SK1402004A3 - Process for preparing calcium salt forms of statins - Google Patents

Abstract

Processes for preparing a calcium salt of a statin from an ester derivative or protected ester derivative of the statin by using calcium hydroxide are provided. The ester or protected ester derivative is contacted with calcium hydroxide to obtain the calcium salt. Preferred statins are rosuvastatin, pitavastatin and atorvastatin, simvastatin and lovastatin. In processes beginning with a protected satin ester derivative, the protecting group is hydrolyzed during salt formation by contact with calcium hydroxide, or is contacted with an acid catalyst followed by contact with calcium hydroxide.

Description

Methods for preparing calcium salts of statins

Technical field

The class of drugs referred to as statins is currently the class of therapeutically most effective drugs available to reduce the concentration of low density lipoprotein (LDL) particles in the blood stream of patients at risk of cardiovascular disease and therefore statins are used in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. High levels of LDL in the blood stream are associated with the formation of coronary lesions, which create a barrier to blood flow, which can cause blood vessels to break, and which may possibly promote thrombosis. Goodman and Gilman, The Pharmacological Basis of Therapeutics, p. 879 (9th Ed. 1996).

Statins inhibit cholesterol biosynthesis in humans by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase enzyme. HMG-CoA reductase catalyzes the conversion of HMG to mevalonate, a rate-determining step in cholesterol biosynthesis. Reduced cholesterol production causes an increase in the number of LDL receptors and a corresponding reduction in the concentration of LDL particles in the blood stream. Reduction of LDL levels in the blood stream reduces the risk of coronary artery disease. J.A.M.A. 1984, 251, 351-74.

Statins currently available include lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin. Lovastatin (described in U.S. Patent 4,231,938) and simvastatin (ZOCOR; described in U.S. Patent 4,444,784 and WO 00/53566) are administered in the form of lactone. Upon absorption, the lactone ring in the liver is opened by chemical or enzymatic hydrolysis to generate the active hydroxy acid.

Pravastatin (PRAVACHOL; described in U.S. Pat. No. 4,346,227) is administered in the form of the sodium salt. Fluvastatin (LESCOL; described in US Patent 4,739,073) and cerivastatin (described in US Patent Nos. 5,006,530 and 5,177,080), which are also administered in the form of the sodium salt, are fully synthetic compounds that are partially structurally different from fungal derivatives of this class, which contains a hexahydronaphthalene ring. Atorvastatin and two new superstatins, rosuvastatin and pitavastatin, are administered in the form of calcium salts. The structural formulas of these statins are shown below.

Atorvastatin is a trivial chemical name for [A- (R *, R *)] -2- (4-fluorophenyl) -β, 6-dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) acid] (carbonyl) -1 H -pyrrole-1-heptane. Fragrant atorvastatin acid tends to lactonase. The systemic chemical name of atorvastatin lactone is (2R-trans) -5- (4-fluorophenyl) -2- (1-methylethyl) -N, 4-diphenyl-1- [2-tetrahydro-4-hydroxy-6-oxo-2Lf -pyran-2-yl) ethyl] -1H-pyrrole-3-carboxamide. Atorvastatin and the corresponding racemic lactone are described in U.S. Pat. No. 4,681,893.

The lactone form is described in U.S. Patent 5,273,995. In Examples 4 and 5 of the '995 patent, the lactone is prepared by dissolving 1,1-dimethylethyl (R) -4- [2- (4-fluorophenyl) -5- (1-methylethyl) 3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrol-1-yl] -5-hydroxy-3-oxo-1-heptanoate in tetrahydrofuran and triethylborane followed by addition of tert-butyl carboxylic acid. After cooling, methanol is added followed by sodium borohydride. The mixture was poured into an ice / hydrogen peroxide / water mixture. Trichloromethane is added and the mixture is separated. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated. The product was dissolved in tetrahydrofuran and methanol and added to a sodium hydroxide solution. The mixture was concentrated to remove the organic solvent, added to water and extracted with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The residue was dissolved in toluene and concentrated. The product was recrystallized from ethyl acetate and hexane to give the lactone.

The lactone can also be prepared using the procedures described in U.S. Patent No. 5,003,080. For example, in Example 2, Method A, to methyl cis-2- (4-fluorophenyl) 4

-β, 5-dihydroxy-5- (1-methylethyl) -3-phenyl-4- (phenylamino) carbonyl-1 H -pyrrole-1-heptane is treated with sodium hydroxide and after dilution with water and separation, the remaining layer is rinsed with hexane, and ethyl acetate followed by concentration with hydrochloric acid solution. After separation, the upper layer is washed with hydrochloric acid and concentrated. The residue was dissolved in toluene.

As described in the '080 patent, the lactone can also be prepared by mixing (±) -cis-6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetic acid (Example 2, Method B ); (±) - (2α, 4α, 6a) or (±) - (2a, 4β, 6β) -6- (2-aminoethyl) -2-phenyl-1,3-dioxane-4-acetic acid (Example 2, method C); (±) -cis-9- (2-aminoethyl) -6,10-dioxaspiro [4.5] -decane-7-acetic acid (Example 2, Method D); (±) - cis - (4- (2-Aminoethyl) -1,5-dioxaspiro [5.5] undecan-2-acetic acid (Example 2, Method E);

or (±) - (2a, 4a, 6a) or (±) - (2α, 4β, 6β) -6- (2-aminoethyl) -2-methyl-1,3-dioxane-4-acetic acid (Example 2, method F and G) with (±) -4-fluoro-α- [2-methyl-1-oxopropyl] -γ-οχο-β, β-diphenylbenzenebutanamide in dimethylsulfoxide. After heating, the solution is poured into a mixture of diethyl ether and saturated ammonium chloride in water. After separation, the organic layer is washed with water and sodium hydroxide. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate, then hydrochloric acid was added and the solution was concentrated. The residue was dissolved in toluene.

Another method of preparing the lactone of the '080 patent is by mixing (+) - cis-1,1-dimethylethyl-6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate (Example 2, method H); (±) - (2,

4α, 6a) or (±) - (2a, 4β, 6β) -1,1-dimethyl-6- (2-aminoethyl) -2-phenyl-1,3-dioxane-4-acetate (Example 2, Method I ) or (±) cis-1,1-dimethylethyl (4- (2-aminoethyl) -1,5-dioxaspiro [5.5] 5 undecane-2-acetate (Example 2, method J) with (±) -4-fluoro -α- [2-methyl-1-oxopropyl] -γ-οχο-β, β-diphenylbenzene butanamide in heptane / toluene (9: 1) After heating, the solution was poured into a mixture of tetrahydrofuran and ammonium chloride in water. The organic layer was washed with brine, followed by the addition of hydrochloric acid After stirring, sodium hydroxide was added to the organic layer, quenched with water / hexane, separated, the aqueous layer was acidified with dilute hydrochloric acid, extracted with ethyl acetate and concentrated. .

The lactone or the free acid can be used to prepare a pharmaceutically acceptable calcium salt, (2: 1) calcium salt of [R- (R *, R * j] -2- (4-fluorophenyl) -β, 5-dihydroxy-5) acid. - (1-methylethyl) -3-phenyl-4 [(phenylamino) carbonyl] -1R-pyrrole-1-heptane Animal models have shown that atorvastatin calcium reduces plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA Atorvastatin is marketed by PFIZER in the form of the hemi-calcium salt trihydrate under the trade name LIPITOR, in the form of 10mg, 20mg, 40mg and 80mg tablets. The atorvastatin hydrochloride has the following structural formula:

β

This hemi-calcium salt is described in U.S. Pat. No. 5,273,995, which discloses that the calcium salt is obtained by crystallization from a brine solution obtained by transposing the sodium salt with calcium chloride and further purified by recrystallization from a -5: 3 mixture of ethyl acetate and hexane.

U.S. Patent No. 5,298,627 also discloses a process for preparing a hemi-calcium salt. In Example 1 of this patent, (4R-cis) -1- [2- [6- [2- (diphenylamino) -2-oxoethyl] -2,2-dimethyl-1,3-dioxan-4-yl] ethyl ] -5- (4-fluorophenyl) -2- (1-methylethyl) -N, 4-diphenyl-1 H -pyrrole-3-carboxamide is dissolved in methanol and reacted with hydrochloric acid to give [F- *, R *}] - 5- (4-fluorophenyl) -β, δ-dihydroxy-2- (1-methylethyl) -N, N, 4-triphenyl-3 - [(phenylamino) carbonyl] -1 H -pyrrole- The filtrate was rinsed with tert-butyl methyl ester and the aqueous layer was acidified using aqueous hydrochloric acid and extracted with tert-butyl methyl ester to give the sodium salt of [R- (R *, R *)] - 2- (4-Fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrole-1-heptane The sodium salt is converted to the hemicalcium salt by adding calcium acetate in water.

In an analogous manner, (4R-cis) -6- (2-aminoethyl) -2,2-dimethyl-N ' _from N-bis (phenylmethyl) -1,3-dicxane-4-acetamide is converted to [R- (R) *, R *)] - 5- (4-fluorophenyl) -β, 5-dihydroxy-2- (1-methylethyl) -4-phenyl-3 - [(phenylamino) carbonyl] -7,2,2'-bis ( phenylmethyl) -1H-pyrrole-1-heptanamide, which is further converted to the hemicalcium salt (Example 2); (4R-cis) -6- (2-aminoethyl) -N, N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide is converted to [R- (R * _Z R *)] - N, N-diethyl-5- (4-fluorophenyl-β, 5-dihydroxy-2- (1-methylethyl) -4-phenyl-3 - [(phenylamino) carbonyl] -4-pyrrole-1-heptanamide (4R-cis) -6- (2-aminoethyl) -N-butyl-N, 2,2-trimethyl-1,3-dioxane-4-acetamide is converted to [R] - (R *, R *)] - N-butyl-5- (4-fluorophenyl) -1-dihydroxy-N-methyl-2- (1-methylethyl) -4-phenyl-3 - [(phenylamino) carbonyl] -1H-pyrrole-1-heptanamide, which is further converted to the hemicalcium salt (Example 4); (4R-cis) -6- (2-aminoethyl) -N- (1,1-dimethylethyl) -2,2-dimethyl N - (phenylmethyl) -1,3-dioxane-4-acetamide is converted to [R- (R * _Z R *)] - N- (1,1- (dimethylethyl) -5- (4-fluorophenyl) - β, δ-dihydroxy-2- (1-methylethyl) -4-phenyl-3 - [(phenylamino) carbonyl] -N- (phenylmethyl) -4-pyrrole-1-heptanamide, which is further converted to the hemicalcium salt (example And (4R-cis) -1 - [[6- (2-aminoethyl) -2,2-dimethyl-1,3-diox-4-yl] acetyl] piperidine is converted to [R- (R *)]. _From R *)] - 1- [ 3,5-dihydroxy-7-oxo-7- (1-piperidinyl) heptyl] -5- (4-fluorophenyl-2- (1-methylethyl) -4-diphenyl-1H-pyrrole-3-carboxamide, which is further converted to the hemicalcium salt (Example 6).

Rosuvastatin is a trivial chemical name for [S- [R *, S * - (R)]] - 7- [4- (4-fluorophenyl) -6- (1-methylethyl) -2- [methyl (methylsulfonyl) amino] ] -5-pyrimidinyl] -3,5-dihydroxy-6-heptenoic. Rosuvastatin is in the process of being approved for the manufacture of a medicinal product marketed under the trade name CRESTOR, which contains rosuvastatin calcium. Rosuvastatin, its calcium salt (2: 1) and its lactone form are described and claimed in U.S. Pat. No. 5,260,440. The process of the '440 patent prepares rosuvastatin by introducing 4- (4-fluorophenyl) -6-isopropyl-2- (N- methyl-N-methylsulfonylamino) -5-pyrimidinecarbaldehyde to react with methyl (3R) -3- (tert-butyldimethylsilyloxy) -5-oxo-6-triphenylphosphoranylidene hexanoate in acetonitrile at reflux. The silyl group is then cleaved using hydrogen fluoride and then reduced with NaBH ₄ to give rosuvastatin methyl ester.

The ester is then hydrolyzed with sodium hydroxide in ethanol at room temperature, followed by removal of ethanol and addition of ether to give rosuvastatin sodium. The sodium salt is then converted to the calcium salt using a multi-stage process. The sodium salt is dissolved in water and kept under a nitrogen atmosphere. Calcium chloride is then added to the solution obtained by precipitation of rosuvastatin calcium (2: 1). Thus, the process of the '440 patent prepares rosuvastatin calcium via the sodium salt intermediate.

U.S. Patent No. 6,316,460 discloses a pharmaceutical composition of rosuvastatin.

The pharmaceutical compositions comprise rosuvastatin or a salt thereof and a polyvalent tribasic phosphate salt. The '460 patent does not disclose any salt for the preparation of rosuvastatin calcium.

Of pitavastatin (£) -3,5-dihydroxy-7- [4 '- (4-fluorophenyl) -2 ' cyklopropylchinolin ^3-1-yl] hept-6-enoic acid. Pitavastatin, its calcium salt (2: 1) and its lactone are described in three related patents US 5 011 930, US 5 856 336 and US 5 872 130.

The '930 patent prepares pitavastatin ethyl ester according to Example 1. First, by reaction of 2-amino-4'-fluorobenzophenone with ethylisobutyrylacetate, 4- (4'-fluorophenyl-2'-1'-cyclopropyl) quinolin-3'-yl carboxylate is prepared which is then converted to 4- (4'-fluorophenyl) -3-hydroxymethyl-2- (1'-cyclopropyl) quinoline, which is converted to 4-4'-fluorophenyl-2- (1-cyclopropyl) quinolin-3'-ylcarboxyaldehyde which is converted to 3- (3'-ethoxy-1'-hydroxy-2'-propenyl) -4- (4'-fluorophenyl) -2- (1'-cyclopropyl) quinoline which is converted to (E) -3- [4 '- (4-fluorophenyl) -2' - (1-cyclopropyl) quinolin-3 '+ yl] propenaldehyde, which is converted to ethyl (E) -7- [4- (4-fluorophenyl-2' - ( 1-cyclopropyl) quinolin-3'-yl] -5-hydroxy-3-oxohepto-6-enoate which is converted to ethyl (E) -3,5-dihydroxy-7- [4 '- (4-fluorophenyl)] -2 '- (l-cyclopropyl) -quinolin-3'-yl] hept-6-enoate.

The resulting ester, ethyl (E) -3,5-dihodroxy-7- [4- (4-fluorophenyl) -2 '- (1-cyclopropyl) quinolin-3'-yl] hept-6-enoate, is converted to sodium the salt of Example 2 using an aqueous sodium hydroxide solution. The compound was dissolved in ethanol to which aqueous sodium hydroxide solution was added. The resulting mixture was stirred and the ethanol was removed under reduced pressure. Water was then added and the mixture was further extracted with ether. The aqueous layer is then lyophilized to give the final product, or the aqueous layer is slightly acidified with a dilute hydrochloric acid solution. The acidified aqueous layer is then extracted with ether. After extraction, the ether layer was dried over anhydrous magnesium sulfate. The ether was then removed under reduced pressure to give the sodium salt. The '930 patent and related patents do not disclose the preparation of a calcium salt of any compound.

These patents disclose the preparation of lactone by dissolving the sodium salt prepared in anhydrous toluene, refluxing the solution, and removing toluene under reduced pressure. The crude solid is then recrystallized from diisopropyl ether to give the lactone, [4 '- (4-fluorophenyl) -2' - (1'-methylethyl) quinolin-3'-ylethynyl] -4-hydroxy-3,4,5,6 tetrahydro-2H-pyran-2-one. The lactone is further reduced using palladium / carbon under a nitrogen atmosphere.

U.S. Patent No. 6,335,449 improves prior art processes for preparing pitavastatin by reacting quinoline aldehyde with diethyl cyanomethyl phosphonate to form a nitrile intermediate for the synthesis of pitavastatin. U.S. Patent 6,335,449 does not disclose how to prepare calcium or any other pitavastatin salt.

Simvastatin is the trivial medical name of the chemical compound butanoic acid, 2,2-dimethyl-, 1,2,3,7,8, 8α-hexahydro-3,7-dimethyl-8- [2- (tetrahydro-4-hydroxy-6) oxo-2H-pyran-2-yl) ethyl] -1-naphthalenyl ester, [IS] - [1a, 3a, 7b, 8b- (2S *, 4S), - 8ab]]. (CAS Registry No. 79902-63-9). Simvastatin is marketed under the designation ZOCOR and is described in U.S. Patents 4,444,784 and 6,002,021 as well as in WO 00/53566. These documents describe the preparation of lactone and the open form of simvastatin.

Of these documents, only WO 00/53566 describes the preparation of the calcium salt of the open form of simvastatin. In a typical example, method WO 00/53566 hydrolyzes the simvastatin lactone with sodium hydroxide and then adds a source of calcium, such as calcium acetate hydrate.

None of the aforementioned known processes for producing calcium statin salts, for example atorvastatin, pitavastatin, rosuvastatin and simvastatin, discloses how to prepare a calcium salt or treatment via a sodium salt intermediate. In addition, some processes are highly sensitive, are not consistently reproducible, and have inappropriate filtration and drying properties for large-scale production. In order to obtain a stable product, it is desirable to have fewer steps than previous methods using a process that is easy to reproduce and can be customized for mass production.

SUMMARY OF THE INVENTION

The invention provides novel processes for preparing calcium statin salts having the general formula:

wherein R represents an organic radical, wherein in this method the statin ester derivative is selected from the group consisting of:

contacting a sufficient amount of calcium hydroxide, wherein R ¹ is an alkyl group having 1 to 8 carbon atoms, and

R ² , R ³ and R ⁴ each independently represent a hydrogen atom, or the same or different hydrolysable protecting group, or R ² and R ³ together with the oxygen atom to which they are attached form a hydrolyzable cyclic protecting group.

The reaction may be carried out in the presence or absence of a phase transfer catalyst. Preferred phase transfer catalysts are quaternary ammonium salts, for example tetrabutylammonium bromide (TBAB) and triethylbenzylammonium chloride (TEBA). Heating of the reaction mixture is preferred to accelerate the reaction.

Preferred statins are atorvastatin, rosuvastatin, pitavastatin and simvastatin. In a preferred embodiment, R @ ^2, R ³ and R ⁴ are hydrogen. Each of R ² , R ³ or R ⁴ may also mean the same or different protecting group which is subsequently hydrolyzed using calcium hydroxide in one step together with hydrolysis of the ester group, i. -COOR ¹ , or is hydrolyzed using an acid catalyst followed by hydrolysis of the -COOR ¹ ester group. Preferred protecting groups are silyl groups, for example a trialkylsilyl group which can be hydrolyzed with calcium hydroxide, and acetonide which can be hydrolyzed with an acid catalyst. Acetone forms a cyclic hydrolyzable protecting group, i. dioxane.

In another aspect, the invention provides methods for preparing a statin calcium salt having the general formula:

OH OH O

OH wherein R represents an organic radical, wherein in carrying out this process:

calcium hydroxide and the statin ester derivative described above are added to a mixture of water and an alcohol having 1 to 4 carbon atoms, the mixture is heated, the statin calcium salt precipitates and the calcium salt is separated.

Formation of the ester is a known method of protecting a carboxylic acid-derived group and masking its acidic proton. Green, T.W .; Wuts, P. G. M. Protective Groups in Organic Synthesis 3rd ed., Chapter 5 (John Wiley & Sons: New York 1999) (Greene & Wuts). It is also well known that carboxylic acids which have been protected as esters can be deprotected by ester hydrolysis with a strong base. Id. at 377-78.

Sodium hydroxide is a strong base with a dissociation constant of 6.37 (ρΚ · _ο = -0.80), Handbook of Chemistry and Physics 81. ed. 8-45 (CRC Press: Boca Raton 2000-01), and its use as a reagent for deprotecting ester protected carboxylic acids is described in the prior art. Green & Wuts, p. 377. Calcium hydroxide [(Ca (OH) 2], with a first dissociation constant of 3.74-10 ^-3 (pKb = 2.43) and a second dissociation constant of 4.0-10 ^-2 (pKb = 1.40), is much a weaker base than sodium hydroxide Handbook of Chemistry and Physics 63rd ed. D-170 (CRC Press: Boca Raton 1983).

Calcium hydroxide is not on the list of reagents that are used to hydrolyse esters in the well-known overview of functional group transformations in organic syntheses. Larock R. C. Comprehensive Organic Transformations 2nd ed., Section NITRILES, CARBOXYLIC ACIDS AND DERIVATIVES, Subsect. 9.17, p. 1959-68 (Wiley-VCH: New York 1999). The use as a reagent for deprotecting ester protected carboxylic acids is not described in a known book referring to methods of protecting and deprotecting organic functional groups. Greene & Wuts. p. 377-79. In fact, U.S. Pat. No. 5,273,995 warns against the use of excess sodium hydroxide in the preparation of the sodium salt, as it could hinder the formation of calcium hydroxide in the event of the later addition of calcium chloride to the sodium salt solution. It does not appear likely that ester-protected forms of statins, such as atorvastatin, can be converted directly to the respective hemi-calcium salts such as gambling atorvastatin calcium without prior treatment of the ester with a strong base such as sodium hydroxide which hydrolyzes them and subsequent displacement of sodium ions by contacting the sodium salt with a calcium salt such as calcium chloride or calcium acetate.

As used herein, an ester derivative is a compound obtained by replacing a hydroxyl proton in a carboxylic acid group in the form of an open ring statin or a statin with a dihydroxy acid substituent attached to a hydroxyl oxygen atom through a carbon atom. Such ester derivatives include e.g. compounds in which the substituent attached to the hydroxyl oxygen of the carboxylic acid is an alkyl group having 1 to 8 carbon atoms. The ester derivative used for the conversion may be a mixture of derivatives containing different esters. For example, a methyl ester derivative can be added to ethanol, resulting in the conversion of a portion of the methyl esters to the ethyl esters. The statin ester derivative can be prepared by methods known in the art or can be purchased from commercial sources. The ester derivative also includes the lactone form of the statin or the ring-closed statin form. The lactone form is a cyclic ester in which a statin ester group is incorporated into a ring. The ester derivative mixture also includes a mixture of open and closed ring statins.

The invention relates to a statin having the general formula:

OH wherein the organic radical R is attached to a diolpentanoic acid group. These statins include, e.g. pravastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin, pitavastatin, lovastatin and simvastatin. Of these, atorvastatin, rosuvastatin, pitavastatin and simvastatin are preferred.

R denotes an organic radical which is attached to the diolpentanoic acid group. Depending on the particular statin, the R radical may mean:

pravastatin: 1,2,6,7,8,8a-hexahydro-6-hydroxy-2-methyl-8- (2-methyl-1-oxobutoxy) -1-naphthalomethyl radical;

fluvastatin: 3- (4-fluorophenyl) -1- (1-methylethyl) -1 H -indol-2-yl] ethylene radical;

cerivastatin: 4- (4-fluorophenyl) -5-methoxymethyl) -2,6-bis (1-methylethyl) -3-pyridinylethylene radical;

atorvastatin: 2- (4-fluorophenyl) -5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyroletyl radical;

rosuvastatin: [4- (4-fluorophenyl) -6- (1-methylethyl) -2- [methyl (methylsulfonyl) amino] -5-pyrimidinyl] ethylene radical;

pitavastatin: [4 '- (4'-fluorophenyl) -2'-cyclopropylquinolin-3'-yl] ethylene radical.

The R radical may also be an open ring radical, i. dihydroxy acid, simvastatin or lovastatin. These open ring forms also have a diolpentanoic acid group. The terms simvastatin and lovastatin as used herein include both the lactone form and the open ring form. When the statin is simvastatin or lovastatin, then the R radical is:

simvastatin: 1,2,6,7,8,8a-hexahydro-2,6-dimethyl-8- (2,2-dimethyl-1-oxobutoxy) -1-naphthalomethyl radical.

lovastatin: 1,2,6,7,8,5a-hexahydro-2,6-dimethyl-1- 8- (2-methyl-1-oxobutoxy) -1-naphthalomethyl radical.

The calcium salt of these and other statins can be prepared by the methods of the invention such that the organic radical attached to the diolpentanoic acid group or the corresponding lactone defines a statin compound, i. a compound that inhibits the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase enzyme. See, for example, WO 00/53566. Thus, the meaning of R should not be limited to the organic radical attached to the diolpentanoic acid group or to the corresponding lactone statins explicitly described or exemplified herein. The invention includes all hydrates, solvates and anhydrous forms of the calcium salt and other polymorphic forms, crystalline or amorphous, of these statins.

The invention illustrates the preparation of a calcium salt of these statins, for example, for the preparation of atorvastatin hemi-calcium salt. As regards the fact that the subject matter of the invention for the preparation of atorvastatin hemi-calcium salt differs from the preparation of another statin, it will be apparent to those skilled in the art that atorvastatin is used for illustrative purposes only; and that various aspects of the preparation of the atorvastatin hemi-calcium salt are readily modified in the preparation of other statins, and such modifications will be within the scope of the invention.

The invention provides processes for preparing a statin hemi-calcium salt by converting a statin ester derivative of the formula:

OH OH · O

or

OH wherein R represents an organic radical and R ¹ represents an alkyl group having 1 to 8 carbon atoms, to the corresponding hemicalcium salt having the general formula:

OH OH O

ca

2+

contacting the ester derivative with a sufficient amount of calcium hydroxide. A sufficient amount as used herein refers to the amount of calcium hydroxide that sufficiently converts the ester derivative to the corresponding hemi-calcium salt. By sufficiently converted as used herein is meant an amount that is greater than about 50% (mole), preferably greater than about 70%, and more preferably greater than about 90%, of the statin ester derivative and this amount is converted to the corresponding casino. calcium salt. Most preferably, more than about 95% of the statin ester derivative is converted to the corresponding gambling calcium salt.

An unexpected advantage of this method is that calcium hydroxide has two roles. It acts as a basic catalyst for ester hydrolysis and delivers calcium ions to form the hemi-calcium salt. Another important practical advantage of this method is that the amount of calcium hydroxide need not be as strictly controlled as the amount of sodium hydroxide and calcium chloride / acetate used in other processes which, unlike the method of the invention, involve a stepwise method of hydrolyzing the ester derivative NaOH followed by displacement of sodium ions with calcium ions.

The ester statin derivative may be provided in pure form or in admixture with other statin ester derivatives. The statin ester derivative, optionally in admixture with other statin ester derivatives, is dissolved or suspended, preferably in a mixed solvent containing a C 1 -C 4 alcohol and water. Preferred alcohols are ethanol and isopropyl alcohol (IPA), and a preferred solvent mixture comprises about 5% to about 15% water in ethanol or IPA, more preferably about 10% water and about 90% ethanol (v / v) or IPA. Whether the statin ester derivative dissolves in a mixed solvent depends on such factors as the choice of the C 1 -C 4 alcohol, the water content, temperature and purity of the statin ester derivative. The calcium hydroxide is then suspended in the solvent and the basic hydrolysis reaction mixture is maintained until the ester derivative is consumed. The consumption of the statin ester derivative can be monitored by any conventional method, such as TLC, HPLC, and NMR. After the statin ester derivative is consumed, the statin hemicalcium salt is isolated from the basic hydrolysis reaction mixture by conventional means. Adding an additional source of calcium to provide the Ca ²⁺ ion of atorvastatin hemi-calcium is not necessary.

According to a preferred embodiment, a base hydrolysis method, the statin ester derivative is added in an amount sufficient to provide about 10 mmol.l ^-1 to about 1 mol. I ^'1 mixed solvent.

Preferably, about 1 equivalent to about 6 equivalents of calcium hydroxide, based on 1 equivalent of the ester derivative, is used. More preferably, from about 1 to about 2 equivalents are used.

Calcium hydroxide is only sparingly soluble in a mixed solvent of a C 1 -C 4 alcohol and water, and only a small fraction will be available in solution for catalytic hydrolysis at any point in time. To accelerate basic hydrolysis, a phase transfer catalyst may be added to increase the solubility of calcium hydroxide. Phase transfer catalysts are known in the art and include, for example, tetra-n-butylammonium bromide (TBAB), benzyltriethyl ammonium chloride (TEBA). ammonium tetramethyl n-butyl chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, ammonium tetraethyl chloride, ammonium benzyltributyl chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, ammonium tetramethyl chloride and polyethylene. The most preferred phase transfer catalyst is TBAB. In use, the phase transfer catalyst should be used in a substoichiometric amount, preferably from about 0.05 equivalents to about 0.25 equivalents, more preferably about 0.1 equivalents, based on the statin ester derivative.

To accelerate the reaction, the mixture can be heated to the reflux temperature of the mixed solvent. The preferred elevated temperature range is from about 40 ° C to about 70 ° C.

After depletion of the statin ester derivative, the statin hemi-calcium salt or solvate thereof is isolated from a basic hydrolysis reaction mixture. As part of the isolated hemi-calcium statin salt, the reaction mixture is preferably filtered to remove excess suspended calcium hydroxide. The reaction mixture is preferably hot filtered to prevent precipitation of the statin-hemi-calcium salt on the calcium hydroxide filter cake.

After filtration to remove suspended calcium hydroxide, the statin hemicalcium salt can be isolated from the filtrate by precipitation. According to a preferred isolation technique, precipitation of the statin hemi-calcium salt from the filtrate is induced by the gradual addition of water. A volume of water roughly equal to the volume of the filtrate is added over a few hours. Preferably, the gradual addition of water is also carried out at elevated temperature, e.g. from about 40 ° C to about 65'C. Precipitation of the statin hemi-calcium salt by the gradual addition of water gave the statin hemi-calcium salt in crystalline form and prevents the formation of a gelatinous precipitate. Alternatively, the statin hemicalcium salt can be isolated by conventional means. After all the necessary purification steps, the isolated hemicalcium statin salt can be used as an active ingredient to formulate a pharmaceutical product.

The filtration characteristics and purity of the statin mercapto salt can be further improved by redissolving the crystalline product in a reaction mixture of water and alcohol by warming the mixture to a temperature sufficient to dissolve the entire precipitate and obtain a clear solution. The solution is preferably slowly cooled and maintained over a few hours, preferably at room temperature, until formation of multiple crystals is observed. After filtration and drying, and all other optional purification steps, the hemicalcium salt of the statin or solvate thereof can be used as an active ingredient in a pharmaceutical product.

Statins are sometimes prepared through an intermediate in which one or both of the hydroxyl groups in the diolpentanoic acid group (open ring form) or the hydroxyl group of the lactone (ring closed form) are protected by a hydrolyzable protecting group and the carboxyl group is protected via an ester derivative as described up. For example, U.S. Pat. No. 5,260,440, incorporated herein by reference, uses a silyl protecting group during the synthesis of rosuvastatin. U.S. Patent Nos. 6,002,021 and 4,444,784, incorporated herein by reference, use a silyl protecting group during the synthesis of simvastatin. Brower, PL et al. Tet. Lett. 1992, 33, 2279-82 and Baumann, KL et al. Tet. Lett. 1992, 33, 2283-2284, incorporated herein by reference, prepare atorvastatin via a dioxane intermediate having an acetonide protecting group, i. R ² and R ³ together with the oxygen atom to which they are attached form a hydrolyzable cyclic protecting group.

These compounds, referred to herein as protected ester derivatives of statins, can be converted according to the invention into the corresponding hemicalcium salt. Thus, in a further embodiment, the invention relates to processes for preparing a statin calcium salt having the general formula:

OH OH O

OH wherein R represents an organic radical which comprises providing a statin derivative ester selected from the group consisting of:

or * Or ^{3 λ} o

in contact with a sufficient amount of calcium hydroxide, wherein R ¹ is an alkyl group having 1 to 8 carbon atoms, and R ² , R ³ and R ⁴ each independently represent a hydrogen atom or the same or different hydrolysable protecting group, or R ² and R ³ , together with the oxygen atom to which they are attached form a hydrolyzable cyclic protecting group. The protecting group used is preferably hydrolysable under acidic or basic conditions. Preferred protecting groups R ² , R ³ and R ⁴ of this embodiment of the invention include, for example, silyl groups, with trialkylsilyl and alkyldiarylsilyl being more preferred, and tert-butyldimethylsilyl being most preferred; and a cyclic protecting group such as R ² and R ³ is, for example, a dioxane group.

U.S. Patent No. 6,294,680, incorporated herein by reference, discloses other protecting groups used in the synthesis of statins, particularly simvastatin. The disclosed cyclic protecting groups include dioxane, cyclic sulfate, cyclic phosphate, or borylidene, which are optionally substituted with an alkyl and aryl group. Other protecting groups including boric acid are described in WO 95/13283, incorporated herein by reference, and esterification with acetic anhydride is described in U.S. Patent 5,159,104, incorporated herein by reference. U.S. Patent 6,100,407, incorporated herein by reference, discloses additional protecting groups. The protecting groups described in these documents can be used in the methods of the invention.

Surprisingly, it has been found that the silyl group can be hydrolyzed and removed by contact with calcium hydroxide. Thus, the use of a silyl group allows the deprotection and ester conversion to the calcium salt to be carried out in a single step, in the same solvent. The use of calcium hydroxide eliminates the need for a separation step in the acid hydrolysis of a silyl protecting group, for example with hydrogen halide such as hydrogen fluoride, to remove the protecting group required by the methods of U.S. Patent No. 5,260,440 and U.S. Patent 4,444,784. applied to any statin with silyl or other protecting groups R ² , R ³ and R ⁴ capable of hydrolysis with calcium hydroxide. The protected rosuvastatin disclosed in U.S. Pat. No. 5,260,440 is possible e.g. use of a modification of reducing the ketone to give hydrogen as R ^2nd It is also possible to use the silyl-protected simvastatin disclosed in U.S. Patents 4,444,784 and 6,002,021.

Some of the protecting groups are best hydrolyzed under acidic conditions. Thus, an acid catalyst is added prior to contacting the protected statin derivative with calcium hydroxide, resulting in hydrolysis of the protecting group. Examples of such acid catalysts include acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, zinc bromide, and hydrochloric acid or other hydrogen halide, with acetic acid and hydrochloric acid being preferred. The resulting diol ester is then converted to the calcium salt by contacting it with calcium hydroxide. This method can also be carried out in a single container. The diol ester is prepared as described above and then reacted with calcium hydroxide to form atorvastatin hemi-calcium salt in the same vessel without changing the solvents. A preferred solvent is a mixture of water and an alcohol of up to 4 carbon atoms, with ethanol being the preferred alcohol. Preferably, the pH of the reaction is less than about 3, more preferably less than about 1.

A preferred protecting group which is removed by means of an acid catalyst is acetonide, i. a compound wherein the diol forms a cyclic hydrolyzable protecting group, i. dioxane. Preferably, any acetone formed during the reaction of the acetonide with the acid catalyst is removed, e.g. evaporation under reduced pressure.

Now, a single vessel process using an acid catalyst will be described:

Cmorej)

Atorvastatin o-calcium salt of o

The pharmaceutical compositions may be formulated as medicaments for oral, parenteral, rectal, transdermal, buccal or nasal administration. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, capsules, hard or gelatin capsules, sublingual tablets, syrups and suspensions. Suitable forms for parenteral administration include aqueous or non-aqueous solutions or emulsions, while suitable forms for rectal administration include suppositories with a hydrophilic or hydrophobic vehicle. For topical administration, the invention provides suitable transdermal delivery systems known in the art, and for nasal delivery provides suitable aerosol delivery systems known in the art.

The pharmaceutical compositions of the invention comprise a statin hemi-calcium salt, in particular atorvastatin hemi-calcium, rosuvastatin hemi-calcium, pitavastatin hemi-calcium, simvastatin hemi-calcium, and lovastatin hemi-calcium. In addition to the active ingredient (s), the pharmaceutical compositions of the invention may contain one or more excipients. The choice of suitable excipients and amount for use can be readily determined by one of ordinary skill in the formulation of pharmaceutical compositions based on experience and consideration of standard procedures and on the basis of reference work in the art. U.S. Patent No. 6,316,460, incorporated herein by reference, and the latest edition of the Handbook of Pharmaceutical Excipients of the American Pharmaceutical Association can be used as a guide. Dosage and formulation of LIPITOR (atorvastatin hemi-calcium) and other pharmaceuticals can also be used as a guide.

DETAILED DESCRIPTION OF THE INVENTION

Generally

Unless otherwise specified, the reagents were used as received.

[R- (R *, R *)] - 2- (4-fluorophenyl) -β, δ-dioxane-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1R -pyrrole-1-tert-butylheptane (dioxane 2, R ¹ = tert-butyl) was prepared by a condensation reaction between the corresponding diketone and the corresponding chiral amine resulting in the formation of the pyrrole ring. It can also be prepared by known methods. Brower, PL et al. Tet. Lett. 1992, 33, 2279-82; Baumann, KL et al. Tet. Lett. 1992, 33, 2283-84. The following HPLC conditions were used to determine the composition of the acid hydrolysis mixtures in the examples: Waters Spherisorb S3 ODS1 (7.6 x 100 mm), 70:30 acetonitrile: water, 0.6 mL • min ^-1 , 20μ1 sample, UV detection γ = 254.

Example 1

Preparation of atorvastatin calcium from dioxane ester derivative

In a flask equipped with a magnetic stirrer, [R- (R *, R * j] -2- (4-fluorophenyl) -β, 5-dioxane-5- (1-methylethyl) -3-phenyl-4 - [( phenylamino) carbonyl] -1R-pyrrole-1-tert-butylheptanoic acid (2.0 g) was suspended in 80% aqueous acetic acid (50 mL) and the mixture was stirred at room temperature for about 20 h until a clear solution was obtained. the solution was evaporated to dryness and traces of acetic acid were removed by azeotropic distillation with toluene (3 x 50 mL) to give a powder.

The above powder (200 mg, 0.32-10 ^-3 mol) was dissolved in ethanol (8 mL) to which was added saturated calcium hydroxide solution (8 mL) containing tetrabutylammonium bromide (10 mg). The mixture was stirred and heated to about 45 ° C for about 24 h. Additional saturated calcium hydroxide solution (4 mL) was added. After stirring at room temperature for about 20 minutes, the reaction was complete. The purity of the resulting product was analyzed by HPLC. The white precipitate was filtered off under vacuum and dried at about 65 ° C for about 18 h. After drying, 77% yield of atorvastatin calcium (142 mg) was obtained.

Example 2

Preparation of atorvastatin calcium from dioxane ester derivative

In a flask equipped with a magnetic stirrer, [R- (E *, E *)] - 2- (4-fluorophenyl) -β, 5-dioxane-5- (1-methylethyl) -3-phenyl-4 - [( phenylamino) carbonyl] -1H-pyrrole-1-tert-butylheptanoic acid (10.0 g, 15.29-10 ^-3 mmol) was suspended in 80% aqueous acetic acid (150 mL). The mixture was stirred overnight at room temperature until a clear solution was obtained. The clear solution was evaporated and traces of acetic acid were removed by azeotropic distillation with toluene (3 x 100 mL) to give an oily product containing toluene.

The oily product was introduced into a mixture of ethanol (100 mL) and water (20 mL). A mixture of calcium hydroxide (5.5 eq., 6.22 g, 84.0-10 ^-3 mmol) and 5% (w / w dioxane ester derivative) tetrabutylammonium bromide (0.46 g) was added. The mixture was heated to about 45 ° C for about 3 h until the reaction was complete. The still hot mixture was filtered under vacuum to remove excess calcium hydroxide. The mixture was then cooled to room temperature and then water (200 mL) was added with stirring. After stirring at room temperature for about 20 minutes, the reaction was complete. The purity of the resulting product was analyzed by HPLC. The white precipitate was filtered under vacuum and dried at about 65 ° C for about 18 h. After drying, 84% yield of atorvastatin calcium (7.44 g) was obtained.

Example 3

Preparation of atorvastatin lactone from dioxane ester derivative

In a flask equipped with a magnetic stirrer, (R- (R *, R *)] -2- (4-fluorophenyl) -β, 5-dioxane-5- (1-methylethyl) -3-phenyl-4 - [( phenylamino) carbonyl] -1R-pyrrole-1-tert-butylheptanoic acid (0.5 g, 0.76-10 ^-3 mmol) was dissolved in a 1: 1 mixture of trifluoroacetic acid and tetrahydrofuran (4 mL) in the presence of a catalytic amount of water. The mixture was stirred at room temperature for about 24 h. The obtained solution was evaporated and traces of trifluoroacetic acid were removed by azeotropic distillation with ether (3 x 10 mL) to give a white solid (0.3 g). the substance is a 40:60 mixture of atorvastatin and atorvastatin lactone.

Example 4

Preparation of atorvastatin lactone from dioxane ester derivative

In a flask equipped with a magnetic stirrer, [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dioxane-5- (1-methylethyl) -3-phenyl-4 - [( phenylamino) carbonyl] -lH-pyrrole-1-tert-butylheptanoic ester (0.2 g, 0.30 * 10 ³ mmol) and zinc bromide (3.5 eq., l, 07-10 ^"3 mol) dissolved in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for about 24 h. Water (30 mL) was added and the mixture was stirred for about 3 h. The aqueous layer was extracted with dichloromethane (3 x 10 mL), while the organic layer was dried over anhydrous sodium sulfate and filtered. The organic layer was then evaporated under reduced pressure to give the title product (150 mg). HPLC analysis showed the resulting product to be a 57:43 mixture of atorvastatin and atorvastatin lactone.

Example 5

Preparation of atorvastatin lactone from dioxane ester derivative

In a flask equipped with a magnetic stirrer, [JR- (R *, R *)] -2- (4-fluorophenyl) -β, 5-dioxane-5- (1-methylethyl) -3-phenyl-4 - [( phenylamino) carbonyl] -1R-pyrrole-1-tert-butylheptagic acid (0.2 g) was suspended in 90% aqueous acetic acid (4 mL). The mixture was stirred at about 50 ° C for about 5 days. The resulting solution was evaporated to dryness and traces of acetic acid were removed by azeotropic distillation with toluene (3 x 15 mL) to give a powder. HPLC analysis showed that the product was a 54:46 mixture of atorvastatin and atorvastatin lactone.

Example 6

Preparation of atorvastatin lactone from dioxane ester derivative

In a flask equipped with a magnetic stirrer, a 3% aqueous hydrochloric acid solution (1 mL) and [R- (R *, R *)] -2- (4-fluorophenyl) -β, 6-dioxane-5- (1- methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrole-1-tert-butylheptanoic acid (0.2 g) was dissolved in methanol (2 mL). The mixture was stirred at about 110 ° C for about 4 h and then stirred overnight at room temperature. The resulting solution was evaporated to dryness to give a powder. HPLC analysis showed that the powder was a 54:46 mixture of atorvastatin and atorvastatin lactone.

Example 7

Preparation of calcium form of rosuvastatin from ester derivative

In a flask equipped with a magnetic stirrer, methyl 7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -pyrimidin-5-yl] - (3R, 5S) -dihydroxy- ( E) -6-heptenoate was dissolved in ethanol to which a saturated calcium hydroxide solution containing 5% (w / w ester ester) tetrabutylammonium bromide was added. The mixture was stirred and heated to about 45 ° C for about 24 h. Additional saturated calcium hydroxide solution was added. After stirring for about 20 minutes at room temperature, the reaction was complete and rosuvastatin calcium was obtained.

Example 8

Preparation of calcium form of rosuvastatin from ester derivative

In a flask equipped with a magnetic stirrer, methyl 7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -pyrimidin-5-yl] - (3R, 5S) -dihydroxy- { E) -6-heptenoate was placed in a mixture of ethanol and water. A mixture of calcium hydroxide and 5% (w / w ester ester) tetrabutylammonium bromide was added. The mixture was heated to about 45 ° C for about 3 h until the reaction was complete. The still hot mixture was filtered under vacuum to remove excess calcium hydroxide. After stirring at room temperature for about 20 minutes, the reaction was complete and rosuvastatin calcium was obtained.

Example 9

Preparation of the calcium form of pitavastatin from an ester derivative

In a flask equipped with a magnetic stir bar, ethyl (E) -3,5-dihydroxy-7- [4 '- (4-fluorophenyl) -2'-cyclopropylquinolin-3'-yl] hept-6-enoate was dissolved in ethanol to which saturated calcium hydroxide solution containing 5% (w / w ester derivative) tetrabutylammonium bromide was added. The mixture was stirred and heated to about 45 ° C for about 24 h. Additional saturated calcium hydroxide solution was added. After stirring at room temperature for about 20 minutes, the reaction was complete and pitavastatin calcium was obtained.

Example 10

Preparation of the calcium form of pitavastatin from an ester derivative

In a flask equipped with a magnetic stirrer, ethyl (E) -3,5-dihydroxy-7- [4 '- (4-fluorophenyl) -2'-cyclopropylquinolin-3'-yl] hept-6-enoate was placed in a mixture of ethanol and water. . A mixture of calcium hydroxide and 5% (w / w ester ester) tetrabutylammonium bromide was added. The mixture was heated to about 45 ° C for about 3 h until the reaction was complete. The still hot mixture was filtered under vacuum to remove calcium hydroxide. The mixture was then cooled to room temperature and water was added with stirring. After stirring at room temperature for about 20 minutes, the reaction was complete and pitavastatin calcium was obtained.

It is to be understood that the above exemplary embodiments are illustrative only and in no way limit the scope of the invention as defined by the appended claims.

they do not include a detailed description of conventional methods to those skilled in the art, unambiguously Examples which are known in the art and are described in a number of publications. The contents of all documents mentioned herein are incorporated herein by reference.

Claims (26)

A process for preparing a calcium salt of a statin having the general formula: wherein R represents an organic radical, characterized in that the statin ester derivative is selected from the group consisting of: contact with sufficient calcium hydroxide, where R ¹ represents an alkyl group having 1 to 8 carbon atoms and R ² , R ³ and R ⁴ each independently represent a hydrogen atom or the same or different hydrolysable protecting group, or R ² and R ³ together with the oxygen atom to which they are attached form a hydrolyzable cyclic protecting group. The method of claim 1, wherein R is an organic radical derived from a statin selected from the group consisting of pravastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin, pitavastatin, simvastatin and lovastatin. The method of claim 2, wherein the statin is selected from the group consisting of atorvastatin, rosuvastatin, pitavastatin, and simvastatin. 4. The method of claim 3, wherein the statin is rosuvastatin. The method of claim 3, wherein the statin is pitavastatin. The method of claim 3, wherein the statin is simvastatin. The method of claim 3, wherein the statin is atorvastatin. Process according to Claim 1, characterized in that it is carried out in a mixture of water and an alcohol having 1 to 4 carbon atoms. The method of claim 1, wherein the contacting is carried out at an elevated temperature. The method of claim 1, wherein the contacting is carried out in the presence of a phase transfer catalyst. The method of claim 1, further comprising the step of isolating the statin calcium salt. 12. The process according to claim 1, characterized in that R ² and R ³ are hydrogen. The process of claim 1 wherein R ⁴ is hydrogen. 14. The process according to claim 1, characterized in that at least one of ^R2 and ^R3 is a trialkylsilyl protecting group. 15. The method according to claim 1, characterized in that R ⁴ is a trialkylsilyl protecting group. The process of claim 1, further comprising the preliminary step of contacting the ester derivative when the ester derivative has at least one protecting group with an acid catalyst to hydrolyze the protecting group. 17. The method of claim 16, wherein the ester derivative has the general formula: R ' 18. The method of claim 17 wherein R is an atorvastatin-derived organic radical. 19. A pharmaceutical composition comprising a statin salt prepared by the method of claim 1 and a pharmaceutically acceptable excipient. 20. A process for the preparation of rosuvastatin calcium, which comprises providing an ester of 1-8 carbon atoms of 7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidine- 5-yl] - (3R, 5S) -dihydroxy- (E) -6-heptenoate in contact with a sufficient amount of calcium hydroxide. 21. A process for the preparation of rosuvastatin calcium, which comprises contacting the lactone form of rosuvastatin with a sufficient amount of calcium hydroxide. A process for the preparation of pitavastatin calcium, wherein the ester has from 1 to 8 carbon atoms (E) -3,5-dihodroxy-7- [4 '- (4-fluorophenyl) -2' - (1-cyclopropyl) (quinolin-3'-yl) -hept-6-enoate is contacted with a sufficient amount of calcium hydroxide. 23. A process for the preparation of pitavastatin calcium, which comprises contacting the lacton form of pitavastatin with a sufficient amount of calcium hydroxide. 24. Method of preparation general formula: calcium salt of a statin having OH ΟΗ _; O where R represents an organic radical, includes: (a) adding calcium hydroxide and a statin ester derivative selected from the group consisting of: OÉ * OÍČ Ó a into a mixture of water and an alcohol having 1 to 4 carbon atoms, wherein R ¹ represents an alkyl group having 1 to 8 carbon atoms and R ² , R ³ and R ⁴ each independently represent a hydrogen atom or the same or different hydrolysable protecting group, or R ² and R ³ together with the oxygen atom to which they are attached form a hydrolyzable cyclic protecting group; b) heating the mixture; c) precipitation of the statin calcium salt; and d) separating the calcium salt. 25. The method of claim 24, wherein R is an organic radical derived from a statin selected from the group consisting of pravastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin, pitavastatin, simvastatin and lovastatin. 26. The method of claim 25, wherein the statin is selected from the group consisting of atorvastatin, rosuvastatin, pitavastatin, and simvastatin. 27th statin The method of claim is rosuvastatin. 2 6, indicate the by that 28th statin The method of claim is pitavastatin. 26, characterized by the by that 29th statin The method of claim is simvastatin. 26, characterized by the by that 30th statin The method of claim is atorvastatin. 26, characterized by the by that 31st The method of claim 24, characterized by because of R ² R ³ is also a hydrogen atom. 32. The method according to claim 24, characterized in that R ⁴ is hydrogen. 33. The method according to claim 24, characterized in that at least one of ^R2 or ^R3 is a trialkylsilyl protecting group. 34. The method according to claim 24, characterized in that R ⁴ is a trialkylsilyl protecting group. 35. The method of claim 24, further comprising the step of contacting an ester derivative having at least one protecting group with an acid catalyst to hydrolyze the protecting group. The method of claim 35, wherein the ester derivative has the general formula: 37. The process of claim 36 wherein R is an atorvastatin-derived organic radical. 38. The method of claim 24, wherein the water / alcohol mixture is about 5% to about 20% water / alcohol (v / v). 39. The process of claim 24, further comprising adding a phase transfer catalyst to the mixture in step (a). The method of claim 24, wherein the mixture is heated to about 40 ° C to about 70 ° C. 41. The method of claim 24, comprising the filtration step between steps (b) and (c). 42. The method of claim 24, wherein the precipitation is accomplished by adding water. that is