Pyrimidine derivatives synthesis

The reaction product of 2-amino-4,6-diphenylpyridine-3-nitrile and ethyl acetoacetate was described by Jahine et al.32 as a 2-oxo-2//-pyrido[l,2-a]-pyrimidine derivative. Synthesis of 4-oxo-4f/-pyrido[l,2- ]pyrimidines (next section), however, makes the 4-oxo structure more likely. 

Pyrimidine derivatives, synthesis using ketene dithioacetals 89H-(29)1409. 

Chloromethyl heterocyclic intermediates, 0.1% petrolatum (risk of active sensitisation) (histamine antagonist synthesis) (Sonnex and Rycroft 1986) 5-(i-Chlorovinyl)-2,4-dichloropyrimidine, 1% aqua (pyrimidine derivative synthesis) (Hodgson 1980) Cistoran, 0.5% petrolatum (H2 antagonist synthesis) (Valsecchi et al. 1989)... 

A major type of reaction in this class is the cyclization of 4-amino- or 4-halo-pyrimidines carrying 5-cyanoethyl or 5-ethoxycarbonylethyl groups, which cyclize to 7-amino or 7-oxo derivatives of 5,6-dihydropyrido[2,3- f]pyrimidine, e.g. (131)->(63). The intermediates may sometimes be prepared by reaction of 4(6)-aminopyrimidines with acrylonitrile, or even via a pyrimidine ring synthesis from an amidine and a cyanoacetic ester or malononitrile derivative, e.g. (132) -> (133) (7lJOC2 85, 72BCJ1127). 

Examination of the pyrazino[2,3-rf]pyrimidine structure of pteridines reveals two principal pathways for the synthesis of this ring system, namely fusion of a pyrazine ring to a pyrimidine derivative, and annelation of a pyrimidine ring to a suitably substituted pyrazine derivative (equation 76). Since pyrimidines are more easily accessible the former pathway is of major importance. Less important methods include degradations of more complex substances and ring transformations of structurally related bicyclic nitrogen heterocycles. 

The condensation of 1,3-dicarbonyl compounds 1 with amidines 2 catalyzed by acids or bases to give pyrimidine derivatives 3 is regarded as the Pinner pyrimidine synthesis. ... 

For the preparation of triazolopyrimidines three main types of synthesis are in use. The first of these proceeds from a pyrimidine derivative (especially the 4,5-diamino derivatives) and closes the triazole ring. The second method proceeds, on the contrary, from derivatives of u-triazole to close the pyrimidine ring. The third method finally is one which yields the derivatives through substitution or replacement of substituents in compounds prepared by one of the first-named procedures. 

In a similar way, 1,3-dinitrogen systems such as diamines, amidines, guanidines, aminothiazoles, aminopyridines, ureas and thioureas react with alkynyl-carbene complexes generating the corresponding heterocycles. Of particular interest is the reaction with ureas, as the process can be applied to the easy synthesis of pyrimidine derivatives [88] (Scheme 41). 

Microwave-Promoted Synthesis of Bicyclic Pyrimidine Derivatives on Solid-Phase... 

As already described for the all-carbon-Diels-Alder reaction, a hetero-Diels-Alder reaction can also be followed by a retro-hetero-Diels-Alder reaction. This type of process, which has long been known, is especially useful for the synthesis of heterocyclic compounds. Sanchez and coworkers described the synthesis of 2-aminopyridines [48] and 2-glycosylaminopyridines 4-144 [49] by a hetero-Diels-Alder reaction of pyrimidines as 4-143 with dimethyl acetylenedicarboxylate followed by extrusion of methyl isocyanate to give the desired compounds (Scheme 4.30). This approach represents a new method for the synthesis of 2-aminopyridine nucleoside analogues. In addition to the pyridines 4-144, small amounts of pyrimidine derivatives are formed by a Michael-type addition. 

In an approach toward the synthesis of tetraponerine, Gevorgyan and co-workers explored the double pyrrolization of pyrimidine derivatives 276 via a copper-catalyzed cyclization to give tricycles 277 (Equation 76) <2002OL4697, 2004JOC5638>. 

Another important vitamin is folate, which is required for purine and pyrimidine nucleotide synthesis. Since folate and its derivatives are generally lipo-phobic anions, they do not traverse biological membranes via simple diffusion but rather have to be taken up into the cells by specific transport processes... 

The first example describes the synthesis of a pyrimidine derivative. Starting from a, 3-unsaturated ketones (see Schemes 1, 8), a library of different heterocycles was prepared in research (Felder and Marzinzik 1998). In preparation for any large-scale synthesis, the availability of starting materials is always considered (Lee and Robinson 1995). For this work, we had to replace Rink amide resin B (Rink 1987), which was used by our colleagues in research for the synthesis of pyrimidine 1 due to its unavailability in large quantities (see Fig. 1). It was replaced with the Rink amide acetamido resin 4, which is well established in peptide amide synthesis (Bernatowicz et al. 1989) and easily accessible. 

Scheme 3. Synthesis of the pyrimidine derivative in liquid phase...

In summary, we demonstrated the possibility of the fast scale-up of solid-phase supported synthesis. In one case (pyrimidine derivate), the research protocols could be used directly with only minor modifica-... 

Meisenbach M, Allmendinger T, Mak CP (2003) Scale-up of the synthesis of a pyrimidine derivative directly on solid support. Org Proc Res Dev 7 553-558... 

Table 18 Synthesis of [1,2,4]triazolo[4,3-c]pyrimidine derivatives by earlier recognized methods...

Reduction is used for carbonyl functionalities [71, 230] such as thioesters [231], amides [232], and carbamates [233], as well as for sulfur [234] and selenium [122] compounds. Recently, the synthesis of a potential carbohydrate vaccine is described via an reduction-oxidation sequence [235]. An efficient solid-phase synthesis of pyrimidine derivatives that involved reduction of the corresponding nitro derivatives was developed by Makara et al. in 2001 (Scheme 3.9) [236]. 

In MCRs involving aminoazoles and carbonyl compounds, Meldrum s acid can also be used as reagent. The comprehensive review of the application of Meldrum s acid in the synthesis of pyridine and pyrimidine derivatives including reactions with aminoazoles was recently published [113]. In this connection, further we give only few selected facts concerning positional selectivity of such reactions. 

Scheme 17 Synthesis of 4-aryl-2-cyanounino-3,4-dihydro-lH-pyrimidine derivatives...

Tu SJ, Cao LJ, Zhang Y, Shao QQ, Zhou DX, Li CM (2008) An efficient synthesis of pyrido 2,3-d pyrimidine derivatives and related compounds under ultrasound irradiation without catalyst. Ultrason Sonochem 15 217-221... 

Tu SJ, Zhang Y, Jiang H, Jiang B, Zhang JY, JiaRH, Shi F (2007) A simple synthesis of furo 3, 4 5,6 pyrido 2,3-d pyrimidine derivatives through multicomponent reactions in water. Eur J Org Chem 1522-1528... 

The lithiation of4-chloro-2,6-dimethoxypyrimidine has also been used in a synthesis of inhibitors of lumazine synthase <1999BML39, 1999JOC3838>, and other pyrimidine derivatives to be successfully lithiated and derivatized at the... 

New pyrazolo[l,5-a]pyrimidine derivatives have been synthesized. These compounds are potent angiotensin-ll receptor antagonists <99CPB928>. Pyrazolot3,4-ri]dihydropyridazinone derivatives have been obtained by the reaction of 5-methyl-4-methoxycarbonyl-3-acetyl-1-phenylpyrazole with different hydrazines <99TL3891>. A direct synthesis of pyrazolo [3,4-b]pyridines 69 from pyrazole 67 and benzothiazole 68, through a Friendlander condensation, has been described <99SC655>. 

The published work on the synthesis of this system involved the reaction of anthranilic acid with a reactive pyrimidine derivative. Thus, 4-chloropyrimidines (520) condense with 2-aminobenzaldehyde (47JCS726) or an anthranilic acid derivative [66T(S)227 68ZC103 89MI2] to give the pyrimido-[6,1 -b]quinazolines (521). 

Interaction of substituted dienediamines with ethylenediamine yields im-idazo[3,2-n]pyridine derivatives (95JHC477). 3-Arylaminoindoles, with distinct enamine properties, are the starting materials for the synthesis of indolo[3,2-b]quinoline derivatives [96KFZ(7)42]. a-Carboline derivatives can be obtained from enamine-based 3-dimethylamino-2-indolinones [96KFZ(9)35, 96KFZ(10)32], The synthesis and transformation of enamines based on the pyrido[l,2-n]pyrazine ring system into imidazo[l,2-n]pyridine and imidazo[l,2-a]pyrimidine derivatives have been reported... 

Other cycloadditions of interest include the photoaddition [Eq. (52)] of pyrimidine derivatives such as cytosine to the carcinogenic hydrocarbon benzo[a]pyrene,191 and the photoaddition of allene as a vital step [Eq. (53)] in the synthesis of an annotinine derivative.192... 

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