SK722003A3 - Process for the crystallization of losartan potassium - Google Patents
Process for the crystallization of losartan potassium Download PDFInfo
- Publication number
- SK722003A3 SK722003A3 SK72-2003A SK722003A SK722003A3 SK 722003 A3 SK722003 A3 SK 722003A3 SK 722003 A SK722003 A SK 722003A SK 722003 A3 SK722003 A3 SK 722003A3
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- Prior art keywords
- losartan
- potassium
- acetone
- methanol
- losartan potassium
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- 239000002083 C09CA01 - Losartan Substances 0.000 title claims abstract description 34
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229960000519 losartan potassium Drugs 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000002425 crystallisation Methods 0.000 title description 3
- 230000008025 crystallization Effects 0.000 title description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000012296 anti-solvent Substances 0.000 claims abstract description 9
- -1 triphenylmethyl (trityl) protecting group Chemical group 0.000 claims abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 2
- 239000001257 hydrogen Substances 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- FDKIDFYIEWFERB-UHFFFAOYSA-N [2-butyl-5-chloro-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol;potassium Chemical compound [K].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 FDKIDFYIEWFERB-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 16
- 229960004773 losartan Drugs 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- QQPGGBNMTNDKEY-UHFFFAOYSA-N [2-butyl-5-chloro-3-[[4-[2-(2-trityltetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NN(N=N2)C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C1 QQPGGBNMTNDKEY-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- LZTRCELOJRDYMQ-UHFFFAOYSA-N triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Tento vynález sa vzťahuje na spôsob prípravy kryštalického Iosartanu draselného Losartan Potassium polymorfný tvar IThe present invention relates to a process for the preparation of crystalline Iosartan potassium Losartan Potassium polymorphic form I
Losartan je taktiež známy ako 2-n-butyl-4-chloro-5-hydroxymetyl-l- [[2'- (2Htetrazol-5-yl) bifenyl-4-yl] metyl] imidazol draselná soľ aje užitočná pri liečení hypertensie.Losartan is also known as the 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2'- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl] imidazole potassium salt and is useful in the treatment of hypertension.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Losartan je známy tým, že zamedzuje pôsobenie oktapeptridového hormonálneho angiotensinu II taje užitočný preto pri zmiernení hypertensie. Ďalej bolo uvádzané, že losartan, keď je aplikovaný s močopudným liekom, ako furosemidom alebo hydrochlorotiazidom, pôsobí zosilneným anti-hypertenzívnym účinkom. Poskytnutie Iosartanu s nesteroidným protizápalovým liekom môže zabrániť reálnym chybám.Losartan is known to oktapeptridového prevents the action of the hormone angiotensin II t and is useful therefore in alleviating angiotensin induced hypertension. It has further been reported that losartan, when administered with a diuretic drug such as furosemide or hydrochlorothiazide, exerts an enhanced anti-hypertensive effect. Providing Iosartan with a non-steroidal anti-inflammatory drug may prevent real errors.
Losartan je známy tým, že vykazuje polymorfizmus (vid’US patent 5,608,075). V US patente 5,608,075 boli uvedené dva polymorfné tvary, Form I a Form II, spolu s metódou ich prípravy. Charakteristické vlastnosti týchto polymorfných tvarov boli popísané prostredníctvom tvaru rôntgenového difrakčného obrazca, DSC termogramami, FTIR spektrami, Ramanovými spektrami a pevnou fázou 13C NMR.Losartan is known to exhibit polymorphism (see US Patent 5,608,075). In US Patent 5,608,075, two polymorphic shapes, Form I and Form II, have been reported, together with a method for their preparation. The characteristics of these polymorphic shapes have been described by X-ray diffraction pattern, DSC thermograms, FTIR spectra, Raman spectra and solid state 13 C NMR.
Polymorfný tvar I bol pripravený v US patente 5,608,075 pridaním vodného roztoku Iosartanu draselného k refluxnej zmesi izopropanolu a cyklohexénu a odstránením vody destiláciou potrojného azeotropu cyklohexanu/izopropanolu/vody pri 64°C. Losartan draselný tvar I vykryštalizuje pri 69°C.Polymorph form I was prepared in US Patent 5,608,075 by adding an aqueous solution of Iosartan potassium to a reflux mixture of isopropanol and cyclohexene and removing water by distilling a triple cyclohexane / isopropanol / water azeotrope at 64 ° C. Losartan potassium form I crystallizes at 69 ° C.
Vo WO 98/18787 bola uvedená metóda na prípravu polymorfného tvaru I, pri ktorej roztok draselnej soli vo vodnom izopropanole je ohrievaný tak, aby bol znížený obsah vody asi na 2,6% odstránením zmesi izopropanolu a vody, nastane značné naočkovanie so suspenziou v cyklohexene losartan draselný, až kým suspenzia zostane nerozpustená a voda je odstránená na 0,02-0,11 destilovaním temamého azeotropu pri súčasnom pridávaní cyklohexénu. Vykryštalizovaný materiál je získaný filtráciou.WO 98/18787 discloses a method for preparing polymorphic form I in which a solution of the potassium salt in aqueous isopropanol is heated to reduce the water content to about 2.6% by removing the isopropanol / water mixture, a significant seeding with a suspension in cyclohexene losartan potassium until the suspension remains undissolved and water is removed to 0.02-0.11 by distilling the topic azeotrope while adding cyclohexene. The crystallized material is obtained by filtration.
U obidvoch týchto uvedených metód kryštalický Losartan Potassium bol získaný zo smesi izopropanolu a cyklohexénu a tento kryštalický materiál bol charakterizovaný ako polymorfný tvar I. Kryštalizácia popísaná vo WO 98/18787 si vyžaduje primeranú presnosť na stále získanie polymorfu tvaru I a zmes rozpúšťadiel, cyklohexén a izopropanol sú ťažko oddelitelné. Vynálezcovia majú prekvapivý objav, že losartan draselný polymorfného tvaru I môže byť pripravený v jednej nádobe reakciou z trifenylmetylom chráneného Losartanu s hydroxidom draselným v metanole/acetone bez oddelenia voľnej kyseliny Losartanu a nevyžaduje sa očkovanie.In both of these methods, crystalline Losartan Potassium was obtained from a mixture of isopropanol and cyclohexene and this crystalline material was characterized as polymorphic form I. The crystallization described in WO 98/18787 requires adequate accuracy to still obtain a polymorph I and solvent mixture cyclohexene and isopropanol. they are difficult to separate. The inventors have the surprising discovery that losartan potassium of polymorphic form I can be prepared in a single vessel by reaction from triphenylmethyl protected Losartan with potassium hydroxide in methanol / acetone without separation of Losartan free acid and no vaccination is required.
Podstata vynálezuSUMMARY OF THE INVENTION
Tento vynález sa vzťahuje na spôsob výroby losartanu draselného Form I bez používania rozpúšťacej zmesi izopropanolu a cyklohexénu. Typicky kyselina bez Losartanu je daná do rozpúšťadla a je pridaný hydroxid draselný, aby sa získal číry roztok, ktorý je potom zahustený pri zníženom tlaku, aby väčšia časť rozpúšťadla bola odstránená. Je pridaný antisolvent, aby sa vykryštalizoval losartan draselný. Rozpúšťadlá na prípravu losartanu draselného zahrnujú metanol, etanol, butanol, ale uprednostňuje sa realizácia metanolom. Antisolvent je zvolený zbežných rozpúšťadiel, ako octan etylnatý, nitril kyseliny octovej, toluén a acetón, ale uprednostňovaným antisolventom je acetón.The present invention relates to a process for producing losartan potassium Form I without using a solvent mixture of isopropanol and cyclohexene. Typically, the acid without Losartan is added to the solvent and potassium hydroxide is added to obtain a clear solution, which is then concentrated under reduced pressure to remove most of the solvent. An antisolvent is added to crystallize losartan potassium. Solvents for preparing losartan potassium include methanol, ethanol, butanol, but methanol is preferred. The antisolvent is selected from common solvents such as ethyl acetate, acetic nitrile, toluene and acetone, but the preferred antisolvent is acetone.
Kyselina bez Losartanu alebo trifenylmetylom chránený Losartan môže byť pripravený použitím reakcií a techník popísaných v US patente 5,138,069 a WO 93/10106.Losartan-free acid or triphenylmethyl-protected Losartan can be prepared using the reactions and techniques described in US Patent 5,138,069 and WO 93/10106.
Alternatívne 2-n-butyl-4chloro-5-hydroxynetyl-l- [[2'- [ (2-trifenylmetyl) tetrazol-Alternatively 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2'- [(2-triphenylmethyl) tetrazole-
5-yl] bifenyl-4-yl] metyl] imidazol (v tom odkaz na Trityl Losartan), kľúčový medzičlánok5-yl] biphenyl-4-yl] methyl] imidazole (including a reference to Trityl Losartan), key intermediate
JJ
Trityl LosartanTrityl Losartan
pri výrobe losartanu je refluxovaný hydroxidom draselným v liehu, uprednostnené v metanole, aby bola odstránená ochrana a vytvorený losartan draselný, ktorý je potom oddelený v požadovanom polymorfnom tvare I destiláciou metanolu a pridaním antisolventu ako acetonitritu, toluénu, octanu etylnatého a uprednostnené acetónu. Tak reakcia ako aj kryštalizácia môže byť urobená v tej istej nádobe a nie sú potrebné nákladné oddelovacie techniky, ako extrakcia alebo oddelenie kyseliny bez Losartanu. Takáto metóda získania losartanu draselného v polymorfnom tvare I priamo z trityl lozartanu nie je dodnes uvádzaná v literatúre a preto predstavuje predmet tohto vynálezu. Okrem toho popísaná príprava je robená zásadne za bezvodých podmienok a takto sa vyhýba azeotropickej destilácii na odstránenie vody. Požadovaný losartan draselný tvaru I je získaný priamo, to jest bez potreby oddelenia volnej kyseliny Losartanu, čo pôsobí zvýšenie efektívnosti a prispieva k zníženým výrobným nákladom.in the manufacture of losartan, it is refluxed with potassium hydroxide in alcohol, preferably in methanol, to remove protection and form losartan potassium, which is then separated in the desired polymorph I by distillation of methanol and addition of an antisolvent such as acetonitrite, toluene, ethyl acetate and preferred acetone. Both the reaction and the crystallization can be carried out in the same vessel and expensive separation techniques such as Losartan-free extraction or acid separation are not required. Such a method for obtaining losartan potassium in polymorphic form I directly from trityl lozartan has not been reported to date in the literature and is therefore an object of the present invention. In addition, the described preparation is carried out essentially under anhydrous conditions and thus avoids azeotropic distillation to remove water. The desired I-shaped losartan potassium is obtained directly, i.e. without the need to separate the free acid of Losartan, which increases efficiency and contributes to reduced production costs.
Typicky trityl losartan je rozpustený v 6-8 násobnom objemovom diele v metanole a je pridané ekvimolekulárne množstvo hydroxidu draselného. Výsledná zmes je refluxovaná niekoľko hodín, kým sa pozoruje zmiznutie trityl losartanu. Tritanol je získaný späť filtráciou a metanol je destilovaný pri zníženom tlaku. Ku zvýšku je pridaný acetón a pokračuje sa v destilácii, aby boly odstránené posledné stopy metanolu. Losartan draselný je získaný ako voľne stekavá suspenzia v acetóne, ktorá je filtrovaná a usušená. Diferenciálna snímacia kalorimetrická analýza a rôntgenový difrakčný obrazec dokazujú, že je to polymorfná modifikácia I.Typically, trityl losartan is dissolved in a 6-8 fold volume in methanol and an equimolecular amount of potassium hydroxide is added. The resulting mixture is refluxed for several hours until the disappearance of trityl losartan is observed. Tritanol is recovered by filtration and the methanol is distilled under reduced pressure. Acetone is added to the residue and distillation is continued to remove the last traces of methanol. Losartan potassium is obtained as a free-flowing suspension in acetone, which is filtered and dried. Differential scanning calorimetric analysis and X-ray diffraction pattern show that it is a polymorphic modification I.
Nasledovné príklady ďalej ilustrujú prípravu polymorfného tvaru I losartan draselný a neznamenajú jej obmedzenie.The following examples further illustrate the preparation of Losartan potassium polymorph I and do not limit it.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad č. 1Example # 1
100 gm (0,152 mol) 2-n-butyl-4-chloro-5-hydroxymetyl-l- [ [2'- [ (2-trifenylmetyl) tetrazol-5-yl] bifenyl-4-yl] metyl] imidazol (trityl losartan) bol daný do 650 ml metanolu. Bol pridaný 10 g 85%-ho hydroxidu draselného (0,152 mol) a zmes bola refluxovaná v dusíkovej atmosfére takmer 6 hodín. Reakčná hmota bola ochladená na 8-10°C a tritanol ako vedľajší produkt bol odstránený filtráciou a umývaný 50 ml ochladeného metanolu. Filtrát bol ošetrený 1 g dreveného uhlia a filtrovaný. Roztok metanolu bol potom zahustený pri 45-50°C, aby bola odstránená väčšia časť metanolu. Bolo pridané 200 ml acetónu a pokračovalo sa v destilácii pri zníženom tlaku, aby množstvo bolo zredukované približne na 120 ml. Biela kryštalická suspenzia bola ochladená na teplotu miestnosti, filtrovaná a produkt bol umývaný 50 ml acetónom a usušený vo vákuovej sušiarni, aby bol získaný Losartan Potassium. Výťažok: 60 g (teoreticky 86,58%). DSC analýza (obr. 1) a rontgenový difrakčný obrazec (obr. 2) súhlasí s tým, ktorý je uvedený pre polymorfný tvar I.100 gm (0.152 mol) of 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2'- [(2-triphenylmethyl) tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole (trityl) losartan) was placed in 650 ml of methanol. 10 g of 85% potassium hydroxide (0.152 mol) was added and the mixture was refluxed under nitrogen for nearly 6 hours. The reaction mass was cooled to 8-10 ° C and the tritanol by-product was removed by filtration and washed with 50 mL of cooled methanol. The filtrate was treated with 1 g charcoal and filtered. The methanol solution was then concentrated at 45-50 ° C to remove most of the methanol. 200 ml of acetone was added and distillation was continued under reduced pressure to reduce the amount to about 120 ml. The white crystalline suspension was cooled to room temperature, filtered, and the product was washed with 50 mL acetone and dried in a vacuum oven to obtain Losartan Potassium. Yield: 60 g (86.58% of theory). The DSC analysis (Fig. 1) and the X-ray diffraction pattern (Fig. 2) agree with that given for polymorphic form I.
Príklad č. 2Example # 2
K suspenzii 5gm (11,82 m.mol.) 2-n-butyl-4-chloro-5-hydroxymetyl-l- [ [2'- [ (2Htetrazol-5yl] bifenyl-4-yl] metyl] imidazol (kyselina losartanu v 25 ml metanole, 0,75 g (86%) (11,52 m.mol.) bol pridaný prášok hydroxidu draselného a masa bola pomiešaná pri teplote okolia aby sa získal takmer čistý roztok. Tento bol filtrovaný a vyčistený roztok bol zahustený, aby sa odstránila väčšia časť metanolu pri 45-50°C pri zníženom tlaku. Bolo pridaných 25 ml acetónu a pokračovala sa destilácia, aby sa destilovala väčšia časť zmesi metanolu a acetónu. Zvýšok bol zriedený 25 ml acetónom a obsah bol ochladený 10 minút na 20-25°C a produkt bol filtrovanýý v dusíkovej atmosfére a umývaný 5 ml acetónom. Produkt bol usušený pri 55-60°C pri zníženom tlaku, aby bolo získaných 4,88 g (teoreticky 89,5%) losartanu draselného tvaru I (DSC, XRPD).To a suspension of 5 gm (11.82 mmol) of 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2'- [(2H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole (acid) of losartan in 25 mL of methanol, 0.75 g (86%) (11.52 mmol) was added potassium hydroxide powder, and the meat was stirred at ambient temperature to give an almost pure solution, this was filtered and the purified solution was concentrated to remove most of the methanol at 45-50 ° C under reduced pressure 25 mL of acetone was added and distillation was continued to distill most of the methanol-acetone mixture. The residue was diluted with 25 mL of acetone and cooled to 10 min. 20-25 ° C and the product was filtered under a nitrogen atmosphere and washed with 5 mL acetone The product was dried at 55-60 ° C under reduced pressure to give 4.88 g (theoretically 89.5%) of potassium form I losartan ( DSC, XRPD).
Príklad č. 3Example # 3
K suspenzii 5 gm. (11,82 m.mol) losartanovej kyseliny v 25 ml suchého etanolu bol pridaný 0,75 g (86%) (11,52 m. mol) prášku hydroxidu draselného a masa bola pomiešaná 25 minút pri teplote okolia aby sa získal číry roztok. Etanol bol odstránený pri 45-50°C pri zníženom tlaku. Bolo pridaných 25 ml acetónu a pokračovala destilácia, aby sa destilovala zmes etanolu a acetónu pri zníženom tlaku. Zvyšok bol zmiešaný s 25 ml acetónom pri 2025°C a produkt bol filtrovaný v dusíkovej atmosfére a umývaný 10 ml acetónu. Produkt bol usušený pri 55-60°C pri zníženom tlaku aby bolo získaných 4,85 g (teoreticky 89%) losartanu draselného tvaru I (DSC).To a suspension of 5 gm. (11.82 mmol) of losartanoic acid in 25 ml dry ethanol was added 0.75 g (86%) (11.52 mmol) of potassium hydroxide powder and the meat was mixed at ambient temperature for 25 minutes to obtain a clear solution. . Ethanol was removed at 45-50 ° C under reduced pressure. 25 ml of acetone was added and distillation continued to distill the ethanol-acetone mixture under reduced pressure. The residue was mixed with 25 mL acetone at 2025 ° C and the product was filtered under a nitrogen atmosphere and washed with 10 mL acetone. The product was dried at 55-60 ° C under reduced pressure to give 4.85 g (theoretically 89%) of potassium form I losartan (DSC).
Príklad č. 4Example # 4
Losartan draselný tvaru Ibol pripravený z kyseliny losartanovej vmetanole, ako je popísané v príklade 2 a miesto acetónu bol používaný octan etylnatý. Výťažok 4,95 g (teoreticky 91%).Potassium losartan Ibol prepared from losartanic acid in methanol as described in Example 2 and ethyl acetate was used instead of acetone. Yield 4.95 g (theoretically 91%).
Príklad č. 5Example # 5
Losartan draselný tvaru I bol pripravený z kyseliny losartanovej podľa postupu popísaného v príklade 2 a ako antisolvent na oddelenie produktu bol pridaný acetonitril. Výťažok 4,8 g (teoreticky 88%).Form I potassium losartan was prepared from losartanoic acid according to the procedure described in Example 2 and acetonitrile was added as an antisolvent to separate the product. Yield 4.8 g (theoretically 88%).
Príklad č. 6Example # 6
K suspenzii 5 g losartanu v 25 ml n-butanolu bol pridaný 0,75 g 86% práškového hydroxidu draselného a zmes bola premiešavaná pri 20-25°C, aby bol získaný číry roztok. N-butanol etanol bol destilovaný pri zníženom tlaku a pri teplote pod 75°C. Bolo pridaných 25 ml acetónu pri 20-25°C a a filtrovaný aby sa získal losartan draselný tvaru I. Výťažok: 4,8 g (teoreticky 88%).To a suspension of 5 g of losartan in 25 ml of n-butanol was added 0.75 g of 86% potassium hydroxide powder and the mixture was stirred at 20-25 ° C to obtain a clear solution. The N-butanol ethanol was distilled under reduced pressure and below 75 ° C. 25 ml of acetone were added at 20-25 ° C and filtered to obtain losartan potassium form I. Yield: 4.8 g (theoretically 88%).
Príklad č. 7Example # 7
Losartan draselný bol pripravený reakciou kyseliny lozartanovej v n-butanole s hydroxidom draselným ako je popísané v 6. príklade a produkt bol oddelený ako polymorfný tvar I pridaním octanu etylnatého ako antisolventu miesto acetónu. Výťažok: 4,85 g (teoreticky 89%).Losartan potassium was prepared by reacting losartanic acid in n-butanol with potassium hydroxide as described in Example 6 and separating the product as polymorphic form I by adding ethyl acetate as an antisolvent instead of acetone. Yield: 4.85 g (89% of theory).
Príklad č. 8Example # 8
Losartan draselný bol pripravený v n-butanole ako je uvedené v 6. príklade losartan draselný tvaru I bol oddelený toluénom. Výťažok: 4,9 g (teoreticky 90%)Losartan potassium was prepared in n-butanol as described in Example 6, losartan Form I was separated with toluene. Yield: 4.9 g (theoretically 90%)
Príklad č. 9Example # 9
Losartan draselný bol pripravený v n-butanole, ako je popísané v 6. príklade a tvar Ibol získaný pridaním kyseliny octovej. Výťažok: 4,8 g (teoreticky 88%).Losartan potassium was prepared in n-butanol as described in Example 6 and the Ibol form obtained by the addition of acetic acid. Yield: 4.8 g (88% of theory).
Claims (5)
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|---|---|---|---|
| IN403CH2001 | 2001-05-18 | ||
| PCT/IN2001/000205 WO2002094816A1 (en) | 2001-05-18 | 2001-11-20 | Process for the crystallization of losartan potassium |
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| SK72-2003A SK722003A3 (en) | 2001-05-18 | 2001-11-20 | Process for the crystallization of losartan potassium |
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| EP (1) | EP1294712A1 (en) |
| JP (1) | JP2004520446A (en) |
| BG (1) | BG107478A (en) |
| SI (1) | SI21236A (en) |
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| WO (1) | WO2002094816A1 (en) |
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| US20030135041A1 (en) | 2002-01-04 | 2003-07-17 | Orchid Chemicals & Pharmaceuticals Limited, India | Synthesis of ceftiofur intermediate |
| AU2003278422A1 (en) * | 2002-10-31 | 2004-05-25 | Ranbaxy Laboratories Limited | Amorphous form of losartan potassium |
| ITMI20030328A1 (en) * | 2003-02-25 | 2004-08-26 | Dinamite Dipharma S P A In Forma A Bbreviata Diph | POLYMORPHS OF LOSARTAN POTASSIUM AND PROCEDURE FOR THEIR PREPARATION. |
| WO2004076442A1 (en) * | 2003-02-28 | 2004-09-10 | Ranbaxy Laboratories Limited | Polymorphs of losartan |
| WO2004087691A1 (en) * | 2003-04-03 | 2004-10-14 | Ipca Laboratories Limited | A process for the synthesis of losartan potassium |
| US7345071B2 (en) | 2003-05-07 | 2008-03-18 | Ipca Laboratories Limited | Process for the synthesis of Losartan potassium |
| DE602004029373D1 (en) * | 2003-08-27 | 2010-11-11 | Zentiva Ks | METHOD FOR REMOVING THE TRIPHENYLMETHANE GRIP |
| ITMI20032472A1 (en) * | 2003-12-16 | 2005-06-17 | Dinamite Dipharma S P A In Forma A Bbreviata Diph | PROCEDURE FOR THE PREPARATION OF LOSARTAN POTASSIUM CRYSTALLINE |
| WO2005066158A2 (en) * | 2004-01-06 | 2005-07-21 | Ipca Laboratories Limited | An improved process for the synthesis of losartan potassium |
| EP1713795A2 (en) | 2004-02-11 | 2006-10-25 | Teva Pharmaceutical Industries Ltd. | Candesartan cilexetil polymorphs |
| EP1729766A1 (en) * | 2004-03-01 | 2006-12-13 | LEK Pharmaceuticals D.D. | Pharmaceutical formulation |
| EP1742938A1 (en) * | 2004-05-05 | 2007-01-17 | Teva Pharmaceutical Industries Ltd. | Preparation of candesartan cilexetil in high purity |
| WO2010046804A2 (en) * | 2008-10-21 | 2010-04-29 | Alembic Limited | A process for preparation of losartan potassium form i |
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| US5138069A (en) * | 1986-07-11 | 1992-08-11 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
| KR100212257B1 (en) * | 1991-11-18 | 1999-08-02 | 미리암 디. 메코나헤이 | Method for preparing tetrazolylphenylboronic acid intermediate for synthesizing AII receptor antagonist |
| PT937068E (en) * | 1996-10-29 | 2002-07-31 | Merck & Co Inc | PROCESS FOR THE CRYSTALLIZATION OF LOSARTAN |
| HU222773B1 (en) * | 2000-04-21 | 2003-10-28 | Richter Gedeon Vegyészeti Gyár Rt. | Process for producing a known tetrazole derivative |
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| BG107478A (en) | 2004-01-30 |
| EP1294712A1 (en) | 2003-03-26 |
| WO2002094816A1 (en) | 2002-11-28 |
| JP2004520446A (en) | 2004-07-08 |
| SI21236A (en) | 2003-12-31 |
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