WO2010026110 6-substituted benzoxazines

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Scaffold: benzoxazines

Biological target:

5-Hydroxytryptamine receptor 5A: 5-HT5A

Activity:

Antagonist

Steps Conditions Reactions
a BH3 1M THF Hydroxyl synthesis (acid carboxylic reduction)
b TBM-Cl / Imidazole / DMF TBM protection
c Thiophosgene / DCM Thioisocyanate synthesis
d

1. 2-methoxybenzylamine / ACN  

2. TBAF.3H2O / EDC / ACN

Cyclisation
e H2 / Raney-Nickel / THF Primary amine synthesis (Nitro reduction)
f Cyclopropanecarbonyl chloride / NaHCO3 / AcOEt Amide synthesis
Steps Conditions Reactions
a Dimethylsulfamoyl chloride / DIEA / DMAP / ACN
Steps Conditions Reactions
a ZnCN / Pd(PPh3)4 / DMF Cyanide synthesis
b NH2-OH / Na2CO3 / EtOH / H2O Nucleophilic substitution
c CDI / AcOH / THF Cyclisation
Steps Conditions Reactions
a

1. Pyridine / DCM

2. DIEA / DCM

Urea synthesis
Steps Conditions Reactions
a Triethyl phosphonoacetate / NaH / 1,2-dimethoxyethane Alkene synthesis (Wittig reaction)
b H2 / Pd(OH)2 / EtOH Alkene reduction
c NaBH3CN / CHO / EtOH Secondary amine synthesis (Reductive amination)
d HCl 3N Carboxylic acid synthesis (Ester hydrolysis)
e TBTU / DIEA / DCM Amide synthesis (TBTU coupling)
Steps Conditions Reactions
a tert-Bu-Xphos / Pd2dba3 / NaOtBu / tert-butanol / dioxane   Buchwald-Hartwig amination
Steps Conditions Reactions
a Tributyl-(vinyl)-stannane / Pd(PPh3)4 / Toluene Stille coupling
b 3-bromopyridine / tri(o-tolyl)phosphine / Et3N / Pd(OAc)2 / DMF Heck reaction
c Styrene / tri(o-tolyl)phosphine / Et3N / Pd(OAc)2 / ACN Heck reaction
d Cyclopropylboronic acid / tricyclohexylphosphine / potassiumphosphate / Pd(OAc)2 / toluene / H2O Suzuki reaction
Steps Conditions Reactions
a NaOAc / NH2-OH / EtOH Oxime synthesis
b H2 / Raney-Nickel / THF / MeOH Primary amine synthesis
c

1. 2-methoxybenzylamine / ACN

2. TBAF.3H2O / EDC / ACN

Cyclisation
d H2 / Raney-Nickel / THF Primary amine synthesis (Nitro reduction)
e Chloroacetyl chloride / Na2CO3 / Acetone Amide synthesis
f 1-methylpiperazine Tertiary amine synthesis (nucleophilic substitution)

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