The present invention relates to the field of organic synthesis, in particular to the synthesis of benzodiazepines with stimulating activity on serotonin receptors, especially lorcaserin.

Background of the Invention

Obesity strongly affects millions of people worldwide and the number of obese people is largely increasing. There is a great challenge to successfully treat obesity by pharmacotherapy. As a response to this challenge the efforts in the development focus on 5-HT2C receptor agonists for the treatment of this life threatening disorder. Benzodiazepines were identified as most promising selective 5-HT2C receptor agonists. (R)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine hydrochloride (Formula 1 ) with the INN name lorcaserin hydrochloride was registered as the first representative of this pharmacological group.

1

8-Chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine was firstly prepared in racemic form by Smith & Smith (WO 03/0863069). The synthesis is a long and a typical laboratory procedure, which uses industrially unfavoured reagents such as trifluoroacetic anhydride, iodine chloride and palladium catalysts. The process, which starts from easily available 2-(4-chlorophenyl)ethanamine (formula 2) is finished by intramolecular Heck cyclization of the allylic intermediate (formula 22) in the presence of palladium catalyst to form the exo-methylene derivative (formula 23), which is further hydrogenated using Pd/C and deprotected to give racemic lorcaserin according to the formula 9 (Scheme 1 ).

24 23

Scheme 1. First synthetic process to give the racemic lorcaserin.

Thereafter, the first preparation of optical active lorcaserin (formula 1 ) was disclosed in the patent application WO 05/019179 by using classical optical resolution of a racemic mixture with tartaric acid, further advanced in WO 12/030938. Additionally, the document describes three improved synthetic pathways using an Friedel-Crafts cyclisation approach (Scheme 2).

7 3

Scheme 2. Synthesis of chiral lorcaserin via chemical optical resolution. Two prior art routes start from 2-(4-chlorophenyl)ethylamine (formula 2), but further transformations enabled a more simple and efficient process. An amino intermediate is then acylated with chloropropionyl chloride to form the amide precursor (formula 10) which is either cyclized in the presence of aluminum chloride as a Lewis acid reagent and which is finally reduced to racemic lorcaserin (formula 9) or, alternatively, which is first reduced to form the compound according to the formula 12 and which is finally cyclized.

The third route starts from 2-(4-chlorophenyl)ethanol (formula 7) which is first brominated using expensive phosphorous tribromide. The bromide according to the formula 3 is transformed to the alcohol precursor (formula 8) with an excess of 1 - amino-2-propanol. Afterwards, the alcohol is substituted with thionyl chloride in the presence of catalytic amount of dimethylacetamide to give the same solid hydrochloride precursor according to the formula 12 obtained in the second route.

Further, an improvement of the process of Scheme 2 was described in WO 07/120517, which provides a more detailed description concerning the improvement of the isolation procedure of the Friedel-Crafts cyclization reaction product by using a Si0 ₂ -H ₂ 0 mixture to quench the reaction.

In the disclosure of the patent application WO 08/0701 1 1 (Scheme 3), the synthesis starts with a coupling reaction between 2-(4-chlorophenyl)acetic acid (formula 13) and 1 -amino-2-propanol in the presence of various coupling reagents (trifluorophenylboric acid, phenylboric acid, EDC or toluenesulfonic acid/dimethoxypropane). The resulting amide (formula 14), optionally in a mixture with the minor dihydrooxazole compound (formula 15), is then reduced using various reducing agents (borane in tetrahydrofuran or dimethylsulfide, sodium boronhydride in presence of iodine) to afford the alcohol precursor according to the formula 8 which is further transformed to lorcaserin (formula 1 ) as described in the previous publications.

Scheme 3. Synthesis via 2-acetamido and dihydrooxazole precursors.

Further, the publication WO 09/1 1 1004 describes a further improvement of the process of Scheme 2 using a new bromination methodology including HBr gas instead of expensive PBr ₃ (Scheme 4). The publication also discloses a problem dialkylation of 1 - amino-2-propanol with the bromide according to the formula 3 to produce the impurity represented by the formula 16, which is reduced to the content of less than 10% in the desired product according to the formula 8.

Scheme 4. Improvement of synthetic process via bromo intermediates.

Another publication (WO 10/148207) discloses a further improvement of the processes of Schemes 2 and 4 by using a new chlorination methodology applying thionyl chloride instead of dangerous HBr gas and expensive PBr ₃ . A reaction of compound 17 with 1 - amino-2-propanol is also described (Scheme 5).

17 8 12

Scheme 5. Improvement of synthetic process via chloro intermediates The known routes shown in the above Schemes 1 to 3 require the preparation of various halo intermediates, which leads to a considerable amount of synthesis steps. Furthermore, all processes lead to racemic final products which need separation of enantiomers, wherein at least half of material is lost by elimination of unwanted enantiomer.

There is an intense interest to develop novel, simple and industrial acceptable processes for the preparation of lorcaserin or related compounds. Special focus is especially oriented to efficient methodologies for production of enantiopure compound by asymmetric approaches.

So far, enzymatic reduction of unsubstituted 2-phenyl-2-propenenitrile to optical active 2-phenyl-2-propanenitrile using Baker's yeast was once described (P. G. Dumanski et al. Journal of Molecular Catalysts B: Enzymatic 2001 , 77, 905-908) with moderate yield (64 %). There is no example of enzymatic reduction of substituted nitrile material, especially with EWG groups (preferably N0 ₂ , halogen) which strongly influence on efficiency and stereoselectivity of the process. Stereoselective reduction of 2-phenyl-2- propenoic acid and its methyl ester mediated by Baker's yeast was also mentioned but very low efficiency was established.

Asymmetric reductions of substituted acrylic acid derivatives using catalytic hydrogenation were successfully achieved with moderate to high enantioselectivities using high pressures of hydrogen and precious metal catalysts, such as Ir-SpinPHOX (Y. Zhang et al. Chem. Commun. 2010, 46, 156-158), Ir complex with chiral spiro aminoposphine ligands (S.-F. Zhu et al. Angew. Chem. Int. Ed. 2012, 51, 8872-8875), Rh complex with R-SMS-Phos ligands (B. Zupancic et al. Org. Lett. 2010, 12, 3022- 3025). There is still a need for approaches, which would use cheaper catalysts and less rigorous conditions.

Enzymatic reductions of β-nitro styrenes or 2-phenyl-1 -nitropropenes to optical active nitroalkanes using different nitroreductases have been studied (H. Ohta, et. al. Chem. Lett. 1987, 1, 191 -192; H. Ohta, et. al. J. Org. Chem. 1989, 54, 1802-1804; M. Takeshita, et. al. Heterocycles 1994, 37, 553-551 ; R. R. Bak, et. al. Aust. J. Chem. 1996, 49, 1257-1260; A. F. McAnda, et. al. J. Chem. Soc. Perkin Trans 1, 1998, 501 - 504; Y. Kawai, et. al. Tetrahedron Asymmetry 2001 , 12, 309-318; Y. Kawai, et. al. Terahedront. Lett. 2001 , 42, 2267-3368; Y. Meah, et. al. PNAS 2000, 97, 10733-10738; M. A. Swiderska, et. al. Org. Lett. 2006, 8, 6131 -6133; A. Fryszkowska, et. al. J. Org. Chem. 2008, 73, 4295-4298) but no successful conversions of m-chloro-2-phenyl-1 - nitropropene using Baker ^' s yeast have been disclosed.

On the other hand such a substrates (β,β-disubstituted nitroolefines) have been successfully transformed to optical active nitroalkanes using

a. ) asymmetric conjugative reductions based on CuF ₂ /Josiphos or CuOiBu / BINAP catalytic systems in organic solvents only (C. Czekelius, et. al. Angew. Chem.. Int. Ed. 2003, 115, 4941 -4945; C. Czekelius, et. al. Org. Lett. 2004, 6, 4575-4577); b. ) direct asymmetric catalytic hydrogenation using expensive Rh chiral catalyst at very high (more than 50 atm) H ₂ pressures (S. Li, et. al. Angew. Chem. Int. Ed. 2012, 51, 8573-8576); and

c. ) asymmetric transfer hydrogenation where only thiourea-type catalysts as chiral inductors (Jacobsen type organocatalysts; N.J.A. Martin, et. al. J. Am. Chem. Soc. 2007, 129, 8976-8977; J. Wu, et. al. J. Am. Chem. Soc. 2005, 127, 4584-4585) or chiral diamine type Ir(lll) complex (O. Soltani, et. al. Org. Lett. 2009, 11, 4196-4198), were used.

Intramolecular cyclization of substituted N-acetyl protected benzyl acetals to enamine compounds were presented but only six-membered ring was formed (C. D. Perchonck et al. J. Org. Chem. 1980, 45, 1950-1953). There is no positive result of intramolecular cyclization of less (un)reactive unprotected amine (R = H).

This invention has the object to provide a new, simple, economical and environmentally benign highly enantioselective synthesis to optically active 8-chloro-1 -methyl-2, 3,4,5- tetrahydro-1 /-/-benzo[c ]-azepine from a new starting point proceeding via novel intermediates. In order to establish optical active final product, it is an object of the present invention to provide highly enantioselective methodologies based on an enzymatic and chemical approaches. Especially, the present invention has the object to provide novel asymmetric, efficient chemical catalytic systems. Such asymmetric methodologies are also developed with an emphasis on green and sustainable development, where pure water instead of toxic, expensive and pollutant solvents is used as green solvent. Attention is also focused on the important last stages, where improved closing reactions of final intermediates to lorcaserin are presented. Summary of the invention

In order to solve the above objects, the present invention provides a novel asymmetric synthetic route for synthesizing 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/- benzo[c/]azepine (compound A), or a salt thereof, preferably lorcaserin, or a salt thereof. This approach is illustrated in Scheme 6.

Scheme 6. Illustrative asymmetric synthesis route to compound A, or a salt thereof. The substituents A, B, R, R-i, and PG and ^* are defined according to the following items, the sequence of the steps (e1 ) and (e2) is interchangeable.

The synthetic route is simple, industrial friendly and enables transformations with no racemization of chiral intermediates. Further, the synthesis route requires simple and/or commercially available reagents and catalysts. The efficient and highly selective asymmetric approach is advantageous in comparison with low efficiency of chemical optical resolution of racemic mixture of final lorcaserin used in the prior art. By means of the synthetic route as being illustrated in Scheme 6, the present invention performs the final ring closing in the para-position relative to the CI substituent so that the chirality of the methyl substituent in the present invention is not prone for racemization compared to the prior art final ring closing performed in the meta-position relative to the CI substituent as illustrate by the above Schemes 1 to 3.

The following items summarize in more details aspects and preferred features or embodiments, which contribute to solve the objects of the present invention alone or in combination.

1 . Method for asymmetrically synthesizing 8-chloro-1 -methyl-2,3,4,5-tetrahyd benzo[c/]azepine being illustrated by the following formula A, or a salt thereof:

wherein ^* in the formulae denotes an asymmetric carbon atom in (R) or (S) configuration being enantiomerically enriched, essentially enantiopure or enantiopure, the method comprising the steps:

(a) reducing the compound according to the formulae la or lb:

la lb

wherein the substituents A and B represent groups, which are convertible to the aminomethyl group -CH ₂ -NHR', wherein R' is H or CH ₂ CH(OR)2 (wherein R is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R may bond together to constitute a C ₂ - or C ₃ -alkylene chain for forming a 5- or 6-membered ring), by an asymmetric enzymatic, biomimetic or catalytic reduction to give the compound according to the formula II:

II

wherein the asymmetric enzymatic, biomimetic or catalytic reduction leads to the (R) or the (S) configuration being enantiomerically enriched, essentially enantiopure or enantiopure;

(b) converting the compound according to the formula II to a compound according to the formula IV, or a salt there

IV

wherein R is defined as above, and ^* represents the same configuration as for the compound according to the formula II; by

(b1 ') converting the compound according to the formula II, if the substituent A is not -CONHCH ₂ CH(OR)2, wherein R is defined as above, to a compound according to the formula III, or a salt thereof:

III

wherein ^* represents the same configuration as for the compound according to the formula II; followed by;

(b2') converting the compound according to the formula III from the step (bV) to a compound according to the formula IV, preferably by alkylation with XCH ₂ CH(OR)2 (wherein X is tosylate, mesylate, triflate or a halogen, preferably CI or Br, and R is defined as above) or by reductive amination reaction with OHC-CH(OR) ₂ , wherein R is defined as above;

or (b1 ") converting the compound according to the formula II, if the substituent A is -CONHCH ₂ C(OR)2, wherein R is defined as above, to a compound according to the formula IV;

(c) optionally and preferably protecting the secondary amino group of the compound according to the formula IV to prepare a compound according to the formula V:

V

wherein PG is an amino protection group, which is preferably selected from unsubstituted or substituted benzyl, unsubstituted or fluorinated CrC ₄ -alkanesulfonyl, or unsubstituted or para-substituted benzenesulfonyl, or CrC ₆ -alkanoyl, or arylcarbonyl and wherein ^* represents the same configuration as for the compound according to the formula II;

(d) cyclizing the compound according to the formula IV or V by a Friedel-Crafts reaction to obtain a compound according to the formula VI:

VI

wherein R-i is hydrogen or PG, wherein PG is defined as above, and ^* represents the same configuration as for the compound according to the formula II;

(e) converting the compound according to the formula VI to give the compound according to the formula A, or a salt thereof:

A

wherein ^* represents the same configuration as for the compound according to the formula II;

by applying the steps of:

(e1 ) reducing the compound according to the formula VI; and (e2) if R-ι is PG, deprotecting the group PG, wherein PG is defined as above, wherein the step (e1 ) is preferably applied prior to the step (e2);

(f) optionally improving the enantiomeric excess using chiral chromatography or by performing a chiral resolution via selective crystallization of diastereoisomeric salt with a resolving agent, preferably tartaric acid, followed by anion exchange.

2. Asymmetric method according to item 1 , wherein the compounds are produced with the asymmetric carbon atom indicated by ^* being enantiomerically enriched, essentially enantiopure or enantiopure in the (R) configuration, preferably with an ee of at least 60 % ee, more preferably of at least 90 % ee or more, still more preferably of at least 98 % ee.

3. Asymmetric method according to item 1 or 2, wherein

A in the compound according to the formula la is selected from -CN, -COY (with Y being OH, C C ₆ -alkoxy, NH ₂ , or NH-CH ₂ CH(OR) ₂ , wherein R is defined as above), -CH ₂ -N0 ₂ , -CH ₂ -NO, -CH ₂ N ₃ , and wherein A is preferably -CN, -COOH, -COOMe, -COOEt, -CONH ₂ or -CONH-CH ₂ CH(OR) ₂ , most preferably -CN; and

B in the compound according to the formula lb is selected from =CH-N0 ₂ , =CH-NO, and =CH-N ₃ , and wherein B is preferably =CH-N0 ₂ .

4. Asymmetric method according to any one of items 1 to 3, wherein an asymmetric enzymatic reduction is applied in step (a) with the enzymes being selected from reductases of natural or recombinant sources, and wherein the natural reductases are preferably used as isolated enzymes, in mixtures or in a fermentation process with reductases rich microorganisms.

5. Asymmetric method according to item 4, wherein the enzyme is baker's yeast, and wherein the asymmetric enzymatic reduction is preferably carried out using baker's yeast containing fungi of the species Saccharomyces cerevisiae in a water medium, preferably containing a buffer of pH 7-9, most preferably a phosphate buffer of pH 8, optionally in a mixture with a water immiscible solvent, which is preferably selected from hydrocarbons, and wherein the substrate selected from the compound according to the formula la or lb may be added undissolved or dissolved in a microorganism friendly water miscible solvent, preferably selected from alcohols or acetone, most preferably ethanol.

6. Asymmetric method according to any one of items item 1 to 5, wherein the asymmetric enzymatic reduction is applied for the compound la with A being represented by CN (la-CN) or -COOMe (la-Me) or for the compound lb with B being represented by =CH-N0 ₂ (lb-N0 ₂ ); and

wherein the asymmetric enzymatic method is preferably applied for the compound Ib- N0 ₂ being dissolved in a microorganism friendly water miscible solvent, preferably ethanol, using baker's yeast containing fungi of the species Saccharomyces cerevisiae in a water medium and for the compound la-CN added undissolved using baker's yeast containing fungi of the species Saccharomyces cerevisiae in a water medium in a mixture with a water immiscible solvent, preferably petroleum ether.

7. Asymmetric method according to any one of items 1 to 3, wherein an asymmetric biomimetic reduction is applied in step (a) in the presence of a hydrogen donor and an organocatalyst, wherein 1 ,4-dihydropyridines are preferably used as proton donors, which are more preferably selected from diethyl 1 ,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate or di-i-butyl 1 ,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate, and wherein the organocatalyst is selected from chiral derivatives of thioureas, urea sulfinamides and imidazolones, which are preferably selected from enantiopure Λ/-[2- (3-(3,5-bis(trifluoromethyl)phenyl)ureido)cyclohexyl]-ie f-butyl-sulfinamide, 2-[[3,5- bis(trifluoromethyl)phenyl]thioureido]-/V-benzyl-/V,3,3-trim ethylbutanamide,

[(dimethylamino)carbonyl]-2,2-dimethylpropyl]thioureido]c yclohexyl]imino]methyl]-5- ie f-butyl-4-hydroxyphenyl pivalate, 2-ie f-butyl-3-methyl-5-benzyl-4-imidazolidinone.

8. Asymmetric method according to item 7, wherein the asymmetric biomimetic reduction is applied for the compound lb with B being represented by =CH-N0 ₂ (lb-N0 ₂ ), preferably by using 2-[[3,5-bis(trifluoromethyl)phenyl]thioureido]-/V-benzyl- /V,3,3-tri methylbutanamide as an organocatalyst.

9. Asymmetric method according to any one of items 1 to 3, wherein an asymmetric catalytic reduction is applied in step (a) in the presence of hydrogen or a hydride donor and of a catalyst, selected from a transition metal, which is preferably selected from ruthenium, rhodium, iridium and copper, in a combination with a chiral ligand preferably selected from phosphine and diphosphine ligands.

10. Asymmetric method according to item 9, wherein the asymmetric catalytic reduction is performed with hydrogen under the pressure of 1 to 50 bar, preferably 1 to 5 bar.

1 1 . Asymmetric method according to item 9, wherein a hydride donor is used for the asymmetric catalytic reduction, which is preferably selected from mono-, di- or tri- d- C ₆ -alkyl or aryl substituted silanes, most preferably from phenylsilane or triethylsilane and/or alkyl substituted polyhydrosiloxanes, preferably polymethylhydrosiloxane (PMHS).

12. Asymmetric method according to any one of items 9 to 1 1 , wherein the transition metal is copper, which is used in the form of copper (I) salts, preferably in the form of copper (I) chloride, or in the form of copper (II) compounds, preferably selected from copper (II) halogenide, nitrate, sulfate, hydroxide or carbonate, more preferably from hydroxide or basic carbonate (Cu(OH) ₂ -CuC0 ₃ ).

13. Asymmetric method according to any one of items 9 to 12, wherein the chiral diphosphine ligands are selected from ferrocene containing ligands, preferably selected from the Josiphos group, Mandyphos or Walphos group of ligands and wherein the chiral phosphine ligands are preferably selected from oxazoline type ligands (PHOX).

14. Asymmetric method according to any one of items 9 and 1 1 to 13, wherein the asymmetric catalytic reduction uses a combination selected from the group consisting of Cu(OH) ₂ /Walphos, Cu(OH) ₂ /PHOX, Cu(OH) ₂ CuC0 ₃ /Walphos, Cu(OH) ₂ CaC0 ₃ /PHOX or CuCI/PHOX preferably in the presence of phenylsilane and polymethylhydrosiloxane (PMHS).

15. Asymmetric method according to item 14, wherein the asymmetric catalytic reduction is performed in water not containing organic solvents or optionally in a biphasic system with a water immiscible solvent, preferably toluene.

16. Asymmetric method according to any one of items 1 to 3 and 9 to 15, wherein the asymmetric catalytic reduction is applied for the compound la with A being represented by -COOMe (la-Me), for the compound la with A being represented by -CN (la-CN) or for the compound lb with B being represented by =CH-N0 ₂ (lb-N0 ₂ ), and wherein the asymmetric catalytic reduction is most preferably applied for the compound lb using a combination as defined by item 14.

17. Asymmetric method according to any one of items 1 to 16, wherein the compound according to the formula ll-N0 ₂ is reduced in step (b1 ') to give the compound according to the formula III by inorganic reducing agents selected from inorganic sulfides, selected from sodium hydrogensulfide, sulfide or polysulfide, from sodium dithionite or thiourea dioxide in basic conditions, or by catalytic hydrogenation, preferably using platinum, palladium or vanadium catalysts, or low-valent metal salts, preferably selected from iron (II) or tin (II) salts or elemental metal in the presence of acids, preferably zinc or iron in hydrochloric acid or acetic acid, optionally diluted by a water miscible solvent selected from CrC ₄ -alcohol and tetrahydrofuran, wherein the reduction most preferably uses zinc in methanolic HCI.

18. Asymmetric method according to any one of items 1 to 7 and 9 to 15, wherein the compound according to the formula II with A being represented by -CONH ₂ or -CN is reduced in step (b1 ') to give the compound according to the formula III by catalytic hydrogenation on Raney® Ni or by using a hydride, selected from boron hydrides, preferably selected from borane complexes, such as BH ₃ .THF, aluminum hydrides, such as lithium aluminum hydride or DIBALH, the reduction most preferably using BH ₃ .THF.

19. Asymmetric method according to any one of items 1 to 7 and 9 to 16, wherein the compound according to the formula II with A being represented by -CONHCH ₂ C(OR) ₂ is reduced in step (b1 ") to give the compound according to the formula IV by a hydride, selected from borohydrides, preferably lithium borohydride, boron hydrides, preferably selected from borane complexes, such as BH ₃ .THF, or aluminum hydrides, such as lithium aluminum hydride or DIBALH, to give the compound according to the formula IV.

20. Asymmetric method according to any one of items 1 to 7, 9 to 16, and 19, wherein the step (b1 ") further comprises a step of converting the residue A, which may be represented by -COY (Y is CrC ₆ -alkoxy or NH ₂ ), to give the compound according to the formula II with A being represented by -CONHCH ₂ C(OR) ₂ .

21 . Asymmetric method according to any one of items 1 to 20, wherein the preferred step (c) is used for introducing the amino protecting group PG, which is selected from

(i) unsubstituted benzyl or substituted, preferably omethyl, p-nitro, p-methyl or p-methoxy substituted benzyl, by a reaction with the corresponding halogenide, selected from chloride, bromide or iodide in basic conditions;

(ii) unsubstituted or fluorinated CrC ₄ -alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para-substituted, preferably p- methyl (tosyl, Ts) substituted benzenesulfonyl by a reaction with the corresponding sulfonyl halogenide, preferably chloride, such as tosyl chloride (TsCI), or sulfonyl anhydrides, such as triflic anhydride (Tf ₂ 0) in basic conditions; or

(iii) unsubstituted or substituted CrC ₆ -alkanoyl, preferably acetyl or arylcarbonyl, preferably benzoyl by a reaction with corresponding acyl halogenide, preferably chloride, or acyl anhydride, such as acetic anhydride (Ac ₂ 0) or benzoyl chloride in basic conditions.

22. Asymmetric method according to any one of items 1 to 21 , wherein the step (d) is accomplished in the presence of a Lewis acid, preferably selected from AICI ₃ , FeCI ₃ , InCIs, lnBr ₃ , Bi(OTf) ₃ , BiCI ₃ , Sc(OTf) ₃ , TeCI ₄ , most preferably from anhydrous AICI ₃ .

23. Asymmetric method according to any one of items 1 to 22, wherein the Friedel- Crafts reaction is carried out without solvent (neat conditions) or in a solvent, which is preferably selected from nitromethane, aromatic hydrocarbons, preferably nitrobenzene, chlorinated hydrocarbons, preferably dichloromethane, and wherein the cyclization of the unprotected compound according to the formula V is preferably accomplished under neat conditions.

24. Asymmetric method according to any one of items 1 to 23, wherein, if R-i is represented by PG, the step (e) proceeds by

(e1 ) reducing the compound according to the formula VI to give the compound according to the formula VII:

VII

wherein PG is the same as defined for the formula V, and ^* represents the same configuration as for the formula II; and

(e2) deprotecting the compound according to the formula VII to give the compound according to the formula A, or a salt thereof.

25. Asymmetric method according to any one of items 1 to 24, wherein the reduction in the step (e1 ) is accomplished by using reducing agents selected from boron hydrides, such as alkali metal borohydrides, preferably NaBH ₄ , or borane complexes, preferably BHs-THF, aluminum hydrides, preferably LiAIH ₄ , DIBALH, RedAI, by NEt ₃ /HC0 ₂ H, or by catalytic hydrogenation using metal transition catalysts preferably selected from palladium, platinum, nickel, ruthenium, most preferable by catalytic hydrogenation using metal transition catalysts.

26. Method for an asymmetrical catalytic reduction of a compound according to the formulae la or lb:

la lb

wherein the substituents A and B represent groups, which are convertible to the aminomethyl group -CH ₂ -NHR', wherein R' is H or CH ₂ CH(OR) ₂ (wherein R is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R may bond together to constitute a C ₂ - or C ₃ -alkylene chain for forming a 5- or 6-membered ring), wherein the asymmetric catalytic reduction is applied in an aqueous medium in the presence of a hydride donor and of a copper catalyst, which is used in the form of copper (I) salts, preferably in the form of copper (I) chloride, or in the form of copper (II) compounds, preferably selected from copper (II) halogenide, nitrate, sulfate, hydroxide or carbonate, more preferably from hydroxide or basic carbonate (Cu(OH) ₂ -CuC0 ₃ ), in a combination with a chiral ligand selected from Walphos or PHOX type ligands. 27. Asymmetric method according to item 26, wherein the aqueous medium is water not containing organic solvents or a biphasic system with a water immiscible solvent, preferably toluene, wherein the aqueous medium is preferably water not containing organic solvents.

28. Asymmetric method according to item 26 or 27, wherein the hydride donor is selected from mono-, di- or tri- CrC ₆ -alkyl or aryl substituted silanes, most preferably from phenylsilane or triethylsilane and/or alkyl substituted polyhydrosiloxanes, preferably polymethylhydrosiloxane (PMHS).

29. Asymmetric method according to any of items 26 to 28, wherein the asymmetric catalytic reduction uses a combination selected from the group consisting of Cu(OH) ₂ /Walphos, Cu(OH) ₂ /PHOX, Cu(OH) ₂ CuC0 ₃ /Walphos, Cu(OH) ₂ CaC0 ₃ /PHOX or CuCI/PHOX preferably in the presence of phenylsilane and polymethylhydrosiloxane (PMHS)

30. Asymmetric method according to any of items 26 to 29, wherein

A in the compound according to the formula la is selected from -CN, -COY (with Y being OH, C C ₆ -alkoxy, NH ₂ , or NH-CH ₂ CH(OR) ₂ , wherein R is defined as above), -CH ₂ -N0 ₂ , -CH ₂ -NO, -CH ₂ N ₃ , and wherein A is preferably -CN, -COOH, -COOMe, -COOEt, -CONH ₂ or -CONH-CH ₂ CH(OR) ₂ , most preferably -CN; and

B in the compound according to the formula lb is selected from =CH-N0 ₂ , =CH-NO, and =CH-N ₃ , and wherein B is preferably =CH-N0 _2.

31. Compound represented by the formula la-Y:

la-Y

wherein Y is CrC ₆ -alkoxy, preferably methoxy.

32. Use of the compound according to item 31 as an intermediate in the synthesis of the compound A, preferably lorcaserin, or its salts. 33. Compound represented by one of the formulae ll-CN and ll-Me in the form of the enantiomerically enriched, essentially enantiopure or enantiopure (R) or (S) enantiomer:

(R)-W-CN (R)-W-Me (S)-W-Me

34. Use of the compound according to item 33 as an intermediate in the synthesis of compound A, or a salt thereof, preferably the (RJ-enantiomer for the synthesis of lorcaserin, or a salt thereof.

35. Compound according to one of the formulae III, IV or V:

IV v wherein ^* in the formulae denotes an asymmetric carbon atom in (R) or (S) configuration being enantiomerically enriched, essentially enantiopure or enantiopure, wherein R is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R may bond together to constitute a C ₂ - or C ₃ -alkylene chain for forming a 5- or 6- membered ring, and wherein PG is represented by acetyl or tosyl.

36. The compound according to item 35, which is enantiomerically enriched, essentially enantiopure or enantiopure in the (R) configuration.

37. Use of the compound according to item 35 or 36 as an intermediate in the synthesis of compound A, or a salt thereof, preferably the (RJ-enantiomer for the synthesis of lorcaserin, or a salt thereof.

38. Asymmetric method for producing one of the compounds according to item 35 or 36, the method at least comprising the step (a) of an asymmetrical enzymatic, biomimetic or catalytic reduction as defined according to any one of items 1 to 16 and 26 to 30.

39. Compound represented by the formula VI in the form of the enantiomencally enriched, essentiall enantiopure or enantiopure (R) or (S) enantiomer:

(R)-v\ (S)- \ wherein R ¹ is selected from hydrogen, unsubstituted benzyl or substituted benzyl, preferably σ-methyl, p-nitro, p-methyl or p-methoxy benzyl, unsubstituted or fluorinated CrC ₄ -alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl or unsubstituted or d-C ₆ -alkanoyl, preferably acetyl or arylcarbonyl, preferably benzoyl.

40. The compound according to item 39, which is enantiomencally enriched, essentially enantiopure or enantiopure in the (R) configuration.

41 . Use of the compound according to item 39 or 40 as an intermediate in the synthesis of compound A, or a salt thereof, preferably the (RJ-enantiomer for the synthesis of lorcaserin, or a salt thereof.

42. Compound represented by the formula VII in the form of the enantiomencally enriched, essentially enantiopure or enantiopure (R) or (S) enantiomer:

(R)- \\ (S)- \\ wherein PG is selected from unsubstituted benzyl or substituted benzyl, preferably ct- methyl, p-nitro, p-methyl or p-methoxy benzyl, unsubstituted or fluorinated Ci-C ₄ - alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl or unsubstituted or CrC ₆ -alkanoyl, preferably acetyl or arylcarbonyl, preferably benzoyl. 43. The compound according to item 42, which is enantiomerically enriched, essentially enantiopure or enantiopure in the (R) configuration.

44. Use of the compound according to item 42 or 43 as an intermediate in the synthesis of compound A, or a salt thereof, preferably the (RJ-enantiomer for the synthesis of lorcaserin, or a salt thereof.

The following Scheme 7 illustrates a preferred and non-limiting exemplary way to yield the preferred compound lorcaserin, or a salt thereof.

Scheme 7. Exemplary asymmetric synthesis route to lorcaserin, or a salt thereof.

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 an industrially applicable, economical and simple enantioselective process for the preparation of serotonin antagonizing chiral 8-chloro-1 - methyl-benzo[c/]azepine or related compounds, or its salts, particularly lorcaserin, as well as key intermediates for the synthesis thereof. For 8-chloro-1 -methyl- benzo[c/]azepine and related compounds, or its salts, particularly lorcaserin, the synthetic route described herein benefits from simple reactions, mild reaction conditions and readily available and cheap chemicals. The starting styrenes for the overall synthesis are readily available by simple processes known to a skilled person. The chiral reduction of styrenes according to the invention applies enzymatic, biomimetic or catalytic approaches with easy available and cheap enzymes, reagents, catalysts and ligands leading to corresponding chiral 2-propyl substituted benzenes with high ee. Such intermediates are easily converted to chiral 1 -methyl-2,3,4,5-1 /-/- benzodiazepines with retention of chirality.

The term "enantiomerically enriched" as used herein means that one enantiomer predominates over the other expressing 10 to 70 % ee, preferably 30 to 70 % ee, more preferably 60 to 70 % ee.

The term "essentially enantiopure" as used herein means an enantiomeric excess (ee) of 70 % ee or more, preferably 80 % ee or more, more preferably 90 % ee or more, most preferably 97 % ee or more.

The term "enantiopure" as used herein means an enantiomeric excess (ee) of 98 % ee or more, preferably 99 % ee or more.

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

In a first embodiment, the present invention provides a method for asymmetrically synthesizing 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo[c/]azepine being illustrated by the following formula A, or a salt thereof: wherein ^* in the formulae denotes an asymmetric carbon atom in (R) or (S) configuration being enantiomerically enriched, essentially enantiopure or enantiopure, the method comprising the steps:

(a) reducing the compound according to the formulae la or lb:

la lb

wherein the substituents A and B represent groups, which are convertible to the aminomethyl group -CH ₂ -NHR', wherein R' is H or CH ₂ CH(OR) ₂ (wherein R is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R may bond together to constitute a C ₂ - or C ₃ -alkylene chain for forming a 5- or 6-membered ring), by an asymmetric enzymatic, biomimetic or catalytic reduction to give the compound according to the formula II:

II

wherein the asymmetric enzymatic, biomimetic or catalytic reduction leads to the (R) or the (S) configuration being enantiomerically enriched, essentially enantiopure or enantiopure;

(b) converting the compound according to the formula II to a compound according to the formula IV, or a salt thereof:

IV

wherein R is defined as above, and ^* represents the same configuration as for the compound according to the formula II; by

(b1 ') converting the compound according to the formula II, if the substituent A is not -CONHCH ₂ CH(OR)2, wherein R is defined as above, to a compound according to the formula III, or a salt thereof:

III

wherein ^* represents the same configuration as for the compound according to the formula II; followed by;

(b2') converting the compound according to the formula III from the step (bV) to a compound according to the formula IV, preferably by alkylation with XCH ₂ CH(OR)2 (wherein X is tosylate, mesylate, triflate or a halogen, preferably CI or Br, and R is defined as above) or by reductive amination reaction with OHC-CH(OR) ₂ , wherein R is defined as above;

or

(b1 ") converting the compound according to the formula II, if the substituent A is -CONHCH ₂ C(OR)2, wherein R is defined as above, to a compound according to the formula IV;

(c) optionally and preferably protecting the secondary amino group of the compound according to the formula IV to prepare a compound according to the formula V:

V wherein PG is an amino protection group, which is preferably selected from unsubstituted or substituted benzyl, unsubstituted or fluorinated CrC ₄ -alkanesulfonyl, or unsubstituted or para-substituted benzenesulfonyl, or CrC ₆ -alkanoyl, or arylcarbonyl and wherein ^* represents the same configuration as for the compound according to the formula II;

(d) cyclizing the compound according to the formula IV or V by a Friedel-Crafts reaction to obtain a compound according to the formula VI:

VI

wherein R-i is hydrogen or PG, wherein PG is defined as above, and ^* represents the same configuration as for the compound according to the formula II;

(e) converting the compound according to the formula VI to give the compound according to the formula A, or a salt thereof:

A

wherein ^* represents the same configuration as for the compound according to the formula II;

by applying the steps of:

(e1 ) reducing the compound according to the formula VI; and

(e2) if R-i is PG, deprotecting the group PG, wherein PG is defined as above, wherein the step (e1 ) is preferably applied prior to the step (e2);

(f) optionally improving the enantiomeric excess using chiral chromatography or by performing a chiral resolution via selective crystallization of diastereoisomeric salt with a resolving agent, preferably tartaric acid, followed by anion exchange.

According to the embodiment, the configuration (R) or (S) of the enantiopure compound according to the formula A or the predominant enantiomer in the enantiomerically enriched mixture thereof is determined in the step (a) depending on the selection of an enzyme or enzymatic method in the enzymatic approach or on the selection of a catalyst in the biomimetic or the catalytic approach. For illustration only, a skilled person may simply take a ligand of reverse chirality in a catalytic system to obtain a product of reverse chirality. The initial configuration, created in the step (a) is retained through the step (b) to (f) to the final compound according to the formula A, or a salt thereof, without substantial racemization or inversion.

In a preferred aspect, an enzymatic or a catalytic system is selected to produce compounds of configuration (R), which are suitable intermediates for preparation of the obesity drug lorcaserin. Such compounds are illustrated as formulae (R)-W, (R)-\\\, (R)- IV, (R)M, (R)M\, (R)-V\\ as shown in Scheme 8.

(R)-V (R)-V\ (R)-V\\

Scheme 8. Chiral intermediates for the preparation of lorcaserin.

If the substituent A contains at least one proton in a-C atom the starting compound can exist in structures la and/or lb. Generally they are different compounds which can lead in conditions of the reaction of the step (a) to the same product of the formula II, using same or different approaches in view of reagents, enzymes or process conditions. In some cases one of the structures is preferred. For instance, if the substituent A or B, respectively, contains an electron withdrawing group, such as nitro, the structure lb is preferred. Furthermore, in some cases the structures may be transformable in conditions of the reaction of the step (a) behaving like tautomers.

The most preferred starting compounds according to the general formula la according to the embodiment are selected from acrylonitrile according to the formula la-CN or acrylic esters of the formula la-Y, wherein Y is CrC ₆ -alkoxy, preferably methoxy (la-Me) being illustrated by Scheme 9.

la-CN la-Y la-Me

Scheme 9. Most preferred starting compounds according to the formula la.

Such a-aryl substituted acrylic derivatives can be easily prepared according to state of the art from corresponding aryl substituted acetates or acetonitrile by formaldehyde derivatives in various reaction conditions, preferably by Ν,Ν,Ν',Ν'- tetramethylaminomethane (TDAM) in acetic anhydride (Scheme 10).

Vlll-Me la-Me

Scheme 10. Preparation of 2-(m-chlorophenyl) substituted acrylic derivatives Notably, the compound represented by the formula la-Y:

la-Y wherein Y is CrC ₆ -alkoxy, preferably methoxy, represents a novel and suitable intermediate for use in the synthesis of compound A, preferably lorcaserin, or its salts.

The most preferred starting compound according to the general formula lb according to the embodiment is selected from a β-styrene according to the formula lb-N0 ₂ :

Ib-N0 ₂

Such β-styrene can be easily prepared according to state of the art from corresponding acetophenone and nitro methane or from a-styrene and sodium nitrite in the presence of ammonium cerium nitrate in acidic medium (Scheme 1 1 ).

X

Scheme 11. Preparation of β-nitrostyrene lb-N0 ₂ .

If applying the enzymatic approach to the asymmetric reduction of step (a), the enzymes are preferably selected from reductases of natural or recombinant sources, wherein the natural reductases are used as isolated enzymes, in mixtures or in a fermentation process with reductases rich microorganisms. The most preferred approach according to the invention uses baker's yeast, which contains various reductases. Surprisingly, although the baker's yeast is not a selective source of reductases, the transformation with the baker's yeast according to the step (a) gives the compounds according to the formula II in high yield and enantiomeric excess, Furthermore, this reduction is comprehensive for the compounds la and lb with most of substituents A or B, respectively.

Due to the high efficiency, the enzymatic reduction according to the step (a) is most preferably carried out using baker's yeast containing fungi of the species Saccharomyces cerevisiae in a water medium, preferably containing a buffer of pH 7-9, most preferably the phosphate buffer of pH 8, optionally in a mixture with a water immiscible solvent, preferably selected from hydrocarbons. The mixture is optionally pre-prepared by adding a feed, preferably selected from glucose tempering it at the temperature from 15 to 40 °C, preferably at 35 °C. A substrate selected from a compound according to the formula la or lb is added undissolved or dissolved in a microorganism friendly water miscible solvent, preferably selected from alcohols or acetone, most preferably ethanol. The bioreaction mixture is usually stirred for 3 hours to 5 days, preferably 1 day, at the temperature from 15 to 40 °C, preferably at 35 °C. The product can be isolated by removal of biomaterial followed by extraction and can be purified by the methods of state of the art.

In special but not limited embodiments, the nitro compound lb-N0 ₂ is reduced to the compound according to the formula ll-N0 ₂ with high ee, the acrylic ester la -Me to the compound according to the formula ll-Me and the acrylonitrile la-CN to the compound according to the formula ll-CN with very high ee (Scheme 12). The favored configuration of the products according to the formula II prepared by the bioreaction with the baker's yeast is (R).

la-CN ll-CN

Scheme 12. Baker's yeast conversion of styrene derivatives to chiral 2-arylpropane derivatives.

Notably, the compounds represented by the formulae ll-CN and Il-Me as enantiomerically enriched, essentially enantiopure or enantiopure (R) or (S) enantiomers:

(R)-U-CN (R)-W-Me (S)-W-Me

represent novel and suitable intermediates for the synthesis of compound A, preferably their (RJ-enantiomers for the synthesis of lorcaserin, or a salt thereof.

If applying the biomimetic approach the reduction according to the step (a), this biomimetic reduction is preferably performed in the presence of a hydrogen donor and an organocatalyst. The biomimetic reaction represents a reaction, which mimics a bioreaction by using unnatural reagents. As used herein the reduction mimics a bioreduction, such as a transfer hydrogenation which is usually performed with NADH dehydrogenases in nature. 1 ,4-dihydropyridines, also named Hantzsch esters, are preferably used as proton donors in the biomimetic reactions. As a proton donor any Hantzsch ester can be used, but the simplest and the cheapest representatives such as diethyl 1 ,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate or di-i-butyl 1 ,4-dihydro- 2,6-dimethyl-3,5-pyridine dicarboxylate are most preferred.

Organocatalysts for the biomimetic transfer hydrogenation reaction are selected from chiral derivatives of thioureas, urea sulfinamides and imidazolones, which are preferably selected from enantiopure Λ/-[2-(3-(3,5- bis(trifluoromethyl)phenyl)ureido)cyclohexyl]-ie f-butyl-sulfinamide, 2-[[3,5- bis(trifluoromethyl)phenyl]thioureido]-/V-benzyl-/V,3,3-trim ethylbutanamide,

[(dimethylamino)carbonyl]-2,2-dimethylpropyl]thioureido]c yclohexyl]imino]methyl]-5- ie f-butyl-4-hydroxyphenyl pivalate, 2-ie f-butyl-3-methyl-5-benzyl-4-imidazolidinone (McMillan type catalyst). The organocatalysts play a role of chiral inductors for the generation of a particular configuration at the chiral carbon atom in the position 2 of the resulting 2-arylpropane (indicated by ^* ), which is dependent on configuration of the organocatalyst. Such reaction system have been investigated only weakly until now, described only for Jacobsen thiourea type catalysts. The catalytic systems of combination of a Hantzsch ester with cheaper urea type and MacMillan type catalysts have not been investigated, yet, and are described herein for the first time.

The transfer hydrogenation reaction is preferably applied on nitrostyrenes (compound according to the formula lb-N0 ₂ ). The reactions are usually performed in an organic solvent, preferably selected from aromatic or aliphatic hydrocarbons, most preferably toluene, at the temperature from 10 to 100 °C, preferably from 30 to 45 °C, for 6 hours to 5 days, preferably from 12 hours to 2 days. Such biomimetic approach gives moderate to high ee of at least 60 % ee, preferably at least of 90 % ee and at least 90 % conversion, in most cases a full conversion to the compound according to the formula ll-N0 ₂ .

If applying the catalytic approach in the asymmetric reduction according to the step (a), this catalytic reduction is performed by use of hydrogen or a hydride donor in the presence of a catalyst, preferably selected from a transition metal, which is preferably selected from ruthenium, rhodium, iridium and copper, in a combination with a chiral ligand preferably selected from phosphine and diphosphine ligands. The reaction with hydrogen is usually performed under the pressure of 1 to 50 bar, preferably 1 to 5 bar. More preferred is the use of hydride donors, preferably selected from mono-, di- or tri- CrC ₆ -alkyl or aryl substituted silanes, most preferably from phenylsilane or triethylsilane and/or alkyl substituted polyhydrosiloxanes, preferably polymethylhydrosiloxane (PMHS).

The transition metal can be introduced into the reaction system in the form of a complex with the corresponding ligand or in the form of a salt, oxide, hydroxide in particular valence states with separate addition of a ligand or its predecessor. For industrial purposes, it is more preferred to use a less toxic and cheap metal. Surprisingly, copper catalysts show high efficiency in reduction of a-substituted styrene and, furthermore, in the combination with particular phosphine ligands, also high enantioselectivity. Copper is preferably introduced in the form of Cu(l) salts, preferably in the form of copper (I) chloride, or in the form of copper (II) compounds, selected from copper (II) halogenides, nitrate, sulfate, hydroxide or carbonate, preferably from hydroxide or basic carbonate. The term copper (II) basic carbonate ("basic CuC0 ₃ ") as used herein, refers to malachite (Cu(OH) ₂ .CuC0 ₃ ) or the azurite (Cu ₃ (OH) ₂ (C0 ₃ )2) form of copper (II) carbonate. In a most preferred embodiment the malachite form of copper (II) basic carbonate Cu(OH) ₂ .CuC0 ₃ represents a readily available and surprisingly effective catalytic system for reductions, acting as a metal and a base activator in one molecule.

Diphosphine ligands are preferably selected from commercially available ferrocene containing ligands, selected from the Josiphos, Mandyphos or Walphos group of ligands. Phosphine ligands are preferably selected from oxazoline type ligands (PHOX).

The combinations Cu(OH) ₂ /Walphos, Cu(OH) ₂ /PHOX, Cu(OH) ₂ CuC0 ₃ /Walphos, Cu(OH) ₂ CaC0 ₃ /PHOX or CuCI/PHOX in the presence of phenylsilane and the additive PMHS are highly efficient and therefore especially preferred. Enantioselective reduction of nitrostyrene according to the formula lb-N0 ₂ using these combinations gives the compound according to the formula ll-N0 ₂ of at least 88 % ee, preferably of at least 95 % ee, most preferably of at least 98 % ee. Remarkably, the reduction, which is first used in this invention, can be successfully preformed in water media, which is highly advantageous for industrial use, while the prior art methodology based on copper fluoride or ie f-butylate with Josiphos or BINAP ligands does not work in aqueous medium. Such a catalytic reduction represents a novel key synthesis step to be preferably applied in the synthesis of the compound according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof, and can therefore also suitably be used for producing the novel and suitable intermediates according to the formulae III, IV and V:

IV wherein ^* in the formulae denotes an asymmetric carbon atom in (R) or (S) configuration being enantiomerically enriched, essentially enantiopure or enantiopure, wherein R is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R may bond together to constitute a C ₂ - or C ₃ -alkylene chain for forming a 5- or 6- membered ring, and wherein PG is represented by acetyl or tosyl. In general, such novel intermediates according to the formulae III, IV and V are suitably produced by a method applying at least the asymmetric key step (a) as described herein.

Thus, in a preferred but not limited embodiment a copper based asymmetric catalytic reduction of the compound according to the formula lb-N0 ₂ is performed in an aqueous medium, such as water not containing organic solvents or optionally in a biphasic system with a water immiscible solvent, preferably toluene. In the first step, the copper compound is preferably mixed with the ligand creating compound after which the catalyst is created in 15 to 60 minutes. The procedure is usually followed by the addition of reducing agent, such as phenylsilane and the additive PMHS. Finally, the nitrostyrene is added, followed by a second portion of silane. The reaction is normally performed at a temperature from 10 - 50 °C, preferably from 20 to 30 °C in 6 hours to 2 days, preferably in one day. The product can be extracted from the aqueous medium and can then be isolated and purified by the methods of the state of the art. In the step (b), the group A in the compound according to the formula II is converted to the aminomethyl group in a reaction or in a set of reactions, wherein at least one consists of a reduction. Preferably, the group A in the compound according to the formula II is represented by -CN, -COY (with Y being OH, C C ₆ -alkoxy, NH ₂ , or NH- CH ₂ CH(OR) ₂ , wherein R is defined as above), -CH ₂ -N0 ₂ , -CH ₂ -NO, -CH ₂ N ₃ , and wherein A in the compound according to the formula II is most preferably selected from -CN (ll-CN), -COOMe (ll-Me), and -CH ₂ -N0 ₂ (ll-N0 ₂ )

In a special case, the compound according to the formula ll-N0 ₂ is reduced to the compound according to the formula III by inorganic reducing agents selected from inorganic sulfides, selected from sodium hydrogensulfide, sulfide or polysulfide, from sodium dithionite or thiourea dioxide in basic conditions, or by catalytic hydrogenation, preferably using platinum, palladium or vanadium catalysts, or low-valent metal salts, preferably selected from iron (II) or tin (II) salts or elemental metal in the presence of acids, preferably zinc or iron in hydrochloric acid or acetic acid, optionally diluted by a water miscible solvent selected from CrC ₄ -alcohol and tetrahydrofuran. Most preferably, zinc in methanolic HCI is used, which reaction can be performed at 0 - 50 °C, preferably at room temperature for 15 - 120 min, preferably for 20 - 40 min.

In a special case the compound according to the formula II, wherein A is represented by -CO-NH ₂ or CN (ll-CN) is catalytically hydrogenated on Raney® Ni or is reduced by a hydride, selected from boron hydrides, preferably selected from borane complexes, such as BH ₃ .THF, aluminum hydrides, such as lithium aluminum hydride or DIBALH to give the compound according to the formula III.

In another special case the compound according to the formula II, wherein A is -COY (with Y being OH, C C ₆ -alkoxy, NH ₂ , or NH-CH ₂ CH(OR) ₂ , wherein R is defined as above) is transformed to the compound according to the formula IV comprising at least one of the following steps:

i. hydrolyzing the compound according to the formula II wherein A is -COY (with Y being d-C ₆ -alkoxy, NH ₂ ), in the presence of a strong acid, preferably selected from hydrochloric or sulfuric acid, or in the presence of a strong base, preferably selected from alkali metal hydroxides, to give the compound according to the formula II, wherein A is represented by C0 ₂ H, ii. coupling the compound according to the formula II, wherein A is represented by 2H with a compound according to the formula XI:

XI by means of coupling reagents selected from activated isoureas, or carbodiimides, preferably N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in 0 - 50 %, preferably 5 - 20 % molar excess, optionally in the presence of bases, which are preferably selected from tertiary amines, such as triethylamine, ethyldiisopropylamine or N-methylmorpholine, or via preparation of reactive acid derivatives, such as halogenides, by reacting the acid with e.g. thionyl chloride or oxalyl chloride, or mixed anhydrides by reacting the acid with e.g. CrC ₄ -alkyl or benzyl chloroformates to give the compound according to the formula II, wherein A is represented by -CONHCH ₂ CH(OR) ₂ .

iii. reducing the carbonyl group of the compound of formula II, wherein A is represented by -CONHCH ₂ CH(OR)2 by a hydride, selected from borohydrides, preferably lithium borohydride, boron hydrides, preferably selected from borane complexes, such as BH ₃ .THF, or aluminum hydrides, such as lithium aluminum hydride or DIBALH, to give the compound according to the formula IV.

If applying the sub-step (b2') in the step (b), the compound according to the formula III is preferably reacted with the compound represented by the above defined formula XCH ₂ CH(OR)2 (wherein X is preferably CI or Br, and R is preferably methyl or ethyl), most preferably chloroacetaldehyde dimethyl acetal or bromoacetaldehyde diethyl acetal, optionally in the presence of a base, or with the compound represented by the above defined formula OHC-CH(OR) ₂ (wherein R is preferably methyl or ethyl) under conditions of reductive amination by using alkali metal borohydrides, preferably selected from sodium borohydride or sodium triacetoxyborohydride, or by catalytic hydrogenation on palladium on supporter, preferably 10 % palladium on charcoal, to obtain the compound according to the formula IV.

The compounds according to the formula III or IV are optionally isolated as solid salts, preferably hydrochlorides. In one alternative, the compounds are first isolated as oils in a crude state or in a purified state following purification by e.g. column chromatography. Then, the crude or purified oil is diluted by an organic solvent, preferably selected from tetrahydrofuran, followed by addition of an acid, such as hydrochloric acid or gaseous hydrogen chloride. The salt, such as hydrochloride, is then precipitated and filtered off. In another alternative, the compounds according to the formula III or IV can be extracted by partitioning the reaction mixture between concentrated aqueous sodium chloride solution (brine), which is acidified by an acid, such as hydrochloric acid, and an organic solvent, preferably dichloromethane, wherein the salt is forced to the organic phase which is afterwards separated off and concentrated to give the compound according to the formula III or IV in the form of a salt, preferably as hydrochloride salt.

In the step (d) of this embodiment, the compound according to the above defined formula IV (where R is preferably selected but not limited to methyl or ethyl) is intramoleculary cyclized under Friedel-Crafts reaction conditions to give products depending on the reaction conditions. If the Friedel-Crafts reaction is performed without solvents in molten phase (neat conditions), the reaction yields the compound according to the below formula V , which can be isolated in the form of hydrochloride by partitioning between brine and dichloromethane. If the reaction is performed in a solvent, such as dichloromethane, the intermediate compounds according to the below formulae XII and/or XIII, wherein R is defined as above, preferably represented by methyl or ethyl, can also be isolated, under some conditions as predominate products. In so

VI, XII XIII

In order to guarantee a more univocal process, the reaction should be forced to yield the final product with a double bond according to the formula V .

Such a Friedel-Crafts alkylation reaction applied in the present invention are preferably accomplished in the presence of a Lewis acids, preferably selected from AICI ₃ , FeCI ₃ , InCIs, lnBr ₃ , Bi(OTf) ₃ , BiCI ₃ , Sc(OTf) ₃ , TeCI ₄ , most preferably from anhydrous AICI ₃ . The Friedel-Crafts reaction is carried out without solvent (neat conditions) or in a solvent, selected from nitromethane, aromatic hydrocarbons, preferably nitrobenzene, chlorinated hydrocarbons, preferably dichloromethane for 10 min to 36 hours. The Friedel-Crafts reaction is preferably carried out without solvent (neat conditions) for cyclizing the compound according to the formula IV, where the secondary amine is unprotected.

It was surprisingly found by the inventors, that if the secondary amino group of the compound according to the formula IV is protected by an amino protection group (PG), the Friedel Crafts reaction leads univocally to product with the double bond according to the formula VI (with R-i being represented by PG). Thus, the compound according to the formula IV may preferably be transformed in step (c) to the compound according to the formula V:

V

wherein ^* is defined as above. The amino protecting group PG as used herein means a group that protects the secondary amine of the compound according to the formula IV such that this group is applicable to the Friedel-Crafts reaction conditions applied in step (d). Such an amino protecting group PG is thus limited only by its suitability to perform under the reaction conditions of said reactions step (d) and can be selected from known "amino protecting groups" as recited in "Greene's Protective Groups in Organic Synthesis", 4th Edition (Peter G. M. Wuts, Theodora W. Greene; ISBN: 978-0- 471 -69754-1 ). Preferably, the amino protecting group PG used in the present invention is selected from

- unsubstituted benzyl or substituted, preferably omethyl, p-nitro, p-methyl or p- methoxy substituted benzyl, by a reaction with the corresponding halogenide, selected from chloride, bromide or iodide in basic conditions;

- unsubstituted or fluorinated CrC ₄ -alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p- methyl (tosyl, Ts) substituted benzenesulfonyl by a reaction with the corresponding sulfonyl halogenide, preferably chloride, such as tosyl chloride (TsCI), or sulfonyl anhydrides, such as triflic anhydride (Tf ₂ 0) in basic conditions; or

- or unsubstituted or substituted CrC ₆ -alkanoyl, preferably acetyl or arylcarbonyl, preferably benzoyl by a reaction with corresponding acyl halogenide, preferably chloride, or acyl anhydride, such as acetic anhydride (Ac ₂ 0) or benzoyl chloride in basic conditions.

The media of the protection reactions are preferably selected from aprotic solvents, preferably dichloromethane.

The resultant compound according to the formula V is converted in step (d) under the same Friedel-Crafts reaction conditions as described for the compound according to the formula IV above, to give the compound according to the formula Vl ₂ :

Vl ₂

wherein ^* and PG are the same as shown for the compound according to the formula V above.

The compound according to the formula Vl ₂ is usually isolated by quenching the reaction mixture with water, neutralizing the mixture with a base, such as sodium hydroxide, and extracting the product with a water immiscible solvent, followed by removal of the solvent.

In the step (e), the compound according to the formula Vl ₂ is reduced in the sub-step (e1 ) to a compound according to the formula VII:

VII

using reducing agents preferably selected from boron hydrides, such as alkali metal borohydrides, preferably NaBH ₄ or borane complexes, preferably BH ₃ -THF, aluminum hydrides, preferably LiAIH ₄ , DIBALH, RedAI, by NEt ₃ /HC0 ₂ H, or by catalytic hydrogenation using metal transition catalysts preferably selected from palladium, platinum, nickel, ruthenium, most preferable by catalytic hydrogenation using metal transition catalysts.

In the sub-step (e2) of step (e), the amino protection group PG of the compound according to the formula VII is deprotected using standard protocols, known to a skilled person, which may be selected from acid or alkali hydrolysis or hydrogenation, to give the final product according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof.

Alternatively, the compound according to the formula V is reduced in the sub-step (e1 ) of step (e) by using the reducing agents as described for the reduction of the compound according to the formula Vl ₂ above, thereby yielding the final compound according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof.

However, due to the possibility of enamine-imine tautomery on unprotected intermediates, the synthetic route, wherein the protection-(c)/de-protection-(e2) protocol is used, is more robust in easier achieving better yields and purity. Therefore, it is preferred to introduce an amino protection group PG by means of the step (c) prior to the Friedel-Crafts alkylation applied in step (d).

Because of the same reason, an alternative route wherein the compound according to the formula V is first de-protected in sub-step (e2) to the compound according to the formula V followed by a reduction of sub-step (e1 ) to give the final product according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof, is usually less suitable.

The compound according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof, being prepared according to the steps (a) to (e) of the invention is enantiomerically enriched, essentially enantiopure or enantiopure in the enantiomer, which is created in excess in the key step (a). The catalytic system used for the reduction of the compounds according to the formula la and lb prefers one of the enantiomers, either (R) or (S), preferably (R). The initial configuration, created in the key step (a) is retained through the step (b) to (f) to give the final compound according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof, without substantial changes. The enantiomeric excess may be only slightly diminished by minor racemization or even improved by optional crystallizations or purifications of intermediates. The preferred (R) enantiomer of the compound according to the formula II leads through steps from (b) to (e) to antiobesity drug lorcaserin, or a salt thereof.

A preferred but non-limiting embodiment of an advantageous method for the preparation of the (R) isomer of the compound according to the formula II, preferably II-NO ₂ , which leads to lorcaserin, or a salt thereof, is making use of the baker's yeast, which gives the preferred enantiomer in high ee and yield. Applying the biomimetic or the catalytic approach, the preferential configuration of the chiral carbon atom is defined by selection of the catalytic system, wherein the configuration of the organic catalyst or the ligand of metal catalyst determines the predominate configuration.

If the final product according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof, is enantiomerically enriched, the enantiomerically excess is preferably improved by performing a chiral resolution via selective crystallization of diastereoisomeric salt with a resolving agent, preferably tartaric acid, followed by anion exchange to yield a product with at least 90 % ee or more, most preferably 97 % ee or more. If the final product is essentially enantiopure, the final steps optionally include purification in order to remove chemical impurities and transformation into a pharmaceutical salt. In a preferred mode, the compound according to the formula (R)-A (lorcaserin) is transformed into the hydrochloride salt (lorcaserin hydrochloride, compound according to the above formula 1 ), by treating it with HCI in a solvent such as acetone or ether, and wherein the residue is optionally re-suspended or recrystallized from a solvent to obtain a crystalline and purified product.

Notably, the compound represented by the formula VI in the form of the enantiomerically enriched, essentially enantiopure or enantiopure (R) or (S) enantiomer:

(R)M\ (S)- \ wherein R ¹ is selected from hydrogen, unsubstituted benzyl or substituted benzyl, preferably σ-methyl, p-nitro, p-methyl or p-methoxy benzyl, unsubstituted or fluorinated CrC ₄ -alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl or unsubstituted or CrC ₆ -alkanoyl, preferably acetyl or arylcarbonyl, preferably benzoyl, represents a novel and suitable intermediate for the synthesis of compound A, or a salt thereof, with the (RJ-enantiomer being suitable for the synthesis of lorcaserin, or a salt thereof.

Notably, the compound represented by the formula VII in the form of the enantiomerically enriched, essentially enantiopure or enantiopure (R) or (S) enantiomer:

(R)- \\ (S)- \\

wherein PG is selected from unsubstituted benzyl or substituted benzyl, preferably a- methyl, p-nitro, p-methyl or p-methoxy benzyl, unsubstituted or fluorinated C1-C4- alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl or unsubstituted or CrC ₆ -alkanoyl, preferably acetyl or arylcarbonyl, preferably benzoyl, represents a novel and suitable intermediate for the synthesis of compound A, or a salt thereof, with the (RJ-enantiomer being suitable for the synthesis of lorcaserin, or a salt thereof.

An illustrative overview of the method of the present invention will be given on the basis of preferred and non-limiting experimental details below and is also illustrated by the above Schemes 6 and 7.

By virtue of the above described synthesis, the present invention for the first time provides an asymmetric synthesis of 8-chloro-1 -methyl-benzo[c ]azepine derivatives, preferably lorcaserin, or its salts. Various asymmetric methodologies can be used on the intermediates in order to selectively and efficiently establish asymmetric step, using simple and commercially available reagents and catalysts or baker's yeast as a cheapest way of enzymatic approach. One approach uses novel, simple and highly enantioselective catalytic systems based on simple Cu(ll) and Cu(l) catalysts (copper (II) hydroxide, basic copper (II) carbonate and copper (I) chloride) and readily available chiral ligands, used for reduction of unsaturated intermediates in pure aqueous medium under mild reaction conditions. There is no need for hazardous high hydrogen pressures (asymmetric catalytic hydrogenation) and toxic, pollutant and expensive organic solvents as usual.

In this way, the present invention provides a facile, economically and selective synthesis. Moreover, the invention provides an insight about new key intermediates for the synthesis of such compounds and their respective production way. The present invention presents efficient, simple and highly selective asymmetric approach to final lorcaserin, or a salt thereof. This is more advantageous and much more efficient in comparison with chiral resolution of enantiomers using chiral chromatography or classical optical resolution via diastereoisomeric salts what are well known approaches used in prior art.

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

Example 1 : Preparation of (£)-1 -chloro-3-(1 -nitroprop-1 -en-2-yl)benzene from 1 - chloro-3-(prop-1 -en-2-yl)benzene

x lb-N0 ₂

Starting material 1 -chloro-3-(prop-1 -en-2-yl) (23 mmol; 3.5 g) was dissolved in chloroform (80 mL) in a 250 mL flask equipped with a magnetic stir bar. Afterwards sodium nitrite (230 mmol; 15.9 g) and cerium(IV) ammonium nitrate (CAN; 23 mmol; 12.6 g) were added and the reaction mixture was vigorously stirred for 15 minutes. Acetic acid (276 mmol; 15.8 mL) was then slowly added drop wise (60 min) and the reaction system was intensively stirred at 30 °C until TLC showed total consumption of starting material. After the completion of the reaction, the reaction mixture was filtered, the solvent was evaporated under reduced pressure, the organic residue was diluted with water and neutralized with a saturated solution of NaHC0 ₃ . The aqueous layer was extracted with EtOAc (3 x 100 mL), the organic phases were washed with brine and dried under Na ₂ S0 ₄ . After evaporation of the solvent under reduced pressure, the crude product was obtained which was purified with flash column chromatograph (Si0 ₂ ; n-hexane-EtOAc = 10 : 1 ) to afford yellow solid product (6.2 g, 72% yield).

1H NMR (500 MHz, CDCI ₃ , ppm) δ 7.45-7.30 (m, 4ArH), 7.24 (m, 1 H), 2.65 (m, 3H); ¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 148.2, 140.1 , 136.9, 135.5, 130.4, 126.4, 125.0, 18.5.

Example 2: Enzymatic synthesis of (R)-1 -chloro-3-(1 -nitropropan-2-yl)benzene in aqueous medium using baker ^' s yeast

Ib-N0 ₂ (R)-\\-N0 ₂

D-Glucose (5 g) was totally dissolved in aqueous phosphate buffer (100 mL) at pH 8 in a 500 mL flask equipped with magnetic stir followed by addition of dry Baker ^' s yeast (type Saccharomyces Carevisiae; 10 g) and the reaction mixture was stirred at 35 °C. Afterwards, the nitro alkene starting material lb-N0 ₂ in EtOH solution (100 g/L) was slowly added drop wise and the reaction system was vigorously stirred (900 rpm) under nitrogen for 24 hours at 35 °C. The reaction system was diluted with CH ₂ CI ₂ , filtered through Celite ^® , the phases were separated and the aqueous phase was again extracted with CH ₂ CI ₂ . The combined organic phases were washed with brine, released through an extraction disc and dried over Na ₂ S0 ₄ . After evaporation of the solvent, yellow oily product (87 mg; 86% yield) was obtained and characterized with GC-MS (m/z = 154; M-N0 _2; CI) analysis, HPLC chiral chromatography (97% optical purity was obtained) and NMR spectroscopy.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.38-7.10 (m, 3ArH + 1ArH), 4.55-4.45 (m, 2H, - CH ₂ N0 ₂ ), 3.65-3.57 (m, 1 H), 1.38 (d, J = 7.5 Hz, 3H);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 142.9, 134.8, 130.3, 127.9, 127.2, 125.2, 81.4, 38.35, 18.7. Example 3: Reductive transformation of (R)-1 -chloro-3-(1 -nitropropan-2-yl) to (R)-2-(3- chlorophenyl)propan-2-amine hydrochloride salt

11-NO2 III.HCI

Chiral 1 -chloro-3-(1 -nitropropan-2-yl)benzene ll-N0 ₂ (180 mg) was dissolved in THF (4.5 mL) in a flask equipped with a magnetic stir bar and a rubber septum was placed and methanol (0.5 mL) was then added. The reaction system was cooled down to 0 °C and fine zinc powder was added followed by slow addition (30 min) of acetic or hydrochloric acid (30 equiv. according to starting material). After addition, the reaction system was vigorously stirred for 4 hours at 30 °C. The zinc powder was filtered off, the residue was diluted with water, the pH was adjusted to 1 1 and the aqueous phase was extracted then with two portions (100 mL) of EtOAc. The organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated to afford crude liquid optical active product (105 mg; 78% yield; 95% optical purity). Hydrogen chloride solution in THF (2M, 1 .5 mL) was added to the crude product at 0 °C and afterwards fine white crystals were filtered off, dried in vacuum and characterized with GC-MS analysis and NMR spectroscopy.

¹ H NMR (500 MHz, DMSO, ppm) δ 8.30 (bs, 3H), 7.30-7.15 (m, 4ArH), 3.18 (m, 1 H), 2.96 (m, 2H), 1.24 (d, J = 9 Hz, 3H).

¹³ C NMR (125 MHz, DMSO, ppm) δ 145.4, 133.2, 130.5, 127.2, 126.9, 126.1 , 44.5, 37.1 , 19.2.

Example 4: Asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2- yl)benzene via organocatalytic biomimetic transfer hydrogenation using urea- sulfinamide type chiral catalyst

lb-N0 ₂ ll-N0 ₂ β,β-Disubstituted nitroalkene lb-N0 ₂ (0.5 mmol; 100 mg) and chiral organocatalyst /V-[(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)cyclohexyl] -ie f-butyl-sulfinamide (0.075 mmol; 15 mol%) were added in a test tube equipped with magnetic stir bar to dry toluene (0.6 ml_). Such reaction system was stirred under N ₂ for 30 min at 30 °C. Afterwards the reducing agent diethyl 1 ,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate (Hantzsch ester; 1 .1 eq. according to substrate; 0.5 mmol; 140 mg) was added in two portions and the reaction mixture was vigorously stirred at 40 °C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, the organic residue was extracted with two portions of methyl ie f-butyl ether (MTBE, 100 ml_), the combined organic phases were washed with brine and purified with flash chromatography (Si0 ₂ ; n-pentane : MTBE). Finally, yellow oily product was obtained (full conversion; 75 mg, 76% isolated yield) which was characterized with chiral HPLC analysis and NMR spectroscopy. HPLC chiral analysis of the enantiomeric mixture showed 70 % enantiomeric excess.

Example 5: Asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2- yl)benzene via organocatalytic biomimetic transfer hydrogenation using thiourea-/V- benzyl-trimethylbutanamide type chiral catalyst

lb-N0 ₂ ll-N0 ₂ β,β-Disubstituted nitroalkene lb-N0 ₂ (0.5 mmol; 100 mg) and chiral organocatalyst 2-[[3,5-bis(trifluoromethyl)phenyl]thioureido]-/V-benzyl-/V, 3,3-trimethylbutanamide (0.075 mmol; 15 mol%) were added in a test tube equipped with a magnetic stir bar to dry toluene (0.6 ml_). Such reaction system was stirred under N ₂ for 30 min at 30 °C. Afterwards, the reducing agent diethyl 1 ,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate (Hantzsch ester; 1 .1 eq. according to substrate; 0.5 mmol; 140 mg) was added in two portions and the reaction mixture was vigorously stirred at 40 °C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, the organic residue was extracted with two portions of MTBE (100 ml_), the combined organic phases were washed with brine and purified with flash chromatography (Si0 ₂ ; n-pentane : MTBE). Finally, yellow oily product was obtained (full conversion; 80 mg, 80% isolated yield) which was characterized with chiral HPLC analysis and NMR spectroscopy. HPLC chiral analysis of the enantiomeric mixture showed 90 % enantiomeric excess.

Example 6: Asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2- yl)benzene via organocatalytic biomimetic transfer hydrogenation using thiourea- cyclohexyl-imino type chiral catalyst

lb-N0 ₂ ll-N0 ₂ β,β-Disubstituted nitroalkene lb-N0 ₂ (0.5 mmol; 100 mg) and chiral organocatalyst [(dimethylamino)carbonyl]-2,2-dimethylpropyl]thioureido]cycl ohexyl]imino]methyl]-5- ie f-butyl-4-hydroxyphenyl pivalate (0.075 mmol; 15 mol%) were added in a test tube equipped with a magnetic stir bar to dry toluene (0.6 mL). Such reaction system was stirred under N ₂ for 30 min at 30 °C. Afterwards, the reducing agent diethyl-1 ,4-dihydro- 2,6-dimethyl-3,5-pyridinedicarboxylate (Hantzsch ester; 1 .1 equv. according to substrate; 0.5 mmol; 140 mg) was added in two portions and the reaction mixture was vigorously stirred at 40 °C for 48 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the organic residue was extracted with two portions of MTBE (100 mL), the combined organic phases were washed with brine and purified with flash chromatography (Si0 ₂ ; n-pentane : MTBE). Finally, yellow oily product was obtained (90% conversion; 67 mg, 66% isolated yield) which was characterized with chiral HPLC analysis and NMR spectroscopy. HPLC chiral analysis of the enantiomeric mixture showed 85 % enantiomeric excess.

Example 7: Asymmetric synthesis of optical active 1 -chloro-3-(1 -nitropropan-2- yl)benzene via organocatalytic transfer hydrogenation using imidazolidinone type chiral catalyst

Ib-NO, ll-NO, β,β-Disubstituted nitroalkene lb-N0 ₂ (0.5 mmol; 100 mg) and chiral organocatalyst 2-ie f-butyl-3-methyl-5-benzyl-4-imidazolidinone (McMillan type catalyst; (0.075 mmol; 15 mol%) were added in a test tube equipped with a magnetic stir bar to dry toluene (0.6 mL). Such reaction system was stirred under N ₂ for 30 min at 30 °C. Afterwards, the reducing agent diethyl-1 ,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (Hantzsch ester; 1 .1 equv. according to substrate; 0.5 mmol; 140 mg) was added in two portions and reaction mixture was vigorously stirred at 40 °C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, the organic residue was extracted with two portions of MTBE (100 mL), the combined organic phases were washed with brine and purified with flash chromatography (Si0 ₂ ; n-pentane : MTBE). Finally, yellow oily product was obtained (100% conversion; 42 mg, 42% isolated yield) which was characterized with chiral HPLC analysis and NMR spectroscopy. HPLC chiral analysis of the enantiomeric mixture showed 65 % enantiomeric excess. Example 8: Copper(ll) hydroxide/chiral phosphine ligand catalysed asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2-yl)benzene via conjugate reduction in pure water

lb-N0 ₂ ll-N0 ₂

Catalyst Cu(OH) ₂ (0.05 mmol) and chiral ligand 4-ie/f-butyl-2-[(S _p )-2- (diphenylphosphino)ferrocenyl]-2-oxazoline (0.025 mmol) were added to water (2.5 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N ₂ for 45 min at 27 °C. Afterwards, the reducing additive PMHS (0.05 mmol) followed by a first portion of the reducing agent PhSiH ₃ (0.75 equiv. according to starting material) were added and the reaction system stirred for 30 min to turn into black color. The starting material β,β-disubstituted nitroalkene lb-N0 ₂ (0.5 mmol) was then added followed by a second portion of PhSiH ₃ (0.75 equiv.) and the reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 24 h. The reaction system was diluted with water, extracted with two portions of EtOAc (25 mL), the combined organic phases were washed with brine and the solvent was evaporated under reduced pressure. Crude oily product was purified on flash chromatography (Si0 ₂ ; n-hexane : EtOAc = 1 : 1 ) to afford pure final product (85 mg; 85% isolated yield) which was characterized with chiral HPLC and NMR analysis. HPLC chiral analysis of the enantiomeric mixture showed 88 % enantiomeric excess.

Example 9: Copper(ll) hydroxide/chiral diphosphine ligand catalysed asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2-yl)benzene via conjugate reduction in pure water

H ₂ 0; 900 rpm

lb-N0 ₂ ll-N0 ₂ Catalyst Cu(OH) ₂ (0.75 mmol) and chiral ligand diphenylphosphino-phenyl-ferrocenyl- ethylbis[3,5-bis-trifluoromethyl)phenyl]phosphine (0.4 mmol; 2.1 mol%) were added to water (15 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N ₂ for 45 min at 27 °C. Afterwards, the reducing additive PMHS (0.75 mmol) followed by a first portion of reducing agent PhSiH ₃ (0.75 equiv. according to starting material) were added and the reaction system stirred for 30 min. The starting material β,β-disubstituted nitroalkene lb-N0 ₂ (7.5 mmol) was then added followed by a second portion of PhSiH ₃ (0.75 equiv.) and the reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 48 h. The reaction system was diluted with water, extracted with two portions of EtOAc (100 mL), the organic phases were washed with NaHC0 ₃ and brine, dried under anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. Crude oily product was purified on flash chromatography (Si0 ₂ ; n-hexane : EtOAc = 5 : 1 ) to afford pure final product (1 .37 g; 92% isolated yield) which was characterized with chiral HPLC and NMR analysis. HPLC chiral analysis of the enantiomeric mixture showed 95 % enantiomeric excess.

Example 10: Basic copper(ll) carbonate/chiral phosphine ligand catalysed asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2-yl)benzene via conjugate reduction in aqueous toluene

lb-N0 ₂ II-NO2

Catalyst basic CuC0 ₃ (0.05 mmol) and chiral ligand 4-ie/f-butyl-2-[(S _p )-2- (diphenylphosphino)ferrocenyl]-2-oxazoline (0.025 mmol) were added to toluene (2.5 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N ₂ for 45 min at 27 °C. Afterwards, the reducing additive PMHS (0.05 mmol) followed by a first portion of reducing agent PhSiH ₃ (0.75 equiv. according to starting material) were added and reaction system stirred for 30. The starting material β,β-disubstituted nitroalkene lb-N0 ₂ (0.5 mmol) was then added followed by a second portion of PhSiH ₃ (0.75 equiv.) and water. The reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 24 h. The reaction system was diluted with water, the phases were separated in separating funnel, the organic phase were washed with NaHC0 ₃ and brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. Crude oily product was purified on flash chromatography (Si0 ₂ ; n-hexane : EtOAc = 5 : 1 ) to afford pure final product (88.5 mg; 89% isolated yield) which was characterized with chiral HPLC and NMR analysis. HPLC chiral analysis of the enantiomeric mixture showed 98% enantiomeric excess.

Example 11 : Basic copper(ll) carbonate/chiral diphosphine ligand catalysed asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2-yl)benzene via conjugate reduction in aqueous toluene

toluene / H ₂ 0; 900 rpm lb-N0 ₂ ll-N0 ₂

Catalyst basic CuC0 ₃ (0.05 mmol) and chiral ligand diphenylphosphino-phenyl- ferrocenyl-ethylbis[3,5-bis-trifluoromethyl)phenyl]phosphine (0.025 mmol) were added to toluene (2.5 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N ₂ for 45 min at 27 °C. Afterwards, the reducing additive PMHS (0.05 mmol) followed by a first portion of reducing agent PhSiH ₃ (0.75 equiv. according to starting material) and water were added and the reaction system stirred for 30 min. The starting material β,β-disubstituted nitroalkene lb-N0 ₂ (0.5 mmol) was then added followed by a second portion of PhSiH ₃ (0.75 equiv.) and the reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 24 hours. The reaction system was diluted with water, the phases were separated in a separating funnel, the organic phase were washed with NaHC0 ₃ and brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. Crude oily product was purified on flash chromatography (Si0 ₂ ; n-hexane : EtOAc = 5 : 1 ) to afford pure final product (55 mg; 56% isolated yield) which was characterized with chiral HPLC and NMR analysis. HPLC chiral analysis of the enantiomeric mixture showed 96% enantiomeric excess. Example 12: Copper(l) chloride/chiral phosphine ligand catalysed asymmetric synthesis of optically active 1 -chloro-3-(1 -nitropropan-2-yl)benzene via conjugate reduction in pure water

Catalyst CuCI (0.025 mmol) and chiral ligand 4-ie/f-butyl-2-[(S _p )-2- (diphenylphosphino)ferrocenyl]-2-oxazoline (0.0125 mmol) were added to water (2.5 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N ₂ for 45 min at 27 °C. Afterwards, the reducing additive PMHS (0.05 mmol) followed by a first portion of reducing agent PhSiH ₃ (0.75 equiv. according to starting material) were added and the reaction system stirred for 30 min to turn into black color. The starting material β,β-disubstituted nitroalkene lb-N0 ₂ (0.25 mmol) was then added followed by a second portion of PhSiH ₃ (0.75 equiv.) and the reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 24 h. The reaction system was diluted with water, extracted with two portions of EtOAc (25 mL), the combined organic phases were washed with brine and the solvent was evaporated under reduced pressure. Crude oily product was purified on flash chromatography (Si0 ₂ ; n-hexane : EtOAc = 1 : 1 ) to afford pure final product (56 mg; 57% isolated yield) which was characterized with chiral HPLC and NMR analysis. HPLC chiral analysis of the enantiomeric mixture showed 98% enantiomeric excess.

Example 13: Preparation of methyl 2-(3-chlorophenyl)acrylate from methyl 2-(3- chlorophenyl)acetate

Vlll-Me la-Me Ν,Ν,Ν',Ν'-tetramethyldiaminomethane (TMDAM, 48.9 mmol; 6.9 ml.) was added to the solution of the starting material methyl 2-(3-chlorophenyl)acetate Vlll-Me (16.3 mmol; 3 g) in Ac ₂ 0 (48.9 mmol; 4.7 mL) and the reaction mixture was stirred at 70 °C overnight. After cooling to room temperature, the reaction mixture was neutralized by addition of saturated aqueous solution of NaHC0 ₃ (15 mL) followed by addition of water (15 mL) and extraction with EtOAc (2 x 50 mL). The combined organic layers were dried over MgS0 ₄ , filtered and the solvent was removed by evaporation. The residue was purified by flash chromatography (eluent: EtOAc/n-heptane, EtOAc gradient 2 - 20 %). Colorless oily product (1 .6 g; 50 % yield) was obtained and characterized with ¹ H and ¹³ C NMR.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.42 (s, 1 H), 7.30 (m, 3H), 6.42 (s, 1 H), 5.93 (s, 1 H), 3.84 (s, 3H);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 166.6, 140.0, 138.3, 133.9, 129.3, 128.4, 128.2, 128.0, 126.5, 52.3.

Example 14: Enzymatic synthesis of optically active methyl 2-(3- chlorophenyl)propanoate from methyl 2-(3-chlorophenyl)acrylate using Baker ^' s yeast

Ia-Me Il-Me

A reaction mixture, which contained 2-(3-chlorophenyl)acrylate la -Me (2.7 mmol; 0.53 g), enzyme (yeast from Saccharomyces cerevisiae, 26.5 g), petroleum ether (26.5 mL) and water (79.5 mL), was stirred overnight at room temperature. The reaction mixture was filtered through Celite ^® pad. The filter pad was washed with CH ₂ CI ₂ and the solvent was removed under reduced pressure. Final product was characterized with ¹ H NMR spectroscopy and HPLC chiral analysis (60 % ee). Example 15: Basic copper(ll) carbonate/chiral phosphine ligand catalysed asymmetric synthesis of optically active ethyl-2-(3-chlorophenyl)propanoate via conjugate reduction in aqueous toluene

la-Me Il-Me

Catalyst basic CuC0 ₃ (0.05 mmol) and chiral ligand 4-ie/f-butyl-2-[(S _p )-2- (diphenylphosphino)ferrocenyl]-2-oxazoline (0.025 mmol) were added to toluene (2.5 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N ₂ for 45 min at 27 °C. Afterwards, the reducing additive PMHS (0.05 mmol) followed by a first portion of reducing agent PhSiH ₃ (0.75 equiv. according to starting material) were added and the reaction system stirred for 30 min. The starting material methyl-2-(3-chlorophennyl)acrylate la-Me (0.5 mmol) was then added followed by a second portion of PhSiH ₃ (0.75 equiv.) and water. The reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 24 h. The reaction system was diluted with water, phases were separated in a separating funnel, the organic phase was washed with NaHC0 ₃ and brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. Crude oily product was purified on flash chromatography (Si0 ₂ ; n-hexane : EtOAc = 5 : 1 ) to afford pure final product (82 mg; 86% isolated yield) which was characterized with chiral HPLC, GC-MS and NMR analysis. HPLC chiral analysis of the enantiomeric mixture showed 30% enantiomeric excess.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.40-7.18 (m, 4ArH), 3.68 (q, 1 H), 3.66 (s, 3H), 1 .46 (d, 3H);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 174.4, 142.40, 134.2, 129.9, 127.8, 127.4, 125.8, 52.2, 45.1 , 18.5. Example 16: Preparation of 2-(3-chlorophenyl)acrylonitrile from 2-(3- chlorophenyl)acetonitrile

VIII-CN la-CN

Λ/,Λ/,Λ/',Λ/'-tetramethyldiaminomethane (TMDAM, 99.3 mmol; 13.5 mL) was added to the solution of the starting material 2-(3-chlorophenyl)acetonitrile VIII-CN (33.1 mmol; 5 g) in Ac ₂ 0 (99.3 mmol; 9.3 mL) and the reaction mixture was stirred at 70 °C overnight. After cooling to room temperature, the reaction mixture was neutralized by addition of saturated aqueous solution of NaHC0 ₃ (40 mL) followed by addition of water (40 mL) and extraction with EtOAc (2 x 100 mL). The combined organic layers were washed with 0.1 M HCI (2 x 100 mL), dried over MgS0 ₄ , filtered and the solvent was removed by evaporation. The residue was purified by flash chromatography (eluent: EtOAc/n- heptane, EtOAc gradient 12 - 100 %). White crystalline product (1.6 g; 30 % yield) was obtained and characterized with ¹ H and ¹³ C NMR.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.59 (m, 1 H), 7.50 (td, 1 H), 7.39 (m, 2H), 6.37 (s, 1 H), 6.18 (s, 1 H);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 135.2, 134.1 , 130.3, 130.0, 129.6, 125.8, 124.1 , 121 .9, 1 17.2.

Example 17: Enzymatic synthesis of optically active (R)-2-(3- chlorophenyl)propanenitrile from 2-(3-chlorophenyl)acrylonitrile using Baker ^' s yeast

la-CN (R)-II-CN

A reaction mixture, which contained 2-(3-chlorophenyl)acrylonitrile la-CN (3.1 mmol; 0.5 g), yeast (yeast from Saccharomyces cerevisiae, 30 g), petroleum ether (25 mL) and water (50 mL), was stirred overnight at room temperature. After completion, the reaction mixture was filtered through Celite ^® pad. The filter pad was washed with CH ₂ CI ₂ . After removal of solvent by evaporation, the residue was purified by flash chromatography (eluent: EtOAc/n-heptane, EtOAc gradient 2 - 20 %. Colorless oily product (0.27 g; 54 % yield; 98.8 % ee) was obtained and characterized with ¹ H and ¹³ C NMR.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.34 (m, 3H), 7.26 (m, 1 H), 3.89 (q, 1 H), 1.65 (d, 3H);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 138.9, 135.0, 130.5, 128.4, 127.0, 125.0, 121.0, 30.9, 21 .3.

Example 18: Copper(ll) hydroxide/chiral diphosphine ligand catalysed asymmetric synthesis of optically active 2-(3-chlorophenyl)acrylonitrile II-CN via conjugate reduction in pure water

II-CN

la-CN

Catalyst Cu(OH) ₂ (0.05 mmol) and chiral ligand diphenylphosphino-phenyl-ferrocenyl- ethylbis[3,5-bis-trifluoromethyl)phenyl]phosphine (0.025 mmol; 5 mol%) were added to water (2.5 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N ₂ for 30 min at 27 °C. Afterwards, the reducing additive PMHS (0.05 mmol) followed by a first portion of reducing agent PhSiH ₃ (0.75 equiv. according to starting material) were added and the reaction system stirred for 30 min. The starting material la-CN (0.5 mmol) was then added followed by a second portion of PhSiH ₃ (0.75 equiv.) and the reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 20 h. The reaction system was diluted with water, extracted with two portions of EtOAc (80 mL), the organic phases were washed with NaHC0 ₃ and brine, dried under anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. Crude product was purified on flash chromatography (Si0 ₂ ; n- hexane : EtOAc = 5 : 1 ) to afford pure final product (65 mg; 78% isolated yield) which was characterized with chiral HPLC and NMR analysis. Example 19: Copper(ll) hydroxide/chiral phosphine ligand catalysed asymmetric synthesis of optically active 2-(3-chlorophenyl)acrylonitrile II-CN via conjugate reduction in pure water

II-CN

la-CN

Catalyst Cu(OH) ₂ (0.05 mmol) and chiral ligand 4-ie/f-butyl-2-[(S _p )-2- (diphenylphosphino)ferrocenyl]-2-oxazoline (0.025 mmol; 5 mol%) were added to water (2.5 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N ₂ for 30 min at 27 °C. Afterwards, the reducing additive PMHS (0.05 mmol) followed by a first portion of reducing agent PhSiH ₃ (0.75 equiv. according to starting material) were added and reaction system stirred for 30 min. The starting material la-CN (0.5 mmol) was then added followed by a second portion of PhSiH ₃ (0.75 equiv.). The reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 20 h. The reaction system was diluted with water, extracted with EtOAc, the organic phase were washed with NaHC0 ₃ and brine, dried over anhydrous Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. Crude product was purified on flash chromatography (Si0 ₂ ; n-hexane : EtOAc = 5 : 1 ) to afford pure final product (67 mg; 80% isolated yield) which was characterized with chiral HPLC and NMR analysis.

Example 20: Copper(l) chloride/chiral phosphine ligand catalysed asymmetric synthesis of optically active 2-(3-chlorophenyl)acrylonitrile II-CN via conjugate reduction in pure water

II-CN

la-CN

Catalyst CuCI (0.05 mmol) and chiral ligand 4-ie/f-butyl-2-[(S _p )-2- (diphenylphosphino)ferrocenyl]-2-oxazoline (0.05 mmol; 5 mol%) were added to water (2.5 mL) in a test tube equipped with a magnetic stir bar. Such reaction system was vigorously stirred under N ₂ for 30 min at 27 °C. Afterwards, the reducing additive PMHS (0.05 mmol) followed by a first portion of reducing agent PhSiH ₃ (0.75 equiv. according to starting material) were added and the reaction system stirred for 30 min to turn into black color. The starting material la-CN (0.5 mmol) was then added followed by a second portion of PhSiH ₃ (0.75 equiv.) and the reaction system was vigorously stirred under nitrogen atmosphere at 27 °C for 24 h. The reaction system was diluted with water, extracted with two portions of EtOAc (50 mL), the combined organic phases were washed with brine and the solvent was evaporated under reduced pressure. Crude oily product was purified on flash chromatography (Si0 ₂ ; n-hexane : EtOAc = 1 : 1 ) to afford pure final product (50 mg; 60% isolated yield) which was characterized with chiral HPLC and NMR analysis.

Example 21 : Synthesis of (R)-2-(3-chlorophenyl)propan-1 -amine from (R)-2-(3- chlorophenyl)propanenitrile

( ?)-ll-CN {R)-\\\

Optical active starting material (R)-2-(3-chlorophenyl)propanenitrile (R)-II-CN (1 .3 mmol; 0.22 g) was dissolved in toluene (5 mL) under nitrogen atmosphere and cooled down to 0 °C. BHs-THF (4.3 mmol; 4.3 mL; 1 M in THF) was slowly added to the solution and such reaction mixture was stirred under reflux for 4 hours. After cooling to room temperature, the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (10 mL). The organic phase was washed with brine (5 mL), dried over MgS0 ₄ , filtered and the solvent was removed under reduced pressure. Colorless oily product was obtained (0.18 g; 80 % yield; > 99 % ee) and characterized with ¹ H and ¹³ C NMR.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.22 (m, 3H), 7.08 (d, 1 H), 2.83 (m, 2H), 2.72 (m, 1 H), 1 .23 (d, 3H), 1 .08 (bs, NH);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 145.5, 133.3, 130.5, 127.3, 126.9, 126.2, 44.6, 37.3, 19.3. Example 22: Preparation of 2-(3-chlorophenyl)-/V-(2,2-dimethoxyethyl)propan-1 -amine from 2-(3-chlorophenyl)propan-1 -amine

III IV-Me

Potassium carbonate (29.4 mmol; 4.1 g) and 2-chloro-1 ,1 -dimethoxyethane (29.4 mmol; 3.3 mL) were added to the solution of 2-(3-chlorophenyl)propan-1 -amine III (19.6 mmol; 3.3 g) in DMF (50 mL) under nitrogen atmosphere. The reaction mixture was stirred overnight at 120 °C. After cooling it down to room temperature, water (30 mL) was added and the mixture was extracted with EtOAc (3 x 60 mL). The combined organic phases were washed with brine (60 mL), dried over MgS0 ₄ , filtered and evaporated under reduce pressure to remove the solvent. The residue was purified by flash chromatography (EtOAc : n-heptane; gradient elution 12 - 100 %). Colorless oily product (1 .5 g; 28 % yield) was obtained which was characterized with ¹ H and ¹³ C NMR.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.22 (m, 3H), 7.10 (d, 1 H), 4.41 (t, 1 H), 3.33 (s, 6H), 2.91 (m, 1 H), 2.74 (m, 4H), 1 .24 (d, 3H).

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 147.5, 134.3, 129.8, 127.3, 126.5, 125.5, 103.7, 56.9, 53.9, 51 .0, 39.9, 19.8.

The same experiment was done with (R)-2-(3-chlorophenyl)propan-1 -amine to give (R)-2-(3-chlorophenyl)-/V-(2,2-dimethoxyethyl)propan-1 -amine with a comparable yield.

Example 23: Preparation of 2-(3-chlorophenyl)-/V-(2,2-diethoxyethyl)propan-1 -amine

III IV-Et Potassium carbonate (643 mg, 2 equiv.) and bromoacetaldehyde diethyl acetal (0.4 mL, 1 .1 equiv.) were successively added into a solution of 2-(3-chlorophenyl)propan-1 - amine III (480 mg, 2.3 mmol) in DMF (10 mL). The reaction was heated to 80°C and was stirred overnight. The reaction was cooled down to room temperature and was diluted with water (40 mL) and MTBE (40 mL). The phases were separated and water phase was re-extracted with MTBE (40 mL). The combined organic phase was washed with water (20 mL), dried over sodium sulfate, filtered and concentrated. A pure sample was obtained by purification on reverse phase column purification (Systag 25-M, C18, 10 to 90% MeCN in water) to yield 2-(3-chlorophenyl)-/V-(2,2-diethoxyethyl)propan-1 - amine IV-Et (227 mg, 35%).

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.24-7.13 (m, 3H), 7.10 (d, J =7.4 Hz, 1 H), 4.54 (t, J = 5.6 Hz, 1 H), 3.63 (m, 2H), 3.47 (m, 2H), 2.90 (hex, J = 7.1 Hz, 1 H), 2.77 (d, J = 7.2 Hz, 2H), 2.72 (dd, J = 5.5 Hz, J = 12.1 Hz, 1 H), 2.66 (dd, J = 5.8 Hz, J = 12.1 Hz, 1 H), 1 .24 (d, J = 6.9 Hz, 3H), 1 .16 (t, J = 7.1 Hz, 3H), 1 .14 (t, J = 7.1 Hz, 3H).

1 ³ C NMR (125 MHz, CDCI ₃ ppm) δ 147.4, 134.3, 129.8, 127.3, 126.5, 125.5, 101 .9, 62.4, 56.8, 52.0, 39.9, 19.7, 16.3.

The same experiment was done with (R)-2-(3-chlorophenyl)propan-1 -amine to give (R)- 2-(3-chlorophenyl)-/V-(2,2-diethoxyethyl)propan-1 -amine with a comparable yield.

Example 24: Preparation of 2-(3-chlorophenyl)-/V-(2,2-dimethoxyethyl) propan-1 -amine hydrochloride

III IV-Me.HCI

2-(3-chlorophenyl)propan-1 -amine III (1 g, 4.8 mmol) in methanol (2 mL) was treated with dimethoxyacetaldehyde (60% in H ₂ 0, 1.46 mL, 2 equiv.) and the solution was stirred at room temperature for 48 hours. 10% Pd/C (100 mg, 10 wt%) was added and the reaction atmosphere was flushed several times with nitrogen and hydrogen alternatively. The hydrogen pressure was set at 1 atmospheres and the reaction was stirred for 4 hours. The reaction was filtrated on Celite® and concentrated. The residue was dissolved in CH ₂ CI ₂ (20 mL) and the solution was washed with 2:1 solution of brine and HCI 1 M (20 / 10 mL). The CH ₂ CI ₂ phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in toluene (40 mL) and the solution was extracted three times with water (3 * 30 mL). The combined water phase was saturated with NaCI and the solution was extracted twice with CH ₂ CI ₂ (2 ^χ 30 mL). The combined CH ₂ CI ₂ phases were dried over sodium sulfate, filtered and concentrated to give clean product IV-Me.HCI characterized by ¹ H NMR.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.33-7.22 (m, 3H), 7.18 (d, J =7.2 Hz, 1 H), 4.89 (t, J = 5.0 Hz, 1 H), 3.49 (m, 1 H), 3.44 (s, 3H), 3.42 (s, 3H), 3.31 (m, 1 H), 3.19 (m, 1 H), 3.08 (m, 1 H), 3.00 (m, 1 H), 1.44 (d, J = 6.9 Hz, 3H).

The same experiment was done with (R)-2-(3-chlorophenyl)propan-1 -amine to give (R)-2-(3-chlorophenyl)-/V-(2,2-dimethoxyethyl)propan-1 -amine hydrochloride.

Example 25: Preparation of 7-chloro-1 -ethoxy-5-methyl-2,3,4,5-tetrahydro-1 H- benzo[d]azepine

IV-Et Xlll-Et Xll-Et

Compound IV-Et (1 13 mg, 0.35 mmol) was dissolved in CH ₂ CI ₂ (3.5 mL) and the solution was treated with aluminum chloride (82 mg, 1 .75 equiv.). The solution was stirred overnight at room temperature. The solution was diluted with CH ₂ CI ₂ (20 mL) and brine (20 mL). The phases were separated and the water phase was re-extracted with CH ₂ CI ₂ (10 mL). The combined DCM was dried over sodium sulfate, filtered and concentrated. The obtained crude mixture was analyzed and the compound Xlll-Et was characterized / detected with GC-MS analysis (m/z : 240 (M + 1 ); CI) as a major product and 7-chloro-1 -hydroxy-5-methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine as a minor product. Example 26: Synthesis of (R)-8-chloro-1 -methyl-2,3-dihydro-1 H-benzo[d]azepine under solvent-free conditions

(R)-IV-Me.HCI (RJ-V

The starting material (R)-IV-Me.HCI (50 mg; 0.25 mmol) was mixed with anhydrous aluminum chloride (69 mg; 3 equiv.). The fine mixture was heated to 90 °C to obtain a molten phase and stirred overnight. The solution was diluted with CH ₂ CI ₂ (20 mL) and washed brine (20 mL). The phases were separated and the water phase was re- extracted with CH ₂ CI ₂ (10 mL). The combined CH ₂ CI ₂ was dried over sodium sulfate, filtered and concentrated. The obtained crude mixture was analyzed and the obtained final product was characterized / detected with GC-MS analysis (m/z : 193) 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).

Example 27: Synthesis of (R)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H- benzo[d]azepine from (R)-8-chloro-1 -methyl-2,3-dihydro-1 H-benzo[d]azepine

(R)-Vli (R)-A

To a solution of (R)-8-chloro-1 -methyl-2,3-dihydro-1 H-benzo[d]azepine (R)-V (0.13 mmol; 0.026 g) in THF (2 mL) was added Pt0 ₂ (5 mg) and several drops of H ₂ 0. The reaction mixture was stirred at 25 °C under 5 bar of hydrogen for 24 hours. After filtration through Celite® pad, the solvent was removed by evaporation under reduced pressure. The product was detected by GC-MS (m/z = 195) and R-enantiomer was confirmed by chiral HPLC and compared with known literature data. Example 28: Synthesis of N-(2-(3-chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)-4- methylbenzenesulfonamide from 2-(3-chlorophenyl)-N-(2,2-dimethoxyethyl)propan-1 - amine

IV-Me V-Me-Ts

A solution of 2-(3-chlorophenyl)propan-1 -amine IV-Me (2.95 mmol; 0.76 g) in CH ₂ CI ₂ /pyridine (8/1 , 4.2 mL) was cooled to 0 °C and afterwards a solution of TsCI (5.31 mmol; 1 .0 g) in CH ₂ CI ₂ (1 .8 mL) was added. The reaction mixture was allowed to warm at room temperature and stirred for 2.5 hours. The reaction mixture was washed with 2M HCI (2 x 4.3 mL) and saturated aqueous solution of NaHC0 ₃ (4.3 mL). The organic layer was dried over MgS0 ₄ , filtered and evaporated under reduced pressure to remove solvent. The residue was purified by flash chromatography (eluent: EtOAc/n- heptane, EtOAc gradient 7 - 60 %). Colorless oily product (0.85 g; 71 % yield) was obtained and characterized with ¹ H and ¹³ C NMR.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.64 (d, 2H), 7.28 (d, 2H), 7.19 (m, 2H), 7.08 (m, 2H), 4.43 (t, 1 H), 3.45 (m, 1 H), 3.36 (d, 6H), 3.13 (m, 4H), 2.42 (s, 3H), 1.25 (d, 3H); ¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 146.2, 143.4, 136.6, 134.2, 129.8, 129.7, 127.6, 127.2, 126.7, 125.5, 104.6, 56.5, 55.3, 55.1 , 50.8, 38.2, 21.5, 18.6.

The same experiment was done with (R)-2-(3-chlorophenyl)-N-(2,2- dimethoxyethyl)propan-1 -amine to give (R)-N-(2-(3-chlorophenyl)propyl)-N-(2,2- dimethoxyethyl)-4-methylbenzenesulfonamide with a comparable yield. Example 29: Synthesis of N-(2-(3-chlorophenyl)propyl)-N-(2,2- dimethoxyethyl)acetamide from 2-(3-chlorophenyl)-N-(2,2-dimethoxyethyl)propan-1 - amine

IV-Me V-Me-Ac

The starting material 2-(3-chlorophenyl)-N-(2,2-dimethoxyethyl)propan-1 -amine IV-Me (2.5 mmol; 0.65 g) was dissolved in CH ₂ CI ₂ (6 mL) under nitrogen atmosphere and cooled down to 0 °C. After addition of TEA (3.8 mmol; 0.5 mL) and AcCI (3.8 mmol; 0.27 mL), the reaction mixture was allowed to warm to room temperature and stirred overnight. After addition of water (6 mL), the phases were separated. The organic phase was dried over MgS0 ₄ , filtered and the solvent was removed by evaporation. The residue was purified by flash chromatography (eluent: EtOAc/n-heptane, EtOAc gradient 12 - 100 %). Colorless oily product (0.43 g; 57 % yield) was obtained and characterized with ¹ H and ¹³ C NMR.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.20 (m, 3H), 7.09 and 7.02 (each td, 1 H), 4.49 and 4.22 (each t, 1 H), 3.76-3.72 and 3.53-3.15 (m, 4H), 3.37 and 3.32 (d and s, 6H), 3.01 and 2.86 (sex and dd, 1 H), 2.08 and 1.87 (each s, 3H), 1.27 and 1.21 (each d, 3H); ¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 171 .4 and 171 .0, 146.6 and 145.5, 134.4 and

134.1 , 129.9 and 129.7, 127.4 and 126.6, 127.1 and 127.0, 125.6 and 125.5, 103.7 and

103.2, 57.2, 55.1 , 53.8, 51.7, 48.4, 38.7 and 37.6, 21.8 and 21 .3, 18.5 and 18.0.

Example 30: Synthesis of 8-chloro-1 -methyl-3-tosyl-2,3-dihydro-1 H-benzo[d]azepine from N-(2-(3-chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)-4-methyl benzene sulfonamide

V-Me-Ts Vl-Ts

A solution of N-(2-(3-chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)-4-methyl benzene sulfonamide V-Me-Ts (2.1 mmol; 0.85 g) in CH ₂ CI ₂ (10 mL) was added to a suspension of AICI ₃ (8.3 mmol; 1 .1 g) in CH ₂ CI ₂ (15 mL) under nitrogen atmosphere. The reaction mixture was stirred for 10 min at room temperature and then was cooled to 0 °C. After quenching with 1 M NaOH (1 1 mL) and H ₂ 0 (1 1 mL), the phases was separated. The aqueous phase was extracted with CH ₂ CI ₂ (3 x 15 mL). The combined organic phases were dried over MgS0 ₄ , filtered and solvent was removed by evaporation. Yellow solid product (0.6 g; 85 % yield) was obtained and characterized with ¹ H and ¹³ C NMR.

1H NMR (500 MHz, CDCI ₃ , ppm) δ 7.72 (d, 2H), 7.32 (d, 2H), 7.10 (m, 1 H), 7.05 (m, 2H), 6.89 (dd, 1 H), 5.55 (d, 1 H), 4.06 (m, 1 H), 3.14 (m, 2H), 2.42 (s, 3H), 1.17 (d, 3H); ¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 145.3, 144.2, 135.8, 132.2, 131.8, 131.5, 130.0, 129.4, 128.1 , 127.0, 126.6, 126.1 , 107.4, 50.3, 40.1 , 21.6, 18.0.

The same experiment was done with (R)-N-(2-(3-chlorophenyl)propyl)-N-(2,2- dimethoxyethyl)-4-methylbenzene sulfonamide to give (R)-8-chloro-1 -methyl-3-tosyl- 2,3-dihydro-1 H-benzo[d]azepine with a comparable yield. Example 31 : Synthesis of 1 -(8-chloro-1 -methyl-1 H-benzo[d]azepin-3(2H)-yl)ethanone from N-(2-(3-chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)acetamide

V-Me-Ac Vl-Ac

A solution of N-(2-(3-chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)acetamide V-Me-Ac (1 .44 mmol; 0.43 g) in CH ₂ CI ₂ (5 mL) was added to a suspension of AICI ₃ (5.8 mmol; 0.77 g) in CH ₂ CI ₂ (10 mL) under nitrogen atmosphere. The reaction mixture was stirred for 10 min at room temperature and then was cooled to 0 °C. After quenching with 1 M NaOH (7 mL) and H ₂ 0 (7 mL), the phases was separated. The aqueous phase was extracted with CH ₂ CI ₂ (3 x 10 mL). The combined organic phases were dried over MgS0 ₄ , filtered and the solvent was removed by evaporation. The residue was purified by flash chromatography (eluent: EtOAc/n-heptane, EtOAc gradient 7 - 60 %). Colorless oily product (0.07 g; 20 % yield) was obtained and characterized with ¹ H and ¹³ C NMR.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.37 and 6.69 (each dd, 1 H), 7.13 (m, 3H), 5.72 and 5.61 (each d, 1 H), 4.99 (m, 1 H), 3.43 and 2.98 (each d, 1 H), 3.32 (m, 1 H), 2.35 and 2.32 (each s, 3H), 1 .12 and 1.07 (each d, 3H);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 169.3, 146.2, 132.7, 132.0, 131.9, 131.6, 128.4, 128.3, 127.2, 126.7, 126.4, 125.8, 109.7, 60.4, 50.2, 44.9, 40.3, 22.1 , 16.8.

The same experiment was done with (R)-N-(2-(3-chlorophenyl)propyl)-N-(2,2- dimethoxyethyl)acetamide to give (R)-1 -(8-chloro-1 -methyl-1 H-benzo[d]azepin-3(2H)- yl)ethanone with a comparable yield. Example 32: Synthesis of 8-chloro-1 -methyl-3-tosyl-2,3,4,5-tetrahydro-1 H- benzo[d]azepine from 8-chloro-1 -methyl-3-tosyl-2,3-dihydro-1 H-benzo[d]azepine

Vl-Ts Vll-Ts

To a solution of 8-chloro-1 -methyl-3-tosyl-2,3-dihydro-1 H-benzo[d]azepine Vl-Ts (0.54 mmol; 0.19 g) in methanol (3 mL) was added Pt0 ₂ (20 mg) and several drops of HCI. The reaction mixture was stirred at 25 °C under 5 bar of hydrogen for 48 hours. After filtration through Celite® pad, the solvent was removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (6 mL), washed with water (6 mL), dried over MgS0 ₄ , filtered and evaporated to the dryness. After purification by flash chromatography (eluent: n-heptane/EtOAc, EtOAc gradient 7 - 60 %), the product was characterized with ¹ H and ¹³ C NMR.

¹ H NMR (500 MHz, CDCI ₃ , ppm) δ 7.62 (d, 2H), 7.27 (d, 2H), 7.07 (m, 2H), 7.05 (m, 2H), 6.97 (d, 1 H), 3.28-2.92 (m, 6H), 2.40 (s, 3H), 1.40 (d, 3H);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 146.0, 143.3, 137.8, 135.2, 132.4, 131.3, 129.7, 127.5, 127.1 , 126.3, 53.5, 48.1 , 40.0, 35.9, 21 .5, 17.5.

Example 33: Synthesis of 1 -(8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[d]azepin- 3(2H)ethanone from 1 -(8-chloro-1 -methyl-1 H-benzo[d]azepin-3(2H)-yl)ethanone

Vl-Ac Vll-Ac

To a solution of 1 -(8-chloro-1 -methyl-1 H-benzo[d]azepin-3(2H)-yl)ethanone Vl-Ac (0.21 mmol; 0.05 g) in THF (2 mL) was added Pt0 ₂ (10 mg) and several drops of H ₂ 0. The reaction mixture was stirred at 25 °C under 5 bar of hydrogen for 48 hours. After filtration through Celite® pad, the solvent was removed by evaporation under reduced pressure. The product was detected by GC-MS (m/z = 237). Example 34: Synthesis of 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine from 8-chloro-1 -methyl-3-tosyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine

Vll-Ts

A reaction mixture of 8-chloro-1 -methyl-3-tosyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine Vll-Ts (0.17 mmol, 59 mg), phenol (0.55 mmol, 53 mg), 48% HBr (0.45 mL) and propionic acid (0.09 mL) was stirred under reflux for 6 hours. After cooling to room temperature, the reaction mixture was quenched with water (2 mL) followed by extraction with Et ₂ 0 (2x5 mL). The aqueous phase was basified with 8M NaOH (pH≥ 9) and product was extracted with CH ₂ CI ₂ (3x5 mL). The combined organic phases were dried over MgS0 ₄ , filtered and evaporated to the dryness. Obtained product was detected by GC-MS (m/z = 195).

Example 35: Synthesis of 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine from 1 -(8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[d]azepin-3(2H)ethanone

Vll-Ac A-HCI

1 -(8-Chloro-1 -methyl-4,5-dihydro-1 H-benzo[d]azepin-3(2H)ethanone Vll-Ac (0.19 mmol, 0.044 g) was treated with 12M HCI (3 mL) for 24 hours under reflux. After evaporation under reduced pressure, the product was detected by GC-MS (m/z = 195).