U.S. patent application number 11/806090 was filed with the patent office on 2008-02-07 for process for the preparation of zonisamide and the intermediates thereof.
This patent application is currently assigned to Apotex Pharmachem Inc.. Invention is credited to Bhaskar Reddy Guntoori, Nageib Mohamed, Allan W. Rey, Gamini Weeratunga, Eckardt C.G. Wolf.
Application Number | 20080033181 11/806090 |
Document ID | / |
Family ID | 38174605 |
Filed Date | 2008-02-07 |
United States Patent
Application |
20080033181 |
Kind Code |
A1 |
Weeratunga; Gamini ; et
al. |
February 7, 2008 |
Process for the preparation of Zonisamide and the intermediates
thereof
Abstract
The present invention provides a novel and improved process for
the preparation of Zonisamide and the intermediates thereof. In one
aspect of the present invention, the process provides for: the
preparation and isolation of a novel crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid of formula 1; the direct
chlorination of the acid of formula 1 into its acid chloride of
formula 2; and the in situ conversion of the intermediate acid
chloride of formula 2 into Zonisamide. ##STR1##
Inventors: |
Weeratunga; Gamini;
(Brantford, CA) ; Wolf; Eckardt C.G.; (Brantford,
CA) ; Mohamed; Nageib; (Oakville, CA) ; Rey;
Allan W.; (Brantford, CA) ; Guntoori; Bhaskar
Reddy; (Brantford, CA) |
Correspondence
Address: |
IVOR M. HUGHES, BARRISTER & SOLICITOR,;PATENT & TRADEMARK AGENTS
175 COMMERCE VALLEY DRIVE WEST
SUITE 200
THORNHILL
ON
L3T 7P6
CA
|
Assignee: |
Apotex Pharmachem Inc.
|
Family ID: |
38174605 |
Appl. No.: |
11/806090 |
Filed: |
May 30, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11304563 |
Dec 16, 2005 |
|
|
|
11806090 |
May 30, 2007 |
|
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Current U.S.
Class: |
548/241 |
Current CPC
Class: |
C07D 261/20
20130101 |
Class at
Publication: |
548/241 |
International
Class: |
C07D 261/20 20060101
C07D261/20 |
Claims
1. A process for the preparation of 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.
2. The process according to claim 1 wherein the at least one
amidating agent in step (b) is ammonia gas.
3. The process according to claim 1 or 2 wherein the amidation
reaction is carried out in the presence of at least one organic
solvent.
4. The process according to claim 3 wherein the at least one
organic solvent is selected from the group consisting of
C.sub.3-C.sub.6 ketones, C.sub.2-C.sub.4 nitriles and
C.sub.2-C.sub.7 esters.
5. The process according to claim 4 wherein the C.sub.3-C.sub.6
ketones are selected from the group consisting of methyl isobutyl
ketone and methyl ethyl ketone.
6. The process according to claim 4 wherein the C.sub.2-C.sub.4
nitriles are selected from the group consisting of propionitrile
and acetonitrile.
7. The process according to claim 3 wherein the at least one
organic solvent is acetonitrile.
8. The process according to claim 4 wherein the C.sub.2-C.sub.7
esters are selected from the group consisting of ethyl acetate,
ethyl propionate, and isopropyl acetate.
9. The process according to claim 3 wherein the at least one
organic solvent is ethyl acetate.
10. The process of claim 1 wherein the
1,2-benzisoxazole-3-methanesulfonyl chloride is prepared by a
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 in the presence of at least one
aprotic organic solvent to form 1,2-benzisoxazole-3-methanesulfonyl
chloride.
11. The process according to claim 10 wherein the amount of the at
least one chlorinating agent of step (b) is about 0.5 to about 5
mol equivalents relative to the crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid.
12. The process according to claim 10 or 11 wherein the at least
one chlorinating agent of step (b) is selected from the group
consisting of oxalyl chloride, phosphorus pentachloride, and
phosphorus oxychloride.
13. The process according to claim 10 or 11 wherein the at least
one chlorinating agent of step (b) is phosphorus oxychloride.
14. The process according to claim 10 or 11 wherein the at least
one aprotic organic solvent is selected from the group consisting
of C.sub.2-C.sub.4 nitriles, C.sub.6-C.sub.9 aromatic hydrocarbons,
C.sub.3-C.sub.10 acyclic or cyclic ethers, C.sub.3-C.sub.6 ketones,
C.sub.2-C.sub.7 esters, C.sub.5-C.sub.10 aliphatic hydrocarbons;
C.sub.1 to C.sub.3 chlorinated solvents and combinations
thereof.
15. The process according to claim 12 wherein the at least one
aprotic organic solvent is selected from the group consisting of
C.sub.2-C.sub.4 nitriles, C.sub.6-C.sub.9 aromatic hydrocarbons,
C.sub.3-C.sub.10 acyclic or cyclic ethers, C.sub.3-C.sub.6 ketones,
C.sub.2-C.sub.7 esters, C.sub.5-C.sub.10 aliphatic hydrocarbons;
C.sub.1 to C.sub.3 chlorinated solvents and combinations
thereof.
16. The process according to claim 13 wherein the at least one
aprotic organic solvent is selected from the group consisting of
C.sub.2-C.sub.4 nitriles, C.sub.6-C.sub.9 aromatic hydrocarbons,
C.sub.3-C.sub.10 acyclic or cyclic ethers, C.sub.3-C.sub.6 ketones,
C.sub.2-C.sub.7 esters, C.sub.5-C.sub.10 aliphatic hydrocarbons;
C.sub.1 to C.sub.3 chlorinated solvents and combinations
thereof.
17. The process according to claim 14 wherein the C.sub.2-C.sub.4
nitriles are selected from the group consisting of acetonitrile and
propionitrile; the C.sub.6-C.sub.9 aromatic hydrocarbons are
selected from the group consisting of benzene, toluene, and
xylenes; the C.sub.3-C.sub.10 acyclic or cyclic ethers are selected
from the group consisting of dimethoxyethane, diethyl ether,
diisopropyl ether, and tetrahydrofuran; the C.sub.3-C.sub.6 ketones
are selected from the group consisting of methyl isobutyl ketone
and methyl ethyl ketone; the C.sub.2-C.sub.7 esters are selected
from the group consisting of ethyl acetate, ethyl propionate, and
isopropyl acetate; the C.sub.5-C.sub.10 aliphatic hydrocarbons are
selected from the group consisting of hexanes, heptanes, and
octanes; and the C.sub.1 to C.sub.3 chlorinated solvents are
selected from the group consisting of dichloromethane and
chloroform.
18. The process according to claim 15 or 16 wherein the
C.sub.2-C.sub.4 nitriles are selected from the group consisting of
acetonitrile and propionitrile; the C.sub.6-C.sub.9 aromatic
hydrocarbons are selected from the group consisting of benzene,
toluene, and xylenes; the C.sub.3-C.sub.10 acyclic or cyclic ethers
are selected from the group consisting of dimethoxyethane, diethyl
ether, diisopropyl ether, and tetrahydrofuran; the C.sub.3-C.sub.6
ketones are selected from the group consisting of methyl isobutyl
ketone and methyl ethyl ketone; the C.sub.2-C.sub.7 esters are
selected from the group consisting of ethyl acetate, ethyl
propionate, and isopropyl acetate; the C.sub.5-C.sub.10 aliphatic
hydrocarbons are selected from the group consisting of hexanes,
heptanes, and octanes; and the C.sub.1 to C.sub.3 chlorinated
solvents are selected from the group consisting of dichloromethane
and chloroform.
19. The process according to claim 10 or 11 wherein the at least
one aprotic organic solvent of step (b) is acetonitrile.
20. The process according to claim 12 wherein the at least one
aprotic organic solvent of step (b) is acetonitrile.
21. The process according to claim 13 wherein the at least one
aprotic organic solvent of step (b) is acetonitrile.
22. The process according to claim 10 or 11 wherein the at least
one aprotic organic solvent of step (b) is xylenes.
23. The process according to claim 12 wherein the at least one
aprotic organic solvent of step (b) is xylenes.
24. The process according to claim 13 wherein the at least one
aprotic organic solvent of step (b) is xylenes.
25. The process of claim 10 wherein the crystalline form of
anhydrous 1,2-benzisoxazole-3-methanesulfonic acid is prepared by a
process comprising the steps of: (a) preparing
1,2-benzisoxazole-3-methanesulfonic acid in a reaction mixture; (b)
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 (c) isolating the
crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic
acid.
26. The process according to claim 25 wherein the at least one
anti-solvent is selected from the group consisting of
C.sub.6-C.sub.9 aromatic hydrocarbons and C.sub.5-C.sub.10
aliphatic hydrocarbons.
27. The process according to claim 26 wherein the C.sub.6-C.sub.9
aromatic hydrocarbons are selected from the group consisting of
benzene, toluene, and xylenes; and the C.sub.5-C.sub.10 aliphatic
hydrocarbons are selected from the group consisting of hexanes,
heptanes, and octanes.
28. The process according to claim 25 wherein the at least one
anti-solvent is xylenes.
29. A crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid when prepared by the
process according to any one of claims 25 to 28.
30. The crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid of claim 29 characterized
by an X-Ray powder diffraction (XRPD) pattern having 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.
31. The crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid of claim 29 characterized
by an XRPD pattern having peaks 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 degrees two theta.
32. The crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid according to any one of
claims 29 to 31 having a water content of less than about 2.0%.
33. The crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid according to claim 32
having a water content of about 0.8% to about 1.5%.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional application of U.S. application Ser.
No. 11/304,563, filed on Dec. 16, 2005.
FIELD OF THE INVENTION
[0002] 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
[0003] 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 (ZONEGRAN.TM.).
[0004] 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. ##STR2##
[0005] 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 et al.,
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 A1 and International Patent Application Publication
No. WO 02/0705495 A14).
[0006] 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. ##STR3##
[0007] 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.
[0008] 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). ##STR4##
[0009] 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 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. Pat. 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.
[0010] International Patent Application Publication No. WO
03/020708 A1 discloses the chlorination of sodium
1,2-benzisoxazole-3-methanesulfonate with a very large excess of
phosphorous oxychloride (POCl.sub.3) to form
1,2-benzisoxazole-3-methanesulfonyl chloride (2) which is isolated
and subsequently converted to zonisamide by treatment with ammonia
gas (Scheme 4). ##STR5##
[0011] The disadvantage of this process is that the very large
excess of POCl.sub.3 (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
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.degree. C.
and for approximately 16 hours at 100.degree. C.), and no further
details about the compound are provided in WO 03/020708.
[0012] In Japanese unexamined (Kokai) Patent Application No.
JP53077057 A2, there is mention of converting a 3-methanesulfonic
acid of the general formula (VII) ##STR6## directly into a
methanesulfonic acid halide of the general formula (II) ##STR7##
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.
[0013] International Patent Application Publication No. WO
03/072552 A1 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
sodium 1,2-benzisoxazole-3-methanesulfonate and, again, large
excesses of highly corrosive chlorinating agents were used.
[0014] Clearly, an industrial process overcoming the deficiencies
of the prior art processes, which would provide zonisamide in a
high-yield, cost-effective, environmentally friendlier and safe
manner was required.
[0015] 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
[0016] 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.
[0017] 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.
[0018] It is a further object of the present invention to provide a
new process for the preparation of
1,2-benzisoxazole-3-methanesulfonyl 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.
[0019] 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.
[0020] 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.
[0021] 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%.
[0022] In accordance with one aspect of the present invention,
there is provided a crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid.
[0023] 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.
[0024] 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%.
[0025] 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: [0026] (i) preparing
1,2-benzisoxazole-3-methanesulfonic acid in a reaction mixture;
[0027] (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 [0028] (iii)
isolating the crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid.
[0029] 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.
[0030] In another embodiment of the present invention, the
sulfonation of 1,2-benzisoxazole-3-acetic acid comprises the steps
of: [0031] (a) preparing a mixture of 1,2-benzisoxazole-3-acetic
acid and at least one aprotic organic solvent; [0032] (b) adding
chlorosulfonic acid to the mixture from step (a); and [0033] (c)
heating the mixture from step (b).
[0034] In another embodiment of the present invention, the at least
one aprotic organic solvent is selected from the group consisting
of C.sub.1-C.sub.3 chlorinated solvents and C.sub.4-C.sub.6 cyclic
ethers. The C.sub.1-C.sub.3 chlorinated solvents may be selected
from the group consisting of dichloromethane and dichloroethane and
the C.sub.4-C.sub.6 cyclic 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.
[0035] 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.
[0036] In another embodiment of the present invention, the mixture
from step (b) is heated to a temperature of about 0.degree. C. to
about 100.degree. C. and preferably about 20.degree. C. to about
80.degree. C.
[0037] In another embodiment of the present invention, the at least
one anti-solvent is selected from the group consisting of
C.sub.6-C.sub.9 aromatic hydrocarbons, C.sub.5-C.sub.10 aliphatic
hydrocarbons, and C.sub.1-C.sub.3 halogenated hydrocarbons. The
C.sub.6-C.sub.9 aromatic hydrocarbons may be selected from the
group consisting of benzene, toluene, and xylenes; the
C.sub.5-C.sub.10 aliphatic hydrocarbons may be selected from the
group consisting of hexanes, heptanes, and octanes; and the
C.sub.1-C.sub.3 halogenated hydrocarbons may be selected from the
group consisting of dichloromethane and dichloroethane. In a
preferred embodiment of the present invention, the at least one
anti-solvent is xylenes.
[0038] 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.
[0039] 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.
[0040] In another embodiment of the present invention, the
crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic
acid is thereafter converted to zonisamide.
[0041] In accordance with another aspect of the present invention,
there is provided a process for the preparation of
1,2-benzisoxazole-3-methanesulfonyl chloride, said process
comprising the steps of: [0042] (a) preparing and subsequently
isolating a crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid; and [0043] (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.
[0044] 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: [0045] (a) preparing and
subsequently isolating a crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid; [0046] (b) treating 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; [0047] (c)
treating the 1,2-benzisoxazole-3-methanesulfonyl chloride obtained
in step (b) with at least one amidating agent to form zonisamide;
and [0048] (d) isolating the zonisamide formed in step (c).
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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 C.sub.2-C.sub.4 nitriles, C.sub.6-C.sub.9 aromatic hydrocarbons,
C.sub.3-C.sub.10 acyclic or cyclic ethers, C.sub.3-C.sub.6 ketones,
C.sub.2-C.sub.7 esters, C.sub.5-C.sub.10 aliphatic hydrocarbons;
C.sub.1 to C.sub.3 chlorinated solvents and combinations thereof.
The C.sub.2-C.sub.4 nitriles may be selected from the group
consisting of acetonitrile and propionitrile; the C.sub.6-C.sub.9
aromatic hydrocarbons may be selected from the group consisting of
benzene, toluene, and xylenes; the C.sub.3-C.sub.10 acyclic or
cyclic ethers may be selected from the group consisting of
dimethoxyethane, diethyl ether, diisopropyl ether, and
tetrahydrofuran; the C.sub.3-C.sub.6 ketones may be selected from
the group consisting of methyl isobutyl ketone and methyl ethyl
ketone; the C.sub.2-C.sub.7 esters may be selected from the group
consisting of ethyl acetate, ethyl propionate, and isopropyl
acetate; the C.sub.5-C.sub.10 aliphatic hydrocarbons may be
selected from the group consisting of hexanes, heptanes, and
octanes; and the C.sub.1 to C.sub.3 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.
[0053] 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 at a
temperature of about 50.degree. C. to about 160.degree. C.,
preferably about 50.degree. C. to about 140.degree. C. and more
preferably about 50.degree. C. to about 85.degree. C.
[0054] 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.
[0055] 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.
[0056] 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 from
solution in at least one organic solvent.
[0057] 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
C.sub.6-C.sub.9 aromatic hydrocarbons and C.sub.5-C.sub.10
aliphatic hydrocarbons. The C.sub.6-C.sub.9 aromatic hydrocarbons
is selected from the group consisting of benzene, toluene and
xylenes and the C.sub.5-C.sub.10 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.
[0058] 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.
[0059] 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.
[0060] 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 C.sub.3-C.sub.6 ketones and
C.sub.2-C.sub.7 esters. The C.sub.3-C.sub.6 ketones may be selected
from the group consisting of methyl isobutyl ketone and methyl
ethyl ketone. The C.sub.2-C.sub.7 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.
[0061] 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.degree. C. to about 50.degree. C. and
preferably about -10.degree. C. to about 30.degree. C.
[0062] 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: [0063] (a) reacting
1,2-benzisoxazole-3-acetic acid with chlorosulfonic acid to form
1,2-benzisoxazole-3-methanesulfonic acid; [0064] (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 [0065] (c)
treating the 1,2-benzisoxazole-3-methanesulfonyl chloride obtained
in step (b) with at least one amidating agent to form zonisamide in
situ.
[0066] 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: [0067] (a) reacting
1,2-benzisoxazole-3-acetic acid with chlorosulfonic acid to form
1,2-benzisoxazole-3-methanesulfonic acid; [0068] (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; [0069] (c) isolating the crystalline form of
anhydrous 1,2-benzisoxazole-3-methanesulfonic acid obtained in step
(b); [0070] (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 [0071] (e)
treating the 1,2-benzisoxazole-3-methanesulfonyl chloride obtained
in step (d) with at least one amidating agent to form
zonisamide.
[0072] 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: [0073] (a) preparing a crystalline
form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid; [0074]
(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 [0075] (c)
treating the 1,2-benzisoxazole-3-methanesulfonyl chloride obtained
in step (b) with at least one amidating agent to form zonisamide in
situ.
[0076] 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: [0077] (a) preparing a crystalline
form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid; [0078]
(b) reacting the crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid obtained in step (a) with
at least one chlorinating agent neat or in the presence of at least
one organic solvent to form 1,2-benzisoxazole-3-methanesulfonyl
chloride; and [0079] (c) reacting the
1,2-benzisoxazole-3-methanesulfonyl chloride obtained in step (b)
without isolation with ammonia gas in the presence of at least one
organic solvent.
[0080] 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: [0081] (a) reacting
1,2-benzisoxazole-3-acetic acid with chlorosulfonic acid to form
1,2-benzisoxazole-3-methanesulfonic acid; [0082] (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; [0083] (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 [0084] (d) transforming
the 1,2-benzisoxazole-3-methanesulfonyl chloride obtained in step
(c) in situ into zonisamide by the addition of ammonia.
[0085] 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.
[0086] In accordance with another aspect of the present invention,
there is provided a process for preparing
1,2-benzisoxazole-3-methanesulfonyl chloride, said process
comprising the steps of: [0087] (a) preparing a crystalline form of
anhydrous 1,2-benzisoxazole-3-methanesulfonic acid; and [0088] (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.
[0089] 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.
[0090] 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.
[0091] In accordance with another aspect of the present invention,
there is provided a process for preparing zonisamide, said process
comprising the steps of: [0092] (a) preparing
1,2-benzisoxazole-3-methanesulfonyl chloride in a reaction mixture;
and [0093] (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
[0094] The present invention will be further understood from the
following description with references to the drawings in which:
[0095] FIG. 1 illustrates the X-ray powder diffraction (XRPD)
pattern of a novel crystalline form of anhydrous
1,2-benzisoxazole-3-methanesulfonic acid.
DETAILED DESCRIPTION OF THE INVENTION
[0096] The present invention relates to a novel process for the
preparation of zonisamide, also known as
1,2-benzisoxazole-3-methansulfonamide.
[0097] 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).
[0098] 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.
[0099] 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%). ##STR8##
[0100] 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.
[0101] 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)
[0102] 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 20.degree. C. The
mixture was heated to 60-65.degree. C. for 91/2 h and cooled to
room-temperature. CELITE.TM. (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.degree. C. for three hours and then
gradually cooled to 0-5.degree. C. and filtered. The precipitate
was filtered off under a nitrogen atmosphere and washed with 400 mL
1,4-dioxane/xylenes (v/v=1:9). It was dried at 60.degree. C. for
approximately 16 hours in a vacuum oven (<1 mm Hg) to give
218.14 g crystalline anhydrous 1,2-benzisoxazole-3-methanesulfonic
acid (90.6%) with a HPLC purity of 99.4%.
[0103] Crystalline anhydrous 1,2-benzisoxazole-3-methanesulfonic
acid was characterized as follows:
[0104] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. (ppm) 10.75
[1H, s (br)], 8.05 (1H, ad, J=8.1 Hz), 7.69 (1H, ad, J=8.6 Hz),
7.62 (1H, at, J=7.7 Hz), 7.37 (1H, at, J=7.3 Hz), 4.28 (2H, s)
[0105] .sup.13C NMR (75 MHz, DMSO-d.sub.6): .delta. (ppm) 162.6,
153.8, 130.2, 124.6, 123.4, 121.7, 109.4, 48.1
[0106] LRMS (ES+): 214.2 (100, M+H.sup.+)
[0107] HRMS: 213.0093 (calculated for C.sub.8H.sub.7NO.sub.4S:
213.0096)
[0108] XRPD:
[0109] 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 K.alpha.,
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 FIG. 1.
[0110] 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.)
EXAMPLE 2
Preparation of Zonisamide Through Chlorination in Acetonitrile
[0111] 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.degree. 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
CELITE.TM., 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
[0112] It was characterized as follows:
[0113] .sup.1H NMR (DMSO-d.sub.6): .delta. [ppm] 7.98 (1H, ad,
J=7.9 Hz), 7.78 (1H, ad, J=8.5 Hz), 7.68 (1H, at, J=7.7 Hz), 7.44
(1H, at, J=7.4 Hz), 7.27 (2H, s(br)), 4.86 (2H, s)
[0114] .sup.13C NMR (DMSO-d.sub.6): .delta. [ppm] 162.8, 150.8,
130.5, 123.9, 123.3, 121.1, 109.6, 50.9
[0115] LRMS (ES.sup.-): 211.10 (34, M-H.sup.+)
[0116] 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
[0117] 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 CELITE.TM. and
evaporated to dryness to yield 1,2-benzisoxazole-3-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
Preparation of Zonisamide Through Chlorination in Neat Phosphorous
Oxychloride
[0118] 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 excess phosphorous
oxychloride. The mixture was treated as in Example 3 to yield pure
zonisamide.
EXAMPLE 5
Preparation of Zonisamide Through Chlorination in
Dichloroethane
[0119] 1,2-Benzisoxazole-3-methanesulfonic acid (1) (1.00 g, 4.7
mmol) was mixed with 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 CELITE.TM. and
evaporated to give 1,2-benzisoxazole-3-methanesulfonyl chloride
(2). It was converted into zonisamide in analogy to the previous
examples.
[0120] While the foregoing provides a detailed description of
preferred embodiments of 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.
* * * * *