SI22126A - Procedure of preparation of candesartan cilexetil - Google Patents
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- SI22126A SI22126A SI200500283A SI200500283A SI22126A SI 22126 A SI22126 A SI 22126A SI 200500283 A SI200500283 A SI 200500283A SI 200500283 A SI200500283 A SI 200500283A SI 22126 A SI22126 A SI 22126A
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- 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
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Abstract
Description
POSTOPEK ZA PRIPRAVO KANDESARTAN CELEKSETILAPROCEDURE FOR THE PREPARATION OF CANDESARTAN CELEXETIL
Področje izumaFIELD OF THE INVENTION
Predloženi izum se nanaša na izboljšan postopek za pripravo kandesartana ter njegovih farmacevtsko sprejemljivih soli in estrov kot aktivnih sestavin zdravila za zdravljenje hipertenzije ter sorodnih bolezni in stanj.The present invention relates to an improved process for the preparation of candesartan and its pharmaceutically acceptable salts and esters as active ingredients of a medicament for the treatment of hypertension and related diseases and conditions.
Tehnični problemA technical problem
Kandesartan cileksetil s formulo (I) je kemično opisan kot (+/-)-1[[(cikloheksiloksi)karbonil]oksi]etil-2-etoksi-1 -[[2'-( l/f-tetrazol-5-il)-1,1 '-bifeniI-4il]metil]-Lf/-benzimidazol-7-karhoksilat. Zaradi svoje sposobnosti, da inhibira encim, ki pretvori angiotenzin, se na široko uporablja za zdravljenje hipertenzije ter sorodnih bolezni in stanj. Z kandesartan cileksetilom kot angiotenzin Π receptorskim antagonistom se izognemo stranskim učinkom kalcijevih antagonistov, ima pa visoko stabilnost in očitne kurativne učinke. Trenutno se prodaja kot racemna zmes. Pripravijo ga po objavljenih patentih, npr. EP 0 720 982 BI in EP 0 459 136.Candesartan cilexetil of formula (I) is chemically described as (+/-) - 1 [[(cyclohexyloxy) carbonyl] oxy] ethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) ) -1,1'-biphenyl-4-ylmethyl] -L-N-benzimidazole-7-carboxylate. Due to its ability to inhibit the angiotensin converting enzyme, it is widely used to treat hypertension and related diseases and conditions. Candesartan cilexetil as an angiotensin receptor antagonist avoids the side effects of calcium antagonists, but has high stability and obvious curative effects. Currently sold as a racemic mixture. It is prepared according to published patents, e.g. EP 0 720 982 BI and EP 0 459 136.
(I)(I)
Kot je tukaj spodaj navedeno, bi bilo zelo koristno, da zagotovimo učinkovitejši in bolj ekonomičen tehnološki postopek za pridobivanje kandesartan cileksetila.As outlined below, it would be very useful to provide a more efficient and economical technological process for the manufacture of candesartan cilexetil.
Ozadje izumaBACKGROUND OF THE INVENTION
V EP 0 720 982 Bi je opisana priprava, kandesartan cileksetila z deprotekcijo trifenilmetilnega (trdilnega) dela v metanolu in v prisotnosti klorovodikove kisline. Slabe strani tega postopka so zelo nizki izkoristki in produkt je treba čistiti s kromatografijo. V EP 0 668 272 je nadalje opisan izboljšan postopek odstranitve zaščitne skupine ob uporabi brezvodnega vodikovega klorida v metanolu. Izkoristki so rahlo izboljšani glede na EP 0 720 982 BI, vendar je delež razpadnih produktov še vedno precej visok. Slabe strani zgoraj omenjenih postopkov so, da vključujejo uporabo močno korozivnih kislin in je tudi potrebo, da se reakcijska zmes obdeluje s kompleksnimi ekstrakcijami ali kromatografskim čiščenjem.EP 0 720 982 Bi describes the preparation, candesartan cilexetil, by deprotection of triphenylmethyl (solid) moiety in methanol and in the presence of hydrochloric acid. The disadvantages of this process are very low yields and the product must be purified by chromatography. EP 0 668 272 further describes an improved process for removing a protecting group using anhydrous hydrogen chloride in methanol. The yields are slightly improved compared to EP 0 720 982 BI, but the share of decomposition products is still quite high. The disadvantages of the above mentioned processes are that they involve the use of highly corrosive acids and there is also a need for the reaction mixture to be treated by complex extractions or chromatographic purification.
V WO 2005/021535 je opisana priprava kandesartan cileksetila z deprotekcijo trdilnega dela s solvoliz» pri temperaturah refluksa v brezvodnem Cl do C5 alkoholu ob nevtralnih ali rahlo bazičnih pogojih. Pretvorba v kandesartan cileksetil je med 76 % in 91 %, kar še vedno ni optimalno v industrijski proizvodnji, in reakcijski čas je 24 ur, kar je še ena slaba stran z stališča uporabe v industriji. Nadalje daljši reakcijski časi pri temperaturah refluksa običajno vodijo do višjih nivojev razpadnih produktov.WO 2005/021535 describes the preparation of candesartan cilexetil by the deprotection of a solid with solvolysis at reflux temperatures in anhydrous Cl to C5 alcohol under neutral or slightly basic conditions. Conversion to candesartan cilexetil is between 76% and 91%, which is still not optimal in industrial production, and the reaction time is 24 hours, which is another downside from an industry use standpoint. Further, longer reaction times at reflux temperatures usually lead to higher levels of decay products.
V WO 2005/037821 je opisana deprotekcija tetrazolilne skupine s (+/-)-1[[(cildoheksiloksi)karbonilloksi]etil-2-etoksi-N[[2'-(7V’'tnfenilmetiltetrazol-5-il)-l,r'bifenil-4-il]metill-lH-benzimidazol-7-karboksilata (tritil kandesartan cileksetila) z uporabo metansulfonske, toluen sulfonske, mravljične in trifluoroocetne kisline ali preprosto z refluktiranjem tritil kandesartan cileksetila v zmesi toluena, metanola in vode. Slabe strani teh postopkov so, da re fikcija odstranitve zaščitne skupine ni končana in da produkt večinoma izolirajo v obliki viskoznega olja zaradi prisotnih nečistot.WO 2005/037821 describes the deprotection of a tetrazolyl group with (+/-) - 1 [[(cydohexyloxy) carbonyloxy] ethyl-2-ethoxy-N [[2 '- (7''phenylmethyltetrazol-5-yl) -1. r'biphenyl-4-yl] methyl-1H-benzimidazole-7-carboxylate (trityl candesartan cilexetil) using methanesulfonic, toluene sulfonic, formic and trifluoroacetic acid or simply by refluxing trityl candesartan cilexetil in a mixture of toluene, methanol and methanol. The disadvantages of these processes are that the deprotection reaction of the protecting group is not complete and that the product is mostly isolated in the form of viscous oil due to impurities present.
V WO 2005/051928 so opisani postopki za pripravo tetrazolilnih spojin, ki vključujejo odstranitev zaščitnih skupin z /V-zaščitene tetrazolilne spojine, zlasti kandesartan cileksetila, z organskimi kislinami. Ker uporabijo nizke reakcijske temperature, od 30 °C do 35 °C, izkoristki niso višji kot 60 % in uporabijo dodatne ekstrakcije in čiščenja z aktivnim ogljem in s pomočjo celita, kar je jasen znak za prisotnost neželenih stranskih produktov in/ali prisotnost izhodnega materiala.WO 2005/051928 describes methods for the preparation of tetrazolyl compounds, which include the removal of the protecting groups of the? / V-protected tetrazolyl compounds, in particular candesartan cilexetil, with organic acids. Because they use low reaction temperatures of 30 ° C to 35 ° C, the efficiencies are no higher than 60% and use additional extractions and purification with activated carbon and celite, which is a clear indication of the presence of unwanted by-products and / or the presence of starting material .
Povzetek izumaSummary of the Invention
Pri predloženem izumu gre za izboljšano sintezo za pripravo kandesartana ter njegovih farmacevtsko sprejemljivih soli in estrov kot aktivnih sestavin zdravila za zdravljenje hipertenzije ter sorodnih bolezni in stanj, ki obsega odstranitev tetrazolilne zaščitne skupine v organskem topilu in v prisotnosti Lewisove kisline. Kot Lewisove kisline so mišljene normalno vse vrste, ki imajo prazno orbitalo in/ali dostopno LUMO ter vse vrste s popolnim ali delnim pozitivnim nabojem. Običajno uporabimo Lewisove kisline, kot borov trifluorid, aluminijev trihalid in/ali cinkov dihalid.The present invention provides an improved synthesis for the preparation of candesartan and its pharmaceutically acceptable salts and esters as active ingredients of a medicament for the treatment of hypertension and related diseases and conditions comprising the removal of a tetrazolyl protecting group in an organic solvent and in the presence of Lewis acid. Normally, Lewis species is intended to mean all species having an empty orbit and / or accessible LUMO and all species with full or partial positive charge. Usually, Lewis acids such as boron trifluoride, aluminum trihalide and / or zinc dihalide are used.
Pri prednostni izvedbi predloženega izuma gre za izboljšano deprotekcijsko reakcijo, ki vodi do kandesartana ter njegovih farmacevtsko sprejemljivih soli in estrov, ki obsega odstranitev trifenilmetilne (tritilne) zaščitne skupine s tetrazolilnega dela v polarnem organskem topilu in v prisotnosti Lev/isove kisline. Kot Levvisovo kislino prednostno uporabimo cinkov dihalid, vključno cinkov difluoiid, diklorid, dibromid ali dijodid. Najbolj prednostno uporabimo cinkov diklorid.A preferred embodiment of the present invention is an improved deprotection reaction leading to candesartan and its pharmaceutically acceptable salts and esters comprising removing the triphenylmethyl (trityl) protecting group from the tetrazolyl moiety in a polar organic solvent and in the presence of Lev / isoic acid. Zinc dihalide, including zinc difluoid, dichloride, dibromide or diiodide, is preferably used as Levvis acid. Most preferably, zinc dichloride is used.
Nepričakovano smo ugotovili, da pri pripravi kandesartana ter njegovih farmacevtsko aktivnih estrov in soli, prednostno kandesartan cileksetila, deprotekcijska reakcija tetrazolilne zaščitne skupine, zlasti kadar je teitrazolilna zaščitna skupina tritil, vodi do mnogo višjih dobitkov, Če jo izvajamo v polarnem organskem topilu in v prisotnosti Lewisove kisline. Reakcijski časi so krajši v primerjavi z deprotekcijskimi postopki iz znanega stanja tehnike in torej pripravimo kandesartan cileksetil z nižjimi nivoji nečistot.It has been unexpectedly found that in the preparation of candesartan and its pharmaceutically active esters and salts, preferably candesartan cilexetil, the deprotection reaction of the tetrazolyl protecting group, especially when the teitrazolyl protecting group is trityl, leads to much higher yields, when carried out in a polar organic solvent and in the presence Lewis acids. Reaction times are shorter compared to deprotection procedures in the prior art and therefore candesartan cilexetil is prepared with lower impurity levels.
Pri nadaljnjem vidiku gre pri predloženem izumu za kandesartan cileksetil, v bistvu brez 2-okso nečistot, s strukturno formulo (Π)A further aspect of the present invention is candesartan cilexetil, substantially free of 2-oxo impurities, having the structural formula (Π)
H kjer je Ri alkil ali alkilaril, kot metil, etil, benzil itd.; in je R2 H ali tetrazolilna zaščitna skupina, kot npr. trifenihnetilna (tritilna) zaščitna skupina.H wherein R1 is alkyl or alkylaryl such as methyl, ethyl, benzyl, etc .; and R 2 is H or a tetrazolyl protecting group, such as e.g. triphenyneethyl (trityl) protecting group.
V nadaljevanju so opisane prednostne izvedbe; izuma.Preferred embodiments are described below; of the invention.
Podroben opis izumaDETAILED DESCRIPTION OF THE INVENTION
Pri predloženem izumu gre za izboljšano sintezo za pripravo kandesartan cileksetila, ki obsega odstranitev trifeuilmetilne (tritilne) zaščitne skupine v organskem topilu in v prisotnosti Lewisove kisline.The present invention provides an improved synthesis for the preparation of candesartan cilexetil comprising removing the trifeuylmethyl (trityl) protecting group in an organic solvent and in the presence of Lewis acid.
Izhodni material, ki je derivat kandesartana ali njegova prosta kislina, prednostno kandesartan ester, najbolj prednostno (+/-)-7-[[(cikloheksiloksi)karboniljoksi]etil“2etoksi-1 - [[2-(//-trifenjlmetiltetrazol-5-il)-1, l'-bifenil-4-iljmetil]- lH-benzimidazol-7karboksilat (tritil kandesartan cileksetil) lahko pripravimo, kot je opisano npr. v J. Med. Chem. 1993, 36, 2343-2349 ali po katerikoli drugi metodi priprave, znani v stroki, in ga lahko uporabimo v njegovi trdni ali raztopljeni obliki. Torej lahko tritil kandesartan cileksetil uporabimo kot izolirano spojino, v obliki raztopine ali kot neizolirano reakcijsko zmes.Starting material being a candesartan derivative or free acid, preferably candesartan ester, most preferably (+/-) - 7 - [[(cyclohexyloxy) carbonyloxy] ethyl] 2ethoxy-1 - [[2 - (// - triphenylmethyltetrazol-5 -yl) -1,1'-biphenyl-4-ylmethyl] -1H-benzimidazole-7carboxylate (trityl candesartan cilexetil) can be prepared as described e.g. in J. Med. Chem. 1993, 36, 2343-2349 or by any other method of preparation known in the art and can be used in its solid or dissolved form. Thus, trityl candesartan cilexetil can be used as an isolated compound, as a solution or as an uninsulated reaction mixture.
Pri prvi izvedbi predloženega izuma gre za izboljšano deprotekcijsko reakcijo, ki vodi do kandesartana ter njegovih farmacevtsko sprejemljivih soli in estrov, ki obsega odstranitev zaščitne skupine s tetrazolilnega dela v polarnem organskem topilu in v prisotnosti Lewisove kisline, ki je klasična vrsta s pomanjkanjem elektronov, kot npr. borov trifluorid, aluminijev trihalid, cinkov dihalid itd. Prednostno uporabimo cinkov dihalid in najbolj prednostno cinkov diklorid. Pri prednostni izvedbi je tetrazolilna zaščitna skupina trifenilmetilna (tritilna) zaščitna skupina.The first embodiment of the present invention is an improved deprotection reaction leading to candesartan and its pharmaceutically acceptable salts and esters, comprising removing the protecting group from the tetrazolyl moiety in a polar organic solvent and in the presence of Lewis acid, which is a classical electron-deficient species, such as e.g. boron trifluoride, aluminum trihalide, zinc dihalide, etc. Preferably zinc dihalide and most preferably zinc dichloride are used. In a preferred embodiment, the tetrazolyl protecting group is a triphenylmethyl (trityl) protecting group.
Postopek za pripravo (+/-)-l-[[(cikloheksiloksi)karboni].]oksiIetil-2-etoksi“l-[[2'-(\Htetrazol-5“il)-l, r-bifenil-4-il]raelil]-lTf-benzimidazol-7-karboksilata (kandesartan cileksetila) obsega:Process for the preparation of (+/-) - 1- [[(cyclohexyloxy) carbonyl].] Oxyethyl-2-ethoxy "1 - [[2 '- (\ Hetrazol-5" yl) -1,1-biphenyl-4- yl] raelyl] -lT-benzimidazole-7-carboxylate (candesartan cilexetil) comprises:
i. transesterifikacijo ali esterifikacijo tetrazolilnega zaščitenega kandesartanskega derivata ali tetrazolilnega zaščitenega kandesartana v njegovi kislinski obliki v tetrazolilni zaščiteni kandesartan cileksetil, ii. obdelavo tetrazolilnega zaščitenega kandesartan cileksetila z Lewisovo kislino v primernem organskem topilu, iii. dodatek drugega topila, prednostno vode, in segre vanje reakcijske zmesi, iv. izolacijo dobljenega kandesartan cileksetila.i. transesterification or esterification of a tetrazolyl protected candesartan derivative or tetrazolyl protected candesartan in its acid form into tetrazolyl protected candesartan cilexetil, ii. treatment of tetrazolyl protected candesartan cilexetil with Lewis acid in a suitable organic solvent, iii. addition of another solvent, preferably water, and heating of the reaction mixture, iv. isolation of the obtained candesartan cilexetil.
Pri prednostni izvedbi obsega postopek za pripravo (+/-)-1[f(cikloheksiloksi)karbonil]oksi]etil'2-etoksi-l·-[[2'-(lH-tetΓazol-5-il)-l,Γ-bifenil-4il]metil]-l//-benzimidazol-7-karboksilata (kandesartan cileksetila):In a preferred embodiment, the process comprises preparing (+/-) - 1 [f (cyclohexyloxy) carbonyl] oxy] ethyl'2-ethoxy-1 · - [[2 '- (1H-tetazazol-5-yl) -1,, -biphenyl-4yl] methyl] -1H-benzimidazole-7-carboxylate (candesartan cilexetil):
i. obdelavo l-[[(cildoheksiloksi)karbonil]oksi]etil-2-etoksi-1 -[ [(2-(77tiifenilmetiltetrazol-5-il)-1, r-bifenil4<l]metil]-lH-benzimidazol-76 karboksilata (tritil kandesartan cileksetila) z Levvisovo kislino v primernem organskem topilu, ii. dodatek drugega topila, prednostno vode, in segrevanje reakcijske zmesi, iii. izolacijo dobljenega kandesartan cileksetila.i. treatment of 1 - [[(cyldohexyloxy) carbonyl] oxy] ethyl-2-ethoxy-1 - [[(2- (77thiphenylmethyltetrazol-5-yl) -1,1-biphenyl4 <1] methyl] -1H-benzimidazole-76 carboxylate (trityl candesartan cilexetil) with Levvis acid in a suitable organic solvent, ii) addition of another solvent, preferably water, and heating of the reaction mixture, iii) isolation of the resulting candesartan cilexetil.
Prednosten postopek za pripravo kaudesartan cileksetila je tisti, pri katerem je Lewisova kislina cinkov dihalid, prednostao cinkov diklorid. Lewisovo kislino dodamo v količini med 0,4 in 1,5 ekvivalenti, prednostno v količini med 0,6 in 1,2 ekvivalenti, najbolj prednostno v količini med 0,7 in 1,0 ekvivalenti.A preferred process for the preparation of caudesartan cilexetil is one in which zinc dichloride is preferred by Lewis acid. Lewis acid is added in an amount of between 0.4 and 1.5 equivalents, preferably in an amount of between 0.6 and 1.2 equivalents, most preferably in an amount of between 0.7 and 1.0 equivalents.
Drugo topilo, prednostno vodo, lahko dodamo v količini med 0,5 % (v/v) in 10 % (v/v), prednostno med 1 in 5 %.Another solvent, preferably water, can be added in an amount of between 0.5% (v / v) and 10% (v / v), preferably between 1 and 5%.
Kot drugo topilo lahko dodamo polama organska topila, pred ali med segrevanjem. Prednostno je drugo topilo voda.Organic solvents may be added as a second solvent, before or during heating. Preferably, the second solvent is water.
Reakcijsko zmes segrevamo pri temperaturi med 0 °C in 120 °C, prednostno pri temperaturi refluksa, 0,5 do 10 ur, prednostno 2 do 4 ure.The reaction mixture is heated at a temperature between 0 ° C and 120 ° C, preferably at reflux temperature, for 0.5 to 10 hours, preferably for 2 to 4 hours.
Kot primerna organska reakcijska topila tanko uporabimo alkohole, acetate, etre, amide, nitrile in njihove zmesi. Pri prednostni izvedbi je organsko topilo alkohol in pri najbolj prednostni izvedbi je organsko topilo metanol.Alcohols, acetates, ethers, amides, nitriles and mixtures thereof are thinly used as suitable organic reaction solvents. In a preferred embodiment, the organic solvent is alcohol and in the most preferred embodiment, the organic solvent is methanol.
Pretvorba izhodnega materiala je skoraj popolna, ker manj kot 2 % izhodne spojine (tritil kandesartan cileksetila) ostane v reakcijski zmesi. Količina stranskega produkta 2-okso-kandesartan cileksetila v reakcijski zmesi je manjša kot 2 %.The conversion of the starting material is almost complete because less than 2% of the starting compound (trityl candesartan cilexetil) remains in the reaction mixture. The by-product of 2-oxo-candesartan cilexetil in the reaction mixture is less than 2%.
Izolacija dobljenega kandesartan cileksetila vključuje kristalizacijo, obarjanje, liofilizacijo, ekstrakcijo, vključno ekstrakcije pri super-kritičnih pogojih, ali uporabo komprimiranih plinov, razpršilno sušenje ali katerikoli drug postopek, znan strokovnjaku.Isolation of the resulting candesartan cilexetil involves crystallization, precipitation, lyophilization, extraction, including extraction under super-critical conditions, or use of compressed gases, spray drying or any other process known to one skilled in the art.
Pri prednostnem postopku po dokončanju stopnje deprotekcije ohladimo reakcijsko zmes na temperaturo pod 30 °C, nevtraliziramo na vrednost pH med 5 in 8, prednostno na vrednost pH med 6 in 7, z raztopino baze, kije lahko anorganska baza, kot NaOH, KOH, LiOH, Ca(OH)2, Na2CO3, NaHCO3, K2CO3, KHCO3, anorganski fosfati, ah organska baza, kot amini. Prednostno uporabimo karbonate in fosfate ter najbolj prednostno uporabimo hidrogenkarbonate kot baze za nevtralizacijo reakcijske zmesi.In the preferred process, after completion of the deprotection step, cool the reaction mixture to a temperature below 30 ° C, neutralize to a pH between 5 and 8, preferably to a pH between 6 and 7, with a solution of a base which may be an inorganic base such as NaOH, KOH, LiOH , Ca (OH) 2 , Na 2 CO 3 , NaHCO 3 , K 2 CO 3 , KHCO 3 , inorganic phosphates, ah organic base, such as amines. Preferably carbonates and phosphates are used, and most preferably hydrogen carbonates are used as bases to neutralize the reaction mixture.
Po nevtralizaciji uparimo hlapne komponente reakcijske zmesi v vakuumu, reakcijski zmesi dodamo topilo, ki se ne meša z vodo, skupaj z nekaj vode in kandesartan cileksetil ekstrahiramo v organsko fazo. Organske frakcije zberemo, izperemo z vodo ali slanico in sušimo nad desikantom, npr. brezvodnim natrijevim ali magnezijevim sulfatom(VI), Ekstrakcije izvedemo pri temperaturi pod 50 °C, prednostno pod 30 °C in najbolj prednostno pod 20 °C.After neutralization, the volatile components of the reaction mixture were evaporated in vacuo, the water-immiscible solvent was added to the reaction mixture, together with some water, and candesartan cilexetil was extracted into the organic phase. The organic fractions were collected, washed with water or brine and dried over desiccant, e.g. anhydrous sodium or magnesium sulfate (VI), the Extractions are carried out at a temperature below 50 ° C, preferably below 30 ° C and most preferably below 20 ° C.
Kot topila za ekstrakcijo, ki se ne mešajo z vodo, lahko uporabimo acetate (npr. etil acetat, metil acetat, izopropil acetat, propil acetat, butil acetat, izobutil acetat), etre (npr. dietil eter, drizopropil eter, terc.-butil metil eter), halogenirane ogljikovodike (kot metilen klorid), toluen in ogljikovodike (heptan, heksan, cikloheksan).Acetates (e.g., ethyl acetate, methyl acetate, isopropyl acetate, propyl acetate, butyl acetate, isobutyl acetate), ethers (e.g. diethyl ether, drosopropyl ether, tert- butyl methyl ether), halogenated hydrocarbons (such as methylene chloride), toluene and hydrocarbons (heptane, hexane, cyclohexane).
Organsko fazo delno uparimo v vakuumu, dokler v posodi ne ostane med 1/2 in 1/5 izhodnega volumna, in koncentratu dodamo nepolamo topilo. Kot nepolama topila lahko dodamo ogljikovodike (heptan, heksan, cikloheksan), toluen in etre. Po dodatku nepolamega topila zmes mešamo in hladimo pod 20 °C 2 do 24 ur.The organic phase was partially evaporated in vacuo until there remained between 1/2 and 1/5 of the output volume in the vessel, and a non-polar solvent was added to the concentrate. Hydrocarbons (heptane, hexane, cyclohexane), toluene and ethers can be added as non-polar solvents. After the addition of the non-polar solvent, the mixture was stirred and cooled below 20 ° C for 2 to 24 hours.
Oboijen ali kristaliziran produkt zberemo in sušimo 10 ur pri temperaturi med 10 °C in 50 °C, dokler ne dobimo kandesartan cileksetila, ki vsebuje manj kot okoli 5000 ppm rezi dualnih topil. Za sušenje dobljenega, kandesartan cileksetila lahko uporabimo vse sušilne metode, znane povprečnemu strokovnjaku, kot npr. sušenje na zraku, vakuumsko sušenje, sušenje z »fiuid bed«, vključno sušenje z »fluid bed«z vlažnim zrakom, in »spray drying« sušenje. Prednostno uporabimo vakuumsko sušenje.The crystallized or crystallized product was collected and dried for 10 hours at a temperature between 10 ° C and 50 ° C until candesartan cilexetil containing less than about 5000 ppm slice of dual solvents was obtained. For drying the obtained candesartan cilexetil, all drying methods known to the average person, such as e.g. air drying, vacuum drying, fiuid bed drying, including fluid bed drying with moist air, and spray drying. Vacuum drying is preferred.
Surov produkt lahko prekristaliziramo iz organskih topil, kot alkohola, ketona in nitritov in/ali njihovih zmesi. Uporabimo lahko tudi zmesi gornjih topil z etri, halogeniranimi ogljikovodiki in ogljikovodiki. Kristalne oblike produktov, kristaliziranih iz gornjih topil, so bile enake, kot je opisano v Chem. Pharm. Buli. 47(2) J82-186 (1999).The crude product may be recrystallized from organic solvents such as alcohol, ketone and nitrites and / or mixtures thereof. Mixtures of the above solvents with ethers, halogenated hydrocarbons and hydrocarbons may also be used. The crystalline forms of the products crystallized from the above solvents were the same as described in Chem. Pharm. Buli. 47 (2) J82-186 (1999).
Med kristalizacijskim postopkom in med filtracijo se lahko tvorijo solvati kandesartan cileksetila.Candesartan cilexetil solvates may form during the crystallization process and during filtration.
Pomembno je, da kontroliramo velikost delcev kandesartan cileksetila med njegovo pripravo. Povprečna velikost delcev, uporabljenih pri našem delu, je 10 do 100 pm, prednostno pod 50 pm, ki jih običajno dobimo s kristalizacijo kandesartan cileksetila iz organskih topil ali njihovih zmesi z vodo ob mešanju. Če ni mešanja, lahko s kristalizacijo iz organskih topil ali njihovih zmesi z vodo tudi dobimo večje delce, npr. s povprečnim premerom nad 100 pm, ki jih je treba mleti ali predelati na kakršenkoli drug način, ki zmanjša velikost delcev, pred njihovo uporabo v farmacevtskih formulacijah. Vendar ni dovolj kontrolirati le povprečne velikosti delcev, ampak tudi porazdelitev velikosti delcev.It is important to control the particle size of candesartan cilexetil during its preparation. The average particle size used in our work is 10 to 100 µm, preferably below 50 µm, usually obtained by crystallization of candesartan cilexetil from organic solvents or mixtures thereof with water with stirring. In the absence of mixing, crystallization from organic solvents or mixtures thereof with water can also yield larger particles, e.g. having an average diameter of more than 100 µm, which must be ground or processed in any other way that reduces the size of the particles before being used in pharmaceutical formulations. However, it is not enough to control only the average particle size, but also the particle size distribution.
Povprečna velikost delcev in porazdelitev velikosti delcev sta pomembni, da zagotovimo, da je tehnološki postopek industrijsko primeren, t.j,, da ne povzroči segregacije sestavin zmesi za tabletiranje, če je ne tabletiramo/Isomprimiramo takoj po pripravi zmesi za tabletiranje.Average particle size and particle size distribution are important to ensure that the process process is industrially suitable, i.e., that it does not cause segregation of the components of the tabletting compound unless tableted / Isompressed immediately after preparation of the tabletting mixture.
Druga izvedba predloženega izuma se nanaša na kandesartan cileksetil, v bistvu brez 2-okso nečistot, s strukturno formulo (TT)Another embodiment of the present invention relates to candesartan cilexetil, substantially free of 2-oxo impurities, having the structural formula (TT)
kjer je Ri alkil ali alkilaril, kot metil, etil, benzil itd.; in je R2 H ali tetrazolilna zaščitna skupina, kot npr. trifenilmetilna zaščitna skupina.wherein R1 is alkyl or alkylaryl such as methyl, ethyl, benzyl, etc .; and R 2 is H or a tetrazolyl protecting group, such as e.g. triphenylmethyl protecting group.
Pri prvi prednostni izvedbi gre pri predloženem izumu za kandesartan cileksetil, v bistvu brez 2-okso nečistot. Pri predloženem izumu gre tudi za postopek za sintetiziranje kandesartan cileksetila, ki obsega količino 2-okso nečistot ne večjo kot 0,10 %, prednostno ne večjo kot 0,05 %.The first preferred embodiment of the present invention is candesartan cilexetil, substantially free of 2-oxo impurities. The present invention also provides a method for synthesizing candesartan cilexetil comprising an amount of 2-oxo impurities of not more than 0.10%, preferably not more than 0.05%.
2-okso nečistote smo določili s pomočjo HPLC metode, ld obsega:The 2-oxo impurity was determined by HPLC method, ld comprising:
OpremaEquipment
HPLC: Agilent 1100HPLC: Agilent 1100
Ovrednotenje podatkov: ChemStatiomData evaluation: ChemStatiom
Kromatografeki pogoji:Chromatographic conditions:
Kolona;Column;
Zorbax Eclipse XDB C-l 8, 1,8 pm, 50 x 4,6 mmZorbax Eclipse XDB C-l 8, 1.8 pm, 50 x 4.6 mm
Mobilna faza:Mobile Phase:
topilo A: 0,0IM natrijev dihidrogenfosfat, pH 2,5 topilo B: acetonitrilsolvent A: 0.0IM sodium dihydrogen phosphate, pH 2.5 solvent B: acetonitrile
Gradient:Gradient:
Naknadni potek:Follow-up:
Temperatura kolone: Hitrost tečenja:Column temperature: Flow rate:
Detekcija:Detection:
Injekcija:Injection:
min °C 1,0 ml/minmin ° C 1.0 ml / min
UV, 225 nm μΐUV, 225 nm μΐ
Referenčna raztopina (RS)Reference solution (RS)
RSl: Raztopiti 5 mg standarda kandasartan cileksetila in 5 mg vsakega od kandesartanskih intermediatov tritil kandesartan cileksetila in tritil kandesartana v acetonitrilu in razredčiti na 10,0 ml. RS2: Razredčiti 1,0 ml te raztopine na 100,0 ml z acetonitrilom.RSl: Dissolve 5 mg of candasartan cilexetil standard and 5 mg of each of the candesartan intermediates of trityl candesartan cilexetil and trityl candesartan in acetonitrile and dilute to 10.0 ml. RS2: Dilute 1.0 ml of this solution to 100.0 ml with acetonitrile.
Testne raztopine (TS)Test solutions (TS)
TS1: Razredčiti 20,0 μΐ reakcijske raztopine na 20,0 ml z acetonitrilom.TS1: Dilute 20.0 μΐ of the reaction solution to 20.0 ml with acetonitrile.
TS2: Raztopili okoli 10 mg snovi, ki jo je treba preiskati, v acetonitrilu in razredčiti na 25,0 ml z acetonitrilom.TS2: Dissolved about 10 mg of the substance to be investigated in acetonitrile and diluted to 25.0 ml with acetonitrile.
Kadar kromatograme snemamo ob predpisanih pogojih, je retencijski čas kandesartana okoli 7 minut, relativni retencijski čas tritil kandesartan cileksetila je okoli 1,2, relativni retencijski čas tritil kandesartana je okoli 2,1 in relativni retencijski časi 2~okso kandesartan cileksetila, Ph3COH, Ph3COMe, Ph3COEt so okoli 0,6, 0,8, 1,3, 1,4. Postopek ovrednotenja so površinski %.When chromatograms are recorded under the prescribed conditions, the retention time of candesartan is about 7 minutes, the relative retention time of trityl candesartan cilexetil is about 1.2, the relative retention time of trityl candesartan is about 2.1, and the relative retention times are 2 ~ oxo candesartan cilexetil, Ph 3 COH , Ph 3 COMe, Ph 3 COEt are about 0.6, 0.8, 1.3, 1.4. The evaluation process is surface%.
Predloženi izum ilustrirajo naslednji primeri, ne da bi bil nanje omejen.The present invention is illustrated by the following examples without being limited thereto.
Tališča smo posneli na Koffletjevem aparatu za tališča in IR spektre smo posneli na Paragon 100 Perkin-Elmer FT-IR spektrometru.Melting points were recorded on a Kofflet melting point apparatus and IR spectra were recorded on a Paragon 100 Perkin-Elmer FT-IR spectrometer.
PrimeriExamples
Primerjalni primer (WO 2005/021535, primer 12)Comparative Example (WO 2005/021535, Example 12)
Zmes tritil kandesartan cileksetila (0,43 g) in metanola (8,6 ml) mešamo in refluktiramo 24 ur. Po tem času reakcijsko zmes analiziramo s HPLC.A mixture of trityl candesartan cilexetil (0.43 g) and methanol (8.6 ml) was stirred and refluxed for 24 hours. After this time, the reaction mixture was analyzed by HPLC.
Kandesartan cileksetil: 64,9 %Candesartan Cilexetil: 64.9%
Tritil kandesartan cileksetil: 0,64 %Trityl candesartan cilexetil: 0.64%
2-okso kandesartan cileksetil: 8,0 %.2-oxo candesartan cilexetil: 8.0%.
Zmes uparimo na 1/4 in po ohlajenjn filtriramo oborjene kristale. Filtrat uparimo in kristaliziramo iz cikloheksana. Dobimo bele kristale (HPLC površinski %: kandesartan cileksetil: 76,1 %, tritil kandesartan cileksetil: 1,2 %, 2-okso kandesartan cileksetil: 10,9%.The mixture was evaporated to 1/4 and the precipitated crystals were filtered off after cooling. The filtrate was evaporated and crystallized from cyclohexane. White crystals were obtained (HPLC surface%: candesartan cilexetil: 76.1%, trityl candesartan cilexetil: 1.2%, 2-oxo candesartan cilexetil: 10.9%.
Primerjalni primer (WO 2005/037821. primer 5)Comparative Example (WO 2005/037821. Example 5)
Raztopino tritil kandesartan cileksetila (0,43 g), mravljnične kisline (0,38 ml), metilen klorida (1,7 ml) in metanola (0,9 ml) mešamo 5 ur pri 25 °C. Po tem času analiziramo reakcijsko zmes:A solution of trityl candesartan cilexetil (0.43 g), formic acid (0.38 ml), methylene chloride (1.7 ml) and methanol (0.9 ml) was stirred for 5 hours at 25 ° C. After this time, the reaction mixture is analyzed:
HPLC površinski %, 5h: kandesartan cileksetil: 68,1 %, tritil kandesartan cileksetil:HPLC surface%, 5h: candesartan cilexetil: 68.1%, trityl candesartan cilexetil:
12.4 %, 2-okso kandesartan cileksetil: 0,5 %12.4%, 2-oxo candesartan cilexetil: 0.5%
HPLC površinski %, 7h: kandesartan cileksetil: 64,6 %. tritil kandesartan cileksetil: 14,9 %, 2-okso kandesartan cileksetil: 1,7 %HPLC surface%, 7h: candesartan cilexetil: 64.6%. trityl candesartan cilexetil: 14.9%, 2-oxo candesartan cilexetil: 1.7%
HPLC površinski %, 23h: kandesartan cileksetil: 61,6 %, tritil kandesartan cileksetil:HPLC surface%, 23h: candesartan cilexetil: 61.6%, trityl candesartan cilexetil:
18.4 %, 2-okso kandesartan cileksetil: 2,2 %.18.4%, 2-oxo candesartan cilexetil: 2.2%.
Primer 1Example 1
Zmes 0,43 g (0,5 mmol) tritil kandesartan cileksetila, 15 ml metanola, ZnCl2 (0,05 g; 0,37 mmol) in vode (0,4 ml) mešamo pri temperaturi refluksa 2,5 ure. Reakcijsko zmes analiziramo (površinski % HPLC: kandesartan cileksetil: 75,5 %, tritil kandesartan cileksetil: 1,2 %, 2-okso kandesartan cileksetil: 1,6 %) in ohladimo na sobno temperaturo. Nato zmes nevtraliziramo do pH 6,11 z dodatkom nasičene raztopine NaHCOj in metanol uparimo. Dodamo etil acetat (15 ml) in vodo (10 ml) in zmes mešamo. Po ločenju faz izperemo organsko fazo z vodo (10 ml). Organsko fazo sušimo nad Na2SO4, filtriramo in uparimo na 1/4 izhodnega volumna. Oljnemu ostanku dodamo heptan (10 ml) in ohladimo pod 0 °C. Oborjeni produkt zberemo s filtracijo in posušimo.A mixture of 0.43 g (0.5 mmol) of trityl candesartan cilexetil, 15 ml of methanol, ZnCl 2 (0.05 g; 0.37 mmol) and water (0.4 ml) was stirred at reflux for 2.5 hours. The reaction mixture was analyzed (surface% HPLC: candesartan cilexetil: 75.5%, trityl candesartan cilexetil: 1.2%, 2-oxo candesartan cilexetil: 1.6%) and cooled to room temperature. The mixture was then neutralized to pH 6.11 by the addition of saturated NaHCO3 solution and the methanol was evaporated. Ethyl acetate (15 ml) and water (10 ml) were added and the mixture stirred. After separation of the phases, the organic phase was washed with water (10 ml). The organic phase was dried over Na 2 SO 4 , filtered and evaporated to 1/4 of the output volume. Heptane (10 ml) was added to the oil residue and cooled to 0 ° C. The precipitated product was collected by filtration and dried.
Claims (18)
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
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SI200500283A SI22126A (en) | 2005-10-07 | 2005-10-07 | Procedure of preparation of candesartan cilexetil |
SI200600041A SI22127A (en) | 2005-10-07 | 2006-03-03 | Procedure of preparation of candesartan cilexetil |
EA200800706A EA015727B1 (en) | 2005-10-07 | 2006-09-29 | Process for the preparation of candesartan cilexetil |
CNA2006800403167A CN101296923A (en) | 2005-10-07 | 2006-09-29 | Procedure of preparation of candesartan cilexetil |
PCT/EP2006/009489 WO2007042161A1 (en) | 2005-10-07 | 2006-09-29 | Process for the preparation of candesartan cilexetil |
EP06792325A EP1945629B1 (en) | 2005-10-07 | 2006-09-29 | Process for the preparation of candesartan cilexetil |
US12/089,444 US7884212B2 (en) | 2005-10-07 | 2006-09-29 | Process for the preparation of candesartan cilexetil |
SI200631267T SI1945629T1 (en) | 2005-10-07 | 2006-09-29 | Process for the preparation of candesartan cilexetil |
UAA200804373A UA91073C2 (en) | 2005-10-07 | 2006-09-29 | Process for the preparation of candesartan cilexetil |
AT06792325T ATE543812T1 (en) | 2005-10-07 | 2006-09-29 | METHOD FOR PRODUCING CANDESARTAN-CILEXETIL |
NO20082140A NO20082140L (en) | 2005-10-07 | 2008-05-07 | Process for making candesartan lexile |
US12/755,606 US20100197933A1 (en) | 2005-10-07 | 2010-04-07 | Process for the Preparation of Candesartan Cilexetil |
US13/267,690 US20120029201A1 (en) | 2005-10-07 | 2011-10-06 | Process for the preparation of candesartan cilexetil |
Applications Claiming Priority (1)
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SI200500283A SI22126A (en) | 2005-10-07 | 2005-10-07 | Procedure of preparation of candesartan cilexetil |
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