Optimization of a process for the production of (R)-2-hydroxy-4-phenylbutyric acid — an intermediate for inhibitors of angiotensin converting enzyme

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Abstract

(R)-2-Hydroxy-4-phenylbutyric acid, an intermediate in the manufacture of inhibitors of angiotensin converting enzyme, can be produced continuously in an enzyme membrane reactor by enzymatic reduction of its corresponding α-keto acid. d-Lactate dehydrogenase (d-LDH) from Staphylococcus epidermidis was chosen as the most appropriate enzyme to carry out the NADH-dependent reduction. Formate dehydrogenase (FDH) was used for NADH regeneration. Detailed kinetic measurements and a mathematical model for the coupled enzyme reactions were applied to calculate the optimal conditions for continuous production of the α-hydroxy acid. A mass of 3.1 kg (R)-2-hydroxy-4-phenylbutyric acid was synthesized in a 220 ml enzyme membrane reactor over a period of 4 weeks. A mean space-time-yield of 165 g l−1 d−1 was achieved at low enzyme consumptions of 150 U kg−1 α-hydroxy acid for FDH and d-LDH.

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    Enantiomerically pure ethyl-(R)-2-hydroxy-4-phenylbutyrate, ((R)-HPB ester, (R)-1) is an essential building block for the production of angiotensin-converting enzyme (ACE) inhibitors (Sheldon et al., 1991) (Fig. 1) e.g. Benazepril (I), Lisinopril (II), Spirapril (III), Enalapril (IV), Quinapril (V), Delapril (VI), Ramipril (VII), Cilazapril (VIII) etc., and numerous methods have been developed for its preparation. These include: a) chemical resolution (Nohira and Yoshida, 1989) (b) asymmetric reduction of its prochiral precursor 2-oxo-4-phenylbutyric acid or its ethyl ester by chemical reagents (Herold et al., 2000; Blaser and Jalett, 1993) or enzymes (Schmidt et al., 1992a; Dao et al., 1998; Schmidt et al., 1992b; Fadnavis and Radhika, 2004) (c) enantioselective enzymatic hydrolysis of cyanohydrin prepared from hydrocinnamaldehyde (Neidermeyer et al., 1991; Osprian et al., 2004; Fadnavis et al., 2004) and esters of 2-hydroxy-4-arylbutyrate (Huang and Tsai, 2004; Sugai and Ohta, 1991; Palomo et al., 2003; Kalaritis et al., 1990; Liese et al., 2002; Ou and Li, 2012; Bastida et al., 1998). Further, an enzymatic approach using lactonase for selective hydrolysis of cis- and trans-2-hydroxy-4-phenyl-4-butyrolactones has also been reported (Chen et al., 2010).

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