WO2007000121A1 - A method for the production of the hemi-calcium salt of (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid - Google Patents
A method for the production of the hemi-calcium salt of (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid Download PDFInfo
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- WO2007000121A1 WO2007000121A1 PCT/CZ2006/000039 CZ2006000039W WO2007000121A1 WO 2007000121 A1 WO2007000121 A1 WO 2007000121A1 CZ 2006000039 W CZ2006000039 W CZ 2006000039W WO 2007000121 A1 WO2007000121 A1 WO 2007000121A1
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- rosuvastatin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention concerns a new method of producing the hemi-calcium salt of (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3i-,55)-3,5- dihydroxyhept-6-enoic acid, known under the INN name rosuvastatin, of formula I.
- This substance is an important hypolipidemic and hypocholesteric drug.
- Rosuvastatin is produced, according to patent EP 521471, usually from the sodium salt of (E)- 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3i?,5jS)- 3,5-dihydroxyhept-6-enoic acid and a suitable, water-soluble calcium salt, preferably from calcium chloride.
- the starting sodium salt can be obtained, according to the aforementioned patent, from the methyl ester of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]- pyrimidin-5-yl](3i2,55)-3,5-dihydroxyhept-6-enoic acid of formula II by hydrolysis with ethanolic sodium hydroxide, or, more recently, according to international patent application WO 00/49014, from tert-butyl (E)-(6-[2-[4-(4-fluorophenyl)-6-iso ⁇ ro ⁇ yl-2- [methyl(methylsulfonyl)ammo]pyrimidin-5-yl]vinyl](4i?,6S)-2,2-dimethyl-[l,3]dioxan-4-yl)- acetate of formula III.
- This intermediate is first converted, by stirring with hydrochloric acid and then with sodium hydroxide, into the sodium salt of the corresponding acid.
- the calcium salt is then obtained by adding calcium chloride to a solution of the sodium salt in water.
- the salt prepared in this way is contaminated with inorganic substances; residual sodium hydroxide, for example, reacts with the calcium salt, yielding water-insoluble calcium hydroxide. Filtration of such a salt is, according to application WO 04014872, a lengthy process. A still improved method for the preparation of amorphous rosuvastatin, with higher yields, is published in application WO 04108691.
- This invention concerns a new, improved method for the production of the hemi-calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3i-,5iS)-3,5-dihydroxyhept-6-enoic acid (rosuvastatin) I which eliminates the aforementioned shortcomings.
- the invention involves a new method for the production of the hemi-calcium salt of (E)-7-[4- (4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3i?,55)-3,5- dihydroxyhept-6-enoic acid I, wherein a solution of the calcium salt of (E)-7-[4-(4- fluoropheny ⁇ - ⁇ -isopropyl-l-tmethy ⁇ methylsulfony ⁇ aminolpyrimidin-S-ylKS ⁇ j S ⁇ -S ⁇ - dihydroxyhept-6-enoic acid, with possible admixture of calcium hydroxide or other sodium, potassium or lithium salts with inorganic anions, is transferred into an organic solvent partially miscible with water, selected from the group including R 1 COOR 2 , R 1 COR 2 , or R 1 OH, wherein R 1 and R 2 independently mean hydrogen or a residue
- the amount of the extraction solvent needed is only about a quarter the amount needed for extraction of the sodium, potassium, or lithium salts. Because of its simplicity, the procedure is especially suitable for industrial production.
- Formulae V and XIII also include cyclic amides, in which case XR stands for pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl residues.
- Both methyl ester II and ethyl ester of rosuvastatin are commercially available and can be used directly or after protecting the free OH groups. Synthesis of the methyl ester of rosuvastatin II is described in patent EP 521471.
- the OH groups Prior to the basic hydrolysis of compounds of formula V, the OH groups are deprotected. It has been found out that besides usual acid hydrolysis with, e.g., trifluoroacetic acid, p- toluenesulfonic acid, or diluted hydrochloric acid, the deprotection can be carried out by reaction with methanol with a catalytic amount of iodine.
- reaction mixture is extracted with a mixture of demineralized water and a C 5 to C 7 hydrocarbon (e.g. hexane), in the course of which the alkali salt of rosuvastatin moves into the aqueous phase.
- a C 5 to C 7 hydrocarbon e.g. hexane
- the procedure includes adding an organic solvent partially miscible with water selected from the group including R 1 COOR 2 , R 1 COR 2 , or R 1 OH, wherein R 1 and R 2 independently mean hydrogen or a residue of a C 1 to C 10 aliphatic hydrocarbon, C 6 aromatic hydrocarbon, C 5 or C 6 cyclic hydrocarbon, or a combination of an aliphatic and aromatic or cyclic hydrocarbon, to the solution of the sodium, potassium, or lithium salt, and then a suitable calcium salt, such as especially calcium chloride or calcium acetate, is gradually added to the thoroughly stirred solution, in the course of which the calcium salt of rosuvastatin moves, virtually quantitatively, into the organic solvent.
- an organic solvent partially miscible with water selected from the group including R 1 COOR 2 , R 1 COR 2 , or R 1 OH, wherein R 1 and R 2 independently mean hydrogen or a residue of a C 1 to C 10 aliphatic hydrocarbon, C 6 aromatic hydrocarbon, C 5 or C 6 cyclic hydrocarbon,
- esters or amides V, XIII, or lactone IV of rosuvastatin can be hydrolyzed directly with calcium hydroxide, hi this case, calcium hydroxide is first added to a solution of the rosuvastatin derivative in a suitable solvent, e.g.
- pentane, hexane, heptane, cyclohexane), or the solid product can be obtained by cooling the solution and subsequent filtration.
- the solution can also be evaporated to dryness, the evaporation residue being then redissolved in a suitable solvent (e.g. methyl ethyl ketone, acetone), and the solid product being isolated either by precipitation with a suitable anti-solvent (pentane, hexane, heptane, cyclohexane), or by spraying the solution into the stream of an inert gas, by which method the product obtained is not contaminated with hydrocarbon solvents.
- a suitable solvent e.g. methyl ethyl ketone, acetone
- Tetrahydrofuran (75 ml) is added to weighed lactone IV (5 g, 10.8 mmol). A solution of 40% NaOH (10 ml) is added to the solution obtained over 5 minutes, and the heterogenous mixture is stirred vigorously for 3 hours and then poured into a separatory funnel containing demineralized water (150 ml) and hexane (50 ml). After shaking, the organic layer is poured out, and the aqueous layer is extracted with a mixture of hexane (40 ml) and tetrahydrofuran (10 ml). After complete separation, ethyl acetate (40 ml) is poured into the aqueous phase and calcium acetate (2 g) is added.
- aqueous phase is reextracted with ethyl acetate (20 ml).
- the ethyl acetate extract is washed with demineralized water (2 x 5 ml), dried, concentrated in a vacuum evaporator to 30 ml, and added dropwise to hexane (150 ml). 4.5 g (83 %) of amorphous rosuvastatin is obtained.
- Example 3 By the procedure described in Example 1, with the difference that potassium hydroxide, instead of sodium hydroxide, was used for hydrolysis of the ester, the potassium salt of rosuvastatin was obtained, which was further processed by the procedure described in Example 1. 4.2 g of amorphous rosuvastatin was obtained.
- Example 3
- IX Methyl ester IX (1.07 g) was dissolved in acetone (5.5 ml) and dimethoxypropane (5.5 ml). P- toluenesulfonic acid (0.1 g) was then added, and the mixture was stirred at room temperature for 1.5 hours.
- Acetonitrile 60 ml is added to weighed ester IX (3 g), and, after all the substance is dissolved, 10% HCl (4 ml) is poured in. This mixture is stirred at room temperature for 20 hours. Then, 4% NaOH (13 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 17 hours and then poured into a separatory funnel containing demineralized water (60 ml) and hexane (40 ml). After shaking, the organic layer is poured out, and the aqueous layer is extracted with toluene (40 ml).
- ethyl acetate 100 ml is poured into the aqueous phase, and 10% HCl (5.5 ml) is added. After separation, the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate solution is washed with demineralized water (2 x 10 ml), dried with calcium sulphate, and concentrated in a vacuum evaporator. The evaporation residue is refluxed in toluene (50 ml) for 4 hours, and, after cooling down, a white crystalline product (1.4 g) is filtered by suction.
- Tetrahydrofuran (15 ml) is added to weighed ester IX (1 g), and, after all the substance is dissolved, 10% HCl (4 ml) is poured in. This mixture is stirred at room temperature for 24 hours. Then, 40% NaOH (2 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 17 hours and then poured into a separatory funnel containing demineralized water (30 ml) and hexane (10 ml). After shaking, the organic layer is poured out, and the aqueous layer is extracted with a mixture of hexane (8 ml) and tetrahydrofuran (2 ml).
- ethyl acetate (10 ml) is poured into the aqueous phase and calcium acetate (0.4 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate solution is washed with demineralized water (2 x 3 ml), dried with calcium sulphate, and concentrated in a vacuum evaporator. The substance is then added to cyclohexane (30 ml), leading to the formation of a white amorphous substance. After filtration by suction and drying, 0.7 g (75 %) of rosuvastatin is obtained. HPLC: 99.3 %.
- ethyl acetate (30 ml) is poured into the aqueous phase and calcium acetate (0.4 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate solution is washed with demineralized water (2 x 3 ml), dried with calcium sulphate, and evaporated using a vacuum evaporator. After being dissolved in methyl ethyl ketone (5 ml), the substance is put to cyclohexane (30 ml), leading to the formation of a white amorphous substance. After filtration by suction and drying, 0.7 g of rosuvastatin is obtained. HPLC: 99.0 %.
- ethyl acetate (30 ml) is poured into the aqueous phase and calcium acetate (0.4 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate solution is washed with demineralized water (2 x 3 ml), dried with calcium sulphate, and evaporated using a vacuum evaporator. After being dissolved in methyl ethyl ketone (5 ml), the substance is put to pentane (30 ml), leading to the formation of a white amorphous substance. After filtration by suction and drying, 0.7 g of rosuvastatin is obtained. HPLC: 99.4 %.
- Tetrahydrofuran (15 ml) is added to weighed amide X (1 g), and, after all the substance is dissolved, 40% solution of LiOH (2 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously at 60 °C for 17 hours and then poured into a separatory funnel containing demineralized water (30 ml) and hexane (10 ml). After shaking, the organic layer is poured out, and the aqueous layer is extracted with hexane (8 ml). After complete separation, ethyl acetate (30 ml) is poured into the aqueous phase and calcium acetate (0.4 g) is added.
- Tetrahydrofuran 35 ml is added to weighed methyl ester II (6 g). 40% solution of LiOH (10 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 3 hours and then poured into a separatory funnel containing demineralized water (150 ml) and hexane (50 ml). After complete separation, ethyl acetate (40 ml) is poured into the aqueous phase and calcium acetate (2 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml).
- Tetrahydrofuran 35 ml is added to weighed ethyl ester XI (6 g). 40% solution of NaOH (10 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 3 hours and then poured into a separatory funnel containing demineralized water (150 ml) and hexane (50 ml). After complete separation, ethyl acetate (40 ml) is poured into the aqueous phase and calcium acetate (2 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml).
- Tetrahydrofuran (10 ml) is added to weighed lactone IV (0.5 g).
- Calcium hydroxide (0.2 g) is added to the solution, and the heterogenous mixture is stirred vigorously at 25 °C for 3 hours and then filtered. After being diluted with ethyl acetate (10 ml) and washed with water (2 x
- Tetrahydrofuran 35 ml is added to weighed tert-butyl ester XII (5 g). 40% solution of LiOH (10 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 3 hours and then poured into a separatory funnel containing demineralized water (150 ml) and hexane (50 ml). After complete separation, ethyl acetate (40 ml) is poured into the aqueous phase and calcium acetate (2 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml).
- the ethyl acetate extract is washed with demineralized water (2 x 5 ml), dried, and evaporated, and the evaporation residue is dissolved in acetone and sprayed into the stream of an inert gas. 4.5 g of amorphous rosuvastatin is obtained.
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Abstract
A method of producing the hemi-calcium salt of rosuvastatin, i.e. of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid of formula (I), in the crystalline or amorphous solid state, wherein a) the lactone of formula (IV), or ester or amid of general formulae (V) or (XIII), wherein X is either oxygen or amino group, R1CR2 is a protecting group, wherein R1 and R2 are preferably selected from C1 to C3 alkyls, and R is an alkyl selected from C1 to C10 alkyls, preferably methyl, ethyl or tert-butyl, after removing the protecting group in the case of the compound of formula (V), ia converted, by alkaline hydrolysis with an alkali metal or Ca2+ base, into a salt of rosuvastatin, b) in the case that an alkali metal base was used in step (a), the resulting alkali salt of rosuvastatin is converted into the calcium salt of rosuvastatin by reaction with a calcium salt in aqueous environment, c) crude calcium salt of rosuvastatin of formula (I) is extracted into a solvent partially miscible with water selected from the group including R1COOR2, R1COR2, or R1OH, wherein R1 and R2 independently mean hydrogen or a residue of a C1 to C10 aliphatic hydrocarbon, C6 aromatic hydrocarbon, C5 or C6 cyclic hydrocarbon, or a combination of an aliphatic and aromatic or cyclic hydrocarbon, d) the solution of the calcium salt of rosuvastatin prepared according to step (c) is further washed with water, and e) the product of formula (I) is isolated by cooling the solution and filtration, or by adding an anti-solvent and filtration, or by spraying into the stream of an inert gas.
Description
A method for the production of the hemi-calcium salt of (jE)-7-[4-(4-fluorophenyl)-6- isopropyl^-^ethylCmethylsulfony^ammolpyrimidin-S-ylKSRjSS^-SjS-dihydroxyhept-β- enoic acid
Technical Field
The invention concerns a new method of producing the hemi-calcium salt of (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3i-,55)-3,5- dihydroxyhept-6-enoic acid, known under the INN name rosuvastatin, of formula I.
This substance is an important hypolipidemic and hypocholesteric drug.
Background Art
Rosuvastatin is produced, according to patent EP 521471, usually from the sodium salt of (E)- 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3i?,5jS)- 3,5-dihydroxyhept-6-enoic acid and a suitable, water-soluble calcium salt, preferably from calcium chloride.
The starting sodium salt can be obtained, according to the aforementioned patent, from the methyl ester of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]- pyrimidin-5-yl](3i2,55)-3,5-dihydroxyhept-6-enoic acid of formula II by hydrolysis with ethanolic sodium hydroxide, or, more recently, according to international patent application WO 00/49014, from tert-butyl (E)-(6-[2-[4-(4-fluorophenyl)-6-isoρroρyl-2- [methyl(methylsulfonyl)ammo]pyrimidin-5-yl]vinyl](4i?,6S)-2,2-dimethyl-[l,3]dioxan-4-yl)- acetate of formula III.
This intermediate is first converted, by stirring with hydrochloric acid and then with sodium hydroxide, into the sodium salt of the corresponding acid. The calcium salt is then obtained by adding calcium chloride to a solution of the sodium salt in water. However, the salt prepared in this way is contaminated with inorganic substances; residual sodium hydroxide, for example, reacts with the calcium salt, yielding water-insoluble calcium hydroxide. Filtration of such a salt is, according to application WO 04014872, a lengthy process. A still improved method for the preparation of amorphous rosuvastatin, with higher yields, is published in application WO 04108691. Authors of further patent application WO 00042024 declare that the substance prepared according to patent EP 521471 had an amorphous structure, but the method of its preparation was difficult to reproduce. According to further patent application WO 03016317, it is also possible to obtain the calcium salt by reaction of calcium hydroxide with the lactone of formula IV
(IV)
It follows from our earlier findings that it is possible to extract the said salt, from an aqueous solution of the sodium or potassium salts of rosuvastatin, with an organic solvent, and thus separate it from inorganic impurities. However, this method has turned out, especially when working on a large scale, to be not too effective, because it is necessary to carry out multiple extraction with ethyl acetate to obtain a quantitative yield. The calcium salt was then obtained by repeated washing of the aforementioned extract with a water-soluble calcium salt.
This invention concerns a new, improved method for the production of the hemi-calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3i-,5iS)-3,5-dihydroxyhept-6-enoic acid (rosuvastatin) I which eliminates the aforementioned shortcomings.
Disclosure of Invention
The invention involves a new method for the production of the hemi-calcium salt of (E)-7-[4- (4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3i?,55)-3,5- dihydroxyhept-6-enoic acid I, wherein a solution of the calcium salt of (E)-7-[4-(4- fluoropheny^-β-isopropyl-l-tmethy^methylsulfony^aminolpyrimidin-S-ylKSΛjS^-S^- dihydroxyhept-6-enoic acid, with possible admixture of calcium hydroxide or other sodium, potassium or lithium salts with inorganic anions, is transferred into an organic solvent partially miscible with water, selected from the group including R1COOR2, R1COR2, or R1OH, wherein R1 and R2 independently mean hydrogen or a residue of a C1 to Cio aliphatic hydrocarbon, C6 aromatic hydrocarbon, C5 or C6 cyclic hydrocarbon, or a combination of an aliphatic and aromatic or cyclic hydrocarbon, the solution of the calcium salt I is then washed with water, and solid calcium salt of rosuvastatin of formula I is obtained by cooling and/or adding an anti-solvent and by filtration, or by spraying into the stream of an inert gas.
This procedure is based on the surprising finding that the calcium salt of (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3i?,5iS)-3,5- dihydroxyhept-6-enoic acid can be quantitatively transferred into solvents of the ester, ketone, or alcohol type of formulae R1COOR2, R1COR2, or R1OH, wherein R1 and R2 have the aforementioned meanings.
In performing the invention, wherein the calcium salt is transferred from the aqueous phase into an organic phase, the amount of the extraction solvent needed is only about a quarter the amount needed for extraction of the sodium, potassium, or lithium salts. Because of its simplicity, the procedure is especially suitable for industrial production.
Detailed description of the invention:
Esters or amides of rosuvastatin of formulae V and XIII, wherein X is either O, NH or N-R, and R, R1, R2 stand for any hydrocarbon residues, or rosuvastatin lactone of formula IV, can be hydrolyzed in a suitable solvent with sodium, potassium, or lithium hydroxides upon formation of the corresponding salt of rosuvastatin. Formulae V and XIII also include cyclic amides, in which case XR stands for pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl residues. Preferred general substances of formulae V and XIII include the methyl ester (X = 0, R = methyl) or ethyl ester (X = O, R = ethyl) and also the respective iV-methyl amide (X = NH, R = methyl). Both methyl ester II and ethyl ester of rosuvastatin are commercially available and can be used directly or after protecting the free OH groups. Synthesis of the methyl ester of rosuvastatin II is described in patent EP 521471.
Prior to the basic hydrolysis of compounds of formula V, the OH groups are deprotected. It has been found out that besides usual acid hydrolysis with, e.g., trifluoroacetic acid, p-
toluenesulfonic acid, or diluted hydrochloric acid, the deprotection can be carried out by reaction with methanol with a catalytic amount of iodine.
After the basic hydrolysis is carried out, the reaction mixture is extracted with a mixture of demineralized water and a C5 to C7 hydrocarbon (e.g. hexane), in the course of which the alkali salt of rosuvastatin moves into the aqueous phase.
After the organic phase is poured out, the sodium, potassium, or lithium salt of rosuvastatin is subsequently converted into the calcium salt by action of a suitable calcium salt in water. To prevent its precipitation from water, the procedure includes adding an organic solvent partially miscible with water selected from the group including R1COOR2, R1COR2, or R1OH, wherein R1 and R2 independently mean hydrogen or a residue of a C1 to C10 aliphatic hydrocarbon, C6 aromatic hydrocarbon, C5 or C6 cyclic hydrocarbon, or a combination of an aliphatic and aromatic or cyclic hydrocarbon, to the solution of the sodium, potassium, or lithium salt, and then a suitable calcium salt, such as especially calcium chloride or calcium acetate, is gradually added to the thoroughly stirred solution, in the course of which the calcium salt of rosuvastatin moves, virtually quantitatively, into the organic solvent. C1 to C4 alkyl esters of acetic acid (e.g. ethyl acetate) are particularly suitable solvents for the extraction. Alternatively, esters or amides V, XIII, or lactone IV of rosuvastatin can be hydrolyzed directly with calcium hydroxide, hi this case, calcium hydroxide is first added to a solution of the rosuvastatin derivative in a suitable solvent, e.g. tetrahydrofuran, and after the reaction is completed, the reaction mixture is extracted into an organic solvent selected from the group including R1COOR2, R1COR2, or R1OH, or their mixture, wherein R1 and R2 have the aforementioned meanings; C1 to C4 alkyl esters of acetic acid (e.g. ethyl acetate) are particularly suitable. Thus obtained solution of the calcium salt of rosuvastatin is then washed with water, dried with calcium sulphate, and concentrated in a vacuum evaporator. There are various ways to obtain the solid calcium salt of rosuvastatin of formula I from the solution. The partially concentrated solution can be precipitated into a suitable solvent (e.g. pentane, hexane, heptane, cyclohexane), or the solid product can be obtained by cooling the solution and subsequent filtration. The solution can also be evaporated to dryness, the evaporation residue being then redissolved in a suitable solvent (e.g. methyl ethyl ketone, acetone), and the solid product being isolated either by precipitation with a suitable anti-solvent (pentane, hexane, heptane, cyclohexane), or by spraying the solution into the stream of an inert gas, by which method the product obtained is not contaminated with hydrocarbon solvents.
When using the aforementioned methods according to the invention, it is possible to obtain product I with purity higher than 98.5 %.
The methods used are shown in Scheme 1. Reactions i to iv illustrate the methods of preparation of some starting substances, and reactions v to x illustrate preparation of rosuvastatin from various starting substances.
The invention is further demonstrated in the following examples, which illustrate the preferred alternatives of production of rosuvastatin according to the invention. However, the examples do not in any way limit the extent of the invention.
Examples
Example 1
(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl3(3i?,55)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I
Tetrahydrofuran (75 ml) is added to weighed lactone IV (5 g, 10.8 mmol). A solution of 40% NaOH (10 ml) is added to the solution obtained over 5 minutes, and the heterogenous mixture is stirred vigorously for 3 hours and then poured into a separatory funnel containing demineralized water (150 ml) and hexane (50 ml). After shaking, the organic layer is poured out, and the aqueous layer is extracted with a mixture of hexane (40 ml) and tetrahydrofuran (10 ml). After complete separation, ethyl acetate (40 ml) is poured into the aqueous phase and calcium acetate (2 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate extract is washed with demineralized water (2 x 5 ml), dried, concentrated in a vacuum evaporator to 30 ml, and added dropwise to hexane (150 ml). 4.5 g (83 %) of amorphous rosuvastatin is obtained.
1H NMR (DMSO) δ: 1.22 (d, J = 7, 6H); 1.41 (m, IH); 1.61 (m, IH); 2.18 (dd, J = 3, 2H); 3.43 (m, IH); 3.45 (s, 3H); 3.57 (s, 3H); 3.83 (m, IH); 4.25 (m, IH); 5.56 (dd, J = 7.16, IH); 6.58 (d, J = 16, IH); 7.33 (m, 2H); 7.76 (m, 2H) MS for C22H28FN3O6SNa [M + Na]+, calculated 504.1, measured 503.8. HPLC: 99.0 %.
Example 2 (E)-7-[4-(4-Fluorophenyl)-6-isoρropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3JR,55)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I
By the procedure described in Example 1, with the difference that potassium hydroxide, instead of sodium hydroxide, was used for hydrolysis of the ester, the potassium salt of rosuvastatin was obtained, which was further processed by the procedure described in Example 1. 4.2 g of amorphous rosuvastatin was obtained.
Example 3
Methyl (E)-(6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl-(methylsulfonyl)ainino]- ρyrimidin-5-yl]vmyl](4i?,65)-2,2-dimethyl-[l,3]dioxan-4-yl)-acetate IX Methyl ester IX (1.07 g) was dissolved in acetone (5.5 ml) and dimethoxypropane (5.5 ml). P- toluenesulfonic acid (0.1 g) was then added, and the mixture was stirred at room temperature for 1.5 hours. Then, alkalization with triethylamine (0.12 ml) was carried out, and the solution was evaporated. After adding ethyl acetate (60 ml), the mixture was shaken with water (2 x 8 ml). The organic layer was dried with Na2SO4 and evaporated. The crude product was crystallized from isopropyl alcohol. 0.88 g of white crystals of acetonide IX was obtained, which were recrystallized from isopropyl alcohol.
1H NMR (CDCl3) δ: 7.62 (m, 2H); 7.08 (m, 2H); 6.52 (dd, IH, //=16.21, /2=1.30); 5.45 (dd, IH, //=16.23, J2=5.36); 4.45 (m, IH); 4.35 (m, IH); 3.70 (s, 3H); 3.56 (s, 3H); 3.51 (s, 3H); 3.37 (sept, IH, /=6.68); 2.56 (dd, IH, //=15.68, J2=6.71); 2.38 (dd, IH, //=15.69, /2=6.39); 1.49 (s, 3H); 1.40 (s, 3H); 1.68 (m, IH); 1.27 (d, 3H, J=6.69); 1.23 (d, 3H, J=6.66).
Example 4
N-Methylamide of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]- pyrimidin-5-yl](3i?,5<S)-3,5-dihydroxyhept-6-enoic acid X
1.5 ml of 40% MeΝH2/MeOH was added to crude methyl ester of rosuvastatin IX (1.22 g) in 10 ml of MeOH. The mixture was stirred at 20 °C for 5 hours. After evaporation and crystallization from the mixture ethyl acetate/hexane, 1.0 g of amide X was obtained.
Example 5
N-Methylamide of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]- pyrimidin-5-yl](3i?,5(S)-3,5-dihydroxyhept-6-enoic acid X
1.35 ml of 1.83 M MeNH2ATHF was added to 570 mg of lactone IV in 7 ml of THF. The mixture was stirred at 20 0C for 4 hours and then evaporated. 570 mg of white crystalline substance X was obtained by crystallization from the mixture ethyl acetate/hexane.
1H NMR (CDCl3) δ: 7.65 (m, 2H); 7.05 (m, 2H); 6.60 (dd, IH, J/=16.07, J2=I.33); 6.05 (d, IH, J=4.45); 5.45 (dd, IH, J/=16.06, J2=5.32); 4.45 (m, IH); 4.15 (m, IH); 3.55 (s, 3H); 3.50
(s, 3H); 3.35 (sept, IH, J=6.65); 2.78 (d, 3H, J=4.80); 2.28 (d, 2H, 5.78); 1.25 (d, 6H, J=6.69).
Example 6
Lactone of rosuvastatin IV
Acetonitrile (60 ml) is added to weighed ester IX (3 g), and, after all the substance is dissolved, 10% HCl (4 ml) is poured in. This mixture is stirred at room temperature for 20 hours. Then, 4% NaOH (13 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 17 hours and then poured into a separatory funnel containing demineralized water (60 ml) and hexane (40 ml). After shaking, the organic layer is poured out, and the aqueous layer is extracted with toluene (40 ml). After complete separation, ethyl acetate (100 ml) is poured into the aqueous phase, and 10% HCl (5.5 ml) is added. After separation, the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate solution is washed with demineralized water (2 x 10 ml), dried with calcium sulphate, and concentrated in a vacuum evaporator. The evaporation residue is refluxed in toluene (50 ml) for 4 hours, and, after cooling down, a white crystalline product (1.4 g) is filtered by suction. 1H NMR (CDCl3) δ: 7.60 (m, 2H); 7.08 (m, 2H); 6.70 (dd, IH, J/=16.1, J2=l35); 5.45 (dd, IH, J/-16.08, J2=5.97); 5.25 (m, IH); 4.30 (pent, IH, J=3.71); 3.55 (s, 3H); 3.50 (s, 3H); 3.32 (sept, IH, J=6.69); 2.75 (m, IH); 2.65 (m, IH), 1.92 (m, OH); 1.90 (m, IH); 1.68 (m, IH); 1.25 (d, 3H, J=6.66); 1.23 (d, 3H, J=6.67).
Example 7
(E)-7- [4-(4-Fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5 - yl](3i?,5jS)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I
Tetrahydrofuran (15 ml) is added to weighed ester IX (1 g), and, after all the substance is dissolved, 10% HCl (4 ml) is poured in. This mixture is stirred at room temperature for 24 hours. Then, 40% NaOH (2 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 17 hours and then poured into a separatory funnel containing demineralized water (30 ml) and hexane (10 ml). After shaking, the organic layer is poured out, and the aqueous layer is extracted with a mixture of hexane (8 ml) and tetrahydrofuran (2 ml). After complete separation, ethyl acetate (10 ml) is poured into the aqueous phase and calcium acetate (0.4 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate solution is washed with demineralized water (2 x 3 ml), dried with calcium sulphate, and concentrated in a vacuum evaporator. The substance is then added to
cyclohexane (30 ml), leading to the formation of a white amorphous substance. After filtration by suction and drying, 0.7 g (75 %) of rosuvastatin is obtained. HPLC: 99.3 %.
Example 8 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3i?,55)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I
Methanol (15 ml) is added to weighed ester IX (1 g), and, after all the substance is dissolved, a catalytic amount of iodine is added. This mixture is stirred at room temperature for 24 hours. Then, 40% NaOH (2 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 30 minutes and then poured into a separatory funnel containing demineralized water (30 ml) and hexane (10 ml). After shaking, the organic layer is poured out, and the aqueous layer is extracted with a mixture of hexane (8 ml) and tetrahydrofuran (2 ml). After complete separation, ethyl acetate (30 ml) is poured into the aqueous phase and calcium acetate (0.4 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate solution is washed with demineralized water (2 x 3 ml), dried with calcium sulphate, and evaporated using a vacuum evaporator. After being dissolved in methyl ethyl ketone (5 ml), the substance is put to cyclohexane (30 ml), leading to the formation of a white amorphous substance. After filtration by suction and drying, 0.7 g of rosuvastatin is obtained. HPLC: 99.0 %.
Example 9
(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3i?,5jS)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I Tetrahydrofuran (15 ml) is added to weighed ester IX (1 g), and, after all the substance is dissolved, 50% aqueous trifluoroacetic acid is poured in. This mixture is stirred at room temperature for 24 hours. Then, 40% NaOH (2 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 30 minutes and then poured into a separatory funnel containing demineralized water (30 ml) and hexane (10 ml). After shaking, the organic layer is poured out, and the aqueous layer is extracted with a mixture of hexane (8 ml) and tetrahydrofuran (2 ml). After complete separation, ethyl acetate (30 ml) is poured into the aqueous phase and calcium acetate (0.4 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate
(20 ml). The ethyl acetate solution is washed with demineralized water (2 x 3 ml), dried with calcium sulphate, and concentrated in a vacuum evaporator. After cooling down and filtration, 0.65 g (70 %) of rosuvastatin is obtained. HPLC: 99.0 %.
Example 10
(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3i?,5<S)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I
Methanol (10 ml) is added to weighed ester IX (1 g), and, after all the substance is dissolved, a catalytic amount of j?-toluenesulfonic acid is added. This mixture is stirred at room temperature for 24 hours. Then, 40% NaOH (2 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 30 minutes and then poured into a separatory funnel containing demineralized water (30 ml) and hexane (10 ml). After shaking, the organic layer is poured out, and the aqueous layer is extracted with a mixture of hexane (8 ml) and tetrahydrofuran (2 ml). After complete separation, ethyl acetate (30 ml) is poured into the aqueous phase and calcium acetate (0.4 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate solution is washed with demineralized water (2 x 3 ml), dried with calcium sulphate, and evaporated using a vacuum evaporator. After being dissolved in methyl ethyl ketone (5 ml), the substance is put to pentane (30 ml), leading to the formation of a white amorphous substance. After filtration by suction and drying, 0.7 g of rosuvastatin is obtained. HPLC: 99.4 %.
Example 11 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3i?,5,S)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I
Tetrahydrofuran (15 ml) is added to weighed amide X (1 g), and, after all the substance is dissolved, 40% solution of LiOH (2 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously at 60 °C for 17 hours and then poured into a separatory funnel containing demineralized water (30 ml) and hexane (10 ml). After shaking, the organic layer is poured out, and the aqueous layer is extracted with hexane (8 ml). After complete separation, ethyl acetate (30 ml) is poured into the aqueous phase and calcium acetate (0.4 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate solution is
washed with demineralized water (2 x 3 ml), dried with calcium sulphate, and concentrated using a vacuum evaporator. The solution is then put to cyclohexane (30 ml), leading to the formation of a white amorphous substance. After filtration by suction and drying, 0.75 g of rosuvastatin is obtained. HPLC: 99.5 %.
Example 12
(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3i?,55)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I
Tetrahydrofuran (35 ml) is added to weighed methyl ester II (6 g). 40% solution of LiOH (10 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 3 hours and then poured into a separatory funnel containing demineralized water (150 ml) and hexane (50 ml). After complete separation, ethyl acetate (40 ml) is poured into the aqueous phase and calcium acetate (2 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate extract is washed with demineralized water (2 x 5 ml), dried, and evaporated, and the evaporation residue is dissolved in acetone and sprayed into the stream of an inert gas. 4.5 g (74 %) of amorphous rosuvastatin is obtained. HPLC: 99.1 %.
Example 13
(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3i?,5<S)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I
Tetrahydrofuran (35 ml) is added to weighed ethyl ester XI (6 g). 40% solution of NaOH (10 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 3 hours and then poured into a separatory funnel containing demineralized water (150 ml) and hexane (50 ml). After complete separation, ethyl acetate (40 ml) is poured into the aqueous phase and calcium acetate (2 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate extract is washed with demineralized water (2 x 5 ml), concentrated, and then put to cyclohexane. After filtration, the solid substance is stirred in isopropanol (40 ml) for 2 hours and then filtered by suction. 3.8 g of rosuvastatin is obtained. HPLC: 99.2 %.
Example 14
(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3i?,55)-3,5-dihydroxyhept-6-enoic acid, hemi-calciuni salt I
Tetrahydrofuran (10 ml) is added to weighed lactone IV (0.5 g). Calcium hydroxide (0.2 g) is added to the solution, and the heterogenous mixture is stirred vigorously at 25 °C for 3 hours and then filtered. After being diluted with ethyl acetate (10 ml) and washed with water (2 x
5 ml), the extract is dried with calcium sulphate, and, after being concentrated, it is put dropwise to 20 ml of pentane. After filtration by suction, 0.35 g of amorphous rosuvastatin is obtained. The product is then stirred with n-butanol (5 ml), and, after filtration by suction, 0.30 g of rosuvastatin is obtained. HPLC: 99.5 %.
Example 15
(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3.R,5(S)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I Tetrahydrofuran (10 ml) is added to weighed methyl ester II (0.5 g). Calcium hydroxide (0.2 g) is added to the solution, and the heterogenous mixture is stirred vigorously at 25 0C for 3 hours and then filtered. After being diluted with ethyl acetate (10 ml) and washed with water (2 x 5 ml), the extract is dried with calcium sulphate, and, after being concentrated, it is put dropwise to 20 ml of pentane. After filtration by suction, 0.35 g of amorphous rosuvastatin is obtained. HPLC: 99.0 %.
Example 16
(JE)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3/-,55)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I Tetrahydrofuran (10 ml) is added to weighed ethyl ester XI (0.5 g). Calcium hydroxide (0.2 g) is added to the solution, and the heterogenous mixture is stirred vigorously at 25 0C for 3 hours and then filtered. After being diluted with ethyl acetate (10 ml) and washed with water (2 x 5 ml), the extract is dried with calcium sulphate, and, after being concentrated, it is put dropwise to 20 ml of cyclohexane. After filtration by suction, 0.30 g of amorphous rosuvastatin is obtained. HPLC: 99.0 %.
Example 17
(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3i?,5)S)-3,5-dihydroxyhept-6-enoic acid, hemi-calcium salt I
Tetrahydrofuran (35 ml) is added to weighed tert-butyl ester XII (5 g). 40% solution of LiOH (10 ml) is added to the solution over 5 minutes, and the heterogenous mixture is stirred vigorously for 3 hours and then poured into a separatory funnel containing demineralized water (150 ml) and hexane (50 ml). After complete separation, ethyl acetate (40 ml) is poured into the aqueous phase and calcium acetate (2 g) is added. After 10 minutes of vigorous stirring, the phases are separated, and the aqueous phase is reextracted with ethyl acetate (20 ml). The ethyl acetate extract is washed with demineralized water (2 x 5 ml), dried, and evaporated, and the evaporation residue is dissolved in acetone and sprayed into the stream of an inert gas. 4.5 g of amorphous rosuvastatin is obtained.
HPLC: 99.2 %.
Claims
1. A method for the production of the hemi-calcium salt of rosuvastatin, i.e. of (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3i?,5)S)-3!,5- dihydroxyhept-6-enoic acid of formula I,
in the crystalline or amorphous solid state, characterized in that a) the lactone of formula IV
or the ester or amide of general formulae V or XIII
wherein X is either oxygen or amino group, R1CR2 is a protecting group, wherein R1 and R2 are preferably selected from C1 to C3 alkyls, and R is an alkyl selected from C1 to C10 alkyls, preferably methyl, ethyl or tert-butyl, after removing the protecting group in the case of the compound of formula V,
are converted, by alkaline hydrolysis with an alkali metal or Ca2+ base, into a salt of rosuvastatin, b) in the case wherein an alkali metal base was used in step (a), the resulting alkali salt of rosuvastatin is converted into the calcium salt of rosuvastatin by reaction with a calcium salt in aqueous environment, c) crude calcium salt of rosuvastatin of formula I is transferred into a solvent partially miscible with water selected from the group including R1COOR2, R1COR2, or R1OH, wherein R1 and R2 independently mean hydrogen or a residue of a C1 to C10 aliphatic hydrocarbon, C6 aromatic hydrocarbon, C5 or C6 cyclic hydrocarbon, or a combination of an aliphatic and aromatic or cyclic hydrocarbon, d) the solution of the calcium salt of rosuvastatin prepared according to step (c) is further washed with water, and e) the product of formula I is isolated by cooling the solution and filtration, or by adding an anti-solvent and filtration, or by spraying into the stream of an inert gas.
2. The method according to claim 1 characterized in that alkaline hydrolysis of the starting compound of formula IV, V, or XIII is carried out using a hydroxide from the group of NaOH, KOH, LiOH, and Ca(OH)2.
3. The method according to claim 1 characterized in that an ester of formula R3COOR3 ', wherein R3 is hydrogen or C1 to C3 alkyl, and R3' is C1 to C4 alkyl, is used as the partially miscible solvent in step (c).
4. The method according to claim 3 characterized in that a C1 to C4 alkyl ester of acetic acid is used.
5. The method according to claim 4 characterized in that ethyl acetate is used.
6. The method according to claim 1 characterized in that the methyl ester of (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3i?,55)-3,5- dihydroxyhept-6-enoic acid of formula II
7. The method according to claim 1 characterized in that ethyl ester of (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5- dihydroxyhept-6-enoic acid of formula XI
9. The method according to claim 1 characterized in that lactone of formula IV
10. The method according to claim 1 characterized in that the alkali salt of rosuvastatin prepared according to step (a) is converted into the calcium salt of rosuvastatin by reaction with a calcium salt, such as calcium chloride or calcium acetate, in a two-phase system comprising an aqueous phase and a phase formed by a solvent partially miscible with water selected from the group including R1COOR2, R1COR2, or R1OH, wherein R1 and R2 independently mean hydrogen or a residue of a C1 to C10 aliphatic hydrocarbon, C6 aromatic hydrocarbon, C5 or C6 cyclic hydrocarbon, or a combination of an aliphatic and aromatic or cyclic hydrocarbon, the resulting substance of formula I moving from the aqueous phase into the organic solvent at the same time; after the aqueous phase is separated, the solution of the substance of formula I is washed with water, and solid calcium salt of rosuvastatin of formula I is obtained by cooling and filtration, or by adding an anti-solvent and filtration, or by spraying into the stream of an inert gas.
11. The method according to claim 1 characterized in that starting lactone IV, or a compound from the group of substances of general formula V after deprotection, or a compound from the group of substances of general formula XIII, is directly reacted with calcium hydroxide under formation of the calcium salt of rosuvastatin I, which is then, after adding an organic solvent, quantitatively moved into said solvent selected from the group including R1COOR2, R1COR2, or R1OH, wherein R1 and R2 independently mean hydrogen or a residue of a C1 to C10 aliphatic hydrocarbon, C6 aromatic hydrocarbon, C5 or C6 cyclic hydrocarbon, or a combination of an aliphatic and aromatic or cyclic hydrocarbon, the solution of substance I is further washed with water, and solid calcium salt of rosuvastatin of formula I is obtained by cooling and filtration, or by adding an anti-solvent and filtration, or by spraying into the stream of an inert gas.
12. The method according to claim 11 characterized in that the starting compound from the group of substances of general formulae IV, V or XIII is reacted with calcium hydroxide in the environment of tetrahydrofuran.
13. The method according to any of claims 1 to 10 characterized in that solid substance I is isolated in the amorphous form by spraying its solution in an organic solvent, e.g. acetone or methyl ethyl ketone, into the stream of an inert gas.
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