NO178335B - Optically active r when producing optically active - Google Patents

Description

The present invention relates to optically active α-halogen ketals used as intermediates in the production of optically active α-arylalkanoic acids.

The α-arylalkanoic acids form a very large class of compounds, among which many have assumed considerable commercial importance in recent years as anti-inflammatory and analgesic drugs.

These include 2-(4-isobutylphenyl)-propionic acid known as Ibuprofen, 2-(3-phenoxyphenyl)-propionic acid known as Fenoprofen, 2-(2-fluoro-4-diphenyl)-propionic acid known as Flurbiprofen, 2-£ 4-2(thienyl-carbonyl)-phenylj-propionic acid known as Suprofen, 2-(6-methoxy-2-naphthyl)-propionic acid in which the (S) isomer is known as Naproxen and others.

Another group of 4-arylalkanoic acids are well known as intermediates in the manufacture of pyrethroid insecticides. These include 2-(4-chlorophenyl)-3-methyl-butyric acid and 2-(4-difluoromethoxyphenyl)-3-methyl-butyric acid.

A number of the d1-arylalkanoic acids exist as a mixture of optically active isomers.

Very often a decidedly higher biological activity is associated with one enantiomer which is thus much more significant than the other from an industrial point of view.

A particularly significant example is 2-(6-methoxy-2-naphthyl)-propionic acid in which the (S) isomer (Naproxen) exhibits pharmacological properties that are decidedly better than the properties of the (R) isomer and of the racemic mixture, so that in practice, only the (S) isomer is used as a pharmaceutical drug.

Among the many methods for synthesizing 3-arylalkanoic acids that have recently appeared in the literature are those

most interesting are those that use rearrangement of aryl-alkyl ketals that are functionalized on the alkyl position in the dT position of the ketals. These include the methods described

European patent applications 34871 (Blaschim), 35305 (Blaschim), 48136 (Sagami), 64394 (Syntex), 89711 (Blaschim), and 101124 (Zambon) and in Italian patent applications 21841 A/82 (Blaschim and CNR), 22760 A/82 (Zambon) and 19438 A/84 (Zambon) and in the publication J. Chem Soc, Perkin I., 11, 2575 (1982).

All these methods lead to racemic mixtures of the two optical isomers.

Optically active d-arylalkanoic acids can be prepared by separating the enantiomer from the racemic mixture obtained using the above procedures (e.g. using optically active bases), or by using some of the indicated rearrangements to optically active ketals, which has previously been produced and isolated, such as e.g. described in European patent applications 67698 (Sagami) and 81993 (Syntex).

However, the production of optically active ketals as described in these European patent applications is relatively labor-intensive and expensive, and also involves the production of intermediates by sophisticated methods and with low yields, and is not suitable for industrial production.

Dissolution of α-arylalkanoic acids from the racemic mixture in the usual way, i.e. by using optically active bases, has the disadvantages common to all these processes: material costs, labor-intensive and equipment-intensive preparation for recombination and racemization of the unwanted optical isomer .

It is thus important to possess a stereoselective process for producing the desired isomer directly. Such a process avoids the subsequent resolution of the d- and 1-isomers using optically active bases such as cinchonidine, brucine, <A-phenyl-ethylamine, N-methyl-glucamine and the like.

Eliminating the dissolution steps results in a significant saving, both in terms of material costs and labor and equipment.

The savings can be particularly significant in the case of compounds suitable for pharmaceutical use as a substantially pure, optically active isomer such as S(+)2-(6-methoxy-2-naphthyl)-propionic acid ("Naproxen") or one for - runs from it which can easily be converted into this acid.

For ease of understanding, the meaning of certain terms used in the following description will be explained as follows: "Chiral" denotes a chemical structure with at least one asymmetric center. The configuration of an asymmetric carbon atom is classified as "R" or "S" according to the Cahn-Ingold-Prelog method.

"Enantiomer" or "enantiomorph" denotes a molecule that cannot be superimposed on its respective mirror image. A necessary and sufficient condition for a molecule to exhibit optical activity (ie be an enantiomer) is that such a molecule cannot be superimposed on its mirror image. This phenomenon usually occurs in organic chemistry when a carbon atom is bonded to four different atoms or chemical groups. "Enantiomer" and "optical isomer" are often used interchangeably in this regard.

"Enantiomeric excess" or "e.e." refers to a definition; i.e. the percentage of the dominant enantiomer minus the percentage of the other. Thus, a mixture of 95% (+) isomer and 5% (-) isomer will have a 90% e.e. "Optical yield" or "optical purity" can be defined as enantiomeric excess. However, this strictly refers to the measured rotation exhibited by the mixture which may or may not reflect the true amounts of the enantiomers. In the present description, the two expressions are used interchangeably.

"Optical active" denotes a system or compound that rotates the plane of polarized light.

"Epimers" are two diastereoisomers that have a different configuration only at a chiral center.

"Diastereoisomers" are stereoisomers that are not mirror images of each other: They have the same configuration at at least one asymmetric center and at the same time different configuration at at least one asymmetric center.

"Diastereotope" denotes the case in which two atoms or groups in a molecule, e.g. CX2WY is in such a position that replacing one of these with a group Z leads to

diastereoisomers.

"Stereoselective synthesis" refers to any reaction in which one among a plurality of stereoisomers is formed exclusively or predominantly. "Enantioselective synthesis" refers to any reaction in which one of two enantiomers is formed exclusively or in a dominant amount. "Racemization" denotes the conversion of the molecules of one enantiomer into a racemic mixture of both. The invention thus relates to new optically active α-halogen ketals, characterized by having the formula

wherein Ar denotes 6-methoxy-2-naphthyl, 5-bromo-6-methoxy-2-naphthyl, 5-bromo-6-hydroxy-2-naphthyl, 5-chloro-6-methoxy-2-naphthyl, 4-chlorophenyl , 4-(2-methylpropyl)phenyl; R denotes linear or branched C1-C4 alkyl; Rx and R2 which may be the same or different, denote a hydroxy, 0"M<+>, 0R3 or NR4R5 group wherein R3 is C1-C8 alkyl; M is the cations of an alkali metal; R4 and R5, which may be the same or variously denotes a C1-C4 alkyl group;

X denotes a hydrogen, chlorine, bromine or iodine atom, and where the carbon atoms indicated by an asterisk both have (R) or (S) configuration. Thus the ketals of formula A are optically active.

It has been found that when ketals of formula A wherein

X is hydrogen, is reacted with achiral halogenation reagents, a chemoselective halogenation takes place in a high yield on the diastereotopic carbon atom in the cA position in relation to the ketal group, and in the thus obtained cA halogen ketals (formula A, X = Cl, Br , I) only one of the epimers is formed or it strongly dominates over the other. It means nothing that the absolute configuration R,R or S,S of the chiral centers already present on the starting ketals A (X=H) is untouched. To the best of our knowledge, a stereoselective halogenation in the d-position of a ketal has never previously been described. Furthermore, it has been found that the ketals of formula A in which X=C1, Br, I give high yields of ec-arylalkanoic acids in which the enantiomeric ratio reflects the epimeric ratio in the starting ketals, or depending on the rearrangement conditions, where the acid enantiomeric ratio is higher than the epimeric ratio of the starting ketals.

To the best of our knowledge, this is the first time that a rearrangement of ketals has been described that gives rise to chemically pure c-arylalkanoic acids that have an enantiomeric excess greater than the epimeric excess of the starting ketals.

The ketals of formula A which constitute intermediates used in the preparation of optically active α-arylalkanoic acids are prepared by ketalization of a ketone of formula

in which Ar and R have the meanings given above, by means of L(+)-tartaric acid (2R, 3R-dihydroxybutanedioic acid or D(-)-tartaric acid (2S, 3S-dihydroxybutanedioic acid or derivatives thereof.

The ketones of formula II are products which are known or which are easily prepared by known methods, e.g. by Fri-edel-Craft acylation. The ketalization reaction is carried out according to conventional methods, e.g. in the presence of an acid catalyst and an orthoester. Alternatively, water formed during the reaction can be removed by azeotropic distillation, e.g. with benzene, toluene, xylene, heptane or other suitable solvents. The absolute configuration and optical purity of the ketals of formula A in which X=hydrogen is the same as that of the starting diol (tartaric acid or derivative thereof). By thus starting from L(+)-tartaric acid, the obtained ketal of formula A has both carbon atoms marked with an asterisk in formula A in the R configuration.

This reaction is particularly suitable for the preparation of compounds of formula A in which R 1 and R 2 denote an OR 2 group, by reacting the ketones of formula II with a tartaric acid ester. The ketals of formula A in which R 1 and R 2 are different from OR 2 are preferably prepared from these latter compounds by suitable transformation of the OR 2 group.

By e.g. starting from esters of formula A in which R^ and R2 are OR^ groups, the corresponding monosalts (e.g. R^ = 0 M+ and R2 = OR^) can be prepared by partial saponification with an equivalent of a base (e.g. e.g. alkali hydroxide) and from these the corresponding monoacids (e.g. R^ = OH, R2 = OR^) can be produced by acidification.

Hydrolysis of the esters with two equivalents of an alkaline base leads to the formation of the corresponding salts R^ = R2 = 0 M+ which upon acidification give the free dicarboxylic acids R^ = R2 = OH which are the starting compounds for the production of various derivatives such as other mono- or di-esters (R^ and/or R2 = OR^) or mono- or di-amides (R2 and/or R2 = N<R>^<R>^).

The amides can also be obtained directly from the esters of formula A by treatment with a suitable amine of formula 4^-5-N-H. As previously indicated, the compounds A in which X = H are usable as starting compounds for the preparation of the compounds of formula A in which X denotes a chlorine, bromine or iodine atom.

The compounds of formula A are halogenated with known halogenating agents such as e.g. bromine, quaternary ammonium perhalides, sulfuryl chloride, copper chloride or bromide, N-bromine or N-chlorosuccinimide, N-chlorophthalimide, pyridine or pyrrolidone perbromide or pyridine perchloride or the analogous iodides, hexachloro-2,4-cyclohexadienone, iodine and iodide chloride, or analog systems.

It has been found that the halogenation of ketals having the carbon atoms marked with an asterisk in formula A both in the R configuration, i.e. ketals prepared from L(+)-tartaric acid or a derivative thereof (i.e. the naturally occurring tartaric acid) gives rise to of a mixture of epimeric d\-halogen ketals in which the epimer in which the carbon atom bonded to the halogen is in S configuration strongly predominates. As the configuration of the carbon atoms marked with an asterisk in formula A remains unchanged, the major epimer of the o^-halogen ketals derived from naturally occurring tartaric acid or a derivative thereof will hereafter be designated as RRS-epimer and the minor epimer as RRR-epimer.

It has also been found that starting from ketals derived from D(-)-tartaric acid, the main epimer has the carbon atom bound to the halogen atom in the R configuration. From the observations stated above, it is clear that the described halogenation reaction is a new stereoselective reaction. The ratio of the epimers RRS/RRR is generally higher than 75:25, and in most cases it is higher than 94:6. Depending on the substrate and reaction conditions, it is also possible to obtain the RRS epimer as the only chemically pure <A-halogenketal, the other epimer RRR being present in an amount of less than 1% at all.

In general, the yields of o<-halogen ketals are higher than 90%.

The stereoselectivity of the halogenation reaction is only slightly affected by the polarity of the solvent. A number of solvents such as carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, benzene, toluene, acetonitrile, cyclohexane, ethyl acetate, carbon disulphide, acetic acid, etc. can be used. The best results are obtained by using solvents with low polarity. The reaction can be carried out at room temperature with satisfactory results. The stereoselectivity of the halogenation reaction increases by reducing the reaction temperature. The reaction will still take place at temperatures up to -70°C.

Preferably, traces of an inorganic acid are necessary to start up the halogenation reaction, which is usually completed within a few minutes. In terms of yields and stereoselectivity, the preferred halogenation reaction is bromination. Said reaction is preferably carried out with bromine as halogenating agent at a temperature between -40 and +20°C in solvents such as carbon tetrachloride, methylene chloride, 1,2-dichloroethane and carbon disulphide.

The peculiar characteristics of the ketals of formula A and in particular the high stereoselectivity shown in the halogenation reaction were completely unpredictable on the basis of current knowledge of stereoregulated reactions.

Regardless of the above, the fact is that the ketals of formula A in which X = halogen exist in the form of diastereoisomers which can be easily separated by known methods, e.g. in the case of fractional crystallization also important.

If necessary, it is therefore possible to separate the desired isomer of the ketal of formula A and subject this to rearrangement to form cA-arylalkanoic acids in essentially pure optically active form.

It is also important to note that tartaric acid and esters,

in particular L(+)-tartaric acid and methyl and ethyl esters have prices that are competitive with the price of the glycols described as ketalizing agents in the methods according to the state of the art, and that the production of the tartaric acid derivatives (esters, amides, salts) obviously does not constitute an expensive process.

The possibility of having groups of different species i

the ketals of formula A in terms of the substituents and R2 make it possible to vary the hydrophilic and lipophilic properties of specified ketals within wide limits, from compounds containing polar groups (alkali salts, amides) to lipophilic compounds (esters of long-chain alcohols).

This wide choice makes it possible to choose the ketal of formula A which is most suitable for the experimental conditions (solvents, temperature, catalysts) used in the various processes for the production of -arylalkanoic acids or their derivatives by rearrangement.

Regarding the rearrangement of the ketals of formula A (where X = Cl, Br, I) it has been found that the ketals of the configuration RRS (where S is the configuration of the carbon atom bonded to the halogen atom) give the S-enantiomer of the corresponding ε-arylalkanoic acid.

This is particularly important because (a) the S-enantiomer of cA-arylalkanoic acid is generally the more biologically active isomer, and the o^-arylalkanoic acids currently on the market in optically active form all have the S configuration, and (b) the ketals of formula A with the configuration RRS is obtained selectively by halogenation of the ketals of formula A, X = H which in turn is easily prepared from the suitable ketone and the naturally occurring L(+)-tartaric acid (or a derivative thereof) which

is a cheap material.

To convert the optically active ketals of formula A

(X = Cl, Br, I) it is necessary to use a rearrangement method which gives optically active e4.-arylalkanoic acids with an enantiomeric ratio very close to that of the epimers in the starting ketals. This means that the reaction must be stereo-specific and that the reaction conditions are such that no racemization takes place in the end products. It has been found that the known methods give oC-arylalkanoic acids with an enantiomeric ratio equal to or lower than the epimeric ratio in the starting ketals. A new enantioselective rearrangement method has also been found which overcomes the limitations stated above.

Such a method is here defined as enantioselective in so far as the enantiomeric composition (ratio between enantiomers S and R) of the thus obtained cA -arylalkanoic acids deviates from the epimeric composition of the starting ketals of formula A and more precisely and quite surprisingly corresponds to an increase in the optical purity of the o(-arylalkanoic acid in relation to the epimeric composition of the starting ketals.

Thanks to this new, surprising relocation process that starts from e.g. a mixture of epimeric ketals of formula A (in which X = Cl, Br, I) sufficiently enriched in RRS-epimers, it is possible to obtain in optically pure form the S-enantiomer of the corresponding <^-arylalkanoic acid.

It is worth noting that the yield of the new redeposition process is as high as 80-90%.

The enantioselective process consists mainly in rearrangement of a ketal of formula A in which X is a chlorine, bromine or iodine atom, in aqueous medium at an acidic pH, at a temperature between room temperature and 100 °C. The above rearrangement conditions are unexpected and surprising in that it is well known that treatment of a ketal with water under acidic conditions is generally a method of converting ketals to the corresponding ketones and alcohol or diol. The previously known α-haloalkyl-aryl ketals will consequently, under the above-mentioned reaction conditions, undergo rapid hydrolysis to form the corresponding α-haloalkyl-aryl ketone and alcohol or

diol.

In contrast, the ketals of formula A according to the invention, when these are treated in an aqueous acidic medium, will give the corresponding ones

<*-arylalkanoic acids in high yield as ketones are present, if at all, in negligible amounts.

The rearrangement process is preferably carried out using ketals of formula A (in which X = Cl, Br, I) which are soluble or at least partially soluble in water under the reaction conditions, i.e. the ketals of formula A in which Rx and/or R2 are hydrophilic groups .

The rearrangement is preferably carried out by heating the ketal of formula A in water at a pH between 3.5 and 6.5. The desired pH values can be maintained by adding a suitable amount of a buffer.

The reaction duration depends mainly on the nature of the ketal of formula A and the reaction temperature. In general, a high conversion rate is reached after a few hours.

Generally, the ^-arylalkanoic acids are poorly soluble in water, which is why the optically active o(-arylalkanoic acid can be isolated by simple filtration after the reaction has ended. A pharmaceutical product with a purity required according to the U.S. Pharmacopeia is obtained by a simple acid-base treatment of the product isolated by filtration. As far as is known, it is the first time that a rearrangement of halogen ketals for the production of c(-arylalkanoic acids is carried out in water as the only reaction solvent. The main advantages of the present rearrangement process from an industrial point of view can be summarized as follows: (a) the process is enantioselective and gives oC-arylalkanoic acids in high yield and with an enantiomeric ratio that is higher than the epimeric ratio of the starting ketals; (b) the reaction solvent is water with the consequent economic and safety advantages; (c) no metal catalyst is necessary and (d) the optically active M-arylalkanoic acid is separated from the reaction mixture by simple filtration.

By considering the overall process for the preparation of optically active α-arylalkanoic acids, it can be stated that it consists of two completely new steps: the stereoselective halogenation of a ketal of formula A in which X is hydrogen, and the enantioselective rearrangement of the ketal thus obtained by formula A wherein X is a chlorine, bromine or iodine atom.

More specifically, the overall process for the selective preparation of the S-enantiomer of an α-arylalkanoic acid consists of two entirely new steps: the stereoselective halogenation of the appropriate ketals of formula A in which X is hydrogen and in which the carbon atoms marked with an asterisk are both in the R- configuration, during selective formation of the epimer RRS of the ketal of formula A in which x is a chlorine, bromine or iodine atom, and the enantioselective rearrangement of the thus obtained ketal in water under acidic conditions. Such a process is possible thanks to the unexpected characteristics of the ketals of formula A which are exhibited both in the α-halogenation step and in the aqueous rearrangement step.

The rearrangement method can also be carried out in a less advantageous way depending on the starting kettle. When e.g. Ar in the ketals of formula A in which X is an iodine atom is the 6-methoxy-2-naphthyl group and R is methyl, these can be rearranged according to the procedure described in European patent application 89711 or by oxidation as described in Italian patent application 21841 A /82.

Likewise, the ketals of formula A wherein X is any halogen atom can be rearranged in the presence of certain metal salts as described in European Patent Applications 34871 and 35305 and in J. Chem. Soc, Perkin I., 11, 2575 (1982), or in a protic polar medium under neutral or slightly alkaline conditions, optionally in the presence of an inert diluent, as described in Italian patent application 22760 A/82 or in European patent application 101124 .

The latter method has significant advantages in terms of its industrial practice and due to the fact that it does not require the presence of metal salts as catalysts. The rearrangement reactions indicated above generally lead to the formation of ol-arylalkanoic acids in the form of their derivatives, in particular esters. These are then hydrolysed to the corresponding free acids by conventional methods. Among the optically active o\-arylalkanoic acids, the most important from a pharmacological point of view is 2-(6-methoxy-2-naphthyl)-propionic acid in which the S(+) isomer is known as Naproxen. In a specific embodiment, the invention relates to compounds of formula

(in which R1 # R2 and X have the meanings given for formula A, Y denotes a hydrogen atom or a chlorine or bromine atom and Z denotes a hydrogen atom, methyl or an alkali metal), which is used in the production of Naproxen by rearrangement. The carbon atoms indicated by an asterisk have R configuration and when X is different from hydrogen the carbon atom to which it is bonded has S configuration.

A compound of formula B in which X denotes a halogen atom and Z is methyl can be rearranged in the presence of certain metal salts such as Ag and Zn, or in a polar solvent under neutral or weakly basic conditions.

Furthermore, a compound of formula B in which Z represents an alkali metal can be redeposited in an aqueous or organic medium under neutral or alkaline conditions. In any case, the preferred embodiment is rearrangement of the ketals of formula B (wherein X = Cl, Br, I) in water under acidic conditions. The rearrangement of the epimer RRS of the ketals of formula B leads to S(+)-Naproxen or its direct precursors, e.g. containing Y substituent. When producing Naproxen, it is necessary to eliminate the substituent Y when this is a chlorine or bromine atom. This is done by hydrogenolysis either on the α-arylalkanoic acid or the relative ester. The reaction involving the rearrangement of the compounds of formula A, in particular when carried out in a medium free of alcohols and glycols under mild conditions, may lead to the formation of new intermediate esters of formula (wherein Ar, R, Rx and R2 have the meanings indicated for formula A) and R 6 is OH. Hydrolysis of the compounds of formula C then leads to the corresponding arylalkanoic acids. Likewise, the rearrangement of the compounds of formula B when carried out in a medium free of alcohols and glycols can lead to the formation of intermediate esters of formula:

(in which R 1 , R 2 , R 8 and Y have the meanings given for formula B, and Z denotes a hydrogen atom or methyl), which on hydrolysis forms the c 3 -arylalkanoic acid known as Naproxen or its immediate precursor. Also in this case where the conversion of the halogen ketals to the arylalkanoic acids takes place in two steps, essentially no racemization takes place, and the desired optically active arylalkanoic acid is obtained selectively and in a dominant amount. The compounds of formula C are new compounds which constitute a further aspect of the invention, as these have interesting properties which make them useful from different aspects. As already indicated, the compounds of formula C form the corresponding o 3 -arylalkanoic acids on hydrolysis. Due to the presence of the two asymmetric carbon atoms in the alcoholic part (the atoms to which the COR₂ and COR₂₂ groups are attached) the esters of formula C are furthermore useful for the optical resolution of the β-arylalkanoic acids. The resolution of an acid into its optical isomers is generally accomplished by forming salts with an optically active base. Use of the compounds C constitutes a new method for dissolving mixtures of optically active substances

cArarylalkanoic acids by forming an ester with tartaric acid or one of its derivatives, instead of forming a salt with an optically active base. Use of the compounds of formula C for dissolving a G 3 -arylalkanoic acid is particularly advantageous when esters of formula C are obtained enriched with the desired isomer by means of the above-mentioned process for rearrangement of the ketals (A).

It is obvious that the compounds of formula C are useful for the optical resolution of o<-arylalkanoic acids regardless of the method of preparation.

In this regard, it is possible to prepare the compounds of formula C by esterification of a racemic <X-arylalkanoic acid (or one already rich in one of the two enantiomers) regardless of how it has been prepared. The compounds of formula D prepared by rearrangement of a compound of formula B or prepared by esterification of racemic 2-(6-methoxy-2-naphthyl)-propionic acid or one of its immediate precursors using tartaric acid or one of its derivatives are useful for separation by crystallization, the ester of formula D which on hydrolysis gives Naproxen in essentially pure form.

The following examples illustrate the invention.

Example 1

Preparation of the compound 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R)-dicarboxylic acid dimethyl ester. 46.5 g (0.217 mol) 1-(6-methoxy-2-naphthyl)-propan-1-one, 300 g L(+) tartaric acid dimethyl ester and 94 g (0.887 mol) trimethylorthoformate were gradually heated to complete dissolution . 1.48 g (0.0154 mol) methanesulfonic acid was then added and the resulting solution was refluxed for two hours, cooled to room temperature whereupon the reaction mixture was slowly added to 500 ml of a 10% solution of Na 2 CO 3 . The reaction mixture was extracted with methylene chloride and the organic extracts were repeatedly washed with water. The organic phase was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure. The residue was crystallized from 250 ml of methanol. 51.68 g (0.138 mol) of the desired product was obtained (yield 63.6%) with the following characteristics:

Sm.p. = 73-74°C

f^Jp0 = +33.04 (c = 1%, CHC1)

I.R. (Nujol): 1770,1740 cm"<1> (extended C = 0)

NMR (CDCl 3 - TMS, 200 MHz) cf (ppm): 0.94 (t, 3H, J = 7.5 Hz); 2.08 (q, 2H, J = 7.5 Hz); 3.46 (s, 3H); 3.84 (s, 3H); 3.90 (s, 3H); 4.86 (2H, ABq, A\) = 10.80, J = 6 Hz); 7.1-7.9

(m, 6H) .

Example 2

Preparation of the mixture of the diastereoisomers of 2-(1-bromo-ethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester.

To a solution of 37.4 g (0.1 mol) of the compound obtained in example 1 in 100 ml of 1,2-dichloroethane was added 48.2 g (0.1 mol) of tetra-n-butylammonium perbromide TN(n.C4Hg )4 Br3].

The reaction mixture was kept at 20°C for 24 hours and was then slowly added with stirring to 200 ml of a 10% solution of Na 2 CO 3 . The reaction mixture was extracted with 2 x 200 ml toluene, and the combined organic extracts were washed with 3 x 100 ml of a 2% solution of Na2HCO3. The organic phase was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure. 48 g of the crude product was purified by chromatography on a silica gel column (eluent hexenrdiethylether = 75:25) to give 13 g of the desired mixture of diastereoisomers. The ratio between the two diastereoisomers (1:2) determined by <1>H-NMR (200 MHz) is 7:3.

Diastereoisomer 1 (RRS):

<1>H-NMR (CDCl3-TMS), fT(ppm): 1.68 (d, 3H, J = 7.5 Hz); 3.54 (s, 3H); 3.90 (s, 3H); 4.08 (s, 3H); 4.48 (q, 1H, J = 7.5 Hz); 4.94 (2H, ABq,dO= 26.8; J = 7.2 Hz); 7.1-8.0 (6H, m). Diastereoisomer 2 (RRR): <1>H-NMR (CDCl3-TMS), cT(ppm): 1.64 (d, 3H, J = 7.5 Hz); 3.58 (s, 3H); 3.89 (s, 3H); 4.08 (s, 3H); 4.50 (q, 1H, J = 7.5 Hz); 4.89 (2H, ABq,4^ = 36.3, J = 6.3 Hz); 7.1-8.0 (6H, m).

Example 3

Preparation of 2(R)-hydroxy-3(R)-[2-(6-methoxy-2-naphthyl)-propanoyl]-butanedioic acid dimethyl ester.

A mixture of the diastereoisomers 1:2 = 67:33 obtained according to example 2 (5 g, 0.011 mol) dissolved in 61 ml of C^C^ and kept at 0°C under an inert atmosphere was added 2.33 g (0.012 mol) silver tetrafluoroborate. The reaction mixture was kept at 0°C for 30 minutes, after which the temperature was allowed to rise to room temperature.

The mixture was filtered and the precipitate was washed with C₂C₂. The organic phases were washed with water and dried over Na 2 SO 4 . The solvent was evaporated under reduced pressure to give a mixture of diastereoisomeric esters (ratio determined by NMR, 200 MHz, A:B = 64:36). <1>H-NMR (CDC13 - TMS), (f, (ppm) :

Diastereoisomer A (RRS):

1.62 (d, 3H, J = 8 Hz); 3.22 (s, 3H); 3.83 (s, 3H); 3.92 (s, 3H); 3.21 (d, 1H, J = 7.2 Hz); 3.95 (q, 1H, J = 8 Hz); 4.68 (dd, 1H, JCH_OH = 7.2 Hz, JCH_CH = 2.47 Hz); 5.37 (d, 1H,

J = 2.47 Hz); 7.1-7.8 (6H, aromatic protons).

Diastereoisomer B (RRR):

1.66 (d, 3H, J = 8 Hz); 3.58 (s, 3H); 3.72 (s, 3H); 3.92 (s, 3H); 3.24 (d, 1H, J = 7.6 Hz); 3.97 (q, 1H, J = 8 Hz), 4.78 (dd, 1H, JCH_OH = 7.6 Hz, JCH_CH = 2.47 Hz); 5.45 (d, 1H, J = 2.47 Hz); 7.1-7.8 (6H, aromatic protons)

Example 4

Preparation of 2-(6-methoxy-2-naphthyl)-propionic acid.

A mixture of diastereoisomeric esters A and B prepared as described in example 3 (ratio A:B = 62:38) (3.2 g), 24 ml of dimethoxyethane, 24 ml of 12 N hydrochloric acid was kept under stirring at 95°C for 2, 5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with C₂C₂. The combined organic extracts were washed with a saturated solution of sodium bicarbonate. The aqueous phase was acidified to form 1.3 g of 2-(6-methoxy-2-naphthyl)-propionic acid.

An analytically pure sample obtained by column chromatography on silica gel (eluent hexane: diethylether = 1:1) with &* °] = +12.9° (c = 1%, CHCl 3 ) was esterified with diazomethane. The methyl ester obtained was analyzed by H-NMR (200 MHz) using an optically active shifter (Europium (III)-tris-£3-(heptafluoropropyl-hydroxymethylene)-d-camphorate3 in CDCl3). The enantiomeric ratio was (+)S:(-)R = 62:38.

Example 5

Preparation of 2-(6-methoxy-2-naphthyl)-propionic acid.

A mixture of diastereoisomeric ketals prepared as described in Example 2, ratio 1:2 = 67:33 was heated to 125°C in ethylene glycol in the presence of potassium acetate for 20 hours. After working up the reaction mixture, a mixture of esters was obtained which was hydrolyzed as described in example 4. (+)(S)-2-(6-methoxy-2-naphthyl)-propionic acid (Naproxen) was obtained with an optical purity of 40%, melting point = 151-152°C.

Example 6

Preparation of the diastereoisomeric mixture of the compound 2-(-1-brothiethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester.

To a solution of 3.74 g (0.01 mol) 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester in 70 ml (3.74 g; 0.01 mol) kept at 0°C under an inert atmosphere, a solution of 3.2 g (0.02 mol) bromine in 7 ml CC14 cooled to 0°C, added dropwise in within an hour.

The mixture was kept at 0°C for two hours and. was then poured with vigorous stirring into 250 mL of a 10% aqueous solution of Na 2 CO 3 and extracted with O 2 Cl 2 (3x50 mL). The combined organic extracts were dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue (5 g, 0.0093 mol; yield 93%) consisted of a mixture of the two diastereoisomers identified as 3 and 4. The ratio of the diastereoisomers 3:4, determined by H-NMR was 95:5.

The main isomer has the same configuration (S) as diastereoisomer 1 described in example 2 with respect to the aliphatic carbon atom bound to bromine.

Diastereoisomer 3 (RRS):

2H-NMR (200 MHz) (CDCl3 - TMS), 0°(PPm) :1/66 <d' 3H' J = 6.8 Hz); 3.52 (s, 3H); 3.88 (s, 3H); 4.05 (s, 3H); 4.46 (q, 1H, J = 6.8 Hz); 4.94 (2H, ABq, J = 6 Hz); 7.28-8.24 (5H, aromatic protons).

Diastereoisomer 4 (RRR):

<1>H-NMR (200 MHz) (CDCl 3 - TMS), ff (ppm): 1.63 (d, 3H, J = 6.8 Hz); 3.56 (s, 3H); 3.87 (s, 3H); 4.05 (s, 3H); 4.48 (q, 1H, J = 6.8 Hz); 4.91 (2H ABq, J = 6 Hz); 7.28-8.24 (5H, aromatic protons).

HPLC analysis (high pressure liquid chromatography) was performed under the following conditions: Hewlett Packard instrument mod. 1084/B with variable wavelength UV detector:

Analytical conditions:

Column BRAWNLEE LABS RP8 (5 ) in 250 mm x 4.6 mm inner diameter.

Solvent A: bidistilled water, flow rate

0.9 ml/min.

Solvent B: methanol, flow rate 1.1 ml/min. Temperature of solvent A: 60°C.

Temperature of solvent B: 40°C.

Column temperature: 50°C.

Wavelength (A): 254 nanometers.

Injection: lO<y>tl of a solution containing 3 mg/ml of a sample in acetonitrile.

Retention times:

Diastereoisomer 3: 18.20 min.

Diastereoisomer 4: 19.90 min.

A mixture of diastereoisomers 3 and 4 in a ratio of 95:5 obtained as described above was chromatographed on silica gel using a mixture of diethyl ether: hexane = 3:7 as eluent 1. The collected fractions were separately analyzed by HPLC. The fractions containing diastereoisomer 3 which exhibited a diastereoisomeric purity higher than 99% were collected. The solvent was evaporated under vacuum to give the pure diastereoisomer 3.

■"•H-NMR (200 MHz) (CDC13 - TMS) delta (ppm) : 1.66 (d, 3H, J = 7.5 Hz); 3.52 (s, 3H); 3.88 (s , 3H); 4.05 (s, 3H); 4.46 (q, 1H, J = 7.5 Hz); 4.94 (2H, ABq, J = 7.2 Hz); 7.28-8 .24 (5H, aromatic protons)

Example 7

Preparation of a mixture of diastereoisomers of the compound 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester .

The reaction described in Example 6 was repeated with different solvents and at different temperatures according to the following procedure.

To a solution of 0.01 mol of 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester in the solvent specified in the following table (70 ml) kept under an inert atmosphere at the indicated temperature, a solution of 0.02 mol of bromine in 7 ml of the same solvent, cooled to the indicated temperature, was added to the mixture. The reaction mixture thus obtained was kept at the specified temperature until the conversion was complete. The reaction mixture was then worked up as described in example 6. The ratio between diastereoisomers 3 and 4 is indicated in the table.

Example 8

Preparation of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester.

To a solution of 70 g (0.187 mol) 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester in 175 ml 1 ,2-dichloroethane kept at -30°C under an inert atmosphere and with stirring became a bromine solution

(59.8 g; 0.374 mol) in 140 ml of 1,2-dichloroethane added over two hours. The reaction mixture was kept at -30°C until complete conversion of the starting product, and was then slowly added dropwise to 1000 ml of a 10% solution of Na 2 CC> 2 with vigorous stirring. The organic phase was separated, washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The mixture of the two diastereoisomers 3,4 was obtained in a ratio of 9:1. The above ratio was determined by HPLC and """H-NMR.

Example 9

Preparation of 2(R)-hydroxy-3(R)-[2-(5-bromo-6-methoxy-2-naphthyl)-propanoyl-butanedioic acid dimethyl ester.

To a solution of 2.66 g (0.005 mol) 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R )-dicarboxylic acid dimethyl ester (ratio between diastereoisomer 3 and diastereoisomer 4 = 85:15 determined by HPLC) in 20 ml of 1,2-dichloroethane kept under stirring at -15°C under an inert atmosphere was added 1.17 g (0.006 mol) of silver tetrafluoroborate .

The reaction mixture was kept at -15°C for two hours and then allowed to warm to room temperature over the course of one hour and was filtered. The organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum.

The desired product was obtained (2.2 g; 0.0047 mol; yield 94%) as a mixture of two diastereoisomers designated as C and D, in a ratio C:D = 84:16 determined by """H-NMR ) .Diastereoisomer C (RRS) - The data were consistent with the given structure; the data referring to the aliphatic part are analogous to those of diastereoisomer A described in Example 3.

Diastereoisomer D (RRR) - The data were consistent with the given structure; the data referring to the aliphatic part are analogous to those of diastereoisomer B described in Example 3.

Diastereoisomer C was separated in pure form by crystallization from methanol. Sm.p. = 124-126°C; ft^]^ = +60.2 (c = 1% in CHCl 3 ).

Example 10

Preparation of s(+)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid.

(a) a mixture of: 2 (R) -hydroxy-3 (R) -£"2-(5-bromo-6-methoxy-2-naphthyl-propanoy])Jbutanedioic acid dimethyl ester (diastereoisomer C according to example 9; 0, 5 g; 1.065 mmol)

0.170 g (4.26 mmol) of sodium hydroxide

2.5 ml of water

3.5 ml of methanol was kept under stirring at room temperature for 18 hours. The mixture was diluted with water and extracted with dichloromethane. The aqueous phase was acidified with concentrated HCl and extracted with dichloromethane.

The organic phase was then washed with water, dried and the solvent was evaporated under vacuum. The impure acid thus obtained was purified by chromatography on silica gel (eluent hexane: diethylether = 8:2).

S(+)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid in pure form was obtained; melting point = 155-157°C; /"ertj^g +20.5 (c = 0.5% in CHCl3. By starting from this acid, debromination according to the method described in Belgian patent document 892689 yields Naproxen with the same optical purity as the 5-bromo starting derivative.

(b) a mixture of: 2(R)-hydroxy-3(R)-[2-(bromo-6-methoxy-2-naphthyl)-propanoyl-butanedioic acid dimethyl ester (diastereoisomer C obtained according to Example 9; 0, 2 g; 0.426 mmol) 3 mL 1,2-dimethoxyethane 3 mL concentrated HCl was kept at 95°C for two hours. The reaction mixture was then cooled to room temperature, diluted with water and extracted with Cl 2 Cl 2 . The organic phase was washed with water and extracted with 10% sodium bicarbonate. The basic aqueous extract was acidified with concentrated HCl and extracted with Cl 2 Cl 2 . The organic extract was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure. Optically pure S(+)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid was obtained: £"^578 = +44'9 <c = °'5% 1 CHCl3).

This acid was debrominated to form Naproxen with the same optical purity, following the procedure described in Belgian patent document 892689: L<*\]^ 0 = +66° (c = 1% in CHCl3).

Example 11

Preparation of 2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid.

A mixture of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester prepared as described in Example 8 (2.66 g; 5 mmol; diastereoisomer 3:diastereoisomer 4=9:1 as determined by HPLC), 1.7 g (20 mmol) sodium bicarbonate and water were refluxed for 22 hours. The reaction mixture was cooled to room temperature and was extracted with diethyl ether. The aqueous phase was acidified with concentrated HCl and the precipitate was filtered off and washed with water.

The impure acid thus obtained (1.13 g) was purified on a silica gel column (eluent: hexane: diethyl ether in the ratio 8:2). 2-(5-Bromo-6-methoxy-2-naphthyl)-propionic acid (0.92 g; 3 mmol; yield 60%) was obtained, mp 156-158°C; /p^J^S +23'5 (C = °'5% 1 CHC13)

Example 12

Preparation of 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid diethyl ester.

20.0 g (0.093 mol) 1-(6-methoxy-2-naphthyl)-propan-1-one, 160 g diethyl ester of L(+)-tartaric acid and 37 g (0.25 mol) triethyl orthoformate were slowly heated to complete resolution. 0.68 g (0.007 mol) of methanesulfonic acid was added and the solution was refluxed for one hour.

The reaction mixture was cooled to room temperature and was added to 250 ml of a 10% solution of Na 2 CO 2 with vigorous stirring. The reaction mixture was extracted with CH 2 Cl 2 and the organic extracts were repeatedly washed with water.

The organic phase was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure. The impure product was gradually heated to 180°C (external bath) under a pressure of 0.1 mmHg.

The desired product was obtained (33.6 g; 0.084 mol; yield 90%) with the following characteristics:

[fO £° = +20.59° (c = 1%, CHC13)

I.R (pure ): 1770,1740 cm<-1> (extended C = 0)

<1>H-NMR (CDCl3 - TMS) cT (ppm): 0.95 (t.3H, J = 6.4 Hz); 1.02 (t, 3H, J = 7.3 Hz); 1.3 (t, 3H, J = 7.3 Hz); 2.08 (q, 2H,

J = 6.4 Hz); 3.9 (s, 3H); 3.88 (dq, 2H, J = 11 Hz, J = 7.3 Hz); 4.30 (q, 2H, J = 7.3 Hz); 4.82 (ABq, 2H, J = 5.94 Hz); 7-8 (6H, aromatic protons).

Example 13

Preparation of the diastereoisomeric mixture of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid diethyl ester.

To a solution of 2 g (0.005 mol) 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid diethyl ester in 35 ml of CCl ^ was added to a solution of 1.6 g (0.01 mol) of bromine in 3.5 ml of CCl^ under an inert atmosphere and at 20°C. The mixture was kept at 20°C for two hours and was then worked up as described in Example 6.

The desired diastereoisomeric mixture was obtained (designated as 5 and 6) in a yield of 93%.

The ratio between the diastereoisomers, determined by HPLC is 5:6 = 91.5:8.5.

Diastereoisomer 5 (which is the dominant one) exhibited the same configuration (S) as diastereoisomer 1 (Example 2) and as diastereoisomer 3 (Example 6) in terms of the aliphatic carbon atom attached to bromine.

<1>H-NMR (CDC13 - TMS) (200 MHz)

Diastereoisomer 5 (RRS): (T (ppm) 1.04 (t, 3H, J = 7 Hz); 1.31 (t, 3H, J = 7 Hz); 1.65 (d, 3H, J = 6 .8 Hz); 3.92 (dq, 2H,

J = 11.3 Hz, J = 7 Hz); 3.98 (s, 3H); 4.3 (q, 2H, J = 7 Hz); 4.48 (q, 1 H, J = 6.8 Hz); 4.88 (ABq, 2H, J = 6.5 Hz); 7.2-8.2 (5H, aromatic protons).

Diastereoisomer 6 (RRR) : ( P (ppm) 1.09 (t, 3H, J = 7 Hz); 1.29 (t, 3H, J = 7 Hz); 1.62 (d, 3H, J = 6 .8 Hz); 3.98 (s, 3H); 4.29 (q, 2H, J=7 Hz); 4.85 (ABq, 2H, J = 6.5 Hz); 7.2-8, 2 (5H, aromatic protons).

HPL analysis performed under essentially the same conditions as described in Example 6, with the only difference that the percentage of solvent B was 58% (total flow rate 2 ml/min.).

Diastereoisomer 5: retention time 24.03 minutes. Diastereoisomer 6: retention time 25.00 minutes.

Example 14

Preparation of 2-ethyl-2-(6-methoxy-2-naphthyl-1,3-dioxolane-4(R),5(R)-dicarboxylic acid.

A mixture of 4.68 g (12.5 mmol) of 2-ethyl-2-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester, 1 g (25 mmol) of NaOH and 50 ml of water were kept under stirring at room temperature for five hours.

The reaction mixture was filtered and the aqueous phase was acidified with concentrated HCl to pH 1. The reaction mixture was extracted with diethyl ether, and the combined organic extracts were washed with water and dried over Na 2 SO 4 . Evaporation of the solvent in vacuo gave 2-ethyl-2-(- methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid (3.46 g; 10 mmol; yield 80%, m.p. = 100-102°C.

<1>H-NMR (200 MHz) (CDC13 - TMS) delta (ppm): 0.92 (t, 3H, J = 7 Hz); 2.07 (q, 2H, J = 7 Hz); 3.86 (s, 3H); 4.78 (2H, ABq, A V = 4.2; J = 5.8 Hz); 7.0-8.0 (6H, aromatic protons).

A sample esterified with diazomethane in diethyl ether gave the starting methyl ester with unchanged ^HNMR, I.R., m.p., and

Example 15

Preparation of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid.

A mixture consisting of the two diastereoisomers of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4 (R),' 5 (R)-dicarboxylic acid dimethyl ester, in a ratio of 9:1 (6.65 g; 12.5 mmol), 1 g (25 mmol) of NaOH, 10 ml of dimethoxyethane and 10 ml of water were kept under stirring at room temperature for two hours.

The reaction mixture was diluted with water and extracted with diethyl ether. The aqueous phase was then acidified to pH 1 with concentrated HCl and was extracted with diethyl ether. The combined organic extracts were washed with water and dried over Na 2 SO 4 . Evaporation of the solvent under vacuum gave the two diastereoisomers of 2-(1-bromo-ethyl)-2-(5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4(R),5(R)-dicarboxylic acid (5.8 g; 11.5 mmol; yield 92%) indicated by numbers 7 and 8. The ratio of diastereoisomers 7 and 8, determined by < 1>HNMR (200 MHz ) was 9:1.

Diastereoisomer 7 (RRS) (CDCl 3 - TMS) delta (ppm): 1.60 (d, 3H, J = 7 Hz); 4.00 (p, 3H); 4.49 (q, 1H, J = 7 Hz); 4.87 (2H, ABq,4J >= 18.9; J = 6.5 Hz); 7.2-8.2 (5H, aromatic protons).

Example 16

Preparation of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid.

A mixture of 2-[l (S)bromethylJ-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester (diastereoisomer 3 in pure form; 6.65 g; 12.5 mmol), 1 g (25 mmol) of NaOH, 10 mL of dimethoxyethane and 10 mL of water were stirred at room temperature for two hours.

The reaction mixture was diluted with water and

extracted with diethyl ether. Then the aqueous phase was acidified to pH 1 with concentrated HCl and was extracted with diethyl ether. The combined organic extracts were washed with water and dried over Na 2 SO 4 . Evaporation of the solvent under vacuum gave 2-[X(S)-bromomethylJ-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolan-4(R), 5(R )-dicarboxylic acid (diastereoisomer 7) .

■"■H NMR (200 MHz) (CDC13 - TMS) delta (ppm): 1.60 (d, 3H, J = 7 Hz); 4.00 (s, 3H); 4.49 (q, 1H, J = 7 Hz); 4.87 (2H, ABq, & rf= 18.9; J = 6 Hz); 7.2-8.2 (5H, aromatic protons).

Example 17

Preparation of 2(R)-hydroxy-3(R)-C2-(5-bromo-6-methoxy-2-naphthyl)-propanoyl-butanedioic acid dimethyl ester.

To a mixture of diastereoisomers 3 and 4 in the ratio 94:6 (determined by HPLC) (10.0 g; 0.0188 mol) in 75 ml of 1,2-dichloroethane kept under stirring at +15°C under an inert atmosphere was added a solution of 4.4 g (0.0226 mol) of silver tetrafluoroborate in 30 ml of 1,2-dichloroethane over 15 minutes. The reaction mixture was kept at +15°C for seven hours, and was then slowly poured into 100 ml of cooled water in such a way that the temperature did not exceed +10°C. The mixture was then filtered on celite and the filtrate was washed with 100 ml of CH 2 Cl 2 .

The organic phase was washed with water (2x200 mL) and dried over Na2SO4> Evaporation of the solvent under reduced pressure gave a residue (7.2 g; 0.0154 mol; yield 82%) consisting of a mixture of diastereoisomeric esters (diastereoisomeric ratio C:D = 91:9, determined by """H NMR analysis.

Example 18

Preparation of the compound 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid diisopropyl ester.

10.3 g (0.048 mol) of 1-(6-methoxy-2-naphthyl)-propan-1-one, 94 g of the di-isopropyl ester of L(+)-tartaric acid and 7.57 g (0.071 mol) of trimethylorthoformate were gradually heated to complete dissolution. 0.37 g (0.0039 mol) of methanesulfonic acid was then added to the reaction mixture, and the solution was boiled under reflux for 2.5 hours (temperature of the solution = 90°C). The reaction mixture was cooled and slowly added to 100 ml of a 10% solution of Na 2 CO 3 with vigorous stirring. The reaction mixture was extracted with CH 2 Cl 2 and the organic extracts were washed with 100 ml of water. The organic phase was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure to give 94 g of crude product. The impure product was then slowly heated to 220°C (external bath) at 0.2-0.3 mmHg. The residue was purified by chromatography on a silica gel column (eluent: hexane:diethylether = 85: 15) to give 2-ethyl-2(6-methoxy-2-naphthyl)-1,3-dioxolan-4(R), 5(R )-dicarboxylic acid di-isopropyl ester (14.2 g; 0.033 mol; yield 69%).

I.R. (pure): 1770, 1740 cm"<1> (extended C = 0).

<1>H NMR (CDCl3 - TMS) (200 MHz) delta (ppm): 0.95 (t, 3H, J = 7.6 Hz); 0.96 (d, 3H, J = 6.4 Hz); 1.05 (d, 3H, J = 6.4 Hz); 1.29 (d, 6H, J = 6.4 Hz); 3.8 (s, 3H); 4.75 (ABq, 2H, J = 6.6 Hz); 4.79 (q, 1H, J = 6.4); 5.14 (ept., 1H, J = 6.4); 7-8 (m, 6H).

Example 19

Preparation of the diastereoisomeric mixture of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid di-isopropyl ester .

A solution of 1.6 g (0.01 mol) of bromine in 3.5 ml of CCl^ was added dropwise at 15°C and under an inert atmosphere during one hour to a solution of 2.15 g (0.005 mol) 2 -ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid diisopropyl ester in 35 ml CCl 2 . The mixture was kept at 15°C for two hours and was then worked up as described in Example 6. The desired diastereoisomeric mixture (isomers 9 and 10) was obtained in a yield of 94%.

The ratio between the two diastereoisomers as determined by HPLC was 9:10 = 93.9:6.1. <1>H NMR (CDCl3 - TMS) (200 MHz).

Diastereoisomer 9 (RRS): delta (ppm): 0.96 (d, 3H, J = 6.4 Hz); 1.06 (d, 3H, J = 6.4 Hz); 1.3 (d, 6H, J = 6.4 Hz); 1.67 (d, 3H, J = 7.2 Hz); 3.98 (s, 3H); 4.47 (q, 1H, J = 7.2 Hz); 4.80 (ABq, 2H, J = 6.6 Hz); 4.80 (m, 1H, J = 6.4 Hz); 5.15 (m, 1H, J = 6.4 Hz); 7.2-8.2 (5H, aromatic protons). Diastereoisomer 10 (RRS): delta (ppm): 0.96 (d, 3H, J = 6.4 Hz); 1.06 (d, 3H, J = 6.4 Hz); 1.28 (d,' 6H, J = 6.4 Hz); 1.63 (d, 3H, J = 7.2 Hz); 3.98 (s, 3H); 4.47 (q, 1H, J = 7.2 Hz); 4.80 (ABq, 2H, J = 6.6 Hz); 4.80 (m, 1H, J = 6.4 Hz); 5.15 (m, 1H, J = 6.4 Hz); 7.2-8.2 (5H, aromatic protons).

The HPLC analysis was carried out as described in Example 6 with the exception that the percentage amount of solvent B was 62.5% (total flow rate 2 ml/min). Diastereoisomer 9: retention time 23.68 minutes. Diastereoisomer 10: retention time 24.46 minutes.

Example 20

Preparation of [ 2 (R) hydroxy-3(R)-2-(5-bromo-6-methoxy-2-naphthyl)-propanoyl^-butanedioic acid di-isopropyl ester.

Following the procedure described in Example 17, a mixture of diastereoisomeric ketals 9 and 10 (Example 19) in a ratio of 9:10 = 94:6 determined by HPLC (2.0 g; 3.4 mmol) was treated to give a residue (1.6 g) which after purification by chromatography on a silica gel column (eluent hexane:diethylether =1:1) gave a mixture of diastereoisomeric esters (E and F) in the ratio 90:10 (determined by H NMR analysis).

<1>H-NMR (CDC13 - TMS) (200 MHz).

Diastereoisomer E (RRS): delta (ppm): 0.55 (d, 3H, J = 6.12 Hz); 1.02 (d, 3H, J = 6.12 Hz); 1.24 (d, 3H, J = 6.12 Hz); 1.27 (d, 3H, J = 6.12 Hz); 1.61 (d, 3H, J = 7 Hz); 3.17 (d, 1H, J = 6.8 Hz); 4.00 (q, 1H, J = 7 Hz); 4.02 (s, 3H); 4.52 (ept, 1H, J = 6.12 Hz); 4.62 (dd, 1H, JCH_CH = 2.2 Hz, JCH-OH = 6.8 Hz); 5.13 (ept/ 1H' J = 6.12 HZ); 5.30 (d' 1H' J = 2.2 Hz); 7.2-8.2 (5H, aromatic system). Diastereoisomer F (RRR): delta (ppm): 0.95 (d, 3H, J = 6.12 Hz); 1.12 (d, 3H, J = 6.12 Hz); 1.14 (d, 3H, J = 6.12 Hz); 1.19 (d, 3H, J = 6.12 Hz); 1.62 (d, 3H, J = 7 Hz); 3.17 (d, 1H, J = 6.8 Hz); 4.00 (q, 1H, J = 7 Hz); 4.02 (s, 3H); 4.52 (ept, 1H, J = 6.12 Hz); 4.62 (dd, 1H, JCH_CH <=><2.>2 Hz); JCR_ OH = 6.8 Hz). 5.13 (ept, 1H, J = 6.12 Hz); 5.41 (d, 1H, J = 2.2 Hz); 7.2-8.2 (5H, aromatic system).

Example 21

Preparation of 2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid.

A mixture of diastereoisomers E and F (Example 20) in the ratio E:F = 90:10 (0.35 g; 0.648 mmol), 4.6 ml of dimethoxyethane and 4.6 ml of 12 N HCl was kept at 88°C in stirring for two hours. The reaction mixture was cooled to room temperature and then worked up as described in example 10(b). The impure product thus obtained was eluted through a silica gel column (eluent hexane:ethylether = 8:2) to form 2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid: m.p. = 148-151°C; S^ J\ j8 +38° (c = 0.5% CHCl3)

The methyl ester of the above-mentioned acid obtained by esterification with diazomethane and analyzed by """H-NMR (200 MHz) with formation of optically active shift agent (europium (III) tris-O-(heptafluoro-propylhydroxymethylene)-d-cam-foratj in CDCl^ exhibited a ratio between the enantiomers of S(+):R(-) = 90:10.

Example 22

Preparation of 2 (R) hydroxy-3 (R)-C2-(5-bromo-6-methoxy-2-naphthyl)-propanoyl-butanedioic acid diethyl ester.

Following the procedure described in Example 17, a mixture of diastereoisomeric ketals 5 and 6 (Example 13) with a ratio of 5:6 = 93:7, determined by HPLC (2.41 g; 4.3 mmol) was treated to form of 1.95 g of a residue which on elution through a silica gel column (eluent hexane:diethylether = 1:1) gave a mixture of diastereoisomeric esters indicated as G and H (1.77 g; 3.6 mmol; yield 83%) in ratio G:H = 86:14 determined by """H-NMR, 200 MHz.

<1>H-NMR (CDC13 - TMS) (200 MHz):

Diastereoisomer G (RRS): delta (ppm): 0.76 (t, 3H, J = 7.2 Hz); 1.27 (t, 3H, J = 7.2 Hz); 1.58 (d, 3H, J = 7 Hz); 3.10 (d, 1H, J = 7.12 Hz); 3.58 (q di AB, 2H, Jgem = 12 Hz, J = 7.2 Hz); 4 (q, 1H, J = 7 Hz); 4.01 (s, 3H); 4.27 (q, 2H, J = 7.2 Hz); 4.65 (dd, 1H, JCH_OH = 7.12 Hz); JCH_0H <=><2>.4 Hz); 5.32 (d, 1H, J = 2.4 Hz); 7.2-8.2 (5H, aromatic protons). Diastereoisomer H (RRR): delta (ppm): 1.08 (t, 3H, J = 7.2 Hz); 1.14 (t, 3H, J = 7.2 Hz); 1.62 (d, 3H, J = 7 Hz); 3.1 (d, 1H, J = 7.12 Hz); 3.58 (q di AB, 2H, Jgem = 12 Hz, J = 7.2 Hz); 4.00 (q, 1H, J = 7Hz); 4.01 (s, 3H): 4.27 (q, 2H,

J = 7.2 Hz); 4.65 (dd, 1H, JCH_OH = 7.12 Hz; JCH_CH = 2.4 Hz); 5.44 (d, 1H, J = 2.4 Hz); 7.2-8.2 (5H, aromatic protons).

Example 23

A mixture of diastereoisomeric esters G and H prepared as described in example 22 (ratio G:H = 86:14)

(0.64 g; 1.28 mmol), 9 mL of dimethoxyethane and 9 mL of 12 N HCl were

was kept at 95°C (the temperature of the bath) with stirring for one hour.

The reaction mixture was cooled to room temperature and then worked up as described in example 10(b). The impure acid thus obtained was eluted through a silica gel column (eluent hexane:diethylether = 1:1).

2-(5-Bromo-6-methoxy-2-naphthyl)-propionic acid was obtained. Sm.p. = 149-151°C and fdij^g +33.94° (c = 0.5%, CHCl 3 ).

A sample was esterified with diazomethane and the methyl ester obtained was analyzed by <1>H-NMR (200 MHz) using an optically active shift agent (europium (III) tris/<3>-(e<p>tafluor<p> ro<p>yl-h<y>drox<y>meth<y>len)-d-camphorate J in CDC13).

The enantiomeric ratio was S(+):R(-) = 86:14.

Example 24

Preparation of 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(S), 5(S)-dicarboxylic acid dimethyl ester.

20 g (0.093 mol) 1-(6-methoxy-2-naphthyl)-propan-1-one, 129 g dimethyl ester of D(-) tartaric acid and 29 g (0.27 mol) trimethylorthoformate were gradually heated to complete heating solution. To the reaction mixture was then added 0.74 g (7.7 mmol) of methanesulfonic acid and the solution was refluxed (84°C) for one hour, then cooled to room temperature and the mixture was very slowly poured into 250 ml of a 10% -ig solution of Na2C03 under vigorous stirring. The mixture was extracted with 250 ml of CH 2 Cl 2 and the organic extracts were washed with water. The organic phase was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure. 40.3 g of the crude product was gradually heated to 180°C at 0.1-0.5 mmHg with stirring. 33.3

g residue was crystallized from 100 ml methanol to give the desired product (23.7 g; 0.0635 mol; yield 68%) with the following characteristics: mp. 72-73 °C; = -34.0° (c = 1%, CHCl 3 ). I.R. ("Nujol"): 1770, 1740 cm 1 (extended C = 0). <1>H-NMR (CDC13 - TMS) (200 MHz).

These data are identical to those for the compound 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester described in Example 1.

Example 25

Preparation of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(S), 5(S)-dicarboxylic acid dimethyl ester.

By proceeding as described in example 19 starting from 9.35 g (0.025 mol) 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4 (S), 5(S) -dicarboxylic acid dimethyl ester, the desired mixture of diastereoisomers was obtained (identified as 3' and 4') in 93% yield. The ratio between the diastereoisomers as determined by HPLC is 3':4' = 93:7. Diastereoisomer 3' which is the dominant one is the enantiomer of diastereoisomer 3 described in Example 6. <1>H-NMR (CDC13 - TMS) (200 MHz). Diastereoisomer 3' (SSR): the data are identical to those of diastereoisomer 3 described in Example 3.

Diastereoisomer 4<1> (SSS): the data are identical to those of diastereoisomer 4 described in Example 6.

HPLC analysis was performed as described in Example 6. Diastereoisomer 3': retention time 18.41 minutes. Diastereoisomer 4': retention time 19.33 minutes.

Example 26

Preparation of 2 (S)-hydroxy-3 (S)(5-bromo-6-methoxy-2-naphthyl)-propanoyl-butanedioic acid dimethyl ester.

Proceeding as described in Example 17 gave the diastereoisomeric mixture of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(S) , 5(S)-dicarboxylic acid dimethyl ester (compounds 3' and 4' according to example 25 in the ratio 3':4' = 93:7; 2.66 g; 5.0 mmol) a mixture of the desired diastereoisomers (1.98 g; 4.2 mmol; yield 84.4%) identified as compounds C and D<*>. The ratio determined by 1H-NMR (200 MHz) is C':D' = 85:15.

<1>H-NMR (CDC13 - TMS) (200 MHz).

Diastereoisomer C (SSR): the data are identical to those of diastereoisomer C described in Example 9.

Diastereoisomer D' (SSS): the data are identical to those of dia-

stereoisomer D described in Example 9.

Example 27

Preparation of R(-)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid.

A mixture of diastereoisomers C and D' prepared according to Example 26 (ratio C':D' = 85:15; 1.2 g; 2.56 mmol), 18 ml of dimethoxyethane and 18 ml of 12 N HCl was kept at 88 °C with stirring for one hour. The reaction mixture was cooled to room temperature and then worked up as described in example 10(b). The impure acid thus obtained was eluted through a silica gel column (eluent hexane:diethylether 1:1).

2-(5-Bromo-6-methoxy-2-naphthyl)-propionic acid was obtained. Sm.p. = 146-148°C; [ ck]^ Q = -33.39° (c= 0.5%; CHC13)

This acid was esterified with diazomethane and the methyl ester obtained was analyzed by <1>H-NMR (200 MHz) using an optically active shifter (europium (III)-tris^3-(heptafluoropropylhydroxymethylene)-d-camphoratj in CDCl3) .

The ratio between the enantiomers is R(-):S(+) = 85:15. The methyl ester crystallized from methanol and hydrolyzed with an acid gives R(-)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid in optically pure form.

Example 28

Preparation of 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester.

• 465 g (2.17 mol) 1-(6-methoxy-2-naphthyl)-propan-l-one, 773 g (4.34 mol) dimethyl ester of L(+) tartaric acid and 461 g (4.34 mol ) trimethylorthoformate was gradually heated until complete dissolution. To the solution was added 15 g (0.155 mol) methanesulfonic acid. The reaction mixture was kept at 100°C for four hours and the volatile compounds were distilled from (about 400 g). The reaction mixture was cooled to 50°C and slowly poured with stirring into 5 l of a 10% aqueous solution of NaHCO 3 . The mixture was extracted with CH 2 Cl 2 and the organic extract was washed with water and

dried over Na 2 SO 4 . Evaporation of the solvent under reduced pressure gave a residue containing the desired product as determined by HPLC analysis (743 g; yield 91.6%). An analytically pure product was obtained by crystallization from 1.3 L of methanol (672 g; 1.8 mol; yield 82.8%).

Example 29

Preparation of 2-ethyl-2 4-(2-methylpropyl)-phenylj-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester.

A mixture of 110 g (0.58 mol) of 1-T4-(2-methylpropyl)-phenylj-propan-l-one, 206 g (1.16 mol) of the dimethyl ester of L(+) tartaric acid and 122.7 g ( 1.16 mol) of trimethylorthoformate was gradually heated to complete dissolution (50°C). 3.9 g (0.04 mol) methanesulfonic acid was then added to the solution.

The reaction mixture was heated to 85°C and was kept at this temperature for two hours and was then cooled to room temperature and worked up as described in example 1. 210 g of the crude product was eluted through a silica gel column (eluent hexane:diethylether = 8:2 ) and the desired product was obtained (175.2 g; 0.501 mol; yield 86.5%) with the following characteristics: I.R. (pure 1730-1760 cm"<1> (extended C = 0).

■"•H-NMR (CDC13 - TMS) (200 MHz) delta (ppm): 0.84 (d, 6H, J

= 6.4 Hz); 0.89 (t, 3H, J = 7.5 Hz); 1.8 (t-ept, 1H, JCH_

CH -6.4 Hz, JCH_CH = 7.1 Hz); 1.97 (q, 2H, J = 7.5 Hz);

2.41 (d, 2H, J = 7.1 Hz); 3.78 (s, 3H); 3.84 (s, 3H); 4.78 (AB, 2H, J = 5.7 Hz); 7-7.4 (AA'BB', 4H, aromatic protons).

Example 30

Preparation of diastereoisomers of the compound 2-(1-bromomethyl)-2-[4-(methylpropyl)-phenyl]-1,3-dipxolane-4(R),5(R)-dicarboxylic acid dimethyl ester.

To a solution in 70 ml of 1,2-dichloroethane of 7.0 g (20 mmol) of 2-ethyl-2-f4-(2-methylpropyl)-phenyl^i,3-dioxolane-4(R), 5(R )-dicarboxylic acid dimethyl ester (obtained as described in Example 29), deoxygenated and added hydrobromic acid (0.324 g;

4 mmol) was added dropwise over the course of one hour and under an inert atmosphere at +15°C a solution of 3.20 g-(20 mmol) bromine in 7.0 ml of 1,2-dichloroethane which had previously been deoxygenated. The mixture was kept at 15°C for a further hour and was

then worked up as described in example 6. The residue thus obtained was eluted through a silica gel column (eluent hexane:diethylether = 8:2) forming a mixture of the desired diastereoisomers, identified as 11 and 12, in a yield of 77%. The relationship

between compounds 11 and 12 as determined by HPLC is 88:12. <1>H-NMR (CDC13 - TMS) (200 MHz): Diastereoisomer 11 (RRS): delta (ppm): 0.87 (d, 6H, J = 6.4 Hz); 1.61 (d, 3H, J = 7.1 Hz); 1.84 (t-ept, 1H, JCH_CH =

6.4 Hz, JCH_CH = 7.1 Hz); 2.45 (d, 2H, J = 7.1 Hz); 3.53 (s,

3H); 3.84 (s, 3H); 4.38 (q, 1H, J = 7.1 Hz); 4.9 (AB, 2H, J = 5.9 Hz); 7-7.4 (AA'BB', 4H, aromatic protons). Diastereoisomer 12 (RRR): delta (ppm): 0.87 (d, 6H, J = 6.4 Hz); 1.58 (d, 3H, J = 7.1 Hz); 1.87 (t-ept, 1H, JCH_CH <=>

6.4 Hz, JCH_CH = 7.1 Hz); 2.53 (d, 2H, J = 7.1 Hz); 3.6 (s, 3H); 3.83 (s, 2 3H); 4.41 (q, 1H, J = 7.1 Hz); 4.85 (AB, 2H, J = 6.5 Hz); 7-7.4 (AA'BB', 4H aromatic protons).

The HPLC analysis was carried out under the following conditions: Hewlett Packard instrument mod. 1090 with a UV detector (mod. 1040 DAD) with variable wavelength.

Analytical conditions:

column BROWNLEE LABS RPS (5^/), 250 mm x 4.6 mm (inner diameter) .

Solvent A: bi-distilled water.

Solvent B: acetonitrile:methanol = 40:60. Flow rate: 2 ml/min.

Percent of solvent B: 54%.

Column temperature: 50%.

Wavelength ( ^): 222 nanometers.

Injection: 4 µl of a solution containing 0.5 mg/ml product in acetonitrile:methanol 40:60.

Retention times: diastereoisomer 11 = 22.61 minutes,

diastereoisomer 12 = 23.63 minutes.

Example 31

Preparation of 2(R)-hydroxy-3(R)-(2-(4-(2-methylpropyl)-phenyl)-propanoyl-butanedioic acid dimethyl ester.

Proceeding under analogous conditions to those described in Example 17 from a mixture of diastereoisomers 11 and 12 (3.0 g; 7.0 mmol) (ratio determined by HPLC, 11:12 = 88:12) was after a reaction time of six hours at +28°C after working up the reaction mixture a mixture of diastereoisomeric esters indicated here as I and J was obtained. <1>H-NMR (CDC13 - TMS) (200 MHz) Diastereoisomer I (RRS): delta (ppm): 0.87 (d, 6H, J = 6.4 Hz); 1.485 (d, 3H, J = 7.1 Hz); 1.8 (t-hept, 1H, JCH_CH =

6.4 Hz, JCH_CH = 7.1 Hz); 2.42 (d, 2H, J = 7.1 Hz); 3.15

(d, 1H, J = 7.05 Hz); 3.32 (s, 3H); 3.78 (s, 3H); 3.8 (q, 1H, J = 7.1 Hz); 4.67 (dd, 1H, JCH_CH =2.3 Hz, JCH_0H = 7.05

Hz); 5.36 (d, 1H, J = 2.3 Hz); 7.02-7.16 (AA'BB', 4H, aromatic protons).

Diastereoisomer J (RRR): delta (ppm): 0.87 (d, 6H, J = 6.4 Hz); 1.525 (d, 3H, J = 7.1 Hz); 1.825 (t-hept, 1H, JCH_CH

= 6.4 Hz, JCH_CH <=> 7.1 Hz); 2.43 (d, 2H, J = 7.1 Hz); 3.15

(d, 1H, J = 7.05 Hz); 3.62 (s, 3H); 3.69 (s, 3H); 3.69 (s, 3H); 3.82 (q, 1H, J = 7.1 Hz); 4.73 (dd, 1H, JCH_CH = 2.3 Hz, JCH_0H <=><7>.05 Hz); 5.43 (d, 1H, J = 2.3 Hz); 7.04-7.2 (AA'BB'f 4 H, aromatic protons).

Example 32

Preparation of 2-£4-(2-methylpropyl)-phenyl-3-propionic acid (Ibuprofen).

By proceeding in an analogous manner as described in example 10(b), impure 2-T4-(2-methylpropyl)-phenylj-propionic acid was obtained from a mixture of diastereoisomeric esters I and J, prepared as described in example 31 (1, 37 g; 3.74 mmol). After chromatography on silica gel, the pure acid was obtained (0.7 g). f^J<20> = +19° (c = 1%, 95% ethanol).

Example 33

Preparation of 2-(1-bromomethyl)-2-£*4-(2-methylpropyl)

-phenylJj-1,3-dioxolane-4(R),5(R)-dicarboxylic acid.

A solution of diastereoisomers 11 and 12 (see Example 30) (10.0 g; 0.0233 mol) in 20 mL of methylene chloride was added dropwise to a solution of 1.87 g (0.0466 mol) of sodium hydroxide in 25 mL of water and 100 ml of methanol kept under stirring at 20°C. The reaction mixture was stirred at this temperature for one hour. The solvent was evaporated under reduced pressure. The residue was taken up in 100 ml of water and acidified to pH 1 with concentrated HCl. The solution was extracted with 3 x 50 ml of diethyl ether. The organic phase was extracted with 3 x 50 ml of 10% sodium bicarbonate solution. The alkaline solution was acidified to pH 1 with concentrated HCl and was extracted with 3 x 50 ml of diethyl ether. The combined organic phases were dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product (8.3 g, acidimetric determination: 92%; yield 81%). HPLC analysis of a sample esterified with diazomethane showed that the ratio between the two diastereoisomers 13 and 14 was 87:13. <1>H-NMR (CDC13 - TMS) delta (ppm) Diastereoisomer 13 (RRS): delta (ppm): 0.87 (d, 6H, J = 6.4 Hz); 1.59 (d, 3H, J = 7.1 Hz); 1.95 (t- ept, 1H, JCH_CH =

6.4 Hz, JCH_CH = V Hz); 2.55 (d, 2H, J = 7Hz); 4.42 (q, 1H,

J = 7.1 Hz); 4.88 (AB, 2H, J = 6.4 Hz); 7-7.4 (AA<1>BB', 4H, aromatic protons); 8.2 (p, 2H).

Diastereoisomer 14 (RRR): delta (ppm): 0.87 (d, 6H, J =6.4 Hz); 1.58 (d, 3H, J = 7.1 Hz); 1.95 (t- ept, 1H, JCH_CH =

6.4 Hz, JCH_CH = 7 Hz); 2.55 (d, 2H, J = 7 Hz); 4.42 (q, 1H, J = 7.1 Hz2; 4.8 (AB, 2H, J = 6.4 Hz); 7-7.44 (AA<1>BB<1>, 4H, aromatic protons ); 8.2 (s, 2H).

Example 34

Preparation of ( + )-2 (R)-hydroxy-3 (R)-O-(S) (6-Methoxy-2-naphthyl)-propanoyl-butanedioic acid dimethyl ester.

A solution of 4.45 g (0.044 mol) of triethylamine in 10 ml of methylene chloride was added dropwise over five minutes to a mixture of 44.5 g (0.25 mol) of 2(R),3(R)-dihydroxy- butanedioic acid dimethyl ester (L(+) tartaric acid dimethyl ester) and 90 ml of methylene chloride, cooled to -10°C and kept under stirring, followed by the dropwise addition over 20 minutes of a solution of 5.0 g (0.020 mol) S (+)2-(6-methoxy-2-naphthyl)-propionyl chloride in 25 ml of methylene chloride, prepared as described in Japanese patent application 57/145841 (CA. 98, 72492h).

The reaction mixture was then poured into 200 ml of a 10% sodium bicarbonate solution, extracted with 100 ml of methylene chloride and the organic phase was washed with dilute hydrochloric acid and dried over sodium sulfate. 5.5 g of residue was obtained by evaporation of the solvent under reduced pressure, and this was crystallized from a mixture of heptane and diethyl ether (1:1, 165 ml).

The desired product (diastereoisomer A, see example 3) (2.75 g) was obtained with the following characteristics:

I.R. (C = 5%, CHCl 3 ) 1750 cm"<1>

&v 7 20 = +73/7o (c = 1%^ CHCl3)

Sm.p. = 77-79°C.

<1>H-NMR (CDC13 - TMS) (200 MHz): delta (ppm): 1.58 (d, 3H,

J = 7.4 Hz); 3.07 (s, 3H); 3.31 (d, 1H, J = 7.4 Hz); 3.79 (s, 3H); 3.87 (s, 3H); 3.96 (q, 1H, J = 7.4 Hz); 4.66 (dd, 1H, JCH_CH = 2.3 Hz, JCH_OH = 7.4 Hz); 5.37 (d, 1H, J = 2.3 Hz); 7-7.8 (6H, aromatic system).

A solution of 0.410 g (2.56 mmol) of bromine in 3 ml of 1,2-dichloroethane was added over 15 minutes to a solution of the thus obtained ester in 10 ml of 1,2-dichloroethane cooled to 0°C . The reaction mixture was kept at 0°C for one hour and then poured into 10 ml of a 10% sodium bicarbonate solution and extracted with 10 ml of methylene chloride.

The combined organic phases were washed with 2 x 20 ml of water, dried over sodium sulfate and the solvent was evaporated under reduced pressure.

1.14 g of residue was crystallized from methanol.

(+)-2(R)-hydroxy-3(R)-[ 2-(S)-(5-bromo-6-methoxy-2-naphthyl)-propanoyl)J-butanedioic acid dimethyl ester was obtained (0.0 39

g; 1.9 mmol; dividend 74%; sm.p. 124-126°C; = +61.4°

(c = 1%; CHC1.,).

The chemical-physical data (m.p., Æ^J T D 2 0 and 1H-NMR-200 MHz are similar to those of the diastereoisomeric ester C described in example 9. Treated with palladium on carbon and hydrogen at atmospheric pressure and room temperature in the presence of triethylamine gave the product diastereoisomer A.

Example 35

Preparation of the mixture of diastereoisomers 7 and 8 of -2-(1-bromo-ethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R )-dicarboxylic acid.

A solution of 171 g (1.68 mol) of bromine in 360 ml of carbon tetrachloride was added dropwise over the course of one hour to a solution of 200 g (0.534 mol) of 2-ethyl-2-(6-methoxy-2-naphthyl)- 1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester in 200 ml of carbon tetrachloride kept under an inert atmosphere at 0°C.

The reaction mixture was kept at 0°C for two hours and was worked up as described in example 6. 351 g of the crude product was dissolved in 2000 ml of methanol, and a solution of 38.4 g (0.96 mol) of sodium hydroxide in 384 ml water was added dropwise to the resulting solution at ambient temperature over one hour. The reaction mixture was kept at ambient temperature with stirring for 20 hours. The methanol was evaporated under vacuum. The initial volume was maintained by the addition of water. The pH of the aqueous solution was adjusted to 7 with dilute hydrochloric acid. The solution was then extracted with methylene chloride and the aqueous solution was acidified with concentrated HCl to pH 1. The solution was extracted with 3 x 250 ml of diethyl ether, and the combined organic phases were washed with water and dried over sodium sulfate. The solvent was evaporated under vacuum to give a residue which was crystallized from methylene chloride.

A mixture of the two diastereoisomers 7 and 8 of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)- dicarboxylic acid was obtained (205 g; 0.407 mol; yield 76%) in the ratio 7:8 = 94:6.

Example 36

A mixture of the two diastereoisomers 3 and 4 of 2-(1-bromomethyl)-2-5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester in the ratio 3:4 =

9:1 (1 g; 1.87 mmol), 0.84 g (3.75 mmol) of zinc bromide and 12 mL of 1,2-dichloroethane were heated to reflux (83°C with stirring and under nitrogen for 66 h.

The reaction mixture was cooled to ambient temperature and 5 ml of water was added. The phases were separated and the organic phase was dried over sodium sulfate.

The solvent was evaporated under vacuum to give 0.9 g of a residue to which 10 ml of dioxane and 5 ml of concentrated HCl were added. The mixture was heated to 70°C with stirring for two hours, then diluted with 10 ml of water and extracted with 3 x 20 ml of diethyl ether. The combined organic extracts were washed with water and dried over sodium sulfate. Evaporation of the solvent under vacuum gave a residue which by chromatography on silica gel (eluent hexane:ethylether = 7:3) gave 2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (0.28 g; 0 .9 mmol, yield 48%); sm.p. 166-167°C. £"c*J <20> = +15.44° (c = 0.5, CHCl 3 ).

The ratio between the enantiomeric acids S(+)/R(-) is 65:35.

Example 37

Preparation of 2-(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid methyl ester from 2-(1-(S)-bromomethyl)-2-(5-bromo-6-methoxy-2- naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester.

A mixture of 1.03 g (1.93 mmol) of pure 2-(1-(S)-bromo-ethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane- 4(R), 5(R)-dicarboxylic acid dimethyl ester, 0.6 g (2.31 mmol) silver trifluoromethanesulfonate and 5 mL methanol were heated to reflux for seven hours. The reaction mixture was cooled below room temperature, filtered, poured into water and extracted with dichloromethane. The combined organic extracts were washed with water, dried (Na 2 SO 4 ) and filtered. Evaporation of the solvent under reduced pressure gave the optically pure 2-(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid methyl ester. Sm.p. 94-95°C. [ <K] ~ <20> = +52° (c = 0.5, CHCl-j)

The product was found to be optically pure by 1 H-NMR analysis (200 MHz) carried out in CDCl 2 using an optically active shifter (europium (III) tris-£3-(epta-fluoropropylhydroxymethylene)-d-camphoratj).

Example 38

Bromination of 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid.

0.32 g (2 mmol) bromine was added dropwise over five minutes at 15°C and under argon to a suspension of 0.346 g (1 mmol) 2-ethyl-2-(6-methoxy-2-naphthyl)- 1,3-dioxolane-4(R), 5(R)-dicarboxylic acid. The reaction mixture was heated to 40°C and held at 40°C for 12 hours, then poured into a 10% aqueous solution of sodium bicarbonate and extracted with diethyl ether. The aqueous phase was acidified to pH 1 with concentrated HCl and was extracted with diethyl ether. The combined organic extracts were washed with water, dried (Na 2 SO 4 ) and filtered. Evaporation of the solvent under reduced pressure gave an impure residue which, after purification, gave a diastereoisomeric mixture of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4( R), 5(R)-dicarboxylic acid in ratio 7:8 = 81:19 (determined by 1H-NMR).

<1>H-NMR (90 MHz, acetone-dg-TMS) & (ppm): Diastereoisomer 7 (RRS): 1.70 (3H, d, J = 6.8 Hz); 4.03 (3H, s); 4.66 (1H, q, J = 6.8 Hz); 4.95 (2H, ABq, 4U = 15.31, J = 6.9 Hz); 7.45-8.18 (5H, m). Diastereoisomer 8 (RRR): 1.70 (3H, d, J = 6.8 Hz); 4.03 (3H, s); 4.66 (1H, q, J = 6.8 Hz); 4.95 (2H, ABq, & Y > = 14.46, J = 6.6 Hz); 7.45-8.18 (5H, m).

The diastereoisomeric ratio was confirmed by H-NMR and HPLC analysis of the product obtained by esterification with diazomethane.

Example 39

Preparation of the diastereoisomeric mixture of 2-(1-iodoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester.

A solution of 0.935 g (2.5 mmol) of 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester and 0, 81 g (5 mmol) of iodine monochloride in 5 ml of dichloromethane was kept under nitrogen at 15°C for 24 hours. The reaction mixture was poured into a 10% aqueous solution of sodium bicarbonate and extracted with additional dichloromethane. The combined organic extracts were washed with a 5% aqueous solution of sodium thiosulfate, washed with water, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, eluent hexane:diethylether =7:3) gave the diastereoisomeric mixture of 2-(1-iodoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4( R), 5(R)-dicarboxylic acid dimethyl ester 15 and 16 in the ratio 15:16 = 60:40 (determined by <1>H-NMR).

1 H-NMR (200 MHz, CDCl3 - TMS) ( f (ppm) :

Diastereoisomer 15 (RRS):

1.80 (3H, d, J = 7 Hz); 3.44 (3H, s); 3.84 (3H, s); 3.90 (3H, s); 4.58 (1H, q, J = 7 Hz); 4.95 (2H, KBq,&\) = 20.70,

J = 6 Hz); 7.8-8.0 (6H, m).

Diastereoisomer 16 (RRR):

1.80 (3H, d, J = 7 Hz); 3.58 (3H, s); 3.84 (3H, s); 3.90 (3H, s); 4.58 (1H, q, J = 7 Hz); 4.87 (2H, ABq, to V = 46.04, J = 6.8 Hz); 7.8-8.0 (6H, m).

Example 40

Preparation of 2-(6-methoxy-2-naphthyl)-propionic acid from a diastereoisomeric mixture of 2-(1-iodoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4( R), 5(R)-dicarboxylic acid dimethyl ester.

1.2 g (4.8 mmol) of silver trifluoromethanesulfonate was added under argon and with stirring at 15°C to a solution of a diastereoisomeric mixture of 2-(1-iodoethyl)-2-(6-methoxy-2-naphthyl)- 1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester in the ratio 60:40 (1.6 g; 3.2 mmol) in 20 ml of 1,2-di-

chloroethane. The reaction mixture was kept in the dark at 15°C for three hours, then filtered and poured into water. The organic layer was separated, washed with water, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was dissolved in 5 ml of dioxane and 5 ml of concentrated HCl was added. The mixture was heated to 70°C for two hours, cooled to room temperature, poured into water and extracted with diethyl ether.

The combined organic extracts were washed with water and back-extracted with a 2% aqueous solution of sodium bicarbonate. The aqueous phase was acidified with concentrated HCl and was extracted with diethyl ether. The combined organic extracts were washed with water, dried (Na 2 SO 4 ) and filtered. Evaporation of the solvent under reduced pressure gave 2-(6-methoxy-2-naphthyl)-propionic acid.

Sm.p. = 154-155°C. To^j<20> = +6.02 (c = 1, CHC13).

HPLC analysis, performed as described in J. Pharm. Pollock. 68, 112 (1979) and H-NMR (200 MHz) analysis performed on the methyl ester in CDCl3 using an optically active shift agent (europium (III) tris-£3(heptafluoropropylhydroxymethylene)-d-camphoratj) revealed a enantiomeric ratio S( + ): R(-) = 55:45.

Example 41

Preparation of 2-ethyl-2-(6-hydroxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester.

A mixture of 25 g (0.125 mol) 1-(6-hydroxy-2-naphthyl)-propan-1-one, 178 g (1 mol) 2(R), 3(R)-dihydroxybutanedioic acid dimethyl ester, 54 g (0.51 mol) of trimethylorthoformate and 0.84 g (0.088 mol) of methanesulfonic acid were heated under argon and with stirring to 70°C for four hours.

The reaction mixture was cooled to room temperature, poured into 400 ml of 10% aqueous solution of sodium carbonate and extracted with 4 x 50 ml of diethyl ether. The combined organic extracts were washed with 3 x 150 mL water, dried (NaSO 4 ), filtered and concentrated in vacuo.

Purification of the impure residue by column chromatography (silica gel, eluent hexane:diethylether =1:1) gave pure 2-ethyl-2-(6-hydroxy-2-naphthyl)-1,3-dioxolane-4(R), 5( R)-di-

carboxylic acid dimethyl ester (17 g) as an oil.

<1>H-NMR (90 MHz, CDCl3 - TMS) ( f (ppm):

1.93 (3H, t, J = 6.5 Hz); 2.10 (2H, q, J = 6.5 Hz); 3.43

(3H, p) ; 3.80 (3H, s); 4.83 (2H, ABq,4 ^ = 6, 7, j=6 Hz); 6.00 (1H, s, OH); 7.07-7.85 (6H, m).

Example 42

Preparation of the diastereoisomeric mixture of 2-(1-bromomethyl)-2-(5-bromo-6-hydroxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester.

A solution of 5.12 g (32 mmol) of bromine in 5 ml of carbon tetrachloride was added dropwise over 10 minutes and under argon and at 15°C to a solution of 6 g (16 mmol) of 2-ethyl-2-(6 -hydroxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester in 60 ml of carbon tetrachloride. The reaction mixture was kept at 15°C for two hours and poured into 200 ml of a 5% aqueous solution of sodium thiosulphate. The organic layer was separated, washed with water, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Purification of the impure residue by column chromatography (silica gel, hexane:diethylether =1:1) gave a diastereoisomeric mixture of 2-(1-bromomethyl)-2-(5-bromo-6-hydroxy-2-naphthyl)-1,3 -dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester (8 g; 15 mmol; yield 93%) as a solid. Ratio of diastereoisomers 17:18 = 90:10 (determined by """H-NMR and HPLC).

Sm.p. 116-117°C.

"""H-NMR (200 MHz, CDCl 3 - TMS) <£ (ppm):

Diastereoisomer 17 (RRS):

1.66 (3H, d, J = 7 Hz); 3.52 (3H, s); 3.88 (3H, s); 4.48

(1H, q, J = 7 Hz); 4.96 (2H, ABq, to \ J = 27.80, J = 6.1 Hz); 7.2-8.0 (5H, m).

Diastereoisomer 18 (RRR):

1.62 (3H, d, J = 7 Hz); 3.56 (3H, s); 3.87 (3H, s); 4.48

(1H, q, J = 7 Hz); 4.90 (2H, ABq, A \ J = 35.44, J = 6.3 HZ); 7.2-8.0 (5H, m).

The diastereoisomeric ratio 17 (RRS) : 18 (RRR) = 90:10 was confirmed by conversion of the product into the diastereoisomeric mixture of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2- naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 3 and 4 by following the present procedure: A mixture of 0.52 g (1 mmol) of the product, 1.38 g (10 mmol) of potassium carbonate, 0.426 g (3 mmol) of methyl iodide and 10 ml of acetone were kept under stirring at room temperature for four hours. The reaction mixture was filtered and concentrated in vacuo. The residue obtained was a diastereoisomeric mixture of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester in the ratio 3 (RRS) : 4 (RRR) = 90:10 (determined by <1>H-NMR and HPLC).

Example 43

Preparation of 2-(5-bromo-6-hydroxy-2-naphthyl)-propionic acid.

A mixture of the diastereoisomers 17 and 18 in the ratio 90:10 (see Example 42) (0.57 g; 11 mmol), 0.132 g (33 mmol) of sodium hydroxide and 20 ml of water was heated to 60°C for two hours. The reaction mixture was cooled to room temperature, acidified to pH 1 with concentrated HCl and extracted with diethyl ether. The combined organic phases were washed with water, dried over sodium sulfate and concentrated under vacuum. The residue obtained was purified by chromatography on silica gel to form pure 2-(5-bromo-6-hydroxy-2-naphthyl)-propionic acid. Based on 1 H-NMR analysis as described in Example 4, the ratio of S to R enantiomers was 90:10.

Example 44

Preparation of 2-(1-bromomethyl)-2-(5-bromo-6-hydroxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid.

A mixture of the diastereoisomers 17 and 18 in the ratio 90:10 (see Example 42) (5.6 g; 0.0108 mol), 52 ml of water, 30 ml of methanol and 11.5 ml of an aqueous 10% (w /v) sodium hydroxide solution was stirred at room temperature for six hours. The reaction mixture was then acidified with concentrated HCl to pH 1 and was extracted with diethyl ether.

The combined organic extracts were washed with water and dried over sodium sulfate. Evaporation of the solvent under vacuum gave the diastereoisomers 19 and 20 (4.8 g; 0.0098 mol; yield 90%) in the ratio 19:20 = 92:8.

<1>H-NMR (90 MHz, CDCl3 - TMS) ( f (ppm):

1.66 (d, 3H, J = 7 Hz); 4.63 (q, 1H, J = 7 Hz); 4.93 (2H, ABq, AV = 16.42, J = 6.5 Hz); 7.23-8.15 (m, 5H); 8.27 (1H; wide).

Example 45

Preparation of 2-(5-bromo-6-hydroxy-2-naphthyl)-propionic acid.

A mixture of the diastereoisomers 2-(1-bromomethyl)-2-(5-bromo-6-hydroxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid 19 and 20 (1 .76 g; 3.6 mmol) in the ratio 19:20 = 92:8 (see example 44), 2.4 g (28 mmol) of sodium bicarbonate and 50 ml of water were heated under reflux and with stirring for four hours. The reaction mixture was cooled to room temperature, acidified to pH 1 with 6 N HCl and extracted with diethyl ether. The combined organic phases were washed with water and dried over sodium sulfate. Evaporation of the solvent under vacuum gave an impure product to which 17 mL of dimethoxyethane and 17 mL of 12 N HCl were added. The reaction mixture was heated under reflux and stirring for two hours, cooled and extracted with diethyl ether. The combined organic phases were washed with water and dried over sodium sulfate. Evaporation of the solvent under vacuum gave a residue which was chromatographed over silica gel (eluent diethyl ether: hexane 7:3). In this way the pure acid was obtained CcKI ^ = +42.3° (c = 1 in acetone). A sample was esterified with diazomethane. The methyl ester was analyzed by """H-NMR (200 MHz) using an optically active shifter. The ratio of the enantiomeric acids (+)S/(-)R is 98:2.

Example 46

A solution of 0.6 g (3.08 mmol) of silver tetrafluoroborate in 4 ml of 1,2-dichloroethane was added dropwise to a mixture of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2- naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester (diastereoisomer 3 : diastereoisomer 4 = 94:6, ratio determined by HPLC) (1.33 g; 2.5 mmol) and 10 ml of 1,2-dichloroethane kept under stirring at +15°C. After 73 hours, the reaction mixture was poured into 20 ml of water and filtered through celite. The filtrate was washed with 10 ml of methylene chloride. The organic phase was washed with 2 x 20 ml of water and was dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave 0.95 g of a residue in which the diastereoisomers C and D of esters were present in the ratio C:D = 79:21, as determined by 1H-NMR analysis at 60 MHz.

In an analogue and parallel test in which 0.1 g

(6 mmol) of water was added to the reaction mixture before addition of sodium tetrafluoroborate, the ratio of the dia-, stereoisomers after 73 hours was - C:D = 94:6.

Example 47

Preparation of 1-(4-chlorophenyl)-3-methyl-butan-1-one.

128.6 g (1.07 mol) of 3-methyl-butyryl chloride was added over 15 minutes to a suspension of 153.8 g (1.15 mol) of aluminum chloride in 200 ml of methylene chloride cooled to -5°C and kept under stirring in an inert atomic sphere. After the addition was finished, the mixture was heated to +20°C and 100 g (0.89 mol) of chlorobenzene was added over 15 minutes. The reaction mixture was heated to +45°C for seven hours, then cooled to ambient temperature and poured with stirring into 200 ml of concentrated HCl and 1500 g of ice.

The aqueous phase was extracted with 3 x 300 ml of methylene chloride. The organic extracts were washed with 3 x 700 ml of a 1% sodium hydroxide solution and with 3 x 700 ml of water. After drying over sodium sulfate, the organic solvent was evaporated under reduced pressure to give 161

g of a residue which after recrystallization from 100 ml of n-hexane gave 121.5 g (0.62 mol; yield 69.4%) of 1-(4-chlorophenyl)-3-methyl-butan-1-one. Sm.p. = 39-40°. I.R. (Nujol) = 1680-1700 cm<-1> (extended (c = 0).

<1>H-NMR (CDC13 - TMS) (90 MHz): <f (ppm) :

0.97 (d, 6H, J = 6.7 Hz); 2.27 (m, 1H, JCH_CH<=> 6.7 Hz);

2.77 (part AB of an ABX system, 2H); 7.3-7.9 (AA<1>BB<1>, 4H,

aromatic protons).

Example 48

Preparation of 2-(4-chlorophenyl)-2-(2-methylpropyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester.

A mixture of 40.0 g (0.204 mol) 1-(4-chlorophenyl)-3-butan-l-one, 72.4 g (0.407 mol) 2(R), 3(R)-dihydroxy-butanedioic acid dimethyl ester and 43.1 g (0.406 mol) of trimethylorthoformate was heated gradually until complete dissolution (60°C). 1.4 g (0.015 mol) of methanesulfonic acid was added to the solution which was then heated to 75°C.

After a reaction time of three hours, the mixture was cooled to ambient temperature and poured into 250 ml of a 10% sodium bicarbonate solution with vigorous stirring. The aqueous phase was extracted with 2 x 250 ml of methylene chloride, and the organic extracts were washed with 2 x 400 ml of water. After drying the organic phase over sodium sulfate, the solvent was evaporated under reduced pressure. 68.7 g of the residue obtained was chromatographed over silica gel (eluent hexane:diethylether = (8:2). 41 g (0.115 mol) 2-(4-chlorophenyl)-2-(2-methylpropyl)-1,3- dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester was obtained in a yield of 56.4%.

Sm.p. = 40°C.

foCJ <£>° = +21.6° (c = 1%, CHC13)

I.R. (Nujol) = 1770-1740 cm-1 (extended c = 0).

<1>H-NMR (200 MHz) (CDC13 - TMS): ( f (ppm):

0.87 (d, 6H, J = 6.9 Hz); 1.67 (m, 1H, JCH_CH <=> 6.9 Hz);

1.86 (part AB of an ABX system, 2H); 3.55 (s, 3H); 3.82 (s, 3H); 4.74 (ABq, 2H, J = 6.0 Hz); 7.2-7.4 (AA'BB', 4H, aromatic protons).

Example 49

Preparation of 2-(1-bromo-2-methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester.

A solution of 8.06 g (0.05 mol) of bromine in 18 ml of 1,2-dichloroethane was added over 1 hour and 15 minutes to a solution of 18.0 g (0.05 mol) of 2-(4 -chlorophenyl)-2-(2-methylpropyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid"dimethyl ester in 180 ml of 1,2-dichloroethane to which 3.6 g (0.03 8 mol) of methanesulfonic acid had previously been added, and the reaction mixture was kept under stirring in an inert atmosphere at +15° C. After one hour at 15° C, the mixture was poured into

400 ml of a 10% sodium carbonate solution with vigorous stirring, and was extracted with 2 x 250 ml of methylene chloride. The organic phase was washed with 2 x 400 ml of water and was dried over sodium sulfate. After evaporation of the solvent

under reduced pressure, 20.5 g of residue was obtained, which contains the two diastereoisomers of 2-(1-bromo-2-methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester, here indicated as 21 and 22, in the ratio 21:22 = 97:3 (ratio determined by <1>H-NMR (300 MHz) analysis and confirmed by HPLC analysis.

By crystallization from 60 ml of n-hexane, diastereoisomer 21 was obtained (13.6 g; 0.031 mol); yield 62.5%) and was found to be pure by """H-NMR analysis (300 MHz).

"""H-NMR (300 MHz) (CDC13 - TMS) .

Diastereoisomer 21 (RRS):

0.93 (d, 3H, J = 6.9 Hz); 0.98 (d, 3H, J = 6.6 Hz); 1.70 (m,

<1H>' <J>CH-CH <=><X>'<8><HZ>'-<J>CH-CH3 = 6'6 <HZ>' <J>CH-CH3 ' <6>' <9><Hz>)<; >3.59 (s, 3H); 3.85 (s, 3H); 4.28 (d, 1H, J = 1.8 Hz); 4.87 (ABq, 2H, J = 6.2 Hz); 7.3-7.5 (AA'BB', 4H, aromatic protons) .

The HPLC analysis was carried out under the following conditions: Hewlett Packard instrument mod. 1090 with U.V. detector (mod. 1040 DAD) with variable U.V. wavelength.

Analytical conditions: Brownlee column LABS RP 8 (5yt/) balls; 250 ml x 4.6 mm (inner diameter).

Solvent A: bi-distilled water.

Solvent B: methanol.

Flow rate: 1.7 ml/min.

Percentage of solvent B: 63%.

Column temperature: 40°C.

Wavelength ): 230 nanometers.

Injections: 5 µl of a solution containing 0.5 mg/ml of product in methanol.

Retention times: Diastereoisomer 21 = 11.71 minutes.

Diastereoisomer 22 = 12.85 minutes.

Example 50

Preparation of 2(R)-hydroxy-3(R)-f2(S)-(4-chlorophenyl)

-3-methylbutanoylJ-butanedioic acid dimethyl ester.

A solution of 1.6 g (8.2 mmol) of silver tetrafluoroborate in 15 ml of 1,2-dichloroethane was added over 20 minutes to a mixture of 3 g (6.9 mmol) of 2-(l-bromo-2- methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester (diastereoisomer 21, 0.2 g water and 18 ml 1,2-dichloroethane at 20°C . The reaction mixture was heated to 50°C for seven hours, was cooled to 20°C and poured into 50 ml of water. The mixture was filtered on celite and the precipitate was washed with 30 ml of dichloromethane. The organic phase was separated, washed with water, dried over sodium sulfate and concentrated in vacuo Purification of the impure residue (2.3 g) by column chromatography (silica gel, eluent hexane:diethylether = 1:1) gave the pure diastereoisomer 2(R)-hydroxy-3 (R)-[ 2-(S)-(4-Chlorophenyl)-3-methylbutanoylJ-butanedioic acid dimethyl ester K (1.95 g; 5.2 mmol; yield 75.9%). <1>H-NMR (300 MHz, CDCl 3 - TMS ) delta (ppm): 0.68 (d, 3H, JCH_CH <=> 6.9 Hz); 1.06 (d, 3H, J = 6.2 Hz);

2.33 (m, <1>H, <J>CH_CH <=10>,<6> Hz, <J>CH_CH = 6.9 Hz, JCH_CH <= >6.2 Hz); 3.22 (d, 1H, JCH_CH = 6.95 Hz); 3.24 (d, 1H, J =

10.6 Hz); 3.30 (s, 3H); 3.77 (s, 3H); 4.63 (dd, 1H, JCH_CH<=>

2.6 Hz); 5.36 (d, 1H, JCH_CH = 2.6 Hz) 7.21-7.28 (AA<1>BB<1>,

4H, aromatic protons).

Example 51

Preparation of 2(R)-hydroxy-3(R)- [ 2 (S)-(4-chlorophenyl)

-3-methylbutanoylJ-butanedioic acid.

A mixture of 1 g (2.6 mmol) 2(R)-D(S)-(4-chlorophenyl)-3-methylbutanoyl7~butanedioic acid dimethyl ester (diastereoisomer K), 18.3 ml of 1,2-dimethoxyethane and 18, 3 mL of concentrated HCl was heated with stirring to 70°C for one hour. The reaction mixture was cooled to room temperature, poured into 50 ml of water and extracted with 2 x 50 ml of dichloromethane. The organic phase was extracted with 4 x 50 ml of a 10% aqueous solution of sodium bicarbonate. The aqueous phase was acidified with concentrated HCl to pH 1 and was extracted with 3 x 50 ml of dichloromethane. The combined organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. Crystallization of the residue of 0.8 g gave pure 2(R)-hydroxy-3(R)-Q1(S)-(4-chlorophenyl)-3-methylbutanoyl-butanedioic acid (0.4 g) (diastereoisomer L).

Sm.p. = 173-175°C.

"""H-NMR (300 MHz, CDC13 - TMS) delta (ppm):

Diastereoisomer L (RRS):

0.56 (d, 3H, J = 6.7 Hz); 0.94 (d, 3H, J = 6.5 Hz); 2.20 (m, <1H>'<J>CH-CH3 ' <6>'<7><HZ>'<J>CH-CH3<=><6>'<5><HZ>'<J >CH-CH <=> 10'4 Hz) > 3.16 (d, 1H, J = 10.4 Hz); 4.65 (d, 1H, JCH_CH = 2.1 Hz);

5.33 (d, 1H, J = 2.1 Hz); 7.00-7.27 (AA'BB<1>, 4H, aromatic protons).

<1>H-NMR analysis performed on the corresponding dimethyl ester obtained by reaction with diazomethane revealed only the presence of diastereoisomer K (RRS).

Example 52

Preparation of ( + )-2"(S)-(4-chlorophenyl)-3-methylbutanoic acid.

A mixture of 0.9 g (2.3 mmol) of diastereoisomer K,

16 ml of 1,4-dioxane and 16 ml of concentrated HCl were heated with stirring to 90°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with 30 ml of water and extracted with 3 x 20 ml of dichloromethane. The organic phase was extracted with 5 x 10 ml of a 10% aqueous solution of sodium bicarbonate. The aqueous phase was acidified with concentrated HCl to pH 1 and was extracted with 5 x 10 ml of dichloromethane. The combined organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo.

Purification of the impure residue (0.25 g) by column chromatography (silica gel; eluent hexane:diethylether = 80:20) gave 0.2 g of pure 2(S)-(4-chlorophenyl)-3-methylbutanoic acid. £å] q° = +38.6° (c = 1%, chloroform).

Example 53

Preparation of 2-(1(S)-bromo-2-methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid.

A solution of 10 g (23 mmol) of diastereoisomer 21 in 10 ml of dichloromethane was added dropwise over 15 minutes at 20°C to a solution of 2 g (50.6 mmol) of sodium hydroxide in 25 ml of water and 100 ml of methanol. The reaction mixture was kept at 20°C for one hour and the solvent was removed under reduced pressure. 100 ml of water was added. The solution thus obtained was acidified with concentrated HCl to pH 1 and was extracted with 3 x 75 ml of diethyl ether. The organic phase was extracted with 3 x 75 ml of a 10% aqueous solution of sodium bicarbonate. The aqueous phase was acidified with concentrated HCl to pH 1 and was extracted with 3 x 75 ml of diethyl ether. The combined organic extracts were washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave 2-(1(S)-bromo-2-methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid (diastereoisomer 23 (7.2 g; 19.8 mmol; yield 86%).

<1>H-NMR (300 MHz, CDC13 - TMS) delta (ppm):

Diastereoisomer 23 (RRS):

0.92 (d, 3H, J = 6.6 Hz); 0.98 (d, 3H, J = 6.2 Hz); 1.58

(m, <1>H, <J>CH_CH<=><1>,<8> Hz, <J>CH_CH3<=><6>,<6> Hz, J^.^ <=><6> ,<2>Hz); 4.37 (d, 1 H, J = 1.8 Hz); 4.86 (ABq, 2H, J = 6.2 Hz); 7.36-7.46 (AA1BB', 4H, aromatic protons).

The presence of a diastereoisomer was confirmed by HPLC analysis performed on a sample of the corresponding dimethyl ester (diastereoisomer 21) obtained by reaction with diazomethane.

Example 54

Preparation of 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid; N,N,N1 ,N1 -tetraethylamide.

A mixture of 9.36 g (25 mmol) of 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester, 25 ml of diethylamine and 20 ml of water was kept under stirring at room temperature for 15 hours. The solvent was removed by evaporation at room temperature and under reduced pressure. 50 ml of diethyl ether was added to the residue and the mixture was refluxed for one hour and then cooled to room temperature, filtered and the filtrate was dried under reduced pressure. 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid N,N,N<1>,N<1->tetraethylamide (11 g; 24 mmol; yield 96%).

Sm.p. = 108-112°C.

<1>H-NMR (200 MHz, CDCl 3 - TMS) delta (ppm): 0.83 (t, 3H, J = 7 Hz); 1.11 (t, 12H, J = 7 Hz); 2.00 (q, 2H, J = 7 Hz);

2.79 (q, 8H, J = 7 Hz); 3.83 (s, 3H); 4.32 (2H, ABq, A 0 = 17.8, J = 8 Hz); 6.9-7.8 (6H, aromatic protons).

I.R. (Nujol): 1605, 1630 (extended C = 0).

Example 55

Preparation of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid N,N,N', N'-tetraethylamide.

A mixture of the two diastereoisomers of 2-(1-bromo-ethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester 3 and 4 in the ratio 3:4 = 9:1 (6.65 g; 12.5 mmol), 27.5 ml of diethylamine and 20 ml of water were kept under stirring at room temperature for 15 hours. The solvent was removed under reduced pressure. 50 ml of diethyl ether was added to the residue. The insoluble components were filtered off, washed with diethyl ether and dried under reduced pressure. The diastereoisomeric mixture of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid N,N,N ',N'-tetraethylamide 24 and 25 were obtained (6.75 g; 11 mmol; yield 88%) in the ratio 24: 25 = 9:1 (determined by <1>H-NMR, 200 MHz).

"""H-NMR (200 MHz, CDC13 - TMS) delta (ppm):

Diastereoisomer 24 (RRS):

1.06 (t, 12H, J = 7 Hz); 1.69 (d, 3H, J = 7 Hz); 2.76 (q, 8H, J = 8 Hz); 4.00 (p, 3H) ; 4.55 (2H, ABq, ^ \) = 35.1, J = 8 Hz); 4.54 (q, 2H, J = 7 Hz); 7.2-8.2 (5H, aromatic protons).

Example 56

Preparation of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid disodium salt.

A mixture of the two diastereoisomers of 2-(1-bromo-ethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester in the ratio 3:4 = 9:1 (6.65 g; 12.5 mmol), 1 g (25 mmol) sodium hydroxide, 10 ml dimethoxyethane and 10 ml water were kept under stirring at room temperature for two hours. The reaction mixture was diluted with water and extracted with diethyl ether. The aqueous phase was concentrated under reduced pressure to give the diastereoisomeric mixture of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid disodium salt 26 and 27 (11.5 mmol; yield 92%) in the ratio 26:27 = 9:1 (determined by <1>H-NMR 200 MHz).

Example 57

Preparation of (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid from a diastereoisomeric mixture of 2-(1-bromo-ethyl)-2-(5-bromo-6- methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid 7 and 8 in the ratio 7:8 = 93:7.

A mixture of the two diastereoisomers of 2-(1-bromo-ethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid 7 and 8 in the ratio 7:8 = 93:7 (9.3 g; 18.45 mmol) and 110 ml of an aqueous solution prepared by dissolving 26.1 g of I^HPO^ and 5.7 g of KH2PO4 in 3 84 ml of water was heated with stirring to 100°C for 21 hours. The reaction mixture was cooled to room temperature (pH 4.2), acidified with concentrated HCl to pH 1 and extracted with 3 x 100 mL diethyl ether. The combined organic extracts were washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave a residue which, based on GLC analysis performed on a sample treated with diazomethane, was found to be 2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (4.33 g; 14 .02 mmol; yield 76%) and 1 g of starting diastereoisomer 7.

Purification by column chromatography of the impure reaction product (silica gel; eluent hexane:diethylether =7:3) gave pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (4, 22 g; 13.66 mmol; yield 74%) in 97% enantiomeric excess.

Sm.p. = 168-170°C

= +40.8° (c = 0.5%, chloroform).

HPLC analysis performed as described in J. Pharm. Pollock. 68, 112 (1979) showed an enantiomeric ratio S(+):R(-) = 98.5:1.5. The enantiomeric ratio was confirmed by H-NMR analysis performed in CDCl^ using an optically active shifter (europium(III) tris-£"3-(heptafluoropropyl-hydroxymethylene)-d-camphoratj) on the corresponding methyl ester obtained by treating a sample of the acid with diazomethane.

Example 58

A mixture of the two diastereoisomers of 2-(1-bromo-ethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid 7 and 8 in the ratio 7:8 = 93:7 (2.27 g;

4.5 mmol) and 31.5 ml of an aqueous solution prepared by dissolving 26.1. g K 2 HPO 4 and 5.7 g KH 2 PO 4 in 384 ml water were heated with stirring to 100°C for 42 hours. The reaction mixture was cooled to room temperature (pH 4.2) and was worked up as described in Example 57. (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid was obtained (1.32 g; 4.2 mmol; yield 93%) in 97% enantiomeric excess. The enantiomeric ratio S(+):R(-) = 98.5:1.5 was confirmed by HPLC and by """H-NMR analysis performed as described in Example 57.

Example 59

Preparation of pure 2-(1(S)-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-rdioxolane-4(R),5(R)-dicarboxylic acid (diastereoisomer 7 ).

A mixture of the two diastereoisomers of 2-(1-bromo-ethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid 7 and 8 in the ratio 7(RRS):8RRR) = 94:6,

(134.42 g; 0.266 mol) and 1726 ml of an aqueous solution prepared by dissolving 174 g of K 2 HPO 4 and 38 g of KH 2 PO 4 in 2000 ml of water were heated with stirring to 90°C for 14 h. The reaction mixture was cooled to room temperature (acidic pH), was acidified with concentrated HCl to pH 1 and was extracted with 3 x 150 ml of diethyl ether. The combined organic extracts were washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave a residue which was dried under vacuum at 80°C for 12 hours.

A solution of 1 ml of methanesulfonic acid in 2000 ml of methanol was added to the thus obtained residue of 118 g. The solution was heated to reflux for two hours, was cooled to room temperature, and was neutralized with sodium bicarbonate. The solvent was removed under reduced pressure and 1000 ml of water was added to the residue. The solution was extracted with 2 x 500 ml of diethyl ether. The combined organic extracts were washed with water, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (silica gel; eluent hexane: diethylether = 8:2) gave pure 2-(1(S)-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3- dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 3 (56 g; 0.105 mol).

A solution of 5.32 g (0.133 mol) sodium hydroxide i

70 ml of water was added dropwise over one hour and with stirring to a solution of 35.4 g (0.0665 mol) of diastereoisomer 3 in 250 ml of methanol at 20°C. The reaction mixture was kept at 20°C for two hours, after which the methanol was removed under reduced pressure while the original volume of the solution was maintained by the addition of water. The thus aqueous solution was extracted with dichloromethane, acidified with concentrated HCl to pH 1 and extracted with 3 x 100 ml of diethyl ether. The combined organic extracts were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo.

Crystallization of the residue from dichloromethane gave the pure 2-(1(S)-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R) -dicarboxylic acid (diastereoisomer 7). Sm.p. = 184-186°C

δ<A7 20 = 39.73° (c = 1%, acetone).

<1>H-NMR (200 MHz, esadeuteroacetone-TMS) delta (ppm): 1.68 (d, 3H, J = 7 Hz); 4.03 (s, 3H); 4.66 (q, 1H, J = 7 Hz); 4.95 (2H, ABq, & 0 = 34.67 Hz, J = 6.5 Hz); 7.46-8.18 (m, 5H, aromatic protons).

Example 60

Preparation of (+)-2(S)(2-methylpropyl)-phenyl]-propionic acid.

A mixture of the two diastereoisomers of 2-(1-bromo-ethyl)-2-{4-(2-methylpropyl)-phenylj-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 13 and 14 in the ratio 13:14 = 87:13 (3.29 g; 8.2 mmol) was added to 49 ml of an aqueous solution of 4.26 g K2HPO4 and 0.93 g KH2PO4. The solution (pH 6) was heated to stirring at 100°C for 68 hours. The reaction mixture was cooled to room temperature (pH 5.5), was diluted with 100 ml of water, was acidified with concentrated HCl to pH 1 and was extracted with 3 x 40 ml of diethyl ether. The organic phase was then extracted with 6 x 40 ml of a 10% aqueous solution of sodium bicarbonate. The combined aqueous extracts were acidified with concentrated HCl to pH 1 and extracted with 3 x 50 mL diethyl ether. The combined organic extracts were washed with water, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica gel; eluent hexane:diethylether = 8:2) gave pure 2-O-(2-methylpropyl)-phenylj-propionic acid (0.28 g). G^l^ ° +47.9° (c = 1%, ethanol 95%).

Example 61

A mixture of the two diastereoisomers of 2-(1-bromo-ethyl)-2-T4-(2-methylpropyl)-phenylj-1,3-dioxolane-4(R),5(R)-dicarboxylic acid' 13 and 14 in the ratio 13:14 = 87:13 (3.29 g; 8.2 mmol) was added to 115 ml of an aqueous solution of 16.4 g KH 2 PO 4 and 0.82 g NaOH. The solution (pH 5) was heated with stirring to 100°C for 90 hours.

The reaction mixture was cooled to room temperature

(pH 3.5) and was prepared as described in example 60.

0.66 g of pure 2-C4-(2-methylpropyl)-phenylj-propionic acid

was obtained.

CcåI d° <=> +48.8° (c = 1%, ethanol 95%).

Example 62

A mixture of the two diastereoisomers of 2-(1-bromo-ethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid 7 and 8 in the ratio 7:8 = 94:6 (2.52 g; 5 mmol) were added to 70 ml of an aqueous solution of 10 g KH 2 PO 4 and 1.4 g NaOH. The solution (pH 6) was heated to 90°C for 50 hours. The reaction mixture was cooled to room temperature (pH 6.0) and was worked up as described in Example 57. Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.3 g ; 4.2 mmol; yield 84%) was obtained in 90% enantiomeric excess.

Sm.p. = 168-170°C

ZaJd° 37'85° <c °'5%' chloroform).

The enantiomeric ratio S(+):R(-) = 95:5 was confirmed by HPLC and by H-NMR analysis performed as described in Example 57.

Example 63

The pure diastereoisomer 2-(1(S)-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dioxolane-4( R), 5(R)-dicarboxylic acid 7 (2.52 g; 5 mmol) was added to 70 mL of an aqueous solution of 10 g KH 2 PO 4 and 1.4 g NaOH. The solution (pH 6) was heated to 90°C for 50 hours. The reaction mixture was cooled to room temperature (pH 5.9) and was worked up as described in Example 57. Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.02 g ; 3.3 mmol; yield 66%) was obtained in 98% enantiomeric excess.

Sm.p. = 168-170°C

£K-}d° +40.74° (c = 0.5%, chloroform).

The enantiomeric ratio S(+):R(-) = 99:1 was confirmed by HPLC and by ^H-NMR performed as described in Example 57.

Example 64

Comparative example at pH higher than 7.

2.52 g (5 mmol) of the pure diastereoisomer 7 (RRS) was added to 70 ml of an aqueous solution of 10 g KH 2 PO 4 and 2.5 g NaOH. The solution (pH 7.2) was heated to 90°C for 50 hours. The reaction mixture was cooled to room temperature (pH 7.0) and was worked up as described in Example 57. Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (0.88 g ; 2.85 mmol; yield 57%) was obtained in 78% enantiomeric excess.

Sm.p. = 166-168°C

p° +32.58° (c = 0.5%, chloroform).

The enantiomeric ratio S(+):R(-) = 89:11 was confirmed by HPLC and by """H-NMR as described in Example 57.

Example 65

Comparative example at pH higher than 7.5.

2.52 g (5 mmol) of the pure diastereoisomer 7 (RRS) was added to 70 ml of an aqueous solution of 10 g KH 2 PO 4 and 3 g NaOH. The solution (pH 7.65) was heated to 90°C for 50 hours. The reaction mixture was cooled to room temperature (pH 7.5) and was worked up as described in example 57.

Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.03 g; 3.33 mmol; yield 67%) was obtained in 74% enantiomeric excess.

Sm.p. = 164-168°C

d° = +31.20° (c = 0.5%, chloroform).

The enantiomeric ratio S(+):R(-) = 87:13 was confirmed by HPLC and by """H-NMR as described in Example 57.

Example 66

A mixture of the two diastereoisomers 7 (RRS) and 8 (RRR) in the ratio 7:8 = 94:6 (2.52 g; 5 mmol) was added to 70 ml of an aqueous solution of 10 g KH2PO4 and 0.5 g of NaOH. The solution (pH 5.1) was heated to 90°C for 52 hours. The reaction mixture was cooled to room temperature (pH 4.2) and was worked up as described in example 57.

Optically pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.27 g; 4.11 mmol; yield 82%) was obtained. Sm.p. = 167-169°C

Z~oO 20 = +42.2° (c = 0.5%, chloroform).

The optical purity was confirmed by HPLC and verified by H-NMR as described in Example 57.

Example 67

2.52 g (5 mmol) of the pure diastereoisomer 7 (RRS) was added to 70 ml of an aqueous solution of 10 g KH 2 PO 4 and 0.5 g NaOH. The solution (pH 5.15) was heated to 90 °C for 52 hours. The reaction mixture was cooled to room temperature

(pH 4.2) and was prepared as described in example 57. Optically pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid was obtained (1.30 g; 4 .20 mmol; yield 84%).

Sm.p. = 168-170°C

CoLji° = +42.2° (c = 0.5% chloroform).

1

The optical purity was confirmed by HPLC and by H-NMR as described in Example 57.

Example 68

2.52 g (5 mmol) of the pure diastereoisomer 7 (RRS) was added to 35 ml of an aqueous solution prepared by dissolving 26.1 g of KH 2 PO 4 and 5.7 KH 2 PO 4 in 384 ml of water. The solution was heated to 100°C for 45 hours. The reaction mixture was cooled to room temperature (pH 4.1) and was worked up as described in Example 57. Optically pure ( + )-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.3 g; 4.2 mmol; yield 84%) was obtained.

Sm.p. = 168-170°

EcL]* 0 = +42.23° (c = 0.5%, chloroform).1

The optical purity was confirmed by HPLC and by H-NMR as described in Example 57.

Example 69

A mixture of the two diastereoisomers 7 (RRS) and 8 (RRR) in the ratio 7:8 = 93:7 (2.52 g; 5 mmol) was added to 70 ml of an aqueous solution of 10 g of KH 2 PO 4 . The solution (pH 4.2) was heated to 90°C for 50 hours. The reaction mixture was cooled to room temperature (pH 3.2) and was worked up as described in Example 57. Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (0.65 g ; 2.10 mmol; yield 42%) was obtained in 94% enantiomeric excess.

Sm.p. = 164-165°C

£*0d° = +40'08° <c = °'5%' chloroform).

The enantiomeric ratio S(+):R(-) = 97:3 was confirmed by HPLC and by """H-NMR as described in Example 57.

Example 70

A solution of the two diastereoisomers of 2-(1-bromo-ethyl)-2-(5-bromo-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid N, N,N',N'-tetraethylamide 24 (RRS) and 25 (RRR) in the ratio 24:25 = 9:1 (2.93 g; 5 mmol) in 70 ml of water was heated to 90°C for 50 hours. The reaction mixture was cooled to room temperature (pH 5.6) and was worked up as described in Example 57. Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (0, 58 g) was obtained in 98% enantiomeric excess.

Sm.p. = 164-165°C

£cLj 20 = +41.74° (c = 0.5%, chloroform).

The enantiomeric ratio S(+):R(-) = 99:1 was confirmed by HPLC and by """H-NMR as described in Example 57.

Example 71

A mixture of the two diastereoisomers of 2-(1-bromo-ethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid N,N,N',N'-tetraethylamide 24 (RRS) and 25 (RRR) in the ratio 24:25 = 9:1 (2.93 g; 5 mmol) was added to 70 ml of an aqueous solution of 10 g KH 2 PO 4 and 0.5 g NaOH. The solution (pH 5.7) was heated to 90°C for 50 hours. The reaction mixture was cooled to room temperature (pH 4.2) and was worked up as described in Example 57. 0.54 g of pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid was obtained in 98% enantiomeric excess.

Sm.p. = 166-168°C

fo<t>j p° = +41.86° (c = 0.5%, chloroform).

The enantiomeric ratio S(+):R(-) = 99:1 was confirmed by HPLC and by """H-NMR as described in Example 57.

Example 72

2.52 g (5 mmol) of the pure diastereoisomer 7(RRS) was added to 70 ml of an aqueous solution of 10 g KH 2 PO 4 and 0.5 g NaOH. The solution (pH 5.15) was heated to 50°C for 52 hours. The reaction mixture was cooled to room temperature and worked up as described in Example 57.

Optically pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (0.63 g, 1.25 mmol; yield 25%) was obtained. Melting point=168-170°C

[a]D<20>=+42.18° (c=0.5%, chloroform).

Example 73

2.52 g (5 mmol) of the pure diastereoisomer 7(RRS) was added to 70 ml of an aqueous solution of 10 g KH 2 PO 4 and 0.5 g NaOH. The solution (pH 5.15) was heated to 70°C for 52 hours. The reaction mixture was cooled to room temperature and worked up as described in Example 57.

Optically pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.41 g, 2.8 mmol; yield 56%) was obtained.

Melting point=168-170°C

[a]D<20>=+42.2° (c=0.5%, chloroform)

Example 74

2.52 g (5 mmol) of the pure diastereoisomer 7(RRS) was added to 70 ml of an aqueous solution containing 0.5 g of NaOH. The solution was brought to pH 5.2 by the addition of acetic acid and then heated to 100°C for 52 hours. The reaction mixture was cooled to room temperature and worked up as described in Example 57.

Optically pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.24 g, 4 mmol; yield 80%) was obtained.

Melting point=168-170°C.

[a]D<20>=+42° (c=0.5%, chloroform)

Example 75

2.52 g (5 mmol) of the pure diastereoisomer 7(RRS) was added to 70 ml of an aqueous solution containing 0.5 g of NaOH. The solution was brought to pH 5.25 by adding citric acid and then heated to 90°C for 52 hours.

The reaction mixture was cooled to room temperature and worked up as described in Example 57. Optically pure (+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.31 g, 4.25 mmol ;

yield 85%) was obtained.

Melting point=168-170°C.

[a]0<20>=+42° (c=0.5%, chloroform)

Example 76

A mixture of the two diastereoisomers 3 and 4 of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)- Dicarboxylic acid dimethyl ester in the ratio 3:4 = 9:1 (1 g; 1.87 mmol), 0.84 g (3.75 mmol) zinc bromide and 12 ml 1,2-dichloroethane were heated to reflux (83°C), under stirring and under nitrogen for 66 hours.

The reaction mixture was cooled to ambient temperature and

5 ml of water was added. The phase was separated and the organic phase was dried over sodium sulfate. The solvent was evaporated under vacuum to give (0.9 g) of a residue which after column chromatography (SiO 2 , eluent: dichloromethane) gave a mixture of two diastereoisomers of 2-bromo-3-[2-(6-methoxy- 2-Naphthyl)propanoyl]-butaneacetic acid dimethyl ester M and N (0.7 g, 1.31 mmol, yield 70%) in the ratio M:N = 63.35. ^-MNR (CDCl3-TMS), 6, (ppm-):

Diastereoisomer M (RRS):

1.62 (d, 3H, J=8 Hz); 3.22 (s, 3H); 3.83 (s, 3H); 3.92 (s, 3H); 3.95 (q, 1H, J=8 Hz); 3.44 (d, 1H, J=2.47 Hz); 5.37 (d, 1H, J=2.47 Hz); 7.1-7.8 (5H, aromatic protons). Diastereoisomer N (RRR): 1.66 (d, 3H, J=8 Hz); 3.58 (s, 3H); 3.72 (s, 3H); 3.92 (s, 3H); 3.97 (q, 1H, J=8 Hz), 3.48 (d, 1H, J=2.47 Hz); 5.45 (d, 1H, J=2.47 Hz); 7.1-7.8 (5H, aromatic protons).

Example 77

Preparation of the compound 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid di-n-butyl ester.

2-(6-methoxy-2-naphthyl)-propan-1-one (15 g; 0.07 mol), L(+)tartaric acid di-n-butyl ester (40 g), and 150 g of n-butanol were gradually heated to complete dissolution.

0.1 g (0.01 mol) of sulfuric acid was then added, and the resulting solution was heated to 70°C for 2 hours; while the solvent was removed in vacuo. The reaction mixture was slowly added to a 500 ml 10% solution of Na 2 CO 3 . It was extracted with methylene chloride and the organic extracts were repeatedly washed with water.

The organic phase was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure.

The residue was purified by column chromatography to give the desired product (22.9 g; 0.05 mol; yield 71%).

Example 78

Preparation of the diastereoisomeric mixture of the compound 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid-di -n-butyl ester.

To a solution of 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid di-n-butyl ester.

(4.58 g; 0.01 mol) in 70 ml of CC14 kept at 0°C under an inert atmosphere, a solution of (3.2 g; 0.02 mol) bromine in 7 ml of CC14 cooled to 0°C was added dropwise in within 1 hour. The mixture was kept at 0°C for two hours and was then poured with vigorous stirring into 250 ml of a 10% aqueous solution of Na 2 CO 3 and was extracted with CH 2 Cl 2 .

The combined organic extracts were dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The residue (5.73 g, 0.0093 mol; yield 93%) consisted of a mixture of two diastereoisomers identified as 28 and 29.

The ratio between the diastereoisomers 28:29 determined by HPLC and 3-NMR is 95:5.

Example 79

Preparation of 2(R)-hydroxy-3(R)-[2-(5-bromo-6-methoxy-2-naphthyl)-propanoyl]-butaneacetic acid di-n-butyl ester. To a solution of 2.76 g (0.006 mol; ratio of diastereoisomer 28 to diastereoisomer 29=95:5 determined by HPLC) 2-(1-bromo-ethyl)-2(5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4(R),5(R)-dicarboxylic acid di-n-butyl ester in 20 ml of 1,2-dichloroethane kept under stirring at -15°C under an inert atmosphere was added (1.17 g ; 0.006 mol) of silver tetrafluoroborate. The reaction mixture was kept at -15°C for 2 hours, then brought to room temperature over 1 hour and filtered. The organic phase was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The desired product was obtained (2.6 g; 0.0047 mol; yield 94%) as a mixture of two diastereoisomers indicated as P and Q in a ratio P:Q = 95:5 determined by <X>H-NMR, 200 MHz.

Example 80

Preparation of S(+)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid.

A mixture of: (0.22 g; 0.4 mmol)

-1,2-dimethoxyethane (3 mL) -2(R)-hydroxy-3(R)-[2-(5-bromo-6-methoxy-2-naphthyl)-propanoyl]-butanedioic acid-di-n -butyl ester (diastereoisomers P and Q in a ratio P:Q = 95:5) and (3 ml) concentrated HCl were kept at 95°C for two hours. The reaction mixture was then cooled to room temperature, diluted with water and extracted with CH 2 Cl 2 . The organic phase was washed with water and extracted with 10% sodium bicarbonate.

The basic aqueous extract was acidified with concentrated HCl and extracted with CH 2 Cl 2 .

The organic extract was washed with water, dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure.

The pure S(+)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid was obtained (0.11 g, 0.36 mmol, yield 90%)

[α]578<20>=+41.85° (c=0.5% in CHCl 3 ).

Example 81

A mixture of the two diastereoisomers of 2-(1-iodo-ethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 15 and 16, in the ratio 15:16=60:40 (4.12 g; 8.2 mmol), prepared as described in Example 39, was added to a standard solution of 50 ml of KH2PO4 (1 g; 7.3 mmol) and K 2 HPO 4 (4.3 g; 24.7 mmol).

The solution was heated to 100°C for 20 hours.

The reaction mixture was cooled to room temperature and worked up as described in Example 57.

Pure 2-(6-methoxy-2-naphthyl)-propionic acid was obtained (1.13 g; yield 60%) with an enantiomeric ratio S(+):R(-)=90:10.

Example 82

Preparation of 2-(6-methoxy-2-naphthyl)propionic acid from 2-(1-chloroethyl)-2-(6-methoxy-2-naphthyl)-1.3-dioxolane-4(R).

5( R )-dicarboxylic acid

A mixture of the two diastereoisomers of 2-(1-chloroethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid in a ratio of 60:40 (24 mmol) and 168 mL of an aqueous solution of (14.6 g) K 2 HPO 4 and (3.19 g) KH 2 PO 4 , pH 6.6 was heated with stirring at 98°C for 110 h.

The reaction mixture was cooled to room temperature (pH 5.7) and was worked up as described in example 57.

Pure 2-(6-methoxy-2-naphthyl)-propionic acid was obtained in 48% optical purity.

[a]D<20>=31.6° (c=1%, chloroform)

The enantiomeric ratio S(+):R(-)=74:26 was confirmed by HPLC and by <x>H-NMR analysis.

Claims (4)

1. Optically active α-halogen ketals, characterized in that they have the formula wherein Ar denotes 6-methoxy-2-naphthyl, 5-bromo-6-methoxy-2-naphthyl, 5-bromo-6-hydroxy-2-naphthyl, 5-chloro-6-methoxy-2-naphthyl, 4-chlorophenyl , 4-(2-methylpropyl)phenyl; R denotes linear or branched C1-C4 alkyl; Rx and R2 which may be the same or different, denote a hydroxy, O~M<+>, OR3 or NR4R5 group wherein R3 is C1-C6 alkyl; M is the cation of an alkali metal; R4 and R5, which may be the same or different, denote a C1-C4 alkyl group; X denotes a hydrogen, chlorine, bromine or iodine atom, and where the carbon atoms indicated with an asterisk both have (R) or (S) configuration. 2. Optically active α-halogen ketals according to claim 1, characterized in that they have the formula where R1r R2 and X have the meanings given for formula (A), Y denotes a hydrogen or bromine atom and Z denotes a hydrogen atom or a methyl group. 3. Optically active esters of α-arylalkanoic acids, characterized in that they have the formula wherein Ar, R, Rx and R2 are as defined in claim 1 and R6 is OH. 4. Optically active tartaric acid esters according to claim 3, characterized in that they have formula in which R1r R2, R6 are as defined for formula (C), Y denotes a hydrogen, chlorine or bromine atom and Z denotes a hydrogen atom or a methyl group.