ES2270722A1 - Method of obtaining amorphous calcium atorvastatin - Google Patents

Abstract

The invention relates to a novel method of obtaining amorphous calcium atorvastatin from N-phenyl-2-[1-phenyl-2-(4-fluorophenyl)-2-oxo]ethyl-4-methyl-3-oxo-pentanamide (II) and (3R,5R)-7-amino-3,5-(O- isopropylidene)dihydroxy-heptanoate of terc-butyl (III), by reacting same with toluene reflux in the presence of an acid catalyst, using a series of synthesis, isolation and hydrolysis steps, after which the crude amorphous atorvastatin obtained is purified, isolated and dried, said steps being performed under very smooth reaction conditions using very short reaction times, moderate temperatures and minimal amounts of reagents, thereby producing a high-quality product.

Description

Procedure for obtaining atorvastatin Calcium amorphous.

Object of the invention

The present invention relates to a new process that allows obtaining amorphous calcium atorvastatin from N- phenyl-2- [1-phenyl-2- (4-fluorophenyl) -2-oxo] ethyl-4-methyl-3 -oxo-pentanamide (II) and (3 R , 5 R ) -7-amino-3,5- ( O- iso-propylidene) tert - butyl dihydroxy heptanoate (III).

The process of the present invention is, by both, provide a new simple, economical and easy industrial scaling to obtain atorvastatin Calcium amorphous.

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 HMG-CoA reductase enzyme, which catalyzes the formation of mevalonic acid, the limiting stage of the cholesterol biosynthetic pathway (Shaw, MK; Newton, RS; Sliskovic, DR; Roth, BD; Ferguson, E .; Krause, BR Biochem. And Biophys. Research Comm . 1990 170 (2) 726-34).

Atorvastatin, which is chemically known as (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3, 5-dihydroxy-heptanoic acid or (? R ,? R ) -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, of formula I, and can be obtained in amorphous form or in various crystalline forms (polymorphs).

one

\hbox{sales farmacéuticamente aceptables mediante un proceso no
 enantioselectivo, tal como se representa en el esquema
1.}

Atorvastatin is described in US Patent 4681893 as a substance useful for the inhibition of cholesterol synthesis. This patent describes the preparation of racemic atorvastatin in the form of lactone, hydroxy acid or

 ? pharmaceutically acceptable salts by a non-process
 enantioselective, as represented in the scheme
one.} 

Scheme one

2

\hbox{etilo y lactonización en tolueno y en caliente, tal como
se muestra en el  esquema 2.}

The preparation of atorvastatin in the form of lactone by another non-enantioselective method is described in US Patent 5003080. The "Paal-Knorr" reaction between (±) -7-amino-3,5- ( O- isopropylidene) tert - butyl dihydroxyheptanoate and (±) - N -phenyl-2- [1-phenyl-2 - (4-fluorophenyl) -2-oxo] ethyl-4-methyl-3-oxopentanamide in heptane-toluene (9: 1) at reflux causes the formation of (±) -7- [3-phenyl-4-phenylcarbamoyl -2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5- ( O- isopropylidene) tert - butyl dihydroxyheptanoate, which is then transformed to lactone by acid hydrolysis (acetal breakage), followed by basic hydrolysis (ester breakage), extractions with diethyl ether, acidification, acid extraction in acetate

 ? {ethyl and lactonization in toluene and hot, such as
is shown in scheme 2.} 

Scheme 2

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US 5273995 describes the preparation of the calcium salt of atorvastatin from the enantiomerically pure lactone form. The procedure begins with the reaction between an aldehyde and a chiral ester acetate. The resulting hydroxy ester is transformed to (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoate tert -butyl, and this is treated with sodium hydroxide in an organic medium, purified by the addition of water and diethyl ether (diethyl ether) and extraction, acidified, extracted with ethyl acetate and finally lactonized in a medium of 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.

Scheme 3

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4

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This method has the disadvantage that it involves many stages between obtaining the atorvastatin tert - butyl ester and its calcium salt, possibly to ensure an acceptable quality of the final product, but this makes it unfeasible at the industrial level.

Another method of obtaining calcium atorvastatin is described in US patent 5298627. The procedure uses the "Paal-Knorr" reaction for the preparation of an enantiomerically pure amide, which is subsequently transformed to the lactone form. This is converted to calcium salt by dissolving in methanol, treatment with sodium hydroxide and transforming the resulting sodium salt into the desired compound by adding an aqueous solution of calcium acetate at room temperature. Calcium atorvastatin is obtained by crystallization after
cooling.

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Scheme 4

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5

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Also in this case there are many operations between obtaining the precursor amide of lactone and this and from lactone to final calcium atorvastatin.

In US 5342952 and US 5397792, describes the preparation of atorvastatin calcium salt from of sodium salt. The procedure includes the preparation of a enatiomerically pure amide, which is subsequently transformed into atorvastatin sodium The sodium salt dissolved in water and methanol is transformed to calcium salt by adding calcium acetate hydrous.

Scheme 5

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6

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In this case the hydrolysis of diphenylamide to transform it into sodium salt requires reaction conditions more extreme (it is done at 70 ° C and in 4 hours).

There are several patents describing the obtaining of calcium atorvastatin from intermediate (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1- tert - butyl (IV) -3,5- (O-isopropylidene) dihydroxyheptanoate by various methods.

Thus, in US Patent 6528661 the obtaining calcium atorvastatin from the treatment of compound IV under acidic conditions, such as acetic acid in water, which results in mixtures of free acid and lactone from atorvastatin These mixtures, dissolved in ethanol, are treated with calcium hydroxide, sometimes in the presence of an agent of phase transfer, and hot, to transform them into atorvastatin calcium.

       \ newpage
    

Scheme 6

7

This method has the disadvantage that due to Low solubility of calcium hydroxide periods are necessary of long times or high temperatures (70 ° C) to transform mixtures of acid and lactone to calcium salt of atorvastatin.

In WO 02059087 another method of obtaining calcium atorvastatin is described which consists in treating the tert - butyl ester IV dissolved in a non-hydroxylic solvent with acidic conditions to deprotect the hydroxyl groups and subsequently with a metal hydroxide to hydrolyze the ester. A large part of the organic solvent is then distilled off, water is added to the concentrate and a process of purification of the solution is carried out by extraction with an organic solvent immiscible with water, stirring and phase separation. The aqueous phase containing the atorvastatin metal salt is neutralized and treated with a calcium salt to precipitate calcium atorvastatin.

The drawback of this method is that it they use toxic solvents like tetrahydrofuran and not very suitable for industrial use due to its flammability.

In WO 02083637 the tert - butyl ester IV dissolved in methanol is treated with aqueous acid to protect the hydroxyl groups and then sodium hydroxide dissolved in water is added to obtain the sodium salt. This is purified by extractions with organic solvent and treatment with activated carbon and then treated with calcium chloride in methanol medium and water to obtain calcium atorvastatin.

Hydrolysis is carried out in very dilute media ( exclusively ) of methanol and for long periods of time (15 hours for acid hydrolysis and 5 hours for basic hydrolysis). There is a subsequent step of solvent distillation. And the final conversion of sodium salt to calcium salt is carried out ( exclusively ) in aqueous calcium chloride.

In WO 03068739 a IV solution in tetrahydrofuran first with hydrochloric acid aqueous and later with aqueous alkali metal hydroxide for obtain atorvastatin sodium salt, which is purified by addition of water and hexane and phase separation and then extracted with ethyl acetate. The resulting solution treatment with another aqueous solution of calcium salt by stirring energetic leads to the formation of atorvastatin calcium salt, which is isolated by slow addition of hexane over the acetate phase of ethyl.

Also in this case the time periods for carry out hydrolysis are very long (6-24 hours for acid hydrolysis and 15-20 hours for basic hydrolysis) and the number of operations performed for the transformation of sodium salt to calcium salt is high (washing of the aqueous solution of the sodium salt with hexane, re-extraction in ethyl acetate, treatment of the resulting solution with aqueous solution of a salt of calcium, phase separation and hexane addition on the phase organic to precipitate the calcium salt of atorvastatin).

Description of the invention

The procedure for obtaining amorphous calcium atorvastatin proposed by the invention resolves the problem presented fully satisfactory previously, in the different aspects commented; since it It is a simple method, which can be easily applicable to industrial scale and that does not cause type problems environmental.

More specifically, the object procedure of the present invention, comprises the formation of atorvastatin calcium by four stages of synthesis, which are performed in very mild reaction conditions, involving reaction times very short, moderate temperatures and minimum amounts of reagents, as can be seen in the following scheme:

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9

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These process steps are described in continued in more detail:

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(a) Formation of the compound of formula IV

The first stage consists in reacting the compound of formula II,

10

with the compound of formula III,

eleven

at toluene reflux in the presence of an acid catalyst, to form the compound of formula IV. Be employ between 1.0 and 1.1 equivalents of the compound of formula III in relation to the compound of formula II. The acid catalyst is select between pivotal acid and acetic acid, preferably pivotal acid, higher boiling point and are used between 0.2 and 0.4 equivalent.

12

The reaction is carried out by a system azeotropic water removal, which is generated in the course of the reaction, and it lasts for a time between 8 and 12 hours, preferably for 10 hours, at a temperature between 80 ° C and 90 ° C.

(b) Isolation of the compound of formula IV

The isolation of the compound of formula IV is performs by precipitation from a very crude reaction complex obtained in step (a), and allows obtaining a substrate of Adequate purity and easy handling for the following stages of synthesis The isolation process includes:

-

Partial elimination of toluene used as solvent in step (a) by distillation. The volume of toluene is reduced to 70% or 80% and distillation is carried out preferably under vacuum.

-

Dissolution of the resulting concentrate with 96% ethanol or absolute ethanol, preferably ethanol from 96% to save the process.

-

Adding water to the previous solution slowly to obtain a mixture of compound IV in toluene, ethanol and water, so that the preferred final proportion of Ethanol-water is 3: 1.

-

Maturation of the resulting mixture until the complete precipitation of the compound of formula IV during a Period from 4 to 12 hours.

-

Suspension Filtration resulting.

-

Washed of the solid isolated with a cold mixture of water ethanol, preferably in a 3: 1 ratio.

-

Finally, vacuum dried to obtain the compound of formula IV.

The purity of the compound of formula IV obtained, determined by HPLC, is greater than 96%, which allows to perform the deprotection stages of the hydroxyl groups (step c) and of formation of atorvastatin sodium salt by basic hydrolysis (step d) adjusting the quantities of reagents needed, which it implies a minimization of costs, a reduction of by-products of the reactions, mainly salts, and a decreased risk of possible degradations. All of it positively affects the improvement of the quality of the final calcium atorvastatin.

(c) Deprotection of hydroxyl groups of the compound of formula IV

The group deprotection stage hydroxyl of compound IV can be carried out in three ways alternatives.

The first (c1) consists in reacting the compound of formula IV in methanol solution and in the presence of ethylene glycol (1,2-ethanediol) and a hydrogen chloride generating agent to form (3 R , 5 R ) -7- Methyl [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoate, of formula V.

13

The hydrogen chloride generating agent is selects between acetyl chloride, trimethylsilyl chloride and thionyl chloride, preferably acetyl chloride. The reaction it is carried out between 15 and 25 ° C, preferably at 20 ° C, and requires between 2 and 3 hours.

The highest degree of compound transformation of formula IV in the compound of formula V and with the minimum amount of reaction byproducts is achieved using between 2.5 and 3.5 equivalents of the hydrogen chloride generating agent, preferably using 3 equivalents of acetyl chloride with with respect to the compound of formula IV.

A competitive advantage of step (c1) over other patented processes is that, simultaneously with the deprotection of protected hydroxyl groups in the form of dimethylacetal, the conversion of the tert - butyl ester of compound IV into methyl ester occurs, the which is more easily hydrolyzed in the next stage of hydrolysis.

The second alternative (c2) is to react the compound of formula IV in ethanol solution with a solution of hydrochloric acid to form (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- ( Tert-Butyl 4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxy-heptanoate, of formula VI.

14

The formation of the compound of formula VI, which is produced by the release of hydroxyl groups by breaking the dimethylacetal of the compound of formula IV, requires a period of 0.5 to 1.5 hours and is performed between 40 and 60 ° C, preferably at 50 ° C The hydrochloric acid solution used may be of a concentration between 1 M and 6 M, preferably 1 M, and are used between 1.5 and 2.5 equivalents, preferably 2 equivalents of hydrochloric acid.

The third alternative (c3) is to react the compound of formula IV dissolved in dioxane with another solution of hydrochloric acid to form (3 R , 5 R ) -2- [2- (3-phenyl-4-phenylcarbamoyl-2 - (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl-4-hydroxy-tetrahydropyran-2-one, of formula VII.

fifteen

The transformation of the compound of formula IV into the compound of formula VII implies, in addition to the deprotection of the hydroxyl groups, the hydrolysis of the tert - butyl ester and the spontaneous conversion, under these conditions, of the resulting hydroxy acid form in its lactone.

The reaction requires between 2.5 and 3.5 hours to complete and performed at a temperature between 15 and 25 ° C. The hydrochloric acid solution used may be of a concentration between 1 M and 6 M, preferably 6 M, and are used between 3 and 4 equivalents, preferably 3.5 equivalents of acid hydrochloric.

The compounds of formulas V, VI and VII do not they isolate at this stage, but are used directly from the medium end of the reaction for the realization of the next step.

(d) Hydrolysis in basic medium and obtaining salt atorvastatin sodium

The basic hydrolysis step of the compounds of formulas V, VI and VII with formation of sodium atorvastatin, of formula VIII, is carried out by adding an aqueous solution of freshly prepared sodium hydroxide (not carbonated) on the final medium of the reaction of any of the three synthetic alternatives of step (c)
previous.

16

The concentration of the aqueous solution of sodium hydroxide and the number of equivalents used, as well as the preferred optimum reaction temperature and time, vary in function of the synthetic alternative that is followed in step (c). Thus, for the conversion of compound V into compound VIII, it is add to the final reaction medium of step (c1) between 1.7 and 2.2 equivalents of sodium hydroxide with respect to compound IV, preferably 2 equivalents of a 2 M aqueous solution. these conditions and at a temperature between 15 and 25 ° C the reaction It ends after 15 - 45 minutes.

For the conversion of the compound of formula VI in the compound of formula VIII, they are added to the final medium of the step (c2) between 3.5 and 4.5 equivalents of sodium hydroxide with respect to compound IV, preferably 3.8 equivalents of a 2M aqueous solution. The optimal reaction time is between 0.5 and 1.5 hours, and the optimum temperature between 35 and 50 ° C, preferably 40 ° C

Finally, the conversion of the compound of formula VII in the compound of formula VIII is achieved by addition to the reaction medium of step (c3) of 4.5 to 5.5 equivalents of sodium hydroxide with respect to compound IV, preferably 5 equivalents of a 3M aqueous solution. Salt formation Atorvastatin sodium, of formula VIII, takes place over a period of time between 15 and 45 minutes at a temperature between 15 and 25 ° C

Thus, the compounds of formula V, VI and VII undergo basic hydrolysis for very short times and in mild temperature conditions. Salt is obtained in this way Atorvastatin sodium in aqueous solution.

(e) Purification of atorvastatin sodium salt

Atorvastatin sodium is purified by washed with a suitable organic solvent, which allows removal of apolar impurities contained in the final medium of reaction of the previous stage and obtaining a substrate of Purity suitable for the next stage. The purification process understands:

-

Adding water to the final medium of reaction of step (d), in which the sodium salt of atorvastatin in aqueous solution. After the addition of water, the final ratio between it and the organic solvent must be in the range of 1: 1 to 2: 1. Thus, when obtaining of compound VIII in step (c) is performed according to the alternative (c1), the preferred final proportion of water-methanol It is 1: 1. In the case of obtaining it through step (c2), the preferred final proportion of water-ethanol is also 1: 1. However, when atorvastatin sodium is obtained according to step (c3), the preferred final proportion of Water-dioxane is 2: 1.

-

Washed of atorvastatin sodium salt by dissolution treatment aqueous with an organic solvent and subsequent separation of phases, discarding the organic phase. The organic solvent that is used is toluene, hexane, cyclohexane, butyl acetate or mixtures of them with each other or with ethyl acetate. Solvents Preferred are toluene, hexane and mixture of hexane and acetate. ethyl.

-

Addition of ethanol in the event that the atorvastatin sodium proceed from stage (c3) so that it is in dissolution with a mixture of water-ethanol 1: 1 before to proceed to the conversion to calcium salt.

Sodium salt of purified atorvastatin It has a good purity and is used dissolved in water and alcohol in the next stage of obtaining calcium atorvastatin.

(f) Formation of amorphous calcium atorvastatin

Atorvastatin calcium salt forms at from the aqueous solution of sodium atorvastatin stage above by adding an organic or inorganic calcium salt, to Choose between calcium acetate, calcium chloride and nitrate calcium, 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 ° C and 60 ° C. Subsequently, the addition of a salt is carried out. calcium in aqueous solution over the previous solution. The Addition is done slowly, preferably between 0.5 and 1 hour. Preferred calcium salts are calcium acetate. monohydrate, calcium chloride dihydrate and calcium nitrate tetrahydrate The volume of water added is such that the proportion final water and alcohol be 1.5: 1.

Once the addition is finished, it is allowed to cool the resulting mixture progressively until it reaches temperature ambient. Once this temperature is reached, the mixture is maintained with stirring for a time ranging from 4 to 12 hours, until the complete precipitation of raw amorphous calcium atorvastatin in the means, medium. Optionally, the reaction mixture can be cooled further up to a temperature between 0 ° C and 5 ° C to improve performance in the precipitation.

(g) Isolation of raw calcium atorvastatin amorphous

Raw Calcium Atorvastatin Isolation amorphous is easily produced by suspension filtration resulting obtained in the previous stage. Once isolated, wash with plenty of distilled water to remove excess salts.

(h) Drying of amorphous raw calcium atorvastatin

Raw amorphous calcium atorvastatin isolated on the previous stage is dried in a vacuum oven for several hours, preferably at a temperature between 40 ° C and 60 ° C and during a time that varies between 6 and 10 hours.

(i) Purification of raw calcium atorvastatin amorphous

The procedure described in the invention ends with obtaining amorphous calcium atorvastatin from Pharmaceutical quality from amorphous calcium atorvastatin raw obtained in the previous stage.

To do this, raw amorphous calcium atorvastatin it is suspended in a mixture of low molecular weight alcohol, preferably ethanol, and water, in a 3: 1 ratio, and the mixture resulting is heated to a temperature between 50 ° C and 70 ° C until you get a solution. It is then treated with coal active at the same dissolution temperature during a period of time between 30 and 60 minutes, after which the suspension to remove the bleaching agent and collect the solution of calcium atorvastatin, which is practically colorless

About the resulting solution of atorvastatin calcium water is added, at a temperature between 40 ° C and 60 ° C, preferably at 50 ° C, so that the final proportion water-alcohol be 1.5: 1. Optionally, before the addition of water, the mixture can be concentrated by distillation, at atmospheric or reduced pressure, both to reduce the volume and amortize the capacity of the reactors involved, as for Increase the degree of recovery. Finished the addition, which preferably it is done slowly, let the resulting mixture to room temperature and is maintained in stirring several hours for maturation of the desired compound, that precipitates in the middle. Optionally, the reaction mixture up to a temperature between 0 ° C and 5 ° C between 0.5 and 1 hour to improve precipitation performance. The amorphous calcium atorvastatin is isolated by filtration, washed with water and dried in a vacuum oven at a temperature between 20 ° C and 60 ° C in the presence of phosphorus oxide (V) during a period of 6 to 10 hours, obtaining a quality product Pharmaceutical

Examples of embodiment of the invention

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

Example one

Preparation of (3 R , 5 R) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropyl-pyrrol-1-yl] -3,5- ( O- isopropylidene) dihydroxyheptanoate from tert -butyl

In a 500 ml reactor equipped with stirring and azeotropic water separation system (Dean-Stark) 44.0 g (105.4 mmol) of N- phenyl-2- [1-phenyl-2- (4- fluorophenyl) -2-oxo] ethyl-4-methyl-3-oxopentanamide, 29.1 g (106.4 mmol, 1.01 equivalents) of (3 R , 5 R ) -7-amino-3.5- ( O- Isopropylidene) tert - butyl dihydroxyheptanoate and 200 ml of toluene. The resulting mixture is stirred and heated to 90 ° C. At this temperature, 3.2 g (31.6 mmol, 0.3 equivalents) of pivotal acid dissolved in 5 ml of toluene are added. The mixture is then heated to a temperature of 110 ° C and is maintained in these conditions for 10 h.

Isolation of (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropyl-pyrrole-1-yl] -3,5- ( O- isopropylidene) dihydroxyheptanoate from tert -butyl

The above reaction crude is allowed to cool to room temperature and 160 ml of toluene is removed by distillation under reduced pressure. The resulting concentrate is treated with 300 ml of ethanol (96%) and 100 ml of water is added slowly over this solution for 1 h. The resulting suspension is kept under stirring for 3 h, filtered and the isolated solid is washed with a mixture of ethanol and cold water (3: 1). The solid is then dried with a vacuum oven for 10 h at 40 ° C. 36.2 g of a pale yellow solid are obtained which is identified as (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3.5- ( O- Isopropylidene) tert -butyl dihydroxyheptanoate.

1 H NMR ( 400 MHz, CDCl 3 ): δ 1.04 (q, 1 H, J = 11.9, H4a), 1.29 and 1.36 (2 xs, 2 x 3 H, CMe 2), 1.33 (m, 1 H, H4b), 1.43 (s, 9 H, CMe 3), 1.53 (d, 6 H, J = 7.2 , CH me _ {2}), 1.6-1.7 (m, 2H, H6a H6b and), 2.23 (dd, 1H, J = 15.2} {2a2b, J {2a3 } = 6.2, H2a), 2.38 (dd, 1H, J = 15.2} {2a2b, JAB = 6.8} {2b3, H2b), 3.57 (hept, 1H, C H (Me) 2), 3.68 (m, 1 H, H5), 3.82 (m, 1 H, H7a), 4.06 (m, 1 H, H7b), 4.15 ( m, 1 H, H3), 6.86-7.26 (m, 15 H, aromatic H and NH).

13 C NMR ( 100.6 MHz, CDCl 3 ): δ 19.6 (C Me 2), 21.5 and 21.7 (CH Me 2), 26.1 (CHMe_ {2}), 28.1 (C I _ {3}), 29.9 (C I _ {2}), 35.9 (C4), 38.0 (C6), 40.8 (C7 ), 42.4 (C2), 65.9 (C5), 66.2 (C3), 80.7 ( C Me3), 98.6 ( C Me2), 115.2, 115.3, 115.4, 119.5, 121.5, 123.5, 126.5, 128.2, 128.3, 128.3, 128.8, 130.5, 133.1, 133.2, 134, 6, 138.4, 141.5, 161.0, 163.5, 164.8, 170.2 (2 x Ph, p -FC 6 H 4, C pyrrole, 2 X CO) .

Example 2

Formation of (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropyl-pyrrol-1-yl] -3,5- tert - butyl dihydroxyheptanoate

A suspension is prepared with 3.3 g (5.0 mmol) of (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl ] -3,5- ( O- Isopropylidene) tert -butyl dihydroxy heptanoate in 25 ml of ethanol (96%) and 10 ml (10 mmol, 2 equivalents) of 1 M aqueous hydrochloric acid are added thereto. The resulting mixture is heated to 50 ° C and allowed to stir at this temperature for 30 min. A solution of (3 R, 5 R) is obtained -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropilpirrol-1-yl] -3,5-dihydroxy-heptanoate tert -butyl in ethanol and water, which is used for the next stage.

Example 3

Atorvastatin sodium formation

On the solution of (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropyl-pyrrole-1-yl] -3,5-dihydroxyheptanoate tert - Butyl of Example 2 9.5 ml (19 mmol) of a 2M aqueous solution of sodium hydroxide is added. The mixture is stirred for 30 minutes at 50 ° C until complete formation of the atorvastatin sodium salt. To the solution 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 2M HCl solution.

Example 4

Preparation of raw amorphous calcium atorvastatin

The final solution of atorvastatin sodium Example 3 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 After the addition, the mixture is allowed to cool until 20 ° C, stir for 3 h at this temperature, and 1 h more at 0 ° C. After this period, the resulting suspension and solid are filtered. Insulated is washed with water and dried under vacuum at 40 ° C. 2.5 g are isolated of amorphous calcium atorvastatin, whose wealth is 98% per HPLC

Example 5

Preparation of (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropyl-pyrrole-1-yl] -3,5-methyl dihydroxyheptanoate

A mixture consisting of 1.1 ml (15 mmol) of acetyl chloride and 30 ml of ethanol (96%) is prepared and allowed to stir for 5 minutes at 20 ° C. After this period, 0.8 ml (15 mmol) of ethylene glycol and 3.3 g (5.0 mmol) of (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl- are added to the mixture 2- (4-fluorophenyl) -5-isopropilpirrol-1-yl] -3,5- (O -isopropylidene) -dihidroxiheptanoato tert -butyl and kept under stirring for 4 hours at the same temperature. An ethanolic solution of (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoate is obtained, It is used for the next stage.

Example 6

Atorvastatin sodium formation

To the solution of (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoate in ethyl ethanol Example 5, 12 ml (24 mmol) of a 2M aqueous solution of sodium hydroxide is added and the resulting mixture is stirred for 30 minutes at 20 ° C until complete formation of the atorvastatin sodium salt. To the resulting solution of atorvastatin sodium salt is added 20 ml of water and treated with 60 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 2M hydrochloric acid solution.

Example 7

Preparation of raw amorphous calcium atorvastatin

The final solution of atorvastatin sodium Example 6 is heated to 60 ° C and an aqueous solution is added formed by 0.50 g (2.8 mmol) of calcium acetate monohydrate and 14 ml of water After the addition, the mixture is allowed to cool until 20 ° C and stir for 4 h. After this period, it is allowed to cool up to 0 ° C and stir for another hour. Then it filter the resulting suspension and the isolated solid is washed with water and dried under vacuum at 40 ° C. 2.2 g of atorvastatin are isolated amorphous calcium, 90% richness by HPLC.

Example 8

Preparation of (3 R , 5 R ) -2- [2- (3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropyl-pyrrol-1-yl] ethyl-4-hydroxytetrahydropyran-2- ona

A solution of 3.3 g (5.0 mmol) of (3 R , 5 R ) -7- [3-phenyl-4-phenyl-carbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1 is prepared -il] -3,5- ( O- isopropylidene) tert -butyl dihydroxyheptanoate in 15 ml of dioxane. The mixture is cooled to 0 ° C and 1.5 ml (17.5 mmol) of a 36% hydrochloric acid solution is added slowly. The temperature is allowed to rise to 20 ° C and is kept under stirring for 3 hours at this temperature. A solution of the indicated compound in dioxane is obtained, which is used for the next step.

Example 9

Atorvastatin sodium formation

To the final solution of Example 8 (atorvastatin lactone in dioxane) is added 8.3 ml (25 mmol) of a 3M aqueous solution of sodium hydroxide and the mixture is stirred for 30 minutes at 20 ° C. To the resulting solution of the atorvastatin sodium salt is added 50 ml of water and treated with 60 ml of toluene. The phases are separated and the organic phase is discarded. To the aqueous phase the pH is adjusted to 7.8 with 2M hydrochloric acid solution and 60 ml of ethanol are added, obtaining purified sodium atorvastatin in solution for the following
stage.

Example 10

Preparation of raw amorphous calcium atorvastatin

The final solution of atorvastatin sodium Example 9 is heated to 60 ° C and an aqueous solution is added formed by 0.50 g (2.8 mmol) of calcium acetate monohydrate and 30 ml of water After the addition, the mixture is allowed to cool until 20 ° C and stir for 3 h. After this period, the resulting suspension and the isolated solid is washed with water and Dry under vacuum at 40 ° C. 2.47 g of calcium atorvastatin are isolated amorphous, whose wealth is 89% by HPLC.

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Example eleven

Raw amorphous calcium atorvastatin purification

A suspension formed by 5.8 g (5 mmol) of raw amorphous calcium atorvastatin in 145 ml of a mixture of ethanol and water (3: 1) and heated at 60 ° C until it is obtained a solution It is then treated with activated carbon during 30 min at the same temperature. The mixture is filtered again on a bed of celite, and washed with 90 ml of ethanol and water (3: 1). The mixture formed by the filtrate plus the washing solvent is Concentrate to half its volume by pressure distillation atmospheric 30 ml of water are added to the resulting concentrate while maintaining constant agitation. This way you It has a final ratio of water and ethanol from 3 to 2. Once the addition the suspension is cooled to 20 ° C, leaving the solid in maturation for 2 h. After this period the suspension 1 is cooled 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 5.0 g of quality amorphous calcium atorvastatin Pharmaceutical

1 H NMR ( 400 MHz, dmso-d 6 ): δ 1.24 (m, 1 H, H4a), 1.36 (d, 6 H, J = 7.2, CH (Me) 2), 1.40 (m, 1 H, H4b), 1.51-1.62 (m, 2 H, H6a and H6b), 1.96 (dd, 1 H, J 2a2b) = 15.2, J = 8.2} {2a3, H2a), 2.38 (dd, 1H, J = 15.2} {2a2b, J = 3.6} {2b3, H2b), 3.22 (hept, 1 H, C H (Me) 2), 3.52 (m, 1 H, H5), 3.77 (m, 2 H, H3 and H7b), 3.97 ( m, 1 H, H7b) 6.98 (m, 2 H), 7.06 (d, 4 H, J = 4.4), 5.15-7.25 (m, 6 H), 7.50 (d, 2 H, J = 7.6), 9.78 (s, 1 H, NH).

13 C NMR (100.6 MHz, dmso-d 6): 8 22.3 (CH Me 2), 25.7 ( C HMe 2), 39.6 (C6 ), 40.9 (C7), 43.6 (C4), 44.0 (C2), 66.3 (C5 and C3), 115.3, 115.5, 117.5, 119.4, 120, 6, 123.0, 125.4, 127.3, 127.6, 128.4, 128.7, 129.15, 133.3, 133.4, 134.9, 136.0, 139.5, 160.4, 162.8, 166.2, 178.5 (2 x Ph, p -FC 6 H 4, C pyrrole 2 x CO).

[α] 20 λ (dmso, c = 0.93): - 49.0 ° (λ = 366 nm); -29.8 ° (λ = 407 nm); - 22.7 ° (λ = 437 nm); - 11.0 ° (λ = 547 nm); - 9.7 ° (λ = 576 nm).

Claims (23)

1. Procedure for obtaining amorphous calcium atorvastatin, of formula I:

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17

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characterized in that it comprises the following stages: (a) reacting N -phenyl-2- [1-phenyl-2- (4-fluorophenyl) -2-oxo] ethyl-4-methyl-3-oxo-pentanarnide, of formula II,

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18

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with (3 R , 5 R ) -7-amino-3,5- ( O- isopropylidene) tert - butyl dihydroxyheptanoate, of formula III,

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19

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refluxing toluene in the presence of an acid catalyst, to form (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl 2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3, Tert-Butyl 5- ( O- isopropylidene) dihydroxyheptanoate, of formula IV;

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twenty

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(b) isolation of the compound of formula IV; (c) deprotection of hydroxyl groups of compound of formula IV; (d) addition of an aqueous hydroxide solution sodium over the mixture resulting from step (c), to form atorvastatin sodium, of formula VIII; twenty-one (e) purification of the aqueous solution of the compound of formula VIII; (f) react the compound of formula VIII in water and low molecular weight alcohol solution with a organic or inorganic calcium salt to form calcium atorvastatin amorphous (g) Calcium atorvastatin isolation raw amorphous; (h) drying of raw calcium atorvastatin amorphous (i) purification of raw calcium atorvastatin amorphous by dissolving in a mixture of ethanol and water, precipitation of the final product by concentration of the filtrate by water distillation and addition, isolation and drying of the solid formed. 2. Method for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that the acid catalyst used in the first stage of the process is selected from pivotal acid and acetic acid. 3. Procedure for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that the reaction of step (a) is carried out by means of an azeotropic water removal process, which is generated in the course of the reaction, and is prolongs for a time between 8 and 12 hours, at a temperature of 80 - 90 ° C. 4. Process for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that the step (b) of isolation of the compound of formula IV is carried out by precipitation of said compound in a mixture of ethanol and water. 5. Procedure for obtaining amorphous calcium atorvastatin, according to claim 4, characterized in that the ethanol and water are in a 3: 1 ratio. Method for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that step (c) is carried out by reacting the compound of formula IV in a methanol solution and in the presence of ethylene glycol and a chloride chloride generating agent. hydrogen to form (3 R , 5 R ) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl-3,5-dihydroxyheptanoate, of formula V. 22 7. Method for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that step (c) is carried out by reacting the compound of formula IV dissolved in ethanol with an aqueous solution of hydrochloric acid to form (3 R , 5 R ) -7- [3-Phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5- tert - butyl dihydroxyheptanoate, of formula VI. 2. 3 8. Method for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that step (c) is carried out by reacting the compound of formula IV in dioxane solution with a solution of hydrochloric acid to form (3 R , 5 R ) -2- [2- (3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl-4-hydroxytetrahydropyran-2-one of formula VII. 24 9. Process for obtaining amorphous calcium atorvastatin, according to claim 6, characterized in that the hydrogen chloride generating agent is selected from acetyl chloride, trimethylsilyl chloride and thionyl chloride. 10. Method for obtaining amorphous calcium atorvastatin, according to claim 6, characterized in that the preferred amount of hydrogen chloride generating agent used in step (c) is between 2.5 3.5 equivalents. 11. Process for obtaining amorphous calcium atorvastatin, according to claim 7, characterized in that 1.5 to 2.5 equivalents of hydrochloric acid are used to obtain the compound of formula VI of step (c). 12. Process for obtaining amorphous calcium atorvastatin, according to claim 8, characterized in that between 3 and 5 equivalents of hydrochloric acid are used to obtain the compound of formula VII of step (c). 13. Method for obtaining amorphous calcium atorvastatin, according to claim 12, characterized in that the hydrochloric acid solution used can be of a concentration between 1 M and 6 M, preferably 6 M. 14. Method for obtaining amorphous calcium atorvastatin, according to claims 1 and 6, characterized in that in step (d), for the conversion of compound V into compound VIII, between 1.7 and 2.2 equivalents of hydroxide are added sodium with respect to compound IV, preferably 2 equivalents of a 2M aqueous solution, at a temperature between 15 and 25 ° C, maintaining the reaction for 15-45 minutes. 15. Procedure for obtaining amorphous calcium atorvastatin, according to claims 1 and 7, characterized in that in step (d), for the conversion of compound VI into compound VIII, between 3.5 and 4.5 equivalents of hydroxide are added sodium relative to compound IV, preferably 3.8 equivalents of a 2M aqueous solution, with an optimal reaction time is between 0.5 and 1.5 hours, and an optimum temperature between 35 and 50 ° C, preferably 40 ° C . 16. Process for obtaining amorphous calcium atorvastatin, according to claims 1 and 8, characterized in that in step (d), for the conversion of compound VII into compound VIII, between 4.5 to 5.5 equivalents of hydroxide are added sodium with respect to compound IV, preferably 5 equivalents of a 3M aqueous solution, the reaction proceeding in a period of time between 15 and 45 minutes, at a temperature between 15 and 25 ° C. 17. Method for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that in step (e), the purification of the compound of formula VIII in the aqueous phase is carried out by washing with an organic solvent selected from toluene, hexane, cyclohexane, butyl acetate or mixtures thereof with each other or with ethyl acetate, preferably toluene, hexane and mixture of hexane and ethyl acetate. 18. Method for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that the organic or inorganic calcium salt used in step (f) is selected from calcium acetate, calcium chloride and calcium nitrate, in any of its anhydrous or hydrated forms. 19. Procedure for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that step (f) is performed at a temperature between 40 and 60 ° C, adjusting the pH between 7.5 and 8.0. 20. Method for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that the isolation of amorphous crude calcium atorvastatin carried out in step (g) is produced by filtration. 21. Method for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that the drying of amorphous crude calcium atorvastatin is carried out in a vacuum oven for several hours, preferably at a temperature between 40 ° C and 60 ° C , and for a time that varies between 6 and 10 hours. 22. Method for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that in step (i) a mixture of ethanol and hot water in a 3: 1 ratio is used to dissolve the raw calcium atorvastatin. 23. Procedure for obtaining amorphous calcium atorvastatin, according to claim 1, characterized in that in step (i) the final proportion of water and ethanol is 3: 2.