Diaminopyrimidine derivatives

Diaminopyrimidine derivatives (180) were reacted with EMME in boiling ethanol for 30 min, or by heating in DMF for 15-20 min, to give N-(4-amino-5-pyrimidinyl)aminomethylenemalonates (181) in 44-49% yields (68AF1214). 

Trimethoprim is a diaminopyrimidine derivative. It is reasonably basic (p/fa 7.2) and we should remember here that amino substituents are able to utilize their lone pairs and provide resonance stabilization to a conjugate acid. Consequently, aminopyrimidines protonate on a ring nitrogen. If we consider protonation of the two ring nitrogens separately, and then think about potential resonance stabilization, we can predict the site of protonation. 

Baquiloprim is a diaminopyrimidine derivative acting synergistically with sulfonamides (221). In cattle, it is used orally, intravenously, or intramuscularly for treatment of mastitis and infections of the respiratory and gastrointestinal tract, whereas, in swine, it is administered intramuscularly for treatment of the mastitis-metritis-agalactia syndrome and infections of the respiratory and gastrointestinal tract. 

Reduction of tetrazolo[ 1,5- >]pyridazine (274) by sodium borohydride results in the partial reduction of the pyridazine moiety (tetrahydro compound 275 was formed) (76JHC835). The catalytic reduction of the substituted tetrazolo[ 1,5- >]pyrimidine (276) afforded the diaminopyrimidine derivative (277) (85MIP155606). 

Tetroxoprim is another 2,4-diaminopyrimidine derivative with comparable actions to those of trimethoprim. It is exclusively used in combinations with sulfonamides. 

Small-molecule diaminopyrimidine derivatives were shown in 1948 to have an antifolate action. Subsequently, compounds were developed that were highly active against human cells (e.g. the use of methotrexate as an anticancer agent), protozoa... 

Several heterocyclic derivatives have been elaborated from the 6-bromo-6-cyanohex-5-enose (447). For example, the ( )- and (Z)-isomers of (447) reacted with benzylamine to give the cis- and rm j-aziridines (448), respectively, and with guanidine in an alkaline medium to give the diaminopyrimidine derivative... 

A novel type of ring closure is the reaction of 6-amino-5-dichloroacetylaminopyrimidines (285) with sulfur and morpholine under the conditions of a Kindler reaction (B-64MI21605). 7-Morpholinopteridin-6-ones (287) are formed, either via thiooxamide derivatives (286) or via corresponding 7,8-dihydropteridines (284 equation 102). Chloral hydrate also reacts with 2-substituted 5,6-diaminopyrimidin-4-ones to form pteridin-6-ones (56JCS3311, 64JCS565) by a so far unknown mechanism. 

The mechanism of cyclization of diaminopyrimidines by nitrous acid appears not to have been studied in detail. For the preparative procedure an aqueous solution of alkaline nitrite is treated with the diaminopyrimidine either in the form of a salt or with simultaneous addition of hydrochloric or acetic acid. The first phase of the reaction is usually carried out at 0°C, in some cases the reaction being terminated by heating to 50-60°C. With diaminopyrimidines which are sparingly soluble in water, the reaction was carried out in an organic solvent using amylnitrite. Excess nitrous acid can possibly attack the amino groups present. This was employed in some cases for the preparation of the hydroxy derivatives. ... 

Iodopyrimidine 7 was prepared by iodination of 2,4-diaminopyrimidine 6, which was derived from commercially available 2-amino-4-chloro-6-methylpyrimidine (5) via an SNAr reaction with ammonia [8]. Similarly, iodination of 6-chloro-2,4-dimethoxypyrimidine (8) with N-iodosuccinimide in trifluoroacetic acid led to dihalopyrimidine 9 [9],... 

The basic ionization constants of a large number of 2,4-diaminopyrimidines and condensed pyrimidine derivatives have recently been measured and earlier values verified (Roth and Strelitz, 1969). The first protonation occurs at the N-1 ring atom (pAT = 7 40) and the effect of 5-substituents is correlated quite well with -constants for the -t-M substituents (p = 4 85). The —M substituents (—NO2, —CN) show an enhanced base-weakening effect, which may be accounted for in terms of the direct conjugation shown in [65]. This provides additional evidence for protonation at N-1. 

Dealing with the synthesis of dihydropyridopyrimidinones, the procedure was quite similar to the precedent, involving 2,6-diaminopyrimidin-4(3//)-one as enaminocarbonyl partner, various 1,3-dicarbonyl derivatives, and either aliphatic or aromatic aldehydes in water under microwave irradiations (Scheme 11). Interestingly, the guanidine system was unreactive, and a library of tri- and tetracyclic dihydropyridopyrimidinone derivatives was chemoselectively synthesized in high yields and short reaction times from this environmentally friendly procedure. 

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