WO2010000456: Substituted 6-(1-piperazinyl)-pyridazines as 5-HT6 Receptor Antagonists

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Biological target:

5-Hydroxytryptamine receptor 6: 5-HT6

Activity:

Antagonist

Steps Conditions Reactions
a tert-butyl 1-piperazinecarboxylate, DIPEA, CH3CN, 180°C, microwave 30 min. SnAr
b 2,2,6,6-tetramethylpiperidine, butyllithium, iodine, THF, -78°C Iodation
c 2,2,6,6-tetramethylpiperidine, butyllithium, benzaldehyde, THF, -78°C  
d H2, Pd/C, EtOH, 2 days.  
e Dess Martin’s reagent, CH2Cl2, 0°C, 1h. Oxidation
f MnO2, EtOAc, overnight Oxidation
Steps Conditions Reactions
a 4-fluorophenol, N,N-dimethylglycine, CuI, Cs2CO3, dioxane, 100°C, 16h. Ullman-type reaction (ether formation)
b 4-fluorobenzenamine, (S)-BINAP, Pd(OAc)2, Cs2CO3, Et3N, toluene, 100°C, 24h. Buchwald-Hartwig reaction
c benzenesulfinic acid sodium salt, L-proline, CuI, K3PO4, DMSO, 85°C, 18h.   Ullman-type reaction
d [2-(4-fluorophenyl)vinyl]boronic acid, Pd(PPh3)4, K2CO3, dioxane, DMF, 160°C, microwave, 1h. Suzuki coupling reaction  
e 1-ethynyl-4-fluorobenzene, Pd(PPh3)4, CuI, Et3N, 55°C, 3h. Sonogashira coupling reaction
f (E)-(2-phenylvinyl)boronic acid, Pd(PPh3)4, K2CO3, dioxane, DMF, 160°C, microwave, 1h. Suzuki coupling reaction
g 4-fluorobenzenemethanamine, 150°C, 1h. Aromatic nucleophilic substitution
h 4-fluorobenzemethanol. NaH, DMF, 1h. Aromatic nucleophilic substitution
Steps Conditions Reactions
a TFA, CH2Cl2, 3h. Secondary amine formation (Boc-deprotection)
b AMBERLYTETM acid, MeOH, 24h. Secondary amine formation (Boc-deprotection)
c HCl 4M in dioxane, 1h. Secondary amine formation (Boc-deprotection)