HK1187052B - Method for the preparation of high-purity pharmaceutical intermediates - Google Patents

Description

Process for preparing high purity pharmaceutical intermediates

Technical Field

The present invention relates to a process for the preparation of intermediates useful in the preparation of (+) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (methanesulfonyl-methyl-amino) -pyrimidin-5-yl ] - (3R,5S) -dihydroxy-hept-6-enoic acid of formula (I) and pharmaceutically acceptable salts thereof,

a new and industrially advantageous improved process for these intermediates and their use.

(+) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (methylsulfonyl-methyl-amino) -pyrimidin-5-yl ] - (3R,5S) -dihydroxy-hept-6-enoic acid of formula (I) is a pharmaceutically active ingredient known under the International non-patent name (International NonpropriataryName) rosuvastatin, which effectively regulates lipid metabolism. Rosuvastatin exerts its activity by inhibiting the enzyme 2-hydroxy-2-methyl-glutaryl-coenzyme-a reductase in the liver, thereby reducing cholesterol biosynthesis rate and plasma cholesterol concentration. Rosuvastatin of the formula (I), especially in the form of a salt, is a medicament for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

More specifically, the present invention relates to an industrially applicable process for the preparation of high purity rosuvastatin tert-butylammonium (TBA) salt of the formula (III).

According to the process of the present invention, the rosuvastatin TBA salt of the formula (III) is obtained by reacting tert-butylamine directly with a starting material selected from rosuvastatin methyl ester of the formula (IIa), rosuvastatin ethyl ester of the formula (IIb) or rosuvastatin tert-butyl ester of the formula (IIIc) in a suitable solvent. We have found that a particularly suitable starting material is a crystalline form of rosuvastatin ester of the general formula (II):

in formula (II), R represents a methyl group, an ethyl group or a tert-butyl group.

According to another aspect of the present invention, rosuvastatin methyl ester of the formula (IIa) is provided

And a process for the preparation of a new crystalline form of rosuvastatin ethyl ester of the formula (IIb).

According to another aspect of the present invention, there is provided crystalline form II and amorphous modification (modification) of the rosuvastatin TBA salt of the formula (III) for use as a reference during morphological analysis testing of rosuvastatin TBA salt.

Background

(+) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (methylsulfonyl-methyl-amino) -pyrimidin-5-yl ] - (3R,5S) -dihydroxy-hept-6-enoic acid (rosuvastatin) of formula (I) is a known compound which has been disclosed for the first time in European patent application No. 521471 in free acid form and as some pharmaceutically acceptable salts, such as calcium rosuvastatin salt of formula (IV)

And ammonium salts thereof.

Rosuvastatin zinc (2:1) salt of the formula (V)

Has been disclosed in published hungarian patent application P0600293 and published international patent application WO 2007119085.

According to the preparation process disclosed in european patent No. 521471, the preparation of rosuvastatin salts is carried out by saponifying rosuvastatin ester of the formula (II), if necessary, converting the thus obtained rosuvastatin salt into rosuvastatin acid and converting the directly obtained rosuvastatin salt of the formula (I) or rosuvastatin free acid into a pharmaceutically acceptable salt, preferably into calcium salt of the formula (IV).

Rosuvastatin is a photosensitive compound which is susceptible to decomposition, and therefore, another method has been developed with the aim of obtaining rosuvastatin of high purity.

The chemical purity of the pharmaceutical active ingredient is regulated according to strict official regulations promulgated by the health authorities (health authorities). Thus, the maximum limit of its concentration is fixed at 0.1% in the pharmaceutically active ingredient according to ICH guidelines-even in the case of impurities with known chemical structure.

Rosuvastatin salts formed with amines are widely used in the preparation of rosuvastatin salts for the production of final dosage forms. According to the prior art, this rosuvastatin salt with amines is converted into a pharmaceutically acceptable alkali metal or alkaline earth metal salt of rosuvastatin by setting the amine free from this salt using stronger bases, and usually the salt thus obtained is converted into an alkali metal salt and then into a salt form for use as active ingredient in the final dosage form.

Published international patent application WO01060804 relates to crystalline ammonium, methylammonium, ethylammonium, diethanolammonium, tris (hydroxymethyl) -methylammonium, benzylammonium or 4-methoxybenzyl-ammonium salts, which are converted into amorphous rosuvastatin calcium salt by converting the above cited rosuvastatin ammonium salts into rosuvastatin sodium salt using aqueous sodium hydroxide solution, which is converted into rosuvastatin calcium (2:1) salt of the formula (IV) in a second step, and the product is filtered from the aqueous solution. The purity of the product has not been disclosed.

Published international patent application WO2008038132 discloses rosuvastatin salts formed with diamines. Of these salts, only the dibenzylethylenediamine salt was characterized by X-ray diffraction data. This salt is prepared from rosuvastatin of the formula (I) or rosuvastatin sodium salt as starting material.

Published international patent application WO2008067440 discloses a process for the preparation of rosuvastatin calcium salt of formula (IV) in an aqueous solvent starting from dehydropylenamine (dehydroabietylamine) salt of rosuvastatin to rosuvastatin sodium salt. The purity of rosuvastatin calcium salt disclosed in the examples was 99.80% as determined by High Performance Liquid Chromatography (HPLC) and contained 0.14% concentration of diastereomeric impurities, which is very close to the limiting concentration (0.15%).

Published international patent applications WO2004014872 and WO2006136407 have disclosed methods for the direct conversion of several ammonium salts of rosuvastatin to rosuvastatin calcium salt (wherein rosuvastatin sodium salt is not produced). These reactions are carried out in aqueous solvents.

Published international patent application WO2004014872 relates to a process for the preparation of rosuvastatin calcium salt using specific operating parameters, which results in an increased filtration efficiency during the separation of the salt precipitate from water. In this process, rosuvastatin calcium salt of the formula (IV) is obtained from some water-soluble rosuvastatin ammonium salts (ammonium, trihydroxymethyl-methylammonium, methylammonium salts).

Published international patent application WO2005077916 relates to crystalline and amorphous rosuvastatin cyclohexyl-, dicyclohexyl-, isopropyl-, diisopropyl-, and (S) -1-methylbenzyl-ammonium salts. These salts are prepared by reacting rosuvastatin ester, rosuvastatin or rosuvastatin lactone with the corresponding amines and purified by recrystallization. However, the process parameters have not been disclosed or exemplified for processes in which esters or lactones are used as starting materials, and therefore, neither the yield of the process can be determined nor the quality of its product can be determined. Converting the above-mentioned salts into rosuvastatin calcium of the formula (IV) by the following steps: firstly, rosuvastatin ammonium salt is converted into rosuvastatin lactone of the formula (VI)

It is then converted into the sodium salt and reacted with a source of calcium ions in an aqueous medium and filtered to give amorphous rosuvastatin calcium salt having a purity of more than 99.5% (as determined by HPLC). Nevertheless, the concentration of diastereoisomeric impurities is high: using the methods disclosed in the above-cited applications, the concentration of diastereomeric impurities cannot be reduced below about 0.25%. However, this active principle does not comply with the internationally accepted ICH guidelines, since the limit concentration of impurities of known chemical structure is thus set to 0.1% for each impurity. Another drawback of this process is that the ammonium salt is converted to the final product in multiple steps via additional intermediates.

In published international patent application WO2005051921, a purification process of rosuvastatin calcium salt by crystallizing isopropyl-or cyclohexylammonium salt has been disclosed. Rosuvastatin calcium salt is first converted to rosuvastatin of the formula (I), which is then converted to rosuvastatin isopropyl-or cyclohexylammonium salt using ethyl acetate as solvent. The ammonium salt is then converted to the sodium salt in an aqueous medium and the sodium salt is converted to the rosuvastatin calcium salt of the formula (I) (2:1) in an aqueous solvent. The yield of the reaction was 73.6%, purity not disclosed.

In the prior art, there are several methods involving the hydrolysis of rosuvastatin esters using bases. In most cases, the esters are saponified with an aqueous alkali metal hydroxide solution to give the rosuvastatin alkali metal salt. The ammonium salt is prepared by converting rosuvastatin alkali metal or alkaline earth metal salt to rosuvastatin acid of the formula (I) and then reacting with an amine to obtain the ammonium salt.

Thus, for example, the hydrolysis of rosuvastatin methylester of the formula (IIa) with aqueous sodium hydroxide is disclosed in published international patent applications WO2003097614, WO2004052867 and WO 2006017357. According to published international patent application WO2007000121, rosuvastatin methyl ester of the formula (IIa) is hydrolyzed using lithium hydroxide.

The saponification of rosuvastatin tert-butyl ester of the formula (IIc) with sodium hydroxide is disclosed in published international patent applications WO2006100689, WO2006106526, WO2007099561 and WO 2007125547:

the process for the hydrolysis of rosuvastatin ethyl ester of the formula (IIb) using sodium hydroxide is disclosed in the published international patent application WO 2007000121.

In published international patent application WO2005023778, a process for the preparation of rosuvastatin calcium salt starting from rosuvastatin alkyl ester is described. Hydrolyzing the ester with sodium-, potassium-, or barium-hydroxide in an alcoholic solution, evaporating the solution, dissolving the salt in water, extracting the aqueous solution with an organic solvent, removing the organic solvent and adding a calcium source to form a calcium salt, and isolating by filtration. However, this process is demonstrated by an example only for the saponification of rosuvastatin tert-butyl ester of the formula (IIc) with sodium hydroxide.

According to published international patent application WO2006136408 rosuvastatin C may be hydrolyzed by alkali in an aprotic solvent or a mixture of an aprotic solvent and water₁－C₅Alkyl esters to prepare amorphous rosuvastatin calcium salt. Thereafter, the calcium salt is added to the reaction mixture and amorphous rosuvastatin calcium salt is isolated. In the examples, sodium hydroxide was used as the base.

Crystalline forms of rosuvastatin ethyl, isopropyl and tert-butyl esters corresponding to rosuvastatin of the formulae (IIa), (IIb) and (IIc) are each disclosed in the published international patent application WO 2005042522. The crystalline modifications of these esters are characterized by a powder X-ray diffraction pattern. Crystalline rosuvastatin ethylester of formula (IIb) is prepared by purifying the crude product with silica gel using a solvent mixture of toluene-hexane (1: 1). The solution was filtered and evaporated. In the present specification, the crystalline form of rosuvastatin ethyl ester of the formula (IIb) prepared according to the process in the above-mentioned applications is referred to as rosuvastatin ethyl ester crystalline form I.

Published international patent application WO2009019211 discloses a crystalline modification of rosuvastatin methyl ester of the formula (IIa) which is characterized by a powder X-ray diffraction pattern.

In the present specification, this variant is referred to as rosuvastatin methyl ester form I of the formula (IIa). Rosuvastatin methyl ester form I of formula (IIa) was prepared according to the prior art by purification of the crude methyl ester by preparative HPLC using diisopropyl ether-isopropanol (98.5:1.5) solvent mixture. The main fraction collected was concentrated by evaporation, then crystallized at-20 ℃ for 3 days, and filtered. The filtrate was evaporated to dryness, thereby obtaining rosuvastatin methyl ester form I of the formula (IIa).

Published international patent application WO2006136407 relates to a process for the preparation of amorphous rosuvastatin calcium, which comprises hydrolysis of rosuvastatin C in a mixture of water and aprotic organic solvent in the presence of organic nitrogen base (amine, quaternary ammonium hydroxide, amidine, guanidine, etc.)₁－C₅An alkyl ester. The salt thus obtained with the corresponding nitrogen base is converted to rosuvastatin calcium salt by addition of a source of calcium cations. In this application several rosuvastatin ammonium salts are claimed, such as pyrrolidinium, piperidinium, morpholinium, adamantammonium, N-dicyclohexylammonium, N-methyl-cyclohexylammonium, tert-octylammonium. Disclosed are processes for the preparation of certain representatives of the ammonium salt, comprising rosuvastatin TBA salt of the formula (III). Nevertheless, the salt has not been characterized by analytical data. According to the disclosed process, the rosuvastatin TBA salt of the formula (III) has not been used as starting material for the preparation of rosuvastatin calcium salt of the formula (IV). Rosuvastatin esters are hydrolyzed in aqueous solution in an autoclave at a temperature of about 100 ℃. However, therebyThe quality of the ammonium salts obtained is inferior to those obtained by other methods known from the prior art. Depending on the mass of amine used for the reaction, the purity of the product was between 94.5 and 98.9%, as determined by HPLC. In this case, when tert-butylamine was used, the product purity was 98.4%. This purity may then not be improved because during the conversion of the rosuvastatin TBA salt to rosuvastatin calcium salt of the formula (IV) further purification may not be possible and there is no prior art method for purifying rosuvastatin calcium salt of the formula (IV) or rosuvastatin zinc salt of the formula (V).

In published international patent applications WO2007125547 and WO2008044243, processes for preparing rosuvastatin TBA salt of the formula (III) starting from rosuvastatin sodium salt and processes for preparing rosuvastatin calcium salt of the formula (IV) starting from rosuvastatin TBA salt have been disclosed, wherein sodium salt is used as intermediate. The process is carried out in aqueous solution, and the calcium salt is then isolated by filtration. The purity of the product has not been disclosed. In international patent application WO2007125547 crystalline modifications of rosuvastatin TBA salt have been disclosed and characterized by powder X-ray diffraction patterns. In the same application, rosuvastatin tert-butyl-, isobutyl-and sec-butyl ammonium salts are also claimed.

In published international patent application WO2010082072, a process for converting rosuvastatin TBA salt of formula (III) to rosuvastatin calcium (2:1) salt of the formula (IV) and to rosuvastatin zinc (2:1) salt of the formula (V) using an ethyl acetate-water biphasic solvent system is disclosed.

Our research and development work aims to provide a process suitable for the industrial preparation of rosuvastatin TBA salts of the formula (III) in high purity, which complies with the internationally accepted guidelines, by converting rosuvastatin esters of the formula (II) wherein R represents methyl, ethyl or tert-butyl, in water or a mixture of water and a water-miscible organic solvent using mild reaction conditions.

Our object is solved according to the invention.

It is well known in the prior art that most processes starting from rosuvastatin esters proceed via rosuvastatin sodium salt intermediates and that rosuvastatin calcium obtained directly by this process has an unsatisfactory quality. Thus, the sodium salt is typically converted to an ammonium salt suitable for recrystallization. Thus, the necessary purification can be carried out by recrystallising the ammonium salt intermediate. The ammonium salt is then converted to rosuvastatin sodium salt using sodium hydroxide, which upon reaction with a source of calcium cations gives rosuvastatin calcium salt. This process involves several unnecessary steps-even with the most careful procedure-most likely leading to an increased concentration of impurities due to the easily decomposable nature and photosensitivity of rosuvastatin. Thus, in general, neither the end product nor the ammonium salt prepared in this way meets the rules set forth in the guidelines for impurities.

Summary of The Invention

The invention relates in particular to an industrially suitable process for the preparation of high purity rosuvastatin tert-butylammonium (TBA) salt of the formula (III). According to this process, a starting material selected from rosuvastatin methyl ester of the formula (IIa), rosuvastatin ethyl ester of the formula (IIb) or rosuvastatin tert-butyl ester of the formula (IIc) is reacted directly with tert-butylamine in a suitable solvent, and the rosuvastatin TBA salt of the formula (III) thus formed is isolated. It has been found that most advantageously crystalline esters of formula (II) wherein R represents methyl, ethyl or tert-butyl can be used as starting material.

According to another aspect of the present invention, there is provided a process for the preparation of new crystalline forms of rosuvastatin methyl ester of the formula (IIa) and rosuvastatin ethyl ester of the formula (IIb).

According to another method of the present invention, there is provided a process for the preparation of crystalline form II and amorphous rosuvastatin TBA salt, which are suitable as reference materials in analytical tests relating to the morphology of rosuvastatin TBA salt of the formula (III).

In the process of the present invention, rosuvastatin ester of the formula (II) (wherein the meaning of R is methyl, ethyl or tert-butyl), preferably its crystalline form, most preferably rosuvastatin methyl ester crystalline form II of the formula (IIa) or rosuvastatin ethyl ester crystalline form II of the formula (IIb) is reacted in water, in a polar solvent or in a mixture thereof with aqueous tert-butyl ammonium solution, water is removed from the product and the thus obtained rosuvastatin TBA salt of the formula (III) is isolated.

Under the reaction conditions applied, it is expected that the starting material or product will be at least partially converted into rosuvastatin tert-butylamide of the formula (VII),

it is removed in a separate purification step. As is known from the prior art, esters (in the presence of amines) or ammonium salts of carboxylic acids are readily converted into the corresponding amides upon heating. Such side reactions, if present, can reduce the yield of the main reaction and can produce crystalline impurities with high melting points that are difficult to remove from the rosuvastatin TBA product. Surprisingly, it has been found that no detectable amount of this by-product is formed, the reaction yield exceeds 90%, and in several cases the purity of the TBA salt exceeds 99.9%. The purity of the products prepared is so high that it is highly surprising in itself that no purification steps have to be applied.

Detailed Description

According to one aspect, the present invention relates to a process for the preparation of rosuvastatin TBA salt of the formula (III), which process comprises: rosuvastatin ester of the formula (II) wherein R represents methyl, ethyl or tert-butyl is reacted in a polar solvent, preferably in water or a mixture of water and a polar solvent such as water, methanol, acetonitrile, most preferably in acetonitrile with 1.5 to 5 molar equivalents, preferably 2.0 molar equivalents of tert-butylamine at a temperature of 10 ℃ to the boiling point of the solvent, preferably at a temperature of 25 to 50 ℃ for 24 to 72 hours, preferably about 40 hours. The product is then filtered, after removal of water, and washed, thus obtaining rosuvastatin TBA salt of the formula (III) in good yield and high purity. In this way, by directly reacting the rosuvastatin ester with tert-butylamine, rosuvastatin TBA salts can be produced with a purity (as determined by HPLC) of 99.8 to 99.9% without any impurities exceeding the 0.1% limit concentration as specified by the international guidelines and compendia. The product has outstanding purity without the necessity of additional recrystallization. The rosuvastatin TBA salt obtained according to the process of the present invention is directly suitable for the preparation of anhydrous or hydrated forms of rosuvastatin calcium (2:1) salt or rosuvastatin zinc (2:1) salt having a purity of 99.8-99.9% (as determined by HPLC).

Another advantage of the present invention is that it can be carried out in a single reactor and does not necessarily require large amounts of organic solvents and manual extraction or chromatography steps.

By carrying out the process of the present invention, we have found that in most cases rosuvastatin TBA product of the formula (III) can be obtained with a homogeneous morphology. However, in case the solution of the final product of formula (III) is subjected to fractional crystallization, a substantially homogeneous new crystalline form of rosuvastatin TBA can be obtained.

According to another aspect of the present invention, crystalline form II of the rosuvastatin TBA salt of the formula (III) is provided.

The characteristic powder X-ray reflections of the new crystalline form II rosuvastatin TBA salt of the formula (III) are summarized in table 1. The X-ray diffraction pattern of the same material is shown in FIG. 1.

Table 1X-ray reflection position (2 θ ± 0.2 °) and relative intensity (>10%) of rosuvastatin TBA salt [ compound of formula (III) ] crystalline form II

Measuring conditions and apparatus for powder X-ray diffraction method

The instrument comprises the following steps: BRUKERD8ADVANCE powder diffractometer

Ray:

voltage: 40kV

Anode current: 30mA

Accessories:-a mirror

Soller-slit

Sample changer, transport position

A detector: LynxEye

Measurement: continuous θ/θ scans: 4-352 theta degree

Step length: 0.02 degree

Sample preparation: without grinding, measured at room temperature

It is well known in the art that crystalline forms of the same chemical compound may have significantly different physicochemical characteristics, such as stability, filterability, drying rate, dissolution rate, and the like. In an industrial production process, it is of primary importance that the properties of the production batch which influence the further production operations should be reproducible. This characteristic is strongly correlated with the morphology of the drug substance or its intermediates. Analytical testing of the morphology of the product is therefore an important analytical task. Crystalline form II rosuvastatin TBA salt may be used as analytical reference material during the testing of rosuvastatin TBA salt of the formula (III).

Similarly, to support the analytical tests, amorphous forms of rosuvastatin TBA salt of the formula (III) have been prepared.

According to another aspect of the present invention, there is provided an amorphous rosuvastatin TBA salt of the formula (III). Amorphous rosuvastatin TBA salt may be prepared by dissolving rosuvastatin TBA salt in a saturated aliphatic alcohol having 1 to 4 carbon atoms, preferably in methanol, removing the solvent, and drying the solid residue at room temperature for at least 1 day.

A powder X-ray diffraction pattern of the amorphous rosuvastatin TBA salt of the formula (III) is shown in fig. 2. The measurement conditions were the same as described above in connection with crystalline form II of rosuvastatin TBA salt.

Different forms of rosuvastatin TBA salts, such as crystalline form I rosuvastatin TBA salt known from the prior art, the new crystalline form II rosuvastatin TBA salt of the present invention and the new amorphous rosuvastatin TBA salt as described above, can be used as reference material during analytical tests and crystallographic studies relating to rosuvastatin TBA salt of the formula (III).

According to the prior art, it is known that pre-treating the sample, e.g. grinding, prior to powder X-ray diffraction analysis can significantly affect the powder X-ray measurement results. Therefore, no pre-treatment was performed before testing.

The person skilled in the art has identified the solid forms of known chemical compounds by comparing the diffraction patterns of a reference material or specific signals obtained from the measurements of such a material, according to their powder X-ray diffraction patterns and their specific signals (reflections) (diffraction angles, relative intensities). This identification is particularly important for compounds having multiple solid state (amorphous and crystalline) forms.

Crystalline form II rosuvastatin TBA salt of the formula (III) shows an X-ray diffraction signal with maximum intensity at 18.651 ° 2 θ.

The X-ray diffraction signals of crystalline form II rosuvastatin TBA salt with more than 50% relative intensity are as follows: 15.803 and 18.651 ° (2 θ).

The X-ray diffraction signals of crystalline form II rosuvastatin salt of the formula (III) with a relative intensity of more than 25% are as follows: 11.282, 15.803, 18.651, 19.050, 19.832 and 20.512 ° (2 θ).

According to another aspect of the present invention, there is provided a process for the preparation of crystalline form II rosuvastatin TBA salt of the formula (III) comprising: rosuvastatin ester of the formula (II) wherein R represents methyl, ethyl or tert-butyl, preferably in crystalline form, is suspended in water, an aqueous solution comprising an equimolar amount of tert-butylamine is added thereto at a temperature of 10 to 50 ℃, preferably at 25 ℃, optionally repeated 1 to 5 times over 2 to 24 hours with each subsequent addition of tert-butylamine, an aqueous solution comprising 0.1 to 0.5, preferably 0.2 molar equivalents of tert-butylamine is added, the precipitated solid is removed after 72 to 96 hours, and the crystalline form II of the rosuvastatin TBA salt of the formula (III) thus obtained is isolated after crystallization for 48 to 72 hours.

According to a more advantageous embodiment of the present invention, crystalline rosuvastatin ester of the formula (II) (wherein the meaning of R is as defined above) is used for the preparation of rosuvastatin TBA salt. Most preferably, a high purity crystalline ester of formula (II) is used. It has been found that the feedstock is significantly affected by its solid state and morphology. Furthermore, we have established that the quality of the starting material has a significant impact on the purity of the final product.

According to this embodiment, new crystalline form II of rosuvastatin methyl ester of the formula (IIa) or new crystalline form II of rosuvastatin ethyl ester of the formula (IIb) is a particularly advantageous starting material.

Esters of formula (II) wherein R has the meaning as defined above are commercially available as impure (90-95% chemical purity), sometimes as coloured viscous oily liquids or as slightly more pure solids. For example, in european patent No. 521471 rosuvastatin methyl ester of formula (IIa) is characterized as a viscous oil, which is purified by column chromatography before further use. Rosuvastatin methyl ester of the formula (IIa) is prepared according to the method disclosed in published international patent application WO2009019211 by preparative high performance liquid chromatography of crude rosuvastatin methyl ester. The crystalline rosuvastatin ethylester of formula (IIb) is obtained according to the method disclosed in published international patent application WO2005042522 by purification by adsorption on silica gel using hexane-toluene solvent mixture.

During our experiments with further purification of commercial rosuvastatin methyl and ethyl esters, we surprisingly found that new crystalline forms of each ester can be prepared. By crystallizing rosuvastatin methyl ester from different solvents and solvent mixtures, we obtained a new crystalline form showing a higher stability of the new crystalline form.

The fact that rosuvastatin esters of the formulae (IIa) and (IIb) can be prepared in crystalline form without the use of chromatography or adsorption is in itself highly surprising. The crystalline forms of the compounds of formulae (IIa) and (IIb) are particularly suitable as starting materials for the preparation of rosuvastatin TBA salts.

According to another aspect of the present invention, there is provided a new crystalline form II of rosuvastatin methylester of the formula (IIa). The powder X-ray diffraction pattern of the new rosuvastatin methyl ester crystal form II is shown in figure 3. The powder X-ray diffraction data of the new crystals of methyl ester are summarized in table 2. The measurement conditions of the powder X-ray diffraction method are the same as those described for rosuvastatin TBA salt form II.

Table 2 powder X-ray diffraction data (2 θ ± 0.2 °) and relative intensity (>5%) of rosuvastatin methyl ester [ compound of formula (IIa) ] crystalline form II

Peak(s)	Angle of rotation	d value	Strength of	Peak(s)	Angle of rotation	d value	Strength of
								Numbering	2-θ°	Tea tree (Angel)	%	Numbering	2-θ°	Tea tree (Angel)	%
								1	8.721	10.13081	16.7	19	21.695	4.09302	53.7
2	9.371	9.43010	63.6	20	22.374	3.97039	13.3
								3	9.681	9.12830	21.4	21	22.707	3.91291	5.2
4	12.071	7.32604	8.9	22	23.143	3.84011	11.6
								5	13.776	6.42304	6.9	23	23.538	3.77661	7.1
6	15.261	5.80119	5.6	24	23.815	3.73326	10
								7	15.551	5.69369	5.6	25	24.365	3.65023	32.3
8	15.933	5.55810	23	26	24.773	3.59108	24.6
								9	16.519	5.36211	12.2	27	25.091	3.54626	7.7
10	16.660	5.31699	9.5	28	26.352	3.37933	29.2
								11	17.471	5.07202	75.3	29	27.369	3.25605	6.7
12	18.042	4.91268	100	30	29.569	3.01864	6.6
								13	18.836	4.70745	14.5	31	29.812	2.99458	7.6
14	19.553	4.53629	87.7	32	30.892	2.89228	5
								15	19.827	4.47435	20.9	33	31.260	2.85903	5
16	20.239	4.38416	22.8	34	32.475	2.75484	8
								17	20.675	4.29262	11.9	35	33.678	2.65910	7.6
18	21.254	4.17702	10.7

The powder X-ray diffraction signal with the highest relative intensity in the rosuvastatin methyl ester form II diffractogram of formula (IIa) can be observed at 17.471, 18.042 and 19.553 ° 2 θ.

The powder X-ray diffraction signals of crystalline form II rosuvastatin methyl ester of the formula (IIa) having a relative strength of at least 50% are 9.371, 17.471, 18.042, 19.553 and 21.695 ° (2 θ).

The powder X-ray diffraction signals of crystalline form II rosuvastatin methyl ester of the formula (IIa) having a relative strength of at least 25% are 9.371, 17.471, 18.042, 19.553, 21.695, 24.365 and 26.352 ° (2 θ).

According to another aspect of the present invention, there is provided a process for the preparation of crystalline form II rosuvastatin methyl ester of the formula (IIa), wherein crystalline form I rosuvastatin methyl ester of the formula (IIa) or an amorphous or oily liquid:

a) dissolving in a polar solvent, preferably in a saturated aliphatic alcohol containing 1 to 4 carbon atoms or N, N-dimethylformamide, most preferably in ethanol, optionally by heating, mixing the solution with water, and isolating crystalline form II of rosuvastatin methyl ester of the formula (IIa) after cooling and optionally stirring the mixture at room temperature for a period of 24 to 168 hours; or

b) Crystallization from a mixture of water and a polar solvent, preferably from a mixture of water and a saturated aliphatic alcohol containing 1 to 4 carbon atoms and N, N-dimethylformamide; and optionally isolating crystalline form II of rosuvastatin methyl ester of the formula (IIa) after stirring the solution at room temperature for 24-72 hours.

According to another aspect of the present invention, rosuvastatin ethyl ester crystalline form II of the formula (IIb) is provided, which is characterized by the powder X-ray diffraction pattern of fig. 4 and the diffraction data of table 3.

The measurement conditions for powder X-ray diffraction measurements are the same as those described for rosuvastatin methyl ester form II.

A powder X-ray diffraction signal with the highest intensity suitable for identifying rosuvastatin ethyl ester form II of the formula (IIb) can be found at 17.907 and 19.419 degrees 2 theta.

A powder X-ray diffraction signal of rosuvastatin ethyl ester form II of the formula (IIb) having a relative intensity of more than 50% can be found at 9.238, 17.313, 17.907 and 19.419 degrees (2 θ).

A powder X-ray diffraction signal of rosuvastatin ethyl ester form II of formula (IIb) having a relative intensity of more than 25% can be found at 9.238, 9.638, 16.354, 17.313, 17.907, 19.419, 20.137, 21.478, 24.112, 24.376, 24.684 and 26.030 degrees (2 θ).

Table 3 powder X-ray diffraction data for rosuvastatin ethyl ester [ compound of formula (IIb) ] form II: diffraction angle (2 theta + -0.2 DEG) and relative intensity (>5%)

Peak(s)	Angle of rotation	d value	Strength of	Peak(s)	Angle of rotation	d value	Strength of
								Numbering	2-θ°	Tea tree (Angel)	%	Numbering	2-θ°	Tea tree (Angel)	%
								1	8.717	10.13632	12.6	19	22.304	3.98270	19.1
2	9.238	9.56503	65.2	20	22.845	3.88962	12.8
								3	9.638	9.16899	39.7	21	23.448	3.79084	14.5
4	11.942	7.40520	6.5	22	23.630	3.76213	17.4
								5	13.737	6.44123	5.7	23	24.112	3.68803	34.7
6	15.056	5.87970	4.6	24	24.376	3.64866	29.3
								7	15.457	5.72793	5.7	25	24.684	3.60385	25.5
8	15.846	5.58843	17.5	26	26.030	3.42042	37.7
								9	16.354	5.41578	25.2	27	27.068	3.29152	5.6
10	17.313	5.11788	68.3	28	29.128	3.06330	10.9
								11	17.907	4.94952	100	29	29.416	3.03392	7.7
12	18.553	4.77863	16.8	30	30.412	2.93678	5
								13	19.419	4.56742	89	31	30.984	2.88386	5.9
14	20.137	4.40611	27.1	32	31.271	2.85806	5.5
								15	20.574	4.31357	13.1	33	32.027	2.79234	5.1
16	21.005	4.22599	6.1	34	33.062	2.70725	11
								17	21.478	4.13388	47.3	35	33.981	2.63611	511 -->
18	21.775	4.07824	7.4

During the experiments involving the recrystallization of rosuvastatin ethyl ester of the formula (IIb) from different solvents, we found that in most cases a new crystalline form II of rosuvastatin ethyl ester was formed, showing its higher stability. In this experiment, in which the rosuvastatin ethyl ester polymorph prepared according to the process of WO2005042522, which can be named as form I in the present specification, and the new rosuvastatin ethyl ester form II of the present invention are suspended in a solvent for a longer time, rosuvastatin ethyl ester has been completely converted into form II, confirming the higher thermal stability of the new polymorph.

According to another aspect of the present invention, there is provided a process for the preparation of rosuvastatin ethyl ester of the formula (IIb) in crystalline form II, wherein solid crystalline form I or solid amorphous or liquid of rosuvastatin ethyl ester of the formula (IIb):

a) dissolving in a polar solvent, preferably selected from saturated aliphatic alcohols containing 1 to 4 carbon atoms, acetonitrile or N, N-dimethylformamide, preferably in ethanol, optionally by heating, mixing the solution with water and isolating crystalline form II of rosuvastatin ethyl ester after cooling and optionally stirring at room temperature for 24 to 168 hours; or

b) Crystallization from a mixture of water and a polar solvent, preferably from a mixture of water and a saturated aliphatic alcohol containing 1 to 4 carbon atoms, acetonitrile and N, N-dimethylformamide; optionally stirring the reaction mixture for 24-72 hours and isolating rosuvastatin ethyl ester of formula (IIb) form II; or

c) Crystallizing from a solvent selected from the group consisting of saturated aliphatic esters containing 4 to 8 carbon atoms, saturated aliphatic or cyclic ethers containing 4 to 8 carbon atoms, saturated aliphatic ketones having 3 to 6 carbon atoms, aromatic hydrocarbon solvents or from a mixture of any of the solvents mentioned above and water, optionally stirring the reaction mixture for 24 to 72 hours and isolating rosuvastatin ethyl ester form II; or

d) Dissolving in a solvent selected from the group consisting of saturated aliphatic esters having 4 to 8 carbon atoms, saturated aliphatic or cyclic ethers having 4 to 8 carbon atoms or aliphatic ketones having 3 to 6 carbon atoms and aromatic hydrocarbons and, after addition of a saturated aliphatic or alicyclic hydrocarbon, preferably hexane, heptane or cyclohexane, crystallizing crystalline form II of rosuvastatin ethyl ester and optionally stirring the crystals for 24 to 72 hours and isolating.

We have found that by using rosuvastatin methyl ester of the formula (IIa) or rosuvastatin ethyl ester of the formula (IIb) in the process of the present invention, especially using new crystalline forms thereof, rosuvastatin TBA salts of the formula (II) having an unexpectedly high purity of about 99.9% can be obtained.

Thus, during our research and development work through the use of new crystalline forms of rosuvastatin esters of the formula (II) showing stability higher than those known in the prior art, a one-step process has been provided for the preparation of highly pure rosuvastatin TBA salt, which is simple, provides good yields and is suitable for industrial application. The rosuvastatin TBA salt of the formula (III) thus obtained can be converted into rosuvastatin calcium (2:1) or rosuvastatin zinc (2:1) salt according to methods known in the art.

Other aspects of the present invention are shown by the following examples, but the present invention is not limited to these examples.

Preparation of rosuvastatin ethyl ester polymorph [ rosuvastatin ethyl ester form I of formula (IIb) ] disclosed in published International patent application WO2005042522

Reference ratio 1

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 10cm³Hot water, let it cool to 25 ℃. The product in the form of an oil was first isolated and gradually crystallized during 24 hours of stirring. The product was filtered and washed with water. Thus, 0.31g (62%) of the title compound was obtained.

Reference ratio 2

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1cm³Hot ethyl acetate, add 4.5cm while stirring³N-hexane. The mixture was cooled to 25 ℃ while the product precipitated gradually. The solid was filtered, washed with n-hexane and dried. Thus, 0.49g (98%) of the title compound is obtained.

Preparation of the starting Material

Rosuvastatin ethyl ester polymorph [ rosuvastatin ethyl ester form I of formula (IIb) ] prepared according to published international patent application WO2005042522 converted to rosuvastatin ethyl ester form II

Rosuvastatin ethyl ester form I of the formula (IIb) is obtained according to the process disclosed in published international patent application WO 2005042522.

In the recrystallization experiments described below, the filtered product was dried at 30 ℃ in a vacuum of 100-150 mbar. In all experiments rosuvastatin ethyl ester form II of the formula (IIb) showing powder X-ray diffraction pattern and reflections is essentially as shown in figure 4 and table 3.

Example 1

0.50g (0.98mmol) rosuvastatin ethyl ester form I (prepared according to WO 2005042522) was dissolved in 1cm³Hot ethanol, dripping 3cm³And (3) water. The product initially separated as an oil which gradually became a mixture of crystalline and oily phases by the next day. Thereafter, 5cm of the solution was added³Water, and the mixture was stirred at 25 ℃ for 30 hours. Thus, 0.47g (94%) rosuvastatin ethyl ester form II is obtained, which shows the reflections disclosed in table 3 and shows the diffractogram of fig. 4.

Example 2

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1.5cm³Hot 1:1(v/v) ethanol-water solvent mixture. The solution was cooled to 25 ℃ while stirring. After 10 minutes, a thick suspension formed. The product was filtered and dried. Thus, 0.38g (76%) of product was obtained.

Example 3

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1cm³4:1(v/v) Hot ethanol-water mixture, cooled to 25 ℃ while stirring. Thus, a thick suspension was obtained. The solid was filtered and dried. Thus, 0.24g (48%) of product was obtained.

Example 4

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1cm³Hot ethanol. The mixture was cooled to 25 ℃ to give a solidified mass, using 0.5cm³Diluting with ethanol, and cooling to 0-5 deg.C. The solid was filtered and dried. Thus, 0.30g (60%) of product was obtained.

Example 5

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 5cm at 25 deg.C³Ethanol, added in small portions stepwise to 12cm having a temperature of 25 deg.C³And (3) water. The mixture turns milky white in color and the product which separates crystallizes upon stirring. The solid was filtered and dried. Thus, 0.48g (96%) of product was obtained.

Example 6

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1.5cm³A hot 1:1(v/v) methanol-water mixture. After cooling to 25 ℃, the oily mixture gradually crystallized to become a suspension. The solid was filtered and dried. Thus, 0.46g (92%) of product was obtained.

Example 7

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.6cm³Hot methanol. In the first step the mixture is cooled to 25 ℃ and thereafter to 0-5 ℃. The product was gradually isolated. The solid was filtered and dried. Thus, 0.34g (68%) of product was obtained.

Example 8

1.0g (1.96mmol) of rosuvastatin ethyl ester are dissolved in 2cm at 60 deg.C³5:1(v/v) methanol-water mixture, cooled with tap water. Within 10 minutes, crystallization began. Thereafter, another 11cm cooled to 0-5 deg.C was added³A mixture of the same solvents to obtain a mixture suitable for stirring. The mixture was stirred for a further 16 hours, filtered and dried. Thus, 0.79g (79%) of product was obtained.

Example 9

1.0g (1.96mmol) of rosuvastatin ethyl ester are dissolved at 60 deg.CAt 2cm³5:1.5(v/v) methanol-water mixture. Crystallization was started by cooling with tap water while continuously stirring. After about half an hour, the mixture became thick. At this stage, use 9cm³The mixture was diluted with the same solvent mixture and stirred at 25 ℃ for 20 hours and at 0-5 ℃ for 5 hours. The solid was filtered off and dried. Thus, 0.91g (91%) of product was obtained.

Example 10

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.6cm³Hot methanol. Adding into 1cm in small parts³And (3) water. After the initial opalescence, the product separated in a cloudy manner. The mixture was cooled to 25 ℃ and after 2 hours the crystalline mass was filtered and dried. Thus, 0.47g (94%) of product was obtained.

Example 11

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1.5cm at 25 deg.C³Adding methanol in portions, gradually adding into 3.5cm³Distilled water having a temperature of 25 ℃. The initially oily product becomes crystalline within half an hour. The product was filtered and dried. Thus, 0.46g (92%) of product was obtained.

Example 12

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.6cm³Hot methanol. The solution was gradually cooled to 25 ℃ and, during this time, 1.5cm of water was added dropwise³Cyclohexane. The product initially isolated in oily form, and thereafter crystallized upon trituration and cooling. Within 48 hours, a product suitable for filtration was obtained. The solid was filtered and dried. Thus, 0.42g (84%) of product was obtained.

Example 13

0.50g (0.98mmol) of rosuvastatinDissolving ethyl ester in 0.6cm³Hot methanol. The solution was gradually cooled to 25 ℃ and 1.5cm of water was added dropwise³N-hexane. The product initially separated as an oil, which crystallized gradually upon trituration and cooling. After 48 hours, a product suitable for filtration was obtained. The solid was filtered and dried. Thus, 0.44g (88%) of product was obtained.

Example 14

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.6cm³Hot methanol. The solution was gradually cooled to 25 ℃ and 1.5cm of water was added dropwise³N-heptane. The product first separated as an oil, which crystallized upon trituration and cooling. After 48 hours, a product suitable for filtration was obtained. The solid was filtered and dried. Thus, 0.49g (98%) of the title product is obtained.

Example 15

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1cm³Hot isopropanol. The solution is first cooled to 25 ℃ and thereafter to a temperature of 0-5 ℃. The product was slowly isolated, after which it was filtered and dried. Thus, 0.34g (68%) of product was obtained.

Example 16

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1.5cm³A hot 1:1(v/v) isopropanol-water mixture. Upon cooling to 25 ℃, the oily mixture gradually crystallizes, which upon further cooling becomes a thick suspension. By 1cm³The same solvent mixture cooled to 5 ℃ dilutes the suspension. The product was filtered and dried. Thus, 0.39g (78%) of product was obtained.

Example 17

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1cm³Hot isopropanol. To the direction ofWherein 1cm of³And (3) water. The product began to separate in oily form and crystallized by the next day. The solid was filtered and dried. Thus, 0.45g (90%) of product was obtained.

Example 18

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.25cm³Hot n-butanol. On cooling, the product begins to separate in oily form and subsequently crystallizes, which becomes a thick suspension at a temperature of 25 ℃. Using 0.25cm³The suspension was diluted with n-butanol cooled to 5 ℃. The solid was filtered and dried. Thus, 0.16g (32%) of product was obtained.

Example 19

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.25cm³Hot n-butanol, adding 1cm³And (3) water. The product isolated in oily form during the initial phase and crystallized by the next day. By 5cm³The thick suspension was diluted with water. The solid was filtered and dried. Thus, 0.48g (96%) of product was obtained.

Example 20

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.7cm³Hot acetonitrile. Upon cooling to 25 ℃, the product slowly separated. The mixture is further cooled to a temperature of 0-5 ℃. By the next day, a thick crystalline mass was obtained. The mixture was diluted with acetonitrile cooled to a temperature of 0-5 ℃ to give a suspension suitable for filtration. The solid was filtered and dried. Thus, 0.30g (60%) of product was obtained.

Example 21

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 2.5cm at 25 deg.C³And (3) acetonitrile. Gradually dropwise adding 5cm³And (3) water. The product is initially in oily formIsolated and crystallized after 2 days. Using 2.5cm³The thick mixture was diluted with water. The solid was filtered and dried. Thus, 0.44g (88%) of product was obtained.

Example 22

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.7cm³Hot acetonitrile. While the solution was still warm, 1.5cm of the solution was gradually added dropwise³And (3) water. The product initially isolated as an oil crystallized by the next day. The product was filtered and dried. Thus, 0.45g (90%) of product was obtained.

Example 23

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1cm³Hot ethyl acetate. The mixture was cooled to 25 ℃ while the product slowly separated. By cooling to a temperature of 0-5 ℃, a thick crystalline mixture was obtained by the next day. The product was filtered and dried. Thus, 0.49g (98%) of product was obtained.

Example 24

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1cm³Hot ethyl acetate, gradually added dropwise with 7cm³N-hexane. The product initially isolated in oily form, after which it became crystalline by first cooling to 25 ℃ and to a temperature of 0-5 ℃ and by trituration. The solid was filtered and dried. Thus, 0.50g (100%) of product was obtained.

Example 25

0.5g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1cm³Hot isopropyl acetate. The solution is cooled to 25 ℃ and, in a second step, to a temperature of 0-5 ℃. By the next day, a thick crystalline mass was obtained. The solid was filtered and dried. Thus, 0.25g (50%) of product was obtained.

Example 26

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 3.5cm³Hot tert-butyl methyl ether (MTBE). Upon cooling and grinding, the product was continuously isolated. By 2cm³MTBE cooled to a temperature of 0-5 ℃ dilutes the thick suspension. The isolated product was filtered and dried. Thus, 0.38g (76%) of product was obtained.

Example 27

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.5cm³Hot Tetrahydrofuran (THF). Cooling to 25 deg.C, cooling to 0-5 deg.C, and separating out product. By the next day, a thick crystalline mass was obtained in the form of a 0.25cm thick slab³Cooled to a temperature of 0-5 ℃ and diluted with THF. The isolated product was filtered and dried. Thus, 0.25g (50%) of product was obtained.

Example 28

0.50g (0.98mmol) of rosuvastatin ethyl ester at 1.5cm³Stirring in diethyl ether at 35 deg.C, and adding dropwise 0.3cm³Methanol until dissolved. The mixture was cooled to 25 ℃ while maintaining stirring. In the process, the product is continuously separated from the mixture. Then 3cm of the solution was added³Ether, filter the product and dry. Thus, 0.26g (52%) of product was obtained.

Example 29

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.75cm³Hot 2-methoxyethanol. Thereafter, 2cm of the solution was added dropwise³And (3) water. The product initially separates in oily form and crystallizes on cooling. The solid was filtered and dried. Thus, 0.46g (92%) of product was obtained.

Example 30

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.75cm³Hot 2-methoxyethanol. Dropping 1cm³Cyclohexane. The product initially isolated in oily form and crystallized by the next day. The solid was filtered and dried. Thus, 0.46g (92%) of product was obtained.

Example 31

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 1cm³Hot toluene. Upon cooling, the product separates in gelled form, which becomes a thick crystalline mass within half an hour. By 1cm³The suspension is diluted with toluene cooled to a temperature of 0-5 ℃, filtered and dried. Thus, 0.40g (80%) of product was obtained.

Example 32

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.5cm³Hot acetone. On cooling, the product began to separate slowly. Using 0.5cm³The suspension was diluted with cold (0-5 ℃) acetone. The solid was filtered and dried. Thus, 0.20g (40%) of product was obtained.

Example 33a

0.50g (0.98mmol) of rosuvastatin ethyl ester are dissolved in 0.5cm³Hot acetone. Thereafter, 2cm of the solution was added dropwise³And (3) water. The product initially separates in oily form and crystallizes on cooling. The solid was filtered and dried. Thus, 0.50g (100%) of product was obtained.

Preparation of rosuvastatin methyl ester [ compound of formula IIa) ] crystal form II

Rosuvastatin methyl ester of the formula (IIa) used as starting material has been obtained according to the process disclosed in european patent No. 521471 in the form of an oil after column chromatography. In the process disclosed below, the filtered product is dried under vacuum at 30 ℃ at a pressure of 100-150 mbar. In all cases, crystalline form II of rosuvastatin methylester of the formula (IIa) is obtained, which has a powder X-ray diffraction pattern as shown in fig. 3 and the positions and relative intensities of the diffraction signals as shown in table 2.

Example 34

0.50g (1.0mmol) rosuvastatin methyl ester is dissolved in 1.5cm³The ethanol-water solvent mixture was heated to 1:1(v/v) and the solution was cooled to 25 ℃ while stirring. The product was isolated as an oil. Thereafter, the mixture was cooled to a temperature of 0-5 ℃ and stirred for 48 hours while the oil became a crystalline mass. The solid was filtered and dried at 30 ℃ under vacuum (at 100-. Thus, 0.33g (66%) of the product of crystalline form II is obtained, whose powder X-ray diffraction diagram is shown in fig. 3, and the positions and relative intensities of the diffraction lines are shown in table 2.

Example 35

0.50g (1.0mmol) rosuvastatin methyl ester is dissolved in 0.25cm³Hot methanol, while stirring, was added to 1.25cm³And (3) water. The white oil phase was separated and cooled to 25 ℃ while stirring. After stirring for 72 hours, the material became crystalline. The mixture was filtered and dried under the conditions given in example 34. Thus, 0.22g (44%) of product is obtained, having the same morphology as the product obtained in example 34.

Example 36

0.30g (0.60mmol) rosuvastatin methyl ester is dissolved in 0.2cm³Hot N, N-Dimethylformamide (DMF) was added in portions of 2cm³And (3) water. The product separated as a viscous oily mass. The mixture was cooled to 25 ℃ while stirring. After stirring for 48 hours, the crystalline product obtained is filtered and dried according to the method described in example 34. Thus, 0.29g (97%) of product is obtained, having a morphology corresponding to that of the product of example 34The same is true.

Example 37

0.20g (0.40mmol) rosuvastatin methyl ester is dissolved in 2cm³Adding hot isopropanol into the mixture in portions of 8cm³And (3) water. The product separated as a viscous oily mass. The mixture was cooled to 25 ℃. After stirring for 1 week, the product became crystalline. The crystals were filtered and dried according to the method of example 34. Thus, 0.15g (75%) of the product was obtained, which had the same polymorphism as that of the product obtained in example 34.

Example 38

0.30g (0.60mmol) rosuvastatin methyl ester is dissolved in 1cm at 25 deg.C³Methanol, dropwise adding 3cm³Water while stirring. The product separated into a sticky mass which crystallized during the 24 hour stirring period. The crystals were filtered and dried according to the method described in example 34. In this way, 0.24g (80%) of product is obtained, having the same morphology as the product of example 34.

Example 39

0.30g (0.60mmol) rosuvastatin methyl ester is dissolved in 0.4cm at 25 deg.C³DMF. After adding 4cm³After water, the product separated into an oil phase. After stirring for 24 hours, crystalline product was obtained. The crystals were filtered and dried according to the method of example 34. Thus, 0.28g (93%) of product is obtained, having the same morphology as the product of example 34.

Rosuvastatin TBA salt [ compound of formula (III) ] prepared by using rosuvastatin methyl ester [ compound of formula (IIa) ] crystal form II as raw material

Example 40

10.0g (0.020mol) of rosuvastatinStatin methyl ester crystal form II is dissolved in 70cm³Acetonitrile while stirring at 25 ℃. To the clear solution thus obtained 19.8cm was added³1.0M aqueous tert-butylamine (TBA) solution, 3.96cm each time in a period of 2 hours³Portions of 1.0 aqueous MTBA, 4 times total. The next morning, add 3.96cm³A portion of 1.0MTBA in water. The mixture was stirred for a further 24 hours, the solvent was evaporated, ethyl acetate was added and the remaining water was removed by azeotropic distillation. The suspension thus obtained was cooled to 5 ℃, stirred for 1 hour, filtered, washed with cold ethyl acetate and dried. Thus, 10.12g (90%) of a white product with a purity of 99.94% as determined by HPLC was obtained.

EXAMPLE 41

30.0g (0.061mol) rosuvastatin methyl ester form II are suspended in 150cm while stirring at 25 deg.C³And (3) water. To the suspension thus obtained was added 61cm³1.0 aqueous MTBA solution. Thereafter, 12.2cm of each time were added to the reaction mixture over a period of 2 hours³Portions of 1.0 aqueous MTBA, 4 times total. After a reaction time of 16 hours, a further 12.2cm³A portion of 1.0MTBA in water and the reaction mixture was stirred for an additional 24 hours. The product was filtered, washed with cold ethyl acetate and dried. Thus, 28.5g (84%) of a white product with 99.98% purity (HPLC) are obtained.

Rosuvastatin TBA salt [ compound of formula (III) ] prepared from rosuvastatin ethyl ester [ compound of formula (IIb) ] crystal form II

Example 42

30.0g (0.059mol) rosuvastatin ethyl ester form II are dissolved in 210cm while stirring at 25 deg.C³And (3) acetonitrile. To the solution thus obtained was added 59.4cm³1.0 aqueous MTBA solution. Then, in the course of 2 hours, another 12cm was added³Portions of 1.0 aqueous MTBA, 4 times total. The next morning, a further addition was made to the reaction mixture6cm³A portion of 1.0MTBA in water. After a further 24 hours of reaction time, the acetonitrile is evaporated and 200cm of acetonitrile is added to the crystallized mass³And (3) ethyl acetate. Water was removed from the suspension thus obtained by azeotropic distillation. The mixture thus obtained is cooled to a temperature of 0-5 ℃, filtered, the filtered crystals are washed with cold ethyl acetate and dried. Thus, 31.14g (95%) of the white title product with 99.86% purity (HPLC) are obtained.

Example 43

2.0g (0.004mol) rosuvastatin ethyl ester form II are dissolved in 14cm³Acetonitrile, adding 7.5cm³1.0 aqueous MTBA solution. The mixture was stirred in an autoclave at 25 ℃ for 48 hours. Thereafter, the reaction mixture was evaporated and the remaining water was removed by azeotropic distillation with ethyl acetate. The suspension thus obtained is cooled to a temperature of 0-5 ℃, filtered, the filtered solid washed with cold ethyl acetate and dried. Thus, 1.90g (91%) of the product was obtained with a purity of 99.86% as determined by HPLC.

Example 44

1.0g (0.002mol) rosuvastatin ethyl ester form II was dissolved in 7cm³Acetonitrile, 2.18cm³1.0 aqueous MTBA solution. The mixture was stirred in an autoclave at 25 ℃ and 2.5 bar pressure using an argon atmosphere. After 5 hours, 0.6cm was added³1.0 aqueous MTBA solution, and the mixture was allowed to react for an additional 24 hours. Then 1cm of the solution was added³1.0 aqueous MTBA solution, and the reaction was continued for an additional 24 hours. The reaction mixture was evaporated and the remaining water was removed by azeotropic distillation using ethyl acetate. The suspension thus obtained is cooled to a temperature of 0-5 ℃, filtered, the filtered solid washed with cold ethyl acetate and dried. Thus, 1.90g (91%) of the product are obtained with a purity of 99.86% (by HPLC).

Example 45

10.0g (0.02mol) rosuvastatin ethyl ester form II are dissolved in 70cm at 25 DEG C³Acetonitrile, add 35.6cm³1.0 aqueous MTBA solution. The mixture was stirred for 24 hours. Thereafter, 2cm of the solution was added³1.0 aqueous MTBA solution, and the mixture was stirred for an additional 24 hours. The mixture is then worked up according to process variant 1. Thus, 8.69g (80%) of product with 99.90% HPLC purity were obtained.

Example 46

To 2.0g (0.004mol) rosuvastatin ethyl ester form II was added 4.35cm³1.0 aqueous MTBA solution. A thick suspension was formed, which was stirred at 25 ℃ for 2 hours. Thereafter, 0.4cm was added³2 hours later, 2.4cm was added³1.0 aqueous MTBA solution and stirred for an additional 3 hours. Then add 0.8cm³1.0 aqueous MTBA solution, stirred overnight. The mixture was filtered, and the filtered solid was washed by suspension in water and dried. Thus, 1.76g (81%) of product with 99.56% HPLC purity were obtained.

Example 47

To 2.0g (0.004mol) rosuvastatin ethyl ester form II was added 7.95cm³1.0 aqueous MTBA solution. The suspension was stirred at 25 ℃ for 48 hours. The mixture was filtered and used for 2cm³The filtered solid was washed with water and dried. Thus, 1.94g (90%) of the product with 98.95% HPLC purity were obtained.

Example 48

30.0g (0.059mol) rosuvastatin ethyl ester form II are suspended in 120cm³Water, added with 59.4cm of water at 25 ℃ while stirring³1.0 aqueous MTBA solution. Thereafter, another 4 times of 12cm were added to the reaction mixture over a period of 2 hours³A portion of 1.0MTBA in water. The next morning, 6cm³1.0 aqueous MTBA solution. The mixture was stirred for 24 hours, filtered and dried.Thus, 23.2g (71%) of the product were obtained with a purity of 99.50% HPLC.

Example 49

10.0g (0.02mol) rosuvastatin ethyl ester form II are suspended in 100cm³Adding water, stirring, and adding 19.8cm at 25 deg.C³1.0 aqueous MTBA solution. Thereafter, another 4 times of 3.96cm each were added to the reaction mixture over a period of 2 hours³1.0 aqueous MTBA solution. The following day, the addition of 3.96cm was repeated 2 times over a 2 hour period³1.0 aqueous MTBA solution. The mixture was stirred for another 24 hours, thereby obtaining a clear solution. After 1 week the product was precipitated from the solution. The solid was filtered and dried. Thus, 7.89g (73%) of product were obtained (purity by HPLC: 99.51%).

Rosuvastatin TBA salt [ compound of formula (III) ] prepared by using rosuvastatin tert-butyl ester [ compound of formula (IIc) ] as raw material

Example 50

2.0g (0.004mol) rosuvastatin tert-butyl ester is suspended in 14cm³Acetonitrile, 3.7cm³1.0 aqueous MTBA solution with stirring at 25 ℃. After that, in a period of 2 hours, 0.8cm was added 5 times³A portion of 1.0MTBA in water was stirred overnight. The mixture was then heated to 60 ℃ and after stirring for 4 hours, the temperature was raised to 80 ℃. After 6 hours, a further 8 times of 0.8cm each are added to the reaction mixture over a period of 2 hours³1.0 aqueous MTBA solution. The mixture was boiled for a further 27 hours and worked up. The reaction mixture was evaporated and the remaining water was removed by azeotropic distillation using ethyl acetate. The suspension thus obtained is cooled to a temperature of 0-5 ℃, filtered, the filtered solid washed with ethyl acetate and dried. Thus, 1.90g (92%) of the product were obtained (HPLC purity: 99.60%).

Example 51

2.0g (0.004mol) rosuvastatin tert-butyl ester is suspended in 14cm³Acetonitrile, adding 13.4cm³1.0 aqueous MTBA solution with stirring at 25 ℃. The reaction mixture was thereafter heated to 80 ℃, boiled for 36 hours, evaporated and the remaining water removed by azeotropic distillation using ethyl acetate. The suspension thus obtained is cooled to a temperature of 0-5 ℃, filtered, the filtered solid washed with cold ethyl acetate and dried. Thus, 1.90g (92%) of product were obtained. Suspending the product in 19cm³Heating acetonitrile to 80 deg.C, and adding 17cm dropwise³Isopropanol until dissolved. The slightly opalescent solution thus obtained is filtered, cooled to 25 ℃ in a first step and thereafter to a temperature of 0-5 ℃ while stirring. After 2 hours, the solid was filtered, washed with cold acetonitrile and dried. Thus, 1.70g (85%) of the product were obtained (HPLC purity: 99.90%).

Preparation of rosuvastatin TBA salt [ compound of formula (III) ] crystal form II

Example 52

5.0g (0.01mol) of rosuvastatin ethyl ester are suspended in 65cm³Water, 9.9cm was added to the suspension³1.0 aqueous MTBA solution with stirring at 25 ℃. After this time, 1.98cm of 1.4 additional times were added to the reaction mixture over a period of 2 hours³1.0 aqueous MTBA solution. The next day, 2 additional 2 times of 2X1.98cm are added in 2 hours³1.0 aqueous MTBA solution. After stirring for 3 hours, 1.98cm was added 2 times over a period of 2 hours³1.0 aqueous MTBA solution. The precipitated solid was filtered after 4 days. The filtrate was allowed to stand and the precipitated product was filtered over the next 3 days. Thus, 1.44g (26%) of product were obtained (HPLC purity: 99.84%). The powder X-ray diffraction pattern of this product is shown in FIG. 1. The powder X-ray diffraction positions and relative intensities are summarized in table 1.

Preparation of amorphous rosuvastatin TBA salt [ Compound of formula (III) ]

Example 53

0.35g (0.69mmol) of rosuvastatin TBA salt prepared according to the method of example 42 are dissolved in 2.5cm at 25 deg.C³Methanol. The solution thus obtained was evaporated to dryness in vacuo. The residue was dried until the next day at 25 ℃ with air drying. Thus, 0.33g (94%) of amorphous product is obtained, having a powder X-ray diffraction pattern as shown in FIG. 2.

Example 54

3.0g (6mmol) rosuvastatin methyl ester form II are dissolved in 12cm at 25 deg.C³Methanol, while stirring, 5.9cm³1.0 aqueous MTBA solution. Thereafter, 1.2cm of 1.5 additional times were added to the reaction mixture over a period of 2 hours³1.0 aqueous MTBA solution. After stirring for a further 24 hours, the mixture is evaporated. Thus, 3.20g (96%) of amorphous product are obtained.

Preparation of rosuvastatin calcium salt [ compound of formula (IV) ] from rosuvastatin TBA salt [ compound of formula (III) ]

Example 55

1.67g (3.0mmol) of amorphous rosuvastatin TBA salt was added to 10cm at room temperature³Water and 15cm³Ethyl acetate in a two-layer mixture with vigorous stirring. After all the solid had dissolved, 5 times 5X1.5cm of the mixture was added dropwise to the two-layer mixture over a period of 15 minutes³(5X7.5mmol) of a saturated calcium chloride solution. After the addition, the reaction mixture was stirred at room temperature for another 1 hour, and the upper ethyl acetate layer was separated and used for 5cm³The washing is carried out 2 times with 5ml of water each time, 2.0M calcium chloride solution. The residue thus obtained was dissolved in 5cm by azeotropic distillation, removing water from the organic layer by evaporating the ethyl acetate layer to dryness³The ethyl acetate was dried. The solution is stirred for 5 minutes and evaporated to dryness in vacuo at 42-45 ℃ and 50mbar pressure. The residue was taken up in a column of 6cm³Dry cyclohexane was mixed and the suspension was stirred for 30 minutes. Filtering the solid with 5cm³The cyclohexane was dried, washed and dried under vacuum at 50 ℃ for 7 hours. Thus, 1.30g (87%) of product were obtained.

Example 56

1.67g (3.0mmol) of rosuvastatin TBA salt are added to 10cm at room temperature³Water and 15cm³Ethyl acetate in a biphasic mixture with vigorous stirring. After dissolution of the solid, 3X0.4g (3X2.5mmol) of solid calcium acetate was added to the biphasic mixture over a period of 15 minutes. After addition, the reaction mixture was stirred at room temperature for an additional 1 hour, the upper ethyl acetate layer was separated and 3 × 5cm was used³And (4) washing with water. The organic layer was dried by azeotropic distillation, evaporating the ethyl acetate layer to dryness under vacuum. The white residue thus obtained was dissolved in 5cm³The ethyl acetate was dried. The solution was stirred for 5 minutes and evaporated in vacuo at 42-45 ℃ under a pressure of 50 mbar. The residue was taken up in a column of 6cm³The cyclohexane was dried and mixed and the suspension was stirred for 30 minutes. Filtering the solid with 5cm³The cyclohexane was dried, washed and dried under vacuum at 50 ℃ for 7 hours. After drying, 1.36g (91%) of product are obtained.

Preparation of rosuvastatin zinc salt [ compound of formula (V) ] from rosuvastatin TBA salt [ compound of formula (III) ]

Example 57

27.0g (0.049mol) of amorphous rosuvastatin TBA salt was dissolved in 1620cm at a temperature of 20-25 ℃ in a light-tight apparatus³And (4) distilled water. Filtering the solution, and adding dropwise 80cm at 20-25 deg.C³9.59g (0.053mol) of ZnSO prepared with distilled water₄·H₂And (4) O solution. Cooling the suspension to 5-10 deg.C, filtering, and collecting the filtrate with a volume of 100cm³Washing with distilled water. Thereafter, 59.9g of the wet product thus obtained were weighed and suspended in 540cm at a temperature of 5-10 ℃ under an argon atmosphere³Distilled water was continued for 41 hours. The solid was filtered, washed with distilled water and dried in vacuo. Therefore, the temperature of the molten metal is controlled,33.1g (80%) of the title product are obtained.

Example 58

In a light-tight apparatus, 1.16g (0.002mol) of amorphous rosuvastatin TBA salt was added to 11.7cm³Ethyl acetate and 55cm³Distilled water while stirring. Thereafter, 1.27cm of a solution was added dropwise at a temperature of 20 to 25 ℃ in an argon atmosphere³2.23MZnSO₄The aqueous solution was stirred simultaneously. After stirring for 1 hour, the layers were separated and washed with 2X1.3cm³2.23MZnSO₄Aqueous solution, then 1.3cm³The organic layer was washed with water. The organic layer was evaporated, ethyl acetate was repeatedly added, and then the water residue was removed by azeotropic distillation. The suspension thus obtained was cooled, filtered and poured in 2cm³Washed with ethyl acetate and dried in vacuum. 0.70g (0.0007mol) of the product thus obtained are dissolved in 8.2cm³A solution of distilled water in 0.76mg of sodium hydroxide was stirred for 4 hours at 25 ℃ in a stream of argon. The mixture was filtered and the wet product was repeatedly suspended in 8.2cm under argon atmosphere³The alkaline solution having the same composition as exemplified above was further subjected to 2 hours. Filtering the solid with 2cm³The alkaline solution with the same composition was washed and dried under vacuum protected from light. Thus, 0.53g (76%) of the title product is obtained.

Example 59

6.15g (0.011mol) of rosuvastatin TBA salt are dissolved in 370cm in a light-tight apparatus at 20-25 deg.C³And (4) distilled water. Then, 2.15g (0.012mol) of ZnSO is added dropwise at the temperature of 20-25 ℃ in an argon atmosphere₄·H₂O is 17.8cm³Solution in distilled water. Cooling the suspension to 5-10 deg.C, filtering, and collecting the filtrate with a volume of 30cm³Washing with distilled water. Thereafter, the wet product was heated at a temperature of 5-10 ℃ in an argon atmosphere at 123cm³The mixture was stirred in distilled water for 41 hours. After filtration, the mixture was washed with 4X25cm³The solid was washed with distilled water and dried under vacuum in the dark. Thus, 4.60g (81%) of the title product was obtainedA compound (I) is provided.

Example 60

6.20g (0.0112mol) of rosuvastatin TBA salt are dissolved in 370cm in a light-shielding device at a temperature of 20-25 deg.C³And (4) distilled water. Then 2.20g (0.0122mol) of ZnSO is added dropwise at the temperature of 20-25 ℃ in the argon atmosphere₄·H₂O is 17.8cm³Solution in distilled water. Cooling the suspension to 5-10 deg.C, filtering, and collecting the filtrate with a volume of 30cm³Washing with distilled water. Thereafter, the wet product was heated at a temperature of 5-10 ℃ in an argon atmosphere at 125cm³The mixture was stirred in distilled water for 41 hours. After filtration, the mixture was washed with 3X30cm³The solid was washed with distilled water and dried under vacuum in the dark. Thus, 4.80g (84%) of the title product are obtained.

Example 61

1.20g (0.0022mol) rosuvastatin TBA salt is dissolved in 72cm at a temperature of 20-25 ℃ in a light-tight apparatus³And (4) distilled water. Thereafter 0.53g (0.003mol) of ZnSO were added at a temperature of 20 to 25 ℃ in an argon atmosphere₄·H₂O is 4.4cm³A solution in distilled water was added to the reaction mixture. Cooling the suspension to 5-10 deg.C, filtering, and collecting the filtrate with a volume of 5cm³Washing with distilled water. Thereafter, the wet product was heated at a temperature of 5-10 ℃ in an argon atmosphere at 25cm³The mixture was stirred in distilled water for 41 hours. After filtration, the mixture was washed with 3X5cm³The solid was washed with distilled water and dried under vacuum in the dark. Thus, 0.86g (79%) of the title product are obtained.

Example 62

7.50g (0.014mol) of rosuvastatin TBA salt are dissolved in 450cm in a light-tight apparatus at a temperature of 20-25 deg.C³And (4) distilled water. Then dropwise adding into the mixture at 20-25 deg.C in argon atmosphere with a concentration of 22.6cm³2.70g (0.015mol) ZnSO prepared with distilled water₄·H₂And (4) O solution. Thereafter the suspension was cooledCooling to 5-10 deg.C, filtering, and collecting filtrate with a volume of 30cm³The solid was washed with distilled water. 13.8g of the wet product are weighed at 150cm at a temperature of 5-10 ℃ under an argon atmosphere³The mixture was stirred in distilled water for 41 hours. After filtration, the mixture was washed with 3X30cm³The solid was washed with distilled water and dried under vacuum in the dark. Thus, 5.95g (86%) of the title product are obtained.

Example 63

3.50g (0.006mol) of rosuvastatin TBA salt are dissolved in 210cm at 20-25 ℃ in a light-tight apparatus³And (4) distilled water. Then dropping 13cm at 20-25 deg.C in argon atmosphere³1.54g (0.008mol) of ZnSO prepared with distilled water₄·H₂And (4) O solution. Cooling the suspension to 5-10 deg.C, filtering, and using 15cm³The solid was washed with distilled water. Thereafter 6.50g of the wet product were weighed at 110cm under an argon atmosphere at a temperature of 5-10 deg.C³The mixture was stirred in distilled water for 41 hours. After filtration, the mixture was washed with 3X20cm³The solid was washed with distilled water and dried under vacuum in the dark. Thus, 2.65g (82%) of the title product are obtained.

Example 64

2.90g (0.005mol) rosuvastatin TBA salt is dissolved in 175cm at 20-25 ℃ in a light-tight apparatus³And (4) distilled water. Then, 1.28g (0.0068mol) of ZnSO is added dropwise at a temperature of between 20 and 25 ℃ in an argon atmosphere₄·H₂O is at 11cm³Solution in distilled water. Cooling the suspension to 5-10 deg.C, filtering, and filtering with 10cm³Washing with distilled water. Thereafter 5.40g of the wet product were weighed at 85cm at a temperature of 5-10 ℃ under an argon atmosphere³The mixture was stirred in distilled water for 41 hours. After filtration, the mixture was washed with 3X20cm³The solid was washed with distilled water and dried under vacuum in the dark. Thus, 2.30g (86%) of the title product are obtained.

Preparation of rosuvastatin zinc salt [ compound of formula (V) ] from rosuvastatin methyl ester [ compound of formula (IIa) ] crystalline form II

Example 65

2.0g (4.0mmol) rosuvastatin methyl ester form II is dissolved in 8cm at 25 deg.C³Methanol, while stirring, at the same temperature, 4cm³1.0 aqueous MTBA solution. 0.8cm was added 5 more times to the reaction mixture over a period of 2 hours³1.0 aqueous MTBA solution. The compound was stirred for a further 24 hours, evaporated and 20cm of water was added to the residue³Ethyl acetate and 6cm³And (4) distilled water. Dropping 2.2cm of the biphasic mixture at 20-25 deg.C over 10 min³2.2MZnSO₄An aqueous solution. After 1 hour stirring, the layers were separated and washed with 2X10cm³2.2MZnSO₄Aqueous solution and 10cm³The organic layer was washed with distilled water. The organic layer was evaporated, ethyl acetate was repeatedly added, and then residual water was removed by azeotropic distillation. The suspension thus obtained was cooled, filtered and poured in 2cm³Washed with ethyl acetate and dried in vacuum. Thus, 1.24g (60%) of the crude product are obtained, which is treated at a temperature of 0-5 ℃ under an argon atmosphere at a concentration of 0.8mg of sodium hydroxide and 8cm³The aqueous solution was stirred for 36 hours. Thereafter, the mixture was filtered and used for 2cm³The solid was washed with aqueous base having the same composition as described above and dried under vacuum protected from light. Thus, 1.10g (89%) of the title product are obtained.

Example 66

3.0g (6.0mmol) rosuvastatin methyl ester form II is dissolved in 12cm at 25 deg.C³Methanol was added to the mixture at the same temperature while stirring at 5.9cm³1.0 aqueous MTBA solution. Thereafter, 1.2cm of 1.5 additional times were added to the reaction mixture over a period of 2 hours³1.0 aqueous MTBA solution. The mixture was stirred for a further 24 hours, evaporated and purified by addition of 3 × 40cm³Ethyl acetate, and residual water was removed by repeating azeotropic distillation 3 times. To the residue thus obtained was added 34cm³Ethyl acetate and 10cm³And (4) distilled water. Then at the temperature of 20-25 deg.C,within 10 minutes, 3.7cm³2.2MZnSO₄The aqueous solution is added to the biphasic mixture. After 1 hour stirring, the layers were separated and washed with 2X10cm³2.2MZnSO₄Aqueous solution and 10cm³The organic layer was washed with distilled water. The organic layer was evaporated and the remaining water was removed by repeated azeotropic distillation using ethyl acetate. Cooling the suspension, filtering and using 3cm³Washed with ethyl acetate and dried in vacuum. Thus, 2.50g (81%) of the crude product are obtained, which is treated at a temperature of 0-5 ℃ in an argon atmosphere at 1.2mg of sodium hydroxide in 12cm³The solution in distilled water was stirred for 36 hours. The mixture was filtered, washed with aqueous alkali having the same composition as described above and dried under vacuum protected from light. Thus, 2.25g (90%) of the title product are obtained.

Claims (3)

1. A process for the preparation of rosuvastatin TBA salt of the formula (III):

the method comprises the following steps: crystalline form II rosuvastatin methylester of the formula (IIa) using a polar solvent acetonitrile,

wherein said crystalline form II of rosuvastatin methylester of the formula (IIa) has the following use of CuK in powder X-ray diffraction method_αDiffraction signals at the following positions of the radiometric: (2 theta. + -. 0.2 degrees; relative intensity)>5％)：

Peak(s) Angle of rotation d value Strength of Peak(s) Angle of rotation d value Strength of Numbering 2-θ° Tea tree (Angel) ％ Numbering 2-θ° Tea tree (Angel) ％ 1 8.721 10.13081 16.7 19 21.695 4.09302 53.7 2 9.371 9.43010 63.6 20 22.374 3.97039 13.3 3 9.681 9.12830 21.4 21 22.707 3.91291 5.2 4 12.071 7.32604 8.9 22 23.143 3.84011 11.6 5 13.776 6.42304 6.9 23 23.538 3.77661 7.1 6 15.261 5.80119 5.6 24 23.815 3.73326 10 7 15.551 5.69369 5.6 25 24.365 3.65023 32.3

8 15.933 5.55810 23 26 24.773 3.59108 24.6 9 16.519 5.36211 12.2 27 25.091 3.54626 7.7 10 16.660 5.31699 9.5 28 26.352 3.37933 29.2 11 17.471 5.07202 75.3 29 27.369 3.25605 6.7 12 18.042 4.91268 100 30 29.569 3.01864 6.6 13 18.836 4.70745 14.5 31 29.812 2.99458 7.6

Peak(s) Angle of rotation d value Strength of Peak(s) Angle of rotation d value Strength of Numbering 2-θ° Tea tree (Angel) ％ Numbering 2-θ° Tea tree (Angel) ％ 14 19.553 4.53629 87.7 32 30.892 2.89228 51 --> 15 19.827 4.47435 20.9 33 31.260 2.85903 5 16 20.239 4.38416 22.8 34 32.475 2.75484 8 17 20.675 4.29262 11.9 35 33.678 2.65910 7.6 18 21.254 4.17702 10.7

Reacting with 1.5-5 molar equivalents of an aqueous solution of tert-butylamine at a temperature of 25 ℃ for 24-72 hours; the product was then filtered, washed after removal of water.

2. The process of claim 1, characterized in that the removal of water is by addition of ethyl acetate and removal of the remaining water by azeotropic distillation.

3. The process according to claim 1, wherein the concentration of the aqueous solution of tert-butylamine is 1.0M and the aqueous solution of tert-butylamine is added in portions.