Synthesis of novel 5-piperidyl-substituted 7-hydroxy-3H-1,2,3-triazolo[4,5-d]pyrimidines

A series of 8-azapurin-6-ones having a piperidine substituent at position 5 has been synthesized from pipecolinate esters, benzylazides, and cyanoacetamide. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 276–290, February, 2006.     

Synthesis of 8-Aza-2′-deoxyadenosine and related 7-Amino-3H-1,2,3-triazolo[4,5-d]pyrimidine 2′-Deoxyribofuranosides: Stereoselective glycosylation via the nucleobase anion

The synthesis of 8-aza-2′-deoxyadenosine ( = 7-amino-3H-1,2,3 triazolo[4,5-d]pyrimidine N³-(2′-deoxy-β-D-ribofuranoside); 1 ) as well as the N²- and N¹-(2′-deoxy-β-D-ribofuranosides) 2 and 3 is described. Glycosylation of the anion of 7-amino-3H-1,2,3-triazolo[4,5-d]pyrimidine ( 6 ) in DMF yielded three regioisomeric protected 2′-deoxy-β-D-ribofuranosides, i.e. the N³-, N²-, and N⁴-glycosylated isomers 7 (14%), 9 (11%), and 11 (3%), respectively, together with nearly equal amounts of their α-D-anomers 8 (13%), 10 (12%), and 12 (4%; Scheme 1). The reaction became Stereoselective for the β-D-nucleosides if the anion of 7-methoxy-3H-1,2,3-triazolo[4,5-d]pyrimidine ( 13 ) was glycosylated in MeCN: only the N³-, N², and N¹-(2′-deoxy-β-D-nucleosides) 14 (29%), 15 (32%), and 16 (23%), respectively, were formed (Scheme 2). NH₃ Treatment of the methoxynucleosides 14–16 afforded the aminonucleosides 1–3 . The anomeric configuration as well as the position of glycosylation were determined by combination of ¹³ C-NMR , ¹ H-NMR , and 1D-NOE difference spectroscopy. Compound 1 proved to be a substrate for adenosine deaminase, whereas the regioisomers 2 and 3 were not deaminated.     

Regioselective synthesis of 9-substituted-8-azaguanines (5-amino-3-substituted-3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one)

By modifying previously described methods for the synthesis of 9-substituted-guanines from imidazoles, we have developed a new procedure for the regioselective synthesis of 9-substituted-8-azaguanines (5-amino-3-substituted-3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one) from triazoles in high yields. The method seems suitable for the introduction of a variety of substituents including sugars, carbocyclic, acyclic and carboacyclic chains.     

“One pot” synthesis of 2,9-disubstituted 8-azaadenines (3,5-disubstituted 7-amino-3H-1,2,3-triazolo[4,5-d]pyrimidines)

A new simple method for the synthesis of title compounds is described starting from malononitrile, benzyl-azide and an aliphatic or aromatic nitrile.     

Synthesis of 2-amino-6,7-dihydrothieno-[3′,2′:5,6]pyrido[2,3-d]pyrimidin-4-one

2-Amino-6,7-dihydrothieno[3′,2′:5,6]pyrido[2,3-rf]pyrimidin-4-one ( 1 ) was prepared in three steps from S-(3-butynyl)thiosemicarbazide hydroiodide ( 3 ) and diethyl ketomalonate. The featured step in this synthetic sequence was an intramolecular Diels-Alder reaction of the in situ generated 3-(3-butynylthio)-6-carboethoxy-5-chloro-1,2,4-triazine ( 9 ) to provide the key intermediate 5-carboethoxy-6-chloro-2,3-dihydrothieno-[2,3-b]pyridine ( 6 ). In the course of studies directed toward the preparation of 1 , thermolysis of 3-(3-butynyl-thio)-6-carboethoxy-1,2,4-triazin-5(2H)-one ( 2 ) was found to involve competitive intramolecular Diels-Alder and intramolecular coplanar cycloamination processes, providing the 2,3-dihydrothieno[2,3-b]pyridin-6(7H)-one ( 4 ) and the 1,3-thiazino[3,2-b]-1,2,4-triazin-3-one (5) derivatives, respectively.     

8-Aza-2′-deoxyguanosine and Related 1,2,3-Triazolo[4,5-d]pyrimidine 2′-Deoxyribofuranosides

The synthesis of 8-azaguanine N⁹-, N⁸-, and N⁷-(2′-deoxyribonucleosides) 1–3 , related to 2′-deoxyguanosine ( 4 ), is described. Glycosylation of the anion of 5-amino-7-methoxy-3H-1,2,3-triazolo[4,5-d]pyrimidine ( 5 ) with 2-deoxy-3,5-di-O-(4-toluoyl)-α-D -erythro-pentofuranosyl chloride ( 6 ) afforded the regioisomeric glycosylation products 7a/7b, 8a/8b , and 9 (Scheme 1) which were detoluoylated to give 10a, 10b, 11a, 11b , and 12a . The anomeric configuration as well as the position of glycosylation were determined by combination of UV, ¹³C-NMR, and ¹H-NMR NOE-difference spectroscopy. The 2-amino-8-aza-2′-deoxyadenosine ( 13 ), obtained from 7a , was deaminated by adenosine deaminase to yield 8-aza-2′-deoxyguanosine ( 1 ), whereas the N⁷- and N⁸-regioisomers were no substrates of the enzyme. The N-glycosylic bond of compound 1 (0.1 N HCl) is ca. 10 times more stable than that of 2′-deoxyguanosine ( 4 ).     

A Solution-Phase Parallel Synthesis of 5-Substituted 3,6-Dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones

5‐Substituted 7H‐1,2,3‐triazolo[4,5‐d]pyrimidin‐7‐ones ( 4 ) were rapidly prepared by a solution‐phase parallel synthetic method, which includes aza‐Wittig reaction of iminophosphorane ( 1 ) with phenyl isocynate to give carbodiimide ( 2 ) and subsequent reaction of 2 with various amine and alcohols in the presence of catalytic amount of sodium alkoxide in a parallel fashion.     

Fusions of pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidines with N-heterocyclic moieties

Versatile 2-thioxopyrimidine-type building blocks ethyl 3-(2-ethoxy-2-oxoethyl)- 4 -oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylate ( 4 ) and ethyl 4-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylate ( 8 ) were synthesized from diethyl 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate ( 1 ). Derivatives of linear and angular heterocyclic systems having the imidazole and 1,2,4-triazole ring were obtained from the key intermediates 4 and 8 , respectively.     

Direct bromination of dithieno[3,4-b:3′,4′-d]pyridine and dithieno[2,3-b:3′,2′-d]pyridine

Bromination of dithieno[3,4-b:3′,4′-d]pyridine ( 1 ) and dithieno[2,3-b:3′,2′-d]pyridine ( 2 ) has been studied. Disubstitution occurred at both positions of the C ring. The substitution pattern is found to be similar to that of the nitration reaction. The structures of bromo derivatives were established by ¹H and ¹³C nmr spectroscopy.     

Ring closure reactions of pyrido[2,3‐d]pyrimidines to pyrano[2′,3′:4,5]‐ and oxazolo[5′,4′:4,5]pyrido[2,3‐d]pyrimidines

The cyclocondensation of 5‐hydroxy‐pyrido[2,3‐d]pyrimidines 1 with malonates gives pyrano[2′,3′:4,5]‐pyrido[2,3‐d]pyrimidines 2 . Nitration of 1 and reduction with zinc in the presence of carboxylic acids/anhydrides gave 2‐alkyloxazolo[5′,4′:4,5]pyrido[2,3‐d]pyrimidines 4 , which were ring‐opened to 6‐aminopyrido[2,3‐d]pyrimidines 5, 6 and 7 . Cyclization of 6‐aminopyrido[2,3‐d]pyrimidines 6 with benzoylchlorides 8 gave 2‐aryloxazolo[5′,4′:4,5]pyrido[2,3‐d]pyrimidines 9 . Reaction conditions for the cyclization have been studied by differential scanning calorimetry (DSC).     

Synthesis of pyrido[3′,2′:4,5] thieno[3,2-d]pyrimidine derivatives

Pyrido [3′,2′:4,5]thieno[3,2-d] pyrimidine and several of its derivatives have been synthesized.     

“One pot” synthesis of 2-substituted 9-(2′-hydroxy-3′-aminopropyl)-8-azahypoxanthines and 8-azaadenines (5-substituted 3-(2′-hydroxy-3′-aminopropyl) 7-amino and 7-hydroxy-3H-1,2,3-triazolo[4,5-d]pyrimidines)

An example of the generalization of the synthesis of 8-azahypoxanthines A and 8-azaadenines B , interesting from a medicinal point of view, is presented by utilizing l-amino-2-hydroxy-3-azidopropanes.     

Tricyclic heterocyclic systems: Pyrazolo[5′,4′:4,5]-and pyrazolo-[3′,4′:4,5]pyrano[2,3-b]pyridine derivatives

By reacting 2-chloronicotinoyl chloride with acetyl or benzoyl acetate, ethyl 2-methyl- or 2-phenyl-4-oxopyrano[2,3-b]pyridine-3-carboxylates were prepared. The nucleophilic rearrangement of the latter with hydrazines gave rise to the title compounds.     

Nitration of dithieno[3,4-b:3′,2′-d]pyridine and dithieno[2,3-b:3′,2′-d]pyridine

The nitration of dithieno[3,4-b:3′,2′-d]pyridine ( 2 ) and dithieno[2,3-b:3′,2′-d]pyridine ( 3 ) has been studied. Nitration of 2 occurred in both positions of the c-fused thiophene ring, while 3 was predominantly substituted in the 2-position. The structures of the nitro derivatives were proven by extensive use of ¹H and ¹³C nmr spectroscopy.     

Synthesis of 1,2,4-triazolo[4′,3′:1,6]pyridazino[4,5-b]quinoline derivatives

This paper reports the synthesis of 10-phenyl-2H-pyridazino[4,5-b]quinoline-1-thione 10 and its further transformation into the hitherto unknown 12-phenyl-1,2,4-triazolo[4′,3′:1,6]pyridazino[4,5-b]quinoline 4 . 3-Carbethoxy-2-dichloromethyl-4-phenylquinoline 8 was reacted with hydrazine to give 9 which in turn was transformed by the Lawesson Reagent into the corresponding thione 10 . On treating 10 with anhydrous hydrazine, 11 was obtained and subsequently cyclized in the presence of formic or acetic acids to afford the tetracyclic derivatives 4a and 4b , respectively, in satisfactory yields. When 3-carbethoxy-2-chloromethyl-4-phenylquinoline 5 was reacted with hydrazine, compound 7 was the sole isolated product.