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)