HRP20040255A2 - Processes for preparing calcium salt forms of statins - Google Patents

Processes for preparing calcium salt forms of statins Download PDF

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HRP20040255A2
HRP20040255A2 HR20040255A HRP20040255A HRP20040255A2 HR P20040255 A2 HRP20040255 A2 HR P20040255A2 HR 20040255 A HR20040255 A HR 20040255A HR P20040255 A HRP20040255 A HR P20040255A HR P20040255 A2 HRP20040255 A2 HR P20040255A2
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statin
calcium
mixture
atorvastatin
protecting group
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Rami Lidor-Hadas
Revital Lifshitz-Liron
Valerie Niddam-Hildesheim
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Teva Pharma
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Publication of HRPK20040255B3 publication Critical patent/HRPK20040255B3/en

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Description

Reference srodnih prijava References of related applications

Ova prijava poziva se na privremenu prijavu Serial Number 60/312,812, predano 16. 8. 2001. i patentnu prijavu U. S. Patent Application Serial No. 10/037,412, predano 24. 10. 2001. koja se poziva na privremenu prijavu Serial Number 60/249,319, predano 16. 11. 2000., koje su sve ovdje uključene putem reference. This application claims provisional application Serial Number 60/312,812, filed on August 16, 2001, and U.S. Patent Application Serial No. 10/037,412, filed 10/24/2001, which refers to provisional application Serial Number 60/249,319, filed 11/16/2000, all of which are incorporated herein by reference.

Područje izuma Field of invention

Predmetni izum odnosi se na postupke za preparaciju statina u formi kalcijeve soli. The present invention relates to methods for the preparation of statins in the form of calcium salts.

Pozadina izuma Background of the invention

Klasa lijekova nazvanih statini trenutačno su terapeutski najviše efikasni lijekovi na raspolaganju za snižavanje koncentracije čestica lipoproteina niske gustoće (LDL) u krvotoku pacijenata s rizikom kardiovaskularnog oboljenja i tako se statini primjenjuju za liječenje hiperkolesterolemije, hiperlipoproteinemije i ateroskleroze. Visoka razina LDL u krvotoku povezana je s nastajanjem koronarnih oštećenja koja ometaju protok krvi i mogu se probušiti i pokrenuti trombozu. Goodman and Gilman, The Pharmacological Basis of Therapeutics, stranica 879 (9th Ed. 1996). A class of drugs called statins are currently the most therapeutically effective drugs available for lowering the concentration of low-density lipoprotein (LDL) particles in the bloodstream of patients at risk of cardiovascular disease, and thus statins are used to treat hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis. A high level of LDL in the bloodstream is associated with the formation of coronary lesions that impede blood flow and can rupture and initiate thrombosis. Goodman and Gilman, The Pharmacological Basis of Therapeutics, page 879 (9th Ed. 1996).

Statini inhibiraju biosintezu kolesterola kod ljudi kompetitivnom inhibicijom enzima 3-hidroksi-3-metil-glutaril-koenzim A ("HMG-CoA") reduktaza. HMG-CoA reduktaza katalizira konverziju HMG u mevalonat što je korak koji određuje brzinu pri biosintezi kolesterola. Smanjena proizvodnja kolesterola uzrokuje povećanje broja LDL receptora i odgovarajuće smanjenje koncentracije LDL čestica u krvotoku. Smanjenje razine LDL u krvotoku smanjuje rizik oboljenja koronarnih arterija. J. A. M. A. 1984, 251, 351-74. Statins inhibit cholesterol biosynthesis in humans by competitively inhibiting the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A ("HMG-CoA") reductase. HMG-CoA reductase catalyzes the conversion of HMG to mevalonate, which is the rate-determining step in cholesterol biosynthesis. Reduced cholesterol production causes an increase in the number of LDL receptors and a corresponding decrease in the concentration of LDL particles in the bloodstream. Reducing the level of LDL in the bloodstream reduces the risk of coronary artery disease. J.A.M.A. 1984, 251, 351-74.

Trenutačno su na raspolaganju statini koji uključuju lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin i atorvastatin. Lovastatin (iznesen u U. S. Pat. No. 4,231, 938) i simvastatin (ZOCOR; iznesen u U.S. Pat. No. 4,444, 784 i WO 00/53566) daju se u obliku laktona. Nakon apsorpcije laktonski prsten se otvara u jetri uslijed kemijske ili enzimatske hidrolize i dobiva se aktivna hidroksi kiselina. Statins currently available include lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, and atorvastatin. Lovastatin (disclosed in U.S. Pat. No. 4,231, 938) and simvastatin (ZOCOR; disclosed in U.S. Pat. No. 4,444, 784 and WO 00/53566) are administered as lactones. After absorption, the lactone ring is opened in the liver as a result of chemical or enzymatic hydrolysis and an active hydroxy acid is obtained.

Pravastatin (PRAVAKOL; iznesen u U.S. Pat. No. 4,346, 227) daje se kao natrijeva sol. Fluvastatin (LESCOL; iznesen u U.S. Pat. No, 4,739, 073) i cerivastatin (iznesen u U.S. Pat. No. 5,006, 530 i 5,177, 080), također se daju kao natrijeva sol, su u potpunosti sintetički spojevi koji se u dijelu strukturalno razlikuju od gljivičnih derivata ove klase koji sadrže heksahidronaftalenski prsten. Atorvastatin i dva nova "superstatina", rosuvastatin i pitavastatin, daju se kao kalcijeve soli. Strukturne formule ovih statina prikazane su dolje Pravastatin (PRAVAKOL; disclosed in U.S. Pat. No. 4,346, 227) is provided as the sodium salt. Fluvastatin (LESCOL; disclosed in U.S. Pat. No. 4,739,073) and cerivastatin (disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080), also provided as the sodium salt, are fully synthetic compounds that are partially they are structurally different from fungal derivatives of this class that contain a hexahydronaphthalene ring. Atorvastatin and two new "superstatins", rosuvastatin and pitavastatin, are given as calcium salts. The structural formulas of these statins are shown below

[image] [image]

[image] [image]

Atorvastatin je uobičajeni kemijski naziv za [R-(R*,R*)]-2–(4-fluorfenil)-β,δ-dihidroksi-5-(1-metiletil)-3-fenil-4-[(fenilamino)karbonil]-1H-pirol-1-heptansku kiselinu. Slobodna kiselina atorvastatina podložna je laktonizaciji. Sistematski kemijski naziv atorvastatin laktona je (2R-trans)-5-(4-fuorfenil)-2-(1-metiletil)-N,4-difenil-1-[tetrahidro-4-hidroksi-okso-2H-piran-2-il)etil-1H-pirol-3-karboksamid, Atorvastatin i njegov odgovarajući racemični lakton izneseni su U. S. Patent No. 4,681,893. Atorvastatin is the common chemical name for [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid. The free acid of atorvastatin is subject to lactonization. The systematic chemical name of atorvastatin lactone is (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[tetrahydro-4-hydroxy-oxo-2H-pyran-2 -yl)ethyl-1H-pyrrole-3-carboxamide, Atorvastatin and its corresponding racemic lactone are disclosed in U.S. Patent No. 4,681,893.

Laktonski oblik iznesen u U.S. Patent No. 5,273,995 U primjerima 4 i 5 '995 patenta, lakton se priređuje otapanjem 1,1-dimetiletil (R)-7-[2-(4-fluorfenil)-5-(1-metiletil)-3-fenil-4-[(fenilamino) karbonil]-1H-pirol-1-il]-5-hidroksi-3-okso-1-heptanoata u tetrahidrofuranu ili trietilboranu, nakon čega slijedi dodavanje t-butilkarboksilne kiseline. Nakon hlađenja dodaje se metanol pa natrijev borhidrid. Smjesa se ulije u smjesu led / vodik peroksid / voda. Doda se triklormetan i smjesa razdijeli. Organski sloj se osuši iznad magnezijevog sulfata, filtrira i otapalo upari. Produkt se otopi u tetrahidrofuranu i metanolu te doda u otopinu natrij hidroksida. Smjesa se koncentrira da se ukloni organsko otapalo, doda u vodu i ekstrahira dietil eterom. Vodeni sloj se aakiseli kloridnom kiselinom i ekstrahira etilacetatorn. Organski sloj se osuši iznad magnezijevog sulfata, filtrira i otapalo upari. Ostatak se otopi u toluenu i koncentrira. Produkt se prekristalizira iz etilacetata i heksana da se dobije lakton. The lactone form reported in the U.S. Patent No. 5,273,995 In Examples 4 and 5 of the '995 patent, the lactone is prepared by dissolving 1,1-dimethylethyl (R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[( phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoate in tetrahydrofuran or triethylborane, followed by the addition of t-butylcarboxylic acid. After cooling, methanol and sodium borohydride are added. The mixture is poured into the ice / hydrogen peroxide / water mixture. Trichloromethane is added and the mixture is partitioned. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated. The product is dissolved in tetrahydrofuran and methanol and added to the sodium hydroxide solution. The mixture is concentrated to remove the organic solvent, added to water and extracted with diethyl ether. The aqueous layer is acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated. The residue was dissolved in toluene and concentrated. The product is recrystallized from ethyl acetate and hexane to give the lactone.

Lakton se također može prirediti prema postupku iznesenom u U.S. Patent No. 5,003,080. Na primjer, u primjeru 2, postupak A, cis-2-(4-fuorfenil)-β,δ-dihidroksi-5-(1-metiletil)-3-fenil-4-[(fenilamino)karbonil]-1H-pirol-1-heptanska kiselina, metil ester se obradi natrij hidroksidom i nakon razrjeđivanja vodom i odvajanja, preostali sloj se ispere heksanom i etilacetatom, nakon čega slijedi koncentrirana otopina kloridne kiseline. Nakon odvajanja, gornji sloj se ispere koncentriranom kloridnom kiselinom i koncentrira. Ostatak se otopi u toluenu. The lactone can also be prepared according to the procedure set forth in U.S. Pat. Patent No. 5,003,080. For example, in Example 2, Process A, cis-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole The -1-heptanoic acid, methyl ester is treated with sodium hydroxide and after dilution with water and separation, the remaining layer is washed with hexane and ethyl acetate, followed by concentrated hydrochloric acid solution. After separation, the upper layer is washed with concentrated hydrochloric acid and concentrated. The residue is dissolved in toluene.

Kao što je izneseno u '080 patentu, lakton se također može prirediti miješanjem (±)-cis-6-(2-aminoetil)-2,2-dimetil-1,3-dioksan-4-octene kiseline (Primjer 2, postupak B); (±)-(2α,4α, 6α) ili (±)-(2α,4β,6β)-6-(2-aminoetil)-2-fenil-1,3-dioksan-4-octene kiseline (Primjer 2, postupak C); (±)-cis-9-(2-aminoetil)-6,10-dioksaspiro[4.5]dekan-7-octene kiseline (Primjer 2, postupak D); (±)-cis-4-(2-aminoetil)-1,5-dioksaspiro[5.5]undekan-7-octene kiseline (Primjer 2, postupak E); ili (±)-(2α,4α,6α) ili (±)-(2α,4β, β)-6-(2-aminoetil)-2-raetil-1,3-dioksan-4-octene kiseline (Primjer 2, postupak F i G) s (±)-4-fluor-α-[2-metil-1-oksopropil]-γ-okso-N,β-difeniIbenzenbutanamidom u dimetil sulfoksidu. Nakon zagrijavanja, otopina se ulije u smjesu dietiletera i zasićene otopine amonijevog klorida u vodi. Nakon odvajanja, organski sloj se ispere vodom i natrijevim hidroksidom. Vodeni sloj se zakiseli razrjeđenom kloridnom kiselinom i ekstrahira etilacetatom u koji je dodana kloridna kiselina te se otopina koncentrira. Ostatak se otopi u toluenu. As set forth in the '080 patent, the lactone can also be prepared by mixing (±)-cis-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid (Example 2, procedure B); (±)-(2α,4α, 6α) or (±)-(2α,4β,6β)-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetic acid (Example 2, procedure C); (±)-cis-9-(2-aminoethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid (Example 2, procedure D); (±)-cis-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-7-acetic acid (Example 2, procedure E); or (±)-(2α,4α,6α) or (±)-(2α,4β, β)-6-(2-aminoethyl)-2-ethyl-1,3-dioxane-4-acetic acid (Example 2 , procedure F and G) with (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutanamide in dimethyl sulfoxide. After heating, the solution is poured into a mixture of diethyl ether and a saturated solution of ammonium chloride in water. After separation, the organic layer is washed with water and sodium hydroxide. The aqueous layer is acidified with dilute hydrochloric acid and extracted with ethyl acetate to which hydrochloric acid has been added, and the solution is concentrated. The residue is dissolved in toluene.

Drugi postupak za pripremu laktona, prema '080 patentu, uključuje miješanje (±)-cis-1,1-dimetil-6-(2-aminoetil)-2,2-dimetil-1,3-dioksan-4-acetata (Primjer 2, postupak H); (±)-(2α,4α,6α) ili (±)-(2α,4β,6β)-6-(2-aminoetil)-2-fenil-1,3-dioksan-4-acetata (Primjer 2, postupak I); ili (±)-cis-1,1-dimetiletil-(4-(2-aminoetil)-1,5-dioksaspiro[5,5]undekan-2-acetata (Primjer 2, postupak J) s (±)-4-fluor-α-[2-metil-1-oksopropil]-γ-okso-N,β-difenilbenzenbutanamidom u smjesi heptan : toluen (9:1). Nakon zagrijavanja, otopina se ulije u smjesu tetrahidrofurana i otopine amonijevog klorida u vodi. Nakon odvajanja, organski sloj se ispere slanom vodom, nakon čega slijedi dodavanje kloridne kiseline. Nakon miješanja, u organski sloj se doda natrij hidroksid. Reakcija se zaustavlja dodavanjem smjese vode i heksana. Nakon odvajanja, vodeni sloj se zakiseli razrjeđenom kloridnom kiselinom, ekstrahira etilacetatom i koncentrira. Ostatak se otopi u toluenu. Another process for preparing lactones, according to the '080 patent, involves mixing (±)-cis-1,1-dimethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (Example 2, procedure H); (±)-(2α,4α,6α) or (±)-(2α,4β,6β)-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetate (Example 2, procedure AND); or (±)-cis-1,1-dimethylethyl-(4-(2-aminoethyl)-1,5-dioxaspiro[5,5]undecane-2-acetate (Example 2, procedure J) with (±)-4 -fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutanamide in a mixture of heptane : toluene (9:1). After heating, the solution is poured into a mixture of tetrahydrofuran and ammonium chloride solution in water . After separation, the organic layer was washed with brine, followed by the addition of hydrochloric acid. After stirring, sodium hydroxide was added to the organic layer. The reaction was quenched by adding a mixture of water and hexane. After separation, the aqueous layer was acidified with dilute hydrochloric acid, extracted ethyl acetate and concentrated.The residue was dissolved in toluene.

Lakton ili slobodna kiselina mogu se koristiti za pripremu farmaceutski prihvatljive kalcijeve soli, [R-(R*,R*)]-2-(4-fluorfenil)-β,δ-dihidroksi-5-(1-metiletil)-3-fenil-4-[(fenilamino)karbonil]-1H-pirol-1-heptanska kiselina kalcijeva sol (2 : 1) trihidrata. U životinjskim modelima pokazano je da atorvastatin kalcijeva sol snižava razine kolesterola i lipoproteina u plazmi inhibicijom HMG-CoA reduktaze i sinteze kolesterola u jetri. Atorvastatin na tržištu nudi PFIZER kao hemikalcijevu sol trihidrat pod imenom LIPITOR kao tablete od 10, 20, 40 i 80 mg. Atorvastatin hemiklacijeva sol ima sljedeću strukturu: The lactone or free acid can be used to prepare the pharmaceutically acceptable calcium salt, [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) trihydrate. In animal models, atorvastatin calcium salt has been shown to lower plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver. Atorvastatin is offered on the market by PFIZER as hemicalcium salt trihydrate under the name LIPITOR as tablets of 10, 20, 40 and 80 mg. Atorvastatin hemiclation salt has the following structure:

[image] [image]

Hemikalcijeva sol iznesena je u patentu U.S. Patent No, 5,273,995 koji podučava da se kalcijeva sol dobiva kristalizacijom iz slane otopine nastale nadomještanjem natrijeve soli kalcijevim kloridom i dalje pročišćavanjem prekristalizacijom iz 5 : 3 smjese etilacetata i heksana. The hemicalcium salt is disclosed in U.S. Pat. Patent No, 5,273,995 which teaches that the calcium salt is obtained by crystallization from a salt solution formed by replacing the sodium salt with calcium chloride and further purification by recrystallization from a 5:3 mixture of ethyl acetate and hexane.

U.S. Patent No. 5,298,627 također iznosi postupak za pripremu hemiklacijeve soli. U primjeru l ovog patenta, (4R-cis)-1-[2-[6-[2-(difenilamino)-2-oksoetil]-2,2-dimetil-1,3-okaan-4-il]etil]-5-(4-fluorfenil)-2-(1-metiletil)-N,4-difenil-1H-pirol-3-karboksamid se otopi u metanolu i reagira s kloridnom kiselinom da nastane [R-(R*,R*)]-5-(4-fluorfenil)-β,δ-dihidroksi-2-(1-metiletil)-N,N,4-trifenil-3-[(fenilamino)karbonil]-1H-pirol-1-heptanamid, koji se miješa s metanolom i natrij hidroksidom, Filtrat se ispere terc-butilmetil esterom te se vodeni sloj zakiseli primjenom kloridne kiseline i ekstrahira terc-butilmetil esterom da nastane natrijeva sol [R-(R*,R*)]-2-(4-fluorfenil)-β,δ-dihidroksi-5-(1-metiletil)-3-fenil-4-[(fenilamino) karbonil]-1H-pirol-1-heptanske kiseline. Natrijeva sol se prevodi u hemikalcijevu sol dodavanjem kalcijevog acetata u vodi. LOUSE. Patent No. 5,298,627 also discloses a process for the preparation of a hemiclation salt. In Example 1 of this patent, (4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2-dimethyl-1,3-ocan-4-yl]ethyl] -5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide is dissolved in methanol and reacted with hydrochloric acid to form [R-(R*,R* )]-5-(4-fluorophenyl)-β,δ-dihydroxy-2-(1-methylethyl)-N,N,4-triphenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamide, which is mixed with methanol and sodium hydroxide, the filtrate is washed with tert-butylmethyl ester and the aqueous layer is acidified using hydrochloric acid and extracted with tert-butylmethyl ester to form the sodium salt [R-(R*,R*)]-2-(4 -fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid. The sodium salt is converted to hemicalcium salt by adding calcium acetate to water.

U analognom postupku, (4R-cis)-6-(2-aminoetil)-2,2-dimetil-N,N-bis(fenilmetil)-1,3-dioksan-4-acetatamid se pretvara u [R-(R*, R*)]-5-(4 -fluorfenil)-β,δ-dihidroksi-2-(1-metiletil)-4-fenil-3-[(fenilamino)karbonil]-N,N-bis(fenilmetil)-1H-pirol-1-heptanamid koji se dalje pretvara u hemikalcijevu sol (primjer 2). (4R-cis)-6-(2-aminoetil)-N,N-dietil-2,2-dimetil-1,3-dioksan-4-acetatamid se pretvara u [R-(R*,R*)]-N,N-dietil-5-(4-fluorfenil)-β,δ-dihidroksi-2-(1-metiletil)-4-fenil-3-[(fenilamino) karbonil]-N,N-bis(fenilmetil)-1H-pirol-1-heptanamid koji se dalje pretvara u hemikalcijevu sol (primjer 3); (4R-cis)-6-(2-aminoetil)-N-butil-N,2,2-trimetil-1,3-dioksan-4-acetatamid se pretvara u [R-(R*,R*)]-N-butil-5-(4-fluorfenil)-β,δ-dihidroksi-N-metil-2-(1-metiletil)-4-fenil-3-[(fenilamino)karbonil]-1H-pirol-1-heptanamid koji se dalje pretvara u hemikalcijevu sol (primjer 4); (4R-cis)-6-(2-aminoetil)-N-(1,1-dimetiletil)-2,2-dimetil-N-(fenilmetil)-1,3-dioksan-4-acetatamid se pretvara u [R-(R*,R*)]-N-(1,1-dimetiletil)-5-(4-fluorfenil)-β,δ-dihidroksi-2-(1-metiletil)-4-fenil-3-[(fenilamino)karbonil]-N-(fenilmetil)-1H-pirol-1-heptanamid koji se dalje pretvara u hemikalcijevu sol (primjer 5); i (4R-cis)-1-[[6-(2-aminoetil)-2,2-dimetil-1,3-dioksan-4-il]acetil]piperidin se pretvara u [R-(R*,R*)]-1-[3,5-dihidroksi-7-okso-7-(1-piperidinil)heptil]-5-(4-fluorfenil)-2-(1-metiletil)-N-4-difenil-1H-pirol-3-karboksamid koji se dalje pretvara u hemikalcijevu sol (primjer 6). In an analogous procedure, (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide is converted to [R-(R *, R*)]-5-(4 -fluorophenyl)-β,δ-dihydroxy-2-(1-methylethyl)-4-phenyl-3-[(phenylamino)carbonyl]-N,N-bis(phenylmethyl) -1H-pyrrole-1-heptanamide which is further converted into hemicalcium salt (example 2). (4R-cis)-6-(2-aminoethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide is converted to [R-(R*,R*)]- N,N-diethyl-5-(4-fluorophenyl)-β,δ-dihydroxy-2-(1-methylethyl)-4-phenyl-3-[(phenylamino)carbonyl]-N,N-bis(phenylmethyl)- 1H-pyrrole-1-heptanamide which is further converted into hemicalcium salt (example 3); (4R-cis)-6-(2-aminoethyl)-N-butyl-N,2,2-trimethyl-1,3-dioxane-4-acetamide is converted to [R-(R*,R*)]- N-butyl-5-(4-fluorophenyl)-β,δ-dihydroxy-N-methyl-2-(1-methylethyl)-4-phenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamide which is further converted into hemicalcium salt (example 4); (4R-cis)-6-(2-aminoethyl)-N-(1,1-dimethylethyl)-2,2-dimethyl-N-(phenylmethyl)-1,3-dioxane-4-acetamide is converted to [R -(R*,R*)]-N-(1,1-dimethylethyl)-5-(4-fluorophenyl)-β,δ-dihydroxy-2-(1-methylethyl)-4-phenyl-3-[( phenylamino)carbonyl]-N-(phenylmethyl)-1H-pyrrole-1-heptanamide which is further converted into the hemicalcium salt (Example 5); and (4R-cis)-1-[[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetyl]piperidine is converted to [R-(R*,R* )]-1-[3,5-dihydroxy-7-oxo-7-(1-piperidinyl)heptyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N-4-diphenyl-1H- pyrrole-3-carboxamide which is further converted into hemicalcium salt (example 6).

Rosuvastatin je uobičajeni kemijski naziv za [S-[R*,S*-(E)]-7-[4-(4-fluorfenil)-6-(1-metiletil)-2-[metil(metilsulfonil)amino]-5-pirimidinil]-3-5-dihidroksi-6-heptensku kiselinu. Rosuvastatin je u postupku odobravanja za tržište, pod imenom CRESTOR koji sadrži rosuvastatin kalcij. Rosuvastatin, njegova kalcijeva sol (2 : 1) i njegov laktonski oblik izneseni su u patentu U.S. Patent No. 5,260,440. Postupak '440 patenta priprema rosuvastatin reakcijom 4-(4-fluorfenil)-6-izopropil-2-(N-metil-N-metilsulfonil)amino]-5-pirimidinkarbardehida s metil (3R)-3-(terc-butildimetilsililoksi)-5-okso-6-trifenilfosforaniliden heksanatom u acetonitril uz refluks. Sililna skupina se onda cijepa fluorvodikom nakon čega slijedi redukcija pomoću NaBH4 da se dobij e metilni ester rosuvastatina. Rosuvastatin is the common chemical name for [S-[R*,S*-(E)]-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]- 5-pyrimidinyl]-3-5-dihydroxy-6-heptenoic acid. Rosuvastatin is in the process of approval for the market, under the name CRESTOR, which contains rosuvastatin calcium. Rosuvastatin, its calcium salt (2:1) and its lactone form are disclosed in U.S. Pat. Patent No. 5,260,440. The '440 patent process prepares rosuvastatin by reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl)amino]-5-pyrimidinecarbaldehyde with methyl (3R)-3-(tert-butyldimethylsilyloxy)- 5-oxo-6-triphenylphosphoranylidene with hexane in acetonitrile under reflux. The silyl group is then cleaved with hydrogen fluoride followed by reduction with NaBH4 to give rosuvastatin methyl ester.

Ester se onda hidrolizira natrijevim hidroksidom u etanolu pri sobnoj temperaturi, nakon čega slijedi uklanjanje etanola i dodavanje etera da se dobije natrijeva sol rosuvastatina. Natrijeva sol se otopi u vodi i održava u atmosferi dušika. Onda se doda kalcijev klorid u otopinu što dovodi do taloženja rosuvastatin kalcija (2 : 1). Stoga postupak '440 patenta priprema rosuvastatin kalcij preko natrijeva sol intermedijera. The ester is then hydrolyzed with sodium hydroxide in ethanol at room temperature, followed by removal of the ethanol and addition of ether to give the sodium salt of rosuvastatin. The sodium salt is dissolved in water and maintained in a nitrogen atmosphere. Then calcium chloride is added to the solution, which leads to precipitation of rosuvastatin calcium (2:1). Therefore, the process of the '440 patent prepares rosuvastatin calcium via a sodium salt intermediate.

U.S. Patent No. 6,316,460 iznosi farmaceutsku kompoziciju rosuvastatina. Farmaceutske kompozicije sadrže rosuvastatin ili njegovu sol i viševalentu tribazičnu fosfatnu sol. '460 patent ne iznosi postupke za pripremu kalcijeve soli rosuvastatina. LOUSE. Patent No. 6,316,460 is a pharmaceutical composition of rosuvastatin. Pharmaceutical compositions contain rosuvastatin or its salt and a multivalent tribasic phosphate salt. The '460 patent does not disclose procedures for preparing the calcium salt of rosuvastatin.

Pitavastatin je uobičajeni kemijski naziv za (E)-3,5-dihidroksi-7-[4'-(4''-fluorfenil)-2'-ciklopropil-kinolin-3'-il]-hept-6-enska kiselina. Pitavastatin, njegova kalcijeva sol (2 : 1) i njegov laktonski oblik izneseni su u patentima U.S. Patent No. 5,011,930, 5,856,336 i 5,872,130. Pitavastatin is the common chemical name for (E)-3,5-dihydroxy-7-[4'-(4''-fluorophenyl)-2'-cyclopropyl-quinolin-3'-yl]-hept-6-enoic acid. Pitavastatin, its calcium salt (2:1) and its lactone form are disclosed in U.S. Pat. Patent No. 5,011,930, 5,856,336 and 5,872,130.

'930 patent priprema pitavastatin etil ester u skladu s primjerom 1. Prvo se 4-(4'-fluorfenil)-2'-(1'-ciklopropil)-kinolin-3'-il]-karboksilat pripremi reakcijom 2-amino-4'-fluorbenzofenona s etil i zobutirilacetatom koji se onda pretvara u 4-(4'-fluorfenil)-3-hidroksimetil-2-(1'-ciklopropil)-kinolin koji se pretvara u 4-4'-fluorfenil-2-(1'-ciklopropil)-kinolin-3'-il-karboksialdehid koji se pretvara u 3-(3'-etoksi-1'-hidroksi-2'-propenil)-4-(4'-fluorfenil)-2'-(1'-ciklopropil)-kinolin koji se pretvara u (E)-3-[4'-(4"-fluorfenil)-2'-(1-ciklopropil-kinolin-3'-il]propenaldehid koji se pretvara u etil (E)-7-[4-(4''-fluorfenil)-2'-(1''-ciklopropil)-kinolin-3'-il]-5-hidroksi-3-oksohepto-6-enoat koji se pretvara u etil (E)-3,5-dihidroksi-7-[4'-(4"-fluorfenil)-2'-(1''-ciklopropil)-kinolin-3'-il]-hept-6-enoat. The '930 patent prepares pitavastatin ethyl ester in accordance with Example 1. First, 4-(4'-fluorophenyl)-2'-(1'-cyclopropyl)-quinolin-3'-yl]-carboxylate is prepared by reacting 2-amino-4 of '-fluorobenzophenone with ethyl and zobutyryl acetate which is then converted to 4-(4'-fluorophenyl)-3-hydroxymethyl-2-(1'-cyclopropyl)-quinoline which is converted to 4-4'-fluorophenyl-2-(1 '-cyclopropyl)-quinolin-3'-yl-carboxyaldehyde which is converted to 3-(3'-ethoxy-1'-hydroxy-2'-propenyl)-4-(4'-fluorophenyl)-2'-(1 '-cyclopropyl)-quinoline which is converted to (E)-3-[4'-(4"-fluorophenyl)-2'-(1-cyclopropyl-quinolin-3'-yl]propenaldehyde which is converted to ethyl (E )-7-[4-(4''-fluorophenyl)-2'-(1''-cyclopropyl)-quinolin-3'-yl]-5-hydroxy-3-oxohepto-6-enoate which is converted to ethyl (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-(1"-cyclopropyl)-quinolin-3'-yl]-hept-6-enoate.

Nastali ester, etil (E)-3,5-dihidroksi-7-[4'-(4"-fluorfenil)-2'-(1"-ciklopropil)-kinolin-3'-il]-hept-6-enoat, pretvara se u natrijevu sol u skladu s primjerom 2 primjenom vodene otopine natrij hidroksida. Spoj se otopi u etanolu u što se dodaj e vodena otopina natrij hidroksida. Nastala smjesa se miješa i etanol se ukloni pod sniženim pritiskom. Onda se doda voda i smjesa dalje ekstrahira eterom. Vodeni sloj se liofilizira da se dobije konačni produkt, ili vodeni sloj se slabo zakiseli razrjeđenom otopinom kloridne kiseline. Zakiseljeni vodeni sloj se onda ekstrahira eterom. Nakon ekstrakcije eterski sloj se osuši iznad magnezijevog sulfata. Onda se eter ukloni pod sniženim pritiskom da se dobije natrijeva sol. '930 patent i njegovi srodni patenti ne iznose postupke za pripremu kalcijeve soli bilo kojeg spoja. The resulting ester, ethyl (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-(1"-cyclopropyl)-quinolin-3'-yl]-hept-6-enoate , is converted into a sodium salt in accordance with example 2 using an aqueous solution of sodium hydroxide. The compound is dissolved in ethanol to which an aqueous solution of sodium hydroxide is added. The resulting mixture is stirred and the ethanol is removed under reduced pressure. Then water is added and the mixture is further extracted with ether. The aqueous layer is lyophilized to give the final product, or the aqueous layer is slightly acidified with dilute hydrochloric acid solution. The acidified aqueous layer is then extracted with ether. After extraction, the ether layer is dried over magnesium sulfate. The ether is then removed under reduced pressure to give the sodium salt. The '930 patent and its related patents do not disclose processes for preparing the calcium salt of any compound.

Ovi patenti pripremaju lakton otapanjem natrijeve soli pripremljene u suhom toluenu, zagrijavanjem otopine uz refluks i uklanjanjem toluena pod sniženim pritiskom. Sirova krutina se onda prekristalizira iz diizopropil etera da se dobije lakton, [4'-(4"-fluorfenil)-2 -(1''-metiletil)-kinolin-3'-iletinil]-4-hidroksi-3,4,5,6–tetrahidro-2H-piran-2-on. Lakton se dalje reducira pomoću paladija/ugljik u atmosferi dušika. These patents prepare the lactone by dissolving the sodium salt prepared in dry toluene, heating the solution to reflux, and removing the toluene under reduced pressure. The crude solid is then recrystallized from diisopropyl ether to give the lactone, [4'-(4"-fluorophenyl)-2-(1''-methylethyl)-quinolin-3'-ylethynyl]-4-hydroxy-3,4, 5,6-Tetrahydro-2H-pyran-2-one The lactone is further reduced using palladium/carbon under a nitrogen atmosphere.

U.S. Patent No. 6,335,449 poboljšava postupak prethodnog rada za preparaciju pitavastatina reakcijom aldehid kinolina dietil cijanometilfosfonatom da se dobije nitrilni intermedijer za sintezu pitavastatina. U.S. Patent No. 6,335,449 ne iznosi kako se preparira kalcijeva sol ili bilo koja druga sol pitavastatina. LOUSE. Patent No. 6,335,449 improves the procedure of the previous work for the preparation of pitavastatin by reacting aldehyde quinoline with diethyl cyanomethylphosphonate to obtain a nitrile intermediate for the synthesis of pitavastatin. LOUSE. Patent No. 6,335,449 does not disclose how to prepare the calcium salt or any other salt of pitavastatin.

Simvastatin je uobičajeni medicinski naziv za kemijski spoj butanska kiselina, 2,2-dimetil-1,2,3,7,8,8a-heksahidro-3,7-dimetil-8-[2-(tetrahidro-4-hidroksi-6-okso-2H-piran-2-il)-etil]-naftalenil eater, [1S-[1a,3a,7b,8b(2S*,4S),8ab]]. (GAS Registry No. 79902-63-9.). Simvastatin se nalazi na tržištu kao ZOCOR i iznesen je u patentima U. S. Patent No.4,444,784 i 6,002,021, kao i WO 00/53566. Ove reference iznose pripremu laktona i otvorenog oblika simvastatina. Simvastatin is the common medical name for the chemical compound butanoic acid, 2,2-dimethyl-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6 -oxo-2H-pyran-2-yl)-ethyl]-naphthalenyl ether, [1S-[1a,3a,7b,8b(2S*,4S),8ab]]. (GAS Registry No. 79902-63-9.). Simvastatin is marketed as ZOCOR and is disclosed in U.S. Patent Nos. 4,444,784 and 6,002,021, as well as WO 00/53566. These references present the preparation of the lactone and the open form of simvastatin.

Od ovih referenci, samo WO 00/53566 iznosi pripremu kalcijeve soli otvorenog oblika simvastatina. U tipičnom primjeru, postupak WO 00/53566 hidrolizira lakton simvastatina natrijevim hidroksidom nakon Čega slijedi dodavanje izvora kalcija, kao što je kalcij acetat hidrat. Of these references, only WO 00/53566 discloses the preparation of the calcium salt of the open form of simvastatin. In a typical example, the process of WO 00/53566 hydrolyzes simvastatin lactone with sodium hydroxide followed by the addition of a calcium source, such as calcium acetate hydrate.

U gornjim prethodnim radovima, postupci za pripremu kalcijevih soli statina, kao što je atorvastatin, pitavastatin, rosuvastatin i simvastatin, svi ili ne iznose kako se priprema kalcijeva sol ili se odvijaju preko natrijeva sol intermedijera. Dalje, neki postupci su visoko osjetljivi i nisu konzistentno reproducibilni i imaj u nepogodna svojstva prilikom filtriranja i sušenja za proizvodnju na veliko. Poželjno je da se dobije stabilni produkt u manje koraka nego u prethodnim postupcima primjenom postupka koji je lako reproducibilan i primjenjiv za proizvodnju na veliko. In the above prior works, the procedures for preparing the calcium salts of statins, such as atorvastatin, pitavastatin, rosuvastatin and simvastatin, all either do not disclose how the calcium salt is prepared or proceed via the sodium salt intermediate. Furthermore, some processes are highly sensitive and not consistently reproducible and have unfavorable filtering and drying properties for bulk production. It is desirable to obtain a stable product in fewer steps than in previous procedures using a process that is easily reproducible and applicable for mass production.

Sažetak izuma Summary of the invention

Predmetni izum pruža novi postupak za preparaciju statin kalcijevih soli formule: The subject invention provides a new process for the preparation of statin calcium salts of the formula:

[image] [image]

gdje R predstavlja organski radikal, koji obuhvaća dovođenje u kontakt esterskog derivata statina izabranog iz skupine koja se sastoji od where R represents an organic radical, which comprises bringing into contact with an ester derivative of a statin selected from the group consisting of

[image] [image]

i and

[image] [image]

s dovoljnom količinom kalcij hidroksida, with a sufficient amount of calcium hydroxide,

gdje R1 i je C1 do C8 alkil skupina, i where R1 and is a C1 to C8 alkyl group, and

R2, R3 i R4 svaki neovisno predstavljaju atom vodika ili istu ili različitu zaštitnu skupinu koja se može hidrolizirati, ili R2 i R3, zajedno s atomom kisika na koji je svaki vezan, tvore cikličku zaštitnu skupinu koja se može hidrolizirati. R 2 , R 3 and R 4 each independently represent a hydrogen atom or the same or a different hydrolyzable protecting group, or R 2 and R 3 , together with the oxygen atom to which each is attached, form a cyclic hydrolyzable protecting group.

Reakcija se može provoditi s ili bez katalizatora faznog prijelaza. Preferirani katalizatori faznog prijelaza su kvarterne amonijeve soli kao sto je tetrabutilamonij bromid (TBAB) i trietilbenzilamonij klorid (TEBA). Reakcijska smjesa se preferirano zagrijava da se ubrza pretvorba. The reaction can be carried out with or without a phase transition catalyst. Preferred phase transition catalysts are quaternary ammonium salts such as tetrabutylammonium bromide (TBAB) and triethylbenzylammonium chloride (TEBA). The reaction mixture is preferably heated to accelerate the conversion.

Preferirani statini su atorvastatin, pitavastatin, rosuvastatin i simvastatin, U preferiranoj izvedbi, R2, R3 i R4 su atom vodika. Svaki od R2, R3 i R4 mogu također biti ista ili različita zaštitna skupina koja se hidrolizira primjenom kalcij hidroksida u jednom koraku zajedno s hidrolizom esterske skupine, tj., -COOR1, ili se hidrolizira primjenom kiselinskog katalizatora nakon čega slijedi hidroliza esterske skupine -COOR1. Preferirane zaštitne skupine su sililne skupine kao što je trialkilsilil, koji se može hidrolizirati kalcij hidroksidom, i acetonid, koji se može hidrolizirati kiselinskim katalizatorom. Acetonid tvori cikličku zaštitnu skupinu koja se može hidrolizirati, tj. dioksan. Preferred statins are atorvastatin, pitavastatin, rosuvastatin and simvastatin. In a preferred embodiment, R2, R3 and R4 are a hydrogen atom. Each of R 2 , R 3 and R 4 may also be the same or a different protecting group which is hydrolyzed using calcium hydroxide in one step along with hydrolysis of the ester group, i.e., -COOR1, or hydrolyzed using an acid catalyst followed by hydrolysis of the ester group -COOR1 . Preferred protecting groups are silyl groups such as trialkylsilyl, which can be hydrolyzed with calcium hydroxide, and acetonide, which can be hydrolyzed with an acid catalyst. Acetonide forms a cyclic protecting group that can be hydrolyzed, i.e. dioxane.

U drugom aspektu, pruža postupak za preparaciju kalcijeve soli statina formule: In another aspect, it provides a process for preparing the calcium salt of a statin of the formula:

[image] [image]

gdje R predstavlja organski radikal, koji obuhvaća korake: where R represents an organic radical, which includes steps:

dodavanje kalcij hidroksida i esterskog derivata statina opisanog gore u smjesu vode i C1 do C4 alkohola, zagrijavanje smjese, taloženje kalcijeve soli statina i odvajanje kalcijeve soli. adding calcium hydroxide and the statin ester derivative described above to a mixture of water and C1 to C4 alcohol, heating the mixture, precipitating the calcium salt of the statin and separating the calcium salt.

Detaljan opis izuma Detailed description of the invention

Stvaranje estera je dobro poznat način zaštićivanja grupe karboksilne kiseline i maskiranja njenog kiselog protona, Green, T. W. ; Wut s, P. G. M. Protective Groups in Organic Synthesis 3rd ed, poglavlje 5 (John Wiley & Sons: New York 1999) ("Greene & Wuts"). Također je poznato, općenito, da se za karboksilne kiseline koje su zaštićene kao esteri zaštita može skinuti hidroliziranjem estera jakom bazom, Id, na 377-78. Ester formation is a well-known way of protecting a carboxylic acid group and masking its acidic proton, Green, T. W. ; Wut s, P. G. M. Protective Groups in Organic Synthesis 3rd ed, Chapter 5 (John Wiley & Sons: New York 1999) ("Greene & Wuts"). It is also known, in general, that carboxylic acids which are protected as esters can be deprotected by hydrolyzing the ester with a strong base, Id, at 377-78.

Natrij hidroksid je jaka baza s konstantom disocijacije 6,37 (pKb = -0,80), Handbook of Chemistry and Physics 81st ed. 8 - 45 (CRC Press: Boca Raton 2000 - 01) i njena primjena kao reagensa za uklanjanje karboksilnih kiselina zaštićenih esterima se podučava u struci, Greene & Wuts, str, 377. Kalcij hidroksid (Ca(OH)2), s prvom konstantom disocijacije 3,74 × 10-3 (pKb = 2,43) i drugom konstantom disocijacije 4,0 × 10-2 (pKb = 1,40), je mnogo slabija baza od natrij hidroksida. Handbook of Chemistry and Physics 63rd ed. D-170 (CRC Press: Boca Raton 1983). Sodium hydroxide is a strong base with a dissociation constant of 6.37 (pKb = -0.80), Handbook of Chemistry and Physics 81st ed. 8 - 45 (CRC Press: Boca Raton 2000 - 01) and its use as a reagent for removing ester-protected carboxylic acids is taught in the art, Greene & Wuts, p, 377. Calcium hydroxide (Ca(OH)2), with the first constant dissociation 3.74 × 10-3 (pKb = 2.43) and a second dissociation constant 4.0 × 10-2 (pKb = 1.40), is a much weaker base than sodium hydroxide. Handbook of Chemistry and Physics 63rd ed. D-170 (CRC Press: Boca Raton 1983).

Kalcij hidroksid nije nabrojen među reagensima koji se koriste za hidroliziranje estera u dobro poznatoj zbirci transformacija funkcionalnih grupa u organskoj sintezi. Larock R. C. Coraprehensive Organic Transformations 2nd ed, Section NITRILES, CARBOKILIC ACIDS AND DERIVATIVES, Sub-sect. 9.17, str. 1959 - 68 (Wiley-VCH: New York 1999). Njegova primjena kao reagensa za uklanjanje karboksilnih kiselina zaštićenih esterima se ne podučava u dobro poznatoj referentnoj knjizi o postupcima za zaštićivanje i uklanjanje zaštite organskih funkcionalnih skupina. Greene & Wuts, str. 377 -79. U stvari, U.S. Patent No. 5,273,995 upozorava da se ne upotrebljava suvišak natrij hidroksida za preparaciju natrijeve soli kako bi se spriječilo nastajanje kalcijevog hidroksida kada se kasnije kalcij klorid dodaje u otopinu natrijeve soli. Čini se da nije bilo prihvaćeno da se esterski zaštićene forme statina kao, što je atorvastatin, mogu pretvoriti direktno u odgovarajuće hemikalcij soli, kao što je atorvastatin hemi-kalcij, bez prethodne obrade estera jakom bazom kao što je natrij hidroksid hidroksid da dođe do njegove hidrolize, te onda zamjenom natrijevog iona dovođenjem u kontakt natrijeve soli s kalcijevom soli kao što je kalcij klorid ili kalcij acetat. Calcium hydroxide is not listed among the reagents used to hydrolyze esters in the well-known collection of functional group transformations in organic synthesis. Larock R. C. Comprehensive Organic Transformations 2nd ed, Section NITRILES, CARBOCYLIC ACIDS AND DERIVATIVES, Sub-sect. 9.17, p. 1959 - 68 (Wiley-VCH: New York 1999). Its use as a reagent for the deprotection of ester-protected carboxylic acids is not taught in a well-known reference book on procedures for the protection and deprotection of organic functional groups. Greene & Wuts, p. 377 -79. In fact, the U.S. Patent No. 5,273,995 warns against using excess sodium hydroxide to prepare the sodium salt in order to prevent the formation of calcium hydroxide when calcium chloride is later added to the sodium salt solution. It does not appear to have been accepted that ester-protected forms of statins such as atorvastatin can be converted directly to the corresponding hemicalcium salts, such as atorvastatin hemi-calcium, without first treating the ester with a strong base such as sodium hydroxide hydroxide to reach its hydrolysis, and then replacing the sodium ion by bringing the sodium salt into contact with a calcium salt such as calcium chloride or calcium acetate.

Kako se ovdje koristi, "esterski derivat" je spoj nastao zamjenom hidroksilnog protona karboksilne kiselinske skupine u statinskoj formi otvorenog prstena ili dihidroksi kiseline sa supstituentom vezanim na hidroksilni atom kisika kroz ugljik. Takvi esterski derivati uključuju, npr., spojeve gdje supstituent vezan na hidroksilni kisik hidroksilne kiseline je C1 - C8 alkil skupina. Esterski derivat korišten za pretvorbu može biti smjesa derivata koji sadrže različite estere. Na primjer, metil esterski derivat može se dodati u etanol što dovodi do pretvorbenih metil estera u etil estere. Esterski derivat statina može se proizvesti postupcima poznatim u struci ili se može komercijalno kupiti. Esterski derivat također uključuje laktonsku ili formu zatvorenog prstena statina. Laktonska forma je ciklički ester u kojem esterska skupina statina je uključena u prsten. Smjesa esterskih derivata također uključuje smjesu formi statina s otvorenim ili zatvorenim prstenom. As used herein, an "ester derivative" is a compound formed by replacing the hydroxyl proton of a carboxylic acid group in a statin form of an open ring or dihydroxy acid with a substituent attached to the hydroxyl oxygen atom through carbon. Such ester derivatives include, for example, compounds where the substituent attached to the hydroxyl oxygen of the hydroxyl acid is a C1 - C8 alkyl group. The ester derivative used for conversion can be a mixture of derivatives containing different esters. For example, a methyl ester derivative can be added to ethanol leading to the conversion of methyl esters to ethyl esters. The ester derivative of a statin can be produced by methods known in the art or can be purchased commercially. The ester derivative also includes the lactone or ring-closed form of statins. The lactone form is a cyclic ester in which the ester group of the statin is included in the ring. The mixture of ester derivatives also includes a mixture of statin forms with an open or closed ring.

Predmetni izum je usmjeren na statine općenite formule: The subject invention is directed to statins of the general formula:

[image] [image]

u kojoj organski radikal R je vezan na diol pentansku kiselinsku skupinu. Ovi statini uključuju, npr., pravastatin, fluvastatin, cerivastatin, atorvastatin, pitavastatin, rosuvastatin, lovastatin i simvastatin. Od ovih, atorvastatin, pitavastatin, rosuvastatin i simvastatin su preferirani. in which the organic radical R is attached to the diol pentanoic acid group. These statins include, for example, pravastatin, fluvastatin, cerivastatin, atorvastatin, pitavastatin, rosuvastatin, lovastatin and simvastatin. Of these, atorvastatin, pitavastatin, rosuvastatin and simvastatin are preferred.

R se odnosi na organski radikal vezan na diol pentansku kiselinsku skupinu. Ovisno o statinu, R radikal može biti: R refers to the organic radical attached to the diol pentanoic acid group. Depending on the statin, the R radical can be:

pravastatin: 1,2,6,7,8,8a-heksahidro-6-hidroksi-2-metil-8-(2-metil-1-oksobutoksi)-1-naftalen etil radikal. pravastatin: 1,2,6,7,8,8a-hexahydro-6-hydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene ethyl radical.

fluvastatin: 3-(4-fluorfenil)-1-(1-metiletil)-1H-indol-2-il]-etilen radikal. fluvastatin: 3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-ethylene radical.

cerivastatin: 4-(4-fluorfenil)-5-metoksimetil-2,6bis(l-metiletil)-3-piridinil-etilen radikal. cerivastatin: 4-(4-fluorophenyl)-5-methoxymethyl-2,6bis(1-methylethyl)-3-pyridinyl-ethylene radical.

atorvastatin: 2-(4-fluorfenil)-5-metiletil)-3-fenil-4-[(fenilamino)karbonil]-1H-pirol-etil radikal. atorvastatin: 2-(4-fluorophenyl)-5-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-ethyl radical.

rosuvast atin; [4-(4-fluorfenil)-6-(1-metiletil)-2-[metil(metilsulfonil)amino]-5-pirimidinil]-etilen radikal. rosy atin; [4-(4-Fluorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-ethylene radical.

pitavastatin: [4'-(4"-fluorfenil)-2'-ciklopropil-kinolin-3'-il]-etilen radikal. pitavastatin: [4'-(4"-fluorophenyl)-2'-cyclopropyl-quinolin-3'-yl]-ethylene radical.

R radikal može također biti forme otvorenog prstena, tj. dihidroksi kiseline, simvastatin ili lovastatina. Ove forme otvorenog prstena također imaju diol pentan kiselinsku skupinu. Kako se ovdje koristi, izrazi lovastatin i simvastatin uključuju i laktonski oblik i oblik otvorenog prstena. Kada je statin lovastatin ili simvastatin, R radikal je: The R radical can also be of the open ring form, i.e. dihydroxy acid, simvastatin or lovastatin. These ring-opened forms also have a diol pentane acid group. As used herein, the terms lovastatin and simvastatin include both the lactone form and the ring-opened form. When the statin is lovastatin or simvastatin, the R radical is:

simvastatin: 1,2,6,7,8,8a-heksahidro-2,6 -dimetil-8-(2,2-dimetil-1-oksobutoksi)-1-naftalen etil radikal. simvastatin: 1,2,6,7,8,8a-hexahydro-2,6-dimethyl-8-(2,2-dimethyl-1-oxobutoxy)-1-naphthalene ethyl radical.

lovastatin: 1,2,6,7,8,8a-heksahidro-2,6-dimetil-1-8-(2-metil-1-oksobutoksi)-1-naftalen etil radikal. lovastatin: 1,2,6,7,8,8a-hexahydro-2,6-dimethyl-1-8-(2-methyl-1-oxobutoxy)-1-naphthalene ethyl radical.

Kalcijeva sol ovih i drugih statina može napraviti postupcima predmetnog izuma tako da organski radikal vezan na diol pentansku kiselinsku skupinu ili odgovaraj ući lakton definira spoj koji je statin, tj., spoj koji inhibira enzim 3-hidroksi-3-metil-glutaril-koenzim A ("HMG-CoA") reduktaza. Vidi, npr., WO 00/53566. Tako, R ne treba uzeti da je ograničen na organski radikal vezan na diol pentansku kiselinsku skupinu ili odgovaraj ući lakton stat ina ovdje izričito iznesen ili naveden kao primjer. Svi hidrati, solvati i bezvodni oblici kalcijeve soli i drugih njegovih polimorfnih formi, kristalni ili amorfni, ovih statina su unutar dometa predmetnog izuma. The calcium salt of these and other statins can be made by the methods of the present invention so that the organic radical attached to the diol pentanoic acid group or the corresponding lactone defines a compound that is a statin, i.e., a compound that inhibits the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A ("HMG-CoA") reductase. See, eg, WO 00/53566. Thus, R should not be taken to be limited to the organic radical attached to the diol pentanoic acid group or the corresponding lactone statin expressly set forth or exemplified herein. All hydrates, solvates and anhydrous forms of the calcium salt and its other polymorphic forms, crystalline or amorphous, of these statins are within the scope of the present invention.

Predmetni izum ilustrira preparaciju kalcijeve soli ovih statina primjenom preparacije atorvastatin hemi-kalcij a kao primjera. Do raspona da je jedan aspekt preparacije atorvastatin hemi-kalcija različit od onog sa drugo statin, stručnjak u području bi uvažio da se atorvastatin koristi samo za ilustrativnu svrhu; i da različiti aspekti preparacije atorvastatin hemi-kalcija mogu se spremno modificirati za preparaciju drugih statina, a da su i dalje unutar duha i dometa predmetnog izuma. The present invention illustrates the preparation of the calcium salt of these statins using the preparation of atorvastatin hemi-calcium as an example. To the extent that one aspect of the preparation of atorvastatin hemi-calcium is different from that of another statin, one skilled in the art would appreciate that atorvastatin is used for illustrative purposes only; and that various aspects of the preparation of atorvastatin hemi-calcium can be readily modified for the preparation of other statins while still being within the spirit and scope of the present invention.

Predmetni izum pruža postupak za preparaciju statin hemi-kalcijeve soli konverzijom derivata formule: The subject invention provides a process for the preparation of statin hemi-calcium salt by converting derivatives of the formula:

[image] [image]

ili or

[image] [image]

gdje R predstavlja organski radikal i R1 je C1 do C8 alki l skupina, u odgovarajuću hemi-kalcijevu sol formule: where R represents an organic radical and R1 is a C1 to C8 alkyl group, into the corresponding hemi-calcium salt of the formula:

[image] [image]

dovođenjem u kontakt esterskog derivata s dovoljnom količinom kalcij hidroksida. "Dovoljna količina", kako se ovdje koristi, odnosi se na količinu kalcij hidroksida koja temelj no prevodi esterski derivat u odgovarajuću hemi-kalcijevu sol. "Temeljno prevodi", kako se ovdje koristi, znači takvu količinu da je veća od oko 50% (na molarnoj bazi), preferirano veća od oko 70%, i više preferirano veća od oko 90% statin esterskog derivata se prevodi u odgovarajuću hemi-kalcijevu sol. by contacting the ester derivative with a sufficient amount of calcium hydroxide. "A sufficient amount", as used herein, refers to an amount of calcium hydroxide which substantially converts the ester derivative into the corresponding hemi-calcium salt. "Thoroughly translates", as used herein, means such an amount that greater than about 50% (on a molar basis), preferably greater than about 70%, and more preferably greater than about 90% of the statin ester derivative is converted to the corresponding hemi- calcium salt.

Neočekivana prednost ovog postupka je da kalcij hidroksid ispunjava dvije uloge. Djeluje kao bazični katalizator za hidrolizu estera i opskrbljuje kalcijevim ionima za stvaranje hemi-kalcijeve soli. Druga značaj na praktična prednost postupka je da količina kalcij hidroksida ne mora biti tako oprezno kontrolirana kao količina natrij hidroksida i smjese kalcij klorid/acetat koje se koriste u drugim postupcima koji, u suprotnosti s predmetnim izumom, uključuju postupak u slijedu hidroliziranja esterskog derivata pomoću NaOH nakon čega slijedi zamjena natrijevih iona kalcijevim ionima. An unexpected advantage of this procedure is that calcium hydroxide fulfills two roles. It acts as a basic catalyst for the hydrolysis of esters and supplies calcium ions for the formation of hemi-calcium salts. Another significant practical advantage of the process is that the amount of calcium hydroxide does not have to be as carefully controlled as the amount of sodium hydroxide and the calcium chloride/acetate mixture used in other processes which, in contrast to the present invention, include a step of hydrolyzing the ester derivative with NaOH followed by replacement of sodium ions with calcium ions.

Statinski derivat može se pružiti u čistom obliku ili u smjesi s drugim statinskim esterskim derivatima. Statinski esterski derivat, opciono u smjesi s drugim statinskim esterskim derivatima, otopi se ili suspendira preferirano u miješanom otapalu koje obuhvaća C1 - C4 alkohol i vodu. Preferirani alkohol i su etanol i izopropil alkohol ("IPA") i preferirana smjesa otapala sadrži oko 5% do oko 15% vode u etanolu ili IPA, više preferirano oko 10% vode i oko 90% etanola (v/v) ili IPA. Da li se Statinski esterski derivat otapa u smjesi otapala ovisi o takvim faktorima kao izbor C1 - C4 alkohola, omjer vode, temperatura i čistoća statinskog esterskog derivata. Kalcij hidroksid se onda suspendira u otapalu i reakcijska smjesa sa bazičnu hidrolizu se održava dok se statinski eaterski derivat ne potroši. Potrošnja statinskog esterskog derivata može se pratiti bilo kojim uobičajenim načinom kao što je TLC, HPLC i NMR. Nakon što je statinski esterski derivat potrošen, statin hemi -kalcij se izolira iz reakcijske smjese za bazičnu hidrolizu uobičajenim putem. Nije potrebno da se dodaje drugi izvor kalcija da se pruži Ca2+ ion za atorvastatin hemi-kalcij sol. The statin derivative can be provided in pure form or in a mixture with other statin ester derivatives. The statin ester derivative, optionally in admixture with other statin ester derivatives, is dissolved or suspended preferably in a mixed solvent comprising C1 - C4 alcohol and water. Preferred alcohols are ethanol and isopropyl alcohol ("IPA") and the preferred solvent mixture comprises about 5% to about 15% water in the ethanol or IPA, more preferably about 10% water and about 90% ethanol (v/v) or IPA. Whether the statin ester derivative dissolves in the solvent mixture depends on such factors as the choice of C1 - C4 alcohol, water ratio, temperature and purity of the statin ester derivative. The calcium hydroxide is then suspended in the solvent and the reaction mixture with basic hydrolysis is maintained until the statin ether derivative is consumed. Consumption of the statin ester derivative can be monitored by any conventional means such as TLC, HPLC and NMR. After the statin ester derivative is consumed, statin hemi-calcium is isolated from the reaction mixture for basic hydrolysis by the usual route. It is not necessary to add another source of calcium to provide the Ca2+ ion for atorvastatin hemi-calcium salt.

Prema preferiranom postupku za provođenje postupka bazične hidrolize, statinski esterski derivat se dodaje u količini dovoljnoj za dobivanje oko 10 mmol L-1 do oko 1 mol L-1 miješanog otapala. According to a preferred procedure for carrying out the basic hydrolysis procedure, the statin ester derivative is added in an amount sufficient to provide about 10 mmol L-1 to about 1 mol L-1 of the mixed solvent.

Preferirano, koristi se oko l ekvivalent do oko 6 ekvivalenata esterskog derivata. Preferably, about 1 equivalent to about 6 equivalents of the ester derivative is used.

Kalcij hidroksid se samo slabo otapa u smjesi otapala C1 - C4 alkohol : voda i samo njegov manji dio će biti u otopini sposoban da katalizira hidrolizu odjednom. Da se ubrza bazična hidroliza, može se dodati katalizator faznog prijelaza da se poveća topljivost kalcij hidroksida. Katalizatori faznog prijelaza dobro su poznati u struci i uključuju, na primjer, tetra-n-butilamonij bromid ("TBAB"), tri etilbenzilamonij klorid ("TEBA"), tetra-n-butil amonij klorid, tetra-n-butilamonij bromid, tetra-n-butilamonij jodid, tetraetilamonij klorid, benziltributilamonij bromid, benziltrietilamonij bromid, tetrametilamonij klorid i polietilen glikol. Najviše preferirani katalizator faznog prijelaza je TBAB, Kada se koristi, katalizator faznog prijelaza treba se koristiti u količini ispod stehiometrijske, preferirano od oko 0,05 do oko 0,25 ekvivalenata, više preferirano oko 0,1 ekvivalenata u odnosu na statinski esterski derivat. Calcium hydroxide is only slightly soluble in a mixture of solvents C1 - C4 alcohol: water and only a small part of it will be in solution capable of catalyzing hydrolysis at once. To speed up basic hydrolysis, a phase transition catalyst can be added to increase the solubility of calcium hydroxide. Phase transition catalysts are well known in the art and include, for example, tetra-n-butylammonium bromide ("TBAB"), triethylbenzylammonium chloride ("TEBA"), tetra-n-butyl ammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetraethylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, tetramethylammonium chloride and polyethylene glycol. The most preferred phase transition catalyst is TBAB. When used, the phase transition catalyst should be used in an amount below stoichiometric, preferably from about 0.05 to about 0.25 equivalents, more preferably about 0.1 equivalents relative to the statin ester derivative.

Smjesa se može zagrijati do temperature refluksa miješanog otapala kako bi se ubrzala reakcija. Preferirani raspon temperature je od oko 40°C do oko 70°C. The mixture can be heated to the reflux temperature of the mixed solvent to accelerate the reaction. The preferred temperature range is from about 40°C to about 70°C.

Nakon što se statinski esterski derivat potroši, statin hemi-kalcij ili njegov solvat se izolira iz smjese za bazičnu hidrolizu. Kao dio postupka izolacije statin hemi-kalcija, reakcijska smjesa se preferirano filtrira da se ukloni suvišak suspendiranog kalcij hidroksida. Reakcijska smjesa se preferirano filtrira dok je vruća da se spriječi taloženje statin hemi-kalcija na filtarskom kolaču kalcij hidroksida. After the statin ester derivative is consumed, statin hemi-calcium or its solvate is isolated from the base hydrolysis mixture. As part of the statin hemi-calcium isolation procedure, the reaction mixture is preferably filtered to remove excess suspended calcium hydroxide. The reaction mixture is preferably filtered while hot to prevent precipitation of statin hemi-calcium on the calcium hydroxide filter cake.

Nakon filtriranja da se ukloni suspendirani kalcij hidroksid, statin hemi-kalcij se može izolirati iz filtrata taloženjem. Prema preferiranom postupku izolacije, taloženje statin hemi-kalcija iz filtrata se izaziva polaganim dodavanjem vode. Kroz jedan sat vremena doda se volumen vode grubo jednak volumenu filtrata. Preferirano, polagano dodavanje vode se također provodi pri povišenoj temperaturi, npr. od oko 40°C do oko 65°C. Taloženje statin hemi-kalcija polaganim dodavanjem vode daje statin hemi-kalcij u kristalnom obliku i sprečava nastajanje želatinoznog taloga. Alternativno, statin hemi-kalcij može se izolirati na bilo koji konvencionalni način. Nakon neophodnih koraka pročišćavanja, izoliran statin hemi-kalcij može se koristiti kao aktivni sastojak za formuliranje farmaceutskog proizvoda. After filtration to remove suspended calcium hydroxide, statin hemi-calcium can be isolated from the filtrate by precipitation. According to the preferred isolation procedure, precipitation of statin hemi-calcium from the filtrate is induced by the slow addition of water. After one hour, a volume of water roughly equal to the volume of the filtrate is added. Preferably, the slow addition of water is also carried out at an elevated temperature, eg from about 40°C to about 65°C. Precipitation of statin hemi-calcium by slow addition of water gives statin hemi-calcium in crystalline form and prevents the formation of a gelatinous precipitate. Alternatively, statin hemi-calcium can be isolated by any conventional means. After the necessary purification steps, the isolated statin hemi-calcium can be used as an active ingredient to formulate a pharmaceutical product.

Svojstva filtriranja i čistoća statin hemi-kalcija mogu se dalje poboljšati ponovnim otapanjem kristalnog produkta u smjesi alkohola i vode zagrijava njem do temperature dovoljne da se sav talog otopi što dovodi do bistre otopine. Otopina se preferirano hladi kroz nekoliko sati i drže, preferirano na temperaturi okoline, dok kristali ne prestanu nastajati. Nakon filtriranja i sušenja, i bilo kojeg opcionog koraka pročišćavanja, statin hemi-kalcij ili njegov solvat može se koristiti kao aktivni sastojak farmaceutskog proizvoda. The filtration properties and purity of statin hemi-calcium can be further improved by redissolving the crystalline product in an alcohol-water mixture and heating it to a temperature sufficient to dissolve all the precipitate resulting in a clear solution. The solution is preferably cooled over several hours and kept, preferably at ambient temperature, until the crystals stop forming. After filtration and drying, and any optional purification steps, statin hemi-calcium or a solvate thereof can be used as the active ingredient of a pharmaceutical product.

Statini se ponekad prepariraju preko intermedijera u kojem su jedna ili obje hidroksilne skupine u pentanska kiselina diolnoj skupini (oblik otvorenog prstena) ili hidroksilna skupina laktona (oblik zatvorenog prstena) zaštićene putem zaštitne grupe koja se može hidrolizirati i karboksilna skupina je zaštićena putem gore opisanog esterskog derivata. Na primjer, U. S. Patent No, 5,260,440, uključen ovdje putem reference, koristi silil zaštitnu grupu za vrijeme sinteze rosuvastatina, Patenti U.S. Patent No.4,444,784 i 6,002,021, uključeni ovdje putem reference, koriste silil zaštitnu grupu za vrijeme sinteze simvastatina. Brower, P. L. et al Tet. Lett. 1992, 33, 2279 - 82 i Baumann, K. L. et al Tet. Lett. 1992, 33, 2283 -2284, uključeni ovdje putem reference, prepariraj u atorvastatin preko dioksan intermedijera koji ima acetonidnu zaštitnu skupinu, tj. R2 i R3 zajedno s atomom kisika na koji je svaki vezan, tvore cikličku zaštitnu grupu koja se može hidrolizirati. Statins are sometimes prepared via an intermediate in which one or both hydroxyl groups in the pentanoic acid diol group (open-ring form) or the hydroxyl group of the lactone (closed-ring form) are protected by a hydrolyzable protecting group and the carboxyl group is protected by the above-described ester derivatives. For example, U.S. Patent No, 5,260,440, incorporated herein by reference, utilizes a silyl protecting group during the synthesis of rosuvastatin, U.S. Pats. Patent Nos. 4,444,784 and 6,002,021, incorporated herein by reference, utilize a silyl protecting group during the synthesis of simvastatin. Brower, P.L. et al Tet. Lett. 1992, 33, 2279-82 and Baumann, K.L. et al Tet. Lett. 1992, 33, 2283 -2284, incorporated herein by reference, prepare atorvastatin via a dioxane intermediate having an acetonide protecting group, i.e., R2 and R3 together with the oxygen atom to which each is attached form a hydrolyzable cyclic protecting group.

Ovi spojevi, nazvani ovdje "zaštićeni statinski esterski derivati", mogu se prevesti u skladu s predmetnim i žurnom u odgovarajuću hemi-kalcij sol. Tako, u drugoj izvedbi, predmetni izum je usmjeren na postupak za preparaciju statin hemi-kalcijeve soli formule: These compounds, referred to herein as "protected statin ester derivatives", can be converted according to the subject and quickly into the corresponding hemi-calcium salt. Thus, in another embodiment, the present invention is directed to a process for the preparation of statin hemi-calcium salt of the formula:

[image] [image]

gdje R predstavlja organski radikal koji obuhvaća dovođenje u kontakt esterskog derivata statina izabranog iz skupine koja se sastoji od: where R represents an organic radical comprising contacting an ester derivative of a statin selected from the group consisting of:

[image] [image]

i and

[image] [image]

s dovoljnom količinom kalcij hidroksida, gdje R1 je C1 do C8 alkil skupina, i R2, R3 i R4 svaki neovisno predstavljaju atom vodika ili istu ili različitu zaštitnu skupinu koja se može hidrolizirati, ili R2 i R3, zajedno s atomom kisika na koji je svaki vezan, tvore cikličku zaštitnu skupinu koja se može hidrolizirati. Zaštitna skupina koja se koristi se preferirano hidrolizira u kiselim ili bazičnim uvjetima. Preferirane zaštitne skupine R2, R3 i R4 u skladu s ovom izvedbom predmetnog izuma uključuju, na primjer, sililne grupe, gdje su trialkilsilil i alkildiarilsilil skupine više preferirane i t-butil-dimetil-silil je najviše preferirana; i cikličke zaštitne skupine tako da R2 i R3 tvore, na primjer, dioksan. with a sufficient amount of calcium hydroxide, wherein R 1 is a C 1 to C 8 alkyl group, and R 2 , R 3 and R 4 each independently represent a hydrogen atom or the same or a different hydrolyzable protecting group, or R 2 and R 3 , together with an oxygen atom to which each bound, form a cyclic protecting group that can be hydrolyzed. The protecting group used is preferably hydrolyzed under acidic or basic conditions. Preferred protecting groups R 2 , R 3 and R 4 according to this embodiment of the present invention include, for example, silyl groups, where trialkylsilyl and alkyldiarylsilyl groups are more preferred and t-butyl-dimethyl-silyl is most preferred; and cyclic protecting groups such that R 2 and R 3 form, for example, dioxane.

U.S. Patent No. 6,294,680, uključen ovdje putem reference, iznosi dodatne zaštitne grupe koje se koriste u sintezi statina, naročito simvastatina. Iznesene zaštitne grupe uključuju dioksan, ciklički sulfat, ciklički fosfat ili boriliden, koji su opciono supstituirani alkilnim ili arilnim skupinama. Druge zaštitne grupe uključuju bornu kiselinu, iznesenu u WO 95/13283, uključen ovdje putem reference, i esterifikaciju anhidridom octene kiseline, izneseno u U.S, Patent No. 5,159,104, uključen ovdje putem reference. U.S. Patent No. 6,100,407, uključen ovdje putem reference, iznosi dodatne zaštitne grupe. Zaštitne grupe iznesene u ovim referencama mogu se koristiti u skladu s predmetnim izumom. LOUSE. Patent No. 6,294,680, incorporated herein by reference, discloses additional protecting groups used in the synthesis of statins, particularly simvastatin. Exemplary protecting groups include dioxane, cyclic sulfate, cyclic phosphate, or borylidene, which are optionally substituted with alkyl or aryl groups. Other protecting groups include boric acid, disclosed in WO 95/13283, incorporated herein by reference, and esterification with acetic anhydride, disclosed in U.S. Patent No. 5,159,104, incorporated herein by reference. LOUSE. Patent No. 6,100,407, incorporated herein by reference, discloses additional protecting groups. The protecting groups set forth in these references may be used in accordance with the present invention.

Iznenađujuće je nađeno da se sililna grupa može hidrolizirati i ukloniti u kontakt s kalcij hidroksidom. Stoga primjena sililne grupe omogućava uklanjanje zaštitne grupe i konverziju estera u kalcijevu sol u jednom koraku, u istom otapalu. Primjena kalcij hidroksida uklanja potrebu za odvojenim korakom kiselinske hidrolize sililne zaštitne grupe, npr. halovodika kao što je fluorvodik, za uklanjanje zaštitne grupe, kao što je potrebno u postupcima patenata U. S. Patent No. 5,260,440 i U.S. Patent No.4,444,784. Tako, postupak predmetnog izuma primjenjuje se na bilo koji statin sa sililnom ili drugom zaštitnom skupinom R2, R3 i R4 koja se može hidrolizirati kalcij hidroksidom. Zaštićeni rosuvastatin iznesen u U.S. Patent No. 5,260,440, npr., može se koristiti, uz modifikaciju da se reducira keton da se dobije atom vodika kao R2. Simvastatin zaštićen sililom iznesen u patentima U.S. Pat. No.4,444,784 i 6,002,021 također se može koristiti. Surprisingly, it was found that the silyl group can be hydrolyzed and removed by contact with calcium hydroxide. Therefore, the application of the silyl group enables the removal of the protecting group and the conversion of the ester into a calcium salt in one step, in the same solvent. The use of calcium hydroxide eliminates the need for a separate step of acid hydrolysis of the silyl protecting group, e.g., a hydrogen halide such as hydrogen fluoride, to remove the protecting group, as required in the processes of U.S. Patent No. 5,260,440 and U.S. Pat. Patent No. 4,444,784. Thus, the process of the present invention is applicable to any statin with a silyl or other protecting group R2, R3 and R4 that can be hydrolyzed with calcium hydroxide. Proprietary rosuvastatin brought to the U.S. Patent No. 5,260,440, e.g., may be used, with the modification to reduce the ketone to provide a hydrogen atom as R 2 . Simvastatin protected by silyl disclosed in U.S. patents. Pat. Nos. 4,444,784 and 6,002,021 may also be used.

Neke od zaštitnih grupa se najbolje mogu hidrolizirati u kiselinskim uvjet ima. Tako, prije dovođenja zaštićenog statinskog esterskog derivata u kontakt s kalcij hidroksidom, kiselinski katalizator se doda za hidroliziranje zaštitne grupe. Primjeri takvih kiselinskih katalizatora uključuju octenu kiselinu, trifluorctenu kiselinu, p-toluensulfonsku kiselinu, cink bromid i kloridnu kiselinu ili drugi halovodik, s tim da su octena kiselina i kloridna kiselina preferirane. Nastali diol ester se onda prevodi u kalcijevu sol dovođenjem u kontakt s kalcij hidroksidom. Postupak se također može provoditi u jednoj posudi. Nastali diol ester, kako je opisano gore, onda reagira s kalcij hidroksidom da nastane atorvastatin hemi-kalcij u jednoj posudi, bez promjene otapala. Preferirano otapalo je smjesa vode i C1 - C4 alkohola s tim da je etanol preferiran. Preferirani pH za reakciju je manje od oko 3, više preferirano manje od oko 1. Some of the protecting groups can best be hydrolyzed under acidic conditions. Thus, before bringing the protected statin ester derivative into contact with calcium hydroxide, an acid catalyst is added to hydrolyze the protecting group. Examples of such acid catalysts include acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, zinc bromide, and hydrochloric acid or other hydrogen halides, with acetic acid and hydrochloric acid being preferred. The resulting diol ester is then converted to the calcium salt by bringing it into contact with calcium hydroxide. The procedure can also be carried out in one container. The resulting diol ester, as described above, is then reacted with calcium hydroxide to form atorvastatin hemi-calcium in one pot, without changing the solvent. The preferred solvent is a mixture of water and C1 - C4 alcohol, with ethanol being preferred. A preferred pH for the reaction is less than about 3, more preferably less than about 1.

Preferirana zaštitna skupina koja se uklanja kiselinskim katalizatorom je acetonid, tj. spoj u kojem diol tvori cikličku zaštitnu skupinu koja se može hidrolizirati, tj. dioksan. Preferirano, aceton koji nastaje za vrijeme reakcije acetonida s kiselinskim katalizatorom se uklanja, npr. uparavanjem pod sniženim tlakom. The preferred protecting group which is removed by an acid catalyst is an acetonide, i.e. a compound in which the diol forms a hydrolysable cyclic protecting group, i.e. dioxane. Preferably, the acetone formed during the reaction of the acetonide with the acid catalyst is removed, eg by evaporation under reduced pressure.

Postupak u jednoj posudi uz primjenu kiselinskog katalizatora ilustriran je kako slijedi: A one-pot process using an acid catalyst is illustrated as follows:

[image] [image]

Farmaceutske kompozicije mogu se prirediti kao medikamenti za davanje oralno, parenteralno, rektalno, transdermalno, bukalno (pod jezik) ili nazalno. Prikladne forme za oralno davanje uključuju tablete, prešane ili presvučene pilule, dražeje, sašete, čvrste ili želatinske kapsule, tablete za pod jezik, sirupe i suspenzije. Prikladne forme za parenteralno davanje uključuju vodenu ili nevodenu otopinu ili emulziju, dok za rektalno davanje prikladne forme za davanje uključuju aupozitorije s hidrofilnim ili hidrofobnim prijenosnim sredstvom. Za topičko davanje, izum pruža prikladne transdermalne prijenosne sisteme poznate u struci i za nazalno davanje dani su prikladni aerosolni prijenosni sistemi poznati u struci. Pharmaceutical compositions can be prepared as medicaments for oral, parenteral, rectal, transdermal, buccal (sublingual) or nasal administration. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sublingual tablets, syrups and suspensions. Suitable forms for parenteral administration include an aqueous or non-aqueous solution or emulsion, while for rectal administration suitable forms for administration include suppositories with a hydrophilic or hydrophobic carrier. For topical administration, the invention provides suitable transdermal delivery systems known in the art and for nasal administration, suitable aerosol delivery systems known in the art are provided.

Farmaceutske kompozicije predmetnog izuma sadrže statin hemikalcij, naročito atorvastatin hemikalcij, rosuvastatin hemikalcij, pitavastatin hemikalcij, simvastatin hemikalcij i lovastatin hemikalcij. Dodatno uz aktivni sastojak(e), farmaceutske kompozicije predmetnog izuma mogu sadržavati jedan ili više ekscipijenata. I zbor ekscipijenata i količine koje će se koristiti može lako odrediti formulacijski stručnjak na osnovi iskustva i uzimanja u obzir standardnih procedura i referentnih radova u području. U.S. Pat. No. 6,316, 460, uključen ovdje putem reference, i najnovije izdanje Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, može se koristiti kao vodič. Doziranje i formulacija LIPITOR®a {atorvastatin hemi-kalcij) i drugih farmaceutika može se također koristiti kao vodič. The pharmaceutical compositions of the subject invention contain statin hemicalcium, especially atorvastatin hemicalcium, rosuvastatin hemicalcium, pitavastatin hemicalcium, simvastatin hemicalcium and lovastatin hemicalcium. In addition to the active ingredient(s), the pharmaceutical compositions of the present invention may contain one or more excipients. Both the set of excipients and the amounts to be used can be readily determined by the formulation expert based on experience and consideration of standard procedures and reference works in the field. LOUSE. Pat. But. 6,316, 460, incorporated herein by reference, and the most recent edition of the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, may be used as a guide. The dosage and formulation of LIPITOR® (atorvastatin hemi-calcium) and other pharmaceuticals can also be used as a guide.

Primjeri Examples

Općenito In general

Ako nije drugačije naznačeno, reagensi su primijenjeni takvi kakvi su dobiveni. [R-(R*,R*)]-2-(4-fluorfenil)-β,δ-dioksan-5-(1-metiletil)-3-fenil-4-[(fenilamino) karbonil]-1H-pirol-1-terc-butilheptanski ester (dioksan 2, R1 = t-butil) priređen je reakcijom kondenzacije između odgovarajućeg diketona i odgovarajućeg kiralnog amina da nastane pirolni prsten. Također mogu se prirediti poznatim postupcima. Brower, P.L. et al. Tet. Lett. 1992,33, 2279-82; Baumann, K. L. et al. Tet. Lett. 1992,33, 2283-84. Sljedeći HPLC uvjeti korišteni su za određivanje sastava smjesa dobivenih kiselinskom hidrolizom objavljenom u primjerima: Waters Spherisorb S3 ODS1 (7.6 × 100 mm), 70 : 30 acetonitril : voda, 0.6 ml min-1, 20 μl uzorak, UV detekcija γ = 254, Unless otherwise indicated, reagents were used as received. [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole -1-tert-butylheptane ester (dioxane 2, R1 = t-butyl) was prepared by a condensation reaction between the corresponding diketone and the corresponding chiral amine to form the pyrrole ring. They can also be prepared by known procedures. Brower, P.L. et al. Aunt. Lett. 1992, 33, 2279-82; Baumann, K.L. et al. Aunt. Lett. 1992,33, 2283-84. The following HPLC conditions were used to determine the composition of the mixtures obtained by acid hydrolysis published in the examples: Waters Spherisorb S3 ODS1 (7.6 × 100 mm), 70 : 30 acetonitrile : water, 0.6 ml min-1, 20 μl sample, UV detection γ = 254,

Primjer 1 Example 1

Preparacija atorvastatin kalcija iz dioksan ester derivata Preparation of atorvastatin calcium from dioxane ester derivative

U tikvici opremljenoj magnetskom miješalicom suspendiran je [R-(R*,R*)]-2-(4-fluorfenil)-β,δ-dioksan-5-(1-metiletil)-3-fenil-4-[(fenilamino) karbonil]-1H-pirol-1-terc-butilheptanski ester (2.0 g) u 80% vodenoj otopini octene kiseline (50 ml). Smjesa je miješana na temperaturi okoline oko 20 sati dok nije dobivena bistra otopina. Bistra otopina uparena je do suhog i tragovi octene kiseline uklonjeni su azeotropnom destilacijom s toluenom (3 × 50 ml) da se dobije prašak. [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino ) carbonyl]-1H-pyrrole-1-tert-butylheptane ester (2.0 g) in 80% aqueous acetic acid (50 ml). The mixture was stirred at ambient temperature for about 20 hours until a clear solution was obtained. The clear solution was evaporated to dryness and traces of acetic acid were removed by azeotropic distillation with toluene (3 x 50 ml) to give a powder.

Gore dobiveni prašak (200 mg, 0.32 x 10-3 mol) otopljen je u etanolu (8 ml) u koji je dodana zasićena otopina kalcij hidroksida (8 ml) koji je sadržavao tetrabutil amonij bromid (10 mg). Smjesa je miješana i zagrijavana na temperaturi od oko 45°C oko 24 sata. Dodatna zasićena otopina kalcij hidroksida (4 ml) je dodana. Nakon oko 20 minuta miješanja na temperaturi okoline, reakcija je bila potpuna. Čistoća nastalog produkta analizirana je pomoću HPLC. Bijeli talog je filtriran u vakuumu i sušen na temperaturi od oko 65°C oko 18 sati. Nakon sušenja, iskorištenje je bilo 77% atorvastatin kalcij soli (142 mg). The powder obtained above (200 mg, 0.32 x 10-3 mol) was dissolved in ethanol (8 ml) to which was added a saturated solution of calcium hydroxide (8 ml) containing tetrabutyl ammonium bromide (10 mg). The mixture was mixed and heated at a temperature of about 45°C for about 24 hours. Additional saturated calcium hydroxide solution (4 ml) was added. After about 20 minutes of stirring at ambient temperature, the reaction was complete. The purity of the resulting product was analyzed by HPLC. The white precipitate was filtered under vacuum and dried at a temperature of about 65°C for about 18 hours. After drying, the recovery was 77% of atorvastatin calcium salt (142 mg).

Primjer 2 Example 2

Preparacija atorvastatin kalcija iz dioksan ester derivata Preparation of atorvastatin calcium from dioxane ester derivative

U tikvici opremljenoj magnetskom miješalicom suspendiran je [R-(R*,R*)]-2-(4-fluorfenil)-β,δ-dioksan-5-(1-metiletil)-3-fenil-4-[(fenilamino)karbonil]-1H-pirol-1-terc-butilheptanski ester (10.0 g, 15.29 × 10-3 mmol) u 80% vodenoj otopini octene kiseline (150 ml). Smjesa je miješana na temperaturi okoline preko noći dok nije dobivena bistra otopina. Bistra otopina uparena je do suhog i tragovi octene kiseline uklonjeni su azeotropnom destilacijom s toluenom (3 x 100 ml) da se dobije uljast produkt koji sadrži toluen. [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino )carbonyl]-1H-pyrrole-1-tert-butylheptane ester (10.0 g, 15.29 × 10-3 mmol) in 80% aqueous acetic acid (150 ml). The mixture was stirred at ambient temperature overnight until a clear solution was obtained. The clear solution was evaporated to dryness and traces of acetic acid were removed by azeotropic distillation with toluene (3 x 100 ml) to give an oily product containing toluene.

Uljasti produkt je stavljen u smjesu etanola (100 ml) i vode (20 ml). Dodana je smjesa kalcij hidroksida (5.5 ekv., 6.22 9, 84.0 × 10-3 mol) i 5% (w/w dioksan ester derivata) tetrabutil amonij bromida (0.46 g). Smjesa je zagrijavana na temperaturi od oko 45°C oko 3 sata dok reakcija nije bila završena. Dok je smjesa bila vruća, provedeno je filtriranje u vakuumu da se ukloni suvišak kalcij hidroksida. Smjesa je onda ohlađena do temperature okoline nakon čega je, uz miješanje, dodana voda (200 ml). Nakon oko 20 minuta miješanja na temperaturi okoline, reakcija je bila potpuna. Čistoća nastalog produkta analizirana je pomoću HPLC. Bijeli talog je filtriran u vakuumu i sušen na temperaturi od oko 65°C oko 18 sati. Nakon sušenja, iskorištenje je bilo 84% atorvastatin kalcij soli (7.44 g). The oily product was placed in a mixture of ethanol (100 ml) and water (20 ml). A mixture of calcium hydroxide (5.5 eq., 6.22 9, 84.0 × 10-3 mol) and 5% (w/w dioxane ester derivative) tetrabutyl ammonium bromide (0.46 g) was added. The mixture was heated at a temperature of about 45°C for about 3 hours until the reaction was complete. While the mixture was hot, vacuum filtration was performed to remove excess calcium hydroxide. The mixture was then cooled to ambient temperature, after which water (200 ml) was added with stirring. After about 20 minutes of stirring at ambient temperature, the reaction was complete. The purity of the resulting product was analyzed by HPLC. The white precipitate was filtered under vacuum and dried at a temperature of about 65°C for about 18 hours. After drying, the yield was 84% of atorvastatin calcium salt (7.44 g).

Primjer 3 Example 3

Preparacija atorvastatin kalcija iz dioksan ester derivata Preparation of atorvastatin calcium from dioxane ester derivative

U tikvici opremljenoj magnetskom miješalicom otopljen je [R-(R*,R*)]-2-(4-fluorfenil)-β,δ-dioksan-5-(1-metiletil)-3-fenil-4-[(fenilamino) karbonil]-1H-pirol-1-terc-butilheptanski ester (0.5 g, 0.76 × 10-3 mol) u 1:1 smjesi trifluorctena kiselina -tetrahidrofuran (4 ml) u prisutnosti katalitičke količine vode. Reakcijska smjesa je miješana na temperaturi okoline 24 sata. Dobivena otopina je uparena i tragovi trifluorctene kiseline uklonjeni su azeotropnom destilacijom s eterom (3 × 10 ml). Dobivena je bijela krutina (0.3 g). Temeljeno na HPLC analizi, bijela krutina bila je smjesa atorvastatina i atorvastatin laktona u omjeru 40 : 60, istim redom. [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino ) carbonyl]-1H-pyrrole-1-tert-butylheptane ester (0.5 g, 0.76 × 10-3 mol) in a 1:1 mixture of trifluoroacetic acid-tetrahydrofuran (4 ml) in the presence of a catalytic amount of water. The reaction mixture was stirred at ambient temperature for 24 hours. The resulting solution was evaporated and traces of trifluoroacetic acid were removed by azeotropic distillation with ether (3 × 10 ml). A white solid (0.3 g) was obtained. Based on HPLC analysis, the white solid was a 40:60 mixture of atorvastatin and atorvastatin lactone, respectively.

Primjer 4 Example 4

Preparacija atorvastatin kalcij a iz dioksan ester derivata Preparation of atorvastatin calcium from dioxane ester derivative

U tikvici opremljenoj magnetskom miješalicom otopljen je [R-(R*,R*)]-2-(4-fluorfenil)-β,δ-dioksan-5-(1-metiletil)-3-fenil-4-[(fenilamino)karbonil]-1H-pirol-1-terc-butilheptanski ester (0.2 g, 0.30 × 10-3 mol) i cink bromid (3,5 ekv, 1.07 × 10-3 mol) u diklormetanu (5 ml). Reakcijska smjesa je miješana na temperaturi okoline 24 sata. Voda (30 ml) je dodana i smjesa miješana oko 3 sata. Vodeni sloj je ekstrahiran diklormetanom (3 x 10 ml), dok je organski sloj osušen natrij sulfatom i filtriran. Organski sloj je onda uparen pod sniženim tlakom da se dobije nastali produkt (150 mg). Temeljeno na HPLC analizi, nastali produkt bio je smjesa atorvastatina i atorvastatin laktona u omjeru 57 : 43, istim redom. [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino )carbonyl]-1H-pyrrole-1-tert-butylheptane ester (0.2 g, 0.30 × 10-3 mol) and zinc bromide (3.5 eq, 1.07 × 10-3 mol) in dichloromethane (5 ml). The reaction mixture was stirred at ambient temperature for 24 hours. Water (30 ml) was added and the mixture was stirred for about 3 hours. The aqueous layer was extracted with dichloromethane (3 x 10 ml), while the organic layer was dried with sodium sulfate and filtered. The organic layer was then evaporated under reduced pressure to give the resulting product (150 mg). Based on HPLC analysis, the resulting product was a mixture of atorvastatin and atorvastatin lactone in a ratio of 57:43, in the same order.

Primjer 5 Example 5

Preparacija atorvastatin kalcija iz dioksan ester derivata Preparation of atorvastatin calcium from dioxane ester derivative

U tikvici opremljenoj magnetskom miješalicom suspendiran je [R-(R*,R*)]-2-(4-fluorfenil)-β,δ-dioksan-5-(1-metiletil)-3-fenil-4-[(fenilamino) karbonil]-1H-pirol-1-terc-butilheptanski ester (0.2 g) u 90% vodenoj otopini octene kiseline (4 ml). Smjesa je miješana na temperaturi oko 50°C oko 5 dana. Nastala otopina je uparena do suhog i tragovi octene kiseline uklonjeni su azeotropnom destilacijom s toluenom (3 x 15 ml) da se dobije prašak. Temeljeno na HPLC analizi, nastali produkt bio je smjesa atorvastatina i atorvastatin laktona u omjeru 54 : 46, istim redom. [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino ) carbonyl]-1H-pyrrole-1-tert-butylheptane ester (0.2 g) in 90% aqueous acetic acid solution (4 ml). The mixture was stirred at a temperature of about 50°C for about 5 days. The resulting solution was evaporated to dryness and traces of acetic acid were removed by azeotropic distillation with toluene (3 x 15 ml) to give a powder. Based on HPLC analysis, the resulting product was a mixture of atorvastatin and atorvastatin lactone in a ratio of 54:46, in the same order.

Primjer 6 Example 6

Preparacija atorvastatin kalcija iz dioksan ester derivata Preparation of atorvastatin calcium from dioxane ester derivative

U tikvici opremljenoj magnetskom miješalicom otopljena je 3% vodena otopina kloridne kiseline (1 ml) i [R-(R*,R*)]-2-(4-fluorfenil)-β,δ-dioksan-5-(1-metiletil)-3-fenil-4-[(fenilamino)karbonil]-1H-pirol-1-terc-butilheptanski ester (0.2 g) u metanolu (2 ml). Smjesa je miješana na temperaturi oko 110°C oko 4 sata i onda miješana preko noći na temperaturi okoline. Nastala otopina je uparena do suhog da se dobije prašak. Temeljeno na HPLC analizi, nastali produkt bio je smjesa atorvastatina i atorvastatin laktona u omjeru 54 : 46, istim redom. A 3% aqueous solution of hydrochloric acid (1 ml) and [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl) were dissolved in a flask equipped with a magnetic stirrer. )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptane ester (0.2 g) in methanol (2 ml). The mixture was stirred at a temperature of about 110°C for about 4 hours and then stirred overnight at ambient temperature. The resulting solution was evaporated to dryness to obtain a powder. Based on HPLC analysis, the resulting product was a mixture of atorvastatin and atorvastatin lactone in a ratio of 54:46, in the same order.

Primjer 7 Example 7

Preparacija rosuvastatin kalcija iz esterskog derivata Preparation of rosuvastatin calcium from an ester derivative

U tikvici opremljenoj magnetskom miješalicom otopljen je metil 7-[4-(4-fluorfenil)-6-izopropil-2-(N-metil-N-metilsulfonilamino)pirimidin-5-il]-(3R,5S)-dihidroksi-(E)-6-heptenoat u etanolu u koji je dodana zasićena otopina kalcij hidroksida koja sadrži 5% (w/w esterskog derivata) tetrabutil amonij bromida. Smjesa je miješana i zagrijavana na temperaturi oko 45°C oko 24 sata. Dodana je dodatna zasićena otopina kalcij hidroksida. Nakon oko 20 minuta miješanja na temperaturi okoline, reakcija je bila potpuna, što je dovelo do nastajanja rosuvastatin kalcija. Methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-( E)-6-heptenoate in ethanol to which was added a saturated calcium hydroxide solution containing 5% (w/w ester derivative) tetrabutyl ammonium bromide. The mixture was mixed and heated at a temperature of about 45°C for about 24 hours. Additional saturated calcium hydroxide solution was added. After about 20 minutes of stirring at ambient temperature, the reaction was complete, leading to the formation of rosuvastatin calcium.

Primjer 8 Example 8

Preparacija rosuvastatin kalcija iz esterskog derivata Preparation of rosuvastatin calcium from an ester derivative

U tikvici opremljenoj magnetskom miješalicom metil 7-[4-(4-fluorfenil)-6-izopropil-2-(N-metil-N-metilsulfonilamino)pirimidin-5-il]-(3R,5S)-dihidroksi-(E)-6-heptenoat stavljen je u smjesu etanola i vode. Doda se smjesa kalcij hidroksida i 5% (w/w esterskog derivata) tetrabutil amonij bromida. Smjesa je zagrijavana na temperaturi oko 45°C oko 3 sata dok reakcija nije bila potpuna. Dok je smjesa vruća, provede se filtriranje u vakuumu da se ukloni suvišak kalcij hidroksida. Smjesa se onda ohladi do temperature okoline nakon čega, uz miješanje, doda se voda, Nakon oko 20 minuta miješanja na temperaturi okoline, reakcija je potpuna, što je dovelo do nastajanja rosuvastatin kalcija. In a flask equipped with a magnetic stirrer, methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E) -6-heptenoate was placed in a mixture of ethanol and water. A mixture of calcium hydroxide and 5% (w/w ester derivative) tetrabutyl ammonium bromide is added. The mixture was heated at a temperature of about 45°C for about 3 hours until the reaction was complete. While the mixture is hot, vacuum filtration is carried out to remove excess calcium hydroxide. The mixture is then cooled to ambient temperature after which, with stirring, water is added. After about 20 minutes of stirring at ambient temperature, the reaction is complete, leading to the formation of rosuvastatin calcium.

Primjer 9 Example 9

Preparacija pitavastatin kalcija iz esterskog derivata Preparation of pitavastatin calcium from the ester derivative

U tikvici opremljenoj magnetskom miješalicom otopi se etil (E)-3,5-dihidroksi-7-[4'-(4"-fluorfenil)-2'-ciklopropil-kinolin-3'-il]-hept-6-enoat u etanolu u koji se doda zasićena otopina kalcij hidroksida koja sadrži 5% (w/w esterskog derivata) tetrabutil amonij bromida. Smjesa je miješana i zagrijavana na temperaturi oko 45°C oko 24 sata. Dodana je dodatna zasićena otopina kalcij hidroksida. Nakon oko 20 minuta miješanja na temperaturi okoline, reakcija je bila potpuna, sto je dovelo do nastajanja pitavastatin kalcija. In a flask equipped with a magnetic stirrer, ethyl (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-cyclopropyl-quinolin-3'-yl]-hept-6-enoate is dissolved in ethanol to which a saturated solution of calcium hydroxide containing 5% (w/w ester derivative) of tetrabutyl ammonium bromide was added. The mixture was stirred and heated at a temperature of about 45°C for about 24 hours. An additional saturated solution of calcium hydroxide was added. After about 20 minutes of stirring at ambient temperature, the reaction was complete, leading to the formation of pitavastatin calcium.

Primjer 10 Example 10

Preparacija pitavastatin kalcija iz esterskog derivata Preparation of pitavastatin calcium from the ester derivative

U tikvici opremljenoj magnetskom miješalicom etil (E)-3,5-dihidroksi-7-[4'-(4"-fluorfenil)-2'-ciklopropil-kinolin-3'-il]-hept-6-enoat stavljen je u smjesu etanola i vode. Doda se smjesa kalcij hidroksida i 5% (w/w esterskog derivata) tetrabutil amonij bromida. Smjesa je zagrijavana na temperaturi oko 45°C oko 3 sata dok reakcija nije bila potpuna. Dok je smjesa vruća, provede se filtriranje u vakuumu da se ukloni suvišak kalcij hidroksida. Smjesa se onda ohladi do temperature okoline nakon čega, uz miješanje, doda se voda. Nakon oko 20 minuta miješanja na temperaturi okoline, reakcija je potpuna, što je dovelo do nastajanja pitavastatin kalcija. In a flask equipped with a magnetic stirrer, ethyl (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-cyclopropyl-quinolin-3'-yl]-hept-6-enoate was placed in a mixture of ethanol and water. A mixture of calcium hydroxide and 5% (w/w ester derivative) tetrabutyl ammonium bromide was added. The mixture was heated at a temperature of about 45°C for about 3 hours until the reaction was complete. While the mixture was hot, filtration was carried out in vacuo to remove excess calcium hydroxide. The mixture was then cooled to ambient temperature after which water was added with stirring. After about 20 minutes of stirring at ambient temperature, the reaction was complete, leading to the formation of pitavastatin calcium.

Kada je tako opisan izum s obzirom na pojedine preferirane izvedbe i ilustriran primjerima, stručnjak u području može uvažit i modifikacije izuma kako je opisan i ilustriran koje ne odstupaju od duha i dometa izuma kako je iznesen u specifikaciji. Primjeri su dani da pomognu u razumijevanju izuma, ali nisu namijenjeni, i ne treba ih tako tumačiti, da ograniče njegov domet na bilo koji način. Primjeri ne uključuju detaljne opise konvencionalnih metoda. Takve metode su dobro poznate onima s običnim znanjem u području i opisane su u brojnim publikacijama. Sve reference ovdje su uključene u svojoj potpunosti. When the invention is thus described with regard to certain preferred embodiments and illustrated by examples, the expert in the field can also appreciate modifications of the invention as described and illustrated that do not deviate from the spirit and scope of the invention as stated in the specification. The examples are provided to assist in the understanding of the invention, but are not intended, and should not be construed, to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. All references are incorporated herein in their entirety.

Claims (42)

1. Postupak za preparaciju kalcij soli statina formule: [image] gdje R predstavlja organski radikal naznačen time da obuhvaća dovođenje u kontakt ester derivata statina izabranog iz skupine koja se sastoji od: [image] i [image] s dovoljnom količinom kalcij hidroksida gdje R je C1 do C8 alkil skupina, i R2, R3 i R4 svaki neovisno predstavljaju atom vodika ili istu ili različitu zaštitnu skupinu koja se može hidrolizirati, ili R2 i R3, zajedno s atomom kisika na koji je svaki vezan, tvore cikličku zaštitnu skupinu koja se može hidrolizirati.1. Procedure for the preparation of calcium salts of statin formulas: [image] where R represents an organic radical characterized in that it comprises bringing into contact an ester derivative of a statin selected from the group consisting of: [image] and [image] with a sufficient amount of calcium hydroxide where R is a C1 to C8 alkyl group, and R 2 , R 3 and R 4 each independently represent a hydrogen atom or the same or a different hydrolyzable protecting group, or R 2 and R 3 , together with the oxygen atom to which each is attached, form a cyclic hydrolyzable protecting group. 2. Postupak prema patentnom zahtjevu 1 naznačen time da R je organski radikal iz statina izabranog iz grupe koja se sastoji od pravastatina, fluvastatina, cerivastatina, atorvastatina, rosuvastatina, pitavastatina, simvastatina i lovastatina.2. The method according to patent claim 1 characterized in that R is an organic radical from a statin selected from the group consisting of pravastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin, pitavastatin, simvastatin and lovastatin. 3. Postupak prema patentnom zahtjevu 2 naznačen time da se statin izabere iz grupe koja se sastoji od atorvastatina, rosuvastatina, pitavastatina i simvastatina.3. The method according to patent claim 2 characterized in that the statin is selected from the group consisting of atorvastatin, rosuvastatin, pitavastatin and simvastatin. 4. Postupak prema patentnom zahtjevu 3 naznačen time da je statin rosuvastatin.4. The method according to patent claim 3 characterized in that the statin is rosuvastatin. 5. Postupak prema patentnom zahtjevu 3 naznačen time da je statin pitavastatin.5. The method according to patent claim 3 characterized in that the statin is pitavastatin. 6. Postupak prema patentnom zahtjevu 3 naznačen time da je statin simvastatin.6. The method according to claim 3, characterized in that the statin is simvastatin. 7. Postupak prema patentnom zahtjevu 3 naznačen time da je statin atorvastatin.7. The method according to claim 3, characterized in that the statin is atorvastatin. 8. Postupak prema patentnom zahtjevu 1 naznačen time da se postupak provodi u smjesi vode i C1 do C4 alkohola.8. The process according to patent claim 1 characterized in that the process is carried out in a mixture of water and C1 to C4 alcohol. 9. Postupak prema patentnom zahtjevu 1 naznačen time da se dovodi u kontakt kod povišene temperature.9. The method according to patent claim 1 characterized in that it is brought into contact at an elevated temperature. 10. Postupak prema patentnom zahtjevu 1 naznačen time da se dovođenje u kontakt odvija u prisutnosti katalizatora faznog prijelaza.10. The method according to patent claim 1 characterized in that the bringing into contact takes place in the presence of a phase transition catalyst. 11. Postupak prema patentnom zahtjevu 1 naznačen time da dalje obuhvaća korak izoliranja kalcijeve soli statina.11. The method according to patent claim 1 characterized in that it further comprises the step of isolating the calcium salt of the statin. 12. Postupak prema patentnom zahtjevu 1 naznačen time da R2 i R3 su oba atom vodika.12. The method according to patent claim 1 characterized in that R2 and R3 are both hydrogen atoms. 13. Postupak prema patentnom zahtjevu 1 naznačen time da R4 je atom vodika.13. The method according to claim 1, characterized in that R4 is a hydrogen atom. 14. Postupak prema patentnom zahtjevu 1 naznačen time da najmanje jedan od R2 ili R3 je trialkilsilil zaštitna skupina.14. The method according to patent claim 1 characterized in that at least one of R2 or R3 is a trialkylsilyl protecting group. 15. Postupak prema patentnom zahtjevu 1 naznačen time daR4je trialkilailil zaštitna skupina.15. The method according to patent claim 1 characterized in that R4 is a trialkylallyl protecting group. 16. Postupak prema patentnom zahtjevu 1 naznačen time da dalje obuhvaća prethodni korak dovođenja esterskog derivata u kontakt, gdje esterski derivat ima najmanje jednu zaštitnu skupinu, s kiselinskim katalizatorom da se hidrolizira zaštitna skupina.16. The method according to patent claim 1 characterized in that it further comprises the previous step of bringing the ester derivative into contact, where the ester derivative has at least one protecting group, with an acid catalyst to hydrolyze the protecting group. 17. Postupak prema patentnom zahtjevu 16 naznačen time da esterski derivat ima formulu: [image] 17. The method according to patent claim 16 characterized in that the ester derivative has the formula: [image] 18. Postupak prema patentnom zahtjevu 17 naznačen time da R je organski radikal iz atorvastatina.18. The method according to patent claim 17 characterized in that R is an organic radical from atorvastatin. 19. Farmaceutska kompozicija naznačen time da obuhvaća statinsku sol priređenu postupkom prema patentnom zahtjevu 1 i farmaceutski prihvatljiv ekscipijent.19. A pharmaceutical composition characterized in that it comprises a statin salt prepared by the process according to patent claim 1 and a pharmaceutically acceptable excipient. 20. Postupak za preparaciju rosuvastatin kalcij soli naznačen time da obuhvaća dovođenje u kontakt C1 do C8 eatera 7-[4-(4-fluorfenil)-6-izopropil-2-(N-metil-N-metilsulfonilamino)pirimidin-5-il]-(3R,5S)-dihidroksi-(E)-6-heptenoata s dovoljnom količinom kalcij hidroksida.20. Process for the preparation of rosuvastatin calcium salt characterized in that it comprises bringing into contact C1 to C8 ether 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl ]-(3R,5S)-dihydroxy-(E)-6-heptenoate with a sufficient amount of calcium hydroxide. 21. Postupak za preparaciju rosuvastatin kalcij soli naznačen time da obuhvaća dovođenje u kontakt laktonske forme rosuvastatina s dovoljnom količinom kalcij hidroksida.21. The method for the preparation of rosuvastatin calcium salt characterized in that it comprises bringing the lactone form of rosuvastatin into contact with a sufficient amount of calcium hydroxide. 22. Postupak za preparaciju pitavastatin kalcij sol naznačen time da obuhvaća dovođenje u kontakt C1 do C8 estera (E)-3,5-dihodroksi-7-[4'-(4''-fluorfenil)-2'-(1"-ciklopropil)-kinolin-3'-il]-hept-6-enoata s dovoljnom količinom kalcij hidroksida.22. Process for the preparation of pitavastatin calcium salt characterized in that it comprises bringing into contact C1 to C8 ester (E)-3,5-dihydroxy-7-[4'-(4''-fluorophenyl)-2'-(1"- cyclopropyl)-quinolin-3'-yl]-hept-6-enoate with a sufficient amount of calcium hydroxide. 23. Postupak za preparaciju pitavastatin kalcij sol naznačen time da obuhvaća dovođenje u kontakt laktonske forme pitavastatina s dovoljnom količinom kalcij hidroksida.23. A process for the preparation of pitavastatin calcium salt characterized in that it includes contacting the lactone form of pitavastatin with a sufficient amount of calcium hydroxide. 24. Postupak za preparaciju kalcijeve soli statina formule: [image] gdje R predstavlja organski radikal naznačen time da obuhvaća krake: a) dodavanje kalcij hidroksida i esterskog derivata statina izabranog iz grupe koja se sastoj i od: [image] i [image] u smjesu vode C1 do C4 alkohola, gdje R je C1 do C8 alkil skupina i R2, R3 i R4 svaki neovisno predstavljaju atom vodika ili istu ili različitu zaštitnu skupinu koja se može hidrolizirati, ili R2 i R3, zajedno s atomom kisika na koji je svaki vezan, tvore cikličku zaštitnu skupinu koja se može hidrolizirati; b) zagrijavanje smjese; c) taloženje kalcij soli statina; i d) odvajanje kalcij soli.24. Procedure for the preparation of the calcium salt of the statin formula: [image] where R represents an organic radical characterized by including arms: a) addition of calcium hydroxide and an ester derivative of a statin selected from the group consisting of: [image] and [image] into a mixture of water and C1 to C4 alcohol, where R is a C1 to C8 alkyl group and R 2 , R 3 , and R 4 each independently represent a hydrogen atom or the same or a different hydrolyzable protecting group, or R 2 and R 3 , together with the oxygen atom to which each is attached, form a hydrolyzable cyclic protecting group; b) heating the mixture; c) precipitation of statin calcium salts; and d) separation of calcium salts. 25. Postupak prema patentnom zahtjevu 24 naznačen time da R je organski radikal iz statina izabranog iz grupe koja se sastoji od pravastatina, fluvastatina, cerivastatina, atorvastatina, rosuvastatina, pitavastatina, simvastatina i lovastatina.25. The method according to patent claim 24 characterized in that R is an organic radical from a statin selected from the group consisting of pravastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin, pitavastatin, simvastatin and lovastatin. 26. Postupak prema patentnom zahtjevu 25 naznačen time da se statin izabere iz grupe koja se sastoji od atorvastatina, rosuvastatina, pitavastatina i simvastatina.26. The method according to patent claim 25 characterized in that the statin is selected from the group consisting of atorvastatin, rosuvastatin, pitavastatin and simvastatin. 27. Postupak prema patentnom zahtjevu 26 naznačen time da je statin rosuvastatin.27. The method according to claim 26, characterized in that the statin is rosuvastatin. 28. Postupak prema patentnom zahtjevu 26 naznačen time da je statin pitavastatin.28. The method according to claim 26, characterized in that the statin is pitavastatin. 29. Postupak prema patentnom zahtjevu 26 naznačen time da je statin simvastatin.29. The method according to claim 26, characterized in that the statin is simvastatin. 30. Postupak prema patentnom zahtjevu 26 naznačen time da je statin atorvastatin.30. The method according to claim 26, characterized in that the statin is atorvastatin. 31. Postupak prema patentnom zahtjevu 24 naznačen time da R2 i rs su oba atom vodika.31. The method according to patent claim 24 characterized in that R2 and rs are both hydrogen atoms. 32. Postupak prema patentnom zahtjevu 24 naznačen time daR4je atom vodika.32. The method according to claim 24, characterized in that R4 is a hydrogen atom. 33. Postupak prema patentnom zahtjevu 24 naznačen time da najmanje jedan od R2 ili R3 je trialkilsilil zaštitna skupina.33. The method according to patent claim 24 characterized in that at least one of R2 or R3 is a trialkylsilyl protecting group. 34. Postupak prema patentnom zahtjevu 24 naznačen time da R4 je trialkilsilil zaštitna skupina.34. The method according to patent claim 24 characterized in that R4 is a trialkylsilyl protecting group. 35. Postupak prema patentnom zahtjevu 24 naznačen time da dalje obuhvaća prethodni korak dovođenja esterskog derivata u kontakt, gdje esterski derivat ima najmanje jednu zaštitnu skupinu, s kiselinskim katalizatorom da se hidrolizira zaštitna skupina.35. The method according to patent claim 24 characterized in that it further comprises the previous step of bringing the ester derivative into contact, where the ester derivative has at least one protecting group, with an acid catalyst to hydrolyze the protecting group. 36. Postupak prema patentnom zahtjevu 35 naznačen time da ester derivat ima formulu: [image] 36. The method according to patent claim 35 characterized in that the ester derivative has the formula: [image] 37. Postupak prema patentnom zahtjevu 36 naznačen time da R je organski radikal iz atorvastatina.37. The method according to patent claim 36 characterized in that R is an organic radical from atorvastatin. 38. Postupak prema patentnom zahtjevu 24 naznačen time da smjesa vode i alkohola je od oko 5% do oko 20% smjesa vode i alkohola (v/v).38. The method according to patent claim 24 characterized in that the mixture of water and alcohol is from about 5% to about 20% mixture of water and alcohol (v/v). 39. Postupak prema patentnom zahtjevu 24 naznačen time da dalje obuhvaća dodavanje katalizatora faznog prijelaza u smjesu koraka (a).39. The method according to patent claim 24 characterized in that it further comprises the addition of a phase transition catalyst to the mixture of step (a). 40. Postupak prema patentnom zahtjevu 24 naznačen time da se smjesa zagrijava od oko 40°C do oko 70°C.40. The method according to patent claim 24 characterized in that the mixture is heated from about 40°C to about 70°C. 41. Postupak prema patentnom zahtjevu 24 naznačen time da dalje obuhvaća korak filtriranja između koraka (b) i (c).41. The method according to patent claim 24 characterized in that it further comprises a filtering step between steps (b) and (c). 42. Postupak prema patentnom zahtjevu 24 naznačen time da se taloženje događa dodavanjem vode.42. The method according to patent claim 24 characterized in that precipitation occurs by adding water.
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