- A Stereoselective Synthesis of the ACE Inhibitor Trandolapril
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A conceptually novel and stereoselective synthesis of the enantiopure octahydroindole building block and its conversion into the ACE inhibitor trandolapril was achieved. Key steps include the α-allylation of a protected l -pyroglutamic acid derivative, a highly diastereoselective Hosomi-Sakurai reaction and a Ru-catalyzed ring-closing metathesis of a 4,5-diallylated proline. This way, the synthesis of trandolapril was efficiently achieved in 25% overall yield (12 steps).
- Chiha, Slim,Spilles, Matthias,Neud?rfl, J?rg-Martin,Schmalz, Hans-Günther
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p. 813 - 816
(2019/04/25)
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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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Page/Page column 23
(2015/01/07)
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- PROCESS FOR THE SYNTHESIS OF AN ACE INHIBITOR
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A process for the synthesis of trandolapril which comprises condensing N-[I-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride with trans octahydro-1H- indole-2-carboxylic acid in a first organic solvent comprising a water immiscible inert organic solvent and in the presence of a base, and isolating trandolapril from a second organic solvent. N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride may also be condensed with (2S,3aR,7aS) octahydro-1H-indole-2-carboxyIic acid in a first organic solvent and in the presence of a base, and trandolapril isolated. There is also provided a process for the resolution of racemic trans octahydro-1H-indole-2-carboxylc acid.
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Page/Page column 12; 9
(2008/06/13)
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- Method for producing {n-[1-(s)-carbalkoxy-3-phenylpropyl]-s-alanyl-2s, 3ar, 7as-octahydroindole-2-carboxylic acid} compounds
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A method for preparing optionally substituted {N-[1-(S)-carbalkoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid} and pharmaceutically acceptable salts thereof, wherein a racemic mixture of optionally substituted trans-octahydroindole-2-carboxylic acid is reacted with the N-carboxyanhydride of {N-[1-(S)-alkoxycarbonyl-3-phenylpropyl]-L-alanine}, which is optionally substituted on the phenyl ring, in a suitable inert solvent, and subsequently the resulting optionally substituted {N-[1-S-carbalkoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid}, preferably trandolapril, is isolated, and polymorphic forms A and B of trandolapril.
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- Process for the preparation of intermediates of trandolapril and use thereof for the preparation of trandolapril
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A process for the preparation of an intermediate of trandolapril, (2S,3aR,7aS)-perhydroindole-2-carboxylic acid of Formula II is provided. Also provided are processes for preparing trandolapril.
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Page/Page column 6
(2010/10/20)
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- PREPARATION OF TRANDOLAPRIL
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A process for preparing trandolapril, (2S,3aR,7aS)-1-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, and intermediates that are useful in the process.
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Page/Page column 5
(2010/11/28)
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- Process for the synthesis of ?2S, 3aR, 7aS|-octahydroindole-2-carboxylic acid and its conversion to trandolapril
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The present invention describes a novel method for the synthesis of (2S,3aR,7aS)-octahydroindole-2-carboxylic acid of formula III using a new intermediate of formula II and conversion of the product of formula-III to trandolapril of formula I
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Page/Page column 14
(2010/11/24)
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- METHOD FOR PRODUCING {N-[1-(S)-CARBALKOXY-3-PHENYLPROPYL]-S-ALANYL-2S, 3AR, 7AS-OCTAHYDROINDOL-2-CARBOXYLIC ACID} COMPOUNDS
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The invention relates to a method for producing optionally substituted {N-[1-(S)-carbalkoxy-3-phenylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindol-2-carboxylic acid} and the pharmaceutically acceptable salts thereof. To this end, a racemic mixture of optionally substituted trans-octahydroindol-2-carboxylic acid is reacted with the N-carboxyanhydride of {N-[1-(S)-alkoxycarbonyl-3-phenylpropyl]-L-alanine}, which is optionally substituted on the phenyl ring, in an appropriate inert solvent, and the obtained optionally substituted {N-[1-(S)-carbalkoxy-3-phenylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindol-2-carboxylic acid}, preferably trandolapril, is subsequently isolated, as well as polymorphous forms A and B of trandolapril.
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Page/Page column 6; 18-19; 20
(2008/06/13)
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- A METHOD FOR THE PREPARATION OF (2S, 3AR, 7AS)-OCTAHYDRO-1H-INDOLE-2-CARBOXYLIC ACID AS KEY INTERMEDIATE IN THE PREPARATION OF TRANDOLAPRIL BY REACTING A CYCLOHEXYL AZIRIDINE WITH A DIALKYL MALONATE
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A method for the synthesis of a compound of formula (I) as a mixture of enantiomers, formula (I) (wherein R1 is H or an acid protective group and H+A- indicates an optional acid with which the compound of formula (I) may form an ammonium salt) said method comprising; A) reacting a cyclohexyl aziridine with a dialkyl malonate, whereby to provide a trans-fused 3-alkylcarbonyl-octahydro-indol-2-one; B) decarbonylation at the 3-position, conversion of the ketone of the resulting trans-octahydro-indol-2-one to an optionally protected carboxylic acid group; and C) optionally removing any N-substitution if necessary.
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Page/Page column 21-23
(2010/02/12)
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- NOVEL CRYSTALLINE FORMS OF TRANDOLAPRIL
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The present invention relates to two novel crystalline polymorphs of trandolapril, processes for their preparation and the pharmaceutical compositions containing them.
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- A study on the stereochemical purity of trandolapril and octahydro-1H-indole-2-carboxylic acid by HPLC method
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HPLC conditions for the identification of stereoisomers and stereochemical purity of the key intermediate in Trandolapril synthesis, octahydro-1H-indole-2-carboxylic acid, and final drug were elaborated. The chemical and stereochemical purity of synthetic Trandolapril was proved to be as high as 99.3-99.8%, on both non chiral and chiral RP - columns.
- Cendrowska, Iwona,Bankowski, Krzysztof,Iskra-Jopa, Joanna
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p. 141 - 144
(2007/10/03)
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