U.S. patent application number 11/330681 was filed with the patent office on 2006-08-03 for process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride.
Invention is credited to Stefano Bianchi, Paola Daverio, Silvia Mantovani, Valeriano Merli, Alessandro Spreafico.
Application Number | 20060173215 11/330681 |
Document ID | / |
Family ID | 36282949 |
Filed Date | 2006-08-03 |
United States Patent
Application |
20060173215 |
Kind Code |
A1 |
Merli; Valeriano ; et
al. |
August 3, 2006 |
Process for the preparation of 1-amino-3,5-dimethyladamantane
hydrochloride
Abstract
A process for the preparation of memantine hydrochloride,
intermediates thereof and its hydrochloric acid form are
provided.
Inventors: |
Merli; Valeriano; (Cremella
Lecco, IT) ; Mantovani; Silvia; (Milano, IT) ;
Daverio; Paola; (Milano, IT) ; Bianchi; Stefano;
(Breccia, IT) ; Spreafico; Alessandro; (Lecco
(LC), IT) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
36282949 |
Appl. No.: |
11/330681 |
Filed: |
January 11, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60642957 |
Jan 11, 2005 |
|
|
|
60677599 |
May 3, 2005 |
|
|
|
Current U.S.
Class: |
564/124 |
Current CPC
Class: |
C07C 2603/74 20170501;
C07C 209/62 20130101; C07C 233/06 20130101; C07C 211/38 20130101;
C07C 231/06 20130101; C07C 209/62 20130101; C07C 211/38 20130101;
C07C 231/06 20130101; A61P 25/16 20180101 |
Class at
Publication: |
564/124 |
International
Class: |
C07C 231/06 20060101
C07C231/06 |
Claims
1. A process for the preparation of
n-acetamido-3,5-dimethyladamantane, comprising: reacting
1-halo-3,5-dimethyladamantane and a nitrile in the presence of
phosphoric acid at a temperature of about 500 to about 100.degree.
C. for a sufficient period of time to obtain
n-acetamido-3,5-dimethyladamantane.
2. The process of claim 1, wherein the
1-halo-3,5-dimethyladamantane is
1-bromo-3,5-dimethyladamantane.
3. The process of claim 1, wherein the phosphoric acid and
1-halo-3,5-dimethyladamantane are present in a phosphoric
acid:1-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.degree. to about 90.degree. 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 of
1-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
1-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-dimethyladamantane, 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 2.theta., and an x-ray powder
diffraction pattern substantially as depicted in FIG. 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 2.theta..
14. A process for the preparation of
1-amino-3,5-dimethyladamantane, comprising: dissolving
n-acetamido-3,5-dimethyladamantane in a solvent selected from the
group consisting of C.sub.3-6 alcohols in the presence of a strong
inorganic base for a sufficient period of time to obtain
1-amino-3,5-dimethyladamantane.
15. The process of claim 14, wherein dissolving
n-acetamido-3,5-dimethyladamantane is performed at a temperature of
about 90.degree. C. to reflux.
16. The process of claim 15, wherein dissolving
n-acetamido-3,5-dimethyladamantane is performed at a temperature of
about 125.degree. to about 135.degree. 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 respect to
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
1-amino-3,5-dimethyladamantane to memantine hydrochloride.
28. A process for the preparation of memantine hydrochloride,
comprising: reacting 1-halo-3,5-dimethyladamantane and a nitrile in
the presence of phosphoric acid at a temperature of about 500 to
about 100.degree. 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 of C.sub.3-6 alcohols in
the presence of a strong inorganic base for a sufficient period of
time to obtain 1-amino-3,5-dimethyladamantane; and converting the
1-amino-3,5-dimethyladamantane to memantine hydrochloride.
30. A process for the preparation of memantine hydrochloride,
comprising: a) reacting 1-halo-3,5-dimethyladamantane and a nitrile
in the presence of phosphoric acid at a temperature of about
50.degree. to about 100.degree. 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 of C.sub.3-6 alcohols in the presence of a strong
inorganic base for a sufficient period of time to obtain
1-amino-3,5-dimethyladamantane; and c) reacting the
1-amino-3,5-dimethyladamantane with hydrogen chloride or
hydrochloric acid to obtain memantine hydrochloride.
Description
RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional Patent
Application No. 60/642,957, filed Jan. 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 1-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. ##STR1##
[0004] Three strategies for the synthesis of memantine
hydrochloride are disclosed in the prior art:
[0005] A) N-acetyl-memantine alkaline hydrolysis, disclosed in U.S.
Pat. No. 3,391,142, Czech Patent Publication No. CZ282398B6,
Japanese Patent Publication No. JP 2002 275142A2, and Chinese
Patent Publication No. CN 1335299;
[0006] B) Reaction of 1-halo-3,5-dimethyladamantane and urea at
high temperature, and alkaline hydrolysis of the resulting
adamantyl urea intermediate, disclosed in U.S. Pat. No. 4,122,193
and Chinese Patent Publication No. CN1400205A; and
[0007] C) Electrophylic substitution on metallated
3,5-dimethyladamantane by chloramine, disclosed in U.S. Pat. No.
5,599,998.
[0008] U.S. Pat. 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. ##STR2##
[0009] In the first reaction, 1-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.degree. 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.
[0010] Czech Patent Publication No. CZ282398B6 discloses the
synthesis of memantine according to the following scheme, which is
carried out under pressure. ##STR3##
[0011] Japanese Patent Publication No. JP 2002 275142A2 discloses
the synthesis of n-acetyl-memantine according to the following
scheme with a yield of 45 percent. ##STR4##
[0012] Chinese Patent Publication No. CN 1335299 discloses
memantine hydrochloride synthesis according to the scheme.
##STR5##
[0013] U.S. Pat. No. 4,122,193 discloses pharmacological
compositions and methods for treating living mammals suffering from
hyperkinesias, as well as memantine hydrochloride, hydrobromide,
and sulphate synthesis, where the hydrochloride is prepared
according to the following scheme with a yield of 78 percent.
##STR6##
[0014] Chinese Patent Publication No. CN1400205A discloses
memantine hydrochloride synthesis according to the following
scheme. ##STR7##
[0015] U.S. Pat. No. 5,599,998 discloses memantine synthesis with a
yield of 48 percent according to the following scheme. ##STR8##
[0016] 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.
[0017] The deficiencies of the prior art processes described above
include, but are not limited to the production of undesirable
byproducts, such as Br.sub.2 and SO.sub.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 1-bromo-3,5-dimethyladamantane and acetonitrile in
presence of 96 percent sulphuric acid. The very high reaction
temperatures, typically from 190.degree. to 225.degree. C. are
required in the alkaline hydrolysis of n-acetyl-memantine in
diethylene glycol or ethylene glycol and in the reaction between
1-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
[0018] 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.
[0019] In a first embodiment, the present invention is directed to
a process for the synthesis of n-acetamido-3,5-dimethyladamantane
by reacting 1-halo-3,5-dimethyladamantane and a nitrile, in the
presence of phosphoric acid, at a temperature of about 55.degree.
to about 90.degree. C. and for a period of time sufficient to
produce n-acetamido-3,5-dimethyladamantane, and recovering
n-acetamido-3,5-dimethyladamantane.
[0020] 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
2.theta., and an x-ray powder diffraction pattern substantially as
depicted in FIG. 1.
[0021] 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.theta..+-.0.2 degrees 2.theta., or as depicted in
FIG. 2.
[0022] In a another embodiment, the invention is directed to a
process for the synthesis of memantine, comprising: solvolysis of
n-acetamido-3,5-dimethyladamantane in a solvent selected from the
group consisting of C.sub.4-6 alcohols in the presence of a strong
inorganic base for a adequate period of time to obtain
1-amino-3,5-dimethyladamantane; and recovering an anhydrous
alcoholic solution of 1-amino-3,5-dimethyladamantane.
[0023] In a further embodiment, the invention is directed to a "one
pot" process for the synthesis of memantine from
1-halo-3,5-dimethyladamantane without the isolation of
n-acetyl-3,5-dimethyladamantane.
[0024] Preferably, the memantine prepared by the above processes is
subsequently converted into a memantine hydrochloride.
[0025] Preferably, the memantine prepared by the above processes
has a yield which is not less than 80%.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 illustrates a characteristic X-ray powder diffraction
pattern of n-acetamido-3,5-dimethyladamantane Form I.
DESCRIPTION OF THE INVENTION
[0027] As used herein, the preface "halo-" refers to chloro, bromo,
iodo, and fluoro.
[0028] 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.
[0029] In a first embodiment, the present invention is directed to
a process for the synthesis of n-acetamido-3,5-dimethyladamantane
by providing 1-halo-3,5-dimethyladamantane, as shown below in
Scheme 1 and labelled as the 1.sup.st step. This process is
performed by reacting ##STR9## 1-halo-3,5-dimethyladamantane and a
nitrile, in the presence of phosphoric acid at about 500 to about
100.degree. C. and for a period of time sufficient to produce
n-acetamido-3,5-dimethyladamantane, and then recovering
n-acetamido-3,5-dimethyladamantane.
[0030] Preferably the 1-halo-3,5-dimethyladamantane used is
1-bromo-3,5-dimethyladamantane
[0031] Preferably, the reaction temperature is about 65.degree. to
about 90.degree. 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.
[0032] 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
1-halo-3,5-dimethyladamantane, most preferably, about 3 to about 6
moles/mole of 1-halo-3,5-dimethyladamantane.
[0033] Preferably, before the start of the reaction, the phosphoric
acid is added drop-wise at a temperature below 40.degree. C. for a
period of about 15 minutes. The amount of phosphoric acid is in a
phosphoric acid:1-halo-3,5-dimethyladamantane mole ratio within a
range of 2:1 to 4:1.
[0034] 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.
[0035] 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.
[0036] As discussed above, the process disclosed in U.S. Pat. No.
3,391,142 involves a Ritter reaction between
I-bromo-3,5-dimethyladamantane and acetonitrile in a large amount
of concentrated sulphuric acid. Due to the oxidizing power of
sulphuric acid, bromine and SO.sub.2 are by products of the
reaction according to following scheme. ##STR10##
[0037] 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. Pat. No. 3,391,142, easing large scale industrial
production.
[0038] 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 2.theta., and an x-ray powder diffraction pattern
substantially as depicted in FIG. 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 2.theta..
[0039] 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.
##STR11##
[0040] The process of the invention comprises: dissolving
n-acetamido-3,5-dimethyladamantane in a solvent selected from the
group consisting of C.sub.3-6 alcohols in the presence of a strong
inorganic base for a sufficient period of time to obtain
I-amino-3,5-dimethyladamantane; and recovering an anhydrous
alcoholic solution of 1-amino-3,5-dimethyladamantaie.
[0041] Preferably, dissolving n-acetamido-3,5-dimethyladamantane is
by heating at about 90.degree. C. to reflux, and, more preferably,
to a temperature in the range of about 125.degree. to about
135.degree. C. 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.
[0042] The desired product, 1-amino-3,5-dimethyladamantane, may be
recovered by a variety of methods known in the art. In one
protocol, the solution of 1-amino-3,5-dimethyladamantane is cooled,
preferably to about 50.degree. to about 80.degree. C., the reaction
mixture is washed with water, distilling n-butanol and water until
a semisolid residue of 1-amino-3,5-dimethyladamantane (memantine
free base) is obtained.
[0043] 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 1-amino-3,5-dimethyladamantane
to obtain memantine HCl, and memantine HCl is recovered. Most
preferably, the solution of 1-amino-3,5-dimethyladamantane is first
concentrated under 50 mm Hg vacuum at a temperature of about
55.degree. C., to obtain a residue which is suspended in an organic
solvent, such as ethyl acetate, while maintaining the temperature
at about 50.degree. C. The suspension is then cooled to about
20.degree. C. for about one hour, washed with water, and dried to
obtain memantine HCl. ##STR12##
[0044] The alkaline solvolysis of the acetamido moiety, as
described in U.S. Pat. No. 3,391,142 and CZ 282398, requires
refluxing the reactants in diethylene glycol, methanol, ethanol, or
isopropyl alcohol. In contrast, in the present invention C.sub.4-6
alcohols are used. In 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.
[0045] In a further embodiment, the invention is directed to a "one
pot" process for the synthesis of memantine hydrochloride from
1-halo-3,5-dimethyladamantane without the isolation of
n-acetamido-3,5-dimethyladamantane. The process of the invention
comprises: [0046] a. reacting 1-halo-3,5-dimethyladamantane and a
nitrile, in the presence of phosphoric acid at about 50.degree. to
about 100.degree. C. and for a period of time sufficient to produce
n-acetamido-3,5-dimethyladamantane, [0047] b. dissolving
n-acetamido-3,5-dimethyladamantane in a solvent selected from the
group consisting of C.sub.3-6 alcohols in the presence of a strong
inorganic base for a sufficient period of time to obtain
1-amino-3,5-dimethyladamantane; and [0048] c. recovering an
alcoholic solution of 1-amino-3,5-dimethyladamantane.
[0049] Preferably, the solution of 1-amino-3,5-dimethyladamantane
is then converted into memantine's acid addition salt form, most
preferably memantine hydrochloride.
EXAMPLES
Example 1
Synthesis of 1-acetamido-3,5-dimethyladamantane
[0050] The following examples are provided to illustrate
embodiments of the present invention.
[0051] The first step in the synthesis of
1-acetamido-3,5-dimethyladamantane, follows the following synthetic
scheme. ##STR13##
[0052] At room temperature, the 500 g (2.056 mol) of
1-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, 806 g of 75% phosphoric acid (6.2 moles) were added drop wise
over a period of about 15 minutes, maintaining the temperature
below 40.degree. C. The resulting biphasic mixture was heated to
870.+-.2.degree. C., and maintained at that temperature for 3
hrs.
[0053] The 1000 ml of n-butyl alcohol and 770 ml of water were
added, providing a homogeneous solution. Sodium hydroxide 30%
(337.5 g) 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.
[0054] The phases were separated. The organic phase was then
concentrated under a vacuum of 45 mm Hg to a residual volume of
600-650 ml with an increase in the internal temperature to about
70.degree. C. The residual suspension was cooled to 60.degree. C.,
and 500 ml of acetone and 2000 ml of water were added in sequence.
The resulting suspension was cooled to 0.degree. C. in one hour,
and the suspension was stirred at 0.degree. C. for 1 hour. The
resulting solid was filtered, and washed twice with 400 ml of
water. The solid was dried overnight at 50.degree. C. An amount of
dried solid of 434.0 g, 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
[0055] Ten grams (0.045 mol) of n-acetyl-memantine, 75 ml of
n-butanol, and 10.5 g sodium hydroxide flakes (0.263 mol) 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.degree. C., and
maintained at 120.degree. C. for 10 hours. The reaction mixture is
cooled to 80.degree. 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. 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 70.degree. C. until an oily residue (10.5 g) is
obtained to obtain memantine free base.
[0056] (Optionally to the oily residue AcOEt 100 ml 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.degree. C. for 1 h to obtain memantine HCl
[0057] Memantine HCl is isolated by filtration, washed twice with
AcOEt (10 ml each), and dried under vacuum at 55.degree. C.
MMN.HCl=7.2 g; yield: 74%)
Example 4
Synthesis of Memantine HCl from n-acetyl memantine
[0058] Steps 2 and 3 of the synthesis of
1-amino-3,5-dimethyladamantane synthesis, memantine HCl, follow the
following synthetic scheme. ##STR14##
[0059] 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.degree..+-.2.degree. C., and maintained at
130.degree..+-.2.degree. C. for 10 to 11 hours. The reaction
mixture was cooled to 50.degree. C., 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.
[0060] 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 90 ml
at a temperature of 55.degree. C. Following the vacuum
concentration, 250 ml of ethyl acetate were added to the residue,
while maintaining the temperature at 50.degree. C. The suspension
was cooled to 20.degree. C., stirred at 20.degree. C. for one hour,
and filtered and washed three times with 30 ml of ethyl acetate.
The product was dried at 50.degree. to 55.degree. 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
[0061] As discussed above, memantine hydrochloride may be produced
in a "one pot" process.
[0062] First, 22 g (0.09042 mol) of 1-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 funnel, during which period
the internal temperature rose to 34.degree. C. The biphasic mixture
was then warmed to 65.degree. 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.
[0063] 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.
[0064] Then, 49.1 g of 89.9% KOH (0.787 mol) and 100 ml of
n-butanol were added to the anhydrified organic phase. The
suspension was then warmed to 130.degree..+-.2.degree. C. 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.degree. 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.
[0065] 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 50 ml, providing a semisolid residue.
Ethylacetate in an amount of 100 ml was added to residue, and the
resulting suspension was stirred at 20.degree. to 22.degree. C. for
one hour, filtered, and washed with three 12 ml volumes of
ethylacetate. The filtered material was dried under vacuum at
50.degree. to 55.degree. 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.
[0066] 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.
* * * * *