Патент USA US2111913код для вставки
roasted Mesa, was i ' “a ~ annals ’ a: or‘ soar 5 , . I donut ct. Wollillhm, N‘ No Brewing. Application some a, lost, . ’ 3 strains. latest My present invention relates to a new process tor the manufacture of. sulphanilamide and, more speci?cally, to a process by which sulphanilamide, or p-aminobenzene sulphonamide, may be manu s lectured irom cheap and readily available raw materials, such as the lay-products from the man uiacture oi saccharin. v . in; . in i935, Damask (Deutseh. Med. ‘Wochsch: 61, use, 1935) described the remarkable protection W atlorded to mice infected with virulent strains of hemolytlc streptococci by injections of azo dyes containlne the sulphonamide group para to the ace linkage. However, Colebrooh, Buttle, Comb, éO’hleara and Kenny (Lancet, 2, 1319, 1323, Dec. 315 5, 1936) found that these dyes have no in hihiting or bacteriostatic activity on hemolytic streptococci in vitro. By reduction with mag ncsluinpowder in vacuo, or with sodium form aldehyde sulphoirylate (Lona and Bliss, Journal of the American Medical Association, vol. .108, No. 1, pg. 33), these azo dyes acquired an inhibi tory effect in vitro comparable to that of the compound p-aminobenrene sulphonamide, here obtained. The yields of this process are not sat isfactory and the product obtained is usually con taminated by impurities and by-products, which are chemotherapeutically inactive. I ?nd that sulphanilamide may he obtained in an exceptionally pure state and in quantitative yield by submitting henzamide-p-sulphonarnide to a Hoi‘mann reaction. As is well lrnown to all persons skilled in the art, the Hoimann'reacticn involves the conversion of compounds oi‘ the type 10 REONI-lz to compounds ‘of.’ the type litlt'l’l-ls (where . R represents an alkyl or an aryl group) by react-i insthe former with a halogen in the presence oi an excess oi tree allrali, or with the ‘chemical equivalent thereof, an ‘ aqueous solution of an 15' alkaline or alkaline earth hypohalite in the pres ence of free alkali. The reaction'may he ‘reps-e7 sented ‘by the following equation: C ONE): NHa ' +No0 common» ' +Nsoi+uao 0:; inatter referred to as sulphanilamide. They con cluded, therefore, as did Treiouel, Nitti and Eovet (@olnntes iendus Soc. Biol. 120, 756, 1935) that these aso sulphonamide dyes have no activity per se but are similarly reduced ,in vivo to the chemo s 0mm ' o emu, ‘the conversion of henaamide--p~sulphonamide to sulphanilan'llde proceeds smoothly under the usual conditions of the Hermann reaction. Thus, therapeutically active principle, sulphanilamide. ~ benramide~p-sulphommide (1 mol.) may heidis 30 Numerous subsequent reports have con?rmed this conclusion and, at the present time, sulphanil amide is mine widely used for peroral and paren teral administration to humans in cases of hem olytic streptococcus conditions such as erysipelas, septicemia, puerperal sepsis, ~ osteomyelitis of streptococcic origin, peritonitis, soarlatina, streptocmcus memnsitis, Ludwic’s angina, “ otitis media, etc,‘ as well as in pneumonia, especially where the causative organism is pneumococcus 40 type m. A'tremendousnew ?eld for the use of sulphanilamide has recently'alsobeen opened by the remarkable cures obtained with its use in the treatment of gonorrhea (Bees and Colston, Jour ml of the American Medical Association, vol. 45 lot, No. 2, pg. 1855, 1937.) . , Heretoi’ore, sulphanilamide has been manu factored exclusively by the process originally de scribed by Gelgno (Journal fur ‘Praktische Chemie, (2), vol; 77, pg. M2) or by‘ minor modi?cations _ 50 thereof. y'i'his process involves reacting N-acetyl solved in aqueous caustic soda (2 mole) and sodi um hypochlorite (1"mol.) added to the resultant solution. alternatively, henzamiole-p-sulphom amide (l moi.) may be dissolved “in aqueous caustic soda (ll mols) and chlorine has (1 mol.) ' missed into the resultant solution. Alternatively, » 35 henzamlde-p-sulphonamide (1 mol.) may be re acted with a solution of chlorine gas (1 mol.) in aqueous caustic soda (t mols). On neutralizing the reaction mixtures in each case after the re- ' moval oi? all the available chlorine, a quantita 40 tive yield of sulphanilamide may be obtained. A sinylereorystallization from water yields a prod- 7 not suitable for human consumption. It is not the purpose of mm invention to’ limit the manufacture oi.’ sulphanilamide to benzamide 45 pvsulphonamide obtained from any speci?ed raw materials. Obvious means of preparing this inter mediate will occur to any person smiled in the art. However, the by-products obtained in the manufacture‘ of saccharin may cheaply and sim 50 or N-benzyl-sulphanilic acid with phosphorus ' Jply he convertw. to benzamide-pesulphonamide and are, therefore, of importance in this process. v‘pentachloride, converting the resultant N-acetyl or N-loenzyl-‘sulphouyl chloride to the correspond- ' ing amide and subjecting the letterto an acid or _ 5s alkaline hydrolysis, wherebysulphanilamide is _ German Patent #353717 describes the prepara tion of benzamide-psulphonamide from benzoic- ' p-sulphonic .acid, or a salt thereof, by reacting 2 I - 2,111,918 the latter with phosphorus pentachloride to form and illustrate this invention but in no way'limit benzoyl chloride-p-sulphonylchloride, then with - it to the reagents, proportions or conditions de-e ammonia. to form the diamide. Benzoic-p-sul phonic acid may readily be obtained by the oxidaé 5 tion of toluene-p-sulphonic acid or toluene-p scribed therein. . ' ' ' ' Example I 20.0 kgs._of.benzamide-p-sulphonamide. is dis- 5 solved ‘in 160.0 liters of a 5% (‘1.3” Bé.) solution of caustic soda in the cold. and 55.0 liters of 14% charin. . > German Patents #96,125 and #103,298 describe sodium hypochlorite solution is added. The so 10 the- preparation of benzamide-p-sulphonamide lution is .then heated gradually to 40° 0., and sul 10 phur dioxide is passed into it until a negative re‘ 'by the anfi'nonolysisv3 of ethyl benzoate-p-sul phonyl chloride. The latter may be obtained by \ action to potassium iodide-starch paper is ob ethyiating benzoic-p-sulphonic acid and reacting tained. The reaction mixture is then neutralized to' phenolphthalein with 420 Bé. sulphuric acid, the resultant ester with phosphorus pentachlo sulphonyl chloride (Remsen, Annalen, 1'78, 284, 290), by-products of the manufacture of sac— 15 ride. and the copious precipitate of sulphanilamide'15 > Asa starting point in the synthesis of benz amide-p-sulphonamide, I prefer to use p-toluene sulphonamide. on oxidation (alkali dichromate ‘in acid solution, alkali permanganate in acid which forms on standing overnight is ?ltered off. After a single recrystallization from water, 15.8 . to 16.4 kgs. of pure sulphanilamide is obtained (92% to 95% of the theoretical, based on the benzamide-p-sulphonamide consumed). 20 Example II benzoic acid are obtained (Remsen, Annalen, 1'18, , 17.5 kgs. of technical p-toluene sulphonamide 297). p-Sulphonamidobenzoicacid is then es is suspended in a cold solution of 50.0 kgs. of po teri?ed in the usual manner, preferably by the tassium dichromate and 75.0 kgs. of 66°, Bé. sul 20 or alkaline solution, alkali ferricyanide in alka line solution) good yields of p-sulphonamido 25 use of an alkylating agent, such as a dialkyl sul phate, an alkyl halide, an alcohol in the pres ence of a condensing agent such as dry hydro chloric acid gas or a dehydrating agent such as concentrated sulphuric acid, etc." 30 After ashort time, separation of. p-sulphonamido benzoic acid commences and at the end of two hours, the entire reaction mixture is -a thick 30 verted to benzamide-p-sulphonamide by am-. benzoate with an excess of dry ammonia gas at normal orincreased pressure in an autoclave, a 35 quantitative yield of benlzamide-p-sulphonamide is obtained. By reacting ethyl-p-sulpho‘namido - ’ benzoate with concentrated aqua ammonia at or dinary temperatures, benzamide-p-sulphona mide is obtained in yields of 65% to 85% of the ' 4o theoretical, depending on the concentration of . the ammonia and the reaction time. ' commences and the amide goes into solution. Alkyl-p-sulphonamidobenzoate may be con monolysis. By reacting ethyl-p-sulphonamido - phuric acid in 125.0 liters of water. The mixture 25 is warmed slightly and mixed until the reaction The re maining 15% to 35% of the ethyl-p-sulphon amidobenzoate‘is hydrolyzed to the ammonium salt of -sulphonaminobenzoic acid, which ‘is 45 readily s luble in water and may thus be sep arated from the substantially insoluble benza mide-p-sulphonamide by ?ltration and returned to the process.- ' One of the di?iculties encountered in the pres 50 cut processes of manufacturing saccharin is the separation of the para and the ortho isomers of the crude toluene sulphonyl chloride. If this separation is not attempted but the combined toluene sulphonamides are converted to the corre 55 sponding ethyl sulphonamidobenzoates; as de scribed above, an excellent means is provided of obtaining both saccharin and benzamide-p-sul phonamide in a single operation. ’ The conversion of ethyl-o-sulphonamido-ben o0 zoate to saccharin by reaction with ammonia is rapid and quantitative (German Patent #103, 298). The combined‘ ethyl sulphonamidobenzo ates are reacted with aqua ammonia, and the re action mixture is then diluted and ?ltered from 65 the insoluble benzamide-p-sulphonamide. The ?ltrate now contains the ammonium salts of sac- charin and p-sulphonamidobenzoic acid in so1u~ . tlon. Thesaare separated by fractional precipi tation with mineral acid, as described in German 70 Patent #64524. p-Sulphonamidobenz‘oic acid precipitates out ?rst, is ?ltered of! and returned to the process. Saccharin-then precipitates out *“"*"*on~furtheracidi?cation, in- good, yield and in a state of great purity. magma. The heating is now,discontinued, the reaction mixture is cooled to room temperature and ?ltered. The precipitate of p-sulphonami dobenzoic acid on the ?lter is then thoroughly washed until the washwater is free of chromium. 35 The ?lter cake of p-sulphonamidobenzoic acid is now dissolved in’ 80.0 liters of 5% (.7.3°~ Bé.) solution of caustic soda and 15.4 kgs. of dlethyl sulphate is added. Thef mixture is stirred until the diethyl sulphate has. completely disappeared 40 and for an ‘hour thereafter.’ I » The precipitate of ethyl-p-sulphonamidoben zoate is now ?ltered 01! and added to 50.0 liters of 27° Bé. aqua ammonia. After standing for 24 hours at room temperature, 100.0 liters of water 45 is added, and the precipitated benzamide-p-sul phonamide is ?ltered on’. On acidifying the ?l trate with 42° Bé. sulphuric acid, p-sulphonami vdobenzoic acid is precipitated, ?ltered on‘, and returned to the process. 1 ' 50 The benzamide-p-sulphonamide thus obtained is converted to sulphanilamide as described in ExampleI. . . Example-III J , 22.0 kgs. of technical p-toluene sulphonamide is dissolved in-12.5 kg. of 38% (35.2” Bé.) caustic soda and 60.0 liters of water at a temperature not exceeding 35° 0., and 40.0 kg. of potassium per manganate ‘is added to the solution, with con- my stant stirring in the course of three to four hours. The temperature should not be allowed to rise above 35° C. (lining the addition of the per— manganate. Stirring is continued for three hours after all the permanganate has been added and 05 - the reaction mixture is'then ?ltered or cen trifuged. The precipitate- of manganese dioxide is washed with 5011' liters of water and the ?ltrate and wash water are combined. ' 42° Bé. sulphuric acid is added to the combined. 70 “ solution until the reaction is faintly acid to Congo red. About 5.0 kgs. of unchanged p#toluene sul phonamide is precipitated, ?ltered oil! and re- 2 turned to the process. ‘To the filtrate is added 75 ‘The following examples are intended to de?ne‘ 715.4 kgs. of diethyl sulphate.v The ‘mixture is 75 3 2,111,913 ~ stirred until the diethyi sulphate has completely : . From 100.0 kgs. of mixed toluene sulphon~ amides, the yields are 50.7. kgs. of saccharin and disappeared, and for an hour thereafter. 31.4 kgs. of salphanilamide. , v 1 - The precipitate of ethyi-p-sulphonamidoben In the preceding examples, the amount used of zoate thus obtained is converted to benzamide-p-' .u alkylating agent, e. g. diethyl sulphate, may be decreased to substantially half ‘of that indicated Example IV by increasing the reaction time 'and temperature. Having. described my invention, what I claim 10.0 kgs. of toluene is added in the course of four hours to 15.0 kgs. of chlorsulphonic-acid and desire to protect by Letters Patent is: 1. A process for the manufacture of sulphanii 10 at —5° C. The mixture is then‘ stirred for two ' hours at —5° to —10° C. and. poured on 10.0 kgs. amide which comprises submitting benzamide p-sulphonamide to a Hofmann reaction. of ice and 10.0 kgs. of water. 2. A process for the manufacture'ot sulphanii The resultant mixture of 10.0 kgs. of o-toluene ‘ sulphonylchloride' and-7.5 kgs. of p-toluene sul _ amide which comprises reacting benzamide-p phonyl chloride is' decanted from the aqueous sulphonamide with a halogen in the presence of sulphonamide as described in Example 11. ‘ layer and added to 15.0 kgs. of 27° Bé. aqua am monia in the course of four hours. The mixture alkali metal hydroxide. I » ' 3. A process for the manufacture of. sulphanii amide which comprises reacting vbenzamide-p ' is stirred at a temperature of 30°~35° C. for two hours, washed free of ammonium chloride with ‘suiphonamide with an alkali‘ metal hypohalite 20 'in the presence of an alkali metal hydroxide. 20 5.0 liters of water and ?ltered. There is thus ob tained about 14.0 kgs. of a mixture ‘containing 57% of o-toluene sulphonamide and-43% ‘of p toluene sulphonamide. _ _ . 17.5 kgs. of the mixture of toluene sulphon 25 amides is treated as described in Example 11. The ?ltrate from the precipitate of benzamlde 4. A process for the’manuiacture of- sulphanil- . ' amide which comprises reacting an ester of p-‘sul- , phonamidobenzoic- acid with ammonia and sub mitting the resultant benzamide-p-sulphonamide to a Hofmann reaction. . ' ' 25' 5. A‘ process for the manufacture of sulphanii-' p-sulphonamide is fractionally precipitated with ~ amide which comprises reacting ethyl-p-sulphon- I 42° Bé. sulphuric acid as described in German amidobenzoate with ammonia and submitting the Patent #64524. p-Sulphonamidobenzoic acid is Y resultant benzamide-p-sulphonamide to'a Hof 30 precipitated ?rst, ?ltered 011 and returned to the mann reaction. _ .. > ' 6. As a step in a process for the manufacture .of sulpanilamide, the ammonolysis-ot an ester of ‘ precipitated. The benzamide-p-sulphonamide thus obtained p-sulphonamidobenzoic acid. _ v .~ JONAS KAMLE'I'. " is converted'to sulphanilamide ‘as described in‘ ‘ process. On further acidi?cation, saccharin, is - 35 Example I.