HK1077302B - Method for producing 2-[-5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane - Google Patents

Description

Process for producing 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman

The invention relates to 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans of formula I

A process for the preparation of enantiomerically pure compounds comprising formula I and salts thereof, characterized in that 5- (4-fluorophenyl) pyridine-3-carbaldehyde is reacted directly with 2-aminomethylchroman or a salt thereof under reducing conditions to give the compound of formula I, and if desired, the obtained compound of formula I is converted into one of its salts by treatment with an acid.

The compound 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman is disclosed in US5,767,132 as a racemate and as an enantiomerically pure compound. US5,767,132 likewise describes the preparation of physiologically acceptable salts (column 9, lines 6 to 32) and the preparation (examples 5 and 19).

2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl group of the formula I]Chromans and salts thereof are selective dopamine D₂Receptor antagonists and 5-HT_1AA receptor agonist. They are therefore suitable for the preparation of medicaments for the prophylaxis and/or treatment of diseases secondary to cerebral infarction (stroke), such as stroke and cerebral ischemia, for the prophylaxis and control of brain disorders, such as migraine, anxiety, the treatment of states of stress and depression, centrally-caused sexual dysfunction, disorders of sleep and nutrient uptake, or for the treatment of psychoses, such as schizophrenia, schizoaffective disorders or cyclic psychoses.

The term "anxiety state" also means panic disorder, obsessive-compulsive disorder or obsessive-compulsive personality disorder, specific anxiety disorders, social anxiety disorder, acute stress disorder, post-traumatic stress disorder, generalized anxiety disorder, substance-induced anxiety disorder with or without agoraphobia, and anxiety disorder caused by medical condition factors.

2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans of the formula I and their salts are furthermore suitable for the elimination of cognitive deficits, for improving learning and memory and for the treatment of Alzheimer's disease. They can likewise be used for the treatment of side effects in hypertension therapy, endocrinology and gynecology, for example for the treatment of acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome or unwanted postpartum lactation.

These compounds can therefore be used as pharmaceutically active ingredients in humans and veterinary medicine. They can furthermore be used as intermediates for the preparation of other pharmaceutically active ingredients.

Since 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans, in particular (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans and (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans and salts thereof are very promising pharmaceutically active ingredients, their preparation is of great importance.

The object of the present invention was therefore to find a new efficient synthesis route for the above compounds.

In the known synthesis of 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans, described in U.S. Pat. No. 4, 5,767,132, examples 5 and 19 as racemates and enantiomerically pure compounds, the racemates and enantiomerically pure compounds of 2-aminomethylchromans or the corresponding salts of these compounds are reacted with 3- (chloromethyl) -5- (4-fluorophenyl) pyridine. However, the starting material 3- (chloromethyl) -5- (4-fluorophenyl) pyridine is skin-irritating and may cause allergic reactions. Furthermore, "haloamino compounds", such as 3- (chloromethyl) -5- (4-fluorophenyl) pyridine, have a tendency to decompose exothermically, because both alkylating and alkylatable functional groups are present in a single molecule (chem. -Ing. -Tech.1979, 51, 928-.

The invention therefore relates to a process for the preparation of 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans of the formula I,

it is characterized in that

(1) Reacting 5- (4-fluorophenyl) pyridine-3-carbaldehyde of the formula II

Directly reacting with 2-aminomethylchroman or its salt under reducing conditions to give a compound of formula I, and

(2) the resulting compound of formula I is converted to one of its salts by treatment with an acid.

The advantage of the novel process over the process disclosed in US5,767,132 is that the inhibition of double alkylation reduces by-products. After the conversion process, the active ingredient is free of by-products having two arylpyridine groups, which simplifies the purification of the active ingredient.

In contrast to the routes for preparing secondary amines by reacting aldehydes with primary amines disclosed in the standard literature (Houben-Weyl, Methoden der organischen Chemie, Vol. 11/1), it is not necessary to eliminate water in the process according to the invention to obtain the aldimine intermediate. In contrast, the aldehyde, according to the invention 5- (4-fluorophenyl) pyridine-3-carbaldehyde, can be combined directly with 2-aminomethylchroman under reducing conditions.

The advantage over reductive amination occurring under standard conditions is therefore that a smaller number of reagents and a lower heat load are required. This also results in fewer impurities and side reactions. In particular, it is not necessary to heat for several hours in the presence of a catalyst, i.e. an acid, such as an azeotrope-forming solvent for p-toluenesulfonic acid. Typical side reactions of thermally loaded aldehydes are, for example, disproportionation to alcohols and acids or oligomerization to eliminate water, for example to give substituted trioxane.

In addition, it has been found that the reactive form (free base) of the 2-aminomethylchroman need not be prepared separately, but can be prepared in situ directly from the storage stable salt form of the amine. The omission of separation of the free base means that at least one liquid/liquid partition is not necessary. This additionally limits the consumption of solvent.

The invention therefore relates to a process as described above, characterized in that the reactive form of 2-aminomethylchroman is prepared in situ from a salt of 2-aminomethylchroman.

Particularly suitable salts of 2-aminomethylchroman are 2-aminomethylchroman maleate, 2-aminomethylchroman hydrochloride and 2-aminomethylchroman carbonate. According to the invention, the use of 2-aminomethylchroman hydrochloride is particularly advantageous.

The 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans of the formula I contain a chiral centre in the 2-position of the chroman structure and may therefore be present in racemic or optically active forms. Formula I encompasses the racemates and enantiomerically pure compounds (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman and (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman.

The racemates include the racemates of 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans, which can be resolved mechanically or chemically into isomers by methods known per se. The diastereoisomers are preferably formed from the racemic mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the D and L forms of the amino acids, or various optically active camphorsulfonic acids, such as β -camphorsulfonic acid.

Chromatographic separation of the enantiomers by means of a column packed with an optically active resolving agent, for example dinitrobenzoylphenylglycine, is also advantageous; examples of suitable eluents are hexane/isopropanol/acetonitrile mixtures, for example in a volume ratio of 82: 15: 3, or as described in, for example, WO 97/47617.

Resolution of diastereomers can also be carried out by standard purification methods, such as fractional crystallization (a.collet, s.h.wilen, Enantiomers, Racemates and resolution (enertiomers, racemes and solutions), wiley (new york) 1981).

It is, of course, also possible to use 2-aminomethylchromans ((R) -2-aminomethylchroman or (S) -2-aminomethylchroman) which are already optically active, and to obtain optically active compounds of the formula I by the above-described process.

Racemic 2-aminomethylchromans are commercially available or can be prepared by known synthetic methods.

(R) -or (S) -2-aminomethylchromans can be prepared by known synthetic methods.

The preparation can be carried out, for example, starting from commercially available chroman-2-carboxylic acids by the following reaction:

(1) reacting with thionyl chloride to obtain acyl chloride,

(2) reacting with chiral amine to obtain diastereoisomer mixture of amide,

(3) the diastereoisomers are resolved by the above-mentioned conventional methods,

(4) reducing the diastereomeric amide to the corresponding N-substituted 2-aminomethylchroman, and

(5) dealkylation, for example by catalytic hydrogenation, gives enantiomerically pure 2-aminomethylchromans. Depending on the configuration of the chiral amine, the (R) or (S) enantiomer is obtained.

The invention likewise relates to processes for the preparation of (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans of the formula Ia and salts thereof,

it is characterized in that

(1) Reacting 5- (4-fluorophenyl) pyridine-3-carbaldehyde of the formula II

Directly reacting with (R) -2-aminomethyl chroman or a salt thereof under reducing conditions to obtain a compound of formula Ia,

(2) the resulting compound of formula Ia is converted to one of its salts by treatment with an acid. (S) -2-aminomethylchroman was used in an analogous manner to give the (S) enantiomer of Compound I.

Alternatively, (R) -2-aminomethylchroman can also be prepared by reacting racemic 2-aminomethylchroman with (S) -N-toluenesulfonylproline, followed by resolution of the racemate by crystallization. The solubilities of the racemic amine and the two diastereomeric salts of enantiomerically pure N-toluenesulfonyl- (S) -proline are so different that the pure (R)/(S) diastereomer of formula III can be obtained by conventional crystallization. Thus, (R) -2-aminomethylchroman N- (tosyl) - (S) -prolinate of formula III is formed.

The enantiomerically pure (R) -2-aminomethylchroman is subsequently liberated from the compound of formula III by alkaline extraction. (R) -N-tosylproline was used in a similar manner to give (S) -2-aminomethylchroman.

The invention furthermore relates to a process for the preparation of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans or of their salts, characterized in that (S) -aminomethylchromans are used, which are prepared from racemic aminomethylchromans by resolution of the racemate using (S) -N-toluenesulfonyl proline.

The invention likewise relates to the diastereoisomeric salt (S) -2-aminomethylchroman N- (tosyl) - (R) -prolinate.

The compounds of formula III are valuable intermediates in the synthesis of the above-described (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans and salts thereof.

The present invention therefore relates to a process for the preparation of the above-mentioned (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans or salts thereof, characterized by using (R) -aminomethylchromans, which are prepared from racemic aminomethylchromans by resolution of the racemate using (S) -N-toluenesulfonyl proline.

The invention likewise relates to the diastereoisomeric salt (R) -2-aminomethylchroman N- (tosyl) - (S) -prolinate.

The preparation of (R) -2-aminomethylchroman N- (tosyl) - (S) -prolinate and the subsequent alkaline extraction are described in example 4. The X-ray structural analysis of the salt is shown in fig.1 and 2. The relative configuration of the two asymmetric centers can be confirmed by fig.1 and 2. The configuration of (R) -2-aminomethylchroman can be derived from the absolute configuration of the natural amino acid (S) -proline.

FIG. 1(FIG. 1): x-ray structural analysis of (R) -2-aminomethylchroman N- (tosyl) - (S) -proline salt;

fig. 2(fig. 2): x-ray structural analysis of (R) -2-aminomethylchroman N- (tosyl) - (S) -proline salt.

5- (4-fluorophenyl) pyridine-3-carbaldehyde can be prepared by known synthetic methods. The preparation can be carried out, for example, starting from commercially available 5- (4-fluorophenyl) nicotinic acid by the following reaction:

(1) for example, reduction to 5- (4-fluorophenyl) -3-hydroxymethylpyridine in the presence of borohydride, followed by

(2) For example usingManganese dioxide (MnO)₂) The alcohol is oxidized to give the desired aldehyde.

An alternative method of preparation of the aldehyde is reduction of 3-cyano-5- (4-fluorophenyl) pyridine, for example by hydrogenation, or use of a hydride, for example diisobutylaluminum hydride or lithium tri-tert-butoxyaluminum hydride.

The reaction of 5- (4-fluorophenyl) pyridine-3-carbaldehyde with 2-aminomethylchroman hydrochloride, especially (R) -2-aminomethylchroman hydrochloride, is carried out under reducing reaction conditions, for example in the presence of a borohydride or hydrogenation catalyst.

Suitable borohydrides are lithium borohydride, sodium cyanoborohydride, potassium borohydride or boron hydride, which are located on a polymeric support material, for example of the Amberlyst A-26 BH 4-type. Particular preference is given to sodium borohydride which has been reacted first with methanol to give sodium trimethoxyborohydride.

Any solvent is suitable for the reaction in the presence of borohydride as long as it does not interfere with the feedstock. Particularly suitable are protic solvents, such as alcohols, for example ethanol or methanol, or mixtures thereof.

Suitable reaction temperatures are from 0 to 70 ℃, preferably from 10 to 50 ℃ and particularly preferably from 20 to 35 ℃.

The invention also relates to a process as described above, characterized in that the reaction is carried out in the presence of borohydride.

The reaction of 5- (4-fluorophenyl) pyridine-3-carbaldehyde with 2-aminomethylchroman hydrochloride, especially (R) -2-aminomethylchroman hydrochloride, can likewise be carried out in the presence of hydrogen and a hydrogenation catalyst.

Suitable hydrogenation catalysts are, for example, metals of the eighth subgroup, such as Raney nickel, palladium or platinum. The palladium or platinum catalyst may be located on a support material, for example activated carbon, calcium carbonate, barium sulfate or strontium carbonate, in the form of its oxide, for example platinum oxide, or in finely divided form.

The reaction is preferably carried out at a pressure of from 1 to 200 bar, at a temperature of from-80 to +150 ℃, particularly preferably at room temperature and atmospheric pressure.

Suitable solvents are, for example, alcohols, such as methanol, ethanol or isopropanol; carboxylic acids, such as acetic acid; esters, such as ethyl acetate; or ethers, such as Tetrahydrofuran (THF) or dioxane. It is likewise possible to use solvent mixtures of the abovementioned solvents, if desired aqueous solvent mixtures.

The invention therefore relates to a process as described above, characterized in that the reaction is carried out in the presence of hydrogen and a hydrogenation catalyst.

The resulting base of formula I can be converted with an acid into the relevant acid addition salt. Suitable acids for this reaction are those which form physiologically acceptable salts. Thus, it is possible to use inorganic acids, such as sulfuric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, nitric acid, sulfamic acid; and organic acids, in particular aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic mono-or polycarboxylic acids, sulfonic acids or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane-or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono-and di-sulfonic acids and lauryl sulfuric acid.

In a preferred embodiment, the salt formation is carried out in ethanol, and precipitation with hydrochloric acid (37%) gives 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman dihydrochloride hemihydrate, (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman dihydrochloride hemihydrate or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman dihydrochloride hemihydrate.

The present invention relates to the process as described above, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman dihydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman dihydrochloride is prepared.

In a likewise preferred embodiment, the salt formation is carried out at-5 ℃ and a stoichiometric amount of 37% aqueous hydrochloric acid is added to a 7% ethanolic solution of the base to give (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

The invention relates in particular to a process as described above, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride is prepared.

Without further elaboration, it is believed that one skilled in the art will be able to utilize the preceding description to its fullest extent. The preferred embodiments should therefore be considered as merely illustrative disclosures, but in no way limiting.

All temperature details above and below are given in ° c. In the following examples, "conventional work-up" means adding water if necessary, adjusting the pH to 2 to 10 if necessary, depending on the structure of the final product, extracting the mixture with ethyl acetate or dichloromethane, separating the phases, drying the organic phase over sodium sulfate, evaporating, and purifying the product by chromatography on silica gel and/or crystallization.

Example 1:

to 150ml of ethanol was added 20.3g of (R) -2-aminomethylchroman hydrochloride, and 36.8g of a 20% ethanol solution of sodium ethoxide was added dropwise with stirring. To this suspension was added 20.5g of 5- (4-fluorophenyl) pyridine-3-carbaldehyde at 35 ℃ and the mixture was stirred for another 3 hours. After addition of 4.2g of sodium borohydride, the mixture is stirred for a further 4 hours and then 62ml of water are added dropwise at room temperature. The pH of the reaction mixture was then adjusted to pH 4 over the course of one hour with 37% hydrochloric acid. The crystals were filtered off, washed with ethanol and dried under reduced pressure to give 27.2g of (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride (yield 69%).

Example 2:

to 130g of methanol was added 20.27g of 2-aminomethylchroman hydrochloride, followed by 20.4g of 30% sodium methoxide in methanol. To this white suspension was added 20.43g of 5- (4-fluorophenyl) pyridine-3-carbaldehyde at 35 ℃, the mixture was stirred for 1.5 hours, and then 4.20g of sodium borohydride was added in portions. After 15 hours, 56.4ml of water were added and the pH of the mixture was adjusted to pH 2 with 37% hydrochloric acid. After cooling the suspension to 0 ℃ the crystals are filtered off, washed with methanol and dried under reduced pressure to give 28.2g of 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride (yield 64%).

Example 3:

5.07g of (R) -2-aminomethylchroman and 5.00g of 5- (4-fluorophenyl) pyridine-3-carbaldehyde were dissolved in 38ml of THF, and 6g of 5% palladium-on-charcoal was added under stirring. The mixture was hydrogenated at room temperature and atmospheric pressure with stirring. When the consumption of hydrogen was complete, the catalyst was filtered off and the solvent was distilled off to give 8.66g of (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman (yield 68%).

Example 4:

(1) to 300ml of an aqueous solution of 31.0g NaOH was added 45.0g of (S) -proline. After the solid was dissolved, 74.6g of p-toluenesulfonyl chloride was added, and the mixture was stirred at 70 ℃ for 4 hours. After the mixture was cooled to room temperature, 30ml of 37% hydrochloric acid was added, and the solution was extracted several times with methyl t-butyl ether. The organic phases were collected, evaporated and the residue dissolved in 60ml ethanol. The mixture is then slowly added dropwise to a solution of 42.2g of rac-2-aminomethylchroman in 200ml of ethanol. The precipitate obtained is filtered off, washed with ethanol and dried to yield 43.0g of (R) -2-aminomethylchroman N- (tosyl) - (S) -proline salt (77% of the theoretical yield), characterized by FIGS. 1 and 2.

(2) 20.4g of (R) -2-aminomethylchroman N- (tosyl) - (S) -proline salt are suspended in 60ml of toluene and extracted with 2.07g of NaOH in 40ml of water. The aqueous phase was back-extracted with toluene and evaporated together with the first organic phase. The residue is dissolved in 500ml of ethanol and 4.88g of 37% hydrochloric acid are then added. After stirring the mixture at room temperature, the suspension is cooled to-10 ℃ and the crystalline solid is filtered off and dried to constant weight, yielding 7.95g of (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride (85% of theory). According to HPLC, the material is enantiomerically pure.

HPLC data:

column: daicel Crownpak CR (+) (150 x 4mm, fill material 5 μm)

Mobile phase: 90% water (with HClO)₄Adjusted to pH 2. 0) 10% methanol

Flow rate: 1.2 ml/min

Retention time: 53 minutes

Claims (28)

1. A process for the preparation of 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans of formula I and salts thereof,

the method is characterized in that:

(1) reacting 5- (4-fluorophenyl) pyridine-3-carbaldehyde of the formula II

Directly reacting with 2-aminomethylchroman or a salt thereof under reducing conditions to give a compound of formula I, and, optionally

(2) The resulting compound of formula I is converted to one of its salts by treatment with an acid.

2. A process according to claim 1, characterized in that the reactive form of 2-aminomethylchroman is prepared in situ from a salt of 2-aminomethylchroman.

3. A process according to claim 1 or 2, characterized in that the reaction is carried out in the presence of borohydride.

4. A process according to claim 1 or 2, characterized in that the reaction is carried out in the presence of hydrogen and a hydrogenation catalyst.

5. A process according to claim 1 or 2, characterized in that (R) -2-aminomethylchroman is used.

6. A process according to claim 3, characterized in that (R) -2-aminomethylchroman is used.

7. A process according to claim 4, characterized in that (R) -2-aminomethylchroman is used.

8. A process according to claim 1 or 2, characterized in that there is employed (R) -2-aminomethylchroman prepared from racemic aminomethylchroman by resolution of the racemate using (S) -N-toluenesulfonylproline.

9. A process according to claim 3, characterized in that there is employed (R) -2-aminomethylchroman prepared from racemic aminomethylchroman by resolution of the racemate using (S) -N-toluenesulfonylproline.

10. A process according to claim 4, characterized in that there is employed (R) -2-aminomethylchroman prepared from racemic aminomethylchroman by resolution of the racemate using (S) -N-toluenesulfonylproline.

11. A process according to claim 5, characterized in that there is employed (R) -2-aminomethylchroman prepared from racemic aminomethylchroman by resolution of the racemate using (S) -N-toluenesulfonylproline.

12. A process according to claim 7, characterized in that there is employed (R) -2-aminomethylchroman prepared from racemic aminomethylchroman by resolution of the racemate using (S) -N-toluenesulfonylproline.

13. A process according to claim 1 or 2, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride is prepared.

14. A process according to claim 3, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride is prepared.

15. A process according to claim 4, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride is prepared.

16. A process according to claim 5, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride is prepared.

17. A process according to claim 7, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride is prepared.

18. A process according to claim 8, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride is prepared.

19. A process according to claim 10, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride is prepared.

20. A process according to claim 12, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride is prepared.

21. A process according to claim 1 or 2, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman dihydrochloride is prepared.

22. A process according to claim 3, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman dihydrochloride is prepared.

23. Process according to claim 4, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane dihydrochloride is prepared.

24. Process according to claim 5, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane dihydrochloride is prepared.

25. Process according to claim 7, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane dihydrochloride is prepared.

26. The process according to claim 8, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman dihydrochloride is prepared.

27. Process according to claim 10, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane dihydrochloride is prepared.

28. The process according to claim 12, characterized in that (R) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman dihydrochloride is prepared.