- 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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- PROCESS FOR THE PREPARATION OF PERINDOPRIL ERBUMINE SALT AND NOVEL POLYMORPH (S) THEREOF
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A single pot process for the preparation of perindopril erbumine salt according to which condensation of (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid benzyl ester para toluene sulfonate with N-((S-)-ethoxy carbonyl -1-ethyl-(S)-alanine, catalytic hydrogenation of benzyl ester of (2S, 3aS, 7aS)-1-{2-[1-(ethoxycarbonyl)-(S)-butylamino]-(S)propionyl}- octahydro-indole-2-carboxylate and conversion of (2S,3aS, 7aS)-1-{2-[1-ethoxycarbonyl)_(S)-butylamino]-(S)-propionyl}octahydroindole-2-carboxylic acid to its perindopril erbumine salt are carried out in a single pot using a single solvent such as isopropyl acetate to obtain perindopril erbumine salt of very high purity. Also a novel polymorph S of perindopril erbumine having X-ray diffraction peaks of 9.10, 14.64, 15.37, 16.58, 17.39, 19.99, 20.62, 21.50, 22.15, 22.60, 24.20, 27.55 ± 0.2 at 2Θ values. Also processes for preparing the novel polymorph S.
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Page/Page column 12; 12-13
(2008/12/07)
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- SALTS OF PERINDOPRIL
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The present invention relates to new salts of perindopril, particularly to a new calcium salt and new amine salts of perindopril, to a process for their preparation and to a pharmaceutical formulations containing the new salts.
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Page/Page column 15-16
(2009/03/07)
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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 7-8
(2010/11/27)
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- NEW CRYSTALLINE FORM OF PERINDOPRIL ERBUMINE
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The present invention relates to new crystalline form of the ACE inhibitor perindopril and processes for the preparation thereof.
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Page/Page column 9
(2008/06/13)
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- NOVEL METOD FOR THE SYNTHESIS OF PERINDOPRIL AND THE PHARMACEUTICALLY-ACCEPTABLE SALTS THEREOF
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A process for the synthesis of perindopril of formula (I): and its pharmaceutically acceptable salts.
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Page/Page column 2
(2008/06/13)
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- NOVEL METHOD FOR THE SYNTHESIS OF PERINDOPRIL AND THE PHARMACEUTICALLY-ACCEPTABLE SALTS THEREOF
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Process for the synthesis of perindopril of formula (I): and its pharmaceutically acceptable salts.
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Page/Page column 2
(2008/06/13)
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- PROCESS FOR THE SYNTHESIS OF PERINDOPRIL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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A process for the synthesis of perindopril of formula (I): and its pharmaceutically acceptable salts.
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Page/Page column 2
(2008/06/13)
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- PROCESS FOR SYNTHESIS OF PERINDOPRIL AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF.
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Process for the synthesis of perindopril of formula (I): and pharmaceutically acceptable salts thereof.
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Page/Page column 3
(2008/06/13)
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- Process for the synthesis of perindopril and pharmaceutically acceptable salts thereof.
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Process for the industrial synthesis of perindopril of formula (I): and pharmaceutically acceptable salts thereof.
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Page/Page column 2
(2010/11/26)
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- Process for the preparation of perindopril and salts thereof
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The present invention describes a novel method for the synthesis of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid, or of one of its aryl esters of formula XIII wherein X and Y are a hydrogen atom, a halogen, alkyl, alkoxyl or nitro group, and the conversion of the paranitrobenzyl ester of formula X into Perindopril of formula I or one of its salts.
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Page/Page column 12-13
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF PERINDOPRIL
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The present invention relates to an improved process for the preparation of silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole. Also provided is an improved process for the preparation of perindopril and its pharmaceutically acceptable salts.
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Page/Page column 12
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF CRYSTALLINE PERINDOPRIL
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The present invention relates to a new process for the preparation of crystalline perindopril. The present invention also relates to new alkyl ammonium salts of perindopril and the processes for the preparation thereof.
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Page/Page column 16
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF N-[1-(S)-ETHOXYCARBONYL-1-BUTYL]-(S)-ALANINE-DMT COMPLEX AND ITS USE IN THE PREPARATION OF PERINDOPRIL
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A compound N-[l-(S)-ethoxycarbonyl-l-butyl]-(S)-alanine-DMT complex of Formula (II) is provided. Also provided is a process for the preparation of N-[l-(S)-ethoxycarbonyl-l-butyl]-(S)- alanine-DMT complex and its use in preparing perindopril or a pharmaceutically acceptable salt thereof.
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Page/Page column 11
(2008/06/13)
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- PROCESS FOR INDUSTRIALLY VIABLE PREPARATION OF PERINDOPRIL ERBUMINE
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The invention relates to a novel method for the preparation of perindopril erbumine of Formula (VIII) by converting the esters of (S, S, S)- octahydroindole-2-carboxylic acid of Formula (I) where R is methyl, ethyl, tertiary butyl, benzyl, substituted benzyl.
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Page/Page column 11-12
(2010/11/25)
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- Process for the preparation of perindopril
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A process for preparing perindopril is provided comprising condensing an N-[(S)-1-carbethoxybutyl]-(S)-alanyl halide of formula II: wherein X is a halide with an (2S,3aS,7aS)-2-carboxyperhydroindole of formula III: wherein R is hydrogen or a protecting group.
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Page/Page column 3-4
(2010/11/23)
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- AN IMPROVED PROCESS FOR THE PURIFICATION OF PERINDOPRIL
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A dicyclohexyamine salt of compound of formula I, namely perindopril, having an X-ray powder diffraction pattern with characteristic peaks (2θ): 8.462, 10.624, 18.693, 9.424, 17.272, 14.177, 19.499, 20.765, 21.409, and 14.540. Formula (I). A process for preparation of the said salt of perindopril and its use in the purification of an impure perindopril and a process for purification of perindropril comprising formation of its salt with dicyclohexylamine. The present invention also relates to preparation of Perindopril tert-butyl amine salt directly from Perindopril dicyclohexylamine salt without isolating the free base.
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Page/Page column 10-11
(2008/06/13)
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- Process for for synthesis of (2S,3aS,7aS)-1-(S)-alanyl-octahydro-1H-indole-2- carboxylic acid derivatives and use in the synthesis of perindopril
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The present invention relates to a compound of general formula IVA, wherein R is selected from substituted or unsubstituted arylalkyl groups; and HA represents an acid capable of forming a salt.
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Page/Page column 8-9
(2008/06/13)
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- PROCESS FOR PREPARING PERINDOPRIL ERBUMINE
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The present invention relates to a new process for preparing perindopril erbumine (I), useful in the treatment of hypertension. The invention relates to obtaining 1-[(2S)-2-[[(1S)-1(ethoxycarbonyl)butyl]amino]-1-propionyl] (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid, tert-butylamine salt that comprises reacting an active ester of N-[2(S)-(ethoxycarbonyl)butyl]-L-alanine with an organic salt of perhydroindole-2-carboxylic acid, followed by the addition of t-butylamine and an acid to the reaction medium, in any order, or else a salt formed from an acid and tert-butylamine, and separating the product by conventional means.
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Page/Page column 7-8
(2008/06/13)
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- Novel method for synthesising perindopril and the pharmaceutically acceptable salt thereof
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Process for the synthesis of perindopril of formula (I): and pharmaceutically acceptable salts thereof.
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Page/Page column 2
(2008/06/13)
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- Novel method for the synthesis of perindopril and the pharmaceutically acceptable salts thereof
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Process for the synthesis of perindopril of formula (I): and its pharmaceutically acceptable salts.
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Page/Page column 2
(2008/06/13)
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- Novel method of synthesising perindopril and the pharmaceutically acceptable salts thereof
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Process for the synthesis of perindopril of formula (I): and its pharmaceutically acceptable salts.
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Page/Page column 2
(2008/06/13)
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- Novel method for the synthesis of perindopril and the pharmaceutically acceptable salts thereof
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Process for the synthesis of perindopril of formula (I): and its pharmaceutically acceptable salts.
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Page/Page column 2
(2008/06/13)
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- Novel method for the synthesis of perinidopril and the pharmaceutically acceptable salts thereof
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Process for the synthesis of perindopril of formula (I): and its pharmaceutically acceptable salts.
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Page/Page column 7
(2008/06/13)
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- Process for making (2S, 3aS, 7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl) butyl] amino]-1-oxopropyl] octahydro-1H-indole-2-carboxylic acid
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The present invention discloses a process for the synthesis and isolation of (2S, 3aS, 7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]-1-oxopropyl] octahydro-1H-indole-2-carboxylic acid and its tert-butylamine salt, by condensing (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid benzyl ester and N[(S)1-carboxybutyl]-(S)-alanine ethyl ester in nonreactive solvents in turn avoiding the formation of impurity viz. N-acetyl (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester (Formula V). The de-protection of benzyl ester group is optimized and then isolation of the product from aqueous layer by extraction using an organic solvent, which eliminates the need of lyophilization. The process of the present invention yields perindopril erbumnine salt of Formula 1B free of contaminants derivable from dicyclohexylcarbodiimide and impurities originated by the use of ethyl acetate.
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Page/Page column 4
(2008/06/13)
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- A PROCESS FOR THE PREPARATION OF PERINDOPRIL
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The present invention provides an improved process for the preparation of Perindopril of Formula (I) and its pharmaceutically acceptable salts.
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Page/Page column 8
(2010/11/25)
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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 13
(2010/02/14)
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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)-l-((2S)-2-(((1S)-l-(ethoxycarbonyl)butyl)amino)-l-oxopropyl)octahydro-lH-indol-2-carboxylic acid and of pharmaceutically acceptable salts thereof as well as to intermediates useful in said process.
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Page/Page column 10-11
(2010/02/14)
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- Process for the preparation of perindopril
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A process for preparing a novel intermediate in the preparation of perindopril is provided. Also provided are improved processes for the preparation of perindopril erbumine comprising (a) reacting a compound of Formula (15) with a silylated octahydroindole-1H-2-carboxylic acid to form perindopril; and (b) reacting perindopril with tert-butylamine to form perindopril erbumine of Formula I:
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Page/Page column 4-5
(2008/06/13)
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- NOVEL METHOD FOR PREPARATION OF CRYSTALLINE PERINDOPRIL ERBUMINE
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A process for preparation of crystalline perindopril erbumine of formula (II) which exhibits the X-ray (powder) diffraction pattern like that shown in the figure. The process comprises reacting a solution of perindopril of formula (I), in a solvent selected from N, N-dimethylformamide or dimethyl acetals of lower aliphatic aldehydes and ketones with tertiary butylamine and crystallization of the erbumine salt thus obtained by heating the reaction mixture to reflux, filtering hot, cooling gradually to 20 oC to 30 oC, and further cooling to 0o C to 15 oC for 30 minutes to 1 hour and finally filtering off and drying the crystals.
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Page/Page column 28-29;34-35; 51; 38-39 52; 53
(2010/02/11)
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- NEW CRYSTALLINE FORM OF PERINDOPRIL
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The present invention relates to the process for a preparation of ACE inhibitor perindopril starting from the stereospecific amino acid N-[(S)-carbethoxy-1-butyl]-(S)-alanine, which is protected by trimethylsilyl group and converted to reactive acid chloride using thionylchloride or its complex with 1-H-benzotriazole (1:1), which reacts with (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid with a protected carboxyl group. This invention relates also to a new crystalline form of perindopril and to a new amorphous form of perindopril.
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Page/Page column 20
(2008/06/13)
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- PROCESS FOR PURE PERINDOPRIL TERT-BUTYLAMINE SALT
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Pure perindopril tert-butylamine salt is obtained by extracting an aqueous solution of perindopril or its salt contaminated with impurities with a suitable organic solvent such as methylenedichloride at a pH of 4.0 to 6.5, separating the organic layer, isolating perindopril from the organic layer and converting it into tert-butylamine salt.
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Page/Page column 8-9
(2008/06/13)
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- PROCESS AND PRODUCT
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A process of preparing perindopril of formula (I), or a pharmaceutically acceptable salt thereof which process comprises protecting a compound of formula (II) where R denotes a hydrogen atom, in the presence of benzene sulphonic acid as a catalyst, to obtain the benzene sulphonic acid salt of an ester of formula (III) where Rl is a carboxyl protecting group and reacting said ester of formula (III) with N-[(S)-1-carbethoxybutyl]-(S)-alanine to obtain a compound of formula (IV) where Rl is as defined above; and deprotecting a compound of formula (IV) to yield perindopril of formula (I), or a pharmaceutically acceptable salt thereof. There is also provided by the present invention the benzene sulphonic acid salt of an ester of formula (III), and perindopril or a pharmaceutically acceptable salt thereof prepared by the above process.
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- A process for the preparation of perindopril, its analogous compounds and salts thereof using 2,5-dioxo-oxazolidine intermediate compounds
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A process for the preparation of a compound of formula (IV) or an ester or a salt thereof comprising1) reacting a compound of formula (I) (wherein Ra represents C1-4alkyl, Rb represents C1-4alkyl and Rc represents C1-6alkyl) with a compound of formula X2C=O (wherein each X independently represents a leaving group) to give a compound of formula (II) (wherein Ra, Rb and Rc are as hereinbefore defined); and2) reacting said compound of formula (II) with a compound of formula (III) (wherein Rd represents hydrogen or a protecting group), compounds of formula (II), and a process for the preparation of compounds of formula (I).
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