WO2004099138A2 - Procede et produit - Google Patents

Procede et produit Download PDF

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Publication number
WO2004099138A2
WO2004099138A2 PCT/GB2004/002029 GB2004002029W WO2004099138A2 WO 2004099138 A2 WO2004099138 A2 WO 2004099138A2 GB 2004002029 W GB2004002029 W GB 2004002029W WO 2004099138 A2 WO2004099138 A2 WO 2004099138A2
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WO
WIPO (PCT)
Prior art keywords
formula
compound
perindopril
process according
pharmaceutically acceptable
Prior art date
Application number
PCT/GB2004/002029
Other languages
English (en)
Other versions
WO2004099138A3 (fr
Inventor
Rajendra Narayanrao Kankan
Dharmaraj Ramachandra Rao
Original Assignee
Cipla Limited
Wain, Christopher, Paul
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 Cipla Limited, Wain, Christopher, Paul filed Critical Cipla Limited
Publication of WO2004099138A2 publication Critical patent/WO2004099138A2/fr
Publication of WO2004099138A3 publication Critical patent/WO2004099138A3/fr

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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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel process for the industrial synthesis of perindopril. More particularly, the present invention relates to a novel process for the industrial synthesis of perindopril in which (2S,3aS,7aS)-2-carboxyperhydroindole is esterified to protect the carboxylic group and is then condensed with N-[(S)-1- carbethoxybutyl]-(S)-alanine, and the product resulting from the condensation is then subjected to deprotection of the carboxyl carried by the heterocyclic ring.
  • the present invention further relates to pharmaceutical dosage forms of perindopril prepared by a process according to the present invention.
  • Perindopril exerts an inhibiting activity on certain enzymes, such as carboxypeptidases, enkephalinases or kininase ⁇ .
  • perindopril inhibits the conversion of angiotensin I decapeptide to angiotensin II octapeptide, which in certain cases is responsible for arterial hypertension, by acting on the conversion enzyme.
  • perindopril can thus reduce or even suppress the activity of these enzymes, which are responsible for hypertensive disorder or for cardiac insufficiency.
  • perindopril can be distinguished from other conversion enzyme inhibitors by its intensity and duration of action.
  • Perindopril, the preparation thereof and its therapeutic use have been described in EP 0,049,658.
  • R denotes a hydrogen atom, lower alkyl or benzyl group.
  • the starting material for the synthesis of a compound of formula (II), employed by some of the prior art processes, is 2-carboxyindole, which is readily available and relatively inexpensive (EP 0,0371,231).
  • 2-carboxyindole is subjected to catalytic reduction over rhodium to give a mixture of the two cis endo isomers of (2S,3aS,7aS) and (2R,3aR,7aR) configuration respectively.
  • the separation of the (2S,3aS,7aS) isomer, which can be used in the synthesis of perindopril, from the (2R,3aR,7aR) isomer generally requires the use of methods which are particularly arduous to employ.
  • EP 0,115,345 employs several stages requiring the esterification of the carboxylic acid group with benzyl alcohol, the conversion of the amino ester to a salt with (S)-N-benzyloxycarbonyl phenylalanine, the separation of the S,S,S isomer by fractional crystallization, and the liberation of the amino group, optionally followed by the liberation of the carboxylic acid group.
  • EP 0,308,341 describes the preparation of the (2S,3aS,7aS)-2-carboxyperhydroindole as the benzyl ester p-toluene sulphonate salt and its further conversion to perindopril.
  • the present invention now provides a process of preparing perindopril of formula (I), or a pharmaceutically acceptable salt thereof
  • the Ri carboxyl protecting group is an optionally substituted aralkyl group, preferably a protecting benzyl group, suitably selected from unsubstituted benzyl, 4- halo phenylmethyl and 4-C 1- alkoxy phenylmethyl.
  • the present invention provides a process of preparing perindopril of formula (I), or a pharmaceutically acceptable salt thereof
  • R denotes a hydrogen atom
  • a benzyl alcohol suitably selected from unsubstituted benzyl alcohol, 4-halo benzyl alcohol or 4-C 1-4 alkoxy benzyl alcohol, in the presence of benzene sulphonic acid as a catalyst, to obtain the benzene sulphonic acid salt of a benzyl protected ester of formula (TTT)
  • Ri is a protecting benzyl group, suitably selected from unsubstituted benzyl, 4- halo phenylmethyl and 4-C ⁇ -4 alkoxy phenylmethyl;
  • Ri in above formulae (TTT) and (IV) represents unsubstituted benzyl, 4- chloro phenylmethyl or 4-methoxy phenylmethyl.
  • preferred benzyl alcohols for reaction with a compound of formula (II) in above defined step (i) are unsubstituted benzyl alcohol, 4-chloro benzyl alcohol and 4-methoxy benzyl alcohol.
  • a compound of formula (II) is reacted with the benzyl alcohol, in the presence of benzene sulphonic acid, with simultaneous removal of water formed in the reaction, suitably either under Dean-Stark conditions, or by use of molecular sieves, to give after isolation the benzene sulphonic acid salt of the benzyl ester of (2S,3aS,7aS)-2-carboxyperhydroindole of formula (TTT), which is then reacted with N-[(S)-l-carbethoxybutyl]-(S)-alanine in the presence of N, N- dicyclohexylcarbodiimide and hydroxy benzotriazole.
  • the benzene sulphonic acid salt of the benzyl ester of (2S,3aS,7aS)-2-carboxyperhydroindole of formula (TTT) is preferably basified and reacted with N-[(S)-l-carbethoxybutyl]-(S)-alanine in the presence of N, N- dicyclohexylcarbodiimide and hydroxy benzotriazole, in a water immiscible solvent, such as ethyl acetate.
  • the benzene sulphonic acid is used in a molar ratio, or in a slight excess of the molar equivalent, with respect to (2S,3aS 5 7aS)-2-carboxyperhydroindole of formula (11). It is further preferred that esterification of a compound of formula (TT) is carried out in a hydrocarbon solvent, such as toluene or xylene, and is typically carried out at reflux temperature for a period of 12 to 24 hours.
  • a hydrocarbon solvent such as toluene or xylene
  • Deprotection of a compound of formula (IV) is typically carried out under mild hydrogenation conditions, suitably using palladium on carbon as the catalyst, in a water immiscible solvent, such as ethyl acetate, under alkaline or neutral conditions.
  • a water immiscible solvent such as ethyl acetate
  • the deprotection can be carried out in the presence of an organic base.
  • deprotection is carried out in the presence of a base which forms a pharmaceutically acceptable salt with the free acid of perindopril formed by the deprotection and a preferred base is thus tert-butyl amine, which can be used in molar quantities with respect to a compound of formula (IV), to give after isolation, perindopril as the erbumine salt which is provided in a very pure form, with very high optical and chromatographic purity.
  • Deprotection of a compound of formula (TV) can also be carried out with suitable oxidizing agents, such as cerric ammonium nitrate or the like.
  • hydrogenation of a compound of formula (TV) is carried out using a solvent, such as an alcoholic solvent, under basic conditions, at pressures ranging from atmospheric to 50 psi for 5 to 10 hours, followed by isolation of the salt of perindopril directly from the reaction mixture.
  • a solvent such as an alcoholic solvent
  • a suitable alcoholic solvent can be isopropanol.
  • (2S,3aS,7aS)-2-carboxyperhydroindole of formula (H) is prepared from commercially available indole-2-carboxylic acid, or an ester thereof, by a series of reaction steps, including acetylation, reduction, resolution and further hydrogenation, and an overall process according to the present invention for the preparation of perindopril erbumine can be represented by the following reaction scheme.
  • Ri is a protecting benzyl group, suitably selected from unsubstituted benzyl, 4- halo phenylmethyl and 4-C 1-4 alkoxy phenylmethyl, and more preferably Ri is unsubstituted benzyl, 4-chloro phenylmethyl or 4-methoxy phenylmethyl.
  • the present invention provides the benzene sulphonic acid salt of an ester of formula (TTT)
  • Ri is a protecting benzyl group, suitably selected from unsubstituted benzyl, 4- halo phenylmethyl and 4-C ⁇ -4 alkoxy phenylmethyl.
  • the present invention provides benzene sulphonic acid salts of the following intermediate compounds suitable for use in the preparation of perindopril, or a pharmaceutically acceptable salt thereof
  • TTT compound of formula (TTT) substantially as hereinbefore described as an intermediate in the preparation of perindopril, or a pharmaceutically acceptable salt thereof.
  • Perindopril as provided by a process according to the present invention has therapeutic utility as an ACE inhibitor.
  • the present invention further provides a method of inhibiting ACE in a patient in need thereof comprising administering to said patient an effective ACE inhibitory amount of perindopril (preferably perindopril erbumine) as provided according to the present invention.
  • the present invention also provides use of perindopril as provided according to the present invention (preferably perindopril erbumme) in the manufacture of a medicament for inhibiting ACE.
  • perindopril as provided according to the present invention (preferably perindopril erbumme)
  • a patient can be in need of treatment to inhibit ACE, for example when the patient is suffering from hypertension, chronic congestive heart failure, or the like.
  • Inhibition of ACE reduces levels of angiotensin H and thus inhibits the vasopressor, hypertensive and hyperaldosteronemic effects caused thereby.
  • Inhibition of ACE would also potentiate endogenous levels of bradykinin.
  • An effective ACE inhibitory amount of perindopril as provided according to the present invention is that amount which is effective in inhibiting ACE in a patient in need thereof which results, for example, in a hypotensive effect.
  • perindopril as provided according to the present invention can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes.
  • perindopril as provided according to the present invention can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, and the like.
  • Oral administration is generally preferred.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the disease state to be treated and the stage of the disease.
  • Perindopril as provided according to the present invention can be administered in the form of pharmaceutical compositions or medicaments which are prepared by combining the perindopril according to the present invention with pharmaceutically acceptable carriers, diluents or excipients therefor, the proportion and nature of which are determined by the chosen route of administration, and standard pharmaceutical practice.
  • the present invention provides pharmaceutical compositions comprising an effective ACE inhibitory amount of perindopril as provided according to the present invention (preferably perindopril erbumme), together with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.
  • perindopril as provided according to the present invention including salts thereof, are typically formulated in oral dosage form of 2mg, 4mg or 8mg.
  • pharmaceutically acceptable it is meant that the carrier, diluent or excipient must be compatible with perindopril as provided according to the present invention, and not be deleterious to a recipient thereof.
  • compositions or medicaments are prepared in a manner well known in the pharmaceutical art.
  • the carrier, diluent or excipient may be a solid, semi-solid, or liquid material, which can serve as a vehicle or medium for the active ingredient. Suitable carriers, diluents or excipients are well known in the art.
  • Pharmaceutical compositions according to the present invention may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solutions, suspensions or the like.
  • the pharmaceutical compositions may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • perindopril as provided by the present invention may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups and the like.
  • the tablets, pills, capsules, and the like may also contain one or more of the following adjuvants: binders, such as microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch or lactose; disintegrating agents such as alginic acid, com starch and the like; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; and sweetening agents, such as sucrose or saccharin.
  • binders such as microcrystalline cellulose, gum tragacanth or gelatin
  • excipients such as starch or lactose
  • disintegrating agents such as alginic acid, com starch and the like
  • lubricants such as magnesium stearate
  • glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin.
  • the dosage unit form may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.
  • tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • perindopril as provided according to the present invention may be incorporated into a solution or suspension.
  • the solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; and buffers such as acetates, citrates or phosphates.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

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

Abstract

L'invention concerne un procédé de préparation de perindopril de formule (I) ou un sel pharmaceutiquement acceptable de ce dernier, lequel procédé consiste à protéger un composé de formule (II), dans laquelle R désigne un atome d'hydrogène, en présence d'acide benzène sulfonique en tant que catalyseur pour obtenir le sel d'acide benzène sulfonique d'un ester de formule (III), dans laquelle R1 représente un groupe protecteur carboxyle, puis à faire réagir ledit ester de formule (III) avec la N-[(S)-1-carbéthoxybutyl]-(S)-alanine pour obtenir un composé de formule (IV), dans laquelle R1 est tel que défini ci-dessus, et à déprotéger un composé de formule (IV) pour produire le perindopril de formule (I) ou un sel pharmaceutiquement de ce dernier. La présente invention concerne également le sel d'acide benzène sulfonique d'un ester de formule (III) et le perindopril ou sel pharmaceutiquement acceptable de ce dernier préparé par le procédé susmentionné.
PCT/GB2004/002029 2003-05-12 2004-05-12 Procede et produit WO2004099138A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN468MU2003 2003-05-12
IN468/MUM/2003 2003-05-12

Publications (2)

Publication Number Publication Date
WO2004099138A2 true WO2004099138A2 (fr) 2004-11-18
WO2004099138A3 WO2004099138A3 (fr) 2004-12-23

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005100317A1 (fr) * 2004-04-13 2005-10-27 Neopharma Limited Procede pour la preparation de perindopril
ES2255872A1 (es) * 2004-12-31 2006-07-01 Quimica Sintetica, S.A. Procedimiento para la preparacion de perindopril erbumina.
EP1679072A1 (fr) * 2005-01-06 2006-07-12 IPCA Laboratories Limited Procédé de synthèse de dérivés de l'acide (2S, 3aS, 7aS)-1-(S)-alanyl-octahydro-1H-indole-2-carboxylique et application à la synthése du perindopril
EP1864973A1 (fr) * 2006-06-09 2007-12-12 Sochinaz SA Procede de preparation de perindopril et de sels de celui-ci
WO2016178591A2 (fr) 2015-05-05 2016-11-10 Gene Predit, Sa Marqueurs génétiques et traitement de l'obésité masculine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0308341A1 (fr) * 1987-09-17 1989-03-22 Adir Et Compagnie Procédé de synthèse industrielle du périndopril et de ses principaux intermédiaires de synthèse
WO2001058868A1 (fr) * 2000-04-06 2001-08-16 Les Laboratoires Servier Procede de synthese du perindopril et de ses sels pharmaceutiquement acceptables
EP1323729A1 (fr) * 2003-03-12 2003-07-02 Les Laboratoires Servier Nouveau procédé de synthèse de l'acide (2S, 3aS, 7aS)-perhydroindole-2-carboxylique et de ses esters, et application à la synthèse du perindopril
EP1338591A1 (fr) * 2003-02-28 2003-08-27 Les Laboratoires Servier Nouveau procédé de synthèse de l'acide (2S, 3aS, 7aS)-perhydroindole-2-carboxylique et de ses esters, et application à la synthèse du perindopril

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0308341A1 (fr) * 1987-09-17 1989-03-22 Adir Et Compagnie Procédé de synthèse industrielle du périndopril et de ses principaux intermédiaires de synthèse
WO2001058868A1 (fr) * 2000-04-06 2001-08-16 Les Laboratoires Servier Procede de synthese du perindopril et de ses sels pharmaceutiquement acceptables
EP1338591A1 (fr) * 2003-02-28 2003-08-27 Les Laboratoires Servier Nouveau procédé de synthèse de l'acide (2S, 3aS, 7aS)-perhydroindole-2-carboxylique et de ses esters, et application à la synthèse du perindopril
EP1323729A1 (fr) * 2003-03-12 2003-07-02 Les Laboratoires Servier Nouveau procédé de synthèse de l'acide (2S, 3aS, 7aS)-perhydroindole-2-carboxylique et de ses esters, et application à la synthèse du perindopril

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PASCARD C ET AL: "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" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 34, no. 2, 1991, pages 663-669, XP001156382 ISSN: 0022-2623 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005100317A1 (fr) * 2004-04-13 2005-10-27 Neopharma Limited Procede pour la preparation de perindopril
US7666896B2 (en) 2004-04-13 2010-02-23 Cipla Limited Process for the preparation of perindopril
ES2255872A1 (es) * 2004-12-31 2006-07-01 Quimica Sintetica, S.A. Procedimiento para la preparacion de perindopril erbumina.
EP1679072A1 (fr) * 2005-01-06 2006-07-12 IPCA Laboratories Limited Procédé de synthèse de dérivés de l'acide (2S, 3aS, 7aS)-1-(S)-alanyl-octahydro-1H-indole-2-carboxylique et application à la synthése du perindopril
EP1987828A1 (fr) 2005-01-06 2008-11-05 IPCA Laboratories Limited sels de perindopril et utilisation de ceux-ci dans la thérapie de l'hypertension
EP1864973A1 (fr) * 2006-06-09 2007-12-12 Sochinaz SA Procede de preparation de perindopril et de sels de celui-ci
WO2016178591A2 (fr) 2015-05-05 2016-11-10 Gene Predit, Sa Marqueurs génétiques et traitement de l'obésité masculine

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