Note: Descriptions are shown in the official language in which they were submitted.
CA 02578559 2007-02-14
~ , .
TITLE OF THE INVENTION
Process for the preparation of zonisamide and the intermediates thereof.
FIELD OF THE INVENTION
The present invention relates to a novel and improved process for the
preparation of zonisamide and the intermediates thereof. In particular, the
present invention relates to a process for the preparation of zonisamide via a
novel crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid,
a
novel chlorination procedure to generate the 1,2-benzisoxazole-3-
methanesulfonyl chloride and a subsequent novel amidation procedure.
BACKGROUND OF THE INVENTION
Zonisamide is known as 1,2-benzisoxazole-3-methanesulfonamide or 3-
(sulfamoylmethyl)-1,2-benzisoxazole and has anti-convulsant as well as anti-
neurotic effects. It is marketed as an anti-epileptic drug (ZONEGRANTM).
The synthesis of zonisamide has been achieved by several routes, most of which
begin by the conversion of 4-hydroxycoumarin into 1,2-benzisoxazole-3-acetic
acid.
Scheme I
OH CO2H
0'_010 NH2OH x HCV O'OrN
Base A variety of bases have been used in this reaction including sodium
methoxide
(generated in situ from sodium metal and methanol; T. Posner, Chem. Ber. , 42,
1909, 2523), pyridine (Mustafa etal., Tetrahedron, 19, 1963, 1831), sodium
acetate (Casini et al., J. Heterocyclic Chem., 1965, 385), alkali carbonates
and
aliphatic amines (United States Patent Application Publication No. US
2002/0183525 Al and International Patent Application Publication No.
WO 02/0705495 A14).
CA 02578559 2007-02-14
2
Two routes have been utilized to convert the 1,2-benzisoxazole-3-acetic acid
intermediate into zonisamide. Scheme 2 depicts the initial route for its
preparation by a bromination, decarboxylation and nucleophilic substitution
sequence to give sodium 1,2-benzisoxazole-3-methanesulfonate (Gianella et al.,
Chimie Therapeutique, 7(2), 1972, 127; and Uno et al., J. Med Chem., 22(2),
1979, 180). This process provides zonisamide in ca. 44% overall yield.
Scheme 2
Br
CO2H COzH Br S03Na
I~ N Br2/HOA c N aq. HzSOa_ I N Na2SO3_ C N
/ O Or / 0 Or
Disadvantages of this process include the fact that the 1,2-benzisoxazole-3-
methylbromide intermediate is a strong lachrymator and therefore it is
undesirable to handle, especially on scale-up. Also, this intermediate is not
very
crystalline and tends to separate as an oil before solidifying thereby leading
to
difficulties with respect to isolation and purification.
Scheme 3 shows the second route by forming sodium 1,2-benzisoxazole-3-
methanesulfonate via sulfonization of 1,2-benzisoxazole-3-acetic acid to 1,2-
benzisoxazole-3-methanesulfonic acid (1).
Scheme 3
COZH S03H SO3Na
N CISO3H (),6 N NaOH (),6N
p I
Originally the chlorosulfonization was carried out using excess chlorosulfonic
acid as a solvent (H. Uno and M. Kurokawa, Chem. Pharm. Bull, 26(11), 1978,
3498). Besides undesired ecological and safety issues that the extremely
corrosive chlorosulfonic acid poses, disulfonization occurs. The removal of
disulfonated product needs additional purification steps which results in loss
of
CA 02578559 2007-02-14
3
material and costs time, solvent and labour, etc. Later it was discovered that
the
use of 1,4-dioxane moderates the reactivity of chlorosulfonic acid thereby
minimizing concomitant side reactions (U.S. Patent No. 4,172,896). However, to
achieve this, the reaction was carried out in 1,2-dichloroethane, which is a
cancer
suspect agent. This solvent poses other safety and environmental problems due
to its flammability and effects on the ozone layer, respectively.
International Patent Application Publication No. WO 03/020708 Al discloses the
chlorination of sodium 1,2-benzisoxazole-3-methanesulfonate with a very large
excess of phosphorous oxychloride (POC13) to form 1,2-benzisoxazole-3-
methanesulfonyl chloride (2) which is isolated and subsequently converted to
zonisamide by treatment with ammonia gas (Scheme 4).
Scheme 4
SO3Na S42CI S42NH2
POCI3 NH3
p' N p ():~ N , ()'OrN
/
2 Zon isamide
The disadvantage of this process is that the very large excess of POC13 (8.1
mol
equivalents) must be removed before isolation of 1,2-benzisoxazole-3-
methanesulfonyl chloride (2) and subsequent conversion to zonisamide. Direct
chlorination of 1,2-benzisoxazole-3-methanesulfonic acid (1) into 1,2-
benzisoxazole-3-methanesulfonyl chloride (2) is not described in WO 03/020708.
In fact, WO 03/020708 teaches that since 1,2-benzisoxazole-3-methanesulfonic
acid (1) is a more hygroscopic compound than its alkaline or earth alkaline
salts,
it is recommended to isolate the product as a salt rather than the free
sulfonic
acid. Further, it is taught in WO 03/020708 that due to differences in their
solubilities, it is preferable to convert the 1,2-benzisoxazole-3-
methanesulfonic
acid (1) into its salts for easier separation from the reaction mixture.
WO 03/020708 also discloses a 1,2-benzisoxazole-3-methansulfonic acid
monohydrate Form I having a water content of about 7.6% (measured by Karl
CA 02578559 2007-02-14
4
Fischer titration). A 1,2-benzisoxazole-3-methanesulfonic acid (1) having a
lower
water content of 2.8% (measured by Karl Fischer titration) was obtained from
the
monohydrate but only after drying under very harsh conditions (drying for two
days at 60 C and for approximately 16 hours at 100 C), and no further details
about the compound are provided in WO 03/020708.
In Japanese unexamined (Kokai) Patent Application No. JP53077057 A2, there
is mention of converting a 3-methanesulfonic acid of the general formula (VII)
X CH2SO3H
(VII)
directly into a methanesulfonic acid halide of the general formula (II)
X I ~CH2SO3Y
N
(1I)
using a halogenating agent, wherein X is a hydrogen atom or a 5- or 6-
position
halogen atom and Y indicates a halogen atom, but no further details about the
3-
methanesulfonic acid (VII) have been given.
International Patent Application Publication No. WO 03/072552 Al discloses the
conversion of sodium 1,2-benzisoxazole-3-methanesulfonate into 1,2-
benzisoxazole-3-methanesulfonyl chloride (2) using thionyl chloride and
catalytic
amounts of N,N-dimethylformamide (DMF). Although the conversion of 1,2-
benzisoxazole-3-methanesulfonic acid (1) to the corresponding 1,2-
benzisoxazole-3-methanesulfonyl chloride (2) is generally mentioned in this
application, experimental details have only been given for the conversion of
the
CA 02578559 2007-02-14
sodium 1,2-benzisoxazole-3-methanesuIfonate and, again, large excesses of
highly corrosive chlorinating agents were used.
Clearly, an industrial process overcoming the deficiencies of the prior art
processes, which would provide zonisamide in a high-yield, cost-effective,
5 environmentally friendlier and safe manner was required.
None of the prior art has characterized the existence of any crystalline forms
of
anhydrous 1,2-benzisoxazole-3-methanesulfonic acid. There is a continuing
need to investigate crystalline forms of 1,2-benzisoxazole-3-methanesulfonic
acid
which can provide useful intermediates for zonisamide synthesis.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a new and improved process
for
the preparation of zonisamide that overcomes the disadvantages of the prior
art
processes.
It is another object of the present invention to provide a novel crystalline
form of
anhydrous 1,2-benzisoxazole-3-methanesulfonic acid and a method for its
preparation, which sulfonic acid type compound is useful as an intermediate in
a
process for the preparation of zonisamide.
It is a further object of the present invention to provide a new process for
the
preparation of 1,2-benzisoxazole-3-methanesulfonyi chloride which process
involves the direct chlorination of the novel crystalline form of anhydrous
1,2-
benzisoxazole-3-methanesulfonic acid with at least one chlorinating agent.
It is still a further object of the present invention to provide a new process
for the
preparation of zonisamide which involves the in situ amidation of 1,2-
benzisoxazole-3-methanesulfonyl chloride with at least one amidating agent.
Further and other objects of the present invention will be realized by those
skilled
in the art from the following summary of the invention and detailed
description of
embodiments thereof.
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6
Through investigations in our laboratory we have found that the product of
sulfonating 1,2-benzisoxazole-3-acetic acid may be isolated as the sulfonic
acid
type compound, namely 1,2-benzisoxazole-3-methanesulfonic acid, in a
crystalline anhydrous form with a water content of less than about 2%.
In accordance with one aspect of the present invention, there is provided a
crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid.
In an embodiment of the present invention, the crystalline form of anhydrous
1,2-
benzisoxazole-3-methanesulfonic acid is characterized by an X-Ray powder
diffraction (XRPD) having the most characteristic peaks at about 9.32 0.2,
13.59 0.2, 13.78 0.2, 18.64 0.2, 22.03 0.2, 22.27 0.2, 25.31 0.2 and
25.56 0.2 degrees two theta.
In another embodiment of the present invention, the crystalline form of
anhydrous
1,2-benzisoxazole-3-methanesulfonic acid has a water content of less than
about
2.0%, preferably about 0.8% to about 1.5%.
In accordance with another aspect of the present invention, there is provided
a
process for preparing a crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid, said process comprising the steps of:
(i) preparing 1,2-benzisoxazole-3-methanesulfonic acid in a reaction
mixture;
(ii) adding at least one anti-solvent to the mixture from step (a) to
precipitate the crystalline form of anhydrous 1,2-
benzisoxazole-3-methanesulfonic acid; and
(iii) isolating the crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid.
In an embodiment of the present invention, the 1,2-benzisoxazole-3-
methanesulfonic acid is prepared by sulfonating 1,2-benzisoxazole-3-acetic
acid
using chlorosulfonic acid in at least one aprotic organic solvent.
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7
In another embodiment of the present invention, the sulfonation of 1,2-
benzisoxazole-3-acetic acid comprises the steps of:
(a) preparing a mixture of 1,2-benzisoxazole-3-acetic acid and at least
one aprotic organic solvent;
(b) adding chlorosulfonic acid to the mixture from step (a); and
(c) heating the mixture from step (b).
In another embodiment of the present invention, the at least one aprotic
organic
solvent is selected from the group consisting of C1-C3 chlorinated solvents
and
C4-C6 cyclic ethers. The C1-C3 chlorinated solvents may be selected from the
group consisting of dichloromethane and dichloroethane and the C4-C6 cyciic
ethers may be selected from the group consisting of tetrahydrofuran and 1,4-
dioxane. In a preferred embodiment of the present invention, the at least one
aprotic organic solvent is 1,4-dioxane.
In another embodiment of the present invention, the chlorosulfonic acid is
added
to the mixture from step (a) in a molar ratio of 1,2-benzisoxazole-3-acetic
acid:chlorosulfonic acid of about 1:1.1.
In another embodiment of the present invention, the mixture from step (b) is
heated to a temperature of about 0 C to about 100 C and preferably about 20 C
to about 80 C.
In another embodiment of the present invention, the at least one anti-solvent
is
selected from the group consisting of C6-C9 aromatic hydrocarbons, C5-C10
aliphatic hydrocarbons, and CI-C3 halogenated hydrocarbons. The C6-C9
aromatic hydrocarbons may be selected from the group consisting of benzene,
toluene, and xylenes; the C5-C10 aliphatic hydrocarbons may be selected from
the group consisting of hexanes, heptanes, and octanes; and the Cl-C3
halogenated hydrocarbons may be selected from the group consisting of
CA 02578559 2007-02-14
8
dichloromethane and dichloroethane. In a preferred embodiment of the present
invention, the at least one anti-solvent is xylenes.
In another embodiment of the present invention, the crystalline form of
anhydrous
1,2-benzisoxazole-3-methanesulfonic acid is isolated by filtration under an
inert
atmosphere and exclusion of moisture.
In another embodiment of the present invention, the crystalline form of
anhydrous
1,2-benzisoxazole-3-methanesulfonic acid is thereafter converted to 1,2-
benzisoxazole-3-methanesulfonyl chloride.
In another embodiment of the present invention, the crystalline form of
anhydrous
1,2-benzisoxazole-3-methanesulfonic acid is thereafter converted to
zonisamide.
In accordance with another aspect of the present invention, there is provided
a
process for the preparation of 1,2-benzisoxazole-3-methanesulfonyi chloride,
said process comprising the steps of:
(a) preparing and subsequently isolating a crystalline form of
anhydrous 1,2-benzisoxazole-3-methanesulfonic acid; and
(b) directly chlorinating the crystalline form of anhydrous 1,2-
benzisoxazole-3-methanesulfonic acid obtained in step (a)
with at least one chlorinating agent to form 1,2-
benzisoxazole-3-methanesulfonyl chloride.
In accordance with another aspect of the present invention, there is provided
a
process for the preparation of zonisamide, said process comprising the steps
of:
(a) preparing and subsequently isolating a crystalline form of
anhydrous 1,2-benzisoxazole-3-methanesulfonic acid;
(b) treating the crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid obtained in step (a) with at least one
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= 9
chlorinating agent to form 1,2-benzisoxazole-3-
methanesulfonyl chloride;
(c) treating the 1,2-benzisoxazole-3-methanesulfonyl chloride obtained
in step (b) with at least one amidating agent to form
zonisamide; and
(d) isolating the zonisamide formed in step (c).
In an embodiment of the present invention, the amount of the at least one
chlorinating agent used to treat 1,2-benzisoxazole-3-methanesulfonic acid to
form 1,2-benzisoxazole-3-methanesulfonyl chloride is about 0.5 to about 5 mol
eq relative to the crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid.
In another embodiment of the present invention, the at least one chlorinating
agent used to treat 1,2-benzisoxazole-3-methanesulfonic acid to form 1,2-
benzisoxazole-3-methanesulfonyl chloride may be selected from the group
consisting of oxalyl chloride, phosphorus pentachloride, and phosphorus
oxychloride. In a preferred embodiment of the present invention, the at least
one
chlorinating agent used to treat 1,2-benzisoxazole-3-methanesulfonic acid to
form 1,2-benzisoxazole-3-methanesulfonyl chloride is phosphorus oxychloride.
In another embodiment of the present invention, the step of treating the 1,2-
benzisoxazole-3-methanesulfonic acid with the at least one chlorinating agent
to
form 1,2-benzisoxazole-3-methanesulfonyl chloride is carried out neat.
In another embodiment of the present invention, the step of treating the 1,2-
benzisoxazole-3-methanesulfonic acid with the at least one chlorinating agent
to
form 1,2-benzisoxazole-3-methanesulfonyl chloride is carried out in the
presence
of at least one aprotic organic solvent. The at least one aprotic organic
solvent
may be selected from the group consisting of C2-C4 nitriles, C6-C9 aromatic
hydrocarbons, C3-Clo acyclic or cyclic ethers, C3-C6 ketones, C2-C7 esters, C5-
Clo aliphatic hydrocarbons; C, to C3 chlorinated solvents and combinations
CA 02578559 2007-02-14
thereof. The C2-C4 nitriles may be selected from the group consisting of
acetonitrile and propionitrile; the C6-Cg aromatic hydrocarbons may be
selected
from the group consisting of benzene, toluene, and xylenes; the C3-Clo acyclic
or
cyclic ethers may be selected from the group consisting of dimethoxyethane,
5 diethyl ether, diisopropyl ether, and tetrahydrofuran; the C3-C6 ketones may
be
selected from the group consisting of methyl isobutyl ketone and methyl ethyl
ketone; the C2-C7 esters may be selected from the group consisting of ethyl
acetate, ethyl propionate, and isopropyl acetate; the C5-Clo aliphatic
hydrocarbons may be selected from the group consisting of hexanes, heptanes,
10 and octanes; and the C, to C3 chlorinated solvents may be selected from the
group consisting of dichloromethane and chloroform. In a preferred embodiment
of the present invention, the at least one aprotic organic solvent is
acetonitrile. In
another preferred embodiment of the present invention, the at least one
aprotic
organic solvent is xylenes.
In another embodiment of the present invention, the step of treating the 1,2-
benzisoxazole-3-methanesulfonic acid with the at least one chlorinating agent
to
form 1,2-benzisoxazole-3-methanesulfonyI chloride is carried out at a
temperature of about 50 C to about 160 C, preferably about 50 C to about
140 C and more preferably about 50 C to about 85 C.
In another embodiment of the present invention, the step of treating the 1,2-
benzisoxazole-3-methanesulfonyl chloride with the at least one amidating agent
to form zonisamide is carried out in situ.
In another embodiment of the present invention, prior to the step of treating
the
1,2-benzisoxazole-3-methanesulfonyI chloride with the at least one amidating
agent, the 1,2-benzisoxazole-3-methanesulfonyI chloride is isolated.
In another embodiment of the present invention, prior to the step of treating
the
1,2-benzisoxazole-3-methanesulfonyI chloride with the at least one amidating
agent, the 1,2-benzisoxazole-3-methanesulfonyI chloride is isolated from
solution
in at least one organic solvent.
CA 02578559 2007-02-14
' 11
In another embodiment of the present invention, the at least one organic
solvent
from which the 1,2-benzisoxazole-3-methanesulfonyl chloride is isolated prior
to
the step of treating the 1,2-benzisoxazole-3-methanesulfonyl chloride with the
at
least one amidating agent, is selected from C6-C9 aromatic hydrocarbons and C5-
Clo aliphatic hydrocarbons. The C6-C9 aromatic hydrocarbons is selected from
the group consisting of benzene, toluene and xylenes and the C5-C10 aliphatic
hydrocarbons may be selected from hexanes, heptanes and octanes. In a
preferred embodiment, the at least one organic solvent from which the 1,2-
benzisoxazole-3-methanesulfonyl chloride is isolated is xylenes. In another
preferred embodiment, the at least one organic solvent from which the 1,2-
benzisoxazole-3-methanesulfonyl chloride is isolated is toluene.
In another embodiment of the present invention, prior to the step of treating
the
1,2-benzisoxazole-3-methanesulfonyl chloride with the at least one amidating
agent, the 1,2-benzisoxazole-3-methanesulfonyl chloride is isolated by
evaporation.
In another embodiment of the present invention, the at least one amidating
agent
used to treat the 1,2-benzisoxazole-3-methanesulfonyl chloride to form
zonisamide is selected from the group consisting of aqueous ammonia, masked
ammonia and ammonia gas. The masked ammonia may be an ammonium salt
selected from the group consisting of ammonium carbonate, ammonium acetate
and ammonium formate. The ammonia gas may be anhydrous ammonia gas
consisting of less than about 200 ppm water, preferably less than about 20 ppm
water. In a preferred embodiment of the present invention, the at least one
amidating agent is ammonia gas.
In another embodiment of the present invention, the step of treating the 1,2-
benzisoxazole-3-methanesulfonyl chloride with the at least one amidating agent
is carried out in the presence of at least one organic solvent. The at least
one
organic solvent may be selected from the group consisting of C3-C6 ketones and
C2-C7 esters. The C3-C6 ketones may be selected from the group consisting of
CA 02578559 2007-02-14
12
methyl isobutyl ketone and methyl ethyl ketone. The C2-C7 esters may be
selected from the group consisting of ethyl acetate, ethyl propionate, and
isopropyl acetate. In a preferred embodiment of the present invention, the at
least one organic solvent is ethyl acetate.
In another embodiment of the present invention, the step of treating the 1,2-
benzisoxazole-3-methanesulfonyl chloride with the at least one amidating agent
to form zonisamide is carried out at a temperature of about -50 C to about 50
C
and preferably about -10 C to about 30 C.
In accordance with another aspect of the present invention there is provided a
process for the preparation of zonisamide, said process comprising the steps
of:
(a) reacting 1,2-benzisoxazole-3-acetic acid with chlorosulfonic acid to
form 1,2-benzisoxazole-3-methanesulfonic acid;
(b) treating the 1,2-benzisoxazole-3-methanesulfonic acid obtained in
step (a) with at least one chlorinating agent to form 1,2-
benzisoxazole-3-methanesulfonyl chloride; and
(c) treating the 1,2-benzisoxazole-3-methanesulfonyl chloride obtained
in step (b) with at least one amidating agent to form
zonisamide in situ.
In accordance with another aspect of the present invention there is provided a
process for the preparation of zonisamide, said process comprising the steps
of:
(a) reacting 1,2-benzisoxazole-3-acetic acid with chlorosulfonic acid to
form 1,2-benzisoxazole-3-methanesulfonic acid;
(b) adding at least one anti-solvent to the mixture from step (a) to
precipitate the 1,2-benzisoxazole-3-methanesulfonic acid in
a crystalline anhydrous form;
CA 02578559 2007-02-14
13
(c) isolating the crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid obtained in step (b);
(d) treating the crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid isolated in step (c) with at least one
chlorinating agent to form 1,2-benzisoxazole-3-
methanesulfonyl chloride; and
(e) treating the 1,2-benzisoxazole-3-methanesulfonyl chloride obtained
in step (d) with at least one amidating agent to form
zonisamide.
In accordance with another aspect of the present invention, there is provided
a
process for the preparation of zonisamide, said process comprising the steps
of:
(a) preparing a crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid;
(b) directly chlorinating the crystalline form of anhydrous 1,2-
benzisoxazole-3-methanesulfonic acid obtained in step (a)
with at least one chlorinating agent to form 1,2-
benzisoxazole-3-methanesulfonyl chloride; and
(c) treating the 1,2-benzisoxazole-3-methanesulfonyl chloride obtained
in step (b) with at least one amidating agent to form
zonisamide in situ.
In accordance with another aspect of the present invention, there is provided
a
process for the preparation of zonisamide, said process comprising the steps
of:
(a) preparing a crystalline form of anhydrousl,2-benzisoxazole-3-
methanesulfonic acid;
(b) reacting the crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid obtained in step (a) with at least one
CA 02578559 2007-02-14
14
chlorinating agent neat or in the presence of at least one
organic solvent to form 1,2-benzisoxazole-3-methanesulfonyI
chloride; and
(c) reacting the 1,2-benzisoxazole-3-methanesulfonyI chloride obtained
in step (b) without isolation with ammonia gas in the
presence of at least one organic solvent.
In accordance with another aspect of the present invention, there is provided
a
process for the preparation of zonisamide, said process comprising the steps
of:
(a) reacting 1,2-benzisoxazole-3-acetic acid with chlorosulfonic acid to
form 1,2-benzisoxazole-3-methanesulfonic acid;
(b) precipitating the 1,2-benzisoxazole-3-methanesulfonic acid
obtained in step (a) in a crystalline anhydrous form by the
addition of at least one anti-solvent;
(c) converting the crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid obtained in step (b) into 1,2-
benzisoxazole-3-methanesulfonyl chloride by treatment with
at least one chlorinating agent; and
(d) transforming the 1,2-benzisoxazole-3-methanesulfonyI chloride
obtained in step (c) in situ into zonisamide by the addition of
ammonia.
In accordance with another aspect of the present invention, there is provided
a
process to convert a crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid directly into its corresponding 1,2-benzisoxazole-3-
methanesulfonyl chloride.
In accordance with another aspect of the present invention, there is provided
a
process for preparing 1,2-benzisoxazole-3-methanesulfonyI chloride, said
process comprising the steps of:
CA 02578559 2007-02-14
(a) preparing a crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid; and
(b) treating the 1,2-benzisoxazole-3-methanesulfonic acid obtained in
step (a) with at least one chlorinating agent to form 1,2-
5 benzisoxazole-3-methanesulfonyl chloride.
In accordance with another aspect of the present invention, there is provided
a
process for preparing 1,2-benzisoxazole-3-methanesulfonyl chloride, wherein
said process comprises the step of chlorinating a crystalline form of
anhydrous
1,2-benzisoxazole-3-methanesulfonic acid.
10 In accordance with another aspect of the present invention, there is
provided a
process for preparing a crystalline form of anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid, said process comprising the steps of preparing 1,2-
benzisoxazole-3-methanesulfonic acid in a reaction mixture and adding at least
one anti-solvent to the reaction mixture.
15 In accordance with another aspect of the present invention, there is
provided a
process for preparing zonisamide, said process comprising the steps of:
(a) preparing 1,2-benzisoxazole-3-methanesulfonyl chloride in a
reaction mixture; and
(b) treating the 1,2-benzisoxazole-3-methanesulfonyl chloride obtained
in step (a) with at least one amidating agent to form
zonisamide in situ.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will be further understood from the following
description
with references to the drawings in which:
Figure 1 illustrates the X-ray powder diffraction (XRPD) pattern of a novel
crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid.
CA 02578559 2007-02-14
16
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel process for the preparation of
zonisamide, also known as 1,2-benzisoxazole-3-methansulfonamide.
The starting material for use in the process of the present invention is 1,2-
benzisoxazole-3-acetic acid. It is prepared according to processes known in
the
prior art, for instance, processes starting with 4-hydroxycoumarin and
hydroxylamine (Casini et al., J. Heterocyclic Chem., 1965, 385).
The novel process of the present invention is based on an easy to scale up
procedure involving the sulfonation of 1,2-benzisoxazole-3-acetic acid, direct
chlorination of 1,2-benzisoxazole-3-methanesulfonic acid, and subsequent
amidation of 1,2-benzisoxazole-3-methanesulfonyl chloride to zonisamide.
The process of the present invention is more efficient than the prior art
processes
in that it permits isolation of the 1,2-benzisoxazole-3-methanesulfonic acid
(1)
intermediate from the sulfonating reaction mixture, rather than its salt (for
example sodium salt), and direct chlorination of this compound to generate 1,2-
benzisoxazole-3-methanesulfonyl chloride. We have found that by judicious
choice of the reagents, solvents and reaction conditions, the 1,2-
benzisoxazole-
3-methanesulfonic acid (1) intermediate can be precipitated directly from the
sulfonating reaction mixture by using an anti-solvent. An unexpected advantage
of this process is that it provides the 1,2-benzisoxazole-3-methanesulfonic
acid
(1) intermediate in a crystalline anhydrous form having a low water content
(typically equal to or below about 2.0% as measured by Karl Fischer
titration).
This facilitates the subsequent transformation of the 1,2-benzisoxazole-3-
methanesulfonic acid (1) intermediate into the corresponding 1,2-benzisoxazole-
3-methanesulfonyl chloride (2) intermediate by treatment with an unexpectedly
small excess (ca. 0.7 mol equivalents) of chlorinating agent, for example
phosphorous oxychloride. This also facilitates the subsequent in situ
transformation of the 1,2-benzisoxazole-3-methanesulfonyl chloride (2)
intermediate by amidation into zonisamide in excellent yield (85-90%).
CA 02578559 2007-02-14
17
C02H SO3H SO2CI SO 2NH2
C)- CIS03H/ POCI / ~ NH3(gas) ~ N 1,4-0ioxane ~ N CH3CN ~/ 0 N O N
1 2 Zonisamide
It should be noted that this process reduces the amount of corrosive reagents
and increases the over-all yield relative to the prior art processes. This is
advantageous in terms of reducing the environmental impact of the process and
improving the overall safety.
Further details of the preferred embodiments of the present invention are
illustrated in the following examples which are understood to be non-limiting.
EXAMPLE 1
Preparation of Crystalline Anhydrous 1,2-Benzisoxazole-3-methanesulfonic
acid (1)
1,2-Benzisoxazole-3-acetic acid (200 g; 1.13 mol) was suspended in 1,4-dioxane
(600 mL). The mixture was cooled in an ice-bath and chlorosulfonic acid (82.6
mL, 1.24 mol, 1.1 eq) was added maintaining the internal temperature below
C. The mixture was heated to 60-65 C for 9'/2 h and cooled to room-
15 temperature. CELITET"" (20 g) was added followed by xylenes (1000 mL) and
the
mixture was stirred for one hour at room temperature. It was filtered and
concentrated. The suspension obtained was heated to 50-60 C for three hours
and then gradually cooled to 0-5 C and filtered. The precipitate was filtered
off
under a nitrogen atmosphere and washed with 400 mL 1,4-dioxane/xylenes (v/v
20 = 1: 9). It was dried at 60 C for approximately 16 hours in a vacuum oven
(51
mm Hg) to give 218.14 g crystalline anhydrous 1,2-benzisoxazole-3-
methanesulfonic acid (90.6%) with a HPLC purity of 99.4%.
Crystalline anhydrous 1,2-benzisoxazole-3-methanesulfonic acid was
characterized as follows:
CA 02578559 2007-02-14
18
' H NMR (300 MHz, DMSO-d6): S(ppm) 10.75 [1 H, s(br)], 8.05 (1 H, ad, J = 8.1
Hz), 7.69 (1 H, ad, J = 8.6 Hz), 7.62 (1 H, at, J = 7.7 Hz), 7.37 (1 H, at, J
= 7.3 Hz),
4.28 (2H, s)
13C NMR (75 MHz, DMSO-d6): S(ppm) 162.6, 153.8, 130.2, 124.6, 123.4, 121.7,
109.4, 48.1
LRMS (ES+): 214.2 (100, M+H +)
HRMS: 213.0093 (calculated for C8H7NO4S: 213.0096)
XRPD:
The XRPD system was a PANalytical X'Pert Pro MPD theta-theta diffractometer
having a X'Celerator high-speed detector and a spinning sample stage. The
Radiation source was Copper Ka, and the Power setting was 45 kV and 40 mA.
The Step size was 0.08 degrees 2 theta, and the Step time was 6.72 seconds.
An Incident beam fixed divergence slit of 0.25 degree was used, along with a
fixed anti-scatter slit of 0.5 degrees. The Diffracted beam anti-scatter slit
was 5
mm, and the Incident and diffracted beam soller slits were 0.04 rad. The main
peaks in the XRPD pattern have the following 2 theta angles at about 9.32 0.2,
13.59 0.2, 13.78 0.2, 17.31 0.2, 18.64 0.2, 19.20 0.2, 20.07 0.2, 20.11 0.2,
22.03 0.2, 22.27 0.2, 24.02 0.2, 24.19 0.2, 24.37 0.2, 24.69 0.2, 25.31 0.2,
25.56 0.2, 26.65 0.2, 28.09 0.2, 30.74 0.2, and 31.17 0.2. The most
characteristic peaks in the XRPD pattern have the following 2 theta angles at
about 9.32 0.2, 13.59 0.2, 13.78 0.2, 18.64 0.2, 22.03 0.2, 22.27 0.2,
25.31 0.2 and 25.56 0.2. The XRPD pattern is provided in Figure 1.
KF 0.17% (The water content after 2 years storage was 0.51 % as measured by
KF. It was determined to be pure by NMR.)
CA 02578559 2007-02-14
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EXAMPLE 2
Preparation of Zonisamide through Chlorination in Acetonitrile
1,2-Benzisoxazole-3-methanesulfonic acid (1) (20.0 g, 93.8 mmol) was mixed
with acetonitrile (60 mL) and heated to reflux. The clear solution was cooled
to
65 C and phosphorous oxychloride (5.7 mL; 62.3 mmol) was added. The mixture
was heated to reflux for 10 hours and then cooled to room temperature. Ethyl
acetate (100 mL) was added and the mixture was filtered through CELITET""
which was subsequently washed with ethyl acetate (40 mL). The filtrate was
cooled in an ice bath and ammonia gas was bubbled through the solution for 1
hour. The mixture was concentrated and water (100 mL) was added. The mixture
was heated to reflux and cooled. It was concentrated, cooled in an ice-bath
and
filtered to yield crude zonisamide. Purification was achieved by
recrystallization
from iso-propanol/water. The yield of purified product was 78.8 %.
It was characterized as follows:
' H NMR (DMSO-d6): b[ppm] 7.98 (1 H, ad, J= 7.9 Hz), 7.78 (1 H, ad, J= 8.5
Hz),
7.68 (1 H, at, J=7.7 Hz), 7.44 (1 H, at, J= 7.4 Hz), 7.27 (2H, s(br)), 4.86
(2H, s)
13C NMR (DMSO-d6): 8[ppm] 162.8, 150.8, 130.5, 123.9, 123.3, 121.1, 109.6,
50.9
LRMS (ES"): 211.10 (34, M-H+)
EA: C 45.12% (calc. 45.28%); H 3.70% (calc. 3.80%); N 13.00% (calc. 13.20%)
EXAMPLE 3
Preparation of Zonisamide through Chlorination in Xylenes
1,2-Benzisoxazole-3-methanesulfonic acid (1) (1.00 g, 4.7 mmol) was mixed with
xylenes (10 mL) and phosphorous oxychloride (1.0 mL, 11 mmol) and heated to
reflux until the reaction was complete. The mixture was filtered through
CELITET"" and evaporated to dryness to yield 1,2-benzisoxazole-3-
CA 02578559 2007-02-14
methanesulfonyl chloride (2) as a light brown solid. It was dissolved in ethyl
acetate (10 mL), cooled in an ice-bath and treated with ammonia. Work-up
analogous to example 2 gave pure zonisamide.
EXAMPLE 4
5 Preparation of Zonisamide through Chlorination in Neat Phosphorous
Oxychloride
1,2-Benzisoxazole-3-methanesulfonic acid (1) (2.13 g, 10 mmol) was mixed with
phosphorous oxychloride (7 mL, 75 mmol) and refluxed until the reaction was
complete. The mixture was diluted with xylenes and concentrated to remove
10 excess phosphorous oxychloride. The mixture was treated as in Example 3 to
yield pure zonisamide.
EXAMPLE 5
Preparation of Zonisamide through Chlorination in Dichloroethane
1,2-Benzisoxazole-3-methanesulfonic acid (1) (1.00 g, 4.7 mmol) was mixed with
15 1,2-dichloroethane (10 mL) and phosphorous oxychloride (2.0 mL, 21 mmol).
The mixture was heated to reflux until the reaction was complete, filtered
through
CELITET"' and evaporated to give 1,2-benzisoxazole-3-methanesulfonyl chloride
(2). It was converted into zonisamide in analogy to the previous examples.
While the foregoing provides a detailed description of preferred embodiments
of
20 the present invention, it is to be understood that this description is only
illustrative
of the principles of the invention and is not limitative. Numerous
modifications,
variations and adaptations may be made to the particular embodiments of the
invention described above without departing from the scope of the invention,
which is defined in the claims.
