FI92688B - Process for the preparation of optically active &alpha-arylalkane carboxylic acids - Google Patents

Abstract

The invention relates to a process for the preparation of α-arylalkane carboxylic acids of the formula <IMAGE> wherein Ar is an optionally substituted aryl group and R is C1 -4 alkyl. In the process a ketal of the formula I <IMAGE> wherein Ar and R are as defined above, R1 and R2 are hydroxy, an optionally substituted amino group or a O'M' or OR3 group, wherein R3 is alkyl, cycloalkyl, phenyl or benzyl and M' is an alkali metal cation, X is halogen or optionally estherized hydroxy group, and the carbon atoms indicated by an asterisk are both simultaneously either in R or S configuration, is isomerized in one or two steps.

Description

92688

Process for the preparation of optically active α-arylalkanecarboxylic acids

This invention relates to a process for the preparation of optically active α-arylalkanecarboxylic acids using as intermediates optically active ketals which are converted to said acids.

It is well known that α-arylalkanecarboxylic acids form a large group, many of which are useful as anti-inflammatory and analgesic drugs.

Among these, mention may be made of 2- (4-isobutylphenyl) -propionic acid, known as Ibuprofen, 2- (3-phenoxyphenyl) -propionic acid, known as phenoprofen, 2- (2-fluoro-4-diphenyl) -propionic acid, known as Flurbiprofen, 2 - ([4- (2-thienylcarbonyl) -phenyl] -propionic acid, known as Suprofen, 2- (6-methoxy-2-naphthyl) -propionic acid, of which 20 S The (+) isomer is known as Naproxen et al.

Another group of α-arylalkanecarboxylic acids are useful as intermediates in the synthesis of pyrethroid insecticides, among which may be mentioned 2- (4-chlorophenyl) -3-methylbutyric acid and 2- (4-difluoromethoxyphenyl) -3-25 methylbutyric acid.

Many α-arylalkanecarboxylic acids have at least one center of asymmetry on the carbon atom in the α-position relative to the carboxyl and are therefore in the form of stereoisomers. Often, one isomer (enantiomer) is associated with significantly higher biological activity.

Particularly clear is, for example, 2- (6-methoxy-2-naphthyl) propionic acid, the S (+) enantiomer (Naproxen) of which has clearly stronger pharmacological properties than the R (-) enantiomer or their racemic se-35. bicarbonate solution.

92688 2

Among the recently described methods for preparing α-arylalkanecarboxylic acids, the most interesting are those involving the rearrangement of alkyl-aryl ketals substituted at the α-position with respect to ketal groups.

Mention may be made of the methods described in EP-A-34871 (Blashim), 35305 (Blashim), no. 89711 (Blashim) and 101124 (Zambon), in IT Patent Applications 21841 A / 82 (Blashim and CNR), 22760 A / 82 (Zambon) and 10 19438 A / 83 (Zambon) and in Chem. Soc. Perkin I.

11, 2575 (1982).

In all these processes, more or less expediently obtain α-arylalkanecarboxylic acids as racemic mixtures.

The preparation of optically active α-arylalkanecarboxylic acids can be carried out by separating the isomers from the racemic mixtures thus obtained by conventional methods, i. with optically active bases, or by carrying out the above-mentioned rearrangement reaction with optically active ketals prepared by the methods described in EP-A-67698 (Sagami) and 81993 (Syntex).

All of the above processes use as starting materials for the preparation of α-arylalkanecarboxylic acids ketals obtained by reacting arylalkyl ketones with aliphatic alcohols or glycols. A process for the preparation of optically active α-arylalkanecarboxylic acids has now been invented using as intermediates chiral, enantiomerically pure ketals of arylalkyl ketones of formula I 30 as defined below having two asymmetric centers in the ketal group, each of which is R or each. This method gives α-arylalkanecarboxylic acids having an optical purity equal to or greater than that of the ketals used as intermediates.

3 92683

The invention therefore relates to a process for the preparation of optically active α-arylalkanecarboxylic acids of the formula

Ar-CH-COOH,

5 I

R

wherein Ar is naphthyl substituted in the 6-position by a C 1-4 alkoxy group and in the 5-position by a hydrogen or halogen atom, or Ar is phenyl substituted in the 4-position by a C 1-4 alkyl group or a halogen atom, and R is C 1-4 alkyl . In a first step of the process according to the invention, an alkylaryl ketal of formula (I) is prepared.

R. “CO H

V-c * 'Λ (I) 2 0 kr CH-R "

X

wherein Ar and R are as defined above; R 1 and R 2 independently represent a hydroxy group or a group OR 3 or N (R 3) 2, wherein R 3 is a C 1-4 alkyl group; and X is a chlorine, bromine or iodine atom or a hydroxy, C 1-4 alkanoyloxy, C 1-4 alkylsulfonyloxy or arylsulfonyloxy group; and the asterisked carbon atoms are each simultaneously in the R or S configuration, and the ketal of formula (I) is in the form of epimers with respect to the carbon atom attached to the group X by reacting L (+) - or D (-) - tartaric acid or a derivative thereof of formula R, -CO-CH-CH-CO-Rj

II

35 OH OH

92688 4 wherein R 1 and R 2 are as defined above, to react with a) a ketone of formula

Ar-CO-CH-R

[(II)

5 X

wherein Ar, R and X are as defined above, in the presence of an acid catalyst and an orthoester at a temperature of 50-90 ° C, or by azeotropically distilling off the water formed in the ketalization in the presence of a suitable organic solvent, or b) with a ketal of formula r50 , or6 c 15 Ar ^ N \: hr (m) x wherein Ar, R and X are as defined above and Rs and R620 are a C1-4 alkyl group, in an inert gas atmosphere in the presence of an acid catalyst under anhydrous conditions at 20-125 ° C, and if desired by changing the formula A ketal of formula (I) wherein R 1 = R 2 = OR 3 to a corresponding ketal of formula (I) wherein R 1 and / or R 2 is OH by treating it with a strong base at room temperature in an aqueous medium and then adjusting the pH to 1, or if desired converting a ketal of formula (I) wherein R 1 = R 2 = OR 3 to the corresponding ketal of formula (I) wherein R 1 and / or R 2 is N (R 3) 2 by treating it with an amine of formula R 3 NH in an aqueous medium at room temperature.

The ketal of formula I thus obtained is converted in the process according to the invention to the above-mentioned α-arylalkanecarboxylic acid in one step in an aqueous medium at an acidic pH of 92688 at a temperature between room temperature and 150 ° C to give the corresponding α-arylalkanecarboxylic acid. silicic acids having an enantiomeric ratio greater than that of the ketal epimers of formula I used as starting material.

When X in formula I is a C 1-4 alkanoyloxy group, it may be, for example, acetoxy. The arylsulfonyloxy group X represents a group of the formula -O-SO 2 -R 7 wherein R 7 is preferably a C 6 -C 20 alkylaryl group. Specific examples of 10 C 1-4 alkylsulfonyloxy and arylsulfonyloxy groups X include mesylate, benzenesulfonate and tosylate.

The above-mentioned method step (a), i.e. ketalization of a ketone of formula II with L (+) - or D (-) - tartaric acid or a derivative thereof, is carried out by heating in the presence of an acid catalyst or orthoester; alternatively, the water formed in the ketal formation is distilled azeotropically in the presence of a suitable organic solvent such as benzene, toluene, xylene or heptane.

This process is particularly suitable for the preparation of ketals of the formula I in which R1 and R2 are the same or different O3 groups. By using such ketals as starting materials, it is possible to prepare all ketals in which R1 and R2 are as defined above in connection with formula I.

For example, hydrolysis of ketals of formula I wherein R 1 = R 2 = OR 3 with one equivalent of base (e.g. alkali hydroxide) gives the corresponding mono-salts (e.g. R 1 = ΟΉ +, R 2 = OR 3); from the latter, the corresponding monoacids (e.g. R 1 = OH, R 2 = OR 3) are prepared by adding an acid.

Hydrolysis of ketals where R 1 = R 2 = OR 3 with two equivalents of base (e.g. alkali hydroxide) gives the corresponding salts (e.g. R 1 = R 2 = O "M +) which are obtained by acid addition with the corresponding dicarboxylic acid-35 derivatives (R 1 = R 2 = OR 3). The latter can be easily converted to other derivatives such as esters (e.g. R 1 and / or R 2 = R 3 O) or amides.

Amide derivatives can also be prepared directly from ketals of formula I wherein R 1 = R 2 = R 3 by reacting them with the appropriate amine of formula R 1 NH.

In an alternative preparation of the ketal of formula I (b), i.e. in the trans-ketalization reaction of the ketal of formula III with said L (+) - or D (-) - tartaric acid 10 or a derivative thereof, an acid catalyst is used. Suitable acid catalysts are inorganic or sulfonic acids. Again, it is possible to modify the meanings of R 1, R 2 and X as described above. Both the ketone of formula II and the ketal of formula III are known compounds which can be readily prepared by known methods. It is noteworthy that the asterisked carbon atoms in the ketal of formula I have the same configuration as the starting tartaric acid, i.e. they are each in the R or S configuration, regardless of the method of preparation.

It has quite surprisingly been found that the reactions for the preparation of ketals of formula I by process (a) and process (b) above are stereoisomeric and, depending on the reaction conditions, can also be steroselective in the sense that they give ketals of formula I. a mixture in which one of the two epimers (relative to the carbon atom attached to the X group) is predominant or strongly predominant. By selecting a suitable ketone of formula II and a suitable tartaric acid derivative, it is possible to prepare essentially the desired optically active epimer. It is clear that by using as starting material an already optically active ketone of the formula II, it is possible to prepare ketals of the formula I in which the ratio of the two epimers is higher than the enantiomer of the original ketones. relationship.

92688 7

Notwithstanding the foregoing, it is also important that the ketals of formula I be in the form of epimers which can be easily enriched or which can be separated by known methods, for example by crystallization.

It is thus possible to separate the desired epimer of the ketal of formula I and carry out the rearrangement to give the corresponding optically active α-arylalkanicarboxylic acid in almost pure form. Separation of the isomer, which is performed on the precursor, is often more suitable than separation of the isomers from the final product (resolution), because the separation of the intermediate is cheaper.

In the process according to the invention, the alkylaryl ketal of the formula I is reacted in one step and leads to α-arylalkanecarboxylic acids having an enantiomeric ratio higher than the epimeric ratio of the starting ketals.

Such a process is defined here as enathioselective in that the enantiomeric composition (ratio of S and R enantiomers) in the α-arylalkanecarboxylic acids thus prepared is different from the epimeric composition of the ketals of formula I used as starting materials for the rearrangement reaction and corresponds exactly to astonishingly increasing the optical purity of α-arylalkanecarboxylic acids.

This enantioselective rearrangement process is novel and involves treating a ketal of formula I wherein X is other than a hydroxide in aqueous solution at an acidic pH of 30 between room temperature and 150 ° C.

The above reaction conditions are particularly unexpected and surprising because it is known that treatment of a ketal with water under acidic conditions is a common method for converting it to the corresponding 3,92688 ketones and alcohols or diols. Correspondingly, previously known α-substituted alkylaryl ketals are rapidly hydrolyzed to give the corresponding alkylaryl ketone and alcohol or diol.

This new rearrangement process is preferably carried out using ketals of the formula I which are water-soluble or at least partially water-soluble under the reaction conditions, i.e. ketals of the formula I in which R1 and / or R2 are hydrophilic groups.

10 Depending on the nature of the ketal, a co-solvent may be used. The rearrangement is preferably carried out by heating a ketal of formula I in water at pH 4-6.

The desired pH can be maintained by adding an appropriate amount of buffer.

The duration of the reaction depends mainly on the nature of the ketal of formula I and the reaction temperature.

Usually, α-arylalkanecarboxylic acids are sparingly soluble in water, therefore, at the end of the reaction, the optically active α-arylalkanecarboxylic acid can be separated by simple filtration.

To the applicant's knowledge, the rearrangement of ketals to produce α-arylcarboxylic acids is carried out for the first time in an aqueous medium with water being essentially the only reaction solvent.

The main advantages of this conversion process from an industrial point of view can be summarized as follows: (1) the process is enantioselective and yields α-arylalkanecarboxylic acids with an enantiomeric ratio higher than that of the starting materials; 30 (2) the reaction solvent is water, which has economic and safety benefits; (3) no metal catalysts are required; and (4) the optically active α-arylalkanecarboxylic acid is separated from the reaction mixture by filtration.

92688 9

Among the optically active α-arylalkanecarboxylic acids, the most pharmaceutically important is 2- (6-methoxy-2-naphthyl) propionic acid, the S (+) enantiomer of which is commonly known as Naproxen.

In a particular embodiment of the present invention, a ketal of formula (IV) is prepared

R -CO H

1 v __ / 10 «Λ N- *,

15 Y

wherein R 1, R 2 and X are as defined in formula I, Y is a hydrogen, chlorine or bromine atom and Z is methyl.

A compound of formula IV wherein Y is hydrogen can be used in the process of the invention for the preparation of Naproxen by a rearrangement reaction.

As stated above, the conversion of the ketals of formula I to α-arylalkanecarboxylic acids is a process which does not result in significant racemization of the final products and selectively produces the desired optically active α-arylalkanecarboxylic acids.

The following examples are provided to illustrate the invention.

Example 1 Ketalization of 3 0 2-bromo-1- (6-methoxy-2-naphthyl) propan-1-one with 2 (R) .3 (R) -dihydroxymeric acid dimethyl ester (Lf +) - 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 orthoformate (2.5 g, 0.0236 10,92688 moles) and trifluoromethanesulfonic acid (0.075 g, 0.0005 moles) were maintained at 50 ° C for 60 hours with stirring under a nitrogen atmosphere. The reaction mixture was poured into 10% aqueous sodium carbonate solution and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave a crude product which was purified by column chromatography (silica gel; eluent hexane: diethyl ether 8: 2).

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

Diastereoisomer 1 (RRS) 1 H-NMR (200 MHz, CDCl 3 -TMS), δ (ppm): 1.68 (d, 3H, J = 7.5 Hz); 3.54 (s. 3H); 3.90 (S, 3H), * 4.08 (s, 3H), 4.48 (q, 1H, J = 7.5 Hz); 4.94 (2H, ABq, Av = 26.8, J = 7.2 Hz); 7.1-8.0 (6H, aromatic protons).

Diastereoisomer 2 (RRR) * 1 H-NMR (200 MHz, CDCl 3 -TMS), δ (ppm): 1.64 (d, 3H, J = 7.5

Hz); 3.58 (s. 3H); 3.89 (s. 3H); 4.08 (s. 3H); 4.50 (q, 1 H, J = 7.5 Hz); 4.89 (2H, ABq, Av = 36.3, J = 6.3 Hz); 7.1-8.0 (6H, aromatic protons).

Example 2 2- (1-Bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4R. Preparation of a 1: 1 mixture of 5 (R) -dicarboxylic acid pond diastereoisomers.

H00C H

y ^

ri (J) XC00H

35 X1 92688

A mixture of the two diastereoisomers 3 and 4 of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4- (R), 5 (R) -dicarboxylic acid diethyl ester (prepared in the same manner as in Example 1) (21.18 g, 0.044 mol) in a ratio of (isomer 3: isomer 4) 1: 1, sodium hydroxide (3.52 g, 0.088 mol), dimethoxyethane (35 ml) and water (35 ml). ml), stirred at room temperature for 2 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. The solvent was evaporated under reduced pressure to give two diastereoisomers 5 and 6 of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid. (16 g, 0.0367 mol, 85.5% yield) in a ratio (5: 6) of 1: 1 (determined by 1 H-NMR at 200 MHz). A sample prepared by esterification in diethyl ether with diazomethane gave two diastereoisomers of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-20 4 (R), 5 (R) -dicarboxylic acid dimethyl ester. 1 and 2 mixtures (1: 2) 1: 1 (determined by HPLC and 200 MHz 1 H-NMR).

Example 3 Preparation of 2- (1-chloroethyl-2- (6-methoxy-2-naphthyl) -1,3-25-dioxolane-4 (R), 5 (R1-dicarboxylic acid dimethyl ester)

A mixture of 2-chloro-1- (6-methoxy-2-naphthyl) -propan-1-one (12.4 g, 0.05 mol), 2 (R), 3 (R) -dihydroxybutanecarboxylic acid dimethyl ester (75 g) and trime-30 style orthoformate (25 g, 0.236 mol) were gradually heated to 50 ° C.

Trifluoromethanesulfonic acid (2.4 g, 0.016 mol) was added to the solution. The reaction mixture was kept under a nitrogen atmosphere at 50 ° C for 45 hours; then it was continued as described in Example 1. Purification of the crude product 92688 12 (19.2 g) thus obtained by column chromatography (silica gel); eluent hexane: diethyl ether 6: 4) gave a mixture of the desired diastereoisomers 7 and 8 in a ratio (7: 8) of 52:48 (determined by HPLC). 5 H-NMR (200 MHz, CDCl 3 -TMS):

Diasterooisomer 7 (RRS) δ (ppm): 1.49 (d, 3H, J = 6.6 Hz); 3.48 (s. 3H); 3.85 (s. 3H); 3.89 (s, 3 H); 4.41 (q, 1H, J = 6.65 Hz); 4.95 (ABq, 2H, J = 6Hz); 7.1-8.0 (6H, aromatic protons).

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

HPLC analyzes were performed on a Hewlett Packard instrument (model 1084 / B adjustable wavelength in a UV detector).

Column: Brownlee Labs RPB (5 microns) size 250 mm x 4.6 mm

Solvent A: water, rate 0.96 ml / min Solvent B: methanol, rate 1.04 ml / min Solvent A temperature: 40 ° C Column temperature: 50 ° C Wavelength: 254 nm

Injection: 10 μΐ of a solution with a concentration of 3 mg / ml in acetonitrile

Retention time: diastereoisomer 7: 12.46 min diastereoisomer 8: 13.21 min Example 4 2- (1-chloroethyl) -2- (6-ethoxy-2-naphthyl) -1,3-dioxolane-4 (R Preparation of 5-dicarboxylic acid

According to the procedure described in Example 2, starting from 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dime-35 style ester A mixture of the diastereoisomer (38.4 g, 92688 13 0.094 mol; 7: 8 = 1; 1, determined by HPlC) gave a mixture of the two diastereoisomers 9 and 10 of the desired compound (32.5 g, 0.085 mol, 90.0% yield). ) in a ratio of (9:10) to 1: 1.

The ratio of diastereoisomers was determined by HPLC analysis obtained by esterification with diazomethane.

1 H-NMR (CDCl 3 -TMS), δ (ppm), significant results: Diastereoisomer δ 1.44 (d, 3H, J = 6.85 Hz); 4.42 (q, 1H, J = 6.85 Hz); 4.88 (Abq, 2H, J = 6Hz); 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 5 Preparation of 2- (1-bromoethyl) -2- [S-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R, 5 (R1-dicarboxylic acid polyethyl ester)

A solution of bromine (13.42 g, 0.084 mol) in carbon tetrachloride (30 ml) was added dropwise over 1 hour to Liu-20 oxy containing 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) 1 The two diastereoisomers of 3-dioxolane-4 (R), 5 (R) -dicarboxylic acid diethyl ester 3 and 4 in a ratio of (3: 4) 1: 1 (38.48 g, 0.082 mol) in carbon tetrachloride (457 ml) were stirred. At 0 ° C under an inert atmosphere. The reaction mixture was kept at 0 ° C for 1 hour; then it was poured into a well-stirred 10% aqueous sodium bicarbonate solution (500 ml). The organic phase was separated, washed with water (2 x 500 mL) and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave 2- (1-bromoethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) - a mixture of diastereoisomers 11 and 12 of the diethyl ester of dicarboxylic acid (43.6 g; purity 98% and ratio 1: 1, determined by HPLC).

92688 14

Example 6 Diastereoisomeric mixture of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R) .5 (R) -dicarboxylic acid NNN'.N'-tetraethylamide manufacture 5

, CH3CH2l2NCO

^ con (ch2ch3) 2 “i6W’cr“ CH30

A mixture of 2 and 2 diastereoisomers of 2- (1-bromoethyl) -2- (6-methoxy-2-15 naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester in a ratio of 1: 1 (12.5 moles; prepared as described in Example 1), diethylamine (27.5 ml) and water (20 ml) were kept under stirring at room temperature for 15 hours. The Liu-20 traps were removed at room temperature under reduced pressure, and diethyl ether (50 mL) was added to the residue. The precipitate was filtered off and dried in vacuo. Diastereoisomers of 2- (1-bromoethyl) -2- (6-methoxy-naphthyl) -1,3-dioxolane-4- (R), 5 (R) -dicarboxylic acid Ν, Ν, Ν ', N'-tetraethylamide were obtained. Mixtures of 13 and 14 (11 mmol; 88% yield) in a ratio of 1: 1 (determined by 1 H-NMR of 200 MH).

Example 7 Preparation of a mixture of diastereoisomers of 2- (1-acetoxyethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R1.5 (R) -dicarboxylic acid trimethyl-30 ester)

Add 2-acetoxy-1,1-dimethoxy-1- (5-bromo-6-methoxy-2-naphthyl) propane (1.22 g, 3.46 moles) under argon to a solution obtained by heating at 65 ° C. in a mixture of 2 (R), 3 (R) -dihydroxysuccinic acid dime-35 style ester (20 g), thionyl chloride (1 ml) and methane-15 92688 sulfonic acid (0.03 g). The reaction mixture was heated at 95 ° C for 30 minutes; then it was 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 by column chromatography gave diastereoisomers 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 of mixture (10:16) 65:35 (determined by 1 H-NMR and HPLC). Crystallization from methanol gave a mixture of diastereoisomers (15:16) 95: 5.

1 H-NMR (90 MHz, CDCl 3 -TMS), δ (ppm):

Diastereoisomer 15 (major component): 1.28 (3H, d, J = 6 15 Hz); 1.93 (3 H, s); 3.47 (3 H, s); 3.87 (3H, s); 4.00 (3H, s); 4.96 (2H, ABq, Av = 12.35, J = 5.4 Hz); 5.38 (1H, q, J = 6Hz); 7.23-8.30 (5H, aromatic protons). Diastereoisomer 16 (minor component); 1.23 (3H, d, J = 6Hz); 2.05 (3 H, s); 3.60 (3 H, s); 3.87 (3 H, s); 4.00 (3H, S), 4.90 (2H, ABq, Av = 22.95, J = 7 Hz); 5.38 (1H, q, J = 6Hz); 7.23-8.30 (5H, aromatic protons).

Example 8 Preparation of a mixture of diastereoisomers of 2- (1-acetoxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R) .5 (R1-dicarboxylic acid dimethyl ester)

2-Acetoxy-1,1-dimethoxy-1- (6-methoxy-2-naphthyl) -propane (23.5 g, 73.8 mmol) was added under argon to a solution obtained by heating the mixture at 65 ° C. with 2 (R), 3 (R) -dihydroxysuccinic acid di-30 methyl ester (150 g), thionyl chloride (15.6 mL) and methanesulfonic acid (0.7 g, 7.4 mmol). The reaction mixture was heated at 95 ° C for 30 minutes; then it was 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.

16 S2688

Purification of the residue by column chromatography (silica gel, eluent dichloromethane: hexane 7: 3) gave 2- (1-acetoxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), A mixture of 5 (R) -dicarboxylic acid dimethyl ester Dias-5 stereoisomers 17 and 18 (15 g, 34.7 mmol; 47% yield) in a ratio of (17:18) to 64:36 (determined by 1 H-NMR and HPLC) * 1 H-NMR (90 MHz, CDCl 3 -TMS), δ (ppm);

Diastereoisomer 17 (major component): 1.23 (3H, d, J = 6 Hz); 1.95 (3 H, s); 3.45 (3 H, s); 3.83 (3 H, s); 3.88 (3 H, s); 4.90 (2H, ABq, Av = 6.82, J = 5.4 Hz); 5.33 (1H, q, J = 6Hz); 7.06-8.00 (6H, aromatic protons). Diastereoisomer 18 (minor component): 1.20 (3H, d, J = 6 Hz); 2.00 (3 H, S); 3.57 (3 H, s); 3.81 (3 H, S); 3.88 (3 H, s); 4.80 (2H, ABq, Av = 15.54, J = 6.6 Hz); 5.33 (1H, q, J = 6Hz); 7.06-8.00 (6H, aromatic protons).

Example 9 Preparation of a mixture of diastereoisomers of 2- (1-hydroxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R) .5 (R) -dicarboxylic acid dimethyl ester

At room temperature, a mixture of diastereoisomers 17 and 18 of 2- (1-acetoxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester in a ratio of 1 was added dropwise at room temperature. : 1 (4.33 g 10 mmol) dissolved in a solution of methanol (20 ml) in sodium hydroxide (4 g 100 mmol) in water (40 ml). The reaction mixture was kept at room temperature for 24 hours, 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 a diastereoisomeric mixture of 2- (1-hydroxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid (3 , 26 (g) as a crude product.

! 17,92688 The crude product thus obtained was added to a solution of methanesulfonic acid (0.086 g, 0.9 mmol) in methanol (300 mL). The solution was heated at reflux for 2 hours, cooled to room temperature, diluted with di-chloromethane (300 mL) and poured into water (100 mL). The organic phase was separated, washed with water and 2% aqueous sodium carbonate solution, dried over sodium sulfate and filtered. After evaporation of the solvent under reduced pressure, the crude reaction product obtained was crystallized from methanol to give 2- (1-hydroxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 ( A mixture of diastereoisomers 19 and 20 of the dimethyl ester of R) -dicarboxylic acid (3 g, 7.7 mmol; 77% yield) in a ratio of 56:44 (determined by 1 H-NMR and HPLC).

15 H-NMR (90 MHz, CDCl 3-TMS) δ (ppm):

Diastereoisomer 19 (major component): 1.06 (3H, d, J = 6

Hz); 3.13 (1H, d, J = 7.5 Hz); 3.30 (3 H, s); 3.83 (3 H, s); 3.90 (3 H, s); 4.16 (1H, dg, Jch-ch52® Hz), Jch-oh = 7 r 5 Hz); 5.06 (2H, ABq, Av = 11.11, J = 4.2 Hz); 7.13-8.00 (6H, aromatic-20 protons).

Diastereoisomer 20 (minor component); 1.13 (3H, d, J = 6Hz); 3.13 (1H, d, J = 7.5 Hz); 3.56 (3 H, s); 3.82 (3 H, S); 3.90 (3 H, s); 4.16 (1H, dq, Jch-ciT5 ^ Hz, Jch-oh = 7 # 5 Hz); 4.97 (2Η, ABq, Av = 2.94, J = 1.5 Hz); 7.13-8.00 (6H, 25 aromatic protons).

Example 10 2-R 1 -M-methylphenylsulfonylloxy) ethyl-2-16-methoxy-2-naphthyl -1,3-dioxolane-4 (R). Preparation of a mixture of diastereoisomers of 5 (R1-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 1,2-dichloroethane (100 g) was added dropwise under argon. ml), to a solution obtained by heating at 95 ° C a mixture of 2 (R), 3 (R) -dihydroxy-92688 18 succinic acid dimethyl ester (75 g), thionyl chloride (7.5 ml) and methanesulfonic acid (0.37 g, 3.8 mmol). The reaction mixture was heated at 125 ° C for 1 hour, during which time 1,2-dichloroethane was distilled off.

The reaction mixture was then poured into 10% aqueous sodium carbonate 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 2- [1- (4-methylphenylsulfonyloxy) ethyl] -2- (6-methoxy-2-naphthyl) -1,3-dioxilane. A mixture of siastereoisomers 21 and 22 of 4 (R), 5 (R) -dicarboxylic acid dimethyl ester (10.8 g, 19.81 mmol; 57% yield) in a ratio of (21:22) to 40:60 (determined by 1 H-NMR and HPLC).

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

Diastereoisomer 22 (major component): 1.40 (3H, d, J = 6

Hz); 2.30 (3 H, s); 3.43 (3 H, s); 3.81 (3 H, s); 3.90 (3 H, 20 s); 4.80 (2 H, s); 4.90 (1H, q, J = 6Hz); 6.90-7.80 (10H, aromatic protons).

Diastereoisomer 21 (minor component): 1.37 (3H, d, J = 6 Hz); 2.26 (3 H, s); 3.43 (3 H, s); 3.83 (3 H, s); 4.76 (2 H, s); 4.90 (1H, q, J = 6Hz); 6.90-7.80 (10 H, aromatic 25 protons).

A new purification by column chromatography (silica gel, eluent dichloromethane: hexane = 1: 1) gave the pure major diastereoisomer 22.

Example 11 Preparation of a Diacetereoisomeric Mixture of Dimethyl Isomer of 2 - 2- (1-Methanesulfonyl) -2- [6-methoxy-2-naphthyl] -1H-1,3-dioxolane-4 (R] -5 (R] -dicarboxylic acid

A solution of 1,1-dimethoxy-2-methanesulfonyloxy-1- (6-methoxy-35-2-naphthyl) -propane (24 g, 68 mmol) in 1,2-dichloroethane (140 mL) was added dropwise under argon. to a solution prepared by heating a mixture of 2 (R), 3 (R) -dihydroxysuccinic acid dimethyl ester (120 g), thionyl chloride (12 ml) and methanesulfonic acid (0.6 g, 7, 4 mmol). The reaction mixture was heated at 125 ° C for 1 hour, during which time 1,2-di-5 chloroethane was distilled off.

The reaction mixture was then poured into 10% aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic solutions 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 2- (1-methanesulfonyloxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4- (R) A mixture of diastereoisomers 23 and 24 of 5 (R) -dicarboxylic acid dimethyl ester (20 g, 42.7 mmol; 63% yield) in a ratio of (23:24) to 63:37 (determined by 1 H-NMR and HPLC) . After crystallization from methanol, a diastereoisomeric mixture was obtained in a ratio of (23 (RRS): 24 (R-RR)] 80:20.

1 H-NMR (90 MHz, CDCl 3 -TMS), δ (ppm):

Diastereoisomer 23 (RRS): 1.38 (3H, d, J = 6 Hz); 2.93 (3 H, s); 3.37 (3 H, s); 3.90 (3 H, s); 4.80 (1H, q, J = 6Hz); 5.03 (2H, ABq, Av = 5.09, J = 4.2 Hz); 7.06-8.00 (6H, aromatic protons).

Diastereoisomer 24 (RRR); 1.38 (3H, d, J = 6Hz); 2.93 (3 H, s); 3.53 (3 H, s); 3.80 (3 H, s); 3.90 (3 H, s); 4.80 (1H, q, J = 6Hz); 4.97 (2H, ABq, Av = 11.94, J = 6.3 Hz); 7.06-8.00 (6H, aromatic protons).

Example 12 Preparation of 2- (6-methoxy-2-naphthyl) -propionic acid methyl ester 2- (1-Methanesulfonyloxy-ethyl) -2-C6-methoxy-2-naphthyl) -1,3-dioxolane-4R). From a mixture of diastereoisomers of 5 (R) -dicarboxylic acid dimethyl ester in a ratio of 80:20.

35 Mixture of diastereoisomers 23 and 24 of 2- (1-methanesulfonyloxyethyl) -2- (6-methoxy-2- • // 688 20 naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester (23:24) 80:20 (Ig, 2.13 mmol), methanol (7.5 mL) and water (2.5 mL) were heated in a sealed tube 150 at 5 ° C for 5 h.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 10; eluent dichloromethane) gave 2- (6-methoxy-2-naphthyl) -propionic acid methyl ester (0.4 g, 1.64 mmol; 77% yield).

Sp. = 88 ° C.

[α] D 20 = + 48.02 ° (c = 1%, chloroform) 15 1 H-NMR (200 MHz) analyzes performed in CDCl 3 using an optically active transition reagent (europium (III) -tris- [ 3-heptafluoropropylhydroxymethylene) -d-camphorate]) showed an enantiomeric ratio of [S (+): R (-)] of 80:20.

Example 13 Preparation of 2- (6-methoxy-2-naphthyl) propionic acid 2-N-bromoethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolan-4 (R) .5 (R) of a mixture of diastereoisomers of dicarboxylic acid 25 A mixture of two diastereoisomers of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid 5 and 6 (5: 6) 1: 1 (12.75 g, 30 mmol) and an aqueous solution (180 mL) prepared by dissolving K 2 HPO 4 (26.1 g) and KH 2 PO 4 (5.7 g) in water (382 30 ml), heated with stirring at 100 ° C for 21 hours. The reaction mixture was cooled to room temperature (pH 3.7), acidified to pH 1 with concentrated HCl and extracted with diethyl ether (3 x 100 mL). The combined organic extracts were washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure 92688 21 gave 2- (6-methoxy-2-naphthyl) -propionic acid as a crude product which was purified by column chromatography (silica gel; eluent hexane: diethyl ether 1: 1) · 5 Pure acid (5 4.84 g, 21 mmol, 70% yield)

50% optical purity (enantiomeric excess). Sp. 154-155 ° C

HPCL analyzes performed as described in J.Pharm. Sci. 68. 112 (1979), show a ratio of ena-10 thiomers of S (+): R (-) = 75:25.

The ratio of enantiomers was confirmed by 1 H-NMR (200 MHz) analyzes performed as described in Example 12 with the corresponding methyl ester.

Example 14 Preparation of 2- (6-methoxy-2-naphthyl) propionic acid 2- (1-bromoethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R) -5 (R1-dicarboxylic acid) NNN'N'-tetraetvvliamidista

A mixture of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R) -5 (R) -dicarboxylic acid 20 Ν, Ν, Ν'Ν ' The two diastereoisomers 13 and 14 of tetraethylamide 1: 1 (1.07 g, 2 mmol) and water (4 mL) were heated with stirring at 100 ° C for 16 h (acidic pH). Continuation as in Example 13 and purification by column chromatography (silica gel; eluent hexane: diethyl ether-25 R 1: 1) gave pure 2- (6-methoxy-2-naphthyl) propionic acid (0.124 g, 0.54 mmol; yield). 27%) with an optical purity of 40%.

Sp. 154-155 ° C

[α] D = + 26.4 ° (c = 1%, chloroform) The ratio of enantiomers [S (+): R: R (-)] 70:30 was confirmed by HPLC and NMR analyzes which was performed as described in Example 13.

92688 22

Example 15 Preparation of 2- (e-methoxy-2-naphthyl-propionic acid) 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R) .5R) - A mixture of the two diastereoisomers 9 and 10 of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid ( 9:10) 1: 1 (24 mmol) and an aqueous solution of K 2 HPO 4 (14.6 g) and KH 2 PO 4 (3.19 g) (168 mL) and pH 6.6 were heated with stirring to 98 ° C. at 110 hours. The reaction mixture was cooled to room temperature (pH 5.7), acidified to pH 1 with concentrated hydrochloric acid and extracted with diethyl ether (4 x 50 mL). The organic phase was extracted with 10% aqueous sodium bicarbonate (4 x 50 mL). The combined aqueous extracts were acidified to pH 1 and extracted with diethyl ether (4 x 90 mL). The combined organic extracts were washed with water, dried over sodium sulfate and concentrated in vacuo.

The residue (4.8 g), 1,2-dimethoxyethane (72 mL) and 20 concentrated HCl (36 mL) were heated with stirring at 75 ° C for 2 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with dichloromethane. The organic phase was washed with water and extracted with 10% aqueous sodium bicarbonate solution. The basic phase was acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. After evaporation of the solvent under reduced pressure, 2- (6-methoxy-2-naphthyl) propionic acid was obtained as a crude product. It was purified by column chromatography (silica gel; eluent hexane: diethyl ether 7: 3) to give pure 2- (6-methoxy-2-naphthyl) -propionic acid with an optical purity of 48%.

[α] D = 31.6 ° (c = 1%, chloroform) 92688 23

The ratio of enantiomers S (+): R (-) = 74: 26 was confirmed by HPLC and 1 H-NMR analyzes performed as described in Example 13.

Example 16 A mixture of two diastereoisomers 9 and 10 of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1'3-dioxolane-4 (R), 5 (R) -dicarboxylic acid (9:10) 1: 1 (10 mmol) and an aqueous solution (140 mL) of KH 2 PO 4 (20 g) and sodium hydroxide (1 g) at pH 4.9 was heated under reflux for 240 h.

The reaction mixture was cooled to room temperature (pH

3.6) and was treated as described in Example 15. Pure 2- (6-methoxy-2-naphthyl) -propionic acid with an optical purity of 62% was obtained.

[Α] D = + 40.9 ° (col%, chloroform)

The ratio of enantiomers [S (+): R (-)] 81:19 was confirmed by HPLC and 1 H-NMR analyzes performed as described in Example 13.

Example 17 A mixture of 2- (1-bromoethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid diastereoisomers 25 and 26 in a ratio of 1: 1 (2.52 g; 5 mmol; prepared as described in Example 2 using diastereoisomers 11 and 12 as starting materials) and 25 aqueous solution (70 ml) of KH 2 PO 4 (10 g) and sodium hydroxide (1.4 g) and having a pH of 6, was heated at 90 ° C for 50 hours. The reaction mixture was cooled to room temperature (pH 5.9) and worked up as described in Example 13.

Pure 2- (5-bromo-6-methoxy-2-naphthyl) propionic acid (0.83 g, 2.7 mmol; 54% yield) was obtained with an optical purity of 70%.

Sp. = 166 - 168 ° C

[Α] D = + 29.4 ° (c = 0.5%, chloroform) 92688 24

The ratio of enantiomers [S (+): R (-)] 85:15 was confirmed by HPLC and 1 H-NMR performed as described in Example 13.

Example 18 A mixture of 2- (1-bromoethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid two diastereoisomers 25 and 26 in ratios (25:26) 1: 1 (2.52 g, 5 mmol) and an aqueous solution (70 mL) of KH 2 PO 4 (10 g) and sodium hydroxide (0.5 g) at pH 10 5.15, heated at 90 ° C for 52 hours. The reaction mixture was cooled to room temperature (pH 4.40) and worked up as described in Example 13.

Pure 2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid (0.72 g; 2.33 mmol; 47% yield) was obtained with an optical purity of 68%.

Sp. = 168-170 ° C.

[α] β ° = + 28.8 ° (c = 0.5%, chloroform)

The ratio of enantiomers [S (+): R (-)] 84:16 was confirmed by HPLC by 1 H-NMR analyzes performed as described in Example 13.

Claims (4)

92688 25 1. I 35 OH OH 92688 26 wherein R 1 and R 2 are as defined above, to react with a) a ketone of formula Ar-CO-CH-R I (II) X wherein Ar, R and X are as defined above, in the presence of an acid catalyst and an orthoester at a temperature of 50 to 90 ° C, or by azeotropically distilling off the water formed in the ketalization in the presence of a suitable organic solvent, or b) with a ketal of formula r50 ^ y3R6 Ar / \ hR <ΙΙΓ) X wherein Ar, R and X are as defined above and R 5 and Ra 20 represent a C 1-4 alkyl group, in an inert gas atmosphere in the presence of an acid catalyst under anhydrous conditions at 20 to 125 ° C, and if desired by modifying the ketal of formula (I) , where R 1 = R 2 = OR 3, to the corresponding ketal of formula (I) wherein R 1 and / or R 2 is OH by treating it with a strong base at room temperature in an aqueous medium and then adjusting the pH to 1, or if desired by changing the pH of formula (I). ) wherein R 1 = R 2 = O 3 R 3 to the corresponding ketal of formula (I) wherein R 1 and / or R 2 is N (R 3) 2 by treatment with an amine of formula R 3 NH in an aqueous medium at room temperature, and (I), is converted to the above-mentioned α-arylalkanecarboxylic acid in one step in an aqueous medium at an acidic pH range of temperature sa, 35 between room temperature and 150 ° C to give the corresponding oarylalkanecarboxylic acids having an enantiomeric ratio higher than that of the ketal epimers of formula (I) used as starting material. r A process for the preparation of optically active α-arylalkanecarboxylic acids of the formula Ar-CH-COOH R wherein Ar is naphthyl substituted in the 6-position by a C 1-10 alkoxy group and having a hydrogen or halogen atom in the 5-position, or Ar is phenyl substituted in the 4-position by a C 1-4 alkyl group or a halogen atom, and R is C 1-4 alkyl, characterized in that an alkyl aryl ketal of formula (I) is prepared R, -CO H> - <\ v I IxO-R 0. 6 2 A is CH-R 'X wherein Ar and R are as defined above; R1 and R2 are. independently a hydroxy group or an OR3 group, or N (R3) 2, wherein R3 is a C1-4 alkyl group; and X is a chlorine, bromine or iodine atom or a hydroxy, C 1-4 alkanoyloxy, C 1-4 alkylsulfonyloxy or arylsulfonyloxy group; and the asterisked carbon atoms are each simultaneously in the R or both s-configuration, and the ketal of formula (I) is in the form of epimers relative to the carbon atom attached to the group X by introducing L (+) - or D (-) - tartaric acid or a derivative thereof of formula R, -CO-CH-CH-CO-Ro Process according to Claim 1, characterized in that the acid catalyst is a mineral or sulfonic acid. Process according to Claim 1, characterized in that the acidic pH range is in the range from 4 to 6. Process according to Claim 1, characterized in that Ar is naphthyl substituted in the 6-position by a methoxy group and hydrogen or a halogen atom in the 5-position. 92688 28