NO172390B - ANALOGY PROCEDURE FOR STEREOSPECIFIC PREPARATION OF THERAPEUTIC ACTIVE FURO (3,4-C) PYRIDINE ENANTIOMERS - Google Patents

Abstract

The present invention relates to stereospecific processes for the preparation of enantiomers of 3-substituted-furo [3,4-c] pyridine of formula I, wherein R, Rog R represents various substituents, comprising the steps of oxidizing a racemic pyridine derivative of formula II, reduction of the resulting ketone with a reducing agent, stereospecific locking or blocking of the OH group of the enantiomeric alcohol, opening of the acetonide ring and cyclization of the resulting compound.

Description

The present invention relates to stereospecific methods for the preparation of enantiomers of 3-substituted-furo[3,4-c]pyridine with the general formula I

where

R3 stands for a phenyl group which is optionally substituted with one or more chlorine, bromine or fluorine atoms;

R4 stands for a hydrogen or a halogen atom, and

R6 stands for a straight-chain or branched alkyl group with up to 6 carbon atoms.

Our previous Norwegian patent no. 156 373 and patent applications no. 84 1322, 85 0399, 85 3418, 85 3475 and 85 4277 describe groups of such derivatives, as well as methods for obtaining them. However, these methods have generally given racemic mixtures of the aforementioned compounds.

It has now been discovered that in most cases one of the optical isomers of a specific compound has a more significant therapeutic activity than the other isomer.

For that reason, it is of interest to find methods for a selective, or at least predominant, production of a specific isomer of each of these compounds.

The invention provides a stereospecific process for the preparation of a furo[3,4-c]pyridine derivative of formula I, as defined above, wherein the process includes the following steps: (a) oxidation of a racemic pyridine derivative of general formula II where R3/R4 and R6 are as defined above, with a common oxidizing agent, such as bipyridinium chlorochromate or sodium hypochlorite in an organic solvent (the pyridine derivative exists in racemic form); (b) reduction of the resulting ketone with the general formula III

where R3, RA and R6 are as defined above, with any chiral reducing agent such as: B-Ipc-9-BBN (Alpine - borane, Aldrich), N,B - Enanthrane (Aldrich), Ipc2BCl (Aldrich), BH3-AMDPB (2:1) (see S. Itsuno, J. Chem. Soc., Chem. Comm. 1981, 315), (R,R-2,5-dimethylborolane (see S. Masamune, J. Am. Chem. Soc, 1986, 108, 7402), N,B - Enantride (Aldrich), LiBHA-DBC-t-BuOH (see K. Soal, J. Chem. Soc, Chem. Comm., 1984, 413), NaBH ^-IBA-DIPGF (see S. Itsuno, J. Chem. Soc, Perkin Trans. 1, 1981, 900), K-Glucoride (see H.C. Brown, J. Org. Chem., 1986, 51, 1934), LiAlH ^-Darvon Ale (see H. Mosher, J. Am. Chem. Soc, 1972, 94, 9254), LiAlH 4 -MEP-ArOH (see J.P. Vigneron,

Tetrahedron 1976, 32, 939), LiAlH^-Diamine (see M. Asami, Heterocycles, 1979, 12, 499), LiAlH4-Aminobutanol (see T. Sato, Tet. Letters 1982, 23, 4111), Binal H (see R. Noyori, J. Am. Chem. Soc, 1979, 101, 3129), LiAlH4-DBP-EtOH (see K. Yamamoto, J. Chem. Soc, Chem. Comm., 1984, 1490), LiAlH4-MEP- NEA (see K.J. Koga, J. Chem. Soc, Chem. Comm. 1980, 1026), LiAlH4-MEP-EAP (see S. Terashima, Chem. Letters 1984, 239), TBADH (thermo-anaerobium brockii alcohol dehydrogenase, Sigma chem. Co.), CBS reagent (see E.J. Corey et al., J. Am. Chem. Soc, 1987, 109, 5551), MDBH2 and MDBC12 (M. Bonato et al., in press), or any any catalyst suitable for asymmetric hydrogenation.

The starting material II is an intermediate in the usual process for the preparation of the furo[3,4-c]pyridine derivatives I.

The reduction of the ketone III with the selected reducing agent is conveniently carried out in tetrahydrofuran or any suitable mixture of ethers and hydrocarbons, and proceeds according to the following Reaction Scheme 1, to give the corresponding enantiomeric alcohols, where R3, R4 and R6 are as defined above.

(c) stereospecific locking or blocking of the OH group of the selected enantiomeric alcohol, where the locking agent may be a halogen, for example by the OH group being substituted with a chlorine atom, and where the blocking agent may be common ether- or ester groups; (d) opening of the acetonidation ring with protic acids with simultaneous release of the CH2OH and OH groups on the pyridine ring, it being sometimes necessary to protect said CH2OH and OH groups by acetylation or by tosylation or by means of a corresponding method;

(e) cyclizing the resulting compound and, if necessary, deblocking the phenoxy group.

Following a first synthetic route (Scheme 2), the reduction of the ketone III with the selected reducing agent leads to the compounds IV or V, which, on treatment with a chlorinating agent in a suitable solvent, give compounds of the general formula VI or VII, where R3, RA and R5 is as defined above.

The chlorinating agent can be, for example, triphenylphosphine with carbon tetrachloride as solvent or SO 2 C 12 with methylene chloride as solvent. In the latter case, the addition of pyridine leads to an inversion of the stereochemical configuration of the chlorine derivative at the beginning of the reaction sequence. Bromine derivatives can be used instead of chlorine derivatives with similar results.

The conversion of compounds VI and VII to the corresponding furo[3,4-c]pyridine derivatives is achieved by cleavage of the acetonidation in acidic medium, followed by cyclization in protic solvents or mixtures thereof, at room temperature or by gentle heating.

The reaction series is shown in the following reaction core.

During all synthesis steps, the use of any procedure that can easily racemize the carbinol center should be avoided.

Following another synthesis route where the configuration of the reagents' asymmetric carbon is not affected, a first step consists in prior protection of the secondary alcohol function with a stable group in an acidic medium. The protecting groups can be ethers, such as t-butyldiphenylsilyl, or methoxyethoxy-2-methyl (MEM) can be used, as described by E.J. Corey, J.L. Gras & P. Ulrich, Tetrahedron Letters, 1976, (11), 809 and S. Hanessian & P. Lavallee, Can. J. Chem., 1975, 5J3, 2975, or esters such as acetate, benzoate or the like. The opening of the isopropylidene ring is carried out with protic acids. Trifluoroacetic acid was chosen for this synthesis.

Alcohol protection in the 3- and 4'-positions of the pyridine ring is achieved respectively by acetylation and tosylation in the case of ether protection (Reaction Core 3) or only by tosylation (the 4'-position) in the case of ester protection (Reaction Scheme 4), according to conventional methods that are generally used in organic chemistry. Removal of the protecting groups when ethers are used can be achieved with various Lewis acids such as TiClA or ZnBr2 in methylene chloride, as described by E.J. Corey, J.L. Gras & P. Ulrich, Tetrahedron Letters, 1976, (11), 809 or trimethylsilyl chloride, sodium iodide, as described by J.H. Rigby & J.Z. Wilson, Tetrahedron Letters, 1984, (14), 1429. The removal of the protecting groups when esters have been used involves basic reagents such as MeOH/NH3, MeOH/NaOMe, NaOH, K2CO3.

Finally, the cyclization and removal of the protecting acetyl group, leading to the final product, is achieved by an attack from the corresponding alcoholate on the 4' carbon bearing the leaving group (tosyloxy).

Compounds IV and V can be converted into the corresponding predominant (+) and predominant (-) furo[3,4-c]pyridine derivatives.

The method can easily be applied to different R3 substituents, and the invention is easier to understand through the description of the synthesis of the (+)-form of the furo-pyridine derivative where RA stands for H, R6 for CH3 and R3 for p-chlorophenyl. The description is given for both synthesis routes.

The secondary starting alcohol can be obtained as described in former Norwegian patent 156 373. When a (-)-form of furo[3,4-c]pyridine derivative is to be prepared, the secondary starting alcohol in the following step should be the corresponding

(-) form instead of the (+) form.

MANUFACTURE OF:

(+) or (-)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro[3,4-c]pyridine

EXAMPLE OF SYNTHETIC PATHWAY 1

Step 1

2,2,8-trimethyl-5-(4-chloro-a-chlorobenzyl)pyrido-[4,3-e]-1,3-dioxane 88 mg (0.275 mmol) (+)-2,2,8- Trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido[4,3-e]-1,3-dioxane was poured into a 5 ml flask and dissolved in 1 ml methylene chloride, after which the flask was sealed under a nitrogen atmosphere. 22 µl (0.27 mmol) of anhydrous pyridine was injected via a syringe. 3 6 µl (0.54 mmol) thionyl chloride was then added dropwise. After the starting material had disappeared (2 hours later) (as determined by TLC), the solvent was evaporated under reduced pressure.

The residue was then dissolved in methylene chloride (50 ml), the pyridinium hydrochloride filtered off and the solution transferred to a separatory funnel.

The methylene chloride fraction was washed with 2 x 10 mL 2N HCl, the organic layer was dried over Na 2 SO 4 , filtered and evaporated to dryness on a rotary evaporator (90 mg).

Dividend: 9 6.5%.

Step 2

(+)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]pyridine 90 mg (-)-2,2,8-trimethyl-5- (4-Chloro-α-chlorobenzyl)-pyrido[4,3-e]-1,3-dioxane was dissolved in 1 mL of TFA/H 2 O (9:1) and the rate of acetal cleavage followed by HPLC. After 18 hours, the solvent was removed under a stream of nitrogen and reduced under pressure. The residue was dissolved in methanolic ammonia and brought to dryness under a stream of nitrogen.

The crude residue was then dissolved in methanol (1 mL) and heated for 30 minutes. After cooling and filtering, a solid crystallized out which, by elemental analysis, proved to be entirely in accordance with the formula for the title compound.

Yield: 66%, m = 52 mg.

If we start from (-)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane, the corresponding (- ) derivative in the corresponding dividend.

EXAMPLE OF SYNTHETIC PATHWAY 2 (Reakionsskierna 3)

Step 1

(+)-2,2,8-trimethyl-5-[4-chloro-a-methoxyethoxy-2-methoxy)-benzyl]-pyrido[4,3-e]-1,3-dioxane

In a 0.1 liter reactor, the solution of 3.8 g

(11.8 mmol) (+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane (90% (+ ), 10% (-)) prepared in 24 ml anhydrous tetrahydrofuran.

0.44 g of sodium hydride in 80% oil dispersion (14.8 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 4 hours, then cooled to 0°C. 2.2 g (17.8 mmol) of methoxyethoxy-2-methyl chloride was added over 10 minutes. Stirring was continued for 17 hours at 20°C.

A saturated solution of sodium bicarbonate was added and the organic phase obtained after decantation was dried over sodium sulfate.

After filtration and removal of the solvent, an orange oil was purified by preparative HPLC. 2.4 g of a clear yellow oil was obtained in a yield of 49.5%.

The identity and structure of this compound was confirmed by proton 4I-NMR and elemental analysis.

According to chiral phase HPLC, the enantiomeric composition contained 90% (+), 10% (-).

Step 2

(+)-2-methyl-3-hydroxy-4-hydroxymethyl-5-[4-chloro-a-methoxy-ethoxy-2-methoxy)-benzyl]pyridine

2.4 g (5.8 mmol) (+)-2,2,8-trimethyl-5-[4-chloro-a-(methoxy-ethoxy-2-methoxy)-benzyl]-pyrido-[4,3- ε]-1,3-dioxane was poured into a 50 ml reactor and treated with 20 ml trifluoroacetic acid/water 1:1 at room temperature.

The reaction mixture was heated to 40°C for 4 hours. The solvent was evaporated in vacuo. The resulting oil was taken up in 25 ml of methanolic ammonia. The solvent was again evaporated under vacuum and the residue treated with 100 ml of dichloromethane. Insoluble material was filtered off. The filtrate was concentrated under vacuum to give 1.75 g of a brown oil.

Yield: 81%.

The product was purified by HPLC; 1.12 g (total yield 52%), was obtained as a white powder.

The identity and structure of this compound was confirmed by proton 3-NMR and elemental analysis.

The enantiomeric composition could not be determined by chiral phase HPLC.

Step 3

(+)-2-methyl-3-acetyloxy-4-hydroxymethyl-5-[(4-chloro-a-methoxy-ethoxy-2-methoxy)-benzyl]pyridine

In a 50 ml reactor, 0.7 g (1.9 mmol) of (+)-2-methyl-3-hydroxy-4-hydroxymethyl-5-[4-chloro-a-methoxyethoxy-2-methoxy)-benzyl]pyridine dissolved in 15 ml of anhydrous toluene. 0.3 ml

(2.46 mmol) of N,N-dimethylaniline was added with stirring, followed by 0.5 mL (2.46 mmol) of acetic anhydride.

The reaction mixture was kept at 40°C for 6 hours, then cooled and washed with 3 x 50 ml of a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and the solvent removed under vacuum.

0.8 g of a brown oil was obtained which was purified by HPLC. 0.39 g was recovered, yield 50%, as a yellow oil.

The identity and structure of this compound was confirmed by 3-NMR and elemental analysis.

The enantiomeric composition could not be determined by chiral phase HPLC.

Step 4

(+)-2-methyl-3-acetyloxy-4-(tosyloxymethyl)-5-[4-chloro-a-methoxyethoxy-2-methoxy)-benzyl]-pyridinium

In a 50 ml reactor, 0.3 g (1.5 mmol) of tosyl chloride was poured into 10 ml of acetone. A 0.3 g (0.7 mmol) solution of (+)-2-methyl-3-acetyloxy-4-hydroxymethyl-5-[(4-chloro-a-methoxyethoxy-2-methoxy)-benzyl]pyridine in 10 ml of acetone was added at room temperature.

0.14 g (1 mmol) of potassium carbonate was then added. The reaction mixture was refluxed for 4 hours and filtered.

The filtrate was concentrated under vacuum. 0.76 g of a brown oil was purified by HPLC. 0.3 g of a thick yellow oil was obtained in a yield of 75%.

The identity and structure of this compound was confirmed by proton 3-NMR and elemental analysis.

According to chiral phase HPLC, the enantiomeric composition contained 90% (+), 10% (-).

Step 5

(+)-2-methyl-3-acetyloxy-4-tosyloxymethyl-5-[4-chloro-α-hydroxy-benzyl]-pyridine

In a 0.1 liter reactor, a solution of 0.3 g (0.53 mmol) (+)-2-methyl-3-acetyloxy-4-tosyloxymethyl-5-[4-chloro-a- methoxyethoxy-2-methoxy)-benzyl]-pyridine in 20 ml of CH 3 CN, at room temperature.

0.8 g (5.3 mmol) of sodium iodide and 0.7 ml (5.3 mmol) of chlorotrimethylsilane were added. The resulting orange suspension was stirred at room temperature for 1 hour. Hydrolysis of the reaction mixture was carried out in 20 ml of methanol at room temperature. The solvents were evaporated and the remaining oil taken up in 50 ml of ethyl ether, washed twice with 50 ml of sodium thiosulphate solution and twice with a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate.

After filtration and removal of the solvent, a thick brown oil was recovered which was purified by HPLC. 0.157 g was obtained as a white powder in a yield of 63%.

The identity and structure of this compound was confirmed by proton 4I-NMR and elemental analysis.

According to chiral phase HPLC, the enantiomeric composition contained 90% (+), 10% (-).

Step 6

(+)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]-pyridine

In a 10 ml flask, a solution of 100 mg (0.2 mmol) of (+)-2-methyl-3-acetyloxy-4-tosyloxymethyl-5-[4-chloro-Q!-hydroxybenzyl]pyridine was prepared under nitrogen pressure in 1 ml DMF. 12 mg (0.4 mmol) of sodium hydride (80% oil dispersion) was added with stirring at 20°C. The reaction mixture was stirred at room temperature for 1 hour, then diluted with 5 ml of water and acidified with 1 ml of 6N HCl.

The product was filtered off and purified by HPLC. 44 mg was obtained as a white powder in a yield of 50%.

The identity and structure of this compound was confirmed by proton <X>H-NMR and elemental analysis.

According to chiral phase HPLC, the enantiomeric composition contained 80% (+), 20% (-).

This amount represents approx. 10% total racemization based on the starting (+)-2,2,8-trimethyl-5-(4-chloro-a-hydroxy-benzyl)-pyrido-[4,3-e]-1,3-dioxane.

By starting with the corresponding (-) derivative in Step 1, the final corresponding (-) derivative was obtained in a slightly lower yield.

EXAMPLE ACCORDING TO SYNTHESIS 2 fReaction charts 4)

Step 1

2,2,8-trimethyl-5-(4-chloro-α-acetoxybenzyl)-pyrido-[4,3-e]-1,3-dioxane

210 mg (0.66 mmol) (+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane was poured into in a 2 ml ampoule and dissolved in 500 µl pyridine and 110 µl acetic anhydride (1.16 mmol). The reaction mixture was stirred for 18 hours and then poured into 30 mL of saturated NaHCO 3 . Stirring was continued at room temperature for 1 hour and the mixture was then extracted with 3 x 30 mL CH 2 Cl 2 . The combined CH 2 Cl 2 layers were washed with 3 x 20 mL 2N HCl. The organic phase was dried over Na 2 SO 4 , filtered and the filtrate evaporated to dryness. 24 g was obtained as a white solid in a yield of 100%.

According to TLC on silica, this compound proved to be homogeneous and according to HPLC to be chemically pure (99.1%). Optical purity according to chiral HPLC was 6.2% (-), 93.7% (+).

Step 2

(+)-2-methyl-3-hydroxy-4-hydroxymethyl-5-[4-chloro-α-acetoxybenzyl]pyridine

0.24 g (0.66 mmol) (+)-2,2,8-trimethyl-5-(4-chloro-α-acetoxybenzyl)-pyrido-[4,3-e]-1,3-dioxane was poured into a 10 ml round bottom flask and dissolved in 3.3 ml TFA/H20 (10:1). The reaction mixture was stirred at room temperature for 1.5 hours, after which the solvent was removed by rotary evaporation. 1 mL of methanolic ammonia was added to the crude product (excess TFA was neutralized) and the mixture was then evaporated to dryness under high vacuum. According to HPLC, the crude product consisted of 90% of the desired diol acetate together with 4.4% unreacted starting material.

Steps 3 and 4

(+)-2-methyl-3-hydroxy-4-tosyloxymethyl-5-[4-chloro-α-hydroxybenzyl]pyridine

0.24 g (0.66 mmol) of (+)-2-methyl-3-hydroxy-4-hydroxymethyl-5-[4-chloro-α-acetoxybenzyl]pyridine was poured into a 25 ml round bottom flask and dissolved in 10 ml methylene chloride. 190 mg (1 mmol) of p-toluenesulfonyl chloride and 75 mg (1 mmol) of pyridine were then added. The reaction mixture was stirred at room temperature for 18 hours, after which the solvent was removed under reduced pressure. 5 ml of methanolic ammonia was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum, redissolved in

1 ml of methanol and purified by TLC on silica. 170 mg of the title compound was obtained as a whitish solid. Step 5 (+)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]pyridine 62 mg (0.144 mmol) (+)-2-methyl- 3-hydroxy-4-tosyloxymethyl-5-[4-chloro-α-hydroxybenzyl]pyridine was poured into a 2 ml vial and dissolved in 500 µl HMPT. 14 mg (0.3 mmol) NaH (50% oil dispersion) was then added and the mixture stirred at room temperature for 1 hour.

The reaction mixture was diluted with 2.5 mL of H 2 O and acidified with 2 drops of 6N HCl. The resulting solid precipitate of the title compound was isolated by filtration.

The crude solid was dissolved in methanol, deposited on a

100 µU silica TLC plate and eluted with CH 2 Cl 2 /MeOH (7:1). The major UV band co-eluting with a spot of authentic (+)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]pyridine was scraped off and the organic material isolated by thoroughly washing the silica gel with methanol. The methanol filtrate was evaporated to give 27 mg of a white solid. This compound was found to be the title compound by coelution with authentic (+)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]pyridine by TLC and by HPLC .

The optical purity of the sample, determined by chiral phase

HPLC, was 14.6% (-), 85.4% (+).

The value represents a total racemization of 7.5% based on (+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3- the dioxane starting material.

(+)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]pyridine has been prepared from (+)-2,2,8-trimethyl- 5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane in a total yield for the 5 steps of approx. 45%.

The preparation of (-)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]pyridine from (-)-2,2,8-trimethyl-5 -(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane following the same procedure gave a slightly better overall yield (48%).

The compounds obtained according to the invention are of interest in the various pharmaceutical areas described in the previous patents mentioned on page 1.

The invention also relates to therapeutic preparations, an active ingredient which is an enantiomer or a mixture of enantiomers, where one enantiomer is predominant.

Appropriate administration methods are described in the previously mentioned patents on page 1, but the doses are lower than in the mentioned patents, which is due to the improved activity of the selected enantiomer or of the enantiomer mixtures in which the mentioned enantiomer is predominant.

This is evident, for example, from the comparison between the diuretic effect of the two enantiomers with the corresponding racemic form in normal WKY rats. The experiment was carried out with groups of 10 rats that were given 10 or 20 mg/kg per os, with each animal receiving 2.5 ml of physiological serum per 100 g of body weight, either in pure form for control animals, or supplemented with the appropriate amount of the test compound given to animals treated with the racemic mixture or with each of the enantiomers.

The results are indicated in the following table. It appears from this that the (+)-isomer at 10 mg/kg is at least as active as the racemic mixture at 20 mg/kg and that in such doses it is 58% better in terms of the Na<+>/K<+> elimination rate concerns. The dose/effect ratio also exhibits a maximum, and the optimal dose for normal rats is approx. 6 mg/kg per os.

A similar experiment was carried out on genetically hypertensive SHR-SP rats at the dosage of 3 mg/kg per os. Both for the enantiomers and for the racemic mixture, urine volume collected during 6 hours was 10% more favorable for the (+)-derivative than for the racemic mixture.

ADMINISTRATION

Preferred administration is via tablets and capsules. For tablets, each dosage unit comprises from 5 to 100 mg, or preferably 10 to 25 mg, of active substance together with a suitable carrier, such as starch.

DOSAGE

In human therapy, doses in the range from 50 to 150 mg/day are used for at least 1 week and preferably longer.

Claims (2)

1. Analogous method for the stereospecific preparation of therapeutically active enantiomers of 3-substituted-furo[3,4-c]pyridine of the general formula I where R3 stands for a phenyl group which is optionally substituted with one or more chlorine, bromine or fluorine atoms; R4 stands for a hydrogen or halogen atom, and R6 stands for a straight-chain or branched alkyl group with up to 6 carbon atoms, characterized by the following' steps: (a) oxidation of a racemic pyridine derivative with it general formula II wherein R 3 , R 1 , and R 6 are as defined above, with a common oxidizing agent; (b) reduction of the resulting ketone with the general formula III wherein R 3 , R A , and R 6 are as defined above, with any chiral reducing agent, or any suitable catalyst for asymmetric hydrogenation, which, according to the agent chosen, affords the following compounds: (c) stereospecific locking or blocking of The OH group of the selected enantiomeric alcohol; (d) opening of the acetonidation ring with protic acids with simultaneous release of the CH 2 OH and OH groups on the pyridine ring; (e) cyclizing the resulting compound and, if necessary, deblocking the phenoxy group. 2. Method according to claim 1, for the preparation of a compound of formula I where R3 stands for p-chlorophenyl, R4 stands for H and R6 stands for CH3, characterized in that a corresponding starting material with formula II is used.