FI93642C - Process for Preparation of Optically Active -arylalkanecarboxylic Acids - Google Patents

Description

Ο 7 f. A O 7 -J 0 t L ·

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, in which an optically active ketal is first formed and this is converted in two steps to said acid.

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, 2- (4-isobutyl-phenyl) -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, having 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, including 2- (4-chlorophenyl-25) -3-methylbutyric acid and 2- (4-difluoromethoxyphenyl) -3-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 mixture.

2

07 C A O

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 as defined below having two asymmetric centers in the ketal group, each of which is R, each By this method, α-arylal-35-cyanocarboxylic acids are obtained which have either equal or 93642 3 higher optical purity compared to the ketals used as intermediates.

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

Ar-CH-COOH,

B

wherein Ar is naphthyl substituted in the 6-position by a C 1-10 alkoxy group and has 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 a C 1-4 alkoxy group -kyyli.

In a first step of the process according to the invention, an alkylaryl ketal of formula (I) is prepared stereoselectively.

R -CO H

1 \ * * / <20 H o i C0-R2 (T)

X

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 carbon atoms marked with an asterisk are both 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 reacting L (+) - or D (-) - tartaric acid or a derivative thereof with is the formula 4 93642 * *

R-CO-CH-CH-CO-R

1 I I

_ OH OH

5 where R! and R 2 is as defined above to react a) with a ketone of formula

Ar-CO-CH-R

| (II)

10 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 RO / OR6 5 \ / c 20 / \ (III)

With CH-R

x wherein Ar, R and X are as defined above and R 5 and R 8 represent a C 1-4 alkyl group, in 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 by modifying a ketal of formula (I) wherein R 1 = R 2 = R 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 changing the 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 treatment with an amine of formula R 3 NH in aqueous; in medium at room temperature.

„93642

D

The ketal of formula I thus obtained is converted in the process according to the invention to the abovementioned α-arylalkanecarboxylic acid in two steps in an organic medium free of alcohols and glycols under mild conditions, whereby the intermediate of formula R CO-R is separated.

Ar-CH-COO-CH-CH-R1 () (V) 10 co-r2

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 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 20 or a derivative thereof, is carried out by heating in the presence of an acid catalyst or an 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 OR3 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 a base (e.g. alkali hydroxide) gives the corresponding mono-salts (e.g. R 1 = OH +, R 2 = OR 3); from the latter 35 the corresponding monoacids (e.g. R 1 = OH, R 2 = O 3 R 3) are prepared by adding acid.

6 g 7 c. a o ^ · J O H Z.

By hydrolyzing ketals with R! = R 2 = R 3, two equivalents of base (e.g. alkali hydroxide) give the corresponding salts (e.g. R 1 = R 2 = O'M +), which are obtained by adding the corresponding dicarboxylic acid-5 derivatives (R 1 = R 2 = OH). The latter can be easily converted to other derivatives such as esters (e.g. R 1 and / or R 2 = OR 3) or amides.

Amide derivatives can also be prepared directly from ketals of formula I wherein R 1 = R 2 = O 3 R 3 / by reacting them with a suitable amine of formula R 1, R 5 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 15 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 and R 2 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 both 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 that they produce a mixture of ketals of formula I. , wherein 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 mainly 7,93642 desired optically active epimers. 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 ratio of the enantiomers of the original ketones.

Notwithstanding the foregoing, it is also important that the ketals of formula I be in the form of epimers which can be readily 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-arylalkane-nicarboxylic acid in almost pure form. Separation of the isomer 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.

The possibility of preparing ketals of the formula I, which may have many different groups as R 1 and R 2 substituents, makes it possible to vary the hydrophilic and lipophilic nature of said ketals over a wide range: from compounds having strongly polar groups (alkali salts, amides) , lipolylic compounds, (esters of long chain alcohols).

This wide range makes it possible to select the most suitable ketals of the formula I for the practical conditions used in the various processes for the preparation of α-30 arylalkanecarboxylic acids by the repetition reaction.

It is noteworthy that the market price of tartaric acid derivatives, and in particular L (+) - tartaric acid, is competitive with the price of glycols which have hitherto been used in ketalization according to the known reproduction methods mentioned above.

»93642 8 The preparation of α-arylalkanecarboxylic acids by the rearrangement reaction of the catalytes of the formula I can be carried out using experimental methods known for other different ketals in one or two steps. It has been found that methods applied to ketals of formula I (wherein X is other than hydroxide) produce α-arylalkanecarboxylic acids in which the ratio of enantiomers reflects the epimeric ratio of the ketals used as starting materials.

The conversion of the ketals of formula I to α-arylalkanecarboxylic acids is thus a process which does not lead to significant racemization of the final products and selectively produces the desired optically active α-arylalkanecarboxylic acids.

In the process according to the invention, the rearrangement reaction of the compounds of the formula I is carried out in two steps. Then in the first stage, i.e. under mild conditions in an organic solvent without alcohol or glycols, the above-mentioned intermediate esters of formula V are formed, which are new compounds.

Hydrolysis of the compound of formula V, preferably under acidic conditions, affords the corresponding free acids.

As mentioned above, α-arylalkanecarboxylic acids can also be prepared from the ketals of formula I by other transformation reactions shown for other various ketals. The choice of the method of reproduction depends on the nature of the ketals used as starting materials and in particular on the particular substituent X in the ketal itself.

For example, ketals of formula I wherein X is an iodine atom when Ar is a 6-methoxy-2-naphthyl group and R is CH 3 can be readily reproduced using the methods described in EP-A-89711 or II-Patent Application 21841 35 A / 82.

93642 9

Ketals in which X is a halogen atom and Ar is any of the groups mentioned in connection with formula I can be converted by a rearrangement reaction with certain metal salts as catalysts in EP-A-34871 or 35305 and J. Chem. Soc. By the methods described in Perkin I, 11, 2575 (1982); alternatively, their rearrangement can be performed in a polar aerotic environment under neutral or slightly temporal conditions, optionally in an inert solvent according to the method described in IT Patent Application No. 10,760 A / 82 (or EP-A-101124).

Of the latter methods, the latter is preferable because it is easier to perform and because it does not require metal protection as catalysts.

Ketals of formula I wherein X is a readily leaving group such as acyloxy, alkylsulfonyloxy or arylsulfonyloxy can be converted to α-arylalkanecarboxylic acid derivatives by the method described in EP-A-48136.

20 0 In all the above-mentioned transformation reactions, α-arylalkanecarboxylic acids are generally obtained in the form of their derivatives, in particular esters. These are then hydrolyzed to the corresponding acids by known methods.

The alkylaryl ketals of the formula I can also be prepared from optically active α-arylalkanecarboxylic acids by the one-step rearrangement process described in basic application 911886 of this application, which results in an arylalkanecarboxylic acid having a higher enantiomeric ratio than the starting enantiomers.

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 \ * - /

5 / c-cC

H i A C0-R2 (IV)

z P

10 ° C

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. In order to prepare Naproxen, it is necessary to replace the substituent Y (when it is a chlorine or bromine atom) with a hydrogen atom. It is carried out by hydrogenation of the corresponding 2- (5-chloro or 5-bromo-20 6-methoxy-2-naphthyl) propionic acid or its ester.

The rearrangement of the compounds of formula IV carried out according to the invention under mild conditions in an organic solvent without alcohol or glycols leads to the formation of new esters of formula 25

CH CO-R

P ^^ Y ^^^ V-CH-COO-CH-CH-R λ o! CO-R 2 (VI) Ϋ 30 wherein Y, Z, R 1, R 2 and R 10 are as defined above.

Hydrolysis of the esters of formula VI, preferably carried out under acidic conditions, yields Naproxen or a precursor thereof.

Even in this case, where the preparation of α-arylalkanecarboxylic acids is carried out in two steps via intermediate esters of formula V or VI, no significant racemization occurs and the resulting α-arylalkanecarboxylic acids are formed from a mixture in which the second enantiomer predominates.

The following examples are provided to illustrate the invention.

Example 1 2-Bromo-1- (6-methoxy-2-naphthyl) propan-1-one ketalation 10 (R). 3 (R) -dihydroxysuccinic acid dimethyl ester with IL + + 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 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 moles) of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -25 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) 30 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, 3 H), 4.48 (q, 1 H, J = 7.5 Hz); 4.94 (2H, ABq, Δι / = 26.8, J = 7.2 Hz); 7.1-8.0 (6H, aromatic protons).

Diastereoisomer 2 (RRR) 35 1 H-NMR (200 MHz, CDCl 3 -TMS), δ (ppm): 1.64 (d, 3H, J = 7.5 93642 12

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, Au = 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-4 (R) -5 (dR) -dicarboxylic acid pond diastereoisomers.

HOOC H

V p

10 ^ J ^ COOH

(oXnf ^ T "ch3 15 A mixture of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4- (R), 5 (R) -dicarboxylic acid diethyl ester two diastereoisomers 3 and 4 (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) were 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 sulphate. under reduced pressure to give 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid, two diastereoisomers 5 and 6 (16 g , 0.0367 mol, yield 85.5%) in a ratio (5: 6) of 1: 1 (determined by 200 MHz * 1 H-NMR). in diethyl ether with diazomethane, two diastereo-35 isomers of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester were obtained. and 2 mixtures in a ratio of (1: 2) to 1: 1 (determined by HPLC and 200 MHz 1 H-NMR).

93642 13

Example 3 Preparation of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R) .5 (R) -dicarboxylic acid dimethyl ester 5 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 trimethyl orthoformate (25 g). g, 0.236 moles) was 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 thus obtained (19.2 g) by column chromatography (silica gel-15 L); eluent hexane diethyl ether 6: 4) afforded a mixture of the desired diastereoisomers 7 and 8 (7: 8) 52:48 (determined by HPLC). 1 H-NMR (200 MHz, CDCl 3 -TMS):

Diasterooisomer 7 (RRS) δ (ppm): 1.49 (d, 3H, J = 6.6 Hz); Δ 3.48 (s, 3 H); 3.85 (s. 3H); 3.89 (s. 3H); 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, 25 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).

30 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 35 Column temperature: 50 ° C

93642 14

Wavelength: 254 nm

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

Retention times: 5 diastereoisomer 7: 12.46 min diastereoisomer 8: 13.21 min Example 4 Preparation of 2 (R) -hydroxy-3 (R) -β- (6-methoxy-2-naphthyl) -propionylbutanedicarboxylic acid dimethyl ester CH, C00CH, __ | j I j

X i ^^ / ^ YCH-COO-CH-CH-OH

O O C00CH

a / sysy 3 15 3

A solution of silver tetrafluoroborate (2.4 g, 0.0123 mol) in 1,2-dichloroethane (8 ml) was added under inert atmosphere over 15 minutes to a solution of the two diastereoisomers 7 and 8 (4.09 g of 0.01 mol). - 20 lia) in a ratio of (7: 8) 52:48 and stirred at 15 ° C.

The reaction mixture was heated to 50 ° C, kept at 50 ° C for 16 hours, then cooled to room temperature and filtered.

The solution was diluted with dichloromethane (60 mL), washed with water, (2 x 100 mL) and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave a crude product which, after purification by column chromatography (silica gel; eluent: n-heptane: diethyl ether 2: 8), gave a mixture of two diastereoisomers A and B (2.9 g, 0.0074 mol; yield). 74%) in the ratio (A: B) 52:48 (determined at 200 MHz 1 H-NMR).

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

Diastereosimer A (RRS): 1.62 (d, 3H, J-8 Hz); 3.22 (s, 3H); 3.83 (s. 3H); 3.92 (s. 3H); 3.21 (d, 1H, J = 7.2 Hz); 93642 3.95 (q, 1H, J = 8Hz); 4.68 (dd, 1H, J = ch-oh = 7/2 Hz 'Jch-ch = 2.47 Hz); 5.37 (d, 1H, J = 2.47 Hz); 7.1-7.8 (6H, aromatic protons)

Diastereosimer B (RRR): 1.66 (d, 3H, J = 8 Hz); 3.58 (s, 3H); 3.72 (s. 3H); 3.92 (s, 3 H); 3.24 (d, 1H, J = 7.6 Hz); 3.97 (q, 1 H, J = 8Hz); 4.78 (dd, 1H, JCH-oh = 7/6 Hz, JCh-ch = 2.47 Hz); 5.45 (d, 1H, J = 2.47 Hz); 7.1-7.8 (6H, aromatic protons).

Example 5 Preparation of 2- (6-methoxy-2-naphthylpropionic acid)

A mixture of the two ester diastereoisomers A and B (2.2 g, 5.64 mmol; A: B 52:48 prepared as in Example 4), 1,2-dimethoxyethane (22 mL) and concentrated hydrochloric acid (22 mL) was added. ml) was maintained at 95 ° 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 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. An analytically pure sample was obtained by purification by column chromatography (silica gel; eluent hexane: diethyl ether 7: 3). [α] D = = 2.2 ° (c = 1%, chloroform) Example 6 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R15) Preparation of (R) -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 ) A mixture of the two diastereoisomers of the dimethyl ester of dicarboxylic acid (38.4 g, 0.094 mol; ratio 7: 8 = 1; 1, determined by HPCl)) gave a mixture of the two diastereoisomers 9 and 1093642 16 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.

5 '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, 10 1H, J = 6.85 Hz); 4.82 (ABq, 2H, J = 6.7 Hz); 7.0-8.0 (6H, aromatic protons 9.0 (s, 2H)).

Example 7 Preparation of 2- (1-bromoethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4R, 5 (R) -dicarboxylic acid polyethyl ester 15

A solution of bromine (13.42 g, 0.084 mol) in carbon tetrachloride (30 ml) was added dropwise over 1 hour to a solution of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) 1,3- two diastereoisomers of dioxolane-4 (R), 5 (R) -dicarboxylic acid diethyl-20 ester 3 and 4 in a ratio of (3: 4) 1: 1 (38.48 g, 0.082 mol) in carbon tetrachloride (457 ml), the solution was 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) -dicarboxyl. A mixture of diastereoisomers 11-12 of diethyl ester of -30 acid (43.6 g; purity 98% and 1: 1 ratio, determined by HPLC).

93642 17

Example 8 2- (1-Bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R, 1,5 (R) -dicarboxylic acid N, N.N'.N'-tetra- preparation of diastereoisomeric mixture of ethylamide 5

(CH-CH-) _ NCO v H

3 1 1 \ * _ / 1 ^ cON (ch2ch3) 2 Ί: "*

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 solvents 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 N, N, N ', N'-tetraethylamide were obtained. Mixtures of 13 and 14 (11 mmol; 88% yield) in a ratio of 1: 1 (determined by 1 H NMR).

Example 9 2- (1-Acetoxyethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4R). Preparation of a mixture of diastereoisomers of 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-93642 18 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 seo-10 in a ratio (15:16) of 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, Δ »= 12.35, J = 5.4 Hz); 5.38 (1H, q, J = 6

Hz); 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 10 Preparation of a mixture of diastereoisomers of 2- (1-acetoxyethyl) -2- (6-methoxy-2-naphthyl-1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester 25

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.

1β 93642

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-dioxolan-4 (R) A mixture of diastere-5 isomers 17 and 18 of 15 (R) -dicarboxylic acid dimethyl ester (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, 10 s); 4.90 (2H, ABq, Δν = 6.82, J = 5.4 Hz); 5.33 (1H, q, J = 6

Hz); 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, Δν = 15.54, J = 6.6 Hz); 5.33 (1H, q, 15 J = 6 Hz); 7.06-8.00 (6H, aromatic protons).

Example 11 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 was added dropwise 2- ( A 1: 1 mixture of diastereoisomers 17 and 18 of 1-acetoxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester (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.

The crude product thus obtained was added to a solution of methanesulfonic acid (0.086 g, 0.9 mmol) in methanol 93642 20 (300 mL). The solution was heated at 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 was crystallized from methanol to give 2- (1-hydroxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-10 4 (R), 5 ( A mixture of diastereoisomers 19 and 20 of R) -dicarboxylic acid dimethyl ester (3 g, 7.7 mmol; 77% yield) in a ratio of 56:44 (determined by 1 H-NMR and HPLC).

1 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, dq, JCH-ch = 6 Hz), JCH.OH = 7.5 Hz); 5.06 (2H, ABq, Δ) / = 11.77, J = 4.2 Hz); 7.13-8.00 (6H, aromatic protons).

Diastereoisomer 20 (minor component); 1.13 (3H, 20 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-cit® Hz, J ch-oh = "^, 5 Hz); 4.97 (2H, ABq, Δί> = 2.94, J = 1.5 Hz); , 13-8.00 (6H, aromatic protons).

Example 12 2- [1- (4-Methylphenylsulfonyl) ethyl] -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R). Preparation of a mixture of diastereoisomers of dimethyl (5R) -dicarboxylic acid dimethyl ester

A solution of 1,1-dimethoxy-2- (4-methylphenylsulfonyloxy) -1- (6-methoxy-2-naphthyl) propane (15 g, 34.8 mmol) was added dropwise under argon under argon. in dichloroethane (100 ml), to a solution obtained by heating at 95 ° C a mixture of 2 (R), 3 (R) -dihydroxysuccinic acid dimethyl ester (75 g), thionyl chloride 35 (7.5 ml) and methanesulphonic 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 residue by column chromatography (silica gel; eluent dichloromethane: hexane 8: 2) gave 2-10 [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) 40:60 (determined by 1 H-NMR and HPLC :with).

1 H-NMR (200 MHz, CDCl 3 -TMS), δ (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, 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 protons).

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

Example 13 Preparation of a Diacetereoisomeric Mixture of 2- (1-Methanesulfonyl Fluoro) -2- (6-Methoxy-2-Naphthyl) -1,3-Dioxolane-4 (R) .5 (R) -dicarboxylic Acid Dimethyl 30-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) was added dropwise under argon to a solution of prepared by heating at 95 ° C a mixture of dimethyl ester of 2 (R), 3 (R) -dihydroxysuccinic acid (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-dichloroethane was distilled off.

The reaction mixture was then poured into 10% aqueous sodium carbonate 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 = 6 Hz); 5.03 (2H, ABq, Δρ = 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, 25 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, Δ »> = 11.94, J = 6.3 Hz); 7.06-8.00 (6H, aromatic protons).

Claims (3)

1 V-c * / ^ Γ °° -Η2 (T) Ar '^ CH-R In which Ar and R are defined above; R 1 and R 2 independently represent a hydroxy group or a group OR 3 or N (R 3) 2 in which 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 asterisk-indicated carbon atoms simultaneously have either 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 the formula ★ ★ R 1 -CO-CH-CH-CO-Ro 1. in OH OH 93642 27 is R, and R 2 is the same as above, (a) having a ketone of formula Ar-CO -CH-R (II) X is Ar, R and X are the same as above, in the presence of an acid catalyst and an ortho ester at a temperature of 50 -90 ° C or by azeotropic distillation of the water formed during the ketization in the presence of a suitable organ. organic solvent, or (b) having a ketal of the formula R r50 / / / or C6 III (Ar) CH-R X wherein Ar, R and X are the same as above and R R and R6 are a C , in an inert gas atmosphere in the presence of an acid catalyst under anhydrous conditions at a temperature of 20 - 125 ° C and, if desired, by converting a 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 controlling the pH to the value 1, or if desired, by converting a ketal of formula (I), wherein R 1 = R 2 = OR 3, to the corresponding ketal of formula (I), where R h / 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, and the ketal of formula (I) is reacted to the aforementioned an organic medium, which does not contain alcohols or glycols, under mild conditions, wherein an intermediate of the formula 9A is -CH-COO-CH-CH-Rn (V) IU R 2 is Ar, R, R, and R 2 are as defined above and R 10 is OH, Cl, Br or I, and this intermediate is hydrolyzed. A process for the preparation of optically active α-arylalkanecarboxylic acids of the formula Ar-CH-COOH R phenyl substituted at the 4-position with a C 1-4 alkyl group or halogen atom and R is Chalky 1, characterized in that stereoselectively produces an alkylaryl ketal of formula (I) = R-CO H 2. A process according to claim 1, wherein the acid catalyst is a mineral or sulfonic acid. 3. A process according to claim 1, characterized in that Ar is a naphthyl substituted at the 6 position with a methoxy group having at the 5 position hydrogen or a halogen atom.