Process for the production of bretylium tosylate

Abstract

A method of producing pharmaceutical grade bretylium tosylate comprising low amounts of mutagenic impurities. The method comprises forming bretylium tosylate having a purity of less than 99.5% and purifying the bretylium tosylate by: i) forming a slurry of the bretylium tosylate with a mixture of acetone and ethyl acetate; ii) filtering the slurry to obtain purified bretylium tosylate. The bretylium tosylate so produced has a purity of at least 99.5%, and suitably comprises less than 0.5 ppm of the potentially mutagenic impurity ethyl p-toluenesulfonate. The bretylium tosylate so produced also suitably comprises less than 0.5 ppm of the potentially mutagenic impurity 2-bromobenzylbromide.

Claims

1. A method of producing bretylium tosylate having a purity of at least 99.5% and comprising less than 0.5 ppm of ethyl p-toluenesulfonate, the method comprising: a) providing bretylium tosylate having a purity of less than 99.5% by reacting 2-bromo-benzylbromide with dimethylamine to produce (2-bromobenzyl)-dimethylamine and then reacting (2-bromobenzyl)-dimethylamine with ethyl p-toluenesulfonate to produce the bretylium tosylate having a purity of less than 99.5%; and; b) purifying the bretylium tosylate from step a) by: i) forming a slurry of the bretylium tosylate from step a) with a mixture of acetone and ethyl acetate; ii) filtering the slurry to obtain bretylium tosylate; and iii) recrystallizing the bretylium tosylate from step ii) from a mixture of acetone and ethyl acetate to obtain the bretylium tosylate having a purity of at least 99.5%.

2. The method according to claim 1, wherein the mixture of acetone and ethyl acetate in step i) comprises a volume ratio of acetone to ethyl acetate of from 1:1 to 1:5.

3. The method according to claim 1, wherein step i) involves stirring the slurry for at least 20 minutes.

4. The method according to claim 1, wherein steps i) and ii) are repeated at least once.

5. The method according to claim 1, wherein step a) comprises steps: a1) reacting 2-bromo-benzylbromide with dimethylamine in an organic solvent to form a crude reaction product solution of (2-bromobenzyl)-dimethylamine; a2) treating the crude reaction product solution of (2-bromobenzyl)-dimethylamine with an aqueous acid to convert the (2-bromobenzyl)-dimethylamine to an acid salt and separating the crude reaction product solution between an organic phase and an aqueous phase; a3) removing the organic phase from the aqueous phase; a4) treating the aqueous phase with base to convert the (2-bromobenzyl)-dimethylamine salt to a neutral (2-bromobenzyl)-dimethylamine; a5) separating the neutral (2-bromobenzyl)-dimethylamine from the aqueous phase to provide purified (2-bromobenzyl)-dimethylamine; and a6) reacting the purified (2-bromobenzyl)-dimethylamine with ethyl p-toluenesulfonate to form the bretylium tosylate having a purity of less than 99.5%.

6. The method according to claim 5, wherein no further purification step is carried out between step a5) and step a6).

7. The method according to claim 5, wherein step a1) involves adding a solution of 2-bromo-benzylbromide to a solution of dimethylamine.

8. The method according to claim 5, wherein the purified bretylium tosylate comprises less than 0.5 ppm 2-bromobenzylbromide.

9. Bretylium tosylate formed by a method of claim 1, the bretylium tosylate having a purity of at least 99.5% and comprising less than 0.5 ppm of ethyl p-toluenesulfonate.

10. Bretylium tosylate according to claim 9 comprising less than 0.5 ppm 2-bromobenzylbromide.

Description

EXAMPLES

(1) ##STR00001##

Comparative Example 1: Standard Synthesis of (2-Bromobenzyl)-dimethylamine

(2) A solution of 2-bromo-benzylbromide (1.0 kg) in methyl tert-butyl ether (2 litres) is slowly added to a 40% aqueous solution of dimethylamine (1.2 kg). A controlled addition rate is used to maintain the reaction temperature below 40 C. The two-phase reaction is stirred vigorously until substantially complete.

(3) The layers are separated and the aqueous phase is washed with methyl tert-butyl ether. The combined methyl tert-butyl ether layers are then washed with water. The solvent is then removed under reduced pressure to yield (2-bromobenzyl)-dimethylamine as a clear mobile liquid (0.8 kg). Distillation under vacuum yields a clear oil (0.6 kg) with high levels of residual 2-bromobenzyl bromide.

Comparative Example 2: Standard Synthesis of Bretylium Tosylate

(4) (2-Bromobenzyl)-dimethylamine (0.6 kg) and ethyl p-toluenesulfonate (0.587 kg) are dissolved in acetone (1.2 litres) and then heated and stirred at reflux for 12 hours. Ethyl acetate (0.6 litres) is then added and the solution cooled to ambient to crystallise the product, Bretylium Tosylate.

(5) The crude solid product is filtered and washed with ethyl acetate. The filtered solid is then dried under vacuum at 60 C. to yield Bretylium Tosylate (0.48 kilos) containing high levels of residual ethyl p-toluene sulfonate.

Example 3: Synthesis of (2-Bromobenzyl)-Dimethylamine with Low Levels of Residual Mutagenic Impurities

(6) A solution of 2-bromo-benzylbromide (3.0 kg) in methyl tert-butyl ether (6 litres) is slowly added to a 40% aqueous solution of dimethylamine (3.7 kg). A controlled addition rate is used to maintain the reaction temperature below 40 C. The two-phase reaction is stirred vigorously until substantially complete. The reaction is quenched by the careful addition of 37% aqueous hydrochloric acid until a pH of 1-3 is achieved. A controlled addition rate is used to maintain the reaction temperature below 40 C.

(7) The layers are separated and the aqueous phase is washed with methyl tert-butyl ether. The methyl tert-butyl ether washes are discarded.

(8) The aqueous phase is basified (to pH 9-13) with 20% aqueous sodium hydroxide. An oily layer forms and is separated. The aqueous phase is then extracted with methyl tert-butyl ether. The methyl tert-butyl ether extract is added to the first oily layer. The resulting solution is then washed with water. The solvent is then removed under reduced pressure to yield (2-bromobenzyl)-dimethylamine as a clear mobile liquid (2.4 kg) with no detectable levels of residual 2-bromobenzyl bromide.

Example 4: Synthesis of Bretylium Tosylate with Low Levels of Residual Mutagenic Impurities

(9) (2-Bromobenzyl)-dimethylamine (2.4 kg) and ethyl p-toluenesulfonate (2.35 kg) are mixed and then heated and stirred at 60 C. for 3 hours. The thick reaction mass is dissolved in acetone (10 litres). Ethyl acetate (5 litres) is then added and the solution cooled to ambient to crystallise the product, Bretylium Tosylate.

(10) The crude solid product is filtered and the solid is suspended in a 1:3 acetone-ethyl acetate mixture (7 litres). The mixture is gently slurried for 30-60 minutes and the solid is filtered. This slurrying process is then repeated a further two times.

(11) The final slurry is filtered and is washed with ethyl acetate. The filtered solid is then dried under vacuum at 60 C. to yield Bretylium Tosylate (4.3 kilos).

(12) The Bretylium Tosylate is then recrystallised from acetone (9 litres) by heating to 50 C. until dissolution is complete. The solution is then transferred via a 1.0 m in-line filter to a crystallisation vessel and ethyl acetate (4.5 litres) is added. The system is allowed to cool until crystallisation is complete.

(13) The solid is filtered and the filtered solid is washed with ethyl acetate. The solid is then dried under vacuum at 50 C.-60 C. to yield purified Bretylium Tosylate (4.0 kilos) with no detectable levels of ethyl p-toluenesulfonate or 2-bromobenzyl bromide.

(14) TABLE-US-00001 TABLE 1 purity data on three batches of Bretylium Tosylate Table 1 below shows the purity of three different batches of Bretylium Tosylate produced according to the procedures of Examples 3 and 4. Each batch had a purity of at least 99.9% and the potentially mutagenic impurities 2-bromobenzylbromide and ethyl p-toluenesulfonate were not detectable in any of the batches. Impurity Limit T170313 T180204 T180301 Ethyl 0.5 ppm ND ND ND p-toluenesulfonate.sup.1 (2-Bromobenzyl)- 1% ND ND ND dimethylamine.sup.1 Benzenesulfonic acid.sup.1 0.10% ND 0.01% ND Individual unknown 0.05% Complies Complies Complies impurity.sup.1 Total impurities.sup.1 2% 0% 0.01% 0% 2-Bromobenzyl- 0.5 ppm ND ND ND bromide.sup.2 Acetone.sup.3 1000 ppm 73 ppm <24 ppm 43 ppm Ethyl acetate.sup.3 5000 ppm 110 ppm 39 ppm 77 ppm Methyl tert-butyl ether.sup.3 5000 ppm <1 ppm <2 ppm 2 ppm Residue on Ignition 0.1% 0% 0% 0% Assay.sup.1 98.0- 100.0% 99.8% 100.3% 101.0% .sup.1By HPLC. .sup.2By GC. .sup.3By GC headspace analysis

(15) Analytical Method for the detection of Ethyl p-toluenesulfonate

(16) HPLC Conditions:

(17) Column: Zorbax SB phenyl, 5 m, 4.6 mm250 mm column or equivalent

(18) Detector Wavelength: 265 nm

(19) Flow Rate: 1.8 ml/minNote: Start flow rate at 0.9 ml/min and gradually work up to 1.8 ml/min over a 40-50 min period.

(20) Injection Volume: 200 L

(21) Run Time: 20 min.

(22) Mobile Phase: Prepare a mixture of 0.01M Sodium 1-Octanesulfonate solution, Acetonitrile, glacial acetic acid and Triethylamine. (65:35:2:0.5).

(23) Diluent Preparation: Prepare a mixture of 0.01M Sodium 1-Octanesulfonate solution, Acetonitrile, glacial acetic acid and Triethylamine (81:19:2:0.5)

(24) Stock Standard Preparation: Dissolve 40 mg of accurately weighed ethyl p-toluenesulfonate standard to a 200 ml volumetric flask, dilute to volume with diluent and mix.

(25) Working Standard Preparation: Take 2.5 ml of stock standard preparation and dilute to 200 ml with diluent. A further dilution of 1 ml of solution in 10 ml is carried out and made up to the mark with diluent (Concentration 0.00025 mg/ml)

(26) Sample Preparation Transfer about 2.5 g of Bretylium Tosylate, accurately weighed, to a 5 ml volumetric flask, dissolve in and dilute to volume with diluent and mix.

(27) The retention time of ethyl p-toluenesulfonate is about 10 minutes and the calculated limit of detection is 0.0000024% (0.024 ppm).

(28) The area count for ethyl p-toluenesulfonate peak in the sample must not exceed the area count for that of the Working Standard solution.

(29) Analytical Method for the detection of 2-bromobenzyl bromide

(30) GC Conditions:

(31) Column Phenomenex ZB-5 ms 30 m0.32 mm1 m or equivalent

(32) Injector Temperature: 280 C.

(33) Detector Temperature: Flame Ionisation Detection at 280 C.

(34) Column Temperature: 45 C. hold for 2 min. Ramp to 280 C. at 15 C. per/minute and hold for 10 minutes.

(35) Column Flow 1.0 ml/min

(36) Injection Volume 8.0 L (split 1:10)

(37) 2-bromobenzyl bromide Stock Standard Solution (0.25 mg/ml): Accurately weigh 25 mg of 2-bromobenzyl bromide Reference standard in to a 100 ml volumetric flask and dilute to volume with Hexane.

(38) 2-bromobenzyl bromide Identification Standard Solution (0.0025 mg/ml): Further dilute 1 ml of 2-bromobenzyl bromide stock standard solution to 100 mls with hexane.

(39) 2-bromobenzyl bromide Working Standard solution (0.00025 mg/ml): Further dilute 1 ml of 2-bromobenzyl bromide identification standard solution to 10 mls with hexane. This working standard is the equivalent to the 0.00005% 2-bromobenzyl bromide specification.

(40) Bretylium Tosylate Test Solution: Accurately weigh out 5.0 g of Bretylium Tosylate test material. Dissolve in 10 ml of purified water. Pipette 10 mls of hexane into this solution and shake vigorously. Allow the layers to separate and remove the top organic layer. Dry the organic layer with approximately 50-100 mgs of magnesium sulphate. Filter the resulting solution into a HPLC vial and analyse.

(41) (2-Bromobenzyl)-dimethylamine Test Solution: Accurately weigh 5.0 g of (2-bromobenzyl)-dimethylamine. Add 10 ml of purified water and add concentrated hydrochloric acid dropwise with stirring until the oily layer fully dissolves. Pipette 10 mls of hexane into this solution and shake vigorously. Allow the layers to separate and remove the top organic layer. Dry the organic layer with approximately 50-100 mgs of magnesium sulphate. Filter the resulting solution into a HPLC vial and analyse.

(42) The 2-bromobenzyl bromide retention time is 16.7 minutes with a limit of quantitation of 0.00001% (0.1 ppm). The area count for the 2-bromobenzyl bromide peak in the test sample solutions must not exceed the area count for that of the 2-bromobenzyl bromide working standard solution.

(43) In summary, the present invention provides a method of producing pharmaceutical grade bretylium tosylate comprising low amounts of mutagenic impurities. The method comprises forming bretylium tosylate having a purity of less than 99.5% and purifying the bretylium tosylate by: i) forming a slurry of the bretylium tosylate with a mixture of acetone and ethyl acetate; ii) filtering the slurry to obtain purified bretylium tosylate. The bretylium tosylate so produced has a purity of at least 99.5%, and comprises less than 0.5 ppm of the potentially mutagenic impurities ethyl p-toluenesulfonate and 2-bromobenzylbromide, which are used in the formation of the bretylium tosylate and contaminate bretylium tosylate made by certain known methods.

(44) Although a few preferred embodiments have been shown and described, it will be appreciated by those skilled in the art that various changes and modifications might be made without departing from the scope of the invention, as defined in the appended claims.

(45) Throughout this specification, the term comprising or comprises means including the component(s) specified but not to the exclusion of the presence of other components. The term consisting essentially of or consists essentially of means including the components specified but excluding other components except for materials present as impurities, unavoidable materials present as a result of processes used to provide the components, and components added for a purpose other than achieving the technical effect of the invention. Typically, when referring to compositions, a composition consisting essentially of a set of components will comprise less than 5% by weight, typically less than 3% by weight, more typically less than 1% by weight of non-specified components.

(46) The term consisting of or consists of means including the components specified but excluding addition of other components.

(47) Whenever appropriate, depending upon the context, the use of the term comprises or comprising may also be taken to encompass or include the meaning consists essentially of or consisting essentially of, and may also be taken to include the meaning consists of or consisting of.

(48) For the avoidance of doubt, wherein amounts of components in a composition are described in wt %, this means the weight percentage of the specified component in relation to the whole composition referred to.

(49) The optional features set out herein may be used either individually or in combination with each other where appropriate and particularly in the combinations as set out in the accompanying claims. The optional features for each aspect or exemplary embodiment of the invention as set out herein are also to be read as applicable to any other aspect or exemplary embodiments of the invention, where appropriate. In other words, the skilled person reading this specification should consider the optional features for each exemplary embodiment of the invention as interchangeable and combinable between different exemplary embodiments.

(50) Attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

(51) All of the features disclosed in this specification (including any accompanying claims, and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

(52) Each feature disclosed in this specification (including any accompanying claims, and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

(53) The invention is not restricted to the details of the foregoing embodiment(s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.