A novel synthesis of 3-(substituted)pyrimido[4,5-c]pyridazine-5,7(1H,6H)-diones

Abstract

An improved synthesis of 3-(substituted)pyrimido [4,5-c]pyridazine-5,7(1H,6H)-diones, a known subclass of 4-deazatoxoflavins, is reported. The approach involves treatment of 3-methyl-6-(1-methylhydrazinyl) uracil with representative phenyl and alkyl glyoxal monohydrates, which in turn are obtained by selenium dioxide oxidation of the corresponding phenyl and alkyl methyl ketones. The first entry into 4-monosubstituted isomers is also reported. KeywordsPyrimido [4,5-c]pyridazine-57(1H6H)-dione; 4-Deazatoxoflavin; Phenylglyoxal; Cyclizations; 6-(1-Methylhydrazinyl)uracil 1,6-Dimethylpyrimido[4,5-c]pyridazine-5,7(1H,6H)-dione, also known as 4-deazatoxoflavin, and its 3,4-disubstituted analogues have been shown to serve as biomimetics of flavin and 5-deazaflavin in their ability to oxidize amines to carbonyl compounds 1 and to abstract hydrogen equivalents from hydrogen donors under certain conditions (Fig. 1). 2 4-Deazatoxoflavin itself has also demonstrated both inhibitory activity against Pseudomonas and DNA-binding properties 3 while not displaying the generalized cytotoxicity that is characteristic of toxoflavin. 4 There are scattered reports of 3,4-disubstituted 3,5 and 3-mono-substituted 2,6 analogues of 4-deazatoxo flavin, but no reports of 4-monosubstituted analogues. The described syntheses of 3-monosubstitued analogues generally proceed in poor yields and via pathways that produce alternate products. Our goal was to develop an improved synthesis that would lead to clean products and possess generality for a wide range of analogues for biological testing.Our strategy is based on the known reaction of 6-(1-methylhydrazinyl) uracil with glyoxal and α-diketones to yield 3,4-unsubstituted-and 3,4-disubstituted-pyrimido[4,5-c]pyridazine-5,7 (1H,6H)-diones, respectively.3 Despite these prior examples, there are no reports of reaction between this or related 6-(hydrazinyl)uracils and unsymmetrical alkyl or aryl glyoxals. We imagined that reaction could occur by several manifolds. One could proceed via initial hydrazone formation onto either one or both of the aldehyde or ketone moieties, or as is often the case for 6-aminouracils, 7 by nucleophilic attack by the 5-position of the uracil onto either glyoxal carbonyl. Thus, we set out to evaluate a number of reaction conditions to determine if regiochemical preferences for the uracil and glyoxal reaction partners could be established. Initially, we treated 3-methyl-6-(1-methylhydrazinyl)uracil8 with phenylglyoxal monohydrate in refluxing ethanol or water and obtained the result shown in Scheme 1. Upon cooling a precipitate corresponding to ~85% of 3 was confirmed by 1 H NMR and mass spectrometry analysis, and a negative Tollens test for aldehyde. In addition to supporting spectral data, selective hydrazone formation onto the aldehyde moiety under these conditions is well precedented from prior studies on glyoxal hydrazones of methylhydrazine. 9,10 The ~15% cocrystallized impurity plus 5-10% additional material in the mother liquor corresponded to one of two...

A Regioselective One-Pot, Three Component Synthesis of 6-Aryl-4-cyano-3(2H)-pyridazinones in Water

“…Indeed, the pattern of δ (H 5 ) > δ (H 6 ) that is observed for related arylsubstituted cyanopyridazinones is consistent with the observations made by Showalter and coworkers for pyrimidopyridazine derivatives. [38] The product ratios were determined by inspection of the 1 H NMR spectra, using the intensities of the signals assigned to H 5 and H 6 of the pyridazinone rings. The yields and product ratios obtained from procedure B are summarized in Table 2.…”

“…Hence, mixtures of 5-and 6-arylcyanopyridazinones were obtained by this procedure. However, such a rationalization for the regioselectivity is shown to be oversimplistic by the observations of Showalter and coworkers, [38] who noted that in a series of arylglyoxals, the reaction of hydrazine with glyoxal carbonyls depended more on the solvent and acidity of the medium than on the electronic effects of the aryl substituent. They have also reported that in hydroxylic solvents such as water, similar to our reaction conditions, hydrazine can react with both glyoxal carbonyls and this leads to form the mixture of regioisomers.…”

“…They have also reported that in hydroxylic solvents such as water, similar to our reaction conditions, hydrazine can react with both glyoxal carbonyls and this leads to form the mixture of regioisomers. [38] The suggested mechanism for the formation of both 5-arylcyanopyridazinone and 6-arylcyanopyridazinone regioisomers under condition B is shown in Scheme 5. Attempts to alter the product ratio by stirring the reaction mixture for a long time or by heating failed.…”

Synthesis, Characterization, and Docking Evaluations of New Derivatives of Pyrimido[4,5‐c]pyridazine as Potential Human AKT1 Inhibitors

“…6‐(l‐Alkylhydrazino)isocytosines have been also reported to cyclize with 1,3‐diketo esters or with simple α‐keto esters to give the corresponding pyrimido[4,5‐ c ]pyridazines in good yields . Morrison and co‐workers were described the cyclizations of glyoxals with 6‐hydrazinoisocytosines while the synthesis of 3‐(substituted)pyrimido[4,5‐ c ]pyridazine‐5,7(1 H ,6 H )‐diones were performed by Turbiak through the condensation of 3‐methyl‐6‐(1‐methylhydrazinyl)uracil with phenyl and alkyl glyoxal monohydrates . A series of new 4‐aryl‐6,8‐dimethylpyrimido[4,5‐ c ]pyridazine‐5,7(6 H ,8 H )‐dione derivatives were synthesized via three component reactions of 1,3‐dimethylbarbituric acid with arylglyoxals in the presence of hydrazinium dihydrochloride .…”

The first practical approach to new pyrimido[4,5-d]pyridazines: novel chemoselective and regioselective reactions

“…3 A broad spectrum of biological activity have been reported for dihydropyrimidinones and pyridazine derivatives. 4 For example, the pyridazine structure found within the structure of several pharmaceutical drugs such as cadralazine, 5 minaprine, 6 cefozopran, 7 pipofezine (azaphen), The structures and purity of the obtained products were deduced from their infrared (IR), elemental analysis (CHN), and nuclear magnetic resonance (NMR) spectral data. As a suitable evidence for chemoselectivity of the reactions, the 1 H NMR (DMSO-d 6 , 400 MHz) spectrum of compound 4a exhibited two singlets of the nitrogen protons (δ = 10.61 and 10.10), a doublet (δ = 7.35) and singlet signals (δ = 7.20) corresponding to the aromatic protons.…”