WO2010049841 7-azaspiro[3.5]nonane-7-carboxamide compounds as modulator of fatty acid amide hydrolase

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Scaffold: 7-azaspiro[3.5]nonane or spiropiperidine

Biological target:

Fatty acid amide hydrolase: FAAH 

Activity:

Modulator

Steps Conditions Reactions
a Ph3PCH2Br / nBuLi / THF Alkene synthesis (Wittig reaction)
b Cl3CCOCl / Zn-Cu couple / DME Cyclisation
c Zn / NH4Cl / MeOH Reduction              
Steps Conditions Reactions
a MsCl / Et3N / DCM Mesyl synthesis
b NaCN / KI / DMF Cyanide synthesis
c NH2OH / Et3N / EtOH Nucleophilic substitution
d 4-(trifluoromethoxy)benzoyl chloride / DIEA / ACN Cyclisation
Steps Conditions Reactions
a NaBH4 / MeOH
Hydroxyl synthesis (Ketone reduction)
b PPh3 / CBr4 / THF
Bromination (Appel reaction)
c Fe(acac)3 / TMEDA / HMTA / THF
Coupling reaction
Steps Conditions Reactions
a THF Grignard reaction              
b 1. triethylsilane / BF3-OEt2 / TFA 2. Boc2O Dehydroxylation
c H2 / Pd-C / MeOH / AcOEt Benzyl deprotection
d Cs2CO3 / DMF Ether formation (nucleophilic substitution)
e HCl 4N / dioxane Boc deprotection
Steps Conditions Reactions
a THF Grignard reaction
b DAST / DCM Fluorination
Steps Conditions Reactions
a PS-PPh3 / DBAD / DCM Ether synthesis (Mitsunobu reaction)
b 1. TFA / DCM 2. Phenyl (3,4-dimethylisoxazole-5-yl) carbamate / DIEA / ACN Boc deprotection / Coupling reaction
Steps Conditions Reactions
a LiOH / EtOH Carboxylic acid synthesis (Cyanide hydrolysis)
b N,O-dimethylhydroxylamine / HATU / DIEA / DCM Amide synthesis (HATU coupling)
c MeMgBr / THF Weinreb ketone synthesis
d LDA / TMSCl / NBS / THF Bromination
e EtOH Cyclisation
Steps Conditions Reactions
a NiI2 / NaHMDS / 2-aminocyclohexanol / isopropanol Coupling reaction

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