Abstract:
The present invention relates to the economical and separation of benzphetamine hydrochloride and methamphetamine by liquid extraction. An extraction process employing a suitable organic solvent and water at a pH in the range of from about 6 to about 8 provides excellent removal of the methamphetamine by dissolution in the water phase while the benzphetamine dissolves in the organic phase. Simple separation of the two phases results in separation of the two amines.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a national stage application of PCT/US2005/039468, filed Nov. 2, 2005, which claims the benefit of U.S. Provisional Application No. 60/630,008 filed Nov. 22, 2004. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to a process for removal of methamphetamine from benzphetamine hydrochloride thereby providing highly pure benzphetamine hydrochloride by means of a convenient liquid extraction process employing an organic solvent and water. 
     The production of benzphetamine has been known for a considerable period of time and was disclosed in U.S. Pat. No. 2,789,138 to Heinzelman et al. The chemical name of the physioacitve material, benzphetamine, is d-N-methyl-N-benzyl-beta-phenylisopropylamine. According to that patent benzyl chloride is reacted with methamphetamine in the presence of a base, typically sodium carbonate. The reaction is typically carried out in a non-reactive organic solvent such as benzene, toluene, xylene or the like. The product is recovered by mixing the reaction mixture with water, extracting with solvent, then converting the benzphetamine to the hydrochloride by addition of hydrochloric acid. The thus produced acid salt is then fractionally distilled under vacuum at temperatures in the range of from about 155° C. to about 165° C. to obtain the amine. Such purification process has several disadvantages including the exposure of the product to high temperatures, and the need for expensive vacuum pumps and a vacuum still to achieve the desired reduced pressure. 
     The impurity of most concern in the process for preparing benzphetamine hydrochloride is methamphetamine. It is self-evident that any pharmaceutical should be as pure as possible and that such a drug as methamphetamine be eliminated to the extent economically feasible. 
     Extraction of methamphetamine has been the subject of research in the prior art. An activated methamphetamine is shown in U.S. Pat. No. 5,976,812. The activated methamphetamine is in a class of derivatives of very active materials, typically methamphetamine-p-carboxybutyl-maleinimidoethylamide. In the purification process for this type of compound, the derivative is shaken with sodium hydroxide in water forming oil which is extracted three times with toluene. U.S. Pat. No. 4,056,922 discloses that methamphetamine can be extracted at either pH 2 or pH 9 with concentrating agent selected from silica gel and kieslguhr. 
     While there are numerous purification schemes available on an analytical basis to remove materials such as methamphetamine, a convenient large-scale production method to provide highly pure benzphetamine hydrochloride substantially free of methamphetamine is not commercially available other than by vacuum distillation. A convenient, large-scale method to provide benzphetamine hydrochloride has not been heretofore available. 
     BRIEF DESCRIPTION OF THE INVENTION 
     In accordance with this invention there is provided a novel, efficient and large-scale method for separating methamphetamine from benzphetamine hydrochloride. As noted above, the reaction product of benzyl chloride and methamphetamine is typically acidified to provide benzphetamine hydrochloride. It is inevitable that some amount of methamphetamine is found in the benzphetamine hydrochloride product. There has now been discovered a convenient yet effective liquid extraction method for removing methamphetamine from benzphetamine hydrochloride. 
     More particularly, it has been discovered that in a narrow pH range of from about 6.0 to about 8.0 there is a high degree of separation of the two amines between an organic phase and an aqueous phase such that the tertiary amine, benzphetamine hydrochloride is converted to the base that partitions into the organic phase while the secondary amine, methamphetamine hydrochloride, is not converted to its base and thus partitions into the aqueous phase. More particularly, in a pH range of from about 6 to about 6.5 there is nearly complete separation of the amines between the organic phase and the aqueous phase. At such pH range, benzphetamine base is conveniently recovered from the organic phase by separating the organic phase from the aqueous phase. The organic phase is then treated with an acid, typically hydrochloric acid, typically providing a pH that converts the benzphetamine base into the acid salt, typically the hydrochloride salt. Such pH to convert the base to the acid salt is typically below about 4 and more preferably about 1. As is well known, the hydrochloride salt is not soluble in the organic phase and can be recovered by any suitable means. As is known in the prior art, the benzphetamine base is typically an oil at room temperature and can be distilled out under vacuum. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present method utilizes the control of the pH of the system so as to take advantage of the difference in the basicity constants, K b , between benzphetamine hydrochloride and methamphetamine. Both amines in the process of this invention are weak bases. Benzphetamine is a tertiary amine, and methamphetamine is a secondary amine. The literature indicates that secondary and tertiary amines differ in K b  by a factor of 2. However, it has been discovered that the difference between a benzyl amine (benzphetamine) and a methyl amine (methamphetamine) is quite large. That is, the K b  of benzphetamine is about 1/20 th  of the K b  of methamphetamine. It has further been discovered that concentration of benzphetamine in an organic solvent is approximately 70 to 700 times greater than its solubility in water. Thus a nearly complete separation of benzphetamine can be accomplished by solvent extraction because methamphetamine hydrochloride does not partition in the organic solvent such as toluene. 
     In accordance with this invention, crude benzphetamine hydrochloride is added to a vessel containing both an organic solvent and water. While stirring vigorously, the pH of the water phase is adjusted to the range of from about 6.0 to about 8.0 by the addition of a suitable acid or base. At such pH range the benzphetamine hydrochloride is converted to a base, and methamphetamine is converted to an acid salt. Vigorous agitation of the mixture assures adequate contact of both phases with the crude benzphetamine base containing methamphetamine contaminant. Upon contact, the benzphetamine partitions into the organic phase and the methamphetamine hydrochloride partitions into the aqueous phase. This operation is performed at ambient temperature and pressure. The only equipment required is a suitable vessel and an adequate stirrer. Optionally, the process of this invention can be carried out in the reactor in which the benzphetamine hydrochloride is produced. 
     Alternatively, this process works in the opposite direction. A mixture of methamphetamine base and benzphetamine base that is dissolved in an organic solvent may be added to water, and while stirring, the pH may be adjusted to the range of from about 6.0 to about 8.0 with a suitable acid or base. The benzphetamine base remains in the organic phase, while methamphetamine hydrochloride partitions into the aqueous phase. 
     Any number of organic solvents can be employed in the process of this invention. Such solvent must be non-reactive and have sufficient solubility for benzphetamine hydrochloride. Typical organic solvents include aromatic solvents such as benzene, toluene, xylene, and the like; or aliphatic or cyclic aliphatic solvents such as hexane, heptane, cyclohexane, and the like. A preferred organic solvent for the organic phase in the process of this invention is toluene because it is inert to benzphetamine base and has sufficient solvent ability toward the base. 
     Typically, the pH of the aqueous phase is adjusted with a base because the hydrochloride salt provides a low pH. Any number of bases can be employed provided such base does not react with the amines in the mixture and should be stronger bases than either of the amines. Such bases include sodium carbonate, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, alkali metal carbonates and alkali metal bicarbonates such as sodium carbonate or bicarbonate, potassium carbonate or bicarbonate and the like. 
     Usually, the aqueous phase is rendered acid by the addition of the acid salt, benzphetamine hydrochloride. However, should the pH of the aqueous phase require lowering, any number of acids may be added to lower the pH to the required range. Typically, hydrochloric acid would be added to the aqueous phase to lower the pH as it does not provide any additional elements to the process than is necessarily present. Other acids that could be employed include mineral acids such as sulfuric acid, phosphoric acid, at the like; and organic acids such as acetic acid and the like. 
     The volume of the organic phase and the aqueous phase is typically equal in the vessel employed in the process of this invention. Equal ratios are not necessary, however, and the organic phase to aqueous phase ratio may be between 1:3 and 3:1; preferable between 1:2 and 2:1, and more preferably 1:1. 
     After the crude benzphetamine hydrochloride is extracted with the organic solvent and water at a pH in the range of from about 6 to about 8, benzphetamine is in the organic phase, and methamphetamine is in the aqueous phase. The aqueous and organic phases are separated, and benzphetamine hydrochloride may be extracted from the organic phase using, for example, hydrochloric acid. The application of heat to the organic phase may be used to dehydrate the organic phase using distillation, which is more fully described in co-pending U.S. Prov. Appl. entitled “Crystallization Method for Benzphetamine” filed concurrently herewith the same obligations for assignment. 
     Preferred Embodiments 
     EXAMPLE 1 
     To a suitable flask containing 50 ml of deionized water there were added 4 g of crude benzphetamine hydrochloride, having a tan color, and 50 ml of toluene. With vigorous stirring, the pH of the aqueous phase was adjusted to 6.30 with sodium carbonate aqueous solution. The contents of the flask was transferred to a separatory funnel and allowed to settle into two phases. The aqueous layer was decanted. The toluene remaining in the funnel was washed with 25 ml of deionized water and 1.02 equivalents of 37% hydrochloric acid were added. The contents of the funnel were mixed thoroughly by vigorous shaking. The pH of aqueous layer was measured with a paper test strip followed by the addition of a few more drops of hydrochloric acid to bring the pH of the aqueous layer to a range of 0-1. The toluene/acid mixture was transferred to a distillation apparatus consisting of a suitable still, a heating mantle, a magnetic stirrer, a reflux condenser and a Dean Stark trap. After water was collected as a distillate, the apparatus was cooled. The contents of still remained liquid (no solids formed) and a layer of benzphetamine hydrochloride formed. The aqueous layer was drained from the Dean Stark trap and the toluene layer was returned to the still. Upon subsequent heating to the boiling point, the solids dissolved or melted and as distillation continued, sufficient precipitate formed to stop the magnetic stirrer. The toluene/benzphetamine hydrochloride mixture was cooled to room temperature, filtered and washed with additional toluene. There was collected 2.76 g of purified benzphetamine hydrochloride having a white appearance. Analytical analysis, by means of HPLC, of several aspects of the above experiment appear in Table 1 below. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                 Benzphetamine 
                 Metham- 
                 Benzphetamine 
               
               
                   
                 HCl 
                 phetamine 
                 HCl 
               
               
                 Description 
                 Mass (g) 
                 Area % 
                 Area % 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Crude Benzphetamine 
                 4.00 
                 6.10 
                 87.17 
               
               
                 Aqueous Extract 
                 0.05 
                 67.06 
                 20.63 
               
               
                 Aqueous Wash 
                 0.001 
                 18.31 
                 29.28 
               
               
                 Toluene Extract 
                 3.307 
                 0.00 
                 94.19 
               
               
                 Filtrate 
                 0.260 
                 0.07 
                 76.64 
               
               
                 Benzphetamine 
                 2.76 
                 0.00 
                 98.12 
               
               
                 Hydrochloride Product 
               
               
                   
               
             
          
         
       
     
     The overall yield of product in the above procedure was 83%, while the yield through the extraction is 97.8%. There was no detectable methamphetamine in the recrystallized product, and only traces of benzphetamine in the aqueous layer. The above described procedure demonstrates the liquid partitioning of benzphetamine hydrochloride from methamphetamine in high yield and improved color. 
     The partition coefficients for benzphetamine and methamphetamine are presented in Table 2 below. The partition coefficient is defined as the ratio of the equilibrium concentration of the specie in the organic layer to the equilibrium concentration of the specie in the aqueous layer. 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 pH 
                 Benzphetamine 
                 Methamphetamine 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 4 
                 0.600 
                 0.015 
               
               
                 6 
                 73.657 
                 0.000 
               
               
                 8 
                 ∞ 
                 0.124 
               
               
                 10 
                 ∞ 
                 3.366 
               
               
                   
               
             
          
         
       
     
     As indicated by the data in Table 2 above, the partition coefficient at pH 6 is highly favorable for maximum separation of the species. 
     While this invention has been described with respect to various specific examples and embodiments, it is to be understood that the invention is not limited thereto.