FI92688C - Process for the preparation of optically active arylalkanecarboxylic acids - Google Patents

Description

92688

Process for the preparation of optically active α-arylalkanecarboxylic acids

The present invention relates to a process for the preparation of optically active α-arylalkanecarboxylic acids, in which optically active ketals are used as intermediates, which are converted to said acids.

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

Among them, mention may be made of 2- (4-isobutylphenyl) propionic acid known as Ibuprofen, 2- (3-phenoxyphenyl) propionic acid known as Phenophenene, 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 20 S The (+) - isomer is known from 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 at 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.

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

2,92638

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 relative 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 aforementioned rearrangement reaction with optically active ketals prepared by the methods described in EP-A-67698 (Sagami) and 81993 (Syntex).

In all of the above processes, ketals obtained by reacting arylalkyl ketones with aliphatic alcohols or glycols are used as starting materials for the preparation of α-arylalkanecarboxylic acids. 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 as defined below, each of which has two acyramethers in the ketal group. By this method, α-arylalkanecarboxylic acids are obtained which have an optical purity of equal or greater than that of the ketals used as selected products.

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- / (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 an OR 3 or N (R 3) 21 group 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 carbon atoms marked with a star are simultaneously in each R or both 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 introducing L (+) - or D (-) - tartaric acid, or a derivative thereof having the 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 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 r50c Ar 1 N 1: hr (in) x wherein Ar, R and X are as defined above and R 5 and R 6 are C 1 alkyl, under an inert gas atmosphere with the acid catalyst under anhydrous conditions at a temperature of 20 to 125 ° C, and if desired by changing the formula ( 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 OH by treating sitS with a strong base at room temperature in an aqueous medium and then adjusting to pH 1, or if desired by changing a ketal of formula (I) in which R 1 = R 2 = OR 3 to a corresponding ketal of formula (I) in which R 1 and / or R 2 is N (R 3) 2, in which case 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 cumbersome process of the invention to the aforementioned α-arylalkanecarboxylic acid in one step in an aqueous medium at an acidic pH of 5,92688 at room temperature and 150 ° C to give the corresponding a- arylalkanecarboxylic acids having an enantiomeric ratio higher 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 formula I in which R 1 and R 2 are the same or different O 3 R 3 groups. By using such ketals as starting materials, it is possible to prepare all ketals in which R1 and R2 have the same meaning as given above in connection with the 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 30 acids.

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 "+), which are obtained by adding acid to the corresponding dicarboxylic acid-35 derivatives (R 1 = R 2). 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 be prepared mybs 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. In this case as well, it is possible to modify the meanings of R 1, R 2 and X as described above. 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 carbon atoms labeled in the formula I in the ketal of formula I have the same configuration as the tartaric acid used as starting material, i.e. they are each in the R or S configuration.

It has quite surprisingly been found that the reactions for the preparation of ketals of formula I by the above process (a) and process (b) are stereoisomeric and, depending on the reaction conditions, can also be steroselective in the sense that they give the formula I. a mixture of ketals according to which one of the two epimers (with respect to the carbon atom bonded 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 35 is higher than the enantiomer of the original ketones. relationship.

92688 7

Notwithstanding the foregoing, it is also to be understood that the ketals of formula I are in the form of epimers which can be readily enriched or separated by known methods, for example by crystallization from 5 to 1a.

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-arylalkanecarboxylic 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 selected product 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 ketals used as starting materials.

Such a method is defined here as enathioselective in pigs that the enantiomeric composition (ratio of S and R enantiomers) in the α-arylalkanecarboxylic acids thus prepared is different from the corresponding epimer of the ketals of formula I used as starting materials for the rearrangement reaction. ham-25 astonishingly increases the optical purity of α-arylalkanecarboxylic acids.

This enantioselective rearrangement process is novel and is treated with a ketal of formula I, wherein X is other than a hydroxide, in aqueous solution at an acidic pH of 30 at room temperature to 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 8,926,888 ketone and alcohol or diol. 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 a suitable soil buffer.

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

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 industrial advantages of this rearrangement process can be summarized as follows: (1) the process is enantioselective and yields α-arylalkanecarboxylic acids with an enantiomeric ratio greater than the epimer ratio of the starting materials; (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 important from a pharmaceutical point of view 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 to prepare 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 lead to 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-naphthylpropan-1-one with 2 (R) .3 (R) -dihydroxyerosuccinic acid dimethyl ester ester 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 92688 10 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 of 0.9- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R) -dicarboxylic acid dimethyl ester (0.9 g, 0.002 mol) was obtained. in 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, 1H, J = 7.5 Hz); 4.89 (2H, ABq, Aβ = 36.3, J = 6.3 Hz); 7.1-8.0 (6H, aromatic protons).

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

H00C H

V-

ri 0 ^ ^ J, XC00H

1X 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) was 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 stable 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 of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid. and δ (16 g, 0.0367 mol, 85.5% yield) in a ratio of (5: 6) 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 in a ratio of (1: 2) to 1: 1 (determined by HPLC and 200 MHz 1 H-NMR 1α).

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) afforded 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. 3H); 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 available wavelength in a UV detector).

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

Solvent A: water, rate 0.96 ml / min 20 Solvent B: methanol, rate 1.04 ml / min Temperature of solvent A: 40 ° C Column temperature: 50 ° C Wavelength: 254 nm

Injection: 10 μΐ of a 3 mg / ml solution in 25 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, 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dime-35 was used as a starting material. A mixture of the two diastereoisomers of the style ester (38.4 g, 92688 13 0.094 mol; 7: 8 = 1; 1, determined with HPlCl) 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 (9:10) of 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 in 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 Preparation of a diastereoisomeric mixture of 2- (1-bromoethyl-2- [6-methoxy-2-naphthyl-1,3-dioxolane-4 (R) .5 (R) -dicarboxylic acid NNN'.N'-tetraethylamide 5 , CH3CH2) 2NCO x ^ H / 1 l "coN (CH2CH3.2" i6)

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 scavengers were removed at room temperature under reduced pressure and diethyl ether (50 mL) was added to the portion. 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- (S-bromo-e-methoxy-4-naphthyl) -1,3-dioxolane-4 (R1.5 (R1-dicarboxylic acid trimethyl) -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 methanesulfonic 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 2- (1-acetoxyethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid. from a mixture of diastereoisomers 15 and 16 of dimethyl ester 15: 16 in a ratio of (15:16) to 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 = 6 Hz); 7.23-8.30 (5H, aromatic protons). Diastereoisomer 16 (lower 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 = 6 Hz); 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. , containing 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 by fractional column chromatography (silica gel, eluent dichloromethane: hexane 7: 3) gave 2- (1-acetoxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), Mixture of diastereomers 17 and 18 of 5 (R) -dicarboxylic acid dimethyl ester Dias-5 (15 g, 34.7 mmol; 47% yield) in a ratio of (17:18) 64:36 (m / z 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 = 6 Hz); 7.06-8.00 (6H, aromatic protons). Diastereoisomer 18 (lower 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 = 6 Hz); 7.06-8.00 (6H, aromatic protons).

Example 9 Preparation of a mixture of diastereoisomers of dimethyl 2- (1-hydroxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R) .5 (R) -dicarboxylic acid 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 was added dropwise in a ratio of 1 : 1 (4.33 g 10 romol) dissolved in a solution of methanol (20 ml) containing sodium hydroxide (4 g 100 mmol) in water (40 ml). The reaction mixture was kept at room temperature for 24 hours, then acidified with stable 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 to reflux for 2 hours, cooled to room temperature, diluted with dichloromethane (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), A mixture of diastereoisomers 19 and 20 of the dimethyl ester of 5 (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 (bulk 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 = 11.77, J = 4.2 Hz); 7.13-8.00 (6H, aromatic-20 protons).

Diastereoisomer 20 (lower 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 (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 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 bicarbonate solution and extracted with dichloromethane.

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

Purification of the portion 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 = 6 Hz); 6.90-7.80 (10H, aromatic protons).

Diastereoisomer 21 (less inner 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 = 6 Hz); 6.90-7.80 (10 H, aromatic 25 protons).

With a new purification by column chromatography (silica gel, eluent dichloromethane: hexane = 1: 1) fasted to the pure palladium stereoisomer 22.

Example 11 Preparation of a diacetereoisomeric mixture of dimethyl (2-methanesulfonyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R1.5 (R) -dicarboxylic acid dimethyl ester)

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-Methanesulfonyl-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 A mixture of diastereoisomers 23 and 24 of 2- (1-methanesulfonyloxyethyl) -2- (6-methoxy-2-20 * 2688 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 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 = + 48.02 ° (c = 1%, chloroform) 15 1 H-NMR (200 MHz) analyzes in CDCl 3 using 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- (1-bromoethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolan-4 (R) .5 (R ) Dicarboxylic acid diastereoisomers A mixture of two 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid diastereoisomers 5 and 6 in a ratio (5: 6) of 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 h The reaction mixture was cooled to room temperature (pH 3.7), acidified to pH 1 with stable HCl and extracted with diethyl ether (3 x 100 mL). The combined organic extracts were washed with water and dried over sodium sulfate, followed by evaporation of the solvent under reduced pressure to give 2- (6-methoxy-2-naphthyl) -propionic acid as a crude product which was purified by column chromatography eluting with silica gel (silica gel); ethyl ether 1: 1) · 5 Pure acid (4.84 g, 21 mmol; yield 70%)

as an optical purity of 50% (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) .5R) -dicarboxylic acid NN NYNY-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 tetraethylamine 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: 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-naphthylpropionic acid) from 2-fluoroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolan-4 (R) -5R-dicarboxylic acid A mixture of the two diastereoisomers of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid in a ratio of 9 and 10 (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: 110 hours. The reaction mixture was cooled to room temperature (pH 5.7), acidified to pH 1 with stable hydrochloric acid and extracted with diethyl ether (4 x 50 mL). The organic phase was extracted with 10% aqueous sodium bicarbonate solution (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.

From the residue (4.8 g), 1,2-dimethoxyethane (72 ml) and 20 serious HCl (36 ml) were heated with stirring at 75 ° C for 2 hours. 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 stable 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 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 solutions (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 treated 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 treated 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 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) 5 X wherein Ar, R and X are as defined above, the acid catalyst and the orthoester are present at a temperature of 50 to 90 ° C, or the water formed by distillation of the ketalisation is azeotropically removed in the presence of a suitable organic solvent, or b) with a ketal of the formula r50 ^ y3R6 15 a / \ hR (iii) X wherein Ar, R and X have the same meaning as above and R5 and R120 represent a C1-4 alkyl group, under an inert gas atmosphere in the presence of an acid catalyst under anhydrous conditions at a temperature of 20 to 125 ° C, and if desired changing 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 obtaining a pH of 1, or, if desired, by converting a ketal of formula (I) in which R 1 = R 2 = OR 3 to a corresponding rougal ketal of formula (I) in which R 1 and / or R 2 is N (R 3) 2 by treating it with with an amine of R 3 NH in an aqueous medium at room temperature, and the ketal of formula (I) is converted to the aforementioned α-arylalkanecarboxylic acid in one step in an aqueous medium at an acidic pH range of 35 at room temperature and 150 ° C, 27 give the corresponding oarylalkanecarboxylic acids having an enantiomeric ratio higher than that of the ketal epimers of the 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 at the 4-position with 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> * - <ir I Ixo-R 0. 6 2 A is CH-R 'X wherein Ar and R are as defined above; R 1 and R 2 inert. independently hydroxy or OR3 or 25 N (R3) 2 »wherein R3 is a C1-4 alkyl group; and X is a chlorine, bromine or iodine atom or as a hydroxy, C 1-4 alkanoyloxy, C 1-4 alkylsulfonyloxy or arylsulfonyloxy group; and the deliberately labeled carbon atoms are each simultaneously in the R or both 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 placing L (+) - or D (-) - tartaric acid or a derivative thereof having the 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