Pyrimidine-fused Systems

Pyrimidine-fused Systems. - Owing to their pharmaceutical interest, many new thienopyrimidine derivatives are still being synthesized. The reaction of 2-amino-3-cyanothiophens with carbonyl sulphide has been used for the preparation of thieno[2,3-c/j-2-thio-oxopyrimidine. The reaction of 2,5-diamino-3,4-diethoxycarbonylthiophen with phenyl isocyanate in the presence 

A series of compounds of the type (296) has been prepared from 2-amino- 

Pyrimidine-fused Systems.—The Gewald synthesis of thiophen analogues of anthranilic acid has opened the synthetic route to pyrimidine-fused thiophens. The interest in this field is mainly due to the potential pharmacological properties of these systems. Condensation of (603) with forma-mide at 200 °C yields (604). Similarly, (605) was prepared from 3-amino-2-methoxycarbonylthiophen or from its formamide derivative. Derivatives of (604) were also obtained by cyclization of the 2-amino-3-carboxamide 

An alternative synthesis under much milder conditions consists of the reaction of (603) with dimethylformamide chloride, yielding (606), which 

Lecomte, and M. Cugnon de S6vricourt, Bull. Soc. chim. France, 

Csiirds, R. Soos, J. Palink s, and I. Bitter, Acta Chim. Acad. Sci. Hung., 1971, 68, 

Gronowitz, J. Fortea-Laguna, S. Ross, B. Sjoberg, and N. E. Stjemstrom, Acta 

Pyrimidine-fused Systems.—o-Aminothiophencarboxylic acid derivatives have been extensively used for the synthesis of thienopyrimidine derivatives. Thus the mercapto-derivatives (464) have been synthesized by 

The demethyl derivative of (466 n = 1) has been transformed into aromatic thienopyrimidine and derivatives. From 3-amino-2-ethoxycarbonylbenzo-[b]thiophen through reaction with formamide, (472) was obtained, which 

Cugnon de Sevricourt, and J.-M. Lecomte, J. Heterocyclic Chem., 1975, 12, 

Thieno[2,3- /]pyrimidines have been synthesized from 5-acylamino-2,3-dialkylthiophen-4-aldehydes. 2-Amino-3-cyano-thiophens have been transformed into the 2-cyanamino-3-cyano-thiophens and ring-closed to 4-aminothieno[2,3- /]-pyrimidines. Ethyl 3-aminothieno[2,3-6]pyridine-2-carboxylate similarly gives (261), whose reactions have been studied. The thieno-pyrimidone (262) has been desulphurized by Raney nickel to the 4-oxo-pyrimidine (263).  

Sauter and co-workers have reported extensive studies on thienopyrimidines to which additional heterocyclic rings, e.g. the thiazolo- or triazolo-ring, have been fused. Compounds such as (264), (265), (266), (267), and (268) have thus been prepared. 

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The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

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

Pyrimidine-fused Systems.—Starting from the corresponding 2-amino-3-cyanothiophen, (194) has been prepared. Compounds such as (195) have been transformed into (196) and further derivatives of this system. 

Given the extensive presence of the pyrimidine ring in numerous compounds of medicinal value, this chapter will primarily focus on the contemporary methods to construct pyrimidine rings and pyrimidine-fused systems. In addition, the syntheses of a few commercial drugs are discussed to showcase the preparations of pyrimidines in industrial settings. 

Pyrimidines from purines and related fused systems... 

All four possible pyridopyrimidine systems, pyrido[2,3-Chemical Abstracts nomenclature is used throughout this Chapter. For the reasons given above (Section 2.15.1), the pyrido[2,3-fused systems, e.g. (5) and (6) (numbering shown), are also known. The linear benzo fused derivatives of pyrido[3,2-[Pg.201]

Other C—C fused systems are also available by utilization of 1,4-dicarbonyl-type systems. The substituted pyrimidinethione (59) on treatment with polyphosphoric acid readily formed the thiazolo[5,4-d]pyrimidine system (60) without any of the alternative ring closure product (65JOC1916). 

The pyrazole analogues of anthranilic acids or anthranilonitriles are a convenient source of [5.6] fused systems (for a general review see (80T2359)). Thus 5-amino-4-cyanopyrazoles (in some examples an ester or a hydrazido group replaced the cyano group) have been transformed into pyrazolo[3,4-d]pyrimidines (552) and into pyrazolo[2,3-e]diazepinones (553), and 4-amino-5-methoxycarbonylpyrazoles have been converted into pyrazolo[4,3-d]pyrimidines (554). 

Pyrazoles can be prepared by ring opening reactions of fused systems already containing the pyrazole nucleus. Thus several [5.5], [5.6] and [5.7] fused heterocycles have been opened to substituted pyrazoles, usually in basic medium. In general, the method has little preparative interest since another pyrazole derivative has usually been used to build the ring-fused system. However, due to the unexpected structures obtained, two publications are worthy of notice. 6//-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine (638) was readily obtained from the corresponding pyrazolopyrimidine by the action of diazomethane at room temperature (Scheme 59) (81H(15)265). When (638) was treated with potassium hydroxide, the pyrazole (640) was formed, probably via the diazepine (639). 

In recent years, there has been a greater interest in joining certain heterocyclic systems to [60]-fullerene with pyrimidine-fused 3-sulfolenes as one such case. Three derivatives have been examined in membrane model environments and the aggregation of these derivatives has been studied <2000J(P2)301>. Similar studies have been carried out on furo[2,3- ]pyrimidines <1996JST(385)55>. 

Having a cyano group and an amino group ortho to each other on a ring is another system that has led to the formation of fused pyrimidine ring systems. In this case, an aminopyrimidine is the result. Compound 42 in Scheme 5 is one such structure. Treatment of 42a with formamide leads to the amino derivative 43 <1999PS(155)175>. Alternatively 42b provides 44 after treatment with triethyl orthoformate followed by hydrazine <1999PS(155)175>. 

Pyrido[2,3- pyrimidine bicyclic systems represent interesting fused heterocyclic compounds having pharmacological and biological properties. Their syntheses are well documented in the literature. The pyridine or pyrimidine rings have been used as precursors for constructing the second heterocyclic ring. 

A final approach to pyrimido[4,5-( ]pyridazines involves construction of a pyrimidine ring from a 3-aminopyridazine -carboxylic acid derivative as described in both CHEC(1984) and CHEC-II(1996) <1984CHEC(3)329, 1996CHEC-II(7)737>. Further examples of this approach have appeared since the publication of CHEC-II(1996) <2000JCCS951, 2006JHC243> and the approach has been used to prepare peri-fused systems (Scheme 20) <1993JRM1239>. 

A myriad of types of fused-ring pyrimidines derived from thioureas have been reported in the literature. For example, Howard and Lindsey387 reported the [l,3]-dithiino[5,4-d]pyrimidine ring system 223, and other workers made the octahydrobenzo[6]thieno[2,3-d]pyrimidirie 224 in 90% yield.388 The formation of both of these products was via a base-promoted condensation of a thiourea with a carbethoxy group however, in the former case the reaction was intermolecular and in the latter, intramolecular. Other unusual fused systems of this type have... 

Pyrimidines from pteridines and related fused systems 122... 

Biological pyrimidines, tautomerism and electronic structure of, 18, 199 Bipyridines, 35, 281 Boron-substituted heteroaromatic compounds, 46, 143 Bridgehead nitrogen saturated bicyclic 6/5 ring-fused systems with, 49, 193... 

The varied biological activity of coumarins fused with a benzopyrano pyrimidines ring system [1-6] has continued to stimulate a great deal of interest in the development of new methodologies for the synthesis of multi-substituted [ 1 ]benzopyranopyrimidines. 

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