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  
     This application claims priority from U.S. provisional application Ser. No. 60/451,863, filed on Mar. 4, 2003, the contents of which are hereby incorporated by reference. 
    
    
     FIELD OF THE INVENTION  
     The present invention relates to a one step process for the preparation of compounds of the formula (I) 
     
       
                 
         
             
             
         
      
     
     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  
     The compounds of formula (I) 
     
       
                 
         
             
             
         
      
     
     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. 
     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) 
     
       
                 
         
             
             
         
      
     
     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. 
     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 2 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). 
     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. 
     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. 
     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). 
     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. 
     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  
     The present invention is directed to a one-step process for the preparation of the compounds of formula (I) 
     
       
                 
         
             
             
         
      
     
     wherein 
     X is selected from CH 2  or O; 
     R 1  is selected from the group consisting of hydrogen and C 1-4 alkyl; 
     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: 
     
       
                 
         
             
             
         
      
     
     wherein 
     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; 
     comprising 
     
       
                 
         
             
             
         
      
     
     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). 
     The present invention is further directed to a process for the preparation of a compound of formula (Ia), 
     
       
                 
         
             
             
         
      
     
     also known as topiramate, comprising 
     
       
                 
         
             
             
         
      
     
     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). 
     The present invention is further directed to a compound prepared according to any of the processes described herein. 
     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. 
     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. 
     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. 
     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  
     In an embodiment of the present invention, the compound of formula (I) is topiramate, a compound of the formula (Ia) 
     
       
                 
         
             
             
         
      
     
     As used herein, the terms “diacetone fructose” and “DAF” shall mean diacetone-β-D-fructose, a compound of formula (IIa) 
     
       
                 
         
             
             
         
      
     
     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. 
     As used herein, the notation “*” shall denote the presence of a stereogenic center. 
     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. 
     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%. 
     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. 
     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. 
     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. 
     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. 
     One skilled in the art will recognize that the compounds of formula (I) have several stereogenic centers as denoted by the asterisks below. 
     
       
                 
         
             
             
         
      
     
     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. 
     The present invention is directed to a one step process for the preparation of a compound of formula (I) as outlined in Scheme 1. 
     
       
                 
         
             
             
         
      
     
     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), 
     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; 
     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; 
     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; 
     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; 
     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; 
     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; 
     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; 
     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.; 
     to yield the corresponding compound of formula (I). 
     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)). 
     The compound of formula (Ia) may be prepared according to the process outlined in Scheme 2. 
     
       
                 
         
             
             
         
      
     
     Accordingly, a compound of formula (IIa), a known compound also known as diacetone fructose (DAF), is reacted with sulfuryl diamide (also known as sulfamide), 
     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; 
     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; 
     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; 
     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; 
     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; 
     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; 
     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; 
     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.; 
     to yield the corresponding compound of formula (Ia). 
     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)). 
     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. 
     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. 
     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. 
     The following examples describe the invention in greater detail and are intended to illustrate the invention, but not to limit it. 
     EXAMPLE A1 
     Experimental Runs #101–116: 
     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). 
     For experimental runs 101, 102, 103, the mixture was distilled at 41° C., under vacuum, for 30, 35 and 20 minutes, respectively. 
     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. 
     Experimental Runs # 117–139: 
     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. 
     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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
             
               
               
               
             
           
               
                 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  
     Experimental Runs #140–147; Pyridine Base: 
     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). 
     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. 
     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. 
     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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
             
           
               
                 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  
     Experimental Runs #148–156: t-Butylpyridine Base: 
     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). 
     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. 
     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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
             
           
               
                 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  
     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. 
     Run #157, 158, 160, 164–166: 
     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. 
     Run #159,188–198: 
     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. 
     Run #161–163 
     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. 
     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. 
     Run #167–172: 
     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. 
     Run #173 
     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. 
     Run #174–180: 
     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. 
     Run # 181–183 
     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. 
     Run #184 
     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. 
     Run #185–187 
     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. 
     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. 
     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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 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  
     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. 
     Experiment 2: 
     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. 
     Experiments 3–8, 19–21: 
     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 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. 
     Experiment 9: 
     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. 
     Experiments 10, 15–17: 
     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. 
     Experiment 11: 
     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. 
     Experiments 12–14: 
     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. 
     Experiment 18: 
     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. 
     Experiment 19: 
     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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
             
               
               
               
             
           
               
                 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 
               
               
                   
               
               
                 n/r indicates that no full temperature range or reaction time was recorded. 
               
             
          
         
       
     
     EXAMPLE A6  
     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. 
     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.