Abstract:
A process of producing atracurium besylate that substantially reduces the level of impurities in the final product and avoids the repeated use of ether is provided. In accordance with such a process, N, N&#39;-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydropapaverine (Compound 1), methyl benzenesulfonate and a catalytic amount of an insoluble base in a solvent are combined to form a reaction mixture that is maintained for a period of time sufficient for atracurium besylate formation. The reaction mixture is then filtered to remove the insoluble base and the atracuriurn besylate is precipitated.

Description:
TECHNICAL FIELD OF THE INVENTION 
     This invention relates to a process for the preparation and isolation of atracurium besylate. 
     BACKGROUND OF THE INVENTION 
     Existing methods of producing atracurium besylate involve the reaction of N, N&#39;-4,10-dioxa-3,11-dioxotridecylene-,13-bis-tetrahydropapaverine,  CAS registry number 64228-77-9!, hereinafter referred to as Compound 1 with methyl benzenesulfonate to provide the bis-quaternary ammonium product (atracrium besylate). A major shortcoming of existing methods is the incomplete reaction of starting materials resulting in a product containing up to 1.5% of incompletely converted Compound 1. Removal of the incompletely converted Compound 1 from the desired product is difficult. 
     Another problem of existing methods is the removal of residual methyl benzenesulfonate from the desired product. Methyl benzenesulfonate is removed in existing methods by redissolving the crude product, obtained by precipitation with diethyl ether, in a suitable solvent such as acetonitrile and reprecipitating with diethyl ether. The purification by ether precipitation is inefficient and may need to be repeated 3 to 4 times to reduce the methyl benzenesulfonate to acceptably low levels. An improved purification method would require fewer operations and avoid the hazards associated with large-scale use of diethyl ether. 
     There continues to be a need for a method of producing atracurium besylate with improved product purity in an efficient manner which avoids the use of diethyl ether. 
     BRIEF SUMMARY OF THE INVENTION 
     The present invention provides a process of producing atracurium besylate, 2,2&#39;- 1,5-pentanediylbis- oxy(3-oxo-3,1-propanediyl)!!bis 1- 3,4-dimethoxyphenyl)-methyl!-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolinium ! dibenzenesulfonate, wherein Compound 1, methyl benzenesulfonate and a catalytic amount of an insoluble base in a solvent are combined to form a reaction mixture that is maintained for a period of time sufficient for atracurium besylate formation. The reaction mixture is then filtered to remove the insoluble base and then the atracurium besylate is precipitated and collected. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention relates to a process of producing atracurium besylate that substantially reduces the level of impurities in the final product. In accordance with such a process, Compound 1, methyl benzenesulfonate and a catalytic amount of an insoluble base are combined to form a reaction mixture that is maintained for a period of time sufficient for atracurium besylate formation. The reaction mixture is then filtered to remove the insoluble base, followed by subsequent atracufium besylate precipitation and collection. 
     Another embodiment of the present invention incindes forming a reaction mixture comprising, Compound 1, methyl benzenesulfonate and a catalytic amount of an insoluble base in a solvent. Suitable solvents include, but is not intended to be limited to, acetonitrile. The reaction mixture is maintained for a period of time sufficient for atracurium besylate formation. The reaction mixture may then be filtered to remove the insoluble base and the atracurium besylate may be precipitated by diluting with an aromatic hydrocarbon with or without alcohol, and adding to a solution comprising an acetate and a lower aliphatic hydrocarbon. Acetates suitable include, but are not intended to be limited to, ethyl acetate, isopropyl acetate, and methyl acetate. Lower aliphatic hydrocarbons suitable include, but are not intended to be limited to, heptane, hexane, and pentane. In an alternative embodiment, tert-butyl methyl ether (MTBE) may be substituted for the solution of acetate and a lower aliphatic hydrocarbon. 
     The use of an insoluble base in the reaction mixture has the advantage of driving the reaction to completion leading to a purer product. The use of aromatic hydrocarbons with or without an alcohol and an acetate and and a lower aliphatic hydrocarbon has the advantage of avoiding the use of diethyl ether on a large scale for the isolation of the product and reducing the number of precipitations required to purify the bulk drug. 
     Compound 1, or atracurium besylate containing incompletely converted Compound 1, may be dissolved in a solution of acetonitrile and methyl benzenesulfonate at a weight:weight:weight ratio of about 1:0.5-1.5:1.5-2.5, respectively. An insoluble base, including but not intended to be limited to inorganic carbonate and bicarbonates, is added to the reaction mixture at a weight ratio of from about 1.0 to about 50.0 milligram (mg) per gram of atracurim, more preferably from about 1.0 to about 20.0 mg per gram of atracurim, and most preferably from about 2.5 to about 10.0 mg base per gram of atracurium. Inorganic carbonates include, but are not limited to potassium carbonate, calcium carbonate, sodium carbonate, and lithium carbonate. A preferred inorganic, insoluble carbonate base is sodium carbonate. The reaction mixture is maintained, with stirring, until the reaction is complete. Atracurium besylate is precipitated from the reaction mixture and collected. In a preferred embodiment, the reaction mixture is filtered to remove the insoluble base prior to precipitation. 
     In one embodiment of the present invention, precipitation of atracurium besylate may be accomplished by diinting the reaction mixture with an aromatic hydrocarbon. Aromatic hydrocarbons which can be used with the present invention include, but are not intended to be limited to, benzene, xylene and toluene. A most preferred aromatic hydrocarbon is toluene. 
     Yet another embodiment of the present invention utilizes precipitation by diluting with both an alcohol and an aromatic hydrocarbon. Alcohols which can be used with the present invention include, but are not intended to be limited to, methanol, ethanol, 1-propanol, 1-butanol, 2-butanol,iso-butanol, and tert-butanol. When an alcohol is used to dilute with an aromatic hydrocarbon, the ratio of alcohol and aromatic hydrocarbon to atracurium in the reaction mixture depends upon the particular alcohol and hydrocarbon used. A most preferred alcohol is isopropanol. Where the alcohol is isopropanol, a preferred ratio is from about 0.5 to about 5 grams of isopropanol per gram of atracurium, and a more preferred ratio of from about 1.0 to about 1.5 grams of isopropanol per gram of atracurium. Where the aromatic hydrocarbon is toluene, a preferred ratio is about from about 5 to about 15 grams of toluene per gram of atracurium, and a more preferred ratio is about from about 7 to about 10 grams of toluene per gram of atracurium. 
     The diluted reaction mixture is then added slowly to a solution containing an acetate and a lower aliphatic hydrocarbon. Examples of acetates suitable are ethyl acetate, isopropyl acetate, or methyl acetate. Suitabler lower aliphatic hydrocarbons, include but are not intended to be limited to, heptane, penlane or hexane. A preferred acetate is ethyl acetate and a preferred lower aliphatic hydrocarbon is heptane. A preferred ratio of ethyl acetate is from about 25 to about 100 grams of ethyl acetate per gram of atracurium, and a more preferred ratio is about from about 50 to about 100 grams of ethyl acetate per gram of atracurium. For heptane, a preferred ratio is from about 5 to about 25 grams of heptane per gram of atracurium, and a more preferred ratio is about from about 5 to about 15 grams of heptane per gram of atracurium. The solid (precipitated atracurium besylate) is then collected. Collection includes the steps of riteting the reaction mixture, washing the retained material with a solvent such as, but not intended to be limited to, toluene and heptane, and drying the washed material under nitrogen. 
     Any residual methyl benzenesulfonate present in the final product may be removed by reprecipitating the collected product. The reprecipitation may be carded out in similar fashion to the initial precipitation although the ratios of solvents may vary due to less methyl benzenesulfonate being present. The product may be dissolved in a reprecipitation solution, such as acetonitrile with an an aromatic hydrocarbon with or without an alcohol. A preferred alcohol is isopropanol and a preferred hydrocarbon is toluene. 
     Preferred ratios of acetonitrile, isopropanol and. toluene to atracurium are from about 0.5 to about 1.0 gram of acetonitrile, from about 1 to about 2 grams of isopropanol and from about 5 to about 10 grams of toluene per gram of atracurium. The reprecipitation solution is then added slowly to a solution of acetate, such as ethyl acetate (from about 40 to about 50 grams per gram of atracurium) and a lower aliphatic hydrocarbon, such as heptane (from about 5 to about 10 grams per gram atracurium). In an alternative embodiment, tert-butyl methyl ether (MTBE) may be substituted for the solution of acetate and a lower aliphatic hydrocarbon. If necessary, the reprecipitation can be repeated until the level of residual methyl benzenesulfonate is reduced to an acceptable level. 
     The following Examples illustrate embodiments of the present invention and are not limiting of the specification and the claims in any way. 
    
    
     EXAMPLE 1: PREPARATION OF ATRACURIUM BESYLATE 
     Compound 1 (20 grams (gm)), acetonitrile (24 gm), methyl benzenesulfonate (48 gin), and sodium carbonate (0.05 gm) were combined and stirred at ambient temperature. After 17 hours the mixture was filtered, then diluted with isopropanol (30 milliliters (mL)) and toluene (200 mL). The mixture was charged to 5:1 ethyl acetate/heptanes (ethyl acetate/heptane volume of 1.8 L) resulting in a flocculent precipitate. The solids were collected and washed with toluene (300 mL) and heptanes (300 mL). Drying on the filter under a nitrogen stream for one hour afforded the crude atracurium besylate as a free-flowing, slightly off-white powder. 
     The crude product was dissolved in acetonitrile (11 gm), isopropanol (27 gm), and toluene (60 gm), then diluted with an additional volume of toluene (130 mL). Precipitation of the desired product by dropwise addition of this solution to to 5:1 ethyl acetate/heptanes (ethyl acetate/heptane volume of 1.2 L) was followed by collection of the solids and washing as above. The dried atracurium besylate (16.7 gm, 72%) was found to have &lt;0.1% residual methyl benzenesulfonate, and a purity of greater than 98% by HPLC. 
     EXAMPLE 2 Effects of the Ratio of Solvents to Residual Methyl Benzenesulfonate in the Final Product 
     Studies were performed to determine the effect of varying the ratio of solvents on the amount of residual methyl benzenesulfonate (MeOBs) in the product obtained after precipitation. In these studies, the reaction mixture was diluted with isopropanol (IPA) and toluene (Tol) in the ratios shown below, then added to ethyl acetate and heptane (5:1 ethyl acetate/heptane), filtered, washed with toluene, and then heptane. 
     The reaction mixture contained Compound 1, methyl benzenesulfonate and acetonitrile in a weight (gram) ratio of 1:2:0.5. The results are summarized below in Table 1. The Peak Area Percent (PA%) is the absorbance of ultraviolet light at 265 nanometers (nm) as determined by HPLC. 
     
                       TABLE 1______________________________________(IPA:Tol:EA-Hept)/Compound 1              % MeOBs(ml/gram)          (PA % 265 nm)______________________________________(2:10:60)          0.7(1.5:6.50)         1.7(1.5:6:50)         2.7-3.2(1.5:10:60)        1.0______________________________________ 
    
     EXAMPLE 3: Effects of Reprecipitation on ReSidual MeOBs 
     Products obtained from the studies in Example 2 were reprecipitated once by diluting the product with 2 mL of isopropanol and 10 mL of toluene (per gram of isolated solids of atracurium besylate) and analyzed for methyl benzenesulfonate levels. The toluene was heated to a temperature of 50° C.-70° C. prior to dilution. The diluted sample was then added dropwig to 50 mL of a 5:1 (v/v) solution of ethyl acetate and heptane. The results of these studies are summarized below in Table 2. 
     
                       TABLE 2______________________________________% MeOBs before reprecipitation             % MeOBs in final product______________________________________3.1               &lt;0.11.7               &lt;0.12.7-3.2           &lt;0.11.6               &lt;0.1______________________________________ 
    
     EXAMPLE 4: Removal of Methyl Benzenesulfonate from Atracurium Besylate by Reprecipitation in MTBE 
     Crude atracurium besylate (1.0 gm) containing 6.5% methyl benzenesulfonate (HPLC peak area percent, 265 nm) was dissolved in ethanol (3 mL) and toluene (25 mL). The solution was added dropwise to tert-butyl methyl ether (MTBE)(40 mL). The resulting solids were washed with MTBE followed by heptane. HPLC of the dried solids showed 0.5% residual methyl benzenesulfonate. The collected solids were reprecipitated by the procedure described in this example and found to have &lt;0.1% residual methyl benzenesulfonate. 
     EXAMPLE 5: Rework of atracurium besylate containing incompletely reacted Compound 1 
     Atracurium besylate containing 1.3% (HPLC peak area percent, 280 nm) Compound 1 was dissolved in acetonitrile and methyl benzenesulfonate. To this solution was added potassium carbonate and the reaction mixture was stirred for 16 hours. The reaction mixture was found to be free of Compound 1 and partially convened Compound 1.