Lipitor synthesis

The study concerns the desymmetrization of the prochiral dinitrile (16) with preferential formation of the (Ji)-17, which was known to be a chiral intermediate in the synthesis of the cholesterol-lowering therapeutic drug (18) (Lipitor, Sortis, Torvast, etc.) as shown in Scheme 2.3. 

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... 

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. 

The Stetter reaction has also been shown to be an important tool in the synthesis of CI-981, also known as LIPITOR [96]. Roth and co-workers demonstrate the ability of commercially available starting materials 153 and 154 to couple in the presence of 20 mol% thiazolium pre-catalyst 121 (Scheme 23) [97, 98]. Amide 155 was obtained in 80% yield and allowed for the convergent synthesis of CI-981 in nine steps. 

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

Figure 13.17 Novel synthesis route to Lipitor as developed by Diversa (Rouhi, 2002).

This category includes atorvastatin (Lipitor), fluvas-tatin (Lescol), lovastatin (Mevacor), pravastatin (Prava-chol), and simvastatin (Zocor) (Table 25-2). These drugs, known commonly as statins, are characterized by their ability to inhibit an enzyme known as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.96 This enzyme catalyzes one of the early steps of cholesterol synthesis, and drugs that inhibit HMG-CoA reductase decrease cholesterol produc-... 

Lactone 7 can serve as a versatile starting material for the synthesis of a range of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, commonly referred to as statins, which includes Lipitor (8) and Crestor (9) compounds (Scheme 20.7). In a single transformation, the lactone ring can be opened and the chloride can be displaced by either cyanide or hydroxide to access advanced Lipitor or Crestor intermediates, respectively. 

The scale of production of a fine chemical can range from a few t/a up to tens of kt/a. Two of the final intermediates in the synthesis of the world s top selling drug, the anticholesterol Lipitor , or atorvastin, are only produced on a scale of 500 t/a each. The consequence of the smaller scale and more specialist nature of these industries, is that the processes are far more likely to be batch or discontinuous. Thus process units will be flexible to produce more than one product and the product s lifetime in the market may be comparatively short, either for economic or performance reasons. However, product added value is high. 

You decide to treat a patient who has very high levels of serum cholesterol with the statin drug Lipitor (atorvastatin). You know that this drug acts in the metabolic pathway leading to the synthesis of cholesterol. The substrate for the enzyme inhibited by the statin drugs is which of the following ... 

SCHEME 1.1 Green chemistry efficiency in the synthesis of atorvastatin (Lipitor ) by Codexis scientists. Codexis researchers engineered three enzymes to create a more efficient biocatalytic process to make hydroxynitrile, the intermediate that forms the chiral dihydroxy acid side chain essential to atorvastatin s synthesis. rom Angewandte Chemie International Edition, 44, 362, 2005. With permission.)... 

Lovastatin (Mevacor ) (3), simvastatin (Zocor ) (15), pravastatin (Pravachol ) (19), atorvastatin (Lipitor ) (20), cerivastatin (Baycol , withdrawn on August 1, 2003) (21), and fluvastatin (Lescol ) (22) were introduced to lower total cholesterol levels, and especially LDL-cholesterol levels to prevent coronary heart disease. These HMG-CoA inhibitors inhibit de novo synthesis of cholesterol in the liver. The rate-limiting enzyme in cholesterol synthesis is HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonate. The resulting decrease in hepatic cholesterol synthesis leads to increased synthesis of... 

An interesting account of this is provided in Chapter 9, Atorvastatin Calcium (Lipitor) in Contemporary Drug Synthesis, Li, J.-J, Johnson, D.J., Sliskovic, D.R., Roth, B.D., Eds. (Wiley Interscience, Floboken, NJ,... 

Site-specific mutated 2-deoxyribose-5-phosphate aldolase (DERA) was used as catalyst for the synthesis of the key intermediate useful for the preparation of the cholesterol lowering drug atorvastatin (Lipitor) (De Santis et al. 2003). 

When Paal and Knorr discovered the pyrrole synthesis more than a century ago, they had no idea that the reaction bearing their names would have contributed greatly to the manufacture of atorvastatin (Lipitor). Indeed, synthesis of Lipitor is probably the tour de force for the Paal-Knorr pyrrole synthesis. 

Drugs that lower blood cholesterol by retarding its synthesis in the liver are called statins [165] and are epitomized by atorvastatin (Lipitor a pyrrole, not an indole). These drugs function by inhibiting the enzyme hydroxym-ethylglutaryl-coenzyme A (HMG-CoA), crucial for a step in the cholesterol biosynthesis pathway. The one indole... 

Green Biocatalysts for Production of Atorvastatin Codexis, Inc. has developed an enzyme-based process that has greatly improved the yield, efficiency, and safety record for manufacture of atorvastatin, the key building block for Lipitor , one of the world s best-selling drugs, that lowers cholesterol by blocking its synthesis in the liver. The new enzymatic process is dramatically faster and more efficient than previous methods, and also reduces cyanide-related waste, the use of solvents, and the need for purification equipment. 

Atorvastatin (Lipitor) is used to decrease patient serum cholesterol levels. It works by inhibiting an enzyme called HMG-CoA reductase. See "Connections to Biological Chemistry"in Section 10.2 for more information about the action of atorvastatin. In one synthesis of atorvastatin that produces the desired single enantiomer of the final product, the following reagents are used. Draw the structures of synthetic intermediates A and B. 

Atorvastatin (Lipitor) is a popular treatment for high cholesterol. See "The Importance of Hydrogen Bonding in Drug-Receptor Interactions"in Chapter 10 for more information about atorvastatin. One synthesis of atorvastatin involves the following enolate reaction. Draw the predominant product of this reaction, which gives an overall yield of 90%. 

We saw in Section 3.15 that statins (Lipitor, Zocor, Mevacor) lower serum cholesterol levels. These drugs are competitive inhibitors for the enzyme that reduces hydroxymethylglutaryl-CoA to mevalonic acid (page 1197). Recall that a competitive inhibitor competes with the substrate for binding at the enzyme s active site (Section 24.7). Decreasing the concentration of mevalonic acid decreases the concentration of isopentenyl pyrophosphate, so the synthesis of aU terpenes, including cholesterol, is decreased. As a consequence of diminished cholesterol synthesis, the liver forms more LDL receptors— the receptors that help clear LDL from the bloodstream. Recall that LDL (low-density lipoprotein) is the so-caUed bad cholesto-ol (Section 3.15). 

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