ITMI20102416A1 - INTERMEDIATE FOR THE PREPARATION OF AN ACTIVE PRINCIPLE AND PROCESS FOR ITS PREPARATION - Google Patents
INTERMEDIATE FOR THE PREPARATION OF AN ACTIVE PRINCIPLE AND PROCESS FOR ITS PREPARATION Download PDFInfo
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- ITMI20102416A1 ITMI20102416A1 IT002416A ITMI20102416A ITMI20102416A1 IT MI20102416 A1 ITMI20102416 A1 IT MI20102416A1 IT 002416 A IT002416 A IT 002416A IT MI20102416 A ITMI20102416 A IT MI20102416A IT MI20102416 A1 ITMI20102416 A1 IT MI20102416A1
- Authority
- IT
- Italy
- Prior art keywords
- telmisartan
- strontium salt
- temperature
- preparation
- water
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 8
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims description 104
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims description 55
- 229960005187 telmisartan Drugs 0.000 claims description 54
- 159000000008 strontium salts Chemical class 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- -1 telmisartan strontium salt Chemical class 0.000 claims description 10
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000002798 polar solvent Substances 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- HJCCZIABCSDUPE-UHFFFAOYSA-N methyl 2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]methyl]phenyl]benzoate Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(=O)OC HJCCZIABCSDUPE-UHFFFAOYSA-N 0.000 claims description 2
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical group [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 claims description 2
- 229910001866 strontium hydroxide Inorganic materials 0.000 claims description 2
- 239000007787 solid Substances 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000002826 coolant Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000004100 telmisartan derivatives Chemical class 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 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
- 206010011224 Cough Diseases 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 208000010412 Glaucoma Diseases 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
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 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
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940101564 micardis Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 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
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- UJPWWRPNIRRCPJ-UHFFFAOYSA-L strontium;dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Sr+2] UJPWWRPNIRRCPJ-UHFFFAOYSA-L 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Steroid Compounds (AREA)
Description
Domanda di brevetto per invenzione industriale dal titolo: Patent application for industrial invention entitled:
"Intermedio per la preparazione di un principio attivo e processo per la sua preparazione” "Intermediate for the preparation of an active ingredient and process for its preparation"
DESCRIZIONE DESCRIPTION
La presente invenzione riguarda un sale di telmisartan, più in particolare un sale di stronzio di telmisartan, il suo processo di preparazione e il suo utilizzo come intermedio nella sintesi di telmisartan. Inoltre, la presente invenzione riguarda una forma polimorfa di telmisartan. The present invention relates to a telmisartan salt, more particularly a strontium salt of telmisartan, its preparation process and its use as an intermediate in the synthesis of telmisartan. Furthermore, the present invention relates to a polymorphic form of telmisartan.
Telmisartan è un antagonista dei recettori dell’angiotensina II, con elevata affinità per i recettori di tipo 1 (AT1), utilizzato nella terapia dell’ipertensione. Bloccando il recettore, il telmisartan impedisce l’effetto vasocostrittore dell’ormone angiotensina II, determinando la dilatazione dei vasi sanguigni e il conseguente calo della pressione sanguigna, riducendo i rischi dell’ipertensione, come l’ictus. È utilizzato in terapia da solo o in associazione con altri principi attivi, quali ad esempio l’idroclorotiazide. E’ utilizzato anche nel trattamento dell’insufficienza cardiaca, dei disturbi ischemici periferici, dell’angina, per prevenire la progressione dell’insufficienza cardiaca in seguito ad infarto miocardico e nel trattamento del glaucoma. Inoltre, agendo come modulatore selettivo del recettore PPAR-γ, che regola i livelli di insulina ed il metabolismo del glucosio, il telmisartan protegge dai danni renali e vascolari causati dal diabete. Telmisartan is an angiotensin II receptor antagonist, with high affinity for type 1 (AT1) receptors, used in the treatment of hypertension. By blocking the receptor, telmisartan prevents the vasoconstricting effect of the hormone angiotensin II, causing the dilation of blood vessels and the consequent drop in blood pressure, reducing the risk of hypertension, such as stroke. It is used alone or in combination with other active ingredients, such as hydrochlorothiazide. It is also used in the treatment of heart failure, peripheral ischemic disorders, angina, to prevent the progression of heart failure following myocardial infarction and in the treatment of glaucoma. Furthermore, by acting as a selective modulator of the PPAR-γ receptor, which regulates insulin levels and glucose metabolism, telmisartan protects against renal and vascular damage caused by diabetes.
A differenza di quanto avviene per gli altri ACE-inibitori, durante la terapia con telmisartan non si sviluppa tosse come effetto collaterale. Unlike other ACE inhibitors, cough does not develop as a side effect during therapy with telmisartan.
Telmisartan è un composto di formula (I) Telmisartan is a compound of formula (I)
chimicamente noto come acido 2-[4-[[4-metil-6-(1-metilbenzimidazol-2-il)-2-propilbenzimidazol-1 -il]metil]fenil] benzoico, descritto in EP 0 502 314 e commercializzato col nome commerciale Micardis<®>. chemically known as 2- [4 - [[4-methyl-6- (1-methylbenzimidazol-2-yl) -2-propylbenzimidazol-1 -yl] methyl] phenyl] benzoic acid, described in EP 0 502 314 and marketed as trade name Micardis <®>.
Sono state descritte due forme polimorfe di telmisartan, denominate forma A e forma B. Two polymorphic forms of telmisartan have been described, named form A and form B.
La forma A viene ottenuta con il processo descritto in EP 0 502 314 oppure con il processo descritto in US2006/0276525, cioè per cristallizzazione da dimetilsolfossido. Form A is obtained with the process described in EP 0 502 314 or with the process described in US2006 / 0276525, ie by crystallization from dimethyl sulfoxide.
La forma B viene ottenuta per trattamento a caldo di telmisartan grezzo in una miscela di acqua, acido formico ed un adatto solvente organico miscibile negli altri due solventi, come descritto in WO 00/43370. Form B is obtained by heat treatment of crude telmisartan in a mixture of water, formic acid and a suitable organic solvent miscible in the other two solvents, as described in WO 00/43370.
WO 00/43370 descrive anche un processo di preparazione di miscele di telmisartan forma A e B. WO 00/43370 also describes a process for preparing mixtures of telmisartan forms A and B.
In letteratura sono anche descritti diversi sali di telmisartan. Several telmisartan salts are also described in the literature.
WO 03/037876 descrive telmisartan sodico cristallino, preparato per trattamento di una soluzione di telmisartan con una base quale sodio idrossido o sodio metossido. WO 03/037876 discloses crystalline sodium telmisartan, prepared by treating a solution of telmisartan with a base such as sodium hydroxide or sodium methoxide.
WO 2006/044754 descrive telmisartan come sale di potassio e come bisolfato cristallini. WO 2006/044754 describes telmisartan as a crystalline potassium salt and bisulfate.
WO 2006/050921 descrive i sali di sodio, potassio, magnesio e calcio di telmisartan. WO 2006/050921 discloses the sodium, potassium, magnesium and calcium salts of telmisartan.
Il polimorfismo è la proprietà delle molecole di assumere nello stato solido più di una forma cristallina o amorfa. Alcune sostanze sono note esistere in una sola forma cristallina o amorfa; altre, invece, possono presentare due o più forme cristalline. I polimorfi sono solidi distinti, con la stessa formula molecolare, ma con proprietà fisiche distinte, che possono essere vantaggiose o svantaggiose se paragonate a quelle delle altre forme nell’ambito della stessa famiglia di polimorfi. Polymorphism is the property of molecules to assume more than one crystalline or amorphous form in the solid state. Some substances are known to exist in only one crystalline or amorphous form; others, on the other hand, may have two or more crystalline forms. Polymorphs are distinct solids, with the same molecular formula, but with distinct physical properties, which can be advantageous or disadvantageous when compared to those of the other forms within the same family of polymorphs.
La morfologia dei principi attivi chimico organici è importante per il loro sviluppo chimico farmaceutico. Una forma cristallina, rispetto ad altre forme cristalline, può presentare notevoli vantaggi. Un processo appropriato per una forma cristallina può fornire ai produttori di principi attivi diversi vantaggi, quali il ricorso a passaggi o solventi economici o a basso impatto ambientale, resa o purezza del prodotto desiderato più alte. The morphology of the organic chemical active ingredients is important for their chemical-pharmaceutical development. A crystalline form, compared to other crystalline forms, can have significant advantages. An appropriate process for a crystalline form can provide manufacturers of active ingredients with various advantages, such as the use of inexpensive or low environmental impact passages or solvents, higher yield or purity of the desired product.
Il polimorfismo, il numero delle forme cristalline di una sostanza chimico organica, la loro stabilità, il loro comportamento in un organismo vivente non sono mai prevedibili. I diversi polimorfi di una sostanza possiedono energie del reticolo cristallino diverse mostrando, così, proprietà fisiche dello stato solido (quali la forma, la densità, il punto di fusione, il colore, la stabilità, la velocità di dissoluzione, la facilità di macinazione, la granulazione, ecc.) diverse. Queste differenze nella morfologia, nel polimorfismo possono avere effetti drastici sullo scorrimento del solido macinato (lo scorrimento interessa la facilità con cui il materiale è trattato durante la trasformazione in un prodotto farmaceutico), sulla stabilità di trasporto e stabilità di stoccaggio delle diverse forme di somministrazione, sulla capacità di produrre diverse forme di somministrazione, sulla solubilità in solventi polari o non polari, protici o aprotici, sulla solubilità in soluzioni acquose, sulla solubilità nei succhi gastrici, sulla solubilità nel sangue ed infine sulla biodisponibilità. Polymorphism, the number of crystalline forms of an organic chemical substance, their stability, their behavior in a living organism are never predictable. The different polymorphs of a substance possess different crystal lattice energies thus showing physical properties of the solid state (such as shape, density, melting point, color, stability, dissolution speed, ease of grinding, granulation, etc.) different. These differences in morphology, in polymorphism can have drastic effects on the flow of the ground solid (the flow affects the ease with which the material is treated during transformation into a pharmaceutical product), on the transport stability and storage stability of the different administration forms. , on the ability to produce different forms of administration, on solubility in polar or non-polar, protic or aprotic solvents, on solubility in aqueous solutions, on solubility in gastric juices, on solubility in blood and finally on bioavailability.
La velocità di dissoluzione di un principio attivo nel fluido gastrico di un paziente può avere conseguenze terapeutiche, in quanto determina la concentrazione massima che il principio attivo somministrato per via orale può raggiungere nel sangue. Altre proprietà importanti delle forme polimorfe influiscono sulla facilità di trasformare la forma del principio attivo in dosaggi farmaceutici, sulla capacità di scorrimento di una forma in polvere o granulata e sulle proprietà di superficie che determinano se i cristalli della forma aderiranno l'un l'altro una volta compattati in una compressa. The rate of dissolution of an active ingredient in a patient's gastric fluid can have therapeutic consequences, as it determines the maximum concentration that the orally administered active ingredient can reach in the blood. Other important properties of polymorphic forms affect the ease of transforming the form of the active ingredient in pharmaceutical dosages, the flowability of a powdered or granulated form, and the surface properties that determine whether the crystals of the form will adhere to each other once compacted into a tablet.
Una forma polimorfa può avere un comportamento termico diverso rispetto a quello di una forma amorfa o di qualsiasi altra forma polimorfa. Il comportamento termico può essere misurato in laboratorio mediante tecniche quali il punto di fusione capillare, la calorimetria a scansione differenziale (Differential Scanning Calorimetry, DSC) e può essere usato per distinguere le varie forme polimorfe. Una forma polimorfa può possedere proprietà spettroscopiche distinte che possono essere rilevabili mediante la diffrazione a raggi X (X-Ray Powder Diffraction, XRPD). A polymorphic form can have a different thermal behavior than that of an amorphous form or any other polymorphic form. Thermal behavior can be measured in the laboratory using techniques such as capillary melting point, Differential Scanning Calorimetry (DSC) and can be used to distinguish various polymorphic forms. A polymorphic form may possess distinct spectroscopic properties which can be detectable by X-Ray Powder Diffraction (XRPD).
La scoperta di forme polimorfe nuove di un composto farmaceutico dà un’ulteriore possibilità per migliorare le caratteristiche di tale prodotto. The discovery of new polymorphic forms of a pharmaceutical compound gives a further possibility to improve the characteristics of this product.
Allarga il repertorio di forme che un esperto di tecnica farmaceutica ha a disposizione per la progettazione di una forma farmaceutica con un profilo di rilascio mirato, o con altre caratteristiche, quali la fluidità e la velocità di dissoluzione nei liquidi acquosi. It broadens the repertoire of forms available to a person skilled in the pharmaceutical art for the design of a pharmaceutical form with a targeted release profile, or with other characteristics, such as fluidity and dissolution rate in aqueous liquids.
La presente invenzione riguarda un sale di stronzio di telmisartan di formula (II) The present invention relates to a telmisartan strontium salt of formula (II)
In un ulteriore aspetto, la presente invenzione riguarda un processo di preparazione del sale di stronzio di telmisartan di formula (II) che comprende: In a further aspect, the present invention relates to a process for preparing the strontium salt of telmisartan of formula (II) which comprises:
(a) la sospensione dell’estere metilico di telmisartan in una miscela di solventi polari, preferibilmente acqua e metanolo, ad una temperatura compresa tra 50*0 e 90*0; (a) the suspension of the methyl ester of telmisartan in a mixture of polar solvents, preferably water and methanol, at a temperature between 50 * 0 and 90 * 0;
(b) l’aggiunta di un sale di stronzio; (b) the addition of a strontium salt;
(c) la filtrazione della soluzione ed il lavaggio con acqua ad una temperatura compresa tra 50*0 e 80*0; (c) filtration of the solution and washing with water at a temperature between 50 * 0 and 80 * 0;
(d) l’essiccamento del sale di stronzio di telmisartan ad una temperatura di circa 60*0 con l’ausilio del vuoto. (d) drying the telmisartan strontium salt at a temperature of about 60 * 0 with the aid of vacuum.
In un ulteriore aspetto, la presente invenzione riguarda un processo di preparazione di telmisartan, in cui il sale di stronzio di telmisartan di formula (II) viene trattato con un acido adatto in un solvente adatto. In a further aspect, the present invention relates to a telmisartan preparation process, in which the strontium salt of telmisartan of formula (II) is treated with a suitable acid in a suitable solvent.
In un ulteriore aspetto, la presente invenzione riguarda l’uso del sale di stronzio di telmisartan di formula (II) come intermedio per la sintesi di telmisartan. In a further aspect, the present invention relates to the use of the strontium salt of telmisartan of formula (II) as an intermediate for the synthesis of telmisartan.
In un ulteriore aspetto, l’invenzione fornisce una nuova forma polimorfa di telmisartan, denominata Forma a. In a further aspect, the invention provides a new polymorphic form of telmisartan, called Form a.
DESCRIZIONE BREVE DELLE FIGURE BRIEF DESCRIPTION OF THE FIGURES
Figura 1 : XRPD del sale di stronzio di telmisartan di formula II Figure 1: XRPD of the strontium salt of telmisartan of formula II
Figura 2: DSC del sale di stronzio di telmisartan di formula II Figure 2: DSC of the strontium salt of telmisartan of formula II
Figura 3: TGA del sale di stronzio di telmisartan di formula II Figure 3: TGA of the strontium salt of telmisartan of formula II
Figura 4: XRPD di telmisartan Forma a Figure 4: XRPD of telmisartan Form a
Figura 5: DSC di telmisartan Forma a Figure 5: DSC of telmisartan Form a
Figura 6: TGA di telmisartan Forma a Figure 6: TGA of telmisartan Form a
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Tutti i termini utilizzati nella presente domanda, salvo indicazioni contrarie, devono essere compresi nel loro comune significato come conosciuti nell'arte. Altre definizioni più specifiche per alcuni termini, come utilizzati in questa domanda, sono messe in evidenza più avanti e si applicano costantemente per tutta la descrizione e le rivendicazioni, a meno che una diversa definizione fornisca esplicitamente una definizione più ampia. All the terms used in the present application, unless otherwise indicated, must be understood in their common meaning as known in the art. Other more specific definitions for some terms, as used in this question, are highlighted below and consistently apply throughout the description and claims, unless a different definition explicitly provides a broader definition.
Il termine “solvente polare” si riferisce ad un solvente che tende a fornire protoni, quale acqua; un alcool, per esempio, metanolo, etanolo, propanolo, iso-propanolo, butanolo, tert-butanolo; o un solvente polarizzato, quale, per esempio, esteri, per esempio, etil acetato, butil acetato; nitrili, per esempio, acetonitrile; eteri, per esempio, tetraidrofurano, diossano; chetoni, per esempio, acetone, metilbutilchetone; e simili. The term "polar solvent" refers to a solvent which tends to provide protons, such as water; an alcohol, for example, methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol; or a polarized solvent, such as, for example, esters, for example, ethyl acetate, butyl acetate; nitriles, for example, acetonitrile; ethers, for example, tetrahydrofuran, dioxane; ketones, for example, acetone, methylbutylketone; and similar.
Ulteriori informazioni sui solventi apolari o polari possono essere trovate nei manuali di chimica organica o in monografie specializzate, per esempio: Organic Solvents Physical Properties and Methods of Purification, 4th ed., John A. Riddick, et al., Voi. Il; in “Techniques of Chemistry Series”, John Wiley & Sons, NY, 1986. Tali solventi sono noti alla persona esperta del ramo, ed è evidente alla persona esperta del ramo che i diversi solventi o loro miscele possono essere preferiti a secondo dei composti specifici e delle condizioni di reazione, essendo la loro scelta influenzata, per esempio, dalla solubilità e reattività dei reagenti, dagli intervalli di temperature utilizzate. Further information on apolar or polar solvents can be found in organic chemistry textbooks or specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., John A. Riddick, et al., Vol. Il; in "Techniques of Chemistry Series", John Wiley & Sons, NY, 1986. Such solvents are known to the person skilled in the art, and it is evident to the person skilled in the art that the different solvents or their mixtures can be preferred according to specific compounds and the reaction conditions, their choice being influenced, for example, by the solubility and reactivity of the reagents, by the temperature ranges used.
Abbiamo ora trovato un sale di stronzio di telmisartan di formula (II), che è praticamente insolubile in acqua. Il sale secondo la presente invenzione è preparato mediante un processo che comprende: We have now found a strontium salt of telmisartan of formula (II), which is practically insoluble in water. The salt according to the present invention is prepared by a process which includes:
(a) la sospensione dell’estere metilico di telmisartan in una miscela di solventi polari, preferibilmente acqua e metanolo, ad una temperatura compresa tra 50*0 e 90*0; (a) the suspension of the methyl ester of telmisartan in a mixture of polar solvents, preferably water and methanol, at a temperature between 50 * 0 and 90 * 0;
(b) l’aggiunta di un sale di stronzio; (b) the addition of a strontium salt;
(c) la filtrazione della soluzione ed il lavaggio con acqua ad una temperatura compresa tra 50*0 e 80*0; (c) filtration of the solution and washing with water at a temperature between 50 * 0 and 80 * 0;
(d) l’essiccamento del sale di stronzio di telmisartan ad una temperatura di circa 60*0 con l’ausilio del vuoto. (d) drying the telmisartan strontium salt at a temperature of about 60 * 0 with the aid of vacuum.
L’estere di telmisartan è sospeso in una miscela di solventi polari protici ed aprotici. Qualunque solvente polare protico e aprotico, noto alla persona esperta del ramo, può essere usato. Preferibilmente la miscela di solventi è acqua e metanolo, ad una temperatura compresa tra 50*0 ed 90*0, preferibilmente tra 65*0 e 85*0. Alla sospensione c osi ottenuta si aggiunge un sale di stronzio, preferibilmente stronzio idrossido, si filtra il solido e lo si lava con acqua ad una temperatura compresa tra 50*0 e 80*0, preferibilmente tra 65*0 e 75Ό. Il solido ottenuto viene essiccato in stufa ad una temperatura di 60*0 con l’ausilio del vuoto, a dare il sale di stronzio di telmisartan di formula (II). The telmisartan ester is suspended in a mixture of polar protic and aprotic solvents. Any protic and aprotic polar solvent known to one skilled in the art can be used. Preferably the solvent mixture is water and methanol, at a temperature between 50 * 0 and 90 * 0, preferably between 65 * 0 and 85 * 0. A strontium salt, preferably strontium hydroxide, is added to the suspension thus obtained, the solid is filtered and washed with water at a temperature between 50 ° and 80 ° 0, preferably between 65 ° and 75 °. The solid obtained is dried in an oven at a temperature of 60 * 0 with the aid of vacuum, to give the strontium salt of telmisartan of formula (II).
Il sale di stronzio di telmisartan di formula (II) è caratterizzato da un XRPD comprendente picchi principali come riportato nella seguente Tabella 1 ed in accordo con la Figura 1 . The strontium salt of telmisartan of formula (II) is characterized by an XRPD comprising main peaks as reported in the following Table 1 and in accordance with Figure 1.
Il nuovo sale di stronzio di telmisartan di formula (II) è stato inoltre caratterizzato mediante calorimetria a scansione differenziale (DSC) e TGA, rispettivamente in Figura 2 e Figura 3. The new strontium salt of telmisartan of formula (II) was also characterized by differential scanning calorimetry (DSC) and TGA, respectively in Figure 2 and Figure 3.
L’utilizzo del sale di stronzio di telmisartan secondo la presente invenzione consente di ottenere sia l’intermedio stesso sia il composto finale, telmisartan, in forma sostanzialmente pura. The use of the strontium salt of telmisartan according to the present invention allows to obtain both the intermediate itself and the final compound, telmisartan, in substantially pure form.
Senza essere legati ad alcuna teoria, è presumibile che l’elevato grado di purezza ottenuto con il sale di stronzio di formula (II) sia dovuto alla sua insolubilità in acqua che rende più semplice l’isolamento dopo l’idrolisi dell’estere. Without being tied to any theory, it is presumed that the high degree of purity obtained with the strontium salt of formula (II) is due to its insolubility in water which makes it easier to isolate after ester hydrolysis.
In un ulteriore aspetto, la presente invenzione fornisce un processo di preparazione di telmisartan Forma a, mediante trattamento del sale di stronzio di telmisartan di formula (II) con un acido adatto in un solvente adatto, preferibilmente acqua. Qualunque acido noto alla persona del ramo può essere usato per il processo. Adatti acidi possono essere acidi inorganici, per esempio acido cloridrico, solforico e simili; preferibilmente acido cloridrico. In a further aspect, the present invention provides a process for preparing telmisartan Form a, by treating the strontium salt of telmisartan of formula (II) with a suitable acid in a suitable solvent, preferably water. Any acid known to the person in the art can be used for the process. Suitable acids can be inorganic acids, for example hydrochloric, sulfuric acid and the like; preferably hydrochloric acid.
In un ulteriore aspetto, la presente invenzione fornisce una forma polimorfa di telmisartan, denominata Forma a e caratterizzata da un XRPD comprendente picchi principali come riportato nella seguente Tabella 2 ed in accordo con la Figura 4. In a further aspect, the present invention provides a polymorphic form of telmisartan, named Form a and characterized by an XRPD comprising main peaks as reported in the following Table 2 and in accordance with Figure 4.
Telmisartan Forma a è stato inoltre caratterizzato mediante calorimetria a scansione differenziale (DSC) e TGA, rispettivamente in Figura 5 e Figura 6. Telmisartan Forma a was also characterized by differential scanning calorimetry (DSC) and TGA, respectively in Figure 5 and Figure 6.
La presente invenzione sarà illustrata ora per mezzo di alcuni esempi, senza tuttavia limitarla. The present invention will now be illustrated by means of some examples, without however limiting it.
Gli spettri di diffrazione XRPD sono stati effettuati mediante un diffrattometro APD 2000 PRO GNR a temperatura ambiente, usando un tubo CuKa (40 kV, 30 mA) quale fonte di raggi X. I dati sono stati raccolti mediante una scansione continua 2Θ, ad una velocità di scansione di 0,047s nell’intervallo 3°-40°in 2 Θ. XRPD diffraction spectra were performed by an APD 2000 PRO GNR diffractometer at room temperature, using a CuKa tube (40 kV, 30 mA) as the X-ray source. Data was collected by continuous 2Θ scanning, at a speed scan of 0.047s in the range 3 ° -40 ° in 2 Θ.
L’analisi termica DSC è stata effettuata mediante un calorimetro differenziale a scansione Perkin Elmer Pyris 1 (3,5 mg, scan 20-6000, 20Ο/ΐΎΐιη) a panieri forati. The DSC thermal analysis was carried out using a Perkin Elmer Pyris 1 differential scanning calorimeter (3.5 mg, scan 20-6000, 20Ο / ΐΎΐιη) with perforated baskets.
L’analisi TGA è stata effettuata mediante un calorimetro differenziale a scansione Perkin Elmer Pyris 1. The TGA analysis was carried out using a Perkin Elmer Pyris 1 differential scanning calorimeter.
Esempio 1 Example 1
In un pallone a tre colli, munito di agitatore, refrigerante e termometro, è stato sospeso telmisartan estere metilico (3 g) in acqua (30 mi) e metanolo (15 mi). Alla sospensione è stato aggiunto stronzio idrossido ottaidrato (1 ,66 g). La sospensione è stata scaldata fino a 80Ό ± 5Ό e lasciata sotto agitazione per 18 ore. Il metanolo è stato distillato, il prodotto è stato filtrato ad una temperatura di circa 70Ό, il solido ottenuto è stato lavato con acqua alla stessa temperatura ed essiccato in stufa sottovuoto ad una temperatura di 60Ό. Sono stati ottenuti 2,3 g di s ale di stronzio di telmisartan. In a three-necked flask, equipped with stirrer, coolant and thermometer, telmisartan methyl ester (3 g) in water (30 ml) and methanol (15 ml) was suspended. Strontium hydroxide octahydrate (1.66 g) was added to the suspension. The suspension was heated to 80Ό ± 5Ό and left under stirring for 18 hours. The methanol was distilled, the product was filtered at a temperature of about 70Ό, the solid obtained was washed with water at the same temperature and dried in a vacuum oven at a temperature of 60Ό. 2.3 g strontium s ale of telmisartan was obtained.
Esempio 2 Example 2
In un pallone a tre colli, munito di agitatore, refrigerante e termometro, è stato sospeso il sale di stronzio di telmisartan (2,3 g), ottenuto come descritto nell’esempio 1 , in acqua (15 mi). La miscela è stata scaldata fino a circa 80*0 ed è stata aggiunta una soluzione di H CI 37% fino a pH acido. Dopo aver lasciato sotto agitazione per 30 minuti, la sospensione è stata raffreddata, il solido bianco ottenuto è stato filtrato ed essiccato in stufa sottovuoto ad una temperatura di 60*0. Sono stati o ttenuti 2,1 g di telmisartan Forma a. The strontium salt of telmisartan (2.3 g), obtained as described in example 1, in water (15 ml) was suspended in a three-necked flask, equipped with a stirrer, coolant and thermometer. The mixture was heated to about 80 ° C and a 37% HCl solution was added to acid pH. After having left under stirring for 30 minutes, the suspension was cooled, the white solid obtained was filtered and dried in a vacuum oven at a temperature of 60 ° C. 2.1 g of telmisartan Form a was taken.
Claims (9)
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19901921A1 (en) * | 1999-01-19 | 2000-08-03 | Boehringer Ingelheim Pharma | Polymorphs of telmisartan, process for their preparation and their use in the manufacture of a medicament |
| WO2006044648A1 (en) * | 2004-10-15 | 2006-04-27 | Teva Pharmaceutical Industries Ltd. | Process for preparing telmisartan |
| US20060276525A1 (en) * | 2005-05-18 | 2006-12-07 | Itai Adin | Processes of preparing highly pure telmisartan form A, suitable for pharmaceutical compositions |
| WO2009006860A2 (en) * | 2007-07-09 | 2009-01-15 | Zentiva A.S. | A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan) |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19901921A1 (en) * | 1999-01-19 | 2000-08-03 | Boehringer Ingelheim Pharma | Polymorphs of telmisartan, process for their preparation and their use in the manufacture of a medicament |
| WO2006044648A1 (en) * | 2004-10-15 | 2006-04-27 | Teva Pharmaceutical Industries Ltd. | Process for preparing telmisartan |
| US20060276525A1 (en) * | 2005-05-18 | 2006-12-07 | Itai Adin | Processes of preparing highly pure telmisartan form A, suitable for pharmaceutical compositions |
| WO2009006860A2 (en) * | 2007-07-09 | 2009-01-15 | Zentiva A.S. | A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan) |
Non-Patent Citations (1)
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| CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP001156954, ISSN: 0340-1022, ISBN: 978-3-540-36760-4, DOI: DOI:10.1007/3-540-69178-2_5 * |
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