reduces the quantity of undesirable byproducts, such that less phosphoric acid is used compared to the large amount of sulphuric acid used in the U.S. Patent No. 3,391,142, easing large scale industrial production. [00034] The present invention is also directed to a crystalline form of a memantine intermediate n-acetamido-3,5-dimethyladamantane, designated herein as Form I, characterized by at least one of an x-ray powder diffraction pattern, having peaks at about 6.1, 12.2, and 15.5 degrees 20, and an x-ray powder diffraction pattern substantially as depicted in Figure 1. Form I can be further characterised by x-ray powder diffraction peaks at about 12.9, 13.9, 16.8, 18.3, 19.0, 20.4, and 24.5 degrees 20.
[00035] In a another embodiment, the invention is directed to a process for the synthesis of memantine using n-acetamido-3,5-dimethyladamantane, and is summarized in Scheme 2.
Figure imgf000008_0001
Scheme 2
[00036] The process of the invention comprises: dissolving n-acetamido-3,5- dimethyladamantane in a solvent selected from the group consisting of C3-6 alcohols in the presence of a strong inorganic base for a sufficient period of time to obtain l-amino-3,5-dimethyladamantane; and recovering an anhydrous alcoholic solution of 1 -amino-3 ,5-dimethyladarnantane.
[00037] Preferably, dissolving n-acetamido-3,5-dimethyladamantane is by heating at about 90°C to reflux, and, more preferably, to a temperature in the range of about 125° to about 1350C. Preferably, the solvent is n-butanol. The solvent is preferably in a volume/weight ratio of between about 2:1 and about 5:1 with respect to the n-acetamido-3,5- dimethyladamantane, most preferably about 4:1. Preferably, the strong inorganic base is an alkali metal hydroxide, most preferably KOH or NaOH. The strong inorganic base is in an amount of about 4 to about 12 moles/mole of n-acetamido-3,5-dimethyladamantane, most preferably about 5 to about 6 moles/mole of n-acetamido-3,5-dimethyladamantane. A sufficient period of time is preferably about 5 to 15 hours, more preferably about 9 to about 12 hours, and most preferaby about 10 to about 11 hours.
[00038] The desired product, l-amino-3,5-dimethyladamantane, may be recovered by a variety of methods known in the art. In one protocol, the solution of l-amino-3,5-dimethyladamantane is cooled, preferably to about 50° to about 80°C, the reaction mixture is washed with water, distilling n-butanol and water until a semisolid residue of l-amino-3,5-dimethyladamantane (memantine free base) is obtained. [00039] Preferably, the solution of 1 -amino-3 ,5 -dimethyladamantane is then converted into a memantine acid addition salt form, preferably memantine hydrochloride, as summarized in Scheme 3. In this process, HCl is combined with l-amino-3,5-dimethyladamantane to obtain memantine HCl, and memantine HCl is recovered. Most preferably, the solution of l-amino-3,5-dimethyladamantane is first concentrated under 50mm Hg vacuum at a temperature of about 55°C, to obtain a residue which is suspended in an organic solvent, such as ethyl acetate, while maintaining the temperature at about 5O0C. The suspension is then cooled to about 200C for about one hour, washed with water, and dried to obtain memantine HCl.
Figure imgf000009_0001
Scheme 3 [00040] The alkaline solvolysis of the acetamido moiety, as described in U.S. Patent
No. 3,391,142 and CZ 282398, "requires refluxing the reactants in diethylene glycol, methanol, ethanol, or isopropyl alcohol, hi contrast, in the present invention C4-6 alcohols are used, hi addition, as disclosed in CZ 282398, the solvolysis is carried out under pressure, while, in the process of this invention, this is unnecessary. Under such conditions, the solvolysis is completed in about 10 hours.
[00041] hi a further embodiment, the invention is directed to a "one pot" process for the synthesis of memantine hydrochloride from l-halo-3,5-dimethyladamantane without the isolation of n-acetamido-3,5-dimethyladamantane. The process of the invention comprises: a. reacting l-halo-3,5-dimethyladamantane and a nitrile, in the presence of phosphoric acid at about 50° to about 100°C and for a period of time sufficient to produce n-acetamido-3,5-dimethyladamantane, b. dissolving n-acetamido-3,5-dimethyladamantane in a solvent selected from the group consisting OfC3-6 alcohols in the presence of a strong inorganic base for a sufficient period of time to obtain l-amino-3,5-dimethyladamantane; and c. recovering an alcoholic solution of l-amino-3,5-dimethyladamantane. [00042] Preferably, the solution of l-amino-3,5-dimethyladamantane is then converted into memantine's acid addition salt form, most preferably memantine hydrochloride.
EXAMPLES
Example 1 - Synthesis of l-acetamido-3,5-dimethyladamantane
[00043] The following examples are provided to illustrate embodiments of the present invention.
[00044] The first step in the synthesis of l-acetamido-3,5-dimethyladamantane, follows the following synthetic scheme.
Figure imgf000010_0002
Figure imgf000010_0001
[00045] At room temperature, the 500g (2.056 mol) of l-bromo-3,5- dimethyladamantane and 500 ml of 393 g (9.6 mol) acetonitrile were introduced into a three necked round bottom flask equipped with a thermometer, condenser, and mechanical stirrer. Then, 806g of 75% phosphoric acid (6.2 moles) were added drop wise over a period of about 15 minutes, maintaining the temperature below 40°C. The resulting biphasic mixture was heated to 87° ± 2°C, and' maintained at that temperature for 3 hrs.
[00046] The 1000 ml of n-butyl alcohol and 770 ml of water were added, providing a homogeneous solution. Sodium hydroxide 30% (337.5g) was added to produce a biphasic system. The phases were separated, and 350 ml of water were added together with 30% sodium hydroxide (337.5 g) to provide an aqueous phase pH within the range of 5.5 to 7.5. [00047] The phases were separated. The organic phase was then concentrated under a vacuum of 45 mm Hg to a residual volume of 600-650ml with an increase in the internal temperature to about 7O0C. The residual suspension was cooled to 6O0C, and 500 ml of acetone and 2000 ml of water were added in sequence. The resulting suspension was cooled to 0°C in one hour, and the suspension was stirred at O0C for 1 hour. The resulting solid was filtered, and washed twice with 400 ml of water. The solid was dried overnight at 50°C. An amount of dried solid of 434.Og, corresponding to a yield of 95.4 percent was obtained with an HPLC purity of 99.8 percent.
Example 3 — Synthesis of memantine free base from n-acetyl-memantine [00048] Ten grams (0.045 mol) of n-acetyl-memantine, 75 ml of n-butanol, and 10.5g sodium hydroxide flakes (0.263mol) is introduced into a three necked round bottom flask equipped with a thermometer, condenser, and mechanical stirrer at room temperature. The resulting suspension is heated to 1200C, and maintained at 120°C for 10 hours. The reaction mixture is cooled to 800C, and 25 ml of water were added. The phases are separated, 25 ml of water were added to the rich organic phase, and the pH was brought to 10.5-11 with 37% HCl. After stirring, the phases are separated, and 25 ml of water were added to the rich organic phase. After stirring phases are separated again. Obtained butanolic organic phase is concentrated under vacuum at internal temperature 7O0C until an oily residue (10.5g) is obtained to obtain memantine free base.
[00049] (Optionally to the oily residue AcOEt 100ml is added, and the obtained solution is decolorized with charcoal.Gaseous HCl is bubbled through the solution until acid pH. Suspension is stirred at 15°C for Ih to obtain memantine HCl [00050] Memantine HCl is isolated by filtration, washed twice with AcOEt (10 ml each), and dried under vacuum at 55°C. MMN.HC1= 7.2g; yield: 74%) Example 4 - Synthesis of memantine HCl from n-acetyl memantine
[00051] Steps 2 and 3'of the synthesis of l-amino-3,5-dimethyladamantane synthesis, memantine HCl, follow the following synthetic scheme.
Figure imgf000012_0001
[00052] The 50 g (0.2259 mol) of n-acetyl-memantine, 200 ml of n-butanol, and 80.29 g of 89.9 percent potassium hydroxide flakes (1.288 mol) were introduced into a three necked round bottom flask equipped with a thermometer, condenser, and mechanical stirrer at room temperature. The resulting suspension was heated to 130° ± 2°C, and maintained at 130° ± 2°C for 10 to 11 hours. The reaction mixture was cooled to 500C, and 150 ml of water were added. The phases were separated, 75 ml of water were added to the rich organic phase, and the pH is brought to 10.5-11 with 37% HCl. After stirring, the phases were separated, and 75 ml of water were added to the rich organic phase. After stirring, the phases were separated again.
[00053] The resulting solution was filtered, and 23.1 g of 37 percent HCl were added to the filtrate. The solution was concentrated under a 50 mm Hg vacuum to a residual volume of 90ml at a temperature of 550C. Following the vacuum concentration, 250 ml of ethyl acetate were added to the residue, while maintaining the temperature at 5O0C. The suspension was cooled to 200C, stirred at 2O0C for one hour, and filtered and washed three times with 30 ml of ethyl acetate. The product was dried at 50° to 55°C for 20 hours, providing 44.2 g of product at a yield of 90.8 percent.
Example 5 - One-pot process for the synthesis of memantine HCl
[00054] As discussed above, memantine hydrochloride may be produced in a "one pot" process.
[00055] First, 22 g (0.09042 mol) of l-bromo-3,5-dimethyladamantane and 22 ml
(0.4190 mol) of acetonitrile were introduced into a 250 ml three necked round bottom flask equipped with a thermometer, condenser, and mechanical stirrer at room temperature. Then,
41.7 g of 85 percent phosphoric acid (0.3619 mol) were added over a period of about 15 minutes through a dropping runnel, during which period the internal temperature rose to 34°C. The biphasic mixture 'was then warmed to 65°C. After 7 hours, a monophasic system is obtained, and the reaction was complete. The monophasic system was then cooled to room temperature, and the 55 ml of n-butanol, 55 ml of water, and 11 ml of saturated NaCl solution were added. After stirring, the phases were separated, 22 ml of water were added to organic phase, and the pH was adjusted to about 7 with 53 g of 30 percent NaOH. The phases were separated, and 22 ml of water were added to the organic phase. [00056] After stirring, the phases were separated, and water was removed by azeotropic distillation through a plates column. Prior to distillation, the KF was 14 percent; after distillation, the Karl Fisher titration value was 0.08 percent.
[00057] Then, 49.1 g of 89.9% KOH (0.787 mol) and 100ml of n-butanol were added to the anhydrifϊed organic phase. The suspension was then warmed to 130° ± 20C for 10 hours to provide a solution. A sample was checked using gas chromatography to determine whether the reaction had stopped. The solution was then cooled to 50°C, and 80 ml of water were added. After stirring, the phases were separated, 40 ml of water were added to the organic phase, and the pH was adjusted to 10.5 to 11 with a 37 percent solution of HCl. The phases were separated, and the organic layer was washed with 40 ml of water. [00058] Nine grams of a 37 percent HCl solution were added to the butanolic solution.
The solution was then distilled under vacuum to a residual volume of 50ml, providing a semisolid residue. Ethylacetate in an amount of 100 ml was added to residue, and the resulting suspension was stirred at 20° to 22°C for one hour, filtered, and washed with three 12 ml volumes of ethylacetate. The filtered material was dried under vacuum at 50° to 55°C for 5 to 6 hours, providing a dry weight of 16.6 g of memantine hydrochloride from 1-bromo- 3,5-dimethyladamantane in an 86 percent yield.
[00059] While it is apparent that the invention disclosed herein is well calculated to fulfil the objects stated above, it will be appreciated that numerous modifications and. embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications and embodiments as falling within the true spirit and scope of the present invention.

Claims

What is claimed:
1. A process for the"pr6pafation of n-acetamido-3,5-dimethyladamantane, comprising: reacting l-halo-3,5-dimethyladamantane and a nitrile in the presence of phosphoric acid at a temperature of about 50° to about 100°C for a sufficient period of time to obtain n-acetamido-3 ,5-dimethyladamantane.
2. The process of claim 1, wherein the l-halo-3,5-dimethyladamantane is l-bromo-3,5- dimethyladamantane.
3. The process of claim 1, wherein the phosphoric acid and l-halo-3,5-dimethyladamantane are present in a phosphoric acid:l-halo-3,5-dimethyladamantane mole ratio within a range of 2:1 to 4:1.
4. The process of claim 1, wherein reacting the temperature is about 65° to about 90°C.
5. The process of claim 1, wherein the sufficient period of time is about 1 to about 20 hours.
6. The process of claim 5, wherein the sufficient period of time is about 1 to about 10 hours.
7. The process of claim 1, wherein the nitrile is selected from a group selected from the group consisting of propionitrile, butyronitrile, valeronitrile, phenylacetonitrile, and acetonitrile.
8. The process of claim 7, wherein the nitrile is acetonitrile.
9. The process of claim 1, wherein the nitrile is present in an amount of about 2 to about
15 moles/mol ofl-halo-3,5-dimethyladamantane.
10. The process of claim 9, wherein the nitrile is present in an amount of about 3 to about
6 moles/mole of l-halo-3,5-dimethyladamantane.
11. The process of claim 1, further comprising converting the n-acetamido-3,5- dimethyladamantane to memantine hydrochloride. 12. A crystalline form of a memantine intermediate, n-acetamido-3,5- dimethyladamalitaile, tharacterized by at least one of an x-ray powder diffraction pattern, having peaks at about 6.1,
12.2, and 15.5 ± 0.2 degrees 20, and an x-ray powder diffraction pattern substantially as depicted in Figure 1.
13. The crystalline form in claim 12 further characterised by x-ray powder diffraction peaks at about 12.9, 13.9, 16.8, 18.3, 19.0, 20.4, and 24.5 ± 0.2 degrees 20.
14. A process for the preparation of l-amino-3,5-dimethyladamantane, comprising: dissolving n-acetamido-3,5-dimethyladamantane in a solvent selected from the group consisting of C3-6 alcohols in the presence of a strong inorganic base for a sufficient period of time to obtain l-amino-3,5-dirnethyladarnantane.
15. The process of claim 14, wherein dissolving n-acetamido-3,5-dimethyladamantane is performed at a temperature of about 9O0C to reflux.
16. The process of claim 15, wherein dissolving n-acetamido-3,5-dimethyladamantane is performed at a temperature of about 125° to about 135°C.
17. The process of claim 14, wherein the sufficient period of time is about 5 to 15 hours.
18. The process of claim 17, wherein the sufficient period of time is about 9 to 12 hours.
19. The process of claim 18, wherein the sufficient period of time is about 10 to 11 hours.
20. The process of claim 14, wherein the strong base is KOH or NaOH.
21. The process of claim 14, wherein the strong base in an amount of about 4 to about 12 moles/mole of n-acetamido-3,5-dimethyladamantane.
22. The process of claim 14, wherein the strong base in an amount of about 5 to about 6 moles/mole of n-acetamido-3,5-dimethyladamantane.
23. The process of claim 14, wherein the solvent is n-butanol.
24. The process of claim 14, wherein the solvent is in a volume/weight ratio of between about 2:1 to about 5:1 with respect to n-acetamido-3,5-dimethyladamantane.
25. The process of claim 24, wherein the solvent is in a volume/weight ratio of between about 4:1 with fespecrto n-acetamido-3,5-dimethyladamantane.
26. The process of claim 14, further comprising reacting the memantine with hydrogen chloride or hydrochloric acid to obtain memantine hydrochloride.
27. The process of claim 14, further comprising converting the l-amino-3,5-dimethyladamantane to memantine hydrochloride.
28. A process for the preparation of memantine hydrochloride, comprising: reacting l-halo-3,5-dimethyladamantane and a nitrile in the presence of phosphoric acid at a temperature of about 50° to about 100°C for a sufficient period of time to obtain n-acetamido-3,5-dimethyladamantane; and converting the n-acetamido-3,5- dimethyladamantane to memantine hydrochloride.
29. A process for the preparation of memantine hydrochloride, comprising: dissolving n-acetamido-3,5-dimethyladamantane in a solvent selected from the group consisting OfC3-6 alcohols in the presence of a strong inorganic base for a sufficient period of time to obtain l-amino-3,5-dimethyladamantane; and converting the l-amino-3,5-dimethyladamantane to memantine hydrochloride.
30. A process for the preparation of memantine hydrochloride, comprising: a) reacting l-halo-3,5-dimethyladamantane and a nitrile in the presence of phosphoric acid at a temperature of about 50° to about 100°C for a sufficient period of time to obtain n-acetamido-3,5-dimethyladamantane; b) dissolving n-acetamido-3,5-dimethyladamantane in a solvent selected from the group consisting OfC3-6 alcohols in the presence of a strong inorganic base for a sufficient period of time to obtain l-amino-3,5-dimethyladamantane; and c) reacting the l-amino-3,5-dimethyladamantane with hydrogen chloride or hydrochloric acid to obtain memantine hydrochloride.
PCT/US2006/001204 2005-01-11 2006-01-11 Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride WO2006076562A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
MX2007007302A MX2007007302A (en) 2005-01-11 2006-01-11 Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride.
EP06718295A EP1836157B1 (en) 2005-01-11 2006-01-11 Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride
DE602006009619T DE602006009619D1 (en) 2005-01-11 2006-01-11 PROCESS FOR PREPARING 1-AMINO-3,5-DIMETHYLADAMANTANE HYDROCHLORIDE
AT06718295T ATE444950T1 (en) 2005-01-11 2006-01-11 METHOD FOR PRODUCING 1-AMINO-3,5-DIMETHYLADAMANTAN HYDROCHLORIDE
CA002591666A CA2591666A1 (en) 2005-01-11 2006-01-11 Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride
IL183244A IL183244A0 (en) 2005-01-11 2007-05-15 Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride
HR20090676T HRP20090676T1 (en) 2005-01-11 2009-12-17 Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US64295705P 2005-01-11 2005-01-11
US60/642,957 2005-01-11
US67759905P 2005-05-03 2005-05-03
US60/677,599 2005-05-03

Publications (1)

Publication Number Publication Date
WO2006076562A1 true WO2006076562A1 (en) 2006-07-20

Family

ID=36282949

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2006/001204 WO2006076562A1 (en) 2005-01-11 2006-01-11 Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride
PCT/US2006/001202 WO2006076560A1 (en) 2005-01-11 2006-01-11 Polymorphs of memantine hydrochloride

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2006/001202 WO2006076560A1 (en) 2005-01-11 2006-01-11 Polymorphs of memantine hydrochloride

Country Status (12)

Country Link
US (2) US7462743B2 (en)
EP (2) EP1836154A1 (en)
AT (1) ATE444950T1 (en)
CA (2) CA2591666A1 (en)
DE (1) DE602006009619D1 (en)
ES (1) ES2334579T3 (en)
HR (1) HRP20090676T1 (en)
IL (2) IL183237A0 (en)
MX (2) MX2007007301A (en)
PT (1) PT1836157E (en)
SI (1) SI1836157T1 (en)
WO (2) WO2006076562A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007132476A2 (en) * 2006-05-15 2007-11-22 Matrix Laboratories Limited A process for the preparation of memantine hydrochloride
US7405324B2 (en) 2005-05-10 2008-07-29 A.M.S.A. Anonima Materie Sintetiche E. Afini S.P.A. Process for synthesising aminoadamantanes
WO2010069555A1 (en) 2008-12-17 2010-06-24 Merz Pharma Gmbh & Co. Kgaa Method for producing memantine
WO2014115638A1 (en) 2013-01-23 2014-07-31 三菱瓦斯化学株式会社 Manufacturing process for memantine
CN111909041A (en) * 2020-08-12 2020-11-10 山东罗欣药业集团恒欣药业有限公司 Preparation method of medicine for treating neurological diseases

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101528202A (en) * 2006-07-05 2009-09-09 特瓦制药工业有限公司 Pharmaceutical compositions of memantine
CN101038280B (en) * 2007-04-11 2010-09-15 山东省医药工业研究所 HPLC-ELSD measuring method for correlated matter in memantine hydrochloride
US20090247644A1 (en) * 2008-03-28 2009-10-01 Forest Laboratories Holdings Limited Memantine formulations
WO2011125062A1 (en) * 2010-04-08 2011-10-13 Hetero Research Foundation Process for the preparation of memantine hydrochloride
JP2013539790A (en) 2010-10-12 2013-10-28 ザ ジョンズ ホプキンス ユニバーシティ Antitussive composition comprising memantine
CN102875387A (en) * 2012-10-23 2013-01-16 滨州泓瑞医药科技有限公司 Amantadine hydrochloride preparation method
KR102495018B1 (en) 2013-11-15 2023-02-06 아케비아 테라퓨틱스 인코포레이티드 Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
EP3474831A1 (en) 2016-06-23 2019-05-01 Corium International, Inc. Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent
WO2018022814A1 (en) 2016-07-27 2018-02-01 Corium International, Inc. Transdermal delivery systems with pharmacokinetics bioequivalent to oral delivery
MX2019001104A (en) 2016-07-27 2019-10-02 Corium Int Inc Memantine transdermal delivery systems.
KR20230109782A (en) 2016-07-27 2023-07-20 코리움, 엘엘씨 Sodium bicarbonate in situ conversion driven transdermal delivery of amine drug
US11173132B2 (en) 2017-12-20 2021-11-16 Corium, Inc. Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point
JP2019156756A (en) * 2018-03-13 2019-09-19 宇部興産株式会社 Crystal of 1-amino-3,5-dimethyladamantane hydrochloride
PT3843702T (en) 2019-05-31 2023-10-13 Tecnimede Soc Tecnico Medicinal Lda Immediate release fixed-dose combination of memantine and donepezil

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3391142A (en) 1966-02-09 1968-07-02 Lilly Co Eli Adamantyl secondary amines
CZ282398B6 (en) * 1994-04-13 1997-07-16 Lachema A. S. PROCESS FOR PREPARING 1-Ri1-3-Ri2-TRICYCLO(3,3,1,1,e3,7)DECYL-5-AMINE

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH603545A5 (en) * 1972-04-20 1978-08-31 Merz & Co
ATE94384T1 (en) * 1989-04-14 1993-10-15 Merz & Co Gmbh & Co USE OF ADAMANTAN DERIVATIVES FOR PREVENTION AND TREATMENT OF CEREBRAL ISCHAEMIA.
US5614560A (en) * 1991-04-04 1997-03-25 Children's Medical Center Corporation Method of preventing NMDA receptor-mediated neuronal damage
US5599998A (en) * 1994-10-24 1997-02-04 Iowa State University Research Foundation, Inc. Method for the synthesis of adamantane amines
GB9812413D0 (en) * 1998-06-10 1998-08-05 Glaxo Group Ltd Compound and its use
JP2002275142A (en) 2001-03-14 2002-09-25 Daicel Chem Ind Ltd Method for producing amide compound
CN1125033C (en) 2001-08-29 2003-10-22 中国科学院广州化学研究所 Synthesis of memantine hydrochloride
CN1400205A (en) 2002-08-30 2003-03-05 中国科学院广州化学研究所 Preparation method of memantine hydrochloride
CN1240668C (en) * 2003-09-10 2006-02-08 上海医药工业研究院 Method for preparing memantine hydrochloride
WO2005069742A2 (en) * 2003-12-10 2005-08-04 Sun Pharmaceutical Industries Limited Crystal form ii of memantine hydrochloride
WO2005062724A2 (en) 2003-12-31 2005-07-14 Sun Pharmaceutical Industries Limited Novel process for the preparation of aminoadamantane derivatives
WO2007132476A2 (en) 2006-05-15 2007-11-22 Matrix Laboratories Limited A process for the preparation of memantine hydrochloride

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3391142A (en) 1966-02-09 1968-07-02 Lilly Co Eli Adamantyl secondary amines
CZ282398B6 (en) * 1994-04-13 1997-07-16 Lachema A. S. PROCESS FOR PREPARING 1-Ri1-3-Ri2-TRICYCLO(3,3,1,1,e3,7)DECYL-5-AMINE

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GERZON K ET AL: "The Adamantyl Group in Medicinal Agents. I. Hypoglycejmic N-Arylsulfonyl-N'-adamantylureas", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 6, no. 6, November 1963 (1963-11-01), pages 760 - 763, XP002353954, ISSN: 0022-2623 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7405324B2 (en) 2005-05-10 2008-07-29 A.M.S.A. Anonima Materie Sintetiche E. Afini S.P.A. Process for synthesising aminoadamantanes
WO2007132476A2 (en) * 2006-05-15 2007-11-22 Matrix Laboratories Limited A process for the preparation of memantine hydrochloride
WO2007132476A3 (en) * 2006-05-15 2009-10-22 Matrix Laboratories Limited A process for the preparation of memantine hydrochloride
WO2010069555A1 (en) 2008-12-17 2010-06-24 Merz Pharma Gmbh & Co. Kgaa Method for producing memantine
WO2014115638A1 (en) 2013-01-23 2014-07-31 三菱瓦斯化学株式会社 Manufacturing process for memantine
EP2949643A4 (en) * 2013-01-23 2016-09-07 Mitsubishi Gas Chemical Co Manufacturing process for memantine
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
CN111909041A (en) * 2020-08-12 2020-11-10 山东罗欣药业集团恒欣药业有限公司 Preparation method of medicine for treating neurological diseases

Also Published As

Publication number Publication date
US7462743B2 (en) 2008-12-09
EP1836157A1 (en) 2007-09-26
EP1836154A1 (en) 2007-09-26
CA2591666A1 (en) 2006-07-20
SI1836157T1 (en) 2009-12-31
IL183244A0 (en) 2007-08-19
CA2591487A1 (en) 2006-07-20
ES2334579T3 (en) 2010-03-12
IL183237A0 (en) 2007-08-19
ATE444950T1 (en) 2009-10-15
HRP20090676T1 (en) 2010-01-31
MX2007007301A (en) 2008-02-11
DE602006009619D1 (en) 2009-11-19
MX2007007302A (en) 2008-02-11
US20060217573A1 (en) 2006-09-28
PT1836157E (en) 2009-11-24
US20060173215A1 (en) 2006-08-03
EP1836157B1 (en) 2009-10-07
WO2006076560A1 (en) 2006-07-20

Similar Documents

Publication Publication Date Title
EP1836157B1 (en) Process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride
KR100649289B1 (en) New process for the synthesis of 1s-4,5-dimethoxy-1-methylaminomethyl-benzocyclobutane and addition salts thereof, and application in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid
EP1820792B1 (en) Process for the preparation of adamantanamines
RU2388753C2 (en) Method of obtaining intermediate product taking part in irbesartan synthesis
WO2008062472A2 (en) Process for the preparation of memantine
JP3723464B2 (en) Process for producing 11-amino-3-chloro-6,11-dihydro-5,5-dioxo-6-methyl-dibenzo [c, f] [1,2] thiazepine and its application to the synthesis of thianepine
JP5916721B2 (en) Synthetic method of ferroquine by intensive reductive amination
WO2009057140A2 (en) Improved process for memantine hydrochloride
WO2007026373A2 (en) Process for preparing rivastigmine
WO2013190357A1 (en) A process for the preparation of gabapentin
ZA200304484B (en) A process for the preparation of 1-(aminomethyl)cyclohexaneacetic acid.
KR20100118747A (en) Improved preparation method of sarpogrelate hydrochloride
US9902693B2 (en) Preparation method for pyrrolidine-2-carboxylic acid derivatives
CN111807968B (en) Synthetic method of 2- (1-cyclohexenyl) ethylamine
WO1999014184A1 (en) Novel stereoselective processes for the preparation of gabapentin analogues
US20120253074A1 (en) Process for the preparation of o-desmethyl-venlafaxine and salts thereof
KR20140003707A (en) Method for preparing xylylenediamine
WO2003099761A1 (en) Process for the manufacture of sertraline
KR100982720B1 (en) Manufacturing Process of 2-Aminomalonamide as Intermediate for Producing 4-Carbamoyl-1-?-D-ribofuranosylimidazolium-5-olate
KR101073978B1 (en) Manufacturing Process of Optically Active [6-2-(Aminoethyl)-(4R,6R)-2,2-dimethyl-[1,3]dioxan-4-yl]acetic acid Derivative as Intermediate of Atorvastatin
JP4366854B2 (en) 12-amino-4,8-dodecadienenitrile and process for producing the same
KR101325589B1 (en) Process for the preparation of 1-alkyl-2-(2-aminoethyl)pyrrolidines
JP2007529569A (en) Method for preparing fenoldopam mesylate
JP2004051585A (en) METHOD FOR PRODUCING 6-AMINOMETHYL-6,11-DIHYDRO-5H-DIBENZ[b,e]AZEPINE

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200680002066.8

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006718295

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 183244

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2591666

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: MX/a/2007/007302

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 5071/DELNP/2007

Country of ref document: IN

NENP Non-entry into the national phase

Ref country code: DE