PROCESS FOR PREPARATION OF PIPERIDINE CARBOXYLIC ACID
Technical Field
Processes for preparing pure tiagabine, a piperidine carboxylic acid, using
pharmaceutically acceptable acid addition salts of tiagabine esters are provided. L(+)-
tartaric acid, oxalic acid and dibenzoyl L(+)-tartaric acid addition salts of tiagabine esters
are also provided. Further, processes for preparing acid addition salts of tiagabine esters
are provided.
Background of the Invention
Chemically, tiagabine is R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic
acid and is disclosed in U.S. Patent No. 5,010,090. Tiagabine is an amino acid derivative
exhibiting GABA (y-aminobutyric acid, a neurotransmitter in the central nervous system)-
uptake inhibitory properties and exerts useful pharmacological effects on the central
nervous system by selectively enhancing the GABA activity.
U.S. Patent No. 5,354,760 discloses a use of tiagabine ethyl ester hydrochloride for
the preparation of crystalline taigabine hydrochloride monohydrate. No other salt of
tiagabine esters has been reported.
U.S. Patent No. 5,010,090 also discloses the preparation of tiagabine from
tiagabine ethyl ester, wherein tiagabine ethyl ester was purified by column
chromatography on silica using methanol as eluent, which was then converted to tiagabine
hydrochloride. Such a purification processes is cumbersome and expensive.
However, there remains a need for an improved process that avoids
chromatographic techniques for preparing pure tiagabine. Such a process would be
advantageous on a commercial scale.
Summary of the Invention
Provided herein are improved processes of preparing pure tiagabine and acid addition
salts of tiagabine esters. In one aspect, provided are processes for preparing pure tiagabine
comprising the steps of:
a) contacting crude tiagabine ester with one or more acids in one or more inert
solvents to form an acid addition salt of tiagabine ester,
b) optionally isolating the acid addition salt of tiagabine ester as a solid, and
c) converting the acid addition salt of tiagabine ester into pure tiagabine or its
pharmaceutically acceptable salts thereof.
Such processes can include one or more of the following embodiments. For
example, the one or more inert solvents can be one or more alcohols, one or more esters,
one or more ethers, one or more ketones, one or more nitriles, one or more chlorinated
hydrocarbons, one or more cyclic ethers, one or more dipolar aprotic solvents or mixtures
thereof. For example, alcohols can be methanol, ethanol, isopropanol, or mixtures thereof
and ethers can be diethyl ether, diisopropyl ether, tertiary butyl methyl ether or mixtures
thereof.
In another embodiment, acids can be one or more organic acids or one or more
inorganic acids. Organic acids can be one or more of formic acid, acetic acid, succinic
acid, maleic acid, malic acid, citric acid, ascorbic acid, mandelic acid, oxalic acid, tartaric
acid, dibenzoyl tartaric acid, methanesulfonic acid, para toluenesulfonic acid,
benzenesulfonic acid or mixtures thereof. In cases where chiral organic acids are used,
dextro-rotatory isomers of such chiral acids can be used. Inorganic acids can be one or
more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or
mixtures thereof.
In another embodiment, salts of tiagabine ester can be converted to pure tiagabine
by acid hydrolysis or alkaline hydrolysis.
In yet another embodiment, pure tiagabine can be converted to its pharmaceutically
acceptable acid addition salts. For example, pure tiagabine can be converted to tiagabine
hydrochloride by contacting pure tiagabine with hydrochloric acid or hydrogen chloride
gas.
In another embodiment, purification of tiagabine results in chiral purification or
chemical purification. For example, chiral purity of the pure tiagabine or its
pharmaceutically acceptable acid addition salts can be greater than about 99 %, and in
other embodiments, greater than about 99.5 %. Chemical purity of the pure tiagabine
its pharmaceutically acceptable acid addition salts can be greater than about 98.5 %
In another aspect, provided herein are acid addition salts of tiagabine ester of
wherein R is L(+)-tartaric acid, oxalic acid or dibenzoyl L(+)-tartaric acid.
In yet another aspect, also provided are processes for preparing acid addition salts
of tiagabine ester of Formula I,
comprising contacting crude tiagabine ester with one or more acids in one or more inert
solvents and isolating a corresponding acid addition salt of tiagabine ester.
Such processes can include one or more of the following embodiments. For
example, acids can be one or more organic acids or one or more inorganic acids. Organic
acids can be one or more of formic acid, acetic acid, succinic acid, maleic acid, malic acid,
citric acid, ascorbic acid, mandelic acid, oxalic acid, tartaric acid, dibenzoyl tartaric acid,
methanesulfonic acid, para toluenesulfonic acid, benzenesulfonic acid or mixtures thereof.
In cases where chiral organic acids are used, dextro-rotatory isomers of such chiral acids
can be used. Inorganic acids can be one or more of hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, nitric acid or mixtures thereof.
In another embodiment, salts of tiagabine ester can be converted to pure tiagabine
by acid hydrolysis or alkaline hydrolysis.
In another embodiment, pure tiagabine can be converted to its pharmaceutically
acceptable acid addition salts.
In another embodiment, purification of tiagabine results in chiral purification or
chemical purification. For example, chiral purity of the pure tiagabine or its
pharmaceutically acceptable acid addition salts can be greater than about 99 %, and in
other embodiments, greater than about 99.5 %. Chemical purity of the pure tiagabine armaceutically acceptable acid addition salts can be greater than about 98.5 %
Description of the Drawings
FIG. 1 shows a powder X-ray diffraction pattern of L(+)-tartaric acid salt of
tiagabine ethyl ester.
FIG. 2 shows powder X-ray diffraction pattern of oxalic acid salt of tiagabine ethyl
ester.
FIG. 3 shows powder X-ray diffraction pattern of dibenzoyl L(+)-tartaric acid salt
of tiagabine ethyl ester.
FIG. 4 shows an infrared absorption spectrum of L(+)-tartaric acid salt of tiagabine
ethyl ester.
FIG. 5 shows an infrared absorption spectrum of oxalic acid salt of tiagabine ethyl
ester.
FIG. 6 shows an infrared absorption spectrum of dibenzoyl L(+)-tartaric acid salt
of tiagabine ethyl ester.
FIG. 7 shows DSC graph of L(+)-tartaric acid salt of tiagabine ethyl ester.
FIG. 8 shows DSC graph of oxalic acid salt of tiagabine ethyl ester.
FIG. 9 shows DSC graph of dibenzoyl L(+)-tartaric acid salt of tiagabine ethyl
ester.
Detailed Description of the Invention
In one aspect provided are processes for preparing pure tiagabine comprising the
steps of:
a) contacting crude tiagabine ester with one or more acid in one or more inert
solvents to form an acid addition salt of tiagabine ester,
b) optionally isolating the acid addition salt of tiagabine ester in solid state,
and
c) converting the acid addition salt of tiagabine ester into pure tiagabine or
pharmaceutically acceptable salts thereof.
In another aspect, provided are organic acid addition salts of Formula I,
wherein R is L(+)-tartaric acid, oxalic acid or dibenzoyl L(+)-tartaric acid.
In yet another aspect, provided are processes for preparing acid addition salts of
tiagabine ester comprising contacting tiagabine ester with one or more acids in one or
more inert solvents and isolating the corresponding acid addition salts of tiagabine ester.
Crude tiagabine ester can be obtained by methods known in the art, for example,
by a process disclosed in U.S. Patent No. 5,010,090, which is incorporated herein in its
entirety. Crude tiagabine ester can be utilized in the described processes as a solid or in
solution form. For example, a solution of tiagabine ester may be obtained directly from
the last step of a reaction in which tiagabine ester is formed and used for the preparation of
acid addition salt of tiagabine ester.
The term "contacting," as used herein, refers to mixing, dissolving, slurring,
stirring or a combination thereof.
Examples of inert solvents utilized in the described processes include one or more
alcohols (e.g., methanol, ethanol, isopropanol or mixtures thereof); ethers (e.g., diethyl
ether, diisopropyl ether, tertiary butyl methyl ether or mixtures thereof); ketones (e.g.,
acetone, butanone or mixtures thereof); esters (e.g., ethylacetate, isopropylacetate or
mixtures thereof); nitriles (e.g., acetonitrile); chlorinated hydrocarbons (e.g., methylene
chloride, ethylenedichloride or mixtures thereof); dipolar aprotic solvents (e.g.,
dimethylsulfoxide, dimethylformamide or mixtures thereof); cyclic ethers (e.g., dioxane,
tetrahydrofuran or mixtures thereof); or mixtures thereof.
Acid addition salts of tiagabine ester include, for example, salts with inorganic
acids or organic acids. Examples of inorganic acids include, but are not limited to,
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or nitric acid.
Examples of organic acids include, but are not limited to, formic acid, acetic acid, succinic
acid, maleic acid, malic acid, citric acid, ascorbic acid, mandelic acid, oxalic acid, tartaric
acid, dibenzoyl tartaric acid, methanesulfonic acid, para toluenesulfonic acid, or
benzenesulfonic acid. Dextro-rotatory isomers of the above-described acids may be used
for preparing chiral acid addition salts of tiagabine ester.
The described processes may be carried out at room or ambient temperatures, as
well as higher temperatures for suitable durations required for the formation of the salt.
Salts of tiagabine ester may be isolated by concentration, crystallization,
precipitation, cooling, filtration, centrifugation or combinations thereof
Precipitation of salts of tiagabine ester may be spontaneous, depending upon
solvents used and reaction conditions. Precipitation may also occur upon addition of one
or more antisolvents, i.e., solvents in which salt of tiagabine ester is insoluble or sparingly
soluble, to the inert solvent(s) in which salts of tiagabine ester are prepared. Alternatively,
precipitation may be induced by concentration and/or reducing the temperature of the
inert(s) solvent, particularly if the initial temperatures are elevated.
Examples of antisolvents that may be added to precipitate out salts of tiagabine
ester include, but are not limited to, hydrocarbons (e.g., hexane, cyclohexane, toluene,
heptane, octane or mixtures thereof); lower alkyl ethers (diethylether, diisopropylether or
mixtures thereof); or mixtures thereof.
Times and temperatures for crystallizations/precipitations are not critical. For
example, the crystallization/precipitation may be performed at temperatures from about 5
°C to about 40 °C and for times of about 30 minutes to about 3 hours in some
embodiments.
Salts of tiagabine ester in solid state can be isolated to assist in the removal of
impurities. For example, salts of tiagabine ester may be crystallized one or more times
before conversion to tiagabine to provide higher purity tiagabine. In another example,
salts of tiagabine ester in crystalline form can be isolated to assist in obtaining higher
purity tiagabine.
Solvent amounts may be varied depending on the type of solvent(s), lot size etc.
Operation conditions, for example stirring, are not limited for the described processes, and
in some embodiments, crystallization or precipitation may be conducted with or without
stirring.
Conversion of salts of tiagabine ester to pure tiagabine may be achieved by acid
hydrolysis, alkali hydrolysis or hydrogenation, particularly, for example, when benzyl
esters are used. Hydrogenations may be carried out by using convention methods known
to one of ordinary skill in the art, and in particular, can be carried out in the presence of
one or more metal catalysts. Metal catalysts that may be used in hydrogenations include
palladium, nickel and platinum. Acid hydrolyses and base hydrolyses may be carried out
using procedures well known to one of ordinary skill in the art. For example, reagents for
acid hydrolyses include one or more mineral acids, for example, haloacids (HC1, HBr, and
the like or mixtures thereof), sulfuric acid and other mineral acids; and reagents for base
hydrolyses include various mineral hydroxides, for example, Group I hydroxides (e.g.,
sodium hydroxide, potassium hydroxide, and the like, or mixtures thereof).
Solvents used to convert salts of tiagabine ester to pure tiagabine or its
pharmaceutically acceptable salts are not critical and may be the same as those used for
the preparation of salts of tiagabine ester as described above. For example, solvents that
may be used in this conversion step include one or more alcohols (e.g., methanol, ethanol,
isopropanol or mixtures thereof); ethers (e.g., diethyl ether, diisopropyl ether, tertiary
butyl methyl ether or mixtures thereof); ketones (e.g., acetone, butanone or mixtures
thereof); esters (e.g., ethylacetate, isopropylacetate or mixtures thereof); nitriles (e.g.,
acetonitrile); chlorinated hydrocarbons (e.g., methylene chloride, ethylenedichloride or
mixtures thereof); dipolar aprotic solvents (e.g., dimethylsulfoxide, dimethylformamide or
mixtures thereof); cyclic ethers (e.g., dioxane, tetrahydrofuran or mixtures thereof); or
mixtures thereof.
Reaction times and temperatures are not critical. For example, the reaction may be
performed at temperatures from about 20 °C to about 80 °C and at reaction times from
about 1 hour to about 6 hours in some particular embodiments.
Pure tiagabine may be isolated in a manner similar to that detailed above for
isolating salt of tiagabine ester. For example, pure tiagabine may be isolated by
concentration, crystallization, precipitation, cooling, filtration, centrifugation or
combinations thereof.
Tiagabine may be converted to its pharmaceutically acceptable acid addition salts
by adding the corresponding acid in one or more suitable solvents. For example, tiagabine
hydrochloride may be prepared by contacting tiagabine with HC1 (e.g., hydrogen chloride
gas or hydrochloric acid).
Isolation of acid addition salts of tiagabine ester as intermediates in processes for
preparing pure tiagabine or its pharmaceutically acceptable salts results in chemical
purification, as well as chiral purification. Tiagabine or its pharmaceutically acceptable
salts of chemical purity of more than about 99 % may be obtained by the described
processes. Chemical purities of tiagabine or its pharmaceutically acceptable salts may be
more than 98.5 % in some embodiments. Tiagabine or its pharmaceutically acceptable
salts of chiral purity of more than about 99.5% may also be obtained by the described
processes. Chiral purities of tiagabine or its pharmaceutically acceptable salts may be
more than 99.9 % in some embodiments.
Pure tiagabine or its pharmaceutically acceptable salts thereof having less than
about 0.5 % of impurities atRRT 1.13 (as perUSP monograph USP 26-NF 21 suppl.)
can be obtained by the present process. Pure tiagabine or its pharmaceutically acceptable
salts thereof having less than about 0.3 % impurities, and even less than about 0.1 %
impurities may be obtained in some embodiments.
L(+)-tartaric acid salt (i.e., L(+)-tartarate salt) of tiagabine ethyl ester may be
obtained as a crystalline material. Such L(+)-tartaric acid salt of tiagabine ethyl ester may
be characterized by XRD spectra having X-ray peaks at about 6.94, 13.92, 15.18, 16.92,
18.44, 18.72, 19.38, 21.84, 22.86 and 25.22 ± 0.2 degrees two-theta. Oxalic acid salt of
tiagabine ethyl ester may be obtained as a crystalline material. Such oxalic acid salt of
tiagabine ethyl ester may be characterized by XRD spectra having strong X-ray peaks at
about 15.84, 18.26, 21.04 and 26.66 ± 0.2 degrees two-theta and weak peaks at about
13.22, 18.98, 19.88, 24.20 and 24.46 ± 0.2 degrees two-theta. Dibenzoyl L(+)-tartaric acid
salt of tiagabine ethyl ester may be obtained in an amorphous form. Salts described herein
may also be characterized by their IR and DSC graphs.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the
art and are included within the scope of the present invention. The examples are provided
to illustrate particular aspects of the disclosure and do not limit the scope of the present
HPLC-Column LUNA C-18 (150X4.6) 5\i
Example 1: Preparation of tiagabine ethyl ester-L (+) tartrate salt:
L (+) tartaric acid (3.72 g) was added to a stirred solution of crude tiagabine ethyl ester
(14.2 g, HPLC Purity = 70 %) in isopropanol (100 mL) at ambient temperature. The
mixture was stirred at about 70-80 °C for about 1 hour resulting in a clear solution. The
hot solution was filtered to remove insoluble material and the filtrate cooled and stirred at
room temperature for 4 hours to crystallize the product. The obtained product was
recrystallized from isopropanol to yield pure title compound.
HPLC Purity: 99.13%
Melting Point: 129-130 °C
Yield: 9.7 g
Example 2: Preparation of tiagabine ethyl ester-oxalate salt:
A solution of oxalic acid (3.0 g) in isopropanol was added to a stirred solution of crude
tiagabine ethyl ester (12.0 g, HPLC purity = 80 %) in isopropanol at ambient temperature.
The mixture was stirred at about 70-80 °C for about 2 hours resulting in a clear solution.
The hot solution was allowed to cool to room temperature and was stirred for about 4
hours to crystallize the product. The obtained product was filtered and recrystallized from
isopropanol to yield pure title compound.
HPLC Purity: 98.74 %
Melting Point: 154-155°C
Yield: 8.8 g
Example 3: Preparation of tiagabine ethyl ester-dibenzoyl L (+) tartrate salt:
A solution of dibenzoyl L (+) tartaric acid (0.85 g) in isopropyl ether was added to a
stirred solution of crude tiagabine ethyl ester (1.2 g, HPLC purity = 80) in isopropyl ether
(20 mL) at ambient temperature. The mixture was stirred for about 2 hours at room
temperature to crystallize the product. The obtained product was filtered and recrystallized
from isopropyl ether to yield pure title compound.
HPLC Purity: 99.08 %
Melting Point: 70-72 °C
Yield: 1.6g
Example 4: Preparation of tiagabine hydrochioride from tiagabine ethyl ester-L (+)
tartrate salt:
A solution sodium hydroxide (10.8 ml, 8M) was added to a stirred solution of L (+)
tartaric acid salt of tiagabine ethyl ester (12 g, purity: >99.5 %) in ethanol at ambient
temperature. The solution was stirred for about 3 to 5 hours until completion of the
reaction. The mixture was diluted with water (50 mL) and acidified with dilute
hydrochloric acid until a pH of about 1.0 was obtained. The acidic solution was extracted
twice with ethyl acetate (100 mL). The ethyl acetate layer was then washed with water
(25 mL) and concentrated by evaporation under vacuum to yield crude product. Crude
tiagabine hydrochioride was recrystallized from ethanol to yield pure tiagabine

WE CLAIM;
1. A process for preparing pure tiagabine comprising the steps of:
a) contacting crude tiagabine ester with one or more acids in one or more inert
solvents to form an acid addition salt of tiagabine ester,
b) optionally isolating the acid addition salt of tiagabine ester as a solid, and
c) converting the acid addition salt of tiagabine ester into pure tiagabine or its
pharmaceutically acceptable salts thereof.
2. The process of claim 1, wherein the one or more inert solvents are selected from
one or more alcohols, one or more esters, one or more ethers, one or more ketones, one or
more nitriles, one or more chlorinated hydrocarbons, one or more cyclic ethers, one or
more dipolar aprotic solvents or mixtures thereof.
3. The process of claim 2, wherein the one or more alcohols are selected from
methanol, ethanol, isopropanol, or mixtures thereof and the one or more ethers are selected
from diethyl ether, diisopropyl ether, tertiary butyl methyl ether or mixtures thereof.
4. The process of claim 1, wherein the one or more acids are selected from one or
more organic acids or one or more inorganic acids.
5. The process of claim 4, wherein the one or more organic acids are selected from
formic acid, acetic acid, succinic acid, maleic acid, malic acid, citric acid, ascorbic acid,
mandelic acid, oxalic acid, tartaric acid, dibenzoyl tartaric acid, methanesulfonic acid, para
toluenesulfonic acid, benzenesulfonic acid or mixtures thereof.
6. The process of claim 5, wherein the one or more organic acids are chiral and
dextro-rotatory isomers of the chiral acids are used.
7. The process of claim 4, wherein the one or more inorganic acids are selected from
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or mixtures
thereof.
8. The process of claim 1, wherein salts of tiagabine ester are converted to pure
tiagabine by acid hydrolysis or alkaline hydrolysis.
9. The process of claim 8, wherein the pure tiagabine is converted to its
pharmaceutically acceptable acid addition salts.
10. The process of claim 9, wherein the pure tiagabine is converted to tiagabine
hydrochloride by contacting pure tiagabine with hydrochloric acid or hydrogen chloride
gas.
11. The process of claim 1, wherein chiral purity of the pure tiagabine or its
pharmaceutically acceptable acid addition salts is greater than about 99 %.
12. The process of claim 1, wherein chiral purity of the pure tiagabine or its
pharmaceutically acceptable acid addition salts is greater than about 99.5 %.
13. The process of claim 1, wherein chemical purity of the pure tiagabine or its
pharmaceutically acceptable acid addition salts is greater than about 98.5 % by HPLC.
14. An acid addition salt of tiagabine ester of Formula I,
wherein R is L(+)-tartaric acid, oxalic acid or dibenzoyl L(+)-tartaric acid.
15. A process for preparing acid addition salts of tiagabine ester of Formula I,
comprising contacting crude tiagabine ester with one or more acids in one or more inert
solvents and isolating a corresponding acid addition salt of tiagabine ester.
16. The process of claim 15, wherein the one or more acids are selected from one or
more organic acids or one or more inorganic acids.
17. The process of claim 16, wherein the one or more organic acids are selected from
formic acid, acetic acid, succinic acid, maleic acid, malic acid, citric acid, ascorbic acid,
mandelic acid, oxalic acid, tartaric acid, dibenzoyl tartaric acid, methanesulfonic acid, para
toluenesulfonic acid, benzenesulfonic acid or mixtures thereof; or the one or more
inorganic acids are selected from hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, nitric acid or mixtures thereof.
18. The process of claim 16, wherein the one or more organic acids are chiral and
dextro-rotatory isomers of the chiral acids are used.
19. The process of claim 15, wherein the salts of tiagabine ester is converted to pure
tiagabine by acid hydrolysis or alkaline hydrolysis.
20. The process of claim 15, wherein the pure tiagabine is converted to its
pharmaceutically acceptable acid addition salts.
21. The process of claim 15, wherein chiral purity of the pure tiagabine or its
pharmaceutically acceptable acid addition salts is greater than about 99 %; or chemical
purity of the pure tiagabine or its pharmaceutically acceptable acid addition salts is greater than about 98.5% by HPLC.