Thiadiazoles treatment

A wide variety of reagents have been used to convert amidines (282) into 1,2,4-thiadiazoles. Treatment of (282) with sodium hypochlorite followed by potassium thiocyanate at pH 3 produces 5-amino derivatives (284) in moderate to good yields (Scheme 98). In one example an unstable intermediate (283 R = OMe, R = H) was isolated but not fully characterized (65AHC(5)119). Products of type (285) are obtained when amidines are treated with iminochloromethylsulfenyl chlorides (269 Scheme 99) (71T4117). When R is aryl (285) is the exclusive product whereas a mixture of isomers is obtained when R is aroyl. 5-Amino-l,2,4-thiadiazoles related to (284) and (285) also are formed in good yields when (V-haloamidines are treated with isothiocyanates. Thus, 5-methylamino-3-trichloromethyl-1,2,4-thiadiazole (287) is obtained in 73% yield from the reaction of A-bromotri-chloroacetamidine (286) with methyl isothiocyanate (Scheme 100) (78USP4107377). 

Synthesis of Heterocyclic Compounds. Thionyl chloride and pyridine at elevated temperatures convert diarylalkenes, styrenes, and cinnamic acids to benzo[i>]thiophenes and adipic acid to 2,5-bis(chlorocarbonyl)thiophene. Additional heterocycles which have been prepared include thiazolo[3,2-a]indol-3(2//)-ones, oxazolo[5,4- /]pyrimidines, and 1,2,3-thiadiazoles. Treatment of 1,2-diamino aromatic compounds with thionyl chloride gives good yields of fused 1,2,5-thiadiazoles. ... 

Table 15 gives a sampling of other pharmaceuticals derived from hydraziae. Cefazolin, a thiadiazole tetrazole derivative, is one of the most widely used antibacterial dmgs in U.S. hospitals (see Antibiotics, P-LACTAMs). Procarbazine, an antineoplastic, is a monomethyUiydrazine derivative (220). Fluconazole has shown some promise in the treatment of AIDS-related fungal infections. Carbidopa is employed in the treatment of Parkinson s disease. FurazoHdone is a veterinarian antibacterial. 

Treatment of (15) with nitrous acid gives liT-l,2,3-tria2ole-4,5-dicarbonitrile [53817-16-6J (70). The action of thionyl chloride on (15) gives l,2,5-thiadiazole-3,4-dicarbonitrile [23347-22-0] (71). 

The conversion of octachloronaphthalene to octafluoronaphthalene with potassium fluoride and either 18-crown-6, dibenzo-18-crown-6, cis,j>m,cis-dicyclohexano-18-crown-6, cis,anti,cis-dicyclohexano-l 8-crown-6, or irons,syn,trails-dicyclohexano-18-crown-6 demonstrates that 18-crown-6 or dibenzo-18-crown-5 increases the yield and selecuvity and decreases the reaction time [55] Treatment of 3,4-dichloro-],2,5-thiadiazole with potassium fluonde in sulfolane with and without 18-crown-6 present shows that less severe conditions can be used with either 18-crown-6 or dibenzo-18-crown-6 to form 3,4-difluoro-l,2,5-thiadiazole (equation 34)... 

Preparation of thiadiazoles via the Hurd-Mori cyclization has led to the synthesis of a variety of biologically active and functionally useful compounds. Discussion of reactions prior to 1998 on the preparation of thiadiazoles have been compiled in a review by Stanetty et al Recent syntheses of thiadiazoles as intermediates for useful transformations to other heterocycles have appeared. For example, the thiadiazole intermediate 36 was prepared from the hydrazone 35 and converted to benzofuran upon treatment with base. Similarly, the thiadiazole acid chloride 38 was converted to the hydrazine 39 which, upon base treatment, provided the pyrazolone, which can be sequentially alkylated in situ to provide the product 40. ... 

A general synthesis of phosphonyl thiadiazoles has been recently disclosed starting from the hydrazone 55. The hydrazones were prepared from acyl phosphonates, which in turn were made from acid chlorides 54. Thus treatment of the hydrazone 55 with thionyl chloride in the presence of DMF and sodium chloride provided the thiadiazoles in... 

The structure of only one 1,2,4-thiadiazole salt has been determined. Unambiguous synthesis of the imino compound obtained on alkali treatment of the salt formed by the reactions of methyl iodide with 5-amino-1,2,4-thiadiazole established that the salt possesses structure 7 136 pjjjg quatemization exactly parallels the reaction occurring in... 

Treatment of 5,7-diamino-l,3,4-thiadiazolo[3,2-n]pyrimidinium ehloride (25) with Vilsmeier reagent gave the 7-formamido-l,2,4-triazolo[l,5-c]pyrimidin-5-one (27) (90JHC851) (Seheme 42). Compound 27 has presumably been formed via rupture of the 1,3,4-thiadiazole ring of 25 and... 

Reaction of 2-aminoethanethiol hydrochloride with hydroxymethylfurazan 61 in 48% aqueous hydrobromic acid (reflux, 24 h) gave a salt that on treatment with an equimolar amount of 3,4-dimethoxy-l,2,5-thiadiazole 1,1-dioxide and another amine gave compound 62 (84USP4471122) (Scheme 30). 

Therapeutic Function Carbonic anhydrase inhibitor, diuretic, treatment of glaucoma Chemical Name N-[5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl] acetamide Common Name —... 

Then, as described in U.S. Patent 2,55416, the 2-acetylamido-5-mercapto-1,3,4-thiadiazole is converted to the sulfonyl chloride by passing chlorine gas into a cooled (5°-10°C) solution in 33% acetic acid (66 parts to 4 parts of mercapto compound) used as a reaction medium. Chlorine treatment is continued for two hours. The crude product can be dried and purified by recrystallization from ethylene chloride. The pure compound is a white crystalline solid, MP l94°C,with decomposition, when heated rapidly. The crude damp sulfonyl chloride is converted to the sulfonamide by addition to a large excess of liquid ammonia. The product is purified by recrystallization from water. The pure compound is a white, crystalline solid, MP 259°C, with decomposition. The yield of sulfonamide was 85% of theory based on mercapto compound. 

The novel 6a-A, -thia-l,2,4,6-tetraazapentalenes (82 R = C02Et) was prepared by treatment of the known 1,2,3-thiadiazolino salt (81) with Af-methylbenzimidoyl chloride in pyridine. An alternative approach to the synthesis of tetraazapentalenes (82) via 1,2,4-thiadiazoles will be discussed in section 5.5.3.2 <96BSB335>. 

Thiadiazoles have proven of some utility as aromatic nuclei for medicinal agents. For example, the previous volume detailed the preparation of a series of "azolamide" diuretic agents based on this class of heterocycle. It is thus of note that the 1,2,5-thiadiazole ring provides the nucleus for a clinically useful agent for treatment of hypertension which operates by an entirely different mechanism, p-adrenergic blockade. In its preparation, reaction of the amide-nitrile 211 with sulfur monochloride leads directly to the substituted thiadiazole 212. ... 

L abbe has studied the rearrangement reactions of 1,2,3-thiadiazoles to differently substituted 1,2,3-thiadiazoles <1983CC588>. He also studied many 5-azido-l,2,3-thiadiazoles 33 that rearranged to 1,2,3,4-thiatriazoles 34 (Equation 5) <1988BSB163>. He even found that l,2,3-thiadiazole-4-carboxaldehydes 35 upon treatment with amines underwent thermal rearrangement to 1,2,3-triazoles 36 (Equation 6) <1993J(P1)1719>. 

Diaryl-l,2,3-thiadiazoles and 1,2,3-benzothiadiazoles have been alkylated at N-3 with trimethylsilylmethyl trifluoromethanesulfonate and treatment of these salts with cesium fluoride generate new l,2,3-thiadiazol-3-ium-3-methanide 1,3-dipoles (see Section 5.07.8.1) <1999J(P1)1415>. 

A parallel synthesis of 1,2,3-thiadiazoles employing a catch-and-release strategy has been reported using the Hurd-Mori reaction. A polymer-bound tosyl hydrazide resin reacted with a-methylene ketones to afford a range of sulfonyl hydrazones. Treatment of these sulfonyl hydrazones with thionyl chloride causes 1,2,3-thiadiazole formation and cleavage of the resin in one step <1999JOC1049>. 

A new method for the synthesis of 1,2,3-thiadiazoles has been reported. The method starts with the thioanilide derivative 72, which is converted into the hydrazone 73. Oxidative heterocyclization by treatment with hydrogen peroxide gave exclusively the 1,2,3-thiadiazoline 74 (Scheme 8) <2003S2559>. 

The Hurd-Mori synthesis of 1,2,3-thiadiazoles s the most widely used method. The availability of aldehydes and ketones which can then be converted into their corresponding hydrazones and the high yields obtained on treatment of these hydrazones with thionyl chloride mean that this method should always be considered as the first choice. 

A variation using thioacylguanidines affords 5-substituted-3-amino-l,2,4-thiadiazoles. If an amidinothiourea is oxidized, 5-amino-l,2,4-thiadiazoles are obtained. A recent example of this type of synthesis has been reported the amidinothiourea 87 was oxidized to the 1,2,4-thiadiazolium salt 88 on treatment with bromine (Equation 25) <2003SC2053>. 

The preparation of 5-chloro-l,2,4-thiadiazol-2-ium chlorides 95 by treatment of formimidoyl isothiocyanates 94 with a twofold excess of methanesulfenyl chloride has been reported in an unusual variation of a type C synthesis. These salts show interesting chemical behavior toward several nitrogen and carbon nucleophiles. The nature of the N-substituent determines the stability of the salt 95. When the substitutent on nitrogen is /-butyl, the salt 95 decomposes readily in solution to give the 5-chloro-l,2,4-thiadiazole 96 (Scheme 10) <2003HAC95>. 

A novel approach to 1,2,4-thiadiazoles 112 is based on the monocyclic and cascade rearrangement of 1,2,5-oxadiazole-2-oxides 111 <2004PAC1691>. Thus, /V-oxidcs 110 upon treatment with ethoxycarbonyl isothiocyanate undergo cascade rearrangement to give 1,2,4-thiadiazoles 112 via intermediate 111 (Scheme 13). 

A variety of 3-amino- and 3,5-diamino-l,2,4-thiadiazoles have been obtained by the treatment of iminocarbonates with chloroamine at low temperatures (see Equation (27), Section 5.08.9.6). 

The most convenient method of preparing thio derivatives of 1,2,4-thiadiazoles is by a type E synthesis. Treating dipotassium cyanodithioiminocarbonate with chlorine gas affords 5-thio-substituted 1,2,4-thiadiazoles. Alternatively, treatment with sulfur followed by chlorine gas affords 3,5-bisthio-substituted 1,2,4-thiadiazoles <1996CHEC-II(4)307>. 

Inhibitors of cysteine protease cathepsin K, for the treatment of osteoporosis, have been reported. The 1,2,4-thiadiazole derivative 131 showed nanomolar activity <2004JME5057>. 

Addition reactions such as A-alkylation do not occur readily, and trimethylsilylmethylation of 3,4-diphenyl-l,2,5-thiadiazole 8 with trimethylsilylmethyl trifluoromethanesulfonate at 80°C occurred at N-2 < 1999J(P1) 1709>. The electron-rich 3-hydroxy-l,2,5-thiadiazole can be preferentially methylated on N-2 using trimethyl orthoacetate in toluene to afford the 2-methyl-l,2,5-thiadiazol-3-one in 69% yield <2002EJ01763>, although a mixture of 3-hydroxythiadiazole and neat trimethyl orthoacetate showed a 20 80 ratio of N- versus 0-alkylation products by H NMR. Treatment of 3-hydroxy-l,2,5-thiadiazole with /-butyl acetate under acid catalysis (Amberlyst 15) gave almost exclusively the A-alkylated compound <2002BMC2259>. 

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