Pyrimidine 2-mercapto- from

According to the systematic nomenclature these substances were first named l-f-triazolo[d] pyrimidines in compliance with the general principles of the Ring Index/ More recent papers and Chemical Abstracts indexes use the term i -triazolo[4,5-d]pyrimidine (147) in accord with the lUPAC nomenclature. The numbering of substituents when using the last-mentioned name is different from that of the 8-aza analogs. For the formulas of oxygen and sulfur derivatives names derived from the lactim or thiolactim form are almost exclusively in use (in common with the purine derivatives). These derivatives are thus described as hydroxy and mercapto derivatives, respectively. The name 1,2,3,4,6-pentaazaindene is used only rarely for this system. 

The synthesis of 2-substituted pyrimidines from 1,3-dicarbonyl compounds and urea derivatives was first described by Evans2 and was later improved by Hunt, McOmie, and Sayer3 for the preparation of 2-mercapto-4,6-dimethylpyrimidine. Burness4 employed 3-ketobutyraldehyde acetal in this procedure to give 2-mercapto-4-methylpyrimidine. 2-Mercaptopyrimidine has been prepared from 1,1,3,3-tetraethoxypropane and thiourea by variations of this basic method 3 6 6 as well as by the reaction of 2-chloropyrimidine with thiourea 1 or sodium hydrosulfide.8... 

This preparation describes a convenient and general method of synthesis of substituted pyrimidines from compounds containing a /3-dicarbonyl group, either intact or as the corresponding ketal. The usefulness of the 2-mercaptopyrimidines is enhanced by the ease of removal of the mercapto group by desulfurization 9 or oxidation 10 and its replacement by other functional groups.1 ... 

Abstract This presentation is a brief review on the resnlts of our work on iodine interaction with thioamides, selenoamides and amides. The thioamides, benzothia-zole-2-thione (BZT) (1), 6-n-propyl-2-thiouracil (PTU) (2), 5-chloro-2-mercap-tobenzothiazole (CMBZT) (3), N-methyl-benzothiazole-2-thione (NMBZT) (4), benzimidazole-2-thione (BZIM) (5), thiazolidine-2-thione (TZD) (6), 2-mercapto-pyridine (PYSH) (7), 2-mercapto-nicotinic acid (MNA) (8), 2-mercapto-benzoic acid (MBA) (9) and 2-mercapto-pyrimidine (PMT) (10) react with producing three type of complexes of formulae [(HL)IJ(l2) (HL= thioamide and n= 0, 1), [(HL) [I3 ] and [(HL-L)]+[l3 ]. The interaction of seleno-amides, derived from, 6-n-propyl-2-thiouracil (RSelJ) (R= Me- (11), Et- (12), n-Pr- (13) and i-Pr- (14)) with I, have also been studied and produced the complexes [(RSeU)IJ of spoke structure. These complexes are stable in non-polar solvents, but they decompose in polar solvents, producing dimeric diselenide compounds or undertake deselenation. 

The mixture is cooled to 25°, and the crystalline 2-mercapto-4-amino-5-carbethoxypyrimidine is collected on a 10-cm. Buchner funnel and washed successively with five 50-ml. portions of water, 50 ml. of acetone, and 50 ml. of ether (Note 2). The carbethoxy-pyrimidine weighs 152-159 g. (76-80%) and melts with decomposition at 259-260° (Note 3) after being dried for 5 hours at 110° and atmospheric pressure. It is in the form of a cream-colored powder that is sufficiently pure for synthetic purposes. Pure carbethoxypyrimidine can be obtained by recrystallizing the crude product once from 50% acetic acid, using 170 ml. per gram of pyrimidine. 

B. 2-Mercapto-4-hydroxy-5-cyanopyrimidine. The aqueous filtrate from which the crude 2-mercapto-4-amino-5-carbethoxy-pyrimidine separated is cooled overnight at 0°, and the cyano-pyrimidine that precipitates is collected on a suction filter. The crude product is recrystallized from about 200 ml. of 10% acetic acid with 1 g. of decolorizing charcoal added. Two additional recrystallizations done similarly give the pure cyanopyrimidine as faintly yellow crystals, m.p. 265-272° (dec.) (Note 3). The yield is 10-18 g. (7-12%). 

The 2-amino group of 4-oxo-4//-pyrido[l,2-c ]pyrimidines can be transformed to a hydroxy group by sodium nitrite in concentrated sulfuric acid at 0 C.25 5 The 2-hydroxy group can be formed from the 2-mercapto group by treatment with 3" hydrogen peroxide in 1 N potassium hydroxide.167... 

Substituted 2-mercapto-4//-pyrido[l,2-a]pyrimidin-4-ones 121 were prepared by the cyclization of thioamides 120, prepared from 2-pyridyl-isothiocyanate and the appropriate CH acids, in boiling ethanol by the action of sodium ethylate (81CCC2428). 

The mercapto group of 9-mercapto-4//-pyrido[ 1,2-a]pyrimidin-4-ones 513 was alkylated with (het)aralkyl bromides and chlorides in the presence of potassium carbonate in dimethylformamide at ambient temperature for several hours. It also was acylated with carboxyl chlorides in the presence of potassium carbonate in acetone at room temperature or with mixed anhydride, prepared from aryl carboxylic acid and ethyl chloroformate,... 

Ethyl 9-mercapto-4-oxo-4//-pyrido[l, 2-a]pyrimidine-3-carboxylate 513 (R1 = COOEt, R2 = H) was also prepared from disulfide 136 in 54% yield (Scheme 31) (89EUP329126). 

A number of 5- and 7-monosubstituted and 5,7-disubstituted [l,2,4]triazolo[l,5-a]pyrimidines have resulted from reactions on the 5,7-dihydroxy, -aminohydroxy and -hydroxymercapto derivatives. The hydroxy derivatives were amenable to chlorination which was followed by a variety of nucleophilic substitution reactions or hydrogenolyses. The mercapto groups were susceptible to alkylation and subsequent nucleophilic substitution (61CPB801,63CPB845). 

The Traube synthesis has proved to be compatible with many kinds of groups in the starting pyrimidine (R and R in 60), even with the thioxo (mercapto) and primary amino groups. Pyrimidine iV-oxides are also acceptable.Moreover, 8-azapurines with substitutents in the usually difficult 1 and 3 positions have been formed by Traube reactions (refs. 150 and 151, respectively). 2-Pyrimidyl-8-azapurines have also been produced in this way. The Traube reaction permitted amino-acid substituents (as R in 60) to retain full optical purity. Radioactive labeling survived well when a diaminopyrimidine, made in five steps from diethyl malonate-7- C, was cyclized. ... 

Thymine. S-Methyt-2,4(IHt3H)-pyritnidinedione 5 -metbyluracil 2,4 -dihydroxy - 5 -methylpyrimidine. C,H4 -N202 mol wt 126.11. C 47.62%, H 4.80%, N 22.22%, O 25.37%. A pyrimidine derivative constituent of nucleic acids. Originally isolated from thymus nucleic acid Levene, Z. Physiol Chem. 39, 4 (1903). Prepn by heating 2-ethyl-mercapto-4-hydroxy-5-methyl pyrimidine Wheeler, Mer-... 

Mercapto-6-methyl-7-phenylpyrido[2,3- /]pyrimidin-4-ol (6 g m.p. 240-242°) is dissolved in 95% ethanol (1.81) and concentrated aqueous ammonia (150 ml). Raney nickel (18-20 g) is added and the reaction mixture is boiled for 6 h under reflux on the water-bath. Then the catalyst is filtered off and washed with boiling 95 % ethanol (300 ml). The united filtrates are concentrated in a vacuum to 100 ml and the pH is adjusted to 5 by dilute acetic acid. On cooling, white needles separate, having m.p. 245-248° which is raised to 248-250° by re-crystallization from aqueous ethanol. 

Pyrimidine-fused Systems. - Starting from 5-allyl-6-mercapto-... 

Decreased activation of prodrugs Resistance to the purine antimetabolites (mercapto-purine, thioguanine) and the pyrimidine antimetabolites (cytarabine, fluorouradl) can result from a decrease in the activity of the tumor cell enzymes needed to convert these prodrugs to their cytotoxic metabolites. 

Mercapto pyrimidines 82 were synthesized from acetoacetanilide, dihydroxybenzaldehyde, and thiourea, which were readily alkylated with benzyl chloride to afford 2-benzylthio derivatives 83 (Scheme 32). 83 when reacted with different amines in acetic acid furnished 2-amino derivatives 84 (R = Ar), whereas upon reaction with hydrazine hydrate 83 afforded 2-hydrazinyl derivative 84 (R = NH2), which with different aldehydes gave hydrazones 85 (R = 2-furyl, 2-thienyl). Arylidene thiazolidinone 86 was obtained from 84 with carbon disulfide, monochloroacetic acid, and aryl aldehydes, while 84 with ethyl acetoacetate and different aromatic aldehydes provided pyrazoles 87 (Scheme 32) (10MI9). Such tetrasubstituted pyrimidines act as cyclin-dependent kinase (CDK2) inhibitors. 

An example of application of this reaction employing NH OAc as a source of ammonia is depicted in Scheme 12.3. It is a key step in the preparation of a pyrimidine-imidazole-based library, where their biological activities were under study [7-9]. Thus, using glyoxal dimethyl acetal 11, ammonium acetate, and the required asymmetrical 1,2-diketone 10, prepared from 4-fluorobenzoate 9 and 2-mercapto-4-methylpyrimidine 8, the key intermediate 12 was obtained in good yield (86%). 

The molecular weights of the products were within the range of 10 to 10 Da. The product of triphenylantimony dichloride and 4,6-diamino-2-mercapto pyrimidine has a molecular weight of 5.7 x 10 corresponding to a DP of about 1,200. The product from triphenylantimony dichloride and 4,4-diaminodiphenylsulfon is only oligomeric with a molecular weight of 3 x 10 Da corresponding to a DP of 10. 

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