U.S. patent application number 10/661109 was filed with the patent office on 2004-03-11 for process for the prepartion of 1,2-benzisoxazole-3-acetic acid.
Invention is credited to Mendelovici, Marioara, Nidam, Tamar.
Application Number | 20040049053 10/661109 |
Document ID | / |
Family ID | 26955986 |
Filed Date | 2004-03-11 |
United States Patent
Application |
20040049053 |
Kind Code |
A1 |
Mendelovici, Marioara ; et
al. |
March 11, 2004 |
Process for the prepartion of 1,2-benzisoxazole-3-acetic acid
Abstract
The present invention provides a process for preparing
1,2-benzisoxazole-3-acetic acid, comprising the step of reacting
4-hydroxy-coumarin with hydroxyl-amine in the presence of a base.
The present invention further provides a process for preparing a
salt of benzisoxazole methane sulfonic acid, comprising the steps
of 1) sulfonating 1,2-benzisoxazole-3-acetic acid using
chlorosulfonic acid in a solvent mixture comprising methylene
chloride and sodium hydroxide; and 2) isolating the salt of
benzisoxazole methane sulfonic acid.
Inventors: |
Mendelovici, Marioara;
(Rechovot, IL) ; Nidam, Tamar; (Yehud,
IL) |
Correspondence
Address: |
KENYON & KENYON
One Broadway
New York
NY
10004
US
|
Family ID: |
26955986 |
Appl. No.: |
10/661109 |
Filed: |
September 12, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10661109 |
Sep 12, 2003 |
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10090710 |
Mar 4, 2002 |
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6677458 |
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60273172 |
Mar 2, 2001 |
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60294847 |
May 31, 2001 |
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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 |
Claims
What is claimed is:
1. A process for preparing 1,2-benzisoxazole-3-acetic acid,
comprising the step of reacting 4-hydroxy-coumarin with
hydroxyl-amine in the presence of a base.
2. The process according to claim 1, wherein the base is selected
from the group consisting of carbonate salts, aqueous ammonia, and
organic bases.
3. The process according to claim 2, wherein the carbonate salt is
selected from the group consisting of sodium carbonate and
potassium carbonate
4. The process according to claim 2, wherein the organic base is an
amine.
5. The process according to claim 4, wherein the amine is selected
from the group consisting of triethyl-amine, tributyl-amine, and
diethyl-amine.
6. The process according to claim 1, wherein the process is
performed in the presence of an alcohol.
7. The process according to claim 6, wherein the alcohol is a lower
alcohol.
8. The process according to claim 7, wherein the lower alcohol is
selected from the group consisting of ethanol, methanol, n-butanol,
iso-propyl-alcohol, isobutanol, amyl-alcohol, and iso-amyl
alcohol.
9. The process according to claim 6, wherein the process is
performed at a temperature between room temperature and boiling
point of the alcohol.
10. The process according to claim 9, wherein the process is
performed at a temperature between about 40.degree. C. and about
60.degree. C.
11. A process of preparing a salt of benzisoxazole methane sulfonic
acid comprising the steps of: 1) sulfonating
1,2-benzisoxazole-3-acetic acid using chlorosulfonic acid and
dioxane in a solvent mixture comprising methylene chloride and
sodium hydroxide; and 2) isolating the salt of benzisoxazole
methane sulfonic acid.
12. The process according to claim 11, wherein the isolating step
is performed by evaporating the solvent mixture after the
sulfonating step.
13. The process according to claim 11, wherein the isolating step
is performed by salting-out with sodium chloride.
14. The process according to 13, further comprising the step of
cooling after the step of salting-out.
15. The process according to claim 11, wherein the salt of
benzisoxazole methane sulfonic acid is selected from the group
consisting of sodium, calcium, and barium.
16. The process according to claim 11, wherein the preparation of
benzisoxazole methane sulfonic acid is performed at a temperature
of about 40.degree. C. and for a time of about 4 hours.
17. The process according to claim 11, wherein the preparation of
benzisoxazole methane sulfonic acid is performed at a temperature
of about 40.degree. C. and a time of about 5 hours.
18. The process according to claim 11, wherein the preparation of
benzisoxazole methane sulfonic acid is performed at a temperature
of about 40.degree. C. and a time of about 3 hours.
19. The process according to claim 11, wherein the preparation of
benzisoxazole methane sulfonic acid is performed at a temperature
of about 55.degree. C. and a time of about 3.5 hours.
20. The process according to claim 1, wherein the
1,2-benzisoxazole-3-acet- ic acid is thereafter converted to
1,2-benzisoxazole-3-methane sulfonamide.
21. The process according to claim 11, wherein the benzisoxazole
methane sulfonic acid is thereafter converted to
1,2-benzisoxazole-3-methane sulfonamide.
22. 1,2-benzisoxazole-3-methane sulfonamide prepared in accordance
with the process of claim 1.
23. 1,2-benzisoxazole-3-methane sulfonamide prepared in accordance
with the process of claim 11.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefits under 35 U.S.C. .sctn.
1.119(e) of Provisional Application Serial No. 60/273,172, filed
Mar. 2, 2001, and No. 60/294,847, filed May 31, 2001, the
disclosure of which is incorporated by reference in its entirety
herein.
FIELD OF THE INVENTION
[0002] The field of the invention relates to the preparation of
1,2-benzisoxazole-3acetic acid. Within that field, the present
invention relates more particularly to a method for preparing
1,2-benzisoxazole-3-acetic acid comprising the step of reacting
4-hydroxy-coumarin with a hydroxyl-amine in the presence of a
base.
BACKGROUND OF THE INVENTION
[0003] Zonisamide is currently avaiable as an anti-epileptic agent
which possesses anti-convulant and anti-neurotoxic effects.
Zonisamide is also known as 1,2benzisoxazole-3-methane sulfonamide
or 3-(sulfamylmethyl)-1,2-benzisoxazole. It has the following
chemical formula: 1
[0004] The preparation of zonisamide is described in Japanese Pat.
No. 53-77057 and Yakugaku Zasshi, 116(7), 533-47, 1996, both of
which are incorporated herein by reference. These references teach
a synthesis process of zonisamide that involves 4 or 5-steps,
starting from 4-hydroxy-coumarin (4-HC). The synthesis of
zonisamide occurs via the intermediates: namely,
1,2-benzisoxazole-3-acetic acid (BOA) and the sodium salt of
benzisoxazole methane sulfonic acid (BOS-Na).
[0005] Many synthetic routes for preparing zonisamide have been
described in the literature. One of the synthetic routes for
preparing zonisamide is described in U.S. Pat. No. 4,172,896 and
Japanese Pat. No. 53-77057 to Dainnipon. This particular synthetic
route starts from 1,2-benzisoxazole-3-bromo-methane (zonisamide5
bromide). The zonisamide-bromide is converted to
1,2-benzisoxazole-3-methanesulfonic acid sodium salt (BOS-Na) in
the reaction with sodium sulfite as is shown in the following
scheme 1: 2
[0006] Zonisamide-bromide is prepared according to the literature
(Chem. Pharm.
[0007] Bull., (Tokyo), 24, 632, 1976) by the bromination reaction
of 1,2-benzizoxazole-3acetic acid (BOA). BOA is prepared by Posner
reaction (T. Posner, Chem. Ber., 42, 2523, 0913, T.Posner, and
R.Hess, Chem. Ber., 46, 3816, 1913, M. Gianella, F. Gualtieri, C.
Melchiorre and A. Orlandoni, Chem. Therap., 1972, 2, 127) and
starts from 4-hydroxy-coumarin in the reaction with metallic sodium
as shown in the following scheme 2: 3
[0008] The Posner reaction for BOA preparation involves the use of
metallic sodium. When metallic sodium is used in alcoholic
solution, BOA is not the sole reaction product and the
side-reaction product, O-hydroxy-acetophenone-oxime, is obtained in
about 30%.
[0009] The high percentage of the side reaction products as well as
the difficulty of using the aforementioned process on an industrial
scale due to the use of metallic sodium render said process
unfavorable, and thus the need for an improved process for
preparing BOA and BOS-Na intermediates remains.
[0010] According to Dainnipon in the patent Japanese Pat. No.
53-77057, an alternative synthetic route for preparing zonisamide
starts from 4-hydroxy-coumarin may occur via the same intermediates
BOA and BOS-Na as shown in the following scheme 3: 4
[0011] 1,2-benzizoxazole-3-acetic acid (BOA), the product of the
initial step after reacting 4-HC with NH.sub.2OH (scheme 3), is
converted to the intermediate BOS-Na in the sulfonation reaction
with ClSO.sub.3H/dioxane in ethylene chloride at room temperature
for about three hours followed by about 6 hours heating at about
50.degree. C. After the reaction is complete, water and NaOH are
added and the product is isolated as sodium salt (BOS-Na) by
evaporation of the aqueous layer. BOA and BOS-Na are the
intermediates in the zonisamide preparation according to both
synthetic schemes. All the cited references are incorporated by
reference in their entireties herein.
OBJECTS AND SUMMARY OF THE INVENTION
[0012] An object of the present invention is to provide an improved
process for preparing a salt of BOS (e.g., BOS-Na) with higher
purity and lesser side-products.
[0013] Another object of the present invention is to provide an
improved process for preparing a salt of BOS (e.g., BOS-Na) as an
intermediate for the preparation of 1,2benzisoxazole-3-methane
sulfonamide (i.e., zonisamide).
[0014] Another object of the present invention is to provide an
improved process for preparing a salt of BOS (e.g., BOS-Na) in
which the sulfonation of BOA occurs in a solvent of methylene
chloride (instead of ethylene chloride).
[0015] Another object of the present invention is to prepare
1,2-benzisoxazole-3acetic acid (BOA) without the use of metallic
sodium; and thus the process of this invention is substantially
less hazardous.
[0016] Another object of the present invention is to prevent the
formation of side-products, e.g., oximes; and thus, significantly
increasing the yield of BOA, and substantially reducing the burden
of removing the oxime side-product with ether, which by itself is
hazardous.
[0017] Another yet object of the present invention is to prepare
BOA or salts of BOS (e.g., BOS-Na); which are thereafter converted
to 1,2-benzisoxazole-3-methane sulfonamide (i.e., zonisamide).
[0018] The present invention provides a process for preparing
1,2-benzisoxazole-3acetic acid (BOA), comprising the step of
reacting 4-hydroxy-coumarin (4-HC) with hydroxyl-amine in the
presence of a base.
[0019] In a preferred embodiment, the base is selected from the
group consisting of carbonate salts, aqueous ammonia, and organic
bases. In another preferred embodiment, the carbonate salt is
selected from the group of sodium carbonate (Na.sub.2CO.sub.3) and
potassium carbonate (K.sub.2CO.sub.3). In another preferred
embodiment, the organic base is an amine. More preferably, the
amine is selected from the group consisting of triethyl-amine,
tributyl-amine, and diethyl-amine.
[0020] In another preferred embodiment, the present invention
provides a process for preparing 1,2-benzisoxazole-3-acetic acid
(BOA), comprising the step of reacting 4hydroxy-coumarin (4-HC)
with hydroxyl-amine in the presence of a base, said process occurs
in the presence of an alcoholic solvent.
[0021] Preferably, the alcoholic solvent is a lower alcohol. More
preferably, the lower alcohol is selected from the group consisting
of ethanol, methanol, n-butanol, iso-propyl-alcohol, iso-butanol,
amyl-alcohol, and iso-amyl-alcohol.
[0022] In another preferred embodiment, the present invention
provides a process for preparing 1,2-benzisoxazole-3-acetic acid
(BOA), comprising the step of reacting 4hydroxy-coumarin (4-HC)
with hydroxyl-amine in the presence of a base and an alcoholic
solution, wherein said process occurs at a temperature between room
temperature and boiling point of the alcoholic solvent.
[0023] More preferably, the temperature of the reaction is between
about 40.degree. C. and about 60.degree. C.
[0024] The present invention also provides an improved process of
preparing a salt of benzisoxazole methane sulfonic acid, comprising
the steps of: 1) sulfonating 1,2benzisoxazole-3-acetic acid (BOA)
using chlorosulfonic acid and dioxane in methylene chloride and
sodium hydroxide solvents; and 2) isolating the salt of
benzisoxazole methane sulfonic acid.
[0025] The present invention provides an improved process for
preparing a salt of BOS (e.g., BOS-Na) in which the product is
isolated by precipitatation from an aqueous solvent. Preferably,
the precipitation is performed by salting-out with, e.g., sodium
chloride. More preferably, the precipitation is performed by
salting-out and and cooling.
[0026] In another preferred embodiment, the salt of BOS (e.g.,
BOS-Na) is isolated by evaporation.
[0027] Preferably, the salt of BOS may be isolated as BOS-Ba or
BOS-Ca.
[0028] In another preferred embodiment, the preparation of the
BOS-salt (e.g., BOSNa) occurs at about 40.degree. C., preferably at
about 55.degree. C. Preferably, the preparation of the BOS-salt is
performed for a time duration of about 4 hours. More preferably,
the preparation is performed for about 3, about 3.5 and about 5
hours.
[0029] According to the present invention, the reaction was
improved as the reaction (for converting BOA to BOS-Na) is faster
when methylene chloride is used. In other words, the reaction rate
is faster when the solvent of the reaction is changed from ethylene
chloride to methylene chloride.
DETAILED DESCRIPTION OF THE INVENTION
[0030] As used herein, the following abbreviations are used:
1,2-benzisoxazole-3acetic acid (BOA); benzisoxazole methane
sulfonic acid (BOS); sodium salt of benzisoxazole methane sulfonic
acid (BOS-Na); barium salt of benzisoxazole methane sulfonic acid
(BOS-Ba); calcium salt of benzisoxazole methane sulfonic acid
(BOS-Ca), chlorosulfonic acid (ClSO.sub.3H); "organic base" refers
to a base of carbon compounds; "room temperatuer" refers to ambient
temperature of about 20.degree. C. to about 25.degree. C.
[0031] As disclosed in the present application, when methylene
chloride was used to repeat the procedure as disclosed in Japanese
Patent 53-77057, it was found that the reaction was substantially
faster. The reaction was completed in about 12-17 hours of heating
when ethylene chloride was used. In contrast, the reaction was
completed in only about 3-5 hours at about 40.degree. C. when
methylene chloride was used (See, the exp. # 2337 and exp. # 2356
in the Table 1).
[0032] According to the present invention, the process was further
improved as it provides an alterative isolation procedure. It is
known that the product (BOS-Na) can be isolated by evaporation of
an aqueous phase. The present invention also provides two
alternatives in which the product is precipitated from water which
can be induced by the following ways; for example:
[0033] a) BOS-Na may be isolated from water by precipitation by
salting-out; e.g., with sodium chloride (i.e., NaCl) and cooling;
and
[0034] b) BOS-Ba or BOS-Ca may be isolated based on their low
solubility, and can be quantitatively precipitated from water.
Separation of BOS as the barium (Ba) or calcium (Ca) salt
facilitates industrial scale preparation of this intermediate. Once
the salt precipitates, it may be washed with water to reduce the
inorganic salt content.
[0035] A product contaminated with inorganic salts is usually more
hygroscopic than the pure compound; and, its use is problematic in
the POCl.sub.3 reaction.
EXAMPLES
[0036] The present invention is described below in detail with
reference to examples. The present invention is by no means
restricted to these specific examples. The experiments are
summaried as followed.
1TABLE 1 BOS Preparation Experiments Reaction Isolation of the
product Temp. time Salt Exp. Solvent (.degree. C.) (hours) type
Procedure Reference # C.sub.2H.sub.4Cl.sub.2 55.degree. C. 12 Na
Evaporation of the Process as in JP 2337 (ethylene chloride) water
solution 53-77057 # CH.sub.2Cl.sub.2 40.degree. C. 4 Na Evaporation
of the Present process 2356 (methylene water solution chloride) #
CH.sub.2Cl.sub.2 40.degree. C. 5 Na Precipitation from Present
process 2361 water by salting-out with NaCl # CH.sub.2Cl.sub.2
40.degree. C. 3 Ca Precipitation from Present process 2362 water #
CH.sub.2Cl.sub.2 40.degree. C. 3.5 Ba Precipitation from Present
process 2363 water
[0037]
2TABLE 2 % BOA Yield and % Side-Products Under Various Experimental
Conditions Exp. BOA Yield % Unreacted No. Solvent Base (%) % Oxime
4-HC Reference 1 Ethanol Na 68.3 19.8 1 2 Ethanol-water Na-acetate
48.7 30.8 2 3* Ethanol Na.sub.2CO.sub.3 82 0.2 17.5 Present
procedure 4* Methanol Na.sub.2CO.sub.3 87.5 1.1 7.5 Present
procedure 5* n-BuOH Na.sub.2CO.sub.3 98 0.9 1 Present procedure 6*
n-BuOH K.sub.2CO.sub.3 82.9 17 Present procedure *% represents area
of HPLC chromatogram of respective products over total area
Reference 1: Chem. Pharm. Bull., (Tokyo), 24, 632, 1976 T. Posner
and R. Hess, Ber., 46, 3816, 1913 Reference 2: G. Casini, F.
Gualtieri, M. L. Stern, J. Hererocyclic Chem., 2, 385, 1965
Experimental Procedures
Example 1
Reaction with Na.sub.2CO.sub.3/n-BuOH
[0038] 4-Hydroxy-coumarin (10 grams), was added to the mixture of
hydroxyl-amine hydrochloride (15 grams) and sodium carbonate (23
grams) in n-BuOH (100 mL). The reaction mixture was than heated to
reflux and the reflux was maintained for about 13 hours. The
reaction mixture was concentrated on rotavapor and the residue was
washed with water and dried at about 60.degree. C. The product
weighs about 8.56 grams (yield: about 80% w/w).
Example 2
Reaction with K?CO.sub.3/n-BuOH
[0039] 4-Hydroxy-coumarin (10 grams) was added to the mixture of
hydroxyl-amine hydrochloride (15 grams) and potassium carbonate
(9.30 grams) in n-BuOH (100 mL). The reaction mixture was heated at
reflux for about 20 hours.
[0040] The HPLC analysis of the reaction mixture shows the
following composition: about 80% product BOA (w/w), about 15% oxime
(w/w) and about 5% 4-HC (w/w).
Example 3
Reaction with Et.sub.3N/MeOH
[0041] 4-Hydroxy-coumarin (10 grams), hydroxyl-amine hydrochloride
(15 grams) and triethyl-amine (22 grams) in MeOH (50 mL) were
heated at reflux for about 1.5 hours. The residue obtained after
evaporation to dryness was dissolved in aqueous NaHCO.sub.3 and
extracted with ether. After acidification of the aqueous phase the
product was isolated by filtration and washed with water. The yield
is about 73% (w/w).
Example 4
Reaction with Et.sub.2NH/MeOH
[0042] 4-Hydroxy-coumarin (100 grams), hydroxyl-amine hydrochloride
(150 grams) and diethyl-amine (160 grams) in MeOH (500 mL) were
heated at reflux for about 1 hour. The reactiom mixture was
evaporated to dryness and the solid was dissolved in aqueous.
NaHCO.sub.3 and extracted with ether; from the aqueous phase the
product was obtained upon acidification with HCl. The solid was
washed with water and dried on oven at about 60.degree. C. The
solid weighs about 99.82 grams (yield: about 93% w/w).
[0043] It is contemplated that various modifications of the
described modes of carrying out the invention will be apparent to
those skilled in the ar without departing from the scope and spirit
of the invention.
* * * * *