- Hydrogenation N-alkylation of α-alanyl-α-proline with ethyl 2-oxo-4-phenylbutanoate on organometallic catalysts
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New nickel- and palladium-containing catalysts for reductive N-alkylation of α-alanyl-α-proline dipeptide with ethyl 2-oxo-4-phenylbutanoate have been investigated. Based on the empirical data obtained, the optimal scheme for the catalytic synthesis of en
- Abdullaev, M. G.
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- Asymmetric reductive alkylation of alanylproline by the ethyl esters of 4-substituted 2-oxobutenoic acids
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A method was developed for the synthesis of N-[1-(S)-(ethoxycarbonyl)-3- phenylpropyl]alanylproline (enalapril) by reductive alkylation of alanylproline with ethyl 2-oxo-4-phenylbutenoate under the conditions of hydrogenation in the presence of palladium black and 1.6%Pd/C. The yield of enalapril amounted to 65%. With the ethyl ester of the α-oxo acid the diastereoselectivity of formation of the S,S,S-diastereomer was higher than with the saturated synthon. It is assumed that with ethyl 2-oxo-4-phenylbutenoate as synthon a conformationally restricted surface complex is formed between the unsaturated synthon and the active centers of the catalyst. During reductive alkylation of alanylproline by ethyl 2-oxo-4-(2-thienyl)butenoate poisoning of the catalyst occurs.
- Slavinska,Sile,Chipens,Balodis,Rozenthal,Venteris,Lukevics
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- Improved stereoselectivity in the heterogeneous catalytic synthesis of enalapril obtained through multidimensional screening
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A multidimensional screening of catalysts and additives led to the discovery of improved conditions for the diastereoselective reductive amination which produces enalapril. Additives acetic acid and potassium fluoride, which in isolation are detrimental, work together to improve the SSS: RSS selectivity with Ra-Ni in ethanol to 17: 1 from 11: 1.
- Huffman, Mark A.,Reider, Paul J.
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- Overcoming Problems at Elaboration and Scale-up of Liquid-Phase Pd/C Mediated Catalytic Hydrogenations in Pharmaceutical Production
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The practical solutions for scale-up and production of intermediates or precursors of pharmaceuticals by liquid-phase Pd/C mediated hydrogenation can be of considerable interest and deserve broader attention even if they have not been the focus of previously published research due to regulations of patent law. The practical obstacles are persistent and have been known for a long time, but for the most part remained unpublished. The most important discoveries and solutions that contributed to the successful scale-up of hydrogenations for pharmaceutical production were the following: (i) the poisoning of Pd/C catalyst with Fe2+ ions for the selective hydrogenation of 2,6-dimethyl-1-nitrosopiperidine to the corresponding hydrazo compound; (ii) alloying of the deposited Pd metal with Cu for converting the aromatic acid chlorides into the corresponding aldehydes; (iii) alteration of the pH of the reaction mixture to basic values which enhanced the stereoselectivity of paracetamol hydrogenation; (iv) a useful modification of the catalyst preparation process, i.e., the acidification of the catalyst resulted in the hydrogenolysis of benzylic OH in a molecule containing a basic N atom; (v) use of two liquid phases, altogether a four-phase system, which permitted the hydrogenolysis of the S-S bond in a potential catalyst poisoning molecule; (vi) the preservation of the metallic Pd surface of the catalyst by saturation of the reaction mixture with hydrogen, resulting in a high H2/substrate ratio, increased the aldehyde yield in the hydrogenation of 4-chloro-butyric-acid-chloride by avoiding the unwanted poisoning effect of the hydrochloric acid. In the present article, these problems and their solutions, as they emerged during the scale-up of the processes, will be discussed in detail.
- Tungler, Antal,Szabados, Erika
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p. 1246 - 1251
(2016/07/23)
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- PROCESS FOR THE PREPARATION OF AMIDES OF N-[1-(S)-(ETHOXYCARBONYL)-3-PHENYLPROPYL]-L-ALANINE
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A process for the production of amides of N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine is described. The process can be used for the production of key intermediates and finally the ACE inhibitors such as Ramipril, Enalapril, Quinapril, Trandolapril, Delapril and Moexipril starting from N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine by the reaction with the appropriate amines.
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- A PROCESS FOR THE PREPARATION OF COMPOUNDS HAVING AN ACE INHIBITORY ACTION
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The present invention relates to the process for the preparation of compounds of formula (I) having an ACE inhibitory action wherein carboxy group of stereospecific amino acid is activated with an uronium salt in in the presence of an aprotic solvent and an activated amino acid is further transformed with appropriate amine into ACE inhibitor or its precursor.
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- Process for preparing pharmacologically acceptable salt of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl amino acids
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There is provided a process for preparing a pharmacologically acceptable salt of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid which comprises condensing an amino acid and N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine.N-carboxyanhydride under basic condition, carrying out decarboxylation under between neutral and acidic condition to obtain N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid, and forming a pharmacologically acceptable salt thereof, wherein the production of a by-product (3): is suppressed by carrying out in an aqueous liquid a series of operations till formation of the pharmacologically acceptable salt or till isolation of the pharmacologically acceptable salt. The present invention enables to prepare the pharmacologically acceptable salt of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid having high quality, in a commercial scale with high yield and economical efficiency.
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- Soluble alpha-amino acid salts in acetonitrile: practical technology for the production of some dipeptides.
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Alpha-amino acids are soluble in acetonitrile when treated with phosphazene bases. As a result, the protection/deprotection events that are usually required for peptide coupling reactions can be minimized. This is illustrated in the synthesis of the important angiotensin-converting enzyme (ACE) inhibitor enalapril. [reaction: see text]
- Palomo, Claudio,Palomo, Antonio L,Palomo, Francisco,Mielgo, Antonia
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p. 4005 - 4008
(2007/10/03)
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- Ace-inhibitor nitric salts
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Compounds having platelet anti-aggregating activity and antihypertension activity having reduced branchial side effects.
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- One-pot formation of succinimidyl esters by the system chlorophosphate/hydroxysuccinimide/base
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Succinimidyl esters of various carboxylic acids are formed in high yield at ambient to slightly elevated temperature by the system chlorophosphate/hydroxysuccinimide/base.
- Poechlauer, Peter,Hendel, Wolfram
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p. 3489 - 3494
(2007/10/03)
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- Studies on angiotensin converting enzyme inhibitors. V. The diastereoselective synthesis of 2-oxoimidazolidine derivatives
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A diastereoselective synthesis of imidapril (1), which is under clinical study as an antihypertensive drug based on its angiotensin converting enzyme (ACE)-inhibitory activity, was established. N-Alkylation of (2S)-2-amino-4-phenylbutyric acid ester (12) with 3-((2R)-2-methane or toluenesulfonyloxypropionyl)-2-oxoimidazolidine derivative (11) diastereoselectively proceeded in an SN2 fashion to afford tert-butyl (4S)-3-[(2S)-2-[N-[(1S)-1-ethoxycarbonyl)-3-phenylpropyl]amino]propionyl]- 1-methyl-2-oxoimidazolidine-4-carboxylate (13), a precursor of 1. Alternatively, benzyl (2S)-2-[N-(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propionate (15), which is the key building block of 13, was synthesized by the same strategy. This procedure was also applied to the synthesis of enalapril.
- Kubota,Nunami,Yamagishi,Nishimoto,Hayashi
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p. 1374 - 1377
(2007/10/02)
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