Retrosynthesis.

Ester 7 would have allowed for the introduction of unsaturation in the dihydropyridazinone 2 via a bromination and elimination sequence. Amidation followed by treatment with phosphorus oxychloride and cyclization with hydrazine would have then provided FR180204 (Scheme 2).

The FR180204 (1) chemical structure consists of two drug-like motifs, a pyrazolo[1,5-a]pyridine and a pyrazolo[3,4-c]-pyridazine. The disconnection that we envisioned passes though the synthesis of oxopyridazine carboxamide 2 and pyrazolopyridine ketone 3 as key intermediates. The pyrazolopyridine ring system can be accessed via a 3 + 2 cycloaddition of aminopyridium salts and alkynes. We decided to construct this ring system first, as alternate routes involved carrying a reactive alkyne throughout the synthesis of the pyrazolopyridazine ring or its late generation for the proposed cycloaddition. To that end, commercially available reagents 1-aminopyridinium iodide and 4-phenylbut-3-yn-2-one were condensed under basic conditions9 to provide the known ethanone 3 (Scheme 1).10 The latter contained the methyl ketone which would form a template for the stepwise construction of the pyrazolopyridazine ring system. An initial attempt of producing the oxopyridazine carboxamide intermediate involved the introduction of the remaining carbon atoms via the displacement of a α-haloketone with diethylmalonate.11 We found that treatment of 3 with bromine led to poor yields of α-bromoketone 4 with significant α,α-dibromination. Portionwise addition of 1 equiv of tetrabutylammonium tribromide did not circumvent this issue. However, this problem could be resolved via formation of the intermediate trimethylsilyl enol ether and subsequent treatment with NBS. Treatment of 4 with 3 equiv of diethylmalonate in refluxing acetone under basic conditions led to good conversion to 5. Reaction of 5 with 1 equiv of hydrazine led to practically no conversion to the desired ester 7 and recovery of starting material. Heating with multiple equivalents of hydrazine allowed for the ring closure but with uncontrollable simultaneous formation of the corresponding hydrazide 6. Heating with lesser equivalents of hydrazine in the microwave or the use of higher boiling solvents such as isoamyl alcohol did not resolve this problem.

As an alternative route, we turned our attention to a related method for the construction of pyrazolopyridazines, which utilizes 2-oxodiethyl malonate as the source of the carbon atoms of the ring system (Scheme 3).12 Thus, methyl ketone 3 was heated with diethyl 2-oxomalonate to execute an aldol-like process to provide 8. The crude tertiary alcohol was then dissolved in ethanol and heated with excess hydrazine. This led to the precipitation of pure 9, where the pyridazin-3(2H)-one had formed via elimination of water and ring closure. Concomitant formation of the hydrazide had also taken place during the course of the reaction. Refluxing in concentrated hydrochloric acid led to the initial dissolution of 9 and the subsequent precipitation of acid 10. The latter was simply filtered off and washed with water to provide pure 10. A high yielding amidation of 10 was possible with isobutylchloroformate and aqueous ammonia. The pure amide 11 was simply filtered off from the reaction mixture. 11 had to be refluxed with neat phosphorus oxychloride to simultaneously convert the pyridazinone and the carboxamide to the chloropyridazine and nitrile, respectively. At this stage, we felt that purification of nonpolar 12 by flash silica gel chromatography would be useful in providing material with high purity for the last step. Purified 12 was refluxed with hydrazine in ethanol for2 h and then left standing for 16 h to cause the precipitation of FR180204 1. The solid was filtered to provide material which was of at least 95% purity as determined by ¹H NMR spectroscopy and reverse-phase HPLC.