To a solution of (1-cyclopropyl-2-methoxy-vinyl)cyclopropane (128 g,709.4mmol) in tetrahydrofuran (700 mL) was added aqueous hydrochloric acid (250 mL of 3 M,750.0 mmol) and the mixture was stirred at ambient temperature for 16 h then stirred at 55℃ for 4 h and then allowed to cool to ambient temperature over 12 h. The mixture was diluted with 500 mL of brine and the aqueous phase was separated. The aqueous phasewas extracted with 500 mL of MTBE and the organic phases were combined. The organicphases were washed with 500 mL of brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The resulting oil was diluted with 250 mL of MTBE and the residual water was removed using a separatory funnel. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo affording 2,2-dicyclopropy lacetaldehyde (99.2 g,96%) as a light orange oil.
WO2022170122A1
To a solution of tert-butyl 4-(methoxymethylene)-2.,2-dimethyl-piperidine-1-carboxylate (1.7 g, 6.66 mmol) in acetonitrile (170 mL) at 0°C was added HCI (1 M,7.99 mL).The mixture was stirred at 25°C for 16 h. The reaction mixture was quenched by sat. NaHCO3 solution (20 mL) and concentrated under reduced pressure. The residue was then diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mLx 3), dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-formyl-2,2-dimethy-piperidine-1-carboxylate (1.6 g, 99%) as a white solid.
Into a 2000- mL round-bottom flask were placed tert-butyl 2-(methoxymethylidene)-7-azaspiro [3.5]nonane-7-carboxylate (18.0 g,67.3mmol, 1.0 eq), CH3CN (640 mL), water (160 mL), trifluoroacetic acid (15.4 g,134.6 mmol, 2.0 eq). The reactionmixture was stirred for 2 hours at 25℃.The resulting mixture was then quenched by the addition of NaHCO3(aq.) (300 mL), and then extracted with ethyl acetate (2×300 mL). The combined organic phase was washed with brine (2×300 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether=(0:1 to 1:3) to give tert-buty/2-formy-7-azaspiro[3.5]nonane-7-carboxylate (15.0 g, 88%) as a light yellow oil.
