Synthesis of 6-substituted 9-(dihydroxyalkyl) purines

5-Amino-6-chloro-4-dihydroxyalkylaminopyrimidines, which are cyclized to 6-chloro-9-(dihydroxyalkyl)purines, were obtained by the condensation of 5-amino-4,6-dichloropyrimidine with 2-amino-1,3-dihydroxypropane or with 2-amino-1,4-dihydroxybutane. The corresponding 6-hydroxy and 6-amino derivatives were obtained by replacement of the chlorine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 262–264, February, 1971.     

Potential DNA bis-intercalating agents. Bridged bis-(6-chloropurines) and related compounds

Two bis-(6-chloropurines) bridged by conformationally restricted tethers were synthesized as potential DNA bis-intercalating agents. Reduction of 4,6-dichloro-5-nitropyrimidine ( 1 ) afforded 5-amino-4,6-dichloropyrimidine ( 2 ) which was then used as the starting material. Reaction of 2 with 4,4′-diaminodiphenylmethane ( 3 ) and bis-(4-aminophenyl) ether ( 4 ) yielded bis-[4-(N-5-amino-4-chloro-6-pyrimidyl)aminophenyl]methane ( 5 ) and bis-[4-(N-5-amino-4-chloro-6-pyrimidyl)aminophenyl] ether ( 6 ), respectively. Acid-catalyzed condensation of the above pyrimidines, 5 and 6 , with triethyl orthoformate in N,N-dimethylacetamide gave bis-[4-(6-chloro-9-purinyl)phenyl]methane ( 7 ) and bis-[4-(6-chloro-9-purinyl)phenyl] ether ( 8 ). The spectral data on the new compounds will be discussed.     

A Convenient Synthesis of 1-(Dichloro-Pyrimidinyl Carbamyloxy) Alkyl Phosphonates

Abstract

In the study of the nucleophilic addtion reaction of dialkyl I-hydroxyphosphonate and dichloropyrimidinyl isocyanate. We found this reaction was a convenient way for the synthesis of 1-(substituted carbamy1oxy)alkyl phosphonatc derivative. Dialkyl 1 - hydroxyphos-phonate can be easily prepared by addtion of dialkylphosphitc to carbonyl compounds. 4,6-dicloro-2-isocyanato pyrimidine can be synthesized by the reaction of oxalyl chloride and 2-amino-4,6-dichloropyrimidine which can be obtained from 2-amino-4,6-dihydroxy pyrimidine.     

Synthesis of acyclic nucleoside analogs of 6-substituted 2-aminopurines and 2-amino-8-azapurines

Several new acyclonucleoside purine and 8-azapurine analogs have been prepared from 2-amino-4,6-dichloropyrimidine ( 1 ) and 3-amino-1,2-propanediol ( 2a ) and 4-amino-1-butanol ( 2b ), respectively, as the starting materials. The new target compounds are: 2-amino-6-chloro-9-(2,3-dihydroxypropyl)purine ( 6a ), 2-amino-6-chloro-9-(4-hydroxybutyl)purine ( 6b ), 2-amino-6-chloro-9-(2,3-dihydroxypropyl)-8-azapurine ( 7a ), 2-amino-6-chloro-9-(4-hydroxybutyl)-8-azapurine ( 7b ), 9-(2,3-dihydroxypropyl)-8-azaguanine ( 8a ), 9-(4-hydroxybutyl)-8-azaguanine ( 8b ), 9-(2,3-dihydroxypropyl)-8-azathioguanine ( 9a ), and 9-(4-hydroxybutyl)-8-azathioguanine ( 9b ). Also, the requisite intermediate pyrimidine derivatives, 2,5-diamino-4-(2,3-dihydroxypropylamino)-6-chloropyrimidine ( 5a ) and 2,5-diamino-4-(4-hydroxybutylamino)-6-chloropyrimidine ( 5b ) are novel.     

An efficient synthesis of cytostatic mono and bis-alkynylpyrimidine derivatives by the Sonogashira cross-coupling reactions of 2,4-diamino-6-iodopyrimidine and 2-amino-4,6-dichloropyrimidine

A series of 6-alkynyl-2,4-diaminopyrimidine derivatives bearing various substituents at alkynyl moiety was prepared by the Sonogashira cross-coupling reaction of 2,4-diamino-6-iodopyrimidine using Pd(PPh₃)₂Cl₂ as catalyst. The same reaction was applied to 2-amino-4,6-dichloropyrimidine. This compound on reaction with 1 equiv. of alkyne gave 6-alkynyl-2-amino-4-chloropyrimidine derivatives as main products, while reaction with three equivalents of alkyne afforded predominantly 4,6-bis-alkynyl-2-aminopyrimidines. Some of the resulting alkynyl pyrimidines showed considerable cytostatic activity.     

N-(4-Pyrimidyl)ethylamine derivatives

In order to find antitumoral agents, a number of new N-(4-pyrimidyl) ethylamine derivatives have been synthesized from 4,6-dichloropyrimidine, 6-amino-4-chloropyrimidine, 4-chloro-6-hydroxypyrimidine, and various ethylamines substituted in the position.     

2,4,6-Trichloropyrimidine. Reaction with sodium amide

The first reaction between 2,4,6-trichloropyrimidine 1 and anionic nitrogen nucleophiles is described. Treatment of 1 with one equivalent of sodium amide gave mixtures of 4-amino-2,6-dichloropyrimidine 2 and 2-amino-4,6-dichloropyrimidine 3 . Additional quantities of sodium amide failed to provide either diamino- or triaminopyrimidines. Instead, the strongly basic nature of sodium amide led to higher molecular products that were not characterized.     

Amination of 4,6- and 2,4-dichloropyrimidines with polyamines

Amination of a double excess of 4,6-dichloropyrimidine with various diamines in the presence of cesium carbonate in boiling dioxane quantitatively afforded the corresponding N,N′-bis(6-chloropyrimidin-4-yl) derivatives, while its reactions with tri- and tetraamines gave N,N′,N″-tris- and N,N′,N″,N‴-tetrakis(6-chloropyrimidin-4-yl) derivatives. Equimolar amounts of 2,4-dichloro- or 4,6-dichloropyrimidine and diamines reacted in the presence of Pd(0) complexes to form macrocyclic compounds containing pyrimidine fragments. Catalytic reactions of 4 equiv of diamines with 4,6-dichloropyrimidine can lead to the formation of 4,6-bis-(diamino)pyrimidines. Relations between the yield and the nature of diamine and catalytic system were found.     

Reaktionen des 4,6-Dichlor-5-formylpyrimidins

Zusammenfassung Bei der Methanolyse des 4,6-Dichlor-5-formylpyrimidins (I) tritt neben dem 4,6-Dimethoxy-5-formylpyrimidin (III) auch das 4-Methoxy-6-hydroxy-5-formylpyrimidin (IV) als Reaktionsprodukt [in Verhältnis 11] auf. Das Aldoxim V des 4,6-Dichlor-5-formylpyrimidins ist instabil und geht in das 4-Chlor-5-cyano-6-hydroxypyrimidin (VI) über. Beide Reaktionen werden mit Hilfe möglicher Zwischenprodukte erklärt. Hingegen führt Methanolyse des Dimethylacetals von I in guter Ausbeute zum 4,6-Dimethoxy-5-formylpyrimidin (III). Das 4,6-Dichlordimethylacetal (II) wird durch aufeinanderfolgende Sulfanilamidolyse, Methanolyse und Hydrolyse in das Acetal des 4-Sulfanilamido-6-methoxy-5-formylpyrimidins (IX) verwandelt. Die gleiche Reaktionsfolge wird auch mit dem cyclischen Acetal 5-(2-Dioxolano)-4,6-dichlorpyrimidin zu XII durchgeführt.

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During methanolysis of 4.6-dichloro-5-formylpyrimidine (I) 4-methoxy-6-hydroxy-5-formylpyrimidine (IV) is formed as well as 4,6-dimethoxy-5-formylpyrimidine (III) in a ratio of 11. The aldoxime V of 4,6-dichloro-5-formylpyrimidine is not stable and is converted into 4-chloro-5-cyano-6-hydroxypyrimidine (VI). Both reactions are interpreted by considering possible intermediates. On the other hand, methanolysis of the dimethylacetal of I affords a good yield of 4,6-dimethoxy-5-formylpyrimidine (III). The 4,6-dichlorodimethylacetal (II) is converted into the acetal of 4-sulfanilamido-6-methoxy-5-formylpyrimidine (IX) by sulfanilamidolysis followed by methanolysis and hydrolysis. The same series of reactions has also been applied to the cyclic acetal of 5-(2-dioxolano)-4,6-dichloropyrimidine to give XII.

     

Studies on the Synthesis of New 3-(3,5-Diamino-1-substituted-pyrazol-4-yl)azo-thieno[2,3-b]pyridines and 3-(2-Amino-5,7-disubstituted-pyrazolo[1,5-a]pyrimidine-3-yl)azothieno[2,3-b]pyridines

Coupling the diazonium salt of 3-amino-2-cyano-4,6-dimethylthieno[2,3-b]pyridine 1 with malononitrile 2 gave 2-cyano-3-(hydrazonomalononitrile)-4,6-dimethylthieno[2,3-b]pyridine 3 which then reacted with hydrazine compounds 4a-4h to yield corresponding 2-cyano-3-(3,5-diamino-1-substituted-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 5a-5h. The 2-cyano-3-(2-amino-5,7-disubstituted-pyrazolo-[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 7a-7f were obtained in good yield by the cyclocondensation reaction of 2-cyano-3-(3,5-diamino-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridine 5a with the appropriate 1,3-diketones 6a-6f under acidic condition.     

5-Pyrimidylboronic acid and 2-methoxy-5-pyrimidylboronic acid: new heteroarylpyrimidine derivatives via Suzuki cross-coupling reactions

5-Pyrimidylboronic acid and 2-methoxy-5-pyrimidylboronic acid 4 have been synthesised by lithium-halogen exchange reactions on 5-bromopyrimidine and 2-methoxy-5-bromopyrimidine, respectively, followed by reaction with triisopropylborate. Suzuki cross-coupling reactions of 2 and 4 with heteroaryl halides [Na(2)CO(3), Pd(PPh(3))(2)Cl(2), 1,4-dioxane, 95 degrees C] yield heteroarylpyrimidines (heteroaryl = thienyl, quinolyl and pyrimidyl). Two-fold reaction of 2 with 4,6-dichloropyrimidine 12 gave 4,6-bis(5-pyrimidyl)pyrimidine 8(56% yield). Reaction of 4,6-dichloropyrimidine with 2-methoxy-5-pyridylboronic acid gave 4,6-bis(2-methoxy-5-pyridyl)pyrimidine 14 (84% yield). Conversion of into 4,6-bis(2-chloro-5-pyridyl)pyrimidine 15 (63% yield) followed by two-fold Suzuki reaction with 4-tert-butylbenzeneboronic acid gave the penta-arylene derivative 4,6-bis[2-(4-tert-butyl)phenyl-5-pyridyl]pyrimidine 16 (16% yield). Analogous reaction of 12 with 2-methoxy-3-pyridylboronic acid 17 gave 4,6-bis(2-methoxy-3-pyridyl)pyrimidine 18 (64% yield). The X-ray crystal structures of compound 2.0.5H(2)O and compound 18 are reported. The two hydroxyl H atoms in 2 have the usual exo-endo orientation. However, unlike most arylboronic acids, molecule 2 does not form a centrosymmetric hydrogen-bonded dimer. In molecule 18, the pyridine rings form dihedral angles of 39.9 degrees and 22.8 degrees with the central pyrimidine ring.     

Synthesis of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione and its reactions with C-electrophiles

4-Amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-trazole-3-thione is formed from the reaction of 4,6-diphenylpyrimidinecarboxylic acid or its ethyl ester with thiocarbonyl hydrazide. Alkylation of the product leads to S-alkyl derivaties or 6-substituted 3-(4,6-diphenyl-2-pyriimidinyl)-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine. Acetylation of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione gave under different conditions monoacetyl-, diacetyl, and triacetyl derivatives at the amino group and the N₍₂₎ atom, whereas benzoylation gave a benzoyl group at the amino group and 3-(4,6-diphenyl-2-pyrimidinyl)-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1088–1094, July, 2007.     

Synthesis of oxepane ring containing monocyclic, conformationally restricted bicyclic and spirocyclic nucleosides from D-glucose: a cycloaddition approach

Carbohydrate-derived substrates having (i) C-5 nitrone and C-3-O-allyl, (ii) C-4 vinyl and a C-3-O-tethered nitrone, and (iii) C-5 nitrone and C-4-allyloxymethyl generated tetracyclic isoxazolidinooxepane/-pyran ring systems upon intramolecular nitrone cycloaddition reactions. Deprotection of the 1,2-acetonides of these derivatives followed by introduction of uracil base via Vorbrüggen reaction condition and cleavage of the isooxazolidine rings as well as of benzyl groups by transfer hydrogenolysis yielded an oxepane ring containing bicyclic and spirocyclic nucleosides. The corresponding oxepane based nucleoside analogues were prepared by cleavage of isoxazolidine and furanose rings, coupling of the generated amino functionalities with 5-amino-4,6-dichloropyrimidine, cyclization to purine rings, and finally aminolysis.     

Study of Nitrogen- and Sulfur-Containing Heterocycles. 57. Synthesis and Conversion of 4′-Substituted 5-(5-Amino-6-Pyrimidylthio)-2,2-Dimethyl-4,6-Dioxo-1,3-Dioxanes

By reaction of 4-substituted 5-amino-6-mercaptopyrimidines with 5-bromo-2,2-dimethyl-4,6-dioxo-1,3-dioxane, we have obtained 4′-substituted 5-(5-amino-6-pyrimidylthio)-2,2-dimethyl-4,6-dioxo-1,3-dioxanes. We have studied diazotization of these compounds by isoamyl nitrite. In the case of 4′-methoxy- and 4′-dimethylamino-substituted derivatives, we have obtained derivatives of novel heterocyclic systems: pyrimido[5,4-e][1,3,4]thiadiazine and pyrimido[5,4-e][1,3,4]thiadiazine-7-spiro-5′-1,3-dioxane, and in the case of the 4′-isopropylamino-substituted derivative we obtained 4-isopropyl-7-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-1,2,3-triazolo[5,4-d]pyrimidin-7-ylidene.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 613–623, April, 2005.     

Synthesis of derivatives of 5-amino-7-oxo(6h)-1,3-dithiolo[4,5-d]pyrimidine on the basis of 2-amino-(1h,5h)pyrimidine-4,6-dione

The betaine of 2-amino-5-phenyliodonio(1H,5H)pyrimidine-4,6-dione, upon interaction with sodium diethyldithiocarbamate, forms the previously unknown 2-amino-5-diethylaminothiocarbonylthio (1H,5H)pyrimidine-4,6-dione, the cyclization of which in concentrated sulfuric acid leads to salts of 2-diethylimmonio-5-amino(6H)-1,3-dithiolo[4,5-d]pyrimidin-7-one — a new heterocyclic system. The salts serve as the starting material for obtaining 5-amino-7-oxo(6H)-1,3-dithiolo[4,5-d]pyrimidine-2-selenone and -2-thione.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1117–1121, August, 1992.     

Synthesis of 6-amino-4-aryl-5-cyano-3-(3-cyanopyridin-2-ylthiomethyl)-2,4-dihydropyrano[2,3-c]pyrazoles and their hydrogenated analogs. Molecular structure of 6-amino-5-cyano-3-(3-cyano-4,6-dimethylpyridin-2-ylthiomethyl)-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole

Substituted 3-hydroxypyrazoles, which were prepared based on ethyl esters of substituted 4-(pyridin-2-ylthio)- or 4-(1,4-dihydropyridin-2-ylthio)acetoacetic acids and hydrazine hydrate, were used in the synthesis of 6-amino-4-aryl-5-cyano-3-(pyridin-2-ylthiomethyl)-2,4-dihydropyrano[2,3-c]pyrazoles. The molecular and crystal structure of 6-amino-5-cyano-3-(3-cyano-4,6-dimethylpyridin-2-ylthiomethyl)-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole was established by X-ray diffraction analysis.     

Derivatives of n-(pyrimid-4-yl)ethylamine

In order to find compounds possessing antibacterial activity, a number of new derivatives of N-(pyrimid-4-yl)ethylamine have been synthesized from 5-amino-4, 6-dichloropyrimidine, 2-amino-4, 6-dichloro-pyrimidine, 4, 6-dichloro-2-phenylpyrimidine, and 2,4-dichloro-6-methylpyrimidine and various ethylamines substituted in the -position. Several derivatives of 4-(4-methylpiperazinyl)pyrimidine have also been obtained. Results of a biological study of the compounds obtained are presented.For part II, see ¦1¦.     

Synthesis of New 2-[(Substituted-pyrazol-1-yl)carbonyl]-thieno[2,3b]pyridine Derivatives Using 1,3-Diketones,Alkylethoxymethylenes and Ketene Dithioacetals

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate 1,3-diketones 2a-2d in glacial acetic acid afforded 3-amino-2-[(3,5-disubstituted-pyrazo)-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d. 3-Amino-2-[(5-amino-3,4-disubstituted-pyrazol-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 5a-5h were also prepared by treatment of carbohydrazide 1 with appropriate alkylethoxymethylenes and ketene dithioacetals 4a-4h , respectively.     

Pyrazolo[3,4-b]pyridines. I. Xanthine and isoguanine analogs derived from 1-methylpyrazolo[3,4-b]pyridine

The synthesis of 4,6-dihydroxy-l-methylpyrazolo[3,4-b Jpyridine ( 2 ) and 4-amino-6-hydroxy-1-methylpyrazolo[3,4-b] pyridine ( 3 ) as analogs of xanthine and isoguanine has been accomplished from ethyl 5-amino-1-methylpyrazole-4-carboxylate ( 4 ) and 5-amino-1-methylpyrazole-4-carbo-nitrile ( 6 ), respectively.     

An efficient and regiospecific strategy to N7-substituted purines and its application to a library of trisubstituted purines

A regiospecific strategy for the preparation of N(7)-substituted purines in an efficient manner was devised. This approach to 6,7,8-trisubstituted purines relies on the cyclization reactions of suitably substituted pyrimidines (1) with either a carboxylic acid or an aldehyde. The method development for the five-step synthetic strategy outlined here was completed using 5-amino-4,6-dichloropyrimidine (4) as the starting material. The utility of this methodology was demonstrated through the preparation of a 40-membered library of 6,7,8-trisubstituted purines (3) in good yields and high purity.