Pyrimido pyridazin-8 -ones

Pyrimido[5,4-c]pyridazin-8(2i/)-one, 6- N,N-dimethylamino)-2-phenyl-synthesis, 3, 357 Pyrimido[l, 2-6]pyridazin-2-ones H NMR, 3, 333 IR spectra, 3, 335 synthesis, 3, 354, 355 Pyrimido[ 1,2-6]pyridazin-4-ones synthesis, 3, 354, 355 Pyrimido[4,5-c]pyridazinones chlorination, 3, 344 Pyrimido[4,5-d]pyridazin-5-ones... 

When cyclization of the acrylamide (167) was attempted in refluxing 1,2,4-trichlorobenzene, 6-chloro-3-dichloromethylene-3//-imidazo[l,2-6]pyridazin-2-one (35) was formed instead of the expected pyrimido[1,2-6]pyridazin-4-one (34). The latter compound could be obtained by conducting the cyclization in refluxing xylene. Since (34) and (35) are in practice not thermally interconvertible (at 210 °C), it can be assumed that (34) is not a precursor in the formation of (35) (71JOC3506). 

H-Pyrimido[l, 2-6]pyridazin-2-one, 3,4,7-trichloro-nucleophilic displacement reactions, 3, 343 Pyrimido[ 1,2- 6]pyridazin-4-one, 3-ethoxy carbonyl- H NMR, 3, 333 synthesis, 3, 355... 

Pyrimidin-4-one, 2,5,6-triamino- N NMR, 3, 64 (78HCA2108) Pyrimido[4,5-d]pyridazin-5-amine, JV-benzyl-8-chloro-2-phenyl-pXa, UV, 3, 337 <76BSF(2)1549) Pyrimido[4,5-d]pyridazin-5-amine, JV-butyl-8-chloro-2-phenyl-... 

H NMR, 3, 335 (82JOC674) Pyrimido[4,5-c]pyridazin-5-one, 7-amino-1-methyl-4-phenyl-... 

Pyrimido[5,4-c]pyridazin-8-ones chlorination, 3, 345 rearrangement, 3, 345 synthesis, 3, 357... 

Of the possible 10 bicyclic systems containing one bridgehead nitrogen and two extra nitrogen atoms, 1 1 in each ring, nine are known. One new system, pyrimido[l,6-A]pyridazine (system 1 in Table 1), has been reported since CHEC-II(1996) <1996CHEC-II(8)633>. The number of known tricyclic benzo-fused systems is 16. 

Partial saturation of the pyridazino ring of 3-acylamino-4//-pyrimido[l,2-A pyridazin-4-ones and the pyrazino ring of 3-acylamino-4//-pyrazino[l,2-tf]pyrimidin-4-ones in EtOH/AcOH system using Pd/C catalyst, resulted in the respective 6,7,8,9-tetrahydro derivatives in good yields <2000JHC783>. 

A special class of synthesis is the utilization of retro-Diels-Alder (RDA) reactions. A double RDA sequence was used to prepare the pyrimido[l,2-A]pyridazin-3-one 118. In this versatile method both reactants of the parent compound were constructed from cyclopentadiene. The parent compound 117 contains two norbornene units and decomposes on heating in toluene in a double RDA reaction leaving two double bonds in the target heterocycle. Similarily, the parent compound 119 decomposes in a single RDA reaction to yield the benzologue, pyridazino[6,l-3]-quinazolin-10-one 120 (Scheme 13) <2000SL67>. 

A novel class of tricyclic lymphocyte specific kinase (Lck) inhibitors containing the 9,10-dihydro-8//-pyrazolo[l,2-tf]pyrimido[4,5-c]pyridazin-8-one moiety has been reported <2006BML4257, 2006H(68)2037>. The most promising compound, 708, advanced to pharmacokinetic evaluation <2006BML4257>. 

Few reactions of this system were reported in CHEC(1984) <1984CHEC(3)329> and none in CHEC-II(1996), but there has been progress since the appearance of the latter. Although chlorination of pyrimido[5,4-f]pyridazin-8-one is not achieved under conventional conditions <1984CHEC(3)329>, this conversion has been carried out on... 

An extensive HNMR study of pyrimido[l,2-6]pyridazin-2-ones and pyrimido[ 1,2-6]-pyridaziniums has appeared in the literature. Data for some of these compounds are compiled in Table 1. From these data it can be seen that a long range coupling constant (/4,9) is apparent. In addition, only the 4-methyl derivatives of these compounds display a small coupling constant between the 4-methyl group and H-3. No such interactions with H-3 are observed with 2-methyl derivatives. fH NMR data have further demonstrated that methanol and 3-ethoxycarbonylpyrimido[l,2-6]pyridazin-4-one (30) exist in equilibrium with the adduct (31) in deuteriochloroform solution (71JOC2457). 

In the IR spectra, the pyrimido[l, 2-Z> ]pyridazin-2-one carbonyl absorption occurs at a longer wavelength than the isomeric 4-one carbonyl absorption. Thus, the compound (32) exhibits a C=0 absorption at 1643 cm-1 whereas the isomeric (33) exhibits a C=0 absorption at 1708 cm f (71JOC3506). 

HNMR spectroscopy has been used to distinguish between the two isomeric products obtained as a mixture in the reaction of 5,8-dichloro-2-phenylpyrimido[4,5-rf]pyridazine with aliphatic amines. In these reactions the isomeric products are separated by column chromatography and then the chemical shift of the H-4 proton is noted. This proton is shifted to lower field (ca. 8 10.2) for the 5-amino substituted products (39), when compared with the chemical shift (ca. 8 9.9) for the 8-amino substituted products (38) (72CPB1522). Chemical shifts for several pyrimido[4,5-rf]pyridazin-5-ones have also been reported (Table 2) (76BSF1549). 

Chlorinated 2H- pyrimido[l, 2-6 ]pyridazin-2-ones are known to undergo a variety of nucleophilic displacement reactions. Displacement of the chlorine atom in both the 4- and 7-positions of these compounds with methylamine and sodium methanethiolate is facile. Displacement of the chlorine atom in the 3-position does not occur. Therefore, 3,4,7-trichloro-2//-pyrimido[l,2-6]pyridazin-2-one (34) reacts with methanethiol in sodium methoxide to give 3-chloro-4,7-bis(methylthio)-2//-pyrimido[l,2-6]pyridazin-2-one (70) (71JOC3506). 

Phenyl-2//-pyrimido[ 1,2-b]pyridazin-2-one (71) is cleaved by reaction with potassium isopropoxide in refluxing isopropyl alcohol to give the pyrimidinone (72) (72M1591). 

Pyrimido[4,5-d]pyridazine derivatives are readily cleaved under both acidic and basic conditions. Reaction of 2-phenyl-5,8-dimorpholinopyrimido[4,5-hydrochloric acid gives a mixture of four isolated products 2-phenyl-8-morpholinopyrimido[4,5-d]pyridazin-5(6//)-one (96), 4-hydroxy-6-morpholinopyridazin-3(2jy>one (97), 4-amino-5-formyl-3,6-dimorpholinopyridazine (98) and benzoic acid (99). 

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