JP4188826B2 - Method for producing calcium salt type statin - Google Patents

Description

Cross-reference to related applicationsThis application takes advantage of provisional application No. 60 / 312,812 filed August 16, 2001, and provisional application No. 60 / 249,319 filed November 16, 2000. Alleged benefit of U.S. Pat. No. 10 / 037,412 filed Oct. 24, 2001, which is hereby incorporated by reference herein in its entirety.

The present invention relates to a method for producing calcium salt type statins.

Background of the Invention A class of drugs called statins is currently the most therapeutic drug available to reduce the low density lipoprotein (LDL) particle concentration in the bloodstream of patients at high risk of heart disease Therefore, statins are used for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. High levels of LDL in the bloodstream interfere with blood flow and are associated with the formation of coronary lesions that can tear and promote thrombosis. Goodman and Oilman, The Pharmacological Basis of Therapeutics, page 879 (9th Ed. 1996).

  Statins inhibit human cholesterol biosynthesis by inhibiting the 3-hydroxy-3-methyl-glutaryl coenzyme (“HMG-CoA”) reductase enzyme. HMG-CoA reductase catalyzes the conversion of HMG to mevalonate. It is a step that determines the rate of 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 bloodstream. Reduction of LDL levels in the bloodstream reduces the risk of coronary artery disease. J.A.M.A.1984, 251, 351-74.

  Currently available statins include lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin. Lovastatin (disclosed in US Pat. No. 4,231,938) and simvastatin (ZOCOR; disclosed in US Pat. No. 4,444,784 and WO00 / 53566) are administered in lactone form. After absorption, the lactone ring is opened in the liver by chemical or enzymatic hydrolysis to yield an active hydroxy acid. Pravastatin (PRAVACHOL; disclosed in US Pat. No. 4,346,227) is administered as the sodium salt. Similarly administered as a sodium salt, fluvastatin (LESCOL; disclosed in US Pat. No. 4,739,073) and cerivastatin (disclosed in US Pat. Nos. 5,006,530 and 5,177,080) are available in the hexahydronaphthalene ring. It is a completely synthetic compound that is partially structurally different from this class of fungal derivatives. Atorvastatin and two new “superstatins”, rosuvastatin and pitavastatin, are administered as calcium salts. The structural formulas of these statins are shown below.

Atorvastatin is [R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) Carbonyl] -1H-pyrrole-1-heptanoic acid is a common chemical name. The free acid of atorvastatin is easily lactonized. The systematic chemical name of atorvastatin lactone is (2R-trans) -5- (4-fluorophenyl) -2- (1-methylethyl) -N, 4-diphenyl-1- [2-tetrahydro-4- Hydroxy-6-oxo-2H-pyran-2-yl) ethyl] -1H-pyrrole-3-carboxamide. Atorvastatin and its corresponding racemic lactone are disclosed in US Pat. No. 4,681,893.

  Lactone types are disclosed in US Pat. No. 5,273,995. In Examples 4 and 5 of the '995 patent, the lactone is 1,1-dimethylethyl (R) -7- [2- (4-fluorophenyl) -5- (1-methyl) in tetrahydrofuran and triethyl borane. Ethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrol-1-yl] -5-hydroxy-3-oxo-1-heptanoate is dissolved, followed by addition of t-butylcarboxylic acid Manufactured by. After cooling, methanol is added followed by sodium borohydride. This mixture is poured into an ice / hydrogen peroxide / water mixture. Trichloromethane is added and the mixture is separated. The organic layer is dried over magnesium sulfate, filtered and evaporated. The product is dissolved in tetrahydrofuran and methanol and added to the sodium hydroxide solution. The mixture is concentrated to remove the organic solvent, added into water and extracted with diethyl ether. The aqueous layer is acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer is dried using anhydrous magnesium sulfate, filtered and evaporated. The residue is dissolved in toluene and concentrated. The product is recrystallized from ethyl acetate and hexane to produce the lactone.

  Lactones can also be prepared according to the procedure disclosed in US Pat. No. 5,003,080. For example, in Example 2, Method A, cis-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4- (phenylamino) carbonyl-1H— After pyrrole-1-heptanoic acid, methyl ester was treated with sodium hydroxide and diluted with water and separated, the remaining layer was diluted with hexane and ethyl acetate and then concentrated hydrochloric acid solution. To be washed. Upon separation, the upper layer is washed with hydrochloric acid and concentrated. The residue is dissolved in toluene.

  As disclosed in the '080 patent, the lactone is (±) -cis-6- (2-aminoethyl) -2,2 dimethyl-1,3-dioxane-4-acetic acid (Example 2) in dimethyl sulfoxide. , Method B); (±)-(2α, 4α, 6α), or (±)-(2α, 4β, 6β) -6- (2-aminoethyl) -2-phenyl-1,3-dioxane-4 -Acetic acid (Example 2, method C); (±) -cis-9- (2aminoethyl) -6,10-dioxaspiro [4.5] decane-7-acetic acid (Example 2, method D); (±) -cis- (4- (2-aminoethyl) -1,5-dioxaspiro [5.5] undecane-2-acetic acid (Example 2, Method E); or (±)-(2α, 4α, 6α), or ( ±)-(2α, 4β, 6β) -6- (2-aminoethyl) -2-methyl-1,3-dioxane-4-acetic acid (Example 2, Methods F and G), (±) -4 It can also be prepared by mixing with -fluoro-α- [2-methyl-1-oxopropyl] -γ-oxo-N, β-diphenylbenzenebutanamide After heating, the solution is diluted with diethyl ether in water And saturated chloride After separation, the organic layer is washed with water and sodium hydroxide, which is acidified with diluted hydrochloric acid and extracted with ethyl acetate with added hydrochloric acid. The solution is concentrated and the residue is dissolved in toluene.

  Another method for making lactones according to the '080 patent is in (±) -cis-1,1-dimethylethyl-6- (2-aminoethyl) -2,2- in heptane: toluene (9: 1). Dimethyl-1,3-dioxane-4-acetic acid (Example 2, method H); (±)-(2α, 4α, 6α) or (±)-(2α, 4β, 6β) -1,1-dimethyl -6- (2-aminoethyl) -2-phenyl-1,3-dioxane-4-acetic acid (Example 2, Method I); or (±) -cis-1,1-dimethylethyl (4- (2 -Aminoethyl) -1,5-dioxaspiro- [5.5] undecane-2-acetic acid (Example 2, Method J) was converted to (±) -4-fluoro-α- [2-methyl-1-oxopropyl]- including mixing with γ-oxo-N, β-diphenylbenzene butanamide, after heating, the solution is poured into a mixture of tetrahydrofuran and ammonium chloride in water. And then hydrochloric acid is added, and after stirring, sodium hydroxide is present. The reaction is stopped by adding a mixture of water and hexane After separation, the aqueous layer is acidified with diluted hydrochloric acid, extracted with ethyl acetate, and concentrated. The residue is dissolved in toluene.

A pharmaceutically acceptable calcium salt, [R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4- Lactone or free acid is used to produce [(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt (2: 1) trihydrate. In animal models, atorvastatin calcium salt showed low plasma cholesterol and lipoprotein levels by suppressing HMG-CoA reductase and reducing hepatic cholesterol synthesis. Atorvastatin is a tablet of 10, 20, 40 and 80 mg and is marketed by Pfizer as hemicium salt trihydrate under the trade name LIPITOR. Atorvastatin hemi-calcium salt has the following structure:

  Hemicalcium salts are disclosed in US Pat. No. 5,273,995. The document teaches that the calcium salt can be obtained by further purification by crystal formation from a saline solution obtained from sodium salt transfer with calcium chloride and recrystallization from a 5: 3 mixture of ethyl acetate and hexane. .

U.S. Pat. No. 5,298,627 also discloses a method for producing hemicalcium salts. 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-1H-pyrrole-3-carboxamide was dissolved in methanol and reacted with hydrochloric acid [R- (R ^* , R ^* )]-5- (4-fluorophenyl) -β, δ-dihydroxy-2- (1-methylethyl) -N, N, mixed with methanol and sodium hydroxide 4-triphenyl-3-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanamide is formed. The filtrate is washed with tert-butyl methyl ester and the aqueous layer is acidified with aqueous hydrogen chloride and extracted with tert-butyl methyl ester, [R- (R ^* , R ^* )]-2- (4-Fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H pyrrole-1-heptanoic acid sodium Form a salt. This sodium salt is converted to the hemicalcium salt in water by the addition of calcium acetate.

In a similar manner, (4R-cis) -6- (2-aminoethyl) -2,2-dimethyl-N, N-bis (phenylmethyl) -1,3-dioxane-4-acetamide is further added to hemicalcium [R- (R ^* , R ^* )]-5- (4-fluorophenyl) -β, δ-dihydroxy-2- (1-methylethyl) -4-phenyl-3-[(phenyl Amino) carbonyl] -N, N-bis (phenylmethyl) -1H-pyrrole-1-heptanamide (Example 2); (4R-cis) -6- (2-aminoethyl) -N, N -Diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide is further converted to hemicalcium salt [R- (R ^* , R ^* )]-N, N-diethyl-5- (4 -Fluorophenyl) -β, δ-dihydroxy-2- (1-methylethyl) -4-phenyl-3-[(phenylamino) carbonyl] -1H pyrrole-1-heptanamide (Example 3); (4R-cis) -6- (2-aminoethyl) -N-butyl-N, 2,2-trimethyl-1,3-dioxane-4-acetamide Is converted to hemi calcium salt ^{[R- (R *, R *} )] - N- butyl-5- (4-fluorophenyl)-beta, .delta.-dihydroxy -N- methyl-2- (1-methylethyl) Converted to 4-phenyl-3-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanamide (Example 4); (4R-cis) -6- (2-aminoethyl) -N- ( 1,1-dimethylethyl) -2,2-dimethyl-N- (phenylmethyl) -1,3-dioxane-4-acetamide is further converted to hemicalcium salt [R- (R ^* , R ^* ) ] -N- (1,1-dimethylethyl) -5- (4-fluorophenyl) -β, δ-dihydroxy-2- (1-methylethyl) -4-phenyl-3-[(phenylamino) carbonyl] Converted to -N- (phenylmethyl) -1H pyrrole-1-heptanamide (Example 5); and (4R-cis) -1-[[6- (2-aminoethyl) -2,2-dimethyl- [1,3-Dioxane-4-yl] -acetyl] piperidine is further converted to the hemicalcium salt [R- (R ^* , R ^* )]-1- [3,5-dihydroxy-7-o Converted to xoxo-7- (1-piperidinyl) heptyl] 5- (4-fluorophenyl-2- (1-methylethyl) -N-4-diphenyl-1H-pyrrole-3-carboxamide (Example 6) .

Rosuvastatin is [S- [R ^* , S ^* -(E)]]-7- [4- (4-fluorophenyl)]-6- (1-methylethyl) -2- [methyl (methylsulfonyl)] Amino] -5-pyrimidinyl] -3,5-dihydroxy-6-heptenoic acid is the general chemical name. Rosuvastatin is in the process of being approved for sale under the name CRESTOR, including rosuvastatin calcium. Rosuvastatin, its calcium salt (2: 1), and its lactone form are disclosed and claimed in US Pat. No. 5,260,440. The method of the '440 patent consists of 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -5-pyrimidinecarbaldehyde and methyl ( Rosuvastatin is made by reaction with 3R) -3- (tert-butyldimethylsilyloxy) -5-oxo-6-triphenylphosphoranylidene hexanate. The silyl group is then cleaved with hydrogen fluoride and then reduced with NaBH ₄ to give the methyl ester of rosuvastatin.

  The ester is then hydroxylated with sodium hydroxide in ethanol at room temperature, after which the ethanol is removed and ether is added to obtain the sodium salt of rosuvastatin. This sodium salt is then converted to a calcium salt by a multi-step method. This sodium salt is dissolved in water and kept under a nitrogen atmosphere. Calcium chloride is then added to the solution resulting in the precipitation of rosuvastatin calcium (2: 1). Thus, the method of the '440 patent makes rosuvastatin calcium through the sodium salt intermediate.

  US Patent No. 6,316,460 discloses a pharmaceutical composition of rosuvastatin. The pharmaceutical composition comprises rosuvastatin or a salt thereof and a polyvalent tribasic phosphate. The '460 patent does not disclose any method for producing the calcium salt of rosuvastatin.

  Pitavastatin is a general term for (E) -3,5-dihydroxy-7- [4 '-(4 "-fluorophenyl) -2'-cyclopropyl-quinolin-3'-yl] -hept-6-enoic acid Pitavastatin, its calcium salt (2: 1), and its lactone are disclosed in three related US Patent Nos. 5,011,930, 5,856,336, and 5,872,130.

  The '930 patent makes pitavastatin ethyl ester according to Example 1 thereof. The first 4- (4'-fluorophenyl-2 '-(1'-cyclopropyl) -quinolin-3'-yl-carbochelate is a combination of 2-amino-4'-fluorobenzophenone and ethyl isobutyrylacetic acid. Prepared by reaction, and then the compound is converted to 4- (4′-fluorophenyl) -3-hydroxymethyl-2- (1′-cyclopropyl) -quinoline and then 4-4′- Fluorophenyl-2- (1′-cyclopropyl) -quinoiin-3′-yl-carboxaldehyde is converted to 3- (3′-ethoxy-1′-hydroxy-2′-propenyl) -4- ( Converted to 4'-fluorophenyl) -2- (1'-cyclopropyl) -quinoline and then (E) -3- [4 '-(4 "-fluorophenyl) -2'-(1-cyclopropyl ) -Quinolin-3'-yl] propenaldehyde and then ethyl (E) -7- [4- (4 "-fluorophenyl-2 '-(1" -cyclopropyl) -quinoline-3'- Il] -5-hydroxy-3-oxohepta-6-enoate Converted and then ethyl (E) -3,5-dihydroxy-7- [4 '-(4 "-fluorophenyl) -2'-(1" -cyclopropyl) -quinolin-3'-yl] -hepta -6- Converted to enoart.

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

  These patents produce lactones by dissolving the prepared sodium salt in dry toluene, refluxing the solution and removing the toluene under reduced pressure. The crude solid is then recrystallized from diisopropyl ether to yield the lactone, [4 '-(4 "-fluorophenyl) -2'-(1" -methylethyl) quinoline-3'-ylethynyl] -4- Hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one is obtained. The lactone is further reduced using palladium / carbon under a nitrogen atmosphere.

  US Pat. No. 6,335,449 improves prior art method for producing pitavastatin by reacting aldehyde quinoline with diethyl cyanomethylphosphonate to give a nitrile intermediate for the synthesis of pitavastatin To do. US Pat. No. 6,335,449 does not disclose how to produce the calcium salt of pitavastatin or any other salt.

Simvastatin is a compound butanoic acid, 2,2-dimethyl-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8- [2- (tetrahydro-4-hydroxy-6-oxo-2H -Pyran-2-yl) -ethyl] -1-naphthalenyl ester, a generic drug name for [1S ^* -[1a, 3a, 7b, 8b (2S ^* , 4S),-8ab]] (CAS Registration number 79902-63-9). Simvastatin is sold as ZOCOR and is disclosed in US Pat. Nos. 4,444,784 and 6,002,021, and WO 00/53566. These references disclose the preparation of lactones and open forms of simvastatin.

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

  The aforementioned prior art methods for producing calcium statin salts, such as atorvastatin, pitavastatin, rosuvastatin and simvastatin, disclose either how the calcium salt is produced or processed through the sodium salt intermediate. Not. Moreover, some of the methods are very subtle and not always reproducible and have filtration and drying characteristics that are inappropriate for large scale production. It is desirable to obtain a stable product with fewer steps using processes that are more easily reproducible and can withstand large scale production than the previous method.

SUMMARY OF THE INVENTION The present invention provides the following formula:

{Where,
R represents an organic group. }, A novel method for producing a calcium salt of a statin having the following:

{Where,
R ₁ is a C ₁ -C ₈ alkyl group, and
R ₂ , R ₃ and R ₄ independently of one another represent hydrogen or the same or different hydrolysable protecting groups, or R ₂ and R ₃ are each hydrolysable together with the oxygen atom to which they are attached. A cyclic protecting group is formed. The above-mentioned production method comprising contacting an ester derivative of a statin selected from the group consisting of: and a sufficient amount of calcium hydroxide.

  The reaction is carried out with or without a phase transfer catalyst. Preferred phase transfer catalysts are quaternary ammonium salts such as tetrabutylammonium bromide (TBAB) and triethylbenzylammonium chloride (TEBA). Preferably the reactants are heated to facilitate the conversion.

Preferred statins are atorvastatin, rosuvastatin, pitavastatin and simvastatin. In a preferred embodiment, R ₂ , R ₃ and R ₄ are hydrogen. R ₂ , R ₃ and R ₄ may be the same or different protecting groups from each other, and the protecting group may be hydroxylated in one step together with the hydrolysis of the ester group, ie —COOR _1. It is hydrolyzed by the use of calcium or by using an acid catalyst, followed by hydrolysis of the ester group -COOR ₁ . Preferred protecting groups are silyl groups such as trialkylsilyl which can be hydrolyzed by calcium hydroxide, and acetonides which can be hydrolyzed by acid catalysts. Acetonide forms a cyclic hydrolyzable protecting group, ie dioxane.

  In another aspect, the present invention provides the following:

{Where,
R represents an organic group. A calcium salt of a statin having the following steps: adding calcium hydroxide and an ester derivative of a statin as described above to a mixture of water and a C ₁ -C ₄ alcohol, heating the mixture, Precipitating the calcium salt of the statin and separating the calcium salt;
The above manufacturing method is provided.

DETAILED DESCRIPTION OF THE INVENTION Forming esters is a well-known method of protecting carboxylic acid groups and masking their acidic protons. Green, TW; Wuts, PGM Protective Groups in Organic Synthesis 3rd. Ed., Chapter 5 (John Wiley & Sons: New York 1999). It is also generally known that carboxylic acids protected as esters are deprotected by hydrolyzing the ester with a strong base. 377-78 Id.

Sodium hydroxide is a strong base with a dissociation constant of 6.37 (pK _b = -0.80) (Handbook of Chemistry and Physics 81st ed. 8-45 (CRC Press: Boca Ratoi 2000-01)) and protected by esters Its use as a reagent for deprotecting a carboxylic acid formed is taught in the art. Green & Wuts, p. 377. Calcium hydroxide with a first dissociation constant of 3.74 × 10 ⁻³ (pK _b = 2.43) and a second dissociation constant of 4.0 × 10 ⁻³ (pK _b = 1.40) (Ca ( OH) ₂ ) is a much weaker base than sodium hydroxide. Handbook of Chemistry and Physics 63rd ed. D-170 (CRC Press: Boca Raton 1983).

  Calcium hydroxide is not listed among the reagents used for hydrolyzed esters in the well-known overview of functional group transformations in organic synthesis. Larock R.C. Comprehensive Organic Transformations 2nd ed., Sectio NITRILES, CARBOXYLIC ACIDS AND DERIVATIVES, Sub-sect. 9.17, pp. 1959-68 (Wiley-VCH: New York 1999). Its use as a general reagent for deprotecting ester-protected carboxylic acids is not taught by the well-known reference books on how to protect and deprotect organic functional groups. Green & Wuts, pp. 377-79. In fact, U.S. Pat.No. 5,273,995 states that when sodium chloride is later added to the sodium salt solution, excess sodium hydroxide is used in the production of the sodium salt to prevent calcium hydroxide formation. Warning to avoid. A form protected by an ester of a statin such as atorvastatin first treats the ester with a strong base such as sodium hydroxide to hydrolyze it, then a sodium salt and a calcium salt such as calcium chloride or It does not seem to be understood that contacting calcium acetate can be converted directly to the respective hemicalcium salt, such as atorvastatin hemicalcium, without replacing sodium ions.

As used herein, an “ester derivative” refers to from ring opening of a statin or substitution of a hydroxy proton of a carboxylic acid group of a dihydroxy acid type, with the attachment of the substituent to the hydroxy oxygen atom through the carbon. The resulting compound. Such ester derivatives include, for example, compounds in which the substituent attached to the hydroxy oxygen of the carboxylic acid is a C ₁ -C ₈ alkyl group. The ester derivative used for the conversion is a mixture of derivatives including various esters. For example, methyl ester derivatives are added to ethanol resulting in the conversion of some methyl esters to ethyl esters. Ester derivatives of statins can be produced by methods known in the art or can be purchased commercially. Ester derivatives also include statin lactones or ring-closed forms. The lactone type is a cyclic ester in which the ester group of statin is incorporated in the ring. Mixtures of ester derivatives also include mixtures of open or closed statins.

  The present invention has the following general formula:

{Where
The organic group R is bonded to the diol-pentanoic acid group. } Directed to statins with These statins include, for example, pravastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin, pitavastatin, lovastatin and simvastatin. Of these, atorvastatin, rosuvastatin, pitavastatin and simvastatin are preferred.

R represents an organic group bonded to a diol / pentanoic acid group. Depending on the statin, the R group can be:
Pravastatin: 1,2,6,7,8,8a-hexahydro-6-hydroxy-2-methyl-8- (2-methyl-1-oxobutoxy) -1-naphthalene / ethyl group,
Fluvastatin: 3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -ethylene group,
Cerivastatin: 4- (4-fluorophenyl) -5-methoxymethyl) -2,6-bis (1-methylethyl) -3-pyridinyl ethylene group,
Atorvastatin: 2- (4-fluorophenyl) -5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-ethyl group,
Rosuvastatin: [4- (4-fluorophenyl) -6- (1-methylethyl) -2- [methyl (methylsulfonyl) amino] -5-pyrimidinyl] -ethylene group,
Pitavastatin: [4 '-(4 "-Fluorophenyl) -2'-cyclopropyl-quinolin-3'-yl] -ethylene group. The R group is also in the ring-opened form, ie the dihydroxy acid of simvastatin or lovastatin These ring-opened forms are also diol pentanoic acid groups.As used herein, the terms simvastatin and lovastatin include both lactone and ring-opened forms, where the statin is simvastatin or lovastatin. If the R group is the following:
Simvastatin: 1,2,6,7,8,8a-hexahydro-2,6-dimethyl-8- (2,2-dimethyl-1-oxobutoxy) -1-naphthalene / ethyl group,
Lovastatin: 1,2,6,7,8,8a-hexahydro-2,6-dimethyl-1-8- (2-methyl-1-oxobutoxy) -1-naphthalene-ethyl group.

  Calcium salts of these and other statins are compounds in which the organic group attached to the diol pentanoic acid group or the corresponding lactone is a statin, ie 3-hydroxy-3-methyl-glutaryl-coenzyme A ("HMG- CoA ")) can be made by the methods of the invention, such as defining compounds that inhibit the reductase enzyme. See for example WO 00/53566. Thus, R should not be construed to be limited to organic groups attached to the diol-pentanoic acid group of statins or the corresponding lactones as explicitly disclosed or exemplified herein. Any hydrates, solvates and anhydrides, crystalline, or amorphous of these statin calcium salts and other polymorphic forms are within the scope of the present invention.

  The present invention illustrates the preparation of the calcium salts of these statins by using the preparation of atorvastatin hemi-calcium as an example. To the extent that aspects in the production of atorvastatin hemi-calcium differ from those for other statins, those skilled in the art will know that atorvastatin is used for illustrative purposes only; and the various in the production of atorvastatin hemi-calcium It will be appreciated that aspects will be readily modified to produce other statins, but will continue to exist within the essence and scope of the present invention.

  By contacting an ester derivative with a sufficient amount of calcium hydroxide, the present invention provides the following formula:

{Where,
R represents an organic group, and
R ₁ is a C ₁ -C ₈ alkyl group. The statin ester derivative represented by the following formula:

A method for producing a statin hemi-calcium salt by converting to a corresponding hemi-calcium salt having As used herein, “sufficient amount” refers to the amount of calcium hydroxide that substantially converts the ester derivative to the corresponding hemicalcium salt. As used herein, “substantially convert” corresponds to greater than about 50% (mole based), preferably greater than about 70%, more preferably greater than about 90% of statin ester derivatives. The amount is converted to hemicalcium salt. Most preferably, greater than about 95% of the statin ester derivative is converted to the corresponding hemicalcium salt.

  A surprising advantage of this method is that calcium hydroxide fulfills two roles. It functions as a basic catalyst for ester hydrolysis and supplies calcium ions to form hemicalcium salts. Another important practical advantage of the above method is that, in contrast to the present invention, in another method comprising a series of processes in which the ester derivative is hydrolyzed with NaOH and then sodium ions are replaced by calcium ions. The amount of calcium hydroxide does not need to be carefully controlled as much as the amount of sodium hydroxide and chloride / calcium acetate used.

The statin ester derivative can be provided in pure form or in a mixture with other statin ester derivatives. Optionally, the statin ester derivative in a mixture with other statin ester derivatives is preferably dissolved or suspended in a mixed solvent of C ₁ -C ₄ alcohol and water. Preferred alcohols are ethanol and isopropyl alcohol (“IPA”), and preferred solvent mixtures are about 5% to about 15% water, more preferably 10% water and 90% ethanol (v / w) in ethanol. v) or IPA included. Whether or not the statin ester derivative is soluble in the mixed solvent depends on factors such as the choice of C ₁ -C ₄ alcohol, the proportion of water, the temperature, and the 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 statin ester derivative is consumed. The consumption of the statin ester derivative is observed by any conventional method such as TLC, HPLC and NMR. After the statin ester derivative is consumed, statin hemi-calcium is recovered from the basic hydrolysis reaction mixture by conventional methods. There is no need to add other calcium sources to provide Ca ²⁺ ions to the atorvastatin hemi-calcium salt.

According to a preferred procedure for carrying out the basic hydrolysis method, the statin ester derivative is added in an amount sufficient to provide a mixed solvent of about 10 mmoles L ⁻¹ to about 1 mole L ⁻¹ .

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

Calcium hydroxide is slightly soluble in a C ₁ -C ₄ alcohol: water mixture, and only a small portion is present in a solution that can catalyze any one hydrolysis. In order to promote basic hydrolysis, a phase transfer catalyst is added to increase the solubility of calcium hydroxide. Phase transfer catalysts are well known in the art and include, for example, tetra-n-butylammonium bromide (“TBAB”), benzyltriethylammonium chloride (“TEBA”), tetra-n-butylammonium chloride, bromide, Tetra-n-butylammonium, tetra-n-butylammonium iodide, tetraethylammonium chloride, benzyltributylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, tetramethylammonium chloride and polyethylene glycol. The most preferred phase transfer catalyst is TBAB. When used, the phase transfer catalyst should be used in a basic stoichiometric amount, preferably from about 0.05 to about 0.25 equivalent, more preferably about 0.1 equivalent, relative to the statin ester derivative. It is.

  The mixture is heated to the reflux temperature of the mixed solvent to promote the reaction. A preferred temperature range is an elevated temperature of about 40 ° C to about 70 ° C.

  After consumption of the statin ester derivative, statin hemi-calcium or a solvate thereof is recovered from the basic hydrolysis reaction mixture. As part of the recovery of statin hemi-calcium, preferably the reaction mixture is filtered to remove excess suspended calcium hydroxide. In order to prevent statin hemi-calcium precipitation on the calcium hydroxide filtercake, the reaction mixture is preferably filtered while hot.

  After filtration to remove suspended calcium hydroxide, statin hemi-calcium is recovered from the filtrate by precipitation. With the preferred recovery technique, statin hemi-calcium precipitates from the filtrate by the slow addition of water. Approximately the same amount of water as the amount of filtrate is added over about an hour. Preferably, the slow addition of water is also performed at an elevated temperature, for example from about 40 ° C to about 65 ° C. Precipitation of statin hemi-calcium with slow addition of water results in a crystalline form of statin hemi-calcium, preventing the formation of a gelatinous precipitate. Alternatively, statin hemi-calcium is recovered by any conventional method. Even after any necessary purification steps, the recovered statin hemi-calcium is used to formulate a pharmaceutical as an active ingredient.

  The filtration characteristics and purity of statin hemi-calcium can be achieved by re-dissolving the crystalline product in the hydroalcoholic reaction mixture by dissolving all precipitates and heating to a temperature sufficient to produce a clear solution. Further improvement. Preferably, the solution is slowly cooled over several hours and held at ambient temperature until no further crystals are observed. After filtration and drying, and any further optional purification steps, statin hemi-calcium or its solvate is used as the active ingredient of the pharmaceutical product.

Statins are often produced through intermediates. One or both of the hydroxyl groups of the pentanoic acid diol group (ring-opening type) or the hydroxyl group of the lactone (ring-closing type) in the intermediate is protected by a hydrolyzable protecting group, and the carboxyl group is previously described herein. Protected by the ester derivatives described in 1). For example, US Pat. No. 5,260,440, incorporated herein, uses a silyl protecting group during the synthesis of rosuvastatin. US Pat. Nos. 6,002,021 and 4,444,784, incorporated herein, 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, each represent an oxygen atom to which they are attached. Atorvastatin is prepared through a dioxane intermediate with an acetonide protecting group, ie, R ₂ and R ₃ , together with a cyclic hydrolyzable protecting group.

  These compounds, ie “protected statin ester derivatives” as used herein, are converted to the corresponding hemicalcium salts according to the present invention. Thus, in another aspect, the invention provides the following formula:

{Where,
R represents an organic group. Is a method for producing a calcium salt of a statin having the following:

{Where,
R ₁ is a C ₁ -C ₈ alkyl group and R ₂ , R ₃ and R ₄ independently of one another represent hydrogen or the same or different hydrolysable protecting groups, or R ₂ and R ₃ together with the oxygen atom to which each is attached forms a hydrolyzable cyclic protecting group. Are directed to the above-described production method, which comprises contacting an ester derivative of a statin selected from the group consisting of a sufficient amount of calcium hydroxide. The protecting group used is preferably hydrolysable under acidic or basic conditions. Preferred protecting groups R ₂ , R ₃ and R ₄ according to this embodiment of the invention include, for example, silyl groups with more preferred trialkylsilyl and alkyldiarylsilyl, and most preferred t-butyl-dimethyl-silyl; Includes cyclic protecting groups such as R ₂ and R ₃ forms, for example dioxane.

  US Pat. No. 6,294,680, incorporated herein, discloses additional protecting groups used in the synthesis of statins, particularly simvastatin. Disclosed cyclic protecting groups include dioxane, cyclic sulfate, cyclic phosphate or borylidene. They are optionally substituted with alkyl and aryl groups. Other protecting groups are boronic acids disclosed in WO 95/13283, incorporated herein, and esters with acetic anhydride disclosed in US Pat. No. 5,159,104, incorporated herein. Including US Pat. No. 6,100,407, incorporated herein, discloses additional protecting groups. The protecting groups disclosed in these references are used according to the present invention.

It has surprisingly been found that silyl groups are hydrolyzed and removed by contact with calcium hydroxide. Thus, the use of a silyl group makes it possible to remove the protecting group in one step in the same solvent and convert the ester to a calcium salt. The use of calcium hydroxide allows the silyl protecting group to be removed using, for example, a hydrogen halide, such as hydrogen fluoride, to remove the protecting group, as required by the methods of U.S. Patent Nos. 5,260,440 and 4,444,784. Eliminates the need for a separate step of acidic hydrolysis. The method of the present invention compatible with any statin with silyl or other protecting groups R ₂ , R ₃ and R ₄ allows it to be hydrolyzed with calcium hydroxide. Rosuvastatin protected are disclosed in U.S. Patent No. 5,260,440, for example with a modification of reducing the ketone to obtain hydrogen as R _2, can be used. The silyl protected simvastatin disclosed in US Pat. Nos. 4,444,784 and 6,002,021 can also be used.

Some of the protecting groups are best hydrolyzed under acidic conditions. Thus, an acid catalyst is added to the hydrolysis of the protecting group before contacting the protected statin ester derivative with calcium hydroxide. Examples of such acid catalysts include acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, zinc bromide and hydrochloric acid or other hydrogen halides, with acetic acid and hydrochloric acid being preferred. The resulting diol ester is then converted to a calcium salt by contact with calcium hydroxide. The method can also be performed in one pot. The diol-ester is formed as described above and then reacts with calcium hydroxide in the same pot without changing the solvent to form atorvastatin hemi-calcium. A preferred solvent is a mixture of water and a C ₁ -C ₄ alcohol, and the alcohol is preferably ethanol. A preferred pH for the reaction is less than about 3, more preferably less than about 1.

  A preferred protecting group that is removed with an acid catalyst is an acetonide, ie a compound in which the diol forms a cyclic hydrolyzable protecting group, ie dioxane. Preferably, all acetone formed during the reaction of acetonide and acid catalyst is removed, for example by distillation under reduced pressure.

  The one-pot method involving the use of an acid catalyst is described as follows:

  The pharmaceutical composition is manufactured as a medicament to be administered orally, parenterally, rectally, transdermally, buccally or nasally. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard gelatin capsules or gelatin capsules, sublingual tablets, syrups and suspensions . Forms suitable for parenteral application include aqueous or non-aqueous solutions, or emulsions, while dosage forms suitable for rectal administration include suppositories with a hydrophilic or hydrophobic medium. For topical administration, the present invention provides suitable transdermal delivery systems known in the art, and suitable aerosol delivery systems known in the art for nasal delivery. Is provided.

  The pharmaceutical composition of the present invention comprises statin hemi-calcium, particularly atorvastatin hemi-calcium, rosuvastatin hemi-calcium, pitavastatin hemi-calcium, simvastatin hemi-calcium and lovastatin hemi-calcium. In addition to the active ingredient, the pharmaceutical composition of the present invention may contain one or more excipients. The choice of excipients and amounts used can be readily determined by the formulation scientist based on experience and review of standard procedures and references in the field. US Patent No. 6,316,460, incorporated herein, and the latest edition of the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association may be used as guidance. LIPITOR® (atorvastatin hemi-calcium) and other drug dosages and formulations may also be used as guidance.

Unless schematic otherwise indicated, as generally accepted, reagents were used. [R- (R ^* , R ^* )]-2- (4-Fluorophenyl) -β, δ-dioxane-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-tert-butylheptanoate (dioxane 2, R ₁ = t-butyl) was prepared by a condensation reaction between the corresponding diketone forming the pyrrole ring and the corresponding chiral amine. It is also produced 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 mixture obtained in the acidic hydrolysis reported in the examples: Waters Spherisorb S3 ODS1 (7.6 × 100 mm), 70:30 acetonitrile: water, 0.6 ml min ^{− 1} , 20 μl sample, UV detection γ = 254.

Example 1
Preparation of atorvastatin calcium from dioxane ester derivatives In a flask equipped with a magnetic stirrer, [R- (R ^* , R ^* )-2- (4-fluorophenyl) -β, δ-dioxane-5- (1 -Methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-tert-butylheptanoate (2.0 g) was suspended in an 80% aqueous solution of acetic acid (50 ml). I let you. The mixture was stirred at ambient temperature for about 20 hours until a clear solution was obtained. The clear solution was distilled off, dried and traces of acetic acid were removed by azeotropic distillation with toluene (3 × 50 ml) to give a powder.

The previously obtained powder (200 mg, 0.32 × 10 ^-3 mole) was placed in ethanol (8 ml) with a saturated solution of calcium hydroxide (8 ml) containing tetrabutylammonium bromide (10 mg). Melted. The mixture was stirred and heated at a temperature of about 45 ° C. for about 24 hours. Additional saturated calcium hydroxide solution (4 ml) was added. The reaction was complete after about 20 minutes of stirring at ambient temperature. The purity of the resulting product was analyzed by HPLC. The white precipitate was filtered under vacuum and dried at a temperature of about 65 ° C. for about 18 hours. After drying, 77% yield of atorvastatin calcium salt was obtained (142 mg).

Example 2
Preparation of atorvastatin calcium from dioxane ester derivative In a flask equipped with a magnetic stirrer, [R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dioxane-5- ( 1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-tert-butylheptanoate (10.0 g, 15.29 × 10 ⁻³ mmole) was added to 80% of acetic acid. Suspended in aqueous solution (150 ml). The mixture was stirred overnight at ambient temperature until a clear solution was obtained. The clear solution was distilled off and traces of acetic acid were removed by azeotropic distillation with toluene (3 × 100 ml) to give an oily product containing toluene.

The oily product was transferred 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 mmole) and 5% (w / w dioxane ester derivative) tetrabutylammonium bromide (0.46 g) was added. The mixture was heated to a temperature of about 45 ° C. for about 3 hours until the reaction was complete. While the mixture was hot, it was filtered under vacuum to remove excess calcium hydroxide. The mixture was then allowed to cool to ambient temperature, after which water (200 ml) was added with stirring. The reaction was complete after about 20 minutes of stirring at ambient temperature. The purity of the resulting product was analyzed by HPLC. The white precipitate was filtered under vacuum and dried at a temperature of about 65 ° C. for about 18 hours. After drying, 84% yield of atorvastatin calcium salt was obtained (7.44 g).

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, δ-dioxane-5- ( 1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-tert-butylheptanoic acid ester (0.5 g, 0.76 × 10 ^-3 mmole) was added in a catalytic amount. Dissolved in a 1: 1 mixture of trifluoroacetic acid-tetrahydrofuran (4 ml) in the presence of water. The reaction mixture was stirred at ambient temperature for about 24 hours. The resulting solution was distilled off and traces of trifluoroacetic acid were removed by azeotropic distillation with ether (3 × 10 ml). A white solid was obtained (0.3 g). Based on HPLC analysis, the white solid was a mixture of atorvastatin and atorvastatin lactone in a ratio of 40:60, respectively.

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, δ-dioxane-5- ( 1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-tert-butylheptanoate (0.2 g, 0.30 × 10 ⁻³ mmole) and zinc bromide (3.5 etc. Amount, 1.07 × 10 ⁻³ mole) was dissolved in dichloromethane (5 ml). The reaction mixture was stirred at ambient temperature for about 24 hours. Water (30 ml) was added and the mixture was stirred for about 3 hours. The aqueous layer was extracted with dichloromethane (3 × 10 ml) while the organic layer was dried using sodium sulfate and filtered. The organic layer was then evaporated under reduced pressure to give the resulting product (150 mg). Based on HPLC analysis, the resulting product was a mixture of atorvastatin and atorvastatin lactone in a ratio of 57:43, respectively.

Example 5
Preparation of atorvastatin lactone from dioxane ester derivative In a flask equipped with a magnetic stirrer, [R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dioxane-5- ( 1-Methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-tert-butylheptanoate (0.2 g) was dissolved in 90% aqueous solution of acetic acid (4 ml). Suspended. The mixture was stirred at a temperature of 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 × 15 ml) to give a powder. Based on HPLC analysis, the product was a mixture of atorvastatin and atorvastatin lactone in a ratio of 54:46, respectively.

Example 6
Preparation of atorvastatin lactone from dioxane ester derivatives In a flask equipped with a magnetic stirrer, 3% aqueous solution of hydrochloric acid (1 ml) and [R- (R ^* , R ^* )]-2- (4-fluorophenyl) ) -β, δ-dioxane-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-tert-butylheptanoate (0.2 g) in methanol Dissolved in (2 ml). The mixture was stirred at a temperature of about 110 ° C. for about 4 hours and then at ambient temperature overnight. The resulting solution was evaporated to dryness to obtain a powder. Based on HPLC analysis, the powder was a mixture of atorvastatin and atorvastatin lactone in a ratio of 54:46, respectively.

Example 7
Preparation of rosuvastatin calcium from ester derivatives Methyl-7- [4- (4-fluorophenyl) -6-iso-propyl-2- (N-methyl-N-methylsulfonylamino) in a flask equipped with a magnetic stirrer ) -Pyrimidin-5-yl]-(3R, 5S) -dihydroxy- (E) -6-heptenoate, a saturated solution of calcium hydroxide containing 5% (w / w ester derivative) tetrabutylammonium bromide. Dissolved in the added ethanol. The mixture was stirred and heated at a temperature of about 45 ° C. for about 24 hours. Additional saturated calcium hydroxide solution was added. After stirring for about 20 minutes at ambient temperature, the reaction is completed, resulting in rosuvastatin calcium.

Example 8
Preparation of rosuvastatin calcium from ester derivatives In a flask equipped with a magnetic stirrer, methyl-7- [4- (4-fluorophenyl) -6-iso-propyl-2 (N-methyl-N-methylsulfonylamino) -Pyrimidin-5-yl]-(3R, 5S) -dihydroxy- (E) -6-heptenoate is transferred into a mixture of ethanol and water. Add a mixture of calcium hydroxide and 5% (w / w ester derivative) tetrabutylammonium bromide. The mixture is heated at a temperature of about 45 ° C. for about 3 hours until the reaction is complete. While the mixture is hot, it is filtered under vacuum to remove excess calcium hydroxide. The mixture is then cooled to ambient temperature and then water is added with stirring. After stirring for about 20 minutes at ambient temperature, the reaction is completed, resulting in rosuvastatin calcium.

Example 9
Preparation of pitavastatin calcium from ester derivatives In a flask equipped with a magnetic stirrer, ethyl- (E) -3,5-dihydroxy-7- [4 '-(4 "-fluorophenyl) -2'-cyclopropyl- Quinoline-3'-yl] -hepta-6-enoate is dissolved in ethanol with addition of a saturated solution of calcium hydroxide containing 5% (w / w ester derivative) tetrabutylammonium bromide. Heat for about 24 hours at a temperature of 45 ° C. Add additional calcium hydroxide saturated solution.After stirring at ambient temperature for about 20 minutes, complete the reaction, resulting in pitavastatin calcium.

Example 10
Preparation of pitavastatin calcium from ester derivatives In a flask equipped with a magnetic stirrer, ethyl- (E) -3,5-dihydroxy-7- [4 '-(4 "-fluorophenyl) -2'-cyclopropyl- Transfer quinolin-3'-yl] -hepta-6-enoate into a mixture of ethanol and water, add a mixture of calcium hydroxide and 5% (w / w ester derivative) tetrabutylammonium bromide. Until the mixture is heated for about 3 hours at a temperature of about 45 ° C. While the mixture is hot, it is filtered under vacuum to remove excess calcium hydroxide, and then the mixture is cooled to ambient temperature. Then, add water while stirring, after stirring for about 20 minutes at ambient temperature, complete the reaction, resulting in pitavastatin calcium.

  Thus, because the present invention has been described with reference to certain preferred embodiments and described using examples, those skilled in the art will depart from the essence and scope of the present invention as disclosed herein. Without limitation, modifications to the invention as described and illustrated can be understood. The examples are presented to aid in understanding the present invention, but are in no way intended to limit the scope of the present invention and should not be so construed. The examples do not include a detailed description of conventional methods. Such methods are well known to those skilled in the art and are described in numerous publications. All documents mentioned in this specification are hereby incorporated by reference.

Claims (17)

The following formula:

{Where,
R represents an organic group of a statin selected from the group consisting of fluvastatin, rosuvastatin and pitavastatin. } Of a statin calcium salt having the following structure:

{Wherein R ₁ is a C ₁ -C ₈ alkyl group}
Providing an ester having an acetonide protecting group represented by:
Hydrolyzing the acetonide group with an acid catalyst to obtain an ester diol;
The above production method comprising contacting the ester diol with a sufficient amount of calcium hydroxide.   2. The method of claim 1, wherein the statin is selected from the group consisting of rosuvastatin and pitavastatin.   The method of claim 2, wherein the statin is rosuvastatin.   The method of claim 2, wherein the statin is pitavastatin. The method of claim 1, wherein the method is performed in a mixture of water and a C ₁ -C ₄ alcohol.   The method of claim 1, wherein the contacting is performed at an elevated temperature.   The method of claim 1, wherein the contacting is performed in the presence of a phase transfer catalyst.   2. The method of claim 1, further comprising recovering the statin calcium salt. The following formula:

{Where,
R represents an organic group of a statin selected from the group consisting of fluvastatin, rosuvastatin and pitavastatin . For preparing a calcium salt of a statin having the following steps:
a) The following structure:

{Wherein R ₁ is a C ₁ -C ₈ alkyl group}
Providing an ester having an acetonide protecting group represented by:
b) hydrolysis of the acetonide group with an acid catalyst to obtain an ester diol;
c) adding calcium hydroxide and the above ester diol to a mixture of water and a C ₁ -C ₈ alcohol;
d) heating the above mixture;
e) precipitating the calcium salt of the statin; and
f) separating the calcium salt,
The said manufacturing method containing. 10. The method of claim 9 , wherein the statin is selected from the group consisting of rosuvastatin and pitavastatin. 11. The method of claim 10 , wherein the statin is rosuvastatin. 11. The method of claim 10 , wherein the statin is pitavastatin.   10. The method of claim 9, wherein the water and alcohol mixture is a water to alcohol mixture of about 5% to about 20% (v / v).   10. The method of claim 9, further comprising adding a phase transfer catalyst to the mixture of step (c).   The method of claim 9, wherein the mixture is heated to about 40 ° C. to about 70 ° C.   10. The method of claim 9, further comprising a filtration step between steps (d) and (e).   10. A process according to claim 9, wherein the precipitation occurs by addition of water.