[(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate

Conditions: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of simvastatin phenylboronate (5.22 g, 0.010 mol), toluene (31 mL), and neopentyl glycol (1.11 g, 0.0107 mol) was heated under a nitrogen atmosphere at 77 to 79° C. for 1 hour and 40 minutes. The solution was concentrated under reduced pressure at a bath temperature of 60° C. to a final volume of 5 mL and n-heptane (160 mL) was added at a temperature of 50-60° C. The crude simvastatin was filtered and washed with heptane to provide 3.17 g (76%) of simvastatin. By appropriate manipulation of the conditions and reagents, compounds such as the compactin analogue of simvastatin may be prepared. The solution was concentrated under reduced pressure at a bath temperature of 60° C. to a final volume of 5 mL and n-heptane (160 mL) was added at a temperature of 50-60° C The crude simvastatin was filtered washed with heptane

Conditions: temp:106.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of simvastatin phenylboronate (30.0 g) and 1,3-propanediol (450 mL) was heated at 105 to 107° C. at 0.2 mm Hg. After 1 hour, 182 mL of distillate was collected and the reaction was cooled to 20 to 25° C. Deionized water (270 mL) was added and toluene (3×75 mL) was used to extract the mixture. The combined toluene layers were washed with water (2×30 mL). The organic solution was heated at reflux for 1 hour and water was azeotropically removed. The solution was concentrated to a final volume of 24 mL under vacuum at 48 to 50° C. To the concentrated solution was added hexanes (215 mL) over 10 minutes. The resulting slurry was cooled to 0 to 5° C. and filtered. The crude simvastatin was washed with 0 to 5° C. hexanes and dried under vacuum to yield 21.0 g (88%) of simvastatin. 182 mL of distillate was collected the reaction was cooled to 20 to 25° C Deionized water (270 mL) was added to extract the mixture The combined toluene layers were washed with water (2×30 mL) The organic solution was heated at reflux for 1 hour water was azeotropically removed The solution was concentrated to a final volume of 24 mL under vacuum at 48 to 50° C To the concentrated solution was added hexanes (215 mL) over 10 minutes The resulting slurry was cooled to 0 to 5° C. filtered The crude simvastatin was washed with 0 to 5° C. hexanes dried under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Alternatively, III may be dissolved in an organic solvent and recirculated over a supported diol or polyol stationary phase to which the boronate moiety of III becomes attached. The organic solution is concentrated to obtain simvastatin. The organic solution is concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Alternatively, III may be agitated in a mixture of water and an organic solvent, preferably methanol, under high dilution conditions to produce simvastatin in its acid form. Simvastatin acid may be isolated by extraction or crystallization and relactonized to produce simvastatin.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Simvastatin boronate (III) is heated in the presence of a suitable diol solvent selected from ethylene glycol, 1,3-propanediol, or neopentyl glycol, under thermal conditions. The product is isolated by concentration of the reaction mixture, dilution with water, and extraction with an organic solvent. The organic solvent is concentrated to a minimum volume and simvastatin is isolated by the addition of a cosolvent and filtration. The organic solvent is concentrated to a minimum volume

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In U.S. Pat. No. 4,820,850 (89)/CA 1,287,063 (91, Merck), lovastatin is reacted with butylamine to produce lovastatin butylarnide. The two hydroxy groups in the butylamide are protected with tert-butyldimethylsilyl chloride to produce a disilylated lovastatin butylamide. The disilylated lovastatin butylamide is enolized with lithium pyrrolidide and the enolate is alkylated with methyl iodide to produce a disilylated simvastatin butylamide on aqueous workup. The silyl protecting groups are removed using hydrofluoric acid to produce simvastatin butylamide. The simvastatin butylamide is hydrolyzed using sodium hydroxide and, following acidification, the dihydroxy acid form of simvastatin is obtained. The dihydroxy acid compound is reacted with ammonium hydroxide to produce an ammonium salt which is then relactonized by heating to produce simvastatin.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.43 g (3.42 mmole) of simvastatin lactone was dissolved in 10 mL acetonitrile and treated with water (5 mL) and sodium hydroxide (151 mg, 3.78 mmole). The reaction was stirred at room temperature for 3 days, at which time analytical thin-layer chromatography using 4:1 methylene chloride:acetone eluent indicated essentially complete conversion of the starting lactone to a more polar product. The reaction mixture was then diluted to 50 mL with 1:1 acetonitrile:water, frozen and lyophilized to afford 1.22 g (2.66 mmole, 77.8%) of simvastatin sodium as a fluffy white solid. The 400 MHz 1H nuclear magnetic resonance (NMR) spectrum was consistent with the sodium carboxylate product. 1H NMR (Me2SO-d6) δ 7.6 (br s, 1H), 5.95 (d, 1H), 5.8 (in, 1H), 5.5 (s, 1H), 5.1 (s, 1H), 4.6 (s, 1H), 3.7 (br s, 1H), 3.5 (br s, 1H), 2.3 (m, 2H), 2.2 (d, 1H), 2.0 (m, 2H), 1.8 (m, 2H), 1.6–1.3 (5H), 1.2 (br s, 3H), 1.0 (9H), 0.80 (m, 3H), 0.75 (m, 3H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: simvastatin (Zocor); pravastatin (Pravachol); fluvasatin (Lescol).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: statins, for example atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin;

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: statins, for example atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin;

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: simvastatin (Zocor); pravastatin (Pravachol); fluvasatin (Lescol).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: simvastatin (Zocor); pravastatin (Pravachol); fluvasatin (Lescol).