EP1430037A4 - Produits intermediaires de zosinamide et synthese y relative - Google Patents

Produits intermediaires de zosinamide et synthese y relative

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Publication number
EP1430037A4
EP1430037A4 EP02768748A EP02768748A EP1430037A4 EP 1430037 A4 EP1430037 A4 EP 1430037A4 EP 02768748 A EP02768748 A EP 02768748A EP 02768748 A EP02768748 A EP 02768748A EP 1430037 A4 EP1430037 A4 EP 1430037A4
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EP
European Patent Office
Prior art keywords
bos
mixture
benzisoxazole
crystalline
process according
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.)
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Application number
EP02768748A
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German (de)
English (en)
Other versions
EP1430037A1 (fr
Inventor
Tamar Nidam
Marioara Mendelovici
Eduard Schwartz
Shlomit Wizel
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.)
Teva Pharmaceutical Industries Ltd
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Teva Pharmaceutical Industries Ltd
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Publication of EP1430037A1 publication Critical patent/EP1430037A1/fr
Publication of EP1430037A4 publication Critical patent/EP1430037A4/fr
Withdrawn legal-status Critical Current

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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 field of the invention is the sulfonation of a zomsamide intermediate and crystalline forms of the zonisamide intermediate in the form of acid and metallic salts.
  • the present invention relates most particular to novel sulfonation processes for preparing the zonisamide intermediate of benzisoxazole acetic acid and the crystalline forms thereof.
  • Zonisamide is known as l,2-benzisoxazole-3-methane sulfonamide or 3-
  • Zonisamide is currently available as an anti-epileptic agent which possesses anti- convulsant and anti-neurotoxic effects.
  • the second method described in literature for zomsamide preparation includes the preparation of BOA starting f om 4-hydroxy-coumarin, followed by the sulfonation reaction of BOA to BOS.
  • the sulfonation reaction of the zonisamide intermediate i.e., BOA
  • the reagent chlorosulfonic acid is used in a large excess and it is also the reaction solvent.
  • the reactions of this synthetic method are shown in scheme 2:
  • Disulfonated-benzisoxazole derivateive is a main product of the reaction.
  • the synthetic pathway via the sulfonation reaction of BOA comprises two steps lesser as compared to the synthetic pathway via the bromination reaction.
  • the sulfonation reaction requires a large amount of chlorosulfonic acid which poses undesirable environmental problems.
  • the present invention provides an unexpected novel sulfonation process to prepare the intermediate of zonisamide.
  • BOS sulfonation reaction
  • BOS-H sulfonic acid type compound
  • metal salts metal salts
  • alkyl- and aryl-sulfonic acids and their salts can exist as hydrated form (CM. Suter in “The Organic Chemistry ofSulfur , J. Wiley, N.Y., 1946).
  • the widely-known reagent p-toluene-sulfonic acid can exist as monohydrate. It is necessary to develop another method for preparation of the sodium salt of BOS.
  • the present invention provides a sulfonation process for preparing benzisoxazole methane sulfonic acid (BOS).
  • anhydride and sulfuric acid are employed in preparing benzisoxazole methane sulfonic acid (BOS) in a sulfonation process.
  • the present invention provides a sulfonation process for preparing benzisoxazole methane sulfonic acid (BOS) employing chlorosulfonic acid in an organic solvent.
  • the present invention provides a process for preparing an intermediate of zomsamide, comprising the steps of: a) preparing a mixture of chlorosulfonic acid and an organic solvent; b) adding benzisoxazole acetic acid to the mixture; c) heating the mixture; and d) isolating the intermediate of zonisamide.
  • the present invention provides a sulfonation process for preparing benzisoxazole methane sulfonic acid (BOS) employing acyl-sulfates or in situ prepared acyl-sulfates.
  • In situ prepared acyl-sulfates may be obtained from anhydrides and sulfuric acid (H SO ), acyl-halides and H 2 SO 4> or carboxylic acids and H 2 SO 4 .
  • acetic anhydride and sulfuric acid are employed in preparing benzisoxazole methane sulfonic acid in a sulfonation process.
  • the present invention provides a process for preparing an intermediate of zonisamide, comprising the steps of: a) preparing an acyl sulfate in a solution; b) adding benzisoxazole acetic acid to the solution wherein the benzisoxazole acid is sulfonated by the acyl sulfate to form the intermediate of zonisamide; c) heating the solution; and d) isolating the intermediate of zonisamide.
  • the present invention a process for preparing an intermediate of zomsamide, comprising the steps of: a) preparing a mixture of benzisoxazole acetic acid and an anhydride in a solvent to form a mixture; b) preparing an acyl sulfate in the mixture wherein the benzisoxazole acid is sulfonated by the acyl sulfate to form the intermediate of zonisamide; c) heating the mixture; and d) isolating the intermediate of zonisamide.
  • the present invention provides benzisoxazole methane sulfomc acid substantially free of disulfonated benzisoxazole derivatives.
  • the present invention provides zonisamide substantially free of disulfonated benzisoxazole derivatives.
  • the present invention provides zonisamide substantially free of impurities and without the use of dioxane.
  • the present invention generally relates to the crystalline forms of benzisoxazole methane sulfonic acid (BOS-H) and its salts.
  • the present invention provides the crystalline forms of BOS with a metal cation.
  • the present invention provides the crystalline forms of BOS-Na, BOS-Ca, and BOS-Ba.
  • Other metallic salts include, but not limited to, potassium, magnesium, lithium, manganese, cobalt, iron, copper, nickel, zinc, silver and the like.
  • the present invention relates to the zonisamide intermediate BOS in the form of acid and metallic salts which are useful in the zomsamide synthesis.
  • the present invention provides the hydrated crystalline forms of BOS-H and its salts as intermediates in the zonisamide synthesis.
  • the present invention provides a novel crystal form of BOS-Na Form I, characterized by an X-Ray Powder Diffraction (XRD) having the most characteristic peaks at about 5.0, 17.3, 18.0, 18.6, and 19.7 ⁇ 0.2 degrees two theta.
  • XRD X-Ray Powder Diffraction
  • the present invention provides a novel crystal form of BOS-Na Form I, characterized by an X-Ray Powder Diffraction (XRD) having the main peaks at about 5.0, 15.7, 16.5, 17.3, 18.6, 19.1, 19.7, 21.5, 22.8, 23.2, 23.5 and 24.3 + 0.2 degrees two theta.
  • XRD X-Ray Powder Diffraction
  • the present invention provides a novel crystal form of BOS-Na Form I, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the most characteristic peaks at about 3546, 3485, 3440, 1641, 669 and 593 cm "1 .
  • FTIR Furier Transform Infra Red Spectroscopy
  • the present invention provides a novel crystal form of BOS-Na Form I, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following peaks at about 3546, 3485, 3440, 1612, 1513, 1439, 1410, 1382, 1234, 1199, 1048, 918, 855, 760, 669 and 593 cm "1 .
  • FTIR Furier Transform Infra Red Spectroscopy
  • the present invention provides a novel crystal form of BOS-Na Form I having a water content of about 7%.
  • the present invention provides a novel crystal form of BOS-Na Form ⁇ , characterized by an X-Ray Powder Diffraction (XRD) having the main peaks at about 5.3, 16.6, 21.3 and 26.7 ⁇ 0.2 degrees two theta.
  • XRD X-Ray Powder Diffraction
  • the present invention provides a novel crystal form of BOS-Na Form ⁇ , characterized by an X-Ray Powder Diffraction (XRD) having the most characteristic peaks at about 5.3, 15.9, 16.6, 21.3 and 26.7 ⁇ 0.2 degrees two theta.
  • XRD X-Ray Powder Diffraction
  • the present invention provides a novel crystal form of BOS-Na Form ⁇ , characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following peaks at about 3597, 3535, 3496, 3067, 2998, 2951, 1606, 1516, 1438, 1382, 1213, 1064, 1055, 743, 663, 588, 541 and 522 cm -1 .
  • FTIR Furier Transform Infra Red Spectroscopy
  • the present invention provides a novel crystal form of BOS-Na Form II having a water content of about 1.8%.
  • the present invention provides a novel crystal form of BOS-Na Form HI, characterized by an X-Ray Powder Diffraction (XRD) having the most characteristic peaks at about 5.0, 5.3, and 17.8 ⁇ 0.2 degrees two theta.
  • the present invention provides a novel crystal form of BOS-Na Form III, characterized by an X-Ray Powder Diffraction (XRD) having the main peaks at about 5.0, 5.3, 15.7, 17.8 and 21.4 ⁇ 0.2 degrees two theta.
  • the present invention provides a novel crystal form of BOS-Na Form HI, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the most characteristic peaks at about 3604, 1065, 812 and 696 cm '1 .
  • FTIR Furier Transform Infra Red Spectroscopy
  • the present invention provides a novel crystal form of BOS-Na Form HI, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following peaks at about 3604, 3495, 3067, 2998, 2951, 1605, 1516, 1438, 1382, 1215, 1136, 1065, 1052, 777, 747, 696, 588 and 521 cm “1 .
  • FTIR Furier Transform Infra Red Spectroscopy
  • the present invention provides a novel crystal form of BOS-Na Form V, characterized by an X-Ray Powder Diffraction (XRD) having the main peaks at about 6.7, 10.9, 16.1, 21.0, 21.2 and 22.2 ⁇ 0.2 degrees two theta.
  • XRD X-Ray Powder Diffraction
  • the present invention provides a novel crystal form of BOS-Na Form V, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the most characteristic peaks at about 3601, 3520, 1587, 1055, 793, and 753 cm “1 .
  • FTIR Furier Transform Infra Red Spectroscopy
  • the present invention provides a novel crystal form of BOS-Ba Form V having a water content of less than about 1.5%.
  • the present invention provides a novel crystal form of BOS-Ba Form I, characterized by the following X-Ray Diffraction main peaks at about 5.2, 10.4, 12.0, 13.8, 15.6, 17.0, 23.9 and 25.4+ 0.2 degrees two theta.
  • the present invention provides a novel crystal form of BOS-Ba Form I, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following peaks at about 3544, 3491, 2985, 2943, 1626, 1610, 1509, 1437, 1383, 1369, 1223, 1209, 1175, 1153, 1055, 1043, 911, 869, 752, 651, 603, 543 and 511cm "1 .
  • the present invention provides a novel crystal form of BOS-Ba Form I having a water content about 3.5%.
  • the present invention provides a novel crystal form of BOS-Ca Form I, characterized by having the following X-Ray Diffraction main peaks at about 5.4, 11.7, 16.0, 16.7, 17.7, 18.1, 19.1, 20.8, 24.5, 24.9 and 29.2 ⁇ 0.2 degrees two theta.
  • the present invention provides a novel BOS-H monohydrate Form I, characterized by having the following X-Ray Diffraction main peaks at about 13.8, 14.4, 17.4, 17.8, 21.8, 22.2, 25.8, 27.8 ⁇ 0.2 degrees two theta.
  • the present invention provides a novel BOS-H monohydrate Form I having a water content about 7.6%.
  • the present invention provides a novel process for preparing a BOS-H Form I.
  • the present invention further provides a process of preparing a BOS-H Form I, comprising the steps of: 1) preparing a mixture of chlorosulfonic acid in an organic solvent; 2) adding BOA to the mixture; 3) treating the mixture with NaOH to raise pH; and 4) isolating the BOS-H Form I.
  • the present invention provides a novel process for preparing a BOS-Na Form I.
  • the present invention further provides a process of preparing a BOS-Na Form I, comprising the steps of: 1) preparing a mixture of chlorosulfonic acid in an organic solvent; 2) adding BOA to the mixture; 3) treating the mixture with NaOH to raise pH; and 4) isolating the BOS-Na Form I.
  • the present invention provides a novel process for preparing a BOS-Na Form I.
  • the present invention further provides a process of preparing a BOS-Na Form I, comprising the steps of: 1) preparing a mixture of an anhydride and sulfuric acid to form acyl-sulfate in the presence of an organic solvent; 2) adding BOA to the mixture; 3) treating the mixture with NaOH to raise pH; 4) cooling the mixture to form a precipitate; 5) drying the precipitate; and 6) keeping the dry precipitate at room temperature to obtain the BOS-Na Form I.
  • the present invention provides a novel process for preparing a BOS-Na Form II.
  • the invention further provides a process of preparing a BOS-Na Form II, comprising the steps of: 1) preparing a mixture of an anhydride and sulfuric acid to form acyl-sulfate in the presence of ethyl acetate; 2) adding BOA to the mixture; and 3) treating the mixture with NaOH to raise pH; 4) cooling the mixture to form a precipiate; and 5) drying the preciptate at 80°C to obtain the BOS-Na Form II.
  • the present invention provides a novel process for preparing BOS-Na Form III.
  • the present invention further provides a method of preparing a BOS-Na Form ID, comprising the steps of: 1) preparing a mixture of an anhydride and sulfuric acid to form acyl-sulfate in the presence of toluene; 2) adding BOA to the mixture; 3) treating the mixture with NaOH to raise pH; 4) cooling the mixture to form a precipitate; and 5) drying the preciptate at 80°C to obtain the BOS-Na Form HI.
  • the present invention provides a novel process for preparing a BOS-Na Form V.
  • the present invention further provides a method of preparing a BOS-Na Form V, comprising the steps of: 1) preparing a mixture of an anhydride and sulfuric acid to form acyl-sulfate; 2) adding BOA to the mixture; 3) treating the mixture with NaOH to raise pH; 4) cooling the mixture to form a precipitate; and 5) drying the preciptate at about 85°C to obtain the BOS-Na Form V.
  • the present invention provides a novel process for preparing BOS-Ba Form I.
  • the present invention further provides a method of preparing a BOS-Ba Form I, comprising the steps of: 1) preparing a mixture of chlorosulfonic acid and an organic solvent; 2) adding BOA to the mixture; 3) treating the mixture with Ba(OH) 2 , and 4) isolating the BOS-Ba Form I.
  • the present invention provides a novel process for preparing a BOS-Ca Form I.
  • the present invention further provides a method of preparing a BOS-Ca Form I, comprising the steps of: 1) preparing a mixture of chlorosulfonic acid and an organic solvent; 2) adding BOA the mixture; 3) treating the mixture with Ca(OH) 2 ; and 4) isolating the BOS-Ca Form I.
  • Fig. 1 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Na monohydrate novel
  • Fig. 2 depicts the Furier Transform Infra Red Spectroscopy (FTIR) spectrum of BOS-Na novel Form I.
  • Fig. 3 depicts the Differential Thermal Gravimetry (DTG) of BOS-Na novel Form I.
  • FTIR Furier Transform Infra Red Spectroscopy
  • Fig. 4 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Na novel Form II.
  • Fig. 5 depicts the Furier Transform Infra Red Spectroscopy (FTIR) spectrum of BOS-Na novel Form ⁇ .
  • FTIR Furier Transform Infra Red Spectroscopy
  • Fig. 6 depicts the Differential Thermal Gravimetry (DTG) of BOS-Na novel Form H.
  • Fig. 7 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Na novel Form m.
  • Fig. 8 depicts the Furier Transform Infra Red Spectroscopy (FTIR) spectrum of BOS-Na novel Form HI.
  • FTIR Furier Transform Infra Red Spectroscopy
  • Fig. 9 depicts the Differential Thermal Gravimetry (DTG) of BOS-Na novel Form m.
  • Fig. 10 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Na novel Form V.
  • Fig. 11 depicts the Furier Transform Infra Red Spectroscopy (FTIR) spectrum of BOS-Na novel Form V.
  • XRD X-ray Powder Diffraction
  • FTIR Furier Transform Infra Red Spectroscopy
  • Fig. 12 depicts the Differential Scanning Calorimetry (DSC) of BOS-Na novel Form V.
  • Fig. 13 depicts the Thermal Gravimetric Analysis (TGA) thermogram of BOS-Na novel Form
  • Fig. 14 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Ba novel Form I.
  • Fig. 15 depicts the Furier Transform Infra Red Spectroscopy (FTIR) spectrum of BOS-Ba novel Form I.
  • FTIR Furier Transform Infra Red Spectroscopy
  • Fig. 16 depicts the Differential Thermal Gravimetry (DTG) of BOS-Ba novel Form I.
  • Fig. 17 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-Ca novel Form I.
  • Fig. 18 depicts the Differential Thermal Gravimetry (DTG) of BOS-Ca novel Form I.
  • Fig. 19 depicts the X-ray Powder Diffraction (XRD) Pattern for BOS-H monohydrate novel
  • Fig. 20 depicts the Differential Thermal Gravimetry (DTG) of BOS-H monohydrate novel
  • benzisoxazole acetic acid BOA
  • BOS benzisoxazole-methane-sulfomc acid
  • BOS-Na sodium salt of benzisoxazole-methane-sulfonic acid
  • BOS-Ca calcium salt of benzisoxazole-methane- sulfonic acid
  • BOS-Ba barium salt of benzisoxazole-methane-sulfonic acid
  • sulfuric acid H 2 SO 4
  • chlorosulfonic acid ClSO 3 H
  • disulfonation product S-BOS
  • tertiary- butyl alcohol tertiary- butyl alcohol
  • substantially free refers to less than 2-5%.
  • Room temperature refers to ambient temperature.
  • TGA refers to thermogravimetric analysis.
  • the Karl Fisher assay for determining water content is well known and is described in Pharmacopeial Form, Vol. 24, No. 1, p.5438 (Jan.-Feb. 1998). Such an assay permits the determination of water content of a crystal form based on the Loss on Drying Method.
  • TGA is a measure of the thermally induced weight loss of a material as a function of the applied temperature.
  • FTIR Furier Transform Infra Red Spectroscopy.
  • FTIR is a well-known spectroscopy analysis in which absorption of IR energy by the sample results from transitions between molecular vibrational energy levels.
  • FTIR is used, in modern practice, mainly for identification of functional groups in the molecule.
  • different polymorphic forms also show differences in FTIR.
  • the FTIR spectra were collected using Diffuse Reflectance Technique; scanning range: 4000-400cm “1 , 16 scans, resolution: 4.0cm "1 .
  • the present invention relates to more convenient methods for sulfonation of benzisoxazole acetic acid (BOA).
  • the sulfonation process involves a reaction that does not use dioxane and eliminates the problem of the waste.
  • the present sulfonation method relates to the sulfonation reaction of benzisoxazole acetic acid using chlorosulfonic acid in organic solvents like dichloroethane, dichloromethane, toluene, ethylene glycol-dimethylether or heptane using a slight excess of the sulfonating reagent. Under such conditions, the sulfonation reaction is selective.
  • the present sulfonation reaction solvent may be a polar solvent like ethyl-acetate, dichloroethane, t-BuOH, or a non-polar solvent like hexanes, heptane, cyclohexane, toluene, dichlorobenzene or mixture thereof.
  • the present invention has the advantage of the sulfonation reaction using chlorosulfonic acid wherein the reaction is selective and proceeds mainly in the alpha position of benzisoxazole acetic acid.
  • the disulfonated product is obtained at a level of about 2-5%.
  • the present invention also provides a process for preparing benzisoxazole methane sulfomc acid (BOS) employing acyl-sulfates or in situ prepared acyl-sulfates.
  • BOS benzisoxazole methane sulfomc acid
  • In situ prepared acyl-sulfates may be obtained from anhydrides and sulfuric acid, acyl-halides and sulfuric acid, or carboxylic acids and sulfuric acid; all organic acids including fatty acids may react in this way.
  • a more prefe ⁇ ed sulfonation process involves the use of the acyl-sulfates obatined from anhydrides and H 2 SO or acyl-halide and H 2 SO .
  • acyl-sulfates of a practical interest include acetyl-sulfate (obtained from Ac 2 O/H 2 SO 4 or acetylchloride/H SO 4 ), propionyl-sulfate, butyryl-sulfate or other acyl-sulfate (obtained in the same manner from the conesponding anhydride or acyl-halide and H 2 SO 4 ) which are more economics and more easy to handle.
  • the more preferred method uses acetic anhydride and sulfuric acid (H 2 SO 4 ).
  • the more preferred sulfonating reagent "anhydride acetic/H 2 SO " is economic, easy for handling, and excludes the use of dioxane.
  • the sulfonation process using acyl-sulfates is even more selective than that of chlorosulfomc acid in organic solvent.
  • the selective sulfonation proceeds preferentially in the alpha position and the disulfonated side-product is obtained at a low level up to 1%.
  • the sulfonation process for the Ac 2 O/H SO involves a reaction that is performed in polar and non-polar solvents.
  • the polar solvents include ethylacetate, ethylcellosolve, methylcellosolve, dichloroethane, dichloromethane, chloroform or mixture thereof and the like.
  • the non-polar solvents include toluene, heptane, hexanes, alkanes or mixtures thereof and the like.
  • the present invention provides new crystal forms of BOS.
  • the polymorphic modification of this zonisamide intermediate are chemically identical, but exhibit differences in their physical properties such as X-Ray Diffractrogram, Furier Transform Infra Red Spectroscopy and etc.. Differences in mechanical behavior or in the dissolution properties of different polymorphic modifications can significantly influence the ease of processing or the bioavailability ofthese compounds. It is desirable to obtain various crystal or polymorphic forms of zonisamide intermediates.
  • BOS is a hygroscopic compound.
  • BOS-H is a more hygroscopic compound than its alkaline or earth-alkaline salts. Practically, it is recommended to isolate the product as salt rather than the free sulfonic acid.
  • BOS-H and its salts are readily soluble in water and this makes difficult their separation from the reaction mixture.
  • the salts of sulfonic acid are less water-soluble than the inorganic salts and it is preferable to proceed to the conversion of sulfonic acid into its salt (sodium, calcium or barium salt) and to isolate them by salting out with an inorganic salt.
  • BOS salts include generally alkaline salts and earth- alkaline salts.
  • BOS salts include sodium (Na), potassium (K), calcium (Ca), barium (Ba), and Magnesium (Mg).
  • BOS is a strong acid having approximately the same strength as H 2 SO and can forms salts with various cations including silver (Ag), cadium (Ca), zinc (Zn), mercury (Hg), and aluminium (Al).
  • the present invention further provides a crystalline form of benzisoxazole methane sulfonic acid wherein the metal cation is selected from sodium, calcium, barium, potassium, magnesium, lithium, manganese, cobalt, iron, copper, nickel, zinc, and silver.
  • BOS-H and its sodium (Na-), calcium (Ca-) or barium (Ba-) salts are usually obtained from the reaction with 1-2 % water content but they can absorb water from the medium until the hydrate is obtained.
  • Na- sodium
  • Ca- calcium
  • Ba- barium
  • Example 3 Preparation of BOS-Na: Ac 2 O/ H 2 SO 4 in toluene In a 100 mL three necked flask, equipped with thermometer, condenser and mechanical stirrer was charged toluene (40 mL), H 2 SO ,98% (2 mL, 1.3 eq.) and acetic anhydride (3.5 mL, 1.3 eq.) at room temperature.
  • benzisoxazole acetic acid (BOA) was added (5 grams) and the reaction mixture was heated to reflux. The reflux was continued for about 4.5 hours. To the chilled reaction mixture, more reagent was added (2 mL H 2 SO 4; 98% and 3.5 mL acetic anhydride) and the heating was continued for additional 4 hours. After cooling of the reaction mixture to room temperature, ice was added and the mixture was sti ⁇ ed. The organic phase was discarded and to the aqueous phase solid NaOH was added (7.5 grams). The product precipitates upon cooling at -5 °C; the solid was filtrated, washed with toluene and dried in vacuum-oven at -80 °C. The yield was 7.6 g BOS-Na with 92.4% purity on HPLC.
  • BOA benzisoxazole acetic acid
  • Example 4 Preparation of BOS-Na: CISO3H in dichloroethane In a 100 mL three necked flask, equipped with thermometer, condenser and mechanical stirrer was charged dichloroethane (25 mL), 2.5 mL ClSO 3 H (1.3 eq.), and BOA (5 grams). The reaction mixture was heated at reflux for 1.5 hours.
  • Example 5 Preparation of zonisamide from BOS-Na
  • POCI 3 60 mL
  • BOS-Na (19 grams).
  • the reaction mixture was heated to reflux and the reflux was maintained for three hours.
  • the excess of POCl 3 was distilled and to the obtained residue was added ethyl-acetate.
  • the solids were filtered and washed with ethyl-acetate.
  • the solution of ethyl-acetate contains the product 1,2-benzisoxazole methane sulfonyl chloride.
  • BOS-Na monohydrate novel form I was characterized by X-Ray Powder Diffraction (XRD), Furier Transform Infra Red Spectroscopy (FTIR), Differential Thermal Gravimetry (DTG), and Karl-Fischer titration (KF).
  • BOS-Na monohydrate novel form I is characterized by the following X-Ray Diffraction main peaks at about 5.0, 15.7, 16.5, 17.3, 18.6, 19.1, 19.7, 21.5, 22.8, 23.2, 23.5 and 24.3 ⁇ 0.2 degrees two theta.
  • FTIR spectrum of BOS-Na novel form I is characterized by the following peaks at about 3546, 3485, 3440, 1612, 1513, 1439, 1410, 1382, 1234, 1199, 1048, 918, 855, 760, 669 and 593 cm "1 .
  • the combined DTA and TGA profiles of Bos-Na form I is characterized by an endothermic peak at about 100°C.
  • the TGA curve shows a weight loss step of about 7% in this temperature range. This weight loss step is due to water released out of the sample.
  • Water content measured by Karl-Fischer (KF) method is in agreement with TGA weight loss step and is about 7%. This water content is coincident with the expected water content of monohydrate.
  • BOS-Na novel form II was characterized by X-Ray Powder Diffraction (XRD), Furier
  • FTIR Transform Infra Red Spectroscopy
  • TMG Differential Thermal Gravimetry
  • BOS-Na novel form II is characterized by the following X-Ray Diffraction main peaks at about 5.3, 15.9, 16.6, 21.3 and 26.7 ⁇ 0.2 degrees two theta.
  • the most characteristic XRD peaks are at about 5.3, 16.6, 21.3, and 26.7 ⁇ 0.2 degrees two theta.
  • FTIR spectrum of BOS-Na novel form II is characterized by the following peaks at about 3597, 3535, 3496, 3067, 2998, 2951, 1606, 1516, 1438, 1382, 1213, 1064, 1055, 743, 663, 588, 541 and 522 cm '1 .
  • the most characteristic FTIR peaks are at 3571 and 3597 cm "1 .
  • DTG profile of BOS-Na novel form II is characterized by three endothermic peaks at about 243, 265 and 278°C. The sharp weight loss in this temperature range is due to decomposition of the sample.
  • BOS-Na novel form III was characterized by X-Ray powder diffraction (XRD), Furier
  • FTIR Transform Infra Red Spectroscopy
  • TMG Differential Thermal Gravimetry
  • BOS-Na novel form III is characterized by the following X-Ray Diffraction main peaks at about 5.0, 5.3, 15.7, 17.8 and 21.4 ⁇ 0.2 degrees two theta.
  • the most characterisitc XRD peaks are at about 5.0, 5.3, and 17.8 ⁇ 0.2 degrees two theta.
  • FTIR spectrum of BOS-Na novel form III is characterized by the following peaks at about 3604, 3495, 3067, 2998, 2951, 1605, 1516, 1438, 1382, 1215, 1136, 1065, 1052, 777, 747, 696, 588 and 521 cm “1 .
  • the most characteristic FTIR peaks are at about 696, 812, 1065 and 3604 cm "1 .
  • DTG profile of BOS-Na novel form III is characterized by an endothermic peak at about 233°C.
  • the sharp weight loss in this temperature range is due to decomposition of the sample.
  • BOS-Ba novel form V was characterized by X-Ray Powder Diffraction (XRD), Furier Transform Infra Red Spectroscopy (FTIR), Differential Scanning Calorimetry, and Thermal Gravimetric Analysis (TGA).
  • XRD X-Ray Powder Diffraction
  • FTIR Furier Transform Infra Red Spectroscopy
  • TGA Thermal Gravimetric Analysis
  • XRD analysis were performed X-Ray powder diffractometer, Scintag, variable goniometer, Cu-tube, solid state detector.
  • Sample holder A round standard aluminum sample holder with round zero background quartz plate. Scanning parameters: Range: 2-40 degrees two theta. Continuous scan rate: 3 deg./min.
  • BOS-Na novel form V is characterized by the following X-Ray Diffraction main peaks at about 6.7, 10.9, 16.2, 21.0, 21.2 and 22.2 ⁇ 0.2 degrees two theta.
  • FT ⁇ R FTIR spectrum was collected on Perkin-Elmer Spectrum One FTIR spectrometer using Diffused Reflectance technique. Scanning range: 400-4000 cm '1 , number of scans: 16, resolution: 4.0 cm "1 .
  • FTIR spectrum of BOS-Na novel form V is characterized by the following peaks at about 753, 793, 1055, 1587, 3520 and 3601 cm '1 .
  • Heating rate 10°C/min. Number of holes in the crucible:3.
  • DSC profile is characterized by two overlapped endothermic peaks at about 164°C.
  • Mettler TG50 instrument was used for the TGA analysis. Heating rate: 10°C/min. Nitrogen flow: 40 ml/min.
  • TGA thermogram shows LOD value of about 2% in a temperature range of up to 190°C
  • BOS-Ba novel form I was characterized by X-Ray Powder Diffraction (XRD), Furier Transform Infra Red Spectroscopy (FTIR) and by Differential Thermal Gravimetry (DTG).
  • XRD X-Ray Powder Diffraction
  • FTIR Furier Transform Infra Red Spectroscopy
  • TG Differential Thermal Gravimetry
  • BOS-Ba novel form I is characterized by the following X-Ray Diffraction main peaks at about 5.2, 10.4, 12.0, 13.8, 15.6, 17.0, 23.9 and 25.4 ⁇ 0.2 degrees two theta.
  • FTIR spectrum of BOS-Ba is characterized by the following peaks at about 3544, 3491, 2985, 2943, 1626, 1610, 1509, 1437, 1383, 1369, 1223, 1209, 1175, 1153, 1055, 1043, 911, 869, 752, 651, 603, 543 and 511 cm “1 .
  • DTG DTG profile of BOS-Ba novel form I is characterized by an endothermic peak at about 200°C. A weight loss step of about 3.5% is observed in this temperature range.
  • BOS-Ca novel form I was characterized by X-Ray Powder Diffraction (XRD) and by Differential Thermal Gravimetry (DTG).
  • BOS-Ca novel form I is characterized by the following X-Ray Diffraction main peaks at about 5.4, 11.7, 16.0, 16.7, 17.7, 18.1, 19.1, 20.8, 24.5, 24.9 and 29.2+ 0.2 degrees two theta.
  • DTG profile of BOS-Ca novel form I is characterized by two endothermic peaks at about 137 and 165°C.
  • the LOD up to 200°C is about 7.6%.
  • BOS-H monohydrate novel form I BOS-H monohydrate novel form I was characterized by X-Ray Powder Diffraction (XRD), by Differential Thermal Gravimetry (DTG) and by Karl-Fischer titration (KF).
  • BOS-H novel monohydrate novel form I is characterized by the following X-Ray Diffraction main peaks at about 13.8, 14.4, 17.4, 17.8, 21.8, 22.2, 25.8, 27.8 ⁇ 0.2 degrees two theta.
  • DTG DTG profile of BOS-H monohydrate novel form I is characterized by two endothermic peak at about 120 and 175°C. A weight loss step of about 9% is observed in this temperature range.
  • Water content of BOS-H novel form I as was measured by KF titration is about 7.6%. This value is coincident with the expected water content for monohydrate form.
  • the aqueous phase was extracted with methylene chloride and then evaporated to dryness on rotavapor. The solid was dried for two days at 60°C and for -16 hours at 100°C.
  • the product is BOS-H Form I (KF 2.8%).
  • the product was isolated by evaporation to dryness of the aqueous solution and n- BuOH.
  • the obtained solid was than dried in oven at 80°C.
  • BOS-Na (271 grams) was obtained; the solid does not contain water (KF 0.002%).
  • BOS-Na dry was kept in a closed bottle at room temperature. After about 5 months the KF analysis (7.3%) indicates the formation of hydrate-BOS-Na Form I.
  • the solid was washed with ethyl acetate and dried at 80°C for 2 days.
  • the obtained BOS-Na (6.3 grams) contains 1.7% water (by KF). This solid was exposed to the laboratory humidity for one week; the obtained solid is BOS-Na Form I.
  • the reaction mixture was cooled to room temperature and treated with NaOH pearls to precipitate the product upon cooling.
  • the solid was washed with toluene, filtrated and dried at 80°C for two days.
  • the product is BOS-Na Form HI.
  • the crystalline form was obtained during the production of BOS-Na in industrial scale.
  • the preparation of BOS-Na is the laboratory procedure adapted to the large scale.
  • reaction mixture was heated at reflux and then sti ⁇ ed at reflux until the reaction completion (-5 hours). After this, the mixture was cooled to ⁇ 25°C and treated with NaOH. Th reaction product precipitatd on cooling to ⁇ 5°C. The solid was filtrated and washed with ethylacetate.
  • reaction mixture was cooled to room temperature and ice was added.
  • the aqueous phase was extracted with methylene chloride and then held with Ba(OH) 2 (56 grams); the solid was filtrated, washed with water and dried in oven at 100°C for 5 hours.
  • the product is BOS-Ba Form I.
  • the invention provides crystalline forms of benzisoxazole methane sulfonic acid (BOS-H) and its salts (BOS-Na, BOS-Ca, BOS-Ba).
  • BOS-H benzisoxazole methane sulfonic acid
  • BOS-Na, BOS-Ca, BOS-Ba salts
  • BOS-Ba benzisoxazole methane sulfonic acid
  • BOS-Na, BOS-Ca, BOS-Ba salts

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne une nouvelle sulfonation d'un produit intermédiaire de zosinamide. Elle concerne en particulier le processus de sulfonation au moyen d'acide chlorosulfonique, ou d'anhydride acétique et d'acide sulfurique dans un solvant organique. L'invention concerne en outre des formes cristallines de l'acide benzisoxazole méthane sulfonique (BOS-H) et de ses sels (BOS-Na, BOS-Ca, et BOS-Ba) et de nouveaux procédés de préparation de ces composés.
EP02768748A 2001-08-30 2002-08-29 Produits intermediaires de zosinamide et synthese y relative Withdrawn EP1430037A4 (fr)

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US31610901P 2001-08-30 2001-08-30
US316109P 2001-08-30
US34443901P 2001-10-24 2001-10-24
US344439P 2001-10-24
PCT/US2002/027593 WO2003020708A1 (fr) 2001-08-30 2002-08-29 Produits intermediaires de zosinamide et synthese y relative

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CN1636002A (zh) * 2002-02-22 2005-07-06 特瓦制药工业有限公司 制备苯并异噁唑甲基磺酰氯及将其酰胺化形成唑尼沙胺的方法
US7291742B2 (en) * 2003-01-10 2007-11-06 Dipharma S.P.A. Process for the preparation of benzo [d] isoxazol-3-yl-methanesulfonic acid and the intermediates thereof
DE60331257D1 (de) 2003-01-13 2010-03-25 Dainippon Sumitomo Pharma Co Verfahren zur herstellung von 1,2-dichlorethan freien kristallen von zonisamid und hochreinezonisamidkristalle
AU2003304484A1 (en) * 2003-09-29 2005-04-14 Suven Life Sciences Limited Improved process for the preparation of intermediates useful for the preparation of zonisamide
US7745471B2 (en) 2004-06-18 2010-06-29 Chemagis Ltd. Derivatives of 1,2-benzisoxazole-3-methane sulfonic acid as novel intermediates for the synthesis of zonisamide
KR20080046175A (ko) * 2005-09-16 2008-05-26 다이닛본 스미토모 세이야꾸 가부시끼가이샤 1,2-벤지속사졸-3-아세트산의 술폰화법
US7375233B2 (en) 2005-12-16 2008-05-20 Apotex Pharmachem Inc. Process for the preparation of zonisamide and the intermediates thereof
WO2018004993A1 (fr) 2016-07-01 2018-01-04 Res Usa, Llc Réduction des émissions de gaz à effet de serre
US9981896B2 (en) 2016-07-01 2018-05-29 Res Usa, Llc Conversion of methane to dimethyl ether
US9938217B2 (en) 2016-07-01 2018-04-10 Res Usa, Llc Fluidized bed membrane reactor

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JP2005506980A (ja) 2005-03-10

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