Atorvastatin synthesis

Figure 3.5 Directed evolution applied to enzymes for the production of atorvastatin synthesis intermediates. The substrates and products of the evolved enzymes are shown...

Radi S, Stach J, Hajicek J. An improved synthesis of 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for atorvastatin synthesis. Tetrahedron Lett. 2002 43 2087-2090. 

Pandey PS, Rao TS. An efficient synthesis of N3,4-diphenyl-5-(4-fiuorophenyl)-2-isopropyl-lH-3-pyrrolecarboxamide, a key intermediate for atorvastatin synthesis. Bioorg. Med Chem. Lett. 2004 14 129-131. 

Atorvastatin, structure of, 105. 516 ATP (see Adenosine triphosphate) ATZ, see Anilinothiazolinone, 1031-1032 Aufbau principle. 6 Axial bonds (cyclohexane), 119 drawing, 120 Azide, amines from, 929 reduction of, 929 Azide synthesis, 929 Azo compound, 944 synthesis of, 944-945 uses of. 945... 

Liu, J.J., Hsu, C.C. and Wong, C.-H. (2004) Sequential aldol condensation catalyzed by DERA mutant Ser238Asp and a formal total synthesis of atorvastatin. Tetrahedron Letters, 45, 2439-2441. 

A summary of the industrial-scale process development for the nitrilase-catalyzed [93] route to ethyl (/ )-4-cyano-3-hydroxy-butyrate, an intermediate in the synthesis of Atorvastatin (Pfizer Lipitor) from epichlorohydrin via 3-hydroxyglutaronitrile (3-HGN) was recently reported (Figure 8.15) [94], The reaction conditions were further optimized to operate at 3 m (330 gL ) substrate, pH 7.5 and 27 °C. Under these conditions, 100% conversion and product ee of 99% was obtained in 16 h reaction time with a crude enzyme loading of 6% (based on total protein, 0.1 U mg-1). It is noted that at pH < 6.0 the reaction stalled at <50% conversion and at alkaline pH a slowing in reaction rate was observed. Since the starting material is of low cost and the nitrilase can be effectively expressed in the Pfenex (Pseudomonas) expression system at low cost, introduction of the critical stereogenic center... 

Figure 8.15 Nitrilase-catalyzed route to ethyl (f )-4-cyano-3-hydroxybutyrate, an intermediate in the synthesis of Atorvastatin...

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

Scheme 12. Nitrilase-catalyzed synthesis of atorvastatin intermediate by directed evolution...

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

An enzyme (see Section 2.6) called HMG-CoA reductase is involved in the biosynthesis of cholesterol. Drugs such as atorvastatin (Lipitor) and simvastatin (Zocor) are competitive inhibitors of HMG-CoA reductase. They inhibit cholesterol synthesis by increasing the number of LDL receptors to take up the LDL. 

Scheme 1.25 Chemical synthesis of the atorvastatin side chain...

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. 

The answer is d. (Hardman, pp 885-886. Katzung, pp 591-592.) Atorvastatin is a structural analogue of an intermediate formed from the action of HMG-CoA reductase. This could result in a modest decrease in plasma cholesterol. Hepatic cholesterol synthesis may decrease significantly however, nonhepatic tissues increase their rate of synthesis as a compensatory mechanism. The other and perhaps more important effect of the HMG-CoA inhibitors is to increase high-affinity LDL receptors. The plasma LDL is lowered by this action because of an increase in the catabolic rate of LDL and hepatic extraction of LDL precursors. 

Atorvastatin, simvastatin, rosuvastatin Inhibit HMG-CoA reductase Reduce cholesterol synthesis and up-regulate low-density lipoprotein (LDL) receptors on hepatocytes modest reduction in triglycerides Atherosclerotic vascular disease (primary and secondary prevention) t acute coronary syndromes Oral duration 12-24 h Toxicity Myopathy, hepatic dysfunction Interactions CYP-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors... 

Scheme 9. Convergent, enantiospecific synthesis of atorvastatin calcium (1).

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. 

Co-enzyme Q10 concentrations were measured in blood from hypercholesterolemic subjects before and after exposure to atorvastatin 80 mg/day for 14 and 30 days in 34 subjects eligible for statin treatment (11). The mean blood concentration of co-enzyme Q10 was 1.26 pg/ml at baseline, and fell to 0.62 after 30 days of atorvastatin therapy. There was a statistically significant fall detectable after 14 days of treatment. The authors concluded that widespread inhibition of co-enzyme Q10 synthesis could explain the exercise intolerance, myalgia, and myoglobinuria that are observed with statin treatment. 

In a randomized crossover study rifampicin reduced the total AUC of atorvastatin and increased the Qnax of 2-hydroxyatorvastatin acid by 68% (101). It is advisable to increase the dosage of atorvastatin and preferable to administer it in the evening to guarantee adequate concentrations during the period of rapid cholesterol synthesis that occurs at night when rifampicin or other potent inducers of CYP3A4 are co-administered. 

Lescol , Novartis) and atorvastatin (Lipitor , Pfizer) are accessible through enzymatic synthesis. 

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