ES2289945B1 - PROCEDURE FOR OBTAINING TWO ADVANCED INTERMEDIATES AND ITS USE FOR OBTAINING ATORVASTATIN CALCICA AMORFA. - Google Patents

Abstract

The present invention provides a process for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl } -2,2-dimethyl-1,3-dioxan-4-yl} tert-butyl acetate and 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamol-2- (4- fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, key intermediates in the preparation of calcium atorvastatin. The procedure consists in reacting 2-phenyl-1- (4-fluorophenyl) ethanone with 1-bromo-3-methyl-2-butanone under an inert atmosphere and in the presence of a strong base, then reacting the resulting compound () - 2-phenyl-1- (4-fluorophenyl) -5-methylhexan-1,4-dione with 2 - [(4R, 6R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan -4-yl] tert-butyl acetate at toluene and heptane reflux in the presence of an acid catalyst to obtain {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5 tert-butyl acetate, isopropyl-pyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4-yl}, new intermediate from which, after various synthesis steps including halogenation with a halosuccinimide and carbonylation with carbon monoxide in the presence of aniline, said advanced intermediates are obtained for obtaining calcium atorvastatin. The use of these intermediates is also provided to obtain amorphous calcium atorvastatin after a series of stages of hydrolysis, sodium salt formation and isolation of amorphous crude calcium atorvastatin, which is purified to obtain a high quality product.

Description

Procedure for obtaining two Advanced intermediates and their use for obtaining atorvastatin Calcium amorphous.

Object of the invention

The present invention relates to a new procedure that allows obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl, tert-butyl ester of atorvastatin of formula I, and 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, atorvastatin in its lactone form, of formula II, both key intermediates for obtaining calcium atorvastatin.

The object of the present invention is, by both, provide a new simple, economical and easily transposable on an industrial scale to obtain two advanced intermediates that are precursors of atorvastatin Calcium In addition, new intermediates are provided that are isolated during the process.

The present invention fits within the chemical sector and more specifically within the scope of the pharmaceutical industry.

Background of the invention

Atorvastatin calcium is a potent inhibitor of the enzyme HMG-CoA reductase, which catalyzes the formation of mevalonic acid, the limiting stage of the route cholesterol biosynthetics (Shaw, M.K .; Newton, R.S .; Sliskovic, D.R .; Roth, B.D .; Ferguson, E .; Krause, B.R. Biochem and Biophys. Research Comm. 1990 170 (2) 726-34).

Atorvastatin, chemically known as (3R, 5R) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoic acid or either of ([βR, δR) -3-phenyl-4 - [(phenylamino) carbonyl] -2- (4-fluorophenyl) -?, δ-dihydroxy-5- (1-methylethyl) -1 H -1-pyrrol-1-heptanoic (Chemical Abstracts), is used as an antihypercholesterolemic agent, in the form of calcium salt, and can be obtained in amorphous form or in various crystalline forms (polymorphs).

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one

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The compounds object of the present invention, 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl, of formula I, better known as atorvastatin tert-butyl ester, with the groups hydroxyl in positions 3 and 5 protected in the form of acetonide, and the terminal carboxylic acid in the form of an ester tert-butyl, and 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4- hydroxypyran-2-one, of formula II, better known as atorvastatin in the form of lactone, they are key intermediates in the synthesis of calcium atorvastatin.

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There are several patents that describe the synthesis of these intermediates by the reaction of "Paal-Knorr" between N-phenyl-2- [1-phenyl-2- (4-fluorophenyl) -2-oxo] ethyl-4-methyl-3-oxopentanamide with 2 - [(4R, 6R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-yl] acetate of tert-butyl.

Thus, the patent US 5 003 080 describes the preparation of atorvastatin in the form of lactone by means of a non enantioselective procedure. The reaction of "Paal-Knorr" between (±) -2 - [(4 (R, S), 6 (R, S)] - 6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-yl] acetate of tert-butyl and (±) -N-phenyl-2- [1-phenyl-2- (4-fluorophenyl) -2-oxo] ethyl-4-methyl-3-oxopentanamide using as a solvent a heptane-toluene mixture (9: 1) at reflux leads to the formation of a mixture of isomers of the atorvastatin tert-butyl ester, (±) -2- {6- (4R, 6R) - [2- (3-phenyl-4-phenylcarbamoyl-2-fluorophenyl-5-isopropylpyrrol-1-yl) ethyl] -2,2-dimethyl-1 , 3-dioxan-4-yl}, which is subsequently transformed to lactone by hydrolysis acid (acetal rupture), followed by basic hydrolysis (rupture of the ester), thereby obtaining the desired compound as shown in Scheme 1.

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Scheme one

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In US 5 273 995, which describes the preparation of atorvastatin calcium salt from its enantiomerically pure lactone form, compound 2- {6- (4R, 6R) - {2- [ 3-Phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4-yl} enantiomerically pure tert-butyl acetate . The procedure begins with the reaction between an aldehyde and a chiral ester acetate. The resulting hydroxy ester is transformed to 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} - Tert-butyl 2,2-dimethyl-1,3-dioxan-4-yl} acetate, and this is treated with sodium hydroxide in an organic medium, purified by the addition of water and diethyl ether (diethyl ether) and extracted by collecting the aqueous phase, which is acidified and again extracted with ethyl acetate collecting the organic phase, in which the atorvastatin is completely unprotected and finally lactonized in hot toluene. The lactone obtained is dissolved in methanol and water and treated with sodium hydroxide. The resulting sodium salt is transformed into its calcium salt by reaction with an aqueous solution of hot calcium chloride dihydrate. The atorvastatin calcium salt is isolated by cooling the reaction crude, filtering the solid formed, washing and drying, as indicated in the
Scheme 2

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Scheme 2

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In none of the two references cited previously, nothing is said about the characterization of atorvastatin protected tert-butyl ester, 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl. Often this intermediate is obtained as a yellow oil, however its state is solid, which Indicates that it is impurified. These methods present the drawback that, to ensure acceptable quality of final product, many stages are required between obtaining the atorvastatin tert-butyl ester and that of its salt calcium, possibly due to insufficient intermediate purity 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl, which makes the synthesis unfeasible industrial scale

Several crystalline forms of the compound of formula I, as well as procedures for obtaining An amorphous form of it. Thus, in WO 03/024959, describe the crystalline forms I and II of 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl and a process of preparing said crystalline forms from the amorphous form. So by example, to obtain the crystalline form I, a crude is dissolved from 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of amorphous tert-butyl in acetonitrile, heats up the mixture at reflux, let it cool overnight and then crystals are isolated by filtration in a crystalline form called polymorph I.

Also described are procedures of obtaining the compound of formula I in amorphous form, as per example in WO 2005/063741. You get the amorphous form of 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl by precipitation in a mixture of methanol and water, and by evaporation of the solvent in vacuo in several solvents, including acetonitrile, chloroform and methylene chloride

Description of the invention

The procedure for the preparation of two Advanced intermediates and their use for obtaining atorvastatin amorphous calcium that the invention proposes solves in a way the problem described above is fully satisfactory, in the different aspects commented, since it is a method simple, which can be easily adaptable on an industrial scale and that does not cause environmental problems.

More specifically, the process object of the present invention comprises the preparation of 2- {6- (4R, 6R) - [2- (3-phenyl-4-phenylcarbamoyl-2-fluorophenyl-5-isopropylpyrrol-1-yl ) ethyl] -2,2-dimethyl-1,3-dioxan-4-yl} acetate
tert-butyl and 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2 -one, of formulas I and II respectively, by four stages of synthesis, as shown in the Scheme the following:

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(Scheme turns to page next)

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Scheme 1st

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In one aspect of the present invention, provides a simple procedure to obtain two key intermediates in the synthesis of calcium atorvastatin. TO The stages of the process are detailed below:

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a) Formation of the compound of formula V

The first stage of the synthesis consists of make react 2-phenyl-1- (4-fluorophenyl) ethanone, of formula III,

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with 1-Bromo-3-methyl-2-butanone, of formula IV,

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under inert atmosphere and in presence of a strong base, to obtain (±) -2-phenyl-1- (4-fluorophenyl) -5-methylhexan-1,4-dione, of formula V

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The reaction is carried out under the atmosphere of argon, using anhydrous tetrahydrofuran solvent and as strong base one selected from hexamethyldisilazane (NaHDMS) or either lithium diisopropylamide (LDA), preferably NaHDMS. The reaction takes place at a temperature between -70 and -80 ° C, preferably at -78 ° C, and is completed in a time comprised between 3 and 5 hours.

The isolation of the compound of formula V is carried out through a series of simple washing operations which allow obtaining a substrate of purity suitable for Next stages of synthesis. First, it eliminates reduced pressure the solvent of the reaction, then the resulting residue is dissolved in a solvent of medium polarity, preferably ethyl acetate, and finally washed with water and with a saturated solution of sodium chloride. After removing vacuum the ethyl acetate, you get (±) -2-phenyl-1- (4-fluorophenyl) -5-methylhexan-1,4-dione, of formula V.

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b) Formation of the compound of formula VII

The second stage of synthesis consists in doing react the (±) -2-phenyl-1- (4-fluorophenyl) -5-methylhexan-1,4-dione, of formula V, obtained in the previous stage with (2 - [(4R, 6R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-yl] acetate of tert-butyl, of formula VI

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at reflux of a toluene mixture and heptane, in the presence of an acid catalyst, to form {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4- il} acetate of tert-butyl, of formula VII

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The reaction is carried out by a system of azeotropic elimination of water that is generated in the course of the reaction and lasts for a time between 8 and 12 hours, at a temperature between 80 and 90 ° C. As solvent of the reaction a mixture of toluene and heptane is used in a ratio between 8.5: 1 and 9.5: 1, preferably in a proportion of 9: 1. The acid catalyst used in the reaction is selected between pivotal acid and acetic acid, preferably acid pivotal

As in the case of the compound of formula V, the isolation of the compound of formula VII is carried out by a series of simple washing operations that allow to obtain a substrate of adequate purity. First, it eliminates reduced pressure the mixture of reaction solvents, toluene and heptane Subsequently, the resulting residue is dissolved in a medium polar solvent, preferably ethyl acetate, and then washed with a polar solvent, preferably Water. After removing the ethyl acetate, the {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4- il} acetate of tert-butyl with the right purity for use in the following stages of the synthesis.

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c) Formation of the compounds of formulas VIII and X

The third stage of the synthesis consists of prepare the compound of formula VIII, or alternatively in prepare the compound of formula X, from {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4- il} acetate of tert-butyl, of formula VII, obtained in the previous stage

The first alternative consists of the preparation of the compound of formula VIII, where R is a halogen,

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from {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4- il} acetate of tert-butyl, of formula VII, obtained in the previous stage, by reaction with a halosuccinimide, under inert atmosphere and temperature ambient.

The reaction is carried out in a solvent. polar anhydrous, preferably anhydrous dimethylformamide and the halosuccinimide used in the reaction is selected from N-Bromosuccinimide (NBS) and N-iodosuccinimide (NIS), giving rise to the compound of formula VIII, where R is bromine or iodine respectively.

The second alternative consists of the preparation of the alternative compound consists of the formula X,

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where R is a halogen, from of the {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4- il} acetate of tert-butyl, of formula VII, obtained in the stage previous.

In this synthetic alternative, the {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4- il} acetate of tert-butyl of formula VII is transformed initially in 6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula IX, by means of deprotection reactions of the groups hydroxyl and carboxyl, as well as cyclisation of the resulting acid with the right hydroxyl,

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subsequently the compound of formula IX and finally reacted with a halosuccinimide, under inert atmosphere and at room temperature, to obtain the compound of formula X.

The deprotection reaction of the groups hydroxyl of the compound of formula VII is made by dissolving said compound in anhydrous ethanol and reacting it to a temperature between 45 and 55 ° C with a solution of hydrochloric acid and subsequently the saponification of the ester is carried out tert-butyl by treatment with a solution of sodium hydroxide, also at a temperature between 45 and 55 ° C, finally obtaining the compound of formula IX.

The isolation of 6- (4R, 6R) - [2- (3-phenyl-2-fluorophenyl-5-isopropylpyrrol-1-yl) ethyl] tetrahydro-4-hydroxypyran-2-one, of formula IX, is carried out through a series of operations of simple washing that allow to obtain a purity substrate adequate. First, water and hexane is added to a solution of the compound of formula IX. The phases are separated, the aqueous phase, which is adjusted to acidic pH, is extracted with acetate ethyl and finally removed under reduced pressure to obtain 6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula IX.

The final reaction is carried out by dissolving the compound of formula IX in an anhydrous polar type solvent, preferably in anhydrous dimethylformamide and halosuccinimide used in the reaction is selected from N-Bromosuccinimide (NBS) and N-iodosuccinimide (NIS), giving rise to the compound of formula X, where R is bromine or iodine respectively.

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d) Obtaining the compounds of formulas I and II

The fourth stage of synthesis constitutes one of the most relevant aspects of the present invention. This stage it consists in the preparation of the compounds of formulas I and II, by the aminocarbonylation reaction of the corresponding haloderivatives obtained in the previous stage, of formulas VIII and X, respectively.

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The compounds of formula VIII or X, where R is bromine or iodine, are reacted with carbon monoxide and aniline, under an inert atmosphere and in the presence of a catalyst of palladium, of a ligand and of a base, in an anhydrous solvent of polar type

The palladium catalyst used at this stage Contains palladium in its oxidation state 0, more commonly called Pd (0), and is selected from Pd 2 (dba) 3 and Pd (PPh 3) 4, preferably being used Pd 2 (dba) 3. The ligand used in the aminocarbonylation reaction is selected from PPh3 and dppf, preferably using dppf, as a basis for The reaction is used DBU.

The palladium catalyst and the ligand of the reaction must be in adequate proportions to be produce the reaction, finding that the necessary proportion is 10% catalyst and 20% ligand, with respect to the derivative halogenated of formula VIII or X.

The aminocarbonylation reaction is carried out in an autoclave at a constant pressure between 4 and 6 atmospheres, preferably at 5 atmospheres, and at a temperature between 50 and 60 ° C The reaction is completed in a period of time between 12 and 24 hours. The solvent used in the reaction is a anhydrous polar type solvent, preferably using, acetonitrile, dimethylformamide and 1,4-dioxane.

In another aspect of the present invention, provides a series of new compounds that are intermediate useful for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl, of formula I, and of 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula II, key intermediates for the synthesis of atorvastatin calcium:

?

(±) -2-phenyl-1- (4-fluorophenyl) -5-methylhexan-1,4-dione, of formula V,

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?

{6- (4R, 6R) {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4-yl }acetate of tert-butyl, of formula VII,

fifteen

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?

Markush formula compound VIII

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in which if R = Br, VIII is {6- (4R, 6R) - {2- [4-bromo-3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3- dioxan-4-yl} acetate of tert-butyl, of formula VIIIa,

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and if R = I, VIII is {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl-4-iodo] ethyl} -2,2-dimethyl-1,3- dioxan-4-yl} acetate  of tert-butyl, of formula VIIIb

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?

6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula IX

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Markush formula compound X

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in which if R = Br, X is 6- (4R, 6R) - {2- [4-Bromo-3-phenyl-2-fluorophenyl-5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula Xa,

twenty-one

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and if R = I, X is 6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl-4-iodo] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula Xb

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In a final aspect of the present invention, the use of 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl, of formula I, and of 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula II, obtained according to the process herein invention, for the production of calcium atorvastatin in form amorphous

The procedure is simple and consists of dissolve the 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl, of formula I, in ethanol and treat the solution thus obtained with a solution of hydrochloric acid to form 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -3,5-dihydroxy-heptanoate of tert-butyl, of formula XI

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The formation of the compound of formula XI, which is produced by the release of hydroxyl groups by breaking the dimethylacetal of the compound of formula I, requires a period of 0.5 to 1.5 hours and is performed at a temperature between 40 and 60 ° C.

The next stage to obtain amorphous calcium atorvastatin consists of the basic hydrolysis of compound of formula XI, which is carried out by adding a aqueous solution of sodium hydroxide on the final medium of reaction of the previous stage, to obtain the sodium salt of atorvastatin, of formula XII. The basic hydrolysis is completed in a period between 0.5 and 1.5 hours, and the optimum temperature is between 35 and 50 ° C.

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Alternatively, the sodium salt can be obtained of atorvastatin, of formula XII, directly from 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula II, by means of a basic hydrolysis reaction of the compound of formula II with a solution of sodium hydroxide. The hydrolysis is completed in a period between 15 and 45 minutes and the Optimum temperature is between 15 and 25ºC.

Atorvastatin sodium in aqueous solution obtained both from 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2, 2-dimethyl-1,3-dioxan-4-yl} acetate of tert-butyl, of formula I, as of 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula II, it can be purified by washing with a solvent suitable organic, allowing the removal of impurities apolar. For this, water is added to the final reaction medium of the previous stage and an organic solvent. They are then separated the phases, discarding the organic phase. The organic solvent that used is toluene, hexane and a mixture of hexane and acetate ethyl. Purified atorvastatin sodium salt has a high purity and is used dissolved in water and alcohol in the next stage of obtaining calcium atorvastatin.

Finally, atorvastatin calcium salt is obtained from the aqueous solution of atorvastatin sodium from the previous stage by adding a calcium, organic or inorganic, selected from calcium acetate, calcium chloride and calcium nitrate, in any form, anhydrous or hydrated

In practice, the aqueous solution strongly basic atorvastatin sodium of the previous stage fits a pH between 7.5 and 8.0, and heated to a temperature between 40 and 60 ° C Subsequently, the addition of a calcium salt is carried out. in aqueous solution over the previous solution. The salts of Preferred calcium are calcium acetate monohydrate, chloride calcium dihydrate and calcium nitrate tetrahydrate. Finished the addition, the mixture is allowed to cool to room temperature and, after a few hours of maturation, calcium atorvastatin is obtained raw amorphous

Finally, amorphous calcium atorvastatin Raw can be recrystallized. For this, calcium atorvastatin is dissolve in a mixture of ethanol and water 3: 1 and heat to a temperature between 40 and 60 ° C, preferably at 50 ° C. After several hours at this temperature, the mixture is allowed to evolve until room temperature and kept stirring for several hours for maturation of the desired compound, which precipitates in the medium. After filtered and dried in a vacuum oven, atorvastatin is obtained amorphous calcium, of formula XIII.

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The following examples illustrate the preferred embodiments of the present invention and are not intended at all limit the scope of it.

Examples of embodiment of the invention

The following describes the various techniques used for the characterization of the compounds obtained, as well as the equipment used.

Nuclear magnetic resonance

The 1 H-NMR spectra and 13 C-NMR were recorded in the following Equipment: Varian-UNITY-500, Varian-INOVA-400, Varian-INOVA-300, Varian-Gemini-200. The chemical shifts are described in parts per million (δ) and coupling constants (J) are indicated in hertz (Hz). The 1 H-NMR spectra are referenced with respect to the residual proton signal of the deuterated solvent used in each case. The spectra of 13 C-NMR, proton decoupled at all cases are referenced regarding the chemical displacement of the corresponding deuterated solvents.

Infrared

Infrared (IR) spectra were recorded. on a Perkin-Elmer 657 and Perkin spectrometer Elmer-Spectrum One FT-IR. The Spectrum frequencies are indicated in cm -1. The spectra are they dealt with the OMNIC E.S.P. and "Spectrum for Windows" from Perkin-Elmer.

Masses

Mass spectra [MS (ES +)], except otherwise indicated, were recorded by direct injection of the sample in a mass spectrometer by means of the technique of electrospray in positive mode, registering the spectra with a Hewlett Packard 100 MSD spectrometer. The spectra are described in units of mass / load ratio (m / z).

Elemental analysis

The elementary analyzes (AE) were performed in a team Carlo Erba EA 1180.

Melting points

Melting points were measured in an apparatus of Kofler type heated stage and in capillaries with one device Gallenkamp

Optical rotation

The optical rotations ([α] D) are measured on a Perkin-Elmer 241 MC polarimeter at room temperature, with concentrations and solvents indicated in each case.

Example one

Preparation of (±) -2-phenyl-1- (4-fluorophenyl) -5-methylhexan-1,4-dione

Previous Preparation of 2-phenyl-1- (4-fluorophenyl) ethanone: At a suspension of 14.4 g (12.4 mmol) of Pd (PPh3) 4 and 32.6 g (495.6 mmol) of Zn in powder in 400 ml of anhydrous dimethoxyethane (DME), at 0 ° C and low Argon atmosphere, a solution of 33.2 ml (300 mmol) was added of 4-fluorobenzoyl chloride in 400 ml of DME. The The mixture was stirred under these conditions for 5 to 10 minutes. Then, a solution of 30.0 ml (250.0 was added slowly mmol) of benzyl bromide in 400 ml of DME. Then the mixture was allowed to reach room temperature and stirred under Argon atmosphere for two days. Then the material was filtered insoluble and the solvent was removed under reduced pressure. The residue resulting was dissolved in 300 ml of AcOEt and washed sequentially with 5% HCl (3 x 100 ml), H2O (3 x 100 ml) and with a saturated aqueous NaHCO3 solution (3 x 100 ml). The organic phase was washed with a saturated solution of sodium chloride and dried over anhydrous MgSO4. Once the vacuum has been removed solvent 41.2 g of a white solid were obtained, which was identified as 2-phenyl-1- (4-fluorophenyl) ethanone.

On a solution of 40 g (186.9 mmol) of 2-phenyl-1- (4-fluorophenyl) ethanone in 490 ml of anhydrous tetrahydrofuran, kept under an atmosphere of argon and at a temperature of -78 ° C, 343.7 ml of a 0.6M solution of NaHMDS (205.5 mmol) in toluene. It remains in Stir the mixture for 4 hours and then add a solution of 67.9 g (411.5 mmol) of 1-Bromo-3-methyl-2-butanone in 490 ml of anhydrous tetrahydrofuran. The mixture is stirred for 15 minutes and allowed to evolve until reaching temperature. The reaction is completed after 4 hours. After this period of time remove the solvent under reduced pressure, and the resulting residue is  dissolve in ethyl acetate. The resulting solution is washed with water and with a saturated solution of sodium chloride. After removing the solvent in vacuo, 38.8 g of a colorless oil are isolated characterized as (±) -2-phenyl-1- (4-fluorophenyl) -5-methylhexan-1,4-dione.

IR (KBr), \ nu: 2971, 2927, 1710, 1682, 1236, 1156, 843, 701

1 H-NMR (400 MHz, CDCl 3), δ: 7.97 (m, 2 H, H-C (Ar)); 7.27-7.19 (m, 5 H, H-C (Ar)); 7.01 (m, 2 H, H-C (Ar)); 5.04 (dd, J = 10.3, 3.8, 1 H, H-C (2)); 3.61 (dd, J = -17.9, 10.1, 1 H, H_ -C (3)); 2.75 (dd, J = -17.9, 3.8, 1 H, Hb -C (3)); 2.62 (Sept, J = 6.9, 1 H, H-C (5)); 1.11 (d, J = 6.9, 3 H, Me-C (5)); 1.05 (d, J = 6.9, 3 H, H-C (6))

13 C-NMR (75 MHz, CDCl 3), δ: 212.6 (CO-C (4)); 197.3 (CO-C (1)); 167.0, 163.6, 138.4, 131.4, 131.3, 129.1, 127.9, 127.2, 115.5, 115.3 (12 C, C (Ar)); 48.4 (C (2)); 45.1 (C (3)); 40.6 (C (5)); 18.0, 17.9 (Me-C (5), C (6))

MS (ES +): 299 ([M + H] +), 321 ([M + Na] +)

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Example 2

Preparation of 2- {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan- 4-il} ace- tert-butyl tato

In a reactor equipped with agitation and system water separation (Dean-Stark) 38 g are added (127.5 mmol) of (±) -2-phenyl-1- (4-fluorophenyl) -5-methylhexan-1,4-dione, 45.3 g (165.8 mmol) of 2 - [(4R, 6R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-yl] acetate of tert-butyl, 9 g (88.1 mmol) of pivotal acid and 300 ml of a mixture of toluene and heptane 9: 1. The resulting mixture it is heated at a reflux temperature of 90 ° C under an atmosphere of Argon, maintaining vigorous agitation for 10 hours, until The reaction is complete.

Subsequently the solvent is removed in vacuo and the resulting residue is dissolved in 300 ml of AcOEt and so sequentially wash with H2O (3 x 100 ml), with a solution saturated with sodium chloride and dried over MgSO4. One time solvent removed in vacuo, 63 g of a solid were obtained target that was identified as 2- {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan- 4-il} acetate of tert-butyl.

[α] D = + 2.9 (c = 0.65, CHCl3)

IR (KBr), \ nu: 2980, 1727, 1601, 1508, 1227, 1157, 844

1 H-NMR (300 MHz, CDCl 3), δ: 7.30-7.24 (m, 2 H, H-C (Ar)); 7.16 (m, 7 H, H-C (Ar)); 6.18 (s, 1 H, H-C (4 ')); 4.12 (m, 1 H, H-C (3)); 3.96 (m, 1 H, H_ -C (7)); 3.81 (m, 1 H, Hb -C (7)); 3.61 (m, 1 H, H-C (5)); 3.00 (sept, J = 6.8, 1 H, CH-Me2); 2.36 (dd, J = -15.1, 7.1, 1 H, H_ - (2)); 2.21 (dd, J = -15.1, 6.1, 1 H, Hb -C (2)); 1.51 (m, 2 H, H-C (4)); 1.43 (s, 9 H, C (CH 3) 3); 1.33 (m, 12 H, C (CH 3) 2, CH-Me 2); 0.88 (m, 2 H, H-C (6))

13 C-NMR (50 MHz, CDCl 3), δ: 170.1 (CO); 164.6, 159.7, 140.4, 136.4, 132.9, 132.8, 129.8, 129.7, 127.9, 127.7, 127.5, 124.7, 122.4, 115.8, 115.3 (C (Ar)); 103.4 (C (4 ')); 98.6 (C (C-Me2)); 80.5 (C (C-Me3)); 66.0 (C (5)); 65.8 (C (3)); 42.4 (C (2)); 39.6 (C (7)); 37.8 (C (4)); 35.9 (C (6)); 29.9 (C (C-Me2)); 28.0 (C (C-Me3)); 25.5 (C (CH-Me2)); 23.7, 23.2 (C (CH-Me2)); 19.6 (C (C-Me_2))

MS (ES +): 536 ([M + H] +), 558 ([M + Na] +)

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Example 3

Preparation of 2- {6- (4R, 6R) - {2- [4-Bromo-3-phenyl-2-fluorophenyl-5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan- 4-il} acetate of tert-butyl

On a solution of 53.66 g (100 mmol) of 2- {6- (4R, 6R) - {2- [3-phenyl-2-fluorophenyl-5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4-yl} acetate of tert-butyl in 850 ml of anhydrous dimethylformamide under argon atmosphere and maintained at room temperature, it add 21.4 g (120 mmol) of N-bromosuccinimide. The resulting mixture is stirred at room temperature for 8 hours and then the solvent is removed by distillation at reduced pressure A residue that dissolves in 300 ml is obtained of ethyl acetate and washed sequentially with a saturated solution of sodium bicarbonate and with a solution saturated with sodium chloride and dried over magnesium sulfate anhydrous. After removing the solvent under reduced pressure, it is they obtain 43.4 g of a yellow oil that was characterized as 2- {6- (4R, 6R) - {2- [4-Bromo-3-phenyl-2-fluorophenyl-5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan- 4-il} acetate of tert-butyl.

[α] D = + 10.2 (c = 0.6, CHCl3)

IR (KBr), \ nu: 2961, 2927, 2869, 1731, 1603, 1514, 1156, 845, 699

1 H-NMR (300 MHz, CDCl 3), δ: 7.19-7.08 (m, 7 H, H-C (Ar)); 6.95 (m, 2 H, H-C (Ar)); 4.14 (m, 1 H, H-C (3)); 3.98 (m, 1 H, H_ -C (7)); 3.78 (m, 1 H, Hb -C (7)); 3.65 (m, 1 H, H-C (5)); 3.21 (sept, J = 7.1, 1 H, CH-Me2); 2.35 (dd, J = -15.4, 6.8, 1 H, H a -C (2)); 2.20 (dd, J = -15.4, 6.8, 1 H, Hb -C (2)); 1.61 (m, 2 H, H-C (4)); 1.46 (d, J = 7.1, 6 H, CH-Me2); 1.41 (s, 9 H, C (CH 3) 3); 1.32 (s, 3 H, C (CH 3) 2,); 1.27 (s, 3 H, C (CH 3) 2,); 0.84 (m, 2 H, H-C (6))

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13 C-NMR (50 MHz, CDCl 3), δ: 170.1 (CO); 164.6, 159.7, 140.4, 136.4, 132.9, 132.8, 129.8, 129.7, 127.9, 127.7, 127.5, 124.7, 122.4, 115.8, 115.3 (C (Ar)); 103.4 (C (4 ')); 98.6 (C (C-Me2)); 80.5 (C (C-Me3)); 66.0 (C (5)); 65.8 (C (3)); 42.4 (C (2)); 39.6 (C (7)); 37.8 (C (4)); 35.9 (C (6)); 29.9 (C (C-Me2)); 28.0 (C (C-Me3)); 25.5 (C (CH-Me2)); 23.7, 23.2 (C (CH-Me2)); 19.6 (C (C-Me_2))

MS (ES +): 536 ([M + H] +), 558 ([M + Na] +)

Example 4

Preparation of 6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one

On a solution of 880 mg (1.64 mmol) of 2- {6- (4R, 6R) - {2- [3-phenyl-2-fluorophenyl-5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4-yl} acetate of tert-butyl in 13 ml of anhydrous ethanol are added 5.3 ml of a 1M hydrochloric acid solution, leaving the Stir mixture for 5 hours at 50 ° C. After this period of time, 3.1 ml of an aqueous solution of 2M sodium hydroxide, leaving the mixture under stirring for 5 more hours at said temperature Once the reaction is complete, it is added H2O (3 ml) and hexane (21 ml), the phases are separated by collecting the aqueous phase, which is acidified with an acid solution 5% hydrochloric to pH 2. The aqueous phase is extracted with acetate. of ethyl collecting the organic phase, which is washed with a saturated solution of sodium chloride. After drying the organic phase with anhydrous magnesium sulfate and remove the solvent in vacuo, they isolate 271 mg of a white solid that is characterized as 6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one.

P. f .: 189-190ºC

[α] D = + 29.6 (c = 0.25, CHCl3)

IR (CDCl 3), nu: 2971, 1735, 1522, 1048, 927

1 H-NMR (300 MHz, CDCl 3), δ: 7.28 (m, 2 H, H-C (Ar)); 7.18-7.03 (m, 7 H, H-C (Ar)); 6.20 (s, 1 H, H-C (4 ')); 4.47 (m, 1 H, H-C (6)); 4.28 (m, 1 H, H-C (4)); 4.11 (m, 1 H, H_ -C (8)); 3.95 (m, 1 H, Hb -C (8)); 3.00 (sept, J = 6.8, 1 H, CH-Me2); 2.65 (dd, J = -17.6, 4.8, 1 H, H_ -C (3)); 2.53 (ddd, J = -17.6, 3.7, 1.5, 1 H, Hb -C (3)); 2.05 (wide s, 1 H, OH); 1.78-1.49 (m, 4 H, H-C (5), H-C (7)); 1.36 (d, J = 6.8, 3 H, CH-Me2); 1.50 (d, J = 6.8, 3 H, CH-Me2)

13 C-NMR (75 MHz, CDCl 3), δ: 169.7 (CO); 163.8, 160.6, 140.4, 136.3, 132.9, 132.8, 129.5, 127.9, 127.6, 127.5, 124.9, 122.4, 115.9, 115.6 (15 C, C (Ar)), 103.8 (C (4 ')); 73.1 (C (6)); 62.4 (C (4)); 39.6 (C (8)); 38.4 (C (3)); 36.9, 35.55 (C (5), C (7)); 25.6 (C (CH-Me2)); 23.6 (C (CH-Me2)); 23.6 (C (CH-Me2))

MS (ES +): 422 ([M + H] +), 444 ([M + Na] +)

AE for C_ {H} {28} FNO_ {3}:

Calculated: C, 74.09; H, 6.70; N, 3.32;

quad

Found: C, 74.50; H, 6.63; N 3.43

Example 5

Preparation of 2- {6- (4R, 6R) - {2- (3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl-4-iodo] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl

On a solution of 42.15 g (100 mmol) of 6- (4R, 6R) - {2- [3-phenyl-2-fluorophenyl-5-isopropylpyrrol-1-yl] ethyl} te-
Trahydro-4-hydroxypyran-2-one in 850 ml of anhydrous dimethylformamide under argon and maintained at room temperature, 27 g (120 mmol) of N-iodosuccinimide are added. The resulting mixture is stirred at room temperature for 8 hours and then the solvent is distilled off under reduced pressure. A residue is obtained which is dissolved in 300 ml of ethyl acetate and washed sequentially with a saturated solution of sodium bicarbonate and with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, 52 g (for 95%) of a white solid which was characterized as 2- {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) are obtained -4-iodo-5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4-yl} tert-butyl acetate.

P. f .: 142-145ºC

[α] D = + 32.0 (c = 0.1, CHCl3)

IR (CDCl 3), nu: 3347, 2970, 1739, 1519, 1045, 927

1 H-NMR (300 MHz, CDCl 3), δ: 7.26-7.14 (m, 7 H, H-C (Ar)); 7.03 (m, 2 H, H-C (Ar)); 4.46 (m, 1 H, H-C (6)); 4.29 (m, 1 H, H-C (4)); 4.16 (m, 1 H, H_ -C (8)); 3.98 (m, 1 H, Hb -C (8)); 3.00 (sept, J = 7.2, 1 H, CH-Me2); 2.83 (broad s, 1 H, OH); 2.72 (dd, J = -17.6, 4.8, 1 H, H -C (3)); 2.58 (ddd, J = -17.6, 3.7, 1.5, 1 H, Hb -C (3)); 1.85-1.51 (m, 4 H, H-C (5), H-C (7)); 1.48 (d, J = 7.2, 6 H, CH-Me2)

13 C-NMR (75 MHz, CDCl 3), δ: 169.3 (CO); 163.8, 160.5, 137.1, 135.7, 132.88, 132.7, 130.8, 129.6, 128.5, 128.4, 127.4, 126.9, 126.1, 115.6, 115.3 (15 C, C (Ar)); 72.9 (C (6)); 62.5 (C (4)); 40.9 (C (8)); 38.5 (C (3)); 37.3, 35.6 (C (5), C (7)); 27.2 (C (CH-Me2)); 21.5 (C (CH-Me2))

MS (ES +): 476 ([M + H] +), 570 ([M + Na] +)

AE for C_ {26} H_ {27} FNO_ {3}:

Calculated C, 57.05; H, 4.97; N 2.56

quad

Found: C, 56.80; H, 5.08; N 2.74

Example 6

Preparation of 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl- 1,3-dioxan-4-yl} acetate of tert-butyl

At a solution of 200 mg (0.30 mmol) of 2- {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl-4-iodo] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl in 40 ml of anhydrous acetonitrile is Add 8.30 mg (0.009 mmol) of Pd 2 (dba) 3, 10 mg (0.018 mmol) of dppf, 86.0 pl (0.90 mmol) of aniline and 0.14 ml (0.90 mmol) of DBU. Mix It is placed in an autoclave at 50ºC and 5 atm of CO for 18 hours. Once the reaction is complete, the solvent is concentrated to the half the volume and insoluble material is removed by filtration of the reaction crude on celite, which is subsequently washed with ethyl acetate. The filtrate is washed with an acid solution. 5% hydrochloric and with a saturated aqueous chloride solution sodium After drying the solution over anhydrous magnesium sulfate and the solvent removed under reduced pressure, 88.3 g of a slightly yellow oil that solidifies over time, the which is characterized as 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl.

P. f .: 72-75ºC

[α] D = + 4.5 (c = 0.47, CHCl3)

IR (KBr), \ nu: 3394, 2980, 1725, 1660, 1509, 1434, 1314, 1156, 844, 755, 699

1 H-NMR (300 MHz, CDCl 3), δ: 7.20-6.94 (m, 14 H, H-C (Ar)); 6.84 (broad s, 1 H, NH); 4.11 (m, 2 H, 3-H, H a -C (7)); 3.83 (m, 1 H, Hb -C (7)); 3.67 (m, 1 H, H-C (5)); 3.55 (sept, J = 7.1, 1 H, CH-Me2); 2.36 (dd, J = -15.4, 6.1, 1 H, H a -C (2)); 2.20 (dd, J = -15.4, 6.1, 1 H, Hb -C (2)); 1.63 (m, 2 H, H-C (4)); 1.50 (d, J = 7.1, 6 H, CH-Me2); 1.41 (s, 9 H, C (CH 3) 3); 1.28 (s, 3 H, C (CH 3) 2,); 1.23 (s, 3 H, C (CH 3) 2,); 0.86 (m, 2 H, H-C (6))

13 C-NMR (75 MHz, CDCl 3), δ: 170.2 (CO); 164.8, 163.8, 160.6, 141.5, 138.3, 134.6, 133.2, 132.1, 130.4, 128.6, 128.3, 126.5, 123.5, 121.7, 119.5, 115.5, 115.2 (C (Ar)); 98.6 (C (C-Me2)); 80.7 (C (C-Me3)); 66.3 (C (3)); 65.8 (C (5)); 42.4 (C (2)); 40.8 (C (7)); 38.0 (C (4)); 35.9 (C (6)); 29.7 (C (C-Me2)); 28.0 (C (C-Me3)); 26.0 (C (CH-Me2)); 21.7 (C (CH-Me2)); 21.5 (C (CH-Me2)); 19.6 (C (C-Me_2))

MS (ES +): 655 ([M + H] +), 677 ([M + Na] +)

Example 7

Preparation of amorphous calcium atorvastatin

A solution of 3.7 g (5.65 mmol) is prepared from 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl in 25 ml of ethanol and 10 ml of water. On this solution 9.5 ml of a 2M aqueous solution are added of sodium hydroxide. The mixture is stirred for 30 minutes at 50 ° C. until the complete formation of atorvastatin sodium salt. To dissolution of the resulting atorvastatin sodium salt is added 6 ml of water and treated with 80 ml of toluene. The phases are separated and the organic phase is discarded. The pH of the aqueous phase is adjusted to 7.8 with a 2M HCl solution. The aqueous phase of atorvastatin sodium is heated to 60 ° C and an aqueous solution is added formed by 0.50 g (2.8 mmol) of calcium acetate monohydrate and 12 ml of water The mixture is allowed to cool to 20 ° C and stirred for 3 h at this temperature. The resulting suspension is filtered and the Isolated solid is washed with water and dried under vacuum at 40 ° C. They are isolated 2.5 g of amorphous calcium atorvastatin, which are suspended in 50 ml of a mixture of ethanol and water (3: 1) and heated to 60 ° C. TO then, it is treated with activated carbon for 30 minutes at same temperature The mixture is filtered again on a bed of Celite and wash with 90 ml of ethanol and water (3: 1). Mix formed by the filtrate plus the washing solvent is concentrated to half of its volume by distillation at atmospheric pressure. 30 ml of water are added to the resulting concentrate while Maintains constant agitation. This way you have a final ratio of water and ethanol from 3 to 2. Finished the addition the suspension is cooled to 20 ° C, leaving the solid in maturation for 2 h. After this period the suspension is cooled for 1 h at 0 ° C while stirring. A solid is isolated by filtration which is washed with water and dried under vacuum for 14 h at 40 ° C. Be obtain 2.15 g of quality amorphous calcium atorvastatin Pharmaceutical

Claims (21)

1. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl, of formula I 26 or of 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula II, 27 characterized in that it comprises the following stages: a) react 2-phenyl-1- (4-fluorophenyl) ethanone, of formula III, 28 with 1-Bromo-3-methyl-2-butanone, of formula IV, 29 under inert atmosphere and in presence of a strong base, to obtain (±) -2-phenyl-1- (4-fluorophenyl) -5-methylhexan-1,4-dione, of formula V

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30

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b) react the (±) -2-phenyl-I- (4-fluorophenyl) -5-methylhexan-1,4-dione obtained in the previous section, of formula V, with 2 - [(4R, 6R) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-yl] acetate of tert-butyl, of formula

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31

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at reflux of a toluene mixture and heptane, in the presence of an acid catalyst, to form {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4- il} acetate of tert-butyl. of formula VII

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32

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c) react {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan-4- il} acetate of tert-butyl obtained in the previous section, of formula VII, with a halosuccinimide to obtain the halo derivative corresponding, of formula VIII, where R is a halogen,

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33 or carry out a reaction of deprotection of hydroxyl groups of the compound of formula VII, to get 6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula IX, 3. 4 isolation and subsequent reaction with a halosuccinimide to obtain the haloderivative corresponding of formula X where R is a halogen 35 d) react the compound haloderivative obtained in the previous section, of formula VIII, where R is a halogen, with carbon monoxide and aniline, low inert atmosphere and in the presence of a palladium catalyst, of a  ligand, of a base and an anhydrous polar type solvent, for obtain 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-il},  of formula I, 36 or react the haloderivative compound obtained in the previous section, of formula X, where R is a halogen, with low carbon monoxide and aniline inert atmosphere and in the presence of a palladium catalyst, of a ligand, of a base and an anhydrous polar type solvent, for obtain 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula II, 37

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2. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-Isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that in step a) the strong base employed is selected from sodium hexamethyldisilazane and lithium diisopropylamide. 3. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that step a) is prolonged for a time between 3 and 5 hours, at a temperature between -70 and - 80 ° C 4. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-Isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that the mixture of toluene and heptane used in step b) is in a ratio between 8.5: 1 and 9 , 5: 1. 5. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-Isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that the acid catalyst used in step b) of the process is selected from pivotal acid and acetic acid. 6. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that the reaction of step b) is carried out by an azeotropic water removal process, which is generated in the course of the reaction, and lasts for a time between 8 and 12 hours, at a temperature between 80 and 90 ° C. 7. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} - 2,2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) acetate -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that the halosuccinimide used in step c) of the process is selected from N-bromosuccinimide and N-iodosuccinimide. 8. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-Isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that in step c) the deprotection reaction of hydroxyl groups of the compound of formula VII is carried out by dissolving said compound in ethanol anhydrous and reacting it with a solution of hydrochloric acid and subsequently with a solution of sodium hydroxide, at a temperature between 45 and 55 ° C. 9. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-Isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that step c) of the process is carried out under an inert atmosphere and at room temperature. 10. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-Isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that the palladium catalyst used in step d) is selected from Pd2 (dba) 3 and Pd (PPh 3) 4. 11. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-Isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that in step d) the proportion of the palladium catalyst is 10% and the ligand is 20%. 12. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-Isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that in step d) it is used as a DBU base and as a dppf ligand. 13. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that step d) is carried out in an autoclave at a pressure between 4 and 6 atmospheres and at a temperature between 50 and 60 ° C , and is completed in a period of time between 12 and 24 hours. 14. Procedure for obtaining 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2 , 2-dimethyl-1,3-dioxan-4-yl} tert-butyl or 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) - 5-Isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one according to claim 1, characterized in that in step d) the polar anhydrous solvent is selected from acetonitrile, dimethylformamide and 1,4-dioxane. fifteen. (±) -2-phenyl-1- (4-fluorophenyl) -5-methylhexan-1,4-dione, of formula V

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38

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16. {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1,3-dioxan- 4-yl} acetate
tert-butyl, of formula VII

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39

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17. Compound of Markush VIII formula

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40

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in which if R = Br, VIII is {6- (4R, 6R) - {2- [4-bromo-3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl, of formula VIIIa,

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41 and if R = I, VIII is {6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl-4-iodo] ethyl} -2,2-dimethyl-1,3- dioxan-4-yl} acetate of tert-butyl, of formula VIIIb 42 18. 6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula IX 43 19. Markush X formula compound 44 in which if R = Br, X is 6- (4R, 6R) - {2- [4-Bromo-3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one,  of formula For, Four. Five and if R = I, X is 6- (4R, 6R) - {2- [3-phenyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl-4-iodo] ethyl} tetrahydro-4-hydroxypyran-2-one, of formula Xb 46 20. Use of 2- {6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl-1, 3-dioxan-4-yl} acetate of tert-butyl of formula I obtained according to claims 1 to 14, for the production of calcium atorvastatin  in amorphous form. 21. Use of 6- (4R, 6R) - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} tetrahydro-4-hydroxypyran-2-one  of formula II obtained according to claims 1 to 14, for the production of calcium atorvastatin in amorphous form.