(S)-1-(4-Fluorophenyl)-5-(2-oxo-4-phenyloxazolidin-3-yl)pentane-1,5-dione

Off-White Solid

Preparation of ezetimibe; (1-1) Preparation of 3-[5-(fluorophenyl)-l, 5-dioxapentyl]-4(S)- phenyl-2-oxazolidinone (Formula 7); 200 g of 5-(4-fluorophenyl)-5-oxopentanoic acid of formula 8, 16O g of (S)-4-phenyloxazolidine-2-one of formula 9, and 11.6 g of 4-dimethylaminopyridine were dissolved in 600 m.pound. of dichloromethane to prepare a reaction mixture. A solution which was prepared by dissolving 157 g of N, N'-dicyclohexylcarboimide in 200 ml of dichloromethane was added to the reaction mixture and stirred for 2 hours. After completion of the reaction, the resulting reaction mixture was filtered to remove by-products. The filtrate thus obtained was washed successively with 1 I of 6N HCl, 1 .euro. of water, and 1 .euro. of saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and distilled under a reduced pressure to remove the solvent. The residue thus obtained was dissolved in 2 I of methanol by heating and cooled to induce crystallization. 2 .pound. of water was added thereto and stirred for 30 min. The solid thus obtained was isolated by filtering to obtain 289 g of the title compound as a white solid (yield: 86percent).5-(4-Fluorophenyl)-5-oxopentanoic acid (21.02 g, 100.0 mmol) and 4 dimethylamino- pyridine (16.25 g, 133.0 mmol) were dissolved in N, N-dimethylformamide (100 mL, 1.0 M) to afford a copious white precipitate suspended in solution. The reaction was cooled to 2 To the soulution of compound 2 (700 g, 3.33 mol, 1.1 eq) dissolved in THF (5 L) was added triethylamine (1.2 L, 7.87 mol, 2.6 eq) at room temperature under NCompound I (21 g, 0.1 mol) was added to a 500 ml three-necked flask, Triethylamine 20 ml and dichloromethane 250 ml, Stuttgart dropwise pivaloyl chloride (14.4g, 0.12mol), (4S) -4-phenyl-2-oxazolidinone (24.5 g, 0.15 mol), DMF 5 ml, 4, 4-dimethylaminopyridine (1.22 g, 0.01 mol) was added after refluxing for 3 h, After refluxing for 10 h, Ice bath cooling, Then, 200 ml of 5 M hydrochloric acid was added dropwise at 0 ° C, Static stratification, The lower methylene chloride layer was washed successively with saturated sodium bicarbonate solution and water, Dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness, To give 24.9 g of a white solid compound II, Yield 70percent.The compound (4) (30 g, 142.72 mmol) Triethylamine (26 g, 256.91 mmol) was dissolved in dichloromethane (150 ml)Cooling to 5 to 10 ° C, dropwise addition of pivaloyl chloride (17.3g, 142.62mmol), System has exothermic, 30min drop finished, 5 to 10 deg C insulation reaction 2h, To the reaction system was added (S) -4-phenyl-2-oxazolidinone (23.3 g, 142.76 mmol) DMAP (2.4 g, 19.63 mmol), DMF (15 ml), Exothermic The temperature rose to 15 ° C, Heated to 45 reflux reaction 3h, Down to room temperature, Plus dichloromethane (150 ml), The organic phase was washed with water (60 ml) 1N hydrochloric acid (120 ml) Water (60ml) 2.5percent aqueous sodium hydroxide solution (180 ml) Add water (50ml) wash, Organic phase concentrated dry, Plus isopropyl alcohol (60 ml), Stirring for 24 h, Filter, Add isopropyl alcohol (10ml) leaching, To give a white solid, I.e. compound (5) (34.4 g, 68percent yield).Three were added 250ml Flask the In 10g (the S) -3- acryloyl-4-phenyl-2-One (0.046 mol, 1 eq), 14.3g ((l- (4-fluorophenyl) ethenyl) Oxy) trimethylsilane (0.069 mol, for 1.5 eq), 0.12g of iodine (0.0046 mol, 0.10 eq) and toluene 100ml, at 40 stirred until the reaction was complete, then 100ml water was added 0.5g sodium thiosulfate and stirred 30 minutes, the organic phase was separated, the resultingOrganic Phase WAS Washed the with 200ml of Water Twice, at The solvent WAS Evaporated under reduced pressure to give at The crude Product, at The crude Product IS the then recrystallized from 50ml of Isopropanol to give 15.5 G of Product, a yield 94percent.Step 1A. Preparation of (4S)-4-phenyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1, 3 -oxazolidin-2-one (A1 R

Molecular Weight:355.4
XLogP3:2.9
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:6
Exact Mass:355.12198622
Monoisotopic Mass:355.12198622
Topological Polar Surface Area:63.7
Heavy Atom Count:26
Complexity:524
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes