US20080033181A1 - Process for the preparation of Zonisamide and the intermediates thereof - Google Patents

Process for the preparation of Zonisamide and the intermediates thereof Download PDF

Info

Publication number
US20080033181A1
US20080033181A1 US11/806,090 US80609007A US2008033181A1 US 20080033181 A1 US20080033181 A1 US 20080033181A1 US 80609007 A US80609007 A US 80609007A US 2008033181 A1 US2008033181 A1 US 2008033181A1
Authority
US
United States
Prior art keywords
benzisoxazole
group
process according
methanesulfonic acid
anhydrous
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/806,090
Inventor
Gamini Weeratunga
Eckardt Wolf
Nageib Mohamed
Allan Rey
Bhaskar Guntoori
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Apotex Pharmachem Inc
Original Assignee
Apotex Pharmachem Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Apotex Pharmachem Inc filed Critical Apotex Pharmachem Inc
Priority to US11/806,090 priority Critical patent/US20080033181A1/en
Assigned to APOTEX PHARMACHEM INC. reassignment APOTEX PHARMACHEM INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GUNTOORI, BHASKAR REDDY, MOHAMED, NAGEIB, REY, ALLAN W., WEERATUNGA, GAMINI, WOLF, ECKARDT C.G.
Publication of US20080033181A1 publication Critical patent/US20080033181A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to a novel and improved process for the preparation of zonisamide and the intermediates thereof.
  • 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.
  • 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).
  • zonisamide 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 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 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).
  • WO 03/020708 A1 discloses the chlorination of sodium 1,2-benzisoxazole-3-methanesulfonate with a very large excess of phosphorous oxychloride (POCl 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).
  • 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).
  • 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).
  • DMF N,N-dimethylformamide
  • 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%.
  • 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.
  • XRPD X-Ray powder diffraction
  • 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%.
  • 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.
  • the sulfonation of 1,2-benzisoxazole-3-acetic acid comprises the steps of:
  • the at least one aprotic organic solvent is selected from the group consisting of C 1 -C 3 chlorinated solvents and C 4 -C 6 cyclic ethers.
  • the C 1 -C 3 chlorinated solvents may be selected from the group consisting of dichloromethane and dichloroethane and the C 4 -C 6 cyclic ethers may be selected from the group consisting of tetrahydrofuran and 1,4-dioxane.
  • the at least one aprotic organic solvent is 1,4-dioxane.
  • 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.
  • 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.
  • the at least one anti-solvent is selected from the group consisting of C 6 -C 9 aromatic hydrocarbons, C 5 -C 10 aliphatic hydrocarbons, and C 1 -C 3 halogenated hydrocarbons.
  • the C 6 -C 9 aromatic hydrocarbons may be selected from the group consisting of benzene, toluene, and xylenes;
  • the C 5 -C 10 aliphatic hydrocarbons may be selected from the group consisting of hexanes, heptanes, and octanes;
  • the C 1 -C 3 halogenated hydrocarbons may be selected from the group consisting of dichloromethane and dichloroethane.
  • the at least one anti-solvent is xylenes.
  • the crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid is isolated by filtration under an inert atmosphere and exclusion of moisture.
  • the crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid is thereafter converted to 1,2-benzisoxazole-3-methanesulfonyl chloride.
  • the crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid is thereafter converted to zonisamide.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 2 -C 4 nitriles, C 6 -C 9 aromatic hydrocarbons, C 3 -C 10 acyclic or cyclic ethers, C 3 -C 6 ketones, C 2 -C 7 esters, C 5 -C 10 aliphatic hydrocarbons; C 1 to C 3 chlorinated solvents and combinations thereof.
  • the C 2 -C 4 nitriles may be selected from the group consisting of acetonitrile and propionitrile;
  • the C 6 -C 9 aromatic hydrocarbons may be selected from the group consisting of benzene, toluene, and xylenes;
  • the C 3 -C 10 acyclic or cyclic ethers may be selected from the group consisting of dimethoxyethane, diethyl ether, diisopropyl ether, and tetrahydrofuran;
  • the C 3 -C 6 ketones may be selected from the group consisting of methyl isobutyl ketone and methyl ethyl ketone;
  • the C 2 -C 7 esters may be selected from the group consisting of ethyl acetate, ethyl propionate, and isopropyl acetate;
  • the C 5 -C 10 aliphatic hydrocarbons may be selected from the group consisting of hex
  • 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° C. to about 160° C., preferably about 50° C. to about 140° C. and more preferably about 50° C. to about 85° C.
  • 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.
  • the 1,2-benzisoxazole-3-methanesulfonyl chloride 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.
  • the 1,2-benzisoxazole-3-methanesulfonyl chloride 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.
  • 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 6 -C 9 aromatic hydrocarbons and C 5 -C 10 aliphatic hydrocarbons.
  • the C 6 -C 9 aromatic hydrocarbons is selected from the group consisting of benzene, toluene and xylenes and the C 5 -C 10 aliphatic hydrocarbons may be selected from hexanes, heptanes and octanes.
  • 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.
  • the 1,2-benzisoxazole-3-methanesulfonyl chloride 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.
  • 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.
  • the at least one amidating agent is ammonia gas.
  • 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 3 -C 6 ketones and C 2 -C 7 esters.
  • the C 3 -C 6 ketones may be selected from the group consisting of methyl isobutyl ketone and methyl ethyl ketone.
  • the C 2 -C 7 esters may be selected from the group consisting of ethyl acetate, ethyl propionate, and isopropyl acetate.
  • the at least one organic solvent is ethyl acetate.
  • 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.
  • a process for preparing 1,2-benzisoxazole-3-methanesulfonyl chloride comprising the step of chlorinating a crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid.
  • a process for preparing a crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid 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.
  • FIG. 1 illustrates the X-ray powder diffraction (XRPD) pattern of a novel crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid.
  • 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.
  • its salt for example sodium salt
  • 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%).
  • 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.
  • 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° C. The mixture was heated to 60-65° C. for 91 ⁇ 2 h and cooled to room-temperature. CELITETM (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 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 ⁇ , 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 .
  • 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 CELITETM, 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.
  • 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 CELITETM 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.
  • 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.
  • 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 CELITETM and evaporated to give 1,2-benzisoxazole-3-methanesulfonyl chloride (2). It was converted into zonisamide in analogy to the previous examples.

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.
Figure US20080033181A1-20080207-C00001

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This is a divisional application of U.S. application Ser. No. 11/304,563, filed on Dec. 16, 2005.
    • 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 (ZONEGRAN™).
  • 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.
    Figure US20080033181A1-20080207-C00002
  • 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).
  • 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.
    Figure US20080033181A1-20080207-C00003
  • 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).
    Figure US20080033181A1-20080207-C00004
  • 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.
  • 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 (POCl3) to form 1,2-benzisoxazole-3-methanesulfonyl chloride (2) which is isolated and subsequently converted to zonisamide by treatment with ammonia gas (Scheme 4).
    Figure US20080033181A1-20080207-C00005
  • The disadvantage of this process is that the very large excess of POCl3 (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° 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)
    Figure US20080033181A1-20080207-C00006
    directly into a methanesulfonic acid halide of the general formula (II)
    Figure US20080033181A1-20080207-C00007
    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 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.
  • 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.
  • 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-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.
  • 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.
  • 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.
  • 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 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.
  • 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 C1-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 C1-C3 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.
  • 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-methanesulfonyl 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 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-C10 acyclic or cyclic ethers, C3-C6 ketones, C2-C7 esters, C5-C10 aliphatic hydrocarbons; C1 to C3 chlorinated solvents and combinations thereof. The C2-C4 nitriles may be selected from the group consisting of acetonitrile and propionitrile; the C6-C9 aromatic hydrocarbons may be selected from the group consisting of benzene, toluene, and xylenes; the C3-C10 acyclic or cyclic ethers may be selected from the group consisting of dimethoxyethane, 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-C10 aliphatic hydrocarbons may be selected from the group consisting of hexanes, heptanes, and octanes; and the C1 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-methanesulfonyl 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-methanesulfonyl chloride with the at least one amidating agent, the 1,2-benzisoxazole-3-methanesulfonyl chloride is isolated.
  • 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.
  • 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-C10 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 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;
      • (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 anhydrous 1,2-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 chlorinating agent neat or in the presence of at least one organic solvent to form 1,2-benzisoxazole-3-methanesulfonyl chloride; and
      • (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.
  • 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-methanesulfonyl 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-methanesulfonyl chloride, said process comprising the steps of:
      • (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-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.
  • 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.
  • 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:
  • 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
  • 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%).
    Figure US20080033181A1-20080207-C00008
  • 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 20° C. The mixture was heated to 60-65° C. for 9½ h and cooled to room-temperature. CELITE™ (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=1:9). It was dried at 60° 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%.
  • Crystalline anhydrous 1,2-benzisoxazole-3-methanesulfonic acid was characterized as follows:
  • 1H NMR (300 MHz, DMSO-d6): δ (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)
  • 13C NMR (75 MHz, DMSO-d6): δ (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 Kα, 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.
  • 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
  • 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 CELITE™, 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:
  • 1H NMR (DMSO-d6): δ [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)
  • 13C NMR (DMSO-d6): δ [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 CELITE™ 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
  • 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
  • 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™ 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 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.

Claims (33)

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 C3-C6 ketones, C2-C4 nitriles and C2-C7 esters.
5. The process according to claim 4 wherein the C3-C6 ketones are selected from the group consisting of methyl isobutyl ketone and methyl ethyl ketone.
6. The process according to claim 4 wherein the C2-C4 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 C2-C7 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 C2-C4 nitriles, C6-C9 aromatic hydrocarbons, C3-C10 acyclic or cyclic ethers, C3-C6 ketones, C2-C7 esters, C5-C10 aliphatic hydrocarbons; C1 to C3 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 C2-C4 nitriles, C6-C9 aromatic hydrocarbons, C3-C10 acyclic or cyclic ethers, C3-C6 ketones, C2-C7 esters, C5-C10 aliphatic hydrocarbons; C1 to C3 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 C2-C4 nitriles, C6-C9 aromatic hydrocarbons, C3-C10 acyclic or cyclic ethers, C3-C6 ketones, C2-C7 esters, C5-C10 aliphatic hydrocarbons; C1 to C3 chlorinated solvents and combinations thereof.
17. The process according to claim 14 wherein the C2-C4 nitriles are selected from the group consisting of acetonitrile and propionitrile; the C6-C9 aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and xylenes; the C3-C10 acyclic or cyclic ethers are selected from the group consisting of dimethoxyethane, diethyl ether, diisopropyl ether, and tetrahydrofuran; the C3-C6 ketones are selected from the group consisting of methyl isobutyl ketone and methyl ethyl ketone; the C2-C7 esters are selected from the group consisting of ethyl acetate, ethyl propionate, and isopropyl acetate; the C5-C10 aliphatic hydrocarbons are selected from the group consisting of hexanes, heptanes, and octanes; and the C1 to C3 chlorinated solvents are selected from the group consisting of dichloromethane and chloroform.
18. The process according to claim 15 or 16 wherein the C2-C4 nitriles are selected from the group consisting of acetonitrile and propionitrile; the C6-C9 aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and xylenes; the C3-C10 acyclic or cyclic ethers are selected from the group consisting of dimethoxyethane, diethyl ether, diisopropyl ether, and tetrahydrofuran; the C3-C6 ketones are selected from the group consisting of methyl isobutyl ketone and methyl ethyl ketone; the C2-C7 esters are selected from the group consisting of ethyl acetate, ethyl propionate, and isopropyl acetate; the C5-C10 aliphatic hydrocarbons are selected from the group consisting of hexanes, heptanes, and octanes; and the C1 to C3 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 C6-C9 aromatic hydrocarbons and C5-C10 aliphatic hydrocarbons.
27. The process according to claim 26 wherein the C6-C9 aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and xylenes; and the C5-C10 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%.
US11/806,090 2005-12-16 2007-05-30 Process for the preparation of Zonisamide and the intermediates thereof Abandoned US20080033181A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/806,090 US20080033181A1 (en) 2005-12-16 2007-05-30 Process for the preparation of Zonisamide and the intermediates thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/304,563 US7375233B2 (en) 2005-12-16 2005-12-16 Process for the preparation of zonisamide and the intermediates thereof
US11/806,090 US20080033181A1 (en) 2005-12-16 2007-05-30 Process for the preparation of Zonisamide and the intermediates thereof

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US11/304,563 Division US7375233B2 (en) 2005-12-16 2005-12-16 Process for the preparation of zonisamide and the intermediates thereof

Publications (1)

Publication Number Publication Date
US20080033181A1 true US20080033181A1 (en) 2008-02-07

Family

ID=38174605

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/304,563 Expired - Fee Related US7375233B2 (en) 2005-12-16 2005-12-16 Process for the preparation of zonisamide and the intermediates thereof
US11/806,090 Abandoned US20080033181A1 (en) 2005-12-16 2007-05-30 Process for the preparation of Zonisamide and the intermediates thereof

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US11/304,563 Expired - Fee Related US7375233B2 (en) 2005-12-16 2005-12-16 Process for the preparation of zonisamide and the intermediates thereof

Country Status (1)

Country Link
US (2) US7375233B2 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106810507B (en) * 2017-01-23 2019-06-21 珠海市海瑞德生物科技有限公司 A kind of environmentally protective synthetic method of Zonisamide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4172896A (en) * 1978-06-05 1979-10-30 Dainippon Pharmaceutical Co., Ltd. Methane-sulfonamide derivatives, the preparation thereof and composition comprising the same
US20020183525A1 (en) * 2001-03-02 2002-12-05 Marioara Mendelovici Process for the preparation of 1,2-benzisoxazole-3-acetic acid

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6033114B2 (en) 1976-12-16 1985-08-01 大日本製薬株式会社 1,2-benzisoxazole derivative
EP1430037A4 (en) 2001-08-30 2004-11-17 Teva Pharma Zonisamide intermediate and synthesis
AU2003219889A1 (en) 2002-02-22 2003-09-09 Teva Pharmaceutical Industries Ltd. Method for preparing benzisoxazole methane sulfonyl chloride and its amidation to form zonisamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4172896A (en) * 1978-06-05 1979-10-30 Dainippon Pharmaceutical Co., Ltd. Methane-sulfonamide derivatives, the preparation thereof and composition comprising the same
US20020183525A1 (en) * 2001-03-02 2002-12-05 Marioara Mendelovici Process for the preparation of 1,2-benzisoxazole-3-acetic acid

Also Published As

Publication number Publication date
US20070142644A1 (en) 2007-06-21
US7375233B2 (en) 2008-05-20

Similar Documents

Publication Publication Date Title
EP3097096A1 (en) 5-fluoro-4-imino-3-(alkyl/substituted alkyl)-1- (arylsulfonyl)-3,4-dihydropyrimidin-2(1h)-one and processes for their preparation
AU2020267299B2 (en) Methods of making protein deacetylase inhibitors
JPWO2007125736A1 (en) Method for producing methylene disulfonate compound
EP3802515B1 (en) Process for the preparation of apalutamide
CN114805314B (en) Synthesis method of Entecavir
WO2013014665A1 (en) Intermediate compounds and process for the preparation of lurasidone and salts thereof
US5342944A (en) Process for the preparation of 2-alkyl-3,5,6,7- or 8-substituted-4(3H)-quinazolinones
US6936720B2 (en) Method for preparing benzisoxazole methane sulfonyl chloride and its amidation to form zonisamide
US7375233B2 (en) Process for the preparation of zonisamide and the intermediates thereof
JP4028021B2 (en) Method for producing asymmetric 4,6-bis (aryloxy) pyrimidine compound
CA2578559A1 (en) Process for the preparation of zonisamide and the intermediates thereof
WO1992015562A2 (en) Preparation of omega-substituted alkanamide
JP2007291010A (en) Method for producing optically active 2-methylepihalohydrin or the like
WO2007132990A1 (en) Process for the preparation of chiral glycidylphthalimide in highly optical purity
CN110078674B (en) Preparation method of 2-alkyl amino pyrimidone
US20220204455A1 (en) A process for the synthesis of lofexidine
JP2659587B2 (en) 4-aziridinyl pyrimidine derivatives and their production
EP1566381B1 (en) Process for production of 1- 2-(benzimidazol-2-yl- thio)ethyl piperazine or salts thereof
SK10182002A3 (en) Method for producing heterocyclic compounds
JP4925518B2 (en) Method for producing substituted alkylamine derivative
KR950002841B1 (en) Process for the preparation of phenyl-guanidine derivatives
KR100317615B1 (en) A process for the preparation of 8-chloroadenosine 3&#39;,5&#39;-cyclic monophosphate
JPS6343382B2 (en)
CN112135820A (en) Novel process for preparing diaminopyrimidine derivatives or their acid addition salts
JP4619505B2 (en) Process for producing (2S, 4R) -N, N-dimethyl-1-allyloxycarbonyl-4-substituted-2-pyrrolidinecarboxamide

Legal Events

Date Code Title Description
AS Assignment

Owner name: APOTEX PHARMACHEM INC., CANADA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WEERATUNGA, GAMINI;WOLF, ECKARDT C.G.;MOHAMED, NAGEIB;AND OTHERS;REEL/FRAME:019412/0441

Effective date: 20051207

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE