Fluvastatin synthesis

Lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin T LDL catabolism i LDL synthesis i Cholesterol Tldl... 

Biocatalytic Synthesis of 6-Hydroxy Fluvastatin using Mortierella rammaniana DSM 62752 in Shake Flask Culture and on Multi-gram Scale using a Wave Bioreactor... 

Figure 12.3 Synthesis of 5- and 6-hydroxy fluvastatin by microbial biotransformation...

Procedure 3 Synthesis of 6-Hydroxy Fluvastatin with M. rammaniana DSM 62752 in a BioWave Bioreactor on 22 L Scale... 

The synthesis of 6-hydroxy fluvastatin with M. rammaniana DSM 62752 gave high conversion (>95 %) in shake flask culture on 400 mL scale with 0.1 g L of fluvastatin as well as on 22 L scale in a Wave bioreactor-fed batch process at a final substrate concentration of 0.4 g L Instead of the partial purification by a second solid-phase extraction described above, 6-hydroxy fluvastatin can be obtained in high purity ( 95 %) by, for example, preparative medium-pressure liquid chromatography (MPLC) on RP18 silica gel. ... 

Endocrine effects Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Small declines in total testosterone with no commensurate elevation in LH have been noted with the use of fluvastatin. Pravastatin showed inconsistent results with regard to possible effects on basal steroid hormone levels atorvastatin, lovastatin, rosuvastatin, and simvastatin did not reduce basal plasma cortisol concentration or basal plasma testosterone concentration or impair adrenal reserve. Appropriately evaluate patients who display clinical evidence of endocrine dysfunction. Exercise caution when administering HMG-CoA reductase inhibitors with drugs that affect steroid levels or activity, such as ketoconazole, spironolactone, and cimetidine. 

In this chapter we will consider the synthesis of several other second-generation HMG-CoA reductase inhibitors that have been approved for the treatment of patients at risk for CHD due to elevated cholesterol levels. We will first consider fluvastatin (1), marketed as Lescol , which was launched in 1994. Subsequently, we will examine the synthetic stories of rosuvastatin (2), marketed as Crestor , and pitavastatin (3), marketed as Livalo . 

Although this early synthesis of the fluvastatin template (Scheme 12.1) was important for strucmre-activity smdies, a second synthesis (Scheme 12.2) was later developed to facilitate large-scale production of fluvastatin (Repic et al., 2001). As is typical in process development work, this second approach sought to shorten the reaction sequence, eliminate toxic reagents (such as tri-n-butylstannylvinylethoxide), and improve the yield and/or selectivity of reactions in order to reduce the amount of chromatography required to isolate the products. 

Whereas several anti-cholestemic drugs are produced wholly by fermentation, the side chain of several others is accessible through enzymatic synthesis. (3R,5S)-Dihydroxyhexanoate, a key intermediate of fluvastatin, is accessible by reduction of the diketo acid, either by bioreduction with whole cells (85% yield, 97% e.e.), or cell extracts (72% yield, 98.5% e.e.), or, for syn-(3h,5.S)-dihydroxy-6-Cl-hexanoate, regioselective and (ft)-specific reduction with ADH to yield (5S)-6-chloro-3-ketohexanoate. 

Fluvastatin (Lescol, 13.52) is a cholesterol lowering drug (Figure 13.14). Over 50 tons of fluvastatin were produced in 2007, so the producer of fluvastatin requires a very high-throughput synthesis of the drug.20... 

The balanced reaction for a synthesis of an intermediate (13.57) for a fluvastatin analogue is shown here. This reaction relies on a vinyl stannane (13.a). Stannanes are toxic and generate large amounts of waste. Calculate the atom economy for this reaction. 

The HMG-CoA reductase inhibitors (Statins like simvastatin, lovastatin, pravastatin, fluvastatin, etc.) inhibit the enzyme and thereby decrease the hepatic cholesterol synthesis and increase the synthesis of LDL receptors causing increased clearance of LDL and a reduced concentration of LDL cholesterol in plasma. HMG-CoA reductase inhibitors are used to treat elevated LDL which also causes a small reduction in plasma triglycerides and an increase in HDL cholesterol. 

Modulation of epidermal hpid biosynthesis has been reported to boost dmg delivery. It has also been suggested that it is both the hydrophobic nature of the lipids as well as their tortuous, extracellular localization that are responsible for the restriction in the transport of most molecules across the stratum corneum. The function of this barrier depends on three key lipids cholesterol, fatty acid, or ceramides. Delays of synthesis ceramides in the epidermis have been reported as means of barrier perturbation. Inhibitors of lipid synthesis were used to enhance the trans-dermal delivery of lidocaine or caffeine. Alteration of barrier function was produced by either the fatty acid synthesis inhibitor 5-(tetradecyloxy)-2-fiirancarboxylic acid, the cholesterol synthesis inhibitor fluvastatin, or the cholesterol sulfate, which resulted in a further increase in lidocaine absorption (33). 

Fluvastatin is an antihyperlipidemic/HMG-CoA reductase inhibitor that increases the rate at which the body removes cholesterol from blood and reduces production of cholesterol in the body by inhibiting enzyme that catalyzes an early rate-limiting step in cholesterol synthesis, increases HDL, and reduces LDL, VLDL, and triglycerides. 

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