NO173055B - PROCEDURE FOR THE PREPARATION OF ALFA-ARYLALIC ACIDS - Google Patents

Description

The present invention relates to a method for the production of optically active alpha-arylalkanoic acids. It is well known that alpha-arylalkanoic acids represent a large class of compounds, many of which are useful as anti-inflammatory and analgesic drugs.

Among these can be mentioned 2-(4-isobutylphenyl)-propionic acid known as Ibuprofen, 2-(3-'phenoxyphenyl)-propionic acid known as Fenoprofen, 2-(2-fluoro-4-diphenylyl)-propionic acid known as Flurbiprofen, 2-/"4-(2-thienylcarbonyl)-phenyl7-propionic acid known as Suprofen, 2-(6-methoxy-2-naphthyl)-propionic acid whose S(+) isomer is known as Naproxen.

Another group of alpha-arylalkanoic acids are useful as intermediates for the production of pyrethroid insecticides, among which 2-(4-chlorophenyl)-3-methylbutyric acid and 2-(4-difluoro-methoxyphenyl)-3-methylbutyric acid can be mentioned.

Many alpha-arylalkanoic acids have at least one asymmetric center on the carbon atom in the alpha position to the carboxyl group, and they consequently exist in the form of stereoisomers. Often a definitely higher biological activity is associated with one of the isomers (enantiomers).

A particularly clear example is provided by 2-(6-methoxy-2-naphthyl)-propionic acid, whose S(+) enantiomer (Naproxen) has significantly higher pharmacological properties than the R(-) enantiomer and the racemic mixture.

Among the methods for the preparation of alpha-arylalkanoic acids that have been described in recent times, the most interesting are those which comprise rearrangement of alkyl-aryl ketals substituted in the alpha position in relation to the ketal group.

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

All these processes more or less simply give alpha-arylalkanoic acids in the form of a racemic mixture.

Preparation of optically active alpha-arylalkanoic acids can be carried out by dissolving the thus obtained racemic mixtures according to conventional procedures, e.g. with optically active bases, or by carrying out the above-mentioned rearrangement process on optically active ketals which have been previously prepared according to the procedures described in European patent application 67698 (Sagami) and 81993 (Syntex).

All of the methods stated above use as

starting material for the production of alpha a-arylalkanoic acids ketals obtained by reacting aryl-alkyl ketones with aliphatic alcohols or glycols. New chiral, enantiomerically pure ketals of aryl-alkyl ketones have now been found which in the ketal group have two asymmetric centers both in R or S configuration, which are usable as starting materials for the preparation

of optically active alpha a-arylalkanoic acids or their precursors either with equivalent or improved optical purity compared to the starting ketals.

The present invention relates to a method for the production of optically active alpha-arylalkanoic acids of formula

where Ar denotes a naphthyl substituted in the 6-position with a Cx-C4 alkoxy group and in the 5-position with hydrogen or with a halogen atom, or where Ar denotes phenyl substituted in the 4-position with a C^C^alkyl group, or with a halogen atom, and where R

denotes C 1-6 alkyl.

The method according to the invention is characterized in that an alkyl-aryl ketal of formula (I)

wherein Ar and R are as defined above;

R1 and R2', which are the same or different, denote a hydroxy, an OR3 or a :N(R3 )2 group,

R3 denotes a C1-C4 alkyl group,

X denotes a group selected from the group consisting of chlorine, bromine or iodine atom, hydroxy, C₁-C₄-alkanoyloxy and C₁-C₄-alkylsulfonyloxy group,

and wherein the carbon atoms marked with an asterisk are both simultaneously in the R or S configuration, and wherein the ketal of formula (I) exists in the form of epimers with respect to the carbon atom attached to the X group,

is produced by reacting L(+)- or D(-)-tartaric acid or a derivative thereof of formula

in which

Ri and R2 have the meanings given above, with

a) a ketone of formula

wherein Ar, R and X have the meanings given above, in the presence

of an acid catalyst and of an orthoester at a temperature of from 50 to 90°C or by azeotropic distillation of the water formed by the ketalization in the presence of a suitable organic solvent, or with

b) a ketal of formula

wherein Ar, R and X have the meanings given above, R 5 and R 6 denote a C 1 -C 6 alkyl group, in an inert gas atmosphere in the presence of an acid catalyst under anhydrous conditions, at a temperature of from 20 to 125°C, and about desired, by converting the ketal of formula (I) in which R1=R2=OR3 to the corresponding ketal of formula (I) in which Rx and/or R2 =0H by treatment with a strong base at room temperature in an aqueous medium, followed by acidification to pH 1, or if desired, by converting the ketal of formula (I) in which R1=R2=OR3 to the corresponding ketal of formula (I) in which Rx and/or R2 =N(R3)2 by treatment with an amine of formula (R3)2NH an aqueous medium at room temperature, which method is also characterized by the fact that a ketal of formula (I) is rearranged to the above-mentioned alpha-arylalkanoic acid in a single step in an aqueous medium, at an acidic pH, at a temperature between room temperature and 150°C, forming corresponding alpha-arylalkanoic acids with an enantiomeric ratio higher than the epi more ratio of the starting ketal of formula (I), or in two steps by treating indicated ketal of formula (I) in the presence of a metal salt as a catalyst in an organic medium that does not contain alcohols or glycols at a temperature of from 15 to 50° C, forming a compound of general formula in which Ar, R, Rx and R2 have the meanings given above, and where R6 is hydroxy, which is then subjected to hydrolysis under acidic conditions, at from room temperature to 95°C to form alpha- arylalkanoic acids having an enantiomeric ratio equal to the epimeric ratio of the alpha-halogenketal starting material. Ketalization of a ketone of formula wherein Ar, R and X have the meanings given above, with L(+)-tartaric acid or D(-)-tartaric acid or a derivative thereof of formula

wherein Rx and R2 have the meanings given above, is carried out by heating in the presence of an acid catalyst and of an orthoester; alternatively, the water formed during the ketalization is distilled azeotropically in the presence of a suitable organic solvent, such as benzene, toluene, xylene or heptane. This method is particularly suitable for the formation of the ketals of formula I in which Rx and R2, which are the same or different, denote an OR3 group. By starting from the indicated ketals, it is possible to prepare all the ketals in which Rx and R2 have the meanings indicated above.

By direct ketalization, it is also possible to prepare ketals of formula I in which the substituent X has a meaning which is different from the meaning in the starting ketone (II).

By thus starting from a ketone of formula II in which

X is a chlorine or bromine atom, it is possible to obtain a ketal of formula I in which X=OH, by treatment with a strong base, such as an alkali alcoholate.

The ketals of formula I in which X is an alkanoyloxy or alkylsulfonyloxy group can be prepared by reacting the ketals of formula I in which X is hydroxy with the appropriate alkanoyl or alkylsulfonyl halide. If desired, it is possible from the ketals of formula I in which X is an acyloxy group to prepare by hydrolysis the ketals of formula I in which X is hydroxy.

Transketalization of a ketal of formula

wherein Ar, R and X have the meanings given above, R 5 and R 6 denote a C 1 -Q 1 alkyl group forming a 5- or 6-membered ring together with the O-C-O group.

The transketalization reaction is carried out by heating to a temperature of from 20 to T00°C in an inert gas atmosphere a mixture of a ketal of formula III and L(+)- or D(-)-tartaric acid or a derivative thereof, in the presence of an acidic catalyst under anhydrous conditions.

Suitable acid catalysts are inorganic or sulphonic acids. Also in this case it is possible to modify the meanings of R-| , R2 and X according to what is described under (a). Both the ketone of formula II and the ketals of formula III are known compounds which are easily prepared according to known procedures. It is worth noting that the carbon atoms marked with an asterisk in the ketals of formula I, regardless of the preparation method, have the same configuration as the starting tartaric acid, i.e. they are both in R or S configuration.

It has been rather surprisingly found that the reactions for the preparation of the ketals of formula I according to the methods indicated above are diastereogenic and, depending on the reaction conditions, they can also be stereoselective in the sense that they give a mixture of ketals of formula I in which one of the two epimers (in relation to the carbon atom bound to the X group) is dominant or strongly dominant. By choosing the suitable ketone of formula II and the suitable tartaric acid derivative it is possible to obtain essentially the desired optically active epimer.

It is obvious that by starting from an already optically active ketone of formula II it is possible to obtain epimeric ketals of formula I in which the ratio between the two epimers is higher than the ratio between the enantiomers in the starting ketones. Regardless of what is stated here, it is also important that the ketals of formula I exist in the form of epimers which can be easily enriched or separated according to known procedures, e.g. by crystallization. It is thus possible to separate the desired epimer of the ketal of formula I and to rearrange this to form the corresponding optically active alpha-arylalkanoic acid in essentially pure form. An isomer separation carried out on a precursor, i.e. an intermediate compound is often more appropriate than separation (resolution) of the final product due to the lower price of the intermediate.

The possibility of being able to prepare ketals of formula I containing a multitude of different groups in terms of Ri and R2 substituents makes it possible to modulate in a wide range the hydrophilic and lipophilic character of indicated ketals: from compounds with strong polar groups (alkali salts, amides) to lipophilic compounds (esters of long-chain alcohols).

This wide range of options makes it possible to choose the most suitable ketal of formula I in relation to the experimental conditions used in the various methods for producing alpha-arylalkanoic acids by rearrangement.

It is worth noting that tartaric acid derivatives, and in particular L(+)-tartaric acid, have a price on the market that is competitive with the price of the glycols that have hitherto been used for ketalization in accordance with the known rearrangement processes indicated above.

The preparation of alpha-arylalkanoic acids by rearrangement of the ketals of formula I can be carried out using experimental procedures known for other various ketals, in one step or in two steps.

It has also been found that when such processes are applied to the ketals of formula I (in which X is different from hydroxy) these give alpha-arylalkanoic acids in which the -enantiomeric ratio reflects the epimeric ratio in the starting ketals.

It has now been found, which is a further feature of the invention, a new rearrangement process which leads to alpha-arylalkanoic acids with an enantiomeric ratio higher than the epimeric ratio in the starting ketals. Such a process is defined as enantioselective in that the enantiomeric composition (ratio between enantiomers S and R) in the thus obtained alpha-arylalkanoic acids deviates from the epimeric composition of the starting ketals of formula I and quite surprisingly corresponds to an increase in the optical purity of alpha- the arylalkanoic acids. The enantioselective rearrangement process which is a feature of the present invention consists in treating a ketal of formula I in which X is different from hydroxy, in an aqueous medium, at an acidic pH, at a temperature between room temperature and 150°C.

The above reaction conditions are particularly unexpected and surprising in that it is well known that treating a ketal with water under acidic conditions is a general method for converting it to a corresponding ketone and alcohol or diol. Consequently, the known alpha-substituted alkyl-aryl-ketals under such conditions will undergo a rapid hydrolysis which gives the corresponding alkyl-aryl-ketone and alcohol or diol.

The new rearrangement process according to the invention is preferably carried out using ketals of formula I which are soluble or at least partially soluble in water under the reaction conditions, i.e. the ketals of formula I in which R<| and/or R 2 are hydrophilic groups. Depending on the nature of the ketal of formula

In a co-solvent can be used.

The rearrangement is preferably carried out by heating the ketal of formula I in water at a pH between 4 and 6. The desired pH values can be maintained by adding a suitable amount of a buffer.

The reaction duration depends mainly on the nature of the ketal of formula I and the reaction temperature. Generally, the alpha-arylalkanoic acids are poorly soluble in water, which is why the optically active alpha-arylalkanoic acids can be isolated by simple filtration at the end of the reaction. To the best of our knowledge, this is the first time that a rearrangement of ketals for the production of alpha-arylalkanoic acids has been carried out in water mainly as the sole reaction solvent. The main advantages of the present rearrangement process from an industrial point of view can be stated as follows: (1) The process is enantioselective and gives alpha-arylalkanoic acids with an enantiomeric ratio higher than the epimeric ratio of the starting material; (2) the reaction solvent is water with the consequent economic and safety advantages; (3) no metal catalyst is required, and (4) the optically active alpha-arylalkanoic acid is separated from the reaction mixture by filtration.

Among the optically active alpha-arylalkanoic acids, the most significant from a pharmaceutical point of view is 2-(6-methoxy-2-naphthyl)-propionic acid whose S(+) enantiomer is generally known as Naproxen.

In a specific embodiment, the invention relates to the use of ketals of formula IV

wherein Rx , R2 and X have the same meanings as stated for formula I, Y denotes a hydrogen, chlorine or bromine atom, Z denotes a hydrogen atom, a methyl group or an alkali metal, in the preparation of Naproxen by rearrangement.

A preferred embodiment in the synthesis of Naproxen according to the invention consists in rearrangement of a ketal of formula IV in which Z is methyl and X is a halogen atom, in a polar solvent under neutral or slightly alkaline conditions.

An alternative preferred rearrangement procedure consists in treating a compound of formula IV wherein Z represents an alkali metal, in water or in an organic solvent under basic conditions.

The ketals of formula IV in which X is an acyloxy, alkylsulfonyloxy or arylsulfonyloxy group can be rearranged in a protic medium, under neutral or basic conditions.

In each case, the preferred rearrangement procedure of the ketals of formula IV wherein X is different from hydroxy is an enantioselective process in aqueous medium, under acidic conditions according to the invention.

To prepare Naproxen, it may be necessary to replace the substituent Y (when this is a chlorine or bromine atom) with a hydrogen atom. This is carried out by hydrogenolysis of the corresponding 2-(5-chloro- or 5-bromo-6-methoxy-2-naphthyl)-propionic acid or esters thereof.

As previously indicated, the rearrangement of the ketals of formula I to alpha-arylalkanoic acids is a process which does not lead to any significant racemization of the products, and which thus selectively and predominantly gives the desired optically active alpha-arylalkanoic acids.

The rearrangement reaction of the compounds of formula I, in particular when carried out under mild conditions, in organic medium in the absence of alcohols or glycols, can give rise to the formation of new intermediate esters of formula

wherein Ar, R, R^ and R^ have the same meanings as for formula I and R6 is hydroxy. Hydrolysis of the compounds of formula V, carried out preferably under acidic conditions, gives the corresponding free acids. The rearrangement of the compounds of formula IV, when carried out under mild conditions in an organic medium, and in the absence of alcohols or glycols, can consequently give rise to new esters of formula

where Y, Z, R-| , R2 and Rg have the meanings given above.

Hydrolysis of the esters of formula VI, preferably under acidic conditions, yields Naproxen or a precursor thereof. Also in this case in which the preparation of the alpha-arylalkanoic acids is achieved in two steps via the esters of formula V or VI, no significant racemization takes place, and the alpha-arylalkanoic acid obtained consists of a mixture in which one of the enantiomers predominates.

The compounds of formula V and VI are new compounds endowed with interesting characteristics which make them useful in many respects..As already stated, they yield on hydrolysis the corresponding alpha-arylalkanoic acids.

Thanks to the presence of two asymmetric centers (the carbon atoms to which the groups CO-R-| and CO-R2 are bound) in the alcoholic part, they are still useful for the optical resolution of alpha-arylalkanoic acids.

The resolution of an acid into its optical isomers is generally accomplished by forming a salt with an optically active base. By using the compounds of formula V or VI, a new dissolution process for the separation of optically active alpha-arylalkanoic acids is realized. Such a solution which does not include the preparation of a salt with an optically active base, but includes the formation of an ester with tartaric acid or a derivative thereof, is completely new. Said dissolution process is particularly advantageous when the rearrangement of the ketals of formula I gives a mixture of esters of formula V enriched with the desired optical isomer.

Nevertheless, it is clear that the compounds of formulas V and VI are useful for the resolution of alpha-arylalkanoic acids regardless of how they have been prepared.

In fact, it is possible to prepare the compounds of formula V or VI by esterification with tartaric acid or a derivative thereof, of a racemic mixture (or of a mixture rich in one of the optical isomers) of an alpha-arylalkanoic acid prepared

according to any procedure.

The presence of a chiral group in the alcohol moiety is also

the key to obtaining - from a mixture of esters - under alkaline conditions, an equilibrium of the mixture from which the desired isomer can be isolated by crystallization. according to

a specific embodiment of the invention may be the esters of formula VI, prepared by rearrangement of a ketal of formula IV

as well as produced by reacting a racemic 2-(6-methoxy-2-naphthyl)-propionic acid or a precursor thereof with tartaric acid or a derivative thereof, is used in a method for

dissolution of Naproxen or a precursor thereof by fractional crystallization of the esters of formula VI- whose hydrolysis gives Naproxen or a precursor thereof in a substantially pure form.

Specified esters are the ester of S(+)-2-(6-methoxy-2-naphthyl)-propionic acid (or a precursor thereof, such as the 5-chloro or 5-bromo derivative) with the naturally occurring L(+)-tartaric acid (or a derivative thereof, such as an ester or amide).

The following examples illustrate the invention.

Example 1

Ketalization of 2-bromo-1-(6-methoxy-2-naphthyl)-propan-1-one with 2(R),3(R)-dihydroxybutanedioic acid dimethyl ester (L(+)-dimethyltartrate)

A mixture of 1.465 g (0.005 mol) 2-bromo-1-(6-methoxy-2-naphthyl)-propan-1-one, 7.5 g L(+)-dimethyl tartrate, 2.5 g (0.0236 mol) of trimethylorthoformate and 0.075 g (0.0005 mol) of trifluoromethanesulfonic acid were kept under stirring and nitrogen at 50°C for 60 hours. The reaction mixture was poured into a 10% aqueous solution of sodium carbonate and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure of an impure material which was purified by column chromatography (silica gel; eluent - hexane:diethylether = 8:2).

The mixture of the two diastereoisomers of 2-(1-bromomethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 1 and 2, (0 .9 g, 0.002 mol) in the ratio 1:2=1:1 (determined by <1>H-NMR 200 MHz) was obtained. Diastereoisomer 1 (RRS)

<1>H-NMR (200 MHz, CDCl3-TMS), delta (ppm): 1.68 (d, 3H, J=7.5 Hz), 3.54 (s, 3H), 3.90 (s , 3H), 4.08 (s, 3H), 4.48 (g, 1H, J = 7.5 Hz), 4.94 (2H, ABq, AV =26.8, J=7.2Hz), 7.1-8.0 (6H, aromatic protons).

Diastereoisomer 2 (RRR)

<1>H-NMR (200 MHz, CDCl3-TMS), delta (ppm): 1.64 (d, 3H, J=7.5 Hz), 3.58 (s, 3H), 3.89 (s , 3H), 4.08 (s, 3H), 4.50 (q, 1H, J = 7.5 Hz), 4.89 (2H, ABq, &>? =36.3, J=6.3Hz ), 7.1-8.0 (6H, aromatic nrotones).

Example 2

Preparation of the diastereoisomeric mixture of 2-(1-bromomethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R). 5(R)-dicarboxylic acid in the ratio 1:1

A mixture of the two diastereoisomers of 2-(1-bromomethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid diethyl ester 3 and 4 (prepared in a similar manner as described in Example 1) (21.18 g, 0.044 mol, ratio 3:4=1:1), 3.52 g (0.088 mol) of sodium hydroxide, 35 ml of dimethoxyethane and 35 ml of water were kept under stirring at room temperature for two hours. The reaction mixture was diluted with water and extracted with diethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid to pH 1 and extracted with diethyl ether. The organic phase was washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the two diastereoisomers of 2-(1-bromomethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 5 and 6 (16 g, 0.0367 mol; yield 85.5%) in the ratio 5:6=1:1 (determined by <1>H-NMR 200 MHz).

A sample obtained by esterification in diethyl ether with diazomethane gave a mixture of the two diastereoisomers of 2-(1-bromethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5 (R)-dicarboxylic acid dimethyl ester 1 and 2 in the ratio 1:2=1:1 (determined by HPLC and by "<>>H-NMR 200 MHz).

Example 3

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

A mixture of 12.4 g (0.05 mol) of 2-chloro-1-(6-methoxy-2-naphthyl)-propan-1-one, 75 g of 2(R),3(R)-dihydroxybutanedioic acid and 25 g (0.236 mol) of trimethylorthoformate was gradually heated to 50°C.

2.4 g (0.016 mol) of trifluoromethanesulfonic acid was added to the solution. The reaction mixture was kept under nitrogen at 50°C for 45 hours and was then worked up as described in example 1. Purification of the impure material (19.2 g) by column chromatography (silica gel; eluent - hexane:diethylether = 6:4) gave a mixture of the desired diastereoisomers 7 and 8 (5.6 g) in the ratio 7:8=52:48 (determined by HPLC). <1>H-NMR (200 MHz, CDCl3-TMS): Diastereoisomer 7 (RRS) delta (ppm): 1.49 (d, 3H, J=6.65 Hz), 3.48 (s, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 4.41 (q, 1H, J=6.65 Hz), 4.95 (ABq, 2H, J=6 Hz), 7, 1-8.0 (6H, aromatic protons). Diastereoisomer 8 (RRR) delta (ppm): 1.47 (d, 3H, J=6.65 Hz), 3.53 (s, 3H), 3.83 (s, 3H), 3.89 (s, 3H), 4.44 (q, 1H, J=6.65 Hz), 4.92 (ABq, 2H, J=6 Hz), 7.1-8.0 (6H, aromatic protons). HPLC analysis was performed on a Hewlett Packard instrument (mod. 1084/B with a variable wavelength UV detector.

Column: Brownlee Labs RP8 (5 micron), 250 mm x 4.6 mm Solvent A: water, flow rate 0.96 ml/min. Solvent B: methanol, flow rate 1.04 ml/min. Temperature of solvent A: 60°C.

Temperature of solvent B: 40°C.

Column temperature: 50°C.

Wavelength: 254 nm.

Injection: 10 microliters of a 3 mg/ml solution in acetonitrile. Retention times:

Diastereoisomer 7: 12.46 min.

Diastereoisomer 8: 13.21 min.

Example 4

Preparation of 2 ( R) - hydroxy- 3 ( R) ~/ 2- ( 6- methoxy- 2- naphthyl) - propanoyl/- butanedioic acid dimethyl ester

A solution of 2.4 g (0.0123 mol) of silver tetrafluoroborate in 8 ml of 1,2-dichloroethane was added under an inert atmosphere over 15 minutes to a solution of the two diastereoisomers 7 and 8 (4.09 g, 0, 01 mol) in the ratio 7:8=52:48 kept under stirring at 15°C. The reaction mixture was heated to 50°C and held at 50°C for 16 hours, then cooled to room temperature and filtered.

The solution was diluted with 60 ml of dichloromethane, was washed with 2 x 100 ml of water and was dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave an impure material which after purification by column chromatography

(silica gel; eluent - n-heptane:diethylether = 2:8)

gave a mixture of the two diastereoisomeric esters A and B (2.9 g, 0.0074 mol; yield 74%) in the ratio A:B=52:48 (determined by <1>H-NMR 200 MHz).

<1>H-NMR (200 MHz, CDCl3-TMS), delta (ppm):

Diastereoisomer A (RRS): 1.62 (d, 3H, J=8 Hz), 3.22 (s, 3H), 3.83 (s, 3H), 3.92 (s, 3H), 3.21 (d, 1H, J=7.2 Hz), 3.95 (q, 1H, J=8 Hz), 4.68 (dd, 1H, J=CH_OH<=7>,<2> Hz, JCH_CH= 2.47 Hz),

5.37 (d, 1H, J=2.47 Hz), 7.1-7.8 (6H, aromatic protons).

Diastereoisomer B (RRR): 1.66 (d, 3H, J=a Hz), 3.58 (s, 3H), 3.72 (s, 3H), 3.92 (s, 3H), 3.24 (d, 1H, J=7.6 Hz), 3.97 (q, 1H, J=8 Hz), 4.78 (dd, 1H, J=CH_0H<=7>'6 Hz' JCH-CH< =2/4>7 Hz) ' 5.45 (d, 1H, J=2.47 Hz), 7.1-7.8 (6H, aromatic protons).

Example 5

Preparation of 2-(6-methoxy-2-naphthyl)-propanoic acid

A mixture of the two diastereoisomeric esters A and B (2.2 g, 5.64 mmol; ratio A!B=52:48, prepared as described in example 4), 22 ml of 1,2-dimethoxyethane and 22 ml of concentrated hydrochloric acid was held at 95°C for two hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with dichloromethane. The organic phase was washed with water and was extracted with a 10% aqueous solution of sodium bicarbonate. The basic aqueous phase was acidified with concentrated hydrochloric acid and was extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude 2-(6-methoxy-2-naphthyl)-propanoic acid. An analytically pure sample was obtained after purification by column chromatography (silica gel; eluent - hexane:diethylether = 7:3).

/a7D2<0>=+2.2° (c= 1%, chloroform)

Example 6

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

By following the procedure described in example 2 and starting from a mixture of the two diastereoisomers of 2-(1-chloroethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R), 5(R)-dicarboxylic acid dimethyl ester (38.4 g, 0.094 mol, ratio 7:8=1:1, determined by HPLC) a mixture of the two diastereoisomers of the desired product 9 and 10 was obtained (32.5 g, 0.085 mol; 90.0% yield) in the ratio 9:10=1:1.

The diastereoisomeric ratio was determined by HPLC analysis carried out on a sample obtained by esterification with diazomethane.

<1>H-NMR (200 MHz, CDCl3-TMS) delta (ppm), significant data: Diastereoisomer 9: 1.44 (d, 3H, J=6.85 Hz), 4.42 (q, 1H, J =6.85 Hz), 4.88 (ABq, 2H, J=6 Hz), 7.0-8.0 (6H, aromatic protons), 9.0 (s, 2H).

Diastereoisomer 10: 1.44 (d, 3H, J=6.85 Hz), 4.42 (q, 1H, J=6.85 Hz), 4.82 (ABq, 2H, J=6.7 Hz) , 7.0-8.0 (6H, aromatic protons), 9.0 (s, 2H).

Example 7

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

A solution of 13.42 g (0.084 mol) of bromine in 30 ml of carbon tetrachloride was added dropwise over one hour to a solution of the two diastereoisomers of 2-(1-bromomethyl)-2-(6-methoxy-2-naphthyl )-1,3-dioxolane-4(R),5(R)-dicarboxylic acid diethyl ester 3 and 4 in the ratio 3:4=1:1 (39.48 g, 0.082 mol) in 457 ml of carbon tetrachloride kept under stirring at 0 °C and under inert atmosphere. The reaction mixture was kept at 0°C for one hour and then poured into a well-stirred 10% aqueous solution of sodium carbonate (500 ml). The organic phase was separated, washed with 2 x 500 ml water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the diastereoisomeric mixture of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R) ,5(R) -dicarboxylic acid diethyl esters 11 and 12 (43.6 g; purity 98% and ratio 11:12=1:1, determined by HPLC).

Example 8

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

A mixture of the two diastereoisomers of 2-(1-bromomethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 1 and 2 in the ratio 1:2=1:1 (12.5 mmol; prepared as described in example 1), 27.5 ml of diethylamine and 20 ml of water were kept under stirring at room temperature for 15 hours. The solvents were removed at room temperature under reduced pressure and 50 ml of diethyl ether was added to the residue. The precipitate was filtered and dried in vacuo. A diastereoisomeric mixture of 2-(1-bromomethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxo-lan-4 (R),5 (R)-dicarboxylic acid N,N,N', N1-tetraethylamide 13 and 14 (11 mmol; yield 88%) were obtained in the ratio 13:14=1:1 (determined by <1>H-NMR 200 MHz).

Example 9

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

1.22 g (3.46 mmol) of 2-acetoxy-1,1-dimethoxy-1-(5-bromo-6-methoxy-2-naphthyl)-propane was added under argon to a solution obtained by heating to 65° C of a mixture of 2(R),3(R)-dihydroxybutanedioic acid dimethyl ester, 1 ml of thionyl chloride and 0.03 g of methanesulfonic acid. The reaction mixture was heated to 95°C for 30 minutes, poured into a 10% aqueous solution of sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, eluent - dichloromethanerhexane = 9:1) gave the diastereoisomeric mixture of 2-(1-acetoxyethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane -4(R),5(R)-dicarboxylic acid dimethyl ester 15 and 16 (0.7 g, 1.37 mmol; yield 40%) in the ratio 15:16=65:35 (determined by <1>H-NMR and HPLC). Crystallization from methanol gave a diastereoisomer mixture in the ratio 15:16=95:5. <1>H-NMR (90 MHz, CDCl3-TMS), delta (ppm): Diastereoisomer 15 (major): 1.28 (3H, d, J=6 Hz), 1.93 (3H, S), 3 .47 (3H, s), 3.87 (3H, s), 4.00 (3H, s), 4.96 (2H, ABq, AS>=12.35, J=5.4 Hz), 5 .38 (1H, q, J=6 Hz), 7.23-8.30 (5H, aromatic protons).

Diastereoisomer 16 (minor): 1.23 (3H, d, J=6 Hz), 2.05 (3H, S), 3.60 (3H, s), 3.87 (3H, s), 4.00 (3H, s), 4.90 (2H, ABq, £ti =22.95, J=7Hz), 5.38 (1H, q, J=6 Hz), 7.23-8.30 (5H, aromatic protons).

Example 10

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

23.5 g (73.8 mmol) of 2-acetoxy-1,1-dimethoxy-1-(6-methoxy-2-naphthyl)-propane was added under argon to a solution obtained by heating to 65<0>C of a mixture of 150 g 2(R),

3(R)-dihydroxybutanedioic acid dimethyl ester, 15.6 ml of thionyl chloride and 0.7 g (7.4 mmol) of methanesulfonic acid. The reaction mixture was heated to 95°C for 30 minutes and then poured into a 10% aqueous solution of sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (silica gel; eluent - dichloromethane:hexane = 7:3) gave the diastereoisomeric mixture of 2-(1-acetoxyethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4 (R),5(R)-dicarboxylic acid dimethyl ester 17 and 18 (15 g, 34.7 mmol; yield 47%) in the ratio 17:18=64:36 (determined by <1>H-NMR and HPLC).

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

Diastereoisomer 17 (major): 1.23 (3H, d, J=6 Hz), 1.95 (3H, s), 3.45 (3H, s), 3.83 (3H, s), 3.88 (3H, s), 4.90 (2H, ABq, Av=6.82, J=5.4 Hz), 5.33 (1H, q, J=6 Hz), 7.06-8.00 ( 6H, aromatic protons).

Diastereoisomer 18 (minor): 1.20 (3H, d, J=6 Hz), 2.00 (3H, s), 3.57 (3H, s), 3.81 (3H, s), 3.88 (3H, s), 4.80 (2H, ABq, Av =15.54, J=6.6Hz), 5.33 (1H, q, J=6 Hz), 7.06-8.00 (6H , aromatic protons).

Example 11

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

A solution of a diastereoisomeric mixture of 2-(1-acetoxyethyl)-2-(6-methoxy-2-naphthyl)-1,3Tdioxolane—4(R),5(R)-dicarboxylic acid dimethyl ester 17 and 18 in the ratio 17 :18=1:1 (4.33 g, 10 mmol) in 20 ml of methanol was added dropwise at room temperature to a solution of 4 g (100 mmol) of sodium hydroxide in 40 ml of water. The reaction mixture was kept at room temperature for 24 hours and was then acidified with concentrated hydrochloric acid and extracted with diethyl ether. The combined organic extracts were washed with water, dried over sodium sulfate and filtered. Evaporation of the solvent under reduced pressure gave the impure diastereoisomeric mixture of 2-(1-hydroxyethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid

(3.26 g).

The impure product thus obtained was added to a solution of 0.086 g (0.9 mmol) of methanesulfonic acid in 300 ml of methanol. The solution was heated to reflux for 2 hours, cooled to room temperature, diluted with 300 ml of dichloromethane and poured into 100 ml of water. The organic phase was separated, washed with water and with a 2% aqueous solution of sodium bicarbonate, dried over sodium sulfate and filtered. The crude reaction product obtained by evaporating the solvent under reduced pressure was crystallized from methanol to form the diastereoisomeric mixture of 2-(1-hydroxyethyl)-2-(6-methoxy-2-naphthyl)-1,3- dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 19 and 20 (3 g, 7.7 mmol; yield 77%) in the ratio 19:20=56:44 (determined by <1>H-NMR and HPLC ).

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

Diastereoisomer 19 (major): 1.06 (3H, d, J=6 Hz), 3.13 (1H, d, J=7.5Hz), 3.30 (3H, s), 3.83 (3H, s), 3.90 (3H, s), 4.16 (1H, dq, JCH_CH=6 Hz, JCH_OH=7.5 Hz), 5.06 (2H, ABq, =11.77, J=4, 2 Hz), 7.13-8.00 (6H, aromatic protons). Diastereoisomer 20 (minor): 1.13 (3H, d, J=6 Hz), 3.13 (1H, d, J=7.5Hz), 3.56 (3H, s), 3.82 (3H, s), 3.90 (3H, s), 4.16 (1H, dq, JCH_CH=6 Hz, JCH_OH=7.5 Hz), 4.97 (2H, ABq,AV=2.94, J=1 .5 Hz), 7.13-8.00 (6H, aromatic protons).

Example 12

Preparation of the diastereoisomeric mixture of 2-/ 1 -( 4- methyl-phenylsulfony loxy) - ethyl_ 7 - 2- ( 6- methoxy- 2- naphthyl) - 1, 3- dioxolan-4( R), 5 ( R )-dicarboxylic acid dimethyl ester

A solution of 15 g (34.8 mmol) of 1,1-dimethoxy-2-(4-methylphenylsulfonyloxy)-1-(6-methoxy-2-naphthyl)-propane in 100 ml of 1,2-dichloroethane was added dropwise under argon to a solution obtained by heating to 95°C a mixture of 75 g of 2(R),3(R)-dihydroxybutanedioic acid dimethyl ester, 7.5 ml of thionyl chloride and 0.37 g (3.8 mmol) of methanesulfonic acid. The reaction mixture was heated to 125°C for one hour and during this time 1,2-dichloroethane was distilled off.

The reaction mixture was then poured into a 10% aqueous solution of sodium bicarbonate, and was extracted with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (silica gel; eluent - dichloromethane:hexane = 8:2) gave the diastereoisomeric mixture of 2-(1-(4-methylphenylsulfonyloxy)-ethyl)-2-(6-methoxy-2-naphthyl)-1, 3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 21 and 22 (10.8 g, 19.81 mmol; yield 57%) in the ratio 21:22=40:60 (determined by <1>H -NMR and HPLC).

<1>H-NMR (200 MHz, CDCl3-TMS), delta (ppm):

Diastereoisomer 22 (major): 1.40 (3H, d, J=6Hz), 2.30 (3H, s), 3.43 (3H, s), 3.81 (3H, s), 3.90 ( 3H, s), 4.80 (2H, s), 4.90 (1H, q, J=6 Hz), 6.90-7.80 (10 H, aromatic protons).

Diastereoisomer 21 (minor): 1.37 (3H, d, J=6Hz), 2.26 (3H, s), 3.43 (3H, s), 3.83 (3H, s), 4.76 ( 2H, s), 4.90 (1H, q, J=6 Hz), 6.90-7.80 (10 H, aromatic protons).

A further purification by column chromatography (silica gel, eluent - dichloromethane:hexane = 1:1) led to the pure main diastereoisomer 22.

Example 13

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

A solution of 24 g (68 mmol) of 1,1-dimethoxy-2-methanesulfonyloxy-1-(6-methoxy-2-naphthyl)-propane in 140 ml of 1,2-dichloroethane was added dropwise under argon until a solution was obtained by heating to 95°C a mixture of 120 g of 2(R),3(R)-dihydroxy-butanedioic acid dimethyl ester, 12 ml of thionyl chloride and 0/6 g (7.4 mmol) of methanesulfonic acid. The reaction mixture was heated to 125°C for one hour, during which time 1,2-dichloroethane was distilled off. The reaction mixture was then poured into a 10% aqueous solution of sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography in (silica gel; eluent - dichloromethane:hexane = 8:2) gave the diastereoisomeric mixture of 2-(1-methanesulfonyl-oxyethyl)-2-(6-methoxy-2-naphthyl)-1,3- dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 23 and 24 (20 g, 42.7 mmol; yield 63%) in the ratio 23:24=63:37 (determined by <1>H-NMR and HPLC ). Crystallization from methanol gave a diastereoisomer mixture in the ratio 23(RRS):24(RRR) = 80:20.

1h-NMR (90 MHz, CDCl3-TMS), delta (ppm):

Diastereoisomer 23 (RRS): 1.38 (3H, d, J=6Hz), 2.93 (3H, s), 3.37 (3H, s), 3.90 (3H, s), 4.80 ( 1H, q, J=6Hz), 5.03 (2H, ABq,AV=5.09, J=4.2Hz), 7.06-8.00 (6 H, aromatic protons). Diastereoisomer 24 (RRR): 1.38 (3H, d, J=6Hz), 2.93 (3H, s), 3.53 (3H, s), 3.80 (3H, s), 3.90 ( 3H, s), 4.80 (1H, q, J=6Hz), 4.97 (2H, ABq, A>) =11.94, J=6.3Hz), 7.06-8.00 (6 H, aromatic protons).

Example 14

Preparation of 2-(6-methoxy-2-naphthyl)-propanoic acid methyl ester from a diastereoisomeric mixture of 2-(1-methanesulfonyloxyethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4( R), 5(R)-dicarboxylic acid dimethyl ester in the ratio 80:20

The diastereoisomeric mixture of 2-(1-methanesulfonyl-oxyethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 23 and 24 in the ratio 23 :24=80:20 (1 g, 2.13 mmol), 7.5 ml of methanol and 2.5 ml of water were heated in a sealed tube at 150°C for five hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with diethyl ether. The combined organic extracts were washed with water, dried, filtered and concentrated in vacuo. Purification of the residue by column chromatography (silica gel; eluent - dichloromethane) gave 2-(6-methoxy-2-naphthyl)-propanoic acid methyl ester (0.4 g, 1.64 mmol; yield 77%).

Sm.p. = 88OC

fqJD20= +48.00 (C=1%, chloroform)

1H-NMR (200 MHz) analysis performed in CDCl3 using an optically active shift reagent (europium III tris-[3-(epta-fluoropropylhydroxymethylene)-d-camphorate7) showed an enantiomeric ratio S(+):R(-)= 80:20.

Example 1 5

Preparation of 2-(6-methoxy-2-naphthyl)-propanoic acid from a diastereoisomeric mixture of 2-(1-bromethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4( R ), 5( R )-dicarboxylic acid

A mixture of the two diastereoisomers of 2-(1-bromomethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 5 and 6 in the ratio 5 :6=1:1 (12.75 g, 30 mmol) and an aqueous solution (180 ml) prepared by dissolving 26.1 g of K2HPO4 and 5.7 g of KH2PO4 in 384 ml of water was heated with stirring to 100 °C for 21 hours. The reaction mixture was cooled to room temperature (pH 3.7), then acidified with concentrated HCl to pH 1 and extracted with 3 x 100 mL diethyl ether. The combined organic extracts were washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the impure 2-(6-methoxy-2-naphthyl)-propanoic acid which was purified by column chromatography (silica gel; eluent - hexane:diethylether = 1:1). The pure acid (4.83 g, 21 mmol; yield 70%) was obtained in 50% optical purity (enantiomeric excess). Melting point 154-155°C.

HPLC analysis performed as described in J. Pharm. Pollock. 68, 112 (1979) showed an enantiomeric ratio S(+):R(-)=75:25.

The enantiomeric ratio was confirmed by <1>H-NMR (200 MHz) analysis performed as described in Example 14 on the corresponding methyl ester.

Example 16

Preparation of 2-(6-methoxy-2-naphthyl)-propionic acid from 2-(1-bromethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R )- dicarboxylic acid N, N, N', N'- tetraethylamide

A mixture of the two diastereoisomers of 2-(1-bromomethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid N,N,N' ,N'-tetraethylamide 13 and 14 in the ratio 13:14=1:1 (1.07 g, 2 mmol) and 4 ml of water were heated with stirring to 100°C for 16 hours (acidic pH). After work-up as described in example 15 and purification by column chromatography (silica gel; eluent - hexane:diethylether =1:1) pure 2-(6-methoxy-2-naphthyl)-propionic acid was obtained (0.124 g, 0.54 mmol; yield 27%) with 40% optical purity.

Sm.p. 154-155OC.

Zo7d200 + 26.4° (c=1%, chloroform).

The enantiomeric ratio S(+) :R( -) =70:30 was confirmed by HPLC and by <1>H-NMR analysis carried out as described in example 15.

Example 1 7

Preparation of 2-(6-methoxy-2-naphthyl)-propionic acid from 2-(1-chloroethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R )- dicarboxylic acid

A mixture of the two diastereoisomers of 2-(1-chloro-ethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 9 and 10 in ratio 9:10=1:1 (24 mmol) and an aqueous solution (168 ml) of 14.6 g K2HPO4 and 3.19 g KH2PO4 with pH 6.6, was heated with stirring to 98°C for 110 hours. The reaction mixture was cooled to room temperature (pH 5.7), acidified with concentrated HCl to pH 1 and extracted with 4 x 50 ml diethyl ether. The organic phase was extracted with a 10% aqueous solution of sodium bicarbonate (4 x 50 ml). The combined aqueous extracts were acidified to pH 1 and extracted with 4 x 90 mL diethyl ether. the combined organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo.

4.8 g of residue, 72 ml of 1,2-dimethoxyethane and 36 ml of HCl were heated with stirring to 75°C for two hours. After working up the reaction mixture as described in example 5 and purification by column chromatography (silica gel; eluent - hexane:diethylether = 7:3), pure 2-(6-methoxy-2-naphthyl)-propionic acid was obtained in 48% optical purity.

/q7D20= +31f6° (c=1% chloroform).

The enantiomeric ratio S( + ) :R(-)=74:26 was confirmed by HPLC and by ^H-NMR analysis carried out as described in example 15.

Example 18

A mixture of the two diastereoisomers of 2-(1-chloro-ethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 9 and 10 in ratio 9:10=1:1 (10 mmol) and an aqueous solution (140 ml) of 20 g of KH2PO4 and 1 g of sodium hydroxide at pH 4.9 was heated to reflux for 240 hours.

The reaction mixture was cooled to room temperature (pH 3.6) and was worked up as described in example 17. Pure 2-(6-methoxy-2-naphthyl)-propionic acid was obtained in 62% optical purity.

/a7D20= +40.9° (c=1%, chloroform).

The enantiomeric ratio S( + ) :R(-)=81 :1 9 was confirmed by HPLC and by ^H-NMR analysis carried out as described in example 15.

Example 19

A mixture of the two diastereoisomers of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 25 and 26 in the ratio 25:26=1:1 (2.52 g, 5 mmol; prepared as described in example 2 from diastereoisomers 11 and 12) and 70 ml of an aqueous solution of 10 g KH2PO4 and 1.4 g sodium hydroxide with pH 6, was heated to 90°C for 50 hours. The reaction mixture was cooled to room temperature (pH 5.9) and was worked up as described in example 15.

0.83 g (2.7 mmol; yield 54%) of pure 2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid was obtained in 70% optical purity. Sm.p. = 166-168°C.

£aJD20= +29.4°C (c=0.5%, chloroform).

The enantiomeric ratio S (+ ):R(-)=85:15 was confirmed by HPLC and by <1>H-NMR analysis carried out as described in example 15.

Example 20

A mixture of the two diastereoisomers of 2-(1-bromomethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid 25 and 26 in the ratio 25:26=1:1 (2.52 g, 5 mmol) and 70 ml of an aqueous solution of 10 g KH2PO4 and 0.5 g sodium hydroxide with pH 5.15 was heated to 90°C for 52 hours . The reaction mixture was cooled to room temperature (pH 4.40) and worked up as described in example 15.

0.82 g (2.33 mmol; yield 47%) of pure 2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid was obtained in 68% optical purity.

Sm.p. = 168-170°C.

/o7d20= +28.8°C (c=0.5%, chloroform).

The enantiomeric ratio S( + ) :R(-)=84:1 6 was confirmed by HPLC and by 1 H-NMR analysis carried out as described in example 15.

Example 21

Preparation of the diastereomeric mixture of 2(R)-hydroxy-3(R)-/2-(6-methoxy-2-naphthyl)-propanoyl/-butanedioic acid dimethyl ester

A solution of 4.45 g (0.044 mol) triethylamine in 10 ml dichloromethane was added dropwise at -10°C and over five minutes to a mixture of 44.5 g (0.25 mol) 2(R),3 (R)-dihydroxy-butanedioic acid dimethyl ester and 90 ml of dichloromethane. To the thus obtained mixture was added dropwise a solution of 2-(6-methoxy-2-naphthyl)-propionyl chloride (5 g, 0.02 mol; prepared as described in Japanese patent application 57/145841, CA. 98, 72492 h) in 25 ml of dichloromethane at -10°C and during 20 minutes. The reaction mixture was poured into 200 ml of a 10% aqueous solution of sodium bicarbonate and was extracted with 100 ml of dichloromethane. The organic phase was washed with dilute HCl, with water, and was dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the impure diastereoisomeric mixture of 2 (R)-hydroxy-3 (R)-Z"2-(6-methoxy-2-naphthyl)-propanoyl7-butanedioic acid dimethyl ester A and B (5.5 g ) in the ratio A:B=1:1 (determined by <1>H-NMR).

<1>H-NMR (200 MHz, CDCl 3 -TMS), delta (ppm): - all data were identical to those given for diastereoisomers A and B in Example 4.

Crystallization from methanol induced pure crystalline diastereoisomer A gave the pure diastereoisomer A (RRS). Sm.p. = 77-790C.

faJD20=+73.70 (c=<|%, chloroform).

Example 22

Preparation of the diastereoisomeric mixture of 2-(1-bromomethyl)-2-(6-methoxyv-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylase dimethyl ester.

A solution of 11.8 g (34.8 mmol) of 1,1-dimethoxy-2-bromo-1-(6-methoxy-2-naphthyl)-propane in 100 ml of 1,2-dichloroethane was added dropwise under argon to a solution obtained by heating to 95°C a mixture of 75 g of 2(R),3(R)-dihydroxy-butanedioic acid dimethyl ester, 7.5 ml of thionyl chloride and 0.37 g (3.8 mmol) of methanesulfonic acid. The reaction mixture was heated to 125°C for one hour and during this period 1,2-dichloroethane was distilled off.

The reaction mixture was then poured into 10% aqueous sodium bicarbonate solution and extracted with dichloromethane.

The combined organic extracts were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo.

Purification of the residue by column chromatography (silica gel; eluent: dichloromethane:hexane = 8:2) gave the diastereoisomeric mixture of 2-(1-bromomethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4 (R),5(R)-dicarboxylic acid dimethyl ester 1 and 2, 7.2 g (15 mmol; yield 43%) in a 1:1 ratio (determined by <X>H-NMR and HPLC).

Example 23

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

A solution of 13.5 g (34.8 mmol) 1,1-dimethoxy-2-iodo-1-(6-methoxy-2-naphthyl)-propane in 100 ml in 1,2-dichloroethane was added dropwise under argon , to a solution obtained by heating to 95°C a mixture of 75 g of 2(R), 3(R)-dihydroxy-butanedioic acid dimethyl ester, 7.5 ml of thionyl chloride and 0.37 g (3.8 mmol) of methanesulfonic acid. The reaction mixture was heated to 125°C for one hour and during this period 1,2-dichloroethane was distilled off.

The reaction mixture was then poured into a 10% aqueous solution of sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo.

Purification of the residue by column chromatography (silica gel; eluent: dichloromethane:hexane = 8:2) gave the diastereoisomeric mixture of 2-(1-iodoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4 (R),5(R)-dicarboxylic acid dimethyl ester 25 and 26, 5>29 g (10 mmol; yield 29%) in a 1:1 ratio. <X>H-NMR (200 MHz, CDCl3-TMS) 6 (ppm):

Diastereoisomer 25 (RRS)

1.80 (3H, d, J=7 Hz); 3.44 (3H, s); 3.84 (3H, s); 3.90 (3H, s); 4.58 (1H, q, J=7 Hz); 4.95 (2H, ABq, A v = 20.70, J=6 Hz); 7.8-8.0 (6H, m).

Diastereoisomer 26 (RRR)

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

Example 24

Ketalization of 2-bromo-1-(6-methoxyv-2-naphthyl)-propan-1-one with 2(R),3(R)-dihydroxybutanedioic acid diethyl ester (L(+)-diethyltartrate).

A mixture of 1.465 g (0.005 mol) of 2-bromo-1-(6-methoxy-2-naphthyl)-propan-1-one, 10 g of (L(+)-diethyl tartrate, 3 g of triethyl orthoformate and 1 g of sulfuric acid was kept with stirring and under nitrogen at 90°C for 60 hours. The reaction mixture was poured into a 10% aqueous solution of sodium carbonate and was extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave an impure material which was purified by column chromatography (silica gel; eluent: hexane:diethylether = 8:2).

The mixture of the two diastereoisomers of (2-(1-bromomethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolan-4 (R), (5)(R)-dicarboxylic acid diethyl ester 27 and 28 (0.96 g, 0.002 mol) in a 1:1 ratio (determined by <X>H-NMR 200 MHz) was obtained.

<1>H-NMR (CDCl3 - TMS) (200 MHz)

Diastereoisomer 27 (RRS): 6 (ppm)

1.04 (t, 3H, J=7Hz); 1.31 (t, 3H, J=7Hz); 1.65 (d, 3H, J=6.8 Hz); 3.92 (dq, 2H, J=11.3 Hz, J=7 Hz); 3.98 (s, 3H); 4.3 (q, 2H, J=7Hz); 4.48 (q, 1H, J=6.8 Hz); 4.88 (ABq, 2H, J=6.5 Hz); 7.2-8.2 (6H, aromatic protons).

Diastereoisomer 28 (RRR): 6 (ppm)

1.09 (t, 3H, J=7 Hz); 1.29 (t, 3H, J=7 Hz); 1.62 (d, 3H, J=6.8 Hz); 3.98 (s, 3H); 4.29 (q, 2H, J=7 Hz); 4.85 (ABq, 2H, J=6.5 Hz); 7.2-8.2 (6H, aromatic protons).

Example 25

Ketalization of 2-bromo-1-T4-(2-methylpropyl)-phenyl"1-propan-1-one with 2(R),3(R)-dihydroxybutanoic acid dimethyl ester (L(+)-dimethyltartrate).

A mixture of 1.345 g (0.005 mol) 2-bromo-l-[4-(2-methylpropyl )-phenyl]-propan-l-one, 7.5 g L( + )-dimethyltartrate, 2.5 g (0 .0236 mol) of trimethylorthoformate and 0.075 g (0.0005 mol) of trifluoromethanesulfonic acid were kept under stirring and under nitrogen at 90°C for 48 hours. The reaction mixture was poured into a 10% aqueous solution of sodium carbonate and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave an impure material which was purified by column chromatography (silica gel; eluent: hexane: diethylether = 8:2).

The mixture of the two diastereoisomers 2-(1-bromomethyl)-2-[4-(2-methylpropyl)-phenyl]-1, 3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 29 and 30, 0, 64 g (0.00175 mol) in a 1:1 ratio (determined by <1>H-NMR 200 MHz) was obtained.

<1>H-NMR (CDCl3-TMS) (200 MHz):

Diastereoisomer 29 (RRS): 6 (ppm)

0.87 (d, 6H, J=6.4 Hz); 1.61 (d, 3H, J=7.1 Hz); 1.84 (t-ept, 1H, <J>CH-CH3=6.4 Hz, <J>CH-CH2=7.1 Hz); 2.45 (d, 2H, J=7.1Hz); 3.53 (s, 3H); 3.84 (s, 3H); 4.38 (q, 1H, J=7.1 Hz); 4.9 (AB, 2H, J=5.9 Hz); 7-7.4 (AA'BB' , 4H, aromatic protons) .

Diastereoisomer 30 (RRR): 6 (ppm)

0.87 (d, 6H, J=6.4 Hz); 1.58 (d, 3H, J=7.1 Hz); 1.87 (t-ept, 1H, <J>CH-CH3=6.4 Hz, <J>CH-CH2=7.1 Hz); 2.53 (d, 2H,

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

Example 26

Ketalization of 2-bromo-3-methyl-1-(4-chlorophenyl)-butan-1-one with 2(R),3(R)-dihydroxybutanoic acid dimethyl ester (L(+)-dimethyl-tartrate).

A mixture of 1.38 g (0.005 mol) 2-bromo-3-methyl-1-(4-chlorophenyl)-butan-1-one, 7.5 g L(+)-dimethyltartrate, 2.5 g (0 .0236 mol) of trimethylorthoformate and 0.075 g (0.0005 mol) of trifluoromethanesulfonic acid were kept under stirring and under nitrogen at 90°C for 60 hours. The reaction mixture was poured into a 10% aqueous solution of sodium carbonate and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave an impure material which was purified by column chromatography (silica gel; eluent: hexane: diethylether = 8:2).

The mixture of the two diastereoisomers of 2-(1-bromo-2-methylpropyl)-2-(4-chlorophenyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 31 and 32, 1.09 g (0.0025 mol) in a 1:1 ratio (determined by <1>H-NMR 200 MHz) was obtained.

Claims (5)

1. Process for the production of optically active alpha-arylalkanoic acids of formula where Ar denotes a naphthyl substituted in the 6-position with a Cx-C4 alkoxy group and in the 5-position with hydrogen or with a halogen atom, or where Ar denotes phenyl substituted in the 4-position with a C^-C alkyl group, or with a halogen atom, and where R denotes C 1 -C alkyl, characterized in that an alkyl-aryl ketal of formula (I) wherein Ar and R are as defined above; Rx and R2, which are the same or different, denote a hydroxy-, an 0R3 or an N(R3)2 group, R 3 denotes a C 1 -C alkyl group, X denotes a group selected from the group consisting of chlorine-, bromine or iodine atom, hydroxy, C₁-C₂-alkanoyloxy and C₁-C₂-alkylsulfonyloxy group, and wherein the carbon atoms marked with an asterisk are both simultaneously in the R or S configuration, and wherein the ketal of formula (I) exists in the form of epimers with respect to the carbon atom attached to the X group, is produced by reacting L(+)- or D(-)-tartaric acid or a derivative thereof of formula in which Rx and R2 have the meanings given above, with a) a ketone of formula wherein Ar, R and X have the meanings given above, in the presence of an acid catalyst and of an orthoester at a temperature of from 50 to 90°C or by azeotropic distillation of the water formed by the ketalization in the presence of a suitable organic solvent, or with b) a ketal of formula wherein Ar, R and X have the meanings given above, R5 and R6 denote a C1-C6 alkyl group, in an inert gas atmosphere in the presence of an acid catalyst under anhydrous conditions, at a temperature of from 20 to 125°C, and if desired, by converting the ketal of formula (I) in which R1=R2=OR3 to the corresponding ketal of formula ( I) wherein Rx and/or R2 = 0H by treatment with a strong base at room temperature in an aqueous medium, followed by acidification to pH 1, or if desired, by conversion of the ketal of formula (I) wherein R1=R2=OR3 to the corresponding ketal of formula (I) in which Rx and/or R2 =N(R3)2 on treatment with an amine of formula (R3)2NH in an aqueous medium at room temperature, which process is also characterized in that a ketal of formula (I) is rearranged to the above-mentioned alpha-arylalkanoic acid in a single step in an aqueous medium, at an acidic pH, at a temperature between room temperature and 150°C, forming the corresponding alpha -arylalkanoic acids with an enantiomeric ratio higher than the epimeric ratio of the starting ketal of formula (I), or in two steps by treating indicated ketals of formula (I) in the presence of a metal salt as a catalyst in an organic medium that does not contain alcohols or glycols at a temperature of from 15 to 50°C, while forming a compound of general formula wherein Ar, R, R 2 and R 2 have the meanings given above, and where R 6 is hydroxy, which is then subjected to hydrolysis under acidic conditions, at from room temperature to 95°C to form alpha-arylalkanoic acids having an enantiomeric ratio equal to the epimeric ratio of the alpha-halogenketal starting material. 2. Method according to claim 1, characterized in that an inorganic or sulphonic acid is used as acid catalyst. 3. Method according to claim 1, characterized in that the acidic pH is in the range from 4 to 6. 4. Method according to claim 1, characterized in that the suitable organic solvent is selected from the group consisting of benzene, toluene, xylene and heptane. 5. Method according to claim 1, characterized in that Ar is naphthyl substituted in the 6-position with a C 1 -C alkoxy group, and in the 5-position with hydrogen or with a halogen atom. in