Pyrimido! 1,2-6 pyridazine-3-carboxylates

Amino 4-oxo 4//-pyrimido[l,2-4]pyridazin-3-diazonium tetrafluoroborates 73 underwent ring transformation into l-(pyridazin-3-yl)-l//-l,2,3-triazole-4-carboxylates 74 on heating in dry MeOH. Yields dropped drastically when EtOH, instead of MeOH, was used as solvent (Equation 6) <2002ARK143>. 

Mild hydrolysis of ethyl 4-oxo-4//-pyrimido[l,2-a]pyridazine-3-carboxylate in 0.1 N sodium hydroxide solution at room temperature afforded monoethyl (3-pyridazinylamino)methylenemalonate (68TL33). 

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... 

A mechanism has been proposed to account for the formation of each of these products (72YZ1312). Pyrimido[4,5-d]pyridazine-2,4-dione (85) is cleaved by 10% aqueous sodium hydroxide to give 5-hydroxypyridazine-4-carboxylic acid (100). Cleavage with concentrated ammonium hydroxide also occurs, yielding 5-aminopyridazine-4-carboxylic acid (101) (68JHC845). 

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). 

Permanganate oxidation of a pyrrolo[l,2-fe]pyridazine gives the pyri-dazine 84 ° and 4-aminopyridazine-5-carboxylic or -4,5-dicarboxylic add are obtained by oxidation of pyridopyridazines. Aminopyridazinecar-boxylic acids are also obtainable by hydrogenolysis of s-triazolo[4,3-b]pyri-dazines or upon treatment of pyrimido[4,5-c]-, pyrimido[5,4-c]- or pyrimido[4,5-d]pyridazines with hot alkali or ammonia (Eq. i7).20 -206... 

The cyclization of ethyl 3-(4-chloro-2-substituted-pyrimidin-5-yl)-2-diazo-3-oxopropanoates 4 (prepared from the corresponding pyrimidine-5-carbonyl chlorides and ethyl diazoacetate) in the presence of triphenylphosphane yields the corresponding 7-substituted ethyl 4-hydroxy-pyrimido[4,5-c ]pyridazine-3-carboxylates 544 [for a similar reaction of 4 (R = SMe) with hydrazine hydrate cf. ref 50]. 

The pyrimidine ring in pyrimido[4,5-c]pyridazin-5-ol is labile to aqueous base,40,42 yielding 3-aminopyridazine-4-carboxylic acid. 

The reaction of pyridazin-5-amines containing a carbonyl group in the 4-position with various reaction partners, each containing a C-N bond, may also be used to synthesize pyrimido[4,5-tf]pyridazines. Thus, 2-aminopyrimido[4,5-tf]pyridazin-4-ol (2) is formed from ethyl 5-aminopyridazine-4-carboxylate (1) and guanidine.57... 

When pyrimido[4,5-r/]pyridazine-2.4-diol is treated with concentrated aqueous ammonia at elevated temperature the pyrimidine ring is cleaved to give 5-aminopyridazine-4-carboxylic acid quantitatively.57... 

In contrast to the reaction of many 3-aminopyridazines with DMAD and acetylenemono-carboxylates, to give pyrimido[l,2-Z>]pyridazin-2(2//)-ones (see e.g., <83H(20)2225 , 6-amino-3(2//)-pyridazinone reacts by a Michael-type addition to give the aminobutenedioate (Scheme 58), which can be cyclized in acetic acid to the isomeric pyrimido[2,l-f)]pyridazin-4(47/)-one system. Condensation of 3-aminopyridazines and 6-amino-3(2//)-pyridazinones with diethyl ethoxymethyl-enemalonate proceeds in the expected Michael fashion to give aminomethylenemalonates which can be cyclized thermally <88JHC1535>. 

Rosa FA, Machado P, Fiss GF, Vaigas PS, Fernandes TS, Bonacorso HG, Zanatta N, Meutins MAP (2008) Synthesis of ethyl pyrimidine-4-carboxylates from unsymmetrical enamino diketones and their application in the first synthesis of pyrimido[4,5-d] pyridazin-8(7H)-ones. Synthesis 22 3639-3648... 

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