4- Amino-1,2,4-triazole hydrochloride

The residual amine in the filtrate may be isolated in the form of the hydrochloride. The combined solutions are evaporated on a steam bath, 50 ml. of concentrated hydrochloric acid is added, and heating is continued for 2 hours. On cooling, the syrupy solution crystallizes. It is triturated with 50 ml. of ethanol, and the 4-amino-l,2,4-triazole hydrochloride is filtered, washed with a little ethanol, and dried. The yield of the hydrochloride is 10-18 g. (8-15%) the salt melts at 147-148° and may be recrystallized from 95% ethanol, using 10 ml. per gram the melting point is thus raised to 151-152°. 

Another nitrification inhibitor that has received much attention in Japan is 2-ami no-4-chloro-6-methyl pyrimidine. It is manufactured by Mitsui Toatsu Chemicals, Inc. (formerly Toyo Koatsu Industries, Inc.) under the trade name AM. Other nitrification inhibitors that have been used in Japan in compound fertilizers are sulfathiazole, dicyandiamide, thiourea, N-2, 5-dichorphenyl succinamide, 4-amino-l, 2, 4-triazole hydrochloride, and guanylthiourea.50... 

The first attempts to use these aminomethyl triazoles revealed that condensations with orthoesters were sensitive to small changes in conditions. To obtain any product at all, the starting triazole had to be present as a salt, but the nature of the anion governed the course of the reaction. The two best results were as follows. 4-Amino-5-aminomethyl-3-benzyl-1,2,3-triazole hydrochloride and triethyl orthoformate, refluxed in ethanol (1 h), yielded 76% of 9-benzyl-1,6-dihydro-8-azapurine. For reaction with triethyl orthoacetate under similar conations, only the acetate of the triazole gave 9-benzyl-2-methyl-l,6-dihydro-8-azapurine (65% yield). Yet, when the acetate of the triazole was condensed, as above, with triethyl orthoformate, only N,N-... 

This positive halogen compound oxidizes alcohols to aldehydes or ketones and hydrazo compounds to azo compounds under mild conditions and in high yields. The oxidant is converted into bcnzo-triazole hydrochloride. It also oxidizes 1-amino-benzotriazole to benzyne (80% yield, 2 moles of oxidant required) and 2-amino-benzotriazole to cis.cis-1,4-dicyanobutadienc-1,3. ... 

A combination of the preceding type of synthesis and of cyclization of 4-amino-5-arylazopyrimidine can be seen in the novel procedure of Richter and Taylor. Proceeding from phenylazomalonamide-amidine hydrochloride (180), they actually close both rings in this synthesis. The pyrimidine ring (183) is closed by formamide, the triazole (181) one by oxidative cyclization in the presence of cupric sulfate. Both possible sequences of cyclization were used. The synthetic possibilities of this procedure follow from the combination of the two parts. The synthesis was used for 7-substituted 2-phenyl-l,2,3-triazolo[4,5-d]-pyrimidines (184, 185). An analogous procedure was employed to prepare the 7-amino derivatives (188) from phenylazomalondiamidine (186). 

Nagai et al. carried out various transformations with camphor-fused amino[l,2,4]triazine 191 <1998JHC293> (Scheme 39). Reaction of 191 with chlorocarbonylsulfenyl chloride yielded the fused thiadiazolone 192 in high yield (83%). The same starting compound also proved to be suitable for the synthesis of the fused triazole derivative 193. To this end, 191 was first subjected to two subsequent transformations first by dimethylformamide dimethylacetal followed by treatment with hydroxylamine hydrochloride to give an Ar-hydroxyamidine 193 in 90% overall yield, and then this compound was treated with polyphosphoric acid to yield the fused triazole product 194 in 92% yield. 

Cyclocondensation of aminoazoles and a,(3-unsaturated carbonyl compounds or Mannich bases is the most common method for the synthesis of dihydroa-zolopyrimidines [99, 155, 156, 157]. Various alkyl- and aryl-substituted dihy-dropyrimidines were prepared in this way. For example, cyclocondensation of 3-amino-1,2,4-triazole 147 with chalcones 148 leads to 5,7-diaryl-4,7-dihydro-l,2,4-triazolo[l,5-a]pyrimidines 149 [158], while reaction with hydrochlorides of Mannich bases 150 leads to heterocycles 151 (Scheme 3.46). 

Amino-2-imino-4-methylthiazoline hydrochloride (112) and aminium salts (114) react with carboxylic acid anhydrides to give thiazolo[3,2-6]-s-triazoles (113) (76JHC1225, 74JHC459). 

Reaction with phenylhydrazine hydrochloride141 produces the isolable, ring-opened l-acyl-5-phenyl-diaminoguanidine hydrochloride (58), the free base of which is partly oxidized even by atmospheric oxygen to l-acyl-3-amino-5-phenylformazane. Cyclization of 58 with alkali produces arylhydrazino- or arylazo-1,2,4-triazoles (59) heating 58 in butanol produces 3,4-diamino-l,2,4-triazole (60). 

The pyrazole- and thiazole analogues of the 3 -deoxy-3 -amino-4 -methoxy Combretastatin A-4 showed potent antimitotic (IC50 3.0 pM and IC50 10 pM) activity. The former showed also a potent cytotoxic activity (IC50 8.4 nM ). Moderate antimitotic activity (IC50 3.0 pM) and weak cytotoxic activity was observed for a triazole derivative, whereas tetrazole ring confers potent antimitotic (ICso 2.0 pM) as well as cytotoxic activity. Compounds with potent cjdotoxicity were further evaluated in vivo in the Colon murine tumor model. The best antitumor activity in vivo, expressed as tumour growth suppression, was observed for the thiazole and tetrazole derivatives with values comparable to the ones observed for 3 -deoxy-3 -amino Combretastatin A-4 hydrochloride. 

A soln. of 7-amino 1,2,5-thiadiazolo [3,4-d] pyrimidine in HCl-dioxane-water heated 4 hrs. at 82-85° under Ng 4-amino-l,2,5-thiadiazole-3-carboxamidine hydrochloride. Y 81%. — Similarly 7-Amino-u-triazolo[4,5-d]pyrimidine 5-amino-y-triazole-4-carboxamidine hydrochloride. Y 89%. F. e. s. Y. F. Shealy and C. A. O Dell, J. Org. Chem. 30, 2488 (1965). 

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