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WO2006059347A2 - Procede de preparation ameliore de ramipril - Google Patents

Procede de preparation ameliore de ramipril Download PDF

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Publication number
WO2006059347A2
WO2006059347A2 PCT/IN2005/000393 IN2005000393W WO2006059347A2 WO 2006059347 A2 WO2006059347 A2 WO 2006059347A2 IN 2005000393 W IN2005000393 W IN 2005000393W WO 2006059347 A2 WO2006059347 A2 WO 2006059347A2
Authority
WO
WIPO (PCT)
Prior art keywords
acid
solvents
formula
ramipril
ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2005/000393
Other languages
English (en)
Other versions
WO2006059347A3 (fr
Inventor
Sanjay Suri
Tapan Kashyap
Jagat Singh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Morepen Laboratories Ltd
Original Assignee
Morepen Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Morepen Laboratories Ltd filed Critical Morepen Laboratories Ltd
Publication of WO2006059347A2 publication Critical patent/WO2006059347A2/fr
Publication of WO2006059347A3 publication Critical patent/WO2006059347A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

Definitions

  • this invention relates to an improved process for Manufacturing a key intermediate of Ramipril named as (S,S,S)-2-azobicyclo [3,3,0] octane-3-carboxylic acid benzyl ester hydrochloride [(S,S,S)-enantiomer)] by resolution of its racemate. More particularly, the present invention provides a process for separation of diastereomeric mixture of key intermediate, (S 5 S 5 S)- enantiomer, of Ramipril in its pure form. Still more particularly, this invention provides a process that is high yielding, ecofriendly, commercially viable and easy to operate. BACKROUND OF THE INVENTION
  • Ramipril is known for having a long lasting, intense hypotensive action. This is one of the powerful inhibitor of angiotensin- converting enzyme (ACE inhibitor) and is used for controlling high blood pressure of various origins. It can be combined with other antihypotensive, vasodilating or diuretic compounds.
  • Synthesis of Ramipril involves a common intermediate namely 2- azabicyclo [3,3,0] octane-3-carboxylic acid of formula I.
  • This common intermediate is a racemic mixture of (S,S,S) and (R,R,R)- enantiomers, out of that (S,S,S)-being the desired enantiomer for getting Ramipril. These enantiomers are inseparable by known separation techniques due to their zwitterionic nature.
  • EP 0115345 and TL 25(40) 4479-82 (1984) describe a process for resolution of racemic optically active bicyclic immoralpha-carboxylic acid ester to get (S 5 S 5 S)- enantiomer by a process involving conversion of racemic ester into its salt with optically active N-acylated R- or S- aminocarboxylic acids which contain a phenyl nucleus, from the series phenylalanine, phenylglycine, beta-phenyl-alpha- aminobutyric acid, 3,4-dihydroxyphenylalanine, beta phenylserine and tyrosine, crystallizing such salts, decomposing them and isolating the desired enantiomer which can be further converted to Ramipril.
  • the protecting group has to be removed either by hydrogenolysis or treatment with an acid or base to yield Ramipril.
  • the disadvantage of this approach is that it involves two additional steps to install the protecting group in formula II and to remove the ester group from formula IV.
  • the racemic mixture has to be purified by costly and hard to implement silica gel column chromatography to give enantiomerically pure (S,S,S)-compound. Additionally the yield is low.
  • R is benzyl Hb: benzyl (S,S,S) Ha: R is ethyl Hc: benzyl (R 5 R 5 R)
  • R is benzyl (S 5 S 5 S)
  • enantiomerically pure amino ester (II) is either prepared by targeted enantioselective synthesis.
  • the ester protecting group R is removed by hydrogenolysis or treatment with an acid or base.
  • This route is associated with certain difficulties.
  • the efficient large scale enantioselective synthesis of chirally pure compound of formula II is not reported.
  • the reported enantioeselective routes appear to be very low yielding (13% even as low as 5.5%) proving the process unfeasible for commercial implementation.
  • US 6,407,262 describes a process in which the resolution of penultimate step of Ramipril ie, benzyl Ramipril, has been done using solvent selected from a group consisting of nitrile solvent (C 2 -C 4 ), alcohols ( Ci C 6 ), aromatic hydrocarbon solvents (C 6 Cg ), ether solvents (C 3 -Ci 0 ), ketone solvent ( C 3 -Ce) 5 Ester solvent ( C 2 -C 7 ), and hydrocarbon solvents (C 5 -C 1 0), or mixture thereof and adding if desired acid such as maleic acid mandelic acid or benzoic acid or fumaric acid or methsne sulfonic acid or toluene sulfonic acid or halo acids or sulphuric acid or phosphoric acid as resolving agent.
  • solvent selected from a group consisting of nitrile solvent (C 2 -C 4 ), alcohols ( Ci C 6 ), aromatic hydrocarbon solvent
  • the preferred esterifying group is benzyl and preferred acid is maleic acid.
  • the reaction is carried out at -5O 0 C to 5O 0 C. the acid can be replaced by base.
  • the seeding may have to be implemented for precipitation of title compound. It is always advantageous to purify/ resolve the lower intermediates as compared to higher ones as the purification/ resolution losses in yield at higher stages contribute more to the cost due to value addition.
  • the main aim of the present invention is to provide an improved Process For
  • the other object of this invention is to provide an improved process for manufacturing a key intermediate of Ramipril named as (S,S,S)-2-azobicyclo [3,3,0] octane-3-carboxylic acid benzyl ester hydrochloride [(S,S,S)-enantiomer)] by resolution of its racemate.
  • Another object of this invention is to provide a process for separation of diastereomeric mixture of key intermediate, (S,S,S)- enantiomer, of Ramipril in its pure form.
  • Yet other object of this invention is to provide an improved a process that is high yielding, ecofriendly, commercially viable and easy to operate.
  • step (a) converting bicyclic amino acid of formula I to its racemic ester of formula II by any conventional method, (b) treating the said racemic ester of formula II, obtained in step (a) at a temperature in the range of 0.0 to 4O 0 C, with an organic acid in solvent exemplified by ester
  • solvents up to C3, ketonic solvents, halogenated hydrocarbons solvents, hydrocarbons solvents, ethereal solvents or mixture thereof to precipitate salt of desired enantiomer, (c) decomposing of above salt at a temperature in the range of 0.0 to 3O 0 C, to get the
  • Organic acids used in step b) may be tartaric acids or substituted tartaric acids like, , L- tartaric acid, (-) dibenzoyl-L-tartaric acid; maleic acid or substituted maleic acid.
  • Solvents used may be ester solvents like, ethyl acetate, propyl acetate; ketonic solvents like, acetone, methyl isobutyl ketone, methyl ethyl ketone; halogenated hydrocarbons like, chloroform, dichloromethane; hydrocarbons like, hexanes, heptanes, xylenes, toluene, benzene, cyclohexane; ethereal solvents like diethylether, diisopropyl ether, methyl tertiary butyl ether tetrahydrofuran.
  • the reactions in step (b) and (c) is carried out at a temperature in the range of 0.0 to 15 0
  • Step 1 Preparation of (S,S,S)-amino benzyl ester dibenzoyl-L-tartarate salt
  • decolorizing carbon 6 g was added.
  • pH 10.5 - 11.0 pH 10.5 - 11.0 with 10% (w/v) aqueous sodium hydroxide solution.
  • Solvent was evaporated under vacuum to get oily residue.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé efficace permettant de préparer un intermédiaire clé de ramipril appelé [énantiomère (S,S,S)-)] de chlorhydrate de benzylester d'acide (S, S, S)-2-azobicyclo [3, 3,0] octane-3-carboxylique par résolution de son mélange inactif dédoublable. La séparation du mélange diastéréomère de l'intermédiaire clé, l'éniantomère (S, S, S) de ramipril sous sa forme pure est obtenue par utilisation d'acides organiques, tels que l'acide tartrique, les acides tartriques substitués, tels que l'acide D- tartrique, l'acide L- tartrique, l'acide (-) dibenzoyl-L-tartrique, l'acide (+) dibenzoyl-D-tartrique, etc.; l'acide maléïque ou l'acide maléïque substitué; l'acide fumarique ou l'acide fumarique substitué, de préférence, l'acide tartrique, les acides tartriques substitués, tels que l'acide D- tartrique, l'acide L- tartrique, l'acide (-) dibenzoyl-L-tartrique, l'acide (+) dibenzoyl-D-tartrique.
PCT/IN2005/000393 2004-12-01 2005-11-30 Procede de preparation ameliore de ramipril Ceased WO2006059347A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2400DE2004 2004-12-01
IN2400/DEL/2004 2004-12-01

Publications (2)

Publication Number Publication Date
WO2006059347A2 true WO2006059347A2 (fr) 2006-06-08
WO2006059347A3 WO2006059347A3 (fr) 2006-09-08

Family

ID=36440892

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000393 Ceased WO2006059347A2 (fr) 2004-12-01 2005-11-30 Procede de preparation ameliore de ramipril

Country Status (1)

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WO (1) WO2006059347A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009122433A3 (fr) * 2008-03-13 2014-09-04 Ipca Laboratories Limited Procédé de préparation de ramipril

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU191120B (en) * 1983-01-31 1987-01-28 Hoechts Ag,De Process for raceme separation of optically active byciclic imino-alpha-carbonic acid esthers

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009122433A3 (fr) * 2008-03-13 2014-09-04 Ipca Laboratories Limited Procédé de préparation de ramipril

Also Published As

Publication number Publication date
WO2006059347A3 (fr) 2006-09-08

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