Abstract: Piperidine is the most frequently encountered aliphatic heterocycle in medicinal chemistry. Despite its prevalence, there is a constant demand for improvement of ADME (absorption, distribution, metabolism, excretion) properties of piperidine-containing drugs and drug candidates. 2-azabicyclo[2.2.0]hexanes present an exciting class of more rigid and structurally programmable piperidine isosteres. EVA (exit vector analysis) of the most frequently employed piperidine isosteres and 2-azabicyclo[2.2.0]hexanes is presented, and a side-by-side comparison is made. This dissertation describes our endeavors towards the expansion of accessible 2-azabicyclo[2.2.0]hex-5-ene chemical space, our exploration of 2-azabicyclo[2.2.0]hex-5-ene scaffold reactivity in olefin functionalization reactions and installation of synthetically useful handles. The malleability and practicality of 2-azabicyclo[2.2.0]hexane core is demonstrated by preparation of several isosteres of piperidine-containing drugs and lead compounds. A general blueprint for functionalized 2-azabicyclo[2.2.0]hexanes is devised. Special attention is devoted to “pseudoaxial” C5-substituted-2-azabicyclo[2.2.0]hexanes, which could serve as isosteres of piperidines in their thermodynamically unfavorable axial conformations without the need to introduce additional carbon atoms.
La piperidina è l’eterociclo alifatico più frequente nella chimica farmaceutica (medicinal chemistry). Nonostante la sua prevalenza, c’è una costante domanda for il miglioramento delle proprietà ADME (assorbimento, distribuzione, metabolismo, escrezione) di farmaci e candidati farmaci contenenti strutture piperidiniche. Gli 2-azabiciclo[2.2.0]esani rappresentano un’interessante classe di isosteri della piperidina più rigidi e programmabili strutturalmente. L’EVA (exit vector analysis, analisi di vettore di uscita) degli isosteri della piperidina più frequentemente utilizzati e di 2-azabiciclo[2.2.0]esani viene mostrata, ed è stata eseguita una comparazione tra loro. Questa tesi descrive i nostri sforzi verso l’espansione di spazio chimico accessibile dei 2-azabiciclo[2.2.0]es-2-eni, la nostra esplorazione della reattività della struttura di tipo 2-azabiciclo[2.2.0]es-2-ene nelle reazioni di funzionalizzazione delle olefine e l’installazione di appigli sinteticamente utili. La malleabilità e praticabilità del nucleo di tipo 2-azabiciclo[2.2.0]es-2-ene è dimostrata dalla preparazione di diversi isosteri di farmaci e composti guida, contenenti strutture piperidiniche. Un progetto generale per la funzionalizzazione di 2-azabiciclo[2.2.0]es-2-eni è stato elaborato. Un’attenzione particolare è stata riservata ai 2-azabiciclo[2.2.0]es-2-eni con sostituenti sul C5 “psuedoassiali”, che possono servire come isosteri di piperidine nella loro conformazione assiale termodinamicamente sfavorevole, senza la necessità di introdurre atomi di carbonio addizionali.
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To 3-bromo-5-methylpyridine 1-1 (2 g, 11.63 mmol) in diethyl ether (30 ml) at -78 C was added uLi (8.72 ml, 13.95 mmol) dropwise. After 30 min, N-methoxy-N- methylacetamide n-BuLi was added. The resulting mixture was stirred at -78 C for 2 h then at rt overnight, quenched with saturated NH4CI solution and diluted with EtOAc. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give a yellow residue, which was purified by column chromatography (0-65% EtOAc in hexane) to give the desired product 1-2: 1H NMR (400 MHz, CDCI3) δ 8.98 (s, IH), 8.62 (s, IH), 8.04 (s, IH), 2.63 (s, 3H)5 2.41 (s, 3H).
With bis-triphenylphosphine-palladium(II) chloride; tributyl(1-ethoxyvinyl)stannane; potassium carbonate; In water; N,N-dimethyl-formamide; at 110℃; for 1.0h;Microwave irradiation;
The following are successively introduced into a microwave tube: 484 μΙ (4.07 mmol) of 3-bromo-5-methylpyridine in 20 mL of H2O/DMF: (1/3: v/v), 2.03 mL (5.70 mmol) of tributyl(1-ethoxyvinyl)tin, 57.12 mg (0.081 mmol) of bis(triphenylphosphine)palladium(ll) chloride, 1.12 g (8.14 mmol) of potassium carbonate. This mixture is subjected to microwave irradiation at 110C for 1 hour. The reaction mixture is evaporated to dryness and the residue is then taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue obtained is taken up in 6 mL of methanol and 1 mL of 6 N HCl, and the solution is stirred overnight at room temperature. The reaction medium is evaporated to dryness and the residue is taken up in saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give 300 mg of 1-(5- methylpyrid-3-yl)ethanone, the characteristics of which are as follows: LC/MS (method G): ESI+ [M+H]+: m/z 136 tr (min) = 0.78 1H NMR (300 MHz, δ in ppm, DMSO-d6): 2.37 (s, 3H), 2.62 (s, 3H), 8.1 (s, 1 H), 8.63 (s, 1 H), 8.93 (s, 1 H).
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 110℃; for 1.0h;Microwave irradiation;
The following are successively introduced into a microwave tube: 484 μl (4.07 mmol) of 3-bromo-5-methylpyridine in 20 mL of H2O/DMF: (1/3: v/v), 2.03 mL (5.70 mmol) of tributyl(1-ethoxyvinyl)tin, 57.12 mg (0.081 mmol) of bis(triphenylphosphine)palladium(II) chloride, 1.12 g (8.14 mmol) of potassium carbonate. This mixture is subjected to microwave irradiation at 110 C. for 1 hour. The reaction mixture is evaporated to dryness and the residue is then taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue obtained is taken up in 6 mL of methanol and 1 mL of 6 N HCl, and the solution is stirred overnight at room temperature. The reaction medium is evaporated to dryness and the residue is taken up in saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give 300 mg of 1-(5-methylpyrid-3-yl)ethanone, the characteristics of which are as follows: LC/MS (method G): ESI+ [M+H]+: m/z 136 tr (min)=0.78 1H NMR (300 MHz, δ in ppm, DMSO-d6): 2.37 (s, 3H), 2.62 (s, 3H), 8.1 (s, 1H), 8.63 (s, 1H), 8.93 (s, 1H).
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