Abstract:
The present invention is directed to a one-step process for the preparation of fructopyranose sulfamate derivatives of the general formula (I)  
                         
 
     wherein X, R 1 , R 3 , R 4 , R 5  and R 6  are as described in the specification.

Description:
CROSS REFERENCE TO RELATED APPLICATION  
       [0001]    This application claims the benefit of U.S. Provisional Application 60/451,863, filed on Mar. 4, 2003, which is incorporated by reference herein in its entirety. 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    The present invention relates to a one step process for the preparation of compounds of the formula (I)  
                         
 
           [0003]    wherein X, R 1 , R 3 , R 4 , R 5  and R 6  are as hereinafter defined. The compounds of formula (I) are useful for the treatment of epilepsy.  
         BACKGROUND OF THE INVENTION  
         [0004]    The compounds of formula (I)  
                         
 
           [0005]    wherein R 1  is selected from the group consisting of hydrogen and C 1-4 alkyl and wherein X, R 3 , R 4 , R 5  and R 6  are as hereinafter defined, are known compounds that have been found to exhibit anticonvulsant activity and are therefore useful in the treatment of conditions such as epilepsy. These compounds are disclosed in U.S. Pat. No. 4,582,916 and U.S. Pat. No. 4,513,006, which also disclose processes for the preparation of said compounds; and which are hereby incorporated by reference.  
           [0006]    One process disclosed in the above referenced patents is a process for the preparation of the compounds of formula (I) comprising reacting an alcohol of the formula RCH 2 OH with a chlorosulfamate of the formula ClSO 2 NH 2  or ClSO 2 NHR 1  in the presence of a base such as potassium t-butoxide or sodium hydride at a temperature of about −20° C. to 25° C. and in a solvent such as toluene, tetrahydrofuran or dimethylformamide, where R is a moiety of the formula (II)  
                         
 
           [0007]    This process has two major disadvantages. One disadvantage is that the process calls for a combination of NaH and DMF which has an uncontrollable exotherm and is therefore potentially explosive. See J. Buckley et al., Chemical &amp; Engineering News, Jul. 12, 1982, page 5; and G. DeWail, Chemical &amp; Engineering News, Sep. 13, 1982. Another disadvantage is that the process also uses highly toxic and corrosive chlorosulfonyl isocyanate (CSI) to prepare the commercially unavailable sulfamyl chloride (ClSO 2 NH 2 ). The CSI is not only difficult to work with, because of its toxicity and corrosiveness, but also is available from only limited suppliers.  
           [0008]    Another process for the preparation of compound of formula (I) disclosed in the above mentioned U.S. Pat. No. 4,513,006 comprises reacting an alcohol of the formula RCH 2 OH with sulfuryl chloride of the formula SO 2 Cl 2  in the presence of a base such as triethylamine or pyridine at a temperature of about −40° C. to 25° C. in a diethyl ether or methylene chloride solvent to produce a chlorosulfate of the formula RCH 2l OSO   2 Cl 2 . The chlorosulfate of the formula RCH 2 OSO 2 Cl 2  may then be reacted with an amine of the formula R 1 NH 2  at a temperature of about −40° C. to 25° C. in a methylene chloride or acetonitrile solvent to produce the compound of formula (I). This process utilizing diethyl ether, methylene chloride and acetonitrile solvents produces relatively low yields of the desired end product of formula (I).  
           [0009]    A third process disclosed in the two patents mentioned above comprises reacting the chlorosulfate of formula RCH 2 OSO 2 Cl 2  formed as previously described with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile to yield an azidosulfate of the formula RCH 2 OSO 3 N 3 . The azidosulfate is then reduced to the compound of formula I wherein R 1  is hydrogen, by catalytic hydrogenation.  
           [0010]    The disadvantage with this process is that explosions may occur when handling the azide compounds. Also, the process contains an additional chemical transformation involving the reduction of the azide to the NH 2  moiety.  
           [0011]    Maryanoff et al. in U.S. Pat. No. 5,387,700 disclose a process for the preparation of compounds of formula (I) which comprises reacting an alcohol of the formula RCH 2 OH with sulfuryl chloride in the presence of a base, in a solvent selected from the group consisting of toluene, t-butyl methyl ether and tetrahydrofuran, to form a chlorosulfate intermediate of the formula RCH 2 OSO 2 Cl 2 . The chlorosulfate of formula RCH 2 OSO 2 Cl 2  is reacted with an amine of the formula R 1 NH 2 , in a solvent selected from the group consisting of tetrahydrofuran, t-butyl methyl ether and lower alkanol (e.g. methanol or ethanol) to form the compound of formula (I).  
           [0012]    One disadvantage of this process is that the compound of formula (I) is prepared in a batch process wherein the first reaction is carried out, the solvent is removed, the product is isolated, the isolated product is re-dissolved in a second solvent and then reacted to form the final product. This results in a process which requires isolation of a semi-stable, thermally labile ROSO 2 Cl intermediate. Additionally, this process requires handling of multiple solvents and multiple solvent recovery processes for recycling or disposal resulting in a process which is both cost and labor intensive.  
           [0013]    It is an object of the present invention to provide a one step process for the preparation of the compounds of formula (I), a process which uses readily available materials, can be carried out without isolation of intermediates and/or produces relative high yields, thereby allowing for commercial production of the compounds of formula (I).  
         SUMMARY OF THE INVENTION  
         [0014]    The present invention is directed to a one-step process for the preparation of the compounds of formula (I)  
                         
 
           [0015]    wherein  
           [0016]    X is selected from CH 2  or O;  
           [0017]    R 1  is selected from the group consisting of hydrogen and C 1-4 alkyl;  
           [0018]    R 3 , R 4 , R 5  and R 6  are each independently selected from hydrogen or lower alkyl and, when X is CH 2 , R 5  and R 6  may be alkene groups joined to form a benzene ring and, when X is O, R 3  and R 4  and/or R 5  and R 6  together may be a methylenedioxy group of the formula:  
                         
 
           [0019]    wherein  
           [0020]    R 7  and R 8  are same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring;  
           [0021]    comprising  
                         
 
           [0022]    reacting a compound of formula (II) with sulfuryl diamide (also known as sulfamide), at an elevated temperature, in the presence of from 0 to about 10% water, to yield the corresponding compound of formula (I).  
           [0023]    The present invention is further directed to a process for the preparation of a compound of formula (Ia),  
                         
 
           [0024]    also known as topiramate, comprising  
                         
 
           [0025]    reacting a compound of formula (IIa) (also known as diacetone fructose or DAF) with sulfuryl diamide (also known as sulfamide), at an elevated temperature, in the presence of from 0 to about 10% water, to yield the corresponding compound of formula (Ia).  
           [0026]    The present invention is further directed to a compound prepared according to any of the processes described herein.  
           [0027]    Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound prepared according to any of the processes described above.  
           [0028]    An illustration of the invention is a pharmaceutical composition made by mixing a pharmaceutically acceptable carrier and a compound prepared according to any of the processes described above.  
           [0029]    Illustrating the invention is a process for making a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier and a compound prepared according to the processes described above.  
           [0030]    Another example of the invention is the use of a compound prepared according to any of the processes described herein in the preparation of a medicament for treating epilepsy. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0031]    In an embodiment of the present invention, the compound of formula (I) is topiramate, a compound of the formula (Ia)  
                         
 
         [0032]    As used herein, the terms “diacetone fructose” and “DAF” shall mean diacetone-β-D-fructose, a compound of formula (IIa)  
                         
 
         [0033]    As used herein, the term “alkyl”, whether used alone or as part of a substituent group, shall include straight and branched carbon chains. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isopbutyl, sec-butyl, tert-butyl, pentyl, and the like. Unless otherwise noted, the term “lower” when used with alkyl shall mean carbon chain compositions of one to four carbon atoms.  
         [0034]    As used herein, the notation “*” shall denote the presence of a stereogenic center.  
         [0035]    As used herein, the term “elevated temperature” shall mean a temperature greater than about 90° C., preferably a temperature greater than or equal to the reflux temperature of the solvent of the reaction mixture, more preferably a temperature in the range of about 90° C. to about 170° C., more preferably still at a temperature in the range of about 110° C. to about 160° C., more preferably still at a temperature in the range of about 120° C. to about 140° C.  
         [0036]    As used herein, unless otherwise noted, the term “in the presence of from 0 to about 10% water” shall mean that the total molar amount of water relative to the molar amount of DAF is in the range of from 0 to about 10%.  
         [0037]    As used herein, the term “aprotic organic solvent” shall mean any organic solvent that does not yield a proton under the reaction conditions. Suitable examples include, but are not limited to, xylene (for example o-xylene, p-xylene, m-xylene or a mixture thereof), ethyl benzene, mesitylene, tetrahydronaphthalene, pyridine, 1-methyl-2-pyrrolidinone, toluene, 4-methyl-2-pentanone, benzonitrile, dimethylformamide, sulfolane, diphenyl ether, and the like.  
         [0038]    The term “subject” as used herein, refers to an animal, preferably a mammal, more preferably a human, who is or has been the object of treatment, observation or experiment.  
         [0039]    The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.  
         [0040]    As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.  
         [0041]    One skilled in the art will recognize that the compounds of formula (I) have several stereogenic centers as denoted by the asterisks below.  
                         
 
         [0042]    One skilled in the art will further recognize that the processes of the present invention may be used to prepare racemic mixtures of a compound of the formula (I) or any of the stereoisomers of a compound of formula (I), by selection and substitution of appropriate racemic mixtures or stereoisomers of the reagents.  
         [0043]    The present invention is directed to a one step process for the preparation of a compound of formula (I) as outlined in Scheme 1.  
                         
 
         [0044]    Accordingly, a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, is reacted with sulfuryl diamide (also known as sulfamide),  
         [0045]    wherein the sulfuryl diamide is preferably present in an amount greater than or equal to about 0.9 equivalents; more preferably in an amount in the range of about 1.5 to about 3 equivalents; more preferably still in an amount equal to about 2 equivalents;  
         [0046]    preferably in the presence of a non-aqueous organic base such as an organic tertiary amine such as pyridine, 4-picoline, isoquinoline, dimethylbutylamine, 4-dimethylaminopyridine, 4-t-butylpyridine, imidazole, tributylamine, dimethylbenzylamine, and the like; or a non-aqueous inorganic base such as K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , and the like; more preferably, in the presence of a non-aqueous organic tertiary amine; more preferably still, in the presence of pyridine;  
         [0047]    wherein the non-aqueous organic or inorganic base is preferably present in an amount greater than about 1 equivalent; more preferably, in an amount in the range of about 3 to about 6 equivalents; more preferably still, in an amount equal to about 4 equivalents;  
         [0048]    in the presence of from 0% to about 10% water, preferably from 0% to about 5% water, more preferably from 0% to about 3% water;  
         [0049]    preferably in an aprotic organic solvent such as xylene (for example o-xylene, p-xylene, m-xylene or a mixture thereof), ethyl benzene, mesitylene, tetrahydronaphthalene, pyridine, 1-methyl-2-pyrrolidinone, toluene, 4-methyl-2-pentanone, benzonitrile, dimethylformamide, sulfolane, diphenyl ether, and the like; or a mixture of aprotic organic solvents such as diphenyl ether:biphenyl, xylene:toluene, technical grade mixed xylenes, and the like; more preferably in o-xylene, p-xylene, m-xylene, a mixture thereof or a technical grade mixed xylenes;  
         [0050]    alternatively, the solvent may be selected from a non-aqueous organic base such as an organic tertiary amine, for example, pyridine, 4-picoline, isoquinoline, dimethylbutylamine, 4-dimethylaminopyridine, 4-t-butylpyridine, imidazole, tributylamine, dimethylbenzylamine, and the like; preferably, a non-aqueous organic tertiary amine; more preferably, pyridine;  
         [0051]    alternatively still, when the compound of formula (II) is reacted in the presence of a non-aqueous organic base, the non-aqueous organic base may act as the solvent;  
         [0052]    at an elevated temperature, preferably at a temperature in the range of from about 90° C. to about 170° C.; more preferably, at a temperature in the range of from about 110° C. to about 160° C.; more preferably still at a temperature in the range of from about 120° C. to about 140° C.;  
         [0053]    to yield the corresponding compound of formula (I).  
         [0054]    Preferably, the compound of formula (II) is reacted with sulfuryl diamide, according to the process outlined in Scheme 1 above, in the absence of any other alcohol (i.e. an alcohol other than the compound of formula (II)).  
         [0055]    The compound of formula (Ia) may be prepared according to the process outlined in Scheme 2.  
                         
 
         [0056]    Accordingly, a compound of formula (IIa), a known compound also known as diacetone fructose (DAF), is reacted with sulfuryl diamide (also known as sulfamide),  
         [0057]    wherein the sulfuryl diamide is preferably present in an amount greater than or equal to about 0.9 equivalents; more preferably in an amount in the range of about 1.5 to about 3 equivalents; more preferably still in an amount equal to about 2 equivalents;  
         [0058]    preferably in the presence of a non-aqueous organic base such as an organic tertiary amine such as pyridine, 4-picoline, isoquinoline, dimethylbutylamine, 4-dimethylaminopyridine, 4-t-butylpyridine, imidazole, tributylamine, dimethylbenzylamine, and the like; or a non-aqueous inorganic base such as K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , and the like; more preferably, in the presence of a non-aqueous organic tertiary amine; more preferably still, in the presence of pyridine;  
         [0059]    wherein the non-aqueous organic or inorganic base is preferably present in an amount greater than about 1 equivalent; more preferably, in an amount in the range of about 3 to about 6 equivalents; more preferably still, in an amount equal to about 4 equivalents;  
         [0060]    in the presence of from 0% to about 10% water, preferably from 0% to about 5% water, more preferably from 0% to about 3% water;  
         [0061]    preferably in an aprotic organic solvent such as xylene (for example o-xylene, p-xylene, m-xylene or a mixture thereof), ethyl benzene, mesitylene, tetrahydronaphthalene, pyridine, 1-methyl-2-pyrrolidinone, toluene, 4-methyl-2-pentanone, benzonitrile, dimethylformamide, sulfolane, diphenyl ether, and the like; or a mixture of aprotic organic solvents such as diphenyl ether:biphenyl, xylene:toluene, technical grade mixed xylenes, and the like; more preferably in o-xylene, p-xylene, m-xylene, a mixture thereof or a technical grade mixed xylenes;  
         [0062]    alternatively, the solvent may be selected from a non-aqueous organic base such as an organic tertiary amine, for example, pyridine, 4-picoline, isoquinoline, dimethylbutylamine, 4-dimethylaminopyridine, 4-t-butylpyridine, imidazole, tributylamine, dimethylbenzylamine, and the like; preferably, a non-aqueous organic tertiary amine; more preferably, pyridine;  
         [0063]    alternatively still, when the compound of formula (II) is reacted in the presence of a non-aqueous organic base, the non-aqueous organic base may act as the solvent;  
         [0064]    at an elevated temperature, preferably at a temperature in the range of from about 90° C. to about 170° C.; more preferably, at a temperature in the range of from about 110° C. to about 160° C.; more preferably still at a temperature in the range of from about 120° C. to about 140° C.;  
         [0065]    to yield the corresponding compound of formula (Ia).  
         [0066]    Preferably, the compound of formula (IIa) is reacted with sulfuryl diamide, according to the process outlined in Scheme 2 above, in the absence of any other alcohol (i.e. an alcohol other than the compound of formula (IIa)).  
         [0067]    Where the compounds of the present invention have at least one chiral (or stereogenic) center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral (or stereogenic) centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.  
         [0068]    Where the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.  
         [0069]    During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in  Protective Groups in Organic Chemistry , ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene &amp; P. G. M. Wuts,  Protective Groups in Organic Synthesis , John Wiley &amp; Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.  
         [0070]    The following examples describe the invention in greater detail and are intended to illustrate the invention, but not to limit it.  
       EXAMPLE A1  
       [0071]    Experimental Runs #101-116:  
         [0072]    A reactor was charged with DAF, sulfamide, base, and solvent, as described in Table 1. While agitating, the reaction mixture was heated and held at the desired temperature and for the selected amount of time (as listed in Table 2).  
         [0073]    For experimental runs 101, 102, 103, the mixture was distilled at 41° C., under vacuum, for 30, 35 and 20 minutes, respectively.  
         [0074]    The reaction mixtures were cooled to room temperature, then extracted twice with about 50 mL of a 1M aqueous NaOH solution (An 0.3 M solution of aqueous NaOH was used for experimental runs #101-108). The resulting basic product solution was neutralized using 6M aqueous HCl solution. After crystallization, the product solution was filtered, and the wet cake was dried for between 16-20 hours (about 22 hours for experimental runs # 106 and 107) at about 50° C. under vacuum to yield topiramate product. The dry product was analyzed by HPLC.  
         [0075]    Experimental Runs # 117-139:  
         [0076]    A reactor was charged with DAF, sulfamide, base, and solvent, as described in Table 1. While agitating, the reaction mixture was heated and held for a period of about 60 minutes at the desired temperature (as listed in Table 2). After cooling to room temperature, the reaction mixture was extracted twice with about 75 mL of 1M aqueous NaOH solution. The resulting basic product solution was neutralized using 6M aqueous HCl solution. After crystallization, the product solution was filtered, and the wet cake was dried for 16-20 hours (˜24 hours for experimental runs 129, 134, 137 and ˜48 hours for experimental runs # 126, 128, 130, 131, 136) at about 50° C. vacuum to yield topiramate product. Experimental runs # 123, 125 and 135 were expected to yield product, but were abandoned due to difficulties during extraction or crystallization. The dry product was analyzed by HPLC.  
         [0077]    The above described procedures were completed according to the run conditions as listed in Table 1 and 2 below. Topiramate product was produced in all experimental runs except as noted above.  
                                                                         TABLE 1                       Run #   DAF   Sulfamide   Base   Base   Solvent                                101   10.05   g   7.43   g   pyridine   12.14   g   mixed xylenes           38.62   mmol   77.32   mmol       153.48   mmol    100 mL       102   10.0   g   7.39   g   pyridine   12.16   g   mixed xylenes           38.43   mmol   76.9   mmol       153.73   mmol    100 mL       103   10.0   g   7.33   g   pyridine   12.18   g   mixed xylenes           38.43   mmol   76.27   mmol       153.98   mmol    100 mL       104   10.0   g   7.43   g   pyridine   12.34   g   mixed xylenes           38.43   mmol   77.32   mmol       156.01   mol    100 mL       105   10.01   g   7.39   g   pyridine   12.17   g   mixed xylenes           38.47   mmol   76.9   mmol       153.86   mmol    101 mL       106   10.01   g   7.39   g   pyridine   12.45   g   mixed xylenes           38.47   mmol   76.9   mmol       157.4   mmol    101 mL       107   10.01   g   7.44   g   pyridine   12.15   g   mixed xylenes           38.47   mmol   77.42   mmol       153.6   mmol     51 mL       108   10.02   g   7.38   g   4-picoline   12.54   g   mesitylene           38.50   mmol   76.8   mmol       134.65   mmol     50 mL       109   14.98   g   11.08   g   pyridine   18.33   g   mixed xylenes           57.56   mmol   115.3   mmol       231.73   mmol    150 mL       110   9.99   g   7.39   g   Pyridine   12.14   g   O-xylene           38.39   mmol   76.9   mmol       153.48   mmol     99 mL       111   10.04   g   7.31   g   Pyridine   12.14   g   O-xylene           38.58   mmol   76.07   mmol       153.48   mmol    100 mL       112   10.03   g   7.39   g   Pyridine   12.22   g   O-xylene           38.54   mmol   76.9   mmol       154.49   mmol    100 mL       113   10.02   g   7.39   g   Pyridine   12.22   g   O-xylene           38.50   mmol   76.9   mmol       154.49   mmol    100 mL       114   9.98   g   7.38   g   Pyridine   12.25   g   O-xylene           38.35   mmol   76.8   mmol       154.87   mmol    100 mL       115   10.02   g   7.36   g   pyridine   12.4   g   O-xylene           38.5   mmol   76.59   mmol       156.76   mmol     99 mL       116   10.0   g   7.36   g   Pyridine   12.16   g   O-xylene           38.43   mmol   76.59   mmol       153.73   mmol    100 mL       117   29.92   g   22.31   g   Pyridine   36.52   g   O-xylene           114.98   mmol   232.15   mmol       461.49   mmol    302 mL       118   30.06   g   22.3   g   Pyridine   36.68   g   O-xylene           115.51   mmol   232.05   mmol       463.72   mmol    150 mL       119   30.07   g   22.34   g   4-picoline   42.48   g   1:1 O-                                       xylene:4-                                       picoline           115.55   mmol   232.47   mmol       456.14   mmol    150 mL       120   30.03   g   22.22   g   Pyridine   36.58   g   O-xylene           115.4   mmol   231.22   mmol       462.45   mmol     75 mL       121   30.04   g   22.23   g   Pyridine   36.55   g   O-xylene           115.44   mmol   231.32   mmol       462.07   mmol   40.0 mL       122   29.98   g   22.18   g   pyridine   36.37   g   none           115.09   mmol   230.8   mmol       459.8   mmol       123   30.02   g   22.34   g   4-picoline   42.91   g   none           115.36   mmol   232.47   mmol       460.75   mmol       124   30.09   g   22.24   g   iso-quinoline   58.11   g   none           115.63   mmol   231.43   mmol       449.91   mmol       125   30.01   g   22.18   g   4-picoline   42.92   g   tetrahydro-                                       naphthalene           115.32   mmol   230.8   mmol       460.86   mmol     40 mL       126   30.01   g   22.17   g   4-picoline   42.8   g   tetrahydro-                                       naphthalene           115.32   mmol   230.7   mmol       459.57   mmol     41 mL       127   29.99   g   22.34   g   dimethy-   59.95   g   tetrahydro-                           butyl-amine           naphthalene           115.24   mmol   232.47   mmol       757.9   mmol     40 mL       128   30.02   g   22.22   g   pyridine   36.56   g   tetrahydro-                                       naphthalene           115.36   mmol   231.22   mmol       462.2   mmol     40 mL       129   29.95   g   22.32   g   pyridine   36.45   g   diphenyl                                       ether           115.09   mmol   232.26   mmol       460.81   mmol     41 mL       130   30.02   g   22.34   g   4-picoline   43.03   g   diphenyl                                       ether           115.36   mmol   232.47   mmol       462.04   mmol   40.5 mL       131   29.99   g   22.24   g   4-picoline   42.94   g   O-xylene           115.24   mmol   231.43   mmol       461.08   mmol     40 mL       132   30.03   g   22.5   g   pyridine   36.12   g   O-xylene           115.4   mmol   234.31   mmol       456.64   mmol     40 mL       133   10.04   g   7.38   g   iso-quinoline   20.05   g   O-xylene           38.58   mmol   76.8   mmol       155.23   mmol     50 mL       134   30.05   g   22.21   g   4-t-butyl-   62.3   g   O-xylene                           pyridine           115.47   mmol   231.11   mmol       460.76   mmol     40 mL       135   30.08   g   22.45   g   iso-quinoline   59.65   g   diphenylether           115.59   mmol   233.61   mol       461.83   mmol   40.5 mL       136   60.08   g   44.28   g   4-picoline   85.91   g   O-xylene           230.87   mmol   460.77   mmol       922.47   mmol     75 mL       137   59.99   g   44.44   g   Pyridine   73.04   g   O-xylene           230.53   mmol   462.43   mmol       923.39   mmol     75 mL       138   30.04   g   22.5   g   4-t-butyl-   46.66   g   O-xylene                           pyridine           115.44   mmol   234.13   mmol       345.09   mmol     75 mL       139   30.02   g   22.18   g   4-t-butyl-   46.68   g   O-xylene                           pyridine           115.36   mmol   230.8   mmol       345.25   mmol   75.5 mL                  
 
         [0078]    [0078]                                     TABLE 2                       Run #   Time (min)   Temp. (° C.)                                101   ˜65   128-140       102   60   135-136       103   65   132-136       104   60   138-139       105   60   134-137       106   65   130-136       107   60   124-133       108   Not available   130-140       109   80    99-114       110   55   133-135       111   45   130-133       112   50   130-134       113   60   135-137       114   60   134-136       115   62   133-137       116   60   134-135       117   62   135-139       118   60   134-136       119   62   141-146       120   62   130-135       121   60   131-133       122   69   132-134       123   60   150-156       124   62   142-144       125   62   153-157       126   55   130-140       127   60   109-112       128   61   137-141       129   58   139-145       130   67   136-140       131   62   134-144       132   60   130-138       133   60   140-135       134   64   133-132       135   57   130-134       136   64   130-138       137   60   130-132       138   34   130-149       139   41   25-120                    
       EXAMPLE A2  
       [0079]    Experimental Runs #140-147; Pyridine Base:  
         [0080]    Eight experiments were performed to evaluate combined effects of solvent volume, reaction time, and reaction temperature on one-step synthesis of topiramate, starting with diacetone fructose (DAF).  
         [0081]    DAF was combined with sulfamide, pyridine and the chosen volume of o-xylene solvent (in amounts as listed in Table 3) in a 1 liter round-bottomed flask. The charged flask was then submerged in a pre-heated oil bath at the chosen external temperature, and the reaction mixture agitated and heated to the chosen reaction temperature, where it was held for the chosen time before the flask was removed from the oil bath and cooled to room temperature.  
         [0082]    The reaction mixture was then extracted twice with 1M NaOH (75 mL portions). The aqueous extracts were combined and neutralized with 6M HCl to induce product crystallization. The product precipitated as an oil in all cases. The oil was agitated overnight to become filterable crystals. The resulting solids were dried under vacuum for 16-18 hrs at 50° C. The dried product was analyzed by HPLC.  
         [0083]    Following the above procedure the eight experiments were performed with experimental conditions as listed in Table 3 and 4 below. All experimental runs yielded topiramate product.  
                                                                       TABLE 3                           Pyridine Base            Run #   DAF   Sulfamide   Base   o-Xylene                    140   30.01   g   22.24   g   36.56   g   75 mL           115.32   mmol   231.43   mmol   462.2   mmol       141   30.03   g   22.37   g   36.78   g   75.5 mL             115.4   mmol   232.78   mmol   464.98   mmol       142   30.01   g   22.58   g   36.5   g   75.5 mL             115.32   mmol   234.96   mmol   461.44   mmol       143   30.12   g   22.44   g   36.68   g   75 mL           115.74   mmol   233.51   mmol   463.72   mmol       144   30   g   22.34   g   36.88   g   40 mL           115.28   mmol   232.47   mmol   466.25   mmol       145   30.05   g   22.31   g   36.51   g   40 mL           115.47   mmol   232.15   mmol   461.57   mmol       146   30.03   g   22.24   g   36.6   g   40 mL           115.4   mmol   231.43   mmol   462.71   mmol       147   30.07   g   22.34   g   36.61   g   40 mL           115.55   mmol   232.47   mmol   462.83   mmol                  
 
         [0084]    [0084]                       TABLE 4                       Run #   Time (min)   Temp (° C.)                   140   60   130.0-133.4       141   30   130.0-132.7       142   60   130.0-134.3       143   30   130.0-134.7       144   30   130.0-130.3       145   60   130.0-134.9       146   60   130.0-132.8       147   30   130.0-133.9                    
       EXAMPLE A3  
       [0085]    Experimental Runs #148-156: t-Butylpyridine Base:  
         [0086]    Nine experiments were performed to evaluate the combined effects of base equivalents, reaction temperature and reaction time on one-step synthesis of topiramate using 4-tert-butylpyridine and starting with diacetone fructose (DAF).  
         [0087]    DAF was combined with sulfamide, 4-tert-butylpyridine (in amounts as listed in Table 4) and 40 mL o-xylene in a 500 mL round-bottomed flask. The reaction mixture was agitated and heated to the chosen reaction temperature in an oil bath over about 19-23 min. The reaction mixture was maintained at the chosen reaction temperature for the chosen time, and then cooled rapidly to 25° C. The reaction mixture was extracted twice with 1M NaOH (75 mL portions). The aqueous extracts were combined and neutralized using 6M HCl to induce product crystallization. The product precipitated as an oil in all cases, which was agitated overnight to become filterable crystals. The crystals were dried under vacuum for 16-18 hrs at 50° C. The dried product was analyzed by HPLC.  
         [0088]    Following the above procedure the nine experiments were performed with experimental conditions as listed in Table 5 and 6 below. All experimental runs yielded topiramate product.  
                                                                       TABLE 5                           4-t-butylpyridine Base            Run #   DAF   Sulfamide   Base   o-Xylene                    148   30.16   g   22.42   g   47.07   g   40 mL           115.9   mmol   231.4   mmol   348.1   mmol       149   30.20   g   22.21   g   15.67   g   40 mL           116.05   mmol   231.1   mmol   115.9   mmol       150   30.12   g   22.16   g   47.03   g   40 mL           115.7   mmol   230.6   mmol   347.8   mmol       151   30.23   g   22.12   g   31.19   g   40 mL           116.2   mmol   230.2   mmol   231.7   mmol       152   30.10   g   22.75   g   46.76   g   40 mL           115.7   mmol   236.8   mmol   345.8   mmol       153   30.03   g   22.42   g   15.76   g   40 mL           115.4   mmol   233.3   mmol   116.6   mmol       154   30.23   g   22.24   g   46.83   g   40 mL           116.2   mmol   231.5   mmol   346.4   mol       155   30.15   g   22.49   g   46.85   g   40 mL           115.9   mmol   234.1   mmol   346.   mmol       156   30.08   g   22.24   g   15.60   g   40 mL           115.6   mmol   231.5   mmol   115.4   mmol                  
 
         [0089]    [0089]                       TABLE 6                       Run #   Time (min)   Temp (° C.)                   148   44   130.0-150.5       149   60   110.0-126.6       150   60   110.0-129.0       151   28   130.1-146.6       152   29   130.0-151.6       153   15   130.0-141.5       154   30   130.1-143.4       155   15   110.1-117.4       156   30   110.1-113.7                    
       EXAMPLE A4  
       [0090]    Multiple experiments were run to evaluate the effect of solvent and base on the one step process for the preparation of topiramate. Experimental conditions were as listed in Tables 7 and 8, with experimental procedures for the individual runs as described below.  
         [0091]    Run #157, 158, 160, 164-166:  
         [0092]    DAF and sulfamide (in amounts as in Table 8) were transferred to a test tube. The chosen solvent and the chosen base (in amounts as listed in Table 7) were then added to the DAF/sulfamide mixture. The reaction mixture was then agitated and heated, with the reaction mixture maintained at the selected temperature (see Table 8) for the selected time (see Table 8), after which time the upper layer was sampled and analyzed by HPLC.  
         [0093]    Run #159,188-198:  
         [0094]    DAF, sulfamide, o-xylene and the specified amount of the chosen base (see Tables.7 and 8) were transferred into a 500 mL round-bottomed flask. The reaction mixture was then agitated and heated, with the mixture maintained at the chosen temperature for the chosen time (see Table 8) with an oil bath. The reaction mixture was removed from the hot oil, cooled to about room temperature and then extracted twice with 1M NaOH (75 mL portions). The aqueous extracts were combined and neutralized using 6M HCl to induce product crystallization. The resulting solids were dried under vacuum for 16-18 hrs at 50° C. The dried product was analyzed by HPLC.  
         [0095]    Run #161-163  
         [0096]    DAF, sulfamide, 4-picoline, and the chosen solvent (in amounts as in Table 7 and 8) were transferred into a 250 mL round-bottomed flask. The flask was lowered into a heated oil bath and the mixture agitated at the selected holding temperature for the selected reaction time (see Table 8). The reaction mixture was then cooled to room temperature and extracted twice with 1M NaOH (75 mL portions). The aqueous extracts were neutralized with 6M HCl and then maintained at room temperature overnight to allow product to crystallize. The resulting crystalline solids were filtered and dried for 16-18 hrs in a vacuum oven at 50° C. The product was then analyzed by HPLC.  
         [0097]    Note: Although product was expected in run #162, the product did not crystallize and was therefore not analyzed; the product from run #163 was a sticky solid.  
         [0098]    Run #167-172:  
         [0099]    The selected solvent in the selected amount (see Table 7) was transferred to a 125 mL test tube along pyridine (in amounts as in Table 7) and the resulting solution heated to the chosen temperature. A pre-weighed mixture of DAF and sulfamide (in amounts as in Table 8) was then added along with transfer washes of solvent (about 2 mL). The reaction mixture was agitated at the chosen temperature for the chosen time (see Table 8) at which time the upper layer was sampled (some mixtures formed a small, dark second layer) and analyzed by HPLC.  
         [0100]    Run #173  
         [0101]    DAF, sulfamide, pyridine and mixed xylenes (in amounts as listed in Tables 7 and 8) were transferred to a 1000 mL round-bottomed flask in a pre-heated (140° C.) oil bath. The reaction mixture was agitated at the selected reaction temperature for 90 mins. The flask was removed from the oil bath and the residual heat used to distill about 22 g of liquid from the reaction mixture. The reaction mixture was extracted with three portions (90 mL, 30 mL, and 10 mL) of 0.35M NaOH. 1N HCl (50 mL) was added to the aqueous extracts, resulting in the formation of an oil. The mixture was agitated to transform the oil into filterable crystals. The crystals were collected by filtration, washed with water, and dried in a vacuum oven for 16 hrs at 50° C. The product was then analyzed by HPLC analysis.  
         [0102]    Run #174-180:  
         [0103]    DAF, sulfamide, pyridine and the chosen solvent (in amounts as listed in Tables 7 and 8) were transferred to a 500 ml round-bottomed flask. The reaction mixture was then agitated and heated in an oil bath to the target temperature. The reaction mixture was maintained at about the target temperature (listed in Table 8) for the selected time (see Table 8), removed from the hot oil and cooled to about room temperature. To the reaction mixture was then added water (100 mL) water and/or other solvents (MeOH, 0.5M NaOH, or the reaction solvent) as needed, to achieve a heterogeneous mixture consisting of two clear liquid layers. GC analysis was then performed on both layers.  
         [0104]    Run # 181-183  
         [0105]    DAF, sulfamide, 4-tert-butylpyridine, and the selected solvent (in amounts as listed in Tables 7 and 8) were transferred to a 500 mL round-bottomed flask. The reaction mixture was then placed in oil bath and agitated while heating at the selected reaction temperature for the selected time (see Table 8). The reaction mixture was then allowed to cool to room temperature. The reaction mixture was then extracted with the appropriate solvents to yield two clear liquid layers (For run 181 the extraction solvents were water (125 mL) and mixed xylenes (25 mL); for run 182 the extraction solvents were water (150 mL) and methanol (25 mL); for run 183 the extraction solvent was 0.3M NaOH (100 mL)). GC analysis was performed on liquid samples from both layers.  
         [0106]    Run #184  
         [0107]    DAF, sulfamide, dimethylbutylamine and 1,2,3,4-tetrahydronapthalene (in amounts as listed in Tables 7 and 8) were transferred into a 250 mL round-bottomed flask. The flask was placed in a heated oil bath (136° C.) and the mixture agitated while heating at the selected temperature for the selected time (see Table 8). The reaction mixture was cooled to about room temperature and then extracted twice with 1M NaOH (75 mL portions). The aqueous extracts were neutralized using 6M HCl and agitated for 2 hrs to allow crystallization. The crystals were collected by filtration and then dried for about 17 hrs 45 min in a vacuum oven at 52° C. The product was then tested by HPLC analysis.  
         [0108]    Run #185-187  
         [0109]    DAF, sulfamide, isoquinoline and the chosen solvent (in amounts as listed in Tables 7 and 8) were transferred to a 250 mL round-bottomed flask. The reaction mixture was then placed in an oil bath and agitated while heating at the selected reaction temperature for the selected time (see Table 8). The reaction mixture was cooled to about room temperature and then extracted twice with 1M NaOH (75 mL portions). The aqueous extracts were neutralized with 6M HCl and allowed to stand at room temperature for several days to facilitate crystallization. The crystals were collected by filtration and then dried about 16-18hrs in a vacuum oven at 50° C. The dried product was analyzed by HPLC analysis.  
         [0110]    Note: All experimental runs yielded topiramate product except as noted herein. An emulsion was observed to form during the extraction of Experimental Run #187 and although topiramate product was expected, no product was collected. The product collected from Experimental Runs #187, 191, 194 and 197 was expected to be topiramate, but not analyzed.  
         [0111]    Tables 7 and 8 below list the run conditions for the experimental procedures described above. Except as noted above, all experimental runs yielded topiramate product.  
                                                                                                         TABLE 7                       Run#   Base   Base (g)   Solvent   Solvent (mL)                                157   Imidazole   1.01   p-Xylene   15.1           158   4-(Dimethylamino)-   1.77   p-Xylene   15.2           pyridine       159   4-(Dimethylamino)-   42.08   o-Xylene   40           pyridine       160   4-Picoline   1.38   p-Xylene   15       161   4-Picoline   42.48   o-Xylene   150       162   4-Picoline   42.92   Tetrahydro-   40                   napthalene       163   4-Picoline   43.03   Diphenyl Ether   40.5       164   2,6-Lutidine   1.55   p-Xylene   15       165   Pyridine   1.15   p-Xylene   15       166   Pyridine   14.7   pyridine   15       167   Pyridine   1.17   1-Methyl-2-   15                   pyrrolidinone       168   Pyridine   1.14   Toluene   15       169   Pyridine   1.15   4-Methyl-2-   15                   pentanone       170   Pyridine   1.15   Benzonitrile   15       171   Pyridine   1.15   p-Xylene   15.1       172   Pyridine   1.17   Dimethyl-   15                   formamide       173   Pyridine   17.29   mixed xylenes   300       174   Pyridine   18.23   Mesitylene   150       175   Pyridine   18.22   o-Xylene   150       176   Pyridine   18.22   Tetramethylene   150                   sulfone       177   Pyridine   18.22   Biphenyl   150   g       178   Pyridine   18.20   Tetrahydro-   150                   napthalene       179   Pyridine   18.23   Diphenyl Ether   151       180   Pyridine   12.17   3:1 Diphenyl   100.04   g                   Ether:Biphenyl       181   4-tert-   31.17   mixed xylenes   150           Butylpyridine       182   4-tert-   —   4-tert-   75           Butylpyridine       Butylpyridine       183   4-tert-   20.78   mesitylene   100           Butylpyridine       184   Dimethylbutylamine   59.95   Tetrahydro-   40                   napthalene            185   isoquinoline   58.11   isoquinoline   —            186   isoquinoline   20.05   o-Xylene   50           187   isoquinoline   59.65   Diphenyl Ether   40.5       188   Tributylamine   85.49   o-Xylene   40       189   Dimethyl-   62.33   o-Xylene   40           benzylamine       190   Dimethyldodecyl-   98.42   o-Xylene   40           amine       191   Hexadecylamine   83.62   o-Xylene   40       192   Dimethyltetradecyl-   111.22   o-Xylene   40           amine       193   Dimethylhexadecyl-   124.30   o-Xylene   40           amine       194   Dimethyloctadecyl-   137.13   o-Xylene   40           amine       195   morpholine   30.30   o-Xylene   40       196   pyrrolidine   25.74   o-Xylene   40       197   urea   20.29   o-Xylene   40       198   (none)   —   o-Xylene   40                  
 
         [0112]    [0112]                                                     TABLE 8                       Run       Sulfamide   Time   Target       #   DAF (g)   (g)   (min)   Temp (C.)                                157   0.76   0.84   30   115       158   0.74   0.84   30   115       159   30.21   22.21   30   130       160   0.76   0.84   30   115       161   30.07   22.34   62   140       162   30.01   22.18   62   150       163   30.02   22.34   67   140       164   0.75   0.84   30   115       165   0.76   0.84   30   115       166   0.74   0.84   30   115       167   0.73   0.83   31   115       168   0.75   0.85   30   115       169   0.75   0.84   30   115       170   0.76   0.85   30   115       171   0.77   0.85   30   115       172   0.76   0.83   30   115       173   15.02   19.46   90   130       174   15.02   11.08   60   130       175   15.05   11.07   60   130       176   15.01   11.08   60   130       177   15.04   11.08   60   130       178   15.02   11.08   60   130       179   15.03   11.07   60   130       180   10.03   7.38   60   140       181   15.03   11.08   60   130       182   7.49   5.53   60   130       183   10   7.38   60   150       184   29.99   22.34   60   110       185   30.09   22.24   62   140       186   10.04   7.38   60   140       187   30.08   22.45   57   130       188   30.05   22.31   30   130       189   30.03   22.22   30   140       190   30.17   22.26   30   130       191   30.09   22.04   30   130       192   30.1   22.21   30   130       193   30.11   22.28   30   130       194   30.18   22.33   30   130       195   30.06   22.26   30   130       196   30.01   22.26   30   130       197   30.13   22.32   30   130       198   30.02   22.16   30   130                    
       EXAMPLE A5  
       [0113]    Topiramate was prepared according to the process of the present invention. Listed below are experimental procedures for the experiments. Tables 9 and 10 which follow list detailed experimental conditions.  
         [0114]    Experiment 2:  
         [0115]    DAF, sulfamide, pyridine, and o-xylene in amounts as listed in Table 9 below were charged to a 1-liter reactor. The reactor was heated to a jacket temperature of about 155° C. and maintained at that temperature for 30 minutes. The reactor was cooled to 60° C and distillation was started under vacuum, with distillation continued until there was no remaining liquid to distill. 1M NaOH was added to separate the reaction mixture into layers. The bottom, aqueous layer was drained and transferred to a separatory funnel. 1M NaOH was added to separate the layers further. Again, the lower, aqueous layer was drained and transferred to a clean reactor. 6M HCl was added to neutralize solution to pH 7. The product crystallized, was filtered, and then dried to yield topiramate.  
         [0116]    Experiments 3-8, 19-21:  
         [0117]    DAF, sulfamide, pyridine, and o-xylene in amounts as listed in Table 9 below were charged to a 1-liter reactor.  
         [0118]    The reactor was heated and held at the selected temperature for 4 the selected time (see Table 10), then cooled rapidly to 65° C. Once cooled, vacuum was applied, resulting in the distillation of some amount of organic liquids. The temperature during distillation was maintained between 55° C. and 75° C. After distillation, some amount (0 to 200 milliliters) of NaOH (from strength of 1M to 3.5M) was added to split the reaction mixture into two separable phases, organic on top and aqueous on bottom. The bottom, aqueous layer was drained and transferred to a clean reactor. Acid (6M HCl) was added to neutralize the reaction mixture to pH 7. The product crystallized upon neutralization, was filtered and then dried to yield topiramate.  
         [0119]    Experiment 9:  
         [0120]    DAF, sulfamide, pyridine, and o-xylene in the amounts as listed in Table 9 below were charged to a 1-liter reactor. The reactor was heated to the selected temperature. The reactor was held at the maximum temperature for the selected amount of time (see Tables 9 and 10) and then cooled rapidly to 65° C. Once cooled, vacuum was applied, resulting in the distillation of someof the organic liquids. The temperature during distillation was maintained between 55° C. and 75° C. After distillation, 3.5M NaOH was added to split the reaction mixture into two separable phases, organic on top and aqueous on bottom. The bottom, aqueous layer was drained and transferred to a clean reactor. The reactor was then spiked with pyridine (40 mL). Acid (6M HCl) was added to neutralize the reaction mixture to about pH 7. The product crystallized upon neutralization and was then filtered and dried to yield topiramate.  
         [0121]    Experiments 10, 15-17:  
         [0122]    DAF, sulfamide, pyridine, and o-xylene in amounts as listed in Table 9 below were charged to a 1-liter reactor. The reactor was heated to the selected temperature. The reactor was held at the selected temperature for the selected time (see Tables 9 and 10) and then cooled rapidly to 65° C. Once cooled, 3.5M NaOH was added to split the reaction mixture into two separable phases, organic on top and aqueous on bottom. The bottom, aqueous layer was drained and transferred to a clean reactor. Vacuum and heat were applied to distill off aqueous liquid. Acid (6M HCl) was added to neutralize the reaction mixture to about pH 7. If product did not crystallize after neutralization, additional water was added: for Experiment #15 350 mL water was added; for experiments #16 390 mL water was added; for Experiment #17 120 mL water was added. When the product had crystallized, it was filtered and dried to yield topiramate.  
         [0123]    Experiment 11:  
         [0124]    DAF, sulfamide, pyridine, and o-xylene in amounts as listed in Table 9 below were charged to a 1-liter reactor. The reactor was heated to the selected temperature, held at this temperature for the selected time (see Tables 9 and 10) and then cooled rapidly to 65° C. Once cooled, 3.5M NaOH was added to split the reaction mixture into two separable phases, organic on top and aqueous on bottom. The bottom, aqueous layer was drained and transferred to a clean reactor. Vacuum and heat were applied, resulting in the distillation of some of the aqueous liquid. The reactor was heated to 60° C., and acid (6M HCl) was added to neutralize the reaction mixture to pH 7. The reactor was cooled to 1.5° C. and then water was added until crystals formed. The product crystallized and was then filtered and dried to yield topiramate.  
         [0125]    Experiments 12-14:  
         [0126]    DAF and sulfamide, in amounts as listed in Table 9 below were charged to a 1-liter reactor. The reactor was heated to the selected temperature. The reactor was held at the selected temperature for the selected time (see Tables 9 and 10) and then cooled rapidly to about room temperature. Once cooled, 3.5M NaOH was added to split the reaction mixture into two separable phases, organic on top and aqueous on bottom. The bottom, aqueous layer was drained and transferred to a clean reactor. Acid (6M HCl) was added to neutralize the reaction mixture to about pH 7. The product crystallized upon neutralization and was then filtered and dried to yield topiramate.  
         [0127]    Experiment 18:  
         [0128]    DAF, sulfamide, pyridine, and o-xylene in amounts as listed in Table 9 below were charged to a 1-liter reactor. The reactor was heated to the selected temperature. The reactor was held at the selected temperature for the selected time (see Tables 9 and 10) and then cooled rapidly to 65° C. Once cooled, 3.5M NaOH was added to split the reaction mixture into two separable phases, organic on top and aqueous on bottom. The bottom, aqueous layer was drained and transferred to a clean reactor. Vacuum and heat were applied to distill off about half of the aqueous liquid. The remaining aqueous solution was drained and transferred to a beaker. 6M HCl (60 mL) was added to the cleaned reactor. Reaction mixture and additional 6M HCl were dosed into the reactor to maintain about pH 7. Water was added to induce crystallization. The product crystallized and was then filtered and dried to yield topiramate.  
         [0129]    Experiment 19:  
         [0130]    DAF, sulfamide and pyridine, in amounts as listed in Table 9 below were charged to a 1-liter reactor. The reactor was heated to the selected temperature. The reactor was held at the selected temperature for the selected time (see Tables 9 and 10) and then cooled rapidly. Once cooled to 22° C., 3.5M NaOH was added to split the reaction mixture into separable phases. Three fifths of the aqueous layer was drained and transferred to a clean reactor. Acid (6M HCl) was then added to neutralize the reaction mixture to about pH 7. Water 100 mL was added to the reaction mixture. The product crystallized, and was then filtered and dried to yield topiramate.  
                                                             TABLE 9                           DAF   Sulfamide   Pyridine   O-   Jacket            (gms)   (gms)   (gms)   xylene   Temp       Run#   (mmols)   (mmols)   (mmols)   (mL)   (° C.)                                2   29.97   22.26   36.50   40.0   155           115.17   231.63   461.44       3   100.01   73.86   121.40   134.0   145           384.31   768.57   1534.77       4   99.98   73.85   121.78   134.0   145           384.20   768.47   1539.57       5   100.04   78.21   121.82   133.0   145           384.43   813.84   1540.08       6   99.98   73.80   121.49   132.5   145           384.20   767.95   1535.90       7   99.99   73.93   121.66   134.0   145           384.24   769.30   1538.05       8   99.94   72.52   121.43   132.0   145           384.04   754.63   1535.15       9   100.01   73.50   12.11   134.0   145           384.31   764.83   153.10       10   100.01   73.86   121.84   132.0   145           384.31   768.57   1540.33       11   100.07   73.89   121.23   132.0   145           384.54   768.89   1532.62       12   100.01   73.87   0.00   0.0   145           384.31   768.68   0.00       13   100.02   73.72   0.00   0.0   145           384.35   767.12   0.00       14   100.10   73.74   0.00   0.0   145           384.66   767.33   0.00       15   99.97   73.79   121.81   133.0   145           384.16   767.85   1539.95       16   100.12   73.94   121.49   134.0   145           384.74   769.41   1535.90       17   99.99   73.60   121.49   n/r   n/r           384.24   765.87   1535.90       18   99.99   73.88   122.00   135.0   145           384.24   768.78   1542.35       19   100.04   73.45   121.74   0.0   145           384.43   764.31   1539.06       20   100.00   73.87   121.43   134.0   n/r           384.28   768.68   1535.15       21   99.95   73.45   121.12   132.0   145           384.08   764.31   1531.23                  
 
         [0131]    [0131]                                     TABLE 10                           Rxn Time   Rxn Temp.       Run #   (min)   (° C.)                                2   30   130-134       3   30   130-135       4   45   130-136       5   45   130-134       6   43   130-134       7   45   130-134       8   45   130-135       9   48   130-133       10   45   130-134       11   57   130-134       12   60   130-142       13   45   130-143       14   44   130-142       15   45   130-133       16   45   130-134       17   45   130-n/r       18   45   130-134       19   45   130-133       20   n/r   130 n/r       21   45   130 n/r                            
       EXAMPLE A6  
       [0132]    Diacetone fructose (DAF) (780 kg; 780 kg, Batch 1 and 2), pyridine (950.6 kg; 950.0 kg) and xylenes (1950 L; 1950 L) were mixed in a tank and the solution was transferred to a reactor with sulfamide (575 kg; 575 kg). The mixture was heated to 128-133° C. via stepwise heating. More specifically, the mixture was heated from 30 to 65° C. in 80 minutes, then from 65 to 95° C. in 60 minutes, followed by heating from 95 to 113° C. in 60 minutes and 113 to 125° C. in 85 minutes. The reactor jacket temperature was raised in 5° C. increments to heat the batch to 128-133° C. over 30 minutes and then held at the temperature for 30 minutes. The reaction mixture was then cooled at a rate of 30° C. per hour to 40° C. To the mixture was then added purified water (1243 L; 1240 L). The mixture was cooled to 20° C. before 50% NaOH (436 kg; 437 kg) solution was added. Organic and aqueous layers (product layers) were separated and the aqueous layer was filtered and transferred to another reactor. The organic layer was discarded. Purified water (1400 L; 1400 L) was added to the aqueous mixture and residual organics (pyridine and xylene) and water were distilled off under vacuum. The distillation was stopped after distilling a known volume (784 L; 784 L). Glacial acetic acid (214.5 kg; 224.4 kg) was added to neutralize the solution to pH 7. The mixture was seeded with topiramate seeds (1.0 kg; 1.0 kg) and was cooled to 0-5° C. to crystallize the crude topiramate. The crude, wet topiramate (730 kg; 803.8 kg wet yield) was centrifuged and collected.  
         [0133]    While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.