Hydroxyglutaronitrile

A mixture of 493 g. (2.00 moles) of magnesium sulfate hepta-hydrate and 700 ml. of tap water is stirred for 5 minutes and filtered into a 2-1. three-necked flask equipped with a mechanical stirrer and an alcohol thermometer that dips into the solution. The flask is immersed in a cooling bath (Note 1), the stirrer is started, and the solution is cooled to 10°. To the solution is added, in one portion, 143 g. (2.20 moles) of potassium cyanide Caution Toxic), and the stirring is continued for 45 minutes at 8-12° (Note 2). The solution is maintained at this temperature while 102 g. (1.10 moles) of epichlorohydrin (Note 3) is added dropwise with stirring over a period of 1 hour (Note 4). The mixture is allowed to come to room temperature and is stirred for an additional 24 hours at this temperature. 

The dark red-brown reaction mixture is stirred and extracted continuously with 11. of ethyl acetate for 48 hours (Note 5). The 

The bath contained a mixture of trichloroethylene and solid carbon dioxide kept at —20°. 

At this point the mixture has an opaque milky-white appearance caused by precipitation of a little magnesium hydroxide. 

Epichlorohydrin (white label brand) supplied by Eastman Organic Chemicals was used without further purification. 

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Chloro-3-hydroxybutyronitrile, byproduct in preparation of 3-hydroxyglu taronitrile, 46, 49 3-hydroxyglutaronitrile from, 46, 49 1-Chloro-l-methylcyclohexane as precursor of 1-methylcyclohexane-carboxylic acid, 46, 73 Chloromethyl phenyl ether, 47,... 

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]. 

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... 

Bergeron S, Chaplin D, Edwards JH, Ellis BS, Hill CL, Holt-Tiffin K, Knight JR, Mahoney T, Osborne AP, Ruecroft G (2006) Nitrilase-catalyzed desym-metrization of 3-hydroxyglutaronitrile preparation of a statin side-chain intermediate. Org Proc Res Dev 10 661-665 Burns M, Weaver J, Wong J (2005) Stereoselective enzymic bioconversion of aliphatic dinitriles into cyano carboxylic acids. WO 2005100580 DeSantis G, Zhu Z, Greenberg W, Wong K, Chaplin J, Hanson SR, Farwell B, Nicholson LW, Rand CL, Weiner DP, Robertson D, Burk MJ (2002) An enzyme library approach to biocatalysis development of nitrilases for enantioselective production of carboxylic acid derivatives. J Am Chem Soc 124 9024-9025... 

Ethyl phenylacetate, reaction with (2-bromocthyI)benzene, 47, 72 Ethyl 2-phenylhexanoate, 47, 74 Ethyl 2-phenylpropionate, 47, 74 Exchange of oxygen by sulfur in preparation of chloromethylphospho-nothioic dichloride, 46, 21 Extractor, stirred, in isolation of 3-hydroxyglutaronitrile, 46, 49... 

Bergeron, S., Chaplin, D.A., Edwards, J.H., Ellis, B.S.W., Hill, C.L., Holt-Tiffin, K., Knight, J.R., Mahoney, T., Osborne, A.P. and Ruecroft, G., Nitrilase-catalysed desymmetrisation of 3-hydroxyglutaronitrile preparation of a statin side-chain intermediate. Org. Proc. Res. Dev.,... 

An alternative approach, explored by Dowpharma, involved the desymmetrization of prochiral dinitrile (meso)-3-hydroxyglutaronitrile (3-HGN) with a nitrUase provided by Diversa (Figure 6.2b). The resulting (R)-3-hydroxy-4-cyanobutyrate can in several steps be converted into ethyl 6-cyano-3R,5R-dihydroxyhexanoate, an advanced intermediate to atorvastatin. 3-HGN could be easily prepared from... 

Hydroxyglutaronitrile has been prepared by the action of potassium cyanide on 1,3-dichloro-2-propanol 3 s or on 4-chloro-... 

This is a much more convenient and satisfactory synthesis of 3-hydroxyglutaronitrile than earlier ones.3-7 The method can be applied to other epichlorohydrms 2-methylepichlorohydrin and 2-ethylepichlorohydrin have been converted to the corresponding hydroxydinitriles in 71% and 77% yields, respectively 8 The hydroxydinitriles undergo cyclizations to heterocyclic compounds not easily prepared in other ways. Thus hydrogen bromide at 0° converts 3-hydroxyglutaronitrile to 2-amino-6-bromopyridine in 70% yield 9... 

Other approaches have also been developed and are discussed elsewhere, such as an aldol approach (Chapters 19 and 20) and the hydrolysis of 3-hydroxyglutaronitrile (Chapter 20).56 In addition the chemistry has some overlap to approaches to carnitine (see Section 31.3.3.). 

The preparation of pyridine compounds from a,o>-dinitrile systems has been studied by several workers. Johnson et al.101 found that 3-hydroxyglutaronitriles (128) or glutacononitriles (129) react readily with anhydrous hydrogen bromide or iodide to yield the 2-amino-6-halopyridines (130) as their salts, although in no case does hydrogen chloride cause cyclization to the expected 2-amino-6-chloropyridine. 

Vink et al. (2009) used an 0-benzyl protected 3-hydroxyglutaronitrile in the presence of nitrilase from R. erythropolis NCIMB 11540 to produce the corre-... 

FIGURE 17.17 Enzymatic desymmetrization of 3-hydroxyglutaronitrile, key synthon for the production of Lipitor. 

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