GB2033382A

GB2033382A - Production of N-(4'-Chloro-3- sulphamoyl-benzenesulphonyl)-N- methyl-2-aminomethyl-2-methyl tetrahydrofuran

Info

Publication number: GB2033382A
Application number: GB7933926A
Authority: GB
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1978-10-03
Filing date: 1979-10-01
Publication date: 1980-05-21
Also published as: DE2843040A1; GB2033382B; JPS5549367A; CH641174A5; DE2843040C2; JPS5942674B2

Abstract

The process for production of the above compound comprises reacting 4-chloro-3-sulphamoyl-benzene- sulphonic acid chloride in a chlorinated hydrocarbon solvent, with an aqueous solution (containing alkali group carbonate) of N-methyl-2- aminomethyl-2-methyl- tetrahydrofurane-ammonium hydrogen sulphate at a temperature between 20 and 100 DEG C.

Description

SPECIFICATION Production of N-(4'-chloro-3'sulphamoylbenzenesulphonyl)-N-methyl-2amino-methyl-2-methyl-tetrahydrofurane The present invention relates to an unobvious process for the production of the known compound N-(4'-chloro-3'-sulphamoyl benzenesuiphonyl )-N-methyl-2-aminomethyl-2- methyl-tetrahydrofurane and the pharmaceutical use thereof.

The above-mentioned compound is known as a diuretic agent under the generic name "Mefrusid". Hitherto, it was prepared by reacting 4-chloro-3-sulphamoyl-benzene-suíphonic acid chloride (called Sulphochloride 1 500 in the following text) with N-methyl-2-aminomethyl-2methyl-tetra-hydrofu rane-a mmonium hydrogen sulphate (called Amine Sulphate 1 500 in the following text), the reaction being carried out in a solvent mixture of methyl ethyl ketone/water or acetone/water.

In order to obtain from the resulting crude Mefrusid a pure active compound which is suitable for pharmaceutical requirements, additional purification steps were hitherto necessary. The crude product was hitherto dissolved in sodium hydroxide solution and, after treatment with active charcoal, the solution was filtered and the product was precipitated from the filtrate with ammonium chloride solution and then isolated. This purification step was followed by a further recrystallisation by dissolving the product in hot, aqueous methanol, treatment of the solution with active charcoal, filtration, renewed crystallisation and subsequent isolation of the purified active compound.

These purification operations are timeconsuming and expensive, pollute the effluent and greatly reduce the yield.

According to the present invention we provide a process for the production of a compound which is N-(4'-chloro-3'-sulphamoylbenzenesu Iphonyl)-N-methyl-2-aminomethyl-2methyl-tetrahydrofurane, in which 4-chloro-3sulphamoyl-benzene-sulphonic acid chloride is reacted, in a chlorinated hydrocarbon, with an aqueous solution, containing potassium carbonate, of N-methyl-2-aminomethyl-2-methyl- tetrahydrofurane-ammonium hydrogen sulphate at a temperature between 20 and 1000C.

A particularly preferred process for producing Mefrusid in a pure form is one in which Sulphochloride 1 500 is dissolved in a liquid chlorinated hydrocarbon, under the influence of heat, the insoluble material is filtered off and the filtrate is reacted with an aqueous potassium carbonate-Amine-Suiphate 1 500 solution at temperatures between 40 and 800 C, the chlorinated hydrocarbon is then distilled off, the precipitated Mefrusid is dissolved by heating, with the addition of a C1 to C4 alkanol, and, after filtering the mixture and cooling the solution, the Mefrusid which has crystallised out is then isolated.

The Mefrusid obtained in this manner is already so pure that, after simple, single recrystallisation in aqueous alcohol, it can be employed for the preparation of medicaments.

Chlorinated hydrocarbons which are particularly advantageous to use are chlorobenzene or, preferably, 1 ,2-dichloroethane.

Alkanols with 1 to 4 carbon atoms, in particular ethanol, or preferably methanol, are preferably used for the recrystallisation.

The reaction according to the invention is appropriately preferably carried out in a temperature range from 40 to 800C, and especially from 50 to 700C.

It is exceptionally surprising that the reaction of Sulphochloride 1 500 with potassium carbonate Amine Sulphate 1 500 can be carried out using chlorinated hydrocarbons as solvents and that such a pure Mefrusid is obtained by this procedure.

The process according to the invention has a number of advantages. Compared with the process known hitherto, changing of solvents, using active charcoal and the addition of ammonium chloride to precipitate the Mefrusid are dispensed with. Furthermore, the yield of pure Mefrusid is higher than in the case of the process known hitherto.

The following Example illustrates the process of the present invention.

Example 100 g of Sulphochloride 1 500 are dissolved in 1 880 g of 1 2-dichloroethane at the boil.

Insoluble material is filtered off from the hot solution. The filtrate is run into an aqueous solution of 160 ml of water, 70 g of potassium carbonate and 70 g of Amine Sulphate 1 500. The mixture is stirred at 50--600C for 5 hours. 300 ml of water are then added and the aqueous layer is separated off. The 1,2-dichloroethane is distilled off with steam. The 1 2-dichloroethane which has distilled off is dried with calcium chloride, after separating off the water, and is available for re-use.

The same amount by volume of methanol is added to the aqueous Mefrusid suspension, 5 10 g of active charcoal are added and the mixture is heated to the boil.

The hot solution is filtered. The Mefrusid is crystallised out from the cooled filtrate. It is filtered off and washed with 3 x 100 ml of water.

The moist Mefrusid is recrystallised once from aqueous methanol and a Mefrusid which corresponds to the purity requirements for medicaments is obtained.

Claims

1. A process for the production of a compound which is N-(4'-chloro-3'-sulphamoyl benzenesu Iphonyl)-N-methyl-2-aminomethyl-2- methyl-tetrahydrofurane, in which 4-chloro-3sulphamoyl-benzene-sulphonic acid chloride is reacted, in a chlorinated hydrocarbon, with an aqueous solution, containing alkali carbonate, of

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. SPECIFICATION Production of N-(4'-chloro-3'sulphamoylbenzenesulphonyl)-N-methyl-2amino-methyl-2-methyl-tetrahydrofurane The present invention relates to an unobvious process for the production of the known compound N-(4'-chloro-3'-sulphamoyl benzenesuiphonyl )-N-methyl-2-aminomethyl-2- methyl-tetrahydrofurane and the pharmaceutical use thereof. The above-mentioned compound is known as a diuretic agent under the generic name "Mefrusid". Hitherto, it was prepared by reacting 4-chloro-3-sulphamoyl-benzene-suíphonic acid chloride (called Sulphochloride 1 500 in the following text) with N-methyl-2-aminomethyl-2methyl-tetra-hydrofu rane-a mmonium hydrogen sulphate (called Amine Sulphate 1 500 in the following text), the reaction being carried out in a solvent mixture of methyl ethyl ketone/water or acetone/water. In order to obtain from the resulting crude Mefrusid a pure active compound which is suitable for pharmaceutical requirements, additional purification steps were hitherto necessary. The crude product was hitherto dissolved in sodium hydroxide solution and, after treatment with active charcoal, the solution was filtered and the product was precipitated from the filtrate with ammonium chloride solution and then isolated. This purification step was followed by a further recrystallisation by dissolving the product in hot, aqueous methanol, treatment of the solution with active charcoal, filtration, renewed crystallisation and subsequent isolation of the purified active compound. These purification operations are timeconsuming and expensive, pollute the effluent and greatly reduce the yield. According to the present invention we provide a process for the production of a compound which is N-(4'-chloro-3'-sulphamoylbenzenesu Iphonyl)-N-methyl-2-aminomethyl-2methyl-tetrahydrofurane, in which 4-chloro-3sulphamoyl-benzene-sulphonic acid chloride is reacted, in a chlorinated hydrocarbon, with an aqueous solution, containing potassium carbonate, of N-methyl-2-aminomethyl-2-methyl- tetrahydrofurane-ammonium hydrogen sulphate at a temperature between 20 and 1000C. A particularly preferred process for producing Mefrusid in a pure form is one in which Sulphochloride 1 500 is dissolved in a liquid chlorinated hydrocarbon, under the influence of heat, the insoluble material is filtered off and the filtrate is reacted with an aqueous potassium carbonate-Amine-Suiphate 1 500 solution at temperatures between 40 and 800 C, the chlorinated hydrocarbon is then distilled off, the precipitated Mefrusid is dissolved by heating, with the addition of a C1 to C4 alkanol, and, after filtering the mixture and cooling the solution, the Mefrusid which has crystallised out is then isolated. The Mefrusid obtained in this manner is already so pure that, after simple, single recrystallisation in aqueous alcohol, it can be employed for the preparation of medicaments. Chlorinated hydrocarbons which are particularly advantageous to use are chlorobenzene or, preferably, 1 ,2-dichloroethane. Alkanols with 1 to 4 carbon atoms, in particular ethanol, or preferably methanol, are preferably used for the recrystallisation. The reaction according to the invention is appropriately preferably carried out in a temperature range from 40 to 800C, and especially from 50 to 700C. It is exceptionally surprising that the reaction of Sulphochloride 1 500 with potassium carbonate Amine Sulphate 1 500 can be carried out using chlorinated hydrocarbons as solvents and that such a pure Mefrusid is obtained by this procedure. The process according to the invention has a number of advantages. Compared with the process known hitherto, changing of solvents, using active charcoal and the addition of ammonium chloride to precipitate the Mefrusid are dispensed with. Furthermore, the yield of pure Mefrusid is higher than in the case of the process known hitherto. The following Example illustrates the process of the present invention. Example 100 g of Sulphochloride 1 500 are dissolved in 1 880 g of 1 2-dichloroethane at the boil. Insoluble material is filtered off from the hot solution. The filtrate is run into an aqueous solution of 160 ml of water, 70 g of potassium carbonate and 70 g of Amine Sulphate 1 500. The mixture is stirred at 50--600C for 5 hours. 300 ml of water are then added and the aqueous layer is separated off. The 1,2-dichloroethane is distilled off with steam. The 1 2-dichloroethane which has distilled off is dried with calcium chloride, after separating off the water, and is available for re-use. The same amount by volume of methanol is added to the aqueous Mefrusid suspension, 5 10 g of active charcoal are added and the mixture is heated to the boil. The hot solution is filtered. The Mefrusid is crystallised out from the cooled filtrate. It is filtered off and washed with 3 x 100 ml of water. The moist Mefrusid is recrystallised once from aqueous methanol and a Mefrusid which corresponds to the purity requirements for medicaments is obtained. Claims

1. A process for the production of a compound which is N-(4'-chloro-3'-sulphamoyl benzenesu Iphonyl)-N-methyl-2-aminomethyl-2- methyl-tetrahydrofurane, in which 4-chloro-3sulphamoyl-benzene-sulphonic acid chloride is reacted, in a chlorinated hydrocarbon, with an aqueous solution, containing alkali carbonate, of N-methyl-2-aminomethyl-2-methyltetrahydrofurane-ammonium hydrogen sulphate at a temperature between 20 and 1 000C.

2. A process according to Claim 1, in which the alkali carbonate is potassium carbonate.

3. A process according to Claim 1, in which the chlorinated hydrocarbon is 1,2-dichloroethane.

4. A process according to Claim 1 or 2, in which the reaction is carried out at a temperature of50to700C.

5. A process according to any of Claims 1 to 3, in which the compound obtained is recrystallised from an aqueous alcohol solution.

6. A process according to Claim 4, in which the alcohol is an alkanol with 1 to 4 carbon atoms.

7. A process according to Claim 5, in which the alkanol is methanol,.

8. A process according to Claim 1, when carried out substantially as described in the Example.

9. N-(4'-chloro-3'-sulphamoylbenzenesulphonyl)-N-methyl-2-aminomethyl-2 methyl-tetrahydrofurane when produced by the process of any of the foregoing claims.