Ppar-sparing thiazolidinediones and combinations for the treatment of diabetes mellitus and other metabolic diseases
A diabetes, DPP4 technology, applied in metabolic diseases, drug combinations, medical preparations containing active ingredients, etc., can solve problems such as unpleasant side effects of sodium reabsorption, and achieve the effect of small side effects
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Embodiment 1
[0467] Example 1: 5-[4-(2-oxo-2-phenylethoxy)benzyl]-1,3-tetrahydrothiazole-2,4-dione.
[0468]
[0469] Step 1. Preparation of 4-(2-hydroxy-2-phenylethoxy)benzaldehyde.
[0470] To 2-(4-fluorophenyl)oxirane (6.50 g, 54.0 mmol) was added toluene (85 mL), 4-hydroxybenzaldehyde (9.89 g, 81.0 mmol), PEG4000 (polyethylene glycol, 1.15 g ) and 1M NaOH (85 mL), and the stirred mixture was heated at 78 °C overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc, and the organic phase was washed with brine, dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The resulting yellow oil was chromatographed on a medium silica gel column eluting with 0-10% EtOAc / DCM. will mainly contain higher R f The spotty fractions were combined and evaporated in vacuo to give 1.85 g (14%) of the title compound as a yellow oil. Fractions containing mainly the lower Rf spot were combined and evaporated in vacuo to give 0.64 g of the regioisomer as a colorless ...
Embodiment 2
[0477] Example 2: Preparation of 5-{4-[2-(4-fluorophenyl)-2-oxoethoxy]benzyl}-1,3-tetrahydrothiazole-2,4-dione.
[0478]
[0479] Step 1: Preparation of 4-[2-(fluorophenyl)-2-hydroxyethoxy]benzaldehyde
[0480] To a stirred solution of 2-(4-fluorophenyl)oxirane (5.60 g, 40.0 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (7.40 g, 61.0 mmol), 1M NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the reaction mixture was heated at 78°C overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc (2x150 mL), and the combined extracts were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed on silica gel eluting with 30-40% EtOAc / hexanes. will contain higher R f Fractions from the high spot were combined and evaporated in vacuo to give 2.38 g of the regioisomer of the product as a white solid. will contain lower R f Fractions from the high spot were com...
Embodiment 3
[0487] Example 3: Preparation of 5-{4-[2-(2-fluorophenyl)-2-oxoethoxy]benzyl}-1,3-tetrahydrothiazole-2,4-dione.
[0488]
[0489] Step 1: Preparation of 2-(2-fluorophenyl)oxirane
[0490] To a solution of o-fluorostyrene (5.0 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 mL) and water (78 mL) was added N-bromosuccinyl in three portions at 0 °C Amine (8.02 g, 45.0 mol). The reaction was warmed to room temperature and stirred overnight. Sodium carbonate (8.68 g, 81.9 mmol) was added in portions, followed by 1M NaOH (ca. 10 mL), and the reaction was stirred at room temperature overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford 5.31 g (94%) of the title compound as a pale oil which was used without further purification. C 8 h 7 m / zMS(ESI+)138.1(M+H) of FO + .
[0491...
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