Pyrimido pyrimidine-6-carboxylates

Ethyl l-(arylimino)-l//-pyrido[l,2-c]pyrimidine-3-carboxylates exhibited anti-inflammatory activities in the carrageenan mouse paw edema model <2001JME1011>. 2-Arylimino-2,3,6,7-tetrahydro- <2000W020/058308> and 2-aryloxy-6,7-dihydro-477-pyrimido[6,l- ]isoquinolin-4-ones <2000W020/0558309> were patented as PDE inhibitors and as useful agents for treatment of respiratory disorders, respectively. 

Syntheses of pyrimido[l,2- ]pyrimidines by rearrangements have also been described. The 2-(pyrimidin-2-yl)isox-azol-4-carboxylate 191 was transformed by rearrangement and decarboxylation into the 2-ethoxy-pyrimido[l,2-4]-pyrimidine 192 by the action of NaOEt and subsequent acidification (Equation 18) <2004AJC577>. 

Reaction of 6-aminopyrimidines with 2 mol of a-ketoaldehyde in aqueous medium gave rise to the zwitterionic a-iminocarboxylic acids thus, 214 with methylglyoxal gave the pyrimido[l,6- ]pyrimidin-2-carboxylic acid 215 (Equation 26) <2005W02005/039589>. 

Mesoionic pyrimido[l,6- ]pyrimidine 94 exhibited platelet aggregation inhibitory activity <2000BMC1917>. 9-Nitro-hexahydropyrimido[l,6- ]pyrimidines of type 222 have arthropodicidal activity <1997WO97/05145>. The zwitterionic pyrimido[l,6- ]pyrimidine-2-carboxylic acid 215 and related compounds are CFTR channel modulators with potential use to treat mucoviscidosis, asthma or diarrhea <2005W02005/039589>. 

As shown in Scheme 199, the 5-aminopyrimidine stmcture may be also incorporated into a more complex bicyclic system. Thus, diazotization of 3-amino-4-oxo-4//-pyrimido[ 1,23 lpyndazincs 1198 followed by treatment with 50% aqueous tetrafluoroboric acid results in precipitation of salts 1199. When heated with alcohols, nucleophilic attack on the carbonyl group opens the pyrimidine ring. The obtained species 1200 assume conformation 1201 that is more suitable for bond formation between the opposite charged nitrogen atoms. Alkyl l-(pyridazin-3-yl)-l//-l,2,3-triazole-4-carboxylates 1202 are obtained in 31-66% yield <2002ARK(viii)143>. 

The cyclization of diethyl 2-pyrimidinylaminomethylenemalonate in boiling trichlorobenzene gave pyrimido[l, 2-a]pyrimidine-3-carboxylate in 19% yield (72JMC1203). The diethyl N-(4,6-dimethyl 2-pyrimidinylamino)-methylenemalonate could not be cyclized by heating in trichlorobenzene (72JMC1203). 

Matsumoto et al. unsuccessfully tried to isomerize pyrimido[l,6-a]-pyrimidine-6-carboxylate (1033, R = H, R1 = H, Me, pyrrolidine) thermally to the corresponding pyrido[2,3-[Pg.228]

Pyrimido[2,3-<7]pyrimidine-6-carboxylates (1043) were prepared in 28-85% yields on the cyclization of 4-pyrimidinylaminomethylenemalo-nates (54) by heating in boiling 1,2,4-trichloro- or 1,2-dichlorobenzene [87JAP(K) 142177]. 

The cyclization ofthe2-(4-methylpiperazinyl) derivative of1046 (R = 4-methyl-1 -piperaziny 1) afforded pyrimido[2,3-c/]pyrimidine-6-carboxylate (1047, R = 4-methyl-l-piperazinyl, R1 = Et) in 82% yield when it was heated in polyphosphoric acid at 140°C for 20 min (74GEP2341146). 

Bicyclic pyrimidin-4-ones (1100, R = H, n = 0-3 R = Me, n = 1) were also prepared from the appropriate lactim ether and EMME in the presence of ammonia or ammonium acetate [73JAP(K)34897 75MIP1]. Pyrimido[l,2-a]azepine-3-carboxylates (1100, R = H, Ph n = 2) were prepared in the reaction of 7-aminotetrahydro-2//-azepines (R = H, Ph n = 2) and EMME or in the reaction of O-methylcaprolactim and diethyl aminomethylenemalonate in ethanol [73JAP(K)34897 75MIP1]. 

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 variety of methods for the preparation of pyrimido[4,5-,7]pyridazines are discussed in CHEC(1984) < 1984CHEC(3)329> and CHEC-II(1996) <1996CHEC-II(7)737>, and most of the work that has appeared since describes adaptations of the earlier methods. Notable examples include the use of imide hydrazinolysis in a two-step construction of the ring system (Scheme 23) < 1996H(43)1597, 2002JHC571>. In addition, the reaction of 4-(halomethyl)pyrimidine-5-carboxylates with... 

Pyrimido[4,5-c][l,2]thiazines have been synthesized by formation of 4-(alkanesulfonamido)pyrimidine bearing an electrophilic substitutent at C-5, and cyclization of an anion generated adjacent to the sulfonamide. The 5-sub-stituent can be a ketone (Equation 171) <2003W003/062246>, or a carboxylate or nitrile, in which case the product contains a carbonyl group at C-4 (Scheme 89) <2002W002/076463>. 

Data exists for reactions of benzylidenepyruvic acid 26 with 6-chloropyrida-zin-3-amine 309 and with 2-amino-6-(4-methoxyphenyl)-4-oxo-1,2,3,4-tetrahy-dropyrimidine-5-carbonitrile 311 leading to imidazo[l,2-Z ]pyridazine 310 [242] and pyrimido[l,2- ]pyrimidine-2-carboxylic acid 312 [243] (Scheme 3.85). 

The most common synthetic approaches to both types of pyrimidopyrimidine have been described in CHEC-I and in review articles by Delia . In addition some new strategies in the preparation of pyrimido[4,5-rf]pyrimidines have been developed in the last few years. A new approach is the aza-Wittig-type reaction of iminophosphoranes of 5-aminouracils with aromatic isocyanates which leads to functionalized pyrimido[4,5-rf]pyrimidines. Ethyl 1,3-dimethyl-6-(triphenylphosphoranylideneamino)-uracil-5-carboxylate (105) reacts with isocyanates via adduct (106a) intermediates to afford 7-ethoxypyrimido[4,5-. 

Solid-phase syntheses of pyrimidines continue to appear at a rapid pace. A solid-phase synthesis of 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide was directly scaled up in excellent yields and high purity <03OPRD553>. The synthesis of imidazo[l,2-a]pyrimidines 59 via condensation of a solid-supported a-bromoketone and 2-aminopyridines was reported <03TL6265>. Pyrimido[4,5-t/]pyrimidine-2,4(l//,3W) diones have been accessed via a versatile solid-phase synthetic route <03S1739>. A microwave-assisted solid support synthesis of 5-methyl-6-ethylcarboxyIate-2-thioxothieno[3,2-iflpyrimidine-4(l//)-ones from 2-amino-3,5-diethyl carboxylate-4-methylthiophene and monosubstituted thioureas was reported <03BKC1038>. 

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