FI92823B - Optically active arylalkyl ketals - Google Patents

Abstract

The invention relates to optically active α-halogen- ketals of the formula <IMAGE> wherein Ar is optionally substituted aryl; R is alkyl; R1 and R2 are hydroxy or an alkali metal, ether or amino derivative thereof and X is Cl, Br or I; and the carbon atoms indicated by an asterisk are both simultaneously in R or S configuration and α-arylalkylcarboxylic acid esters of the formula <IMAGE> wherein Ar, R, R1 and R2 are as defined in the formula A and R6 is OH, Cl, Br, I or acyl. The compounds are useful intermediates in the preparation of optically active α-arylalkyl carboxylic acids.

Description

92823

This invention relates to novel optically active ketals which can be used as intermediates in the preparation of α-aryl-5-alkanecarboxylic acids of the formula 1 \ c * _. / 10 \ ^ «» 2, *, o o

Ar —- ^ C CH-R

X

15 where

Ar is 6-methoxy-2-naphthyl, 5-bromo-6-methoxy-2-naphthyl, 6-hydroxy-2-naphthyl, 5-bromo-6-hydroxy-2-naphthyl, 4-chlorophenyl or 4- (2 methylpropyl) phenyl; R is straight or branched C 1-4 alkyl; R 1 and R 2 are the same or different and represent hydroxy or O'M *, R 3 or NR 4 R 5, wherein M * is an alkali metal cation and R 3, R 4 and R 5 are the same or different and represent straight or branched C 1-4 alkyl; and X is hydrogen, bromine or iodine, and the carbon atoms marked with an asterisk both have the (R) or (S) configuration; provided that when Ar is 6-methoxy-2-naphthyl or 5-bromo-6-methoxy-2-naphthyl, then X is hydrogen.

The ketals of the invention can be used as intermediates in the preparation of optically active α-aryl-: alkanecarboxylic acids of formula

R

Ar-CH-COOH (I) 35 2 92823 wherein Ar and R are as defined above, by enantioselective total synthesis with two main steps: stereoselective reaction of new chiral (optically active) ketals of formula A wherein X is hydrogen halogenation and stereo-selective rearrangement of the compounds thus obtained. This overall synthesis of α-arylalkanecarboxylic acids is described in patent application 851317.

These α-arylalkanecarboxylic acids include 10 mm. 2- (6-methoxy-2-naphthyl) propionic acid, the (S) -isomer of which is known as Naproxen and has pharmacological properties which are decisively better than those of the (R) -isomer and their racemic mixture, so that in practice only (S) ) isomer has utility as a pharmaceutical drug.

Some of the α-arylalkanecarboxylic acids of formula I are known as intermediates in the preparation of pyrethroid insecticides. These include, for example, 2- (4-chlorophenyl) -3-methylbutyric acid.

Of the methods recently used in the literature to synthesize α-arylalkanecarboxylic acids, the most interesting are those using the rearrangement of arylalkyl ketals in which the functional group is on the alkyl atoms in the α-position relative to the oxygen atoms of the ketal ring. These include the methods described in EP-A-34871 (Blashim), 35305 (Blashim), 48136 (Sagami), 64394 (Syn-tex), 89711 (Blashim) and 101124 (Zambon) and in IT patent applications 21841 (Blashim). and CNR), 22760 A (82 (Zambon) and 30 in J. Chem. Soc., Perkin I, 11. (1982) p. 2575.

; All of these methods result in a racemic mixture of the two optically active isomers.

Optically active α-arylalkanecarboxylic acids can be prepared by separating the desired enantiomer from the racemic mixture obtained using the above

II

3 92823 (e.g. using optically active bases) or applying one of said rearrangement reactions to optically active ketals previously prepared and isolated as described in e.g. EP-5 applications 67698 (Sagami) and 81993 (Syntex).

However, the processes for the preparation of optically active ketals described in these EP applications are rather laborious and expensive and involve the preparation of intermediates by advanced methods with low yields and are not suitable for industrial production.

Separation of isomers of α-arylalkanecarboxylic acids from the racemic mixture by conventional methods, i.e. using optically active bases, has disadvantages common to all these methods: the high cost of materials, labor, and equipment required to remove the unwanted optical isomer and racemization.

Therefore, a stereoselective method for the direct preparation of the desired isomer is important. Such a method avoids the subsequent separation of the d- and 1-isomers using optically active bases such as cinchonidine, brucine, alpha-phenylethylamine, N-methyl-glucamine and the like.

The elimination of separation steps results in significant savings in both material costs and labor and equipment. The savings may be particularly significant for compounds approved for pharmaceutical use as substantially pure optically active isomers such as S (+) - 2- (6-methoxy-2-naphthyl) propionic acid (Naproxen) or its precursor, which can be easily converted to this acid.

For clarity, the meanings of some of the terms used in this specification and claims are listed below: 4,92223 "Chiral" means a chemical structure having at least one asymmetric center. The configuration of an asymmetric carbon atom is defined as "R" or "S" according to the method of Cahn-Ingold Prelog.

5 "Enantiomer" or "enantiomorph" means a Mole rabbit that cannot be superimposed on its corresponding mirror image. A necessary condition for the optical activity of a molecule (i.e., its enantiomericity) is that such a molecule cannot be superimposed on its mirror image. Such a phenomenon usually occurs in organic chemistry when a carbon atom is attached to four different atoms or chemical groups. The "enantiomer" and the "optical isomer" are often used in parallel in this context.

15 "Enantiomeric excess" means a definition;

the percentage of the predominant enantiomer minus the percentage of the other enantiomer. Thus, a mixture of 95% (+) isomer and 5% (-) isomer would have a 90% enantiomeric excess.

"Optical yield" or "optical purity" may be expressed as enantiomeric excess. However, strictly speaking, it refers to the rotation measured on a mixture, which may or may not indicate the ratio of enantiomers. These two terms are used interchangeably in this application.

"Optically active" means a system or compound that reverses the level of polarized light.

"Epimers" are two diastereoisomers having a different configuration at only one chiral center.

"Diastereoisomers" are stereoisomers that are not mirror images of each other: they have the same configuration at at least one asymmetric center and at the same time a different configuration at at least one asymmetric center.

Il 5 92823 "Diastereotropic" means the case where two atoms or groups in a molecule, e.g. CX2WY, are in such a position that replacing them with a group Z gives diastereoisomers.

"Stereoselective synthesis" means any reaction in which only or substantially one stereoisomer is formed from a plurality of stereoisomers.

"Enantioselective synthesis" means any reaction in which only one or only of the two enantiomers is formed.

"Racemization" means the conversion of molecules from one enantiomer to a racemic mixture of both enantiomers.

Since the carbon atoms marked with an asterisk in the ketals of formula A as defined above are simultaneously in the (R) or (S) configuration, they are optically active. The ketals of formula A have been shown to have unexpected properties that allow the preparation of optically active α-arylalkanecarboxylic acids by the enantioselective process disclosed in patent application 851317.

It has been found that when ketals of formula A wherein X is hydrogen are reacted with achiral halogenating agents, chemoselective halogenation occurs in high yield on the diastereotropic carbon atom in the α-position relative to the ketal group and the resulting α-haloketals (formula A, X * Br, I) form only one epimer or there is clearly more of one than the other. It should be noted that the absolute configuration (R, R or S, S) of the chiral centers already present in the original ketals A (X = H) does not change. To the best of the applicant's knowledge, stereoselective halogenation of the alkyl group in the α-position relative to the ketal has not been previously described.

6 92823

In addition, it has been found that ketals of formula A in which X is Br or I give, in high yields, α-arylalkanecarboxylic acids whose enantiomeric ratio reflects the epi-5 ratio of the starting ketals or, depending on the conversion conditions, the enantiomeric ratio of the acid is higher than .

The rearrangement of ketals has not been previously described, resulting in chemically pure α-arylalkanecarboxylic acids in which the excess of the predominant enantiomer is greater than the excess of the predominant epimer in the ketals used as starting materials.

Ketals of formula A are prepared by ketal precipitation from a ketone of formula: 15

Ar-C-CH "-R (II)

II20 (where Ar and R are as defined above) by means of L (+) - tartaric acid (2R, 3R-dihydroxysuccinic acid) or D (-) - tartaric acid (2S, 3S-dihydroxysuccinic acid) or derivatives thereof.

The ketones of formula II are compounds which are known or can be easily prepared by known methods, for example by Friedel-Crafts acylation. The ketalization is carried out by conventional methods, for example in the presence of an acid catalyst or an orthoester. Alternatively, the water formed during the reaction may be removed by azeotropic distillation with, for example, benzene, toluene, xylene, heptane or other suitable solvents. The absolute configuration and optical purity of the ketals of formula A in which X is hydrogen are the same as those of the diol (tartaric acid or its derivative) used as starting material. Thus, when L (+) - tartaric acid is used, the compound of formula A is obtained

II

7 92823 in a ketal at each of the carbon atoms marked with an asterisk in formula A above, the R-configuration.

This process is particularly suitable for the preparation of compounds of formula A in which R 2 and R 2 represent R 3 by the reaction of a ketone of formula II with a tartaric acid ester. Ketals of formula A in which R 3 and R 2 are other than R 3 are preferably prepared from the compounds thus obtained by suitable modification of the group R 3.

For example, using esters of formula A in which R3 and R2 are 0R3 as starting materials, the corresponding mono-salts (for example R3 * 0'M * and R2 = OR3) can be prepared by partial hydrolysis with one equivalent of base (for example sodium hydroxide) and the corresponding monoacids (for example R3 = OH and R2 = OR3) by adding an acid.

Hydrolysis of the esters with two equivalents of base gives the corresponding salts (R3 = R2 = which on addition of acid gives free dicarboxylic acids (R3 = R2 = OH) which can be used as starting materials for the preparation of other derivatives such as mono- or diesters (Rx and / or R2 = OR3 ) or mono- or diamides ((R3 and / or R2 = NR4R5).

Amides are also obtained directly from esters of formula A by treatment with the appropriate R 4 R 5 NH

with an amine according to

As mentioned above, compounds of formula A wherein X is H are useful as starting materials for the preparation of compounds of formula A wherein X is bromine or iodine. In this case, the compounds of the formula A in which X is hydrogen are halogenated with known halogenating agents, for example bromine, quaternary ammonium perhalides, copper bromide, N-bromosuccinimide, pyridine or pyrrolidone perbromide or analogous iodide, iodide or iodide. .

3,92825

It has been found that halogenation of ketals in which the carbon atoms marked with an asterisk in formula A above each have the R-configuration, i.e. ketals prepared from L (+) - tartaric acid or its derivative 5 (e.g. naturally occurring tartaric acid), forms a mixture of epimeric α- haloketals in which the epimer is clearly predominant, the halogen-bonded carbon atom being in the S-configuration. While the configuration of the carbon atoms marked with an asterisk in Formula A above remains unchanged, the major epimer of α-haloketals derived from naturally occurring tartaric acid or a derivative thereof is hereinafter referred to as the RRS epimer and the minor RRR epimer.

It has also been found that using ketals derived from D (-) - tartaric acid as starting materials, the carbon atom attached to the halogen atom of the main epimer is in the R configuration.

It clearly follows from the above that the halogenation reaction described is a stereoselective reaction.

The ratio of epimers to RRS / RRR is generally greater than 75:25 and in most cases greater than 94: 6. Depending on the substrate and reaction conditions, it is also possible to obtain the RRS epimer as the only chemically pure α-haloketal, the second epimer having an RRR, if any, of less than 1%.

In general, yields of α-haloketals are greater than 90%. The stereoselectivity of the halogenation reaction is little affected by the polarity of the solvent. Numerous solvents can be used, such as carbon tetrachloride, 1,2-di- chloroethane, chlorobenzene, benzene, toluene, acetonitrile, cyclohexane, ethyl acetate, sulfur-carbon, acetic acid, etc. For best results, use solvents with low polarity. Reaction 35 can be carried out at room temperature with satisfactory results. The stereoselectivity of the halogenation reaction increases with lowering the reaction temperature. The reaction still takes place even at -70 ° C.

Preferably, small amounts of inorganic acid are used to initiate the halogenation reaction, which usually ends in a few minutes. In terms of yields and stereoselectivity, the best halogenation reaction is bromination. Said reaction is preferably carried out using bromine as the halogenating agent at a temperature of -40 ° C to 10 + 20 ° C and in solvents such as carbon tetrachloride, methylene chloride, 1,2-dichloroethane and carbon disulphide.

The special properties of the ketals of formula A, and in particular their high stereo-15 specificity in the halogenation reaction, were completely unpredictable from what is now known about stereochemically regulated reactions.

Notwithstanding the foregoing, it is also important that the ketals of formula A in which X = ha-20 is a gene are diastereoisomers which can be readily separated by known methods, for example by fractional crystallization. If necessary, it is possible to separate the desired isomer of the ketal of formula A and carry out a rearrangement reaction to give α-arylalkanecarboxylic acid in almost pure optically active form.

It is also important to note that the purchase price of tartaric acid and esters, especially L (+) - tartaric acid and its methyl and ethyl esters, is competitive with the price of glycols described as ketalizing agents in methods known per se, and tartaric acid derivatives (esters, amides, salts) is certainly not an expensive method.

The possibility that ketals of formula A 35 have different groups in nature, namely substituents 10 92823

Rx and R2, make it possible to vary the hydrophilic and lipophilic properties of said ketals over a wide range, from compounds containing polar groups (alkali metal salts, amides) to lipophilic compounds (esters of long-chain alcohols).

Based on this wide choice, ketals of formula A can be selected that are best suited to the experimental conditions (solvents, temperature, catalysts) used in various processes for the preparation of α-arylalkanecarboxylic acids and their derivatives by a rearrangement reaction, as described in patent application 851317.

Of the optically active α-arylalkanecarboxylic acids which can be prepared from the optically active ketals according to the invention, the most important from a pharmacological point of view is 2- (6-methoxy-2-naphthyl) propionic acid, the S (+) isomer of which is known as Naproxen.

Thus, a particular group of compounds of this invention are ketals of formula 20

R. CO H

1 \ "; c-cr H \ 'X'C0R- 0 0:25. _ V <B) Γ -'” 1 y 30 wherein 'R1 »R2 and X are as defined in claim 1, Y is hydrogen or bromine and Z is hydrogen or a methyl group, provided that when Z is a methyl group, X is hydrogen from which Naproxen can be prepared by a rearrangement reaction.

The carbon atoms marked with an asterisk have the R configuration, and when X is other than hydrogen, the carbon atom attached to it has the S configuration.

The following examples further illustrate the invention.

The use of ketals of formula A as intermediates in the preparation of α-arylcanicarboxylic acids is described by way of example in patent application 851317.

Example 1 Preparation of 2-ethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-10 4 (R), 5 (R) -dicarboxylic acid dimethyl ester 1- (6-methoxy-2-naphthyl) propane -1-one (46.5 g; 0.127 mol), L (+) - tartaric acid dimethyl ester (300 g), trimethyl orthoformate (94 g; 0.887 mol) are gradually heated until all the substances are completely dissolved. Methanesulfonic acid (1.48 g; 0.054 mol) is then added and the resulting solution is heated to reflux for 2 hours; it is cooled to room temperature and the reaction mixture is slowly added to 10% Na 2 CO 3 solution (500 mL). Extract with methylene chloride and wash the organic extracts several times with water.

The organic phase is dried over Na2SO4 and the solvent is evaporated off under reduced pressure. The residue is crystallized from methanol (250 ml).

The desired compound having the following properties is obtained:

Sp. 73-74 ° C; [α] D = + 33.04 ° (c = 1%, CHCl 3); IR (Nujol): 1770, 1740 cm-1 (C = 0 stretch oscillation); NMR (CDCl 3 - TMS, 200 MHz), δ (ppm): 0.94 (t, 3H, J - 7.5 Hz); 2.08 (q, 2 H, J = 7.5 Hz); 3.46 (s. 3H); 3.84 (s, 3H); 3.90 (s. 3H); 4.86 (2H, ABq, Δυ = 10.80; J = 6 Hz); 7.1 - 7.9 (m. 6H).

Example 2 Preparation of 2-ethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4,4 (R), 5 (R) -dicarboxylic acid diethyl ester 1- (6-methoxy-2-naphthyl) propane -1-one (20.0 g; 12 92823 0.093 mol), L (+) - tartaric acid diethyl ester (160 g) and triethyl orthoformate (37 g; 0.25 mol) are heated slowly until the substances are completely dissolved.

Methanesulfonic acid (0.68 g; 0.007 mol) is added and the solution is heated to reflux for 1 hour.

The reaction mixture is cooled to room temperature and added to 10% Na 2 CO 3 solution (250 mL) with vigorous stirring. Extract with CH2Cl2 and wash the organic extracts several times with water.

The organic phase is dried over Na2SO4 and the solvent is evaporated off under reduced pressure.

The crude product is gradually heated to 180 ° C (external bath) at a pressure of 0.1 mmHg.

The desired compound (33.6 g; 0.084 mol; yield 90%) is obtained, having the following properties: [α] D 20 = + 20.59 ° (c * 1%, CHCl 3); IR (Neat): 1770, 1740 cm-1 (C = 0 stretch oscillation); 1 H-NMR (CDCl 3 - TMS), δ (ppm): 0.95 (t, 3H, J = 6.4 Hz); 1.02 (t, 3H, J = 7.3 Hz); 1.3 (t, 3H, J = 7.3 Hz); 2.08 (q, 2H, J = 6.4 Hz); 3.9 (s. 3H); 3.88 (dq, 2H, J = 11 Hz, J = 7.3 Hz); 4.30 (q, 2H, J = 7.3 Hz); 4.82 (ABq, 2H, J = 5.94 Hz); 7 - 8 (6H, aromatic protons).

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

A mixture of 2-ethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester (4.68 g; 12.5 mmol ), NaOH (1 g; 24 mmol) and water (50 mL) are stirred at room temperature for 5 hours.

The reaction mixture is filtered and the aqueous phase is acidified to pH 1 with concentrated HCl.

It is then extracted with diethyl ether and the combined organic extracts are washed with water and dried over Na2SO4. The solvent is evaporated in vacuo to give 2-ethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R),> 13 92823 5 (R) -dicarboxylic acid (3.46 g; 10 mmol), yield 80%, m.p. 100-102 ° C.

1 H-NMR (200 MHz) (CDCl 3 - TMS), δ (ppm): 0.92 (t, 3H, J = 7 Hz); 2.07 (q, 2H, J = 7Hz); 3.86 (s. 3H); 4.78 (2H, 5 ABq, Δ υ = 4.2; J = 5.8 Hz); 7.0 - 8.0 (6H, aromatic protons).

A sample of the compound obtained by esterification with diazomethane-1α in diethyl ether gives the original methyl ester having the same 1 H-NMR, IR, m.p. and [a] as shown in Example 1.

Example 4 Preparation of 2-ethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid diisopropyl ester 15 1- (6-methoxy-2-naphthyl) ) propan-1-one (10.3 g; 0.048 mol), L (+) - tartaric acid diisopropyl ester (94 g) and triethyl orthoformate (7.57 g; 0.071 mol) are gradually heated until the substances are completely dissolved.

Methanesulfonic acid (0.37 g; 0.0039 mol) is then added and the solution is heated to reflux for 2.5 hours (solution temperature 90 ° C). The reaction mixture is cooled and added slowly to 10% Na 2 CO 3 solution (100 mL) with vigorous stirring.

Extract with CH 2 Cl 2 and wash the organic extracts several times with water (100 mL).

The organicase is dried over Na 2 SO 4 and the solvent is evaporated off under reduced pressure to give 94 g of crude product. The crude product is then slowly heated to 220 ° C (external bath) at a pressure of 0.2 to 0.3 mmHg.

The residue is purified by silica gel column chromatography (eluent: hexane-diethyl ether 85:15) to give 2-ethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid diisopropyl ester. (14.2 g; 0.022 mol; yield 69%).

35 IR (Neat): 1780, 1740 cm-1 (OO stretch vibration); 14 92823 1 H-NMR (CDCl 3 - TMS) (200 MHz), δ (ppm): 0.95 (t, 3H, J = 7.6 Hz); 0.96 (d, 3H, J = 6.4 Hz); 1.05 (d, 3H, J = 6.4 Hz); 1.29 (d, 6H, J = 6.4 Hz); 3.8 (s. 3H); 4.75 (ABq, 2H, J = 6.6 Hz); 4.79 (q, 1 H, J = 6.4 Hz); 5.14 (ept., 1H, J = δ 6.4 Hz); 7-8 (m. 6H).

Example 5 Preparation of 2-ethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (S), 5 (S) -dicarboxylic acid dimethyl ester 1- (6-methoxy-2-naphthyl) propane 1-One (20 g; 0.093 mol), D (-) - tartaric acid dimethyl ester (129 g) and trimethyl orthoformate (29 g; 0.27 mol) are gradually heated until the substances are completely dissolved. Methanesulfonic acid (0.74 g; 7.7 mol) is then added and the solution is heated to reflux (84 ° C) for 1 hour; it is cooled to room temperature and the mixture is slowly poured into 10% Na2CO3 solution (250 ml) with vigorous stirring. The mixture is extracted with CH 2 Cl 2 (250 mL) and the organic extracts are washed with water.

The organic phase is dried over Na2SO4 and the solvent is evaporated off under reduced pressure.

The crude product (40.3 g) is gradually heated to 180 ° C under a pressure of 0.1 to 0.5 mmHg with stirring.

The residue (33.3 g) is crystallized from methanol (100 ml) to give the desired compound (23.7 g; 0.0635 mol, yield-25 to 68%) having the following properties:

Sp. 72-73 ° C; [α] D = -34.0 ° (c = 1%, CHCl 3); IR (Nujol): 1770, 1740 cm-1 (C = 0 stretch oscillation); 1 H-NMR (CDCl 3 - TMS) (200 MHz): results are the same as for 2-ethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) - for dimethyl ester of dicarboxylic acid is shown in Example 1.

Example 6 Preparation of 2-ethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4,4 (R), 5 (R) -dicarboxylic acid dimethyl ester 1- (6-methoxy-2-naphthyl) propane -1-one (465 g; 2.17 μl 16 92823 1 H-NMR (CDCl 3 - TMS) (200 MHz), δ (ppm): 0.84 (d, 6H, J = 6.4 Hz); 0.89 ( t, 3H, J = 7.5 Hz), 1.8 (t-ept, 1H, JCH-CH = 6'5 Hz 'JCH-CH = 7'1 Hz)' 1'97 (Qr 2H, J = 7.5 Hz), 2.41 (d, 2H, J = 7.1 Hz), 3.78 (s, 3H), 3.84 (s, 3H), 4.78 (AB, 2H, J = 5 .7 Hz); 7-7.4 (AA'BB ', 4H, aromatic protons).

Example 8 Preparation of diastereoisomers of 2- (1-bromoethyl) -2- [4- (2-methylpropyl) phenyl] -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester

To a solution of 2-ethyl-2- [4- (2-methylpropyl) phenyl] -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester (7.0 g; 20 mmol) 1, A solution of bromine (3.20 g; 20 mmol) in 2-dichloroethane (70 ml), deoxygenated and to which 15 hydrobromic acid (0.324 g; 4 mmol) has been added, is added dropwise over 1 hour under an inert atmosphere at + 15 ° C. In 2-dichloroethane (7.0 ml) previously deoxygenated.

The mixture is kept at 15 [deg.] C. for a further hour, then poured into 10% aqueous NaCO3 solution with vigorous stirring, extracted with CH2Cl2, the organic extracts are dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue thus obtained is eluted from a silica gel column (eluent hexane-diethyl ether 8: 2) to give a mixture of the desired diastereoisomers, denoted as compounds 11 and 12, in 77% yield. The ratio of compounds II and 12 determined by HPLC is 88:12.

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

Diastereoisomer 11 (RRS): δ (ppm): 0.87 (d, 6H, J * 30 6.4 Hz); 1.61 (d, 3H, J = 7.1 Hz); 1.84 (t-ept, 1H, JCH-CH * 6'4 Hz 'JCH-CH = 7.1 Hz); / 2.45 (d, 2H, J * 7.1 Hz); 3.53 (s. 3H); 3.84 (s. 3H); 4.38 (q, 1H, J = 7.1 Hz); 4.9 (AB, 2H, J = 5.9 Hz); 7-7.4 (AA'BB ', 4H, aromatic protons).

Diastereoisomer 12 (RRR): δ (ppm): 0.87 (d, 6H, J = • <15 92825 mol), L (+) - tartaric acid dimethyl ester (773 g; 4.34 mol) and trimethyl orthoformate (461 g). 4.34 mol) is gradually heated until the mixture is completely dissolved. Methanesulfonic acid (15 g; 0.155 mol) is added to the solution.

The reaction mixture is kept at 100 ° C for 4 hours and the volatiles are distilled off (about 400 g).

The mixture is then cooled to 50 ° C and poured slowly and with stirring into 10% aqueous Na 2 CO 3 (5 L). Extract with CH 2 Cl 2 and wash the organic extract with water and dry over Na 2 SO 4. Evaporation of the solvent under reduced pressure gave a residue which, by HPLC analysis, contained the desired compound (743 g; yield 91.6%).

Analytically pure compound is obtained by crystallization from 1.3 l of methanol (672 g; 1.8 mol; yield 82.8%). The properties of the compound are the same as shown in Example 1.

Example 7 Preparation of 2-ethyl-2- [4- (2-methylpropyl) phenyl] -1,3-di-20-oxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester L (+) - tartaric acid dimethyl ester (206 g; 1.16 mol), 1- [4- (2-methylpropyl) phenyl] propan-1-one (110 g; 0.58 mol) and trimethyl orthoformate (122.7 g; 1.16 mol). 25 is gradually removed until all substances are completely dissolved (50 ° C). Methanesulfonic acid (3.9 g; 0.04 mol) is added to the solution.

The reaction mixture is heated to 85 ° C and kept at this temperature for 2 hours, then cooled to room temperature and continued as in Example 1. The crude product (210 g) is eluted from a silica gel column (eluent hexane: diethyl ether 8: 2) to give the desired compound (175 , 2 g, 0.501 mol, yield 86.5%) having the following properties: 35 IR (Neat): 1730-1760 cm -1 (C = 0 stretch oscillation);

II

17 92823 6.4 Hz); 1.58 (d, 3H, J * 7.1 Hz); 1.87 (t-ept, 1H, JCH-CH = 6'4 Hz 'JCH-CH = 7.1 Hz); 2.53 (d, 2H, J = 7.1Hz); 3.6 (s. 3H); 3.83 (s. 3H); 4.41 (q, 1H, J = 7.1 Hz); 4.85 (AB, 2H, J = 6.5 Hz); 7 to 7.4 (AA’BB ’, 4H, 5 aromatic protons).

HPLC analyzes were performed under the following conditions: Hawlett Packard model 1090 with UV detector with adjustable wavelength (model 1040 DAD). Analytical conditions: 10 - column BROWNLEE LABS RPS (5 μ) size 250 mm x 4.6 mm (inner diameter) - solvent A: double distilled water - solvent B: acetonitrile: methanol 40:60 - flow rate: 2 ml / min 15 - percentage of solvent B: 54%

- column temperature: 50 ° C

- wavelength (χ): 222 nanometers - injection: 4 μΐ of a solution containing 0.5 mg / ml in acetonitrile: methanol 40:60 20 - retention times: diast. 11: 22.61 min; mixture of diast. 12: 23.63 min.

Example 9 Preparation of 2- (1-bromoethyl) -2- [4- (2-methylpropyl) phenyl] -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid. A solution of diastereoisomers 11 and 12 (see Example 8) (10 g; 0.0233 mol) in methylene chloride (20 ml) is added dropwise to a solution of sodium hydroxide (1.87 g; 0.0466 mol) in water. (25 ml) and methanol (100 ml) and kept under stirring at 20 ° C.

The reaction mixture is stirred at this temperature for 1 hour. The solvent is evaporated off under reduced pressure. The residue is taken up in water (100 ml) and acidified to pH 1 with concentrated HCl.

The mixture is extracted with diethyl ether (3 x 50 ml).

The organic phase is extracted with 10% sodium bicarbonate solution 92823 18 (3 x 50 ml). The alkaline solution is acidified to pH 1 with concentrated HCl and extracted with diethyl ether (3 x 50 mL). The combined organic phases are dried over sodium sulphate and the solvent is evaporated off under reduced pressure to give the crude product (8.3 g; acid analysis 92%; yield 81%).

HPLC analysis of the sample esterified with diazomethane shows a ratio of two stereoisomers 13 and 14 of 87:13. 1 H-NMR (CDCl 3 - TMS), δ (ppm): Diastereoisomer 13 (RRS), δ (ppm): 0.87 (d, 6H, J = 6.4 Hz); 1.59 (d, 3H, J = 7.1 Hz); 1.95 (t-ept, 1H, JCH-CH = 6'4 Hz 'JCH-CH = 7 Hz); 2'55 (d '2H' J = 7 Hz); 4.42 (q, 1 H, J = 7.1 Hz); 4.88 (AB, 2H, J = 6.4 Hz); 7 - 7.4 (ΑΑ'ΒΒ ', 4H, aromatic protons); 8.2 (s. 2H).

Diastereoisomer 14 (RRR), δ (ppm): 0.87 (d, 6H, J = 6.4 Hz); 1.58 (d, 3H, J = 7.1 Hz); 1.95 (t-ept, 1H, JCH-CH "6'4 Hz 'JCH-CH = 7 Hz); 2.55 (d' 2H 'J = 7 Hz); 4.42 (q, 1H, J = 7 , 1 Hz), 4.8 (AB, 2H, J = 6.4 Hz), 7-7.44 (ΑΑ'ΒΒ ', 4H, aromatic protons), 8.2 (s, 2H).

Example 10 Preparation of 2-ethyl-2- (6-hydroxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester 1- (6-hydroxy-2-naphthyl) propane -1-one (25 g; 0.125 mol), 2 (R), 3 (R) -dihydroxysuccinic acid dimethyl ester (25 g, 1 mol), trimethyl orthoformate (54 g, 0.51 mol) and methanesulfonic acid (0.84 mol). g; 0.088 mol) the mixture is heated at 70 ° C under an argon atmosphere and with stirring for 4 hours.

The reaction mixture is cooled to room temperature, poured into 10% aqueous Na 2 CO 3 (400 mL) and. extracted with diethyl ether (4 x 50 ml). The combined organic extracts are washed with water (3 x 150 mL), dried (Na 2 SO 4), filtered and concentrated in vacuo.

After purification of the crude product by column chromatography (silica gel, eluent hexane: diethyl ether 1: 1), pure 2-ethyl-2- (6-hydroxy-2-naphthyl) -1,3-di-

II

19 92823 Oxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester (17 g) as an oil.

1 H-NMR (90 MHz, CDCl 3 - TMS, 200 MHz), δ (ppm): 1.93 (3H, t, J = 6.5 Hz); 2.10 (2H, q, J = 6.5 Hz); 3.43 (3 H, s); Δ 3.80 (3 H, s); 4.83 (2H, ABq, Δ υ = 6.7; J = 6 Hz); 6.0 (1 H, s, OH); 7.07 - 7.85 (6H, m).

Example 11 Preparation of dimethyl 10-2- (1-bromoethyl) -2- (5-bromo-6-hydroxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid ester

A solution of bromine (5.12 g; 32 mmol) in carbon tetrachloride (5 mL) is added dropwise over 10 minutes under an argon atmosphere and at 15 ° C 2-ethyl-2- (6-hydroxy-2-naphthyl) -1,3-dioxolane To the dimethyl ester of -4 (R), 5 (R) -dicarboxylic acid (6 g; 16 mmol) in carbon tetrachloride (60 mL). The reaction mixture is kept at 15 ° C for 2 hours and poured into 5% aqueous sodium thiosulfate solution (200 ml). The organic phase is separated, washed with water, dried (Na 2 SO 4), filtered and concentrated in vacuo.

After purification of the reaction mixture by column chromatography (silica gel, hexane: diethyl ether 1: 1), 2- (1-bromoethyl) -2- (5-bromo-6-hydroxy-2-naphthyl) -1,3-dioxolane is obtained. -4 (R), 5 (R) -dicarboxylic acid dimethyl ester (8 g; 15 mmol; 93% yield) as a solid.

The ratio of diastereoisomers (17:18) is 90:10 (determined by 1 H-NMR and HPLC). Sp. = 116 - 117 eC.

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

Diastereoisomer 17 (RRS) 30 1.66 (3H, d, J = 7 Hz); 3.52 (3 H, s); 3.88 (3 H, s); 4.48 (1H, q, J = 7Hz); 4.96 (2H, ABq, Δ υ = 27.80, J = 6.1 Hz); 7.2 - 8.0 (5 H, m).

Diastereoisomer 18 (RRR) 1.62 (3H, d, J = 7 Hz); 3.56 (3 H, s); 3.87 (3 H, s); 4.48 (1H, q, J = 7Hz); 4.90 (2H, ABq, Δ υ = 35.44, J = 6.3 Hz); 7.2 - 8.0 (5 H, m).

«20 92823

The diastereoisomeric ratio [17 (RRS): 18 (RRR)] is 90:10, which is confirmed by converting the compound 2- (1-bromoethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3- a mixture of diastereoisomers 3 and 4 of dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester according to the following method:

A mixture of the title compound (0.52 g; 1 mmol), potassium carbonate (1.38 g; 10 mmol), methyl iodide (0.426 g; 3 mmol) and acetone (10 mL) is stirred at room temperature for 4 hours. The reaction mixture is filtered and concentrated in vacuo. The residue thus obtained is a mixture of diastereoisomers of 2- (1-bromoethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid [(RRS): 4 (RRR)] 90:10 (determined by 1 H-NMR and HPLC).

Example 12 Preparation of 2- (1-bromoethyl) -2- (5-bromo-6-hydroxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid Mixture of diastereoisomers 17 and 18 relative to 90:10 (see Example 11) (5.6 g; 0.0108 mol), water (52 ml), 20 methanol (30 ml) and 10% (w / v) aqueous sodium bicarbonate solution (11.5 ml). ) is stirred at room temperature for 6 hours.

The reaction mixture is then acidified with concentrated HCl to pH 1 and extracted with diethyl ether. The combined organic extracts are washed with water and dried over sodium sulfate.

After evaporation of the solvent in vacuo, diastereoisomers 19 and 20 are obtained in a ratio (19:20) of 92: 8 (4.8 g; 0.0098 mol; yield 90%).

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

Diastereoisomer 19 (RRS): 1.66 (d, 3H, J = 7 Hz); 4.63 (q, 1 H, J = 7Hz); 4.93 (2H, ABq, Δ υ = 16.42, J = 6.5 Hz); 7.23 - 8.15 (m. 5H); 8.27 (1H, broad).

21 92823

Example 13 Preparation of 2- (4-chlorophenyl) -2- (2-methylpropyl) -1,3-dioxolanyl-4 (R), 5 (R) -dicarboxylic acid dimethyl ester 5 Mixture of 1- (4-chlorophenyl ) -3-methylbutan-1-one (40.0 g; 0.204 mol), 2 (R), 3 (R) -dihydroxymersuccinic acid dimethyl ester (72.4 g; 0.407 mol), is gradually heated until the substances are completely dissolved (60 eC). Methanesulfonic acid) 1.4 g; 0.015 mol) is added to 10 solutions, which are then heated to 75 ° C. After a reaction time of 3 hours, the mixture is cooled to room temperature and poured into 10% sodium bicarbonate solution (250 ml) with vigorous stirring. The aqueous phase is extracted with methylene chloride (2 x 250 ml) and the organic extracts are washed with water (2 x 400 ml). The organic phase is dried over Na2SO4 and the solvent is evaporated off under reduced pressure. The residue obtained (68.7 g) is chromatographed on silica gel (eluent: hexane-diethyl ether 8: 2).

There was thus obtained 2- (4-chlorophenyl) -2- (methylpropyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester (41 g; 0.115 mol; yield 56.4 %). Sp. 40 ° C.

[α] D = + 21.6 ° (c = 1%, CHCl 3); IR (Nujol): 1770-1740 cm -1 (C = 0 stretch vibration); . 25 1 H-NMR (200 MHz) (CDCl 3 - TMS) δ (ppm): 0.87 (d, 6H, J = 6.9 Hz); 1.67 (m, 1H, JCH_CH = 6.9 Hz); 1.86 (AB part in ABX system, 2H); 3.55 (s. 3H); 3.82 (s. 3H); 4.74 (ABq, 2H, J = 6.0 Hz); 7.2-7.4 (AA'BB ', 4H aromatic protons).

Example 14 Preparation of 2- (1-bromo-2-methylpropyl) -2- (4-chlorophenyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester

A solution of bromine (8.06 g; 0.05 mol) in 1,2-dichloroethane (18 ml) is added over 1 hour 15 minutes to a solution of 2- (4-chlorophenyl) -2 - (2-methylpropyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester (18.0 g; 0.05 mol) in 1,2-dichloroethane (180 ml) containing previously added methanesulfonic acid (3.6 g; 0.038 mol), and the reaction mixture is stirred under an inert atmosphere at + 15 ° C. After standing for 1 hour at 15 ° C, the mixture is poured into 10% sodium carbonate solution (400 ml) with vigorous stirring and extracted with methylene chloride (2 x 250 ml). The organic phase is washed with water (2 x 400 ml) and dried over sodium sulfate.

Evaporation of the solvent under reduced pressure gave a residue (20.5 g) containing 2- (1-bromo-2-methylpropyl) -2- (4-chlorophenyl) -1,3-dioxolane-4 (R), The two diastereo-15 isomers of the dimethyl ester of 5 (R) -dicarboxylic acid, referred to herein as diastereoisomers 21 and 22, in a ratio of (21:22) 97: 3 (ratio determined by 1 H-NMR analysis (300 MHz) and confirmed by HPLC analysis) . Crystallization from N-hexane (60 mL) gives diastereoisomer 21 (13.6 g; 0.031 mol; 62.5% yield), which is purified by 1 H-NMR analysis (300 MHz). 1 H-NMR (300 MHz) (CDCl 3 - TMS):

Diastereoisomer 21 (RRS): 0.93 (d, 3H, J = 6.9 Hz); 0.98 (d, 3H, J = 6.6 Hz); 1.70 (m, 1H, JCH_CH * 1.8 Hz, jch_Ch3 = 6.6 Hz, jch_Ch3 “t * 25 6.9 Hz); 3.59 (s. 3H); 3.85 (s, 3H), 4.28 (d, 1H, J = 1.8 Hz); 4.87 (ABq, 2H, J = 6.2 Hz); 7.3-7.5 (AA'BB ', 4H aromatic protons).

HPLC analyzes were performed under the following conditions: Hewlett Packard Model 1090 with UV-adjustable UV detector (Model 1040, DAD).

Analytical conditions: - Brownlee column LABS RP 8 (5 μ granules); 250 x 4.6 mm (inner diameter) 35 - Solvent A: doubly distilled water 23 92823 - Solvent B: methanol - Flow rate: 1.7 ml / min - Solvent B content: 63%

- Column temperature: 40 ° C

5 - Wavelength (λ): 230 nanometers - Injection: 5 μΐ of a solution containing 0,5 mg / ml of the compound in methanol - Retention times:

Diastereoisomer 21: 11.71 minutes 10 Diastereoisomer 22: 12.85 minutes.

Example 15 Preparation of 2- (1 (S) -bromo-2-methylpropyl) -2- (4-chlorophenyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid

A solution of diastereoisomer 21 (10 g; 23 mmol) in dichloromethane (10 mL) is added dropwise at 20 ° C to a solution of sodium hydroxide (2 g; 50.6 mmol) in water (25 mL) and methanol (100 mL). The reaction mixture was kept at 20 ° C for 1 hour and the solvent was removed under reduced pressure. Water (100 mL) was added. The resulting solution was acidified with concentrated HCl to pH 1 and extracted with diethyl ether (3 x 75 mL). The organic phase was extracted with 10% aqueous sodium bicarbonate (3 x 75 mL). acidified with concentrated HCl to pH 1 and extracted with diethyl ether (3 x 75 mL) The combined organic extracts were washed with water and dried over sodium sulfate. -2-methylpropyl) -2- (4-chlorophenyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid (diastereoisomer 23) 30 (7.2 g; 19.8 mmol; 86% yield) ).

1 H-NMR (300 MHz, CDCl 3 - TMS), δ (ppm):

Diastereoisomer 23 (RRS) 0.92 (d, 3H, J = 6.6 Hz); 0.98 (d, 3H, J = 6.2 Hz); 1.58 (m, 1H, JCH_CH -1 »8 Hz» JCH-CH3 = 6.6 Hz, jCH-CH3 "3.2 6.2 Hz); 4.37 (d, 1H, J = 1.8 Hz) 4.86 (ABq, 2H, J = 24 92823 6.2 Hz), 7.36 - 7.46 (AA'BB ', 4H, aromatic protons) The presence of one diastereoisomer was confirmed by HPLC analysis from a sample of the corresponding dimethyl ester (diastereoisomer 21) prepared by reaction with diazomethane.

Example 16 Preparation of 2-ethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid N, N, Ν ', N'-tetraethylamide containing 2-ethyl-2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester (9.36 g; 25 mmol), diethylamine (25 ml) and water (20 ml) were stirred at room temperature for 15 hours. The solvents were removed by evaporation at room temperature under reduced pressure. Diethyl ether (50 ml) was added to the residue, and the mixture was heated under reflux for 1 hour; then it was cooled to room temperature, filtered and the filtrate was dried under reduced pressure. There was thus obtained 2-ethyl-2- (6-methoxy-2-naphthyl-20) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid tetraethylamide (11 g; 24 mmol; yield 96 %).

Sp. 108-112 ° C; 1 H-NMR (200 MHz, CDCl 3 - TMS), δ (ppm): 0.83 (t, 3H, J -7 Hz); 1.11 (t, 12H, J = 7Hz); 2.00 (q, 2H, J = 7Hz); * 2.79 (q, 8H, J = 7 Hz); 3.83 (s. 3H); 4.32 (2H, ABq, Δ.υ - 17.8, J = 8 Hz); 6.9-7.8 (6H, aromatic protons).

IR (Nujol): 1605, 1630 (C = 0 stretch oscillation).

II

Claims (3)

1. Optically Active Ketals of Formula Rn-CO H 1 \ c * _j / H "+ / C0R2 (A, 0 0 10 \ / Ar-C - CH-R X wherein Ar is 6-methoxy-2-naphthyl 5-bromo-6-methoxy-2-naphthyl, 6-hydroxy-2-naphthyl, 5-bromo-6-hydroxy-2-naphthyl, 4-chlorophenyl or 4- (2-methylpropyl) phenyl; R is unbranched or branched C1-4 alkyl; R 1 and R 2 are the same or different and represent hydroxy or a group O'M *, OR 3 or NR 4 R 5, in which M * is an alkali metal cation and R 3, R 4 and R 5 is the same or different and denotes unbranched or branched Cj ^alk alkyl; and X is hydrogen, bromine or iodine, and the carbon-atoms indicated by the asterisk have (R) or (S) configuration, provided that Ar is 6- methoxy-2-naphthyl or 5-bromo-6-methoxy-2-naphthyl, X is hydrogen. 2. The optically active ketals of claim 1, which have the formula RiCO H 30 + - C * / H + 7 7 C0 R0 O (B>, O on p · Y 28 92823 where Rx, R2 and X are as defined in claim 1, Y is hydrogen or bromine and Z is hydrogen or a methyl group, provided that Z is a methyl group, then X is hydrogen.