Spiropiperidine derivatives

Utility Tachykinin Receptor Antagonistics for Treating Respiratory Tract 

Indene (0.10 mole) was dissolved in 60 ml THF, 200 ml 1.0 M lithium bistrimethylsilylamide (0.20 mole) in THF added over 1 hour, and stirred for 30 minutes. Thereafter, N-t-butoxy-carbonyl-bis(2-chloroethyl)amine (0.10 mole) dissolved in 50 ml THF was added, the mixture further stirred 2 hours, and then distilled under reduced pressure. The residue was purified by chromatography on silica gel using n-hexane/EtOAc, 97 3, and the product isolated in 89% yield. H-NMR, IR, and MS data supplied. 

The (2-hydroxy)indane product from Step 2 (8.27 mmol), N-t-butoxycarbonyl-spiro[(2-hydroxy)indane-l,4 -piperidine] were dissolved in 10ml ethyl alcohol, 10.0ml 4M HCl (40.0 mmol) dissolved in dioxane added, the mixture stirred 30 minutes under ice cooling, and then further stirred at ambient temperature 4 hours. The solvent was distilled off under reduced pressure, the residue recrystallized from methyl alcohol/diethyl ether, and the product isolated in 83% yield, mp = 250-251 °C. H-NMR, IR, and MS data supplied. 

l- -2-[(2R)-(3,4-Dichlorophenyl-4-(3,4,5-trimethoxybenzoyl)-morpholin-2-yl]-ethyl spiro [((2S) -hydroxy )indane-1,4 -piperidine] 

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Intramolecular oxidative coupling of silylated phenols 251 with IBTA leads to the formation of spiropiperidine derivatives 253, called aza-anthraquinone-spirodienones (89TL1119) (Scheme 64). The first step of this conversion is the electrophilic attack of reagent on the phenolic group to give intermediate 252. Intramolecular C—C bond formation leads... 

Perhydro-oxazolo[3,4- ]pyridines have long been prepared by condensation between the appropriate piperidyl-2-carbinol and an aldehyde or ketone. For example, the antidepressant spiropiperidine derivative (135) is obtained by the reaction between a-phenyl-2-piperidine methanol and N-benzyl-4-piperidone (81USP4260623). Perhydro-oxazolo[3,4-a]pyridin-3-one (136) is obtained by phosgenation of 2-(hydroxymethyl)piperidinium p-toluene sulfonate followed by cyclization of the resultant chloroformate salt by treatment with triethylamine in dichloromethane. This ring system... 

Studies of extended series of other spiropiperidine derivatives demonstrated that compound (176) is a partial muscarinic agonist that reverses carbon dioxide-induced impairment in mice (203), and that compound (177) is a muscarinic agonist with an affinity for cortical Ml receptors (204). The ( )-spiroquinu-clidine derivative (178) is a selective Mj agonist (205). 

Nargund, R.P., Ye, Z., Palucki, B., Bakshi, R., Patchett, A.A. and Van der Ploeg, L.H. (1999) WO 99/64002. Novel spiropiperidine derivatives with melanocortin-4-receptor agonist activity. Assigned to Merck, Sharp and Dohme Ltd. 

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