Ethyl -4-cyano-3-hydroxybutyrate

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

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

Polymerizable 3-(2-cyano-acryloyloxy)-butyric acid ethyl ester has been prepared in a two-step process using 3-hydroxybutyrate and cyanoacetic acid followed by treatment with formaldehyde. This and related alkyl ester cx-cyanoacrylate monomers are useful as tissue adhesives/sealants in surgical and related medical applications. 

Essential for the economics of the overall process is a simple way to make the amino-component available. A pivotal intermediate is therefore the R)-4-cyano-3-hydroxybutyrate ester, which is accessible by various routes. [397] In variant a) ethyl 4-chloroacetoacetate is reduced enantioselectively with a ketoreductase, and the chlorine is replaced enzymatically by cyanide (Codexis technology). [398]... 

In addition to the compounds listed in Table I, corresponding basic derivatives of the following acids have been reported crotonic isocrotonic levulinic succinic cyano-acetic mono-, di-, and trichloroacetic monobromoacetic monochloro- and monobromopropionic lactic glycolic ethyl- and phenylglycolic (a-hydroxybutyric and mandelic, respectively) and salicylic. Confirmatory evidence for the identities of most of these is completely lacking. 

Atorvastatin calcium (35) is the adive compound of Lipitor that is used as cholesterol-lowering drug. The key motif of this derivative is ethyl (R)-4-cyano-3-hydroxybutyrate [73]. The authors proposed a two-step process that involved the use... 

For conversion of (RH-cyano-3-hydroxybutyrate 15 to ethyl (R)-4-cyano-3-hydroxybulyrate 17,15 (239.5 g) was dissolved in absolute ethanol (480 ml). Concentrated sulphuric acid (3.3 ml) was charged and the mixture was heated at reflux (80°C) for 2.25 h, after which time the conversion was complete. Ethanol was evaporated in vacuo to yield the crude product 17 (290 g, yield 99% ee 98.7%) which was purified by two passes through a wiped film evaporator. The final product 17 was obtained as a colorless liquid (181.5 g, 62% yield) in 97% purity and 98.8% ee. [47]. 

The key chiral building block is hydroxynitrile (HN) or ethyl (7 )-4-cyano-3-hydroxybutyrate whose demand is estimated to be about 200 metric tons annually. Traditional commercial processes are based on ... 

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