ITMI20110397A1 - PROCEDURE FOR THE PREPARATION OF PYAVASTATIN AND ANALOGUES - Google Patents

Description

â € œPROCESS FOR THE PREPARATION OF PITAVASTATIN AND ANALOGSâ €

FIELD OF INVENTION

The present invention relates to a new process for the preparation of synthetic intermediates with β-ketoesterea structure useful in the preparation of statins, in particular Pitavastatin.

STATE OF THE TECHNIQUE

Statins are a class of pharmaceutical compounds useful in the treatment of cholesterolemia. Their mechanism of action is linked to the ability of these molecules to act as inhibitors of the activity of the 3-hydroxy-3-methylglutaric Coenzyme A reductase (HMG-CoA), which results in the hepatic inhibition of biosynthesis cholesterol. The molecular structure of statins is normally made up of a portion A and a side chain as reported below.

OH OH O

A (R) OH

where the link in bold represents a simple or double link.

Their activity is attributed precisely to the presence of the side chain, essentially consisting of a residue of 3,5-dihydroxy heptanoic acid which mimics the 3-hydroxy-3methylglutaric grouping of HMG-CoA.

The (R) configuration at C-3 and the relative syn configuration between the hydroxyls has been shown to be essential for obtaining high inhibitory activity. In all the statins developed and marketed to date, the main chemical problem to be solved was represented precisely by the synthesis of the optically active 3,5-dihydroxy heptanoic acid residue. The problem has so far been solved by using the most diverse methodologies, such as enzymatic and microbiological methods, (see Angew. Chem. Int. Ed.

2005, 44, 362-365), but also synthetics (Helvetica Chimica Acta, 2007, 1069-1081). Among the synthetic methods currently available there are both processes that involve the enantioselective synthesis of the acid, and those that lead to the formation of the racemic and subsequent resolution. All these methodologies have made it possible to obtain optically active synthetic intermediates, now also available on the market, which once inserted in the statin structure lead to the synthesis of the side chain in an optically active form.

In the case of synthetic methods that provide for the resolution of the racemic, or enzymatic ones that do not lead to derivatives of sufficiently high optical purity for the pharmacopoeia specifications, to obtain the statin of interest with enantiomeric excess values greater than 99.5 % treatments are necessary (for example purifications on chiral HPLC or crystallization of diastereoisomeric salts) capable of raising both the value of the enantiomeric excess and the chemical purity in general.

The first statin was mevastatin, isolated from Penicillium citrinum, and subsequently used in the synthesis of the semisynthetic statin pravastatin. The statins present on the market today, for example both semi-synthetic pravastatin and lovastatin, of completely natural origin, are characterized by having the side chain linked to nucleus A with a single C-C or C-N bond (the link in bold in the formula above reported). Recently, however, statins of completely synthetic origin such as rosuvastatin, fluvastatin and pitavastatin, with very high biological activity, have established themselves on the market. These statins are characterized by a side chain linked by a C = C double bond with a strictly (E) geometry (link in bold of the above formula) to the A nucleus of the statin, normally having a complex aromatic structure. Also in this case the approaches to solving the problem of the absolute configuration of the double bond have been the most varied and the proposed syntheses have been both consecutive and convergent. In particular, however, methods have been developed and optimized to obtain in a convergent way the formation of the statin with the double bond with geometry (E). These methods are based on the classical methodologies of the formation of double bonds (E) by means of olefination reactions on suitable aldehydes, present indifferently or on the aromatic portion or on the side chain of the statin, through reactions of Wittig, Horner-Emmons or Julia, as well summarized. in Organic Process Research & Development 2001, 5, 519-527 for fluvastatin.

Although these methods have led to the obtaining of several highly commercially successful statins, these syntheses still suffer in many cases from regioselectivity problems, linked to the formation of the statin impurity with the double bond configuration (Z), problems of costs related to the € ™ use of expensive, delicate or reactive organic bases and reactives to be prepared in situ under sophisticated reaction conditions, and in the case of phosphoranes and phosphonates, used for Wittig, also the problem of disposing of waste containing organic phosphorus.

There is therefore a need for a more advantageous alternative method to prepare statins, in particular those of formula (I), reported here, containing a double bond -C = C- with configuration (E) between the side chain and in nucleus A, and intermediates useful for their synthesis. In particular, this new method should be more simply industrially scalable, foresee the use of possibly more stable and economical reagents, at the same time providing high yields and more environmentally friendly and easily disposable process wastewater.

SUMMARY OF THE INVENTION

It has now surprisingly been found that it is possible to prepare statins of formula (I) containing a double bond -C = C- with configuration (E), from intermediates of formula (II), obtained by Knoevenagel condensation. The intermediates of formula (II) thus obtained have a content of isomer with configuration (Z) lower than 1%, evaluated by HPLC.

DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is a process for the preparation of a compound of formula (II), or a salt thereof,

O OP O

R1

A O

(II)

where A is the residual group of a statin, P is a protecting group, and R1 is hydrogen, an optionally substituted C1-C12alkyl group, cycloalkyl, aryl, or an optionally substituted aryl-C1-C12alkyl group; comprising the condensation of an aldehyde of formula (III)

<A CHO> (III)

where A is as defined above, with a β-ketoacid compound of formula (IV), or a salt thereof,

O OOP O

R1

H O <O> (IV)

where P and R1 are defined as before, in the presence of a catalyst, and if necessary in a solvent, and subsequent spontaneous decarboxylation.

For example A may be the residual group of a statin chosen from among Pitavastatin, Fluvastatin, Glenvastatin, Rosuvastatin, Cerivastatin and Bervastatin. This residue can be represented by one of the cyclical structures shown below.

F F

No.

N N

Pitavastatin Fluvastatin Glenvastatin

F F F

O O N O S

N N N O

Rosuvastatin Cerivastatin Bervastatin

where the dotted line indicates where the side chain attaches to the statin residue. Preferably the residual group A is the nucleus of pitavastatin, fluvastatin or rosuvastatin.

P is one of the protective groups used in sugar chemistry, preferably the tert-butyl dimethylsilyl group.

A C1-C12alkyl group can be linear or branched, unsubstituted or substituted by one or two substituents independently selected from hydroxy, acetoxy and C1-C4alkoxy, preferably a C1-C4alkyl group, more preferably methyl or tert-butyl.

A cycloalkyl group can be for example a C3-C8cycloalkyl group, for example cyclohexyl.

An aryl group is for example a C6-C12aryl group, preferably phenyl or naphthyl, in particular phenyl.

An aryl-C6-C12alkyl group, where the alkyl is unsubstituted or substituted by one or two substituents independently selected from hydroxy, acetoxy and C1-C4alkoxy, is for example benzyl or phenylethyl, preferably benzyl.

Knoevenagel condensation between a compound of formula (III) and one of formula (IV) can be carried out according to known methods, in particular in the presence of a catalyst.

In particular, the catalyst can be a basic or acidic, organic or inorganic catalyst or an amino acid.

An organic basic catalyst can be chosen between a secondary amine and a tertiary amine, either weak or strong, cyclic or acyclic, or one of its salt, for example piperidine or one of its salt, typically acetate salt.

An inorganic basic catalyst can be selected for example between a carbonate of an alkali metal and a hydroxide of an alkali metal, preferably sodium or potassium.

Alternatively, Knoevenagel condensation can be carried out with a Lewis acid catalyst. A Lewis acid can for example be chosen from among ZnCl2, FeCl3, TiCl4, Ti tetraisopropoxide, AlCl3, BF3eterate, a halide, for example a chloride or a trifluoromethanesulfonate of a transition metal of the lanthanide series, preferably lanthanum trifluoromethanesulfonate in both anhydrous form that hydrates.

An amino acid can be, for example, an Î ± -amino acid, β-amino acid, γ-amino acid, Î ́∠amino acid, or a ε-amino acid; if this is an Î ± -amino acid it may have a residue of natural or synthetic origin in the side chain. This amino acid can be selected for example from the group comprising glycine, Î ± -alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, proline, aspartic acid, asparagine, glutamic acid, L, Î ± -aminoadipic acid, Î -alanine, γ-aminobutyric acid, Î ́-aminovaleric acid, ε-aminocapronic acid, taurine and L-phenylserine. It is preferably selected from the group comprising glycine, Î ± -alanine, β-alanine, Î ́-aminovaleric acid and ε-aminocapronic acid; more preferably β-alanine.

The condensation of Knoevenagel, if necessary, can be carried out in a solvent, for example an aprotic polar solvent, typically an amide, for example dimethylformamide, dimethylacetamide or N-methylpyrrolidone, preferably dimethylacetamide; acetonitrile; dimethyl sulfoxide; or in a solvent selected from an ether, for example tetrahydrofuran or dioxane; a chlorinated solvent, for example, dichloromethane, dichloroethane, chloroform or chlorobenzene; an ester, for example ethyl or methyl acetate; a non-polar aprotic solvent typically toluene; or a polar protic solvent, for example water or a C1-C5alkanol, preferably methanol; or a mixture of two or more, preferably two or three, of said solvents.

The reaction can be carried out at a temperature comprised between about 0 ° C and the reflux temperature of the solvent, preferably between about 25 ° C and 85 ° C, more preferably between 35 ° C and 45 ° C.

The crude compound of formula (II) thus obtained has the double bond in configuration (E) and an isomer content in configuration (Z) lower than 1%, evaluated by HPLC.

A further object of the invention is a statin of formula (I), or a salt thereof, with a content of configuration isomer (Z) lower than 1%, preferably between about 0.01 and 0.1 %, evaluated by HPLC.

A compound of formula (II), or a salt thereof, thus obtained, can be converted into a statin of formula (I), or a single salt, according to known methods, for example according to the following scheme reported in WO 03064392 .

OOP O 1) deprotection OHOH <O> R1 2) diastereoselective reduction A OH A O 3) saponification

(II) (I)

where A, P and R1 are as defined above.

Therefore, the invention also provides a process comprising the conversion of a compound of formula (II), or a salt thereof, obtained starting from a compound of formula (IV), into a statin of formula (I), or one of its salt,

OHOH <O>

A OH

(THE)

where A is the residual group of a statin.

In a preferred aspect of the invention a salt of a compound of formula (I), where A is the residue of Pitavastatin, is a salt with (R) -naphthylethylamine [(R) -NEA], having the following formula (IX)

NH2OH OH O

A OH * ;;; (IX); It has indeed been surprisingly found that the salt of Pitavastatin with (R) -naphthylethyl amine, of formula (IX), can be isolated by crystallization, for example from an organic solvent, preferably a ketone, typically acetone, an alkanol, typically isopropanol, or a mixture thereof or a mixture of one or two of them with water, to obtain a product with a high degree of chemical and optical purity, in both cases, equal to or greater than 99%, typically equal to or greater than 99.5%. In particular, the Pitavastatin salt with (R) -naphthylethyl amine of formula (IX) having this degree of purity can be converted into another Pitavastatin salt, for example in the calcium salt, with known methods. ; A Pitavastatin salt thus obtained using a salt of formula (IX) with such purity similarly presents a high degree of both chemical and optical purity, in both cases, equal to or greater than 99%, typically equal to or greater than 99, 5%. This conversion can be carried out, for example, by treating an aqueous solution of the salt of formula (IX) with an acid, to obtain by extraction with an organic solvent, for example an alkyl ester of a carboxylic acid, in particular acetate of ethyl, an ether, in particular t-butyl methyl ether, a solution of Pitavastatin, which can optionally be converted into another pharmaceutically acceptable salt, for example the calcium salt. An acid can be for example an aqueous solution of an organic or mineral acid, preferably an aqueous solution of HCl. ; A further object of the invention is therefore a purification process of Pitavastatin, or one of its salt, comprising the conversion of Pitavastatin or one of its salt, into a salt of Pitavastatin with (R) -naphthylethyl amine, the isolation in crystalline form, and the subsequent conversion into Pitavastatin or another salt thereof. The salt of Pitavastatin with (R) -naphthylethyl amine of formula (IX), in particular in solid form, preferably in crystalline form, is a new compound and constitutes a further object of the invention. The compounds of formula (III) can be prepared as described for example in Organic Process Research & Development 2001, 5, 519-527, for the case of fluvastatin and are commercially available. ; A compound of formula (IV), or a salt thereof, can be prepared starting from a compound of formula (V), or a salt thereof, by selective removal of the ester group R2,; O OOP OO OOP O ;; R2 R1 R1; OO H O <O> ;; (V) (IV); where P is as defined above; R2 is a C1-C12alkyl, cycloalkyl, aryl, or aryl-C1-C12alkyl group; and R1 is as defined above. In a compound of formula (V), when R1 is different from hydrogen, R1 and R2 can be the same or different. Preferably R2à benzyl and R1à ̈ methyl. Preferably R2 can be removed to give the free carboxylic acid of formula (IV) in a selective manner with respect to the protection P and possibly to the R1 group when this is different from hydrogen. For example, according to a preferred aspect of the invention, when in a compound of formula (V) R1à ̈ methyl, R2à benzyl, the removal of the benzyl group can be carried out by catalytic hydrogenation with the methods known to the person skilled in the art. € ™ art. The compounds of formula (IV) and (V), or a salt thereof, are new and constitute a further object of the present invention. A further object of the invention is the use of a compound of formula (IV) in a process for the preparation of a statin of formula (I). ; A compound of formula (V), or a salt thereof, can be prepared by reaction between a compound of formula (VI), or a salt thereof, and a compound of formula (VII), or a salt thereof, in the presence of a solvent ;;; O O O OP OOO <OP O>; R2 R1 R2 R1; O OHXOO O ;; (VI) (VII) (V); where P, R1 and R2 are as defined above and X is a leaving group, preferably a halogen, in particular chlorine, or imidazole. The solvent is preferably an ethereal solvent, for example tetrahydrofuran or apolar aprotic, typically toluene. ; Malonic acid monoester (VI) where R2, being defined as above, is preferably benzyl can first be converted into its magnesium salt by treatment with at least 2 equivalents of a Grignard reagent, for example isopropylmagnesium chloride, and then reacted with a compound of formula (VII), to yield, after spontaneous decarboxylation, the compound of formula (V). ; A compound of formula (VI) is commercially available or can be prepared with known methods for monoesterification of malonic acid. ; A compound of formula (VII), or a salt thereof, can in turn be prepared by activating the carboxyl function of a compound of formula (VIII), or a salt thereof, ;;; O OP O O OP O; R1 R1 ;; H OOX O ;; (VIII) (VII); where P, R1 and X are as defined above. When X is chlorine, the activation of the carboxylic acid of formula (VIII) can be carried out using for example thionyl chloride, when X is imidazole, for example carbonyldiimidazole can be used. ; A compound of formula (VIII) is commercially available or can be prepared for example by chemical desymmetrization of hydroxyglutaric anhydride protected with the protective group P, previously defined, as reported for example in J. Org. Chem. 1994, 59, 7849-7854, or enzymatic desymmetry, as reported in Angew. Chem. Int. Ed. 2005, 44, 362-365. ; A salt of a compound of formula (II), (IV), (V), (VI), (VII) or (VIII) is for example a pharmaceutically acceptable salt. ; If desired, a compound of formula (I), (II), (IV), (V), (VI), (VII) or (VIII) can be converted into a salt thereof, or a salt of a compound of formula (I), (II), (IV), (V), (VI), (VII) or (VIII) can be converted into free acid, according to known methods. ; The following examples illustrate the invention. ; Example 1. Synthesis of a compound of formula (VII): (R) -methyl 3- (tert-butyldimethylsilyloxy) -5- (1H-imidazol-1-yl) -5-oxopentanoate; A solution of (S) - benzyl mandelate (6 g, 24.79 mmol) in anhydrous THF (100 mL) in N2 atmosphere is brought to -78 ° C and a 2.5 M BuLi solution in hexane (10.9 mL, 27.27 mmol) is added drop by drop. The mixture is kept under stirring at -78 ° C for 20 minutes, then a solution of 3 - [(tert-butyldimethylsilyl) oxy] pentanedioic anhydride (6.05 g, 24.79 mmol) in anhydrous THF (25 mL) and the resulting mixture is kept under magnetic stirring at -78 ° C for 2 hours. The reaction is acidified with 1 N HCl and extracted with AcOEt. The organic phase is washed with 1 N HCl and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The reaction crude is purified by flash chromatography on silica gel (eluent: EtPet / AcOEt 4: 1) and the product obtained is dissolved in anhydrous THF (150 ml) and treated with dimethyl dicarbonate (2.47 mL, 23 , 04 mmol) and DMAP (201 mg, 1.65 mmol). The mixture is kept stirred at 25 ° C for 20 minutes, then the solvent is evaporated under reduced pressure and the residue purified by flash chromatography (eluent: EtPet / AcOEt 9: 1). The colorless oil obtained is dissolved in ethyl acetate (90 mL) and the resulting solution is kept under stirring in an H2 atmosphere in the presence of 20% Pd (OH) 2 / C (652 mg, 0.93 mmol) at 20 ° C for 10 hours. The mixture is filtered on perlite and the solvent is evaporated under reduced pressure. The raw reaction product (containing phenylacetic acid as an impurity) is solubilized in anhydrous THF in an N2 atmosphere and treated with 1,1â € ™ -carbonyldiimidazole (3.02 g, 18.68 mmol). The mixture is left under stirring at 20 ° C for 3 hours. The solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel (eluent: EtPet / AcOEt 30:70). 2.85 g of a light yellow oil are obtained (yield 41.6% over 4 passages). ;; <1> H NMR (400 MHz, CDCl3) Î ́: 8.06 (s, 1H); 7.37 (s, 1H), 6.92 (s, 1H); 4.54-5.52 (m, 1H); 3.53 (s, 3H); 3.04-2.96 (s, 2H); 2.50-2.40 (m, 2H); 0.62 (s, 9H); -0.1 (s, 3H), -0.21 (s, 3H). <13> C NMR (100 MHz, CDCl3) Î ́: 170.36; 167.19; 136.06; 130.47; 115.68; 65.69; 51.11; 42.35; 41.41; 24.95; 17.17; -5.58; -5.79. MS (ES <+>): m / z 349 [M + Na] <+>. ; Example 2 Synthesis of a compound of formula (V): (R) -1-benzyl 7-methyl 5- (tert-butyldimethylsilyloxy) -3-oxoheptanediumate; Isopropyl magnesium chloride (2 M in THF, 15.10 mL, 30 , 20 mmol) is added dropwise to a solution of monobenzyl malonate (2.93 g, 15.10 mmol) in anhydrous THF (28 mL) maintained at 0 ° C in an N2 atmosphere. After 30 minutes at 0 ° C the solution is heated to 50 ° C for 30 minutes, then cooled again to 0 ° C and a solution of (VII) prepared as in Example 1 (4.1 g, 12, 58 mmol) in anhydrous THF (28 mL). The mixture is left under stirring at 20 ° C for 12 hours, then 1 M HCl is added and extracted with Et2O. The organic phase is washed with 1 M HCl and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash chromatography on silica gel (eluent: EtPet / AcOEt 9: 1). 3.74 g of a yellow oil are obtained with a yield of 73%. ;; <1> H NMR (400 MHz, CDCl3) Î ́: 7.32-7.28 (m, 5H); 5.12 (s, 2H); 4.57-4.52 (m, 1H); 3.60 (s, 3H); 3.47 (s, 2H); 2.75 (d, J = 6.2H); 2.51-2.37 (m, 2H); 0.81 (s, 9H); 0.03 (d, J = 10, 3H). <13> C NMR (100 MHz, CDCl3) Î ́: 200.23; 170.76; 166.24; 134.93; 128.14; 127.95; 127.83; 127.66; 66.61; 65.06; 51.04; 49.89; 49.54; 41.65; 25.26; 17.42; -5.29; -5.45. MS (ES <+>): m / z 431 [M + Na] <+>. ; Example 3. Synthesis of a compound of formula (VII): (R) -methyl 3- (tert-butyldimethylsilyloxy) -5- (1H-imidazol-1-yl) -5-oxopentanoate; A solution of (R) - benzyl mandelate (49.4 g, 204 mmol) in anhydrous THF (500 mL) in an N2 atmosphere is brought to -78 ° C and a solution of Hexyllithium 2.3 M in THF (97 mL, 224 mmol, 1.1 equivalents) is drop by drop addition. The mixture is stirred at -78 ° C for 30 minutes, then a 3 - [(tert-butyldimethylsilyl) oxy] pentanedioic anhydride solution (50.0 g, 204 mmol) in anhydrous THF (100 mL) is added and the resulting mixture is kept under magnetic stirring at -78 ° C for 2 hours. The reaction heated to â € “15 ° C, is acidified with 1 N HCl and extracted with AcOEt. The organic phase is washed with 1 N HCl and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The raw reaction product is dissolved in cyclohexane (250 ml) and kept under stirring at 20 ° C for 16h. The precipitated solid is filtered, washed with cyclohexane (50 ml) and the organic solution is evaporated under reduced pressure. The oil obtained is dissolved in MeOH (150 mL) and the solution is added to a solution of MeONa 25% in MeOH (370 ml) kept at 7 ° C under stirring in an N2 atmosphere. Once the addition is complete, it is left to react for 1 hour at 7 ° C, the reaction mixture is poured into a 6.5% HCl solution (1000ml) and it is left to react for 10 minutes. It is extracted with AcOEt, the organic phase is washed with brine, anhydrified on Na2SO4, filtered and evaporated under reduced pressure. The resulting oil is dissolved in toluene, extracted with a solution of K2CO35% in water and the aqueous phase is washed with toluene and treated with HCl 37%. The phases are separated and the aqueous phase is extracted with AcOEt, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The raw reaction product is solubilized in toluene in an N2 atmosphere and treated with 1,1â € ™ -carbonyldiimidazole (18.8 g, 115.6 mmol, 1.1 equivalent). The mixture is left under stirring at 20 ° C for 2 hours and then at 5 ° C for 1 hour. The solid in suspension is filtered and the toluene solution thus obtained is used directly in the next step as described in Example 2.; Example 4. Synthesis of a compound of formula (IV): Acid (R) -5- (terbuthyldimethylsilyloxy) - 7-methoxy-3,7-dioxoheptanoic. ; A solution of compound (V) prepared as in example 2 (1.1 g, 2.70 mmol) in AcOEt (30 mL) is kept under stirring in an H2 atmosphere in the presence of 10% Pd / C (287 mg, 0 , 27 mmol) at room temperature for 2 hours. The mixture is filtered on perlite and the solvent is evaporated under reduced pressure at 30 ° C. The reaction crude (885 mg) is used without further purification in the subsequent preparation. ; MS (ES <+>): m / z 341 [M + Na] <+>. Example 5. Synthesis of a compound of formula (II): (R, E) -methyl 3- (tert-butyldimethylsilyloxy) -7- (2-cyclopropyl-4 - (- 4-fluorophenyl) quinolin-3-yl) -5-oxoept-6-enoate; The compound (IV) obtained as in Example 4 (885 mg, 2.78 mmol) is solubilized in DMF (4 mL) in an atmosphere of N2 and 2-cyclopropyl-4- (4 -fluorophenyl) quinoline-3-carbaldehyde (271 mg, 0.93 mmol) and piperidine (46 µL, 0.46 mmol). The mixture is left under magnetic stirring at room temperature for 15 minutes, then it is heated to 40 ° C for 10 hours. The solution is diluted with AcOEt and washed with 1 N HCl and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash chromatography on silica gel (eluent: EtPet / AcOEt 9: 1). 280 mg of a light yellow oil are obtained with a yield of 55%. ;; <1> H NMR (400 MHz, CDCl3) Î ́: 7.93 (d, J = 8, 1H); 7.63-7.57 (m, 2H); 7.36-7.29 (m, 2H); 7.19-7.16 (m, 4H); 6.31 (d, J = 16.1H); 4.57-4.54 (m, 1H); 3.63 (s, 3H); 2.74-2.62 (m, 2H); 2.50-2.38 (m, 2H); 2.34-2.30 (m, 1H); 1.38-1.36 (m, 2H); 1.05-1.03 (m, 2H); 0.79 (s, 9H); 0.03 (s, 3H); -0.02 (s, 3H). <13> C NMR (100 MHz, CDCl3) Î ́: 196.80; 170.89; 163.40; 160.93; 159.51; 146.96; 145.57; 139.70; 133.72; 131.86; 131.27; 131.21; 129.35; 128.57; 126.63; 125.80; 125.46; 125.25; 115.39; 115.18; 65.47; 51.03; 47.61; 41.95; 25.23; 17.43; 15.89; 10.23; 10.16; -5.20; -5.42. MS (ES <+>): m / z 570 [M + Na] <+>. Example 6. Synthesis of a compound of formula (I): (3R, 5S, E) -7- (2cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyept-6-enoic calcium salt (Pitavastatin calcium salt); A solution of (II) prepared as in Example 5 (735 mg, 1.34 mmol) in MeOH (12 mL) is brought to 0 ° C and HCl 2 M (1 mL, 2.01 mmol) drop by drop. The mixture is left under stirring at 20 ° C for 4 hours. The solution is diluted with AcOEt and washed with a saturated solution of NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash chromatography on silica gel (eluent: EtPet / AcOEt 3: 2). A solid is obtained which is dissolved in anhydrous THF (1.5 mL) and MeOH (1.5 mL). The solution is then added dropwise to a suspension of NaBH4 (55 mg, 1.45 mmol) and 1 M diethylmethoxyborane in THF (1.04 mL, 1.04 mmol) in anhydrous THF (6 mL) maintained at -78 ° C. The reaction mixture is kept stirred at -78 ° C and after 30 min it is treated with a saturated solution of NaHCO3 and extracted with AcOEt. The organic phase is washed with water, anhydrified on Na2SO4, filtered and concentrated under reduced pressure. The residue obtained is dissolved in AcOEt (6 mL) and the solution is heated to 50 ° C. A 35% aqueous solution of H2O2 (286 µL, 3.33 mmol) is added and the mixture is left under magnetic stirring at 50 ° C for 1 hour. Then brine (6 mL) is added and left at 50 ° C for 20 minutes; finally an aqueous solution of Na2SO3 (223 mg in 6 mL of H2O) is added and the mixture is kept under stirring at 50 ° C for a further 5 minutes. The organic phase is washed with water, anhydrified on Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash chromatography on silica gel (eluent: EtPet / AcOEt 3: 2). A yellow solid is obtained which is dissolved in MeOH (7 mL) and treated with 1 M NaOH. The mixture is kept under stirring at 20 ° C for 2 hours, then the solvent is evaporated under reduced pressure at 40 ° C. The residue is dissolved in H2O and treated dropwise with an aqueous solution of CaCl2 (103 mg, 0.93 mmol). A white solid is instantly formed, which is kept under stirring at 20 ° C for 10 hours. The precipitate is filtered, washed with H2O and dried under reduced pressure at 40 ° C for 4 hours. 348 mg of pitavastatin calcium salt are obtained as a white solid. ;; <1> H NMR (400 MHz, DMSO) Î ́: 7.80 (d, J = 8, 1H); 7.58 (t, J = 8.1H); 7.36-7.20 (m, 6H); 6.44 (d, J = 16.1H); 6.03 (bs, 1H); 5.56 (dd, J1 = 5, J2 = 16, 1H); 4.86 (bs, 1H); 4.11-4.07 (m, 1H); 3.58-3.56 (s, 1H); 2.04-2.00 (m, 1H); 1.89-1.83 (m, 1H); 1.38-1.33 (m, 1H); 1.19-1.04 (m, 2H); 1.00-0.97 (m, 2H); 0.83-0.77 (m, 2H). <13> C NMR (100 MHz, DMSO) Î ́: 178.13; 163.04; 160.59; 160.50; 145.94; 143.68; 142.28; 133.12; 132.19; 131.89; 129.67; 128.81; 128.39; 125.71; 123.10; 115.36; 115.15; 68.85; 65.67; 44.50; 43.79; 15.38; 10.75. MS (ES <+>): m / z 444 [M + Na] <+>. ; Example 7. Synthesis of a compound of formula (IV): Acid (R) -5- (terbuthyldimethylsilyloxy) -7-methoxy-3,7-dioxoheptanoic; A solution of the compound (V) prepared as in Example 2 (46, 8 g, 115 mmol) in AcOEt (1.3 L) is kept under stirring in an H2 atmosphere in the presence of 10% Pd / C (12.2 g, 5.75 mmol) at room temperature for 3 hours. The mixture is filtered on perlite and the solvent is evaporated under reduced pressure at 30 ° C. The reaction crude (36.6 g) is used without further purification in the subsequent preparation. ; MS (ES <+>): m / z 341 [M + Na] <+>. Example 8. Synthesis of a compound of formula (II): (R, E) -methyl 3 (tert-butyldimethylsilyloxy) -7- (2-cyclopropyl-4 - (- 4-fluorophenyl) quinolin-3-yl) - 5-oxoept-6-enoate; The compound (IV) obtained as in Example 7 (36.6 g, 115 mmol) is solubilized in toluene (550 mL) in an N2 atmosphere and 2-cyclopropyl-4- (4- fluorophenyl) quinoline-3-carbaldehyde (100.5 g, 345 mmol, 3 equivalents), 4 Ã… (70 g) molecular sieves and β-alanine (30.7 g, 345 mmol, 3 equivalents). The mixture is left under mechanical stirring at 40 ° C for 16 hours. The solution is filtered over perlite and concentrated under reduced pressure. The oil obtained is dissolved in AcOEt, washed with 1 N HCl and brine, dried over Na2SO4, filtered and concentrated at reduced pressure. Hexane (430 ml) is added to the reaction crude and the suspension is heated to 40 ° C for 3 hours and then left to cool at room temperature over a period of 16 hours. The solid is filtered, washed with hexane and the organic solution is evaporated under reduced pressure. The oil obtained is used without further purification in the subsequent preparation. Example 9. Synthesis of a compound of formula (IX): Acid (3R, 5S, E) -7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyept- 6-enoic salt of (R) -NEA; A solution of (II) prepared as in Example 8 (27.9 g, 50.9 mmol) in MeOH (470 mL) is brought to 0 ° C and HCl 2 is added M (65 mL, 127.3 mmol, 2.5 equivalents) drop by drop. The mixture is left under stirring at 20 ° C for 16 hours. The organic solvent is evaporated under reduced pressure, AcOEt (500 ml) is added and the organic phase is washed with a saturated solution of NaHCO3, with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash chromatography on silica gel (eluent: toluene / AcOEt 8: 2). A solid (16.3 g, 37.6 mmol) is obtained which is dissolved in anhydrous THF (55 mL) and MeOH (55 mL). The solution is then added dropwise to a suspension of NaBH4 (2.0 g, 52.6 mmol, 1.4 equivalent) and 1 M diethylmethoxyborane in THF (38 mL, 37.6 mmol, 1 equivalent) in THF anhydrous (215 mL) maintained at -78 ° C. The reaction mixture is kept stirred at -78 ° C and after 1 hour it is treated with a saturated solution of NaHCO3 and extracted with AcOEt. The organic phase is washed with water, anhydrified on Na2SO4, filtered and concentrated under reduced pressure. The residue obtained is dissolved in AcOEt (230 mL) and the solution is heated to 50 ° C. A 35% aqueous solution of H2O2 (10.5 ml, 115.8 mmol, 3.08 equivalent) is added and the mixture is left under magnetic stirring at 50 ° C for 1 hour. Then brine (230 mL) is added and left at 50 ° C for 30 minutes; finally an aqueous solution of Na2S2O5 is added (6.6 g in 120 mL of H2O) and the mixture is kept under stirring at 50 ° C for a further 10 minutes. The organic phase is washed with brine, anhydrified on Na2SO4, filtered and concentrated under reduced pressure. The solid obtained is dissolved in MeOH (315 mL) and treated with 1 M NaOH (45 mL, 45 mmol, 1.2 equivalents). The mixture is kept under stirring at 20 ° C for 2 hours, then the organic solvent is evaporated under reduced pressure at 40 ° C. The resulting aqueous phase is washed with methyl t-butyl ether and AcOEt, treated with 1N HCl up to pH = 4.5 and extracted with dichloromethane. The organic solution is dried on Na2SO4, filtered and concentrated under reduced pressure; the residue is dissolved in acetone (40 mL) and a solution obtained by dissolving (R) -NEA (6.5 mL, 40.5 mmol, 1.1 equivalents) in acetone (18 mL) is added to this solution. At the end of the addition, the precipitation of a white solid is observed, hexane (50 mL) is added drop by drop and the suspension is left under stirring at 20 ° C for 16 hours. It is filtered and the solid is subsequently recrystallized several times from acetone and from isopropanol / water. 7.1 g of the title compound are obtained, as a white crystalline solid, having a degree of both chemical and optical purity, in both cases, equal to 99.5%. ;; <1> H NMR (300 MHz, CDCl3) Î ́: 7.97 (d, 1H); 7.95 (d, 1H); 7.82 (d, 1H); 7.76 (d, 1H); 7.64 (d, 1H); 7.61-7.43 (m, 5H); 7.33-7.29 (m, 2H); 7.19-7.08 (m, 4H); 6.55 (d, 1H); 5.54-5.47 (m, 4H); 5.11 (dd, 1H); 4.24-4.14 (m, 1H); 3.82-3.68 (m, 1H); 2.47-2.36 (m, 1H); 1.96 (d, 2H); 1.66 (d, 3H); 1.38-1.19 (m, 3H); 1.15-0.97 (m, 3H). Example 10. Synthesis of a compound of formula (I): (3R, 5S, E) -7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyept-6 -enoic calcium salt (Pitavastatin calcium salt); The compound of formula (IX) obtained as in Example 9 (7.1 g, 12 mmol) is suspended in a biphasic water / AcOEt mixture (30ml / 90 ml). 1 N HCl is added up to pH = 4.1. The phases are separated and the aqueous phase is extracted with AcOEt; water (150 ml) and 30% NaOH are added to the combined organic phases up to pH = 10. The phases are separated and the aqueous phase is washed with AcOEt and methyl t-butyl ether. An aqueous solution of CaCl2 * 2H2O (530 mg, 3.6 mmol, 0.6 equivalent) is added to the aqueous solution by slow dripping. A white solid is instantly formed, which is kept under stirring at 20 ° C for 16 hours. The precipitate is filtered, washed with H2O and dried under reduced pressure at 40 ° C for 4 hours. 3.4 g (7.8 mmoles) of Pitavastatin calcium salt are obtained as a white solid.

Claims (10)

CLAIMS 1. Process for the preparation of a compound of formula (II), or a salt thereof, O OP O R1 <A> O (II) where A is the residual group of a statin, P is a protecting group, and R1 is hydrogen, an optionally substituted C1-C12alkyl group, cycloalkyl, aryl, or an optionally substituted aryl-C1-C12alkyl group; comprising the condensation of an aldehyde of formula (III) <A CHO> (III) where A is as defined above, with a β-ketoacid compound of formula (IV), or a salt thereof, O OOP O R1 H O <O> (IV) where P and R1 are defined as before, in the presence of an amino acid as catalyst, and, if necessary, in a solvent, and the subsequent decarboxylation. 2. A process according to claim 1, where the amino acid catalyst is a Î ± -amino acid, β-amino acid, γ-amino acid, Î ́∠amino acid, or a ε-amino acid; where said Î ± -amino acid may have a residue of natural or synthetic origin in the side chain. 3. A process according to claim 2, where the amino acid catalyst is selected from the group comprising glycine, Î ± -alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, proline, aspartic acid, asparagine, glutamic acid , L, Î ± -aminoadipic acid, β-alanine, γ-aminobutyric acid, Î ́-aminovaleric acid, ε-aminocapronic acid, taurine and L-phenylserine. 4. A process according to claim 3, wherein the amino acid catalyst is selected from the group comprising glycine, Î ± -alanine, β-alanine, Î ́-aminovaleric acid and ε-aminocapronic acid; preferably β-alanine. 5. A process according to claim 1, where the solvent is selected from an aprotic polar solvent; acetonitrile; dimethyl sulfoxide; an ether; a chlorinated solvent; an ester; an apolar aprotic solvent; and a polar protic solvent; or a mixture of two or more, preferably two or three, of said solvents. 6. A process according to claim 1, further comprising the conversion of a compound of formula (II), or a salt thereof, into a statin of formula (I), or a salt thereof, OH OH O <A> OH (I) where A is the residual group of a statin. 7. Process for the purification of Pitavastatin or one of its salt, including the conversion of Pitavastatin, or one of its salt, into a salt of Pitavastatin with (R) -naphthylethyl amine, the isolation in crystalline form and the subsequent conversion into Pitavastatin or in another of its rooms. 8. Process according to claim 7, wherein the Pitavastatin salt in purified form is the calcium salt. 9. Pitavastatin salt with (R) -naphthylethyl amine in solid form, preferably in crystalline form. 10. Pitavastatin salt with (R) -naphthylethyl amine, according to claim 9, having a degree of both chemical and optical purity, in both cases, equal to or greater than 99%, preferably equal to or greater than 99.5% .