- Of enantiomerically enriched indoline - 2 - formic acid
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The invention discloses a synthesis method of enantiomer-enriched indoline-2-formic acid shown in a formula (I). The synthesis method of the enantiomer-enriched indoline-2-formic acid comprises the following steps: by adopting low-cost and available ortho-position halogen substituted benzaldehyde and N-benzoyl substituted glycine as starting materials, carrying out Erlenmeyer-Plochl cyclization, alkaline hydrolysis and asymmetric catalytic hydrogen for constructing a chiral center, and then carrying out acid catalysis, deprotection and cyclization sequentially or cyclization, acid catalysis and deprotection sequentially, so that the enantiomer-enriched indoline-2-formic acid is obtained. The synthesis method of the enantiomer-enriched indoline-2-formic acid has the advantages that raw materials used in the whole process route are low-cost and easily available, harmful substances or multiple danger special processes are not used, reaction conditions are mild, technological operation is simple, production is safe and stable, the product yield is high, the purity is high, less three wastes are produced, and the energy consumption is low, so that the synthesis method of the enantiomer-enriched indoline-2-formic acid is a process route especially applicable to industrial production. The formula (1) is described in the specification.
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Paragraph 0137; 0138; 0139; 0140; 0141
(2017/09/01)
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- Practical access to the proline analogs (S,S,S)- and (R,R,R)-2- methyloctahydroindole-2-carboxylic acids by HPLC enantioseparation
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An efficient methodology for the preparation of the α- tetrasubstituted proline analog (S,S,S)-2-methyloctahydroindole-2-carboxylic acid, (S,S,S)-(αMe)Oic, and its enantiomer, (R,R,R)-(αMe)Oic, has been developed. Starting from easily available substrates and through simple transformations, a racemic precursor has been synthesized in excellent yield and further subjected to HPLC resolution using a cellulose-derived chiral stationary phase. Specifically, a semipreparative (250 mm × 20 mm ID) Chiralpak IC column has allowed the efficient resolution of more than 4 g of racemate using a mixture of n-hexane/tert-butyl methyl ether/2-propanol as the eluent. Multigram quantities of the target amino acids have been isolated in enantiomerically pure form and suitably protected for incorporation into peptides.
- Sayago, Francisco J.,Pueyo, Maria J.,Calaza, M. Isabel,Jimenez, Ana I.,Cativiela, Carlos
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scheme or table
p. 507 - 513
(2012/01/11)
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- Versatile methodology for the synthesis and α-functionalization of (2R,3aS,7aS)-octahydroindole-2-carboxylic acid
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An improved strategy for the effective synthesis of enantiomerically pure (2R,3aS,7aS)-octahydroindole-2-carboxylic acid (Oic), based on the?formation of a trichloromethyloxazolidinone derivative, has been developed. Additionally, the completely diastereoselective α-alkylation of such oxazolidinone provides a very convenient and concise route to enantiopure α-tetrasubstituted derivatives of this Oic stereoisomer.
- Sayago, Francisco J.,Isabel Calaza,Jiménez, Ana I.,Cativiela, Carlos
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- Process for the preparation of perindopril and salts thereof
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The present invention relates to a process for the preparation of the ACE inhibitor (2S,3aS,7aS)-1-((2S)-2-(((1S)-1-(ethoxycarbonyl)butyl)amino)-1-oxopropyl)octahydro-1H-indol-2-carboxylic acid and of pharmaceutically acceptable salts thereof as well as to processes for preparing a N-((S)-1-carbethoxybutyl)-(S)-alanine intermediate and a (2S,3aS,7aS)-octahydroindole-2-carboxylic acid intermediate in a purified form.
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Page/Page column 10
(2010/11/27)
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- Efficient access to N-protected derivatives of (R,R,R)- and (S,S,S)-octahydroindole-2-carboxylic acid by HPLC resolution
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The preparation of the proline analogue (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (Oic) and its enantiomer, (2R,3aR,7aR)-Oic, is described. A racemic precursor has been synthesized in good yield and subjected to HPLC resolution on a chiral column. The high efficiency of both the synthetic and chromatographic procedures has allowed the isolation of multigram quantities of each amino acid in enantiomerically pure form and suitably protected for use in peptide synthesis.
- Sayago, Francisco J.,Jimenez, Ana I.,Cativiela, Carlos
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p. 2358 - 2364
(2008/02/12)
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- Process for the preparation of intermediates of perindopril
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A process for the preparation of (2S, 3aS, 7aS)perhydroindole-2-carboxylic acid is provided comprising (a) esterifying a cis-perhydroindole-2-carboxylic acid with a first alcohol of the formula ROH and a suitable free acid to provide the acid salt (AS) of Formula V: (b) reacting the acid salt of Formula V with a first base to provide a compound of Formula VI: (c) treating the product of step (b) with an L-tartaric containing acid in a second alcohol of the formula ROH to precipitate a compound of Formula VII: (d) reacting the compound of Formula VII with a second base to provide a compound of Formula II (e) hydrolyzing the compound of Formula II to provide the (2S, 3aS, 7aS)perhydroindole-2-carboxylic acid.
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Page/Page column 4
(2010/11/25)
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- Novel method for synthesissing (2s,3as,7as)-perhydroindole-2-carboxylic acid and the esters thereof and the use thereof for perindopril synthesis
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Process for the synthesis of compounds of formula (I): wherein R represents hydrogen or a protecting group. Application in the synthesis of perindopril and pharmaceutically acceptable salts thereof.
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Page/Page column 2
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF PERINDOPRIL
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A process for preparing perindopril (III) or a pharmaceutically acceptable salt thereof, which process comprises a substituted benzyl ester of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (I) with N-[(S)-carbethoxybutyl]-(S)-alanine (II) where R represents a halo, C1-4 alkoxy or nitro substituent.
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Page/Page column 12
(2010/02/14)
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- Configuration and preferential solid-state conformations of perindoprilat (S-9780). Comparison with the crystal structures of other ACE inhibitors and conclusions related to structure-activity relationships
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The conformation of perindoprilat, an antihypertensive drug, is studied in the solid state by X-ray analysis. The resolution of its structure reveals important analogies between its observed conformation and that of several ACE inhibitors of the same family. This comparison points out a constant relative orientation of the functional groups, regardless of the molecular environment. This angular constancy appears to us as not being accidental and is a good argument for the spatial design of the ACE binding site. Although ACE is a carboxydipeptidase, the binding site may not contain two but one unique hydrophobic pocket receiving the C-terminal end of the inhibitors.
- Pascard,Guilhem,Vincent,Remond,Portevin,Laubie
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p. 663 - 669
(2007/10/02)
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- Process for the industrial synthesis of perindopril
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Process for the industrial synthesis of perindopril, in which (2S,3aS,7aS)-2-carboxyperhydroindole is condensed with N-[(S)-1-carbethoxybutyl]-(S)-alanine after protection of the carboxyl group, the product resulting from the condensation being then subjected to deprotection of the carboxyl carried by the heterocyclic ring. The (2S,3aS,7aS)-2-carboxyperhydroindole and N-[(S)-1-carbethoxybutyl]-(S)-alanine are themselves obtained in excellent conditions from 2-carboxyindole and from L-alanine respectively, both available on an industrial scale.
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- SYNTHESIS OF 2S, 3aS, 7aS- AND OF 2S, 3aR, 7aR- PERHYDROINDOLE-2-CARBOXYLIC ACID DERIVATIVES FROM L-ASPARTIC ACID
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Using carbon radicals generated by photolysis of N-hydroxy-2-thio-pyridone esters (mixed anhydrides) the chiral centre of L-aspartic acid has been easily incorporated into the perhydroindole structure of the title compounds.
- Barton, Derek H. R.,Guilhem, Jean,Herve, Yolande,Potier, Pierre,Thierry, Josiane
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p. 1413 - 1416
(2007/10/02)
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- DIASTEREOSELECTIVE SYNTHESIS OF BICYCLIC AMINO ACIDS VIA RING CONTRACTION OF α-CHLOROLACTAMS
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Bicyclic lactams were converted to their α-chloro-derivatives and subjected to ring contraction under basic conditions to give bicyclic acids in diasteroselective fashion.
- Henning, R.,Urbach, H.
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p. 5339 - 5342
(2007/10/02)
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- COUPLING OF β-ACETAMIDO RADICALS WITH α-CHLORO ACRYLONITRILE - A NEW ACCESS TO DISUBSTITUTED PROLINE DERIVATIVES
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β-Acetamido radicals are prepared by reduction of organomercurials and coupled with α-chloro-acrylonitrile.The coupling products are further converted to proline derivatives.
- Henning, R.,Urbach, H.
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p. 5343 - 5346
(2007/10/02)
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