A new approach to the synthesis of lamotrigine and other 3,5-diamino-1,2,4-triazine derivatives

A new in principle method for the synthesis of 6-aryl(hetaryl)-3,5-diamino-1,2,4-triazines by decomposition of pre-synthesized tetrazolo[1,5-b][1,2,4]triazines was developed. The advantages of this method over traditional methods were demonstrated using the synthesis of a modern antiepileptic preparation lamotrigine, as an example.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 713–719, March, 2005.     

Reaktionen vonN-Sulfinylverbindungen mit dem 1,2,4-Trithia-3,5-diborolan-Ringsystem und Substitutionsreaktionen am 1,2,4-Trithia-3,5-diborolan und 1,2-Dithia-4-aza-3,5-diborolidin

The reaction of trimethylsilyl- and pentafluorophenyl-N-sulfinylamine respectively with 3,5-dihalogeno-1,2,4-trithia-3,5-diborolanes yields the 1,2-dithia-4-aza-3,5-diborolidines1-3.Tert-butyl-N-sulfinylamine and 3,5-dimethyl-1,2,4-trithia-3,5-diborolane react analogous. OtherN-sulfinylamines however split the disulfane bridge in 3,5-dimethyl-1,2,4-trithia-3,5-diborolane and the 1,4-dithia-2-aza-3,5-diborolidines5A-7(A) are formed. Besides of boroxines, cyclo-2,4,6-trimethyl-1,3-dioxa-5-aza-2,4,6-triboranes and cyclo-2,4,6-trimethyl-1-oxa-3,5-diaza-2,4,6-triboranes are formed as byproducts,8–10 have been isolated. In 1,2,4-trithia-3,5-diborolanes and 1,2-dithia-4-aza-3,5-diborolidines the bromo-atoms can be substituted by alkyl (13, 14), by amino (15–20) and by isothiocyanato groups. The compounds were characterised analytically and spectroscopically (MS; NMR:¹H,¹¹B,¹⁹F,²⁹Si; IR).

     

Acyl and Sulfonyl Derivatives of 3,5-Diamino-1-R-1,2,4-triazoles

3-Acylamino-5-amino-1-R-1,2,4-triazoles are formed regioselectively on acylating 3,5-diamino-1-R-1,2,4-triazoles with an equimolar amount of anhydrides, carboxylic acid chlorides, and sulfonyl chlorides. With an excess of anhydride and carboxylic acid chloride 3,5-diacylamino-1-R-1,2,4-triazoles are formed. 3-Acylamino-5-amino-1-R-1,2,4-triazoles do not interact with sulfonyl chlorides. The higher reactivity of the 3-amino group towards acylating agents is determined by electronic and not steric factors. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1342–1350, September, 2005.     

Alkylation of acyl and sulfonyl derivatives of 3,5-diamino-1-phenyl-1,2,4-triazole

Alkylation of 3-acylamino-, 5-amino-1-phenyl-3-tosylamino-1,2,4-triazoles and 3,5-diacetylamino-1-phenyl-1,2,4-triazole in the presence of an equimolar amount of sodium methylate in DMSO occurs regioselectively at the amide (sulfamide) group nitrogen atom. The benzylation of 3-acetylamino-5-amino-1-phenyl-1,2,4-triazole with excess base and benzyl chloride also alkylates the amino group at position 5. Alkylamino-1-R-1,2,4-triazoles can be conveniently prepared by alkylation of the corresponding acetylamino-1,2,4-triazoles in the presence of base and subsequent acid hydrolysis of the N-acetyl-N-alkyl derivatives. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 557–567, April, 2009.     

Regioselective single-reactor synthesis of arylsulfonyl derivatives of 3,5-diamino-1,2,4-triazole

Arylsulfonylation of 1-acetyl-3,5-diamino-1,2,4-triazole with arylsulfonyl chlorides in pyridine, with the subsequent hydrolysis of the acetyl group, was studied; a new regioselective method for synthesis of N-(5-amino-1H-1,2,4-triazol-3-yl)arylsulfonamides was developed.     

Pyridazine Derivatives and Related Compounds,Part 17: 1 The Synthesis of Some 3-Substituted Pyridazino[3′, 4′:3, 4]pyrazolo[5, 1-c]-1,2,4-triazines and Their Antimicrobial Activity

The reaction of the hydrazide of pyridazino[3′, 4′:3, 4]pyrazolo[5, 1-c]-1,2,4-triazine-3-carboxylic acid 3 with carbon disulfide in the presence of potassium hydroxide gave the 1,3,4-oxadiazole-2-thione derivative 4. The methylation of this product in an alkaline medium proceeds at the sulfur atom. The reaction of 3 with KOH and carbon disulfide followed by addition of hydrazine hydrate afforded the 4-amino-1,2,4-triazole derivative 6. Compound 3, when heated either with ammonium thiocyanate or with potassium thiocyanate, afforded the same product 7, which underwent cyclodehydration in the presence of acetyl chloride, which led to the 2-acetylamino-1,3,4-thiadiazole derivative 8. In a basic medium, the product was 1,2,4-triazole-3-thione derivative 9. The reaction of 3 with phenyl isothiocyanate provided thiosemicarbazide derivative 10, which underwent cyclodehydration in a basic medium and gave the 1,2,4-triazole derivative 11. The reaction of 3 with formic acid yielded the 3-carboxyl-2′-(formyl)hydrazine derivative 12. The refluxing of the latter with phosphorus pentasulfide in xylene yielded compound 14 (65%). The reaction of compound 12 with phosphorus pentoxide afforded compound 15. Some representative examples were screened for antimicrobial activity.     

Interaction of aminoazoles with Meldrum’s acid and dialkyl ketones or cyclohexanone

Interaction of 3-amino-5-methylpyrazole, 3-amino-5-methylthio-, and 3,5-diamino-1,2,4-triazole with Meldrum’s acid, acetone, ethyl methyl ketone, and cyclohexanone leads to alkyl-substituted pyrazolo[3,4-b]pyridin-6-ones and 1,2,4-triazolo[1,5-a]pyrimidin-7-ones respectively. The structure of 5,5-dimethyl-2-methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-7-one was demonstrated by an X-ray structural investigation. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 595–601, April, 2007.     

Syntheses,crystal structures and thermal analyses of two new ionic complexes based on 3,4-diamino-1,2,4-triazole

Two new ionic complexes, (DATr)₂[Li₂(TNR)₂·2H₂O]·2H₂O (1) and (DATr)[Zn(DATr)Cl₃] (2), were synthesized by using 3,4-diamino-1,2,4-triazole (DATr) as outer cation. X-ray single-crystal diffraction analysis revealed that the two complexes crystallize in triclinic and orthorhombic crystal systems, respectively. Differential scanning calorimetry was applied to assess the thermal decomposition behavior and kinetic parameters of decomposition were studied by using Kissinger’s and Ozawa–Doyle’s methods. Furthermore, the critical temperature of thermal explosion and parameters of thermodynamics were obtained.     

Cascade cyclization reactions of 3,4,5-triamino-1,2,4-triazole with aromatic aldehydes and cycloalkanones

A three-component condensation of 3,4,5-triamino-1,2,4-triazole (1) with aromatic aldehydes 2a–f and dimedone (3) or cyclohexanone (8) afforded partially hydrogenated 9-aryl-[1,2,4]triazolo[5,1-b]quinazolin-8-ones. The structure of 2-amino-6,6-dimethyl-3-(4-nitrobenzylidene)amino-9-(4-nitrophenyl)-5,6,7,9-tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-8-one (4e) was confirmed by X-ray diffraction data. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1178–1182, July, 2006.     

Reactivity of 3,5-bis-(4-amino-1,2,5-oxadiazol-3-yl)-1,2,4-triazole

Alkylation of 3,5-bis(4-amino-1,2,5-oxadiazol-3-yl)-1,2,4-triazole with haloalkanes afforded N-CH₂R derivatives, and nitration furnished the corresponding bis-N-nitramine isolated as a trisodium salt. Treatment of the latter with CH₃I resulted in denitration. Diazotization and oxidation of 3,5-bis(4-amino-1,2,5-oxadiazol-3-yl)-1,2,4- triazole, its N-methyl and N-carboxy derivatives gave rise to the corresponding azido and nitro derivatives. Salts of 3,5-bis(4-amino-1,2,5-oxadiazol-3-yl)-1,2,4-triazol-5-acetic acid with nitrogen-containing bases were synthesized. It was established that the character of reaction products of 3,5-bis(4-amino-1,2,5-oxadiazol-3-yl)-1,2,4-triazole with formaldehyde depended on the acid-base properties of the medium.__________Translated from Zhurnal Organicheskoi Khirmii, Vol. 41, No. 2, 2005, pp. 270–276.Original Russian Text Copyright © 2005 by Sergievskii, Romanova, Mel’nikova, Tselinskii.     

3,5-二烷基-1,2,4-三唑衍生物构筑的两个Cu4I4簇配合物的合成、结构和荧光性质

以3,5-二甲（丙）基-4-氨基-1,2,4-三唑为配体,与CuI在H₂O/MeCN混合溶剂热合成了2个构型不同的Cu₄I₄超分子化合物{[Cu₂（aadmtrz）I₂]·CH₃CN}_n （1）和[Cu₂（dptrz）I]_n （2）（aadmtrz=4-（（1-氨乙基）-氨基）-3,5-二甲基-1,2,4-三唑,dptrz=3,5-二丙基-1,2,4-三唑）,并进行了元素分析,红外,X射线粉末衍射及单晶衍射等表征。2个配合物中Cu₄I₄构型不同,配合物1中,Cu₄I₄簇连结成一个8环椅式-椅式结构,通过配体连接成（4,4）二维菱形格子结构;而配合物2中,Cu₄I₄簇呈畸变的立方烷结构,构成了含有19.5%孔隙率三维孔洞聚合物,其结构可简化为（3,4）-连接的拓朴结构。同时,在常温下研究了2个配合物的固体荧光性质。     

Reaction Of 3-Nitro-1,2,4-triazolederivatives with Alkylating Agents. 1. Alkylation in the Presence of Alkali

Alkylation of 3-nitro-1,2,4-triazole and 5-methyl-3-nitro-1,2,4-triazole with dialkyl sulfates or alkyl halides in the presence of alkali proceeds with a low selectivity for the alkylating agent with the formation of two regioisomers at the N₍₁₎ and N₍₂₎ atoms of the heterocycle. Depending on the reaction conditions the proportion of the N₍₂₎ isomer was 14.6-33.8%. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1020–1025, July, 2005.     

The Mannich reaction in the synthesis of N,S-containing heterocycles 6. New approaches to the synthesis of pyrimido[4,3-b][1,3,5]thiadiazine derivatives

Aminomethylation of 2,6-diamino-4-aryl-4H-thiopyran-3,5-dicarbonitriles in the Mannich reaction with p-toluidine and formaldehyde unexpectedly gave pyrimido[4,3-b][1,3,5]thiadiazine derivatives. The same compounds were obtained in an independent way involving a multicomponent cascade condensation of aromatic aldehydes, cyanothioacetamide, p-toluidine, and formaldehyde. For Part 5, see Izv. Akad. Nauk, Ser. Khim., 2007, 1384 [Russ. Chem. Bull., Int. Ed., 2007, 56, 1437]. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1420–1422, July, 2007.     

Synthesis of Partially Hydrogenated 1,2,4-Triazoloquinazolines by Condensation of 3,5-Diamino-1,2,4-triazole with Aromatic Aldehydes and Dimedone

Three-component condensation of 3,5-diamino-1,2,4-triazole with aromatic aldehydes and dimedone in dimethylformamide gives 2-amino-5-aryl-8,8-dimethyl-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[3,2-b]quinazolin-6-ones. The reaction of 3,5-diamino-1,2,4-triazole with dimedone in the absence of aldehyde involves dimethylformamide as one of the carbonyl components to afford 2-amino-8,8-dimethyl-6,7,8,9-tetrahydro[1,2,4]triazolo[2,3-a]quinazolin-6-one.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 1, 2005, pp. 115–120.Original Russian Text Copyright © 2005 by Lipson, Desenko, Borodina, Shirobokova, Musatov.     

The use of aliphatic aldehydes for the synthesis of 4-alkyl-6-amino- 3,5-dicyanopyridine-2(1H)-thiones

The condensation of aliphatic aldehydes with malononitrile and cyanothioacetamide gives 4-alkyl-2,6-diamino-3,5-dicyano-4H-thiopyrans which recyclize into 4-alkyl-6-amino3,5-dicyanopyridine-2(IH)-thiones. The latter are easily S-alkylated with -haloacetonitriles and -haloacetophenones.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 938–942, April, 1996     

Eco-friendly energetic complexes based on transition metal nitrates and 3,4-diamino-1,2,4-triazole (DATr)

Four eco-friendly energetic metal complexes of 3,4-diamino-1,2,4-triazole (DATr), including manganese (1), cobalt (2), nickel (3), and zinc (4), were synthesized by reacting DATr·HCl with the corresponding metal (Mn(II), Co(II), Ni(II), and Zn(II)) nitrate in aqueous solution and characterized by using Fourier transform-infrared spectroscopy and elemental analyses. The single crystals of 2, 3, and 4 were obtained and determined by X-ray single-crystal diffraction analysis. All three complexes crystallize in the monoclinic crystal system and belong to P2(1)/n space group. The thermal decomposition processes were investigated by differential scanning calorimeter (DSC) and thermogravimetry–derivative thermogravimetry analyses. The results show that the decomposition temperatures of 1–4 are above 260 °C, depending upon their onset DSC peaks. It can be predicted that these complexes based on 3,4-diamino-1,2,4-triazole have good thermal stability. The nonisothermal kinetic parameters of decomposition were calculated by using Kissinger and Ozawa–Doyle’s methods. Furthermore, the sensitivities of these complexes to impact, friction, and flame were determined. Sensitivity tests revealed that 2 was more sensitive to external stimuli compared to the other three complexes.     

Synthesis of 1-Acyl- and 1-Arylsulfonyl Derivatives of 3,5-Diamino-1,2,4-triazole

Acylation of 3,5-diamino-1,2,4-triazole with anhydrides and chlorides of alkane- and arenecarboxylic acids and arenesulfonyl chlorides in aqueous solutions and under phase-transfer catalysis was studied.__________Translated from Zhurnal Prikladnoi Khimii, Vol. 78, No. 5, 2005, pp. 790–795.Original Russian Text Copyright © 2005 by Chernyshev, Gaidukova, Zemlyakov, Taranushich.     

Synthesis of 8,8-R,R-8,9-dihydro[1,2,4]triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]quinazolin-6(7<Emphasis Type="Italic">H</Emphasis>)-ones

Three-component condensation of 3-amino-1,2,4-triazole (or its 5-methyl and 5-methylthio derivatives), dimedone (or cyclohexane-1,3-dione), and dimethylformamide dimethyl acetal afforded 8,8-R, R-8,9-dihydro[1,2,4]triazolo[1,5-a]quinazolin-6(7H)-ones. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2805–2807, December, 2005.     

Synthesis and Physicochemical Properties of Heterocyclic Compounds Based on 5,7-Diimino-2,5,6,7-tetrahydro-1H-cyclopenta[cd]phenalene

N,N'-Bis(7-amino-2,5-dihydro-1H-cyclopenta[cd]phenalen-5-ylidene)-substituted derivatives of 2,5-diamino-1,3,4-thiadiazole, 2,6-diaminopyridine, and 3,5-diamino-1-phenyl-1,2,4-triazole were synthesized. The products are soluble in water, and they attract interest as potential biologically active substances.     

Synthesis of 1,2,4-Triazol-3-ylmethyl-, 1,3,4-Oxa-, and -Thiadiazol-2-ylmethyl-1<Emphasis Type="Italic">H</Emphasis>-[1,2,3]-triazolo[4,5-<Emphasis Type="Italic">d</Emphasis>]pyrimidinediones

Summary. 1-Carbethoxymethyl-4,6-dimethyl-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione was synthesized and treated with hydrazine hydrate to give the corresponding hydrazide. The latter hydrazide was treated either with phenylisothiocyanate or with carbon disulfide/alc. KOH to afford the corresponding thiosemicarbazide and oxadiazole derivatives. Alkylation of 2-mercapto-1,3,4-oxadiazole with dimethyl sulfate or ethyl chloroacetate gave the corresponding 2-methylthio-, and 2-ethylthioglycolate derivatives. Formation of 1,3,4-thiadiazole, 5-mercapto-1,2,4-triazole, and 1,3,4-oxadiazole were carried out by treating of the latter thiosemicarbazide with conc. H₂SO₄, NaOH/HCl, and HgO. Treating of 5-mercapto-1,2,4-triazole with ethyl chloroacetate afforded the thioglycolate ester. Hydrolysis of the latter with hydrazine hydrate afforded the hydrazide derivatives. Condensation of these hydrazides with monosaccharide aldoses gave the corresponding sugar hydrazones. The novel compounds were tested for antiviral activity against hepatitis B virus and showed moderate activities.