SI21965A - Preparation of tetrazole derivative - Google Patents

Preparation of tetrazole derivative Download PDF

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SI21965A
SI21965A SI200500132A SI200500132A SI21965A SI 21965 A SI21965 A SI 21965A SI 200500132 A SI200500132 A SI 200500132A SI 200500132 A SI200500132 A SI 200500132A SI 21965 A SI21965 A SI 21965A
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irbesartan
process according
reaction
trityl
water
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SI200500132A
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Slovenian (sl)
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Silvo Zupancic
Anica Pecavar
Rok Zupet
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Krka, Tovarna Zdravil, D.D., Novo Mesto
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Priority claimed from SI200500004A external-priority patent/SI21964A/en
Application filed by Krka, Tovarna Zdravil, D.D., Novo Mesto filed Critical Krka, Tovarna Zdravil, D.D., Novo Mesto
Priority to SI200500132A priority Critical patent/SI21965A/en
Priority to PCT/SI2006/000001 priority patent/WO2006073376A2/en
Priority to EA200701433A priority patent/EA012852B1/en
Priority to EP06700020A priority patent/EP2049527A2/en
Publication of SI21965A publication Critical patent/SI21965A/en
Priority to NO20073984A priority patent/NO20073984L/en

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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
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The submitted invention relates to a procedure for preparation of irbesartan or its pharmaceutically acceptable salts, which comprises the synthesis of trithyl irbesartan by the reaction of 5-(4-(bromomethyl)biphenyl-2-yl)-1-(triphenylmethyl)tetrazole and 2-n-butyl-4-cyclopentane-2- imidazolin-5-on or its salt in an organic solvent in the presence of a phase transfer catalyst and a base, removal of the protection group and isolation of irbesartan or its pharmaceutically acceptable salt.

Description

Predloženi izum spada na področje organske kemije in se nanaša na sintezo 2-butil-l-[2'-(lHtetrazol-5-il)bifenil-4-il-metil]spiro[2-imidazolin-4.1 '-ciklopentan]-5-ona (v nadaljnjem besedilu imenovanega z njegovim generičnim imenom irbesartan).The present invention relates to the field of organic chemistry and relates to the synthesis of 2-butyl-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl-methyl] spiro [2-imidazolin-4.1' -cyclopentane] -5 -ona (hereinafter referred to as its generic name irbesartan).

TEHNIČNI PROBLEMTECHNICAL PROBLEM

Irbesartan ali 2-butil-l-[2'-(lH-tetrazol-5-il)bifenil-4-il-metil]spiro[2-imidazolin-4.l·ciklopentan]-5-on je antagonist receptorjev angiotenzina II oziroma t.i. receptorjev AT-1 in AT-2. S tem, ko se namesto angiotenzina II na te receptorje veže irbesartan, je preprečeno vazokonstriktivno delovanje angiotenzina II, zato irbesartan deluje kot antihipertenzik.Irbesartan or 2-butyl-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl-methyl] spiro [2-imidazolin-4-yl] cyclopentane] -5-one is an angiotensin II receptor antagonist or you AT-1 and AT-2 receptors. By binding irbesartan to these receptors instead of angiotensin II, vasoconstrictive action of angiotensin II is prevented, therefore irbesartan acts as an antihypertensive agent.

Obstajala je potreba po izboljšanem, v industrijskem merilu uporabnem postopku, ki bi za sintezo irbesartana uporabljal poznane intermediate, kot npr. 5-(4-(bromometil)bifenil-2-il)-l(trifenilmetil)tetrazol, in s katerim bi dosegali visoke izkoristke in visoko stopnjo čistosti končnega proizvoda v primerjavi z obstoječimi postopki.There was a need for an improved, industrially applicable process that would use known intermediates for the synthesis of irbesartan, such as e.g. 5- (4- (Bromomethyl) biphenyl-2-yl) -1 (triphenylmethyl) tetrazole, to achieve high yields and a high degree of purity of the finished product compared to existing processes.

STANJE TEHNIKEBACKGROUND OF THE INVENTION

Sinteza irbesartana je opisana v EP 0 454 511, EP 0 708 103, WO 99/06398, WO 99/38847, WO 2004/007482, WO 2004/065383, WO 2004/072064 ter v člankih.The synthesis of irbesartan is described in EP 0 454 511, EP 0 708 103, WO 99/06398, WO 99/38847, WO 2004/007482, WO 2004/065383, WO 2004/072064 and in articles.

Osnovni patent za irbesartan EP 0 454 511 opisuje postopek priprave irbesartana iz osnovnih kemikalij (npr. ciklopentanona) preko sedmih reakcijskih stopenj in intermediata 4'-(bromo metil)bifenil-2-karbonitrila. Priprava tetrazolskega obroča poteka v zadnji oziroma predzadnji stopnji sinteze s tributilkositrovim azidom kot virom azidnega iona, ki je za uporabo v večjem merilu zelo problematičen reagent.The basic patent for irbesartan EP 0 454 511 describes a process for the preparation of irbesartan from basic chemicals (e.g. cyclopentanone) via seven reaction steps and intermediate 4 '- (bromo methyl) biphenyl-2-carbonitrile. The preparation of the tetrazole ring takes place in the last or last stage of synthesis with tributyltin azide as a source of azide ion, which is a very problematic reagent for use on a larger scale.

W0 2004/007482 opisuje sintezno pot, ki je zajeta že v opisu osnovnega postopka, s tem da pri reakciji alkiliranja 2-/?-butil-4-ciklopentan-2-imidazolin-5-ona z 5-(4-(bromometil)bifenil2-il)-l-(trifenilmetil)tetrazololom uporabi nov katalizator faznega prenosa (PTC katalizator), BU4NHSO4. Reakcija poteka v dveh fazah, vodni in organski. Za razliko od ostalih postopkov, ta sinteza ne uporablja azidov v zadnji reakcijski stopnji, pa tudi pogoji so milejši.WO 2004/007482 describes a synthesis pathway already covered by the description of the basic process, wherein in the alkylation reaction of 2 - [? - butyl-4-cyclopentan-2-imidazolin-5-one with 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazolol uses a new phase transfer catalyst (PTC catalyst), BU4NHSO4. The reaction takes place in two stages, aqueous and organic. Unlike other processes, this synthesis does not use azides in the last reaction step, and the conditions are milder.

EP 0 708 103 ščiti proces za pripravo obeh kristalnih oblik irbesartana, A in B kristalno obliko.EP 0 708 103 protects the process for the preparation of both irbesartan crystalline forms, A and B crystalline form.

KRATEK OPIS RISBBRIEF DESCRIPTION OF THE DRAWINGS

Sl. 1 prikazuje rentgenski praškovni difraktogram tritil irbesartana.FIG. 1 shows an X-ray powder diffractogram of trityl irbesartan.

POVZETEK IZUMASUMMARY OF THE INVENTION

Predloženi izum se nanaša na izboljšano sintezno pot irbesartana iz 5-(4-(bromometil)bifenil2-il)-l-(trifenilmetil)tetrazola po sledeči reakcijski shemi:The present invention relates to an improved synthesis route of irbesartan from 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole according to the following reaction scheme:

V prijavi W0 2004/007482 je opisana reakcija alkiliranja 2-H-butil-4-ciklopentan-2imidazolin-5-ona (1) s 5-(4-(bromometil)bifenil-2-il)-l-(trifenilmetil)tetrazolom (2) z uporabo baze in PTC katalizatorja v dveh fazah, vodni in organski. Ta postopek ne daje optimalnih izkoristkov pretvorbe, zahteva visoke temperature reakcije ter uporabo več topil. Po tem postopku je potrebno tudi posebej izolirati tritil irbesartan (3). Prav tako mora biti pri tem postopku čistota izhodnega intermediata 2 zelo visoka, sicer sta čistota končnega produkta in izkoristek slabša.WO 2004/007482 describes the alkylation reaction of 2-H-butyl-4-cyclopentan-2-imidazolin-5-one (1) with 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole (2) using a two-phase base and PTC catalyst, aqueous and organic. This process does not give optimum conversion efficiencies, requires high reaction temperatures and the use of multiple solvents. Following this procedure, it is also necessary to separately isolate trityl irbesartan (3). Also, in this process, the purity of the intermediate 2 has to be very high, otherwise the purity of the final product and the yield are lower.

Sinteza 2-z?-butil-4-ciklopentan-2-imidazolin-5-ona je opisana v članku J. Med. Chem., 1993, 36, 3371-3380 in v US 5,559,233.The synthesis of 2-z? -Butyl-4-cyclopentan-2-imidazolin-5-one is described in J. Med. Chem., 1993, 36, 3371-3380 and in US 5,559,233.

Sinteza 5-(4-(bromometil)bifenil-2-il)-l-(trifenilmetil)- tetrazola pa je prav tako poznana iz sintez drugih sartanov in je bila opisana v EP 0 253 310, EP 553879 in J. Med. Chem., 1991, 34, 2525-2547.The synthesis of 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) - tetrazole is also known from the syntheses of other sartans and has been described in EP 0 253 310, EP 553879 and J. Med. Chem., 1991, 34, 2525-2547.

V pričujočem izumu smo odpravili pomanjkljivosti postopkov iz stanja tehnike.The present invention has eliminated the disadvantages of the prior art.

PODROBEN OPIS IZUMADETAILED DESCRIPTION OF THE INVENTION

Postopek sinteze irbesartana po predloženem izumu obsega:The process for the synthesis of irbesartan according to the present invention comprises:

sintezo tritil irbesartana (3) v organskem topilu v prisotnosti katalizatorja faznega prenosa in baze, z visokim izkoristkom, odstranitev zaščitne skupine nastalega tritil irbesartana v organskem topilu in izolacijo irbesartana oziroma njegovih farmacevtsko sprejemljivih soli.synthesis of trityl irbesartan (3) in an organic solvent in the presence of a phase transfer catalyst and base, in high yield, removal of the protecting group of the resulting trityl irbesartan in an organic solvent and isolation of irbesartan or its pharmaceutically acceptable salts.

Prvi predmet izuma je sinteza intermediata tritil irbesartana.The first object of the invention is the synthesis of trityl irbesartan intermediates.

Sintezo tritil irbesartana (3) izvajamo z reakcijo med 5-(4-(bromometil)bifenil-2-il)-l(trifenilmetil)tetrazolom in 2-n-butil-4-ciklopentan-2-imidazolin-5-onom ali njegovo soljo tako, da suspendiramo oziroma raztopimo vse reagente in katalizatorje v organskem topilu in reakcijsko zmes segrejemo. Po končani reakciji odparimo topilo do trdnega preostanka, ki ga uporabimo v naslednji reakciji, brez dodatne izolacije.The synthesis of trityl irbesartan (3) is carried out by the reaction between 5- (4- (bromomethyl) biphenyl-2-yl) -1 (triphenylmethyl) tetrazole and 2-n-butyl-4-cyclopentan-2-imidazolin-5-one or its salt by suspending or dissolving all reagents and catalysts in an organic solvent and heating the reaction mixture. After completion of the reaction, the solvent was evaporated to a solid residue which was used in the next reaction without further isolation.

Kot topilo pri reakciji uporabljamo organska topila, ki se mešajo z vodo, kot so DMSO, DMF, DMA ali nitrili. Prednostno se uporablja acetonitril.Organic miscible water miscible solvents such as DMSO, DMF, DMA or nitriles are used as the solvent in the reaction. Acetonitrile is preferably used.

Katalizatorji reakcije (PTC katalizatorji) so tetraalkilamonijeve soli, kot je npr, tetrabutilamonijev bromid, kronski etri, kot je npr. 18-Crown-6, kriptandi, tris(3,6dioksaheptil)amin (TDA) ali piridil sulfoksid. Prednostno je katalizator tetrabutilamonijev bromid.Reaction catalysts (PTC catalysts) are tetraalkylammonium salts such as tetrabutylammonium bromide, crown ethers such as e.g. 18-Crown-6, cryptandi, tris (3,6 dioxaheptyl) amine (TDA) or pyridyl sulfoxide. Preferably, the catalyst is tetrabutylammonium bromide.

Sintezo tritil irbesartana izvajamo pri temperaturi od 15 °C do temperature refluksa topila, prednostno pri temperaturi med 25 °C in 45 °C. Reakcija poteče v času do 6 ur, prednostno do 3 ure.Synthesis of trityl irbesartan is carried out at a temperature from 15 ° C to the reflux temperature of the solvent, preferably at a temperature between 25 ° C and 45 ° C. The reaction proceeds within up to 6 hours, preferably up to 3 hours.

Kot bazo pri reakciji uporabljamo hidrokside alkalijskih kovin, kot FiOH, NaOH ali KOH, prednostno KOH.Alkali metal hydroxides such as FiOH, NaOH or KOH, preferably KOH, are used as the base for the reaction.

Intermediat 2-n-butil-4-ciklopentan-2-imidazolin-5-on lahko uporabljamo v kateri koli obliki, prednostno v obliki soli z mineralnimi kislinami.The 2-n-butyl-4-cyclopentan-2-imidazolin-5-one intermediate can be used in any form, preferably in the form of salts with mineral acids.

Prednost opisanega postopka je tudi v tem, da za izhodni intermediat 5-(4(bromometil)bifenil-2-il)-l-(trifenilmetil)tetrazol ni zahtevana absolutna čistost, pač pa lahko uporabljamo intermediat nižje stopnje čistote, prednostno pa nad 80 % (HPLC area % metoda). Kljub temu je njegova pretvorba do tritil irbesartana v tej stopnji nad 95 %.An advantage of the process described is that the output intermediate 5- (4 (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole does not require absolute purity, but a lower purity intermediate, preferably above 80, can be used % (HPLC area% method). Nevertheless, its conversion to trityl irbesartan is above 95% at this rate.

Izolirani tritil irbesartana lahko po potrebi prekristaliziramo iz organskih topil kot so: DMA, DMF, estri, akloholi, nitrili ali zmesi teh topil oziroma zmest teh topil z nepolamimi topili.The isolated trityl of irbesartan can, if necessary, be recrystallized from organic solvents such as: DMA, DMF, esters, aclochols, nitriles or mixtures of these solvents or mixtures of these solvents with non-polar solvents.

Nadaljnji predmet predloženega izuma je odcep zaščitne skupine tritil irbesartana.A further object of the present invention is the cleavage of the trityl irbesartan protecting group.

Odstranitev tritilne zaščitne skupine tritil irbesartana lahko izvedemo kot je opisano v članku T. W. Greene in P. G. M. Wuts „Protective Groups in Organic Synthesys“, izdanem pri John Wiley and Sons (1981) ali v Protective Groups in Organic Chemistry, izdajatelja J. F. McOmie, objavljeno v Plenum Press.Removal of the trityl protecting group of trityl irbesartan can be performed as described in the TW Greene and PGM Wuts article "Protective Groups in Organic Synthesys" published by John Wiley and Sons (1981) or in Protective Groups in Organic Chemistry by JF McOmie, published in Plenum Press.

Presenetljivo pa smo ugotovili, da reakcijo odstranitve tritilne zaščitne skupine, za razliko od poznanih postopkov, kjer odcep poteka v kislem mediju, z visokim izkoristkom izvedemo tudi v alkalnih pogojih. Tritil irbesartan raztopimo oziroma suspendiramo v alkoholu, dodamo trdno mineralno bazo in zmes segrevamo pri povišani temperaturi, med sobno temperaturo in temperaturo refluksa topila, prednostno pri temperaturi refluksa topila. Po končani reakciji, ki traja do 6 ur, prednostno do 3 ure, reakcijsko zmes uparimo.Surprisingly, we found that, unlike the known processes where the cleavage takes place in an acidic medium, the removal of the trityl protecting group is also carried out in alkaline conditions in high efficiency. Trityl irbesartan is dissolved or suspended in alcohol, a solid mineral base is added, and the mixture is heated at elevated temperature, between room temperature and the solvent reflux temperature, preferably at the solvent reflux temperature. After the reaction lasts up to 6 hours, preferably up to 3 hours, the reaction mixture is evaporated.

Pri reakciji odstranitve tritilne zaščitne skupine lahko uporabimo različne alkohole, kot so npr. metanol, etanol, izopropanol, propanol ali butanol, prednostno metanol. Mineralna baza je lahko KOH, NaOH ali LiOH, prednostno KOH. Lahko pa uporabimo tudi alkoholate: NaOR, KOR, LiOR.In the removal of the trityl protecting group, various alcohols, such as e.g. methanol, ethanol, isopropanol, propanol or butanol, preferably methanol. The mineral base may be KOH, NaOH or LiOH, preferably KOH. Alternatively, alcohols can be used: NaOR, KOR, LiOR.

Pretvorba tritil irbesartana do irbesartana je praktično 100 %, stranski produkt je metil tritil eter, oziroma alkil tritil eter, ki ga odstranimo z ekstrakcijo.The conversion of trityl irbesartan to irbesartan is practically 100%, the by-product is methyl trityl ether, or alkyl trityl ether, which is removed by extraction.

Nadaljnji predmet predloženega izuma je tudi postopek izolacije irbesartana in njegovih farmacevtsko sprejemljivih soli.A further object of the present invention is also a method of isolating irbesartan and its pharmaceutically acceptable salts.

Izolacijo irbesartana izvedemo tako, da preostanku po uparevanju dodamo vodo in vodno fazo ekstrahiramo s primernim organskim topilom. Primerna organska topila so estri, metilen klorid, heptan, heksan ali toluen, prednostno terc,- butil metil eter. Nato ločeno vodno fazo nakisamo s HCI do pH vrednosti med 1,2 in 7, prednostno do pH med 3 in 5. Če ločeno vodno fazo s HCI nakisamo pod pH 1,2 dobimo hidrokloridno sol irbesartana, ki jo lahko pripravimo tudi tako, da izolacijo iz reakcijske zmesi izvedemo po postopkih, opisanih v SI P-200400220 ali SI P-200400292.Isolation of irbesartan is carried out by adding water to the residue after evaporation and extracting the aqueous phase with a suitable organic solvent. Suitable organic solvents are esters, methylene chloride, heptane, hexane or toluene, preferably tert-butyl methyl ether. Subsequently, the aqueous phase is acidified with HCl to a pH of between 1.2 and 7, preferably up to a pH of between 3 and 5. If the aqueous phase is acidified with HCI below pH 1.2, the hydrochloride salt of irbesartan can also be prepared by isolation from the reaction mixture is carried out according to the procedures described in SI P-200400220 or SI P-200400292.

Če smo ločeno vodno fazo nakisali s HCI do pH vrednosti med 1,2 in 7, prednostno do pH med 3 in 5, lahko iz vode izpadli surovi irbesartan nadalje odfiltriramo ali ekstrahiramo v organsko topilo. Ekstrahiramo z organskim topilom, v katerem se irbesartan raztaplja in se ne meša z vodo, kot je npr. metilen klorid. Organsko fazo speremo z vodo, sušimo z ustreznim sušilnim sredstvom in jo uparimo do trdnega preostanka, da dobimo surov irbesartan.If the separated aqueous phase is acidified with HCl to a pH of between 1.2 and 7, preferably to a pH of between 3 and 5, the crude irbesartan recovered from the water can be further filtered or extracted into an organic solvent. It is extracted with an organic solvent in which irbesartan dissolves and is immiscible with water, such as e.g. methylene chloride. The organic phase was washed with water, dried with a suitable desiccant and evaporated to a solid residue to give crude irbesartan.

Izkoristek celotne sinteze irbesartana iz 5-(4-(bromometil)bifenil-2-il)-l(trifenilmetil)tetrazola po tem postopku je nad 95 %.The yield of the entire synthesis of irbesartan from 5- (4- (bromomethyl) biphenyl-2-yl) -1 (triphenylmethyl) tetrazole by this process is above 95%.

Surovi irbesartan lahko dodatno prekristaliziramo. Postopki za kristalizacijo irbesartana so opisani v patentni literaturi kot na primer v EP 0 454 511, EP 0 708 103, WO 99/67236 ali WO 03/050110.Crude irbesartan can be further recrystallized. Methods for crystallizing irbesartan are described in the patent literature, for example, in EP 0 454 511, EP 0 708 103, WO 99/67236 or WO 03/050110.

Prekristaliziramo ga lahko iz topil kot so: alkoholi kot so metanol, etanol, izopropanol, npropanol, butanol, izobutanol; tert-butanol, DMF, DMSO, dioksan, THF, 3-pentanon, 2butanon, 4-metil-2-pentanon, ali kombinacije le-teh topil z vodo.It can be crystallized from solvents such as: alcohols such as methanol, ethanol, isopropanol, npropanol, butanol, isobutanol; tert-butanol, DMF, DMSO, dioxane, THF, 3-pentanone, 2-butanone, 4-methyl-2-pentanone, or combinations thereof with water.

Nadalje iz irbesartana, sintetiziranega po predloženem izumu, pripravimo tudi njegove farmacevtsko sprejemljive soli. Slednje so lahko alkalijske soli (npr. natrijeva, kalijeva, kalcijeva ali magnezijeva sol) ali kislinske adicijske soli kot so hidroklorid, oksalat, citrat, acetat, laktat, ipd.Furthermore, pharmaceutically acceptable salts thereof are prepared from irbesartan synthesized according to the present invention. The latter may 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.

Kot farmacevtsko sprejemljivo sol po tem izumu prednostno omenjamo hidroklorid, ki ga lahko pripravimo tudi tako, da izolacijo iz reakcijske zmesi izvedemo po postopkih, opisanih v SI P-200400220 ali SI P-200400292.Hydrochloride is preferably referred to as the pharmaceutically acceptable salt of the present invention, which can also be prepared by isolation from the reaction mixture according to the procedures described in SI P-200400220 or SI P-200400292.

Hidroklorid irbesartana lahko pripravimo tudi tako, da nakisamo bazično sol irbesartana ali raztopino te soli v vodi ali drugem polarnem topilu s HCI do pH pod 1,2;Irbesartan hydrochloride can also be prepared by acidifying the basic salt of irbesartan or a solution of this salt in water or another polar solvent with HCl to a pH below 1.2;

- če raztopino irbesartana v organskem topilu ali mešanici organskega topila in vode nakisamo s HCI do pH pod 1,2.- if the irbesartan solution in an organic solvent or a mixture of organic solvent and water is acidified with HCl to a pH below 1.2.

Hidroklorid irbesartana lahko po potrebi prekristaliziramo iz organskih topil ob dodatku HCI kot so ketoni estri, alkoholi ali nitrili. Velikost delcev irbesartan hidroklorida, tako seskvihidratne kot tudi brezvodne oblike, smo izmerili s pomočjo laserske difrakcije na aparatu Malvem-Mastersizer Apparatus MS 2000. Povprečni premer delcev je znašal od 10 do 150 mikronov.The irbesartan hydrochloride can, if necessary, be recrystallized from organic solvents with the addition of HCl such as ketone esters, alcohols or nitriles. The particle size of irbesartan hydrochloride, both sesquihydrate and anhydrous forms, was measured by laser diffraction on a Malvem-Mastersizer Apparatus MS 2000. The average particle diameter was 10 to 150 microns.

Rentgenske praškovne difraktograme tritil irbesartana smo posneli z difraktometrom Phillips PW3040/60 X'Pert PRO; CuK« sevanje 0,1541874 nm.X-ray powder diffractograms of trityl irbesartan were recorded with a Phillips PW3040 / 60 X'Pert PRO diffractometer; CuK «radiation 0.1541874 nm.

Kot se tukaj uporabljata, sta naslednja okrajšana izraza: m se nanaša na močno relativno intenziteto od 30 do 100 % in s se nanaša na srednjo relativno intenziteto od 10 do 30 %.As used herein, the following abbreviated terms are used: m refers to a strong relative intensity of 30 to 100% and s refers to a mean relative intensity of 10 to 30%.

Tritil irbesartan karakterizirajo naslednji podatki:Tritil irbesartan is characterized by the following data:

Tipičen rentgenski praškovni difraktogram predstavljajo naslednje 2-theta vrednosti, ki jih spremljajo intenzitete:A typical X-ray powder diffractogram is represented by the following 2-theta values, which are accompanied by intensities:

2Θ(°) 2Θ (°) Intenziteta Intensity 6,47 6.47 m m 8,14 8.14 m m 11,14 11.14 s s 12,03 12.03 s s 13,51 13,51 m m 15,71 15,71 s s 19,00 19,00 m m 20,87 20,87 m m 23,13 23.13 m m

27,95 s27.95 s

28,93 s28,93 s

Prednostno tritil irbesartan karakterizirajo naslednje 2-theta stopinje: 6,47; 8,14; 13,51; 19,00; 20,87; 23,13 ±0.1.Preferably, trityl irbesartan is characterized by the following 2-theta degrees: 6.47; 8.14; 13.51; 19.00; 20.87; 23.13 ± 0.1.

DSC krivuljo kristalnega tritil irbesartana smo posneli s pomočjo dinamičnega diferenčnega kalorimetra DSC 822 Mettler Toledo. Vzorce z natehto približno 3 mg smo posneli s hitrostjo segrevanja 10 °C/min v dušikovi atmosferi in v odprtih aluminijevih lončkih. Izmerili smo onset temperaturo pri okoli 148°C. Onset temperatura pomeni začetek endotermne spremembe taljenja, kar pomeni, da je začetek talilnega intevala (tališče) kristalnega tritil irbesartana pri tej temperaturi.The DSC curve of crystalline trityl irbesartan was recorded using a DSC 822 Mettler Toledo dynamic differential calorimeter. Samples weighing approximately 3 mg were recorded at a heating rate of 10 ° C / min in nitrogen atmosphere and in open aluminum crucibles. The offset temperature at about 148 ° C was measured. Onset temperature means the onset of endothermic melting change, which means that the melting interval (melting point) of crystalline trityl irbesartan is at that temperature.

Predloženi izum je ponazorjen z naslednjimi primeri, ne da bi bil z njimi omejen.The present invention is illustrated by the following examples without being limited thereto.

PRIMERI Primer 1EXAMPLES Example 1

V bučko zatehtamo 0,83 g (3,6 mmol) 2-«-butil-4-ciklopentan-2-imidazolin-5-on hidroklorida, 15 ml acetonitrila, 1,84 g (2,94 mmol) 5-(4-(bromometil)bifenil-2-il)-l(trifenilmetil)tetrazola, 1,3 ml IM tetrabutilamonijevega bromida (v acetonitrilu) in 1,1 g (20 mmol) zdrobljenega KOH. Zmes mešamo pri 40 °C v inertni atmosferi 2,5 uri. Pretvorba izhodne spojine 5-(4-(bromometil)bifenil-2-il)-l-(trifenilmetil)tetrazola v tritilirbesartan je 96 %. Zmes ohladimo, uparimo in ji dodamo 17 ml metanola ter 0,33 g (5,9 mmol) zdrobljenega KOH. Reakcijsko zmes refluktiramo 2,5 uri in nato ponovno uparimo. Pretvorba do irbesartana je praktično 100 %. Dodamo 17 ml vode in 50 ml terc-butil metil etra, mešamo in fazi ločimo. Vodno fazo ponovno ekstrahiramo s 50 ml terc-butil metil etra, nato pa vodno fazo nakisamo z 2 M HCI do pH = 4,5. Suspenzijo ohladimo na 5°C ter oborino odfiltriramo. Dobimo 1,34 g (96 %) surovega irbesartana.Weigh 0.83 g (3.6 mmol) of 2 - [- butyl-4-cyclopentan-2-imidazolin-5-one hydrochloride, 15 ml of acetonitrile, 1.84 g (2.94 mmol) of 5- (4) - (Bromomethyl) biphenyl-2-yl) -1 (triphenylmethyl) tetrazole, 1.3 ml of IM tetrabutylammonium bromide (in acetonitrile) and 1.1 g (20 mmol) of crushed KOH. The mixture was stirred at 40 ° C under an inert atmosphere for 2.5 hours. The conversion of the starting compound 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole to tritylirbesartan is 96%. The mixture was cooled, evaporated and 17 ml of methanol and 0.33 g (5.9 mmol) of crushed KOH were added. The reaction mixture was refluxed for 2.5 hours and then evaporated again. Conversion to irbesartan is practically 100%. 17 ml of water and 50 ml of tert-butyl methyl ether are added, stirred and the phase is separated. The aqueous phase was re-extracted with 50 ml of tert-butyl methyl ether and then the aqueous phase was acidified with 2 M HCl to pH = 4.5. The suspension was cooled to 5 ° C and the precipitate was filtered off. 1.34 g (96%) of crude irbesartan are obtained.

Primer 2Example 2

V bučko damo 0,79 g (3,4 mmol) 2-«-butil-4-ciklopentan-2-imidazolin-5-on hidroklorida, 15 ml acetonitrila, 1,84 g (2,94 mmol) 5-(4-(bromometil)bifenil-2-il)-l-(trifenilmetil)tetrazola, 0,31 g tetrabutilamonijevega bromida in 1,32 g (23,5 mmol) zdrobljenega KOH. Zmes mešamo pri 31 °C v inertni atmosferi 2,5 uri. Pretvorba izhodne spojine 5-(4(bromometil)bifenil-2-il)-l-(trifenilmetil)tetrazola v tritilirbesartan je 95 %. Zmes ohladimo, uparimo in ji dodamo 17 ml metanola ter 0,33 g (5,9 mmol) zdrobljenega KOH. Reakcijsko zmes refluktiramo 2,5 uri in nato ponovno uparimo. Pretvorba do irbesartana je praktično 100 %. Dodamo 17 ml vode in 50 ml /erc-butil metil etra, mešamo in fazi ločimo. Vodno fazo ponovno ekstrahiramo s 50 ml /erc-butil metil etra, nato pa vodno fazo nakisamo s 2 M HCI do pH = 2. Dodamo 40 ml metilen klorida, zmes mešamo in ločimo. Vodno fazo ponovno ekstrahiramo z 10 ml metilen klorida. Združeni organski fazi speremo 2 krat z 20 ml vode, sušimo z Na2SO4 in uparimo do suhega. Dobimo 1,4 g (96 %) surovega irbesartana.0.79 g (3.4 mmol) of 2-butyl-4-cyclopentan-2-imidazolin-5-one hydrochloride, 15 ml of acetonitrile, 1.84 g (2.94 mmol) of 5- (4) are added to the flask. - (Bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole, 0.31 g of tetrabutylammonium bromide and 1.32 g (23.5 mmol) of crushed KOH. The mixture was stirred at 31 ° C under an inert atmosphere for 2.5 hours. The conversion of the starting compound 5- (4 (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole to tritylirbesartan is 95%. The mixture was cooled, evaporated and 17 ml of methanol and 0.33 g (5.9 mmol) of crushed KOH were added. The reaction mixture was refluxed for 2.5 hours and then evaporated again. Conversion to irbesartan is practically 100%. 17 ml of water and 50 ml / erc-butyl methyl ether are added, stirred and the phase is separated. The aqueous phase was re-extracted with 50 ml / erc-butyl methyl ether and then the aqueous phase was acidified with 2 M HCl to pH = 2. 40 ml of methylene chloride was added, the mixture was stirred and separated. The aqueous phase is re-extracted with 10 ml of methylene chloride. The combined organic phases are washed twice with 20 ml of water, dried with Na 2 SO4 and evaporated to dryness. 1.4 g (96%) of crude irbesartan are obtained.

Primer 3 g irbesartana suspendiramo pri sobni temperaturi v 20 ml vode in dodamo 2 ml metanola. Nato suspenzijo nakisamo z 2M HCI do pH 1,03. Zmes segrevamo pod refluksom 10 minut, mešamo pri sobni temperaturi luro in 30 minut na ledu. Oborino odfiltriramo in produkt sušimo v vakuumskem sušilniku pri 50 °C 1 uro. Izoliramo 2,25 g seskvihidratne hidrokloridne soli irbesartana.Example 3 G of irbesartan was suspended at room temperature in 20 ml of water and 2 ml of methanol were added. The suspension was then acidified with 2M HCl to pH 1.03. The mixture was refluxed for 10 minutes, stirred at room temperature at luro and 30 minutes on ice. The precipitate was filtered off and the product was dried in a vacuum oven at 50 ° C for 1 hour. 2.25 g of the sesquihydrate hydrochloride salt of irbesartan is isolated.

Primer 4Example 4

V bučko damo 11,5 g (17,1 mmol) tritilirbesartana, 140 ml metanola ter 3,07 g (54,8 mmol) zdrobljenega KOH. Reakcijsko zmes refluktiramo 2,5 uri in jo uparimo ter dodamo 170 ml vode in 170 ml terc-butil metil etra. Fazi mešamo, ločimo in organsko fazo zavržemo. Vodno fazo pa nakisamo s 1 M HCI do pH = 0,99. Izpadlo oborino mešamo pri sobni temparaturi 4 ure ter jo nato odfiltriramo.11.5 g (17.1 mmol) of tritylirbesartan, 140 ml of methanol and 3.07 g (54.8 mmol) of crushed KOH were placed in the flask. The reaction mixture was refluxed for 2.5 hours and evaporated and 170 ml of water and 170 ml of tert-butyl methyl ether were added. The phases are mixed, separated and the organic phase discarded. The aqueous phase was acidified with 1 M HCl to pH = 0.99. The resulting precipitate was stirred at room temperature for 4 hours and then filtered.

Dobimo 7,55 g (90 %) surovega irbesartan hidroklorida seskvihidrata.7.55 g (90%) of crude irbesartan hydrochloride sesquihydrate are obtained.

Primer 5: Prekristalizacija irbesartan hidroklorida seskvihidrata.Example 5: Recrystallization of irbesartan hydrochloride sesquihydrate.

7,4 g Irbesartan hidroklorida seskvihidrata raztopimo pri višji temperaturi v 18 ml zmesi etil metil keton / 3M HCI (10:1). Nato zmes ohladimo in mešamo pri sobni temperaturi 1 uro in pol ure pri 0 °C. Oborino odfiltriramo in jo sušimo pri 40 °C 2 uri. Dobimo 5,3 g (75 %) irbesartan hidroklorida seskvihidrata.7.4 g of irbesartan hydrochloride sesquihydrate was dissolved at a higher temperature in 18 ml of ethyl methyl ketone / 3M HCl (10: 1). The mixture was then cooled and stirred at room temperature for 1 hour and a half at 0 ° C. The precipitate was filtered off and dried at 40 ° C for 2 hours. 5.3 g (75%) of irbesartan hydrochloride sesquihydrate are obtained.

Primer 6 g tritil irbesartana raztopimo v 25 ml DMF pri povišani temperaturi. Zmes ohladimo na sobno temperaturo in nato nastalo suspenzijo mešamo še 0,5 h na ledu. Dobljeni produkt odfiltriramo in ga speremo s svežim DMF. Dobimo 26 g produkta (93 %).Example 6 g of trityl irbesartan was dissolved in 25 ml of DMF at elevated temperature. The mixture was cooled to room temperature and the resulting suspension was stirred for an additional 0.5 h on ice. The resulting product was filtered off and washed with fresh DMF. 26 g of product (93%) were obtained.

Claims (34)

ZAHTEVKIREQUIREMENTS 1. Postopek za pripravo irbesartana ali njegovih farmacevtsko sprejemljivih soli, označen s tem, da izvedemo1. A process for the preparation of irbesartan or its pharmaceutically acceptable salts, characterized in that a) sintezo tritil irbesartana z reakcijo 5-(4-(bromometil)bifenil-2-il)-l-(trifenilmetil)tetrazola in 2-n-butil-4-ciklopentan-2-imidazolin-5-ona ali njegove soli v organskem topilu v prisotnosti katalizatorja faznega prenosa in baze,a) synthesis of trityl irbesartan by reaction of 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole and 2-n-butyl-4-cyclopentan-2-imidazolin-5-one or its salts in an organic solvent in the presence of a phase transfer catalyst and a base, b) odstranimo zaščitno skupino nastalega tritil irbesartana v organskem topilu inb) remove the protecting group of the resulting trityl irbesartan in the organic solvent; and c) izoliramo irbesartan oziroma njegove farmacevtsko sprejemljive soli.c) isolate irbesartan or its pharmaceutically acceptable salts. 2. Postopek za odstranitev zaščitne skupine tritil irbesartana, označen s tem, da izvedemo reakcijo v alkoholu, z dodatkom mineralne baze in pri povišani temperaturi.2. A process for removing the trityl irbesartan protecting group, characterized in that the reaction is carried out in alcohol, with the addition of a mineral base and at elevated temperature. 3. Postopek po zahtevku la), označen s tem, da je katalizator faznega prenosa tetraalkilamonijeva sol, kronski eter, kriptand, tris(3,6-dioksaheptil)amin ali piridil sulfoksid.Process according to claim 1a), characterized in that the phase transfer catalyst is tetraalkylammonium salt, crown ether, cryptand, tris (3,6-dioxaheptyl) amine or pyridyl sulfoxide. 4. Postopek po zahtevku 3, označen s tem, da je katalizator prednostno tetrabutilamonijev bromid.Process according to claim 3, characterized in that the catalyst is preferably tetrabutylammonium bromide. 5. Postopek po zahtevku la), označen s tem, da je organsko topilo, v kateren izvajamo reakcijo, topilo, ki se meša z vodo, kot so DMSO, DMF, DMA ali nitrili.A process according to claim 1a), characterized in that the organic solvent in which the reaction is carried out is a water miscible solvent such as DMSO, DMF, DMA or nitriles. 6. Postopek po zahtevku 5, označen s tem, daje organsko topilo prednostno acetonitril.Process according to claim 5, characterized in that the organic solvent is preferably acetonitrile. 7. Postopek po zahtevku la), označen s tem, da reakcija poteka pri temperaturi od 15 °C do temperature refluksa topila.A process according to claim 1a), characterized in that the reaction is carried out at a temperature from 15 ° C to the reflux temperature of the solvent. 8. Postopek po zahtevku 7, označen s tem, da reakcija poteka prednostno pri temperaturi med 25 °C in 45 °C.Process according to claim 7, characterized in that the reaction is preferably carried out at a temperature between 25 ° C and 45 ° C. 9. Postopek po zahtevku la), označen s tem, da kot bazo uporabimo hidrokside alkalijskih kovin.Process according to claim 1a), characterized in that alkali metal hydroxides are used as the base. 10. Postopek po zahtevku 9, označen s tem, daje baza prednostno KOH.10. The method of claim 9, wherein the base is preferably KOH. 11. Postopek po zahtevku la), označen s tem, da lahko uporabimo 5-(4-(bromometil)bifenil2-il)-l-(trifenilmetil)tetrazol nižjih stopenj čistote, prednostno nad 80 %.Process according to claim 1a), characterized in that 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole of lower purity levels, preferably above 80%, can be used. 12. Postopek po zahtevku lb) in 2, označen s tem, daje baza KOH, NaOH ali LiOH in da kot alkohol uporabimo metanol, etanol, izopropanol, propanol ali butanol.Process according to claim 1b) and 2, characterized in that the base is KOH, NaOH or LiOH and that methanol, ethanol, isopropanol, propanol or butanol are used as alcohol. 13. Postopek po zahtevku 12, označen s tem, daje baza prednostno KOH.13. The method of claim 12, wherein the base is preferably KOH. 14. Postopek po zahtevku 12, označen s tem, da kot alkohol prednostno uporabimo metanol.Process according to claim 12, characterized in that methanol is preferably used as an alcohol. 15. Postopek po zahtevku lb) in 2, označen s tem, da reakcija poteka pri povišani temperaturi, med sobno temperaturo in temperaturo refluksa topila.A process according to claim 1b) and 2, characterized in that the reaction takes place at elevated temperature, between room temperature and the reflux temperature of the solvent. 16. Postopek po zahtevku 15, označen s tem, da reakcija poteka prednostno pri temperaturi refluksa topila.A process according to claim 15, characterized in that the reaction is preferably carried out at the reflux temperature of the solvent. 17. Postopek po zahtevku lc), označen s tem, daje izolirani irbesartan v katerikoli obliki, kot polimorf, hidrat ali sol.Process according to claim 1c), characterized in that isolated irbesartan is in any form, such as a polymorph, hydrate or salt. 18. Postopek izolacije po zahtevku lc), označen s tem, preostanku po uparevanju reakcijske zmesi dodamo vodo in vodno fazo ekstrahiramo z organskim topilom, ki se malo ali sploh ne meša z vodo.18. The isolation process according to claim 1c), characterized in that water is added to the residue after evaporation of the reaction mixture and the aqueous phase is extracted with an organic solvent which is little or no miscible with water. 19. Postopek po zahtevku 18, označen s tem, da se za ekstrakcijo uporabijo organska topila kot so estri, terc.- butil metil eter, metilen klorid, heptan, heksan ali toluen.Process according to claim 18, characterized in that organic solvents such as esters, tert-butyl methyl ether, methylene chloride, heptane, hexane or toluene are used for the extraction. 20. Postopek po zahtevku 19, označen s tem, da se za ekstrakcijo prednostno uporabi terc,butil metil eter.Process according to claim 19, characterized in that tert, butyl methyl ether is preferably used for the extraction. 21. Postopek po zahtevku 18, označen s tem, da se ločeno vodno fazo nakisa s HCI do pH vrednosti med 1,2 in 7, prednostno do pH med 3 in 5.21. The method of claim 18, wherein the separated aqueous phase is acidified with HCl to a pH of between 1.2 and 7, preferably to a pH of between 3 and 5. 22. Postopek po zahtevku 18, označen s tem, da se ločeno vodno fazo nakisa s HCI do pH vrednosti pod pH 1,2 in izoliramo hidrokloridno sol irbesartana.Process according to claim 18, characterized in that the separated aqueous phase is acidified with HCl to a pH below pH 1.2 and the hydrochloride salt of irbesartan is isolated. 23. Postopek po zahtevku 21, označen s tem, da iz vode izpadli surovi irbesartan nadalje odfiltriramo ali ekstrahiramo v primemo organsko topilo, v katerem se irbesartan raztaplja in ki se ne meša z vodo.Process according to claim 21, characterized in that the crude irbesartan recovered from the water is further filtered or extracted into a suitable organic solvent in which irbesartan is soluble and water immiscible. 24. Postopek po zahtevku 23, označen s tem, da kot topilo za ekstrakcijo uporabimo metilen klorid.Process according to claim 23, characterized in that methylene chloride is used as the solvent for extraction. 25. Postopek po zahtevku 23, označen s tem, da organsko fazo speremo z vodo, sušimo z ustreznim sušilnim sredstvom in jo uparimo do trdnega preostanka, da dobimo surov irbesartan.Process according to claim 23, characterized in that the organic phase is washed with water, dried with a suitable drying agent and evaporated to a solid residue to give crude irbesartan. 26. Postopek po zahtevku 23, označen s tem, da organsko fazo po ekstrakciji nakisamo s HCI do pH vrednosti pod 1,2 in izoliramo hidrokloridno sol irbesartana.26. The process of claim 23, wherein the organic phase is extracted with HCl after extraction to a pH below 1.2 and the hydrochloride salt of irbesartan is isolated. 27. Postopek po zahtevku 23, označen s tem, da odfiltrirani izpadli irbesartan prekristaliziramo iz topil kot so: alkoholi kot so metanol, etanol, izopropanol, «-propanol, butanol, izobutanol, /crZ-butanol; DMF, DMSO, dioksan, THF, 3-pentanon, 2-butanon, 4metil-2-pentanon, ali kombinacije le-teh topil z vodo.A process according to claim 23, characterized in that the filtered effluent irbesartan is recrystallized from solvents such as: alcohols such as methanol, ethanol, isopropanol, N-propanol, butanol, isobutanol, / CrZ-butanol; DMF, DMSO, dioxane, THF, 3-pentanone, 2-butanone, 4methyl-2-pentanone, or combinations thereof with water. 28. Postopek po zahtevku 18, označen s tem, da bazično sol irbesartana ali raztopino te soli v vodi ali organskem topilu ali mešanici obeh nakisamo do pH vrednosti pod 1,2 in izoliramo hidrokloridno sol irbesartana.Process according to claim 18, characterized in that the basic salt of irbesartan or a solution of this salt in water or an organic solvent or a mixture of both are acidified to a pH below 1.2 and the hydrochloride salt of irbesartan is isolated. 29. Trdni tritil irbesartan, označen s temperaturo tališča okoli 148 °C.29. Solid trityl irbesartan, characterized by a melting point of about 148 ° C. 30. Trdni tritil irbesartan, označen z onset temperaturo pri okoli 148°C.30. Solid trityl irbesartan, characterized by an offset temperature at about 148 ° C. 31. Trdni tritil irbesartan, označen z rentgenskim praškovnim difraktogramom s piki pri: 6,47; 8,14; 11,14; 12,03; 13,51; 15,71; 19,00; 20,87; 23,13; 27,95; 28,93 ± 0,1 stopinj 2-theta.31. Solid trityl irbesartan, characterized by an X-ray powder diffraction pattern with dots at: 6.47; 8.14; 11.14; 12.03; 13.51; 15.71; 19.00; 20.87; 23.13; 27.95; 28.93 ± 0.1 degrees 2-theta. 32. Trdni tritil irbesartan iz zahtevka 31, prednostno označen z rentgenskim praškovnim difraktogramom špiki pri: 6,47; 8,14; 13,51; 19,00; 20,87; 23,13 ± 0.1 stopinj 2-theta.32. The solid trityl irbesartan of claim 31, preferably characterized by an X-ray powder diffractogram of Spikes at: 6.47; 8.14; 13.51; 19.00; 20.87; 23.13 ± 0.1 degrees 2-theta. 33. Uporaba tritil irbesartana za pripravo irbesartan hidroklorida.33. Use of trityl irbesartan for the preparation of irbesartan hydrochloride. 34. Proces za pripravo irbesartan hidroklorida, označen s tem, da raztopino alkalne soli irbesartana nakisamo do pH manj od 1,2.34. Process for the preparation of irbesartan hydrochloride, characterized in that the solution of the alkaline salt of irbesartan is acidified to a pH of less than 1.2.
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