DD234422A5 - METHOD FOR PRODUCING NEW, OPTICAL ACTIVE KETALES - Google Patents

Abstract

The invention relates to a process for preparing ketal of the general formula (I), wherein Ar, R, R1 and R2 have the meanings given in the application documents. The carbon atoms provided with both have the same R or S configuration at the same time. For the preparation of this compound, L () or the (-) -tartaric acid or a derivative thereof of the formula is reacted with a ketone of the general formula (II) or with a ketal of the general formula (III). The compounds of the invention can be rearranged to a-arylalkanoic acids.

Description

R _{3 is} a C ₁ -C ₂₄ -alkyl, C ₃ -C ₆ -cycloalkyl, phenyl or benzyl group,

M ^{+ represents} an alkali metal cation,.

R ₄ and R ₅ , which may be the same or different, represent a hydrogen atom, a C ₁ -C ₄ -alkyl radical, a C ₁ -C ₆ -cycloalkyl group, or a {CH ₂ ) _n -CH ₂ OH group with = 1, 2 or 3, or

R ₄ and R ₅ together form a (CH ₂ ) _m group with m = 4 or 5.6 ^ e-CH ₂ -CH ₂ -R ₆ -CH ₂ -CH ₂ - group, in which R _{6 is} an oxygen atom, an NH- or an N-id-Q-alkyl group,

X represents a chlorine, bromine or iodine atom or a hydroxy, acyloxyalkylsulphonyloxy or arylsulphonyloxy group,

wherein the carbon atoms provided with an * are both in the R or S configuration simultaneously, characterized in that L (+) or D (-) tartaric acid or a derivative thereof of the general formula

R ₁ -CO-CH-CH-CO-R ₀

OH OH in which R ₁ and R _{2 have} the meanings given above,

a) with a ketone of the general formula (II)

Ar "" C -Oxi-R, ~ r -j- \

HI \ J - 1- 1

OX

wherein Ar, Rund X have the meanings given above, or

b) with a ketal of the general formula (III)

Ar CH-R

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

R ₈ and R ₉ denote a C ₁ -C ₄ -AlkYIgTUpPe or R ₈ and Rg together represent a C ₂ -C ₆ alkylene group, so that with the 0-C-0-Gnjp ;; 3 a 5- or 6-membered ring, reacts.

2. The method according to item!, Characterized in that one converts a ketal of the general formula (I), wherein R = R ₂ = OR ₃ , by treatment with a strong base in a ketal of the general formula (I), wherein Ri and / or R ₂ = O "M ⁺ , where M ^{+ has} the meanings given in claim 1 and, if desired, converting the last compound by acidification into a ketal of the general formula (I) in which R ₁ and / or R ₂ signify a hydroxy group.

3. The method according to item Ϊ, characterized in that one converts a ketal of the general formula (I) wherein R ₁ = R ₂ = OR ₃ , by treatment with an amine in a ketal of the general formula (I), wherein R ₁ and / or R _{2 are} NR ₄ R ₅ ", wherein R ₄ and R _{5 have} the meanings given in claim 1.

Field of application of the invention

The invention relates to a process for the preparation of new, optically active ketals. These ketals can be used to prepare α-arylalkanoic acids.

Characteristic of the known technical solutions

As is known, the α-arylalkanoic acids constitute a large class of compounds, many of which are useful as anti-inflammatory and malignant drugs.

These include 2- (4-isobutylphenyl) propionic acid, also known as ibuprofen, 2- (3-phenoxyphenyl) propionic acid, also known as ^: enoprofen, 2- (2-fluoro-4-diphenylyl) -propionic acid, also known as flurbiprofen known 2- [4- (2-thienylcarbonyl) -phenyl] -) ropionsäure, also known as Suprofen and 2- (6-methoxy-2-naphthyl) -propionic acid, the S (+) - isomer as Naproxen sekannt. There are also other connections to it.

Another group of α-arylalkanoic acids can be used as intermediates for the preparation of pyrethroid insecticides. These include (2- (4-chlorophenyl) -3-methylbutyric acid and 2- (4-difluoromethoxyphenyl) -3-ethylbutyric acid.

Many α-arylalkanoic acids possess at least one center of asymmetry on the carbon atom which is α -contiguous to the carboxyl group They are therefore in the form of stereoisomers, Often one of the isomers (enantiomers) has a significantly lower biological activity.

A particularly typical example of this is 2- (6-methoxy-2-naphthyl) propionic acid, whose S (+) enantiomer (naproxen) has much more pronounced pharmacological properties than the R (-! Enantiomer and the racemic mixture.

Among the most recently described processes for the preparation of α-arylalkanoic acids, the most interesting are those which proceed via a rearrangement of alkyl-aryl ketals which are substituted in the α-position with respect to the ketal group.

Such methods are described, for example, in European Patent Application Nos. 34871 (Blaschim), 35305 (Blaschim), 48136 Sagami), 64394 (Syntex), 89711 (Blaschim), 101124 (Zambon), in Italian Patent Application No. 21841 A / 82 Blaschim and CNR), 22760 A / 82 (Zambon) and 19438 A / 84 (Zambon) and in J. Chem. Soc. Perkin 1,11,2575 (1982).

All these processes lead in a more or less elegant manner to α-arylalkanoic acids which are in the form of racemic mixtures.

Dptically active .alpha.-arylalkanoic acids can be obtained by separating the thus obtained racemic mixtures by means of customary / empirical, d. H. with optically active bases. It is also possible to carry out the above-described rearrangement process with optically active ketals previously prepared in accordance with the procedures described in European Patent Application Nos. 67698 (Sagami) and 81993 Syntex).

In the production of α-arylalkanoic acids, all of the abovementioned processes use ketals as starting material which have been obtained by reacting arylalkyl ketones with aliphatic alcohols or glycols.

Object of the invention

The process provided by the invention leads to ketals of arylalkyl ketones which are pure enantiomers. In the case of the process according to the invention, therefore, time-consuming and complicated process steps for the separation of acetic mixtures can be avoided. The ketals of arylalkyl ketones obtainable in accordance with the invention can be used as intermediates for the preparation of optically active α-arylalkanoic acids or their precursors which have either a comparable or a greater optical purity with respect to the ketals used as starting compounds.

Explanation of the essence of the invention

The object of the invention is to provide a process for the preparation of chiral ketals of arylalkyl ketones, which are pure enantiomers and which have two asymmetric centers in the ketal group, both having either R or S configuration.

The compounds obtainable according to the invention can be used as intermediates for the preparation of optically active α-kryialkansäuren or their precursors.

The novel ketals obtainable according to the invention have the general formula I.

(D

Xr represents an optionally substituted aryl group,

= i is a Cr-Q-alkyl group,

^ i and R ₂ , which are the same or different, are hydroxy, O "M ⁺ , OR 3 or

~ -R ₄

N>. stand, where

R _{3 is} a C 1 -C ₂₄ -alkyl, C 1 -C 6 -cycloalkyl, phenyl or benzyl group, M ^{+ is} an alkali metal cation,

R ₄ and R ₅ , which may be the same or different, represent a hydrogen atom or a C 1 -C ₄ -alkyl, C ₆ -C ₆ -cycloalkyl or (CH ₂ ) _n -CH ₂ OH group, where n = 1, ₂ or 3 ,or

R ₄ and R ₅ together form a (CH ₂ ) _m group, with m = 4 or 5.6 ^ e-CH ₂ -CH ₂ -R ₆ -CH ₂ -CH ₂ -GrUpPe, wherein R _{6 is} an oxygen

X represents a chlorine, bromine or iodine atom or a hydroxy, acyloxyalkylsulfonyloxy or arylsulfonyloxy group,

wherein the asterisked carbon atoms are both in the R or S configuration simultaneously. The compounds of the general formula I which can be obtained according to the invention, in which X denotes no hydroxy group, can be used for the preparation of α-arylalkanoic acids by means of a rearrangement.

In the compounds of the general formula I obtainable according to the invention, an aryl group preferably denotes an aromatic monocyclic, polycyclic, orthocondensed polycyclic or heteroaromatic group having up to 12 carbon atoms in the aromatic ring, eg. As phenyl, diphenyl, naphthyl, thienyl and pyrrolyl. The optionally present substituents of these aryl groups are, for. B. one or more halogen atoms, Ci-C ₄ alkyl, Qr-Cfs-cycloalkyl, benzyl, hydroxy, C ₁ -C ₄ -alkoxy, C ₁ C ₄ alkylthio, C ₁ -C ₄ -HaIOalkyl, C ₁ -C ₄ -HaIOaikoxy, phenoxy, thienylcarbonyl and benzoyl substituents.

Specific examples of the radical Ar are: 4-isobutylphenyl, 3-phenoxyphenyl, 2-fluoro-4-diphenyl, 4'-fluoro-4-diphenyl, 4- (2-thienylcarbonyO-phenyl, 6-methoxy-2-naphthyl, 5-Chloro-6-methoxy-2-naphthyl, 5-bromo-6-methoxy-2-naphthyl, 4-chlorophenyl, 4-difluoromethoxyphenyl, 6-hydroxy-2-naphthyl, 5-bromo-6-hydroxy-2- naphthyl and 5-chloro-6-hydroxy-2-naphthyl When X in the general formula I denotes an acyloxy group, it is understood to mean, in particular, an acetoxy, trichloroacetoxy, trifluoroacetoxy, benzoyloxy or 4-nitrobenzoyloxy group and generally an acyloxy group which Among an alkylsulfonyloxy and an arylsulfonyloxy group is, in particular, a group of the formula

-0-SO ₂ -R ₇

in which R _{7 is} preferably a C 1 -C ₄ -alkyl or a C _e -C 2 0 -alkylaryl group; In particular, it is possible to cite mesylate, benzenesulfonate and tosylate.

The invention thus provides a process for the preparation of the compound of the general formula I, wherein either (a) a ketone of the general formula II

; Ar-CO-CH-R (II)

wherein Ar, R and X have the meanings given above, with L (+) - tartaric acid or D (- (- tartaric acid or a derivative thereof of the formula

R is -CO-CH-CH-CO-R ₀ i.

¹ ι ² , ·

OH OH '

wherein R ₁ and R _{2 have} the meanings given above, ketalized or (b) a ketal of the general formula III

^R 8 \ / ^R 9 - -

\ (III)

Ar CH-R

wherein Ar, R and X have the meanings given above, R ₈ and Rg is a C ₁ -C ₆ alkyl or together are a C2-C _e are alkylene radical, so that the OC-0-group is a 5- or 6-membered Ring yields, transketalized. The ketalization is carried out by heating in the presence of an acid catalyst and an orthoester. Alternatively, the water formed during the ketalization may be distilled off azeotropically in the presence of a suitable organic solvent such as benzene, toluene, xylene or heptane.

This preparation process is particularly suitable for the preparation of the ketals of general formula I wherein Ri and R ₂ , which may be the same or different, represent an OR ₃ group. Starting from these ketals, it is possible to prepare all ketals in which R ₁ and R _{2 have} the meanings given above.

Thus, for example, the partial hydrolysis of the ketals gives the general formula I wherein Ri = R ₂ = OR ₃ , with one equivalent of a base (eg an alkali hydroxide) to the corresponding monosalts (eg Ri = 0 "M ⁺ , R ₂ = OR ₃ ) from the latter compounds can be obtained by acidification of the corresponding monoacids (eg Ri = OH, R ₂ = OR ₃ ) .The hydrolysis of the ketals with Ri = R ₂ = OR ₃ with two equivalents a base (eg alkali hydroxide) gives the corresponding salts (eg Ri = R ₂ = 0 "M ⁺ ). After acidification, the corresponding dicarboxylic acid derivatives (Ri = R ₂ = OH) are obtained. The latter can be converted without difficulty into other derivatives, such as esters (eg R ₁ and / or R ₂ = OR ₃ ) or amides. The amide derivatives can also be obtained directly from the ketals of general formula I, wherein R ₁ = R ₂ = OR ₃ , by reacting with a suitable amine of the formula R ₄ R ₅ NH.

It is also possible by direct ketalization. To produce ketals of the general formula I, in which the substituent X has a meaning other than the ketone used as starting compound Ii. Thus, starting from a ketone of general formula II where X is a chlorine or bromine atom, a ketal of general formula I wherein X is OH can be obtained by treatment with a strong base such as alkali metal alcoholate.

The ketals of the general formula I in which X is acyloxy, alkylsuifonyloxy or arylsulfonyloxy can be prepared by reacting the ketals of the general formula I in which X represents a hydroxy group with a suitable acyl, alkylsulfonyl or arylsulfonyl halide. If desired, the ketals of the general formula I in which X is an acyloxy group can be prepared by hydrolysis to produce the ketals of the general formula I in which X denotes a hydroxy group.

The transketalization is carried out by reacting a mixture of a ketal of general formula III and L (+) - or D (-! - tartaric acid or a derivative thereof in the presence of an acid catalyst under anhydrous conditions under nertgasatmosphäre to a temperature of 20-100 ⁰ C heated.

Suitable acidic catalysts are inorganic acids or sulfonic acids.

In this case too, it is possible to modify the meanings of R ₁ , R ₂ and X as described in the case of ketalization.

Both the ketones of the general formula II and the ketals of the general formula III are known compounds which can be prepared by known methods.

It should be noted, however, that the carbon atoms provided with an asterisk in the ketals of general formula I, irrespective of the preparation process, have the same configuration as the tartaric acid used as the starting compound, i. they both have R or S configuration.

It has now surprisingly been found that the reactions for preparing the ketals of the general formula I according to the above Dehydrated methods (a) and (b) diastereogenically and depending on the reaction conditions can also be stereoselective in the sense that they are mixed of ketals of the general formula I in which sines of the two epimers (in terms of bound to the group X carbon) predominates or very much outweighs.

By selecting the appropriate ketone of formula II and the appropriate tartaric acid derivative, it is possible to obtain substantially the desired optically active epimer.

Assuming an already optically active ketone of the general formula II, then it is readily apparent that one can obtain Spemere ketals of the general formula I, in which the ratio between the two epimers is greater than that of the enantiomers used in the starting compounds ketones.

Regardless of the above, it is also important to note that the ketals of general formula I exist in the form of epimers, which can be readily enriched or separated according to known methods, for example, by crystallization.

It is thus possible to separate the desired epimer of the ketal of general formula I and to rearrange it so as to obtain the appealing optically active α-arylalkanoic acid in a substantially pure form. Isomer separation performed with a precursor, d. H. with an interconnect, is often much simpler than the separation separation of the final product because the cost of the interconnect is lower.

The possibility of ketals of the general forms! I, which have a large number of different groups with respect to the substituents R 1 and R ₂ , makes it possible to change the hydrophilic and lipophilic character of these ketals over a wide range. This range extends from compounds with strong polar groups (alkali salts, amides) to ipophilic compounds (esters with long-chain alcohols).

Because of these possibilities, one can select that ketal of general formula I which is most suitable for the experimental conditions used in the various processes for the preparation of α-arylalkanoic acids by rearrangement.

It should be emphasized that tartaric acid derivatives, and in particular L (+) - tartaric acid, are available on the market at a price comparable to the price of the glycols previously seeded for ketalization according to the known rearrangement processes described above.

For the preparation of α-arylalkanoic acids via the rearrangement of the ketals of the general formula I, it is possible to use procedures which are known from other different ketals. It can be one-step or two-step procedures.

It has now been found that, when carrying out such processes with the ketals of the general formula I (in which X is not hydroxy), α-arylalkanoic acids are obtained in which the enantiomeric ratio corresponds to the epimeric ratio of the ketals used as starting compounds.

Depending on the nature of the ketal used as the starting compound and especially on the specific substituent X present in the ketal itself.

Thus, for example, ketals of the general formula I in which X represents an iodine atom, when Ar represents a 6-methoxy-2-naphthyl group and R represents CH ₃ , can be prepared without difficulty according to the methods described in European Patent Application No. 89711 or in Italian Patent Application No 21841 A / 82.

Those ketals in which X represents a halogen atom and Ar represents any of the aryl groups may be prepared in the presence of certain metal salts (serving as catalysts) according to the methods described in European Patent Applications Nos. 3,488,171 or 3,5305 and J. Chem. Soc. Rearrange Perkin 1,11,2575 (1982). This rearrangement may alternatively be carried out in a polar protic medium under neutral or weakly alkaline conditions, if desired in the presence of an inert diluent, according to the process described in Italian Patent Application No. 22760A / 82 or in Suropean Patent Application No. 101124 carry out.

* / on the said method is preferably used the latter, since it can be easily carried out and there are no

Metal salts required as catalysts. .. .. _ _ _ ..

The ketals of the general formula I in which X represents a readily leaving group such as acyloxy, alkylsulfonyloxy or phenylsulfonyloxy can be converted into derivatives of α-aryialcanic acids according to the process described in European Patent Application No. 48136.

The above rearrangement processes generally lead to derivatives of the α-arylalkanoic acids, in particular to esters. This is hydrolyzed according to known methods to the corresponding acids.

The invention also relates to a novel rearrangement process which leads to α-arylalkanoic acids in which the enantiomeric ratio is higher than the epimeric ratio of the ketals used as starting compounds.

Such a method is hereby defined as enantioselective. This means that the enantiomeric composition ratio between the enantiomers S and R) of the α-arylalkanoic acids thus obtained differs from the epimeric composition of the ketals of the general formula I used as starting compounds and surprisingly corresponds to an increase in the optical purity of the α-arylalkanoic acids.

3EI the enantioselective rearrangement method according to the invention by treating a ketal of the general formula I, wherein X is not hydroxyl group, in an aqueous medium at an acidic pH at a temperature between room temperature and 15O ⁰ C.

The above-mentioned reaction conditions are particularly unexpected and surprising, since it is well known that the treatment of a ketal with water under acidic conditions is a general method to convert a ketal to the corresponding ketone and an alcohol or diol. Accordingly, the already known alpha-substituted alkylaryl ketals are readily hydrolyzed under such conditions to the corresponding alkylaryl ketone and an alcohol or diol.

The novel rearrangement process according to the invention is preferably carried out with ketals of the general formula I which are soluble or at least partially soluble in water under the reaction conditions. Thus, ketals of general formula I are used in which Ri and / or R _{2 are} hydrophilic groups. Depending on the nature of the ketal of the general formula I, it is also possible to use a further solvent.

The rearrangement is preferably carried out by heating the ketal of general 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 time depends mainly on the nature of the ketal of general formula I and on the reaction temperature.

Usually the a-arylalkanoic acids are only slightly soluble in water. It is therefore possible at the end of the reaction to isolate the optically active a-arylalkanoic acid by simple filtration.

As far as is known, this is the first time that ketals are rearranged in water to produce α-arylalkanoic acids, the water being essentially the sole reaction solvent.

From an industrial point of view, the essential advantages of the rearrangement process according to the invention are the following:

(1) The process is enantioselective and results in α-arylalkanoic acids having an enantiomeric ratio higher than the epimeric ratio of the starting material;

(2) the water used as a solvent to carry out the reaction is cheap and safe to handle;

(3) No metal catalysts are required and

(4) The optically active α-arylalkanoic acid can be filtered off from the reaction mixture.

Of the optically active α-arylalkanoic acids, the most important from a pharmaceutical point of view is 2- (6-methoxy-2-naphthyl) -propionic acid, the S (+) - enantiomer of which is generally known by the name naproxen.

A preferred embodiment of the present invention therefore relates to ketals of the general formula IV

(IV)

wherein R ₁ , R ₂ and X have the meanings given in connection with the general formula I, Y is a hydrogen atom or a chlorine or bromine atom and Z represents a hydrogen atom, a methyl group or an alkali metal.

These compounds are used for the preparation of naproxen by means of rearrangement.

A preferred embodiment of the invention for the preparation of naproxen consists of rearranging a ketal of the general formula IV in which Z represents methyl and X represents a halogen atom in a polar solvent under neutral or weakly alkaline conditions.

An alternative preferred rearrangement method is to treat a compound of general formula IV wherein Z is an alkali metal in water or in an organic solvent under basic conditions.

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

The preferred rearrangement process for the ketals of general formula IV wherein X is not hydroxy, is in each case the enantioselective process in an aqueous medium under acidic conditions.

For the preparation of naproxen it may be necessary to replace the substituents Y (if this substituent is a chlorine or bromine atom) by a hydrogen atom. This is achieved by hydrogenolysis of the corresponding 2- (5-chloro- or 5-bromo-6-methoxy-2-naphthyl) propionic acid or its esters.

As already explained above, the rearrangement of the ketals of the general formula I to a-arylaic acids is a process in which no substantial racemization of the products takes place. The process is selective and results predominantly in the desired optically active α-arylalkanoic acids.

The rearrangement reaction of the compound of the general formula I, in particular when carried out under mild conditions, in an organic medium and in the absence of alcohols or glycols, can be used to form new ester intermediates of the general formula V

! I ^ ¹

Ar-CH-COO-CH-CH-R (V)

* * ι 10

CO-R 2

in which A, R, Ri and R _{2 have} the meanings given in connection with the general formula I and R ₁₀ sine hydroxy group or a chlorine, bromine or iodine atom. Depending on the reaction conditions, R ₁₀ can also have other meanings, such as acetate, propionate, benzoate.

The hydrolysis of the compounds of general formula V, preferably carried out under acidic conditions, leads to the corresponding free acids.

Accordingly, the rearrangement carried out under mild conditions, in an organic medium and in the absence of alcohols or glycols of the compounds of general formula IV to new esters of general formula Vl

CH CO-R

13 I 1

CH-COO-CH-CH-R (VI)

in which Y, Z, R ₁ , R ₂ and Ri _{0 have} the meanings given above. The hydrolysis of the esters of general formula (I), preferably carried out under acidic conditions according to the invention, results in naproxen or a precursor thereof.

Also in this case, where α-arylalkanoic acids are produced in two stages over the first of the general formula V or VI, no substantial racemization takes place. In addition, the obtained a-arylalkanoic acid consists of a mixture in which Jer outweighs one of the enantiomers.

The compounds of general formulas V and VI are novel compounds with interesting characteristics, which make them useful in many respects.

As already stated, they give, after hydrolysis, the corresponding α-arylalkanoic acids. In addition, they can be used for the optical resolution of α-arylalkanoic acids, since they have two centers of asymmetry (the carbon atoms to which the ^ 0-R ₁ and CO-R ^ groups are bonded) in the alcohol unit.

The separation of an acid into its optical isomers is usually carried out by preparing a salt with an optically active base.

By using the compounds of the general formulas V or VI, it is possible to provide a novel separation process for the separation of optically active α-arylalkanoic acids. Such a separation involving the formation of an ester with tartaric acid or a derivative thereof but not the preparation of a salt with an optically active base is novel.

Said separation process is particularly advantageous when the rearrangement of the ketals of the general formula I: u leads to a mixture of esters of the general formula V, which is enriched with the desired optical isomer.

Nevertheless, the compounds of general formulas V and VI can be used to separate α-arylalkanoic acids, irrespective of how the latter were prepared. Thus, it is possible to produce the compounds of the general formulas V or VI by esterification of a racemic mixture (or a mixture which is characteristic of one of the optical isomers) of an α-arylalkanoic acid prepared by any process with tartaric acid or a derivative thereof.

The presence of a chiral group in the alcohol moiety also makes it possible, starting from a mixture of on esters in alkaline conditions, to obtain the equilibrium of the mixture from which the desired isomer can be isolated by crystallization.

According to an expedient embodiment according to the invention, the esters of the general formula VI, be they only by rearrangement of a ketal of the general formula IV or by reaction of racemic 2- (6-methoxy-2-naphthyl) -jropionic acid or a precursor thereof with tartaric acid or a derivative thereof, prepared in a process for separating naproxen or a precursor thereof by fractional crystallization of the ester of general formula (I) whose hydrolysis results in naproxen or a precursor thereof in substantially pure form.

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

A further unexpected characteristic of the esters of the general formulas V and VI is that they are inherently chemically active. In particular, the compounds of the general formula VI are of interest.

The following tables show the test results obtained with respect to the antiinflammatory and antipyretic activity per compounds of general formula VI, in which:

Compound 31R ₁ = R ₂ = OCH ₃₁ R ₁ O = OH ₁ Y = H ₇ Z = CH ₃ ;

Compound b) R ₁ = R ₂ = OCH ₃ , R ₁₀ = OH ₁ Y = Br ₇ Z = CH ₃ . -

The results are compared to those obtained with naproxen and 5-bromo-naproxen (Compound c).

The results show that the new compounds, although their activity is lower than that of naproxen, have an interesting pharmacological activity, so that they may also find practical use in the therapy of humans.

Table I

Anti-inflammatory activity of compounds (a) and (b) when administered orally compared to naproxen and 5-bromo-naproxen (c).

connection

Dose (/ xm / kg / os)

Inhibition (3rd hour)

ED ₅₀

(C.L 95%)

naproxen

10 30

100 10 30

100 10 30

100

300 10 30

TÖO

175 (110-280)

160 (100-250)

196 (120-304)

31 (19-49)

Table II

Antipyretic activity of compound (a) and (b) after oral administration to rats, compared to naproxen and 5-bromo-naproxen (c).

connection

dose

(Μητι / kg / os)

Change in body temperature ( ⁰ C) after! Hour 2 hours

naproxen

10

30 100 300

io "

30 100

30

100

300

10

30

-0.02 +0.02 +0.07 -0.61 +0.01 -0.76 +0.03 -0.81 -0.17 -0.49 -0.68 -0.46 - -0.68 -0.17 -0.66 -1.33 -1.67 -1.42 -1.84 -0.38 -0.52 -1.22 -1.48 -1.86 -1.89

Table III

Antipyretic activity of compounds (a) and (b) upon intraperitoneal administration to rats compared to naproxen and 5-bromo-naproxen (c). *

connection

Dose (/ xrn / kg / ip)

Change in body temperature ("C) after

30 minutes 1 hour 4 hours

(a) (b) (c) naproxen

10 30 10 30 30 100 10

0.26 -0.52 -0.19 0.61 -1.02 -0.56 0.24 -0.52 -0.26 0.77 -0.87 -0.44 0.55 -1.01 +0.06 0.78 -1.45 -0.99 1.00 -1.10 -0.86

The invention will be explained in more detail with reference to the examples

example 1

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

A mixture of 2-bromo-1- (6-methoxy-2-naphthyl) -propan-1-one (1.465 g, 0.005 mol), L (+) - dimethyl tartrate (7.5 g), trimethyl-o-formate ( 2.5 g, 0.0236 mol) and trifluoromethanesulfonic acid (0.075 g, 0.0005 mol) is stirred under nitrogen for 60 h at 50 ° C, the reaction mixture is poured into a 10% aqueous sodium carbonate solution and extracted with dichloromethane. The organic phase is washed with water and dried over sodium sulfate / After removal of the solvent under reduced pressure to give a crude product, which is purified by column chromatography (silica gel, eluent: hexane: diethyl ether = 8: 2).

A mixture of the two diastereomers of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester 1 and 2 is obtained (0.9 g, 0.002 mol) in a ratio 1: 2 = 1: 1 (determined by means of ¹ H-NMR, 200 MHz).

Diastereomer 1 (RRS)

¹ H NMR (20OMHz ₁ CDCl ₃ -TMS) ₁ S (ppm): 1.68 (d, 3H, J = 7.5Hz); 3.54 (s, 3H); 3.90 (s, 3H); 4.08 (2.3H); 4.48 (q, 1H, J = 7.5Hz);

t, 94 (2H, ABq, = 26.8, J = 7.2Hz); 7.1-8.0 (6H ₁ ! Aromatic protons).

Diasteromer2 (RRR)

¹ H-NMR (200MHz, CDCl ₃ -TMS), 5 (ppm): 1.64 (d, 3H, J = 7.5Hz); 3.58 (s, 3H); 3.89 (s, 3H); 4.08 (s, 3H); 4.50 (q, 1H, J = 7.5Hz);

1.89 (2H, ABq, = 36.3, J = 6.3Hz); 7.1-8.0 (6H, aromatic protons).

Example 2

Preparation of diastereomeric mixture of 2- (1-bromoethyl) -2- {6-rnethoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid in the ratio 1: 1

A mixture of the two diastereomers of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid diethyl ester 3 and 4 (similar Prepared as described in Example 1 (21.18g, 0.044 mol, ratio 3: 4 = 1: 1), sodium hydroxide (3.52g, 0.088 mol), dimethoxyethane (35 ml) and water (35mlj stirred for 2 h at room temperature The reaction mixture is diluted with water and extracted with diethyl ether, the aqueous phase is acidified to pH 1 with concentrated hydrochloric acid, extracted with diethyl ether, the organic phase is washed with water and dried over sodium sulfate, and the solvent is removed under reduced pressure Diastereomers of 2- (1-bromoethyl) -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 a ratio of 5: 6 = 1: 1 (determined by means of ¹ H NMR, 200 MHz).

A sample obtained by esterification with diazomethane in diethyl ether gives a mixture of the two diastereomers of Zd-BromethyD ^ -ie-methoxy ^ -naphthyD- ^ S-dioxolan ^ iRJ.SiRl-dicarboxylic acid dimethyl ester 1 and 2 in a ratio 1: 2 = 1: 1 (determined by HPLC and ¹ 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 2-chloro-1- (6-methoxy-2-naphthyl) -propan-1-one (12.4g, 0.05 mol), 2 (R), 3 (R) -dihydroxybutanedioic acid dimethyl ester (75g) and trimethyl -o-formate (25 g, 0.236 mol) is heated slowly to 50 ° C. Trifluoromethanesulfonic acid (2.4 g, 0.016 mol) is added to the solution. The reaction mixture is kept under nitrogen for 45 h at 45 ° C and then worked up as described in Example 1.

After purification by column chromatography (silica gel, eluent hexane: diethyl ether = 6: 4) of the crude product (19.2 g), the mixture of the desired diastereomers 7 and 8 5.6 g) is obtained in a ratio of 7: 8 = 52:48 (determined by

¹ H-NMR (200 MHz, CDCl ₃ -TMS):

Diastereomer 7 (RRS), 8 (ppm): 1.49 (d, 3H, J = 6.65Hz); 3.48 (s, 3H); 3.85 (s, 3H); 3.89 (s, 3H); 4.41 (q, 1H, J = 6.65Hz); 4.95 (ABq, 2H, J = 6Hz); 7.1-8.0 (6H, aromatic protons).

Diastereomer 8 (RRR), 6 (ppm): 1.47 (d, 3H, J = 6.65Hz); 3.53 (s, 3H); 3.83 (s, 3H); 3.89 (s, 3H); 4.44 (q, 1H, J = 6.65Hz); 4.92 (ABq, 2H, J = 6Hz); 7.1-8.0 (6H, aromatic protons).

HPLC analysis was determined using a Hewlett Packard instrument (Model 1084 / B with a variable wavelength UV detector).

Column: Brownlee Labs RP8 (5 micron) spheri 250mm χ 4,6mm.

Solvent A: water, flow 0.96 ml / min;

Solvent B: methanol, flow 1.04 ml / min;

Temperature of the solvent A: 6O ⁰ C;

Temperature of solvent B: 4O ⁰ C;

Column temperature: 50 ^° C .;

Wavelength: 254nm;

Injection: 10 microliters of a 3 mg / ml solution in acetonitrile;

Retention times:

Diastereomer 7: 12.46min;

Diastereomer 8: 13.21 min.

Example 4 Preparation of 2 (R) -hydroxy-3 (R) - [2- (6-methoxy-2-naphthyl) -propanoyl] -butanedioic Acid Dimethyl Ester

CH COOCH ₀ 3 · ι 3

H-COO-CH-CH-OH

i

COOCH

A solution of silver tetrafluoroborate (2.4 g / 0.0123 mol) in 1,2-dichloroethane (8 ml) is added under inert gas atmosphere to a solution of the two diastereomers 7 and 8 (4.09 g, 0.01 mol) (ratio 7: 8 = 52:48), which is kept under stirring at 15 ⁰ C. The reaction mixture is heated to 50 ° C, 16h at 50 ° C, then cooled to room temperature and filtered.

The solution is diluted with 60 ml of dichloromethane, washed with 2 x 100 ml of water and dried over sodium sulfate. After stripping off the solvent under reduced pressure, a crude product is obtained which, after purification by column chromatography (silica gel, eluent n-heptane: diethyl ether = 2: 8), becomes a mixture of two diastereomeric esters A and B (2.9 g, 0.0074 mol; Yield 74%) in the ratio A: B = 52:48 (determined by means of ¹ H-NMR, 200 MHz).

¹ H-NMR (200 MHz, CDCl ₃ -TMS), δ (ppm):

Diastereomer A (RRS): 1.62 (d, 3H, J = 8Hz); 3.22 (s, 3H); 3.83 (s, 3H); 3.92 (s, 3H); 3.21 (d, 1H, J = 7.2Hz); 3.95 (q, 1 H, J = 8 Hz); 4.68 (dd, 1H, J CH-OH = 7.2Hz, J _ch -CH = 2.47Hz); 5.37 (d, 1H, J = 2.47Hz); 7.1-7.8 (6H, aromatic protons).

Diastereomer B (RRR): 1.66 (d, 3H, J = 8Hz); 3.58 (s, 3H); 3.72 (s, 3H); 3.92 (s, 3H); 3.24 (d, 1H, J = 7.6Hz); 3.97 (q, 1H, J = 8Hz); 4.78 (dd, 1H, J _ch -o _H = 2.47Hz); 5.45 (d, 1H, J = 2.47Hz); 7.1-7.8 (6H, aromatic protons).

Example 5 "" '

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

A mixture of the two diastereomeric esters A and B (2.2 g, 5.64 mmol, ratio A: B = 52:48, prepared as described in Example 4), 1,2-dimethoxyethane (22 ml) and 22 ml of concentrated hydrochloric acid is kept for 2 hours at 95 ° C, cool the mixture to room temperature, dilute with water and extract with dichloromethane, wash the organic phase with water and extract with a 10% aqueous sodium bicarbonate solution.

The basic aqueous phase is acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic phase is washed with water and dried over sodium sulfate. After removal of the solvent under reduced pressure gives crude 2- (6-methoxy-2-naphthyl) - propanoic acid. An analytically pure sample is obtained after purification by column chromatography (silica gel, eluent hexane: diethyl ether = 7: 3). iJ, 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

Following the procedure described in Example 2, starting from a mixture of the two diastereomers 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 diastereomers of the desired product 9 and 10 (32.5 g, 0.085 mol: yield 90.0 %) in the ratio 9:10 = 1: 1.

The diastereomer ratio was determined by HPLC analysis performed on a sample obtained by esterification with diazomethane.

¹ H-NMR (CDCl ₃ -TMS), δ (ppm), significant data:

Diastereomer 9: 1.44 (d, 3H, J = 6.85Hz); 4.42 (q, 1H, J = 6.85Hz); 4.88 (ABq, 2H, J = 6Hz); 7.0-8.0 (6H, aromatic protons);

9.0 (s, 2H).

Diastereomer 10: 1.44 (d, 3H, J = 6.85Hz); 4.42 (q, 1H, J = 6.85Hz); 4.82 (ABq, 2H, J = 6.7Hz); 7.0-8.0 (6H, aromatic

Protons); 9.0 (s, 2H).

Example 7 Preparation of diethyl α-d-bromoethyl-α-IB-bromo-e-methoxy-Z-naphtho-O-S-dioxolane-1-IRI-dicarboxylate

A solution of bromine (13.42 g, 0.084 mol) in 30 ml of carbon tetrachloride is added dropwise over 1 h to a solution of the two diastereomers of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) - 1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid diethyl ester 3 and 4 (ratio 3: 4 = 1: 1) (39.48 g, 0.082 mol) in carbon tetrachloride (457 ml), which is obtained under Stirring and under an inert gas atmosphere at 0 ⁰ C stops. The reaction mixture is kept for 1 h at ^{0 0} C, then poured into a well stirred 10% aqueous sodium carbonate solution (500 ml), the organic phase is separated off, washed twice with 500 ml of water and dried over sodium sulfate. After removal of the solvent under reduced pressure, the diastereomeric mixture of 2- (1-bromoethyl) -2- (5-bromo-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 Diastereomeric Mixture of 2- (1-Bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxoan-4 (R), 5 (R) -dicarboxylic Acid-N, IM, N ', N '-tetraethylamid

CH > ^NC ^> C < H I CON (CH ₉ CH ] H0 ^/ "-CH-CHj" J Br ₃ CH ₂ ), (O

A mixture of the two diastereomers of 2- (1-bromoethyl) -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), diethylamine (27.5 ml) and water (20 ml) are kept with stirring for 15 h at room temperature. The solvents are removed at room temperature and under reduced pressure and 50 ml of diethyl ether are added to the residue. The precipitate is filtered off and dried in vacuo. A diastereomeric mixture of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid-N, N-N ', N' Tetraethylamide 13 and 14 (11 mmol, yield: 88%) are obtained in the ratio 13:14 = 1: 1 (determined by means of ¹ H-NMR, 200 MHz).

Example 9

Preparation of the diastereomeric mixture of 2- {1-acetoxyethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester

2-Acetoxy-1,1-dimethoxy-1- (5-bromo-6-methoxy-2-naphthyl) -propane (1.22 g, 3.46 mmol) is added under argon to a solution which is obtained by heating a mixture of 2 (R), 3 (R) -dihydroxybutanedioic acid dimethyl ester (20g), thionyl chloride (1ml) and methanesulfonic acid (0.03g) at 65 ° C. The reaction mixture is heated for 30 min at 95 ⁰ C, then poured into a 10% aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic extracts are washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, eluent dichloromethane: hexane = 9: 1) gives the diastereomeric 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, 40% yield) in the ratio 15:16 = 65:35 (determined by means of ¹ H-NMR and HPLC). After crystallization from methanol to obtain a diastereomeric mixture in the ratio 15:16 = 95: 5.

¹ H-NMROOMHZjCDCI ₃ -TMSLS (PPm):

Diastereomer 15 (main component): 1.28 (3H, d, J = 6Hz); 1.93 (3H, s); 3.47 (3H, s); 3.87 (3H, s); 4.00 (3H, s); 4.96 (2H, ABq, = 12.35, J = 5.4Hz); 5.38 (1H, q, J = 6Hz); 7.23-8.30 (5H, aromatic protons).

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

Example 10

Preparation of the Diastereomeric Mixture of Z-ii-Acetoxyethyl O-methoxy-naphthyl-O-S-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester

2-Acetoxy-1,1-dimethoxy-1- (6-methoxy-2-naphthyl) -propane (23.5 g, 73.8 mmol) is added under argon to a solution which is obtained by heating a mixture of 2 (R. ), 3 (R) -Dihydroxybutandisäure acid dimethyl ester (150 g), thionyl chloride (15.6 ml) and methanesulfonic acid (0.7 g, 7,4mMol) obtained at 65 ⁰ C. The reaction mixture is heated for 30 min at 95 ⁰ C, then poured into a 10% aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic extracts are washed with water, dried over sodium sulfate, filtered and concentrated in vacuo.

After purification of the residue by column chromatography (silica gel, eluent dichloromethane: hexane = 7: 3), the diastereomeric mixture of 2- (1-acetoxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane is obtained. 4 (R), 5 (R) -dicarboxylic acid dimethyl ester 17 and 18 (15 g, 34.7 mmol, 47% yield) in the ratio 17:18 = 64:36 (determined by ¹ H-NMR and HPLC).

¹ H-NMROOMHZjCDCIj-TMSLS (PPm):

Diastereomer 17 (major constituent): 1.23 '(3Kd,' J '= 6Hz); 1.95 (3H, s) ;: 3.45 (3H, sj; 3.83 (3H, s); 3.88 (3H, s); 4.90 (2H, ABq, = 6.82, J = 5.4Hz); 5.33 (1H, q, J = 6) Hz); 7.06-8.00 ' (6H, aromatic protons).

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

Example 11

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

A solution of the diastereomeric mixture of 2- (1-acetoxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester 17 and 18 (ratio 17 : 18 = 1: 1) (4.33 g, 10mMoI) in 20 ml of methanol is added dropwise at room temperature to a solution of sodium hydroxide (4g, 10OmMoI) in 40ml of water. The reaction mixture is kept at room temperature for 24 h, then acidified with concentrated hydrochloric acid and extracted with diethyl ether. The combined organic extracts are washed with water, dried over sodium sulfate and filtered. After removal of the solvent under reduced pressure, the crude diastereomeric mixture of 2- (1-hydroxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4- (R), 5 (R) - dicarboxylic acid (3.26g).

The crude product thus obtained is added to a solution of methanesulfonic acid (0.086 g, 0.9 mmol) in methanol (300 ml). The solution is heated at reflux for 2 h, cooled to room temperature, diluted with 300 ml of dichloromethane and poured into 100 ml of water. The organic phase is separated off, washed with water and with a 2% aqueous sodium carbonate solution, dried over sodium sulfate and filtered. The crude product obtained by stripping off the solvent under reduced pressure

is crystallized from methanol and receives the diastereomeric 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: 77% yield) in the ratio 19:20 = 56:44 (determined by means of ¹ H-NMR and HPLC).

¹ H-NMRSOMHZiCDCI ₃ -TMS) ₁ S (PPm):

Diastereomer 19 (major constituent): 1.06 (3H, d, J = 6Hz); 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 = 6Hz, Jch-oh = 7.5Hz); 5.06 (2H, ABq, = 11.77, J = 4.2Hz); 7.13-8.00 (6H, aromatic protons).

Diastereomer 20 (minor component): 1.13 (3H, d, J = 6Hz); 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 = 6Hz, Jch-oh = 7.5Hz); 4.97 (2H, ABq, = 2.94, J = 1.5Hz); 7.13-8.00 (6H, aromatic protons).

Example 12

Preparation of the diastereomeric mixture of 2- [1- (4-methylphenylsulfonyloxy) ethyl] -2- {6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5, (R) -dicarboxylic acid dimethyl ester

A solution of 1,1-dimethoxy-2- (4-methylphenylsulfonyloxy) -1- (6-methoxy-2-naphthyl) -propane (15 g, 34.8 mmol) in 100 ml of 1,2-dichloroethane is added dropwise under argon a solution obtained by heating a mixture of 2 (R), 3 (R) -dihydroxy-butanedioic acid dimethyl ester (75g), thionyl chloride (7.5 ml) and methanesulfonic acid (0.37 g, 3.8 mmol) at 95 ⁰ C. receives. The reaction mixture is heated frequently 125 ° C and distilled off while 1,2-dichloroethane.

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

The combined organic extracts are 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) gives the diastereomeric 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: 57% yield) in the ratio 21: 22 = 40:60 (determined by ¹ H-NMR and HPLC ).

¹ H-NMR (200 MHz, CDCl ₃ -TMS), δ (PPm):

Diastereomer 22 (major constituent): 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 = 6Hz); 6.90-7.80 (10H, aromatic protons).

Diastereomer 21 (minor component: 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 = 6Hz); 6.90-7.80 (10H, aromatic protons).

Further purification by means of column chromatography (silica gel, eluent dichloromethane: hexane = 1: 1) leads to the pure main diastereomer 22.

Example 13

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

A solution of 1,1-dimethoxy-2-methanesulfonyloxy-1- (6-methoxy-2-naphthyl) -propane (24 g, 68 mmol) in 1,2-dichloroethane (140 ml) is added dropwise under argon to a solution, which is obtained by heating a mixture of 2 (R), 3 (R) -dihydroxybutanedioic acid dimethyl ester (120 g), thionyl chloride (12 ml) and methanesulfonic acid (0.6 g, 74 mmol). The reaction mixture is heated for 1 h at 125 ° C and distilled off while 1,2-dichloroethane.

The reaction mixture is then added to a 100% aqueous sodium bicarbonate solution, extracted with dichloromethane, the combined organic extracts wiped 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) gives the diastereomeric mixture of 2- (1-methanesulfonyloxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 ( R), 5 (R) -dicarboxylic acid dimethyl ester 23 and 24 (20g, 42.7 mmol, 63% yield) in the ratio 23:24 = 63:37 (determined by ' ¹ H-NMR and HPLC). Crystallization from methanol gives a diastereomeric mixture with a ratio of 23 (RRS): 24 (RRR) = 80:20

¹ H-NMROOMHZiCDCI ₃ -TMSKa (PPm):

Diastereomer 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, = 5.09, J = 4.2Hz); 7.06-8.00 (6H, aromatic protons).

Diastereomer 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, = 11.94, J = 6.3Hz); 7.06-8.00 (6Hz, aromatic protons).

Example 14

Preparation of 2- (6-methoxy-2-naphthyl) -propanoic acid ethyl ester from a diastereomeric mixture of dimethyl 2- (1-methanesulfonyloxyethyl) -1-methoxy-1-naphthyl-IS-dioxolane-1-tri, Si-R-dicarboxylate in the ratio 80: 20

The diastereomeric mixture of 2- (1-methanesulfonyloxyethyl) -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 are heated in a sealed tube for 5 h at 150 ° C. The reaction mixture is cooled to room temperature, diluted with water and extracted with diethyl ether. The combined organic extracts are washed with water, dried, filtered and concentrated in vacuo. After purification by column chromatography (silica gel, eluent dichloromethane) of the residue, methyl 2- (6-methoxy-2-naphthyl) -propanoate (0.4 g, 1.64 mmol, 77% yield) is obtained.

M.p. = 88 ° C.

[ _a ] 20 = + 48.02 ° (c = 1%, chloroform).

The ¹ H-NMR (200 MHz) analysis performed in CDCl 3 using an optically active shift reagent (europium-lll-tris [3- (eptafluoropropylhydroxymethylene) -d-camphorate]) shows an enantiomeric ratio S (+): R (-). ) = 80:20.

Example 15

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

A mixture of the two diastereomers of 2- {1-bromoethyl) -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) which is prepared by dissolving 26.1 g of K ₂ HPO ₄ and 5.7 g of KH ₂ PO _{4 in} 284 ml of water. The mixture is heated with stirring 21 h to 100 ⁰ C, the reaction mixture cooled to room temperature (pH 3.7), then purified with concentrated HCl to pH 1 and extracted with 3 χ 100ml diethyl ether. The combined organic extracts are washed with water and dried over sodium sulfate. After removal of the solvent under reduced pressure gives crude 2- (6-methoxy-2-naphthyl) -propanoic acid, which is purified by column chromatography (silica gel, eluent hexane: diethyl ether = 1: 1).

The pure acid (4.83 g, 21 mmol, 70% yield) is obtained in 50% optical purity (enantiomeric excess).

Schmp.154-155 ° C.

As described in J. Pharm. 68,112 (1979), shows an enantiomeric ratio S (+): R (-) = 75:25.

The enantiomeric ratio was confirmed by ¹ H-NMR analysis (200 MHz), which was carried out as described in Example 14 for the corresponding methyl esters.

Example 16

Preparation of 2- {1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R. ) -dicarboxylic acid-N, N, N ', N'-tetraethylamid

A mixture of the two diastereomers 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4- (R), 5 (R) -dicarboxylic acid-N, NSN'-tetraethylamide 13 and 14 in the ratio 13:14 = 1: 1 (1.07 g, 2 mmol) and 4 ml of water is heated with stirring for 16 h (acidic pH) to 100 ⁰ C. The procedure is as described in Example 15 and purified by column chromatography ( Silica gel; eluent:

Hexane: diethyl ether = 1: 1). This gives pure 2- {6-methoxy-2-naphthyl) propionic acid (0.244 g, 0.54 mmol, 27% yield) with 40% optical purity.

Schmp.154-155 ° C. ,

[a] § ° = + 26.4 ° (c = 1%, chloroform).

The enantiomeric ratio S (+): R (-) = 70:30 was confirmed by HPLC and ¹ H NMR analysis (performed as described in Example 15).

Example 17

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

A mixture of the two diastereomers of 2- <1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid9 and 10 in the ratio 9:10 = 1: 1 (24 mmol) and an aqueous solution (168 ml) of 14.6 g K ₂ HPO ₄ and 3.19 g KH ₂ P0 ₄ with a pH of 6.6 are heated with stirring for 110 h at 98 ° C. The reaction mixture is cooled to room temperature (pH 5.7), acidified to pH 1 with concentrated HCl and extracted with 4 χ 50 ml of diethyl ether. The organic phase is extracted with a 10% aqueous sodium bicarbonate solution (4 × 50 ml), the combined aqueous extracts are acidified to pH 1 and extracted with 4 × 90 ml of diethyl ether. The combined organic phases are washed with water, dried over sodium sulfate and concentrated in vacuo.

The residue (4.8g) of 1,2-dimethoxyethane (72ml) and 36ml concentrated HC! is heated with stirring for 2 h at 750 ⁰ C. The reaction mixture is worked as described in Example 5 up, purified by column chromatography (silica gel; eluent: hexane diethyl ether = 7: 3) to give pure 2- (6-methoxy-2-naphthyl) - propionic acid in 48% optical purity. [a] S ° = 4-31.6 ° (c = 1%, chloroform).

The enantiomeric ratio S (+): R (-) = 74:26 was confirmed by HPLC and ¹ H NMR analysis (performed as described in Example 15).

Example 18

A mixture of the two diastereomers of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid 9 and 10 in the ratio 9:10 = 1: 1 (1OmMoI) and an aqueous solution (140 ml) of 20 g KH ₂ PO ₄ and 1 g of sodium hydroxide with a pH 4.9 is heated for 240 h at reflux.

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

[±] 2 ° = + 40.9 ° (c = 1%, chloroform).

The enantiomeric ratio S (+): R (-j -.31: 19 was confirmed by HPLC and ¹ H-NMR analysis (carried out as described in Example 15).

Example 19

A mixture of the two diastereomers of 2- (1-3romethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid 25 and 26 im Ratio 25:26 = 1: 1 (1.52 g, 5 mmol, prepared as described in Example 2, starting from the diastereomers 11 and 12) and an aqueous solution (70 ml) of 10 g KH ₂ PO ₄ and 1.4 g of sodium hydroxide A pH 6 is heated to 90 ^° C. for 50 h. The reaction mixture is cooled to room temperature (pH 5.9) and worked up as described in Example 15. Pure 2- (5-bromo-6-methoxy-2-naphthyl) propionic acid (0.83 g, 2.7 mmol, 54% yield) is obtained in 70% optical purity.

M.p. 166-168 ° C.

[a] l ° = + 29.4 ° (c = 0.5%, chloroform).

The enantiomeric ratio S (+): R (-) = 35:15 was confirmed by HPLC and ¹ H NMR analysis (performed as described in Example 15).

Example 20

A mixture of the two diastereomers of 2- (1-bromoethyl) -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 (2,52g, 5 mmol) and an aqueous solution (70 ml) of 1OgKH ₂ PO ₄ and 0.5 g of sodium hydroxide with pH 5.15 is heated 52h auf90 ⁰ C. The reaction mixture It is cooled to room temperature (pH 4.40) and worked up as described in Example 15 on. Pure 2- (5-bromo-6-methoxy-2-naphthyl) propionic acid (0.72 g, 2.33 mmol, 47% yield) is obtained in 68% optical purity.

M.p. 168-170 ⁰ C.

[a] § ° = + 28.8 ° (c = 0.5%, chloroform).

The enantiomeric ratio S (+): R (-) = 84:16 was confirmed by HPLC and ¹ H NMR analysis (performed as described in Example 15).

Example 21

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

A solution of triethylamine (4.45 g, 0.044 mol) in 10 mL of dichloromethane is added dropwise over 5 minutes at -10 ° C to a mixture of 2 (R), 3 (R) -dihydroxybutanedioic acid dimethyl ester (44.5 g, 0, 25MoI) and 90ml dichloromethane. Is added dropwise to the resulting mixture at -1O ⁰ C for 20min, a solution of 2- (6-methoxy-2-naphthyl) -propionyl chloride (5 g, 0.02 mol; prepared as described in Japanese Patent Application No. 57/145841. CA 98,72492 h) in 25 ml of dichloromethane, the reaction mixture is poured into 200 ml of a 10% aqueous sodium bicarbonate solution and extracted with 100 ml of dichloromethane. The organic phase is washed with HCl and with water and dried over sodium sulfate. Removal of the solvent under reduced pressure gives the crude diastereomeric mixture of 2 (R) -hydroxy-3 (R) - [2- {6-methoxy-2-naphthyl) -propanoyl] -butanedioic acid dimethyl ester A and B (5, 5 g) in the ratio A: B = 1: 1 (determined by means of ¹ H-NMR).

¹ H-NMR (200 MHz, CDClI-TMS), δ (ppm): All data are identical to those given in Example 4 for the diastereomers A and B.

Crystallization from methanol, induced with pure crystalline diastereomer A, gives the pure diastereomer A (RRS).

Mp. 77-79 ⁰ C.

[a] § ° = -73.7 ° (c = 1%, chloroform).

Claims (1)

Invention claim: 1. Process for the preparation of ketals of the general formula (I) Ar represents an optionally substituted aryl group, R is a Cr-Q-alkyl group, R ₁ and R ₂ , which may be the same or different, represent a hydroxy group, O - M ⁺ , OR ₃ or N stand, where