CRYSTALLINE ROSUVASTATIN INTERMEDIATE RELATED APPLICATIONS
[0001] This application claims the benefit of provisional application Serial
Number 60/708,920, filed August 16,2005, and provisional application Serial Number 60/710,930, filed August 23,2005, both of which are incorporated herein by reference.
MELD OF THE INVENTION
[0002] The invention relates to a crystalline intermediate of rosuvastatin and a
process for the preparation thereof.
BACKGROUND OF THE INVENTION
[0003] Rosuvastatin calcium (monocalcium bis (+) 7- [4-(4-fluorophenyl)-6-
isopropyl-2-{N-memyl-N-methylsulfonylammopyrimidin)-5-yl]-(3R,5S)-dihydroxy-
(E)-6-heptenoate) is an HMG-CoA reductase inhibitor., developed by Shionogi for the
once daily oral treatment of hyperlipidaemia (Ann Rep, Shionogi, 1996; Direct
communications, Shionogi, 8 Feb 1999 & 25 Feb 2000). Rosuvastatin calcium has
the following chemical formula: (Formula Removed)
[0004] Rosuvastatin calcium is marketed under the name CRESTOR for
treatment of a mammal such as a human. According to the maker of CRESTOR, it is administered in a daily dose of from about 5mg to about 40 mg for LDL cholesterol reduction.
[0005] One of the key intermediates of the synthesis of Rosuvastatin calcium
is "intermediate 21." "Intermediate 21" refers to t-butyl ester of (+)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methane-sulfonylaminoprimidin)-5-yl)-3(R)hydroxy-5-oxo-(E)-6-heptenoic acid:
(Formula Removed)
[0006] In USRE37,314E, the corresponding methyl ester of intermediate 21
(rather than t-butyl ester) is described as a "syrup" after column chromatograpriy. See example l-(4). In WO03/097614, the same intermediate having a methyl ester is described as a "thick oil." See example 2, step b. In yet another reference, WO03/087112, column chromatography is carried out to purify intermediate 21.
[0007] Generally, an oil is difficult to handle and contains impurities.
Furthermore, chromatography is not preferable for use on an industrial scale.
SUMMARY OF THE INVENTION
SUMMARY OF THE INVENTION
[0008] One embodiment of the invention provides a crystalline rosuvastatin
intermediate or an enantiomer thereof having the following structure:
(Structure Removed)
wherein RI hi such crystalline rosuvastatin intermediate is a carboxy protecting group.
[0009] Another embodiment of the invention provides a process for preparing
the above crystalline rosuvastatin intermediate including crystallizing the intermediate from a solution having at least one organic solvent.
[00010] A further embodiment of the invention provides a process for
preparing rosuvastatin, rosuvastatin lactone or a pharmaceutically acceptable salt thereof including crystallizing the rosuvastatin. intermediate:
(Formula Removed)
wherein R1 is. a carboxy protecting group, from a solution having at least one organic solvent, said organic solvent being optionally in mixture with water, and converting the crystalline intermediate to rosuvastatin, rosuvastatin lactone or a pharmaceutically acceptable salt thereof.
[00011] Another embodiment of the invention provides a pharmaceutical
composition including rosuvastatin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the rosuvastatin, rosuvastatin lactone or salt thereof is prepared by converting crystalline rosuvastatin intermediate having the following structure: (Structure Removed)
wherein R1 is a carboxy protecting group, to rosuvastatin or a pbarmaceutically
acceptable salt thereof.
[00012] One embodiment of the invention provides a process of preparing the
above pharmaceutical composition including mixing the rosuvastatin, rosuvastatin lactone or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptably carrier.
[00013] One embodiment of the invention provides a method of lowering LDL
levels in a mammal comprising administering the pharmaceutical composition of the invention to a mammal.
BRIEF DESCRIPTION OF THE FIGURES
[00014] Fig 1: X-Ray Powder Diffractografn of crystalline Rosuvastatin
intermediate.
[00015] Fig. 2: DSC thermogram of crystalline Rosuvastatin intermediate.
[00016] Fig. 3: FTIR spectrum of crystalline Rosuvastatin intermediate.
DETAILED DESCRIPTION OF THE INVENTION
[00017] One embodiment of the invention provides a crystalline intermediate
("intermediate") or an enantiomer thereof, which is used for the synthesis of rosuvastatin, having the following structure: (Structure Removed)
wherein R1 in such crystalline rosuvastatin intermediate is a carboxy protecting group.
[00018] This crystalline intermediate is suitable for use on an industrial scale,
inter alia because crystalline forms may be easier to handle and process than oil
intermediates. Crystallization also allows for purification of the intermediate.
[00019] R1 in the crystalline rosuvastatin intermediate may be any suitable
carboxy protecting group, including but not limited to phenyl. Preferably, RI in the crystalline rosuvastatin intermediate is a C1 to C4 alkyl group. In one embodiment, R1 is a methyl group.
[00020] In a preferred embodiment, R1 is a tert-butyl, providing "intermediate
21": (Formula Removed)
The crystallization and isolation of intermediate 21 is illustrated in the examples.
[00021] The crystallinity of the intermediate 21 is confirmed by powder X-Ray
Diffraction. Crystalline rosuvastatin intermediate 21 may be characterized by powder x-ray diffraction peaks at 10.5,13.1,15.4,19.0, and 20.4 ± 0.2 degrees two theta. Crystalline rosuvastatin intermediate 21 may be further characterized by powder x-ray diffraction peaks at 11.2,15.7,16.6,18.0,18.6,19.4,21.8, and 23.1 ± 0.2 degrees two theta.
[00022] Crystalline rosuvastatin intermediate 21 may be characterized by an
FTIR spectrum having peaks at 1543,1380,1153, 961, and 847cm-1. The compound
may further be characterized by an FTIR spectrum having peaks at 2980,1606,1508, 1440,1340,1223,1100 and 1065 cm1.
[00023] DSC thermogram for crystalline rosuvastatin intermediate 21 shows an
endothermic peak at about 100°C, and a broad endotherm at about 220°C.
[00024] The intermediate, including intermediate 21, may be obtained as a
solid by crystallization from a solution. The solution may be that of the intermediate in one or more organic solvents, or one or more water-miscible organic solvents in a mixture with water.
[00025] Examples of suitable solvents for crystallization include C6 to C12
aromatic and C5 to C12 aliphatic hydrocarbons, C3 to C8 ethers, C3 to C8 esters, C3 to C8 ketones, C1 to C5 alcohols, C1 to C6 alkylnitriles, and C1 to C6 alkylethers of ethylene glycol. Specific examples of solvents include toluene, n-heptane, n-hexane, cyclohexane, cellosolve, ethyl acetate, n-butyl acetate, t-butyl acetate, methyl t-butyl ether, di-ethyl ether, tetrahydrofuran, methanol, ethaiiol, isopropanol, n-butanol, methyl iso-butyl ketone, diethyl carbonate, butyl lactate, acetone, acetonitrile, mixtures thereof, and mixtures of any of these water miscible organic solvents with water. An example of a water miscible solvent for use as a mixture with water is methanol.
[00026] In a typical crystallization process, the intermediate is dissolved in one
of the solvents, or the mixture of the solvents as provided above. To obtain the
solution, the solvent may have to be heated. Heating is preferably carried out to a
temperature of about 40°C to about 100°C, and more preferably to a temperature of
about 40°C to about 70°C. The solution is then preferably allowed to cool, such to a
temperature of about 20°C to about 30°C, or room temperature. The solution may
then be seeded. After seeding, the reaction mixture, which may be a slurry, may be
further cooled, preferably to a temperature of about -10°C to about 20°C. The
crystallization process maybe carried out overnight, i.e., for about 8 hours.
[00027] In one embodiment, the crystallization process includes heating the
solvent to a temperature of about 40°C to about 70°C to obtain a solution, cooling the
solution to a temperature of about 20°C to about 30°C, seeding, cooling after seeding
to a temperature of about -10°C to about 20°C and recovering the crystalline form.
[00028] The crystallization may result in a sticky solid, as in example 4. In
such instance, such solid may be recrystallized or slurried.
[00029] Crystallization may include adding an anti-solvent to facilitate the
precipitation of the intermediate. The term "anti-solvent" refers to a liquid that, when added to a solution of intermediate in a solvent, induces precipitation of intennediate. The anti-solvent may also be in a binary mixture with the solvent when the solution is prepared. Precipitation of intermediate 21 is induced by the anti-solvent when addition of the anti-solvent causes the intermediate to precipitate from the solution more rapidly or to a greater extent than the intennediate precipitates from a solution containing an equal concentration of the intermediate in the same solvent when the solution is maintained under the same conditions for the same period of time but without adding the anti-solvent. Suitable anti-solvents include water and C5-C12 cyclic or acyclic saturated hydrocarbons. Preferred anti-solvents include water, heptane, and hexane.
[00030] The resulting crystals are then recovered by conventional techniques,
such as filtration. They may be washed with water or an organic solvent. The
crystals are then preferably dried. The temperature may be increased or the pressure
reduced to accelerate the drying process. Drying may be carried out at a temperature
of about 40°C to about 100°C, under a pressure of below about 100 mmHg.
Preferably, drying occurs at a temperature of about 40°C to about 60°C. Drying may
also be performed under atmospheric pressure until constant weight.
[00031] The crystalline intermediate can be used to make rosuvastatin. The
intermediate, which is in the form of a keto ester, is reduced to a diol ester. The
reduction of the ketoester is disclosed in the art. See e.g. US2005/0159615,
incorporated herein by reference in regard to its processes for reduction of statins.
Reagents such as RU-binap, EtB3/NaBH4, MeO-9-BBN/NaBH4 and
diethyhnethoxyborane/NaBH4 may be used for the reduction.
[00032] The diol ester may be further converted into a pharmaceutically
acceptable salt of the statin or a lactone. For example, the diol ester obtained may be reacted with sodium or calcium hydroxide to obtain the sodium or calcium salt. It is also possible to first obtain the sodium salt by reaction with sodium hydroxide, and then convert the sodium salt to calcium salt by using a source of calcium such as calcium chloride or calcium acetate. The basic hydrolysis of the statin diol-ester may be carried out with one or more equivalents of an alkali metal or alkaline earth metal base such as NaOH or Ca(OH)2, in organic solvents such as C3 to C8 ethers (tetrahydrofuran, isopropyl ether), ACN (acetonitrile), C1 to C5 alcohols (MeOH,
EtOH, IPA (isopropyl alcohol), propanol, butanol etc.), C3 to C8 ketones or esters
(acetone, methyl ethyl ketone, methyl isopropyl ketone, ethyl acetate). The
hydrolysis may also be carried out with water, a mixture of the above solvents, or a
mixture of water and the above solvents, preferably at room temperature or fay
heating.
[00033] The present invention comprises pharmaceutical composition
comprising rosuvastatin lactone or a pharmaceutically acceptable salts, and at least
one pharmaceutically acceptable excipient.
[0003 4] The present invention further eucopasses a process for preparing a
pharmaceutical formulation comprising combining rosuvastatin lactone and
pharmaceutically acceptable salt with at least one pharmaceutically acceptable
excipient.
[0003S] The present invention further encompasses the use of rosuvastatin
lactone and pharmaceutically acceptable salts for the manufacture of a pharmaceutical
composition.
[00036] The compositions of rosuvastatin, preferably rosuvastatin lactone and
pharmaceutically acceptable salts, more preferably rosuvastatin calcium are prepared
by mixing a pharmaceutically acceptable excipient with rosuvastatin (or a
pharmaceutically acceptable salt thereof), wherein said rosuvastatin is prepared from
the intermediate in crystalline form.
[00037] Pharmaceutical compositions of the invention include excipients.
Diluents increase the bulk of a solid pharmaceutical composition, and may make a
pharmaceutical dosage form containing the composition easier for the patient and care
giver to handle. Diluents for solid compositions include, for example,
microcrystalline cellulose (e.g. Avicel®), rhicrofine cellulose, lactose, starch,
pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin,
dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin,
magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates
(e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol
and talc.
[00038] Solid pharmaceutical compositions that are compacted into a dosage
form, such as a tablet, may include excipients whose functions include helping to bind
the active ingredient and other excipients together after compression. Binders for
solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g.
carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e,g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polyrnethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
[00039] The dissolution rate of a compacted solid pharmaceutical composition
in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Poiyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrih'n potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
[00040] Glidants can be added to improve the flowability of a non-compacted
solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
[00041] When a dosage form such as a tablet is made by the compaction of a
powdered composition, the composition is subjected to pressure from a punch and
dye. Some excipients and active ingredients have a tendency to adhere to the surfaces
of the punch and dye, which can cause the product to have pitting and other surface
irregularities. A lubricant can be added to the composition to reduce adhesion and
ease the release of the product from the dye. Lubricants include magnesium stearate,
calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor
oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate,
sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
[00042] Flavoring agents and flavor enhancers make the dosage form more
palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
[00043] Solid and liquid compositions may also be dyed using any
pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
[00044] In liquid pharmaceutical compositions of the invention, rosuvastatin
and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin. Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble hi the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
[0004S] Liquid pharmaceutical compositions may also contain a viscosity
enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium algmate, sodium starch glycolate, starch tragacanth and xanthan gum,
[00046] Sweetening agents such as sorbitol, saccharin, sodium saccharin,
sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
[00047] Preservatives and chelating agents such as alcohol, sodium benzoate,
butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetraacetic
acid may be added at levels safe for ingestion to improve storage stability.
[00048] According to the invention, a liquid composition may also contain a
buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate,
sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the
amounts used may be readily determined by the formulation scientist based upon
experience and consideration of standard procedures and reference works in the field.
[00049] The solid compositions of the invention include powders, granulates,
aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and
intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known hi the pharmaceutical arts.
[00050] Dosage forms include solid dosage forms like tablets, powders,
capsules, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and elixirs. The dosage form of the invention maybe a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
[00051 ] The active ingredient and excipients may be formulated into
compositions and dosage forms according to methods known in the art.
[00052] A composition for tableting or capsule rilling may be prepared by wet
granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
[00053] A tableting composition may be prepared conventionally by dry
blending. For example, the blended composition of the actives and excipients may be
compacted into a slug or a sheet and then comminuted into compacted granules. The
compacted granules may subsequently be compressed into a tablet.
[00054] As an alternative to dry granulation, a blended composition may be
compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
[00055] A capsule filling of the invention may comprise any of the
aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step. The oral dosage form of the invention is preferably in the form of an oral capsule having a dosage of about 5 mg to about 40 mg, more preferably capsules of 5,10,20 and 40 mg.
Solid-state Characterization
[00056] Rosuvastatin intermediate of the invention was characterized by X-Ray
powder diffraction (XRD), DSC analysis and FUR spectroscopy.
[00057] XRD Diffractograms were collected on Scintag X-Ray powder
diffractometer model X'TRA, Cu-tube, solid state detector. Scanning parameters: Range: 2-40 deg.26: continuous scan, Rate: 3.00 deg./min.
Thermal analysis
[00058] Differential Scanning Calorimetry was performed on DSC821e,
Mettler Toledo.
The crucible was crimped and punched prior to analysis. Experimental Conditions:
Sample weight: 3-5mg. Heating rate: 10°C/min.
FTIR spectToscopv
[00059] FTIR spectrum was recorded on Perkin-Elmer spectrum One
Spectrometer, Diffuse Reflectance Technique.
[00060] The Sample was finely groiand with Potassium bromide, and the
spectrum was recorded using Potassium Bromide background in a diffused reflectance
accessory.
Examples
"TB21" refers to the t-butyl ester of intermediate 21
Example 1: Crystallization of TB21 in toluene
[00061] TB21 (1.3 g, 56% assay, oil) was dissolved in toluene (1.5 ml) by
heating to 60°C until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed. The mixture was stirred at this temperature
overnight, not causing any precipitation. The solution was then cooled to 0°C, causing precipitation. The solid was then filtered under reduced pressure, washed with some drops of toluene and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (0.20 g).
Example 2: Crystallization of TB21in EtOAc
[00062] TB21 (1.76 g, 56% assay, oil) was dissolved in EtOAc (1.5 ml) by
heating to 60°C until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed. The mixture was stirred at this temperature overnight. No precipitation was observed. The solution was then cooled to 0°C, causing precipitation. The solid was then filtered under reduced pressure, washed with some drops of EtOAc and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (0.35 g).
Example 3: Crystallization of TB21in MeOH
[00063] TB21 (1.25 g, 56% assay, oil) was dissolved in MeOH (1.5 ml) by
heating to 60°C until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed. The mixture was stirred at this temperature overnight. No precipitation was observed. The solution was then cooled to 0°C, causing precipitation. The solid was then filtered under reduced pressure, washed with some drops of MeOH and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (0.45 g).
Example 4: Crystallization of TB21in MeOH:HgO
[00064] TB21 (20 g, 56% assay, oil) was dissolved in MeOH (20 ml) and H2O
(4 ml) at 40°C. The solution was then allowed to cool to 35°C, and seeding was performed. The mixture was allowed to cool to room temperature, and after about 30 minutes starts precipitation. After being stirred at this temperature overnight, the precipitate turned into a sticky semi-solid. The mixture was then heated to 35°C and MeOH (5 ml) was added, so the sticky solid was dissolved. The slurry was then allowed to cool to room temperature, and stirred at this temperature for 2 hours. The solid was then filtered under reduced pressure, washed few drops of MeOH:HaO (5:1) and dried at 50°C under reduced pressure until constant weight to get solid TB21 (5.86 g).
Example 5: Crystallization of TB21inMTBB toethvl t-Butyl ether)
[00065] TB21 (2 g, 56% assay, oil) was dissolved in MTBE (2 ml) under
heating to reflux. The solution was then allowed to cool to room temperature, and seeding was performed causing precipitation. The mixture was stirred at this temperature overnight, and then cooled to 0°C for about 3 hours. The solid obtained was filtered under reduced pressure, washed with some drops of MTBE and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (0.48 g).tallization of'
[00066] TB21 (2 g, 56% assay, oil) was dissolved in IPA (2 ml) by heating to 70°C until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed. Precipitation starts about 1 hour after seeding. The mixture was stirred at room temperature overnight. The slurry was then cooled to 0°C for about 30 minutes. The solid so-obtained was filtered under reduced pressure, washed with some drops of IPA and dried at 50°C under reduced pressure for 72 hrs to get solid TB21 (0.45 g).
Example 7: Crystallization of TB21in n-BuOH
[00067] TB21 (2 g, 56% assay, oil) was dissolved in n-BuOH (2 ml) by heating
to 70°C until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed. No precipitation was observed. The solution was then cooled to 0°C, causing precipitation. The slurry was stirred at this temperature for about 30 minutes. The solid was then filtered under reduced pressure, washed with few drops of n-BuOH and dried at 50°C under reduced pressure for 72 hrs to get solid TB21 (0.25 g).
Example 8: Crystallization of TB21in MIBK (methyl-isobutyl ketonel
[00068] TB21 (2 g, 56% assay, oil) was dissolved in MIBK (2 ml) by heating
to 60°C until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed. No precipitation was observed. The solution was then cooled to 0°C and seeded. No precipitation was observed. The mixture was stirred at room temperature overnight, and after this time there is precipitation. The slurry was then cooled to 0°C for 2 hrs, then filtered under reduced pressure, washed
with few drops of MIBK and dried at 50°C under reduced pressure for 1 8 hrs to get solid TB21 (0.09 g).
[00069] TB21 (2 g, 56% assay, oil) was dissolved in DEC (2 ml) by heating to
60°C until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed. No precipitation was observed. The solution was then cooled to 0°C and new seeding at this temperature induced precipitation. The slurry was stirred at room temperature overnight and then cooled to 0°C for 2 hrs. The solid so-obtained was filtered under reduced pressure, washed with few drops of DEC and dried at 50°C under reduced pressure for 1 8 hrs to get solid TB21 (0.36 g).
Example 10: Crystallization of TB21in Butyl lactate
[00070] TB21 (2 g, 56% assay, oil) was dissolved in Butyl lactate (2 ml) at 100°C until bomogenization. The solution was then allowed to cool to room temperature and seeded. No precipitation was observed. The solution was men cooled to 0°C and new seeding at this temperature did not induced precipitation. The mixture was stirred at room temperature overnight and precipitation, was observed. The slurry was cooled to 0°C for 2 hrs. The solid was then filtered under reduced pressure, washed with few drops of Butyl lactate and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 .(0.20 g).
Example 11: Crystallization of TB21m MeOH:H2O
[00071] TB21 (2 g, 56% assay, oil) was dissolved in MeOH:H2O (5:1,2 ml) by
heating to 55°C until homogenization. The solution was then allowed to cool to room temperature and seeded. Precipitation was observed. The mixture was stirred at room temperature overnight, and then cooled to 0°C for 2 hrs. The solid so-obtained was filtered under reduced pressure, washed with few drops of MeOH:H2O (5:1) and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (0.73 g).
Example 12: Crystallization of TB2 linn-Butyl acetate
[00072] TB21 (2 g, 56% assay, oil) was dissolved in n-BuOAc (2 ml) under
heating. The solution was then allowed to cool to room temperature and seeding was
performed causing precipitation. The mixture was then stirred at room temperature overnight, and then cooled to 0°C for 2 hrs. The solid so-obtained was filtered under reduced pressure, washed and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (0.25 g%).
Example 13: Crystallization of TB21in IPAiHiO
[00073] TB21 (2 g, 56% assay, oil) was dissolved in IPA( 2.5 ml) andH2O (1
ml) by heating to 55°C until homogenization. The solution was then allowed to cool to room temperature and seeding was performed. No precipitation was observed. The mixture was stirred at room temperature overnight and precipitation was observed. The slurry was then cooled to 0°C for 2 hrs. The solid so-obtained was filtered under reduced pressure, washed with few drops of IPAiHaO (2.5:l)and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (0.67 g).
Example 14: Crystallization of TB21inMeOH:H2O
[00074] TB21 (10.68 g, 56% assay, oil) was dissolved in MeOH:H2O (5:1,5
ml) under hearing, until homogenization. The solution was then allowed to cool to room temperature and seeding was performed. No precipitation was observed. The mixture was stirred at room temperature for 72 hours giving a thick slurry. The solid so-obtained was filtered under reduced pressure, washed with few drops of MeOHiHjO (5:1) and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (6.33 g).
Example 15: Crvstalhzation of TB21in MTBE
[00075] TB21 (10 g, 56% assay, oil) was dissolved in MTBE (5 ml) by heating
to reflux until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed. No precipitation was observed. The mixture was stirred at room temperature for 72 hours giving a thick slurry. The solid was then filtered under reduced pressure, washed with some drops of MTBE and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (4.5 g)
pxample 16: Crystallization of TB21 in Acetone H2O
[00076] TB21 (2 g, 56% assay, oil) was dissolved in acetone (1 ml) and H2O
(0.5 ml) by heating to 60°C until homogenization. The solution was then allowed to
cool to room temperature, and seeding was performed. No precipitation was observed. The mixture was stirred at room temperature for 18 hours. After this time, precipitation was observed. The slurry was then cooled to ~10°C for 2 hours. The solid was then filtered under reduced pressure, washed with some drops of AcetonerHjO (2:1) and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (0.63 g)
Example 17; Crystallization of TB21in ACN:H2O
[00077] TB21 (2 g, 56% assay, oil) was dissolved in ACN (1 ml) and H2O (0.5
ml) by heating to 70°C until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed. No precipitation was observed. The mixture was stirred at room temperature for 18 hours. After this time, precipitation was observed. The slurry was then cooled to -10°C for 2 hours. The solid was then filtered under reduced pressure, washed with some drops of AC (2: 1) and dried at 50°C under reduced pressure for 1 8 hrs to get solid TB21 (0.3 Ig)
18: Crystallization ofTB21inMcOH:H2O
[00078] TB21 (2 g, 56% assay, oil) was dissolved in MeOH:H2O (5:1, 1 ml) by
heating to 70°C until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed, causing precipitation. The mixture was stirred at room temperature for 18 hours, giving a slurry. The slurry was then cooled to -10°C for 2 hours. The solid was then filtered under reduced pressure, washed with some drops of MeOEfcEkO (5:1) and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (0.56g)
Example 19: Crystallization of TB21in Et2O:MeOH
[00079] TB21 (2 g, 56% assay, oil) was suspended hi Et2O (5 ml) at
35°C.MeOH (0.5 ml) was added, causing dissolution. The solution was then allowed to cool to room temperature, and seeding was performed, not causing precipitation immediately. The solution was stirred at room temperature for 18 hours. After this time precipitation was observed. The slurry was then cooled to -10°C for 5 hours. The solid was then filtered under reduced pressure, washed with some drops of and dried at 50°C under reduced pressure for 1 8 hrs to get solid TB21 (0.5g)
Example 20: Crystallization of TB21in Cellosolve
[00080] TB21 (2 g, 56% assay, oil) was dissolved in Cellosolve (2 ml) by
heating to 90°C until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed, not causing precipitation immediately. The solution was stirred at room temperature for 18 hours. After this time precipitation was observed. The slurry was then cooled to -10°C for 5 hours. The solid was then filtered under reduced pressure, washed with some drops of Cellosolve and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (0.21g)
Example 21: Crystallization of TB21in MeOH:H2O
[00081] TB21 (10 g, 56% assay, oil) was dissolved in a mixture MeOH:H2O
(5:1,5 ml) by heating to 60°C until homogenization. The solution was then allowed to cool to room temperature, and seeding was performed. The mixture was stirred at room temperature for 18 hours. The solid was then filtered under reduced pressure, washed with some drops of a mixture MeOH:HaO (5:1) and dried at 50°C under reduced pressure for 18 hrs to get solid TB21 (0.56g)
[00082] Having thus described the invention with reference to particular
preferred embodiments and illustrated it with Examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from, the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. All references mentioned herein are incorporated in their entirety.

CLAIMS
What is claimed is:
1. A crystalline rosuvastatin intermediate or an enantiomer thereof having the following structure: (Structure Removed)

SO2CH3 wherein RI in such crystalline rosuvastatin intermediate is a carboxy protecting group.
2. The crystalline rosuvastatin intermediate of claim 1, wherein R1 is a C1 to C4
alky! group.
3. The crystalline rosuvastatin intermediate of claim 2, wherein R1 is a methyl.
4. The crystalline rosuvastatin intermediate of claim 2, wherein R1 is t-butyl.
5. The crystalline rosuvastatin intermediate of claim 4, wherein the crystalline
rosuvastatin intermediate has an X-Ray Diffraction pattern with peaks at 10.5,13.1,
15.4,19.0, and 20.4 ±0.2 degrees two theta.
6. The crystalline rosuvastatin intermediate of claim 5, further characterized by
an X-Ray Diffraction pattern with peaks at 11.2,15.7,16.6,18.0,18.6,19.4, 21.8, and
23.1 ±0.2 degrees two theta.
7. The crystalline rosuvastatin intermediate of any of claims 4-6, wherein the
crystalline rosuvastatin intermediate has an FTIR spectrum with peaks at 1543,1380,
1153, 961, and 847 cm-1.
8. The crystalline rosuvastatin intermediate of claim 7, further characterized by
an FITR spectrum with peaks at: 2980,1606,1508,1440,1340,1223,1100, and 1065
cm"1.
9. The crystalline rosuvastatin intermediate of any of claims 4-8, wherein the
crystalline rosuvastatin intermediate has a DSC thermogram with an endothermic
peak at about 100°C, and a broad endotherm at about 220°C.
10. A process for preparing the crystalline rosuvastatin intermediate of any of
claims 1-9 comprising crystallizing the intermediate from a solution having at least
one organic solvent.
11. The process of claim 10, wherein the organic solvent is a water miscible
solvent.
12. The process of claim 11, wherein the water miscible solvent is in mixture with
water.
13. The process of any of claims 10-12, wherein crystallizing comprises heating a
reaction mixture of the intermediate in the solvent to obtain a solution, followed by
cooling.
14. The process of any of claims 10-13, wherein crystallizing comprises adding an
anti-solvent to the solution.
15. The process of claim 13, wherein the antisolvent is selected from the group
consisting of water, heptane, and hexane.
16. The process of any of claims 10-15, wherein crystallizing comprises seeding
the solution.
17. The process of claim 10-16, wherein crystallizing comprises:

a) heating the solvent to obtain a solution;
b) cooling;
c) seeding; aad
d) recovering the crystalline intermediate.

18. The process of claim 17, wherein cooling is carried out before seeding.
19. The process of claim 18, further comprising cooling the solution both before
and after seeding.
20. The process of any of claims 17-19, further comprising adding an antisolvent
before the recovering step.
21. The process of any of claims 13-20, wherein heating is carried out to a
temperature of about 40°C to about 100°C.
22. The process of claim 21, wherein heating is carried out to a temperature of
about 40°C to about 70°C,
23. The process of any of claims 13-22, wherein cooling is carried out to a
temperature of about -10°C to about 20°C.
24. The process of any of claims 17-23, wherein the recovered crystalline
rosuvastatin intermediate is dried at a temperature of about 40°C to about 100°C.
25. The process of any of claims 10-24, wherein the solvent is selected from the
group consisting of C6 to C12 aromatic and C5 to C12 aliphatic hydrocarbons, C3 to C8
ethers, C3 to C8 esters, C3 to C8 ketones, and C1 to C5 alcohols, and mixtures thereof.
26. The process of claim 25, wherein the solvent is selected from the group
consisting of toluene, n-heptane, n-hexane, cyclohexane, cellosolve, ethyl acetate, n-
butyl acetate, t-butyl acetate, methyl t-butyl ether, di-ethyl ether, tetrahydrofuran,
methanol, ethanol, isopropanol, n-butanol, methyl iso-butyl ketone, diethyl carbonate,
butyl lactate, acetone, acetonitrile, and mixtures thereof.
27. The process of any of claims 10-26, wherein the solvent is a mixture of
MeOH/H2O.
28. The process of any of claims 10-26, wherein the solvent is a mixture of
IPA/H2O.
29. The process of any of claims 10-26, wherein the solvent is toluene.
30. The process of any of claims 10-26, wherein the solvent is acetonitrile.
31. The process of any of claims 10-26, wherein the solvent is a mixture of
ethanol and water,
32. The process of any of claims 10-31, wherein crystallizing comprises:

a) heating the solvent to a temperature of about 40°C to about 70°C to
obtain a solution;
b) cooling the solution to a temperature of about 20°C to about 30°C;
c) seeding;
d) cooling after seeding to a temperature of about -10°C to about 20°C;
and
e) recovering the crystalline intermediate.

33. The process of any of claims 10-32, further comprising converting the
crystalline rosuvastatin intermediate into a lactone or pharniaceutically acceptable salt
ofrosuvastatin.
34. A process for preparing rosuvastatin, rosuvastatin ketone or a
pharmaceutically acceptable salt thereof comprising crystallizing the rosuvastatin
intermediate: (Structure Removed)
wherein R1 is a carboxy protecting group, from a solution having at least one organic solvent, said organic solvent being optionally in mixture with water, and converting the crystalline intermediate to rosuvastatin, rosuvastatin lactone or a pharmaceutically acceptable salt thereof.
35. The process of claim 34, wherein R1 is a C1 to C4 alkyl group.
36. A pharmaceutical composition comprising rosuvastatin or a pharmaceutically
acceptable salt thereof and at least one phaxmaceutically acceptable excipient, wherein
the rosuvastatin, rosuvastatin lactone or salt thereof is prepared by converting
crystalline rosuvastatin intermediate having the following structure: (Structure Removed)
wherein R1 is a carboxy protecting group, to rosuvastatin or a pharmaceutically acceptable salt thereof.
37. The pharmaceutical composition of claim 36, wherein R1 is a C1 to C4 alkyl
group.
38. A process of preparing the pharmaceutical composition of any of claims 36-37
comprising mixing the rosuvastatin, rosuvastatin lactone or a pharmaceutically
acceptable salt thereof with 'a pharmaceutically acceptably carrier.
39. Use of a process according to any of claims 10-35 or 38, in the manufacture of
rosuvastatin or a pharmaceutically acceptable salt thereof.