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.     

Synthesis of 5′-halo-2′,3′-lyxo-epoxy and 2′,3′-unsaturated thieno[3,2-d]pyrimidine nucleosides

A series of thieno[3,2-d]pyrimidine-2,4-dione nucleosides modified in the carbohydrate moiety has been synthesized. In the first part, synthetic routes are described for the replacement of 5′-hydroxyl group in preformed 1-(β-D-ribofuranosyl)thieno[3,2-d]pyrimidine-2,4-dione I by fluoro, iodo or chloro atoms. Reduction of the 5′-iodo substituent of VI was then carried out catalytically using palladium on carbon as catalyst to give the expected 5′-deoxy derivative VIII. The lyxo-epoxide derivative XII was then synthesized by sequential treatment of the 5′-deoxy-5′-chloro derivative X with methanesulfonyl chloride and with sodium hydroxide. In the second part, most of attention has been devoted to apply different methods reported in the literature that allow access to 2′,3′-olefinic derivatives from the corresponding 2′,3′-dihydroxy precursor. The 5′-O-silyl protected bisxanthate XIV either on reduction with tri-n-butyltin hydride or by reductive elimination of the haloacetate XVI afforded the free 2′,3′-olefin nucleoside after removal of the 5′-protecting group. However none of the compounds in this series exhibited significant antiviral activity against HIV at the doses tested.     

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

Nitration of dithieno[3,2-b:3′,2′-d]pyridine ( 4 ) and dithieno[3,2-b:3′,4′-d]pyridine ( 5 ) has been studied. Nitration of 4 occurred in both positions of the C ring, while 5 was predominantly substituted on the 3,4-fused ring. The structures of the nitro derivatives were proven by extensive use of ¹H and ¹³C nmr spectroscopy.     

Studies of thieno[2,3-b]pyrazines in preparation of pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidines and related molecules

A variety of 2,3-disubstituted derivatives of the previously unknown thieno[2,3-b]pyrazine ring system have been employed as a synthetic foundation for pyrazino[2′,3′:4,5]thieno[3,2-d]-pyrimidine and several of its derivatives.     

Synthesis of novel pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidines,pyrido[3″,2″:4′,5′]thieno[3′,2′:4,5]pyrimido[l,6‐a]benzimidazoles and related fused systems

3‐Amino‐4‐aryl‐5‐ethoxycarbonyl‐6‐methylthieno[2,3‐b]pyridine‐2‐carboxamides 3a‐c were prepared from ethyl 4‐aryl‐3‐cyano‐6‐methyl‐2‐thioxo‐1,2‐dihydropyridine‐5‐carbonylates 1a‐c and reacted with some carbonyl compounds to give tetrahydropyridothienopyrimidine derivatives 6a‐c, 7a‐c and 8a‐c , respectively. Treatment of compound 3c with chloroacetyl chloride led to the formation of a next key compound, ethyl 2‐chloromethyl‐4‐oxo‐3,4‐dihydropyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine‐8‐carboxylate 9 . Also, 3‐amino‐2‐benzimidazolylthieno[2,3‐b]pyridine‐5‐carboxylate 5 and 2‐(3′‐aminothieno [2,3‐b]pyridin‐2′‐yl)‐4‐oxo‐3,4‐dihydropyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine‐8‐carboxylate 17 were prepared from 1c. The compounds 5, 9 and 17 were used as good synthons for other pyridothienopyrimidines and pyridothienopyrimidobenzimidazoles as well as for related fused polyheterocyclic systems.     

Synthesis of new heteroaromatic nitrogen ligands: Pyrimido‐[4″,5″:4′,5′]‐thieno[3′,2′:4,5]thieno[3,2‐d]pyrimidines and 1,2,3‐triazine[4″,5″:4′,5′]thieno[3′,2′:4,5]thieno[3,2‐d]‐1,2,3‐triazines

An efficient one‐pot access for the synthesis of the previously unreported tetracyclic fused pyrimido‐[4″,5″:4′,5′]thieno[3′,2′:4,5]thieno[3,2‐d]pyrimidine ( 3 ) and 1,2,3‐triazine[4″,5″:4′,5′]thieno‐[3′,2′:4,5]thieno‐[3,2‐d]‐1,2,3‐triazine ( 5 ) heteroaromatic nitrogen ligands is described. The title compounds 3 and 5 were obtained from 3,4‐diaminothieno[2,3‐b]thiophene‐2,5‐dicarbonitrile and phosgeniminium chloride and sodium nitrite/HCl, respectively. Substituted condensed thieno[2,3‐b]thiophene derivatives 4 and 6 were synthesized by nucleophilic displacement of the chloroderivatives 3 and 5 .     

2-芳氧基-3-对氟苯基-3,5,6,7-四氢-4H-环戊二烯并[4,5]噻吩并[2,3-d]-嘧啶-4-酮衍生物的合成及其抑菌活性

利用三组分氮杂Wittig反应, 以三氢环戊二烯并噻吩基三苯基膦亚胺、对氟苯基异氰酸酯和酚, 合成了13个未见文献报道的2-芳氧基-3-对氟苯基-3,5,6,7-四氢-4H-环戊二烯并[4,5]噻吩并[2,3-d]-嘧啶-4-酮衍生物, 产率58%～73%. 通过IR, 1H NMR, MS 和元素分析对目标化合物的结构进行了表征. 初步探讨了所合成化合物的抑菌活性, 结果显示所合成的化合物对真菌(桔青霉菌)的抑制活性优于对细菌的抑制活性.     

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.     

Synthesis of two novel ring systems via photocyclization: Thieno[2′,3′:4,5]thieno[2,3-c][1,10]phenanthroline and thieno[3′,2′:4,5]thieno[2,3-c][1,10]phenanthroline

The synthesis of thieno[2′,3′:4,5]thieno[2,3-c][1,10]phenanthroline ( 5 ) and thieno[3′,2′:4,5]thieno-[2,3-c][1,10]phenanthroline ( 10 ) are described. Each compound was obtained in four steps from known starting materials. The basic skeleton of the molecule and of the phenanthroline ring were formed via photocyclization. The total assignment of ¹H-nmr spectra was accomplished with the aid of two-dimensional nmr methods.     

Synthesis of thieno[2′,3′(3′,4′ or 3′,2′):5,6]azepino[2,1-a]isoindolediones from N-Thienyl-2(3)-ylmethylphthalimides

Reduction of N-thienybnethylphthalimides 5a-e followed by the Wittig reaction gave the substituted acetic acids 8a-e . Their corresponding acyl chlorides where cyclized in the presence of aluminium trichloride to furnish the cyclic ketones 9a-e . Treatment of these ketones with bromine followed by triethylamine, or with selenium dioxide led to the thienoazepinoisoindolediones 1a-e .     

Synthesis of 4-[(1,3-diaminopyrrolo[3′,4′:4,5]pyrido[2,3-d]-pyrimidin-8-yl)benzoyl]-L-glutamic acid as a potential antifolate

This paper is dedicated to the memory of Professor Roland K. Robins The synthesis of 4-[(1,3-diaminopyrrolo[3′,4′:4,5]pyrido[2,3-d]pyrimidin-8-yl)benzoyl]-L-glutamic acid ( 18 ), a potential antifolate and anticancer agent, has been achieved starting from 1,4-dibromobutan-2-ol with alkyl p-aminobenzoic acids. Condensation of these two agents gave 1-(4-alkoxycarbonylphenyl)pyrrolidin-3-ols 7a,b , which were oxidized to the corresponding pyrrolidin-3-one derivatives 8a,b . Compounds 8a,b were converted into 1,3-diamino-8-(4-alkoxycarbonylphenyl)-7,8-dihydro-9H-pyrrolo[3′,4′:4,5]pyrido[2,3-d]pyrimidines 12a,b in 4 steps. Saponification of 12b the benzoate ester and coupling with di-tert-butyl glutamate afforded a mixture of 7,8-dihydro product 16 and its aromatized derivative 17 . Finally hydrolysis of esters 16 or 17 gave only the title compound 18 . The 7,8-dihydro tricyclic derivatives were easily air-oxidized to form their fully aromatized compounds. The title compound 18 was one tenth less active than MTX against HL-60 cells in culture.     

Synthesis of β‐Lactam‐containing Pyrido[3′,2′:4,5]thieno[3,2‐e][1,4]diazepines

Novel tricyclic 1,4‐diazepine derivatives – pyrido[3′,2′:4,5]thieno[3,2‐e ][1,4]diazepin‐2‐ones – have been synthesized. Azetidin‐2‐one moiety has been incorporated into the 1,4‐diazepine scaffold by [2 + 2]cycloaddition of functionalized ketenes to imine C═N bond, and several tetracyclic azetodiazepines which can be considered as potential compounds of biological interest have been prepared. Stereoselectivity of the cycloaddition was proved by NMR and X‐ray analysis data.     

Synthesis and Reactions of Naphtho[1′,2′:4,5]Furo[3,2‐b]Pyridine and Naphtho[1′,2′:4,5]Furo[3,2‐d]Pyrimidine Derivatives

2‐Acyl‐3‐aminonaphtho[2,1‐b]furan ( 1 ) reacts with activated methylene such as malono nitrile or ethyl cyanoacetate to afford naphtho[1′,2′:4,5]furo[3,2‐b]pyridine 2a,b . Chloroacylation of the amino group in compound ( 1 ) gave compound 3 which reacts with different amines to produce compound 4 .     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 1. Thieno[3′,2′:4,5]thieno[2,3-c]quinoline and thieno[2′,3′:4,5]thieno[2,3-c]quinoline

The synthesis of two previously unknown heterocyclic ring systems, namely, thieno[3′,2′:4,5]thieno[2,3-c]-quinoline and thieno[2′,3′:4,5]thieno[2,3-c]quinoline is reported. These two novel ring systems were assembled by photocyclization of the appropriate anilides.     

Synthesis and reduction of thieno[2′,3′(3′,2′ or 3′,4′):5,6]-azocino[2,1-a]isoindole-7, 13-diones

A synthesis of the thieno[2′,3′(3′,2′ or 3′,4′):5,6]azocino[2,1-a]isoindole-7,13-diones 6a-c was developed from N-thienylethylphthalimides 3a-c using a Wittig reaction followed by a Friedel-Crafts cyclization of acetic acid derivatives 5a-c . Reduction of ketones 6a-c into alcohols 7a-c was stereo specific.     

Synthesis of 4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine

4-Methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine ( 3 ) was synthetized from 2-acetylfuro[3,2-f]benzo[b]furan ( 4 ) or from 2-acetyl-5,6-dihydrofuro[3,2-f]benzo[b]furan ( 10 ). The key step involves a rearrangement-cyclization of azides 6 and 12 to form 4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridin-1(2H) one ( 7 ) and 8,9-dihydro-4-methylfuro[3′,2′:5,6]benzofuro[3,2c]pyridin-1(2H)-one ( 13 ). Introduction of an aminoalkyl chain on carbon 1 was effected by substitution of 1-chloro-4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine ( 8 ).     

Derivatives of condensed thieno[2,3-d]-pyrimidines. 20. Synthesis of 2-substituted 5,6-dihydro-8H-pyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4(3H)-ones and 5,6,7,8-tetrahydrobenzo-[b]thieno[2,3-d]pyrimidin-4-ones

We have developed a method for obtaining 2-substituted 3-amino-6,6-dimethyl-5,6-dihydro-8H-pyrano[4′,3′:4,5]-and 5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-ones, converted by deamination to the corresponding dihydropyranothieno-3H-pyrimidinones. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 441–444, March, 2006.     

Synthesis and reactivity of 3-amino-9-methoxymethyl-7-methyl-3,4-dihydropyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ones

The reaction of acyl derivatives of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate with hydrazine hydrate gives a series of tricyclic 3-amino-3,4-dihydropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ones containing aliphatic, aromatic, or heteroaromatic fragments at C₍₂₎. The reactions of 3-aminopyridothieno[3,2-d]pyrimidin-4-ones with aldehydes, formamide, 2,5-dimethoxytetrahydrofuran, acetic anhydride, and Raney nickel were studied. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1720–1732, November, 2007.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 17. Thieno[3′,2′:4,5]thieno[2,3-c]naphtho-[2,1-f]quinoline and thieno[3′,2′:4,5]thieno[2,3-c]-naphtho[1,2-g]quinoline

The synthesis of two previously unknown novel polycyclic heterocyclic ring systems via photocyclization is described. The structural assignment of the isomeric ring systems, 4 and 5 , was achieved by the total assignment of their ¹H and ¹³C nmr spectra by the concerted usage of two-dimensional nmr methods.     

Synthesis of some pyrimido[4′,5′:4,5]thieno[2,3-b]quinolines and related heterocycles

Several thieno[2,3-b]quinolines 6a-i have been synthesized. These compounds were used as key intermediates in the synthesis of oxazino[4′,5′:4,5]thieno[2,3-b]quinoline 8 , pyrimido[4′,5′:4,5]-thieno[2,3-b]quinolines 9–12 , triazino[4′,5′:4,5]thieno[2,3-b] quinolines 14 and imidazo[4′,5′:4,5]-thieno[2,3-b]quinolines 17 .