CZ2005427A3 - Process for preparing hemi-calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6-heptenoic acid - Google Patents

Abstract

A method for producing rosuvastatin hemicalcium salt, i.e. (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3, 5-dihydroxy-6-heptenic acid of formula I in crystalline or amorphous solid form, wherein: a) a lactone of formula IV or an ester or amide of formula V or XIII wherein X is either oxygen or amino, R 6 .CR.sup.2.n. is a protecting group and R is an alkyl selected from C.sub.1.n. az C.sub.10.n. alkyl, after deprotection of the compound of formula V, with alkaline hydrolysis with an alkali metal base or Ca.sup.2 +. (b) when an alkali metal base is used in (a), the resulting rosuvastatin alkali salt is converted to calcium rosuvastatin by reaction with a calcium salt in an aqueous medium, (c) rosuvastatin crude calcium salt of formula I is converted to a solvent limited to miscible with water selected from R.sup.1.cor.sup.2, r.sup.1.cor.sup.2 or n.sup.1.n.OH where R.sup.1.n. and R.sup.2.n. are independently hydrogen or an aliphatic hydrocarbon radical C.sub.1.n. az C.sub.10, .n. aromatic hydrocarbon C.sub.6, cyclic hydrocarbon C.sub.5.n. or (d) the rosuvastatin calcium salt solution prepared in (c) is further washed with water, and (e) the product of formula (I) is isolated by cooling the solution and filtering or adding an anti-solvent and filtering or spraying into an inert gas stream.

Description

A process for the preparation of rosuvastatin hemi-calcium salt, i.e. (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2 [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxy- 6-heptenic acids of the formula I in crystalline or amorphous form in the solid state in which

a) a lactone of formula IV or an ester or amide of formula V or XIII, wherein X is either oxygen or amino, R'CR ² is a protecting group and R is an alkyl selected from C 1 -C 10 alkyl, after deprotection of the compound of formula V , is converted to rosuvastatin by alkaline hydrolysis with an alkali metal or Ca ²⁺ base,

(b) where an alkali metal base has been used in (a), the formed rosuvastatin alkaline salt is converted to rosuvastatin calcium by reaction with the calcium salt in an aqueous medium;

c) converting the crude rosuvastatin calcium of formula I into a water-miscible solvent selected from R'COOR ² , R'COR ² or R'OH, wherein R ¹ and R ² are independently hydrogen or a C 1 -C 10 aliphatic hydrocarbon residue; a C ₆ aromatic hydrocarbon, a C ₅ or C ₆ cyclic hydrocarbon, or a combination,

(d) the rosuvastatin calcium solution prepared in (c) is further washed with water; and

(e) isolating the product of formula (I) by cooling the solution and filtering or adding an anti-solvent and filtering or injecting it into the

· «* * · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2 [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (37 R, 5 S) -3,5-dihydroxy- 6-heptenic acid

Technical field

The present invention relates to a novel process for the preparation of (2S) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (37 R, 5 S) -3,5 hemi-calcium salt. -dihydroxy-6-heptenoic acid known under the non-proprietary name of rosuvastatin of formula I.

Said drug is an important representative of hypolipidemic and hypocholesteric drugs.

BACKGROUND OF THE INVENTION

Rosuvastatin is produced according to the published patent (EP 521471) usually from (S) -7 [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 55) -3,5-dihydroxy-6-heptenic acid and suitable water-soluble calcium salts, preferably calcium chloride.

The starting sodium salt can be obtained according to the above patent from (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] methyl ester (37 R, 55 R). -3,5-dihydroxy-6-heptenic acid of the 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-Isopropyl 2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] vinyl] (4R, 65) 2,2-dimethyl- [1,3] dioxan-4-yl) acetate of formula III.

9 9 9 9 9 9 9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 • ······· · · * ·· ·· ·· ·· ··

Λ (III) (III)

This intermediate is first converted into the sodium salt of the corresponding acid by stirring with hydrochloric acid and then with sodium hydroxide. The calcium salt is then formed by adding calcium chloride to a solution of the sodium salt in water. However, the salt thus prepared is contaminated with inorganic substances and, for example, residual sodium hydroxide provides water-insoluble calcium hydroxide with the calcium salt. Filtration of such a salt is lengthy according to published application (WO 04014872). An even improved process for the preparation of amorphous rosuvastatin that provides increased yields is disclosed in WO04108691. The authors of another patent application (WO 00042024) claim that the substance prepared according to patent EP 521471 had an amorphous structure, but the process of its preparation was difficult to reproduce. According to another patent application (WO 03016317), the calcium salt can also be obtained by treating the lactone of formula IV with calcium hydroxide.

or other rosuvastatin esters.

(iv) · · · · · · · · · · · ·

Our previous results indicate that it is possible to extract said salt from an aqueous solution of sodium or potassium salt of rosuvastatin into an organic solvent and thereby separate it from inorganic impurities. However, this process, in particular on a larger scale, has proven not to be very effective due to the need to use multiple extraction with ethyl acetate to achieve a quantitative yield. The calcium salt was then obtained by repeated washing of the above water-soluble calcium salt extract.

This invention relates to a novel, improved process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (37, 55) - 3,5-dihydroxy-6-heptenoic acid (rosuvastatin) I, which eliminates the above disadvantages.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides a novel process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (37 R, 55) -3,5 hemi-calcium salt. - dihydroxy-6-heptenoic acid I, which is a solution of (R) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] calcium salt (37) 55) -3,5-dihydroxy-6-heptenoic acid with an optional addition of calcium hydroxide or other sodium, potassium or lithium salts with an inorganic anion is converted into a water-miscible organic solvent selected from the series of R 2 OOR ² , R 2 OR ² or R 4 H, wherein R and R are independently hydrogen or a C 1 -C 10 aliphatic hydrocarbon residue, a C _b aromatic hydrocarbon, a C 5 or C 6 cyclic hydrocarbon, or a combination of an aliphatic and aromatic or cyclic hydrocarbon, the calcium salt solution I is further washed with water and solid calcium the rosuvastatin salt of formula I is obtained by cooling and / or added m anti-solvent and filtration, or by spraying into an inert gas stream.

This whole process is based on the surprising finding that (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3 R, 55) The -3,5-dihydroxy-6-heptenic acid can be quantitatively converted into esters, ketone or alcohol type solvents of the formula R ¹ COOR ² , R 1 OR ² or R ¹ OH, wherein R ¹ and R ² are as defined above.

In an embodiment of the invention where the calcium salt is transferred from the aqueous phase to the organic phase, only about a quarter of the extraction solvent is sufficient, compared to the extraction of the sodium, potassium or lithium salt. The simplicity of the process is particularly suitable for industrial production.

• ·

A more detailed description of the invention follows:

Rosuvastatin esters or amides of formula V and XIII, wherein X is either O, NH or NR and R, R ¹ , R ² is any hydrocarbon residue, or rosuvastatin lactone of formula IV can be hydrolyzed in a suitable solvent with sodium, potassium or lithium hydroxide to form appropriate rosuvastatin salts. Formula V and XIII also include cyclic amides, in which case XR is a pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl residue. Preferred general compounds of formulas V and XIII are the methyl ester (X = O, R = methyl) or the ethyl ester (X = O, R = ethyl) as well as the corresponding N-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 protection of the free OH groups. The synthesis of rosuvastatin II methyl ester is described in the original patent EP 521471.

(A) (ΧΠΙ)

Compounds of formula V are subjected to OH deprotection prior to basic hydrolysis. In addition to conventional acid hydrolysis with, for example, trifluoroacetic acid, p-toluenesulfonic acid or dilute hydrochloric acid, deprotection has been shown to be possible by treatment with methanol with a catalytic amount of iodine.

After basic hydrolysis, the reaction mixture is extracted with a mixture of demineralized water and

A C 5 to C 7 hydrocarbon (eg hexane), wherein the alkali salt of rosuvastatin is transferred to water.

After casting the organic phase, the sodium, potassium or lithium salt of rosuvastatin is subsequently converted into water into the calcium salt by treatment with a suitable calcium salt. To prevent it from precipitating out of the water, an organic solution is added to the sodium, potassium or lithium salt solution.

Solvent limited to miscible with water of selected series R ^ OOR ² , R'COR ² or R'OH, where R ¹ and R ² are independently hydrogen or a C 1 -C 10 aliphatic hydrocarbon radical, C 6 aromatic hydrocarbon, C 5 or C 6 cyclic hydrocarbon, or a combination of an aliphatic and aromatic or cyclic hydrocarbon, and then a suitable calcium salt such as especially chloride is added to the well stirred solution or calcium acetate, whereby a practically quantitative conversion of rosuvastatin calcium into the organic solvent is gradually achieved. Particularly suitable solvents for this conversion are C 1 to C 4 alkyl esters of acetic acid (e.g. ethyl acetate).

Alternatively, rosuvastatin esters or amides V, XIII or lactone IV can be hydrolyzed directly with calcium hydroxide. In this case, to a solution of the rosuvastatin derivative in a suitable solvent such as tetrahydrofuran, calcium hydroxide is first added, and after the reaction is completed, the reaction mixture is transferred to an organic solvent of FCOCO ² , R'COR ² or R'OII, or mixtures thereof, R ¹ and R ² are as defined above, particularly suitable are C 1 to C 4 alkyl esters of acetic acid (e.g. ethyl acetate).

The solution of rosuvastatin calcium thus obtained is subsequently washed with water, dried over calcium sulphate and concentrated in a vacuum evaporator. The solid calcium salt of rosuvastatin I can be obtained from the solution in various ways. The partially concentrated solution may be precipitated into a suitable solvent (such as pentane, hexane, heptane, cyclohexane), or the solid product may be obtained by cooling the solution and filtering. The solution can also be evaporated to dryness, redissolved in a suitable solvent (such as methyl ethyl ketone, acetone) and the solid product isolated either by precipitation into a suitable anti-solvent (pentane, hexane, heptane, cyclohexane), or preferably by injection of the solution into an inert gas stream. a product not contaminated with hydrocarbon solvents is obtained.

With the above methods of the invention, product I with a purity of more than 98.5% can be obtained.

The procedures used are shown in Scheme 1. Reactions i to iv illustrate the preparation of some starting materials and reactions v to x illustrate the preparation of rosuvastatin from various starting materials.

• • • • • •

Scheme 1

• · · ···························

4 · ···

Ca ²⁺

Ca ²⁺

2+

The invention is illustrated in more detail in the following examples which illustrate preferred alternatives for the production of rosuvastatin according to the invention. The examples given do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 (E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5L ₎ -3,5-dihydroxy-6 Heptenic acid, hemi-calcium salt I

To the weighed lactone IV (5 g, 10.8 mmol) was added tetrahydrofuran (75 mL). To this solution is added a solution of 40% NaOH (10 mL) over 5 min and the heterogeneous mixture is vigorously stirred for 3 h and then poured into a separatory funnel containing demineralized water (150 mL) and hexane (50 mL). After shaking, the organic layer is discarded and the aqueous layer is extracted with a mixture of hexane (40 mL) and tetrahydrofuran (10 mL). After complete settling, ethyl acetate (40 mL) was added to the aqueous phase and calcium acetate (2 g) was added. After 10 minutes of vigorous stirring, the phases were separated and the aqueous phase was re-extracted with ethyl acetate (20 mL). The resulting ethyl acetate extract is washed with demineralized water (2 x 5 ml) and, after drying, concentrated to 30 ml in a vacuum evaporator and added dropwise to hexane (150 ml). 4.5 g (83%) of amorphous rosuvastatin are obtained.

1 H 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, 1H); 4.25 (m, IH); 5.56 (dd, J = 7.16, 1H); 6.58 (d, J = 16, 1H); 7.33 (m, 2 H); 7.76 (m, 2H).

MS for C 22 H 28 FN ₃ O ₆ SNa [M + Na] ⁺ calcd 504.1; found 503.8.

HPLC: 99.0%.

Example 2 (E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) 3,5-dihydroxy-6 Heptenic acid, hemi-calcium salt I

Following the procedure described in Example 1, where potassium hydroxide was used instead of sodium hydroxide to hydrolyse the ester, followed by rosuvastatin potassium, which was further treated as 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) amino] pyrimidin-5-yl] vinyl] (47 R, 65) -2,2 Dimethyl- [1,3] dioxan-4-yl) -acetate IX

The methyl ester IX (1.07 g) was dissolved in acetone (5.5 mL) and dimethoxypropane (5.5 mL).

Subsequently, 77-toluenesulfonic acid (0.1 g) was added, and the mixture was stirred for 1.5 h at room temperature.

• room temperature. The mixture was then basified with triethylamine (0.12 ml) and the solution was evaporated. After addition of ethyl acetate (60 mL), the mixture was shaken with water (2 x 8 mL). The organic layer was dried over Na 2 SO 4 and evaporated. The crude product was crystallized from isopropyl alcohol. 0.88 g of white acetonide IX crystals were obtained, which were recrystallized from isopropyl alcohol.

Ή NMR (CDCl ₃ ) δ: 7.62 (m, 2H); 7.08 (m. 2H); 6.52 (dd, 1H, J = 16.21, J = 2.30); 5.45 (dd,

1H, (= 16.23, / == 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, 1H, J = 6.68); 2.56 (dd, 1H, //=15.68, / ₂ = 6.71); 2.38 (dd, 1H, J = 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

(E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxy N-methylamide -6-heptenic acid X

To the crude rosuvastatin IX methyl ester (1.22 g) in 10 mL of MeOH was added 1.5 mL of 40% MeNH 2 / MeOH. The mixture was stirred at 20 ° C for 5h. Evaporation and crystallization from ethyl acetate / hexane gave 1.0 g of amide X.

Example 5

(E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxy-6-N-methylamide -heptenic acids X

To 570 mg of lactone IV in 7 mL of THF was added 1.35 mL of 1.83 M MeNH 2 / THF. The mixture was stirred for 4 h at 20 ° C and then evaporated. Crystallization from ethyl acetate / hexane gave 570 mg of white crystalline substance X.

1 H NMR (CDCl 3) δ: 7.65 (m, 2H); 7.05 (m. 2H); 6.60 (dd, 1H, J = 16.07, J = 2.23); 6.05 (d,

1H, (= 4.45); 5.45 (dd, 1H, J = 16.06, J = 5.25); 4.45 (m, IH); 4.15 (m. 1H); 3.55 (s. 3H); 3.50 (s. 3H); 3.35 (sept, 1H, J = 6.65); 2.78 (d, 3H, J = 4.80); 2.28 (d, 2H, 5.78); 1.25 (d, 6H, J = 6.96).

Example 6

Rosuvastatin Lacton IV

Acetonitrile (60 mL) was added to the weighed ester IX (3 g) and after dissolution of all material was added 10% HCl (4 mL). This mixture is stirred for 20 h at room temperature. Then, a solution of 4% NaOH (13 mL) is added over 5 min and the heterogeneous mixture is stirred vigorously for 17 h and then poured into a separatory funnel containing demineralized water (60 mL) and hexane (40 mL).

99

9

999

9

9 99

9999 99

After shaking, the organic layer was discarded and the aqueous layer was extracted with toluene (40 mL). After complete settling, ethyl acetate (100 mL) was added to the aqueous phase and 10% HCl (5.5 mL) was added. After separation, the aqueous phase is re-extracted with ethyl acetate (20 mL). The resulting ethyl acetate solution is washed with demineralized water (2 x 10 mL) and, after drying with calcium sulfate, is concentrated on a vacuum evaporator. The resulting residue is refluxed in toluene (50 mL) for 4 h and upon cooling, a white crystalline product (1.4 g) is sucked off.

1 H NMR (CDCl ₃ ) δ: 7.60 (m, 2H); 7.08 (m. 2H); 6.70 (dd, 1H, 7 / 1.16 = 7 ₂ = 1.35); 5.45 (dd, 1H, 7 / = 16.08,7 ₂ = 5.97); 5.25 (m. 1H); 4.30 (pent, 1H, J = 3.71); 3.55 (s. 3H); 3.50 (s. 3H); 3.32 (sept, 1H, 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] (3A, 55) 3,5-dihydroxy-6-heptene acid, hemicalcium salt

Tetrahydrofuran (15 mL) was added to the weighed ester IX (1 g) and after dissolution of all material was added 10% HCl (4 mL). This mixture is stirred at room temperature for 24 h. Then, a solution of 40% NaOH (2 mL) is added over 5 min and the heterogeneous mixture is vigorously stirred for 17 h and then poured into a separatory funnel containing demineralized water (30 mL) and hexane (10 mL). After shaking, the organic layer is discarded and the aqueous layer is extracted with a mixture of hexane (8 mL) and tetrahydrofuran (2 mL). After complete settling, ethyl acetate (10 mL) was added to the aqueous phase and calcium acetate (0.4 g) was added. After 10 minutes of vigorous stirring, the phases were separated and the aqueous phase was re-extracted with ethyl acetate (20 mL). The resulting ethyl acetate solution is washed with demineralized water (2 x 3 mL) and, after drying with calcium sulfate, is concentrated on a vacuum evaporator. Thereafter, the substance is added to cyclohexane (30ml) to give a white amorphous substance, after 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] (3R, 5S) 3,5-dihydroxy-6 Heptenic acid, hemi-calcium salt I

Methanol (15 ml) was added to the weighed ester IX (1 g) and a catalytic amount of iodine was added after all of the material had dissolved. This mixture is stirred at room temperature for 24 h. Then, a solution of 40% NaOH (2 mL) is added over 5 min and the heterogeneous mixture is vigorously stirred for 30 min and then poured into a separatory funnel containing demineralized water (30 mL) and hexane (10 mL). After shaking, the organic layer is discarded and the aqueous layer is extracted with a mixture of hexane (8 mL) and tetrahydrofuran (2 mL). After complete settling, ethyl acetate (30 mL) was added to the aqueous phase and calcium acetate (0.4 g) was added. After 10 minutes of vigorous stirring, the phases were separated and the aqueous phase was re-extracted with ethyl acetate (20 mL). The resulting ethyl acetate solution is washed with demineralized water (2 x 3 mL) and, after drying with calcium sulfate, is evaporated in a vacuum evaporator. After dissolution in methyl ethyl ketone (5 ml), the substance is added to cyclohexane (30 ml) to give a white amorphous substance, after 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] (3R, 5S) 3,5-dihydroxy-6 Heptenic acid, hemi-calcium salt I

Tetrahydrofuran (15 ml) was added to the weighed ester IX (1 g) and 50% aqueous trifluoroacetic acid was added after all of the material had dissolved. This mixture is stirred at room temperature for 24 h. Then, a 40% NaOH solution (2 mL) is added to the solution over 5 min and the heterogeneous mixture is vigorously stirred for 30 min and then poured into a separatory funnel containing demineralized water (30 mL) and hexane (10 mL). After shaking, the organic layer is discarded and the aqueous layer is extracted with a mixture of hexane (8 mL) and tetrahydrofuran (2 mL). After complete settling, ethyl acetate (30 mL) was added to the aqueous phase and calcium acetate (0.4 g) was added. After 10 minutes of vigorous stirring, the phases were separated and the aqueous phase was re-extracted with ethyl acetate (20 mL). The resulting ethyl acetate solution is washed with demineralized water (2 x 3 mL) and, after drying with calcium sulfate, is concentrated on a vacuum evaporator. After cooling and filtration, 0.65 g (70%) of rosuvastatin was obtained. HPLC: 99.0%.

Example 10 (E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) 3,5-dihydroxy-6- heptenic acid, hemicalcium salt

Methanol (10 ml) was added to the weighed ester IX (1 g) and after dissolution of all the substance a catalytic amount of p-toluenesulfonic acid was added. This mixture is stirred at room temperature for 24 h. Then, a 40% NaOH solution (2 mL) is added over 5 min and the heterogeneous mixture is stirred vigorously for 30 min and then poured into a separatory funnel containing demineralized water (30 mL) and hexane (10 mL). After shaking, the organic layer is discarded and the aqueous layer is extracted with a mixture of hexane (8 mL) and tetrahydrofuran (2 mL). After complete settling, ethyl acetate (30 mL) was added to the aqueous phase and calcium acetate (0.4 g) was added. After 10 minutes of vigorous stirring, the phases are separated and the aqueous phase is reextracted with ethyl acetate (20 ml).

• ··· · ····· · · ιπ · * ·······

IZ ·· ·· ·· ·· ··· ml). The resulting ethyl acetate solution is washed with demineralized water (2 x 3 mL) and, after drying with calcium sulfate, is evaporated in a vacuum evaporator. After dissolution in methyl ethyl ketone (5 ml), the substance is added to pentane (30 ml) to give a white amorphous material, after 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] (3R, 5S) 3,5-dihydroxy- 6-heptenic acid, hemicalcium salt I

Tetrahydrofuran (15 ml) was added to the weighed amide X (1 g) and after dissolution of all the substance, a 40% LiOH solution (2 ml) was added to the solution over 5 min and the heterogeneous mixture was vigorously stirred for 17 h at 60 ° C. Separating funnels containing demineralized water (30 mL) and hexane (10 mL). After shaking, the organic layer is discarded and the aqueous layer is extracted with hexane (8 mL). After complete settling, ethyl acetate (30 mL) was added to the aqueous phase and calcium acetate (0.4 g) was added. After 10 minutes of vigorous stirring, the phases were separated and the aqueous phase was re-extracted with ethyl acetate (20 mL). The resulting ethyl acetate solution is washed with demineralized water (2 x 3 mL) and, after drying with calcium sulfate, is concentrated on a vacuum evaporator. Then the solution is added to cyclohexane (30 ml) to give a white amorphous substance, after suctioning 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] (3R, 5S) 3,5-dihydroxy-6 Heptenic acid, hemi-calcium salt I

To the weighed methyl ester II (6 g) was added tetrahydrofuran (35 mL). To this solution is added a solution of 40% LiOH (10 mL) over 5 min and the heterogeneous mixture is stirred vigorously for 3 h and then poured into a separatory funnel containing demineralized water (150 mL) and hexane (50 mL). After complete settling, ethyl acetate (40 mL) was added to the aqueous phase and calcium acetate (2 g) was added. After 10 minutes of vigorous stirring, the phases were separated and the aqueous phase was re-extracted with ethyl acetate (20 mL). The resulting ethyl acetate extract is washed with demineralized water (2 x 5 ml) and after drying is evaporated, the residue is dissolved in acetone and injected into a stream of inert gas to give 4.5 g (74%) of amorphous rosuvastatin.

HPLC: 99.1%.

Example 13 ---------------- (E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl (3P, 55) 3,5-Dihydroxy-6-heptenic acid, hemicalcium salt I

To the weighed ethyl ester XI (6 g) was added tetrahydrofuran (35 mL). To this solution is added a solution of 40% NaOH (10 mL) over 5 min and the heterogeneous mixture is vigorously stirred for 3 h and then poured into a separatory funnel containing demineralized water (150 mL) and hexane (50 mL). After complete settling, ethyl acetate (40 mL) was added to the aqueous phase and calcium acetate (2 g) was added. After 10 minutes of vigorous stirring, the phases were separated and the aqueous phase was re-extracted with ethyl acetate (20 mL). The resulting ethyl acetate extract is washed with demineralized water (2 x 5 mL) and, after concentration, is added to cyclohexane, after filtration the solid is stirred in isopropanol (40 mL) for 2 h and filtered off with suction. 3.8 g of rosuvastatin are obtained.

HPLC: 99.2%.

Example 14 (E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) 3,5-dihydroxy-6- heptenic acid, hemicalcium salt

To the weighed lactone IV (0.5 g) was added tetrahydrofuran (10 mL). To the solution thus obtained, calcium hydroxide (0.2 g) is added and the heterogeneous mixture is vigorously stirred for 3 h at 25 ° C and then filtered. After dilution with ethyl acetate (10 ml) and washing with water (2 x 5 ml), the extract is dried with calcium sulfate and, after concentration, added dropwise to 20 ml of pentane. 0.35 g of amorphous rosuvastatin is obtained after aspiration. The product was then stirred with n-butanol (5 ml) after suctioning to obtain 0.30 g of rosuvastatin. HPLC: 99.5%.

Example 15 (E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (37 R, 5 S) 3,5-dihydroxy-6- heptenic acid, hemicalcium salt

To the weighed methyl ester II (0.5 g) was added tetrahydrofuran (10 mL). To the solution thus obtained, calcium hydroxide (0.2 g) is added and the heterogeneous mixture is stirred vigorously for 3 h at 25 ° C and then filtered. After dilution with ethyl acetate (10 ml) and washing with water (2 x 5 ml), the extract is dried with calcium sulfate and, after concentration, added dropwise to 20 ml of pentane. 0.35 g of amorphous rosuvastatin is obtained after aspiration. HPLC: 99.0%.

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Example 16 (E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) 3,5-dihydroxy-6- heptenic acid, hemicalcium salt

To the weighed ethyl ester XI (0.5 g) was added tetrahydrofuran (10 mL). To the solution thus obtained, calcium hydroxide (0.2 g) is added and the heterogeneous mixture is stirred vigorously for 3 h at 25 ° C and then filtered. After dilution with ethyl acetate (10 ml) and washing with water (2 x 5 ml), the extract is dried with calcium sulfate and, after concentration, added dropwise to 20 ml of cyclohexane. 0.30 g of amorphous rosuvastatin is obtained after aspiration. HPLC: 99.0%.

Example 17 (E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3α, 5µ) 3,5-dihydroxy-6-heptene acid, hemicalcium salt

To the weighed tert-butyl ester XII (5 g) was added tetrahydrofuran (35 mL). To this solution is added a solution of 40% LiOH (10 mL) over 5 min and the heterogeneous mixture is stirred vigorously for 3 h and then poured into a separatory funnel containing demineralized water (150 mL) and hexane (50 mL). After complete settling, ethyl acetate (40 mL) was added to the aqueous phase and calcium acetate (2 g) was added. After 10 minutes of vigorous stirring, the phases were separated and the aqueous phase was re-extracted with ethyl acetate (20 mL). The resulting ethyl acetate extract is washed with demineralized water (2 x 5 ml) and after drying is evaporated, the residue is dissolved in acetone and injected into a stream of inert gas to give 4.5 g of amorphous rosuvastatin.

HPLC: 99.2%.

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Claims (7)

A process for the production of rosuvastatin hemi-calcium salt, ie (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2 [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3A, 55) -3 5-dihydroxy-6-heptenic acid of formula I, (i) in crystalline or amorphous form in the solid state, characterized in that a) a lactone of formula IV (iv) or an ester or amide of formula V or XIII (V); Wherein X is either oxygen or amino, R * CR ² is a protecting group wherein R ¹ and R ² are preferably selected from C 1 -C 3 alkyl, and R is alkyl selected from C 1 -C 10 alkyl, preferably methyl, ethyl or tert-butyl -butyl, after deprotection of the compound of formula V, is converted to rosuvastatin by alkaline hydrolysis with an alkali metal or Ca ²⁺ base, (b) where an alkali metal base has been used in (a), the formed rosuvastatin alkaline salt is converted to rosuvastatin calcium by reaction with the calcium salt in an aqueous medium; c) the crude rosuvastatin calcium of formula I is converted into a water-miscible solvent selected from the series R 6 OOR ² , R * COR ² or R'OH, wherein R ¹ and R ² are independently hydrogen or a C 1 -C 10 aliphatic hydrocarbon residue; an aromatic hydrocarbon Ce, a cyclic hydrocarbon C5 or C 6, or a combination of an aliphatic and aromatic or cyclic hydrocarbon, (d) the rosuvastatin calcium solution prepared in (c) is further washed with water; and e) isolating the product of formula I by cooling the solution and filtering or adding an anti-solvent and filtering or injecting it into the inert gas stream. Process according to claim 1, characterized in that the alkaline hydrolysis of the starting compound of the formula IV, V or XIII is carried out with a hydroxide of the group NaOH, KOH, LiOH and Ca (OH) ₂ . The process according to claim 1, wherein an ester of the formula R ³ COOR ³ , wherein R ³ is hydrogen or C 1 -C 3 alkyl, and R ³ is C 1 -C 4 alkyl, is used as the limited miscible solvent of (c). ·· ···· A process according to claim 3, wherein the C 1 -C 4 alkyl ester of acetic acid is used. A process according to claim 4, characterized in that ethyl acetate is used. The process according to claim 1, wherein (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] methyl ester is used as the starting compound. (3 A, 5 S) -3,5-Dihydroxy-6-heptenic acid of formula II. The process according to claim 1, wherein (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5yl] ethyl ester is used as the starting compound. (3R, 5S) -3,5-dihydroxy-6-heptenic acid of formula XI.