WO2010058333 Lactams as beta secretase inhibitors

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Scaffold: Spiropiperidine

Biological target:

β-Secretase: BACE

Activity:

Inhibitor

Steps Conditions Reactions
a CBz-Cl / Et3N / THF Cbz protection
b MeMgBr / Et2O / THF Nucleophilic substitution
c HCl 1N Methoxy deprotection
d Zn / AcOH Alkene reduction
e AcOH Strecker reaction
Steps Conditions Reactions
a Ethyl 3-Chloro-3-oxopropanoate / DMAP / DCM Amide synthesis (coupling reaction)
b MeONa / MeOH Cyclisation
c HCl 6N Decarboxylation
d Cbz-Cl / NaOH / H2O / THF Cbz protection
e NaBH4 / MeOH / THF Hydroxyl synthesis (Ketone reduction)
f SOCl2 / Pyridine /  Dehydration reaction
g HCl 6N / MeOH Cbz deprotection
h H2 / Pd(OH)2 / MeOH Alkene reduction  / Cbz deprotection
Steps Conditions Reactions
a 2-iodopropane / K2CO3 / DMF Ether synthesis (nucleophilic substitution)
b Ethylene glycol / APTS / Toluene Aldehyde deprotection
c Li / chlorodiphenylphosphine / THF Methoxy deprotection
d Sodium triacetoxyborohydride / AcOH / DCE Amine synthesis (Reductive amination)
Steps Conditions Reactions
a

1. n-BuLi / THF

2. (PhSO2)2NF / THF

Fluorination
Steps Conditions Reactions
a CHCl3 / LiHMDS / THF
b NaN3 / 18-crown-6 / DBU / MeOH 
c Zn / AcOH / THF Primary amine synthesis (azido reduction)
d 3-ethoxy-3-oxopropanoic acid / EDCI / Et3N / DCM  Amide synthesis
e NaOEt / MeOH Cyclisation
f HCl 4N / dioxane / H2O Decarboxylation
g NaBH4 / MeOH Hydroxyl synthesis (ketone reduction)
h MsCl / Et3N / DBU / DCM Dehydration reaction
i NaH / THF Substitution nucleophilic
Steps Conditions Reactions
a DiBAL / Toluene Aldehyde synthesis
b NaH / 1,2-dimethoxyethane   Alkene synthesis (Wittig reaction)
c H2 / Pd(OH)2 / MeOH Alkene reduction
d NaH / THF Cyclisation
Steps Conditions Reactions
a LiHMDS / 3-phenyl-2-(phenylsulfonyl)oxaziridine / THF Hydroxyl synthesis
b MnO2 / DCM Oxidation
c LiHMDS / N-(5-chloropyridine-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamide / THF Triflate synthesis
d Phenylboronic acid / K3PO4 / Pd(dppf)Cl2 / THF Suzuki reaction
Steps Conditions Reactions
a 3-fluoroaniline / DBU / MeOH Nucleophilic substitution
b LiBH4 / THF Hydroxyl synthesis (Ester reduction)
c

1. Oxalyl chloride / DMSO / DCM

2. Et3N / DCM

Aldehyde synthesis (Swern reaction)
d NaH / 1,2-dimethoxyethane Alkene synthesis (Wittig reaction) / cyclisation

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