Патент USA US3078282код для вставки
United States Patent 3,978,270 C@ Patented Feb. 19, 1963 2 2 , ethanol,'propanol or butanol in the presence of a catalyst; such as hydrogen chloride. The reaction is performed by employing a substantial molar excess of the alkanol and heating the reaction mixture preferably at or about the re?ux temperature. while gassing wtih a catalyst such 3,078,270, DERIVATIVES 0F BENZOTHIADIAZINE LI-DIOXIDE Warren J. Close and Leo R. Swett, Waukegan, Ill., assign ors to Abbott Laboratories, North Chicago, 111., a cor as hydrogen chloride. Upon completion of the reaction, the reactionniixture is cooled to precipitate the desired poration of Illinois No Drawing. Filed Aug. 14, 1959,'Ser. No. 833,682 11 Claims. (Cl. 260-243) 3 - carboalkoxy - 6-halo-2-alkyl-7-sulfamyl-3,4-djhydro 1,2,4-benzothiadiazine-l,l-tdioxide which is ?ltered o? This invention relates to compounds cor-responding to 10 and, if desired, puri?ed by recrystallization from a suit able -solvent; the formula Alternatively, the excess solvent may be evaporated when the reaction is complete and the residue recrystallized to obtain the desired product. X... The ?nal step of the method is readily carried out by 15 adding anvexcess of_ ammonia or a lower alkylamine to the product obtained in Step B. The reaction is prefer ably carried out at‘ or about the boiling temperature of and a method for their preparation. In the above the amine. When the reaction is complete, the excess formula, X represents chlorine, bromine or tri?uoro ammonia or amine is evaporated and the residue recrys methyl, R represents hydrogen or loweralkyl and R’ 20 tallized from water or aqueous alcohol to obtain the NH \GH-R’ l'\I-—R \sé represents COOH, COO-loweralkyl, CONH2, CONH loweralkyl or CON (loweralkyl)2. desired 3-alkylcarbamyl-6-halo-2-alkyl-7-sulfamyl-3,4-di The term “lower hydro-l,2,4;benzothiadiazine-1,l-dioxide as a crystalline solid. In an alternative method of preparation ,the com alkyl” as employed throughout the speci?cation and claims refers to the alkyl radicals containing from 1 to 4 carbon atoms, inclusive, whether branched or un 25 pounds having the formula branched. These new compounds are crystalline solids and are extremely useful as diuretic agents when admin istered orally or by injection, in non-toxic amounts. The compounds of the present invention can be pre pared as illustrated by the following series of reactions: 30 A. are readily prepared by adding one molecular proportion NH: of diazomethane dissolved in a suitable solvent such as ether to one molecular proportion of a>3-carboxy-6-halo 7 - sulfamyl - 3,4-dihydro-l,2,4-benzothiadiazine-l,lldi 35 oxide dissolved in a suitable solvent such as methanol; HaNOzS SO: Ne $H-COOH The reaction takes place smoothly at room temperature; When the reaction is complete, the ‘solvents are evapo— rated and the residue recrystallized from methanol or other suitable solvents to obtain the desired product.v 40 The compounds of the present invention which corre spond to the formula N—R SO: may be prepared, if desired, by the reaction of one molec ular proportion of a 3-carboxy-6-ha'lo-7-sulfamyl-3,4-di4 hydro-l,2,4-benzothiadiazine-l,l-dioxide with" two molec; N5OH-OOOR’ HZNO IS N--R + 50 ular proportions of an alkylating agent such as diazo methane in-the same manner as that described’when only one molecular proportion of diazomethane isemployed. / The following examples illustrate the invention but S02 55 are not to be construed as a limitation thereof. 3-Carb0xy-6-Chl0r0-7-Sulfamyl-3,4-Dihydro-I EXAMPLE ,2,4 Bénzothiadiazine-I ,1 -Di0xide In the above series of reactions, R, R" and R’” repre sent hydrogen or loweralkyl, R’ represents loweralkyl 60 and X represents chlorine, bromine or tri?uoromethyl. Step A of the method can'be conveniently carried out by heating equimolar amounts of the sulfonamide and glyoxylic acid (preferably an‘alkali metal salt of the acid) 01“ 112N023 N5 on-o OOH \ /NH S02 Asu'spension of 22.8 grams (.081mole) ofi4lami'no-6 in water at or about the boiling temperature‘ and under 65 chlloro-1,3-benzenedisulfonamide in 300 ml.‘ of water was re?ux until the reaction is complete. Upon cooling and heated at the boiling temperature and’ under re?ux. acidifying, the desired 3-carboxy-6-halo~7-sulfamyl-3,4 Thereafter, 8.8’ grams (.12_ mole) of glyoxylic acid-dis; solved in one equivalent of 5% aqueous sodium hydrox dihydro-1,2,4-benzothiadiazine-1,l-dioxide separates as a ide was added portionwise with stirring and the result crystalline solid which is removed vby ?ltration and re 70 ing mixture re?uxed for 1.5 hours. Upon" completion of crystallized from water or alcohol. the reaction, the reaction mixture was'coole'd and acidi In step B of the method, the product obtained in Step tied to precipitate‘ a- white solid. After recrystallization A is esteri?ed with a lower alkanol'such as methanol, 3,078,270 Found: of this solid from water, the desired 3-carboxy-6-chloro-7 sulfamyl - 3,4—dihydro-l,2,4-benzothiadiazine-1,1-dioxide compound was obtained as a hydrate which melted at EXAMPLE 5 125° C. with decomposition. Anal.--Calc’d. for 3-Carbamy [-6-Ch loro-Z-Methyl-7-Szzlfam yl-3,4-Dilz ydro 5 1 ,2,4-Benzotlziadiazine-l ,1 -Dioxide C=25.4%; H=3.2%. C8H8CIN3OGSZ Found: C=25.4%, ' H=3.2%. EXAMPLE 2 N3 on~c~Nm (Ii 01“ 3-Carbamoethoxy-6-Chl0r0~7-Sulfamyl-3,4-Dihydr0 nmms 1,2,4-Benz0thiadiazine-I ,1 -Di0xide /N—CH3 S 02 To 100 ml. of liquid ammonia at room temperature was added 2.9 grams (.0078 mole) of the product prepared in Example 3. The excess ammonia was thereafter evap orated and 20 ml. of water added to the residue. The white solid which precipitated was separated by ?ltration To a solution of 1.71 grams (.005 mole) of 3-carboxy ‘ and found to melt at 245°—247° C. Upon analysis, the nitrogen content of 15.8% was found to agree with the 6 - chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide in 10 m1. of methanol was added portionwise calculated value for 3-carbamyl-6-chloro-2-methyl-7-sul~ with stirring at room temperature, .21 gram (.005 mole) N 0 £amyl-3,4-dihydro-1,2,4-benzothiadiazine-l,l-dioxidc. of diazomethane dissolved in 40 ml. of ether. The sol EXAMPLE 6 vents were thereafter evaporated and the residue recrys tallized from methanol to obtain the above-named prod 6~Chl0ro-3-(Dimethylcarbamyl)~2-Z'rdethyl-7-Sulfamyl uct as a crystalline solid melting at 234°-236° C. 3,4-Dihydr0-1 ,2,4-Benzoth iadiazirze-J ,1 -Di0xia'e Anal.—Calc’d. for C9H1UClN3O5S2: C=30.4%; H=2.8%. Found: C=30.4%; H=3.0%. > EXAMPLE 3 3-Carbom ethoxy-6-Clzl0ro-2-Methyl-7-Sulfamyl-3,4 Dihydro-1,2,4-Benzothiadiazine-1,1-Dioxide 01" H.NO2S __ 30 f‘?CH—'C—-OCH3 it’ \ famyl-3,4-dihydro-1,2,4-benzothiadiazine - 1,1 ~ dioxide to 100 ml. of dimethylamine at room temperature. The ex cess amine was then evaporated and 25 ml. of water added N-CH; S02 This compound was prepared in the same manner as to the residue. The desired product precipitated as a white solid and after recrystallization from a methanol water mixture melted at 265°-267° C. with decomposi that described in Example 2 except that the amount of diazomethane employed was doubled. The compound H=3.9%. ilOIl. Anal.—Calc’d. Found: C=34.6%; fOl' C11H15CH‘I4O5SQI H=4.2%. was found to melt at 224°—225° C. Anal.--Calc’d. for CIOHHCINSOSSZ: C=32.5%; C=32.6%; H=3.5%. H=3.2%. This compound was prepared by adding 7.12 grams (.02 mole) of 3-carbomethoxy-6-chloro-2-methyl-7-sul Found: EXAMPLE 7 3-( n-Buz‘ylcarbamyl) -6-Chl0r0-2-Methyl-7-Sulfamyl 3,4-Dilzydr0-1,2,4-Benz0rhiadiazine-1,I-Dioxia'e In an alternative method of preparation, 20 grams (.053 mole) of 3—carb0xy-6-chloro-2-methyl-7-sulfamyl 3,4 - dihydro-l,2,4~benzothiadiazine-l,l-dioxide monohy drate (M.P.=154° C.) was dissolved in 100 m1. of meth anol to which was added 6 grams of acetone dimethyl acetal and 2 ml. of concentrated hydrochloric acid. Thereafter, two more G-gram portions of the acetal were added at room temperature at one hour intervals. The This compound was prepared by the reaction of 1.0 resulting mixture was heated overnight at 50° C. The gram (.0027 mole) of 3-carbomethoxy-6-chloro-2-methyl solvents were then removed under reduced pressure and the residue recrystallized from a methanol-water mixture 7 - sulfamyl - 3,4 - dihydro - 1,2,4 - benzothiadiazine - 1,1 dioxide with 10 ml. of n-butylamine in a manner similar to obtain the desired 3-carbomethoxy-6-chloro~2-methyl-7 to that described in Example 6. The resulting product sulfamyl - 3,4-dihydro—1,2,4-benzothiadiazine-1,1-dioxide was a white solid which melted at 260° C. which melted at 225° C. EXAMPLE 4 EXAMPLE 8 6-Brom0-3-Carboxy-Z-Methyl-7-Sulfamyl-3,4-Dihydr0 3-Carb0xy-6-Chlore-2-Methyl-7-Sulfamyl-3,4-Dihydro 1,2,4-Benz0thiadiazine-1 ,1 -Di0xide 60 1,2,4-Benzothiadiazine-I,1-Dioxide Neon-oo or: Br‘ HzNOzS- \ N_CH3 S02 Six grams (.02 mole) of 4-amino-6-chloro~3-(methyl sulfamyl)-benzenesulfonamide were dissolved in 60 ml. of water and the resulting solution heated at the boiling temperature and under re?ux. A solution of 2.2 grams (.03 mole) of glyoxylic acid in 10 ml. of water was then added and the reaction mixture heated at the boiling tem perature and under re?ux for one hour. The reaction mixture was thereafter cooled to precipitate the desired above-named product as a hydrate which was separated by ?ltration. M.P.=156°-157° C. AnaL-Calc'd. for A solution of 6.8 grams (.02 mole) of 4-amino-6 bromo - 3 - (methylsulfarnyl)-benzenesulfonamide in 100 ml. of boiling water was prepared and 3.0 grams (.04 mole) of glyoxylic acid added thereto. The resulting mix ture was re?uxed for 90 minutes to complete the reaction. The reaction mixture was then cooled and the desired product which precipitated was separated by ?ltration. It melted at 160°-162° C. with decomposition. Anal.- Calc’d. for Found: C=25.7%; CgH10BI‘N3O6S2'HgOI H==3.2%. 3,078,270 6 E _ This compound was prepared by adding .02 mole of EXAMPLE 9 6 ~Br0m0-3 -Carbometh0xy-2-Mez‘hyl-7-Sulfamyl-3,4 3-carbomethoxy - 6 - chloro-2-methyl-7-sulfamyl-3,4-dihy dro-l,2,4-benzothiadiazine-1,1~dioxide to 100 ml. of Dihydro-I ,2,4-Benz0thiadiazine-J ,1 -Dioxide' monomethylamine at room temperature. The excess amine was thereafter evaporated and the residue crystal lized from a methanol~water mixture to obtain the desired. product as a white, crystalline solid melting at 270°—271 °' C. with decomposition. The product was further identi-‘ ?ed by elemental analysis. To a solution of 2.1 grams (.005 mole) of the product EXAMPLE 14 obtained in Example 8 in 10 ml. of methanol was added By the reaction of 4-amino-6-chloro—3-(isopropyl-sul a solution of .21 gram (.005 mole) of diazomethane in famyD-benzenesulfonamide (M.P.=15S°—l57° C.) with 40 ml. of ether. The addition was carried out with stir gly'oxylic acid as described in Example 4, the desired 3 ring at room temperature. Upon completion of the reac tion, the solvents were evaporated to obtain the desired 15 rcarboxy-6-chloro-2-isopropyl-7-sulfamyl - 3,4 - dihydro‘ 1,2,4~benzothiadiazine-1,1-dioxide is obtained. product as a residue which melted at 224°—228° C. An?l.—-C3.1C’d. for C1QH12BIN3O§S21 2.9%. Found: C=29.0%; H=3.0%. EXAMPLE l0 3-Carboxy-7-SuZfamyl-6-Tri?uoromr‘thyl-3,4-Dihydror 1 ,2,4-Benzothiadiazine-1 ,1 -Di0xia'e Further reaction with excess methanol as described in the alterna H: tive method employed in Example 3 results in the forma tion of 3-carbomethoxy-6-chloro-2-isopropyl-7-sulfamyl 20 3,4#dihydro-1,2,4-benzothiadiazine-l,l-dioxide. In a manner similar to that described in the foregoing; examples, other derivatives of 7-sulfamyl-3,4-dihydro~_ '1,2,4-benzothiadiazine-1,l-dioxide can be prepared of which the following are representative: 3-carboxy-6-chloro-2-n-butyl derivative by the reaction 25 of 4-amino-6-chloro-3~(n-butylsulfamyl) - benzenesulfon amide with glyoxylic acid. Further reaction of this deriv~ ative with methanol, ethanol, n-propyl alcohol or tert. To a- re?uxing solution of 1.0 gram (.003 mole) of butyl alcohol in the presence of hydrogen chloride results 4-amino-6-tri?uorornethyl-l,3-benzenedisulfonamide in 15 30 in the formation of the 3-carbomethoxy-6-chloro-2-n ml. of water was added a solution of 0.33 gram (.0045 butyl;' 3-carbethoxy-6—chloro-2-n-butyl; 3-carbo-n-pro mole) of glyoxylic acid in 10 ml. of water. Following poxy-6~chloro-2-n-butyl and 3-carbo-tert.~butoxy-6-chloro the addition, the reaction mixture was re?uxed for 1.5 Z-n-butyl derivatives, respectively. Subsequent reaction of hours. Upon cooling, the desired product precipitated any of these 3~carboalkoxy-6-chloro-2-n-butyl derivatives with ammonia, monomethylamine, dimethylamine, mono and was separated by ?ltration. IvI.P.=220° C. with de composition. ethylamine, diethylamine, monopropylamine, dipropyl EXAMPLE 11 amine, monobutylamine or dibutylamine will produce the 3-Carb0xy-6—Chl0r0-2-Ethyl-7-Sulfamyl-3,4-Dihydr0 3-carbarnyl - 6 - chloro-2-n-butyl; 3-methylcarbamyl-6 chloro-Z-n-butyl; 3-dimethylcarbamyl~6-chloro-2-n-butyl; 1 ,2,4-Benz0thiadiazine-1 ,1 -Di0xide 40 3-ethylcarbamyl-6-chloro-2-n-butyl; S-diethylcarbamyl-G chloro-Z-n-butyl; 3~propylcarbamyl-6-chloro-2~n-butyl; 3F dipropylcarbamyl-6-chloro-2~n-butyl; 3-butylcarbamyl46i chloro-Z-n-butyl and 3-di'butylcarbamyl-6'chloro-2-n-buty1 derivatives of 7-sulfamyl-3,4-dihydro-1,2,4-benzothiadi azine-Ll-dioxide, respectively. This compound was prepared in the same manner as 3-carboxy-6-bromo-2-ethyl derivative by the reaction of that described in Example 4 by the reaction of 4-amino— 4-arnino-6-bromo-3—(ethylsulfamyl) - benzenesulfonamide 6¢chloro~3-(ethylsulfamyl) - benzenesulfonamide (ll/LR: with glyoxylic acid. Further reaction of this derivative with methanol, ethanol, isopropyl alcohol or sec. butyl alcohol in the presence of hydrogen chloride results in the formation of the 3-carbomethoxy~6-bromo~2-ethyl; 3' 152°~154° C.) and glyoxylic acid. The monohydrate was a white solid which melted at 190°—191° C. with decom position. Upon analysis, the product was found to con tain 30.98% C; 3.92% H and 11.07% N compared to the theoretical values of 30.96% C; 3.63% H and 10.83% N. EXAMPLE 12 carbethoxy-6-bromo-2-cthyl; 3-carbo-isopropoxy-6~bromo 2-ethyl and 3-carbo-sec.-butoxy-6-bromo-2-ethyl deriva tives, respectively. Subsequent reaction of any of these 3_ carboalkoxy-6-brorno-2-ethyl derivatives with ammonia, monomethylamine, dimethylamine, monoethylamine, di 3-Carb0methoxy-6-Chloroh2-Ethyl-7-Sulfamyl-3,4-Dihy droJ ,2 ,4 -B enzoth iadiazine-J ,1 -Di0xide et-hylamine, monopropylamine, dipropylamine, mono butylamine or di‘butylamine will produce the 3-carbamyl_ NH 6-bromo-2-ethyl; 3-methylcarbamyl-6-bromo-2-ethyl; 3j dimethylcarbamyl-6ebromo-2-ethyl; 3 - ethylcarbamyl-6 bromo-2—ethyl; 3-diethylcarbarnyl-6-bromo-2-ethyl; 3~ propylcarbamyl-6-brorno-2-ethyl; 3 - dipropylcarbamyl-6~ This compound was prepared by the reaction of the compound prepared in Example 11 with excess methanol. The procedure was identical to that described in the al ternative method employed in Example 3. The product O) 5 brorno-Z-ethyl; 3-butylcarbamyl-6~brorno-2-ethyl- and. 3' dibutylcarba-myl-6ebromo-2-ethyl derivatives of 7-sul famyl-3,4-dihydro-l,2,4-benzothiadiazine-1,l-dioxide, re spectively. 3-carboxy-6-tri?uorornethyl-Z-methyl derivative by the was a crystalline solid which melted at 222°~224° C. EXAMPLE 13 reaction of 4-amino - 6 - tri?uoromethyl-3-(methylsulfa 6-Ch loro-Z-M ethyl-3- (M ethy lcarbamyl ) -7-S ulfamyl-S ,4 reaction of this derivative with methanol, ethanol, pro~ panol or isobutanol in the presence of hydrogen chloride results in the formation of the 3-carbornethoxy-6-tri~ myD-benzenesulfonamide with glyoxylic acid. Further ?uoromethyl-2-methyl; 3~carbethoxy-6-tri?uoromethyl-2 methyl; 3-carbopropoxy-6-tri?uoromethyl-2-methyl and S02 75 3-carbo-iscbutoxy-6-tri?uoromethyl-2methyl derivatives, 3,078,270 8 respectively. Subsequent reaction of any of these S-carQ In Step C of the method, a mixture of a 2-alkyl-3 b0alkoxy-6-trilluoromethyl-Z-methyl derivatives with am keto-6-halo-7-sulfamyl - 3,4 - dihydro - 1,2,4 - benzothiadi monia, monomethylamine, dimethylarnine, monoethyl amine, diethylarnine, monopropylamine, dipropylamine, azine-l,1-di0xide and an aqueous alkali metal hydroxide solution, preferably sodium hydroxide, is heated at the boiling temperature and under re?ux for a period of time monobutylamine or dibutylamine will produce the 3-car-» bamyl-6-tri?uoromethyl-2-methyl; 3-methylcarbamyl-6-tri to complete the reaction. After treatment with charcoal, the reaction mixture is ?ltered and the ?ltrate acidi?ed ?uoromethyl-Z-methyl; 3-dimethylcarbamyl - 6 - tri?uoro' methyl - 2 ~ methyl; 3-ethylcarbarnyl~6-tri?uoromethyl-2~ methyl; 3-diethylcarbamyl - 6 - tri?uoromethyl-Z-methyl;' 3-propylcarbamyl-G-tri?uoromethyl-Z-methyl; 3~dipropyl~ to obtain the desired 2-alkylsulfamyl-4-sulfamyl-5-halo aniline as a White solid which is separated and dried. What we desire to particularly point out and distinctly '10 carbamyl-6-tri?uoromethyl-Z-methyl; 3-butylcarbamyl-6— claim as our invention is: tri?uoromethyl - 2 ~ methyl and 3-dibutylcarbamyl-6~tri 1. 3-carbomethoxy-6-chlore-2-methyl-7-sulfamyl~3,4-di hydro-1,2,4-benzothiadiazine-1, l-dioxide. 2. 3-carboxy-6»chloro-2-methyI-7-sulfamyl-3,4-dihydro ?uoromethyl~2-methyl derivatives of 7-sulfamyl-3,4-di hydro-1,2,4~benzothiadiazine-1,l-dioxide, respectively. l,2,4-benzothiadiazine-1,l-dioxide. The sulfonamide compounds employed as one of the starting materials in the present invention can be pre~ pared as shown in the following series of reactions where in X is chlorine, bromine or tri?uoromethyl and R is a lower-alltyl radical containing from 1 to 4 carbon atoms, _ 3. B-carbamyl-é-chloro - 2 - methyl-7-sulfamyl-3,4-dihy dro-1,2,4-benzothiadiazine-1,1-dioxide. 4. 6-chloro-3- ( dimethylcarb amyl) -2-methyl-7-sulfamyl~ 3,4-dihydro-l,2,4-benzothiadiazine-l,l-dioxide. 5. 6-bromo-3-carboxy-2-methyl-7-sulfamyl-3,4-dihydro 1,2,4-benzothiadiazine-1, l-dioxidc. 6. 6-bromo-3-carbomethoxy~2~methyl-7-sulfamyl-3,4-di~ hydro-l,2,4-benzothiadiazine-1,l-dioxide. 7. 3-carboxy-7-sulfamyl-6-tri?uorornethyl - 3,4~dihydro 25 1,2,4-benzothiadiazine-1,1-dioxide. 8. 3-carbomethoxy-6-chloro-2-ethyl-7 - sulfamy1-3,4-di hydro-1,2,4-benzothiadiazine-1,l-dioxide. 9. 6-chloro-2-methyl-3-(methylcarbamyl)-7 - sulfamyl 3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide. 30 10. Compounds selected from the group consisting of .(a) a compound corresponding to the formula 35 Step A of the method can be carried out conveniently by heating a mixture of two molecular proportions of X_ mNons- \(|JH-—llI|I-—O-—R’ N‘R 0 S02 and (b) a compound corresponding to the formula urea and one molecular proportion of a 5-halo-2,4-di sulfamylaniline at a temperature of about 180° C. for a 40 /N5 /R' tH—t~N\ period of about one hour. Upon completion of the HgNOzS\ / LR 0 R" reaction, water is added to the reaction mixture which is thereafter heated to effect solution. The aqueous solu S02 tion is then treated with charcoal and ?ltered. The wherein X is a member selected from the group con ?ltrate is acidi?ed to precipitate the desired 3-keto-6-halo 45 sisting of chlorine, bromine and tri?uoromethyl, and R, 7-sulfamyl - 3,4 ~ dihydro - 1,2,4 - benzothiadiazine-Ll-di oxide as a crystalline solid which is separated by ?ltration and dried. Step B of the method is carried out by adding one molecular proportion of an alkali metal hydride, prefer ably sodium hydride, to a solution of one molecular pro portion of a 3-keto-6-halo-7-sulfamyl-3,4-dihydro-1,2,4 benzothiadiazine-1,1-dioxide in dry dimethylformamide. The mixture is stirred and heated to about 70° C. to effect solution. One molecular proportion of an alkyl iodide dissolved in dimethylformamide is thereafter added drop wise and stirring is continued for about two hours at 70° C. When the reaction is complete, the reaction mixture is poured into water and cooled below room temperature R’ and R" are members selected from the group con sisting of hydrogen and lower alkyl. '11. A compound of the formula F36 HrNOgS~ NeoH-o 0 o R \ /NH SO: wherein R is a member selected from the group con sisting of hydrogen and lower alkyl. References Cited in the ?le of this patent Freeman et al.: Iour. Org. Chem,, volume 16 (1951), to precipitate the desired 2-alkyl-3-keto-6-halo-7-sulfa~ 60 page 821. Wagner et al.: Synthetic Organic Chemistry, pages myl-3,4-dihydro - 1,2,4 - benzothiadiazine-l,l-dioxide as a 480-481 and 568-569 (1953). crystalline solid which is separated by ?ltration and dried.