(3S,5R)-Atorvastatin synthesis

Yield:-

Reaction Conditions:

Stage #1: *,S^*)>-5-<2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-<(phenylamino)carbonyl>-1H-pyrrol-1-yl>-3-hydroxy-1-pentanoic acid, 2-hydroxy-1,2,2-triphenylethyl esterwith potassium hydroxide;water in methanol; for 4 h;Heating / reflux;
Stage #2: with hydrogenchloride in water;ethyl acetate; pH=2 - 2.5;

Steps:

5 Preparation of (R)-5-[2-(4-Fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester (5) from (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxy-1-pentanoic acid, (S)-2-hydroxy-1,2,2-triphenylethyl ester (2)

To a suspension of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxyl-1-pentanoic acid, (S)-2-hydroxy-1,2,2-triphenylethyl ester (2) (4.0 g) in 77 mL of MeOH/H₂O (3.5:1, v/v) was added potassium hydroxide (2.8 g). After refluxing for 4 hours the mixture was cooled to room temperature followed by addition of 26 mL water and stirring for 1-2 hours. The recovered (S)-1,1,2-triphenylethanediol was collected by filtration and washed with 30 mL of MeOH/H₂O (1:3, v/v). The solid was dried under reduced pressure at 45-50° C. (1.3 g). The filtrate was evaporated to remove methanol and then 50 mL ethyl acetate was added. The mixture was adjusted to pH 2-2.5 with 1 M HCl solution and the layers were separated. The aqueous phase was further extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered and evaporated. The residue was dissolved in 20 mL THF followed by addition of 1,1'-carbonyldiimmidazole (0.91 g). After stirring for 3 hours at room temperature, the magnesium salt prepared from reaction of magnesium ethoxide (0.86 g) and mono-tert-butyl malonate (2.5 g) in THF was added. The mixture was stirred for 20 hours at room temperature and then the solvent was removed at reduced pressure. The residue was partitioned between ethyl acetate and aqueous 1 M HCl and the layers were separated. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were washed with aqueous saturated NaHCO₃ and brine. After drying and purifying, the β-ketoester 5 (0.48 g) was produced. The analytical data are consistent with the assigned structure. ¹H-NMR (300 MHz, CDCl₃): δ/ppm=1.45(s,9H), 1.53(dd,6H,J₁=1.8 Hz,J₂=7.1 Hz), 1.50-1.80(m,2H), 2.50(s,1H), 2.53(d,1H,J=1.9 Hz), 3.30(s,2H), 3.49-3.61(m,1H), 3.87-4.00(m,2H), 4.08-4.20(m,1H), 6.85(s,1H), 6.95-7.10(m,5H), 7.10-7.22(m,9H).

References:

US2005/203302,2005,A1 Location in patent:Page/Page column 5