WO2010065798 Substituted tetrahydropyran spiro pyrrolidinone and piperidinone, preparation and therapeutic use thereof

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Biological target:

Histamine H3 receptor: H3

Activity:

Modulator

Steps Conditions Reactions
a DIPA, BuLi -78oC, then HMPA, allyl iodide -78oC Nucleophilic substitution
b NaIO4, OsO4, iPrOH/H2O (1/1), 4h Oxidative cleavage of diol
c 2-fluoro-4-bromoaniline, NaBH(OAc)3, HOAc, DCE, overnight Reductive amination
d t-BuOK 1M in THF, THF, 30 min Spiro formation (Intramolecular cyclisation)
e Pd2(dba)3, XPHOS, t-BuONa, toluene, 90oC Buchwald-Hartwig reaction
Steps Conditions Reactions
a p-toluene-sulfonyl chloride, DMAP, CH2Cl2 Tosylate formation (OH activation)
b R-(-)-2-methylpiperidine, K2CO3, CH3CN, 75oC, 20h Nucleophilic substitution (SN2)
c HCl 4N in dioxane, , 0oC to room temperature Secondary amine formation (Boc-deprotection)
Steps Conditions Reactions
a DIPA, BuLi -78oC, then bromobutene -78oC Nucleophilic substitution
b NaIO4, OsO4, iPrOH/H2O 1/1, 4h Oxidative cleavage of diol
c 4-bromoaniline, NaBH(OAc)3, AcOH, DCE, overnight Reductive amination
d t-BuOK 1M in THF, THF Spiro formation (Intramolecular cyclisation)
e Pd2(dba)3, XPHOS, t-BuONa, toluene, 90oC Buchwald-Hartwig reaction

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