US2990409A - Dicyano-i - Google Patents

Description

United States Patent Oflice s Patented June 27, 1961 2,990,409 3,4-DICYANO-1,2,5-THIADIAZOLE Marvin Carmack, 1127 E. 1st St., Bloomington, Ind.;

Daniel Shew, Clifton, NJ. (184 Newman St., Metuchen, NJ.); and Leonard M. Weinstock, Clifton, NJ. (300D 'Crowells Road, Highland Park, NJ.)

No Drawing. Original application July 23, 1958, Ser. No. 750,419. Divided and this application Mar. 3, 1960, Ser. No. 15,021

l'Claim. (Cl. 260-302) This invention relates to new organic compounds. More specifically it relates to new hetrocyclic compounds wherein the hetero atoms are nitrogen and sulfur. Still more specifically, it is concerned with 1,2,5-thiadiazoles substituted at the 3 and 4 positions with carboxy groups, and with derivatives thereof.

This application is a division of our copending application Serial No. 750,419, filed July 23, 1958.

Many heterocyclic organic compounds are known in the scientific literature and have been known for many years. However, prior to this invention 3,4-di-substituted 1,2,5-thiadiazoles were completely unknown. It is an object of this invention to provide for the first time 1,2,5-thiadiazoles substituted at the 3 and 4 positions of the heterocyclic ring. It is a further object to provide a synthesis of such compounds from 4-nitro-2,1,3-benzo thiadiazole. A still further object is the provision of l,2,S-thiadiazole-3,4-dicarboxylic acid by oxidation of, 4-nitro-2,1,3-benzothiadiazole. An additional object is the provision of mono and di-salts of 1,2,5-thiadiazole- 3,4-dicarboxylic acid, and of the hydrocarbon esters of said acid. Still another object is the provision of the amides and acid halides derived from the aforementioned dicarboxylic acid. It is yet another object to make available syntheses of such compounds.

;1,2,5-thiadiazole-3,4-dicarboxylic acid is a new compound having the following structural formula:

- N COOH H I COOH This compound is strongly acidicand very soluble in water andp'olar organic solvents. When pure it exists as ahigh melting crystalline solid. It has been discovered that 1,2,5-thiadia'zole-3,4- dicarboxylic acid may be prepared by oxidationof 4-nitro-2,1,3-benzothiadiazole with permanganate under the conditions described below. This process may be pictured structurally as follows:

2 1% NVCOOH 5 S2 To? 7 1;: NACOOH 4-nitro-2,1,3-benzothiadiazole is a known compound, According to this invention it has been found that treatment of this substance with an alkali or alkaline earth metal permanganate results in oxidation of the benzothiadiazole to 1,2,5-thiadiazole-3,4-dicarboxylic acid.

Itis preferred to employ potassium permanganate as the oxidizing agent although other permanganates such as thesodium or barium compounds may be utilized. The oxidation is normally carried out in an aqueous reaction medium at temperatures between about 40 C, and 75 C.', and preferably in the range of 50-70 C. For best results from 6-8 moles of permanganate are employed for, every mole of 4-nitro-2,1,3-benzothiadiaz ole.

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tion and only a slight excess over this theoretical amount has been necessary to obtain satisfactory results. Larger quantities of oxidizing agent may, of course, be employed if desired.

For convenience in conducting the reaction it is preferred to add the permanganate salt to a solution of 4-nitro-2,1,3-benzothiadiazole gradually over a period of one-half to two hours, either in solution or as a solid. The oxidation proceeds rapidly and is ordinarily substantially complete as soon as the addition of oxidizing agent is finished. -As will be recognized by those skilled, in this art, completion of the reaction may be readily determined by the persistence in the reaction mixture of the characteristic blue-purple permanganate color.

The pH of the reaction medium is important to the successful oxidation of 4-nitro-2,1,3-benzothiadiazole to 1,2,5-thiadiazole-3,4-dicarboxylic acid. For best results, the initial pH of the benzothiadiazole solution should be about 6-7. As the oxidation proceeds the pH will gradually become alkaline until the final pH is about 10. As long as'thepH is about neutral or alkaline the desired product is obtained. An acidic permanganate oxidation, however, should be avoided in the process, i.e. during the oxidationthe reaction mixture should not become strongly acidic. 7

It will be realized that 1,2,5 -thiadiazole-3,4-dicarboxylic acid is formed in the reaction mixture as a salt, the particular salt depending upon the permanganate salt used as the oxidant. Thus, when potassium permanganate is utilized as the oxidizing agent, the dipotassium salt of 1,2,5-thiadiazole-3,4-dicarboxylic acid is formed in the neutral or alkaline oxidation medium; correspondingly,

way of a water insoluble heavy metal salt, preferably the mono-silver salt. For example, the aqueous solution obtained upon oxidation of 4-nitro-2,1,3-benzothiadiazole may be filtered to remove insolubles and the resulting filtrate,-which contains a water soluble alkali metal salt of 1,2,5ethiadiazole-3,4-dicarboxylic acid, made strongly acidic with nitric acid. A water soluble silver salt such as silver nitrate is then added whereupon the highly in-' soluble mono-silver salt of 1,2,5-thiadiazole-3,4-dicarboxylic acid precipitates from solution in a highly pure form. This latter salt may then be converted to substan tially pure free acid by removal of the silver therefrom with an acid such as hydrochloric, hydrobromic, hy-

" is treated with excess base. The mono salts are con-- veniently preparedby treating an aqueous solution of 1,2,5-thiadiazole-3,4-dicarboxylic acid with a base to a,

5 pH of about 3; In synthesizing these salts, we prefer to utilize bases such as ammonium hydroxide, potassium,

hydroxidesodium hydroxide and the like. The salts are,

conveniently i sl atsd y p i t a mm h a ueous. reaction mixturewith acetone. Such salts may be fur ther reacted as discussed below to prepareother useful, derivatives of 1,2,S-thiadiazole-3,4-dicarboxy1ic ,acid.

' solvent.

A- still further embodiment of the invention comprises the esters of 1,2,5-thiadiazole-3,4-dicarboxylic acid, particularly the alkyl esters. The di-lower alkyl esters are obtained by reaction of an alkali metal or ammonium salt of l,2,5-thiadiazole 3,4-dicarboxylic acid with an alkanol in thepresence of a strong acid, It is desirable to-carry-out the esterificationprocess inthe cold, i .e-. at temperatures of about to C. although higherreactitan-temperatures may be used if desired. Thus, lower alkanolic esters such as 3,4-dicarbomethoxy-1,2,5-thia diazole; 3,4-dicarbethoxy-1,2,5;- thiadiazole; 3,4-dicarbopropoxy-l,-2,5- thiadiazole and 3,4 dicarbobutoxy-l,2,5.- thiadiazoleare obtained by suspending'an ammonium or alkali metal salt of the free acid in the appropriate lower alkanol saturatedwith dry hydrogenchloride; Thereaction mixture is held in'the cold for fromv -510hours in order to obtain maximum esterification. These loweralkyl esters, which are high-boiling oilsrnay be recovered from the reaction mixture by methods knownto, one skilled in this art. We'prefer to employ the mono-ammpniumv salt of1,2,5-thiadiazole 3,4-dicarboxylic aoidasstarting ma.- terial for the synthesis of the esters because that salt is highly crystalline and readily purified, However, other salts such as the mono-potassium, themono-sodium, the di-ammonium anddi-potassium salts could also be utilized for this purpose.

Alternatively, the esters may be synthesized in high yield from 1,2,5-thiadiazole-3,4dicarboxylic acid itself by treating said acid with analcohol and the like in the presence of a strong acid.

In a still further embodiment of the invention, he mono esters of l,2,5-thiadiazole-3,4-dicarboxylic acid may. be prepared by treatingthe mono-silver salt with an alkyl iodide, such as methyl or ethyl iodide, in an organic Benzene, toluene or ether are particularly suit: able solvents for this purpose. In this fashionthere may be obtained esters such as the mono-methyl, mono-ethyl, mono-propyl and mono-butyl esters of 1,2,5,.-thiadiazole 3,4-dicarboxylic acid.

Inaccordance with a still further embodiment of this '4' EXAMPLE 1 l ,2,S-thiadiazole-3,4-dicarboxylic acid grams of 4-nitro-2,1,3-benzothiadiazole (0.138 mole) was slurried in 500 ml. of water,- The mixture was heated to 60 C. on a stearn bath and a-sqlution of 131 grams of potassiumpermanganate. (0.828v mole) in 2600 ml; of.

7 water. was. added thereto over a period of 45" minutes, the

temperaturebeing'maintained between 65-70 C; Excess permanganate remaining at the end of the addition period was destroyed by the, addition of a small amount of ethanol. The manganese dioxide was separated from the hot solution by filtration and washedwith 400 ml. of water. The filtrate and washings were combined and the clear, light-yellow solution ofthe dipotassium salt of 1, 2, 5-thiadiazole-3,4edicarboxylic acid was acidified to a pH of about 1 by the addition-of 80 ml. of concentrated nitric acid; The acidified solution was treated with a solution 0f'23i5; grams of silver nitrate in 50 ml. of water and allowed to cool in the ice box. The white, crystallizedmono silver salt of 1,2,5-thiadiazole-3,4-dicarboxylicacid was separated byfiltration and washed with 200 ml. of" water in smallportions. The dried silver salt weighed grams and blackened without melting between 235- 255' C.

The silver salt was slurried in 300 ml. of water and hydrogen sulfide gas passed into the mixture until the formation of silver sulfide was complete. The resulting suspension was treated with 5 grams of activated charphosphorus pentoxide for a few hours.

invention there are provided the amide and acid halide derivatives of 1,2,5 --thiadiazole 3,4'- dicarboxylic acid. The amides are synthesized by treating an ester, and preferably a lower allcyl ester, of the free acid with ammonia. For example, 3-carboxamido 1, 2,5-thiadiazole- 4ecarboxylicacid is obtained by reaction of a mono lower alkyl ester of 1,2,5-thiadiazolc-3,4-dicarboxylic acicL with aqueous a mo i he ',4- de s produc d o treatment-of lower alkyl 1,2,5-thiadiazole-3,4'-dicarboxylate'with anhydrous ammonia inthe cold.

V Alternatively, the dianlide may be prepared fromthe dieacid' halide, e.g. the di-aeid chloride or bromide, by.

contacting said material withammonia. The acid halides areip fqdnwd on treatment of an alkali metal salt 01Ev 1,2,5.

. eral salts, esters, amides, acid halides and like derivatives f f fidesoribed herein may be converted one to another-as deribed in more detail in the detailed examples which fol-' f Jlow; such inter-conversions and reactions, and the newoompqundsproduced thereby are a part of the instant invention. I

coal andfiltered by gravity; the precipitated silver sulfide was washed with ml. of warm water. The combined filtrates and washes were evaporated to a moist residue and the last traces of water were removed by drying over m s as' h adiazole-3,4-dicarboxylic acid thus obtained weighed 14.3 grams. The product melted at 174l78 C. with decomposition. Recrystallization from glacial acetic acid raised the melting point to 184 C.

Aanlysis.Calculated for C H N SO C, 27.5 9; H, 1.15; N, 16.09; S, 18241. Found; C, 28.09; H, l;26;-N, 16.19; S, 18.16.

On standing the substance absorbs water and is converted to the monohydrate.

Analysis.-Calculated for C H N SO C, 25.00; H, 2.10. Found: C, 25.04; H, 2.08.

EXAMPLE 2 Salts-0f I,2,5-thiadiazole-idicarboxyIic acid A. Mono-silver salt.Addit-ion of a silver nitrate solution to an aqueous solution of 1,2,5-thiadiazole-3,4,-dicarboxylic acid. precipitated the mono-silver salt of the acid. The product was purified by recrystallization from hot water. It does not melt, but blackens gradually be.- tween 235-255 C.

B. Mono-ammonium salr.Ammonium hydroxide was added to an aqueous solution of 1,2,5-thiadiazole-3,4- dicarboxylic acid to a pH of 3. On cooling, some of the salt crystallizes and the remainder is precipitated by the addition of acetone to the filtrate. 0n recrystallization from water-acetone the mono-ammonium salt is obtained, melting point 253-254" C.

Analysis-Calculated for C,,H N O S: C, 25.13; H, 2.64; N, 21.99; S, 16.77. Found: C, 25.65; H, 2.67; N, 21.89; 8', 16.53.

C. Diammpm'um salt-An excess of ammonium hydroxide was added to an aqueous solution of 1,2,5.-thiadiazole-3,4-dicarboxylic acid and an equal volume of acetone added to the ammoniacal solution. The precipitated diammonium salt was collected by filtration and dried; The compound was purified by recrystallization from water-acetone, melting point 254-255 C.

A nalysis.Calculated for C H- N S0 C, 21.24; H, 4.66; N, 24.77; S, 14.08. Found: C, 21.66; H; 4.66; N, 24.87; 5-, 14.01; f V

D. Mono-potassium salt-Potassium hydroxide was added toan aqueous solution of1,2,5-thiadiazole-3, 4-dicarhoxylic acid to a pI-lof 3 and an equal portion otacetone was then added. The mono-potassium salt crystallized, and salt was purified by recrystallization from water-acetone, melting point-293 C. .1 Analysis.--Calcu1ated for C HN SO K: C, 22.64; H, 0.48; N, 13.20. Found: C, 22.47; H, 0.31; N, 13.21.

E. Dipotassium salt.The dipotassium salt was prepared and purified in the same manner as the diammonium salt using potassium hydroxide in place of ammonium hydroxide. Melting point 310 C.

' These salts are useful in purifying the free acid, and as intermediates in the synthesis of esters and acid halides of 1,2,5-thiadiazole-3,4-dicarboxylic acid.

' EXAMPLE 3 1,2,5-th iadiazole-3,4-dicaz bxylic acid di-acid chloride One gram of mono-potassium-l,2,5-thiadiazole-3,4- dicarboxylate was added to ml. of thionyl'chloride. The mixture was boiled under reflux for one hour and the excess solvent was then removed in vacuo. The resulting residue was sublimed at reduced pressure (50/ 3 mm.) and 475 mg. of the white crystalline 1,2,5-thiadiazole-3,4- dicarboxylic acid di-acid chloride was obtained. The melting point was 47, C-

Analysis-Calculated for C Cl N SO Cl, 33.60; S, 15.19. Found: Cl, 33.52; '8, 14.70. t

On treatment with ammonia in the cold, this material is converted to 3,4-dicarboxamido-1,2,5-thiadiazole.

' EXAMPLE 4' l 4-carbomethoxy-l,2,5-thiadiazole-S-carboxylic acid Two grams of recrystallized mono-silver-1,2,-5-thiadiazole3,4-dicarboxylate was mixed with 20 ml. of dry benzene and 2.3 grams of distilled methyl iodide, and the resulting mixture stirred for 36 hours. The yellow precipitate of silver iodide was removed by filtration and washed well with ether. The combined filtrate and washes were evaporated under reduced pressure, leaving 4-carbomethoxy-1,2,5-thiadiazole-3-carboxy1ic acid as a clear light yellow oil which slowly crystallized on standing at 0 C. The solid melted at 7478 C. Sublimation of this material at 60/ 0.1 mm. and then recrystallization of the sublimate from a mixture of ether and petroleum ether raised the melting point to 8081 C.

Analysis-Oiled. for C H N SO C, 31.91; H, 2.14; N, 14.89; S, 17.04. Found: C, 31.70; H, 2.12; N, 14.91; S, 16.77.

EXAMPLE 5 4-carb0meth0xy-1,2,5-thiadiazole-3-carboxylic acid A suspension of 8 grams of the mono-silver salt of 1,2,5-thiadiazole-3,4-dicarboxylic acid in a solution of 6 ml. of methyl iodide in 80 ml. of dry ethyl ether was stirred at room temperature in the dark for 43 hours. The resulting solid was removed by filtration and treated with a fresh solution of 5 ml. of methyl iodide in ethyl ether for 76 hours. The yellow precipitate of silver iodide was removed by filtration, and the ether solutions combined. Removal of the ether by distillation in vacuo gave 5 grams of 4-carbomethoxy-1,2,5-thiadiazole-carboxylic acid as a pale yellow viscous oil which slowly solidified on standing.

EXAMPLE 6 4-carboxamido-1 ,2,5-thiadiazole-3-carboxylic acid 1.27 grams of 4-carbomethoxy-1,2,5-thiadiazole-3-carboxylic acid was shaken vigorously with a solution of 2 ml. of concentrated ammonium hydroxide in- 5 ml. of water. A light brown solid separated which was removed by filtration. This was crude 1,2,5-thiadiazole-3,4-dicarboxamide. 'Ihe filtrate was acidified with nitric acid, and the light tan solid which formed was collected by filtration. Recrystallization of this material from 50 ml. of

acetone gave 4-carboxamide-1,2,5-thiadiazole-3carboxylic acid as short colorless prisms, melting point 219-220, 5 C.

Analysis-Calculated for C H N 0 S: C, 27.75; H, 1.75; N,.24.28; S, 18.53. Found: C, 27.88; H, 2.00; N, 24.15; s, 18.32.

. EXAMPLE 7.

4-carbomethoxy-I,2,5-thiadiazole-3-carbonyl chloride 3,4-dicarb0meth0xy-1 ,2,5 -fhiadiazole.

An ice-cooled suspension of 2.12 grams of 1,2,5-thiadiazole.-3,4-dicarboxylic acid mono-ammonium salt in 25 ml. of dry methanol was saturated with hydrogen chloride gas.. The reaction mixture was allowed to stand in the refrigerator for 140 hours, filtered, and the colorless inorganic precipitate washed with methanol. The filtrate was'concentrated'until the formation of two liquid phases. One phase was removed by extraction of the concentrate with three portions of ether totaling ml. Evaporation of the ether extracts yielded a yellow oil which was distilled at 129/ 4 mm. pressure to give 3,4-dicarbomethoxy-1,2,5-thiadiazole as a white viscous liquid which solidifled in the cold. A max. 263-264 log e=4.00, A min. 233 log e=3.13.

EXAMPLE 9 3 ,4 -dicarbomethoxy-1 ,2,5-r h iadiazole 3.9 grams of the mono-ammonium salt of 1,2,5-thiadiazole3,4-dicarboxylic acid was suspended in 45 ml. of methanol. The mixture was cooled in ice and saturated with dry hydrogen chloride. It was then held at about 0-5 C. for 46 hours -at the end of which time the hydrogen chloride was neutralized by the addition of solid sodium bicarbonate. The resulting white precipitate was removed by filtration and washed with methanol. The combined filtrate and washes were evaporated under vacuum to a yellow oil. Ethyl ether was added to dissolve the oil, and the mixture was decanted from a small water layer. The ether was removed in vacuo, and the oil was distilled at 0.2 mm. Three fractions were obtained over a range of 89-97" C., totaling 3.44 grams. These were allowed to solidify partially at room temperature. Pure 3,4dicarbomethoxy-1,2,5-thiadiazole was prepared by combining the solid portions of the three fractions and redistilling at 0.1 mm. The product was a colorless viscous liquid, boiling point 8485 C./ 0.1 mm.

Analysis.-Calcd. for C H N O S: C, 35.64; H, 2.99; N, 13.85; S, 15.88. Found: C, 36.01; H, 3.03; S, 15.77.

EXAMPLE 10 1,2,5-thiadiazole-3,4-dicarboxamide Anhydrous ammonia gas was passed through a solution of 0.75 gram of 3,4-dicarbomethoxy-1,2,5-thiadiazole in 10 ml. of methanol until the solution was saturated. The reaction mixture was then allowed to cool in the cold for several hours. The colorless crystals which deposited were filtered and washed several times with methanol. Recrystallization of the crystals from hot water yielded substantially pure 1,2,5-thiadiazole-3,4-dicarboxamide, melting point 240 C.

Analysis.-Calcd. for C H N O S: C, 27.90; H, 2.34;

7 N,,, .2-: 4; 13-6 F0 13!! C, V27-9n5THrZ-1 'L s 321495 511752;

EXAMPLE 11 1Q2,5-rhiaqliazple-3 4 digarboxgmide 0.504 grams of 4 carbomethoxy-1,2, 5-thiadiazoly3; carbonyl chloride was :added-dropwise to 5 ml. of ice-cold concentrated ammonium hydroxide, 1,2,5-thiadazole-3, 4-dicarboxamideseparated as a white, finely crystalline. w sre ave eds y fil raticm ashed th methan a air-dr ed,

' of==ethyl ether andtheether was then removedby eoncentration and-the oil distilled at a pressureof 02; mm. Thematerial boiling in the temperature range of: -90'-V-9 7 was collected-and furtherredistilled as described in Example-91o give-substantially pure 3,4-dicanbomethoxy- 1r ,2',5 thiadiazoler When this process is. carried out employing ethanol.- as

the solvent: in; plaee; of:- methanol, there, is; Qh aingd, ,4: dicarboethoxyrly2l5rthiadiazole Ih eester anglzotherlowera kyl esters-wh qhta amepared from the free aid:in the. 58- 9: mannermremxfid intermediatee mime-synthesis of thed amide as set'tfort A solution of m qf; SA-rliearbaxaWQ-M thi diaaq -ia 6 q 'phmhwe ox eh qride was fluted ab u 0. mi The eathe chilled and p ed. onto ,0 Qt ema esisieef. The mixture was stirred until theice had melted and then extracted with three 50 ml; portions of ether. The ether extraqtswerercombined; washed-wtih 20 ml; of! sodium ar aa e9hai9n.,wa 1 d with water nd hen: r ed W q m sul Th et e .rem v sl cuQ. leay a xstal es due of, SA- QYQQQ-LZJflmadi: we. means p m 7-49 m e i l aszti e a ainst reelivin nematszdes u h l'i z rl llw edn i as' anslta a as si u sa flh.

W I I Any departure from the above description, which .692: rms e pn s xn inve i n. s memled t b nclml within the scope of claim.

what a la meslie 3,4 yaac:klfiel ad azqle No references v cited.