Enantioselective synthesis of a chiral pyridazinone derivative by lipase-catalyzed hydrolysis

A Short and Efficient Synthesis of a Chiral Pyridazinone Derivative by the Chiral-Pool Method

“…For the extension of the carbon chain, we employed benzyl methyl malonate to suppress the epimerization at the following step to remove one of the ester groups, while dimethyl malonate was used for the previous synthesis of the racemate. 8 Thus, the S N 2 type substitution of 4 with benzyl methyl malonate and sodium hydride in N,N-dimethylformamide provided (R)benzyl methyl 2-[2-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-methyl-2-oxoethyl]malonate (5) in 81% yield as a diastereomeric mixture. The ratio of the diastereomers was found to be 4:6 judging from the integration of the split methyl signals (d = 1.19 and 1.26) in the 1 H NMR spectrum, although we could not assign the correct stereochemistry of each isomer.…”

“…Recently we reported the enantioselective synthesis of the chiral pyridazin-3(2H)-one 1 by the lipase-catalyzed resolution of a 2-(propionyloxymethyl)pyridazin-3(2H)-one derivative in organic solvents containing water. 8 This method would be a practical method for the preparation of the chiral pyridazin-3(2H)-one, because the chemical yield of the product is acceptable, the optical yield is high, and the undesired enantiomer can be recycled. On the other hand, we have pursued another practical method to synthesize the chiral pyridazin-3(2H)-one derivative 1 using (R)-2-chloropropionyl chloride as the starting material.…”

“…This asymmetric synthesis by the chiral-pool method would be one practical method for the chiral pyridazinone derivatives, and could be an alternative to that of lipase-catalyzed resolution. 8…”

Lipase-mediated chiral resolution of racemates in organic solvents

“…A practical method for the synthesis of chiral pyridazinone bearing a pyrazolopyridine ring via lipase-catalyzed resolution of 2-(acyloxymethyl)-4,5-dihydro-5-methylpyridazin-3(2H)-one derivatives 146 was reported by Yoshida et al 102 (Fig. 43).…”