Methanol → HCID 86657799, compound

Participants

Reaction Conditions

Reaction Steps

To a stirred solution of (±)-cis-4-methoxymethoxy-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (1.98 mmol, 0.5 g) in ether (5 mL) at 0° C. was added LAH powder (50 mg) in one lot and continued stirring at 0° C. for additional 20 min followed 10 min at room temperature. TLC analysis of an aliquot of the reaction mixture showed complete consumption of starting material. The reaction mixture was diluted with ether (5 mL), cooled to 0° C., added ethyl acetate drop-wise followed by saturated sodium sulfate. The organic layer was separated, dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with 50% ethyl acetate in hexanes to provide (±)-cis-3-hydroxymethyl-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (0.506 g, 93%) as an oil. To a stirred suspension of sodium hydride (4.16 mmol, 0.1 g) in THF (8 mL) at room temperature was added (±)-cis-3-hydroxymethyl-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (1.84 mmol, 0.506 g) followed 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 1.74 mmol, 0.6 g). The resultant reaction mixture was kept stirring at 50-60° C. for 2 h. The reaction mixture was cooled to room temperature and excess NaH was decomposed by addition of methanol drop-wise. This was diluted with ethyl acetate (20 mL), washed with water (5 mL), separated the organic layer, dried, filtered and concentrated under reduced pressure. The resultant residue was purified by flash silica gel chromatography by eluting with 40% ethyl acetate in hexanes to afford (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (0.93 g, 82% yield) as a light yellow oil.

Provenance & Evidence