CA1318917C - Process for the preparation of optically active alpha-arylalkanoic acids and novel intermediates thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The invention provides optically active esters of alpha arylalkanoic acids of formula

Description

The present invention rela-tes to a process for preparing optically active alpha-arylalkanoic acids and in particular, the presen-t invention concerns an overall enantio-selective process for the preparation of optically active alpha-aryl-alkanoic acids comprising two main steps: a stereoselective halogenation of novel chiral (optlcally active) ketals and a stereoselective rearrangement of the thus obtained products.

In particular the present invention relates to optically active esters of ~ -arylalkanoic acids which are intermediates in the process.

This, application is a devisional application of copending application No. 478,585 filed April 4, 1985.
The alpha-arylalkanoic acids constitute a very large class of compounds, of which many have assumed considerable commercial importance in relatively 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 Flurhiprofen, 2-[4-(2-thienylcarbonyl)-phenyl]-propionic acid known as Suprofen, 2-(6-methoxy-2-naphthyl)-propionic acid, of which the tS) isomer is known as Naproxen, and others.

Another group of alpha-arylalkanoic acids are well known as intermediates in the preparation of pyrethroid insecticides. These include 2-(4-chlorophenyl~-3-methyl-butyric acid and 2-t4-difluoromethoxyphenyl)-3-methyl-butyric acid.

A number of the alpha-arlyalkanoic acids exist as a mixture of optically active isomers.

.~3~8~

Very often, a decidedly higher biologlcal activity is associa-ted with one enantiomer which thus is much more important than -the other from an i.ndustrial vlewpolnt. ~~
A particularly lmportant example i9 Z-(6-methoxy-2-naphthyl)-propio-6 nlc acid, of which the (Sj isorner (Naproxen3possesses pharmacological properties whlch are decldedly better than those of the (R) lsomer and of the raceme mixture, so that in practice i-t ls only the (S) isomer ~hich ls used as pharmaceutlcal drug.
Of the many methods for synthesising alpha-arylalkanoic aclds which have recently appeared in the literature, the most interesting are those which use rearrangement of aryl-alkyl-ketals which are functio-nalised on the alkyl position alpha to the ketal. These include the ~ethods:.:described in:European.,patent.ap~lications.34871.(Blaschim)., 35305 (Blaschim), 48136 (Sagami), 64394 (Syntex), 89711 (Blaschim), and 101124 (Zambon), and in Italian patent applications 21841 A/8Z
(Blaschim and CNR), 22760 A/82 SZambon) and 19438 A/84 (Zambon), and in the publication J. Chem. Soc., Perkin I, 11, 2575 (1982).
All these processes lead to racemicmixtures of the two optical isomers .
Optically active alpha-arylalkanoic acids can be prepared by separating ..the enantiomer ~rom the racemicmixture obtained by using the afore-~aid procedures (for example by using optically active bases), or by applying some of said. rearrangements to optically active ketal~, which have been previou~ly prepared and isolated, as described for example in European patent applications 67698 ~Saga-mi) and 81993 (Syntex).
However, the preparation o~ optically active ketals as described in these European patent applications appears rather laborious and costly, and also involves the preparations of intermediates by sophis ticated methods with low yields, and are not suitable for indus-trial preparation~
The ro~.olution Or alpha-arylalkanoic acids from the racemic mixture in _ 3 _ ~ 3~

a conventional way,that is by using optically active bases has -the d~
common to all these processes: material costs, manufacturing labor and equipment for -the recovery and racemi2ation of` the undesired optical isomer.
Therefore, it is important to have a stereoselective process for pro-ducing the desired isomer directly. Such a process obviates -the neces sity of subsequently resolving the d- and l-isomers using optically active bases, subh as cinchonidine, brucine, alpha-phenyiethylamine, N-methyl-glucamine and the like.
The elimination of resolution steps results in a substantla~ saving, both in material cost and manufacturing labor and equipment.
The savings can be particularly significant with regard to compounds which are approved for pharmaceutical use as a substantialiy pure, optically active isomer,such as S(~2-(6-methoxy-2-naphtyl)-propionic acid (Naproxen) or a precursor thereof which may be easily converted to this acid.
For the sake of clarity we will state hereinafter the meaning of some terms used in the following specification:
"Chiral" refers to a chemical structure having at least an asymmetry center. The con~iguration of an asymmetric carbon atom is classified as "R" or "S" according to the Cahn -Ingold-Prelog method.
'IEnantiomer" or "enantiomorph" refers to a molecule whlch is non-superimposable on its respective mirror image. A necessary and sufficient condition for a molecule to show optical acti~ity (i.e.
to be an enantiomer) is that such a molecule not be superimposable with its mirror image. This phenomenum usually occurs in organic chemi-stry when a carbon atom is attached to four different atoms or chemi-cal groups. "~nantiomer" and "optical isomer" are often used inter-changeably in this context.
"Enantiomeric excess" or "e.a." refer~ to a definition; i.e. th~ per-centage of the predominant enantlomer mlnus that Or the oth~r. rrhus, a mlxture of 95% (~) isomer and S% ~-) isom~r wollld have a 90~

~ 4 ~ ~ 3 1 ~ ~

"Optical yield" or "optlcal purity" may be defined as enantlomeric excess. However, strictly speaking, it refers to the measursd rokation shown by the mixture which may or may not reflect the true proportions of the enantiomers. In thi3 application the ~wo terms are used interchangeably.
"Optically active" refers to a sy3tem or compound which rotate~ the plane of polarized light.
"Epimers" are two dia~tereoisomers which have a different confi6ura-tion at only one chiral center.
"Diastereoisomers" are stereoisomers that are not mirror images of each other: they have the same con~iguratlon at at least one a~ymmetric center and, at the same time, different configura-tion at at least one asymm~tric center.
"Diastereotopic'~ refers to the case in which two atoms or groups in a molecule e.gu CX2WY are in such a position that replacing each of them by a group Z leads to diastereoisomers.
"Stereoselective synthesis" re~srs to ang reaction in which one among a number of stereoisomers is formed exclusively or predominantly.
"Enantioselective synthesis" refers to any reaction ln which one of two enantiomers i5 form0d exclusively or predominantly.
"Race~ization" refers to the conversion of the molecules of one enantiomer into a racemic mixtur0 of both.
We ha~e now prepared new ketals of alkyl-aryl-ke-tones of formula H ~¦ ¦~ COR2 (A) O /O
Ar \ C _ CH - R
in which: X
Ar represents aryl, optionally subs-titu-ted;
R repre6ents linear or branched Cl-C4 alkyl;

~ 3 ~

Rl and ~2~ which can be equal to or different from each o-ther, re-present a hydroxy, a O M , OR3 or NR4R5 group wher~ R3 is Cl-C24 alkyl, C3-C6 cycloalkyl, phenyl or ben~yl; M is -the cation of an alkaline metal;
R~ and R5, which can be equal to or different from each other,re~resent a hydrogen atom,a Ol-C~ alkyl,a C5-C6 cycloalkyl,or a -(CHz) -CH20H
group where n ls 1, 2 or 3 or R4 and R5 taken together con~titute a (CH2)m- group where m i5 4 or 5 or a -CH2-C~2-R -CH -CH - group where R7 is an oxygen atom,a NH group or a Cl-C4 N-alkyl group; X représent~ a hydrogen,chlorine,bromine or iodine atom. The carbon atoms indicated by an asterisk are both contemporaneously ln (R) or (S) configura-tion. Thus the ketals of formula A are optically active.
The ketals of formula (A) have shown quite unexpected properties which allow the realization of the new process according to the present invention.
In fact, we have found that when ketals of formula A, in which X is hydrogen, are reached with achiral halogenating reagents, a chemo- , selective halogenation occurs in high yield on the diastereotopic carbon atom inthe alpha position with respect to the ketal group and in the thus obtained alpha halogen ketals ~formula A; X = Cl, ~r, I) only one of the e~imers is formed or s-trongly prevails over the other. It is worth noting that the absolute configuration (R,R or S,S) of the chiral centers already present on the starting ketals A (X=H) is untouched.
As far as we know, a ~tereoselectiYe halogenation in the alpha position of a ketal has never been previously described.
Moreover, we have found that the ketals of formula A in which X = Cl, 8r, I provide in high yields alpha-arylalkanoic acids in which the enantiomeric ratio reflects the epimeric ratio of the s-tarting ketals or, depending on the rearrangement conditions,the acid enan-tiomeric ratio is higher than the epimeric ratio of -the starting ketals.
'rO our knowledge, it is the Eirst time that a rearrangment of ketals ie described whlch gives rise to chemically pure alptla-arylalkanoic acids - 6 - ~ 3 ~

having an enantiomeric excess higher than ths epimeric exces of the starting ketals.
Thus the present invention provides an enantioselective process for the preparation of alpha-aryl~alkclnoic acids by diastereo-selec-tive halogenation, in the alpha position to the ketal group, of optically active ketals of formula (A) wherein X = H and the enantio-selec-tive rearrangement of the obtained halo-ketals into the correspond ing alpha-arylalkanoic acids.
An enantioselective process for preparing optically active alpha-arylalkanoic acids is completely new.

~ 3 ~

The arylalkanoic acids prepared according to the present invention fall within the formula ' F~
Ar - CH - C00~ (I) in which ~l is a Cl C4 alkyl; Ar is as heretofore defined and prefe-rably a monocyclic, polycycli.c, or or~hocondensed polycyclic aro-matic or heteroaromatic group having up to l2 carbon atorns in the aromatic s~ystem' 5UCII as phenyl, diphenyl,naph~hyl,'hienyl,or pyrrolyl.
The possible substituents of these aromatic g~oups ccmprise one or more halogen atoms, Cl-C4 alkyls, C3-C6 cycloalkyls, benzyl, hydroxy, Cl-C4 alkoxy, Cl-C~ al~ylthio, Cl-C4 haloalk~l, Cl-C4 haloalkoxy, phenoxy, thienvlcarbonyl and benzoyl.
Specific examples of such substituted aryls are 4-isobutyi-phenyl, 3-phenoxy-phenyl, Z-fluoro-~-diphenyl, 4'-fluoro-4-diphenyl, 4-(2-thienyicarbonyl)-phenyl, 6-methoxy-2-naphthyl, 5-chloro-~-methoxy-2-naphthyl and 5-bromo-6-methoxy-2`naphthyl, 4-chloro-phenyl, 4-difluoromethoxy-phenyl, G-hydroxy-2-naphthyl, and 5-bromo-6- hydroxy-2-naphthyl.
The ketals of Eormula (A) which constitute the starting compounds for the new process according to the present invention are prepa-red by ke-talization of a ketone of formula Ar - C - CH2 - R ~II) O
(in which Ar and R have the aforesaid meanings) by means of L(~)-tartaric acid ~2R, 3R-dihydroxy-butanedioic acid) or D(-)~tartaric acid (25, 3S-dihydroxybutanedioic acid) or derivatives thereof.
The ketones of formula II are products which are known or are easily prepared by known methods, for example by Friedel-Crafts acylation.
The ketalization reaction is carried out according to conven-tional methods, for example in the presence of an acid catalyst and ~ 3 an orthoester. Alterna-tively, the water formed during the react-ion can be removed by azeotropic distillation, for example with benzene, toluene, xylene, heptane or other su:i-table solvents.
The absolute configuration and the optical pur:Lty of -the ketals .5 of formula A in which X is hydrogen are the same as those of thestar-ting diol (tartaric acid or derivative thereof). Thus, start-ing from L(~)-tartaric acid, the obtained ketal of formula A has both the carbon atoms marked by an asterisk in formula A hereabove in the R configuration.
This reaction is particularly suitable for preparing compounds of formula (A) ~n which Rl and R2 represent a OR3 group, by react-ing the ketones of formula (II) with a tartaric acid ester.
The ketals of formula (A) in whlch Rl and R2 are other than OR3 are preferably prepared startin~ from these latter compounds by suitable transformation of the OR3 group.
For example, starting from esters of formula (A) in which Rl and R2 are OR3 groups, the corresponding mono-salts (for example Rl = 0 M ~nd R2 = OR3~ can be prepared by partial saponification with one equivalent of a base~for example alkaline hydroxide), and from these the corresponding mono-acids (for example Rl = OH, R2 = OR3) can be prepared by acidlfication.
Hydrolysis of the ester~ with two equivalents of an alkaline base leads to the formation of the corresponding salts ~Rl = R2 = M ) which by acidification produce the free dicarboxylic acids (Rl =
R2 = OH) which are th~ starting compounds for preparing different deriv~tives such as other mono or di-esters (Rl and/or R2 = OR3) or mono or di-amideq (Rl and/or R2 = NR4R5).
. The amides can also be obtained directly from the esters of formu-la (A) by treatment with a suitable amine of formula R4R5-N-H.
As stated heretofore, the compounds (A) wherein X = H are useful as the starting compounds for preparing -the compounds of formula (A) in which X represents a chlorine, bromine or iodlne atom.

9 ~ 3 ~

The compounds of formula (A) are halogenated byknown h~logenating agents for example bromine, quaternary ammonlum perhalides, sul-phuryl chloride, cupric chloride or bromide, N-bromo or N-chloro-succinimide, N-chlo~o-phthalimide, pyridine or pyrrolidone per-bromide or pyridine perchloride or the analogous iodides,hexachloro-2,4-cyclohexadienone, iodine and iodlde chlorlde, or analogous systems.
We have found that the halogenation of ketals having the carbon atoms marked by an asterisk in formula A hereabove both in configu ration R, that is ketals prepared from L(~)-tartaric acid or a de-rivative thereof (i.e. the na-turally occurring tartaric acid), give rise to the formation of a mixture of epimeric alpha-halo ketals in which the epimer in which the carbon atom bonded to the halogen is in the S configuration, strongly prevails. Since the con-figuration of the carbon atoms marked by an asterisk in formula A
hereabove remains unchanged, the major epiMer of the alpha halo--icetals derived from the naturally occurring tartaric acid or a derivative thereof, will be hereinafter referred to as RRS epimer and the minor one as RRR epimer.
We have also found that starting from ketals derived from D(-)-tartaric acid, the ma~or epimer has the carbon atom bonded to the halogen akom in the R configuration.
From the above firldings it clearly results that the described halogenation reaction is a new stereoselective reaction.
The ratio between the epimers RRS/RRR iS generally hlgher than 75:25 and in most of the cases is higher than 94:6. Depending on the substrate and the reactlon conditions it is also possible to obtain the RRS epimer as the only chemically pure alpha-halo-gen-ketal, the other epimer RRR . present, if any, in an amount lower than 1%.
Generally, the yields in alpha-halogen ketals are higher than 90%-- 10 - ~L3~

The stereoselectivity of the halogenation reaction ~s only slightly affected by the polarity of the solvent. a number of solvents such as carbon te-tracllloride, 1,2-dichloroethane, chlorobenzene, benzene, toluene, acetonitrile, cyclohexane, ethylacetate, carbon disulphide, acetic acid and so on,may be used. Best results are obtained by using solvents of` low polarity. The reaction may be carried out at room temperature with satisfactory results. ~'he stereoselectivity of the halogenation reaction increases by lowering the reaction temperature.
The reaction still occurs up to -70C.
Preferably', traces of a mineral acid are required to start-up the halogenation reaction which i~ usually tsrminated in a few mi nutes. As far as yields and stereoselectivity are concerned, the preferred halogenation reation is the bromination. Said reaction is preferably carried out with bromine as the halogenating agent, at a temperature between -40and +20C in solvents such as carbon tetrachloride, methylene chloride, 192-dichloro-ethane and carbon disulphide.
The peculiar characteristics of the ketals of formula A and in particular the shown high stereoselectivity in the halogenation reaction,were completely unpredictable on the base of the present knowledge o~ stereocontrolled reactions.
Independently from the aforesaid, the fact that the ketals of formula (A) where X = halogen ~exist in the form of diastereoisomers easily separable by known methods, for example by ~ractional crystalliza-tion, is also important.
If required, it is therefore possible to separate the desired isomer of the ketal of formula (A) and sub~ect this to rearrangemen-t to obtain the alpha-arylalkalloic acid in the substantially pure optically active form.
It is also important to note that tartaric acids and esters, in particular L(~)-tartaric acid and the relative methyl and ethyl esters, have a commercial cost which is competitlve with that o~

$ ~ ~ 7 the glycols described as ketali~ing agents in the processes of the known art, and the preparation of the tartaric acid derivatives (ester, amides, salts) certainly does not constitute a costly process.
The possibili-ty of having groups of different nature in the ketals of formula A, wi-th reference to the substituen-ts R1 and R2,'enables -to vary the hydrophilic and lipophilic propert;ies of said ketals within wide limits, from compounds containing polar grups (allcaline salts, amides) to lipophilic compounds~esters of long-chain alcohols~.
This wide possibility of choice allows to select the ketal of formula A most suitable for -the experimental conditions (solvents, temperature, catalysts) used in the various proces es for the preparation,of alpha-arylalkanoic acids or their deriva- -tives by rearrangement.
As far as the rearrangement of the ketal3 of formula A (in which X=Cl, Br, I~ is concerned, we have found that the ketals having the configuration RRS (wherein S is'the configuration of the carbon atom bonded to the halogen atom) provide the S-enantiomer of the c,orresponding alpha-arylalkanoic acid.
This is particularly important because (a) the S-enantiomer of alpha-arylalkanoic acid is generally the biologically more active isomer and the alpha-arylalkanoic acids present on the market in optically active form are all of S-configuration and because (b) the ketals of formula A having configuration RRS are selectively obtalned by halogenation of the ketals o~ formula A, X=H in turn easily prepare,d from the appropriate ketone and the naturally occurring L(~)-tartaric acid (or a derivative thereof) which is a really ~nexpensive material.
3~ In order to conveniently transform the optically active ketals of formula A tX=Cl, Br, I) it is necessary to use a rearrangement method which provides optically active alpha-arylalkanoic acids having,an enantiorner~ic ratio very close to that o~ the epimers in the starting - 12 - ~ 4~ r, ketals. This implies that the reaction has to b0 stereospecific and that -the react.ion conditions are such that no racemization occurs in the final products. We have found that the known methods provide alpha arylalkanoic acids having enantiomeric ratio equal to or lower than the epimeric ratio of the starting ketals. We have also found, and this is a further ob~ect of th~ present invention,a n~w enantioselec~ive.rearran-gement method'which overcomes.the above limits.
Such a prOCesG is here~ith defined as enantioselective in so far as the enantiomeric composition ~ratio between enantiomers S and R) of the alpha-arylalkanoic acids thus obtained~differs from the ep~-meric composition of the ~tarting ketals of formula A and more precisely and quite surprisingly corresponds to an increase in the optical purity of the alpha-aryialkanoic acid with respect to the epimeric composition of the starting ketals.
Thanks to this new, surprising rearrangement process, starting from e.g. a mixture of epimeric ketal~.'of formula A (in which X=Cl, Br, I) sufficiently enriched in the RRS epimer,it i~ possible to obtain in a optically pure form the S-enantiomer of the corresponding alpha-arylalkanoic acid.
It is worth noting that the yield of the ~ew rearrangement process is - a~ high as 80-90%.
The enantioselective process object of the present invention essen-tially consists in rearranging a ketal of formula A in which X is a ' chlorine, bromina or iodine atom, in aqueous medium at an acid pH,at a temperature comprised between room temperature and 100C.
The above mentioned rearrangement conditions are particularly un-expected and surprising in that it i8 well known that the treatment of a ketal with water under acidic conditions i8 a general method to convert ketals into the'corresponding ketones and the . -alcohol or diol, Accordingly, the previously known alpha-haloal-kyl-aryl ketals, under the above reaction conditlons, undergo a fast hydrolysis providlng the corresponding alpha haloalkyl-aryl-ketono ~ncl alcollol or dlol.

., - 13 ~

On the contrary, the ketals of formula A obJect of the present invention, when treated in aqueous acid medium, provide in high yield -the corresponding alpha-arylakanoic acids, ketones being pre-sen-t, if any, in negligeable amounts.
The rearrangement process ob~ect of the invention i3 preferably carried out by using ketals of formula A (ln which X-Cl, Dr, I) BO-luble or at leas-t partlally soluble ln water ~nder the reac-tlon conditions, i.e. the ke-tals of formula A in which R and/or R are hydrophilic groups.
The rearrangement is preferably carried out by heating the ketaL
of formula A in water at a pH comprised betwaen 3.5 and 6.5.
The desired pH values may be maintained by adding a sultable amount of a buffer.
The reaction duration depends mainly on the nature of the ke-tal of formula A, and on the reaction temperature. Generally, a high cohversion degree is reached after s~me hours.
Usually, the alpha-arylalkanoic acids are scarcely soluble in water, therefore at the end of the reaction the optlcally active alpha-arylalkanoic acid may be isola-ted by simple filtration. A pharmaceutical product as pure as required by U.S.Pharmacopeia is obtained by sim~le acid-base treatment of the product isolated by filtra-tion~ As far aR we know,this is the first time ~h~t a rearrangement of halogenketals for the preparation of alpha-aryialkanoic acids is carried out in water as the ohly reaction solvent. The main advantage~ of the present rearrangement process from an industrial point o~ view, may be summarized as follows:
(:a? the proce6s is enantioselective and provides alpha-arylalkanoic acids in high yields and with an enantiomeric ratio 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 re-quired and (d) the optically active alpha-arylalkanoic acid is separated from the reaction mixture by simple filtration.

By considering the overall process for the preparation o~
optically active alpha-arylalkanoic acid~ according to the present invention it may be said that it csnsists of two quite new steps: the stereo-selective halogenation of a ketal of formula A in which X is hydrogen and the enantioselective rearrangement of the thus obtained ketal of formula A in which X is a chlorine, bromine! or iodine atom.

More specifically the overall process for the selective preparation of the S-enantiomer of an alpha-arylalkanoic acid according to the present invention consists thus of two quite new steps: the stereo-selective halogenation of the suitable ketal of formula A in which X is hydrogen and in which the carbon atoms marked by an asterisk are both in the R
con~iguration, to selectively obtain the epimer RRS of the ketal of formula A in which X is a chlorine, bromine or iodine atom and the enantioselective rearrangemnt of the thus obtained ketal in water under acidic conditions.

Such a process is possible thanks to the unexpected characteristics of the ketals of ~ormula A shown both in the alpha halogenation step and in the a~ueous rearrangement step.

The rearrangemnt method may be also performed in different less advantageous manners depending on the starting ketal.
For exa~nple, the ketals of ~ormula (A) in which X is a iodine atom, when Ar is the 5-methoxy-2-naphthyl group and R is a methyl, can be rearranged according to the procedure given in European patent application 89711, published September 28, 1983, or by oxidation as described in Italian patent application 21841 A/82 open to public inspection December 11, 1983 (now Italian patent 1,~90,867).

,~

11 3 1 ~ ~

~ikewise, the ketals of formula (A) in which X is any halogen atom can be rearranged in the presence of certain metal salts, as described in European patent applications Nos.
34871 and 35305 and in J~ Chem. Soc., Perkin I, 11, 2575 (1982), or in a protic polar msdium in neutral or weakly alkaline conditions, optionally in the - 14a -presence of an inert diluent, as described in Italian patent appli-cation No. 22760 A/82 or in European patent application lOL,124.
The latter aforesaid method has important advantages relative in particular to its ease of industrial realizatiom and to the fact that it does not require the presence of metal salts as catalysts.
The aforesaid rearrangement reactions lead in general to the forma-tion of alpha-arylalkanoic acids in the form of their derivative, in particular esters. These are then hydrolysed to the corresponding free acids by conventional methods.
Of the optlcally active alpha-arylalkanoic acids, the most import-ant from the pharmacological viewpoint is 2-(6-methoxy-2-naphthyl)-propionic acid, of which the S(~isomer is known as Naproxen.
In a specific embodiment, the present invention relates to compounds of formula ! Rl.C0 H

~ 0 tB) ZO ' \ C
~ I H -CH3 Z-O

' (in which R1, R2 and X have the meanings given for the formula (A), Y represents a hydrogen atom or a chlorine or bromine atom and Z
represents a hydrogen atom, a methyl or an alkaline metal) and their use in the preparation of Naproxen by rearrangement.
The carbon atom~indicated with 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 o~ formula (B) in which X represents a halogen atom and _ 16 -Z a methyl, may be rearranged in the presence of certain metal salts such as Ag and Z~,or in a polar solvent under neutral or slightly alkaline conditions.
Moreover a compound of formula (B) in which Z repressnts an alkaline metal, may be rearranged in an aqueous or organic medium under neutral or alkaline conditions.
In any case the preferred embodiment according to the present invention is the rearrangement of the ketals of formula B (in which 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, for example containing Y
substituent.
In preparing Naproxen, it is necessary to eliminate the substituent Y when this is a chlorine or bromine atom. This is done by hydrogeno-lysis either on the alpha-arylalkanoic acid or on the ~elative ester.
The reaction involving rearrangement of the compounds of formula (A), in particular when conducted in a medium free from alcohols and glycols under mild conditions, can lead to the formation of new lnter-mediate esters of formula R COR

Ar - CH - GOO - CH - fH R6 (c) (in which Ar, R, Rl and R2 have the meanings given for formula A) and R6 i6 OH, Cl, Br or I. Depending on the reaction conditions, R6 can also assume other meanings such as acetate, propionate or benzoate.
Hydrolysis of the compounds of Eormula (C) then leads to the corres-poding alpha-arylalkanoic acid~.
Likewise, the rearrangement of the compounds of formula (B), when carried out in a medium free from alcohol9 and ghycols, can lead to the pro~uction of intermedia-te esters of formula:

- 17 - ~ 3 ~

CH
, 3 C-O-CH-CH-R

z _o ~$~ 2 (in which R1, R2~ R6 and Y have the meanings given for formula (B), and Z represent~ a hydrogen atom or a methyl), whlch on hydrolysis form the alpha-arylalkanoic acid known as Naproxen or lt~ immediate precur~ors. Again in this caF~e, in which the transformation of the halogen ketals to aryl-alkanoic acids takes place in two stages, there i5 no substantial racemisation, and thus the desired optically active aryl-alkanoic acid is selectively and prevalently obtained.
The compounds of formula tc) are new compounds and are provided by the present invention, in that they have interesting properties which make them useful ~rom varlous aspects.
As already stated, the compounds of formula (C) form the Gorrespond-ing alpha-arylalkanoic acids on hydrolysis.
Moreover, because of the presence of the two asymmetric carbon atoms in the alcoholic moiety(the atoms to which the CORl and COR2 groups are bonded respectively), the esters of formula (C) are use~ul for the optical resolution of the alpha-arylalkanoic acids.
The resolution of an acid into its optical iæomers is generally carried out by ~orming salts with an optically active base.
The us~ of the compounds (C) constitutes a new process for the reso-lution of mlxtures of optically active alpha-arylalkanoic acids by forming an ester with tartaric aGid or one of its derivatives, instead of forming a salt with an optically active base.
The use of the compounds of formula (C) for resolving an alpha-aryl-alkanoic acid i~ particularly advantageous when, by mean~ of the aforesaid process for rearranging the ketal6 (A), es-ters of ~ormula (C) are obtained enriched ln the desired isomer.

- 18 ~

I-t i5 evident -that the compounds of formula (C) are useful for the optical resolu-tion of alpha-arylalkanoic acids independently from the rnethod of preparation.
In thls respect, it is possible to prepare the compounds of formula S (C) by es-t0rifying a racendc alpha-arylalkanoic acid ~or.one whlch is already rich in one of the.two .enantiomers) independently from how this ha3 been prepared.
The compounds o~ formula (D), whether prepared by rearrangement of a compound of formula (B) or prepared by esterifying race~c .
2-(6-methoxy-2-naphthyl)-proplonic acid or one of ita immediate precursors using tartaric acid or one of its derivatives, are u~eful for separating, by means of crystallization, the ester of formula (D) which on hydrolysis produces Naprox~n in a substantially pure form.
A further unexpected property of the compounds of formula (C) i5 that they are in themselves pharmacological1y active compounds.
The compounds of formula (D) have proved particularly interesting~
The following tables give the data relative to the anti-inflammato-ry and antipyretic activity of the compounds (D) in which:
1 2 3; .6 ; ; 3 (a) R1 = Rz = OCH3`; R6 = ~; Y = Br; Z = CH3 ~b) compared with ~aproxen and with 5-Br Naproxen. (c) From these data it i3; evident that the n0w considered compounds, although having a lesser activity than Naproxen, still have an interesting activity which could find practical application in human therapy under determined conditions, ~ 3 ~

TABLE 1 - An-ti~inflammatory activity of -the derivatives (a)and (b) with respect to Naproxen and 5-bromo-Naproxen(c) by ora].admi.nistra-tion CompoundDose Inhibi-tion ED50 _ ~M/kg/os (after 3 h1 % (L.C. 95%1 (a) 10 0 175 ; 30 0 (110 ~ 280) lO0 16 (b) 10 3 160 14 (100 - 250 .1~0 20 (c) 10 6 300 56 (120 - 304) Naproxen 10 38 lO0 66 (19 - 49) - ~
, ~L 3 ~ P~
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. c: ~ ~ t~ _ r~ N CG N ID
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n ~ .
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~ . ~ ' . . .
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h ~rl _I O --~ O O ~
,~:, qJ ~ .1 1 .1 1 1 1 1 _. ~~ . . .
a u~ o ~ 5~J ID N ~ T~ O
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Some pratica:L examples of the process according to the present invention are described hereinafter in order to illustrate the invelltion bu-t wi.thout in any way limiting it.

ExamPle l Preparation of the compound 2-ethyl-2-(6-m~thoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester.

1-(6-methoxy-2-naphthyl)-propan-1-c~ne (46.5 g; 0.217 moles), L(+)tartaric acid dimethyl ester (300 g)~ trimethyl orthoformate (94 g; 0.887 moles) are gradually heated up to complete solution. Methane-sulphonic acid (1.48 g; 0.0154 moles~
is then added and the obtained solution is refluxed for 2 hours;
it is cooled at room temperature and the reaction mixture is slowly added to a 10% solution of Na2CO3 (500 ml). It is extracted with methylene chloride and the organic e~tracts are 1~ repeatedly washed with water.

The organic phase is dried on Na2SO~ and the solvent is evaporated under reduced pressure.

The residue is crystallized from methanol (250 ml)~
The desired product is obtained (51.S8 g; 0.138 moles; yield 63.6%) having the following characer~stics:
m.p. = 73-74C

Ed ]D = ~33.04 (C = 1%, C~Cl3) I.R. (Nu~ol a trademark): 1770,1740 cm~l (stretching C=O) NMR ~CDC13 - TMS, 200 MHz) S(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 (Sr 3H);
4.86 ~2H, ABq, ,~ )=10.80, J=6 Hz); 7.1--7.9 (m, 6H) .
Example 2 Preparation of the mixture of the diastereolsomers oE
2-(1-bromo-ethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R~,5(R)-dicarboxylic acid dlmethylester.

3 ~ $ ~

To a solution of the compound obtained in Example 1 (37.4 g; 0.1 mole).

- 23a -, , g ~ ~ r~

in 1,2-dichloro~thane (100 ml), tetra-n-~utylammonium perbromide / N(n.C4Hg)~ Br3 / (48.Z g; 0.1 mole) is added.
The reaction mlxture is Icept at 20C for 24 h and then slowly added under stirring to a 10% solution of Na2C03 (200 ml). It is extracted with toluene (2 x 200 ml) and the combined organic ex~ract~ are washed with a 2% solution ofNal-lC03 ~3 x 100 ml).
The organic phase is ~ried on Na2S0~ and the solvent evapo-rated under reduced pressure. The crude product obtained (48 g) is pu rified by chromatography on a silica gel column (eluent hexene:
diethylether = 75:25) to give 13 g of the desired mix-ture of dia-stereoisomers.
The ratio between the two diastereoisomers (1:2) determined by H-NMR (200 MHz) is 7:3.
Diastereoisomer l (R~S) H-NMR (CDCl3 - TMS), ~ (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 (ZH, ABq,~ ~ =26.8; J=7.2 Hz); 7.1-8.0 (6H,m).
Diastereoisomer 2 (RRR) H-rlMR (CDC13 - TMS), ~ (ppm): 1.64 (d, 3H, J=7.5 Hz); 3.58 (s, 3H); 3.89 (~, 3H); 4.08 (s, 3H); 4.50 tq, lH, J=7.5 Hæ); 4.89 (2H, A~q,~ ~ = 36.3, J=6.3 Hz); 7.1-8.0 (6H,m).

Pr~ ~rO,,t~
of the 2(R)-hydroxy-3(R)-/ 2-(6-methoxy 2-naphthyl)-propanoyl / _ butanedioic acid dimethyl ester.

A mixture of diastereoisomers 1:2 = 67:33, obtained according to example Z (5 g; 0.011 moles) dissolved into CH2C12 t61 ml) and kept at ~C under inert atmosphere is added with silvsr tetrafluoroborate (2.33 g; 0.012 moles). The reaction mixture is kep-t at 0C for - 25 - ~ 3~3'~ ~

30 minutes and then -the temperature is allo~ed to raise up to room temperature.
The mixture i9 fil-tered and the precipitate washed with CH2C12. The organic pha~:es are washed with water and dried 2 4 The solvent is evapo~ated under reduced pressure to give a mixture oE diastereoisomeric esters (ratio determined by NMP~, 200 MH~, A:B = 64:36).
H-NMR (CDC13 - TMS), ~, (ppm- ):
Diastereoisomer A (RRS):
1.62 (d, 3H, J=8 ~Iz); 3.22 (s, 3H); 3.83 (s, 311); 3.92 (s, 3H), 3.21 (d, lH, J=7.2 Hz); 3.95 (q, lH, J=8 H~); 4.68 (dd, lH, JCH oH=7-2 H7, JCH CH=2.47 Hz); 5.37 (d, lH, J =2.47 Hz); 7.1-7.8 (6H, aromatic protons).
Diastereoisomer B (RRR):
1.66 (d, 3H, J=8 Hz); 3.58 (5, 3H); 3.72 (s, 3H); 3.92 (s, 3H);
3.24 (d, lH, J=7.6 Hz); 3.97 (q, lH, J=8 Hz), 4.78 (dd, lH, JCH-OH 7-6 Hz~ JCH-CH = 2-47 Hz); 5-45 (d, lH, J=2.47 Hz); 7.1~7.8 -(6H, aromatic protons).

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

A mixture of diastereoisomer esters A and B prepared as described in Example 3 (ratio A:B = 62:38) (3.2 g) dimethoxyethane (24 ml~, hydrochloric acid ~2 N (24 ml) is kept under stirring, at 95C
for~ Z.5 h. It is cooled to room te0perature, poured into water and extracted with CH2C12.
The combined organic extracts are washed with a sa-turated solution of sodium bicarbonate The aqueous phase is acidified to give the 2-(6-methoxy-2-naphthyl)-propionic acid (1.3 g).

1 3 ~
An analytically pure sample obtained by column chromatography on silica gel (eluant hexene: diethylether=1:1), Wit~l [d~]D = +12-9 (c = 1%, CHC13) i~ esterified with diazomethane.

The obtained methyl ester is analyzed by lH-NMR (200 MHz) using an optically active shift agent (Europium (III) -tris-[3-(eptafluoropropylhydroxymethylene)-d--camphorate] in 10 CDCl 3)-The ~nantiomeric ratio is (~)S:(-)R=62:38.

Example 5 Preparation of the 2-(6-methoxy-2-naphthyl~-propionic acid.

A mixtur~ of diastereoisomeric ketals prepared as described in Example 2, in the ratio 1:2=67:33, is heated at 125C in ethylene glycol, in the presence of pstassium acetate for 20 h. After the work up of the reaction mlxture, a mixture of esters is obtained that are hydrolyzed as described in Example 4. The (~)~S)-2 (6-methoxy-2-naphthyl) propionic acid (Naproxen) is obtained, with an optical purity of 40~; m.p. = 151-152C.
Example 6 Preparation of the diastereoisomeric mixture of the compound 2-~1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester.

To a solution of 2-ethyl-2-(6-methoxy-2-naphthyl)-l~3 dioxolane-4tR), 5(R)-dicarboxylic acid dimethyl ester (3.74 g;
0.01 moles) in CC14 (70 mlJ kept at 0C under inert atmosphere, a ~ ~L 3 ~ 8 9 d~ 7 solution of bromine ~3.2 g; 0.0'2 moles) in CC1~ (7 ml) cooled at 0C is added dropwise in 1 h.

- '26a -13 1 ~ ~ ~ 7 The mixture is Icept at 0C for -two hours, then pG~ed under vi gorous stirring into an 10% a~ueous solution of Na2C03 (250 ml) and extrac-ted wi-th C~I Cl (3 x 50 ml).
The comblned orgaIlic extracts are dried on Na2S04 and the solvent evaporated under vacuum. The residue (5 g; 0.0093 moles;
yield 93%) consists of a mixture o-f the two diastereoisomers ide~-tif`ied wi-th 3 and 4.
The ratio between the diastereoisomers 3:4 determined by HPLC
and H-NMR i5 95:5.
The major isomer has the ~ame configura-tion (S) of the dias-tereoisomer l described in Example 2, refe-rerring to the aliphatic carbon a-tom bonded to bromine.
Diastereoisomer 3 IRRS) H-NMR (200 MHz) (CDC13 - TMS), ~ (ppm):1.66 (d, 3H, J=6.8 Hz);
3.52 (s, 3H); 3.88 (s, 3H); 4.05 (s, 3H); 4.46 (q, lH, J=6.8 Hz);
4.94 (2H ABq, J=6 Hz); 7.28-8.24 (5H, aromatic protons).
Diastereoisomer 4 (RRR) H-NMR (200 MHz) (CDCl3 - TMS) ~ ~ppm): 1.63 (d, 3H, J=6.8 Hz);
3.56 (s, 3H); 3.87 (s, 3H); 4.05 (s, 3H); 4.48 (q, lH, J=6.8 Hz);
4.91 (2H, ABq, J=6 Hz); 7.28-8.24 (5H, aromatic protons).
The HPI.C analysis (high pressure liquid chromatography) has been performed under the following conditions:
Hewlett Packard instru~ent mod. 1084/B with variable wavelength W detector:
AnalYtical conditions:
- Column BRAWNLEE LABS RP8 (5 ~ ) spheri 250 mm x 4.6 mm (internal ~iameter) - Solven-t A: bidistilled water, flow 0.9 ml/min - Solvent B: methanol, flow 1.1 ml/min - Solvent A temperature: 60C
- Solvent B temperature: 40C

- .
- 28 - ~3 - Column temperature: 50C
- Wavelengttl (A ): 254 nanometers - Injecl;ion: 10 ~ 1 of a solution containing 3 mg/ml o~ a sample in acetonitrile.
Retention times:
Diastereoisomer 3 : 18.20 min Diastereoisomer 4 : 19.90 min = . = . = . _ . _ A mixture of diastereoisomers 3 and 4 in ratio 95:5 obtained as above described is chromatographated on silica gel, by using as eluent a mixture of diethylether : hexane = 3 : 7.
The collected fractions are separately analy~ed by HPLC.
The frac-tions containing the diastereoisomer 3 showing a diaste-reoisomeric purity higher than 99%~are collected.
The solvent is evaporated under vacuum -to give the pure diaste-reoisomer 3.
H-NMR (200 MHz) (CDC13-TMS) delta (ppm): 1.66 (d, 3H, J=7.S Hz);
3.52 (s, 3H); 3.83 (s, 3H); 4.05 (s, 3H); 4.46 (q, lH, J=7.5 Hz);
4.94 (2H, ABq, J=7.2 Hz); 7.28-8.24 (5H, aromatic protons).

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

The reaction described in Example 6 has been repeated wi-th different solvents and a-t different temperatures according to the following procedure.
To a solution of 2-ethyl--2-(6-methoxy-2-naphthyl)-1,3-dioxolane--4~R), 5(~)-dLcarboxylic acid dimethyl ester (0.01 moles) Ln -the - 29 - ~3~

solvent indicated in the following Table (70 ml), kep-t under inert atmosphere at the temperature also indicated in -the Table, a solutlon of bromine(o.o2 moles) in -the same solven-t (7.0 ml), pre-coolecl to the temperature of the above mixture, is added.
The so obtained reaction rnix-ture is kept at -the ternperature indica-ted to reach~asubstantially complete conversion. It is then worked up as described in Example 6. The ratio between the diastereaiso-mers 3 and 4 is indicated in the Table.

~ 30 - 1 3 ~

T A B L E

... . . _ .. .. .
Solven-t T Ratio (C) diast. 3 dias-t. 4 Carbon te-trachloride 20 93/7 1 t 2-Dichloroethane 20 93/7 1,2-Dichloroethane O 91J9 1,2-Dichloroethane -30 92/8 1,1,2,Z-Tetrachloroethane 20 89/11 10 Chlorobenzene 20 90/10 Benzene 20 91/9 Benzene 0 92/8 Toluene 20 91/9 Ethylenglycoldimethylether 20 86/14 15 Acetonitrile 20 82/18 Cyclohexane 20 88/12 Orthodichlorobenzene 20 89.2/10.8 Sulfolane 27 78/22 Ethylacetate 20 91/9 Para-dichlorobenzene 60 87/13 Carbondisulfide 15 92.3/7.7 Acetic acid 15 89/11 Hexafluorobenzene 15 90.3/9.7 Molar yield 90-95%

- 31 ~ r~

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

To a solution of 2-ethyl~2-(~methoxy-2-naphthyl)--1,3-dioxolane--4(R), 5(R)-dicarboxyllc acid dime-thyl ester (70 g; 0.187 moles) in 1,2-dichloroethane (175 ml) kept at -30C, under inert atmosphe-re and under stirring, a bromine solution (59.8 g; 0.374 moles) in 1,2-dichloroethane (140 ml) is added in 2 h.
The reaction mixture is kept at -30C up to a complete conversion of the starting product, then is added slowly dropwise to a 10~
solution of Na2C03 (1000 ml) under vigorous stirring.
The organic phase is separated, washed with water, dried on Na2S04 and the solvent evaporated under vacuum. The mixture of the two dias-tereoisomers 3:4 is obtained in a ratio 9:1.
The above ratio has been determined by HPLC and H-N~R.

Preparation of 2(R)-hydroxy-3(R)-L 2-(5-bromo-6-methoxy-2-naphthyl)-propanoyL /-butanedioic acid dimethy}ester.

To a solution of 2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphtyl)-1,3}dioxQ~ 4(R), S(R)-dicarboxylic acid dLme ~ 1 ester (2.66 g; 0. ~ moles;
ratio diastereoisomer 3 to diastereoisomer 4 = 85:15 determined by HPLC) in 1,2-dichloroethane (20 ml), kept under stirring at 15C under inert atmosphere, sllver tetra~luoroborate~(l.l7 g 0.006 moles) is added.
The reaction mixture is kep-t at -15C for 2 h, then allo~ed -to reach room temperature in about 1 h and filtered. The organic pha se is washed with water, dried on Na2S04 and the solvent evaporated under vacuum.

- 32 - ~ 31~ ~ ~ r~

The desired product is obtained (2.2 g; 0.0047 moles; yi.eld 94%) as a mixture o.f -two diastereoisomers named C and D, in a ratio C:D = 84:16 determined by H-NMR, 200 ME~z .
Il-NMR (CDC13 - TMS) Diastereoisomer C (RRS) - The data are consisti.ng ~ith the given 5 tructure; ths da-ta which refer to the aliphatic part are analogous to those of the diastereoisomer A descri-bed in Example 3.
Diastereoisomer D (RRR) - The dat,a . are quite consisting with the given structure; the data which refer to the aliphatic part are analogous to those of diastereoisomer B described in Exampl.e 3.
The diastereoisomer C has been separated in pure form by crystalli-zation from methanol. M.p. = 124 - 126DC; /~ / D = + 60.2 (c = 1%
in CHC13).

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

~a) a mixture of:
- 2(R~-hydroxy-3(R)-/2-(5-bromo-6-methoxy-Z-naphthyl-JPrPan~
butanedioic acid dimethyl ester (diastereoisomer C of Exam-ple 9 ; 0.5 g; 1.065 mmoles) - sodium hydroxide (0.170 g; 4.26 mmoles) - water t2.5 ml) - methanol (3.5 ml) is kept under stirring at room temperature for 18 hours.
The mixture is diluted with water and extracted with dichloro methane. The aqueous phase is acidified with conc. HCI and extracted with dichloromethanc.

- 33 ~

The organic phase is then washed with water, dried and the solvent evaporated under vacuum~ The 50 obtained crude acid is purified by chromatography on silica gel (eluent hexene:
diethyle-ther = 8 : 2).
The S(~)-2-(5-bromo-6-mettloxy-2-naph-th~l)-propionic in the pure form is obtained; m.p. = 15S-157"C;
/C~ / 578 ~ ~ 20.5 (c=0.5% in CIIC13). Star-ting from this acid, by debromination according to -the method descri-bed in the Belgian Patent 89Z.689, Naproxen is obtained ha~ing the same optical purity of the starting 5-Bromo-derivative.
.

b) a mixture-of:
- 2(R~-hydroxy-3(R)-/ 2-(5-bromo-6-methoxy-2-naphthyl)-propa-noyl /-butanedioic acid dimethyl ester (diastereoisomer C obtained according to Example 9 ; 0.2 g; 0.426 mmoles) - 1,2-dimethoxy-ethane (3 ml) - conc. HCl t3 ml) is kep-t at 95C for 2 h. The reaction mixture is then cooled to room temperature, diluted with water and extracted with CH2Cl2.The organic phase is washed with wa-ter and extracted with 10% sodium bicarbonate.
The basic aqueous extract is acidified with conc.HCl and extracted with CH2Cl2.
The organic extract is washed with water, dried on Na2S04 and the solvent evaporated under reduced pressure.
The optically pure S(~)-2-(5-bromo-6-methoxy-2-naphthyl)-propio-nic acid is obtained:
/ ~ / 578 = ~ 4~-9 (c - 0.5% in C~IC13).

- 34 ~ 7 This acid i5 debromina-ted to give Naproxen hav ~ the same ~tiG~
purity, following the procedure described in the Belgian Pa-tent 892.689 /C~ / 20 = ~66(c = 1% in CHCl )-EXAMPLF. 11 Preparation of the 2-(5-bromo- 6-meth~xy-2-naphthyl) propionic acid.
. .
A mixture of 2-~1-bromoethyl)-2-t5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R) 7 5(R)-dicarboxylic acid dimethyl ester prepared according to Example 8 (2.66 g; 5 mmoles; diaster.3:diaster.4 =
9:1 as determined by HPLC), sodium bicarbonate (1.7 g; 20 mmole) and water is refluxed for 22 h. The reaction mixture ls cooled to room temperature and extracted with die-~lethe~. The aqueous phase is acidified wi-th conc.HCl and the precipita-te filtered and washed with water.
The so obtained crude acid (1.13 g) is purified on a sllica gel column (eluent hex~qe:diethyletherin ratio 8:2).
The 2~(5-bromo-6-me-thoxy_2-naphthyl)-propionic acid (0.92 g; 3 mmoles;
yield 60%) is obtained - m.p. = 156-158C; / ~ / 578 = + 23.5 (c = 0.5% in CHC13).

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

1-(6-methoxy-2~naphthyl)-propan-1-one (20.0 g; 0.093 moles), diethyl ester of L(~)-tartaric acid (160 g) and triethyLorthoformate ~37 g;
0.25 moles) are slowly heated up to complete solution.
Methanesulphonic acid (0.68 g; 0.007 moles) is added and the ~;olution i9 refluxed f'or } h.

- 35 ~

The reac-tion mix-ture is cooled to room temperature and added to a 10% solution of Na2C03 (250 ml) under vigorous stirring.It is extracted with Cll2C12 and the organic extracts are repeatedly washed with water.
The organic phase is dried on NQ2SO4 and the solvent is eva-portated under reduced pressure.
The crude product is grad~ally heated up to 180C (external bath) under a pressure of 0.1 mmEIg.
The desired product is obtained (33.6 g~ 0.084 moles; yield 90%) having the following characteristics:
/ ~ / 20 = + 20.59 (c = 1%, C~IC13) I.R. (NEAT): 1770,1740 cm (stretching C=0) H-NMR (CDC13 - TMS) S (ppm): 0.95 (t, 3H, J=6.4~);1.02 (t, 3H, J=7.3Hz);1.3 (t, 3H, J=7.3Hz);2.08 (q, 2H, J=6. ~ );3.9 (s, 3H);
3.88 (dq, 2H, J=1 ~ , J=7.3Hz);4.30(q, 2H, J=7.3Hz);4.82 (ABq, 2H, J=5.~);7-8 (6H, aromatic protons).

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

To a solution of 2-ethyl 2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid diethyl ester (2 g; 0.005 moles) in CC14 (35 ml) is added a solution of brune (1.6 g; 0.01 moles~ in CC14 (3.5 ml),under inert atmosphere, at 20C.
The mixture is kept at 20C for -two hours and thenWD~ced up as de-scribed in Example 6.
The desired diastereoisomericmixture is obtained (named as 5 and 6) in 93% yield.
The ratio between the diastereoisomers , determined by HPLC,ls 5:6 ~ 91.5:~.5.

- 36 - ~ 3 ~

The diastereoisomer 5 (which is the prevalent one) shows the same configuration (S) af the dias-tereoisomer 1 (Example 2) and of diastereoisomer 3 (Example 6) with respect to the aliphatic car-bon atom bonded to bromine.

H-NMR (CDC13 - TMS) (200 MHz) Diastereoiso~ 5 (~RS):S(ppm) 1.04 (t, 3H,J=~); 1.31 (t, 3H, J-~lz);
1.65 (d, 3H, J=6-~-~);3.92 (dq, 2H, J=ll.~lz, J=~lz);3.98 (s, 3H);
4.3 (q, 2H,J=~lZ); 4.48 (q, lH, J=6.8~);4.88 (ABq, 2H, J=6.~);

7.2-8.2 (5H, aromatic pro-tons).
Diast~oiso~ 6(RRR)-S (ppm) 1.09 (t, 3H,J--7HZ~; 1-29 ~t, 3H~ J= ~ );

1.62 (d, 3H, J=6-8Hz);3.98 (s, 3H); 4.29 (q, 2H,J=7Hz); 4.85 (ABq, 2H, J=6~5~);7.2-8.2 (5H, aromatic protons).
HPLC analysis performed under essentially the same conditions as described in Example 6, with the only difference that the percen-tage oE the solvent B is 58% (total flow 2 ml/min).

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

- 37 - ~ 3 ~ 7 .E~AMPL~ 14 Preparation of 2-ethyl-2-(6-methoxy-2-naphttlyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid .5 A mixture of 2-e-thyl-2-(6-methoxy-2-naphthyl) 1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester (~.68 g; 12.5 mmoles), NaOH (1 g, 25 mmoles) and water (50 mL) is kept under stirring at room temperature for 5 h.
The reaction mixture is filtered and the aqueous phase acidified with conc. HCl to pH 1.
It is then extracted with die~wle~er and the~ombined organic ~:
extracts are washed with wa-ter and dried on Na2S04.
Evaporatian of the solvent under vacuum gives 2-ethyl-2-(-methoxy- .
2-naphthyl)~1,3-dioxolane-4(R), 5(R)-dicarboxylic acid (3.46 gj:10 mmoles);
yield 80%), m.p. = 100-102~C.
H NMR (200 MHz) (CDC13-TMS) delta (ppm): O.g2 It, 3~1, J = 7 H~);
2.07 (q, 2H, J = 7 Hz); 3.86 (s, 3H); 4.78 (2H, ABq, ~ ~ = 4.2;
J = 5.8 Hz); 7,0-8,0 (6H, aromatic protons).
A sample esterified with diazomethane in diethyle~ gives the starting methyl ester with unchanged : HNMR, I.R., m.p., and i~7.
.

Preparation of 2-(1-bromoethyl)-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~ bromo-ethyl)-2-¦5-bromo-6-me-thoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester, in ratio 9:1 (6.65 g 12.5 mmole~), NaOH (1 g;
25 mmoles), dimethoxyethane (10 ml) and water (10 ml) is kept under ~tirring at room temperature for 2 h.

~ 3'3 ~ ~ 3~

The reaction mixture is diluted with water and extracted wi-th diethylether.
The aqueous phase is then acidified to pil 1 with conc. HCl and extracted with diethylether.
The combined organic extracts are washed with water and dried on Na SO .

The evaporation of the solvent under vacuum leads to the two diastereoisomers of 2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)~1,3 dioxolane-4(R), 5(R~-dicarboxylic acid (5.8 g;
11.5 mmoles; yield 92%) named with the numbers 7 and 8.
The ratio between the diastereoisomers 7 and 8 , determined by HNMR (200 MH~),is of 9:1.
Diastereoisomer 7 (RRS) (CDC13-TMS) delta (ppm): 1.60 (d, 3H, J = 7 Hz);
4.00 (s, 3H); 4.49 (q, lH, J = 7 Hz); 4.87 (2H, ABq,~ ~ = 18.9;
J = 6.5 Hz): 7.2-8.2 (5H, aromatic protons).

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

A mixture of 2-/l(S)bromoethyl7-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxyllc acid dimethyl ester~diastereoisomer 3 in the pure form; 6.65 g; 12.5 mmoles), NaOH (1 g; 25 mmoles), dimethoxyethane (10 ml) and water (lO ml) is kept under stirring at room temperature for 2 h.
The reaction mixture is diluted with wa-ter and ex-tracted with diethyl-ether. Then the aqueous phase is acidified a-t pH 1 with conc. IICl and extracted with diethylether.

The ~ombined organic extracts are washed with water and dried on NazSO4.
E~x~a~rg of U~ solventunder vacuum gives 2-~l(S)-brollloe-thyl7~2-~5-bromo-3L 3 ~ 7~
6-methoxy-2-naphthyl)-1,3 dioxolane-4(R), 5(R)~dicarboxylic acid (diastereoisomer 7).

lH NMR (200 MHz) (CDC13-TMS) delta (ppm): 1.60 (d, 3H, J = 7 Hz); 4.00 (s, 3H); 4.49 (~, lH, J = 7 Hz); 4.B7 (2H, ABq,~ ~ ~ 18.9; J = 6 Hz); 7.2-8.2 ~5 H, aromatic protons).

Example_17 Preparation of 2(R)-hydroxy-3(R~-[2-(5 bromo-6-methoxy2-naphthyl)-propanol~-butanedioic acid dimethyl ester.

To a mixture of the diastereoisomerd 3 and ~ in ratio 94:6 (determined by HPLC) (10~0 g, 0.0188 moles) in 1,2-dichloroethane (75 ml) kept under stirring at +15C, under inert atmosphere, a solution of silver tetrafluoborate (4.4 g; 0.0226 moles) in 1,2-dichloroethane ~30 ml), is added in 15 min~

The reaction mixture is kept at ~15C for 7 h, poured slowly into cooled water (lO0 ml) in such a manner that the temperture does not overcome +10C. The mixture is then filtered on Celite (a trademark) and the filtrate washed with CH2Cl2 (100 ml).
The organic phase is washed with water (2x200 ml) and dried on Na2SO4. Evaporating of the solvent under reduced pressure gives a residue (7.2 g; 0.0154 moles; yield 82%) consisting of a mixture of diastereoisomeric esters (ratio diast. C:3 ~ 91:9, determined by lH NMR analysis).

.

.

Example 18 Preparation of the compound 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid di-isopropyl ester.l-(S-methoxy-2-naphthyl)-propan-1-one (10.3 g; 0.048 moles), di-isopropyl ester L (+) tartaric acid (94 g) and trimetlylorthoformate~

- 39a-~ 40 - ~3 ~

(7.57 g; 0.071 moLes), are gradually hea-ted up to complete solution.
It is ther~ added me~ncsulphonic acid tO.37 g; 0.0039 moles) and the solution is refluxed for 2.5 h (temperature Or the solution 90C).
~5 The reac-tion mixture is cooled and slowly added t;o a 10% solution o~
Na2C03 (100 ml), under vigorous stirring.
It is extracted wi-th CH2Cl2 and the organic ex-tracts are washed with water (100 ml).
The organic phase is dried on NazSO4 and the solvent is evaporated under reduced pressure to give 94 g of crude product.
~hë: drude product is then slowly heated up to 220C lexternal bath) at 0.2-0.3 mm/Hg. The residue is purified by cromatography ~n a silica ~el column (eluent hexene : diethyl- ' 1~ ether = 85:15)2-ethyl-2(6-me-thoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R) dicarboxylic acid diisopropylester (14.2 g; 0.033 moles; yield 69%) was obtained.
I.R. (Neat): 1770, 1740 Gm ( stretching C = 0) H NMR (CDCi3-TMS) (200 MHz~ delta (ppm): 0.95 (t, 3 H, J = 7.6 Hz);
0.96 (d, 3 H, J = 6.4 Hz); 1.05 (d, 3 H, J = 6.4 Hz); 1.29 (d, 6 H, J = 6.4 Hz); 3.8 (s, 3 H); 4.75 (A~q, 2 H, J = 6.6 Hz); 4.79 (q, 1 H, J = 6.4); 5.14 ~ept., 1 H, J = 6.4); 7-8 (m, 6 H).

Preparation of the diastereoisomer~ mixture of the 2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid diisopropylester.

A s~lu;~ion of brom~e~l6 g; 0.01 moles)in CCl4(3.5 mL) is added drogwise, at 15C, under inert atmosphere, in 1 h to a solution of .2-e-thyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane- 4(Q), 5(R)-dicarboxylic .

-- 41 - ~ 3 ~ 7~

acid diisopropyl ester (2.15 g; 0.005 moles) in CCl4 (35 ml).
5he mixture is kept at 15C fO~ 2 h and then ~orked up as described i~ example 6.
The desired diastereoisomeric mixture (isomers 9 and 10) is obtained in a 94% yield.
The ratlo between the two dias-tereoisorners as detr-rmined by HPLC is 9:10 = 93.9:6.1- . lH NMR (CDC13-TMS) (200 MlIz) Dias-tereoisomer 9 (RRS): delta (ppm): 0.96 (d, 3HI, J = 6.4 Hz);
1.06 (d, 3H, J = 6.4 Hz); 1.3 (d, 6 H, J = 6.4 H~); 1.67 (d, 3H, J=~.2 Hz);3.98 (s, 3H); 4.47 ~q, lH, J = 7.2 Hz); 4.80(ABq, 2H, J = 6.6 H~);
4.80(m, lH, J = 6.4 Hz); 5.15 (m, lH, J = 6.4 Hz); 7.2-8.2 (5H, aromatic protons).
Diastereoisomer 10 (RRS): delta (ppm): 0.96 (d, 3H, J = 6.4 Hzj;
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, lH, J - 7.2 Hz); 4.80(A~q, 2H, J = 6.6 Hz);
4.80~m, lH, J = 6.4 Hz); 5.15 (m, lH, J = 6.4 Hz); 7.2-8.2 (5H, aromatic protons).
HPLC analysis performed as described in ex. 6I with the only difference that the percentage of solvent B~is 62.5% ~to-tal flow 2 ml/min.) Diastereoisomer 9:retention time 23.68 min.
Diastereoisomer lO:retention time 24.46 min.

Preparation of 2(R)hydroxy-3(R)-/2-(5-bromo-6-methoxy-2-naphthyl)-prPanY17-butanedioic acid diisopropylester.

Following the procedure described in ex. 17 a mixture of diastereoisomeric ketals 9 and 10 (ex. 19) in a ratio 9:10 = '~4:6 determined by HPLC (2.0 g; 3.4 mmoles), a residue is obtained (1.6 g)that af~r purification by c~Y~at ~ aphy qn silir~a gel colwn (eluent hexene:dietkylether ~- 1:1) gives a mixture of diastereiosomers ester~ (E ~nd F) in ratio - 42 - ~ 3 ~

~0:10 ~(determined by 11 NMR (200 MHz) analysis) H-NMR (CDC13-TMS) (200 Mllz) Diastereoisomer E (RRS): delta (ppm): 0.55 (d, 311, J = 6.12 I-lz);
1.02 (d, 3~l, J = 6.12 Hz); 1.24 (d, 3H, J = 6.12 Hz); 1.27 td. 3H, J = 6.12 H~); 1.61 (d, 3H, J = 7 Hz); 3.17 (d, lZI, J = 6.8 Hz);
4.00 ~q, lH, J = 7 Hz); 4.02 (s, 3l1); ~.52 (ept, 1ll, J = 6.12 llz) CH-C~I 2.2 Hz, JcH-oH = 6.8 Hz); S.13 (ep-t, lH, J = 6 12 Hz); 5.30 (d, lH, J - 2.2 Hz); 7.2-8.2 (5H, aromatic system).
Dias-tereoisomer F (RRR): delta (ppm): 0.95 (d, 3H, J = 6.1Z Hz);
1.12 (d, 3H, J = 6.12 Hz); 1.14 (d, 3H~ J = 6.1Z Hz); 1.19 (d, 3H, J = 6.12 Hz); 1.62 (d, 3H, J = 7 Hz); 3.17 (d, lH, J = 6.8 Hz);
4.00 (q, lH, J = 7 Hz); 4.02 (s, 3H); 4.52 (ept, lH, J = 6.12 Hz);
4.62 (dd, lH, JC~I C~l = 2.2 Hz, JCH CH = 6.8 Hz); 5.13 (ept, lH, J = 6-12 Hz);
5.41 (d, lH, J = 2.2 Hz); 7.2-8.2 (5H, aroma-tic system).

Preparat~on of the 2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid.

A mixture of dias-tereoisomers E and ~ (ex. 20) in a ratio E:F = 90:10 (0.35 g; 0.648 mmoles), dimethoxyethane (4.6 ml) and 12 N HCl (4.6 ml) is kept at 88C under stirring `for 2 h. It is cooled to room temperature and then it is worked upas described in ex. lO(b).
The so obtained crude pnx~ct ig eluted through a silica gel column (eluent hexene:ethyl ether = 8:2), to give the 2-(5-bromo-6-methoxy-2-naphthyl)propionic acid: m.p. = 148-151C; /d 7 = ~38 (c = 0.5% CHC13).
The methylester of the above acid ob-tained by esterification with diazomethane , analyzed ~ H-NMR (200 M~) using optically active shift ~agent (europium (III) tris-~-(eptafluoro-propylhydroxymethylene)-d-camphorate/ in CDC13,shows a ratio between ,the enantiomers of S(~):R(-) = 90:10.

3 ~ ~ ~

EX~MPLE 22 Preparation of 2(~)hydroxy-3(R)-~2-(5-bromo-6-methoxy-2-naphthyl)-propanoyl7-butanedioic acid diethylester.

Following the p ~ e~eas described in ex.].7 a mixture of diastereo-isomer~ ketals 5 ~nd 6 ~ex. 13) h~ving a ratio 5:6 = 93:7, determined by IIPLC,(2.41 g; 4.3 mmoles), a residue is obtained (1.95 g) tha-t by elutlon through a silica gel column (eluent~hexane : diethylether = 1:1) gives a mixture of diastereoisomericesters named as G and H
~1.77 g; 3.6 mmoles; yield 83%) in ratio G:H = 86:14 de-termined by H-NMR, 200 MHz. H-NMR (CD~13-TMS) (200 MIIz):
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, lH, J = 7.12 Hz);
3.58 (q di AB, 2H, J = 12 Hz, J = 7.2 Hz); 4 (q, lH, J = 7 Hz);
gem 4.01 (s, 3H); 4.27 (q, 2H, J = 7.2 Hz); 4.65 (dd, lH, JCH 0~l = 7.12 Hz~;
JCH OH = 2.4 Hz); 5.32 (d, lH, 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 (dl 1}l, J = 7-12 Hz);
3.58 (q di A8, 2H, Jgem = 12 Hz, J - 7.2 Hz); 4.pO (q, lH, J --7Hz) 4.01 (s, 3H); 4.27 (q1 2H, J = 7.2 Hz); 4.65 (dd, lH, JCH OH = 7.12 ~Z; JcH_cH
= 2.4 Hz), 5.44 (d, lH, J = 2.4 Hz); 7.2-8.2 ~5H, aromaticFrotons).

A mixture of diastereoisomeric es-ters G and H prepared as described in ex. 22 (ratio G:H = 86:14) (0.64 g; 1.28 mmoles), dimethoxyethane (9 ml) - 25 and 12 N HCl (9 ml) is kept at 95C (temperature of the bath) under stirring for 1 h.
It is cooled to room temperature and then it is worked up as described in ex. lQ(b). The so obtained crude acid is elu-ted through a silica gel column (eluent hexane: diethyle:ther _ 1 : 1).
The 2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid is obtained-M.p. = 149-151C and /~7 = ~33.94 (c = 0.5%, CHC13)-44 - ~ 3 ~ $ ~ 5 b ~A sample is esterified wi-th cliazome-thane and the ob-tained methylester is analysed with H-NMR (200 M Hz) . using an optically active shift ager~t ~europium (III) tris /3-(eptafl~loropropyL hyd~oxymethylene) _d -camphorate~in CDC13 ~5 The enantiomers ratio is S~ R(-) = 86:14.

Preparation of 2-ethyl-2-(6-methoxy-2-naph-thyl)-1.3-dioxolane-4(S), 5(S)-dicarboxylic acid dimethylester.

1-(6-methoxy-2-naphthyl)-propan-1-one (20 g; 0.093 moles), dimethylester of D(-)tartaric acid (129 g) and trimethyl orthoformate(29 g; 0.27 moles) are gradually heated up to a complete solution. It is then added methane-sulphonic acid (0.74 g; 7.7 mmoles) and the solution is refluxed (84C) for 1 h; it is cooled to room temperature and the mixture is poured slowly in a 10% solution of Na2C03 (250 ml) under vigorous stirring.
The mixture is extracted with CH2C12 (250 ml) and the organic extracts are washed with water.
The organic phase is dried ~on Na2S04 and the solvent i5 evaporated under reduced pressure.
The c ~ e~roduct (40.3 g) is gradually heated up to 180C at 0.1-0.5 mm/Hg, under stirring.
The residue (33.3 g) is crystallized from methanol (100 ml) thus obtain-ing the desired product (23.7 g; 0.0635 moles ; yield 68%) with the following characteristics:

m.p. 72-73C; /~ ~D = ~34-0 (c = 1%, CHC13) I.R. (Nujol):1770, 1740 cm (stretchlng C = 0) H-NMR (CDC13, TMS) (200 M Hz).
Thel data are identical to those of the compound 2-ethyl-2-(6-methoxy--Z-naphthyl)-1.3-dioxolane--4(R),5(R)-dicarboxylic acid dimethyl ester, descrlb~d in ex. 1.

~ 3 ~

,EXAMPLE Z5 .
Preparation of 2-(1-bromoethyl)-2-(5-bromo-6-me-thoxy-2-nQphthyl)-1,3-dioxolane-4(S), 5(S)-dicarboxylic acid dimethyl ester.

By processing ~8 described in ex. 19 the 2-e-thyl-2-~6-methoxy-2-naph-thyl)-1,3-dioxolane-4(S), 5(S)-dicarboxylic acid dimethyl ester (9.35 g;
0.025 moles) the desired mix-ture of diastereoisomers is obtained (identi-fied as 3' and 4') in 93% yield.
The ratio between the diastereoisomers as determined by HPLC is 3':4' = 93:7.
The diastereoisomer 3', that is the prevailing one is the enantiomer of the diastereoisomer 3 described in ex. 6.
H-NMR (CDC13-TMS) (200 MHz) Diastereoisomer 3' (SSR):the data are identical to those of the diastereo-isomer 3 described in ex. 6.
Diastereoisomer 4' (SSS): the data are identical to those of the diastereo-isomer 4 described in ex. 6.
HPLC analysis performed as described in ex. 6.
Diastereoisomer 3': ret0ntion time 18.41 min.
Diastereoisomer 4': retention time 19.33 min.

-Preparation of 2(S)-hydroxy-3(S)-/2-(5-bromo^6-methoxy-2-napthyl)-propanoyl7-butanedioic acid dimethyl ester.

By processing as described in ex. 17, a diastereoisomericmixture of 2~ bromoethyl)-Z-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane~l(S), S(S)-dicarboxylic acid dimethyl ester (compounds 3' and 4' of ex. 25 in ratio 3l:41 = 93.7; 2.66 g; 5.0 mmoles) a mixture of the desired diastereoisomers is obtained (1.98 g; 4.2 mmoles; yield 84.4%) identified as compounds C' and D').
~The ratio determined by H-NMR (ZOO MHz) is C': D' = 85:15 ~-NMR (CDC13-TMS) (200 Ml Iz ) Diastereoisomer C' (SSR): the data are identical to those of diastereoi-somer C described in ex. 9.
Diastereolsomer D' (SSS): the data are identical to t,hose of diastereoi-somer D described in ex. 9.

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

A mixture of diastereoisomers C' and D' prepared according to ex. 26 (ratio Ct D' = 85:15; 1.2 g; 2.56 mmoles), dime-thoxyethane (18 ml), 12 N HCl (18 ml) is kept at 88C under stirring for 1 h.
The reaction mixture is cooled to room tempera-ture and ls then~orked up as described in ex. 10 (b).
The so obtained crude acid i8 eluted through a silica gel column 6eluent hexane: ,dieth,ylether 1:1~.
The 2-(5-bromo-6-methoxy-2-naphthyl) propionic acid is obtained..
M.p. = 146-148C; fc~7578 = ~33.39 (c = 0.5%; CHC13).
This acid is esterified with diazomethane and the obtained methylester analyzed by H-NMR (200 MHz) using an optically active shift agent ~europium (III)-tris/3-(eptafluoropropylhydroxymethylene)-d-camphorate 7 in CDCl3.
The ratio between the enantiomers is R(-):S(+) = 85:15.
The methylester when crysta}lized from methanol and hydrolized with an acid, leads to the R(-)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid in optically pure form.

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

. .

- 47 ~ r~

1-(6-methoxy-2-naphthyl)-propan-1-one (465 g; 2.17 moles), dimethylester of L(-~) tartaric acid (773 g; 4.34 moles) and trimethyl ~thoformate (461 g; 4.3~ mole~) are gradually heated up to complete solutlon.
The solutlon is added with methanesulFhonic acid(15 g; 0.155 moles).
The reaction mixture is kept at 100C ~or 4 hours, distilling off the volatile compoùnds (about 400 g).
It is cooled to 50C and poured slowly under stirring into a 10% aqueous solution of NaHC03 (5 1). It is extracted with CH2C12 and the organic extrac-t is washed with wa-ter and dried 2 4 By evaporating the sol~ent under reduced pressure, a residue , containing the desired product as determined by HPLC analysis (743 g;
yield 91.6%). is obtained.
An analitycally pure produc-t is ob,tained by crystalli~ing from 1.3 1 of methanol (672 g; 1.8 moles ; yield 82.8%).

Preparation ,of the 2-ethyl-2-/4-(2-methylpropyl)-phenyl7-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethylester.

A mixture of 1-/4~(2-methylpropyl)-phenyl7-propan-1-one (110 g; 0.58 moles), dimethyl ester of L(+) tartaric acid (206 g; 1.16 moles) ana trimethyl orthoform:ate (122.7 g; 1.16 moles) is gradually heated up to complete solution (50C). The solution is added with methanesulpha'nic aci~3.9 g;
0.04 moles).
The reaction mixture is heated to 85~C and kept at this temperature for 2 h, then c~oled to room temperature and ,worked up as described in ex. 1.
Ihecn~b product !(210 g) is eluted through a silica gel column (eluent hexane:~diethylether 8:Z) and the desired product is obtained (175.2 g;

0.501 moles; yield 86.5%) having the following charac-teristics:
I.R.~(Neat): 1730-1760 cm (stretching C = 0) H-NMR (CDC13-TMS) (200 MHz) del-ta (ppm): 0 . 84 ( d , 6H , J = 6 . 4 Hz );
0.89 (t, 3~1, J = 7 . 5 HZ ); 1. 8 (-t-~:p-t~ , JCI-I C~-l -64 HZ ~ JCII-CH ~;
1.97 (q, 2~1, J = 7.5 ~Iz);
2.41 (d, 211, J = 7.1 Hz); 3.78 (9, 311); 3.a4 (s, 3H); 4.78 (AB, 2H, 5 J = 5.7 llz); 7-7.4 (AA'BB', "Il, ~romatic protons).

Preparation of dias-tereoisomers of the compound 2-(1-bromoethyl)-2-/4-(2-methylpropyl)-phenyl7-1,3-dioxolane-4(R), 5(R)-dlcarboxylic acid 10 dimethyl ester.

To a solution in 1,2-dichloroethane (70 ml) of 2~ethyl-2-/4-t2-methylpropyl)-phenyl7-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dime-thylester (7.0 g;
20 mmoles obtained according to ex. 29),deoxygenated and added with hydrobromic 15 acid (0.324 g; 4 mmoles), it is added dropwise in 1 h under inert atmosphere at -~15C, a solution of bromine (3.20 g; 20 mmoles) in 1,2-dichloroethane (7.0 ml) previously deoxygenated.
The mixture is kept at 15C for an additional hour and then worl~ed up as described in example 6.
20 The so obtained residue is eluted through a silica gel column (eluent hexane: diethylether 8:2) to give ~ mixture of the desired diastereoi-somers, identified as 11 and 12, in 77% yie~d.~ -The ratio between the compounds 11 and 12 as determined by HPLC is 88:12 H-NMR (CDC13-TMS) (200 MHz):
25 Diastereisomer 11 (E~RS) : delta (ppm): 0.87 (d, 6H, J = 6.4 Hz);
1.61 (d, 3H, J = 7.1 Hz); 1.84 (t-ept, lH, JC~-~ CH- 6.4 I-lZt JCli CH = 7.1 Hz);

2,45 (d, 211, J = 7.1 Hz); 3.53 (s, 3H);
3.84 (8, 3H); 4.38 (q, lH, J = 7.1 Hz) 4.9 (AB, 2H, J - 5.g Hz);
7-7.4 (AA'BB', 4H, aromatiç prP~tOns).
30 ~iastereoisomer }2 (RRR): delta (ppm): 0.87 (d, 6H, J = 6.4 Hz);

~ 3 ~

~1.58 (d, 3H, J = 7.1 Hz); 1.87 ~t-ept, lH, JCI-~ C~l = 6.~ Hz, Cll-CH2 .1 ~I~); 2.53 (d, 2H, J = 7.1 I~
3.6 (s, 3ll); 3.83 (5, 3~l); 4.41 (q, lH, J = 7.1 llz); 4.85 (Aa, 2H, J = 6.5 1l~); 7-7.4 (~A'BB', 411, aromatic protons).
The ilPLC analysis has been performed under the following conditions:
I-lewlett PaCkard instrument mod. 1090 with a variable wavelength UV de-tec-tor (mod. 1040 DAD).
Analytical conditions:
- column BROWNLEE LABS RPS (5 ~) spheri, 250 mm x 4.6 mm (in-ternal diameter) - solvent A: bidis-tilled water - solvent B:, acetonitrile:methanol = 40:60 - flow: 2 ml~min.
- percentage solvent B: 54%
- column -temperature: 50C
- wavelength (~ ): 222 nanometers - injection: 4 ~ of a solution containing 0.5 mg/ml of product in aceton;trile:methanol 40:60 - retention times: diast. 11 = 22.61 min.
diast. 12 = 23.63 min.

Prepara-tion of 2(R)-hydroxy-3(R)- (2-/4-(2-me-thylpropyl)-phenyl /--propanoyl -butanedioic acid dimethyl ester.

Operating under analogous conditions to -those described in Example 17, ~fter work up o~ the reaction mixture, starting from a mixture of diastereoisomers 11 and 12 (3.0 g; 7.0 mmole ) (ratio determined by HPLC, 11:12 = 88:12), with a rea~ontlme of 6 hours at ~28C
the mixture of diastereoisomeric esters indicated herein as I
and J is obtainedO
H-NMR (CDCl3 - TMS) (200 MHz) Diastereoisomer I (RRS): delta (ppm): 0.87 (d, 6H, J=6.4 H~);
1.485 (d, 3H, J=7.1 Hz); 1.8 (t-hept, lH, JCH CH =6.4 Hz, JCH CH =7.1 Hz); Z.42 (d, 2H, J=7.1 Hz); 3.15 (d, lH, J=7.05 Hz);
3.32 (s, 3H); 3.78 (s, 3H); 3.8 (q, lH, J=7.1 Hz); 4.67 (dd, lH, JcH_cH=2.3 Hz~ JCH-oH=7 05 Hz); 5.36 (d, lH, J=2.3 Hz); 7.02-7.16 (AA'BB', 4H, aromatic protons).
Diastereoisomer J (RRR): delta (ppm): 0.87 (d, ~H~ J=6.4 H~);
1.525 (d, 3H, J=7:1 Hz); 1.825 (t-hept, lH, JCH CH =6.4 H~, JCH CH = 7.1 Hz); 2.43 (d, 2H, J=7.1 Hz); 3.15 (d, lH, J=7.05 Hz);
3.62 (s, 3H); 3.69 (s, 3H); 3.82 (q, lH, J=7.1 Hz); 4.73 (dd, lH, JCH CH=2-3 Hz, JCH oH=7 05 Hz); 5.43 (d, lH, J=2.3 Hz); 7,04-7.2 (AA'BB', 4H, aromatic protons).

A E X f~ L~
25 ~ U~ 32 ,.. , f ,~ ~ i Preparakion of 2-/ 4-(2-methylpropyl)-phenyll -propionic acid (Ibuprofen).

Operating in a analogous manner to that described in Example lO(b), crude 2-/ 4-(2-me-thylpropyl)-phenyl~ -propionic acid is obtained from a mixture of dia~tereoisomeric ester 8 I and J, prep~red as 3 ~ 7 described in Example 31 (1.37 g; 3.74 mmoles). Af~er chromatogra-phy on silica gel, the pure acid is ob-tained (0.7 ~) / ~ / D ~19 (C = 1%, 95% ethanol).

Prepara-tion of 2-(1-bromoethyl)-Z-~ 4-(2-methy:Lpropyl)-phényl_/-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid.

A solution of diastereolsomers 11 and 12 (see Example 30)(10.0 g;
0.0233 moles) in methylene chloride (20 ml) is added dropwise to a solu-tion o~ sodium hydroxide ~l.B7 g; 0.0466 moles) in water 25 ml) and methanol (100 ml), kept under stirring at 20C.
The reaction mixture is kept under stirring at this temperature for 1 hour . The solvent is evaporated under reduced pres-sure. The residue is taken up in water (100 ml) and acidified to pH lr with concentrated HCl.
It is extracted with diethyletller(3 x 50 ml). The organic phase is extracted with a 10% sodium bicarbonate solution (3 x 50 ml).
The alkaline solution is acidified to pH 1,with concentrated HCl and extract-ed with diethyle-ther (3 x 50 ml). The combined organic phases are dried over sodium sulpha-te, and the solvent is evaporated under reduced pressure to give the crude product (8.3 g; acidimetric assay 92%; yield 81%).
HPLC analysis of a sample esterified with diazomethane æhows that the ratio of the two diastereosiomers13 and 14 is 87:13.
H-NMR (CDCl3-TMS) delta (ppm) Dia~tereoisomer 13 (RRS): delta (ppm): 0.87 ~d, 6H, J=6.4 Hz);
1.59 (d, 3H, J57.1 Hz); 1.95 (t- ept, lH, JCH CH =6.4 Hz, CH CH =7 Hæ); 2.55 (d, 2H, J=7 Hz); 4.42 (q, lH, J=7.1 Hz);
~o 4.88 ~AB, 2H, J=6.4 Hz~; 7-7.4 (AA'B~f, 4H, aromatic protons~, 8.2 (9, 2H).

- 52 - 1 3i~

Diastereoisomer 14 (RRR): delta (ppm): 0.87 (d, 6H, J=6.4 Hz);
1.5~ (d, 311, J=7.1 ~1z); 1.95 (t- ept, l1-1, JC~1 C~1 = 6.4 11z, JC~1 C11 = 7 11z); 2.55 (d, 211, J=7 1-1~); 4.42 (q, ~H, J=7.l ~1z);
4.8 ( AB, 211, J-.6.4 Hz); 7-7.44 ( AA ' BB ', ~H, aromatlc protons);
8.2 (s, 2H).

EXAM
Preparation of (+)-2~R)-hydroxy-3(R)-J 2(S)(6-methoxy-2-naphthyl)-propanoyl / -butanedioic acid dimethyl ester.
A solution of triethylamine (4.45 g; 0.044 moles) in methylene chloride (lO ml) is added dropwise in -a period of 5 minutes to a mixture of 2(R),3(R)-dihydroxy-butanedioic acid dimethyl ester (L(~)tartaric acid dimethyl ester )(44.5 g; 0.25 moles) and methylene chloride (90 ml), cooled to -10C and kept under s-tirring, followed by -the dropwise addition in a period of 20 minutes of a solution, in mcthylene chloride (25 ml~ of S(~)2-(6-methoxy-2-naphthyl)--propionyl chloride (5.0 g; 0.020 moles) prepared as described in Japanese patent applica tion 57jl45841 (C.A. 98, 72492h).
The reaction mixture is then poured into a 10% sodium bicarbonate so-lution (200 ml), extracted with methylene chloride (lO0 ml), and the organic phase washed with dilute hydrochloric acid and dried over sodium sulphate. The residue (5.5 g~ is obtained by evaporating the solvent under reduced pressure, and is crystallised from a mixture of heptane and diethylether(l:l, 165 ml).
The desired product (diastereoisomer A, see Example 3) (2.75 g) is obtained, having the following characteristics:
I.R. (C=5% in CHC13) 1750 cm / ~ / D = ~73 7 (C=1%, CHCl3) M.P.= 77-79C

- 53 - ~ d~ r~

H-NMR (CDC13 TMS) (200 Ml-lz): delta (ppm): 1.58 (d, 3H, J=7.4 Hz);
3.07 (s, 311); 3.31 (d, lH, J=7.4 Hz); 3.79 (s, 3~l); 3.87 ~s, 3H);
3 96 (q 1~l J=7.4 Hz); 4.66 (dd, ~ Jc~l-ctl=2 3 ~ ' Cfl-OH
5.37 (d, lH, J=2.3 ~Iz); 7-7.8 (61-1, aromatic system).
A solution of bromine (0.410 g; 2.56 mmoles) in 1,2-dichloroethane (3 ml) is added in 15 minu-tes -to a solution of the ester thus ob-tained in 1,2 dichloroethane (10 ml), cooled to 0C.
The reaction mixture is kept at 0C for 1 hour, and is -then poured into a 10% sodium bicarbonate solution (10 ml) and extracted with me-thylene chloride (10 ml).
The comb~ed or~c phases are washed with wat~r (20 ml x 2), dried over sodium sulphate, and the solvent evaporated under reduced pres-sure.
The residue (1.14 g) is crystallized from methanol. (+)-2(R)-hydroxy-3(R)~2-(S)-(5-bromo-6-methoxy-2-naphthyl)-propanoyl ~butanedioic acid dimethyl ester is obtained (0.889 g; 1.9 mmoles; yield 74%); M.P.
124-126~C; / ~ / D = ~61.4 (C = 1%; CHC13).
The chemical-physical data (M.P., / ~ ~ D and H-NMR-200 MHz) are equal to those of the diastereoisomer ester C described in Exam-ple 9. When treated with palladium-on-carbon and hydro~en at atmo-spheric pressure and room -temperature in the presence of triethyl-amine, the product produces the diastereoisomer A.

Preparatio~ 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)-di-carboxylic acid.

A solution of bromine (171 g; 1.68 moles) in carbon tetrachloride (360 ml) is added dropwise in 1 hour to a solution of 2-ethyl-2-(6~me-thoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid di-methyl ester (200 g; 0.534 moles) in carbon -tetractlloride (2000 ml) kept under an inert atmosphere at 0C.

- 54 ~ 8~

The reac-tion mixture is kept at O~C for 2 hours, and worked as described in Example 6.
The crude product-thus ob-tained (351 g) is dissolved in methanol (2000 ml), and a solution of sodlum hydroxide (38.4 g; 0.96 moles) in water (384 ml) is added dropwise to the resultant solution at am-bient temperature in 1 hour. The reaction mixture i8 kep-t at ambient -temperature under stirring for 20 hours . The methanol is evaporated under vacuum, maintaining -the initial volume of the solution by adding water.
The pH of the aqueous solution obtained is adjusted to 7 wi-th dilute hydrochloric abid. The solution is then extrac-ted with methylene chlo-ride and the aqueous solution is acidified with concentrated HCl to pH 1.
It is extracted with diethylether(3 x 250 ml) and the combined organic phases are washed with water and dried over sodium sulphate. The sol-vent is evapora-ted under vacuum to give a residue that is crystalli-sed from methylene chloride.
A mixture of the two diastereoisomers 7 and 8 of 2-(1-bromoethyl~-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid is obtained (205 g; 0.407 moles; yield 76%) in the ratio of 7:8 = 94:6.

A mixture of the two diastereoisomers 3 and 4 of 2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic aci~ dimethyl ester in the ratio 3:4 = 9:1 (1 g; 1.87 mmoles), zinc bromide (0.84 g; 3.75 mmoles) and 1,2-dichloroethane (12 ml) is heated at reflux (83C),under stirring~ and under nitrogen,for 66 hours.
The reaction mixture is cooled to ambient temperature, and water (5 ml) is added. The phase are separated and the organic phase is dried over 80dium sulphate.

- 55 - ~3~

The solvent i5 evaporated under vacuum to giv~ a residue (0.9 g) to which dioxane (10 ml) and concentrated HCl (~ ml) are add~d. The mixture is heated to 70C under,stirring, for 2 hours, is then diluted with water (10 ml) and extracted with diethyle-ther (3 x 20 ml).

The combined organic ex-trac-ts are washed with water and dried over so-dium sulphate. Evaporatlon of the solvent under vacuwn give5 a re~idue which by chromatography on silica gel (eluent hexane:ethyl ether =
7:3) gives 2-(5-bromo-ô-methoxy-2-naphthyl)-propionic acid (0.28 g;
0.9 mmoles; yield 48%);

M.P. 166-167C
2~
/ ~/ D = +15^44 (C=0.5, CHC13).
The ratio of the enantiomeric acids S(+)/R(-) is 65:35.

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

A mixture of pure 2-(1-(S)-bromoethyl)-2-(5-bromo-6-methoxy-2-naph-thyl)-1,3-dioxolane-4(R),5(R)~dicarboxylic acid dimethyl ester (1.03 g, 1.93 mmol), silver trifluoromethanesulfonate (0.6 g, 2.31 mmol) and methanol (5 ml) i5 heated at reflux for 7 hours. The reaction mixture -is cooled at room temperat~re, filtered, poured into water, and extrac-ted with dichloromethane. The combined organic extracts are ~ashed with water, dried (Na2S04), and-filtered.
Evaporation of the solvent under reduced pressure gives the optically pure 2-(S)-(5-bromo-6-methoxy-2~naphthyl)-propionic acid methyl eæter.
M.P. 94-95C
L ~ - / D ~ + 52(c=0.5, CHCl3) The product is found to be optically pure by H-NMR (200 MHz) analy-sys, carried out in CDCl3 using an optically activc shif-ting agent (Europium (III) Tris-~ 3-(eptafluoropropylhydroxyme-thylen~)-d-aampho-rate.1 ~6 - 3 ~

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

~romine (0.32 g; 2 mmol) is added dropwise, in 5 minutes at 15C
and under argon, to a suspension of 2-eth~1-2--(6-methoxy-2-naph-thyl)-l,3-dioxolane-4(R),5~R)-dicarboxylic acid (0.346 g, 1 mmol).
The reaction mixture is heated at 40~C and kept at 40C for 12 hours;
then it is poured into a 10% aqueous solution of sodium bicarbonate and extracted with diethylether. The aqueous phase is acidified to pH = 1 with conc. HCl and extracted with diethylether. The combined organic extracts are washed with water, dried (Na2S04), and filte-red. Evaporation of the solvent under reduced pressure gives a react-ion crude which, after purification leads to a diastereOisomeric mixture of 2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid in ratio 7:8 = 81:19 (deter-mined by H-NMR).
H-NMR (90 MHz, Acetone-d6-TMS) ~ (ppm):
Diastereoisomer 7 (RRS):
1.70 ~3H, d, J=6.8 Hz); 4.03 (3H,s); 4.66 (lH, q, J-6.8 Hz);
4.95 (2H, A~q,4 ~ = 15.31, J=6.9 Hz); 7.45-8.18 (5H, m).
Diastereoisomer 8 (RRR):
1.70 (3H, d, J=6.8 Hz3; 4.03 (3H, s); 4.66 (lH, q, J=6.8 Hz);
4.95 (2H, ABq,A~=14.46, J=6.6 Hz); 7.45-8,18 (5H, m).
The diastereoisomeric ratio is confirmed analyzing by H-NMR and HPLC the product obtained by esterificatibn with diazomethane.

- 57 _ EXAMPLE 3g 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 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester (0.935 ~, 2.5 mmol) and of iodine monochloride (0.81 g, 5 mmol) in dichloromethane (5 ml) is kept under nitrogen and at 15~C for 24 hours. The reaction mixture is poured into a 10% aqueous solution of sodium bicarbonate, ancl extracted with additional dichloromethane. The combined organic extracts are ~ashed with a 5% aqueous solution of sodium thiosulphate, with water, dried (Na2S04), filtered, and concentrated in vacuo.
Purification of the residue by column chromatography (silical gel, eluent hexane:diethyl ether = 7:3) gives the diastereoisomeric mixture of 2-(1- iod~ethyl)-2-(6-methoxy 2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 15 and 16 in ratio l5:16=
60:40 (determined by H-NMR).
H-NMR (200 MHz, CDC13-TMS) ~ (ppm):
Diastereoisomer 15 (RRS) 1.80 (3H, d, J-7 Hz); 3.44 t3H, s1; 3.84 (3H, s); 3.90 (3H, s);
4.58 (lH, q, J=7 Hz); 4.95 (2H, ABq,4 ~ = 20.70, J=6 Hz); 7.8-3.0 (6H, m).
Diastereoisomer 16 (RRR) 1.80 (3H, d, J=7 Hz); 3.58 (3H, 8); 3.84 ~3H, s); 3.90 (3H, s);
4.58 (lH, q, J=7 Hz); 4.87 (2H, ABq,~ ~=46.04, J=6.8 Hz); 7.8-8.0 (6H, m).

~ - 58 ~3~3~ ~-7 EX~MPL,E 40 Preparation of 2-(6-methoxy-2-naphthyl)-propionic acid from a diastereoisomeric mixture of 2-(1-iodoethyl)-2-(6-methoxy-2-naphtyl)--1,3-dioxolane-4(~),5(R)-dicarboxylic acid dlmethyl es-ter.

Silver trif]uoromethanesulfonate (1.2 g, 4.8 rnmol) is added, under argon and stirring, at 15C to solution of a diastereoisomeric mixture of 2-(1-iodoethyl)-2-(6-me-thoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester in ratio 60:40 (1.~ g, 3.2 mmol) in 1,2-dichloroethane (20 ml). The reaction mixture is kept in the dark at 15C for 3 hours; then it is filtered, poured into water. The organic layer is separated, washed with water, dried (Na2S04), filtered and concentrated in vacuo.
The residue is dissolved into dioxane (5 ml) and conc. HCl (5 ml) is added. The mixture is heated at 70C for 2 hours coolsd at room temperature, poured into water, and extracted with die-thyl ether.
The combined organic extracts are washed with water and back-extracted with a 2% aqueous solution of sodium bicarbonate. The aqueous phase is acidified with conc. HCl and extracted with diethyl ether. The combined organic extracts are washed with water, dried (Na2S04), filtered. Evaporation of the solvent under reduced pressure gives the 2-(6-methoxy-2-naphthyl)-propionic acid.
M.p. = 154-155C.
/ ~ 7D = -~ 6.02 (c = 1,CHC13) HPLC analysis, carried out as described in J. Pharm. Sci. 68, 112 (1979) and H-NMR (200 MH~) analysis carried out on the methyl ester in CDCl3 using an optically active shifting agent (Europium (III) Tris-/3(eptafluoropropylhydroxymethylen)-d-camphorate7) shows an enantiomeric ratio S(+) : R(-) = 55 : 45.

_ 59 _ ~ 3 ~

EXAMPI.E 41 Preparation of 2-ethyl-2-(6-hydroxy-Z-naphtyl)-1,3-~dioxolane-4(R),5~R)-dicarboxylic acid dimethyl ester.

A mixture of 1-(6-hydroxy-2-naphtyl)-propan-1-one (Z5 g, 0.125 mol), 2(R), 3(R)-dihydroxyb~ltalledioic acid dlmetyl este~ (178 g, 1 mol), trimethyl orthoformate (54 g, 0.51 mol), and of methane~ulphonic acid (0.84 g, 0.08a mol) is heated, under argon and under stirring, at 70C for 4 hours.
The reaction mixture is cooled at room temperature, poured into a 10% aqueous solution of sodium carbonate (409 ml), and extracted with diethylether ~4 x 50 ml). The combined organic extracts are washed with water (3 x 150 ml?, dried (Na2S04), filtered, and concentrated in vacuo.
Purification of the crude by column chromatography (silica gel,eluent hexane : diethyl~ther = 1 : 1) gives the pure 2-ethyl-2-~6-hydroxy--2-naphtyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethylester (17 g) as an oil.
H-NMR(90 MHz, CDC13-TMS) ~tppm):
1.93 (3H, t, J = 6.5 Hz); 2,10 (2H, q, J = 6.5 Hz); 3.43 ~3H, s);
3.80 (3H, s); 4.83 (2H,ABq,a~ = 6.7, J = 6 Hz); 6.00 (lH, s, OH);
7.07-7.85 (6H, m).

Preparation of the diastereoisomeric mixture of 2-(1-bromoethyl)-2--(5-bromo-6-hydroxy-2-naphthylj-1,3-dioxolane-4(R),5~R)-dlcarboxylic acid dimethyl ester.

A solution of bromine (5.12 g, 32 mmol) in carbon tetrachloride (5 ml) is added dropwise in 10 minutes, under argon and at 15C, to a solution of 2-ethyl-2-(6-hydroxy-2-naphthyl)-1,3-dioxolan~-4(R),5(R)--~ - 60 -:L 3 ~

dicarboxylic acid dimethyl ester (6 g, 16 mmol) in carbon tetrachloride (60 ml). The reaction mixture is kept at 15C for 2 hours and poured into a 5% aqueous solution of sodium thiosulfate (200 ml).
The org~nlc layer is separated, washed with water, dried (Na2S04), filtered, and concentrated in vacuo.
Purification of the reaction crude by column chromato~raphy (silica .
gel, hexane : diethyl ether = 1 : 1) gives a diastereoisomeric mixture of 2~ bromoethyl)~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 diaster~oisomers 17 : 18 = 90 : 10 (determined by H-NMR and HPLC).
m.p. 116-117C.
H-N~R(200MHz, CDC13TMS) ~ (ppm):
diastereoisomer 17 (RRS) 1.66 (3H, d, J = 7 Hz); 3.52 (3H, s); 3.88 (3H, s); 4.48 (lH, q, J=7 H~):4.96 (2H, ABq,a ~ = 27.80, J =6.1 Hz); 7.2-8.0 (5H, m).
diastereoisomer 18 (RRR)-1.6Z (3H, d, J = 7 Hz); 3.56 (3H, s); 3.87 (3H, s); 4.48 (lH, q, J = 7 Hz); 4.90 (2H, ABq,~ 35.44, J=6.3 Hz); 7.2-8.0 (5H, m).
Tbe diastereoisomeric ratio 17 (RRS) : 18 (RRR) = 90 : 10 is confirmed by converting the product in the diastereoisomeric mixture of 2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2~napnthy~-1,3-dioxolane-4(R),5(R)--dicarbox~lic acid dimethyl ester 3 and 4 following the present procedure:
a mixture of the product (0.52 g, 1 mmol), potassium carbonate (1.38 g, 10 mmol), me-thyl iodide (0.426 g, 3 mmol), and of acetone (10 ml) iS
kept under stirring at room -temperature for 4 hours.
The reaction mixutre si fil-tered and concentrated in vacuo. The residue, so obtained, is a diastereoisomeric mixture of 2~(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dlcarboxyllc acid - 61 - 1 3 3 ~

dimethyl e~ter in ratio 3 (RRS):4(RRR~ = 90 : 10 (determined by H-NMIl and HPLC).

EX~MPL~ 43 Preparation of 2-(5-bromo-6-hydroxy-2-naph-thyl)-propionic acid.

A mixture of the dias-tereoisomers 17 and 18 in the ratio 90:10 (see Example 42) (0.57 g; 11 mmoles), sodium hydroxide (0.132 g; 33 mmoles) and water (20 ml~ is heated to 60~C for 2 hours. The reaction mixtu-re is cooled to room temperature, acidified to pH 1 ~ith concen-trated HCl and extracted with diethylether.
The combined organic phases are washed with water, dried over sodium sulphate and concentrated under vacuum. The residuè thus obtained $s purified by chromatography on silica gel, to give pure 2-(5-bromo-6-hydroxy-2~naphthyl)-propionic acid.
On the basis of H-NMR analysis as described in Example 4, the ratio of the S to R enantiomer is 90:10.

Preparation of 2-(1-bromoethyl)-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 moles), water (52 ml), methanol (30 ml) and an aqueous 10% (w/v) sodium hydroxyde ~olution (11.5 ml) is kept under s~irring at room temperature for 6 hours.
The reaction mixture is then acidified with concentrated ~ICl to pH 1 and extracted with diethylether. The combined organic extracts are washed with .
wa-ter and dried over sodium sulphate.
Evaporation of the solvent under vacuum gives the diastereoisomers 19 and 20 (4.8 g; 0.0098 moles; yield 90%) in the ratio 19:20 = 92:8 6 2 ~ ~ 5 H-NMR (90 MHz., CDCl3-TMS~ S (ppm) Diastereoisomer 19 (RRS):
1.66 (d, 3M, J= 7 ~3z); 4.63 (q, 11-1, J=7 Hz); 4.93 (2H~ ABq,a ~ =16.42, J=6.5 Hz); 7.23-8.15 (m, 511); 8.27 (1l1, broad) Preparation of 2-(5-bromo-6-hydroxy-2-naphthyl~-propionic acid A mixture of the diastereoisomers 2-(1-bromoethyl)-2-(5-bromo-6-hydroxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 19 and 20 (1.76 g; 3.6 mmoles) in the ratio 19:20 = 92:8 (s~e Example 44), sodium bicarbonate (2.4 g; 2~ mmoles) and water (50 ml) is heated under reflux, under stirring , for 4 hours. The reaction mixture, cooled to ambient temperature, is acidified to pH l with 6 N HCl and extracted with diethylether. The combined organic phases are washed with water and dried over sodium sulphate, Evaporating the solvent under vacuum gives a crude product to which dimethoxyethane (17 ml) and 12 N HCl (17 ml) are added. The reaction mixture is heatad under reflux, under stirring for 2 hours, cooled and extracted with diethyl-ether.:The combined organic phases are washed with water and dried over sodium sulphate. Evaporation of the solvent under vacuum gi~es a residue which is chromatographed over silica gel (eluent diethylether-hexane 7:3). In this manner the pure acid is obtained /c~7D = ~42.3 (C_l in acetone). A samples is esterified with diazomethane. The me-thyl ester is analysed by H-NMR (200 MHz) using an opti-cally active shift agent. The ratio of the enantiomeric acids (~)S/(-)~ is 98:2.

A solution of silver tetrafluoroborats (0.6 g; 3.08 mmoles) in l,2-dichloroethane t4 ml) is added dropwise to a mixture of 2-(1-bromo-ethyl)-2-(5-bromo-6-methoxy-2-rlaphthyl)-1,3-dioxolarle-4(R),5(~)-- 63 - ~ 3 ~

-dicarboxylic acid dime-thyl ester (dias-tereoisomer 3 : diastereoiso-mer 4 = 94:6, ratio determined by HPLC) (1.33 g; 2.5 mmoles) and 1,2-dichloroethane (10 mL) kept under stirring at ~15~C.
After 73 hours the reac-tion mixture is poured into water (20 ml) and filtered through celite, -the filtrate beix~g washed ~rith methylene chloride (10 ml~.
The organic phase is washed with wa-ter (2 x 20 ml) and dried over sodium sulphate.
Evaporation of the solvent under reduced pressure gives a residue (0.95 g) in which -the diastereoisomers C and D of the ester are pre-sent in the ratio C:D = 79:21, determined by H-NMR analysis at 60 MHz.
In an analogous test carried out in parallel, in which water (0.1 g;
6 mmoles) was added to the reaction mixture before adding the sodium tetrafluoroborate, the ratio of the diastereoisomers,after 73 hours.
is C:D = 94:6;

Preparation of 1-(4-chlorophenyl)-3-methyl-butan-1-one 3-methyl-butyrryl chloride (12~3.6 g; 1.07 moles) is added in lS
minutes to a suspension of aluminum chloride (153.8 g; 1.15 moles) in methylene chloride (200 ml) cooled to -5C and kept under stirring ~in an inert atmosphere.
At the end oP the addition, the mixture is heated to +20C
ahd chloroben~ene (100 g; 0.89 moles) is added in 15 ~inutes. The reaction mixture is heated to +45C for 7 hours, then cooled to ambiente temperature and poured under stirring. into concentrated HC1 (200 ml) and ice (1500 g).
The aqueous phase is extracted with me-thylene chloride (3 x 300 ml).
The organic extracts are washed with a 1% sodium hydroxide solution ~ - 64 - ~ 3 ~

(3 x 700 ml) and with water (3 x 700 ml~.
After drying over sodium sulphate, the organic solvent is evaporated under reduced pressure to give a residue (161 g) which, after crystal-lization from n~hexane (100 ml) provides 1-(4-c:hlorophenyl)-3-methyl-bu-tan-l-one (121.5 g; 0.62 moles; yield 69.4%).
M.P. = 39-40 I.R. (Nu~ol) = 1680-1700 cm (stretching c=o) H-NMR ~CDCl3-TMS) (90 MHz): ~ (ppm):
0.97 (d, 6H, J=6,7 Hz); 2.27 (m, lH, JC~ CH = 6.7 Hz); 2.77 (~art AB of an ABX system, 2H~; 7.3-7.9 (AA~BB~, 4H aromatic protons) .
Preparation of 2-(4-chlorophenyl)-2-(2-methylpropyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester.
A mixture of 1-(4-chlorophenyl)-3-methyl-butan-1-one (40.0 g; 0.204 moles), 2(R),3(R)-dihydroxy-butanedioic acid dimethyl ester (72.4 g;
0.407 moles) and trimethyl orthoformate (43.1 g; 0.406 moles) is heated gradually untill a complete solution (60DC~. ~ethanesulphonic acid (1.4 g; 0.015 moles) is added to the solution, which is then heated to 75~C.
After a reaction time of 3 hours, the mixture is cooled to ambient temperature a~d poured into a 10% sodium bicarbonate solution (250 ml) under vigorous stirring. The aqueous phase is extracted with methylene chloride (2 x 250 ml) and the o~ganic extracts washed with water (Z x 400 ml). After drying the organic phase over sodium sul-phase, the solvent is evaporated under reduced pressure.
The residue obtained (68.7 g) is chromatographed ov0r silica gel (eluent hexane:diethylether _ 8:2).
2-(4-chlorophenyl)-2-(2-methylpropyl)-1,3-dioxolane-4(R),5(~)-dicarboxylic acid dimethyl ester (41 g; 0.115 moles; yield 56,4%) i9 obtained.

~ 3 ~ 7 li M.P. = 40C
/ ~ / = +21.6 (c = 1%; C~IC13) I.R. (Nujol) = 1770-1740 cm (stretching c=0) H-NMR (200 Ml-l~) (CDC13-TMS): S (ppm):
0.87 (d, 6H, J=6.9 llz); 1.67 (m, lfl, JCI~ C~l = 6-9 ~Iz); 1-86 (part AB of an A~X system, 2ll); 3.55 (8, 3H); 3.8~ (s, 3H);~4.7a (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 es-ter.

A solution of bromine (8.06 g; 0.05 moles~ in 1,2--dichloroethane (18 ml) is added in 1 hour and 15 minutes to a solution of 2-(4-chlorophenyl)-2-(2-methylpropyl)-1,3-dioxolane-4(R),5~R)-dicarboxylic acid dimethyl ester (18.0 g; 0.05 moles) in 1,2-dichLoroethane (180 ml~, to which methanesulphonic acid (3.6 g;
0.038 moles) had been previously added, the reaction mixture being kept under stirring in an inert atmosphere at +15~C. After 1 hours at 15C, the mixture is poured into a 10% sodium carbonate solution (400 ml) under vigorous stirring. and extracted with methy- .
lene chloride (2 x 250 ml).
The organic phase is washed with water (2 x 400 ml) and dried over sodium sulphate.
After evaporating the solvent under reduced pressure, a residue (20.5 g) is obtained which contains the two diastereoisomers of the 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, ln the ratio 21:22 = 97:3 (ratio determined by H-NMR (300 MHz) analysis and Confirmed by HPLC analysis).

- 66 - ~ 7 By crystallization from n-hexane (60 ml), the diastereoisomer 21 is obtained (13.6 g; 0.031 moles; yield 62.5%), and is found to be pure on H-NMR analysis (300 Milz).
H-NMR (300 MHz ) ( CDC13-TMS ) Diastereoisomer 21 (RRS):
0.93 (d, 31-l, J_6.9 Hz); 0.98 (d, 3H, J=6.6 ll~); 1.70 (m, 1~l, CH-CH H~, JCH-C~ =6-6 Hz~ Jc~l_cH =6 9 Hz); 3.59 (s, 3~); 3.85 (s, 3H), 4.28 (d, 1l~, 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 performed under the following conditions:
Hewlet-t Packard instrument mod. 1090 with U.V. variable waveleng-th U.V. detector.(mod. 1040 DAD).
Analytical conditions:
- Brownlee column LABS RP 8 (5 ~ )balls; 250 ml x 4.6 mm (inner diameter) - Solvent A: bidls-tilled water - Solvent B: methanol - Flow: 1.7 ml/min - Percentage solvent B: 63%
~ Column temperature: 40C
- Wavelength ( ~ ~: 230 nanometer - Injection 5 ~ of a solution containing 0.5 mg~ml of product in me-thanol - Retention times:
Diastereoisomer 21 = 11.71 minutes Diastereoisomer 22 = 12.85 minutes ~.~ 3 ~ . 7 Example 50 Preparation of 2(R)-hydroxy-3(R)-l2(S)-(4-chlorophenyl)-3-methylbut anoy~7-butane oic acid dime-thyl ester A solution of silver tetrafluoroborate (1.6 g, 8.2 mmol) in 1,2-dichloroethane (15 ml) was added in 20 minutes to a mixture of 2-(1-bromo--2-methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R),5( R)-dicarboxylic acid dimethyl ester (diastereoisomer 21) (3 g, 6.9 mmol), w~ter (0.2 g)and of 1,2-dichloroethane (18 ml) at 20~C. The reaction mixture was heated at 50C for 7 hours, ccoled at 20C
and poured in water (50 ml). The mixture was filtered on celite and the precipitate washed with dichloromethane (30 ml).
The organic phase was separeted, washed with ~ater~ dried over sodiu~ sulfate, and concentrated in vacuo. Purification of the reaction crude (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-methylbutanoy~-bu-ta-nedioic acid dimethyl ester K (1.95 g, 5.2 mmol; yield 75.9%).
H-NMR (300 MHz, CDCl3-TMS) delta (ppm):
Cll-C~I 6.9 Hz); 1.06(d, 3H, J=6.2 Hz), 2.33(m lH

JCH Cll=10-6 ~Iz~ JCI~ C~l -6-9 Hz~ JC~ Cll =6.2 Hz); 3.22(d, 1~l, JCH C~l =6.9S Hz); 3.24(d, lH, J=10.6 Hz); 3~30(s, 3H); 3.77(s, 3H); 4.63(dd~ lH~ JCH CH=2 6 ~Iz); 5.36(d~ lH~ J =2.6 Hz);
7.21-7.23(AA'88', 4H, aromatic protons).

pl~

-- 68 _ Example 51 Prepara-tion of 2(R)-hydroxy-3(R)-L2(S)-(4-chlorophen~1)-3-methyl-bu~tanoyl~-butandioic acid.

A mixture of 2(R)-hydroxy--3(R)-~ (S)-(4-chlorophenyl)-3-methylbu-tanoyl/-butanedioic acid dimethyl ester (dias-tereoisomer K) (1 g, 2~6 mmol), 1,2-dimethoxyethane tl3-3 ml) and of conc HCl (18.3 ml) was heated, under stirring, at 70C for 1 hour. THe reaction mixture was cooled at room temperature, poured into water (50 ml) and extracted with dichloromethane (2 x 50 ml). The organic phase was extracted with a 10% aqueous solution of sodium bicarbonate (4 x 50 ml). The aqueous phase was acidified with conc HCl to pH
and extracted with dichloromethane (3 x 50 ml). The combined organic phase was washed with water, anhydrified over sodium sulfate, filtered, and concentrated in vacuo.
Crystallization of the residue (0.8 g) gave the pure 2~R)-hydroxy-3(R)-~2(S)-(4-chlorophenyl)-3-methylbutanoyl/-butanedioic acid ~0.4 g) (diastereisomer L).
bl.p. = 173-175C
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, lH, CH-CH3 6 Hz~ JCH-CH =6-5 Hz~ JcH_c~-~=10 4 Hz); 3.16(d, lH, J=10.4 Hz); 4.65(d, lH, JC~ C~l~2.1 Hz); 5.33(d, lH, J=2-1 llz);
7.00-7.27(AA'BB', 4H, aromatic protons).

1 _ 69 H-NMR analysis carried ou-t on the corresponding dirnethyl ester, obtained by reactlon with dia~omethane, showed only the presence the diastereoisomer K (~RS).
Example 52 Preparation of (~)-2(S?-(4-chlorophenyl)-3-methvlbutanoic acid.
A mixture of the diastereoisomer K (0.9 g, 2.3 mmol), 1,4-dioxane ~ (16 ml) and of conc HCl (16 ml) was heated, under stirring, at 90C for 18 hours~ The reaction mixture was cooled at room temperature, diluted with water (30 ml), . and extracted with dichloromethane ~3 x 20 ml~). The organic phase was extracted with a 10% aqueous solu-tion of sodium bicarbonate (5 x 10 ml). The aqueous phase was acidified with conc HCl to pH 1 and extracted with dichloromethane (5 x 10 ml). The combined organic phase was washed with water, dried . ~ over sodium sulfate, and con-centrated in vacuo.
Purification of the reaction crude (0.25 g) by column chroma-tography (silica gel; eluente hexane:di~thylether= 80:20) gave pure 2(S)-(4-chlorophenyl)-3-methylbutanoic acid (0.2 g).
/ ~ /D =~38.6 (c=1%, chloroform) Example 53 Preparation of 2-(l(S)-bromo-2-meth lpropyl?-2-(4-chlorophenyl)-1,3 , . ~ . . Y
-dioxolane-4(R),5(R)-dicarboxylic acid _ 70 _ A solution of the diastercoisomer 21 (10 g, 23 mmol) in dichlometha-ne (lO ml)was added dropwise in 15 minute3 at 20C to a solution of sodium hydroxyde (2 g, 50.6 mmol) in water (25 ml) and methanol (100 ml). The reaction mixture wa~ kept at 20C for 1 hour and the solvent removed under reduced pressure. Water (100 ml) was added. The solution, so obtained, was acidified with conc HCl -to pH 1 and extracted with diethyle-ther (3 x 75 ml). The organic phase was extracted with a l~fi aqueous solution of sodium bicarbonate (3 x 75 ml). The aqueous phase was acidified with conc HCl to pH 1 and extracted with diethylether (3 x 75 ml). The combined organic extracts were washed with water and anhydrified over sodium sul~ate. Evaporation of the solvent under reduced pressure gave the Z-(l(S)-bromo-2-methylpropyl)-2-(4-chlorophenyl) -1,3-dioxolane-4(R),5(R)-dicarboxylic acid (diastereoisomer 23) (7.2 g,l9.8 mmol; yield 86%).
H-NMR (300 MHz, CDCl3-TMS) delta tppm): diastereoisomer 23(RRS) 0.92(d, 3H, J=6.6 Hz); 0.98(d, 3H, J=6.2 Hz); 1.58(m, lH, CH-CH Hz~ JcH-cH =~-6 Hz~ JCH CH =6-2 Hz); 4-37(d, lH, J=1.8 Hz); 4.86(ABq, 2H, ~=6.2 Hz); 7.36-7.46(AA'BB', 4H, aromatic protons).
The presence of one diastereoisomer was con~irmed by HPLC analysis carried out on a sample o~ the corresponding dimethyl ester (diastereoisomer 21) obtained by reaction with diazomethane.
Example 54 Preparation of 2-ethyl-2-(6-methoxy-2-naehthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid N,N!N',N'-tetraethyl amide.

~3~g~7 _ 71 -A mixture of 2-ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(~), 5(R)-dicarboxylic acid dimethyl ester (9.36 g, 25 mmol), diethylamine (25 ml) and of water (20 ml)was kept, under stirring, at room temperature for 15 hours. The solvents were removed by evaporation.a-t room temperature under reduced pressure.
Diethylether (50 ml) was added to the residue and the mixture was refluxed for 1 hour; then it was cooled at 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)-dicarboxyl ic acid N,N,N',N'-tetraethyl amide (11 g, 24 mmol; yield 96%) was so obtained.
M.p.=108-112C
H-NMR 1200 MHz, CDCl3-TMS) delta (ppm): 0.83(t, 3H, J=7 Hz);
l.ll(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, ~ ~ =17.8, J=8 Hz); 6.9-7.8(6H, aromatlc protons).
IR (Nujol): 1605, 1630 (stretching C=0) Exarnple 55 Preparation of 2-(1-bromoethy1)-2~(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5~R_-dicarbox~lic acid N,N,NI,N'-tetraethyl amlde.

~1 3 ~

A mixture of the two diastereoisomers of 2~ bromoethyl)--2-(S-bromo-6-methoxy-2-naphtllyl)-1,3-dioxolane-4(R),5(R)-dicarboxy lic acid dime-thyl ester 3 and 4 in ratio 3:4=9:1 (6.65 g, 12.5 mmol), diethylamine (27.5 ml) and of water (20 ml) ~as kept, under s-tirring, a-t room temperature for 15 hours. The solvents were removed under reduced pressure. Diethylether (50 ml) was added to the residue~ The insoluble was filtered, washed with diethylether, and dried under reduced pressure. The diaste-reoisomeric mixture of 2-(1-bromoethyl)-2-(5-bromo-6--methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarbaxylic acid N,N,N',N'-tetraethyl amide 24 and 25 (6.75 g, 11 mmol; yield 88%), in ratio 24:25=9:1 (determined by H-NMR, 200 MHz) H-NMR (200 MH~, CDCl3-TMS) delta (ppm) :
diastereoisomer 24 ~RRS): 1.06(t, 12H, J=7 ~z); 1.69(d, 3H, J=7 Hz); 2.76(q, 8H, J=8 Hz); 4.00(s, 3H); 4.55(2H, ABq, ~ ~ =35.1, J=8 Hz); 4.54(q, 2H, J=7 Hz); 7.2-8.2(5H, aromatic p~otons).
Example 56 Preparation of ?- (l-bromoethyl)-2-(5-bromo-6~methoxy-Z-naphthyl)-1,3-dioxolane-4(R),S(R)-dicarboxylic acid disodium salt.
A mixture of the two diastereoisomers of 2-(1-bromoethyl)--2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxy lic acid dimethyl es-ter 3 and 4 in ratio 3.4=9:1 (6.65 g, 12.5 mmol~, sodium hydroxyde (1 g, 25 mmol), dimethoxyethane (10 ml), and of water (10 ml) was kept, under stirring, at room temperature for 2 hours. The reaction mixture was diluted wi-th ~a-ter and ex-tracted with diethylether. The aqueous phase was concentrated under reduced pressure to give the diastereoisom~ric mix-ture of 2-(1-bromoethyl)-2-(5-bromo-6-me-thoxy-2-naphthyl)--1,3-dioxolane-4(R),5tR)-dicarboxylic acid disodium salt 26 and 27 (11.5 mmol; yield 92%) in ratio 26:27=9:1 (de-termined by H-NMR
200 MHz).
Example S7 Preparation of (~)-2(S)-(5-br ~ -2-naphthyl)-propio iC
acid from a diastereoisomeric mixture o~ 2-(1-bromo_hyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 7 and 8 in ratio 7:8=93:7 . _ . . _ A mix-ture of the t~lo diastereoisomers of 2-(1-bromoethyl)--2-(5-bromo-6-methoxy-2-naphtyl)-1,3-dioxolane-4(R),5(R)-dicarboxyl ic acid 7 and 8 in ratio 7:8=93:7 (9.3 g, 18.45 mmol) and of an aqueous solution (110 ml) prepared by dissolving K2HP04 ~26.1 g) and KH2P04 (5.7 g) in water ~384 ml) ~as heated, under stirring, at 100C for 21 hours. The reaction mixture was cooled at room temperature (pH 4.2), acidlfied with conc HCl to pH 1, and extracted with diethylether (3 x 100 ml). The combined organic extracts were washed with water and dried - over sodium sulfate. Evaporation of the solvent under reduced pressure gave a residue that on the basis of the GLC analysis carried out on a sample treated with diazomethane was constituted of 2-(5-bro-mo-6-methoxy-2-naphthyl)-propionic acid (4.33 g, 14.02 mmol; yie~
76%) and of the starting diastereoisomer 7 (1.3 g).
Purification by column chromatography of the reaction crude (sllica gel; eluent hexane: diethylether = 7:3) gave the pure (*)-2(S)-(5-bromo-6-methoxy-2-naphthyl)~propionic acid (4.22 g, 13~66 mmol; yield 74%) in 97% enantiomeric excess.
M.p. =168-170C
/ ~ 7D =~40.8 (c=0.5%, chloroform) ~ i 3 _ 74_ HPLC analysis, carried out as described in J.Pharm.Sci. 68, 112 (1979), showed ~n en~n-tiomeric ratio S(+):R(-)=98.5:1.5.
The er~antiomeric ratio was confirmed by H-NMR 200 MHz analysis carried out in CDC13 using an optically active shifting agent (europium (III) tris-L3-(eptafluoropropylhydroxymethylene)--d-camphorate~) on the corresponding me-thyl ester obtanined by treating a sample of acid with diazomethane.
Example 58 A mixture of the two diastereoisomers of 2-(1-bromoethyl)--2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxy lic acid 7 and 8 in ratio 7:8=93:7 (2.27 g, 4.5 mmol) and of an aqueous solu-tion (31.5 ml) prepared dissolving K2HP04 (26.1 g) and KH2P04 (5.7 g) in water (384 ml) was heated, under stirring, at 100C for 42 hours. The reaction mixture was cooled at room temperature (pH 4.2) and worked up as described in example 57.
(+)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid (1.32 g, 4.2 mmol; yield 93%) was obtained in g7% enantiomeric excess.
The enantiomeric ratio S(~):R(-)=98.5:1.5 was confirmed by HPLC
and by H-NMR analysis carried out as described in example 57.
Example 59 Preparation of the pure 2-(l(S)-bromoethyl)--2-(5-bromo~6-methoxy-2-naphthyl)-1,3-dioxola~e-4(R),5(R)-dicarboxy lic acid (diastereoisomer 7).
_ __ ._ A mixture of the two diastereoisomers of 2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxyl ic acid 7 and 8 in ratio 7(RRS):8(RRR)=g4:6 (134.42 g, 0.266 mol) and of an aqueous solution (1726 ml) prepared dissolving K2HP04 (174 g) and KH2P04 (38 g) in water (2000 ml) was heated, under stirring, at 90C for 14 hours. The reaction mixture was cooled at room temperature (acidic pH), acidified with conc HCl -to pH 1, and e~tracted with d.iethylether (3 x 150 ml). The combined organic ex-tracts were wa~hed with water and anhydrified over sodium sulfate. Evaporation of -the solven-t under reduced pressure gave a residue that wa~ dried under vacuo at 80C for 12 hours. A
solution of me-thanesulfonic acid ( 1 ml) in methanol (2000 ml) was added to the resldue (118 g)so obtained. The solution was heated at reflux for 2 hours, cooled at room temperature, neutralized with sodium bicarbonate.The solvent was removed under reduced pressure and water (1000 ml) was added to the residue. The solution was extracted with diethylether ~2 x S00 ml). The c¢mbined organic extracts were washed with water, - dried over sodium sulfate, and concentrated in vacuo. Purification of the residue by column chromatography (silica gel; eluent hexa-ne:diethyle-ther = 8:2) gave the pure 2-(l(S)-bromoethyl)-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 sodium hydroxyde (5.32 g, 0.133 mol) in water (70 ml) was added dropwise in 1 hour, under stirring, to a solution of the diastereoiæomer 3 (35.4 g, 0.0665 mol) in methanol (250 ml) at 20~C. The reaction mixture was kept at 20C for 2 hours; then methanol was removed under reduced pressure mantaining the initial volume of the solution by addition of water~ The aqueous solution, so obtained, was extracted with dichloromethane, acidified with conc HCl to pH 1, and ex-tracted with diethylether (3 x 100 ml).
The combined organic extracts were washed with water, anhydrified over sodium sulfate, filtered, and concentrated in vacuo.

~ ~?3 ~ 3~ r~i Crystallization of the residue from dichloromethane gave the pure 2-(l(S)-bromoe-thyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolarle-4(R),5(R)-dicarboxylic acid (diastereoisomer 7).
M.p.=184-186C

H-NMR (200 MHz, esadeuteroacetone-TMS) delta (ppm): 1.68(d, 3H, J=7 Hz); 4.03(s, 3H); 4.66(q, lH, J=7 Hz); 4.95(2H, ABq, =3~.67 Hz, J=6.5 Hz); 7.46-8.18(m, 5H, aromaticprotons).
Example 60 Preparation of (+?-2(S)-~4-(2-methylpropyl ~ henyl~propionic_acid A mixture of the two dias-tereoisomers of 2-(1-bromoethyl)--2r4-(2-methylpropyl)-phenyl/-1,3-dioxolane-4(R),51R)-dicarboxylic acid 13 and 14 in ratio 13:14=87:13 (3.29 g, 8.2 mmol) was added to an aqueous solution (49 ml) of K2HP04 (4.26-g)and KH2P04 (0.93 g). The solution (pH 6.6) was heated, under stirring, at 100C for 68 hours. The reaction mixture was cooled at room temperature (pH
5.5), diluted with water (100 ml), acidified with con HCl to pH 1, and extracted with diethylether (3 x 40 ml). The organic phase was then extracted with a I0% aqueous solution of sodium bicarbonate (6 x 40 ml?. The combined aqueous extracts were acidified with conc HCl to pH 1 and extracted with diethylether (3 x 50 ml). THe combine organic extracts were washed with water, drie~ over sodium sulfate, and concentrated in vacuo. Purification by column chromatography (silica gel; eluen-t hexane:diethylether =8:2) gave the pure 2~4-(2-methylpropyl)-phenyl/-propionic acid (0.28 8)-/ ~ / 2=+47.90 (c=1%, ethanol 95%) Example 61 d ~J

A mix-ture of the two diastereoisomer of 2-(1-bromoethyl)--2-r4--(2-methylpropyl)-phenyl7-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 13 and 14 in ratio 13:14=87:13 (3.29 g, 8.2 mmol) was added to an aqueous solution tll5 ml)of KH2P04 (L6.4 g) and NaOH (0.82 g). The solution (pH 5) was heated, under stirring, at 100C for 90 hours.
The reaction mixture was cooled at room temperature ~pH 3.5~ and worked up as described in example 60.
Pure 2-r4-~2-methylpropyl)-phenyl7-propionic acid (0.66 g) was obtained.
/ ~ /D =+48.8 (c=1%, ethanol 95Yo) Example 62 A mixture of the two diastereoisomers of 2-(1-bromoethyl)--2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4( R ), 5 ( R ) -dicarboxy lic acid 7 and 8 in ratio 7:8=94:6 (2.52 g, 5 mmol)was added to an aqueous solution (70 ml) of KH2P04 tlO g) and NaOH ~1.4 g). The solution (pH 6) was heated at 90C for 50 hours. The reaction mixture was cooled at room temperature (pH 6.0) and 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.
M.p. ~ 16a-170~C
/ ~ ? D =*37.85 (c=0.5%, chloroform) The enantiomeric ratio S(+):R(-)=95:5 was confirmed by HPLC and by H~NMR analysia carried out as described in example 57.
Example 63 The pure diastereoisomer 2-(l(S)-bromoethyl)-2-(5-bromo--6-methoxy-2-na~hthyl)-1,3-dioxolane-4tR),5tR) dicarboxylic acid 7 t2-52 g, 5 mmol) was added to an aqueoU solution t70 ml) of ~ 3 ~ d KH2P04 (10 g~ and NaOi~ (1.4 g). The solution (pH 6) was heated at 90C for 50 hours. The reaction mixture was cooled at room temperature (pH 5.9) and worked up as described in example 57.
Pure (~)-2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic ~cid (l.OZ
g, 3.3 mmol; yield 66%)was obtained in 9E3% enantiomeric excess.
M.p.=168-170C
L~1D =+40 74 (c=0.5%, chloroform~
The enantiomeric ratio S(~):R(-)=99:1 was confirmed by HPLC and by H-NMR carried out as described in example 57.
Example 64 Comparative example at pH higher than 7.
The pure diastereoisomer 7(RRS) (2.52 g, 5 mmol)was added to an aqueous solution (70 ml)of KH2P04 (10 g) and rlaOH (2.5 g).
The solution (pH 7.2)was heated at 90C for 50 hours. The reaction mixture was cooled at room temperature (pH 7.0)and 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% enatiomeric excess.
M.p.=166-168C
L~ 7D =~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 a-t pH higher then 7.5.
The pure diastereoisomer 7(RRS) ~2.52 g, 5 mmol) was added to an aqueous solution (70 ml) of KH2P04 (10 g) and ~aOH (3 g).
The solution (pH 7.65)was hea-ted at 90C for 50 hours. The reaction mixture was cooled at room temperature (pH 7.5)and worked up as described in example 57.

~$~

Pure (~)-2(S)-(5-bromo~6-methoxy-2-naphU~ propionic acid (1.03 g, 3.33 mmol; yield 67%) was obtained in 74% enatiomeric excess.
M.p.=164-168C
~ ~ 7D =-~31.20 (c=0.5%, chloroform) The enarltiomeric rat~o S(~):R(-)=~7:13 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 ratio 7:8=94:6 (2.52 g, 5 mmol) was added to an aqueous solution (70 ml) of KH2P04 (10 g) a~d NaOH (0.5 g).
The solution (pH 5.1)was heated at 90C for 52 hours. The reaction mix-ture was cooled at room temperature (p~l 4.2)and worked up as described in example 57.
Optically pure (-~)-2(S)-(5-bromo-6-methoxy-2-naphtyl)-propionic acid (1.27 g, 4.11 mmol; yield 82%) was obtained.
M.p.=167-169C
rO~J D =t4Z.2~ (c=0.5%, chloroform) The optical purity was confirmed by HPLC and by H-NMR as described in example 57.
Example 67 The pure diastereoisomer 7(RRS) (2.52 g, 5 mmol) was added to an aqueous solution (70 ml) of KH2P04 (10 g) and NaOH (0.5 g).
The solution (pH 5.15)was heated at 90C for 52 hours. The reaction mixture was cooled at room temperature (pH 4.2)and worked up as described in example 57.
Optically pure (~)-2(S)-(5-bromo-6-methoxy-Z-naphthyl)-propionlc acid (1.30 g, 4.20 mmol; yield 84%) was obtained.
M.p.=168-170C
~ 42.2 (c=0.5%, chloroform) ~ 3 ~ L ~

- 80 ~

The optical purity was confirmed by HPLC and by H-NMR as described in example 57.
~xample 68 The pure diastereoisomer 7(RRS~ (2.52 g, 5 mmol) was added to an aqueous solution (35 ml) prepared dissolving KH2P04 (26.1 g) and Kll2P04 (5.7 g) in water (384 ml).
The solution was heated at 100C for 45 hours. The reaction mixture was cooled at room temperature (pH 4.1)and worked up as described in example 57.
Optically pure (-~)-2(S~-(5-bromo-6-methoxy-2-naphtyl)-propionic acid (1.3 g, 4.2 mmol; yield 84%) was obtained.
M.p.=168-170C
/ ~ ~D =+42.23 (c=0.5%, chloroform) The optical purity was con~irmed 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 ratio 7:8=93'7 (2.52 g, 5 mmol) was added to an aqueou~ solution (70 ml) of KHzP04 (10 g).
The solution (pH 4.2)was heated at 90C for 50 hours. The ~eaction mixture was cooled a-t room temperature (pH 3.2)and worked up as described in example 57.
Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphtyl)~propionic acid (0.65 g, 2.10 mmol; yield 42%) was obtained in 94% enantiomeric ~xcess.
M.p.=164 165C
r~ lD =+40.08 (c=0.5%, chloroform) The enantiomeric ratio S(~):R(-)=97:3 was confirmed by HPLC and by H-NMR as described in example 57.
Example 70 ~ A :~

A solutlon of the two dlastereoisorners of 2-(l~bromoe-thyl)--2-(5-bromo-6-methoxy-2-naphthyl)-1,3-di oxol ane-4(R),5(R)-dicarboxy lic acid N,N,N',N'-tetraethyl amide 24(~RS) and 25(~RR)in ratio 24:25=9:1 (2.93 g, 5 mmol) in water (70 ml)was heated a-t 90C for 50 hours. The reaction mixture was coolecl at room temperature (pH
5.6)and worked up as described in example 57.
Pure (+)-2(S)-(5-bromo-6-methoxy-2-naphtyl)~propionic acid (0.58 g) was obtained in 98% enan-tiomeric excess.
~.p.=164-165C
f ~ ~D =-~41.74 ~c=0.5%, chloroform) The enantiomeric ra-tio 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-bromoethyl)-2--(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxyli c acid N,N,N'!N'-tetrethyl amide 24(RRS) and 25(RRR)in ratio 24:25=9:1 (2.93 g, 5 mmol) was added to an aqueous solution (70 ml) of KH2P04 (10 g) and NaOH (0.5 g).
The solution (pH 5.7)was heated at 90C for 50 hours. The reaction mixture was cooled at room temperature (pH 4.2)and worked up as described in example 57.
Pure (+)-2(S)-t5-bromo-6-methoxy-2-naphtyl)-propionic acid (0.54 g) was obtained in 98% enantio0eric excess.
M.p.al66-168C
~ ~D =~41.86 (c=0.5%, chloroform) The enantiomeric ratio St+):R(-)=99:1 was confirmed by HPLC and by H-NMR as described in example 57.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Optically active esters of alpha arylalkanoic acids of formula (C) in which Ar represents a monocyclic, polycyclic, or orthocon-densed polycyclic aromatic or heteroaromatic group having up to 12 carbon atoms in the aromatic system which group may be substituted by one or more halogen atoms, C1-C4 alkyls, C3-C6 cycloalkyls, benzyl, hydroxyl, alkali metal oxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenoxy, thienylcarbonyl and benzoyl; R represents a linear or branched C1-C4 alkyl radical; R1 and R2, which can be equal or different, represent a hydroxy, O-M+, OR3 or NR4R5, wherein R3 is C1-C24 alkyl, C3-C6 cycloalkyl, phenyl or benzyl; M+ is the cation of an alkaline metal; R4 and R5, which can be the same or different, represent a hydrogen atom, a C1-C4 alkyl, C5-C6 cycloalkyl, or a -(CH2)n-CH2OH where n is 1, 2 or 3 or R4 and R5 together form a -(CH2)m- group where m is 4 or 5 or a -CH2-CH2-R7-CH2-CH2- group where R7 is an oxygen atom, an NH or a N-(C1-C4) alkyl group and R6 is OH, Cl, Br, I or acyl radical.

2. Optically active tartaric esters of formula (D) in which R1 and R2, which can be equal or different, represent a hydroxy, O-M+, OR3 or NR4R5, wherein R3 is C1-C24 alkyl, C3-C6 cycloalkyl, phenyl or benzyl; M+ is the cation of an alkaline metal; R4 and R5, which can be the same or different, represent a hydrogen atom, a C1-C4 alkyl, C5-C6 cycloalkyl, or a -(CH2)n-CH2OH where n is 1, 2 or 3 or R4 and R5 together form a -(CH2)m-group where m is 4 or 5 or a -CH2-CH2-R7-CH2-CH2- group where R7 is an oxygen atom, an NH or a N-(C1-C4) alkyl group and R6 is OH, Cl, Br, I or acyl radical, Y represents a hydrogen, chlorine or bromine atom and Z represents a hydrogen atom, a methyl or an alkaline metal.