Enalapril synthesis

The synthesis of enalapril follows the normal course tor such compounds in that L alanyl-L prolme (27) was reductively alkylated with ethyl 2-oxo 4 phenylbutyiate (26) using sodium cyanoborohydnde as the reducing agent (catalytic reduction may also be used) The product is... 

Spirapril (37) is a clinically active antihypertensive agent closely related structurally and mechanistically to enalapril. Various syntheses are reported with the synthesis of the substituted proline portion being the key to the methods. This is prepared fkim l-carbobenzyloxy-4-oxopro-line methyl ester (33) by reaction with ethanedithiol and catalytic tosic acid. The product (34) is deprotected with 20% HBr to methyl l,4-dithia-7-azospiro[4.4 nonane-8-carboxylate (35), Condensation of this with N-carbobenzyloxy-L-alanyl-N-hydroxysuccinate leads to the dipeptide ester which is deblocked to 36 by hydrolysis with NaOH and then treatment with 20% HBr. The conclusion of the synthesis of spirapril (37) follows with the standard reductive alkylation [11]. 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

In these synthesis, the optically active (R)-cyanohydrin is transformed into the corresponding a-hydroxy carboxylic ester and the hydroxyl funchon is achvated by sulfonylahon. The treatment of the corresponding intermediate with tetra-hydrothieno[3,2-c]pyridine stereoselectively yields the (S)-configured clopidogrel (Scheme 10.23). In the second case, a mutant of the recombinant almond (Pmnus amigdalus) (R)-oxynitrilase isoenzyme 5 catalyzes the formation of enantiopure (R)-2-hydroxy-4-phenylbutyronitrile [54]. Reaction of the sulfonylated hydroxyester derivative with the corresponding dipeptide leads to the formation of enalapril or lisinopril (Scheme 10.24). 

The Merck process group subsequently published a more detailed route amenable towards multikilogram scales (Blacklock et al., 1988). This synthesis begins with treatment of alanine with phosgene to produce A-carboxyanhydride (NCA) 16 (Scheme 10.3). Under basic aqueous conditions this anhydride is coupled with proline to produce, upon acidic work-up, the dipeptide alanyl-proline (14). Enalapril is then prepared in one synthetic step by a diastereoselective reductive amination between ethyl-2— oxo-4-phenylbutyrate (13) and 14. This reaction was the subject of extensive optimization, and it was found that the highest diastereoselectivity was obtained by hydrogenation over Raney nickel in the presence of acetic acid (25%), KF (4.0 equiv.), and 3 A molecular sieves (17 1 dr). Enalapril is then isolated in diastereomerically pure form as its maleate salt (Huffman and Reider, 1999 Huffman et al., 2000). 

Enalapril Angiotensin-converting enzyme 2 Chemical synthesis... 

Today, captopril (Capoten ) ranks among the most frequently used drugs in the treatment of hypertension. Enalapril (Xanef ) has been commercially available since 1985 as a second ACE inhibitor. The discovery of captopril started an avalanche of research into the synthesis of angiotensin-converting enzyme inhibitors. Some new developments should be mentioned at this point ... 

A primary value of the method is to provide economical large-scale preparations of small peptides, especially dipeptides. Two of the best examples are the industrial preparations of the dipeptides H-Ala-Pro-OH and H-Lys(Tfa)-Pro-OH as intermediates in the synthesis of the angiotensin-converting enzyme inhibitors enalapril and lysinopril.P l... 

The NCA coupling method is conceptually simple and elegant. This method is now used in efficient large scale production of peptides, for example for the preparation of semi-synthetic dipeptides Enalapril and Lisinopril (Ref. 247). The synthesis of Ala-Pro which is the key building block to synthesize Enalapril is diagrammed in scheme 195. 

Huffman, M. A. Reider, P.J., Improved Stereoselectivity in the Heterogeneous Catalytic Synthesis of Enalapril Obtained through Multidimensional Screening. Tetrahedron Lett. 1999, 40,831. 

The synthesis of the angiotensin-converting enzyme (ACE) inhibitor enalapril (1) incorporates the natural amino acids L-alanine and L-proline [1,2]. Although the compound can be thought of as a derivative of homophenylalanine, this part of the compound is prepared by a reductive amination with the keto ester (2), while the amino acids are coupled through an A-carboxy anhydride 3 (Scheme 1) [3-7]. 

Lisinopril (8) is another ACE inhibitor [1], Its synthesis is analogous to enalapril, with a protected lysine taking the place of alanine [5,27],... 

Ketene cycloadditions Synthesis of enalapril Carbonyl ene reactions Alder ene reactions... 

ACE-Inhibitors (enalapril and analogs) Lipase aminopeptidase Synthesis of optically active precursors [81]... 

Using the same technique, the hydrolytic resolution of racemic frans-ethyl-2-hydroxy-4-phenylbutanoate (mc-60. Scheme 19), an important intermediate for the synthesis of antihypertension drugs such as Enalapril (61), could be accomplished [79]. The key compound R)-60 was obtained in reasonable yield and op-... 

Opine-type secondary amine dicarboxylic acids are useful chiral intermediates of angiotensin-converting enzyme (ACE)-inhibitors, such as enalapril and lysinopril. In order to extend the use of enzymes in stereoselective synthesis, we screened for an enzyme catalyzing the reversible oxidation-reduction of opine-type secondary amine dicarboxylic acids and isolated a bacterial producer, Arthrobacter sp. strain 1C [15]. Optically active secondary amine dicarboxylic acids have been chemically synthesized as... 

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