Method for preparing ezetimibe and intermediate thereof
A kind of technology of ezetimibe and compound, applied in the field of medicinal chemistry
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Embodiment 1
[0039] Example 1 1-(4-fluorophenyl)-5-((3aS,8aR)-2-carbonyl-2H-indeno[1,2-d]oxazolyl-3(3aH,8H,8aH)- base) pentane-1, the synthesis of 5-dione (compound IV)
[0040]
[0041] Under the protection of nitrogen, 5-(4-fluorophenyl)-5-oxopentanoic acid (Shanghai Kailu Chemical Co., Ltd.) (30g) and diisopropylethylamine (40.8mL, 1.73eq) were dissolved at 0°C in dichloromethane (150ml), then trimethylacetyl chloride (17.6mL, 1.0eq) was added dropwise to the reaction over 30 minutes. Keep stirring the reaction solution at 0°C for about 3 hours, then add (3aS,8aR)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (tri Cycloindenoxazole) (25g, 1.0eq), 4-dimethylaminopyridine (1.745g, 0.1eq) and dry DMF (25ml), warmed to reflux and maintained at this temperature for about 4 hours. Then, after cooling to 10°C, the reaction solution was slowly added to 2N H 2 SO 4(160ml), a solid precipitated out, filtered the precipitate, and dried to obtain 44.5g of 1-(4-fluorophenyl)-5-((3aS, 8aR)...
Embodiment 2
[0042] Example 2 (3aS, 8aR)-3-((S)-5-(4-fluorophenyl)-5-hydroxypentanoyl)-3,3a,8,8a-tetrahydro-2H-indeno[1 , 2-d] Synthesis of oxazolyl-2-one (compound II)
[0043]
[0044] (+)-diisopinepinyl chloride borane heptane solution (Shanghai Feiteng Chemical Co., Ltd.) (69.1ml, 1.2eq, 62%) was added to a solution of compound IV (39g) in tetrahydrofuran (200ml) and kept at Stir at 30°C for 5 hours, then cool to 10°C, add diethylamine (26.5ml, 2.6eq), continue to stir for 2 hours, filter off the precipitate, wash the filter cake with tetrahydrofuran (20ml) and combine the organic phases with water (100ml) The organic phase was washed with water and brine (50ml) and concentrated to give a yellow oil. The oil was dissolved with 110ml of petroleum ether / ethyl acetate=10:1 (v / v), stirred for 14 hours, a white solid precipitated, filtered, and dried to obtain 33.5g of the title compound II, with a yield of 86%. h 1 NMR (300MHz, CDCl 3 ): δ1.82(m, 5H), 2.98(t, 2H), 3.41(s, 3H), 4.68(...
Embodiment 3
[0045] Example 3 (3aS)-3-((2R, 5S)-5-(4-fluorophenyl)-2-((S)-(4-fluorophenylamino)(4-(trimethylsilyloxy Base)phenyl)methyl)-5-(trimethylsilyloxy)pentanoyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazole-2- Ketone (Compound I, PG 1 =PG 2 = Trimethylsilyl) Synthesis
[0046] Under nitrogen protection, compound II (2.06g, 5.58mmol) and (E)-4-((4-fluorophenylamino)methyl)phenol (compound III) (2.401g, 11.15mmol) prepared in Example 2, 2.0eq) was added to dry dichloromethane (20ml), the reaction solution was cooled to -5°C, diethylamine (4.9ml, 29.28mmol, 5.25eq) was added slowly, and trimethylchlorosilane (2.7ml, 20.97mmol, 3.76eq), after the addition, the reaction solution was cooled to -25°C to -30°C, and TiCl was added slowly 4 (0.67ml, 6.13mmol, 1.1eq), Ti(OCH(CH 3 ) 2 ) 4 (0.6ml, 0.37mmol), after stirring for half an hour, keep the temperature at -25°C to -30°C, add acetic acid (1.6ml, 27.88mmol, 5.0eq), and continue stirring for half an hour. The reaction solution was ...
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