Ethyl alaninate hydrogenation

Miscellaneous Reactions. Sodium bisulfite adds to acetaldehyde to form a white crystalline addition compound, insoluble in ethyl alcohol and ether. This bisulfite addition compound is frequendy used to isolate and purify acetaldehyde, which may be regenerated with dilute acid. Hydrocyanic acid adds to acetaldehyde in the presence of an alkaU catalyst to form cyanohydrin the cyanohydrin may also be prepared from sodium cyanide and the bisulfite addition compound. Acrylonittile [107-13-1] (qv) can be made from acetaldehyde and hydrocyanic acid by heating the cyanohydrin that is formed to 600—700°C (77). Alanine [302-72-7] can be prepared by the reaction of an ammonium salt and an alkaU metal cyanide with acetaldehyde this is a general method for the preparation of a-amino acids called the Strecker amino acids synthesis. Grignard reagents add readily to acetaldehyde, the final product being a secondary alcohol. Thioacetaldehyde [2765-04-0] is formed by reaction of acetaldehyde with hydrogen sulfide thioacetaldehyde polymerizes readily to the trimer. 

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). 

Place 45 kg of ethyl N-norvalinate hydrochloride approximately 110 liters of water in a vessel equipped with a stirrer. Alkalify, then pour 23 kg of pyruvic acid very gradually into the solution obtained previously and stir the reaction mixture for 30 min. Place an aqueous suspension of charcoal containing 5% palladium and the alkaline solution of ethyl L-norvalinate obtained previously in a hydrogenation apparatus. Hydrogenate under pressure (30 bars) at room temperature for approximately one day. Filter under vacuum and evaporate the filtrate under reduced pressure, filter off and dry. Treat the residue obtained with ethanol remove the insoluble material, consisting of sodium chloride, by filtration and rinse it with ethanol. Combine the ethanolic solutions evaporate off the ethanol under reduced pressure and crystallize the residue from acetonitrile 34.3 kg of N-[(S)-l-carbethoxybutyl]-(S)-alanine are obtained, that is a 63.9% yield. 

A solution of 2.0 g of t-butyl alanine (S-form) and 3.78 g of ethyl 2-bromo-4-phenylbutanoate in 25 ml of dimethylformamide was treated with 1.8 ml of triethylamine and the solution was heated at 70°C for 18 h. The solvent was removed at reduced pressure and the residue was mixed with water and extracted with ethyl ether. The organic layer was washed with water and dried over magnesium sulfate. Concentration of the solvent at reduced pressure gave the oily t-butyl ester of the intermediate which was found to be sufficiently pure by gas liquid chromatography for further use. A solution of 143.7 g of this t-butyl ester in 630 ml of trifluoroacetic acid was stirred at room temperature for one hour. The solvent was removed at reduced pressure and the residue was dissolved in ethyl ether and again evaporated. This operation was repeated. Then the ether solution was treated dropwise with a solution of hydrogen chloride gas in ethyl ether until precipitation ceased. The solid, collected by filtration, was a mixture of diastereoisomers, melting point 153°-165°C. 

Asymmetric catalytic hydrogenation of the Schiff base prepared from ethyl pyruvate and an optically active amine in different solvents was carried out and supports the chelation hypothesis. Figure 1 shows solvent effects in the synthesis of alanine and a-aminobutyric acid( ). When (g.)-benzylic cimine was used as the asymmetric moiety, the optical purity of the resulting cotiino acid increased with a decrease in solvent polarity(, 2) A temperature effect was also observed, and the optical purity of the cimino acids increased upon lowering the reaction temperature(, , 10). ... 

Physiol. Chem. 143, 292 (1925) by hoiling the ethyl ester of DL-acety]alanine with sodium in abs alcohol Karrer, Helv. Chim. Acta 4, 98 (]92l) as hydrolytic cleavage product of ergonovine and ergometrinine Stoll. Hofmann, ibid. 26, 956 (1943) by catalytic hydrogenation of the ethyl ester of alanine Adkins. Pavlic, J. Am. Chem. Soc. 69, 3039 (1947). 

Alanine 60 Ethyl cyanoacetate (30 g) is converted into / -alanine ethyl ester by catalytic hydrogenation on Pt02 in glacial acetic acid/sulfuric acid. After removal of the catalyst the solution is concentrated in a vacuum so far as possible, and the residue is poured into water (300 ml), treated with finely powdered barium hydroxide (100 g), and boiled for 3 h. Then, after cooling, the barium is precipitated with dilute sulfuric acid and separated by centrifugation. The solution is concentrated greatly in a vacuum, whereupon the -alanine rapidly crystallizes (17 g, 72%) recrystallized from aqueous alcohol-ether, it has m.p. 195°. 

Ohba and co-workers have demonstrated that A -protected a-amino esters are compatible with the Schollkopf oxazole synthesis cf., 38->39). In the case of ammo esters derived from natural amino acids (e.g., 38), the presence of an additional acidic N-H bond in the AABoc ester substrate necessitated the use of an added excess of metalated isocyanide (2.5 equiv was found to be optimal) to obtain maximal yields. Under optimized conditions, oxazoles (39) were obtained in good yield from iV-Boc glycine, alanine, and phenylalanine. Oxazole formation from iV-Boc serine (which possesses an additional acidic site in its hydroxylic side chain) proceeded in good yield (66%) using 3.5 equiv lithiated methyl isocyanide. Notably, no epimerization was detected in the reaction of N-Boc alanine methyl ester with lithiated methyl or ethyl isocyanide under these conditions. Minor epimerization was observed (91-92% ee product) with substrates that lacked a carbamate NH hydrogen e.g., A -Boc proline methyl ester), however. ... 

The acyl carbon of readily available amino acids such as alanine can be converted to a ketone moiety by activation of the acid with carbonyl diimidazole (CDI) and then condensation with an enolate, such as the magnesium enolate of malonic acid, mono ethyl ester. In this particular example, N-Boc alanine was converted to 1.206 using this method O Catalytic hydrogenation of the ketone moiety gave the alcohol group in 1.207, and conversion to the chloride and base induced dehydrohalogen-ation gave ethyl 4-(N-Boc amino)pent-2-enoate (7.205). 

The acid moiety of an amino acid can be activated for acyl substitution rather than converted to an aldehyde for acyl addition. Boc-alanine was converted to an acyl imidazole by reaction with carbonyl diimidazole (CDI see chapter two, section 2.4), and then condensed with the magnesium enolate of the mono ethyl ester of malonic acid to give keto-ester 5.9. Subsequent catalytic hydrogenation of the ketone moiety gave ethyl 3-hydroxy-5-(N-Boc amino)penlanoate, 5.10 Once the o... 

Peptides. N-p-Toluenesulfonyl-DL-alanine mixed with N-phenyltrimethylacet-imidoyl chloride, allowed to stand several hrs. at room temp., the resulting acid chloride dissolved in ether, treated slowly with alanine benzyl ester, and the crude product hydrogenated with Pd-on-carbon in ethyl acetate N-p-toluene-sulfonyl-DL-alanylalanine. Y 80%. F. Cramer and K. Baer, B. 93, 1231 (1960). 

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