Heteroaryl(heterocyclyl)methanol compounds useful in the treatment of hyperglycaemia
A compound, heterocycloalkyl technology, for use in the field of treatment of hyperglycemia and conditions characterized by hyperglycemia
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Embodiment 1
[0433] Example 1: (R)-(5-fluoropyridin-3-yl)((2R,6S)-6-propylpiperidin-2-yl)methanol
[0434] Dihydrochloride
[0435]
[0436] (a) tert-butyl (2R,6S)-2-((R)-(5-fluoropyridin-3-yl)(hydroxy)methyl)-6-propylpiperidine-1-carboxylate and (2R, 6S)-2-((S)-(5-fluoropyridin-3-yl)(hydroxy)methyl)-6-propylpiperidine-1-carboxylic acid tert-butyl ester
[0437]
[0438] To (S)-tert-butyl 2-propylpiperidine-1-carboxylate (300mg, 1.32mmol), TMEDA (0.30mL, 2.0mmol) and Et 2 To the stirred mixture of O (8 mL) was added sec-BuLi (1.3 M in cyclohexane, 1.5 mL, 2.0 mmol) dropwise, keeping the temperature below -70 °C. The mixture was allowed to warm to -30°C over 1 hour, held at that temperature for 1 hour and cooled to -78°C. Add 5-fluoronicotinaldehyde (0.165mg, 1.3mmol) in Et dropwise 2 O (4 mL), and the mixture was stirred at -78 °C for 30 min. Add H 2 O (4 mL), and the mixture was warmed to room temperature and washed with Et 2 O extraction. The combined extracts were subjecte...
Embodiment 2
[0443] Example 2: (S)-(5-fluoropyridin-3-yl)((2R,6S)-6-propylpiperidin-2-yl)methanol
[0444]
[0445] From (2R,6S)-2-((S)-(5-fluoropyridin-3-yl)(hydroxyl)methyl)-6-propylpiperidine-1 according to the procedure in Example 1 step (b) - tert-butyl formate Preparation of the title compound.
[0446] 1 H NMR (400MHz, CD 3OD): δ8.98–8.94(m,1H),8.87–8.85(m,1H),8.57–8.51(m,1H),5.36(dd,J=3.2,0.7Hz,1H),3.83–3.71( m,1H),3.57(dq,J=8.6,4.0Hz,1H),1.98–1.85(m,1H),1.84–1.74(m,3H),1.72–1.56(m,3H),1.55–1.35( m, 3H), 1.03 (t, J=7.3Hz, 3H).
Embodiment 3
[0447] Example 3: (R)-(5-fluoropyridin-3-yl)((2R,5R)-5-propylpyrrolidin-2-yl)methanol maleate
[0448]
[0449] (a) Methyl (R)-2-((tert-butoxycarbonyl)amino)-5-oxoctanoate
[0450]
[0451] n-Propylmagnesium chloride (1M in THF, 4.12 mL, 4.12 mmol) and TMEDA (616 μL, 4.12 mmol) were stirred at room temperature for 1 h and added via syringe pump (0.1 mL / min) to ( R)-5-Oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (500 mg, 2.06 mmol) in THF (5 mL). The mixture was stirred at -78 °C for 2 h, NH 4 Cl (saturated aqueous solution) and with Et 2 O extraction mixture. The combined extracts were washed with brine, washed with Na 2 SO 4 Dried and concentrated. The residue was purified by chromatography to afford the subtitle compound (535 mg, 91%).
[0452] (b) 1-(tert-butyl) 2-methyl (2R,5R)-5-propylpyrrolidine-1,2-dicarboxylate
[0453]
[0454] To (R)-methyl 2-((tert-butoxycarbonyl)amino)-5-oxoctanoate (500 mg, 1.74 mmol) in CH at room temperature...
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