SYNTHESIS OF BICYCLIC AROMATIC SULFONYL CHLORIDES

Abstract: A process for preparing bicyclic aromatic sulfonyl chlorides of the formula wherein, n is 1 or 2; A is -O- or -CH₂-; and B is -O-, -CH₂-, or -NCH₃-; provided at least one of A or B is -O-, which comprises reacting a compound of the formula with a Villsmeier reagent of the formula The bicyclic aromatic sulfonyl chlorides produced by the process can be used to prepare pharmaceutically useful sulfonylureas.

Description: This invention provides a novel process for preparing bicyclic aromatic sulfonyl chlorides. Benzene sulfonylureas of the formula where R is an organic radical, are well known in the art. Several methods of preparing such compounds are known and are generally summarized by Kurzer, Chem . Rev ., 50 , 1 (1952). One synthesis involves reacting a substituted benzene sulfonamide of the formula with an isocyanate of the formula In many cases the required sulfonamide is not commercially available and must be synthesized. Such compounds are routinely prepared by synthesizing the sulfonyl chloride derivative, followed by ammonolysis with ammonium hydroxide or ammonia. Several methods of synthesizing sulfonyl chlorides are taught in the art. Shah et al., J . Med . Chem ., 12 , 938 (1969) describe a procedure for preparing sulfonyl chlorides known as the Meerwein Procedure. The Meerwein Procedure involves diazotization of an analine, followed by reaction with a solution of cupric chloride, concentrated hydrochloric acid, and sulfur dioxide in glacial acetic acid. Breuer et al., Chimie. Therapeutique , 659 (1979) describe two methods for synthesizing bicyclic aromatic sulfonyl chlorides. The first method involves a high temperature sulfonation of bicyclic aromatic com­ pounds using hydrogen sulfate, followed by chlorination of the intermediate sulfonic acid. The second method involves a low temperature chlorosulfonation employing chlorosulfonic acid to both sulfonate and chlorinate. Breuer et al. also synthesized an oxygen con­ taining bicyclic aromatic sulfonamide; dihydrobenzofuran-­ 6-sulfonamide. The synthetic route disclosed utilized the diazonium salt of 3-amino-4-(β-chloroethyl)benzene sulfonamide and did not require the synthesis of the corresponding sulfonyl chloride. Unfortunately, it is not possible to synthesize oxygen containing bicyclic aromatic sulfonyl chlorides by the procedures known in the art. Both the Meerwein Procedure of Shah et al . and the chlorosulfonation method of Breuer et al . cannot be used to prepare oxygen containing bicyclic aromatic sulfonyl chlorides since the conditions employed destroy the oxygen containing ring. According to the present invention there is provided a process for preparing bicyclic aromatic sulfonyl chlorides of the formula wherein, n is 1 or 2; A is -O- or -CH₂-; and B is -O-, -CH₂-, or -NCH₃-; provided at least one of A or B is -O-, which comprises reacting a compound of the formula with a Villsmeier reagent of the formula The process of the invention provides a method of syn­ thesizing oxygen containing bicyclic aromatic sulfonyl chlorides since the conditions employed will not destroy the oxygen containing ring. The present invention relates to a process for preparing bicyclic aromatic sulfonyl chlorides which are useful as intermediates in the formation of sulfonyl­ ureas. In the process of the invention, a bicyclic aromatic compound is reacted with a Villsmeier reagent prepared by reacting approximately equimolar amounts of sulfuryl chloride and dimethylformamide (DMF). While the bicyclic compound and the Villsmeier reagent gen­ erally are employed in approximately equimolar quan­ tities, the Villsmeier reagent can be added in up to about a twenty percent molar excess. The chlorosulfona­ tion reaction is run at temperatures of about 50°C to about 135°C, with the most desired temperature of about 75°C to about 125°C. The reaction generally is substan­ tially complete after about five to ninety minutes, but longer reaction periods are not detrimental. The resulting sulfonyl chloride can be iso­ lated, if desired, but need not be, and is readily con­ verted to a sulfonamide by ammonolysis with ammonium hydroxide or ammonia according to well known techniques. After the sulfonamide is formed, it can be reacted with an isocyanate to yield a sulfonylurea, which compounds are well known in the art. In general, sulfonylureas are taught to have oral hypoglycemic activity. In addition, some antimycotic activity is noted and the compounds have also been prepared as derivatives of carbodiimides. The starting materials for the Villsmeier reagent, DMF and sulfuryl chloride, are commercially available. The bicyclic aromatic starting materials are either commercially available, known in the literature, or can be prepared by methods known in the art. The most preferred compounds which can be made by the process of this invention are, when n is 1, 1,3-benzodioxole-5-sulfonyl chloride and dihydrobenzo­ furan-5-sulfonyl chloride, and, when n is 2, 1,4-benzo­ dioxan-6-sulfonyl chloride. The following examples illustrate the process of this invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way. Example 1 1,3-Benzodioxole-5-sulfonamide A 500 ml 3-neck round bottom flask was charged with 38.7 g (0.52 mole) of dimethylformamide. The con­ tents of the flask were cooled to 0°C and diluted by addition of 70.18 g (0.52 mole) of sulfuryl chloride at a rate such that the temperature of the reaction mixture remained below 20°C. Following complete addition, the reaction mixture was stirred for 10 minutes while main­ taining the temperature at approximately 10°C. After the Villsmeier reagent was formed, 61.06 g (0.5 mole) of 1,3-benzodioxole were added drop­ wise over a period of 5 minutes. The mixture was stirred and heated to 80°C for approximately 10 minutes, and then at 110°C for another 5 minutes. During the reaction the solution turned reddish brown. After about 15 minutes, the reaction mixture was cooled to 40°C and poured into a mixture of 450 gm crushed ice, 200 ml water, and 200 ml of chloroform. The organic layer was separated and added dropwise to 200 ml of concentrated ammonium hydroxide. The alkaline solution was stirred for approximately ninety minutes. The organic and aqueous phases were allowed to separate and a yellow granular precipitate formed at the inter­ face of the two layers. This solid was collected by filtration and washed with 100 ml of water. The resulting solid was dried overnight at 40°C to provide 26.9 g of 1,3-benzo­ dioxole-5-sulfonamide (yield: 26.7%). The product melted at 158-160°C. Both mass spectroscopy and n.m.r. assays indicated the product was 1,3-benzodioxole-5-­ sulfonamide. Example 2 1,4-Benzodioxan-6-sulfonamide A 500 ml 3-neck round bottom flask was charged with 27.78 g (0.38 mole) of dimethylformamide. The contents of the flask were cooled to 0°C and diluted by addition of 51.3 g (0.38 mole) of sulfuryl chloride at a rate such that the temperature of the reaction mixture was maintained below about 20°C. Following complete addition, the reaction mixture was stirred for 10 minutes while maintaining the temperature at approxi­ mately 10°C. After forming the Villsmeier reagent 50.0 g (0.36 mole) of 1,4-benzodioxan were added dropwise over a period of 5 minutes. The reaction mixture was stirred and heated to 125°C for about seventy-five minutes. The reaction mixture was cooled to 40°C and poured into a mixture of 500 gm crushed ice and 200 ml chloroform. The organic layer was separated and added dropwise to a mixture of 450 ml concentrated ammonium hydroxide and 200 ml of water. The alkaline solution was stirred overnight at 25°C. The organic and aqueous phases were allowed to separate and a yellow granular precipitate formed at the interface of the two layers. This solid was recovered, washed, and dried per the procedure of Example 1 to provide 26.3 g of 1,4-benzodioxan-6-sulfonamide (yield: 34.0%). The product solid melted at 196-198°C. Both mass spectro­ scopy and n.m.r. assays indicated the product was 1,4-benzodioxan-6-sulfonamide.

Claims: 1. A process for preparing bicyclic aromatic sulfonyl chlorides of the formula wherein, n is 1 or 2; A is -O- or -CH₂-; and B is -O-, -CH₂-, or -NCH₃-; provided at least one of A or B is -O-, which comprises reacting a compound of the formula with a Villsmeier reagent of the formula 2. The process of claim 1 wherein the product is 1,3-benzodioxole-5-sulfonyl chloride. 3. The process of claim 1 wherein the product is dihydrobenzofuran-5-sulfonyl chloride. 4. The process of claim 1 wherein the product is 1,4-benzodioxan-6-sulfonyl chloride.

Inventors: AIKINS, JAMES ABRAHAM, TAO, EDDIE VI-PING
Applicants: ELI LILLY AND COMPANY
Application year: 1987
Main classification: C07D311
IPC codes: C07D265, C07D311, C07D263, C07D307, C07D317, C07D319