Synthesis of Benazepril

Novartis (Ciba Geigy) has reported the synthesis of Benazepril (163) (Scheme 12.63), an angiotensin-converting enzyme inhibitor, via an intermediate prepared by cinchona-modified Pt asymmetric hydrogenation (10-200-kg scale, >98%, 79-82% ee).5 The low optical purities can be tolerated because enantio-enrichment is relatively easy in the latter stages of the synthesis.22... 

Watthey and Watthey et al. [5-7] reported the synthesis of benazepril using the following procedure (which is illustrated in Scheme 1). 

Scheme 1. Synthesis of benazepril, according to the method of Watthey and...

Scheme 9 Fonnal synthesis of benazepril via Pd-catalyzed y-C-H arylation using the 2-methoxyiminoacetyl (MIA) directing group...

Some developments have been carried out for the enantioselective synthesis of biologically active compounds. One such example is the synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate, an important intermediate for the angiotensinconverting enzyme (ACE) inhibitor benazepril, or for coenzyme A, using the NORPHOS ligand (Scheme 33.9) [21]. 

Scheme 33.9 Enantioselective hydrogenation with Rh-NOR-PHOS complex as a key step in the synthesis of the ACE inhibitor benazepril (see Table 33.2).

The synthesis of the benzazepinone portion of benazepril began with monobromination of 1-tetralone (35), followed by oxime formation to give 36 (Scheme 10.9). A Beckmann rearrangement mediated by polyphosphoric acid provided the ring-expanded lactam 37. Displacement of the a-bromine with potassium phthalimide installed the necessary... 

Heterogeneous enantioselective hydrogenation of a- and fi-keto esters is used for the synthesis of many biologically active compounds (Figure 1.13) [203b,204a,216]. Benazepril,... 

An important step in the asymmetric synthesis of the angiotensin-converting enzyme inhibitor, benazepril HC1 132, was the reduction of the ketoester 128 (obtained from 127 by condensation with diethyl oxalate) with baker s yeast to give the chiral cr-hydroxy ester 129 in high yield and ee (Scheme 17). Direct formation of the 1//-1-benzazepin-2-one 131 from 129 proceeded in 42% yield (without racemization at C-3) or in 74% yield in two steps via 130, again with no racemization <2003TA2239>. 

The first technical application of a cinchona-modified Pt catalyst was reported by Ciba-Geigy in 1986 for the synthesis of methyl (R)-2-hydroxy-4-phenyl butyrate (R)-HPB ester), an intermediate for the ACE inhibitor benazepril depicted in Figure 2.10 [44a],... 

R)-4-phenyl-2-hydroxybutyric acid ethyl ester is an important intermediate for the synthesis of the angiotensin-converting enzyme inhibitor benazepril [3] (see SCHEME 1). Its preparation via hydrogenation of the a-ketoester has been developed and scaled-up into a production process (10-2(X) kg scale, chemical yield >98%, ee 79-82%). One drawback of this process is the instability of the a-ketoester during distillation and storage. The hydrogenation of the a-ketoacid followed by esterification is an alternative route to the desired hydroxyester. 

A comprehensive review of asymmetric hydrogenation, mainly 2-oxo-carboxylic acids and their esters, over heterogeneous catalysts of Pt-alumina modified with alkaloids was presented in Chapter 5 of this book. Here some practical aspects of these catal5i ic systems will be considered. Thus, ethyl (i )-4-phenyl-2-hydroxybutyrate is an important intermediate for the synthesis of the angiotensin-converting enzyme inhibitor Benazepril (Scheme 7.20.) and other carboxyalkyl dipeptides like Enalapril (Scheme 7.21.)... 

The DPAMP-Rh(I) catalyst system was applied to die asymmetric hydrogenation of methyl (Z)-2-acetamido-3-(3-methoxy-4-acetoxyphenyl)acrylate 147 to furnish the corresponding amino acid 148, which is a crucial advanced intermediate in the synthesis of L-DOPA. Likewise, a homophenylalanine intermediate, which is a key component of the antihypertensive (5,5)-benazepril, was obtained from the hydrogenation of ethyl (Z)-2-acetamido-4-phenylcrotonate using the same catalyst and identical reaction conditions. ... 

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