SI20814A - Priprava amorfnega atorvastatina - Google Patents
Priprava amorfnega atorvastatina Download PDFInfo
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- SI20814A SI20814A SI200100010A SI200100010A SI20814A SI 20814 A SI20814 A SI 20814A SI 200100010 A SI200100010 A SI 200100010A SI 200100010 A SI200100010 A SI 200100010A SI 20814 A SI20814 A SI 20814A
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- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title claims abstract description 48
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229960005370 atorvastatin Drugs 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 19
- 159000000007 calcium salts Chemical class 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 12
- 150000002596 lactones Chemical class 0.000 claims description 11
- 239000002244 precipitate Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- -1 tert-amyl Chemical group 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims 8
- 238000010438 heat treatment Methods 0.000 claims 3
- 238000001035 drying Methods 0.000 claims 2
- 238000001914 filtration Methods 0.000 claims 2
- 238000002156 mixing Methods 0.000 claims 2
- 238000000926 separation method Methods 0.000 claims 2
- 238000005406 washing Methods 0.000 claims 2
- 230000003247 decreasing effect Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 230000000326 anti-hypercholesterolaemic effect Effects 0.000 abstract description 2
- 239000002775 capsule Substances 0.000 abstract description 2
- 239000000843 powder Substances 0.000 abstract description 2
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 abstract 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 abstract 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 239000006187 pill Substances 0.000 abstract 1
- 230000009466 transformation Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- UNMYWSMUMWPJLR-UHFFFAOYSA-L Calcium iodide Chemical compound [Ca+2].[I-].[I-] UNMYWSMUMWPJLR-UHFFFAOYSA-L 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- 229940046413 calcium iodide Drugs 0.000 description 1
- 229910001640 calcium iodide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Obesity (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Atorvastatin, substanca s kemijskim imenom hemi kalcijeva sol (R-(R*, R*))-2-(4-fluorofenil)-beta,delta-dihidroksi-5-(1-metiletil)-3- fenil-4((enilamino)karbonil)-1H-pirol-1-heptanojske kisline, ki je poznana kot inhibitor HMG-CoA reduktaze in se uporablja kot antihiperholesterolemik. Atorvastatin se vedno pripravlja v obliki kalcijeve soli, s katero se da pripraviti primerne farmacevtske formulacije kot na primer tablete, kapsule, praške in druge za oralno administracijo primerne oblike. Obstaja lahko v amorfni ali pa v eni od štirih (Form I, II, III in IV) kristaliničnih oblik. Atorvastatin je substanca, ki je v vodi zelo slabo topna, ugotovljeno pa je bilo, da so kristalinične oblike slabše topne od amorfne, kar lahko vpliva tudi na biorazpoložljivost atorvastatina v telesu. Predloženi izum se nanaša na nov postopek direktne pretvorbe intermediata v sintezi atorvastatina 44a ali 44 ali laktona atorvastatina v amorfen atorvastatin.ŕ
Description
LEK, tovarna farmacevtskih in kemičnih izdelkov, d.d.
Naziv izuma
Priprava amorfnega atorvastatina
C07D 207/34
Področje tehnike
Atorvastatin, substanca s kemijskim imenom hemi kalcijeva sol (R-(R*,R*))-2-(4fluorofenil)-p,0-dihidroksi-5-(1-metiletil)-3-fenil-4((enilamino)karbonil)-1 H-pirol-1 heptanojske kisline, je poznana kot inhibitor HMG-CoA reduktaze in se uporablja kot antihiperholesterolemik. Postopki za pripravo atorvastatina in ključnih intermediatov so opisan v seriji ameriških patentov US 5.003.080, US 5.097.045, US 5.103.024, US 5.124.482, US 5.149.837, US 5.155.251, US 5.216.174, US 5.245.047, US 5.248.793, US 5.280.126, US 5.342.952, US 5.397.792. Atorvastatin se vedno pripravlja v obliki kalcijeve soli, s katero se da pripraviti primerne farmacevtske formulacije kot na primer tablete, kapsule, praške in druge za oralno administracijo primerne oblike.
Atorvastatin obstaja lahko v amorfni ali pa v eni od štirih (Form I, II, III in IV) kristaliničnih oblik, ki so opisane v patentnih prijavah WO 97/3958 in WO 97/3959. Znano je, da se amorfne oblike številnih farmacevtskih učinkovin razlikujejo od kristaliničnih oblik v disolucijskih in biorazpoložljivostnih lastnostih (Konno T., Chem. Pharm. Buli., 1990;38;2003-2007). Biorazpoložljivost je za nekatere terapevtske indikacije eden ključnih parametrov po katerih se odločamo, kakšno obliko substance bomo uporabili v farmacevtski formulaciji. Glede na to, da so postopki kristalizacije oziroma priprave amorfne snovi včasih težko vodljivi in kot produkt nastajajo amorfnokristalinične mešanice oziroma kristalinična namesto amorfne oblike, obstaja stalna potreba po postopkih, ki bi omogočali pripravo amorfne oblike brez istočasne tvorbe kristaliničnih oblik, oziroma, ki bi omogočali pretvorbo kristaliničnih oblik v amorfno obliko.
Atorvastatin je substanca, ki je v vodi zelo slabo topna, ugotovljeno pa je bilo, da so kristalinične oblike slabše topne od amorfne, kar lahko povzroča probleme v biorazpoložljivost! atorvastatina v telesu. Za atorvastatin je bilo tudi ugotovljeno, da predhodno razkriti postopki za pripravo amorfnega atorvastatina niso konsistentno ponovljivi, zato je bil pripravljen postopek, ki je omogočal pretvorbo kristaliničnih oblik atorvastatina (ki so nastale pri sintezi atorvastatina) v amorfno obliko. Postopek je opisan v patentni prijavi WO 97/3960 in zaobsega raztapljanje kristaliničnega atorvastatina v ne-hidroksilnem topilu, ki ga nato odstranimo in dobimo amorfen atorvastatin. Kot prednostno uporabljeno ne-hidroksilno topilo je omenjen tetrahidrofuran in njegove mešanice s toluenom. Pomanjkljivost omenjenega postopka je predvsem uporaba okolju neprijaznih topil. Podoben postopek je opisan tudi v WO 00/71116, kjer v nehidroksilnem topilu, kot je na primer tetrahidrofuran, raztopijo kristaliničen atorvastatin, v raztopino atorvastatina dodajo nepolarno organsko topilo oziroma dodajo raztopino atorvastatina nepolarno organsko topilo, tako da se atorvastatin obori. Dobljeno oborino nato odfiltrirajo.
Sinteza atorvastatina je zahtevna in temu primerno visoka je tudi cena končnega proizvoda, zato poizkušamo v postopku priprave atorvastatina zminimalizirati število sinteznih stopenj in na ta način izboljšati izkoristek. Predloženi izum omogoča pretvorbo intermediata 44 oz. 44a, v amorfen atorvastatin, brez predhodne tvorbe lahktona in atorvastatina v obliki kristalov ali mešanice amorfne in kristalne oblike atorvastatina. Izum omogoča tudi pretvorbo atorvastatina v obliki laktona v amorfni atorvastatin brez vmesne tvorbe atorvastatina v obliki kristalov ali mešanice amorfne in kristalne oblike.
Predloženi izum se nanaša na nov postopek za direktno pripravo amorfnega atorvastatina iz intermediata 44 oziroma intermediata 44a (priprava intermediatov je opisana v EP 0 330 172 in WO 94/20492) brez predhodne transformacije le tega v lakton oziroma v atorvastatin v kristalinični obliki.
P
Ri in R2 sta lahko neodvisno vodik, alkil z enim do tremi ogljikovimi atomi, fenil, sli pa Ri in R2 skupaj tvorita (-CH2)n-, pri čemer je lahko n 4 ali 5. V kolikor sta Ri in R2 oba metil potem R3 ne predstavlja tert-butila.
R3 je lahko alkil z enim do osmimi ogljikovimi atomi ali tri do šest členska cikoalkilna skupina. R3 lahko predstavlja tert-butil, tert-amil ali α,α-dimetilbenzil. R3 lahko predstavlja tudi skupino s formulo:
A — N
R4 in R5 lahko neodvisno predstavljata
- alkil z enim do desetimi ogljikovimi atomi
- ciklopropil
- ciklobutil
- ciklopentil
- cikloheksil
- benzil ali fenil
- oziroma oziroma lahko skupaj tvorita
- -(CH2)4- -(CH2)5- -(CH(R6)-CH2)3- -(CH(R6)-CH2)4- -(CH(R6)-(CH2)2-CH(R6))- -(CH(R6)-(CH2)3-CH(R6))- -CH2-CH2-O-CH2-CH2- -CH(R6)-CH2-O-CH2-CH2- -CH(R6)-CH2-O-CH2-CH2(R6)pri čemer predstavlja R6 alkil z enim do štirimi ogljikovimi atomi pri čemer R4 in R5 ne smeta biti oba metil.
Omenjeni izum se nanaša tudi na postopek pretvorbe atorvastatina v obliki laktona v amorfno obliko atorvastatina.
Po postopku, ki je predmet tega izuma, raztopimo intermediat 44 ali 44a v 100 do 300 ml (maksimalno do koncentracije intermediata do 40 g/liter) nehidroksilnega topila, kot na primer tetrahidrofuranu, dodamo kislino, da odstranimo zaščite hidroksilnih skupin na stranski verigi (na mestih 3 in 5). Količina dodane kisline je v molarnem razmerju 0.0005:1 do 0.05:1 (za eno protonske kisline) z intermediatom 44 oz. 44a, prednostno v razmerju med 0.001:1 do 0.01:1. Dobljeno raztopino mešamo pri temperaturi med 5 in 40°C, prednostno pri sobni temperaturi, toliko časa da s tenkoplastno kromatografijo (TLC) ni več možno detektirati intermediata 44 oz. 44a. Nato v raztopino dodajamo bazo, da odstranimo zaščito karboksilne kisline (odstranitev tert-butila oz R3), dokler pH raztopine ni med 8 in 13, prednostno med 9 in 12. Dobljeno raztopino mešamo pri temperaturi med 5 in 40°C, prednostno pri sobni temperaturi, toliko časa da s tenkoplastno kromatografijo (TLC) ni več možno detektirati intermediata 45 oz. 45a.
R-ι, R2 in R3 so enaki, kot je že definirano predhodno.
Raztopino nato skoncentriramo (na primer vakuumsko odparimo) na volumen med 15 in 50% izhodiščnega volumna, prednostno na 1/4 izhodiščnega volumna. Skoncentrirano raztopino razredčimo na 1.5 do 3 kraten volumen z dodatkom vode. K temu dodamo za 1 do 5 kraten volumen dodane vode, prednostno 2 do 3 kraten volumen, topila, ki se z vodo slabo oziroma ne meša in atorvastatin v njem ni oziroma je slabo topen, kot na primer v heksan. Dobljeno raztopino intenzivno premešamo in fazi med seboj ločimo. Vodni fazi previdno med močni mešanjem dodajamo kislino do pH med 6.5 do 8, prednostno do pH med 6.8 in 7.5. Dobljeno raztopino segrejemo na temperaturo med 30 in 40°C, prednostno 35°C in ji med močnim mešanjem dodamo 0.05 do 0.5M, prednostno 0.1 do 0.3M, vodne raztopine kalcijeve soli, prednostno kalcijevega acetata, kalcijevega klorida ali kalcijevega jodida, s temperaturo med 30 in 40°C, prednostno 35°C. Količina dodane soli je v molarnem razmerju z intermediatom 44 oz. 44a med 1.1:1 do 1.5:1, prednostno med 1.13:1 do 1.135:1. Po končanem dodatku mešamo od 0.5 do 3 ure prednostno 1 uro pri temperaturi med 10 in 25°C, prednostno med 20 in 25°C. Dobljeno raztopino ohladimo na temperaturo 2 do 15°C, prednostno na 4 do 10°C. Izpadlo oborino nato odfiltriramo in speremo z vodo. Odfiltrirano oborino nato posušimo in dobimo atorvastatin v amorfni obliki.
Namesto z ohlajanjem raztopine lahko oborimo atorvastatin tudi z dodatkom organskega topila, ki se meša z vodo in v katerem je atorvastatin slabo oziroma ni topen. Možno je tudi obarjanje atorvastatina z koncentriranjem raztopine, na primer na vakuumskem uparjalniku.
V primeru, da je izhodna substanca atorvastatin v obliki laktona, raztopimo lakton v 100 do 300 ml nehidroksilnega topila, kot na primer tetrahidrofuranu, dodamo bazo, na primer NaOH, da odpremo laktonski obroč. Količina dodane baze je v molarnem razmerju 0.0005:1 do 0.051 z laktonom, prednostno v razmerju med 0.001:1 do 0.01:1. Dobljeno raztopino segrejemo na temperaturo 50°C in vzdržujemo na tej temperaturi toliko časa, da s TLC ni več možno detektirati laktonske oblike. V nadaljevanju raztopino skoncentriramo (na primer vakuumsko odparimo) na volumen med 15 in 50% izhodiščnega volumna, prednostno na 1/4 izhodiščnega volumna, nato nadaljujemo s postopkom enako kot v primeru priprave amorfne substance iz intermediatov 44 in 44a.
Predloženi izum prikazujejo, vendar v ničemer ne omejujejo naslednji primeri.
PRIMERI
Primer 1
4.37 g (0.0067 mol) spojine 44 raztopimo v 200 ml THF, dodamo 15 ml 10% HCI in raztopino mešamo pri sobni temperaturi 15 h. Dodamo 3.6 g (0.090 mol) trdnega NaOH in mešamo nadaljnjih 30 h. Skoncentriramo (vakuumsko odparimo) na 50 ml. Dolijemo 50 ml vode in 80 ml heksana. Fazi ločimo in vodni fazi previdno med močnim mešanjem dodajamo 5M HCI do Ph = 7.0-7.5. Raztopino segrejemo na 35°C in ji med mešanjem dolijemo raztopino 0.76 g (0.0043 mol) Ca(OAc)2 χ H2O v 20 ml vode, segreto na 35°C. Po končanem dodatku mešamo še 1h pri sobni temperaturi in nato postavimo v hladilnik za 2h. Izpadlo oborino odfiltriramo in speremo z vodo (2 x 20 ml). Posušimo na 40 st. C v času 18h, izoliramo 3.75 g amorfnega produkta (izkoristek je 95%).
LEK
Lek, tovarna tarna farmacevtskih ličnih izdelkov, d.d.
Claims (6)
1. Postopek za pripravo atorvastatina v amorfni obliki, ki zaobsega:
a) raztapljanje intermediata 44 ali 44a nehidroksilnem topilu pri čemer sta Ri in R2 lahko neodvisno vodik, alkil z enim do tremi ogljikovimi atomi, fenil, ali pa Ri in R2 skupaj tvorita (-CH2)n-, pri čemer je lahko n 4 ali 5; v kolikor sta Ri in R2 oba metil potem R3 ne predstavlja tert-butila;
R3 je lahko alkil z enim do osmimi ogljikovimi atomi ali tri do šest členska cikoalkilna skupina;
R3 lahko predstavlja tert-butil, tert-amil ali α,α-dimetilbenzil;
R3 lahko predstavlja tudi skupino s formulo:
R4 in R5 lahko neodvisno predstavljata
- alkil z enim do desetimi ogljikovimi atomi
- ciklopropil
- ciklobutil
- ciklopentil
- cikloheksil
- benzil ali fenil
- oziroma oziroma lahko skupaj tvorita
- -(CH2)4- -(CH2)5- -(CH(R6)-CH2)3- -(CH(R6)-CH2)4- -(CH(R6)-(CH2)2-CH(R6))-77
- -(CH(R6)-(CH2)3-CH(R6))- -CH2-CH2-O-CH2-CH2- -CH(R6)-CH2-O-CH2-CH2- -CH(R6)-CH2-O-CH2-CH2(R6)pri čemer predstavlja R6 alkil z enim do štirimi ogljikovimi atomi pri čemer R4 in R5 ne smeta biti oba metil,
b) dodajanje kisline in mešanje pri temperaturi med 5 in 40°C,
c) dodajanje baze do pH-ja raztopine med 8 in 13,
d) mešanje pri temperaturi med 5 in 40°C,
e) koncentriranje raztopine na 15 do 50% izhodiščnega volumna
f) dodajanje 1.5 do 3 kratnega volumna vode
g) dodajanje za 1 do 5 kraten volumen dodane vode topila, ki se z vodo slabo oziroma ne meša in atorvastatin v njem ni oziroma je slabo topen
h) mešanje in ločitev obeh faz
i) dodajanje kisline v vodno fazo do pH med 6.5 do 8
j) segrevanje raztopine na temperaturo med 30 in 40°C
k) dodajanje vodne raztopine kalcijeve soli s temperaturo med 30 in 40°C
l) mešanje pri temperaturi med 10 in 25°C
m) ohlajanje raztopine na temperaturo 2 do 15°C, da izpade oborina
n) filtriranje izpadle oborine in spiranje z vodo ter sušenje oborine, da dobimo amorfen atorvastatin.
2. Postopek po zahtevku 1, ki zaobsega namesto stopnje obarjanja z zniževanjem temperature obarjanje z dodatkom organskega topila, ki se meša z vodo in v katerem je atorvastatin slabo oziroma ni topen.
3. Postopek po zahtevku 1, ki zaobsega namesto stopnje obarjanja z zniževanjem temperature obarjanje s koncentriranjem raztopine.
4. Postopek za pripravo atorvastatina v amorfni obliki, ki zaobsega:
a) raztapljanje atorvastatina v obliki laktona v nehidroksilnem topilu
b) odpiranje laktonskega obroča z dodatkom baze in segrevanjem na 50°C
c) koncentriranje raztopine na 15 do 50% izhodiščnega volumna
d) dodajanje 1.5 do 3 kratnega volumna vode
e) dodajanje za 1 do 5 kraten volumen dodane vode topila, ki se z vodo slabo oziroma ne meša in atorvastatin v njem ni oziroma je slabo topen
f) mešanje in ločitev obeh faz
g) dodajanje kisline v vodno fazo do pH med 6.5 do 8
h) segrevanje raztopine na temperaturo med 30 in 40°C
i) dodajanje vodne raztopine kalcijeve soli s temperaturo med 30 in 40°C
j) mešanje pri temperaturi med 10 in 25°C
k) ohlajanje raztopine na temperaturo 2 do 15°C, da izpade oborina
l) filtriranje izpadle oborine in spiranje z vodo ter sušenje oborine, da dobimo amorfen atorvastatin.
5. Postopek po zahtevku 4, ki zaobsega namesto stopnje obarjanja z zniževanjem temperature obarjanje z dodatkom organskega topila, ki se meša z vodo in v katerem je atorvastatin slabo oziroma ni topen.
6. Postopek po zahtevku 4, ki zaobsega namesto stopnje obarjanja z zniževanjem temperature obarjanje s koncentriranjem raztopine.
Priority Applications (30)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200100010A SI20814A (sl) | 2001-01-23 | 2001-01-23 | Priprava amorfnega atorvastatina |
| CA002435954A CA2435954C (en) | 2001-01-23 | 2002-01-22 | Preparation of non-crystalline atorvastatin calcium |
| HR20030575A HRP20030575B1 (hr) | 2001-01-23 | 2002-01-22 | Preparacija nekristalnog atorvastatin kalcija |
| CNB028039688A CN1260213C (zh) | 2001-01-23 | 2002-01-22 | 非结晶阿托伐他汀钙的制备 |
| DK02734878T DK1373202T3 (da) | 2001-01-23 | 2002-01-22 | Fremstilling af ikke-krystallinsk atorvastatincalcium |
| DE60203894T DE60203894T2 (de) | 2001-01-23 | 2002-01-22 | Herstellung von nichtkristallinem atorvastatin?calcium |
| KR1020037009509A KR100882066B1 (ko) | 2001-01-23 | 2002-01-22 | 비결정 아토르바스타틴 칼슘의 제조방법 |
| EP02734878A EP1373202B1 (en) | 2001-01-23 | 2002-01-22 | Preparation of non-crystalline atorvastatin calcium |
| HU0302797A HU227535B1 (en) | 2001-01-23 | 2002-01-22 | Preparation of non-crystalline atorvastatin calcium |
| UA2003076436A UA73829C2 (en) | 2001-01-23 | 2002-01-22 | A method for the preparation of non-crystalline atorvastatin calcium and pharmaceutical composition |
| AT02734878T ATE294159T1 (de) | 2001-01-23 | 2002-01-22 | Herstellung von nichtkristallinem atorvastatin?calcium |
| MXPA03006548A MXPA03006548A (es) | 2001-01-23 | 2002-01-22 | Preparacion de atorvastatin de calcio no cristalino. |
| SK908-2003A SK286593B6 (sk) | 2001-01-23 | 2002-01-22 | Spôsob prípravy nekryštalickej vápenatej soli atorvastatínu |
| PCT/IB2002/000161 WO2002059087A1 (en) | 2001-01-23 | 2002-01-22 | Preparation of non-crystalline atorvastatin calcium |
| BR0206637-8A BR0206637A (pt) | 2001-01-23 | 2002-01-22 | Processo para preparação de atorvastatina em forma não cristalina e de formulação farmacêutica |
| ES02734878T ES2240748T3 (es) | 2001-01-23 | 2002-01-22 | Preparacion de atorvastatina de calcio no cristalina. |
| JP2002559389A JP4336106B2 (ja) | 2001-01-23 | 2002-01-22 | 非晶質アトルバスタチンカルシウムの調製 |
| IL15706802A IL157068A0 (en) | 2001-01-23 | 2002-01-22 | Preparation of non-crystalline atorvastatin calcium |
| AU2002219455A AU2002219455B2 (en) | 2001-01-23 | 2002-01-22 | Preparation of non-crystalline atorvastatin calcium |
| EEP200300333A EE05270B1 (et) | 2001-01-23 | 2002-01-22 | Mittekristallilise kaltsiumatorvastatiini valmistamismeetod |
| SI200230156T SI1373202T1 (sl) | 2001-01-23 | 2002-01-22 | Priprava nekristalnega atorvastatin kalcija |
| CZ20031988A CZ20031988A3 (cs) | 2001-01-23 | 2002-01-22 | Způsob přípravy nekrystalické vápenaté soli atorvastatinu |
| YUP-568/03A RS51010B (sr) | 2001-01-23 | 2002-01-22 | Pripremanje nekristalinskog atorvastatin-kalcijuma |
| PL361763A PL209428B1 (pl) | 2001-01-23 | 2002-01-22 | Sposób wytwarzania soli wapniowej atorwastatyny w postaci niekrystalicznej oraz sposób wytwarzania preparatu farmaceutycznego zawierającego sól wapniową atorwastatyny w postaci niekrystalicznej |
| RU2003124962/04A RU2324679C2 (ru) | 2001-01-23 | 2002-01-22 | Получение некристаллического аторвастатина кальция |
| US10/323,444 US6750353B2 (en) | 2001-01-23 | 2002-12-18 | Preparation of pharmaceutically acceptable atorvastatin salts in non-crystalline form |
| ZA200305307A ZA200305307B (en) | 2001-01-23 | 2003-07-09 | Preparation of non-crystalline at atorvastatin calcium. |
| BG108017A BG108017A (bg) | 2001-01-23 | 2003-07-22 | Пол"-аван... на н...кри''ал...н кал-и...в а'орва''а'ин |
| IL157068A IL157068A (en) | 2001-01-23 | 2003-07-23 | Preparation of non-crystalline atorvastatin calcium |
| US10/677,344 US7074940B2 (en) | 2001-01-23 | 2003-10-03 | Preparation of pharmaceutically acceptable atorvastatin salts in non-crystalline forms |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200100010A SI20814A (sl) | 2001-01-23 | 2001-01-23 | Priprava amorfnega atorvastatina |
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| SI20814A true SI20814A (sl) | 2002-08-31 |
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| SI200100010A SI20814A (sl) | 2001-01-23 | 2001-01-23 | Priprava amorfnega atorvastatina |
| SI200230156T SI1373202T1 (sl) | 2001-01-23 | 2002-01-22 | Priprava nekristalnega atorvastatin kalcija |
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| SI200230156T SI1373202T1 (sl) | 2001-01-23 | 2002-01-22 | Priprava nekristalnega atorvastatin kalcija |
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| Country | Link |
|---|---|
| US (2) | US6750353B2 (sl) |
| EP (1) | EP1373202B1 (sl) |
| JP (1) | JP4336106B2 (sl) |
| KR (1) | KR100882066B1 (sl) |
| CN (1) | CN1260213C (sl) |
| AT (1) | ATE294159T1 (sl) |
| AU (1) | AU2002219455B2 (sl) |
| BG (1) | BG108017A (sl) |
| BR (1) | BR0206637A (sl) |
| CA (1) | CA2435954C (sl) |
| CZ (1) | CZ20031988A3 (sl) |
| DE (1) | DE60203894T2 (sl) |
| DK (1) | DK1373202T3 (sl) |
| EE (1) | EE05270B1 (sl) |
| ES (1) | ES2240748T3 (sl) |
| HR (1) | HRP20030575B1 (sl) |
| HU (1) | HU227535B1 (sl) |
| IL (2) | IL157068A0 (sl) |
| MX (1) | MXPA03006548A (sl) |
| PL (1) | PL209428B1 (sl) |
| RS (1) | RS51010B (sl) |
| RU (1) | RU2324679C2 (sl) |
| SI (2) | SI20814A (sl) |
| SK (1) | SK286593B6 (sl) |
| UA (1) | UA73829C2 (sl) |
| WO (1) | WO2002059087A1 (sl) |
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| US6087511A (en) * | 1996-07-16 | 2000-07-11 | Warner-Lambert Company | Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid) calcium salt (2:1) |
| IN191236B (sl) * | 1999-05-25 | 2003-10-11 | Ranbaxy Lab Ltd |
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