Statins atorvastatin intermediate

For the synthesis of atorvastatin we developed an efficient process that allows for direct cyanation of lactone 2 [21] to cyanomethyl lactone 3 to finally afford the well known atorvastatin precursor 5 (Scheme 6.3) [22]. It is worth pointing out that the two synthetic routes to the advanced statin intermediates 5 and 6 described here avoid ultra-low temperature chemistry, heavy metal catalysts, metal-organic species, and chromatographic purification steps. The DERA-catalyzed chemistry to form the six-carbon chiral unit is cost competitive and operated on a commercial scale. 

In another development, the statin side chain en route to Atorvastatin (Lipitor , Pfizer) is synthesized via the key intermediate alkyl 3-hydroxy-4-cyanobutyrate (Figure 13.17). Instead of the currently practiced six-step route, a much more concise three-step route starts from epichlorohydrin via Cl chain length enhancement by both nucleophilic substitution of chloride and nucleophilic ring opening of the epoxide with cyanide to yield symmetric dicyanoisopropanol. Nitrilase action desymmetrizes the dinitrile intermediate with the creation of a chiral center in C3 to yield (R)-3-hydroxy-4-cyanobutyrate, which is esterified to the key intermediate ethyl (R)-3-hydroxy-4-cyanobutyrate. 

The first entirely synthetic derivative, fluvastatin (see Ref. [19]), and its subsequent derivative, atorvastatin, have a lipid solubility that is intermediate between pravastatin and the lactone prodrugs (see Tab. 4.2), and consequently their liver specificities are less expressed. In order to benefit from selective statin uptake mechanism into the liver cells and thereby decrease passive diffusion into other cell types, the recently introduced rosuvastatin molecule was purposefully made more hydrophilic by the introduction of a sulfonamide group. Indeed, the ratio of IC5 values measured in fibroblasts and hepatocyte cultures became considerable higher than that of atorvastatin (see Tab. 4.1). The pronounced differences of inhibitory potency, lipophilicity and the extent of active OATP-linked transport jointly... 

Itraconazole increases the risk of skeletal muscle toxicity of some statins by increasing their serum concentrations, but not all statins are equally affected. Concomitant use of atorvastatin, lovastatin, and simvastatin with itraconazole should be avoided or the doses should be reduced fluvastatin and pravastatin have much less potential than other statins for chnically significant interactions with itraconazole and other CYP3A4 inhibitors the effects of cerivastatin are intermediate. 

Lovastatin is a member of a class of drugs (atorvastatin and simvastatin are others in this class) called statins that are used to treat hypercholesterolemia. The statins act as competitive inhibitors of the enzyme HMG-CoA reductase. These molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues. While the statins are bound to the enzyme, HMG-CoA cannot be converted to mevalonic acid, thus inhibiting the whole cholesterol biosynthetic process. Recent studies indicate that there may be important secondary effects of statin therapy because some of the medical benefits of statins are too rapid to be a result of decreasing atherosclerotic lesions. Statin therapy has been associated with reduced risks of dementia, Alzheimer disease, ischemic cerebral stroke, and other diseases that are not correlated with high cholesterol levels. Although this is still an active area of research, it appears that the pleiotropic effects of statins may be a result of a reduction in the synthesis of isoprenoid intermediates that are formed in the pathway of cholesterol biosynthesis. 

ADH from Lactobacillus brevis (IBADH) was used for the synthesis of a statin side chain, used as an alternative key intermediate in the synthesis of atorvastatin (Figure 13.2). In this variant, the NADPH-dependent enzyme was highly regio-and stereoselective, reducing fert-butyl 6-chloro-3,5-dioxohexanoate to tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate in 72% yield and with >99.5% ee. The cofactor was recycled in a coupled-substrate approach [1], where isopropanol was concomitantly oxidized to acetone at the expense of NADP, thereby driving the reaction toward product formation. Crude cell extract of recombinant LBADH expressed in E. coli was used in a fed-batch system on 8 1 scale, and a TTN of 2x10 could be calculated for IBADH [13-15]. 

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