Method for preparing N-[4-(2-{[2-(4-methane sulfonamidophenoxy) ethyl] (methyl)amino}ethyl)phenyl]methanesulfonamide (dofetilide)

Abstract

A method for preparing 1-(4-methanesulfonamidophenoxy)-2-[N-(4-methanesulfonamidophenethyl)-N-methylamino]ethane (Dofetilide) of formula I by sulfonylation of 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane of formula II with N-methylsulfonyl-N-methylimidazolium chloride of formula III. ##STR00001##

Claims

1. A method for preparing 1-(4-methanesulfonamidophenoxy)-2-[N-(4-methane-sulfonamidophenethyl)-N-methylamino]ethane (Dofetilide) of formula I ##STR00005## by sulfonylation of 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane of formula II, ##STR00006## characterized in that the sulfonylation is carried out with N-methylsulfonyl-N-methylimidazolium chloride of formula III ##STR00007## in an organic solvent.

2. The method according to claim 1, characterized in that N-methylsulfonyl-N-methylimidazolium chloride prepared by reaction of 1-methylimidazole with methanesulfonyl chloride is used.

3. The method according to claim 1, characterized in that the organic solvent is N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or their mixture.

4. The method according to claim 1, characterized in that the reaction is carried out at a temperature of 20 to 5 C.

Description

EXAMPLES

(1) The substance of the inventive method is clarified in a more detailed way in the examples below. These examples have an illustrative character and do not restrict the scope of the invention in any respect.

Example 1

(2) 1-Methylimidazole (46.6 g, 568 mmol) and subsequently N-methylpyrrolidone (255 ml) are charged into a sulfonation flask fitted with a thermometer, mechanical stirrer and a dropping funnel. The obtained solution is cooled down to 15 C. under a nitrogen atmosphere. During 20 min, methanesulfonyl chloride (60.2 g, 526 mmol) is added dropwise, the temperature of the reaction mixture is maintained in the range of 15 to 7 C. The dropping funnel is rinsed with N-methylpyrrolidone (28 ml). The addition being completed, the mixture is stirred for 5 min at about 10 C. and subsequently a solution of 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane (60.0 g, 210 mmol) in N-methylpyrrolidone (240 ml) is added dropwise during 20 min. The dropping funnel is rinsed with N-methylpyrrolidone (20 ml). During the addition, the temperature is maintained in the range of 12 to 5 C. Then, the reaction mixture is maintained at about 15 to 10 C. for 30 min. After this time period, HPLC conversion is >99.9%. The reaction is stopped by addition of 15.8 g of a 10% aqueous solution of Na.sub.2SO.sub.3. The reaction mixture is left to get heated up to about 0 C. A solution of NaHCO.sub.3 (56.4 g) in water (600 ml) is added dropwise to the reaction mixture. The mixture is extracted with ethyl acetate (6600 ml). The combined organic phases are then washed with a 10% aqueous solution of NaCl (6600 ml). About 9/10 of the solvent volume is removed by distillation at reduced pressure; the final volume should correspond to about 300 ml. During the distillation, crystals start to get separated. Subsequently, the mixture is heated up to boil at atmospheric pressure and stirred under boiling for 1 h. The mixture is cooled down to the room temperature and cyclohexane (300 ml) is added to the obtained suspension during 5 min. The mixture is stirred at room temperature for 1 h. The separated crystals are filtered off and washed with a mixture of ethyl acetate (120 ml) and cyclohexane (120 ml). The product is dried and 83.1 g (90%) of a creamy crystalline substance is obtained. HPLC purity 99.8%. HRMS (ESI+) m/z calculated for [C.sub.19H.sub.27O.sub.5N.sub.3S.sub.2+H].sup.+: 442.1465; found: 442.1461.

Example 2

(3) A solution of 1-methylimidazole (2.33 g, 28.4 mmol) in N,N-dimethylformamide (13 ml) is cooled down to 15 C. Methanesulfonyl chloride (3.01 g, 26.3 mmol) is added to the solution dropwise; the temperature is maintained in the range of 18 to 15 C. The mixture is subsequently stirred at this temperature for 5 min. A solution of 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane (3.0 g, 10.5 mmol) in N,N-dimethylformamide (12 ml) is then added dropwise to the reaction mixture during 20 min. During the addition, the temperature is maintained in the range of 20 to 13 C. The dropping funnel is rinsed with N,N-dimethylformamide (1 ml). The reaction mixture is stirred at 15 C. for 30 min. After this time period, HPLC conversion is >99.9%. A 10% aqueous solution of Na.sub.2SO.sub.3 (0.8 ml) is added to the reaction mixture and the reaction mixture is left to heat up to about 0 C. Subsequently, a solution of NaHCO.sub.3 (2.82 g) in water (30 ml) is added dropwise. The mixture is extracted with ethyl acetate (630 ml). The combined extracts are then washed with a 10% aqueous solution of NaCl (630 ml). The organic phase is concentrated to a volume of about 15 ml. The obtained suspension is heated up to boil for 1 h and then it is cooled down to the room temperature. Cyclohexane (15 ml) is added to the mixture under stirring. The crystalline substance is filtered off and washed with a cooled mixture of ethyl acetate (6 ml) and cyclohexane (6 ml). The product is dried and 3.73 g (80%) of a creamy crystalline substance is obtained. HPLC purity 99.5%. HRMS (ESI+) m/z calculated for [C.sub.19H.sub.27O.sub.5N.sub.3S.sub.2+H].sup.+: 442.1465; found: 442.1461.

Example 3

(4) A solution of 1-methylimidazole (2.33 g, 28.4 mmol) in N,N-dimethylacetamide (13 ml) is cooled down to 18 C. Methanesulfonyl chloride (3.01 g, 26.3 mmol) is added to the solution dropwise; the temperature is maintained in the range of 18 to 15 C. The mixture is stirred at this temperature for 5 minutes. A solution of 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane (3.0 g, 10.5 mmol) in N,N-dimethylacetamide (12 ml) is subsequently added to the reaction mixture dropwise during 20 min. During the addition, the temperature is maintained in the range of 18 to 12 C. The dropping funnel is rinsed with N,N-dimethylacetamide (1 ml). The reaction mixture is stirred at 15 C. for 30 min. After this time period, HPLC conversion is >99.9%. A 10% aqueous solution of Na.sub.2SO.sub.3 (0.8 ml) is added to the reaction mixture and the reaction mixture is left to heat up to about 0 C. Subsequently, a solution of NaHCO.sub.3 (2.82 g) in water (30 ml) is added dropwise. The mixture is extracted with ethyl acetate (630 ml). The combined extracts are then washed with a 10% aqueous solution of NaCl (630 ml). The organic phase is concentrated to a volume of about 15 ml. The obtained suspension is heated up to boil for 1 h and then it is cooled down to the room temperature. Cyclohexane (15 ml) is added to the mixture under stirring. The crystalline substance is filtered off and washed with a cooled mixture of ethyl acetate (6 ml) and cyclohexane (6 ml). The product is dried and 3.59 g (77%) of a creamy crystalline substance is obtained. HPLC purity 99.5%. HRMS (ESI+) m/z calculated for [C.sub.19H.sub.27O.sub.5N.sub.3S.sub.2+H].sup.+: 442.1465; found: 442.1459.