KR20140069378A - Rosuvastatin zinc salt - Google Patents

Abstract

본 발명에 따른 로수바스타틴 아연 염은 로수바스타틴을 아연 알코올레이트, 아연 에놀레이트 또는 무기 또는 유기 아연 염과 반응시키고, 이렇게 수득된 로수바스타틴 아연 염 (2:1)을 분리함으로써 제조된다.The present invention relates to rosuvastatin zinc salts of formula (I), a process for their preparation and pharmaceutical products containing such salts:

The rosuvastatin zinc salt according to the present invention is prepared by reacting rosuvastatin with a zinc alcoholate, zinc enolate or an inorganic or organic zinc salt, and isolating the thus obtained rosuvastatin zinc salt (2: 1).

Description

Rosuvastatin zinc salt {ROSUVASTATIN ZINC SALT}

The present invention relates to a process for the preparation of (+) - 7- [4- (4-fluorophenyl) -6-isopropyl- 2- (N-methyl-N-methylsulfonylamino) (E) -6-heptenecarboxylic acid, a hydrate thereof, a process for the preparation thereof, a medicament containing such a salt, a method for producing a medicament, and a use of the salt in medicaments will be:

(4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methyl-sulfonyl- amino) -pyrimidin- 5- Dihydroxy- (E) -6-heptene-carboxylic acid is known as rosuvastatin as International General Name (INN): <

Rosuvastatin of formula (II) was first introduced in European Patent 521471. Calcium salts of rosuvastatin are used in medicines for the treatment of hypercholesterolemia, hypercholesterolemia and atherosclerosis.

The Health Agency applies stringent quality standards for pharmaceutical active ingredients. Some of these criteria relate to the chemical purity and stability of pharmaceutical active ingredients. Other pharmacopoeial requirements are that pharmaceuticals of satisfactory quality and medicines must have adequate stability. These criteria are determined and released by the corresponding pharmacopoeial provisions.

In the case of rosuvastatin of formula (II), the basic requirements of active pharmaceutical ingredients for use in pharmaceuticals are high purity, suitable stability and the possibility of simple formulation.

According to published international patent application WO 00/042024, amorphous suvastatin of formula (II) obtained according to the process of European patent 521471 may have many difficulties in use in pharmaceutical techniques. To overcome this disadvantage, crystalline forms are produced that have more beneficial physical properties than amorphous products. However, the preparation of the crystalline form of suvastatin calcium salt is a production process requiring a high production volume, resulting in a great loss of the material.

A fundamental problem in the preparation of rosuvastatin calcium salt is that the primary product obtained is poorly filterable and can not be purified in an easy manner. Published International Patent Application WO 04/14872 describes amorphous products with favorable filtration properties. According to the process of this application, advantageous particle size calcium salts are prepared by reacting an alkali metal, ammonium, methylammonium or tris (hydroxymethyl) -methylammonium salt of rosuvastatin with calcium chloride in aqueous solution.

Published International Patent Application WO 01/60804 describes ammonium-, lithium-, or magnesium salts of rosuvastatin of high purity formula (II) to overcome the problems of production that occur during the production of amorphous suvastatin. Starting from the salts mentioned above, it is possible to prepare amorphous suvastatin of suitable quality for pharmaceutical manufacture.

A similar process is disclosed in published international patent application WO 2005/051921 wherein an isopropylammonium or cyclohexylammonium salt of rosuvastatin is produced in high purity and the salt is a sodium salt of rosuvastatin or a high purity amorphous calcium salt .

Published International Patent Application WO 2005/040132 describes amorphous suvastatin calcium salts of high diastereomeric purity. According to the process described, the primary product amorphous, the suvastatin calcium salt is crystallized in the first step, and the product thus obtained is subsequently converted to amorphous.

In summary, according to the field, it can be concluded that the preparation of rosuvastatin calcium salt suitable for pharmaceutical manufacture is a particularly complex process. The crude product must undergo further purification and crystallization steps to obtain a product suitable for its purity and physical properties. It is difficult to carry out an industrial scale process with known processes, and using these known processes often leads to a significant loss of material and is uneconomical.

SUMMARY OF THE INVENTION

The aim of the present inventors' investigation and development work is to develop a pharmaceutical composition which is capable of maintaining or enhancing the pharmacological effect characteristic of the statins and which is [(+) - 7 - (3R, 5S) -dihydroxy-isoquinolin-2-ylmethyl) - [4- (4-fluorophenyl) (E) -6-heptenecarboxylic acid.

The above object is solved according to the present invention.

The present invention relates to a process for the preparation of (+) - 7- [4- (4-fluorophenyl) -6-isopropyl- 2- (N- methyl- N- methylsulfonylamino) pyrimidin- The zinc salt and its reconstituted form of (3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid meet all the above criteria and because the salt is suitable for the production of pharmaceuticals, And excellent stability to light, and can be produced with high purity by an industrially convenient process.

In a first aspect of the present invention there is provided a rosuvastatin zinc salt of formula (I) which can be prepared directly at a high purity suitable for the manufacture of a medicament. The rosuvastatin zinc salt of formula (I) is novel.

The advantage of the rosuvastatin zinc salt of formula (I) as compared to the calcium salt of rosuvastatin known in the art is that the zinc salt can be produced with high quality by a simple process which can be easily scaled up for industrial production It can be. An additional advantage of the rosuvastatin zinc salt is that it can be very easily manipulated and no further processing is required due to pretreatment of the primary product for pharmaceutical formulation.

The rosuvastatin zinc salt of formula (I) is stable to heat and light, which is advantageous during pharmaceutical processing, during formulation and during use as a medicament. The product may advantageously be used for the treatment of disorders of lipid metabolism, such as hypercholesterolemia, hypercholesterolemia and atherosclerosis.

In a second aspect of the present invention, there is provided a process for preparing a rosuvastatin zinc salt of formula (I), comprising reacting rosuvastatin of formula (II) with a zinc compound.

In a first modified process suitable for the preparation of the rosuvastatin zinc salt of formula (I), (+) - 7- [4- (4-fluorophenyl) -6- (E) -6-heptenecarboxylic acid reacts with a zinc alcoholate to give a compound of formula (I) Rosuvastatin zinc of the obtained formula (I) is isolated.

As the zinc alcoholate, the compound of formula (III) may be used in an amount of 0.5 to 0.6 molar equivalents based on the molar amount of rosuvastatin of formula (II):

R-O- Zn -O-R III

In the above formula, R represents a linear or branched alkyl group having 1 to 4 carbon atoms.

The reaction is carried out in a solvent. Suitable solvents include aliphatic alcohols having 1 to 4 carbon atoms such as methanol, ethanol, 2-propanol or 1-butanol; Aliphatic ketones having 3 to 8 carbon atoms; An aliphatic ester having 2 to 8 carbon atoms or an aliphatic ether having 4 to 8 carbon atoms or a mixture thereof.

The preparation of the salt is carried out at room temperature and at the boiling point of the solvent, preferably at a temperature of 25 to 50 占 폚.

The product is separated by evaporation of the solvent. Optionally, the solution may be treated with silica gel prior to solvent evaporation. The evaporation residue is pulverized with an excess of ether having 4 to 8 carbon atoms, preferably diethyl ether, and the solid thus obtained is filtered.

A second possible product separation process is to dissolve the obtained evaporation residue without silica treatment in an aliphatic ester having 2 to 8 carbon atoms and to treat the thus obtained solution with silica. After repeated filtration, the solvent is partially evaporated and the residue is stirred with an excess of ether with 4 to 8 carbon atoms, preferably diethyl ether, and the precipitated product is filtered.

In a modified second step, rosuvastatin of formula (II) is reacted with zinc enolate of formula (IV):

The zinc enolate of formula (IV) is used in an amount of 0.5 to 0.6 molar equivalents based on the molar amount of rosuvastatin in formula (II).

The reaction of the compounds of formulas (II) and (IV) is carried out in a solvent. Suitable solvents are aliphatic alcohols having 1 to 4 carbon atoms. The reaction can be carried out at room temperature and at the boiling point of the solvent, preferably at 25-40 < 0 > C.

The product can be separated by treating the solution with silica, filtering, concentrating the solution by evaporating the solvent, and precipitating the product by adding an excess of ether with 4 to 8 carbon atoms, preferably diethyl ether .

In a modified third step for preparing the rosuvastatin zinc salt of formula (I), (+) - 7- [4- (4-fluorophenyl) -6-isopropyl- - (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] - (3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid with an inorganic or organic Zinc salt, and the thus obtained product of formula (I) is isolated.

In this process, zinc salts of inorganic or organic acids may be used. Preferred zinc salts are zinc chloride, zinc sulfate or zinc acetate.

The starting material is preferably the sodium salt of the compound of formula (II).

The reaction can be carried out in water using a water soluble zinc salt, for example zinc chloride, zinc sulfate or zinc acetate. The reaction may be carried out in an organic solvent, for example, an aliphatic alcohol having 1 to 4 carbon atoms; For example, ketones or aliphatic nitriles having 3 to 10 carbon atoms containing acetone, such as acetonitrile. The above-mentioned solvents may be used in the form of a mixture with one another or a mixture with water.

In a preferred embodiment of the process, zinc chloride dissolved in ethanol or water or zinc sulfate dissolved in water is used, and the reaction is carried out at a temperature of from 25 to 50 캜.

In a particularly preferred embodiment of the present invention, the sodium salt of rosuvastatin of formula (II) is reacted with 0.5 molar equivalent of zinc sulphate in aqueous solution at a temperature of from 25 to 40 캜. The product is separated as an aqueous reaction mixture by washing the product from the aqueous solution by filtration or using an insoluble solvent. The organic phase is then separated, concentrated to a small volume, and the rosuvastatin zinc salt of formula (I) is isolated.

The insoluble solvent advantageous for the extraction of the rosuvastatin zinc salt of formula (I) is an aliphatic ester having 2 to 8 carbon atoms, which is an excellent solvent for the rosuvastatin zinc salt, for example ethyl formate, ethyl acetate or methyl acetate to be. The rosuvastatin zinc salt of formula (I) is isolated by concentrating the extract to a small volume and precipitating the rosuvastatin zinc salt by adding an ether having 4 to 8 carbon atoms, preferably diethyl ether.

The rosuvastatin zinc salts according to the invention are analogous to other rosuvastatin salts, e.g. calcium salts, known in the art, none of which have a definite melting point. Thus, the rosuvastatin zinc salt according to the present invention is characterized by the melt initiation temperature in the examples.

In addition, the zinc salt of rosuvastatin according to the present invention can be obtained in an anhydrous and hydrated form. The rosuvastatin zinc salts of formula (I) are generally obtained in the form of hydrates when the solvent is used during their preparation in an aqueous solvent or solvent mixture. However, in this case, when an organic solvent is used during the salt formation reaction, an anhydrous form is produced.

 In a further aspect of the invention there is provided a pharmaceutical product comprising a rosuvastatin zinc salt of formula (I) in admixture with one or more pharmaceutically acceptable vehicles or adjuvants.

The medicinal product according to the invention generally contains from 0.1 to 95% by weight, preferably from 1 to 50% by weight, most preferably from 5 to 30% by weight of active pharmaceutical ingredient.

The pharmaceutical product according to the present invention may be administered orally or parenterally (e.g., in the form of powders, tablets, coated tablets, chewing tablets, capsules, microcapsules, granules, dragees, lozenges, solutions, suspensions or emulsions) Intravenous, intramuscular or intraperitoneal injection or infusion), rectally (suppository or rectal), intradermal (e.g. patch), transplant, or topically (e.g., ointment, cream, Patch form). Solid, semi-solid or liquid pharmaceutical preparations containing rosuvastatin zinc salts of formula (I) may be prepared according to pharmaceutical techniques known in the art.

Solid pharmaceutical products containing rosuvastatin zinc salts of formula (I) prepared for oral administration can be formulated as a solid pharmaceutical product containing a vehicle or a filler (e.g., lactose, glucose, starch, calcium phosphate, microcrystalline cellulose) (For example, magnesium stearate, talc, polyethylene glycol, polyvinylpyrrolidone), disintegrating agents (e.g., croscarmellose, sodium carboxymethylcellulose, crospovidone) Silicic acid, silicon dioxide) and a surfactant (e.g., sodium lauryl sulfate).

Liquid pharmaceutical products containing a rosuvastatin zinc salt of formula (I) suitable for oral administration may be prepared in the form of solutions, syrups, suspensions or emulsions and may be formulated as suspensions (e.g., gelatin, carboxymethylcellulose) (For example, water, oil, glycerol, propylene glycol, ethanol), a buffer (e.g., acetate, phosphate, citrate buffer) or a stabilizer (e.g., Methyl-4-hydroxy-benzoate).

The liquid pharmaceutical product containing the rosuvastatin zinc salt of formula (I) prepared for parenteral use is a sterile isotonic solution which may contain preservatives and buffers in addition to the solvent.

Semisolid pharmaceutical products containing rosuvastatin zinc salts of formula (I), for example, suppositories contain the active ingredient uniformly dispersed in the vehicle of the preparation (e. G. Polyethylene glycol or cocoa butter).

The pharmaceutical product containing the rosuvastatin zinc salt according to the present invention as an active ingredient contains the compound as a unit dosage form.

A further aspect of the invention is the use of a rosuvastatin zinc salt of formula (I) for the manufacture of a medicament.

The pharmaceutical product containing the rosuvastatin zinc salt according to the present invention can be produced using pharmaceutical techniques known in the art. The active ingredient is mixed with a solid or liquid pharmaceutically acceptable vehicle or adjuvant, and the mixture is brought into a pharmaceutical dosage form. Such methods and pharmaceutically acceptable vehicles or adjuvants are known in the literature (Remington ' s Pharmaceutical Sciences, Edition 19, Mack Publishing Co., Easton, USA, 1990).

A further aspect of the present invention is a method of treating hyperphosphatemia, hypercholesterolemia and atherosclerosis, comprising administering a clinically effective amount of a rosuvastatin zinc salt according to the present invention to a patient in need of such treatment Method.

Further details of the invention are set forth in the following examples, and the scope of the invention is not limited by these examples.

Example  One

(3R, 5S) -7-methoxy-3- (4-fluorophenyl) Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

Yl) - (3R (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidin- , 5S) -dihydroxy- (E) -6-heptenecarboxylic acid was dissolved in 70 ml methanol and 0.60 g (2.13 mmol) zinc acetylacetonate monohydrate was added to this solution at room temperature. The reaction mixture was stirred for 8 hours at room temperature. After this period, 1.0 g of silica was added and the reaction mixture was stirred for 30 minutes. The mixture was filtered, the solvent was evaporated and the filtrate was concentrated to 1/10 volume. The residue was mixed with 20 volumes of diethyl ether and the precipitate was filtered, washed with diethyl ether and dried at 40 < 0 > C under vacuum. In this way, 2.05 g (93%) of product was obtained, which started to melt at a temperature of 137 ° C.

Example  2

(3R, 5S) -7-methoxy-3- (4-fluorophenyl) Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

To a solution of 3.85 g (8.0 mmol) of (+) - 7- [4- (4-fluorophenyl) -6-isopropyl- 2- (N-methyl-N-methylsulfonyl-amino) pyrimidin- ] - (3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid was dissolved in 40 ml of ethyl acetate and to this solution was added 0.62 g (4.0 mmol) zinc ethylate solution in 40 ml of ethanol . The reaction mixture was refluxed for 2 hours. The reaction mixture was cooled, filtered and the solvent was evaporated. The residue was triturated with 50 ml diethyl ether. The suspension was filtered, the solids were dissolved in 50 ml ethyl acetate and the solution was stirred with 2 g silica gel for 3 hours. The silica gel was filtered off, 2/3 of the volume of the solvent was evaporated and the residue was stirred with 10 volumes of diethyl ether. The precipitated salt was filtered off, washed with diethyl ether and dried. In this way, 2.8 g (68%) of rosuvastatin zinc salt, which starts to melt at 137 占 폚, was obtained.

Example  3

(3R, 5S) -7-methoxy-3- (4-fluorophenyl) Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

The reaction is carried out by stirring the reaction mixture at room temperature for 16 hours, following the procedure described in Example 2. [ Thus, 3.0 g (73%) of rosuvastatin zinc salt was obtained.

Example  4

(3R, 5S) -7-methoxy-3- (4-fluorophenyl) Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

Yl) - (3R (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidin- , 5S) -dihydroxy- (E) -6-heptenecarboxylic acid was dissolved in 70 ml of ethyl acetate and 4.2 ml (1.0 mmol / ml) of the ethanolic sodium ethylate solution prepared immediately in this solution was added to the solution / RTI > While stirring, a 2.0 mmole zinc chloride solution prepared in 10 ml of ethanol was added over 30 minutes. The reaction mixture was stirred at 50 < 0 > C for 2 hours, cooled to room temperature and filtered. The filtrate was evaporated to 1/10 volume, and the product was precipitated with 10 volumes of diethyl ether. The product was then filtered and dried at 50 < 0 > C. 1.8 g (86%) of rosuvastatin zinc salt were obtained, which started to melt at 136 占 폚.

Example  5

(3R, 5S) -7-methoxy-3- (4-fluorophenyl) Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

The title compound was prepared according to the procedure of Example 4, except that the reaction was carried out at room temperature. Thus 1.65 g (77%) of the title compound was obtained, which started to melt at 137 占 폚.

Example  6

(3R, 5S) -7-methoxy-3- (4-fluorophenyl) Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

The title compound was prepared according to the procedure of Example 4 except that 2.0 mmol of zinc sulfate dissolved in water as the reagent was used and the reaction was carried out at room temperature. After separation of the aqueous layer, the product was separated by evaporation of 2/3 solvent and the residue was triturated with 10 volumes of diethyl ether. The precipitated solids were filtered and dried at a temperature of 50 < 0 > C. Thus, 1.76 g (81%) of rosuvastatin zinc salt was obtained, which started to melt at 138 占 폚.

Claims (18)

(N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] -pyridin- - (3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1) or a hydrate thereof:

(N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] -pyridin- - (3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1) in an aqueous or organic solvent, 5-yl] - (3R, 5S) -dihydro-2H-pyran-3- (E) -6-heptene-carboxylic acid or a salt thereof with an inorganic or organic zinc compound and isolating the thus obtained rosuvastatin zinc salt of the formula (I)

3. The compound of claim 2, wherein (+) - 7- [4- (4-fluorophenyl) -6-isopropyl- 2- (N-methyl-N-methylsulfonyl-amino) (III), wherein the alcoholate moiety contains an alkyl group having from 1 to 4 carbon atoms, is reacted with a compound of formula (III): < EMI ID = Characterized in that the rosuvastatin zinc salt of formula (I) is reacted with a zinc alcoholate of formula < RTI ID = 0.0 > (I) <
RO-Zn-OR III 3. The compound of claim 2, wherein (+) - 7- [4- (4-fluorophenyl) -6-isopropyl- 2- (N-methyl-N-methylsulfonyl-amino) (II) is prepared by reacting rosuvastatin of formula (II) with a compound of formula (I) wherein R < 2 > IV), preferably zinc acetylacetonate, and isolating the thus obtained rosuvastatin zinc salt of the formula (I)

3. The compound according to claim 2, which is (+) - 7- [4- (4-fluorophenyl) -6- - (3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid with an alkali metal, preferably sodium, with an inorganic or organic zinc salt, preferably zinc chloride, zinc sulfate or acetic acid Reacting with zinc and isolating the rosuvastatin zinc salt of formula (I). Process according to any one of claims 2 to 5, characterized in that the salt formation is carried out at a temperature from room temperature to the boiling point of the solvent, preferably from room temperature to 50 ° C. 6. The composition according to any one of claims 2 to 5, wherein the salt formation is water, aliphatic alcohol having 1 to 4 carbon atoms, aliphatic ketone having 3 to 8 carbon atoms, aliphatic ester having 3 to 8 carbon atoms, carbon Acetone, acetonitrile, ethyl acetate or dioxane, preferably a solvent selected from an aliphatic nitrile having 2 to 5 atoms, an aliphatic nitrile having 2 to 5 atoms, or an aliphatic ether having 4 to 8 carbon atoms, preferably ethanol, acetone, acetonitrile, ethyl acetate or dioxane. The use according to any one of claims 2 to 5, wherein the zinc alcoholate, zinc enolate or inorganic or organic zinc salt used in the salt formation is present in an amount of 0.5 (molar equivalents) based on the molar amount of rosuvastatin or its salt of formula (II) To 0.6 molar equivalents. 6. Process according to any one of claims 2 to 5, characterized in that the rosuvastatin zinc salt of formula (I) is separated from the reaction mixture by precipitation or extraction. 10. A process according to claim 9, characterized in that the extraction is carried out using an aliphatic ester having 2 to 8 carbon atoms. The method according to claim 9, wherein the precipitation is carried out using an aliphatic ester solvent having 2 to 8 carbon atoms and optionally mixed with an ether type antisolvent having 4 to 8 carbon atoms and an aliphatic ether having 4 to 8 carbon atoms ≪ / RTI > 11. The process according to claim 10 wherein the crude rosuvastatin zinc salt of formula (I) is prepared by mixing the extract with an aliphatic ether type solvent having 4 to 8 carbon atoms and reacting the precipitated rosuvastatin zinc salt of formula (I) ≪ / RTI > is separated from the extract by separation. 6. Process according to any one of claims 2 to 5, characterized in that the rosuvastatin zinc salt of formula (I) is obtained in amorphous, crystalline or partially crystalline form. - (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] - ( 3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1). (+) - 7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl- N- methylsulfonyl-amino) pyrimidin- (3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1) together with one or more pharmaceutically acceptable vehicles or adjuvants. 16. A method for preparing a medicament according to claim 15 comprising mixing the rosuvastatin zinc salt according to claim 1 with a pharmaceutically acceptable vehicle or adjuvant and converting the mixture into a pharmaceutical dosage form. (+) - 7- [4- (4-fluorophenyl) -6-isopropyl-2 (1H) -pyridazinone for the preparation of a medicament suitable for the prevention or treatment of hypercholesterolemia, (E) -6-heptenecarboxylic acid zinc salt (2: 1) was prepared in analogy to the procedure described for the synthesis of (2R) - (N-methyl-N-methylsulfonyl-amino) pyrimidin- Usage. A method of treating hypercholesterolemia, hyperproliferative or atherosclerosis, comprising administering to a patient in need of such treatment a pharmacologically effective amount of (+) - 7- [4- (4-fluorophenyl) (E) -6-heptenecarboxylic acid zinc salt < RTI ID = 0.0 > (I) < / RTI & RTI ID = 0.0 > (2: 1). ≪ / RTI >