Background to the invention Atorvastatin {[R-(R*, R*)]-2-(4-fluorophenyl)-ß, â-dihydroxy-5-(1-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-1 H-pyrrole-1-heptenoic acid} is an inhibitor of the enzyme hydroxy- methylglutaryl coenzyme-A reductase (HMG-CoA-R), which plays a key role in the biosynthesis of cholesterol. By virtue of that activity atorvastatin is an effective antihyper- lipoproteinaemic agent and lowers the level of harmful cholesterol in the blood. In that way it contributes to reducing the risk of atherosclerosis and accordingly the risk of infarction and stroke.

The synthesis of that compound is carried out, for example, in accordance with WO 89/07598 via an intermediate of formula III having the name 2- [2- (4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentano ic acid phenylamide.

For the preparation of atorvastatin, that compound is reacted, for example in accordance with WO 89/07598, which is incorporated herein by reference, with a statin side chain derivative of formula 5 wherein R is hydrogen, the radical of an alcohol, for example alkyl, such as lower alkyl, or substituted alkyl, such as naphthyl-or phenyl-lower alkyl, and Ri and R2 are alkyl, especially lower alkyl, more especially methyl, or substituted alkyl, such as phenyl-lower alkyl, and, with subsequent removal of the protecting group, is converted into the lactone analogue of atorvastatin of formula 6 Atorvastatin is formed by subsequent opening of the lactone ring.

The preparation of the key intermediate of formula IIl requires the use of a catalyst selected from 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazolium chloride, 3, 4-dimethyl-5- (2-hydroxy- ethyl)-thiazolium iodide, 3-ethyl-4- (2-hydroxyethyl)-4-methylthiazolium bromide, thiamine hydrochloride and the like in a base, such as N, N-diisopropylethylamine, pyridine, N, N-di- methylamine, triethylamine, 1, 8-diazabicyclo [5.4. 0] undec-7-ene, 4-dimethylaminopyridine, N, N, N', N'-tetramethylethylenediamine or the like. Some of those catalysts, especially those of interest, such as the thiazolium salts, have to be prepared separately.

The aim of the present invention is to provide new processes and intermediates for the preparation of a compound of formula III and of atorvastatin that have advantages over the methods already known and that, especially, enable the intermediates and end products to be prepared in high yields and/or enable reaction times to be significantly shortened.

General description of the invention The above-mentioned aims are achieved by the process according to the invention.

The invention relates especially to a process for the preparation of 2- [2- (4-fluorophenyl)-2- oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of formula III which is obtained by nucleophilic substitution from a compound of formula I wherein X is a nucleofugal leaving group, with a ketoamide of formula 11 in the presence of a base; (i) the compound of formula I being obtained by reacting a ketone of formula 2 with a reagent introducing the radical X; the compound of formula 2 in turn being obtained from a phenylacetic acid derivative of formula fV IV, wherein Y is halogen, acyl bonded via oxo or an activating hydrocarbyloxy or hydrocarbylthio radical, by reaction with fluorobenzene in the presence of a Friedel-Crafts catalyst ; and (ii) the ketoamide of formula 11 in turn being prepared by reacting with aniline an acid derivative of formula V V, wherein Z is hydroxy, halogen, acyl bonded via oxo, lower alkoxy or an activating hydro- carbyloxy or hydrocarbylthio radical.

The invention relates also to a process for the preparation of atorvastatin that comprises the above-mentioned process for the preparation of a compound of formula lU, the reaction to form atorvastatin being carried out preferably by reaction of a compound of formula Ht, as described above, with a compound of formula 5, as mentioned under the heading"Background to the invention", and the lactone compound of formula 6 that is obtainable being converted into the acid of atorvastatin or into a salt thereof.

The invention relates also to those forms of the above-mentioned processes in which an intermediate present at any stage is used as starting material and the remaining process steps are carried out, or those forms in which the process is interrupted at any stage, or a starting compound is formed under the mentioned reaction conditions, or a starting com- pound is used in the form of a reactive derivative or salt, or a compound is prepared in accordance with a process step or process according to the present invention and used further in situ ; and/or to novel intermediates. In preferred embodiments, the starting compounds used are those which result in the intermediates or end products described as being preferred.

The advantages of the process according to the invention include the non-use of organic catalysts, a high overall yield and reduced reaction times for the individual reaction steps, so that the preparation of atorvastatin can be significantly shortened.

Detailed description of the invention: Unless indicated to the contrary, the general terms and reaction conditions used herein- above and hereinbelow preferably have the following meanings, it being possible (especially in the case of the description of preferred embodiments of the invention hereinbelow), instead of the general terms, to use, independently of one another, the more specific definitions, resulting in preferred embodiments of the invention: The prefix"lower"or"-lower"indicates that the radical in question contains preferably not more than 7, especially not more than 4, carbon atoms. Lower alkyl can be linear or can be branched one or more times and is especially methyl or ethyl.

Halogen is especially fluorine, chlorine, bromine or iodine, more especially chlorine or bromine.

A nucleofugal leaving group X is preferably halogen, especially bromine, or the acyloxy radical of an organic sulfonic acid, especially of an alkanesulfonic acid, trifluoromethane- sulfonate or toluenesulfonyloxy, or azido. Bromine is especially preferred.

As base for the reaction of the compound of formula I with the compound of formula 11 (nucleophilic substitution) there are used especially the salts of metals having basic acid radicals, especially metal hydroxides, carbonates or hydrogen carbonates, preferably alkali metal hydroxides, carbonates or hydrogen carbonates, more especially sodium or potassium carbonate, or nitrogen bases, such as tertiary nitrogen bases, especially tri-lower alkyl- amines, such as triethylamine or Hunig's base, or heterocyclic bases, such as pyridine or 4- dimethylaminopyridine. The reaction can also take place under the conditions of phase transfer catalysis, that is to say in the presence of two-phase systems such as water/organic solvent (such as halogenated hydrocarbons, e. g. methylene chloride, chloroform or dichloro- ethane), in the presence of lipophilic quaternary ammonium salts, especially with as hard as possible an anion, such as hydrogen sulfate or chloride, e. g. tetrabutylammonium hydrogen sulfate, Aliquat 336, Adogen 464 (both consisting primarily of methyltrioctylammonium chloride), or tetrabutylammonium chloride, bromide or iodide or the like, the base being present in the aqueous phase.

The nucleophilic substitution is effected in suitable, preferably polar, solvents or solvent mixtures, for example in alcohols, especially methanol or ethanol (especially preferred), or polar aprotic solvents, such as ethers, e. g. dioxane or tetrahydrofuran or especially N, N-di- lower alkyl-lower alkanoylamides, such as dimethylformamide (especially preferred) or dimethylacetamide, hexamethylphosphoric acid triamide or dimethyl sulfoxide, at preferred temperatures of from-10°C to the reflux temperature, preferably from 0 to 50°C, especially from 20 to 30°C. It is also possible to add cryptands, such as crown ethers or polyglycols, but the reaction preferably proceeds without such additives.

As reagent introducing the radical X for the preparation of a compound of formula I from a compound of formula 3 there is used especially an elemental halogen in the presence of a corresponding hydrogen halide, more especially elemental bromine (Br2) in the presence of hydrogen bromide in acetic acid, or quaternary ammonium trihalides, such as tetraalkyl- ammonium trihalides, especially tetra-lower alkylammonium trihalides, such as tetrabutyl- ammonium trihalides, more especially the respective tribromides; it being possible for further aprotic solvents to be present, such as halogenated hydrocarbons, e. g. chloroform, methyl- ene chloride or bromobenzene, and the temperatures being especially from-10°C to the reflux temperature, more especially from 10 to 50°C. For the introduction of other radicals X, the resulting compound of formula I wherein X is halogen, especially bromine, can be con- verted into a different corresponding compound by reaction with a corresponding acid, such as hydrochloric acid (o X = CI), or an organic sulfonic acid in customary solvents, such as water. Alternatively, analogues of compounds of formula I wherein hydroxy takes the place of X can be prepared by mixed benzoin condensation of benzaldehyde with 4-fluorobenz- aldehyde, and the hydroxy group can then be reacted under customary conditions (for example in a manner analogous to that described hereinabove and hereinbelow for the nucleophilic substitution for the preparation of the compound of formula tell) with an acid of formula HX or a salt thereof wherein X is as defined, especially the acyloxy radical of an organic sulfonic acid, as defined above, to form the corresponding sulfonyloxy derivative of formula 1. That derivative can then be converted into the corresponding halogen derivative by nucleophilic substitution in the presence of halide anions, as customary, preferably with alkali metal halides, such as sodium halides, for example in a manner analogous to that described hereinabove and hereinbelow for the nucleophilic substitution for the preparation of the compound of formula Ill. Finally, X = halogen, especially chlorine, can be introduced by reacting 1- (4-fluorophenyl)-2-phenylethane with a sulfuryl halide, especially sulfuryl chloride, in an inert solvent (see DE 246 19 49).

Y in a phenylacetic acid derivative of formula IV is preferably halogen, especially chlorine or bromine, acyl bonded via oxo (= acyloxy ; which yields a mixed acid anhydride or, when acyl is phenylacetyl, a symmetric acid anhydride) or an activating hydrocarbyloxy or hydrocarbyl- thio radical. Acyl is especially lower alkanol, e. g. acetyl (yields the acetic anhydride of the compound of formula IV), benzoyl or phenacetyl itself. Activating hydrocarbyl is preferably unsubstituted or substituted lower alkyl, unsubstituted or substituted aryl (preferably having from 6 to 12 ring atoms) or unsubstituted or substituted heterocyclyl (preferably an unsatura- ted, fully or partially saturated mono-or bi-cyclic ring system having from 4 to 12 ring atoms and up to three hetero atoms selected from nitrogen, sulfur and oxygen) and is especially lower alkyl substituted in the 1-position by esterified carbonyl, such as lower alkoxycarbonyl, cyano or by phenylcarbonyl, especially lower alkoxycarbonylmethyl, such as ethoxycarbonyl- methyl, cyanomethyl or phenacyl (Ph-CO-CH2-), tert-butyl (especially for Y = tert-butylthio), N-benzotriazolyl, N-succinimido, pyridyl, especially 2-pyridyl (more especially for Y = 2- pyridylthio), or electronegatively substituted aryl, such as p-nitrophenyl, 2, 4-dinitrophenyl, pentafluorophenyl or 2,4, 5-trichlorophenyl. It is also possible for azide to take the place of Y (broader embodiment of the invention).

The corresponding acyloxy derivatives of formula IV (Y = acyloxy) can be prepared, for example, by reacting the halides of formula IV (Y = halogen) with the corresponding acids in the presence of bases, as defined above for the nucleophilic substitution for the reaction of compounds of formula I with compounds of formula 11, such as tertiary nitrogen bases, e. g. tri-lower alkylamines, in customary solvents; and the hydrocarbyloxy or hydrocarbylthio derivatives can be prepared by reacting acid halides or acyloxy derivatives of formula IV wherein Y is halogen or acyloxy with the corresponding hydrocarbyl hydroxides or thiols, as customary, preferably with alkali metal halides, such as sodium halides, for example in a manner analogous to that described hereinabove and hereinbelow for the nucleophilic sub- stitution for the preparation of the compound of formula Ill.

The reaction with fluorobenzene in the presence of a Friedel-Crafts catalyst is carried out under customary reaction conditions. As Friedel-Crafts catalyst there is used an acid, such as sulfuric acid or trifluoromethanesulfonic acid, or preferably a Lewis acid, such as AICI3, Fecal3, SbCI5, SnCI4, BF3, TiCI4or ZnCI2, the reaction being carried out preferably in the absence of solvents (fluorobenzene itself serves as solvent) or in the presence of suitable solvents, such as carbon disulfide, nitrobenzene or a halogenated hydrocarbon, such as methylene chloride, 1, 2-dichloroethane or trichloroethylene, the catalyst preferably being used, when Y in formula IV = halogen, in an at least approximately equimolar amount relative to the compound of formula IV, and when Y in formula IV is acyloxy, in at least approximately twice the molar amount relative to the compound of formula IV. The preferred reaction temperatures are from 0 to 75°C, especially from 5 to 50°C, preferably from 20 to 50°C.

Subsequently, if necessary, the complex consisting of catalyst and product is hydrolysed, preferably with water, especially with ice-water or ice.

Halogen, acyl in acyl bonded via oxo (acyloxy) or activating hydrocarbyl in an activating hydrocarbyloxy or hydrocarbylthio radical as Z in compounds of formula V are preferably as defined for Y in compounds of formula IV. The reaction with aniline is then effected directly or in the presence of a base, especially a tertiary nitrogen base, for example as described above for the nucleophilic substitution reaction between a compound of formula 1 and a compound of formula 11, preferably in a solvent, such as a hydrocarbon, e. g. toluene, an ether, especially a cyclic ether, such as dioxane or tetrahydrofuran. The compounds of formula V wherein Z is acyl bonded via oxo or activating hydrocarbyloxy or hydrocarbylthio can be prepared analogously to the compounds of formula IV as described above. It is also possible for azide to take the place of Z (broader embodiment of the invention).

By virtue of the ready accessibility of the compound of formula V wherein Z is lower alkyl, especially methyl or ethyl, the reaction of such a compound of formula V with aniline is especially preferred; it is effected preferably by heating in a solvent, especially a hydro- carbon, such as toluene, in the presence of a catalyst, such as ethylenediamine (see WO 89/07598) or an acid, such as a carboxylic acid, especially a lower alkanecarboxylic acid, such as acetic acid, at preferred temperatures of from 30°C to the reflux temperature, preferably under reflux and with removal of water.

The preparation of atorvastatin comprising the reaction of a compound of formula ill with a compound of formula 5 is carried out preferably by reacting a compound of formula lil, as described above, with a compound of formula 5, as mentioned under the heading"Back- ground to the invention", under conditions analogous to those in WO 89/07598, preferably under the conditions mentioned therein, if necessary with removal of protecting groups, such as the isopropylidene protecting group, and, if necessary, converting the lactone compound of formula 6 that is obtainable into the acid of atorvastatin or into a salt thereof.

The introduction of protecting groups and the various protecting groups themselves, as well as the reagents and reaction conditions employed for their introduction and removal, are known to the person skilled in the art. For example, they can be found in reference works, such as T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, Inc., New York/Weinheim 1999.

The isopropylidene protecting group is removed preferably as described in WO 89/07598, especially by an acid, such as a hydrohalic acid, e. g. HCI.

The cleavage of a lactone is carried out likewise preferably as described in WO 89/07598, especially in the presence of a base, such as an alkali metal hydroxide, e. g. sodium hydroxide.

Salts of atorvastatin are especially pharmaceutically acceptable salts with cations, for example of metals, such as alkali metals and alkaline earth metals, e. g. calcium, potassium or sodium, or with amino or ammonium compounds, such as ammonium ions or lower alkyl- amines.

Where their preparation has not already been described, compounds of formulae IV, V, 5 and 6 are known and can be prepared by processes known perse or are commercially available.

Where, in the present disclosure, reference is made to documents, such as patent appli- cations, reference works or publications, those documents are incorporated herein by refer- ence, especially in respect of the parts of the documents in question which are relevant to those places in the disclosure where reference is made to the documents.

Preferred embodiments of the invention: In the case of the embodiments of the invention described below, for defining reaction conditions it is possible to use, independently of one another, the reaction conditions described above as being preferred, where appropriate and expedient, thus defining further preferred embodiments of the invention.

The invention relates especially to a process for the preparation of atorvastatin, which comprises the preparation of 2- [2- (4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo- pentanoic acid phenylamide of formula lil, or a process for the preparation of the compound of formula III as such, the compound of formula ! II being obtained by nucleophilic substitution from a compound of formula I wherein X is halogen, especially chlorine or more especially bromine, with a ketoamide of formula 11 in the presence of a base, preferably a metal hydroxide, carbonate or hydrogen carbonate, especially an alkali metal hydroxide, carbonate or hydrogen carbonate, more especially sodium or potassium carbonate; (i) the compound of formula I being obtained by reacting a ketone of formula 2 with, as reagent introducing the radical X, an elemental halogen in the presence of a corresponding hydrogen halide, especially elemental bromine (Br2) in the presence of hydrogen bromide in acetic acid; the compound of formula 2 in turn being obtained from a phenylacetic acid derivative of formula IV IV, wherein Y is halogen, by reaction with fluorobenzene in the presence of a Lewis acid as Friedel-Crafts catalyst, especially a Lewis acid selected from Feces, SbCI5, SnC14, BF3, TiCI4, ZnC12 and preferably AtOs ; and (ii) the ketoamide of formula 11 in turn being prepared by reacting with aniline an acid derivative of formula V v wherein Z is lower alkoxy.

Preferred embodiments of the invention will also be found in the claims, which are incorporated herein by reference.

Special preference is given to the process for the preparation of compounds of formula III described in the Examples and to the novel intermediates and process steps described therein.

Examples The following Examples serve to illustrate the invention but do not limit the scope thereof.

Where no mention is made of temperatures, the reactions and process steps are carried out at room temperature.

Abbreviations used: DMF dimethylformamide eq. equivalent (s) HPLC high performance liquid chromatography NMR nuclear magnetic resonance spectroscopy m. p. melting point (°C) The reaction scheme shown below provides an overview of the reactions in the Examples: Reaction scheme relating to the Example : F 1 2 \ C \ F AICI3 \ cri 90% 1 2 Bref Br2 CHCI3 vF \ \ liquantitativell 0 O O O O PhNH2, PhCH3, H+ N reflux, 4 h, about 90 % F 3 -11 reflux, 4 h, about 90 °lo F 3 0 base base about 80 % 0 NU 0.' ill Example : Preparation of 2-2-f4-fluorophenyl)-2-oxo-1-phenylethyll-4-methyl-3-oxo-pen tanoic acid phenvtamide H ! Variant 1: 39 g (0.13 mol) of 2-bromo-1- (4-fluorophenyl)-2-phenylethane I and 27 g (0.13 mol) of 4-methyl-3-oxopentanoic acid anilide 11 are dissolved in 400 ml of DMF and, with stirring, 19 g (0.13 mol) of potassium carbonate are added. The reaction is monitored by HPLC (Macherey & Nagel CC 70/4 Nucleosil 100-5 C 8 Nautilus, 254 nm, water/aceto- nitrile 40: 60,1 ml/min., retention times: amide: 1.1 min, bromide: 2.5 min, product: 3.0 and 3.4 min) and interrupted at about 90 % conversion. The reaction mixture is diluted with water and ethyl acetate, the organic phase is freed of DMF and dried, and the solvent is then removed. The residue is taken up in a small amount of dichloromethane and the product (title compound) is precipitated by slow addition of n-hexane. Further product (title com- pound) is obtained from the mother liquor by concentration by evaporation and chromato- graphy on silica gel. Yield : about 80 % of a white amorphous powder. Diastereoisomeric mixture in a ratio of about from 3: 1 to 4: 1. tH-NMR (CDC13 = 7.26 ppm) of the main isomer: 7.98 (m, 3H, ar); 7.35-7. 00 (m, 11H, ar); 5. 35 (d, 1 H, J = 10. 9, CH); 4.56 (d, 1 H, J = 10. 9, <BR> <BR> CH), 2.96 (sept. , 1H, J = 6.8, CH (CH3) 2), 1.21 (d, 3H, J = 6.8, CH3), 1.19 (d, 3H, J = 6.8,<BR> CH3) Variant 2: 39 g (0.13 mol) of 2-bromo-l- (4-fluorophenyl)-2-phenylethane I and 27 g (0.13 mol) of 4-methyl-3-oxopentanoic acid anilide II are dissolved in 400 ml of ethanol and, with stirring, 19 g (0.13 mol) of potassium carbonate are added. The reaction is monitored by HPLC (Macherey & Nagel CC 70/4 Nucleosil 100-5 Ci$ Nautilus, 254 nm, water/aceto- nitrile 40: 60,1 ml/min., retention times: amide: 1.1 min, bromide: 2.5 min, product: 3.0 and 3.4 min) and interrupted at about 90 % conversion. The reaction mixture is diluted with water and ethyl acetate, the organic phase is freed of DMF and dried, and the solvent is then removed. The residue is taken up in a small amount of ethyl acetate and the product (title compound) is precipitated by slow addition of n-hexane. Further product (title compound) is obtained from the mother liquor by concentration by evaporation and chromatography on silica gel. Yield : about 83 % of a white amorphous powder. Physical data as under variant 1.

The starting materials are prepared as follows : A) Preparation of I : a) 1- (4-Fluorophenvl)-2-phenyethan-1-one 2: (see also H. Buu-Hoi et a/., Recl. Tav. Chim. Pays-Bas 1949, 68, 781; Organikum, 16th edition, VEB Deutscher Verlag der Wissenschaften, Berlin 1986, p. 325 f.) <BR> <BR> 160 g (1.2 eq. ) of powdered aluminium chloride are added to 500 ml (about 5 eq. ) of fluoro- benzene and, with stirring and cooling with ice-water, 138 ml of phenacetyl chloride 1 <BR> <BR> (1.05 eq. ) are added dropwise in such a manner that an internal temperature of 20°C is not exceeded. 15 min after the addition has been completed, the reaction mixture is heated at 50°C for 5 hours and the resulting deep-green solution is maintained at room temperature for a further 9 hours. Hydrolysis is carried out by pouring the reaction mixture onto 500 g of crushed ice and extracting the resulting suspension with 300 ml of 2N HCI. The organic phase is then cautiously washed with sodium hydrogen carbonate solution and saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent, the solid that remains behind is washed intensively with hexane. 193 g (193 mmol), 90 %, of title compound 2 are obtained in the form of a white solid : m. p. 82°C,'H-NMR (CDCI3 = 7.26 ppm): 4.26 (s, 2H, CH2) ; 7.12 (m, 2H, ar); 7.30 (m, 5H, ar); 8.04 (m, 2H, ar). t3C-NMR (CDCI3 = 77. 4 ppm): 196.2, 167.7, 164.3, 134.7, 133.3, 131.6, 131.5, 129.7, 129.0, 127.2, 116.1, 115.8, 45.7. b) 2-Bromo-1-(4-fluorophenyl)-2-phenvlethane l : (see also P. J. Roy et aL, Heterocycles 45 (11), 2239-2246 (1997) in respect of the reaction mechanism and CAS 88675-31-4 in respect of the compound) 273.4 g (1.28 mol) of 1- (4-fluorophenyl)-2-phenylethane 2 are introduced into 2.9 litres of chloroform; 7 ml of a 30 % hydrobromic acid solution in glacial acetic acid are added and 66 ml (1 eq. ) of bromine dissolved in 250 mi of chloroform are added dropwise in such a manner that the bromine immediately reacts away. At the end of the reaction, a slight bromine colouration should remain. 10 % sodium sulfite solution is added and the reaction mixture is then washed with water, sodium hydrogen carbonate solution and saturated sodium chloride solution and dried over sodium sulfate. 375 g (1.28 mol) of the pure title compound I are obtained in the form of a reddish-brown oil which tends to crystallise at low temperature. M. p.: 46°C,'H-NMR (CDCI3 = 7.26 ppm): 6.34 (s, H, CHBr), 7.12 (m, 2H, ar), 7.35 (m, 3H, ar), 7.51 (m, 2H, ar), 8.02 (m, 2H, ar) ; 13C-NMR (CDCIS = 77.3 ppm): 189.8, 167.9, 164.5, 136.0, 132.2, 132.1, 129.5, 129.3, 116.4, 116.1, 51.2.

B) Preparation of If : 4-Methyi-3-oxopentanoic acid anilide 11 is prepared by known processes (see WO 89/07598, which is incorporated herein by reference, Example B) starting from 4-methyl-3-oxopentan- oic acid 3 and aniline in toluene in the presence of ethylenediamine or acetic acid.