Note: Descriptions are shown in the official language in which they were submitted.
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
ZONISAMIDE INTERMEDIATE AND SYNTHESIS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefits under 35 U.S.C. ~1.119(e) of Provisional
Application Serial Nos. 60/316,109 filed August 30, 2001 and 60/344,439 filed
October 24,
2001, the disclosure of which is incorporated by reference in its entirety
herein.
to
FIELD OF THE INVENTION
The field of the invention is the sulfonation of a zonisamide intermediate and
crystalline forms of the zonisamide intermediate in the form of acid and
metallic salts. Within
that field, the present invention relates most particular to novel sulfonation
processes for
15 preparing the zonisamide intermediate of benzisoxazole acetic acid and the
crystalline forms
thereof.
BACKGROUND OF THE INVENTION
2o Zonisamide is known as 1,2-benzisoxazole-3-methane sulfonamide or 3-
(sulfamoylmethyl)-1,2-benzisoxazole. It has the following chemical formula:
O
25 ~ ~ ~NO~~O
~/SwNH2
Zonisamide is currently available as an anti-epileptic agent which possesses
anti-
convulsant and anti-neurotoxic effects.
Several routes for zonisamide synthesis have been described in the literature.
Two of
these synthesis routes start from 4-hydroxy-coumarin via benzisoxazole acetic
acid
(hereinafter; BOA) and sodium salt of benzisoxazole methane sulfonic acid
(hereinafter;
BOS-Na).
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
Scheme 1 represents the first route for zonisamide synthesis. In this route,
the
zonisamide intermediate (BOA) is brominated followed by substitution of the
bromine by
sodium sulfite to give the advanced intermediate sodium salt of BOS (BOS-Na)
as shown as
follows:
OH
/ \ NHzOH HC1 / ~ Br
2
NaB O I ~ N AcO~I-
\ O O \
COOH
/ O / O
I N H2~ I N
\ ~ D \
~COOH Br
B
/ ~ aq.Na2S03 / ~ POCK
\ I ~ N MeOH, SOC \ I ~ N r~
O 3 hrs
Br S~O Na'~'
O
/ ~ 1) ~1c/NH3(P~ /
\ I ~ N 2) crystEtAc \ I N
O O
~CI S~Ng2
O O
Scheme 1
The sulfonation reaction of the zonisamide intermediate (i.e., BOA) with
chlorosulfonic acid (in this case the reagent used also is the reaction
solvent) gives the
disulfonated-benzisoxazole-derivative (S-BOS) as the main reaction by-product.
The
synthetic method of the route shown in scheme 1 is a difficult method due to
the great
sensitivity of the reaction product.
The second method described in literature for zonisamide preparation includes
the
preparation of BOA starting from 4-hydroxy-coumarin, followed by the
sulfonation reaction
of BOA to BOS. The sulfonation reaction of the zonisamide intermediate (i.e.,
BOA) may be
carried out with chlorosulfonic acid. The reagent chlorosulfonic acid is used
in a large excess
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
and it is also the reaction solvent. The reactions of this synthetic method
are shown in scheme
2:
OH
/ I \ NH-z~ s / I O N 1) C~ / I O N
\ O~O ~ ~ 2) NaOH \
COOH S03Na
NH3 /
\ I ~ N ----, \ I ~ N
SOZCi ~ NHz
I
Scheme 2
When the reaction is conducted in chlorosulfonic acid, the sulfonation is not
selective.
Disulfonated-benzisoxazole derivateive (S-BOS) is a main product of the
reaction.
The synthetic pathway via the sulfonation reaction of BOA comprises two steps
lesser
as compared to the synthetic pathway via the bromination reaction. In
addition, the
sulfonation reaction requires a large amount of chlorosulfonic acid which
poses undesirable
2o environmental problems.
U.S. Patent No. 4,172,896 by Uno H. et al. (assigned to Dainippon
Pharmaceutical
Co.) describes the preparation of zonisamide using the sulfonating agent
chlorosulfonic acid:
dioxane complex. A similar reagent (503: dioxane complex) is known in the
literature and
was successfully used for the selective sulfonation of the aromatic ketones.
Chlorosulfonic
acid:dioxane is a selective sulfonating reagent and the disulfonated side
products is obtained
in a low quantity. The reaction is shown in scheme 3.
1) C1SO~H/dioxane ~ I ~N
\ ~ N 2) NaOH \
~H S03Na
BOA BOS-Na
Scheme 3
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
Although the sulfonation method using chlorosulfonic acid: dioxane complex is
selective, this method is not safe because of the serious environmental
problem of the dioxane
present in the reaction waste.
There is a continuous need to improve the sulfonation method that is both
convenient
and environmentally safe. The present invention provides an unexpected novel
sulfonation
process to prepare the intermediate of zonisamide.
l0 Neither patents have characterized the existence of any crystalline forms
of this
product. There is a continuing need to investigate crystalline forms of BOS
which can
provide useful intermediates for zonisamide synthesis.
We found that the product of the sulfonation reaction (BOS) may be isolated as
15 sulfonic acid type compound (BOS-H) or as its salt (metallic salts). Not
depending on the
product type form, the reaction mixture is usually treated with water allowing
the isolation of
the product with variable water content. These compounds have the tendency to
give
hydrates.
2o Furthermore, it is generally known that alkyl- and aryl-sulfonic acids and
their salts
can exist as hydrated form (C.M. Suter in "The Organic Chemistry of Sulfur'',
J. Wiley, N.Y.,
1946). The widely-known reagent p-toluene-sulfonic acid can exist as
monohydrate. It is
necessary to develop another method for preparation of the sodium salt of BOS.
SUMMARY OF THE INVENTION
According to one aspect, the present invention provides a sulfonation process
for
preparing benzisoxazole methane sulfonic acid (BOS).
3o Preferably, anhydride and sulfuric acid are employed in preparing
benzisoxazole
methane sulfonic acid (BOS) in a sulfonation process.
4
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
According to another aspect, the present invention provides a sulfonation
process for
preparing benzisoxazole methane sulfonic acid (BOS) employing chlorosulfonic
acid in an
organic solvent.
According to another aspect, the present invention provides a process for
preparing an
intermediate of zonisamide, comprising the steps of
a) preparing a mixture of chlorosulfonic acid and an organic solvent;
b) adding benzisoxazole acetic acid to the mixture;
c) heating the mixture; and
to d) isolating the intermediate of zonisamide.
According to another aspect, the present invention provides a sulfonation
process for
preparing benzisoxazole methane sulfonic acid (BOS) employing acyl-sulfates or
in situ
prepared acyl-sulfates. In situ prepared acyl-sulfates may be obtained from
anhydrides and
i5 sulfuric acid (HzS04), acyl-halides and HZS04, or carboxylic acids and
H2S04.
Most preferably, acetic anhydride and sulfuric acid are employed in preparing
benzisoxazole methane sulfonic acid in a sulfonation process.
2o According to another aspect, the present invention provides a process for
preparing an
intermediate of zonisamide, comprising the steps of
a) preparing an acyl sulfate in a solution;
b) adding benzisoxazole acetic acid to the solution wherein the benzisoxazole
acid is
sulfonated by the acyl sulfate to form the intermediate of zonisamide;
25 c) heating the solution; and
d) isolating the intermediate of zonisamide.
According to another aspect, the present invention a process for preparing an
intermediate of zonisamide, comprising the steps of
3o a) preparing a mixture of benzisoxazole acetic acid and an anhydride in a
solvent to
form a mixture;
b) preparing an acyl sulfate in the mixture wherein the benzisoxazole acid is
sulfonated by the acyl sulfate to form the intermediate of zonisamide;
c) heating the mixture; and
5
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
d) isolating the intermediate of zonisamide.
According to another aspect, the present invention provides benzisoxazole
methane
sulfonic acid substantially free of disulfonated benzisoxazole derivatives.
According to another aspect, the present invention provides zonisamide
substantially
free of disulfonated benzisoxazole derivatives.
According to another aspect, the present invention provides zonisamide
substantially
to free of impurities and without the use of dioxane.
The present invention generally relates to the crystalline forms of
benzisoxazole
methane sulfonic acid (BOS-H) and its salts.
15 The present invention provides the crystalline forms of BOS with a metal
cation.
Preferably, the present invention provides the crystalline forms of BOS-Na,
BOS-Ca, and
BOS-Ba. Other metallic salts include, but not limited to, potassium,
magnesium, lithium,
manganese, cobalt, iron, copper, nickel, zinc, silver and the like.
2o The present invention relates to the zonisamide intermediate BOS in the
form of acid
and metallic salts which are useful in the zonisamide synthesis.
The present invention provides the hydrated crystalline forms of BOS-H and its
salts
as intermediates in the zonisamide synthesis.
The present invention provides a novel crystal form of BOS-Na Form I,
characterized
by an X-Ray Powder Diffraction (XRD) having the most characteristic peaks at
about 5.0,
17.3, 18.0, 18.6, and 19.7 ~ 0.2 degrees two theta.
The present invention provides a novel crystal form of BOS-Na Form I,
characterized
by an X-Ray Powder Diffraction (XRD) having the main peaks at about 5.0, 15.7,
16.5, 17.3,
18.6, 19.1, 19.7, 21.5, 22.8, 23.2, 23.5 and 24.3 ~ 0.2 degrees two theta.
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
The present invention provides a novel crystal form of BOS-Na Form I,
characterized
by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the most
characteristic
peaks at about 3546, 3485, 3440, 1641, 669 and 593 cm 1.
The present invention provides a novel crystal form of BOS-Na Form I,
characterized
by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the
following peaks at
about 3546, 3485, 3440, 1612, 1513, 1439, 1410, 1382, 1234, 1199, 1048, 918,
855, 760, 669
and 593 cm'.
to The present invention provides a novel crystal form of BOS-Na Form I having
a water
content of about 7%.
The present invention provides a novel crystal form of BOS-Na Form II,
characterized
by an X-Ray Powder Diffraction (XRD) having the main peaks at about 5.3, 16.6,
21.3 and
is 26.7 ~ 0.2 degrees two theta.
The present invention provides a novel crystal form of BOS-Na Form II,
characterized
by an X-Ray Powder Diffraction (XRD) having the most characteristic peaks at
about 5.3,
15.9, 16.6, 21.3 and 26.7~ 0.2 degrees two theta.
The present invention provides a novel crystal form of BOS-Na Form II,
characterized
by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the
following peaks at
about 3597, 3535, 3496, 3067, 2998, 2951, 1606, 1516, 1438, 1382, 1213, 1064,
1055, 743,
663, 588, 541 and 522 cm'1.
The present invention provides a novel crystal form of BOS-Na Form II having a
water content of about 1.8%.
The present invention provides a novel crystal form of BOS-Na Form III,
3o characterized by an X-Ray Powder Diffraction (XRD) having the most
characteristic peaks at
about 5.0, 5.3, and 17.8 t 0.2 degrees two theta.
7
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
The present invention provides a novel crystal form of BOS-Na Form III,
characterized by an X-Ray Powder Diffraction (XRD) having the main peaks at
about 5.0,
5.3, 15.7, 17.8 and 21.4 ~ 0.2 degrees two theta.
The present invention provides a novel crystal form of BOS-Na Form III,
characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum
having the most
characteristic peaks at about 3604, 1065, 812 and 696 cm 1.
The present invention provides a novel crystal form of BOS-Na Form III,
l0 characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum
having the
following peaks at about 3604, 3495, 3067, 2998, 2951, 1605, 1516, 1438, 1382,
1215, 1136,
1065, 1052, 777, 747, 696, 588 and 521 cm'.
The present invention provides a novel crystal form of BOS-Na Form V,
characterized
15 by an X-Ray Powder Diffraction (XRD) having the main peaks at about 6.7,
10.9, 16.1, 21.0,
21.2 and 22.2 ~ 0.2 degrees two theta.
The present invention provides a novel crystal form of BOS-Na Form V,
characterized
by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the most
characteristic
2o peaks at about 3601, 3520, 1587, 1055, 793, and 753 cm 1.
The present invention provides a novel crystal form of BOS-Ba Form V having a
water content of less than about 1.5%.
25 The present invention provides a novel crystal form of BOS-Ba Form I,
characterized
by the following X-Ray Diffraction main peaks at about 5.2, 10.4, 12.0, 13.8,
15.6, 17.0, 23.9
and 25.4~ 0.2 degrees two theta.
The present invention provides a novel crystal form of BOS-Ba Form I,
characterized
3o by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the
following peaks at
about 3544, 3491, 2985, 2943, 1626, 1610, 1509, 1437, 1383, 1369, 1223, 1209,
1175, 1153,
1055, 1043, 911, 869, 752, 651, 603, 543 and 5llcrri'.
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
The present invention provides a novel crystal form of BOS-Ba Form I having a
water
content about 3.5%.
The present invention provides a novel crystal form of BOS-Ca Fonn I,
characterized
by having the following X-Ray Diffraction main peaks at about 5.4, 11.7, 16.0,
16.7, 17.7,
18.1, 19.1, 20.8, 24.5, 24.9 and 29.2t 0.2 degrees two theta.
The present invention provides a novel BOS-H monohydrate Form I, characterized
by
having the following X-Ray Diffraction main peaks at about 13.8, 14.4, 17.4,
17.8, 21.8, 22.2,
l0 25.8, 27.8 ~ 0.2 degrees two theta.
The present invention provides a novel BOS-H monohydrate Form I having a water
content about 7.6%.
15 The present invention provides a novel process for preparing a BOS-H Form
I. The
present invention further provides a process of preparing a BOS-H Form I,
comprising the
steps of 1) preparing a mixture of chlorosulfonic acid in an organic solvent;
2) adding BOA
to the mixture; 3) treating the mixture with NaOH to raise pH; and 4)
isolating the BOS-H
Form I.
The present invention provides a novel process for preparing a BOS-Na Form I.
The
present invention further provides a process of preparing a BOS-Na Form I,
comprising the
steps of 1) preparing a mixture of chlorosulfonic acid in an organic solvent;
2) adding BOA
to the mixture; 3) treating the mixture with NaOH to raise pH; and 4)
isolating the BOS-Na
Form I.
The present invention provides a novel process for preparing a BOS-Na Form I.
The
present invention further provides a process of preparing a BOS-Na Form I,
comprising the
steps of 1) preparing a mixture of an anhydride and sulfuric acid to form acyl-
sulfate in the
presence of an organic solvent; 2) adding BOA to the mixture; 3) treating the
mixture with
NaOH to raise pH; 4) cooling the mixture to form a precipitate; S) drying the
precipitate; and
6) keeping the dry precipitate at room temperature to obtain the BOS-Na Form
I.
9
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
The present invention provides a novel process for preparing a BOS-Na Form II.
The
invention further provides a process of preparing a BOS-Na Form II, comprising
the steps of
1) preparing a mixture of an anhydride and sulfuric acid to form acyl-sulfate
in the presence
of ethyl acetate; 2) adding BOA to the mixture; and 3) treating the mixture
with NaOH to
raise pH; 4) cooling the mixture to form a precipiate; and 5) drying the
preciptate at 80°C to
obtain the BOS-Na Form II.
The present invention provides a novel process for preparing BOS-Na Form III.
The
present invention further provides a method of preparing a BOS-Na Form III,
comprising the
1o steps of I) preparing a mixture of an anhydride and sulfuric acid to form
acyl-sulfate in the
presence of toluene; 2) adding BOA to the mixture; 3) treating the mixture
with NaOH to
raise pH; 4) cooling the mixture to form a precipitate; and 5) drying the
preciptate at 80°C to
obtain the BOS-Na Form III.
15 The present invention provides a novel process for preparing a BOS-Na Form
V. The
present invention further provides a method of preparing a BOS-Na Fonm V,
comprising the
steps of I) preparing a mixture of an anhydride and sulfuric acid to form acyl-
sulfate; 2)
adding BOA to the mixture; 3) treating the mixture with NaOH to raise pH; 4)
cooling the
mixture to form a precipitate; and 5) drying the preciptate at about
85°C to obtain the BOS-Na
20 Form V.
The present invention provides a novel process for preparing BOS-Ba Form I.
The
present invention further provides a method of preparing a BOS-Ba Form I,
comprising the
steps of 1) preparing a mixture of chlorosulfonic acid and an organic solvent;
2) adding BOA
25 to the mixture; 3) treating the mixture with Ba(OH)2, and 4) isolating the
BOS-Ba Form I.
The present invention provides a novel process for preparing a BOS-Ca Form I.
The
present invention further provides a method of preparing a BOS-Ca Form I,
comprising the
steps of 1) preparing a mixture of chlorosulfonic acid and an organic solvent;
2) adding BOA
30 the mixture; 3) treating the mixture with Ca(OH)2; and 4) isolating the BOS-
Ca Form I.
BRIEF DESCRIPTION OF THE DIAGRAMS
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
Fig. 1 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Na
monohydrate novel
Form I.
Fig. 2 depicts the Furier Transform Infra Red Spectroscopy (FTIR) spectrum of
BOS-Na
novel Form I.
Fig. 3 depicts the Differential Thermal Gravimetry (DTG) of BOS-Na novel Form
I.
Fig. 4 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Na novel
Form II.
Fig. 5 depicts the Furier Transform Infra Red Spectroscopy (FTIR) spectrum of
BOS-Na
novel Form II.
Fig. 6 depicts the Differential Thermal Gravimetry (DTG) of BOS-Na novel Form
II.
1o Fig. 7 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Na novel
Form III.
Fig. 8 depicts the Furier Transform Infra Red Spectroscopy (FTIR) spectrum of
BOS-Na
novel Form III.
Fig. 9 depicts the Differential Thermal Gravimetry (DTG) of BOS-Na novel Form
III.
Fig. 10 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Na novel
Form V.
Fig. 11 depicts the Furier Transform Infra Red Spectroscopy (FTIR) spectrum of
BOS-Na
novel Form V.
Fig. 12 depicts the Differential Scanning Calorimetry (DSC) of BOS-Na novel
Form V.
Fig. 13 depicts the Thermal Gravimetric Analysis (TGA) thermogram of BOS-Na
novel Form
V.
2o Fig. 14 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Ba novel
Form I.
Fig. 15 depicts the Furier Transform Infra Red Spectroscopy (FTIR) spectrum of
BOS-Ba
novel Form I.
Fig. 16 depicts the Differential Thermal Gravimetry (DTG) of BOS-Ba novel Form
I.
Fig. 17 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Ca novel
Form I.
Fig. 18 depicts the Differential Thermal Gravimetry (DTG) of BOS-Ca novel Form
I.
Fig. 19 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-H
monohydrate novel
Form I.
Fig. 20 depicts the Differential Thermal Gravimetry (DTG) of BOS-H monohydrate
novel
Form I.
DETAILED DESCRIPTION OF THE INVENTION
As used throughout the text, the following abbreviations are used:
benzisoxazole
acetic acid (BOA); benzisoxazole-methane-sulfonic acid (BOS); sodium salt of
benzisoxazole-methane-sulfonic acid (BOS-Na); calcium salt of benzisoxazole-
methane-
n
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
sulfonic acid (BOS-Ca); barium salt of benzisoxazole-methane-sulfonic acid
(BOS-Ba);
sulfuric acid (HZS04), chlorosulfonic acid (C1S03H), disulfonation product (S-
BOS); tertiary-
butyl alcohol (t-BuOH).
As used herein, the term "substantially free" refers to less than 2-5%. Room
temperature refers to ambient temperature.
As used herein, the term "TGA" refers to thermogravimetric analysis. The Karl
Fisher
assay for determining water content is well known and is described in
Pharmacopeial Form,
to Vol. 24, No. 1, p.5438 (Jan.-Feb. 1998). Such an assay permits the
determination of water
content of a crystal form based on the Loss on Drying Method. TGA is a measure
of the
thermally induced weight loss of a material as a function of the applied
temperature.
As used herein, the term "FTIR" refers to Furier Transform Infra Red
Spectroscopy.
15 FTIR is a well-known spectroscopy analysis in which absorption of IR energy
by the sample
results from transitions between molecular vibrational energy levels. FTIR is
used, in modem
practice, mainly for identification of functional groups in the molecule.
However, different
polymorphic forms also show differences in FTIR. The FTIR spectra were
collected using
Diffuse Reflectance Technique; scanning range: 4000-400crri 1, 16 scans,
resolution: 4.Ocrri 1.
The present invention relates to more convenient methods for sulfonation of
benzisoxazole acetic acid (BOA). The sulfonation process involves a reaction
that does not
use dioxane and eliminates the problem of the waste.
The present sulfonation method relates to the sulfonation reaction of
benzisoxazole
acetic acid using chlorosulfonic acid in organic solvents like dichloroethane,
dichloromethane,
toluene, ethylene glycol-dimethylether or heptane using a slight excess of the
sulfonating
reagent. Under such conditions, the sulfonation reaction is selective.
3o The present sulfonation reaction solvent may be a polar solvent like ethyl-
acetate,
dichloroethane, t-BuOH, or a non-polar solvent like hexanes, heptane,
cyclohexane, toluene,
dichlorobenzene or mixture thereof.
12
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
The present invention has the advantage of the sulfonation reaction using
chlorosulfonic acid wherein the reaction is selective and proceeds mainly in
the alpha position
of benzisoxazole acetic acid. The disulfonated product is obtained at a level
of about 2-5%.
The present invention also provides a process for preparing benzisoxazole
methane
sulfonic acid (BOS) employing acyl-sulfates or in situ prepared acyl-sulfates.
In situ prepared
acyl-sulfates may be obtained from anhydrides and sulfuric acid, acyl-halides
and sulfuric
acid, or carboxylic acids and sulfuric acid; all organic acids including fatty
acids may react in
this way.
A more preferred sulfonation process involves the use of the acyl-sulfates
obatined
from anhydrides and HzS04 or acyl-halide and H2S04. Examples of acyl-sulfates
of a
practical interest include acetyl-sulfate (obtained from Ac20/HZS04 or
acetylchloride/H2S04),
propionyl-sulfate, butyryl-sulfate or other acyl-sulfate (obtained in the same
manner from the
corresponding anhydride or acyl-halide and HZS04) which are more economics and
more easy
to handle.
The more preferred method uses acetic anhydride and sulfuric acid (H2SO4). The
more preferred sulfonating reagent "anhydride acetic/HZS04" is economic, easy
for handling,
2o and excludes the use of dioxane.
The sulfonation process using acyl-sulfates is even more selective than that
of
chlorosulfonic acid in organic solvent. The selective sulfonation proceeds
preferentially in the
alpha position and the disulfonated side-product is obtained at a low level up
to 1 %.
The sulfonation process for the Ac20/HZS04 involves a reaction that is
performed in
polar and non-polar solvents. The polar solvents include ethylacetate,
ethylcellosolve,
methylcellosolve, dichloroethane, dichloromethane, chloroform or mixture
thereof and the
like. The non-polar solvents include toluene, heptane, hexanes, alkanes or
mixtures thereof
and the like.
We observed that the product of the sulfonation reaction in the zonisamide
process
may be obtained with a variable water content. This observation is valid for
BOS-H and its
salts also.
13
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
The present invention provides new crystal forms of BOS. The polymorphic
modification of this zonisamide intermediate are chemically identical, but
exhibit differences
in their physical properties such as X-Ray Diffractrogram, Furier Transfrnm
Infra Red
Spectroscopy and etc.. Differences in mechanical behavior or in the
dissolution properties of
different polymorphic modifications can significantly influence the ease of
processing or the
bioavailability of these compounds. It is desirable to obtain various crystal
or polymorphic
forms of zonisamide intermediates.
to We observed BOS is a hygroscopic compound. We fiu-ther observed that BOS-H
is a
more hygroscopic compound than its alkaline or earth-alkaline salts.
Practically, it is
recommended to isolate the product as salt rather than the free sulfonic acid.
BOS-H and its salts are readily soluble in water and this makes difficult
their
15 separation from the reaction mixture.
However, the salts of sulfonic acid are less water-soluble than the inorganic
salts and it
is preferable to proceed to the conversion of sulfonic acid into its salt
(sodium, calcium or
barium salt) and to isolate them by salting out with an inorganic salt.
The salts of BOS having a practical interest include generally alkaline salts
and earth-
alkaline salts. Examples of BOS salts include sodium (Na), potassium (K),
calcium (Ca),
barium (Ba), and Magnesium (Mg). In general, BOS is a strong acid having
approximately
the same strength as HZS04 and can forms salts with various cations including
silver (Ag),
2s cadium (Ca), zinc (Zn), mercury (Hg), and aluminium (Al).
The present invention further provides a crystalline form of benzisoxazole
methane
sulfonic acid wherein the metal cation is selected from sodium, calcium,
barium, potassium,
magnesium, lithium, manganese, cobalt, iron, copper, nickel, zinc, and silver.
BOS-H and its sodium (Na-), calcium (Ca-) or barium (Ba-) salts are usually
obtained
from the reaction with 1-2 % water content but they can absorb water from the
medium until
the hydrate is obtained.
14
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
The present invention is described in details with reference to examples. The
present
invention is by no means restricted to these specific examples. The
experiments of the
invention are summarized in the following table.
SYNTHESIS OF THE ZONISAMIDE INTERMEDIATE BOS)
Ex. Reagent, eq. nr/solventReaction Sample Purity
Nr. profile
HPLC,
conditions: type % ~'ea,
BOS-Na
S-BOS
BOA
Temp., time
TN 1.3 eq. C1S03H/dichloro-Reflux, 1.5 Reaction90 5.4 0.4
2410 hours
ethane mixture
Isolated99.8 0.15
product
TN 1.3 eq. 50C, 20 hoursReaction58 34
2404
CIS03H/Ethylenglycol- mixture
dimethyl-ether Isolatedn.a. n.a. n.a.
product
TN 1.3 eq. 65C, 3 hours Reaction95 1.8 3.1
2409
C1S03H/Heptane+dichloro- mixture
ethane Isolated99.5 0.15 0.4
product
TN 1.7 eq. C1S03H/TolueneReflux, 20 Reaction63.5 3 32
2412 hours
mixture
TN 1.3 eq. Ac20/HZSO~/dichloro-75C, 2 hours Reaction85.5 0.8 0.1
2394
ethane mixture
TN 2.7 eq. AcZO/HZSO4/Tol.Reflux, 9 Reaction83.4 n.d. 10.7
2396 hours
mixture
Isolated92.4 n.d. 4.5
product
TN 1.3 eq. Ac20/HZSO4/Heptane90C, 1 hours Isolated98.4 n.d. 1.5
2400
product
TN 1.3 eq. Ac20/H2S0~/dichloro-100C, 1.5 Reaction98.5 0.2 0.2
2402 hour
benzene mixture
Isolated99.7 n.d. 0.2
product
TN 1.3 eq. AczO/HZSO4/EtOAc~90C, 4 hoursReaction99.2 0.5 n.d.
2431
mixture
Isolated100
product
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
TN 24301.3 eq. AczO/HZSOq/EtOAc~90C, 4 Reaction99.1 0.5 n.d.
hours
reverse addition mixture
of the
reagents:H2S04 added Isolated100
to the
reaction mixture product
n.a. not analyzed
n.d. not detected
Exuerimental Procedures
Example 1: Preparation of BOS-Na : Ac20/ H~S04 in ethyl-acetate
In a 250 mL reactor, equipped with thermometer, mechanical stirrer and
condenser
was charged ethyl acetate (80 mL),H2S04, 98% (22 grams, 1.3 eq.) and acetic
anhydride (23
grams, 1.3 eq.) and the mixture was cooled to -5°C.
To the above mixture, BOA was added (20 grams, 1 eq.). The reaction was then
heated to reflex and the reflex was continued for 4 hours. After the reaction
completion the
1o reaction mixture was cooled to the room temperture and aqueous NaOH (10%)
was added
(120 mL). Upon stirnng, the product precipitates as sodium salt. After 2 hours
the product
was filtrated, washed with ethyl acetate (2x 25 mL) and dried in vacuum-oven
at ~80 °C. The
yield was 20.33 grams BOS-Na having 100% purity by HPLC).
Example 2: Preparation of BOS-Na: Ac20/ H2S04 in ethyl acetate by drop-wise
addition of
HzS04
In a 250 mL reactor, equipped with thermometer, mechanical stirrer and
condenser
was charged ethyl acetate (80 mL), acetic anhydride (23 grams, 1.3 eq.) and
BOA (20 grams,
1 eq.). The mixture was cooled to above -5°C.
Maintaining the temperature below 0 °C, H2S04 , 98% (22 grams, 1.3 eq.)
was added
drop-wise (the addition required about 20 min.). Then the reaction mixture was
stirred at
reflex for 4 hours. When the reaction was completed the mixture was cooled to
room
temperature and aqueous NaOH (10%) was added (120 mL). After 2 hours stirring
at room
temperature, the reaction product was filtrated , washed with ethyl acetate
(2x25 mL) and
dried in vacuum-oven ~80 °C. The yield was 20.21 grams of BOS-Na that
has a 100% purity.
Example 3: Preparation of BOS-Na: AczO/ HZS04 in toluene
16
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
In a 100 mL three necked flask, equipped with thermometer, condenser and
mechanical stirrer was charged toluene (40 mL), H2S04 ,98% (2 mL, 1.3 eq.) and
acetic
anhydride (3.5 mL, 1.3 eq.) at room temperature.
Then, benzisoxazole acetic acid (BOA) was added (5 grams) and the reaction
mixture
was heated to reflex. The reflex was continued for about 4.5 hours. To the
chilled reaction
mixture, more reagent was added (2 mL H2S04, 98% and 3.5 mL acetic anhydride)
and the
heating was continued for additional 4 hours. After cooling of the reaction
mixture to room
temperature, ice was added and the mixture was stirred. The organic phase was
discarded and
1o to the aqueous phase solid NaOH was added (7.5 grams). The product
precipitates upon
cooling at ~5 °C; the solid was filtrated, washed with toluene and
dried in vacuum-oven at ~80
°C. The yield was 7.6 g BOS-Na with 92.4% purity on HPLC.
Example 4: Preparation of BOS-Na: CIS03H in dichloroethane
In a 100 mL three necked flask, equipped with thermometer, condenser and
mechanical stirrer was charged dichloroethane (25 mL), 2.5 mL C1S03H (1.3
eq.), and BOA
(S grams). The reaction mixture was heated at reflex for 1.5 hours.
Water was added (30 mL) and the phases were separated. To the aqueous phase,
solid
2o NaOH was added (3.5 grams) and the product was filtrated, washed with
dichloroethane
(2x10 mL) and dried in cooling at ~5 °C. The solid was filtrated ,
washed with toluene and
dried in vacuum to affords 5.11 grams BOS-Na, 98.5% purity on HPLC.
Example 5: Preparation of zonisamide from BOS-Na
In a 250 mL three necked flask, equipped with thermometer, mechanical stirrer
and
condenser was charged POC13 (60 mL) and BOS-Na (19 grams). The reaction
mixture was
heated to reflex and the reflex was maintained for three hours. The excess of
POC13 was
distilled and to the obtained residue was added ethyl-acetate. After a few
minutes of stirring,
the solids were filtered and washed with ethyl-acetate. The solution of ethyl-
acetate contains
3o the product 1,2-benzisoxazole methane sulfonyl chloride.
To the chilled solution of the product in ethyl-acetate (~5°C), ammonia
gas was
bubbled until the solution reached pH 12. The solids were filtered and washed
with ethyl-
17
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
acetate. The combined solutions of ethyl-acetate were evaporated on rotovapor
to afford the
product zonisamide (14.88 grams).
CRYSTALLINE FORMS OF THE ZONISAMIDE INTERMEDIATE BOS):
CHARACTERIZATION
Novel Crystal Forms of BOS-Na
BOS-Na Novel Form I
BOS-Na monohydrate novel form I was characterized by X-Ray Powder Diffraction
(XRD),
Furier Transform Infra Red Spectroscopy (FTIR), Differential Thermal
Gravimetry (DTG),
and Karl-Fischer titration (KF).
XRD
BOS-Na monohydrate novel form I is characterized by the following X-Ray
Diffraction main
peaks at about 5.0, 15.7, 16.5, 17.3, 18.6, 19.1, 19.7, 21.5, 22.8, 23.2, 23.5
and 24.3 ~ 0.2
degrees two theta. The most characteristic XRD peaks at about 5.0, 17.3, 18.0,
18.6, 19.7 t
0.2 degrees two theta.
X-Ray Powder Diffraction pattern is given in Fig. 1.
FTIR
FTIR spectrum of BOS-Na novel form I is characterized by the following peaks
at about
3546, 3485, 3440, 1612, 1513, 1439, 1410, 1382, 1234, 1199, 1048, 918, 855,
760, 669 and
593 cm 1. The most characteristic FTIR peaks at about 593, 669, 1641, 3440,
3485 and 3546
cm'.
FTIR spectrum of BOS Na novel form I is given in Fig. 2
DTG
The combined DTA and TGA profiles of Bos-Na form I is characterized by an
endothermic
peak at about 100°C. The TGA curve shows a weight loss step of about 7%
in this
temperature range. This weight loss step is due to water released out of the
sample.
DTG profile is given in Fig. 3.
~8
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
KF
Water content measured by Karl-Fischer (KF) method is in agreement with TGA
weight loss
step and is about 7%. This water content is coincident with the expected water
content of
monohydrate.
BOS-Na Novel Form II
BOS-Na novel form II was characterized by X-Ray Powder Diffraction (XItD),
Furier
Transform Infra Red Spectroscopy (FTIR) and Differential Thermal Gravimetry
(DTG).
XRD
BOS-Na novel form II is characterized by the following X-Ray Diffraction main
peaks at
about 5.3, 15.9, 16.6, 21.3 and 26.7~ 0.2 degrees two theta. The most
characteristic XRD
peaks are at about 5.3, 16.6, 21.3, and 26.7 ~ 0.2 degrees two theta.
X-Ray Powder Diffraction pattern is given in Fig. 4.
FTIR
FTIR spectrum of BOS-Na novel form II is characterized by the following peaks
at about
3597, 3535, 3496, 3067, 2998, 2951, 1606, 1516, 1438, 1382, 1213, 1064, 1055,
743, 663,
588, 541 and 522 cm 1. The most characteristic FTIR peaks are at 3571 and 3597
cm 1.
FTIR spectrum of BOS-Na novel form II is given in Fig. 5.
DTG
DTG profile is given in Fig. 6.
DTG profile of BOS-Na novel form II is characterized by three endothermic
peaks at about
243, 265 and 278°C. The sharp weight loss in this temperature range is
due to decomposition
of the sample.
19
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
BOS-Na Novel Form III
BOS-Na novel form III was characterized by X-Ray powder diffraction (XRD),
Furier
Transform Infra Red Spectroscopy (FTIR) and Differential Thermal Gravimetry
(DTG).
XRD
BOS-Na novel form III is characterized by the following X-Ray Diffraction main
peaks at
about 5.0, 5.3, 15.7, 17.8 and 21.4~ 0.2 degrees two theta. The most
characterisitc XRD
peaks are at about 5.0, 5.3, and 17.8 ~ 0.2 degrees two theta.
X-Ray Powder Diffraction pattern is given in Fig. 7.
FTIR
FTIR spectrum of BOS-Na novel form III is characterized by the following peaks
at about
3604, 3495, 3067, 2998, 2951, 1605, 1516, 1438, 1382, 1215, 1136, 1065, 1052,
777, 747,
696, 588 and 521 cm 1. The most characteristic FTIR peaks are at about 696,
812, 1065 and
3604 cm I.
FTIR spectrum of BOS-Na novel form III is given in Fig. 8.
DTG
2o DTG profile is given in Fig. 9.
DTG profile of BOS-Na novel form III is characterized by an endothermic peak
at about
233°C. The sharp weight loss in this temperature range is due to
decomposition of the
sample.
BOS-Na Novel Form V
BOS-Ba novel form V was characterized by X-Ray Powder Diffraction (XRD),
Furier
Transform Infra Red Spectroscopy (FT1R), Differential Scanning Calorimetry,
and Thermal
Gravimetric Analysis (TGA).
XRD
XRD analysis were performed X-Ray powder diffractometer, Scintag, variable
goniometer,
Cu-tube, solid state detector. Sample holder: A round standard aluminum sample
holder with
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
round zero background quartz plate. Scanning parameters: Range: 2-40 degrees
two theta.
Continuous scan rate: 3 deg./min.
BOS-Na novel form V is characterized by the following X-Ray Diffraction main
peaks at
about 6.7, 10.9, 16.2, 21.0, 21.2 and 22.2~ 0.2 degrees two theta.
X-Ray Powder Diffraction pattern is given in Fig. 10.
FTIR
to FTIR spectrum was collected on Perkin-Elmer Spectrum One FTIR spectrometer
using
Diffused Reflectance technique. Scanning range: 400-4000 cm'I, number of
scans: 16,
resolution: 4.0 cm 1.
FTIR spectrum of BOS-Na novel form V is characterized by the following peaks
at about
753, 793, 1055, 1587, 3520 and 3601 cm''.
FTIR spectrum of BOS-Na novel form V is given in Fig. 11.
DSC
2o DSC 821e, Mettler Toledo instrument was used for the DSC analysis. Sample
weight: 3-5 mg.
Heating rate: 10°C/min. Number of holes in the crucible:3.
DSC profile is characterized by two overlapped endothermic peaks at about
164°C.
DSC profile of BOS-Na noevl form V is given in Fig. 12.
TGA
Mettler TG50 instrument was used for the TGA analysis. Heating rate:
10°C/min. Nitrogen
flow: 40 ml/min.
TGA thermogram shows LOD value of about 2% in a temperature range of up to
190°C.
TGA thermogram of BOS-Na form V is given in Fig. 13.
21
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
Novel Crystal Form of BOS-Ba
BOS-Ba Novel Form I
BOS-Ba novel form I was characterized by X-Ray Powder Diffraction (XRD),
Furier
Transform Infra Red Spectroscopy (FTIR) and by Differential Thermal Gravimetry
(DTG).
XRD
BOS-Ba novel form I is characterized by the following X-Ray Diffraction main
peaks at
about 5.2, 10.4, 12.0, 13.8, 15.6, 17.0, 23.9 and 25.4~ 0.2 degrees two theta.
1o X-Ray Powder Diffraction pattern is given in Fig. 14.
FTIR
FTIR spectrum of BOS-Ba is characterized by the following peaks at about 3544,
3491, 2985,
2943, 1626, 1610, 1509, 1437, 1383, 1369, 1223, 1209, 1175, 1153, 1055, 1043,
911, 869,
752, 651, 603, 543 and 511 cm'.
FTIR spectrum is given in Fig. 1 S.
DTG
2o DTG profile of BOS-Ba novel form I is characterized by an endothermic peak
at about 200°C.
A weight loss step of about 3.5% is observed in this temperature range.
DTG thermogram of BOS-Ba novel form I is given in Fig. 16.
Novel Crystal Form of BOS-Ca
BOS-Ca Novel Form I
BOS-Ca novel form I was characterized by X-Ray Powder Diffraction (XRD) and by
Differential Thermal Gravimetry (DTG).
XRD
BOS-Ca novel form I is characterized by the following X-Ray Diffraction main
peaks at about
5.4, 11.7, 16.0, 16.7, 17.7, 18.1, 19.1, 20.8, 24.5, 24.9 and 29.2~ 0.2
degrees two theta.
X-Ray Powder Diffraction pattern is given in Fg. 17.
22
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
DTG
DTG profile of BOS-Ca novel form I is characterized by two endothermic peaks
at about 137
and 165°C. The LOD up to 200°C is about 7.6%.
DTG themogram of BOS-Ca novel form I is given in Fig. 18.
Novel Crystal Form of BOS-H
BOS-H Novel Form I
1o BOS-H monohydrate novel form I was characterized by X-Ray Powder
Diffraction (XRD),
by Differential Thermal Gravimetry (DTG) and by Karl-Fischer titration (KF).
XRD
BOS-H novel monohydrate novel form I is characterized by the following X-Ray
Diffraction
main peaks at about 13.8, 14.4, 17.4, 17.8, 21.8, 22.2, 25.8, 27.8 ~ 0.2
degrees two theta.
X-Ray Powder Diffraction pattern is given in Fig. 19.
DTG
2o DTG profile of BOS-H monohydrate novel form I is characterized by two
endothermic peak
at about 120 and 175°C. A weight loss step of about 9% is observed in
this temperature
range.
DTG thermogram of BOS-H monohydrate novel form I is given in Fig. 20.
KF
Water content of BOS-H novel form I as was measured by KF titration is about
7.6%. This
value is coincident with the expected water content for monohydrate form.
3o The invention will be better understood from the following experimental
details.
These examples are provided to illustrate specific embodiments of the present
invention but
they are not intended to be limiting in any way.
23
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
Exuerimental Procedure: Preparation of Crystalline Forms of BOS
Preparation of BOS-H Form I
The solution of chlorosulfonic acid (13 ml, 25.5 mmol) in methylene chloride
(100 ml)
was cooled to~-10°C. Dioxane (22.5 grams, 25.5 mmol) was added at this
temperature
followed by the addition of BOA (30 grams, 16.9 mmol). The obtained slurry was
than
heated at reflux for 2.5 hours. The reaction mixture was stirred at room
temperature over
night and after this was held with ice.
The aqueous phase was extracted with methylene chloride and then evaporated to
dryness on rotavapor. The solid was dried for two days at 60°C and for
~16 hours at 100°C.
1o The product is BOS-H Form I (KF 2.8%).
Preparation of BOS-Na Form I
To the chilled solution (0°C) of chlorosulfonic acid (136 grams, 1.167
mol) in ethyl
acetate (400 ml) was added drop-wise dioxane (103 grams, 1.169 mol) followed
by the
15 addition of BOA (180 grams, 1.017 mol). The mixture was than heated at
about 55°C for
about 16 hours. After the reaction completion, the mixture has been cooled to
room
temperature and ice-water was added. The aqueous phase was treated with
aqueous NaOH
until pH 10.
The product was isolated by evaporation to dryness of the aqueous solution and
n-
20 BuOH. The obtained solid was than dried in oven at 80°C. BOS-Na (271
grams) was
obtained; the solid does not contain water (KF 0.002%). BOS-Na dry was kept in
a closed
bottle at room temperature. After about 5 months the KF analysis (7.3%)
indicates the
formation of hydrate-BOS-Na Form I.
25 Preparation of BOS-Na Form I
To the solution of BOA (5 grams, 28.25 mmol) in ethyl acetate (30 ml) was
added
acetic anhydride (3.75 grams, 36.73 mmol) and sulfuric acid 98% (3.6 grams,
36.73 mmol).
During the addition of sulfuric acid the temperature reached ~30°C.
Then the reaction
mixture had been heated at reflex for 1.5 hour.
30 More sulfonating reagent was added (2.1 grams acetic anhydride and 2 grams
sulfuric
acid) and the reflex was continued for more one hour. The reaction mixture was
then cooled
to room temperature and held with aqueous 10% NaOH (32 ml). The product
precipitates
upon cooling to ~5°C. The solid was washed with ethyl acetate and dried
at 80°C for 2 days.
24
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
The obtained BOS-Na (6.3 grams) contains 1.7% water (by KF). This solid was
exposed to
the laboratory humidity for one week; the obtained solid is BOS-Na Form I.
Preparation of BOS-Na Form II
The solution of acetic anhydride (3.75 grams, 36.73 mmol) and sulfuric acid
98% (3.6
grams, 36.73 mmol) in ethyl acetate (30 ml) has been cooled to -5°C.
BOA (S grams, 28.25
mmol) was added and the reaction mixture had been heated at reflux for ~3
hours.
After cooling to room temperature the reaction mixture was held with aqueous
10%
NaOH and cooled to ~5°C to precipitate the product; the solid was dried
for 2 days in oven at
l0 80°C. BOS-Na (4.9 grams) (KF 1.83%) is BOS-Na Form II.
Preparation of BOS-Na Form III
The solution of acetic anhydride (5.75 grams, 56.32 mmol) and sulfuric acid
98% (5.5
grams, 56.12 mmol) in toluene (30 ml) was cooled to ~0°C. BOA was added
(5 grams, 28.25
15 grams) and the reaction mixture was heated at reflux for 5 hours. More
sulfonating reagent
was added (3 grams acetic anhydride and 2.9 grams sulfuric acid) and the
reflux was
maintained for one additional hour.
The reaction mixture was cooled to room temperature and treated with NaOH
pearls to
precipitate the product upon cooling. The solid was washed with toluene,
filtrated and dried
2o at 80°C for two days. The product is BOS-Na Form III.
Preparation of BOS-Na Form V
The crystalline form was obtained during the production of BOS-Na in
industrial
scale. The preparation of BOS-Na is the laboratory procedure adapted to the
large scale.
25 To the chilled (0°C) solution of acetic anhydride (1.3 eq.) and BOA
in ethylacetate,
H2S04 (1.3 eq.) was added drop-wise.
The reaction mixture was heated at reflux and then stirred at reflux until the
reaction
completion (~5 hours). After this, the mixture was cooled to ~25°C and
treated with NaOH.
Th reaction product precipitatd on cooling to ~5°C. The solid was
filtrated and washed with
30 ethylacetate.
The wet material obtained according to this procedure in the industrial batch
was dried
in an industrial drier:
Vacuum: 30 mmHg
Temperature in the jacket: 85°C
CA 02458905 2004-02-26
WO 03/020708 PCT/US02/27593
Mechanical stirring
Time: Several days until the water content was less than 1.5%.
Preparation of BOS-Ba Form I
To the chilled solution of chlorosulfonic acid (13 ml, 19.5 mmol) in methylene
chloride. 10 ml dioxane (17.25 grams, 16.9 mmol) and BOA (30 grams, 16.9 mmol)
were
added. The reaction mixture was heated at reflux for 4.5 hours.
After this the reaction mixture was cooled to room temperature and ice was
added.
The aqueous phase was extracted with methylene chloride and then held with
Ba(OH)Z (56
1o grams); the solid was filtrated, washed with water and dried in oven at
100°C for 5 hours. The
product is BOS-Ba Form I.
Preparation of BOS-Ca Form I
To the chilled at (-5°C) solution of chlorosulfonic acid (13 ml, 19.5
mmol) in
15 methylene chloride (100 ml) dioxane (17.2 grams, 19.5 mmol) and BOA (30
grams, 16.9
mmol) were added. Then the reaction mixture was heated at reflux for 5 hours.
After the reaction completion, ice was added to the cooled reaction mixture
and the
aqueous phase was treated with Ca(OH)2 until pH 12. The product precipitate
after stirring
for ~16 hours. The solid was filtrated, washed with water and then with hexane
and dried in
20 oven at 60°C. The product is BOS-Ca Form I.
From the above it is clear that the invention provides crystalline forms of
benzisoxazole methane sulfonic acid (BOS-H) and its salts (BOS-Na, BOS-Ca, BOS-
Ba).
The present invention further provides the BOS in its acid form and BOS as
salts, both
25 represent intermediates in the preparation of zonisamide.
It is contemplated that various modifications of the described modes of
carrying out
the invention will be apparent to those skilled in the art without departing
from the scope and
spirit of the invention.
26
