The present invention relates to the field of organic synthesis, in particular to the racemisation of chiral by-products in the synthesis of optically active compounds.

Background of the Invention

The preparation of enantiomerically pure amines and alcohols represents a challenging task for industrial production. In recent literature, there are reported several enantioselective methods how to obtain optically active amines and alcohols with low content of the undesired enantiomer. In most cases cheap and simple reagents are not sufficient for obtaining a high enantiomeric excesses, but usually very expensive, hazardous and toxic chiral transition metal catalyzed approaches are used. On the other hand, it is possible to obtain optically pure amines or alcohols from easier available racemic mixtures using a) chiral separation chromatographic techniques; b) classical optical resolution approach through formation of salts; or c) kinetic resolution using enzymes. It is important to know, that a yield of a process is then consequently lower (max. 50%) and at least 50% of the material (undesirable enantiomer) represents losses/waste. This problem is even more expressed if the resolution is carried out on expensive or high-volume products. In order to have an economic and industrial applicable process there is a need for simple and efficient technologies to minimize losses by an undesirable enantiomer or for significantly improving the efficiency to yield the target/desirable enantiomer.

Racemisation techniques represent a practical method for regeneration of undesirable enantiomers. Most of the chiral amines, alcohols and ethers on which racemisation techniques are applied, possess the asymmetric carbon directly attached to the amino or hydroxyl group (a-amines and a-alcohols). There are a number of processes for racemisation of such chiral compounds unlimitedly listed in the following items.

1 ) Transition metal catalyzed hydrogen transfer is the most often used approach for racemisation of α-amines or alcohols. The process utilizes a conversion of optically active a-benzyl amine compound to an imine by reaction with a metal catalyst (hydride storage), followed by recovery of the amine by in situ hydrogenation of the imine to get the racemic mixture. In the case of alcohols the process undergoes via the ketone intermediate (see Scheme 1 ). ? ^H H ^metal M metalH ?H OH

^^CH ₃ Ph-^CH ₃ V Ph^*CH ₃ Ph^'"ci

^' metal H metal

NH ₂ metal NH metalH NH, NH

^CH

"3 V Ph-^CH, P ^CHs Ph^

N ·» ^■ metalH ³ r "

^ metal ^J

Scheme 1 : Racemisation of a-amines and a-alcohols catalyzed by transition metal catalyst via hydrogen transfer reaction.

The method is not limitedly reviewed in the publications such as Ahn, Y. et al., Coord. Chem. Rev. 2008, 647; Blacker, A. J. et al., Org. Proc. Res. Dev. 2007, 11, 642; Samec, J. S. M. et. al., Chem. Eur. J. 2005, 11, 2327; Parvulescu, A. et al. Chem. Commun. 2005, 42, 5307; US 6576795). Predominantly, the use of expensive, toxic and hazardous metal catalyst based on Ir, Ru, Rh, Pd, Ni, Zn for hydrogen transfer reaction is described therein.

2. ) Racemisation with special alkali metal polyaromatic complexes (US 4246424);

3. ) Base induced process (strongly requiring acidic hydrogen atom abstraction reaction on the oposition from amino group, only; US 5183939);

4. ) Enzymatic racemisation (US 2009/0098623; Koszelewski, D., et. al. Chem. Eur. J. 201 1 , 17, 378.; Musa, M. et. al. Org. Biomol. Chem. 2013, 1 1 , 291 1 ).

Most of publications are strongly limited to racemisation of obenzyl amines and obenzyl alcohols.

These methods are ineffective if the chiral carbon atom is in a distant position from amino or hydroxyl groups. For example, the racemisation of amines and alcohols wherein the chiral center is located on the β-position from the amino or hydroxy group (optically active β-amines or alcohols) is a very problematic and challenging task. The activating amino or hydroxy group is too far from the chiral center and consequently the possibility and reactivity for the racemisation is low. There is only one literature example found, wherein a method of racemisation was tested on optically active 3-methyl-2-phenylbutylamine showing full racemisation (US 5969186). The method applies highly reactive alkali metal polyaromatic complexes (sodium naphthalide, potassium biphenyl, sodium anthracide etc.) via single electron transfer process (see Scheme 2).

Scheme 2: Racemisation of 3-methyl-2-phenylbutylamine using sodium napthalenide complex.

Such methodology is efficient but suffers especially from the use of hazardous and carcinogenic polycyclic hydrocarbon aromatics and also from the difficult handling of alkali metal complexes (low stability, toxicity etc.) and as such it is not so convenient for industrial applications especially in pharmaceutical development. It is also less suitable for cyclic amines where substrates under single electron transfer reduction conditions could follow cycle-cleavage reactions.

Therefore, there is a strong need for a simple, economical, industrially friendly and generally applicable racemisation technology, especially for the racemisation of β-aryl substituted amines, alcohols, ethers, thiols or thioethers and derivatives, wherein the chiral center is in the β-position relative to the heteroatom.

Summary of the invention

In order to solve the above objects, the present invention provides a novel efficient, simple and economic racemisation methodology suitably adapted and applicable for the target compounds of optically active β-benzyl amine, hydroxy and thiol compound including cyclic β-benzazepines like lorcaserin. The present invention also provides new methods for inversion of the chirality and a method for increasing the yield of a desired enantiopure product, suitably used in the manufacturing of the target molecule lorcaserin, or its salt, preferably its hydrochloride salt. The present invention further provides novel intermediates of such new methods preferably applied in the manufacturing of the target molecule lorcaserin, or its salt, preferably its hydrochloride salt. The following items summarize in more detail aspects and preferred features embodiments, which contribute to solve the objects of the present invention alone or combination.

1 . Method for racemisation of a compound according to the formula la or lb:

wherein ^* in the formulae donates an asymmetric chiral carbon atom in (R) or (S) configuration being enantiomerically enriched or enantiopure;

wherein

R is represented by a linear, branched or cyclic Ci-Ci ₂ -alkyl;

R' is selected from hydrogen or a group selected from a Ci-Ci ₂ -alkyl group, a d- Ci ₂ -alkanoyl group, a benzoyl group, a CrC ₆ -alkyloxy carbonyl group, a Ci-C ₄ - alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC ₆ -alkoxy, unsubstituted or substituted amino, CrC ₆ -alkyl-subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond;

X is selected from O, S or N-R", wherein R" is selected from groups as defined for R' and is the same or different from R';

A is selected from -CH ₂ -, -CR ¹ R ² - (wherein R ¹ and R ² are same or different and are selected from linear, branched or cyclic, substituted or unsubstituted C ₁ -C ₁₂ - alkyl), -CH ₂ -CH ₂ -, CR ¹ R ² -CR ³ R ⁴ - (wherein R ¹ , R ² , R ³ and R ⁴ are same or different and are selected from linear, branched or cylic, substituted or unsubstituted C Ci ₂ -alkyl), -CR ⁵ =CR ⁶ - (wherein R ⁵ and R ⁶ are same or different and are selected from hydrogen or linear, branched or cyclic, substituted or unsubstituted C ₁ -C ₁₂ - alkyl), -CH ₂ -CO-, -CO-CH ₂ -, >C=0, -S0 ₂ -, and -NR ⁷ - (wherein R ⁷ is selected from hydrogen or linear, branched or cyclic, substituted or unsubstituted Ci-Ci ₂ -alkyl); n represents 0 or 1 , wherein X is directly linked to the benzene ring by a single bond if n is 0;

one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are optionally substituted with halo, nitro, nitroso, cyano, hydroxy or a group selected from a C C ₆ -alkoxy group, a unsubstituted or Ci-Ci ₂ -alkyl mono- or di-substituted amino group, a Ci-Ci ₂ -alkyl group, a Ci-Ci ₂ -alkanoyl group, a benzoyl group, a Ci-C ₆ - alkyloxy carbonyl group, a CrC ₄ -alkanesulfonyl group, and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC ₆ -alkoxy, unsubstituted or substituted amino, CrC ₆ -alkyl- subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond, and wherein bonds between the positions 2 and 3, or 3 and 4, or 4 and 5 are optionally condensed with another six-membered aromatic ring optionally containing one or two nitrogen atoms or with a five-membered aromatic ring containing one oxygen, or one sulfur or 1 to 3 nitrogen atoms or a combination of one oxygen and one nitrogen atom; by treatment with a strong base, which is selected from metal hydroxides, metal alkoxides or metal amides, in order to reduce the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration.

2. The method according to item 1 , wherein the racemization method yields compound according to the formula Ha or lib, respectively:

wherein R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above, and wherein the winding line ~ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the enantiomerically enriched or enantiopure starting configuration. 3. The method according to item 1 or 2, wherein if one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are substituted, at least one of the substituents is selected from an electron withdrawing group selected from halo, nitro, nitroso, cyano, or a group selected from a Ci-Ci ₂ -alkanoyl group, a benzoyl group, a CrC ₆ -alkyloxycarbonyl group, a Ci-C ₄ -alkanesulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups and optional substituents of the carbon atoms are defined as above.

4. The method according to any one of items 1 to 3, wherein R is represented by methyl, ethyl, isopropyl, preferably methyl.

5. The method according to any of items 1 to 4, wherein R' is represented by hydrogen.

6. The method according to any of items 1 to 5, wherein A is represented by -CH2-CH2-, -CH2-CO-, or -CO-CH2-, preferably -CH ₂ -CH ₂ -.

7. The method according to any of items 1 to 6, wherein X is represented by N-R", and wherein R" is preferably selected from hydrogen or one of the above defined C ₁ -C ₁₂ - alkanoyl group (preferably represented by an acetyl or a trifluoracetyl group), Ci-C ₆ - alkyloxy carbonyl group (preferably represented by a benzyloxycarbonyl or an allyloxycarbonyl group), Ci-C ₄ -alkylsulfonyl group (preferably represented by a mesyl group) or benzenesulfonyl group (preferably represented by a tosyl group).

8. The method according to any of items 1 to 7, wherein only the meta-position (3 or 5) in the benzene ring of formulae la and lb is substituted with chloro.

9. The method according to any of items 1 to 8, wherein the compound lb is represented by the following formula lb':

lb' wherein ^* and R" are defined as above, and wherein R" is preferably represented by hydrogen, an acetyl group, a trifluoracetyl group, a benzyloxycarbonyl, an allyloxycarbonyl group, a mesyl group, or a tosyl group. 10. The method according to any of items 1 to 9, wherein the racemisation process is carried out in a high boiling polar aprotic solvent, preferably selected from a group of amides, sulfoxides, and sulfones, more preferably Ν,Ν-dimethylacetamide (DMA), N,N- dimethylformamide (DMF), sulfolane and dimethylsulfoxide (DMSO), and most preferably dimethylsulfoxide.

1 1 . The method according to any of items 1 to 10, wherein the racemisation process is carried out at elevated temperature, preferably 80 °C or more, more preferably 90 °C or more, and most preferably 100 °C or more.

12. The method according to any of items 1 to 1 1 , wherein the strong base is selected from alkali or earth alkali hydroxides (preferably selected from alkali metal hydroxides, more preferably sodium or potassium hydroxide), alkali or earth alkali alkoxides (preferably alkali metal alkoxides, more preferably sodium or potassium ie f-butoxide), or alkali or earth alkali amides (preferably silylamides, more preferably sodium hexamethyldisilazane (NaHMDS)).

13. The method according to any of items 1 to 12, wherein the strong base is added at least equimolar, preferably with a molar excess of 1.25 or more, with respect to the compound according to formula la or lb.

14. Method according to any of items 1 to 13, wherein the enantiomerically enriched or enantiopure starting configuration is the (S) configuration.

15. Compound according to any of formulae 2* to 7*,

2* 3* 4*

6* 7*

wherein ^* in the formulae donates an asymmetric chiral carbon atom in (R) or (S) configuration being enantiomerically enriched or enantiopure, preferably enantiopure. 16. Method for inverting the chirality of a compound according to the formula la or lb

wherein ^* donates the enantiopure (R) or (S) configuration and R, R\ X, A and n are defined as above, and wherein the enantiopure starting configuration is preferably the (S) configuration;

by applying

(a) a racemisation treatment as defined by any of items 1 to 14, thereby at least partially inverting the chirality of the enantiopure starting configuration;

(b) an isolation process for isolating the enantiopure enantiomer according to the formula la or lb, respectively, having inverted chirality by chiral separation chromatographic techniques, by optical resolution approach through the formation of diastereomeric derivatives, salts or complexes or by kinetic resolution using enzymes,

(c) repeating at least once the above steps (a) and (b) for treatment of the residual non-inverted enantiomer having the starting configuration to successively yield the desired enantiomer having inverted chirality.

17. Method for increasing the yield of a desired enantiopure product according to the formula la or lb

wherein ^* donates the enantiopure (R) or (S) configuration and R, R\ X, A and n are defined as above, and wherein the desired configuration is preferably the (R) configuration,

by applying the steps of:

(a') preparation of a racemic intermediate according to a competitive industrially applicable synthesis or preparation of a chiral intermediate, which is enantiomerically enriched in the desired enantiomer by insufficient enantiomeric excess when applying a synthesis of insufficient enantioselectivity;

(b') isolation of a first batch of enantiomerically pure desired enantiomer according to the formula la or lb, respectively, by chiral separation chromatographic techniques, by optical resolution approach through the formation of diastereomeric derivatives, salts or complexes or by kinetic resolution using enzymes;

(c') collecting the undesired enantiomer according to the formula la or lb from side fractions, mother liquors or other process side products resulting from the isolation of the desired enantiomer;

(d')optionally isolation of the undesired enantiomer;

(e') racemising the undesired enantiomer by a racemisation treatment as defined by any of items 1 to 14 to afford a compound according to the formula Ha or lib, respectively:

wherein R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above and wherein the winding line ~ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the configuration of the undesired enantiomer;

(f) isolating the product of the step (e'), which is preferably a racemate, according to the above step (b') to achieve a second batch of the enantiomerically pure desired enantiomer according to the formula la or lb, respectively. 18. The method according to item 17, wherein the steps (b') to (f) are successively repeated several times.

19. Method for synthesizing lorcaserin according to the formula (R)-" , or a salt thereof, preferably the hydrochloride salt thereof:

applying a method as defined by any of items 1 to 1 1 , 13 or 14.

Detailed description of the invention

Hereinafter, the present invention is described in more detail by referring to further preferred and further advantageous embodiments and examples which supplement the above items and which shall not be understood as being limiting.

The present invention provides a very simple, efficient and economic technology for racemisation of amine, alcohol or thioalcohol compounds having chirality in the β- position. It was surprisingly found that this simple technology based on the use of appropriate base in appropriate solvent, enables efficient racemisation of amines, alcohols or thioalcohols where the chiral carbon (benzylic position) is located at the β-position of the heteroatom (amino, hydroxyl or mercapto group) or even more distant therefrom. Up to now it has been only possible to racemise obenzyl amines or o benzyl alcohols where heteroatom (N, O, S) is directly located/bound at asymmetric benzylic position and very strongly increase the reactivity of the compound towards racemisation.

Special focus is oriented in efficient and simple racemisation of an undesired enantiomer of a chiral pharmaceutically active ingredient, preferably lorcaserin or a salt thereof, preferably the hydrochloride salt, or an intermediate for the preparation thereof, wherein the chiral benzylic position is located at the β-position of the amino group. The approach according to the invention enables the use of cheaper and shorter racemic synthetic schemes not requiring expensive and toxic reagents and catalysts, followed by final resolution of enantiomers with chiral chromatography or using classical optical resolution approach without unavoidable loss of more than 50 % of consumed material and energy by wasting the undesired enantiomer. Using this technology, it is possible to almost quantitatively obtain pure enantiomer with simple combination of resolution followed by efficient racemisation of undesirable enantiomer in a cyclic process.

The terms "enantiomerically enriched mixture/product/compound" or "enantiomerical enrichment" as used herein mean a mixture, a product, a compound or a process having or achieving an enantiomerical excess by 10 to 70 % e.e, preferably 30 to 70 % e.e, more preferably 50 to 70 % e.e.

The term "enantiomerically pure", "enantiopure" or "optically pure" compound as used herein means a compound having an enantiomerical excess by at least 70 % e.e., preferably having at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e.

The term "racemization" as used herein refers to the converting of an enantiomerically enriched or enantiopure compound into a mixture where the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration is reduced at least by one-third, more preferably at least by half, and still more preferably by at least by two- third. Most preferably, the racemization results in a mixture where the enantiomers are present in equal quantity (racemic or a racemate).

The term "salt" as used herein refers to any suitable salt form from the respective compound. Preferably, the salt is pharmaceutically acceptable.

In the first embodiment, the invention provides a method for racemisation of a compound according to the formula la or lb:

wherein ^* in the formulae donates an asymmetric chiral carbon atom in (R) or (S) configuration being enantiomerically enriched or enantiopure;

wherein R is represented by a linear, branched or cyclic Ci-Ci ₂ -alkyl;

R' is selected from hydrogen or a group selected from a Ci-Ci ₂ -alkyl group, a d- Ci2-alkanoyl group, a benzoyl group, a CrC ₆ -alkyloxy carbonyl group, a C1-C4- alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC ₆ -alkoxy, unsubstituted or substituted amino, CrC ₆ -alkyl-subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond;

X is selected from O, S or N-R", wherein R" is selected from groups as defined for R' and is the same or different from R';

A is selected from -CH ₂ -, -CR ¹ R ² - (wherein R ¹ and R ² are same or different and are selected from linear, branched or cyclic, substituted or unsubstituted C1-C12- alkyl), -CH ₂ -CH ₂ -, CR ¹ R ² -CR ³ R ⁴ - (wherein R ¹ , R ² , R ³ and R ⁴ are same or different and are selected from linear, branched or cylic, substituted or unsubstituted C Ci ₂ -alkyl), -CR ⁵ =CR ⁶ - (wherein R ⁵ and R ⁶ are same or different and are selected from hydrogen or linear, branched or cyclic, substituted or unsubstituted C1-C12- alkyl), -CH ₂ -CO-, -CO-CH ₂ -, >C=0, -S0 ₂ -, and -NR ⁷ - (wherein R ⁷ is selected from hydrogen or linear, branched or cyclic, substituted or unsubstituted Ci-Ci ₂ -alkyl); n represents 0 or 1 , wherein X is directly linked to the benzene ring by a single bond if n is 0;

one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are optionally substituted with halo, nitro, nitroso, cyano, hydroxy or a group selected from a C C ₆ -alkoxy group, a unsubstituted or Ci-Ci ₂ -alkyl mono- or di-substituted amino group, a Ci-Ci ₂ -alkyl group, a Ci-Ci ₂ -alkanoyl group, a benzoyl group, a Ci-C ₆ - alkyloxy carbonyl group, a CrC ₄ -alkanesulfonyl group, and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC ₆ -alkoxy, unsubstituted or substituted amino, CrC ₆ -alkyl- subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond, and wherein bonds between the positions 2 and 3, or 3 and 4, or 4 and 5 are optionally condensed with another six-membered aromatic ring optionally containing one or two nitrogen atoms or with a five-membered aromatic ring containing one oxygen, or one sulfur or 1 to 3 nitrogen atoms or a combination of one oxygen and one nitrogen atom; by treatment with a strong base, which is selected from metal hydroxides, metal alkoxides or metal amides, in order to reduce the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration.

The racemisation treatment reduces the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration at least by one-third, more preferably at least by half, and still more preferably by at least by two-third. It is most preferred that no enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration is detectable after the racemisation treatment thus achieving a racemic mixture of 0% e.e.

The racemization method thus preferably yields the compound according to the formula Ha or Mb, respectivel :

wherein R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above. The winding line ~ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the enantiomerically enriched or enantiopure starting configuration.

The racemisation treatment is preferably carried out in a high boiling polar aprotic solvent, which is preferably selected from the group of amides, sulfoxides, and sulfones The preferred solvents are Ν,Ν-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), sulfolane and dimethylsulfoxide (DMSO), the most preferred one is dimethylsulfoxide. The solvent preferably consists only of high boiling polar aprotic solvents, which are preferably used anhydrous. One high boiling polar aprotic solvent may be used alone or a mixture of high boiling polar aprotic solvents may be used. Preferably, only DMSO is used. The racemisation treatment is preferably carried out at elevated temperature, preferably at 80 °C or more, more preferably at 90 °C or more, most preferably 100 °C or more. The upper limit of the reaction temperature is not especially limited provided that the reaction temperature is lower than the degradation/decomposition temperature of the educts in the reaction mixture.

The racemisation treatment is suitably accomplished in the presence of metal hydroxides, metal alkoxides or metal amides which are selected from bases the corresponding acid having a pKb of at least 12 in DMSO. Preferably, the base is selected from alkali or earth alkali hydroxides, alkali or earth alkali alkoxides or alkali or earth alkali amides. More preferably the base is selected from alkali metal hydroxides (preferably sodium or potassium hydroxide), alkali metal alkoxides (preferably sodium or potassium ie f-butoxide), or alkali metal silylamides (preferably sodium hexamethyldisilazane (NaHMDS)). The strong base is added in an amount enabling suitable racemisation turnover. The conversion can be performed by submolar, equimolar or excess amounts of the base, but in order to increase the turnover and/or speed up the reaction time, it is preferred to apply the strong base at least equimolar, preferably with a molar excess of 1.25 or more, with respect to the compound according to formula la or lb. The upper limit of the amount of strong base is not particular limited provides that the used amount avoids the decomposition or degradation of the compound to be racemised. However, in the individual case, it may even be desirable to apply such an amount of strong base that leads to racemisation and de-protection of a protecting group at the heteroatom O, N, or S (i.e. groups R', R", R ^b or R ^c ) in one concerted reaction.

The reaction of conversion is preferably prolonged to a full racemisation, in the case of very slow conversion a skilled person can optionally stop the reaction, when a reasonably reduced enantiomeric access, such 50 % e.e. or below, preferably 20 % e.e. or below, is reached. A full racemisation is usually achieved within 48 hours, preferably it takes 12 to 36 hours.

In the compound according to the formula la or lb applied in the method of the present invention, the benzene ring may be substituted as defined above. If one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are substituted, at least one of the substituents is preferably selected from an electron withdrawing group selected from halo, nitro, nitroso, cyano, or a group selected from a Ci-Ci ₂ -alkanoyl group, a benzoyl group, a CrC ₆ -alkyloxycarbonyl group, a Ci-C ₄ -alkanesulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups and optional substituents of the carbon atoms are defined as above. Such electron withdrawing groups may have beneficial impact on the racemisation turnover in the racemisation treatment of the present invention. It is most preferred that a chloro substituent is present in the meta-position (i.e. position 3 or 5) of the benzene ring of formula la or lb with no further substitution on the benzene ring being present.

In the compound according to the formula la or lb applied in the method of the present invention, R is preferably represented by methyl, ethyl, isopropyl, more preferably methyl.

In the compound according to the formula la applied in the method of the present invention, R' is preferably represented by hydrogen. In case of X being O or S, it is especially preferred that R' is represented by hydrogen. In case of X being N-R", it is preferred that R' is hydrogen, while R" is selected from hydrogen or a group selected from a Ci-Ci ₂ -alkyl group, a Ci-Ci ₂ -alkanoyl group, a benzoyl group, a CrC ₆ -alkyloxy carbonyl group, a CrC ₄ -alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC ₆ -alkoxy, unsubstituted or substituted amino, CrC ₆ -alkyl-substituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond, while R" is preferably selected from hydrogen or one of the above defined C Ci2-alkanoyl group (preferably represented by an acetyl or a trifluoracetyl group), d- C ₆ -alkyloxy carbonyl group (preferably represented by a benzyloxycarbonyl or an allyloxycarbonyl group), Ci-C ₄ -alkylsulfonyl group (preferably represented by a mesyl group) or benzenesulfonyl group (preferably represented by a tosyl group). In case of X being N-R" and R' being different from hydrogen, R" may be suitably selected to be the same or different from R', while such amine compounds being substituted by R' and R" may be represented by alkylamides, alkylsulfonamides, tertiary amines, etc.

A typical but not limited set of the open chained chiral benzylic compounds according to the formula la for successful racemisation according to the invention is shown in Scheme 3 with respect to the compound according to the formula la". Experimental details are more precisely shown in the example section. base

T ^X solvent

CH ₃ CH ₃ la" Ma" optically pure/enriched racemate

I ^a = H, F, CI, Br, I, OH, MeO, N0 ₂ ; preferably H or CI (preferably in meta-position);

X= NH, 0, S;

R ^b = -H if X = 0, S and R ^b = -H, -COCH ₂ Ph, -COCH3 or -COOCH ₂ CH=CH ₂ if X = NH;

base= NaOH, KOH, NaOfBu, KOfBu, NaHMDS

solvent= DMSO, sulfolane, DMA, DMF

Scheme 3: Illustrative examples of racemisation technology on preferred open chained chiral benzylic compounds according to formula la".

Further, in the compound according to the formula lb applied in the method of the present invention, R" is selected from hydrogen or a group selected from a CrCi ₂ -alkyl group, a Ci-Ci ₂ -alkanoyl group, a benzoyl group, a CrC ₆ -alkyloxy carbonyl group, a CrC ₄ -alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC ₆ -alkoxy, unsubstituted or substituted amino, CrC ₆ -alkyl-substituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond, while R" is preferably selected from hydrogen or one of the above defined Ci-Ci ₂ - alkanoyl group (preferably represented by an acyl or a trifluoracyl group), Ci-C ₆ - alkyloxy carbonyl group (preferably represented by a benzyloxycarbonyl or an allyloxycarbonyl group), d-C ₄ -alkylsulfonyl group (preferably represented by a mesyl group) or benzenesulfonyl group (preferably represented by a tosyl group).

Additionally, it is preferred that n is 1. Furthermore, it is preferred that the compound according to the formula lb features a benzazepine skeleton having a 7-membered ring annealed to the benzene ring. In this case, it is preferred that A is represented by -CH ₂ -CH ₂ -, -CH ₂ -CO- or -CO-CH ₂ -, more preferably -CH ₂ -CH ₂ -. Another typical but not limited set of the cyclic benzylic compounds according to the formula lb for successful racemisation according to the invention is shown in Scheme 4 with respect to the compound according to the formula lb". Experimental details are more precisely shown in the example section, while table 1 in Example 10 teaches optimal conditions and reagents for racemisation.

lb" Mb

R ^c = -H, -COCH3, -COCF3, -COOCH ₂ CH=CH ₂ , -COCH ₂ Ph;

Scheme 4: Illustrative examples of racemisation technology on cyclic chiral benzylic compounds

The substituents R ^b or R ^c (and R' or R", respectively) may beneficially influence on ease and duration of racemisation conversion. The influence is empirical, a skilled person may decide according to experimental results whether the substitution of the heteroatom X, preferably nitrogen, is done in order to make racemisation easier, the reaction time shorter or temperature lower.

The substituent(s) R ^a (i.e. the substituent(s) on positions 2 to 6 of the benzene ring) may also influence on ease and duration of racemisation conversion. Electron withdrawing substituents, such as chloro have a beneficial effect on duration and completeness of the racemisation, because they enhance acidity of the proton on the carbon atom attached to the aromatic ring.

Applying the racemisation method in a total synthesis of a desired compound the heteroatom can be substituted by protecting groups from previous steps of the synthesis. In such case, a skilled person can decide whether the racemisation is performed on the substituted derivative or by an approach wherein the intermediate is first deprotected and then racemised.

In another embodiment of the invention, the present invention provides novel compounds according to the formulae 2* to 7* as shown in Scheme 5, wherein the compounds shown in Scheme 5 are enantiomerically enriched or enantiopure in (S) or (R) configuration, preferably the (R) configuration. More preferably, such compounds have an enantiomeric excess of 98 % e.e. or more.

6* 7*

Scheme 5: Novel compounds representing suitable intermediates for preparation of optically active pharmaceutics, preferably lorcaserin, or a salt thereof.

Such novel compounds represent suitable intermediates for the synthesis of pharmaceutically active agents, especially lorcaserin, or a salt thereof, preferably the hydrochloride salt thereof. Such intermediates can be achieved by substitution of the heteroatom, which can be done by routine methods well known to a skilled person using reactive alkylation or acylation reagents in the presence of a base or by dehydration techniques using dehydration reagents such as carbodiimides.

In another embodiment, the invention provides a method for inverting the chirality of a compound according to the formula la or lb

wherein ^* donates the enantiopure (R) or (S) configuration and R, R', X, A and n are defined as above, and wherein the enantiopure starting configuration is preferably the (S) configuration;

by applying (a) a racemisation treatment as defined by any of items 1 to 14, thereby at least partially inverting the chirality of the enantiopure starting configuration;

(b) an isolation process for isolating the enantiopure enantiomer according to the formula la or lb, respectively, having inverted chirality by chiral separation chromatographic techniques, by optical resolution approach through the formation of diastereomeric derivatives, salts or complexes or by kinetic resolution using enzymes,

(c) repeating at least once the above steps (a) and (b) for treatment of the residual non-inverted enantiomer having the starting configuration to successively yield the desired enantiomer having inverted chirality.

In the method for inverting the chirality of a compound according to the formula la or lb, the starting compound has preferably an enantiomeric excess of at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e. Besides, the reagents, reaction conditions and the compounds according to formula la or lb including the substituents are the same as for the method of the above first embodiment, while the above described preferences apply also for the method according to this embodiment.

Following the steps (a) and (b) in a repeating manner, it is possible to successively convert almost all starting compound to the desired compound having inverted chirality. For the isolation process in step (b), there can be used for instance an optical resolution approach as described in WO 05/019179 applying tartaric acid protocol or chiral chromatography as described by B. M. Smith et al. (J. Med. Chem. 2008, 57, 305-315).

In another embodiment, the invention provides a method for increasing the yield of a desired enantiopure product according to the formula la or lb

wherein ^* donates the enantiopure (R) or (S) configuration and R, R\ X, A and n are defined as above, and wherein the desired configuration is preferably the (R) configuration,

by applying the steps of:

(a') preparation of a racemic intermediate according to a competitive industrially applicable synthesis or preparation of a chiral intermediate, which is enantiomerically enriched in the desired enantiomer by insufficient enantiomeric excess when applying a synthesis of insufficient enantioselectivity;

(b') isolation of a first batch of enantiomerically pure desired enantiomer according to the formula la or lb, respectively, by chiral separation chromatographic techniques, by optical resolution approach through the formation of diastereomeric derivatives, salts or complexes or by kinetic resolution using enzymes;

(c') collecting the undesired enantiomer according to the formula la or lb from side fractions, mother liquors or other process side products resulting from the isolation of the desired enantiomer;

(d')optionally isolation of the undesired enantiomer;

(e') racemising the undesired enantiomer by a racemisation treatment as defined by any of items 1 to 14 to afford a compound according to the formula Ha or lib, respectively:

wherein R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above and wherein the winding line ~ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the configuration of the undesired enantiomer;

(f) isolating the product of the step (e'), which is preferably a racemate, according to the procedure of the above step (b') in order to achieve a second batch of the enantiomerically pure desired enantiomer according to the formula la or lb, respectively. In the method for increasing the yield of a desired enantiopure product according to the formula la or lb, the resulting desired compound has preferably an enantiomeric excess of at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e. Besides, the reagents, reaction conditions and the compounds according to formula la or lb including the substituents are the same as for the method of the above first embodiment, while the above described preferences apply also for the method according to this embodiment.

In this method of the present invention, the steps (b') to (f) are preferably successively repeated several times. Thereby, it is possible to batch-wise increase the yield of the compound having the desired chirality.

For the isolation process in step (b'), there can be used for instance an optical resolution approach as described in WO 05/019179 applying tartaric acid protocol or chiral chromatography as described by B. M. Smith et al. (J. Med. Chem. 2008, 57, 305-315).

Applying the racemisation technology according to the invention, it is possible to enhance the weight gain of a target chiral product for more than 20 %, preferably for more than 50 % in one step and to enhance the yield by single or multiple recovery over 50 %, preferably over 70 %.

Such protocol is very useful for industrial preparation of pharmaceutically applicable compounds according to the formula la or lb. For example, the (RJ-enantiomer of the compound according to the formula lb' or lb", wherein R ^c and R", respectively, are hydrogen was recently introduced to medical practice as an antiobesity drug (the compound of the formula (R)A .

In the literature, several processes for the preparation of the racemic compound according to the formula lib", wherein R ^c is hydrogen, have been reported (see WO 03/086306, WO 05/019179, WO 08/0701 1 1 ). The preparation of the compound according to the formula (RjA is achieved by using a resolution via a diastereomeric salt with L-(+)-tartaric acid (see WO 05/019179). By triple precipitation from wet tert- butanol enantiomerically pure compound of the formula (R)-" in the form of tartrate is obtained in 98.7 % e.e., but the yield is only 15 %. An amount of 85 % of material, obtained after several troublesome synthetic steps is therefore unrecurrently lost.

By using the process of racemisation according to the invention most of material, which has been removed in the form of the mirror isomer represented by the formula (S)-" and the lost part of the desired (RJ-isomer can be returned to the process losing only the material due to degradation and technical losses.

Therefore, the above methods of the present invention can be suitable used in the synthesis of lorcaserin according to the formula (R)-" , or a salt thereof, preferably the hydrochloride salt thereof.

Detailed description of the ways of carrying out the invention (examples) in a way that examples can be reproduced.

The present invention is illustrated more precisely based on the following examples and with the table which presents a study of the effect of the reaction conditions on racemisation process using novel technology.

In all examples, the optical purity of the starting compounds and final products is indicated by enantiomeric excess (% e.e.). The enantiomeric excess as mentioned herein means an excess of one enantiomer over the racemic mixture. Optical purity is determined using chiral HPLC analysis or by chiral GC-FID. The % e.e. is calculated from percentage ratio of enantiomers x:y, wherein y>x by the mathematical formula 100 - 2x.

Example 1 : Racemisation of optically active (R)-2-phenylpropan-1 -amine using potassium ie f-butoxide

(R)-B 8 The testing compound of the formula {R)-S is commercially available.

Starting material (R)-2-(3-chlorophenyl)propan-1 -amine {{R)-S, 1 mmol; 136 mg; > 98% optical purity) was dissolved in anhydrous DMSO (0.9 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (fresh powder; 1 .25 mmol) was added in two portions in 30 min intervals and the closed reaction system was stirred at 100 °C for 36 hours. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (100 mL). The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained residue (123 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the product under such conditions was analysed also with GC-MS (m/z = 136; CI).

Example 2: Racemisation of optically active (R)-2-phenylpropan-1 -amine using potassium hydroxide

(R)-8

Starting material (R)-2-(3-chlorophenyl)propan-1 -amine ((R)-8, 1 mmol; 136 mg; > 98% optical purity) was dissolved in anhydrous DMSO (0.9 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOH (fresh powder; 2 mmol) was added in four portions in 30 min intervals and the closed reaction system was stirred at 100 °C for 48 hours. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (100 mL). The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained residue (1 16 mg) was analysed with chiral HPLC where 60 % e.e. was detected. Purity and stability of the product under such conditions was analysed also with GC-MS (m/z = 136; CI). Example 3: Racemisation of optically active (S)-2-phenyl-propan-1 -ol in the presence of potassium ie f-butoxide

fSj-9 9

The testing compound of the formula (S)-9 is commercially available.

Starting material (S)-2-phenyl-propan-1 -ol ((S)-8; 1 mmol; 137 mg; > 99% optical purity) was dissolved in anhydrous DMSO (0.9 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (fresh powder; 1 .5 mmol) was added in four portions in one hour intervals and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (100 mL). The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained residue (1 12 mg) was analysed with chiral GC-FID where 50 % e.e. was detected.

Example 4: Racemisation of optically active (S)-2-(3-chlorophenyl)propan-1 -amine using potassium hydroxide

(S)-5 5

The testing compound (S)-2-(3-chlorophenyl)propan-1 -amine {(S)-5) was prepared according to the literature (J. Med. Chem. 56, 4786 (2013)) followed by separation of enantiomers by column chromatography on chiral supporter to its (S)- and (R)- enantiomer.

Starting material (S)-2-(3-chlorophenyl)propan-1 -amine ((S)-5, 1 mmol; 169 mg; > 95% optical purity) was dissolved in anhydrous DMSO (0.8 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOH (fresh powder; 1 .25 mmol) was added in three portions in 30 min intervals and the closed the reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (60 mL). The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained residue (155 mg) was analysed with chiral HPLC where 28 % e.e. was detected. Purity and stability of the product under such conditions was analysed also with GC-MS (m/z = 169; CI) and ¹ H NMR.

¹ H NMR (500 MHz, CDCI ₃ ) δ 8.25 (bs, NH ₂ ), 7.25-7.10 (m, 4ArH), 3.15 (m, 1 H), 2.92 (m, 2H), 1 .15 (d, J= 9 Hz, 3H).

Example 5: Racemisation of optically active (S)-2-(3-chlorophenyl)propan-1 -amine using potassium ie f-butoxide

(S)-5 5

Starting material (S)-2-(3-chlorophenyl)propan-1 -amine {(S)-5, 0.5 mmol; 85 mg; > 95% optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (fresh powder; 0.625 mmol) was added in three portions in 30 min intervals and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted with n-hexane (60 mL) for few times. The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained residue (81 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the product under such conditions was analysed also with GC-MS (m/z = 169; CI) and ¹ H NMR. Example 6: Synthesis of (S)-/V-2-(3-chlorophenyl)propyl)-2-phenylacetamide {(S)-7)

(S)S (S)-7

Starting material (^^-(S-chloropheny^propan-l -amine {(S)-5, 2.5 mmol; > 96% optical purity) was suspended in acetone (10 mL) in a 100 mL flask equipped with magnetic stir bar. Afterwards an aqueous solution of K ₂ C0 ₃ (1 .25 equiv. according to starting compound) was added and the reaction system was cooled down to 0 °C followed by slow addition of phenylacetyl chloride (2.8 mmol). The reaction mixture was vigorously stirred at room temperature. After the completion of the reaction, the reaction system was diluted with CH ₂ CI ₂ , washed with saturated NaHC0 ₃ , the organic phases were dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained oily product (680 mg; 94% yield) was analysed with GC-MS (m/z = 287) and ¹ H, ¹³ C NMR spectroscopy.

¹ H N MR (500 MHz, CDCI ₃ ) δ 7.41 -7.30 (m, 4ArH), 7.28-7.19 (m, 3ArH), 7.17-7.09 (m, 2ArH), 5.40 (bs, NH), 3.55 (m, 1 H), 3.50 (s, 2H), 3.18 (m, 1 H), 2.85 (m, 1 H), 1 .18 (d, J= 9.2 Hz, 3H);

¹³ C N MR (125 MHz, CDCI ₃ ) δ 170.9, 147.3, 146.0, 134.4, 129.8, 129.1 , 127.5, 126.8, 126.6, 125.6, 125.3, 46.0, 43.8, 40.2, 39.4, 19.1 .

Example 7: Racemisation of optical active (S)-/V-2-(3-chlorophenyl)propyl)-2- phenylacetamide in the presence of potassium ie f-butoxide

(S)-7 7 Starting material (S)-/V-2-(3-chlorophenyl)propyl)-2-phenylacetamide {(S)-7, 0.5 mmol; 143.5 mg; > 95% optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (fresh powder; 0.625 mmol) was added in three portions in 30 min intervals and the closed reaction system was stirred at 100 °C for 24 hours. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (100 mL). The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained residue (133 mg) was analysed with chiral HPLC where 45 % e.e. was detected. Purity and stability of the product under such conditions were analysed with GC-MS (m/z = 287; CI).

Example 8: Synthesis of allyl (RJ-(2-(3-chlorophenyl)propyl)carbamate

Starting material (/^.-(S-chloropheny propan-l -amine {(R)-5, 12.2 mmol; > 98% optical purity) dissolved in CH ₂ CI ₂ (25 mL) in a 100 mL flask equipped with magnetic stir bar. Afterwards Et ₃ N (1 .2 equiv. according to starting compound) was added and the reaction system was cooled down to 0 °C followed by slow addition of allyl chloroformate (1 .05 equiv.). The reaction mixture was vigorously stirred at room temperature. After the completion of the reaction, the reaction system was diluted with CH ₂ CI ₂ , washed with saturated NaHC0 ₃ , the organic phases were dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained liquid product (2.61 g; 84% yield) was analysed and confirmed with GC-MS (m/z = 253) and ¹ H NMR spectroscopy. ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.33-7.12 (m, 3ArH), 7.07 (m, 1ArH), 5.85 (m, 1 H), 5.25 (m, 2H), 4.51 (m, 2H), 3.45 (m, 1 H), 3.30 (m, 1 H), 2.90 (m, 1 H), 1.27 (d, J = 9 Hz, 3H).

Example 9: Synthesis of (S)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo/c//azepine

(fs;-i)

The compound of the formula {(S)- ) was prepared following the procedures of examples 8, 9, 10, and 12 in WO 05/019179. The obtained crude racemate of the compound according to the formula 1 was submitted to triple crystallisation through the salt with D-(-)-tartaric acid according to the Example 13 of the same publication to give the title compound in 16 % yield and optical purity of over 98 % e.e.

Example 10: Efficient racemisation of optical pure (S)-8-chloro-1 -methyl-2, 3,4,5- tetrahydro-1 /-/-benzo/c//azepine

fs -i

optical pure racemate

Starting material (S)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo/c//azepine ((SJ-1 , 1 mmol; 198 mg; >98% optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), an appropriate base (1 .25 mmol; see Table 1 ) was added in three portions in 30 min intervals and the closed reaction system was stirred at 90-100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane or n-heptane (60 mL). The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained residue (185 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the product under such conditions were analysed with GC-MS (m/z = 195; CI) and ¹ H NMR.

¹ H NMR (500 MHz, CDCI ₃ ) δ 7.04 (m, 2H), 6.98 (m, J = 9.1 Hz, 1 H), 6.22 (d, J = 9.7 Hz, 1 H), 5.06 (1 H, J = 9.7 Hz, 1 H), 3.32 (m, 1 H), 3.24 (m, 1 H), 1.18 (d, J = 7.1 Hz, 3H).

In a similar reaction protocol as described above, the effect of the reaction conditions on the racemisation process was studied. Several reactions were carried out at various reaction conditions (effect of a base; solvent; temperature). The results are presented in Table 1 .

Table 1.

Example 11 : Synthesis of optical pure 1 -(8-chloro-1 -methyl-4,5-dihydro-1 H- benzo[c/]azepin-3(2H)-yl)ethanone {{(S)-2)

(S)-VHC\ (S)-2

Starting material 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo/c//azepine hydrochloride ((S)-V C\, 2.5 mmol; > 98% optical purity) was dissolved in anhydrous CH ₂ CI ₂ (5 mL) in a 100 mL flask equipped with magnetic stir bar. Afterwards Et ₃ N (1 equiv. according to starting compound) was added and the reaction system was cooled down to 0 °C followed by slow addition of acetyl chloride (2.8 mmol). Such reaction mixture was vigorously stirred at room temperature. After the completion of the reaction, the reaction system was diluted with CH2CI2, washed with saturated NaHC0 ₃ , the organic phases were dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained oily product (570 mg; 96% yield) was analysed with GC-MS (m/z = 237) and ¹ H NMR spectroscopy.

¹ H NMR (500 MHz, DMSO, 75 °C) δ 7.31 -7.05 (m, 3ArH), 3.85 (m, 2H), 3.55 (m, 2H), 3.25-2.86 (m, 3H), 1 .97 (s, 3H), 1 .20 (bs, 3H).

Example 12: Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 /-/- benzo[c/]azepin-3(2/-/)-yl)ethanone using sodium hydroxide

(S)-2

Starting material (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[c/]azepin-3(2/-/)- yl)ethanone {(S)-2, 0.5 mmol; 120 mg; > 98% optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), NaOH (fresh powder; 0.625 mmol) was added in two portions in 30 min intervals and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (60 mL). The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained residue (120 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the product under such conditions were analysed with GC-MS (m/z = 237; CI) and ¹ H NMR. 22% of hydrolysed product (m/z = 195) was also observed.

Example 13: Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 /-/- benzo[c/]azepin-3(2/-/)-yl)ethanone in the presence of potassium ie f-butoxide

(S)-2 2

Starting material (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[c/]azepin-3(2/-/)- yl)ethanone {{(S)-2, 0.5 mmol; 120 mg; > 98% optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (0.625 mmol) was added in two portions in 30 min intervals and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (60 mL). The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and solvent was evaporated under reduced pressure. The obtained residue (120 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the product under such conditions were analysed with GC-MS (m/z = 237; CI) and ¹ H NMR (two conformers). 12% of hydrolysed product (m/z = 195) was also observed. Example 14: Synthesis of optical pure allyl 8-chloro-1 -methyl-4,5-dihydro-1 H- benzo[c/]azepine-3-(2H)-carboxylate {(S)-3)

Starting material 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo/c//azepine hydrochloride (((S)-V C\, 2.5 mmol; > 98% optical purity) was dissolved in anhydrous CH ₂ CI ₂ (5 mL) in a 100 mL flask equipped with magnetic stir bar. Afterwards Et ₃ N (1 equiv. according to starting compound) was added and the reaction system was cooled down to 0 °C followed by slow addition of allyl chloroformate (2.75 mmol). The reaction mixture was vigorously stirred at room temperature. After the completion of the reaction, the reaction system was diluted with CH2CI2, washed with saturated NaHC0 ₃ , the organic phases were dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained liquid product (600 mg; 86% yield) was analysed with GC-MS (m/z = 279) and ¹ H NMR spectroscopy.

¹ H NMR (500 MHz, CDCI ₃ ) δ 7.28-7.17 (m, 2ArH), 7.06-6.97 (m, 1ArH), 5.93 (m, 1 H), 5.32 (m, 1 H), 5.25 (m, 1 H), 4.60 (m, 2H), 3.82-3.30 (m, 4H), 3.05 (m, 2H), 2.86 (m, 1 H), 1 .28 (d, J = 7.0 Hz, 3H).

Example 15: Racemisation of optical pure allyl (S)-8-chloro-1 -methyl-4,5-dihyd benzo[c/]azepine-3-(2/-/)-carboxylate in the presence of potassium ie f-butoxide

Starting material (S)-allyl 8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[c ]azepine-3-(2/-/)- carboxylate {{(S)-3, 0.5 mmol; 1 17 mg; > 98% optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (0.625 mmol) was added in two portions in an 30 min intervals and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (60 mL). The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained residue (1 1 1 mg) was analysed with chiral HPLC where 25 % e.e. was detected. Purity and stability of the product under such conditions were analysed also with GC-MS (m/z = 279; CI) and ¹ H NMR. 28% of hydrolysed product (m/z = 195) was also observed.

Example 16: Synthesis of optical pure 1 -(8-chloro-1 -methyl-4,5-dihydro-1 H- benzo[d]azepine-3-(2H)-yl)-2-phenylethanone)-2-phenylethanon e {(S)-4)

(S)-V C\ (S)-4

Starting material 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo/c//azepine hydrochloride {(S)-1* C\, 3 mmol; > 98% optical purity) was suspended in acetone (15 mL) in a 50 mL flask equipped with magnetic stir bar. Afterwards an aqueous solution of K ₂ C0 ₃ (2 equiv. according to starting compound) was added and the reaction system was cooled down to 0 °C followed by slow addition of phenylacetyl chloride (3.15 mmol). The reaction mixture was vigorously stirred at room temperature. After the completion of the reaction, the organic solvent was evaporated, the residue was extracted with CH ₂ CI ₂ , washed with saturated NaHC0 ₃ , the organic phases were dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained liquid product (865 mg; 92% yield) was analysed with GC-MS (m/z = 313) and ¹ H, ¹³ C NMR spectroscopy.

¹ H N MR (500 MHz, DMSO, 70 °C) δ 7.35-7.05 (m, 8ArH), 4.75-4.85 (m, 5H), 3.30 (s, 2H) 2.85 (m, 2H), 1 .16 (d, J= 7.2 Hz, 3H); ¹³ C N MR (125 MHz, DMSO) δ 169.8, 146.7, 145.9, 138.1 , 137.5, 132.0, 131 .7, 131 .0, 128.9, 128.3, 127.8, 126.3, 125.8, 54.9, 51 .8, 48.3, 43.7, 33.7, 17.7.

Example 17: Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 H- benzo[d]azepine-3-(2H)-yl)-2-phenylethanone)-2-phenylethanon e

(S)-A 4

Starting material (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[d]azepine-3-(2H)-yl)-2- phenylethanone)-2-phenylethanone {(S)-4, 0.5 mmol; 156 mg; > 99% optical purity) was dissolved in anhydrous DMSO (0.9 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), NaOH (fresh powder; 0.625 mmol) was added and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (60 mL). The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained residue (135 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the product under such conditions were analysed with GC-MS (m/z = 313; CI). 25% of hydrolysed product (m/z = 195) was also detected.

Example 18: Preparation of optical pure (R)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/- benzo/c//azepine {(R)- ) in an improved yield

Crude product (15.09 g) prepared according to Example 9 was dissolved in ie f-butanol (70 mL), followed by addition of aqueous solution of L-(+)-tartaric acid (2.35 g of acid in 3,5 mL of water) and seed crystals were added. The solution was stirred at room temperature for 10 hours. The resulting suspension was filtered and the precipitate was washed with acetone. The obtained precipitate was twice recrystallised from wet tert- butanol (60 ml of ie f-butanol/water 6:1 ) and dried to give 4.0 g of tartaric salt of (RjA in >98 % e.e.

Mother liquors from the preparation of tartaric salt and two recrystallisations from wet ie f-butanol (220 mL) were collected and concentrated to about 20 % of volume. First methylene chloride was added followed by 10 % aqueous NaOH. Phases are stirred, separated and the aqueous layer was extracted again with methylene chloride. The organic layers were collected and evaporated to dryness. The residue contains a mixture of both enantiomers with an excess of the undesired (S)-enantiomer in a form of base (35 % e.e.).

The residue (Sj-λ (1 1.5 g, 35 % e.e.) from the previous step was dissolved in anhydrous DMSO (42 mL). During slow heating (10 °C/min), potassium ie f-butoxide (8.0 g) was added in three portions in 30 min intervals. The mixture was then stirred in inert atmosphere at 90-100 °C overnight. After the completion of the reaction, the mixture was cooled down to room temperature and extracted several times with n-heptane (60 mL). The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure to give a residue (10.5 g, with < 2 % e.e. of (Sj-isomer).

The residue was treated as described in the first paragraph of this example to give 2.52 g of L-(+)-tartaric salt of (R)-" in >98 % e.e. The crop was added to the original crop to give 6.52 g of tartaric salt (overall yield 24 %).

The L-(+)-tartaric acid salt of (R)-" (6.52 g) was dissolved in aqueous NaOH (5 g in 40 ml of water), stirred for 10 minutes at room temperature and was then twice treated with 100 of methylene chloride. The combined organic extracts were washed with water (100 mL) and evaporated to dryness on the pump to get free amine (R)-" (4.72 g crude weight).

To a clean, dry 25 mL round bottom flask were added the free amine (R)-" (4.72 g), 65 mL of methylene chloride, and 40 mL of ether, which is saturated with HCI. The mixture was stirred for 5 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid, the HCI salt. The salt was re-dissolved in methylene chloride (65 mL) and an additional 40 mL of with ether saturated with HCI was added and the solution was again stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure to give the desired hydrochloride salt of 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-3-benzazapine {(R)-V C\) (3.88 g). A gain by applying the process according to the invention reaches about 60 % (6.52 g comparing to 4.0 g of tartaric salt was obtained). It is possible to re-racemise mother liquors from tartaric salt preparation and recrystallisation liquors of the second crop of the product with further improvement of yield. A skilled person may combine different approaches of recovery, for example he may racemise only the liquor from tartaric salt preparation, which is much more enriched in undesired isomer and may treat recrystallisation liquors, which are rich in the desired isomer by other approaches. By repeatable recovery the yield may exceed 50 % before one crop of liquors must be discarded due to accumulation of degradation products.