Патент USA US2117260код для вставки
Patented May 10, ‘1938 2,117,260 UNITED STATES PATENT OFFICE I 2,117,280 SUBSTITUTED P - AMINO - BENZENE - SUL PHONAMIDES AND PROCESS OF PMDUC ING THEM Elmer 11. Stuart, Indianapolis, Ind., minor to Lilly and Company, Indianapolis, Ind., a corporation of- Indiana No Drawing. Application June 26, 1937, Serial No. 150,545 10 Claims. (Cl. 260-106) My invention relates to substituted p-amino end, preferably, I boil a slightly acidi?ed aqueous benzene-sulphonamides, particularly p-mandelyl solution of the p-acetylmandelylamino-benzene sulphonamide for several hours, to remove the acetyl radical. The reaction is apparently as follows: amino—benzene-sulphonamide and its intermedi ate p - acetylmandelylamino - benzene - sulphon 5 amide, and to the procws of producing them; both a (I? H- lee-(5Q t (2) 10 0=c-cn, H 0 H I'M-i0 in +H,o-> (is + o=c~om 10 (Acetic acid) 0: I-NIL O=B—'NH! 15 15 (g-Aoetylmandelylamino enzone-sulphonamide) (p-Mandelylamino benzene~sulphonamide) in their racemic and in their optically active forms. The - p-mandelylamino - benzene-sulphonamide This new compound, p-mandelylamino-ben- thus obtained, when recrystallized from alcohol, 20 zene-sulphonamide, in its raoemic form as well as in its d and 1 forms, on oral administration, has is a white crystalline solid, which melts at- about 20 232° C. corrected. Assay for sulphur indicates excellent protective and curative properties against various infections, including urinary infections; and its toxicity is low. the correctness of the formula given. Both my intermediate product and my ?nal The intermedi- product, p - acetylmandelylamino - benzene - sol 25 ate product, p-acetylmandelylamino-benzenesulphonamide, also has therapeutic properties. phonamide and p-mandelylamino-benzene-sul phonamide respectively. are sparingly soluble in 25 While variants of my method may be used in preparing p-mandelylamino - benzene- sulphonamide, the method I prefer is as follows: 30 p-Arnino-benzene-sulphonamide is treated, in water, and more soluble in alcohol; the inter~ mediate product being soluble in ethyl alcohol to the extent of about two parts per hundred, and the ?nal product to the extent of slightly less solution or suspension in a non-polar solvent, than one part per hundred. Both can be admin such for instance as chloroform or benzene, with acetylmandelyl chloride (a method for preparing which is described in Organic Syntheses, volume 35 4, page 1, published 1925 by John Wiley and Sons, Inc., New York); and the whole is then treated to drive o? the solvent. This produces a reaction as follows: H I’ *0 + ‘5 o H " lei-60 t o H (1) istered orally, most conveniently in tablet form, in the treatment of various infections, and are found to be effective. The following is an example of the process of manufacturing my new product: To about 70 grams of p-amino-benzene-sul phonamide are added about 500 cc. of benzene, or-tLiz-O ---> o=c-oni o=o-0Hi o= —-NH.| (p-Amlno- 50 benzene-sulphonsmldo) ‘ (Acetylmandelyl chloride) 0: —-NH, (p-Acetylmandclylamlno benzene'sulphonamide) The p-acetylmandelylamino-benzene-sulphon- to form a suspension; and then there is added amide is a new product, an intermediate in my about 71 grams (about a molecular equivalent or present invention although it also has valuable properties in combating infections. when ?rst 55 produced this is a light-tan-colored powder, but on recrystallization from alcohol it is obtained slightly less) of acetylmandelyl chloride. The mixture is boiled on a water bath until about half of the benzene or slightly more than half is 55 evaporated; and then substantially all the re in the form of white crystals, which melt at maining benzene is removed by evaporation in 187.5-189.5° 0., corrected. In order to obtain my ?nal product, I remove so the acetyl group in any suitable manner. To this vacuo. This leaves a light-tan-colored solid, which is the p-acetylmandelylamino-benzene~ sulphonamide, my intermediate product. If de 2 2,117,260 sired, this intermediate product may be purified by recrystallization from alcohol; but puri?ca which compound melts at‘ about 1875-1895‘ C., tion at this stage is not necessary unless it is desired to use this intermediate product as the more soluble in alcohol. ?nal product. and is sparingly soluble in water and slightly 3. The new compound, p-mandelylamino-ben zene-sulphonamide, which has the following structural‘ formula: , To produce the final product, the intermediate product obtained as above, whether or not it HO has been subjected to recrystallization, has added iii(50 to it about 1200 cc. of water and about 50 cc. 10 of concentrated (36%) hydrochloric acid. These amounts of water and hydrochloric acid are not critical. The mixture obtained is re?uxed for 10 several hours, conveniently about four hours, and then cooled to room temperature. In such re 15 ?uxing, there is usually at ?rst a considerable O: —NH: 3 foaming, with the particles'cf solid matter largely in and on the foam; but as the re?uxing con tinues the'foam disappears, and the solid particles which compound is sparingly soluble ‘h water and tend to distribute themselves more or less uni slightly more soluble in alcohol. 20 formly through the liquid, which I think is an indication that the reaction has been substan tially completed. On cooling, this solid matter zene-sulphcnamide set forth in claim 3. arated from the liquid by decantation and/or 25 ?ltration. This solid matter is of a light-tan color as thus ?rst obtained; but on recrystalliza tion from alcohol it is obtained in the form of - . ylamino-benzene-sulphonamide, which consists in causing p-amino-benzene-sulphonamide to react with acetylmandelyl chloride in a non I polar solvent. 7. The process of producing p-mandelylarnino~~ benzene-sulphonamide, which consistsin caus Whether my intermediate product and my ?nal 30 product are of the racemic (d1) form, or of the levo form or the dextro form, may be controlled ing p-amino-benrzene-sulphonamide to react with acetylmandelyl chloride in a non-polar sol vent 'to produce peacetylmandelyiamino-benzene suiphonamide,‘ and treating. the p-acetylmandel-~ ylamino-benzene-sulphonamide to remove the as desired by selecting the initial .acetylmandelyl chloride of the racemic or of the levo or the dextro form; for the form of my intermediate 35 and final products corresponds to the form of that acetylmandelyl chloride in respect of op tical rotation. All theseforms of my intermedi ate product and of my final» product are ef ?cacious in the treatment of infections. acetyl group therefrom. ~ .8. The process o‘fproducing p-mandelylamino- . _ ben‘zehe-sulphcnamidd?hich consists in treating p-acetylmandelylamino-fbenzene-sulphonamide to ‘1 claim as my invention: remove the acetyl group therefrom. 1. The substituted p-amino-benzenersulphon V ._ 40 9. The process ‘of‘producing p-mandelylamino benzene-sulphonamide’, which consists in causing amides, in which a hydrogen atom of the p amino'g'roup is replaced by a radical of the class p-amino-benzene-sulphonamide to react with acetylmandelyl chloride in a non-polar solvent consisting of the mandelyl and the acetyl-man to produce p-acetylmandelylamino-benzene-sul 45 phonamide, and boiling the p-acetylmandelyl delyl groups. 2. The new compound, p-acetylmandelylami no-benzene-sulphonamide, which has the fol lowing structural formula: 50 e 5..The dextro form of the p-émandelyllmmo benzene-sulphonamide set forth in claim 3. 6. The process of producing p-acetylmandel tends to settle to the bottom, and may be sep white crystals. . , 4. The levo form of the p-mandelylamino-ben amino-benzene-sulphonamide so obtained in a slightly acidulated aqueous solution to remove the acetyl radical and thus produce the desired p ieiaié <3 mandelylamino-benzene~sulphonamide. . 50 1G. The process of producing p-mandelylami ~su3phona1nide, which consists in boil noubenzei M icle in a 51.1 "' ' lylainino-benzene-sulphonam a. 9 ?ulated aqueous solution to re move the ace yl radical and thus produce the 55 desired p-mandelylaminoebehzene-sulphonamide. ‘ H. STUART.