Formal Synthesis of the Ace Inhibitor Benazepril·hcl via an Asymmetric Aza-michael Reaction

A formal enantioselective synthesis of benazepril·HCl (4), an anti-hypertensive drug, is reported. Our synthesis employed an asymmetric aza-Michael addition of L-homophenylalanine ethyl ester (LHPE, 1) to 4-(2-nitrophenyl)-4-oxo-but-2-enoic acid methyl ester (6) as the key step to prepare


Introduction
Angiotensin converting enzyme (ACE) inhibitors [1] constitute a major class of anti-hypertensive drugs that has been widely studied and developed over the past few decades.Among the familiar ACE inhibitors that have come to the market or to the clinic, most contain an unnatural chiral amino ethyl ester, L-homophenylalanine ethyl ester (LHPE, 1), in their framework, such as enalapril (2) [2], lisinopril (3) [3], and benazepril•HCl (4) [4] (Figure 1).Among them, benazepril•HCl (4) is the most potent one, having less side-effects and better stability due to its unique skeleton, different from that of the others.Compound 4 has been a quite popular subject over the years in both academic and industrial sectors, but only a few papers have been published concerning its synthesis.Both Watthey [4] and Boyer [5] used α-tetralone as starting material to prepare benazepril•HCl (4), and both their synthesis went through rather tedious resolution processes.Herein, we describe a convergent pathway in which compound 8, a key chiral intermediate to benazepril•HCl (4), was prepared through an asymmetric aza-Michael reaction.

Results and Discussion
First, we used commercially 40% aqueous glyoxylic acid and o-nitroacetophenone (5) as starting materials to prepare 4-(2-nitrophenyl)-4-oxo-but-2-enoic acid methyl ester (6) via an aldol condensation reaction [8] (Scheme 2).A large coupling constant (15.6 Hz) for the olefinic protons, which appeared at δ 7.3 and 6.4, suggested a trans geometry for the double bond.With an optically active amine as the chiral nucleophile, the aza-Michael addition to α,β-unsaturated carbonyl compounds should proceed in an asymmetric fashion, and thus one diastereomer should be generated predominately.However, equal amount of the two diastereomers would be produced through the equilibrium of a reversible addition-elimination process.To resolve this problem, we have tested the following two ways: 1) selecting suitable aza-Michael reaction conditions to achieve dynamic resolution, in which solvent would be the main factor.The differences in solubility or solvent effect between the two diastereoisomers can be employed to improve the diastereoselectivity through the equilibrium of the reversible aza-Michael reaction [6].In addition, the reaction stoichiometry, temperature, reaction time, and acidity may also exert certain influences on the diastereoselectivity. 2) introducing metallic counterions to affect the reversibility of the aza-Michael reaction through metallic chelation, or formation of amino-metal complex to modify the nucleophilicity of the amino group [9].The results are discussed in detail below: a.All reactions were carried out under room temperature.And the ratio of unsaturated ester 6 to LHPE 1 was 1.00:1.05b.Diastereomeric ratios were taken directly from 1 H-NMR by comparison of the characteristic peaks of the two diastereomers at δ3.74 for (S,S)-form and δ3.71 for (R,S)-form.c.The conversions were determined from the characteristic 1 H-NMR peak of the unsaturated ester 6 at δ3.80.d.The isolated yields of ester 7 were around 90% for most of the reactions listed in Table 1.
The stoichiometric ratio of unsaturated ester 6 to LHPE 1 could be adjusted from 2.00 to 0.50, but some excess LHPE 1 accelerated the reaction rate, so the best ratio of ester 6 to LHPE 1 was 1.00:1.10(Table 2, entry 5), which lead to the highest observed diastereomeric selectivity of 4.50:1.In addition, the suitable reaction concentrations of unsaturated ester 6 were 1%~20% (w/w), as lower concentrations resulted in lower conversion yields and higher concentrations resulted in lower diastereomeric ratios (Table 2, entries 21~22).
The optimum reaction temperature range was 20~40°C.Lower temperatures prolonged the reaction times, which might lower the diastereomeric ratios, while higher reaction temperatures would enhance the reversibility of the aza-Michael reaction, which likewise might also lower the diastereomeric ratio (Table 2, entries 7~9).Consequently, we did most reactions at a temperature of 20°C.
Reaction times of 15~35 hours are suitable for this asymmetric aza-Michael reaction (Table 2, entries 3, 10~16), because shorter times would result in lower conversion and prolonged times would lower the diastereomeric ratios.This may due to the fact that the aza-Michael reaction is a kinetically controlled process at the beginning and then becomes a thermodynamic equilibrium.Noteworthy, although a high diastereselectivity was achieved in CH 2 Cl 2 in short time, decreasing diastereomeric ratios of product 7 and significant amounts of the starting reactants were observed after a long time.This phenomenon may be accounted for by the occurrence of the retro-Michael process [10].We also found that alkaline additives such as NEt 3 could accelerated the aza-Michael reaction but could not improve the diastereoselectivity (Table 2, entries 23~25).a.The amount of solvent was based on the concentration 1~10% of unsaturated ester 6.
b.For diastereomeric ratios, conversions, and isolated yields, please see Table 1.
b.The starting materials were separated out.
d.The concentration of unsaturated ester 6 was <0.1% and the addition product was non-detectable over a long reaction time.
On the other hand, we had also studied the effects of introducing metallic counterions in the aza-Michael reaction.We originally wished to cause a "metal chelate effect" in which the metal ion becomes chelated with the heteroatoms of compound 7 to form a rather stable conformation that mayn decrease the reversibility of the aza-Michael reaction.However, the current results indicated that we did not observe any significant change in diastereselectivity with or without the additive metallic compounds.In fact, some transition metal salts even blocked the aza-Michael reaction [11].
After the aza-Michael reaction, a 4:1 mixture of the two diastereomers was obtained.The mixture was reduced by Pd/C catalyzed hydrogenation, and then the resulting amino functionality reacted in situ with the ester group intramolecularly to give the cyclized (2S,3'S)-caprolactam 8 (Scheme 1) and according to the literature [7], benazepril•HCl 4 could be easily obtained from compound 8.

Conclusions
This report has offered a novel strategy for the asymmetric synthesis of the ACE inhibitor benazepril•HCl (4).Through an asymmetric aza-Michael reaction, we kinetically synthesized (2S,3'S)-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylamino)-4-phenylbutyric acid ethyl ester (8), a known key intermediate for the preparation of compound 4. Our results indicated that the diastereoselectivity of this 1,4-addition reaction was greatly influenced by solvent effects, but was not so sensitive to other influencing factors, such as stoichiometry, reaction temperatures, and counterion effects.Thus, this report not only offers an ecomomical synthesis to benazepril•HCl (4), but also offers useful knowledge for the preparation of chiral β-keto-aminoesters in general.

Table 1 .
Solvent Effect of Asymmetric Aza-Michael Reaction.

Table 2 .
The Variation of Reaction Conditions on the Aza-Michael Reaction.