sign in sign up
<<
Home , Acipimox

(19) TZZ Z_¥__T

(11) EP 2 013 188 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 239/42 (2006.01) A61K 31/505 (2006.01) 07.09.2016 Bulletin 2016/36 A61P 3/06 (2006.01)

(21) Application number: 07733847.3 (86) International application number: PCT/HU2007/000030 (22) Date of filing: 12.04.2007 (87) International publication number: WO 2007/119085 (25.10.2007 Gazette 2007/43)

(54) ZINC SALT ROSUVASTATIN-ZINKSALZ SEL DE ZINC DE ROSUVASTATINE

(84) Designated Contracting States: • TÁPAI, Sándorné AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 2230 Gyömrö (HU) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR (74) Representative: Stolmár & Partner Designated Extension States: Patentanwälte PartG mbB et al AL BA HR MK RS Blumenstraße 17 80331 München (DE) (30) Priority: 13.04.2006 HU 0600293 (56) References cited: (43) Date of publication of application: EP-A- 1 336 405 WO-A-01/60804 14.01.2009 Bulletin 2009/03 WO-A-03/068739 WO-A-2004/108691 WO-A-2006/017698 (73) Proprietor: Egis Gyógyszergyár Nyilvánosan Múködö • DATABASE WPI Derwent Publications Ltd., Részvénytársaság London, GB; AN 2006-089591 XP002448430 1106 Budapest (HU) ZHAO ZHIQUAN [CN]: "An Anti-hyperlipemia Composition" & WO 2005/123082 A (LUNAN (72) Inventors: PHARMACEUTICAL COMPANY L [CN];) 2005 • VÁGÓ, Pál • GRAUL A ET AL: " CALCIUM" 1173 Budapest (HU) DRUGS OF THE FUTURE, BARCELONA, ES, vol. • SIMIG, Gyula 22, no. 9, 1997, pages 956-968, XP000904817 1126 Budapest (HU) ISSN: 0377-8282 • CLEMENTIS, György 1118 Budapest (HU) Remarks: • TÖMPE, Péter Thefile contains technical information submitted after 1116 Budapest (HU) the application was filed and not included in this specification

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 013 188 B1

Printed by Jouve, 75001 PARIS (FR) EP 2 013 188 B1

Description

FIELD OF THE INVENTION

5 [0001] The present invention relates to the zinc salt of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl- sulphonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenecarboxylic acid of the Formula (I),

10

15

20

25 its hydrates, process for their preparation, medicinal products containing said salts and the use of said salts in the medicine.

(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl-sulphonyl- amino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6- 30 heptene-carboxylic acid of the Formula (II)

[0002]

35

40

45

50 is known under the International Nonproprietary Name (INN) rosuvastatin.

TECHNICAL BACKGROUND OF THE INVENTION

[0003] Rosuvastatin of the Formula (II) has been disclosed for the first time in European Patent No. 521471. The 55 calcium salt of rosuvastatin is used in the medicine for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. [0004] The health authorities are setting strict quality criteria towards pharmaceutically active ingredients. Some of these criteria are related to the chemical purity and stability of the pharmaceutically active ingredients. Other official

2 EP 2 013 188 B1

requirement is the manufacture of the medicinal product in satisfactory quality and that the medicinal product shall have appropriate stability. Such criteria are determined by and published in the corresponding articles of pharmacopoeias. [0005] In the case of rosuvastatin of the Formula (II), basic requirements for the active pharmaceutical ingredient intended for the use in medicinal products are high purity, appropriate stability and the possibility of simple formulation. 5 [0006] According to published International Patent Application No. WO 00/042024, the amorphous rosuvastatin of the Formula (II) obtained according to the process of European Patent No. 521471 can be used in the pharmaceutical technology with great difficulties. In order to eliminate this disadvantage, crystalline forms having more advantageous physical properties than the amorphous product are prepared. The manufacture of crystalline rosuvastatin calcium salt, however, is a manufacturing process requiring high production volume and results in great loss of material. 10 [0007] The basic problem in the manufacture of the calcium salt of rosuvastatin resides in the fact that the primary product obtained is poorly filterable and can not be purified in an easy way. Published International Patent Application WO 04/14872 discloses non-crystalline product having advantageous filterability. According to the process of said ap- plication, the calcium salt of advantageous particle size is prepared by reacting an alkaline metal, ammonium, methyl- ammonium or tris(hydroxymethyl)-methylammonium salt of rosuvastatin with calcium chloride in an aqeuous solution. 15 [0008] In the published International Patent Application No. WO 01/60804, there are disclosed high purity ammonium-, lithium- or magnesium salts of rosuvastatin of the Formula (II) in order to solve production problems which arose during the manufacture of amorphous rosuvastatin. Starting from the above-mentioned salts, it is possible to prepare amorphous rosuvastatin in a quality suitable for the manufacture of medicinal products. [0009] Published International Patent Application WO 2005/051921 discloses a similar process, wherein isopropy- 20 lammonium or cyclohexylammonium salts of rosuvastatin are produced in high purity and said salts are transformed into sodium salt or high purity amorphous calcium salt of rosuvastatin. [0010] Published International Patent Application No. WO 2005/040134 discloses amorphous rosuvastatin calcium salt of high diastereomeric purity. [0011] In WO 2005/123082 A1 is described a pharmaceutical composition comprising acipimox and rosuvastatin or 25 its pharmaceutically acceptable salts, esters or solvates. As preferred rosuvastatin salts are mentioned sodium salts, calcium salts, potassium salts, magnesium salts, zinc salts, and iron salts. As suitable rosuvastatin esters are mentioned esters formed with aliphatic alcohols, aromatic alcohols, heterocyclic alcohols, in particular methyl esters, ethyl esters, allyl esters, phenyl esters of rosuvastatin. [0012] WO 2004/108691 A1 describes a process for the production of rosuvastatin calcium (2:1). 30 [0013] The process comprises the following steps:

a) reaction of a (1-6C) alkyl ester of (E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] py- rimidin-5-yl] vinyl} (4R, 6S) -2, 2-dimethyl [1, 3] dioxan-4-yl) acetic acid in a water miscible organic solvent with aqueous acid at an elevated temperature; 35 b) reaction of the resulting solution with an aqueous alkali metal hydroxide and optionally washing the resulting aqueous alkali metal salt solution with a suitable organic solvent;

c) adjustment of the pH of the resulting solution to between pH6 and pH 11; 40 d) removal of the water miscible organic solvent;

e) optional filtration of the resulting mixture;

45 f) addition of a water soluble calcium salt to the filtrate so as to form (E)-7- [4-(4- fluorophenyl)-6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S)-3, 5- dihydroxyhept-6-enoic acid calcium salt; and

g) isolation of the product of step f).

50 [0014] A. Graul et al. Drugs of the future 1997, 22(9), 956-968 describes the synthesis of Atorvastatin calcium, its pharmaceutical activity and clinical studies done with the compound. [0015] EP 1 336 405 describes formulations of atorvastatin stabilized with alkali metal additions. The amorphous atorvastatin may be one or more of atorvastatin calcium, atorvastatin magnesium, atorvastatin aluminum, atorvastatin iron, and atorvastatin zinc. In the examples amorphous atorvastatin and atorvastatin magnesium is used as the phar- 55 maceutical ingredient. [0016] WO 2006/017698 describes pharmaceutical compositions comprising a and an omega-3 oil. As are used , fiuvastatin, atorvastatin, , , rosuvastatin, and . Preferred statin salts are a calcium salt of pravastatin, a calcium salt of , a magnesium salt of pravastatin and a zinc salt of

3 EP 2 013 188 B1

pravastatin. [0017] WO 03/068739describes a method ofmanufacturing an amorphous formof the hemi-calcium saltof atorvastatin. [0018] According to the disclosed process, the primary product amorphous rosuvastatin calcium salt is crystallized in the first stage, the product thus obtained is subsequently transformed into the amorphous form. 5 [0019] In summary, it can be concluded that according to the state of the art, the manufacture of rosuvastatin calcium salt suitable for the preparation of medicinal products is a particularly intricate process. The crude product must be submitted to further purification and crystallization steps in order to obtain a suitable product with regard to purity and physical properties. The known processes are difficult to operate in an industrial scale process and the use of such known processes often results in a significant loss of material and is therefore uneconomical. 10 SUMMARY OF THE INVENTION

[0020] The objective of our research-development work was to develop a new salt of [(+)-7-[4-(4-fluorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenecarboxylic acid of the 15 Formula (II) having high stability which maintains or enhances the pharmacological effect characteristic to the group of statins and which can be prepared in a quality suitable for the manufacture of medicinal products. [0021] The above objective is solved according to the present invention. [0022] The basis of the present invention is the surprising recognition that the zinc salt of (+)-7-[4-(4-fluorophenyl)-6- isopropyl-2-(N-methyl-N-methyl-sulphonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenecarboxylic acid of the 20 Formula (I) and its hydrated forms satisfy all the above criteria, since said salt is suitable for the production of medicinal products, has excellent stability towards heat and light and can be produced in high purity by industrially convenient processes.

DETAILED DESCRIPTION OF THE INVENTION 25 [0023] According to the first aspect of the present invention, there is provided the rosuvastatin zinc salt of the Formula (I), which can be prepared in high purity directly suitable for the manufacture of medicinal products. Rosuvastatin zinc salt of the Formula (I) is new. [0024] The advantage of the rosuvastatin zinc salt of the Formula (I) compared to the calcium salt of rosuvastatin 30 known according to the state of the art resides in the fact that the zinc salt can be prepared in high quality, by a simple process which can be easily scaled up to industrial production. Further advantage of the rosuvastatin zinc salt is that it can be manipulated very easily and that the pre-treatment of the primary product for pharmaceutical formulation does not require further processing. [0025] Rosuvastatin zinc salt of the Formula (I) is stable towards heat and light, which is an advantage during phar- 35 maceutical processing, formulation and during the use as medicine. The product can be advatageously used for the treatment of the disorders of lipid metabolism, such as hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. [0026] According to the second aspect of the present invention, there is provided a process for the preparation of rosuvastatin zinc salt of the Formula (I), which comprises reacting rosuvastatin of the Formula (II) with a zinc compound. [0027] According to the first process variant suitable for the preparation of rosuvastatin zinc salt of the Formula (I), 40 (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl-sulphonyl-amino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6- heptenecarboxylic acid of the Formula (II) is reacted with a zinc alcoholate and the rosuvastatin zinc of the Formula (I) thus obtained is isolated. [0028] As zinc alcoholate, a compound of the Formula (III)

45 R-O-Zn-O-RIII

wherein R represents a straight or branched-chain alkyl group comprising 1 to 4 carbon atoms, can be used in a 0.5 to 0.6 molar equivalent amount calculated on the basis of the molar amount of rosuvastatin of the Formula (II). 50 [0029] The reaction is carried out in a solvent. Suitable solvents are aliphatic alcohols comprising 1 to 4 carbon atoms, e.g. methanol, ethanol, 2-propanol or 1-butanol; aliphatic ketones comprising 3 to 8 carbon atoms; aliphatic esters comprising 2 to 8 carbon atoms or aliphatic ethers comprising 4 to 8 carbon atoms or the mixtures thereof. [0030] The preparation of the salt is carried out at a temperature between room temperature and the boiling temperature of the solvent, preferably at a temperature between 25 and 50 °C. 55 [0031] The product is isolated by evaporating the solvent. Optionally the solution can be treated with silica gel before the solvent evaporation. The evaporation residue is triturated with a large excess of an ether comprising 4 to 8 carbon atoms, preferably with diethyl ether and the solids thus obtained are filtered. [0032] A second possibility to isolate the product is dissolving the evaporation residue obtained without silica treatment

4 EP 2 013 188 B1

in an aliphatic ester comprising 2 to 8 carbon atoms and treating the thus obtained solution with silica. After repeated filtration, the solvent is partly evaporated and the residue is stirred with a large excess of an ether comprising 4 to 8 carbon atoms, preferably with diethyl ether and the precipitated product is filtered. [0033] According to the second process variant, rosuvastatin of the Formula (II) is reacted with a zinc enolate of the 5 Formula (IV).

10

[0034] The zinc enolate of the Formula (IV) is used in a 0.5 to 0.6 molar equivalent amount calculated on the basis of the molar amount of rosuvastatin of the Formula (II). 15 [0035] The reaction of the compounds of the Formulae (II) and (IV) is performed in a solvent. Suitable solvents are aliphatic alcohols comprising 1 to 4 carbon atoms. The reaction can be carried out at a temperature between room temperature and the boiling temperature of the solvent, preferably between 25-40 °C. [0036] The product can be isolated by treating the solution with silica, filtering, concentrating the solution by evaporating the solvent and precipitating the product by adding a large excess of an ether comprising 4 to 8 carbon atoms, preferably 20 by the addition of diethylether. [0037] According to the third variant for the preparation of rosuvastatin zinc salt of the Formula (I), the alkali metal salt of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]-(3R,5S)- dihydroxy-(E)-6- heptenecarboxylic acid of the Formula (II) is reacted with an inorganic or organic zinc salt of inorganic or organic acids and the thus obtained product of the Formula (I) is isolated. 25 [0038] In the process, zinc salts of inorganic or organic acids are preferably selected from zinc chloride, zinc sulfate or zinc acetate. [0039] The starting substance is preferably the sodium salt of the compound of the Formula (II). [0040] The reaction can be carried out in water using a water-soluble zinc salt, e.g. zinc chloride, zinc sulfate or zinc acetate. The reaction can also be carried out in organic solvents, e.g. in aliphatic alcohols comprising 1 to 4 carbon 30 atoms; in ketones comprising 3 to 10 carbon atoms including acetone or in aliphatic nitriles, such as acetonitrile. The above-mentioned solvent can be used in the form of mixtures with each other or with water. [0041] According to a preferable embodiment of the process, zinc chloride dissolved in ethanol or in water or zinc sulfate dissolved in water are used and the reaction is carried out at a temperature between 25 and 50 °C. [0042] According to the particularly preferable embodiment of the present invention, the sodium salt of rosuvastatin 35 of the Formula (II) is reacted with a 0.5 molar equivalent amount of zinc sulfate in an aqueous solution at a temperature between 25 to 40 °C. The product is isolated from the aqueous reaction mixture either by filtration or by washing out the product from the aqueous solution using a water-immiscible solvent. Subsequently the organic phase is separated, concentrated to a small volume and the rosuvastatin zinc salt of the Formula (I) is isolated. [0043] Advantageous water-immiscible solvents for the extraction of rosuvastatin zinc salt of the Formula (I) are 40 aliphatic esters comprising 2 to 8 carbon atoms, which are good solvents for rosuvastatin zinc salt, e.g. ethylformate, ethylacetate or methylacetate. Rosuvastatin zinc salt of the Formula (I) is isolated by concentrating the extract to a small volume and precipitating rosuvastatin zinc salt by addition of an ether comprising 4 to 8 carbon atoms, preferably diethylether. [0044] The rosuvastatinzinc salt accordingto the present inventionis similar to otherrosuvastatin saltsknown according 45 to the state of the art, for example, the calcium salt in the respect that none of them have definite melting temperature. Therefore the rosuvastatin zinc salt according to the present invention is characterized in the examples by the starting temperature of the melting. [0045] Furthermore it has been found that the zinc salt of rosuvastatin according to the present invention can be obtained in anhydrous as well as in hydrated form. Rosuvastatin zinc salt of the Formula (I) is generally obtained in the 50 form of hydrate in the case when the solvent used during the preparation thereof in an aqueous solvent or solvent mixture. In the case, however, when organic solvents were used during the salt formation reaction, the anhydrous form is produced. [0046] According to a further aspect of the present invention, there are provided medicinal products comprising rosu- vastatin zinc salt of the Formula (I) in admixture with one or more pharmaceutically acceptable vehicles or auxiliary agents. 55 [0047] The medicinal products according to the present invention generally contain the active pharmaceutical ingredient in the concentration of 0.1 to 95 percent by weight, preferably, 1 to 50 percent by weight, the most advatageously 5 to 30 percent by weight. [0048] The medicinal products according to the present invention can be administered orally (e.g. in the form of

5 EP 2 013 188 B1

powders, tablets, coated tablets, chewing tablets, capsules, microcapsules, granules, dragees, lozenges, solutions, suspensions or emulsions), parenterally (e.g. as intravenous, intramuscular or intraperitoneal injections or in the form of infusions), rectally (as suppositories or retention enemas), transdermally (e.g. as patches), in the form of implants or can be administered topically (e.g. in the forms of ointments, creams or patches). The solid, semisolid or liquid medicinal 5 preparations containing the rosuvastatin zinc salt of the Formula (I) can be prepared according to the methods of pharmaceutical technology known according to the state of the art. [0049] Solid medicinal products containing rosuvastatin zinc salt of the Formula (I) prepared for oral administration can contain vehicles or filling agents (e.g. lactose, glucose, starch, calcium phosphate, microcrystalline cellulose), binding agents (e.g. gelatine, sorbitol, polyvinylpyrrollidone), disintegrants (e.g. croscarmellose, sodium carboxymethylcellulose, 10 crospovidone), tabletting aids (e.g. magnesium stearate, talc, polyethyleneglycols, s ilicic acid, silica, silicon dioxide) and surfactants (e.g. sodium laurylsulfate). [0050] Liquid medicinal products containing rosuvastatin zinc salt of the Formula (I) suitable for oral administration can be prepared in the form of solutions, syrups, suspensions or emulsions and can contain suspending agents (e.g. gelatine, carboxymethylcellulose), emulsifiers (sorbitane monooleate), solvents (e.g. water, oils, glycerol, propylene 15 glycol, ethanol), buffers (e.g. acetate, phosphate, citrate buffer) or stabilizers (e.g. methyl-4-hydroxybenzoate). [0051] Liquid medicinal products containing rosuvastatin zinc salt of the Formula (I) prepared for parenteral use are sterile isotonic solution, which can contain conserving agents and buffers besides the solvent. [0052] Semisolid medicinal products containing rosuvastatin zinc salt of the Formula (I), e.g. suppositories contain the active ingredient homogeneously dispersed in the vehicle (e.g. polyethylene glycol or coca butter) of the preparation. 20 [0053] Medicinal products containing rosuvastatin zinc salt according to the present invention as active ingredient contain said compound as unit dosage forms. [0054] A further aspect of the present invention is the use of rosuvastatin zinc salt of the Formula (I) for the manufacture of medicines. [0055] The medicinal products containing rosuvastatin zinc salt according to the present invention can be produced 25 using the methods of pharmaceutical technology known from the state of the art. The active ingredient is admixed with solid or liquid pharmaceutically acceptable vehicles or auxiliary agents and the mixture is brought to a pharmaceutical dosage form. The methods and pharmaceutically acceptable vehicles or auxiliary agents are known from the literature (Remington’s Pharmaceutical Sciences, Edition 18, Mack Publishing Co., Easton, USA, 1990). [0056] The zinc salt of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl-sulphonylamino)pyrimidin-5-yl] 30 -(3R,5S)-dihydroxy-(E)-6-heptenecarboxylic acid of the Formula (I) can be used for the treatment of hyperlipoproteinemia, hypercholesterolemia and atherosclerosis, which comprises administering the patient in need of such treatment the rosuvastatin zinc salt according to the present invention in a clinically effective dose. [0057] Further details of the present invention are disclosed in the following examples without limiting the invention itself to said examples. 35 Example 1

(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]- (3R,5S)-dihydroxy-(E)-6- heptenecarboxylic acid zinc salt (2:1) 40 [0058] 4.16 mmol (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl] -(3R,5S)-dihydroxy-(E)-6-heptenecarboxylic acid are dissolved in 70 ml methanol and 0.60 g (2.13 mmol) zinc acety- lacetonate monohydrate are added to this solution at room temperature. The reaction mixture is stirred at room temper- ature for eight hours. After this period, 1.0 g of silica are added and the reaction mixture is stirred for 30 minutes. The 45 mixture is filtered and the filtrate is concentrated to one-tenth volume by evaporating the solvent. The residue is mixed with 20-fold volume of diethylether, the precipitate is filtered, washed with diethylether and dried at 40 °C in vacuo. Thus 2.05 g (93 %) product is obtained, which starts melting at the temperature of 137 °C. IR (KBr): 3423, 1546, 1381, 1156 cm -1. HNMR (DMSO-d6, 500 MHz): δ 7.72 (dd, J=5.9 Hz, 7.7 Hz, 2H), 7.27 (t, J=8.5 Hz, 2H), 6.52 (d, J=15.9 Hz, 1H), 5.54 50 (dd, J=5.1 Hz, 15.9 Hz, 1H), 4.94 (b, 2H), 4.21 (m, 1H), 3.84 (m, 1H), 3.55 (s, 3H), 3.46 (s, 3H), 3.40 (m, 1H), 2.26 (d, J=13.7 Hz, 1H), 2.16 (dd, J=7.7 Hz, 14.5 Hz, 1H), 1.52 (m, 1H), 1.38 (m, 1H), 1.22 (d, J=6.4 Hz, 6H) ppm.

Example 2

55 (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]- (3R,5S)-dihydroxy-(E)-6- heptenecarboxylic acid zinc salt (2:1)

[0059] 3.85 g (8.0 mmol) (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]

6 EP 2 013 188 B1

-(3R,5S)-dihydroxy-(E)-6-heptenecarboxylic acid are dissolved in 40 ml of ethylacetate and to this solution are added the solution of 0.62 g (4.0 mmól) zinc ethylate in 40 ml of ethanol. The reaction mixture is refluxed for two hours. The reaction mixture is cooled, filtered and the solvent is evaporated. The residue is triturated with 50 ml of diethylether. The suspension is filtered, the solids are dissolved in 50 ml of ethylacetate and the solution is stirred with 2 g of silica gel fo r 5 three hours. The silica gel is filtered off, two-third volume of the solvent is evaporated and the residue is stirred in with tenfold volume of diethylether. The precipitated zinc salt is filtered, washed with diethylether and dried. Thus 2.8 g (68 %) of rosuvastatin zinc salt is obtained which starts melting 137°C.

Example 3 10 (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]- (3R,5S)-dihydroxy-(E)-6- heptenecarboxylic acid zinc salt (2:1)

[0060] The process disclosed in Example 2 is followed with the difference that the reaction is carried out by stirring 15 the reaction mixture at room temperature for sixteen hours. Thus 3.0 g (73 %) of rosuvastatin zinc salt are obtained.

Example 4

(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]- (3R,5S)-dihydroxy-(E)-6- 20 heptenecarboxylic acid zinc salt (2:1)

[0061] 4.16 mmol (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl] -(3R,5S)-dihydroxy-(E)-6-heptenecarboxylic acid are dissolved in 70 ml of ethylacetate and to this solution, 4.2 ml (1.0 mmol/ml) freshly prepared ethanolic sodium ethylate solution are added at room temperature. Under continous stirring, 25 the solution of 2.0 mmol zinc chloride prepared in 10 ml of ethanol are added over a period of 30 minutes. The reaction mixture is stirred for two hours at 50 °C, then cooled to room temperature and filtered. The filtrate is evaporated to one- tenth volume and the product is precipitated with tenfold volume of diethylether. Subsequently, the product is filtered and dried at 50 °C. Thus 1.8 g (86 %) of rosuvastatin zinc salt are obtained, which starts melting at 136 °C.

30 Example 5

(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]- (3R,5S)-dihydroxy-(E)-6- heptenecarboxylic acid zinc salt (2:1)

35 [0062] The title compound is prepared according to the process of Example 4 with the modification that the reaction is carried out at room temperature. Thus 1.65 g (77%), of the title compound are obtained, which starts melting at 137°C.

Example 6

40 (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]- (3R,5S)-dihydroxy-(E)-6- heptenecarboxylic acid zinc salt (2:1)

[0063] The title compound is prepared according to the process of Example 4 with the difference that as reagent, 2.0 mmol zinc sulphate dissolved in water are used and the reaction is performed at room temperature. After separation of 45 the aqeuous layer, the product is isolated by evaporating two-third of the solvent and triturating the residue in tenfold volume of diethylether. The precipitated solid is filtered and dried at the temperature of 50 °C. Thus 1.76 g (81 %) of rosuvastatin zinc salt are obtained, which starts melting at 138 °C.

50 Claims

1. (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]- (3R,5S)-dihydroxy-(E)- 6-heptenecarboxylic acid zinc salt (2:1) of the Formula (I)

55

7 EP 2 013 188 B1

5

10

15

and hydrates thereof.

20 2. Process for the preparation of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2- (N-methyl-N-methylsulphonyl-amino)pyrimi- din-5-yl]-(3R,5S)-dihydroxy- (E)-6-heptenecarboxylic acid zinc salt (2:1) of the Formula (I), which comprises reacting (+)-7- [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulphonyl-amino)pyrimidin-5-yl]-(3R,5S)-dihy- droxy-(E)-6-heptene- carboxylic acid of the Formula (II)

25

30

35

40 or a salt thereof in aqueous or organic solvent with a zinc alcoholate of the Formula (III)

R-O-Zn-O-R III

wherein the alcoholate residue contains an alkyl group having 1 to 4 carbon atoms, and isolating the thus obtained 45 rosuvastatin zinc salt of the Formula (I), or rosuvastatin of the Formula (II) is reacted with a zinc enolate of the Formula (IV)

50

55 and the thus obtained rosuvastatin zinc salt of the Formula (I) is isolated, or the salt of (+)-7- [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)- pyrimidin-5-yl]-(3R,5S)-di- hydroxy-(E)-6-heptenecarboxylic acid with an alkali metal is reacted with an inorganic or organic zinc salt of an inorganic or organic acid and rosuvastatin zinc salt of the Formula (I) is isolated.

8 EP 2 013 188 B1

3. Process according to claim 2, characterized in that the alkali metal is sodium.

4. Process according to claim 2, characterized in that the inorganic or organic zinc salt of an inorganic or organic acid is selected form the group of zinc chloride, zinc sulphate and zinc acetate. 5 5. Process according to claim 2, characterized in that the salt formation is carried out in case of the reaction with a zinc alcoholate or zinc enolate at a temperature between room temperature and the boiling temperature of the solvent, and in case of reaction with zinc chloride or zinc sulfate zinc chloride is dissolved in ethanol or water and zinc sulfate is dissolved in water and the salt formation is carried out at a temperature between 25 and 50 °C. 10 6. Process according to claim 2, characterized in that in the case of reaction with a zinc alcoholate, the salt formation is carried out in a solvent selected from aliphatic alcohols having 1 to 4 carbon atoms, aliphatic ketones having 3 to 8 carbon atoms, aliphatic esters having 3 to 8 carbon atoms, or aliphatic ethers having 4 to 8 carbon atoms, in case of reaction with a zinc enolate, the salt formation is carried out in aliphatic alcohols comprising 1 to 4 carbon 15 atoms, and in case of salt formation with an inorganic or organic zinc salt of an inorganic or organic acid the salt formation is carried out in water, aliphatic alcohols comprising 1 to 4 carbon atoms, ketones comprising 3 to 10 carbon atoms, or aliphatic nitriles.

7. Process according to claim 2, characterized in that as solvent in case of the reaction with zinc alcoholate methanol, 20 ethanol, 2-propanol or 1-butanol and in case of reaction with zinc chloride, zinc sulphate or zinc acetate acetone or acetonitrile, is used.

8. Process according to claim 2, characterized in that the zinc alcoholate or zinc enolate used for salt formation is used in 0.5 to 0.6 molar equivalent amount calculated on the molar amount of rosuvastatin of the Formula (II) or 25 salt thereof.

9. Process according to claim 2, characterized in that rosuvastatin zinc salt of the Formula (I) is isolated from the reaction mixture by precipitation.

30 10. Process according to claim 9, characterized in that the precipitation is carried out using an aliphatic ester-type solvent having 2 to 8 carbon atoms optionally mixed with an aliphatic ether containing 4 to 8 carbon atoms and an ether type antisolvent having 4 to 8 carbon atoms.

11. Process according to claim 2, characterized in that the rosuvastatin zinc salt of the Formula (I) is obtained in 35 amorphous, crystalline or partly crystalline form.

12. The use of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulphonyl-amino)pyrimidin-5-yl]-(3R,5S)-di- hydroxy-(E)-6-heptene- carboxylic acid zinc salt (2:1) for the preparation of medicinal products.

40 13. Medicinal products containing (+)-7-[4-(4-fluorophenyl)-6-isopropyl- 2-(N-methyl-N-methylsulphonyl-amino)pyrimi- din-5-yl]- (3R,5S)- dihydroxy-(E)-6-heptenecarboxylic acid zinc salt (2:1) of the Formula (I) in admixture with one or more pharmaceutically acceptable vehicle or auxiliary agent.

45 Patentansprüche

1. (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]- (3R,5S)-dihydroxy-(E)- 6-heptencarbonsäure-Zinksalz (2:1) der Formel (I)

50

55

9 EP 2 013 188 B1

5

10

15

und Hydrate davon. 20 2. Verfahren für die Herstellung von (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl- amino)py- rimidin-5-yl]- (3R,5S)-dihydroxy-(E)-6-heptencarbonsäure-Zinksalz (2:1) der Formel (I), welches umfasst Reagieren von (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]- (3R,5S)-dihydro- xy-(E)-6-heptencarbonsäure der Formel (II) 25

30

35

40

oder einem Salz davon in wässrigem oder organischem Lösemittel mit einem Zinkalkoholat der Formel (III)

R-O-Zn-O-R III 45 wobei der Alkoholatrest eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen enthält, und Isolieren des so erhaltenen Rosuvastatin-Zinksalzes der Formel (I), oder Rosuvastatin der Formel (II) mit einem Zinkenolat der Formel (IV) reagiert wird

50

55

und das so erhaltene Rosuvastatin-Zink-Salz der Formel (I) isoliert wird, oder das Salz der (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl-amino)pyrimidin-5-yl]-

10 EP 2 013 188 B1

(3R,5S)-dihydroxy-(E)-6-heptencarbonsäure mit einem Alkalimetall wird mit einem anorganischen oder organischen Zinksalz einer anorganischen oder organischen Säure umgesetzt und das Rosuvastatin-Zinksalz der Formel (I) isoliert.

5 3. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass das Alkalimetall Natrium ist.

4. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass das anorganische oder organische Zinksalz einer anorganischen oder organischen Säure ausgewählt ist aus der Gruppe von Zinkchlorid, Zinksulfat und Zinkacetat.

10 5. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass die Salzbildung durchgeführt wird im Fall der Re- aktion mit einem Zinkalkoholat oder Zinkenolat bei einer Temperatur zwischen Raumtemperatur und Siedetempe- ratur des Lösemittels, und im Fall der Reaktion mit Zinkchlorid oder Zinksulfat, Zinkchlorid in Ethanol oder Wasser gelöst wird und Zinksulfat in Wasser gelöst wird und die Salzbildung bei einer Temperatur zwischen 25 und 50 °C durchgeführt wird. 15 6. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass im Fall der Reaktion mit einem Zinkalkoholat die Salzbildung in einem Lösemittel durchgeführt wird ausgewählt aus aliphatischen Alkoholen mit 1 bis 4 Kohlenstoff- atomen, aliphatischen Ketonen mit 3 bis 8 Kohlenstoffatomen, aliphatischen Estern mit 3 bis 8 Kohlenstoffatomen, oder aliphatischen Ethern mit 4 bis 8 Kohlenstoffatomen, im Fall der Reaktion mit einem Zinkenolat die Salzbildung 20 durchgeführt wird in aliphatischen Alkoholen umfassend 1 bis 4 Kohlenstoffatome, und im Fall der Salzbildung mit einem anorganischen oder organischen Zinksalz einer anorganischen oder organischen Säure die Salzbildung durchgeführt wird in Wasser, aliphatischen Alkoholen umfassend 1 bis 4 Kohlenstoffatome, Ketonen umfassend 3 bis 10 Kohlenstoffatome, oder aliphatischen Nitrilen.

25 7. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass als Lösemittel im Fall der Reaktion mit Zinkalkoholat Methanol, Ethanol, 2-Propanol oder 1-Butanol und im Fall der Reaktion mit Zinkchlorid, Zinksulfat oder Zinkacetat Aceton oder Acetonitril verwendet wird.

8. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass das Zinkalkoholat oder Zinkenolat, das für die 30 Salzbildung verwendet wird, in 0,5-0,6 molarer Äquivalenzmenge, berechnet auf die molare Menge an Rosuvastatin der Formel (II) oder eines Salzes davon, verwendet wird.

9. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass das Rosuvastatin-Zinksalz der Formel (I) aus dem Reaktionsgemisch durch Fällung isoliert wird. 35 10. Verfahren gemäß Anspruch 9, dadurch gekennzeichnet, dass die Fällung durchgeführt wird unter Verwendung eines aliphatischen esterartigen Lösemittels mit 2 bis 8 Kohlenstoffatomen, optional gemischt mit einem aliphatischen Ether mit 4 bis 8 Kohlenstoffatomen und einem etherartigen Anti-Lösemittel mit 4 bis 8 Kohlenstoffatomen.

40 11. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass Rosuvastatin-Zinksalz der Formel (I) in amorpher, kristalliner oder teilweise kristalliner Form erhalten wird.

12. Die Verwendung von (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl- amino)pyrimidin-5-yl]- (3R,5S)-dihydroxy-(E)-6-heptencarbonsäure-Zink-Salz (2:1) für medizinische Produkte. 45 13. Medizinische Produkte enthaltend (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonyl- amino)py- rimidin-5-yl]- (3R,5S)-dihydroxy-(E)-6-heptencarbonsäure-Zink-Salz (2:1) der Formel (I) in Beimischung mit einem oder mehreren pharmazeutisch verträglichen Trägern oder Hilfsmitteln.

50 Revendications

1. Sel de zinc d’acide (+)-7-[4-(4-fluorophényl)-6-isopropyl-2-(N-méthyl-N-méthylsulfonylamino)pyrimidin-5-yl] -(3R,5S)-dihydroxy-(E)-6-heptènecarboxylique (2/1) de la Formule (I) 55

11 EP 2 013 188 B1

5

10

15

et hydrates de celui-ci. 20 2. Procédé de préparation de sel de zinc d’acide (+)-7-[4-(4-fluorophényl)-6-isopropyl-2-(N-méthyl-N-méthylsulfony- lamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptènecarboxylique (2/1) de la Formule (I), qui comprend faire réa- gir de l’acide (+)-7-[4-(4-fluorophényl)-6-isopropyl-2-(N-méthyl-N-méthylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-di- hydroxy-(E)-6-heptènecarboxylique de la Formule (II) 25

30

35

40

ou un sel de celui-ci dans un solvant aqueux ou organique avec un alcoolate de zinc de la Formule (III)

R-O-Zn-O-R III 45 dans lequel le résidu d’alcoolate contient un groupe alkyle ayant 1 à 4 atomes de carbone, et isoler le sel de zinc de rosuvastatine ainsi obtenu de la Formule (I), ou la rosuvastatine de la Formule (II) est mise à réagir avec un énolate de zinc de la Formule (IV)

50

55

et le sel de zinc de rosuvastatine ainsi obtenu de la Formule (I) est isolé, ou le sel d’acide (+)-7-[4-(4-fluorophényl)-6-isopropyl-2-(N-méthyl-N-méthylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-di-

12 EP 2 013 188 B1

hydroxy-(E)-6-heptènecarboxylique avec un métal alcalin est mis à réagir avec un sel de zinc inorganique ou orga- nique d’un acide inorganique ou organique et le sel de zinc de rosuvastatine de la Formule (I) est isolé.

3. Procédé selon la revendication 2, caractérisé en ce que le métal alcalin est le sodium. 5 4. Procédé selon la revendication 2, caractérisé en ce que le sel de zinc inorganique ou organique d’un acide inor- ganique ou organique est sélectionné parmi le groupe du chlorure de zinc, du sulfate de zinc et de l’acétate de zinc.

5. Procédé selon la revendication 2, caractérisé en ce que la formation de sel est effectuée dans le cas de la réaction 10 avec un alcoolate de zinc ou un énolate de zinc à une température comprise entre la température ambiante et la température d’ébullition du solvant, et dans le cas de la réaction avec du chlorure de zinc ou du sulfate de zinc, du chlorure de zinc est dissous dans de l’éthanol ou de l’eau et du sulfate de zinc est dissous dans de l’eau, et la formation de sel est effectuée à une température comprise entre 25 et 50°C.

15 6. Procédé selon la revendication 2, caractérisé en ce que dans le cas de la réaction avec un alcoolate de zinc, la formation de sel est effectuée dans un solvant sélectionné parmi des alcools aliphatiques ayant 1 à 4 atomes de carbone, des cétones aliphatiques ayant 3 à 8 atomes de carbone, des esters aliphatiques ayant 3 à 8 atomes de carbone ou des éthers aliphatiques ayant 4 à 8 atomes de carbone, dans le cas de la réaction avec un énolate de zinc, la formation de sel est effectuée dans des alcools aliphatiques comprenant 1 à 4 atomes de carbone, et dans 20 le cas de la formation de sel avec un sel de zinc inorganique ou organique d’un acide inorganique ou organique, la formation de sel est effectuée dans de l’eau, des alcools aliphatiques comprenant 1 à 4 atomes de carbone, des cétones comprenant 3 à 10 atomes de carbone ou des nitriles aliphatiques.

7. Procédé selon la revendication 2, caractérisé en ce que, comme solvant, du méthanol, de l’éthanol, du 2-propanol 25 ou du 1-butanol est utilisé dans le cas de la réaction avec un alcoolate de zinc et de l’acétone ou de l’acétonitrile est utilisé dans le cas de la réaction avec du chlorure de zinc, du sulfate de zinc ou de l’acétate de zinc.

8. Procédé selon la revendication 2, caractérisé en ce que l’alcoolate de zinc ou l’énolate de zinc utilisé pour la formation de sel est utilisé en une quantité équivalente molaire de 0,5 à 0,6 calculée sur la quantité molaire de 30 rosuvastatine de la Formule (II) ou de sel de celle-ci.

9. Procédé selon la revendication 2, caractérisé en ce que le sel de zinc de rosuvastatine de la Formule (I) est isolé du mélange réactionnel par précipitation.

35 10. Procédé selon la revendication 9, caractérisé en ce que la précipitation est effectuée en utilisant un solvant de type ester aliphatique ayant 2 à 8 atomes de carbone mélangé en option avec un éther aliphatique contenant 4 à 8 atomes de carbone et un antisolvant de type éther ayant 4 à 8 atomes de carbone.

11. Procédé selon la revendication 2, caractérisé en ce que le sel de zinc de rosuvastatine de la Formule (I) est obtenu 40 sous forme amorphe, cristalline ou partiellement cristalline.

12. Utilisationde sel de zinc d’acide (+)-7-[4-(4-fluorophényl)-6-isopropyl-2-(N-méthyl-N-méthylsulfonylamino)pyrimidin- 5-yl]-(3R,5S)-dihydroxy-(E)-6-heptènecarboxylique (2/1) pour la préparation de produits médicaux.

45 13. Produits médicaux contenant du sel de zinc d’acide (+)-7-[4-(4-fluorophényl)-6-isopropyl-2-(N-méthyl-N-méthylsul- fonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptènecarboxylique (2/1) de la Formule (I) en mélange avec un ou plusieurs excipients ou agents auxiliaires pharmaceutiquement acceptables.

50

55

13 EP 2 013 188 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• EP 521471 A [0003] [0006] • WO 2005123082 A1 [0011] • WO 00042024 A [0006] • WO 2004108691 A1 [0012] • WO 0414872 A [0007] • EP 1336405 A [0015] • WO 0160804 A [0008] • WO 2006017698 A [0016] • WO 2005051921 A [0009] • WO 03068739 A [0017] • WO 2005040134 A [0010]

Non-patent literature cited in the description

• A. GRAUL et al. Drugs of the future, 1997, vol. 22 • Remington’s Pharmaceutical Sciences. Mack Pub- (9), 956-968 [0014] lishing Co, 1990 [0055]

14