The Synthesis and Characterization of a Novel Insulin Sensitizing Agent

Abstract

A novel and succinct route to 2-hydroxy-4,6-diarylbenzophenones has been developed through condensation of aryl 1,3-diketones with chalcones. The resultant compounds stimulate insulin-dependent glucose uptake into adipocytes, and improve insulin sensitivity in a rodent model of diabetes.

Key words

cyclizations - diabetes - 2-hydroxybenzophenones - Michael additions - phenols

References

• 1 Dimroth K. Neubauer G. Chem. Ber.  1959,  92:  2046 
• 2 Oganesyan ET. Pyshchev AV. Butenko LI. Pharm. Chem. J.  1999,  33 (9):  480 
• 3 Ivanov Kh. Tcholakova Ts. Synthesis  1981,  392 
• 4 Murray WV. Wachter MP. J. Org. Chem.  1990,  55:  3424 

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Experimental Procedure for the Conversion of 6 to 1: Diketoacid 6 (7.8 g, 33 mmol) is combined with trans-chalcone (6.25 g, 30 mmol) in 125 mL of EtOH. Piperidine (20 mL) is added, and the resultant solution is heated at 100 °C for 16 h. The volatiles are removed in vacuo; the residue is taken up in 600 mL of 0.1 N aq NaOH and extracted once with 100 mL of Et₂O. The aqueous phase is acidified to pH 3 with 1 N H₃PO₄ and extracted with two 150 mL portions of EtOAc. These organic extracts are washed with brine, dried over Na₂SO₄, filtered through Celite and concentrated to give 7 as a semisolid. Crude 7 is dissolved in 250 mL of CHCl₃; a solution of 1.6 mL of bromine (1 equiv) in 10 mL of CHCl₃ is added dropwise over 5 min, and the resultant solution is allowed to stir at ambient temperature for 1 h. The volatiles are removed in vacuo; residual bromine is chased with CHCl₃. The residue is dissolved in 250 mL of CHCl₃ and cooled to -20 °C; 8 mL of DBU is added dropwise, and the resultant solution is warmed to ambient temperature and stirred for 15 h. The volatiles are removed in vacuo; the residue is taken up in 600 mL of 0.1 N aq NaOH and stirred for 3 h with 100 mL of Et₂O. The ether extract is removed; the aqueous phase is acidified to pH 3 with 1 N H₃PO₄ and extracted with two 150 mL portions of EtOAc. These organic extracts are washed with brine, dried over Na₂SO₄, and filtered through Celite. Reduction in volume to ca. 75 mL provides a solid, which is collected by filtration to give 3.4 g (27% yield) of 1. Further concentration of the mother liquors provides a second crop of solid 1 (0.9g, 7%).

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Analytical data for compound 1: ¹H NMR (DMSO, 400 MHz): δ = 7.67 (d, 2 H, J = 7.4 Hz), 7.54 (t, 1 H, J = 7.4 Hz), 7.40-7.50 (m, 10 H), 7.15-7.20 (m, 4 H), 6.77 (s, 1 H), 2.83 (m, 2 H), 2.38 (m, 2 H). ¹³C NMR (DMSO, 100 MHz):
δ = 197.0, 174.0, 152.6, 143.9, 140.7, 139.5, 138.1, 137.7, 133.1, 128.9, 128.8, 128.5, 128.2, 128.1, 127.4, 127.3, 127.1, 126.9, 126.0, 123.0, 33.5, 22.1. MS (ESI+): m/z = 405, 423, 445. MS (ESI-): m/z = 421.