WO2009149734A1 - Processus destiné à la préparation d’irbésartan et de produits intermédiaires - Google Patents

Processus destiné à la préparation d’irbésartan et de produits intermédiaires Download PDF

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Publication number
WO2009149734A1
WO2009149734A1 PCT/EP2008/004787 EP2008004787W WO2009149734A1 WO 2009149734 A1 WO2009149734 A1 WO 2009149734A1 EP 2008004787 W EP2008004787 W EP 2008004787W WO 2009149734 A1 WO2009149734 A1 WO 2009149734A1
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WIPO (PCT)
Prior art keywords
formula
compound according
tetrazole
protecting group
compound
Prior art date
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Ceased
Application number
PCT/EP2008/004787
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English (en)
Inventor
Jirí Stohandl
Pavel Bobal
Jaroslav Frantisek
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Ratiopharm GmbH
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Ratiopharm GmbH
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Priority to PCT/EP2008/004787 priority Critical patent/WO2009149734A1/fr
Publication of WO2009149734A1 publication Critical patent/WO2009149734A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a new method for the production of irbesartan, having the chemical name 2-n-butyl-4-spirocyclopentane-1 -[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2- imidazolin-5-one, and pharmacologically acceptable salts thereof. Furthermore the invention relates to new (intermediate) compounds which are suitable for the production of irbesartan.
  • Irbesartan is particularly useful in the treatment of cardiovascular ailments such as hypertension and heart failure. Irbesartan and its production have been described for the first time in EP 0 454 511.
  • the disclosed synthetic pathways comprise the following steps:
  • Irbesartan exists in more than one polymorph forms.
  • Polymorph forms A and B are disclosed in EP 0 708 103 and DE 695 19 788, respectively.
  • WO 03/050110 discloses an amorphous form of irbesartan.
  • a subject of the present invention is a method for producing a compound according to formula VIII or its pharmacologically acceptable salts,
  • Vl wherein in formula Vl R 1 is hydrogen or a tetrazole-protecting group, provided that before or after the hydrogenation step the tetrazole-protecting group is removed, if R 1 is other than hydrogen.
  • R 1 is hydrogen or a tetrazole-protecting group.
  • One of the key aspects of the invention is the production of a compound of general formula IV or a pharmaceutically acceptable salt thereof.
  • the compounds of general formula I or pharmaceutically acceptable salts thereof can be prepared by reacting a compound of general formula I or a pharmaceutically acceptable salt thereof
  • X represents a leaving group, such as halogen or an other suitable leaving group, preferably selected from the group consisting of Cl 1 Br 1 1 1 triflate, mesylate, tosylate, most preferably Cl.
  • reaction of a compound of general formula I with a compound of general formula Il to give a compound of general formula IV is preferably carried out as a one-pot two-step process.
  • a compound of general formula I is reacted with a compound of general formula II.
  • the reaction of the first step is preferably carried out in the presence of a Bronsted base.
  • suitable Bronsted bases are alkali metal carbonates, alkali metal bicarbonates or organic bases like amines, such as, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, diethylamine, triethylamine or diisopropylamine. Triethylamine is preferred.
  • the reaction is carried out in a suitable inert solvent.
  • suitable inert solvents are ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran), ketones (preferably acetone, methylisobutylketone or methylethylketone), chlorinated hydrocarbons (preferably dichloromethane) or nitrogen containing organic solvents (preferably N-methyl pyrrolidone or dimethylformamide).
  • ethers preferably diethyl ether
  • cyclic ethers preferably tetrahydrofuran
  • ketones preferably acetone, methylisobutylketone or methylethylketone
  • chlorinated hydrocarbons preferably dichloromethane
  • nitrogen containing organic solvents preferably N-methyl pyrrolidone or dimethylformamide
  • reaction can be carried out e.g. at room temperature (20 to 25 0 C) or elevated temperatures, for example at temperatures between 50 0 C and the boiling point of the solvent. Preferably the reaction is carried out at room temperature.
  • reaction product of the reaction of a compound of general formula I with a compound of general formula Il can be isolated. Such reaction product is referred to as compound according to formula III
  • reaction product of the reaction of a compound of general formula I with a compound of general formula Il i.e. the compound according to formula III
  • a compound of general formula IV preferably by a ring closing reaction.
  • the ring closing reaction is preferably carried out using a suitable base.
  • suitable bases are Bronsted bases like alkali metal carbonates, alkali metal bicarbonates, alkali mental hydroxides, or organic bases like amines, such as, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, diethylamine, triethylamine, or diisopropylamine.
  • Sodium hydroxide is preferred.
  • the ring closing reaction is advantageously carried out in the presence of a suitable solvent and at elevated temperatures, preferably at temperatures between 50 0 C and the boiling point of the solvent.
  • suitable inert solvents are water, ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran), ketones (preferably acetone, methylisobutylketone or methylethylketone), alcohols (preferably methanol, ethanol, isopropanol or butanol), chlorinated hydrocarbons (preferably dichloromethane) or nitrogen containing organic solvents (preferably N-methyl pyrrolidone or dimethylformamide), or mixtures thereof.
  • a mixture of methanol and water is especially preferred.
  • Compounds of general formula IV can be converted in pharmaceutically acceptable salts of compounds of general formula IV using known methods of salt formation by the reaction of compounds of general formula I with a suitable acid or base.
  • R 1 represents hydrogen or a tetrazole-protecting group are prepared from a compound according to formula IV.
  • the compound according to formula IV or pharmaceutically acceptable salts thereof are reacted with a compound of general formula V
  • R 1 represents hydrogen or a tetrazole protecting group and L represents a leaving group.
  • the leaving group L is an atom or group of atoms capable of detaching from the compound of formula V.
  • the leaving group L is selected from the group consisting of Cl, Br, I, triflate, mesylate and tosylate. Most preferably the leaving group is Br.
  • a tetrazol protecting group could be any organic residue capable of reversible forming a covalent bond with the tetrazol ring.
  • Suitable tetrazole protecting groups in the residue of the above-given general formulae V and Vl are known from EP-A-291969.
  • Suitable tetrazole protecting groups are in particular p-nitrobenzyl, beta-propionitrile, trialkyltin, triphenylmethyl, 1-methyl-1-phenylethyl or tert-butyl. Particularly preferred is triphenylmethyl.
  • R 1 is triphenylmethyl and L is halogen, especially Br.
  • the above described reaction is preferably carried out in the presence of a Bronsted base.
  • Bronsted bases are alkali metal carbonates, alkali metal bicarbonates, alkali mental hydroxides, alkali metal hydrides, earth alkali metal hydrides, or organic bases like amines, such as, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, calcium hydride, diethylamine, triethylamine, or diisopropylamine.
  • Sodium hydride is preferred.
  • the reaction is preferably carried out in a suitable inert solvent.
  • suitable inert solvents are ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran), ketones (preferably acetone, methylisobutylketone or methylethylketone), chlorinated hydrocarbons (preferably dichloromethane) or nitrogen containing organic solvents (preferably N-methyl pyrrolidone or dimethylformamide).
  • Dimethylformamide is especially preferred.
  • the reaction is preferably carried out at elevated temperatures, preferably at temperatures between 50 0 C and the boiling point of the solvent, more preferably at the boiling point of the solvent.
  • the preparation of irbesartan is carried out by converting compounds of general formula Vl to irbesartan comprising a hydrogenation step and (if necessary) a deprotection step.
  • the deprotection step is only necessary if R 1 in formula Vl is the tetrazol protecting group (and not hydrogen). In this case the order of the two steps is optional. If R 1 in formula Vl is a tetrazol-protecting group, routes A and B are possible.
  • route A the compound of formula Vl is hydrogenated in a first step and subsequently the tetrazole-protecting group is removed.
  • route B the compound of formula Vl is deprotected in a first step and subsequently hydrogenated.
  • irbesartan can be prepared by the reaction of a compound of general formula Vl with a suitable hydrogenating agent to produce a compound according to formula VII
  • R 1 represents a tetrazole-protecting group.
  • the compound of formula VII can be further converted to irbesartan by applying a deprotection step.
  • irbesartan can be prepared by the reaction of a compound of general formula Vl in a deprotection step to produce a compound according to formula Via,
  • the preparation of irbesartan from compounds of general formula Vl can be carried out with or without isolation of the reaction product of the first step (i.e. with or without isolation of compounds VII and Via).
  • the hydrogenation step is carried out using a suitable hydrogenating agent.
  • a suitable hydrogenating agent is hydrogen, preferably in the presence of a metal catalyst such as nickel or palladium. Most preferably Raney nickel is used, particularly in the presence of dimethylformamide, methanol or water.
  • the reaction can be carried out at normal pressure or preferably at elevated pressure, e.g. from 2 to 10 bar.
  • the deprotection step i.e. the removal of the tetrazole-protecting group R 1 is carried out for example using a suitable acid in a suitable solvent.
  • suitable acids are Lewis acids like metal halides, such as metal chlorides, metal bromides or metal iodides, preferably zinc halides, most preferably zinc chloride, or Bronsted acids like strong organic or inorganic acids, such as hydrohalic acids like hydrochloric acid or hydrobromic acid, sulfuric acid, trichloroacetic acid, trifluoroacetic acid or methanesulfonic acid, preferably hydrohalic acids, most preferably hydrochloric acid.
  • Lewis acids like metal halides, such as metal chlorides, metal bromides or metal iodides, preferably zinc halides, most preferably zinc chloride
  • Bronsted acids like strong organic or inorganic acids, such as hydrohalic acids like hydrochloric acid or hydrobromic acid, sulfuric acid, trichloroacetic acid, tri
  • the sodium hydride (3.1 g, 77.2 mmol, 60 % in mineral oil previously washed with n- hexane) was suspended in anhydrous DMF (50 ml) and 2-(2-thienyl)-1 ,3-diazaspiro[ 4.4]non-1 -en-4-one (17.0 g, 77.2 mmol) in DMF (100 ml) was added. The mixture was stirred at room temperature for 15 minutes and 5-(4'-bromomethyl-biphenyl-2-yl)-1-trityl- 1 H-tetrazole (43.0 g, 77.2 mmol) was added.
  • the suspension turned to solution and the mixture was stirred for 1 hour at the same temperature.
  • the volume of the solvent was then reduced to 20 % and 1 M HCI solution (100 ml) was added dropwise over 1 hour.
  • the precipitated solid was filtered off and the pH of the filtrate was adjusted to 2.5 - 3.0 with a 1 M NaOH solution.
  • the mixture was cooled to about 5 0 C and stirred for additional 2 hours at the same temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé pour la production d’irbésartan, connu sous le nom chimique de 2-n-butyl-4-spirocyclopentane-1-[(2'-(tétrazol-5-yl)biphényl-4-yl)méthyl]-2- imidazolin-5-one, et de ses sels pharmaceutiquement acceptables. En outre, l’invention concerne de nouveaux composés (intermédiaires) qui sont appropriés à la production d’irbésartan.
PCT/EP2008/004787 2008-06-13 2008-06-13 Processus destiné à la préparation d’irbésartan et de produits intermédiaires Ceased WO2009149734A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2008/004787 WO2009149734A1 (fr) 2008-06-13 2008-06-13 Processus destiné à la préparation d’irbésartan et de produits intermédiaires

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2008/004787 WO2009149734A1 (fr) 2008-06-13 2008-06-13 Processus destiné à la préparation d’irbésartan et de produits intermédiaires

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WO2009149734A1 true WO2009149734A1 (fr) 2009-12-17

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991014679A1 (fr) * 1990-03-20 1991-10-03 Sanofi Derives heterocycliques n-substitues, leur preparation, les compostions pharmaceutiques en contenant
WO2005051943A1 (fr) * 2003-11-28 2005-06-09 Ranbaxy Laboratories Limited Procédés de préparation d'irbesartan très pur

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991014679A1 (fr) * 1990-03-20 1991-10-03 Sanofi Derives heterocycliques n-substitues, leur preparation, les compostions pharmaceutiques en contenant
WO2005051943A1 (fr) * 2003-11-28 2005-06-09 Ranbaxy Laboratories Limited Procédés de préparation d'irbesartan très pur

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BOLLIKONDA SATYANARAYANA YASARENI SUMALATHA ET AL: "IMPROVED SYNTHESIS OF IRBESARTAN, AN ANTIHYPERTENSIVE ACTIVE PHARMACEUTICAL INGREDIENT", SYNTHETIC COMMUNICATIONS, TAYLOR & FRANCIS, PHILADELPHIA, PA, vol. 35, no. 14, 28 June 2005 (2005-06-28), pages 1979 - 1982, XP009060948, ISSN: 0039-7911 *
SATYANARAYANA B ET AL: "A new entry to antihypertensiv active pharmaceutical ingredient, irbesartan and its analogues", HETEROCYCLIC COMMUNICATIONS, FREUND PUBLISHING HOUSE, TEL AVIV, vol. 12, 1 January 2006 (2006-01-01), pages 323 - 328, XP009089512, ISSN: 0793-0283 *
YE P ET AL: "Novel and expeditious microwave-assisted three-component reactions for the synthesis of spiroimidazolin-4-ones", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC; US, vol. 71, no. 8, 14 April 2006 (2006-04-14), pages 3137 - 3140, XP002416260, ISSN: 0022-3263 *

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