PROCESS FOR THE PREPARATION OF CYCLOPROPYL SULFONAMIDE

The invention comprises a novel process for the preparation of cyclopropyl sulfonamide of the formula

Cyclopropyl sulfonamide is a versatile building block for many biologically active compounds (J.Li et al., Synlett 2006, No.5, 725-728).

The compound can be prepared by a three step synthesis comprising a) the conversion of chloropropane sulfonyl chloride of the formula

with tert.-butyl amine to form the N-tøt.-butyl-(3-chloro) propyl sulfonamide of the formula

b) the subsequent ring closing of the N-£er£.-butyl-(3-chloro) propyl sulfonamide of the formula III with n-butyl lithium to form the cyclopropane sulfonic acid tert.-butyl- amide of the formula

and finally c) the cleaving off of the tert.-butyl group with trifiuoro acetic acid (J.Li et al., Synlett 2006, No.5, 725-728; PCT Publ. WO 2006/086381).

The current synthesis requires the isolation of the intermediates of step a) and b) the N- RAU/13.06.2008

ter£.-butyl-(3-chloro) propyl sulfonamide of the formula III and the cyclopropane sulfonic acid føt.-butylamide of the formula IV. Furthermore the cleavage of the tert.- butyl group with a large excess trifluoro acetic acid is under an environmental aspect and with regard to a synthesis on a technical scale not desirable.

Object of the present invention was therefore to find a process alternative which does not require the isolation of the intermediate products and which is able to substitute the trifluoro acetic acid by a more environment friendly alternative.

The object could be achieved with the process of the present invention as outlined below.

The process for the preparation of cyclopropyl sulfonamide of the formula

is comprising

a) the conversion of chloropropane sulfonyl chloride of the formula

with tert.-butyl amine to form the N-tøt.-butyl-(3-chloro) propyl sulfonamide of the formula

b) the subsequent ring closing of the N-£er£.-butyl-(3-chloro) propyl sulfonamide of the formula III with a n-alkyl lithium to form the cyclopropane sulfonic acid tert.- butylamide of the formula

and finally

c) the cleaving off of the tert.-butyl group in the presence of an acid to form cyclopropyl sulfonamide of the formula I, whereby the process is characterized in that it

is performed without the isolation of the intermediates N- £er£.-butyl-(3-chloro) propyl sulfonamide of the formula III and cyclopropane sulfonic acid terf.-butylamide of the formula IV.

Step a)

The first step a) comprises the conversion of chloropropane sulfonyl chloride of the formula II with tert.-butyl amine to form the N-£er£.-butyl-(3-chloro) propyl sulfonamide of the formula III.

The reaction is usually performed in the presence of an organic solvent which is not or only poorly miscible with water, such as in methyltetrahydrofuran, tert.-butyl methyl ether or toluene, preferably in toluene.

The formation of the N-£er£.-butyl-(3-chloro) propyl sulfonamide of the formula III could be performed with a substantial excess of tert. -butyl amine. However, it was found preferable to substitute a substantial part of the excess of tert.-butyl amine by triethylamine.

The conversion in step a) is commonly performed at a reaction temperature of

-50 ⁰ C to 40 ⁰ C, preferably of -10 ⁰ C to 20 ⁰ C.

Upon completion of the amide formation the reaction mixture can then be treated with aqueous hydrochloric acid. The organic layer can be separated from the aqueous layer and after washing the organic layer with water and subsequent azeotropic removal of water, the N-£er£.-butyl-(3-chloro) propyl sulfonamide of the formula III can be made available to the conversion in step b) in the form of a solution in the respective organic solvent, preferably in toluene.

Step b)

Step b) comprises the ring closure of the N-£er£.-butyl-(3-chloro) propyl sulfonamide of the formula III with a n-alkyl lithium to form the cyclopropane sulfonic acid terf.-butylamide of the formula IV.

As a rule the toluene solution obtained from step a) is concentrated before tetrahydrofuran is added as second solvent.

The n-alkyl lithium base is selected from n-butyl lithium or n-hexyl lithium, preferably n-butyl lithium.

- A -

At least two equivalents of n-alkyl lithium base are required for the ring closing reaction.

The conversion in step b) is thus performed in a solvent mixture of tetrahydrofuran and toluene in a ratio of approx. 3:1 at a reaction temperature of- 70 ⁰ C to 0 ⁰ C, preferably -50 ⁰ C to -20 ⁰ C.

Upon completion of the reaction the reaction mixture is usually brought to ambient temperature and treated with water. The cyclopropane sulfonic acid tert.- butylamide of the formula IV can be made available for step c) in the form of a toluene/ tetrahydrofuran solution after separation of the organic layer from the aqueous layer and after washing the organic layer with water.

Step c)

Step c) comprises the cleaving off of the tert.-butyl group in the presence of an acid to form the cyclopropyl sulfonamide the formula I.

Suitable acid for the conversion in step c) is formic acid.

The solution of cyclopropane sulfonic acid terf.-butylamide obtained from step b) is therefore after removal of the solvents by distillation expediently treated with formic acid or with a mixture of formic acid and water at a reaction temperature of 60 ⁰ C to 100 ⁰ C, preferably 70 ⁰ C to 90 ⁰ C until the conversion is completed.

In order to achieve a complete conversion it is mandatory to steadily bubble nitrogen through the mixture during the entire reaction.

Isolation and purification of the cyclopropyl sulfonamide of the formula I can happen by removal of residual amounts of formic acid by co-evaporation with toluene and subsequent crystallization of the residue with a mixture of toluene and ethanol. A ratio toluene to ethanol of > 3:1 was found to be preferable.

With the processes of the present invention the cyclopropyl sulfonamide of the formula I can be obtained in an overall yield of 70-75% and with an assay of min. 99 %(area).

Example 1

To a solution of 36.6 g (0.50 mol) tert.-butylamine and 50.4 g (0.50 mol) triethylamine in 400 mL of toluene were added at 0 ⁰ C to 5°C 3-chloropropane sulfonyl chloride (73.0 g, 0.41 mol) within 30 to 60 minutes and the resulting mixture was stirred at 5°C for 10 minutes. The mixture was then allowed to warm to room temperature and treated with 200 mL of hydrochloric acid (1 molar). The layers were allowed to separate and the aqueous layer was removed. The organic layer was washed with water ( Ix 100 mL). From the organic layer approx. 250 mL of toluene were distilled off. THF (700 mL) was added and distillation was continued until a residual volume of approx. 600 mL was obtained in the reaction vessel. The mixture was cooled to -30 ⁰ C and treated at this temperature with 385 g of BuLi (15% in hexane, 2.2 eq). After 30 minutes at -30 ⁰ C the mixture was warmed to 0 ⁰ C treated with water (200 mL). The layers were allowed to separate. The aqueous layer was removed and the organic layer was washed with water ( Ix 100 mL) and concentrated. The residue was treated with formic acid (300 mL) at 80 ⁰ C for 20 hours. During the entire reaction a slight stream of nitrogen was bubbled through the solution. After complete conversion the mixture was concentrated to dryness. Residual amounts of formic acid were removed by co-evaporation with toluene (2x250 mL). The remaining residue was treated with toluene (100 mL) and ethanol (35 mL), heated to 70 to 75°C and stirred at this temperature until a clear solution was obtained. The solution was cooled to 50 ⁰ C and treated at this temperature with 300 mL of toluene. The mixture was then cooled to -10 to -15°C and stirred at this temperature for 5 hours. The crystals were filtered off, washed with 50 ml of pre-cooled toluene and dried at 50 ⁰ C / <30 mbar to afford 34.5 g (69.9%) of cyclopropyl sulfonamide as colorless crystals with a purity of 99.8% (GC, %area).

Example 2

To a solution of 18.3 g (0.25 mol) terf.-butylamine and 25 g (0.25 mol) triethylamine in 200 mL of toluene were added at 10 ⁰ C to 20 ⁰ C 3-chloropropane sulfonyl chloride (36.0 g, 0.21 mol) within 30 to 60 minutes and the resulting mixture was stirred at 15°C for 30 minutes. The mixture was treated with 90 mL of hydrochloric acid (1 molar). The layers were allowed to separate and the aqueous layer was removed. The organic layer was washed with water (1x50 mL). From the organic layer toluene was distilled off and replaced by THF. The resulting mixture (150 ml) was cooled to -25°C and treated at this temperature with 21O g (0.49 mol) of BuLi (15% in hexane). After 30 minutes at -25°C the mixture was warmed to 0°Cand treated with water (100 mL). The layers were allowed to separate. The organic layer was washed with water (4x 100 mL). The combined aqueous layers were treated with 37% hydrochloric acid (32 mL) and then extracted with toluene (2x100 mL). The combined organic layers were concentrated to a residual volume of 200 mL and then washed with water (2x20 mL). The organic layer was concentrated to dryness. The residue was treated with formic acid (135 mL) and water (15 mL) at 80 ⁰ C for 7 hours. During the entire reaction a slight stream of nitrogen was bubbled through the solution. After complete conversion the mixture was concentrated to dryness. Residual amounts of formic acid were removed by co-evaporation with toluene (2x 100 mL). The resulting residue was dissolved in ethanol (60 mL) at 64°C and treated with 1.0 g of charcoal. The charcoal was filtered off and washed with ethanol (20 mL). The mixture was heated to reflux temperature and concentrated to a residual volume of approximately 40 mL. The solution was then treated within 30 minutes at 70 ⁰ C with toluene (125 mL). The mixture was allowed to cool to -10 ⁰ C within 4 hours and stirred at this temperature for 5 hours. The crystals were filtered off, washed with 40 mL of pre-cooled toluene and dried at 50 ⁰ C / <30 mbar to afford 18.73 g (75 %) of cyclopropyl sulfonamide as colorless crystals with a purity of 99.9% (GC, %area)