EP2049527A2 - Herstellung von irbesartan - Google Patents

Herstellung von irbesartan

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Publication number
EP2049527A2
EP2049527A2 EP06700020A EP06700020A EP2049527A2 EP 2049527 A2 EP2049527 A2 EP 2049527A2 EP 06700020 A EP06700020 A EP 06700020A EP 06700020 A EP06700020 A EP 06700020A EP 2049527 A2 EP2049527 A2 EP 2049527A2
Authority
EP
European Patent Office
Prior art keywords
irbesartan
process according
trityl
salt
water
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.)
Withdrawn
Application number
EP06700020A
Other languages
English (en)
French (fr)
Inventor
Silvo Zupancic
Anica Pecavar
Rok Zupet
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.)
KRKA dd
Original Assignee
KRKA Tovarna Zdravil dd
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
Priority claimed from SI200500004A external-priority patent/SI21964A/sl
Application filed by KRKA Tovarna Zdravil dd filed Critical KRKA Tovarna Zdravil dd
Publication of EP2049527A2 publication Critical patent/EP2049527A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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 belongs to the field of organic chemistry and relates to the synthesis of 2-butyl-l-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl-methyl]spiro[2- imidazoline-4.r-cyclopentan]-5-one (in further specification named by its generic name "irbesartan”).
  • Irbesartan or 2-butyl-l-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl-methyl]spiro[2- imidazoline-4.1'-cyclopentan]-5-one is an angiotensin II receptor antagonist i.e. an antagonist of the so-called AT-I and AT-2 receptors.
  • Irbesartan by binding on these receptors instead of angiotensin II, prevents the vasoconstrictive action of angiotensin II and therefore acts as an antihypertensive agent.
  • Basic patent for irbesartan EP 0 454 511 describes a process for the preparation of irbesartan from basic chemicals (e.g. cyclopentanone) through seven reaction steps and the intermediate 4'-(bromo methyl)biphenyl-2-carbonitrile.
  • the preparation of tetrazole ring takes place in the last or the penultimate synthesis step with tributyltin azide as the source of the azide ion, which is very problematic reagent for the use on a larger scale.
  • WO 2004/007482 describes a synthesis path, which is already comprised in the description of the basic process and whereat in the reaction of alkylating 2- «-butyl-4- cyclopentane-2-imidazolin-5-one with 5-(4-(bromomethyl)bi ⁇ henyl-2-yl)- 1 - (triphenylmethyl)tetrazole a new phase transfer catalyst (PTC catalyst) Bu 4 NHSO 4 is used.
  • PTC catalyst phase transfer catalyst
  • Bu 4 NHSO 4 is used.
  • the reaction takes place in two phases, in an aqueous and an organic one. In contrast to other processes this synthesis does not use azides in the last reaction step and also the conditions are milder.
  • EP 0 708 103 claims a process for preparation of both crystal forms of irbesartan, A and B crystal forms
  • Fig. 1 shows an x-ray powder diffractogram of trityl irbesartan.
  • the present invention relates to an improved synthesis path for irbesartan from 5-(4- (bromomethyl)biphenyl-2-yl)-l-(triphenylmethyl)tetrazole according to the following reaction scheme:
  • the process of synthesis of irbesartan according to the present invention comprises: a synthesis of trityl irbesartan (3) in an organic solvent in the presence of a phase transfer catalyst and a base, with a high yield, a removal of the protecting group of the formed trityl irbesartan in an organic solvent and an isolation of irbesartan or its pharmaceutically acceptable salts.
  • the first object of the invention is the synthesis of the intermediate trityl irbesartan.
  • the syntesis of trityl irbesartan (3) is carried out by a reaction between 5-(4- (bromomethyl)biphenyl-2-yl)- 1 -(triphenylmethyl)tetrazole and 2-/z-butyl-4- cyclo ⁇ entane-2-imidazolin-5-one or a salt thereof in such a manner that all reagents and catalysts are suspended or dissolved, respectively, in an organic solvent and the reaction mixture is heated. After the completed reaction the solvent is evaporated to a solid residue, which is used in the following reaction without additional isolation.
  • reaction solvent there are used organic solvents that are miscible with water such as DMSO, DMF, DMA and nitriles.
  • DMSO dimethyl methoxysulfoxide
  • DMF dimethyl methoxysulfoxide
  • DMA dimethyl methoxysulfoxide
  • nitriles a compound that is miscible with water
  • acetonitrile is used.
  • Reaction catalysts are tetralkylammonium salts such as tetrabuylammonium bromide, crown ethers such as 18-crown-6, cryptands, tris(3,6- dioxaheptyl)amine (TDA) or pyridyl sulfoxide.
  • the catalyst is tetrabutylammonium bromide.
  • the synthesis of trityl irbesartan is carried out at a temperature from 15 0 C to reflux temperature of the solvent, preferably at a temperature between 25°C to 45 0 C. The reaction is completed within up to 6 hours, preferably within up to 3 hours.
  • alkali metal hydroxides such as LiOH, NaOH or KOH are used, preferably KOH.
  • the intermediate 2- «-butyl-4-cyclopentane-2-imidazolin-5-one can be used in any form, preferably in the form of a salt with mineral acids.
  • An advantage of the described process is also that for the starting intermediate 5-(4- (bromomethyl)biphenyl-2-yl)-l-(triphenylmethyl)tetrazole no absolute purity is required, but an intermediate with a lower degree of purity can be used, yet preferably above 80 % (HPLC area % method). Nevertheless, its conversion to trityl irbesartan in this step is above 95 %.
  • the isolated trityl irbesartan may be, if necessary, recrystallized from organic solvents such as DMA, DMF, esters, alcohols, nitriles or mixtures of these solvents or mixtures of these solvents with non-polar solvents.
  • organic solvents such as DMA, DMF, esters, alcohols, nitriles or mixtures of these solvents or mixtures of these solvents with non-polar solvents.
  • a further subject of the present invention is a cleavage of the protecting group of trityl irbesartan.
  • a removal of the trityl protecting group of trityl irbesartan can be carried out as described in the article T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, published by John Wiley and Sons (1981) or in Protective Groups in Organic Chemistry, ed. J. F. McOmie, published by Plenum Press.
  • Trityl irbesartan is dissolved or suspended in an alcohol, a solid mineral base is added and the mixture is heated at an elevated temperature between room temperature and the reflux temperature of the solvent, preferably at the reflux temperature of the solvent. After completed reaction lasting up to 6 hours, preferably up to 3 hours, the reaction mixture is evaporated.
  • methanol e.g. methanol, ethanol, isopropanol, propanol or butanol, preferably methanol
  • the mineral base may be KOH, NaOH or LiOH, preferably KOH.
  • alcoholates NaOR, KOR, LiOR can be used.
  • a further object of the present invention is a process of isolation of irbesartan and its pharmaceutically acceptable salts.
  • irbesartan is carried in such a manner that water is added to the evaporation residue and the aqueous phase is extracted with a suitable organic solvent.
  • suitable organic solvents are esters, methylene chloride, heptane, hexane or toulene, preferably tert-butyl methyl ether.
  • the separated aqueous phase is acidified with HCl to a pH value between 1.2 and 7, preferably to a pH between 3 and 5.
  • the hydrochloride salt of irbesartan is obtained, which can also be prepared by carrying out the isolation from the reaction mixture according to processes described in SI P-200400220 or SI P-200400292.
  • the hydrochloride salt of irbesartan can also be obtained in such a manner that the separated aqueous phase is not acidified, but directly poured into an aqueous HCl solution with pH value under 1.2.
  • the separated aqueous phase is acidified with HCl to a pH value between 1.2 and 7, preferably to a pH between 3 and 5, the crude irbesartan, which precipitated from water, may be further filtered off or extracted into an organic solvent. It is extracted with an organic solvent in which irbesartan is soluble and which is not miscible with water, such as methylene chloride. The organic phase is washed with water, dried with a suitable drying agent and evaporated to a solid residue in order to obtain crude irbesartan.
  • the crude irbesartan may be additionally recrystallized. Processes for crystallization of irbesartan are described in the patent literature such as in EP 0454511, EP 0708103, WO 99/67236 or WO 03/050110.
  • solvents such as alcohols e.g. methanol, ethanol, isopropanol, w-propanol, butanol, isobutanol, tert-butanol; DMF, DMSO, dioxan, THF, 3-pentanone, 2-butanone, 4-methyl-2-pentanone or combinations of these solvents with water.
  • irbesartan synthesized according to the present invention there can be further prepared its pharmaceutically acceptable salts.
  • They can be alkali salts (e.g. sodium, potassium, calcium or magnesium salts) or acid addition salts such as hydrochloride, oxalate, citrate, acetate, lactate and the like.
  • hydrochloride e.g. sodium, potassium, calcium or magnesium salts
  • hydrochloride e.g. sodium, potassium, calcium or magnesium salts
  • oxalate e.g. sodium, potassium, calcium or magnesium salts
  • citrate e.g. sodium, potassium, calcium or magnesium salts
  • a pharmaceutically acceptable salt according to this invention preferably hydrochloride is mentioned, which can also be prepared in such a manner that the isolation from the reaction mixture is carried out according to the processes described in SI P-200400220 or SI P-200400292.
  • Irbesartan hydrochloride can also be prepared in such a manner that a basic salt of irbesartan or a solution of this salt in water or some other polar solvent is acidified with HCl to a pH under 1.2; an irbesartan solution in an organic solvent or a mixture of an organic solvent and water is acidified with HCl to a pH under 1.2. a solution of a basic salt of irbesartan is poured directly into an aqueous HCl solution with pH value under 1.2.
  • Irbesartan hydrochloride can optionally be recrystallized from organic solvents such as ketones, esters, alcohols or nitriles under the addition of HCl.
  • m relates to a strong relative intensity from 30 to 100 % and "s” relates to medium relative intensity from 10 to 30 %.
  • a typical x-ray powder diffractogram is represented by the following 2-theta values accompanied by the intensities: 2 ⁇ (°) ( ⁇ 0.1) Intensity
  • trityl irbesartan is characterized by the following degrees 2-theta: 6.47; 8.14; 13.51; 19.00; 20.87; 23.13 ⁇ 0.1.
  • the DSC curve of crystal trityl irbesartan was recorded by means of differential scanning calorimeter DSC 822 Mettler Toledo. Samples with a weight of about 3 mg were recorded with a heating rate of 10 °C/min in nitrogen atmosphere and in open aluminum pots. The onset temperature was measured at about 148°C. The onset temperature means the beginning of the endothermal change of melting, which means that the beginning of the melting interval (melting point) of crystal trityl irbesartan is at this temperature.
  • the suspension was cooled to 5 0 C and the precipitate was filtered off. 1.34 g (96 %) of crude irbesartan were obtained.
  • Irbesartan (2 g) was suspended at room temperature in water (20 ml) and methanol (2 ml) was added. Then the suspension was acidified with 2M HCl to pH 1.03. The mixture was heated under reflux for 10 minutes, stirred at room temperature for one hour and on ice for 30 minutes. The precipitate was filtered off and the product was dried in a vacuum dryer at 5O 0 C for one hour. 2.25 g of sesquihydrate hydrochloride salt of irbesartan were isolated.
  • Irbesartan hydrochloride sesquihydrate (7.4 g) was dissolved at an elevated temperature in 18 ml of a mixture ethyl methyl ketone/3M HCl (10: 1). The mixture was then cooled and stirred at room temperature for 1 hour and at 0 0 C for 30 minutes. The precipitate was filtered off and dried at 40 0 C for 2 hours. 5.3 g (75 %) of irbesartan hydrochloride sesquihydrate were obtained.
  • Trityl irbesartan 28 g was dissolved in DMF (25 ml) at an elevated temperature. The mixture was cooled to room temperature and then the formed suspension was stirred for 30 minutes on ice. The obtained product was filtered off and washed with fresh DMF. 26 g (93 %) of the product were obtained.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP06700020A 2005-01-05 2006-01-04 Herstellung von irbesartan Withdrawn EP2049527A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SI200500004A SI21964A (sl) 2005-01-05 2005-01-05 Priprava tetrazolskega derivata
SI200500132A SI21965A (sl) 2005-01-05 2005-05-05 Priprava tetrazolskega derivata
PCT/SI2006/000001 WO2006073376A2 (en) 2005-01-05 2006-01-04 Preparation of irbesartan

Publications (1)

Publication Number Publication Date
EP2049527A2 true EP2049527A2 (de) 2009-04-22

Family

ID=36129763

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06700020A Withdrawn EP2049527A2 (de) 2005-01-05 2006-01-04 Herstellung von irbesartan

Country Status (5)

Country Link
EP (1) EP2049527A2 (de)
EA (1) EA012852B1 (de)
NO (1) NO20073984L (de)
SI (1) SI21965A (de)
WO (1) WO2006073376A2 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1916246A3 (de) * 2006-10-11 2008-06-18 Cadila Pharmaceuticals Limited Verbesserter Herstellungsprozess für Olmesartanmedoxomil
GB0700993D0 (en) * 2007-01-18 2007-02-28 Rainbow Engineering Services Novel compounds
GB0700992D0 (en) * 2007-01-18 2007-02-28 Rainbow Engineering Services Novel compounds
EP2194050A1 (de) 2008-12-08 2010-06-09 KRKA, tovarna zdravil, d.d., Novo mesto Neues Verfahren zur Herstellung von Irbesartan
CN120392084B (zh) * 2025-04-10 2026-04-07 常州江苏大学工程技术研究院 一种组成创面状态诊断用穿戴式pH传感器的pH敏感电极及其应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1668612A (zh) * 2002-07-16 2005-09-14 特瓦制药工业有限公司 厄贝沙坦的新合成方法
SI1509517T1 (sl) * 2003-01-16 2008-10-31 Teva Pharma Nova sinteza irbesartana
WO2004072064A1 (en) * 2003-02-05 2004-08-26 Teva Pharmaceutical Industries Ltd. Synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)-1,3-diazaspirol[4,4]-non-ene-4-one
SI21849A (sl) * 2004-07-29 2006-02-28 Krka, Tovarna Zdravil, D.D., Novo Mesto Priprava hidrokloridnih soli tetrazolskega derivata

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006073376A3 *

Also Published As

Publication number Publication date
EA200701433A1 (ru) 2008-02-28
NO20073984L (no) 2007-10-05
WO2006073376A3 (en) 2006-09-21
SI21965A (sl) 2006-08-31
EA012852B1 (ru) 2009-12-30
WO2006073376A2 (en) 2006-07-13

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