Friedel-Crafts alkylation of olefin

The present invention relates to the field of organic synthesis, in particular to the synthesis of benzo[d]azepines with stimulating activity on serotonin receptors, especially lorcaserin.

Background of 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. Benzo[d]azepines were identified as most promising selective 5-HT2C receptor agonists. (R)-8-chloro-l- methyl-2,3,4,5-tetrahydro-lH-benzo[d]azepine hydrochloride (Formula 1) with the INN name lorcaserin hydrochloride was registered as the first representative of this pharmacological group.

8-Chloro-l-methyl-2,3,4,5-tetrahydro-lH-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 . Additionally, the document describes three improved synthetic pathways using an Friedel- Crafts cyclisation approach (Scheme 2).

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 l-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 08/070111 (Scheme 3), the synthesis starts with a coupling reaction between 2-(4-chlorophenyl)acetic acid (formula 13) and l-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 09/111004 describes a further improvement of the process of Scheme 2 using a new bromination methodology including H Br gas instead of expensive PBr ₃ (Scheme 4) . The publication also discloses a problem dialkylation of l-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 H Br gas and expensive PBr ₃ . A reaction of compound 17 with l-amino-2-propanol is also described (Scheme 5) .

17 12

Scheme 5. Improvement of synthetic process via chloro intermediates

The known routes shown in the above Schemes 2 to 5 require the preparation of various halo intermediates, which leads to a considerable amount of synthesis steps. Despite various improvements as described above, they still need corrosive reagents, such as phosphorous tribromide, gaseous hydrogen bromide or thionyl chloride. The halo intermediates are genotoxic compounds and release corrosive hydrogen halides during Friedel-Crafts cyclisation .

There is an intense interest to develop novel, simple and industrial acceptable processes for the preparation of lorcaserin or related compounds. Special focus is also oriented in final synthetic steps where efficient methodologies for the closing of final intermediates to give lorcaserin, or related compound, represent big obstacle and challenge.

Summary of the Invention

The object of the present invention is to provide a short, facile, effective and industrially applicable process for obtaining 8-chloro- l-methyl-2, 3,4,5- tetrahydro- l H-benzo[d]azepine (formula 9), or its salt, preferably lorcaserin hydrochloride (formula 1) . It is a further object of the present invention to provide a simple and effective ring closing methodology for obtaining 8-chloro- l-methyl-2,3,4,5-tetrahydro- l H-benzo[d]azepine (formula 9), or its salt, preferably lorcaserin hydrochloride (formula 1) . The present invention has the further object to provide a novel intermediate suitably used in the process for producing 8-chloro-l-methyl-2,3,4,5-tetrahydro- l H- benzo[d]azepine (formula 9), or its salt, preferably lorcaserin hydrochloride (formula 1) and a process for producing the novel intermediate. The following items summarize the aspects and preferred features or embodiments which contribute to solve the objects of the present invention alone or in combination.

1. Method for preparing 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[c/] azepine according to the formula 9 :

or a salt thereof, wherein * in the formulae denotesean asymmetric C atom, in the form of a racemate, essentially enantiopure or enantiopure, by:

(A) reacting the compound according to the form

or salt thereof, under neat conditions (without the presence of solvents) the presence of a Friedel Crafts reagent.

2. The method according to item 1, wherein the compound according to formula 4 is in the form of a solid salt, preferably selected from the hydrobromide or the hydrochloride salt, wherein the compound is most preferably the hydrochloride salt according to the formula 5 :

3. The method according to item 1 or 2, wherein the Friedel Crafts reagent is a Lewis acid, preferably selected from transition metal and aluminium compounds, more preferably selected from zinc or aluminium salts, preferably chloride salts, wherein the most preferred Lewis acid is aluminium chloride, and wherein the Friedel Crafts reagent, which is preferably said Lewis acid, is preferably used in excess molar amounts, preferably from 1.1- to 10-fold molar excess, more preferably from 1.25- to 2-fold molar excess.

4. The method according to any one of items 1 to 3, wherein the reaction step (A) is carried out at a temperature at which the mixture is liquid, preferably at the temperature higher than 60 °C, more preferably higher than 90 °C, most preferably at the temperature of 110 - 130 °C.

5. The method according to any of items 1 to 4, wherein the reaction step (A) is carried out until no further consumption of the compound according to the formula 4, or the salt thereof, can be detected, preferably for at least 2 hours, preferably from 2 to 24 hours, more preferably from 4 to 10 hours, most preferably for 6 hours.

6. The method according to any of items 1 to 5, wherein the method comprises the work-up steps of:

(b) quenching the reaction mixture, which is obtained by reacting the compound according to the formula 4, or a salt thereof, under neat conditions (without the presence of solvents) in the presence of a Friedel Crafts reagent, by adding the hot molten phase to water or an aqueous solution of a salt or mixture of salts; and/or

(c) extracting the product from the aqueous phase to a water

immiscible solvent; and/or

(d) isolating the compound according to the formula 9, or a salt thereof; and wherein the method preferably comprises any of steps (b) to (d).

7. The method according to item 6, wherein the reaction mixture is cooled down in step (b) to a temperature at which it is still liquid, preferably it is cooled down to 80-100 °C, more preferably to 85-95 °C, most preferably to 90 °C, and quenched with an aqueous medium, wherein the quenching mixture is preferably an aqueous solution of inorganic salts, preferably an aqueous solution of sodium chloride in a concentration of at least 5 % (w/w), preferably from 10 % (w/w) to saturation (brine).

8. The method according to item 6 or 7, wherein the product is extracted with a water immiscible solvent according to step (c) after the quenched reaction mixture is neutralised .

9. The method according to items 6 or 7, wherein in step (b) brine is used for quenching the reaction mixture and wherein in step (c) the quenched reaction mixture is not neutralised, but the product is extracted by a water immiscible solvent, preferably dichloromethane, in the form of the hydrochloride salt according to the formula 6:

and wherein the hydrochloride salt is isolated in step (d) by evaporating the water immiscible solvent, and wherein the residue is optionally re- suspended or recrystallized from a solvent to obtain a crystalline and purified product.

10. The method according to any of items 6 to 9, wherein the water immiscible solvent is selected from ethers, esters, haloalkanes, aromatic or aliphatic hydrocarbons or a mixture, preferably selected from haloalkanes and esters, and if brine is used also from a solvent which is miscible with pure water, but immiscible with brine, such as C ₄ -C ₅ -alcohols,

tetrahydrofuran and acetonitrile, and wherein dichloromethane as the water immiscible solvent is specifically preferred . 11. The method according to any of items 6 to 8 and 10, wherein the compound according to the formula 9 is isolated in step (d) as a base (free amine) by evaporation the water immiscible solvent.

12. The method according to any of items 6 to 8, 10, and 11, wherein the compound according to the formula 9 is transformed to the hydrochloride salt according to the formula 6 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.

13. The method according to any of items 1 to 12, wherein the method yields a racemic mixture of the compound according to the formula 9, or a salt thereof, which is preferably the compound according to the formula 6.

14. The method according to any of items 1 to 13, wherein the method further comprises the step of:

(e) transforming the compound according to the formula 6 or 9 to essentially enantiopure or enantiopure lorcaserin hydrochloride according to the formula 1:

by performing a chiral resolution via selective crystallization of diastereoisomeric salt with a resolving agent, preferably tartaric acid, followed by anion exchange.

15. The method according to any of items 1 to 14, the method further comprising the step of:

(Α') reacting the compounds A and B:

B to obtain in a nucleophilic substitution reaction or in a reductive amination reaction the compound according to the formula 4, or a salt thereof;

wherein if -X is -NH ₂ , then -Y is a leaving group, which is preferably selected from a halogen or -OS0 ₂ R, or if -X is a carbonyl (=0; i.e. A = (4- chlorophenyl)acetaldehyde) or a leaving group, which is preferably selected from a halogen or -OS0 ₂ R, then -Y is -NH ₂ ;

wherein the halogen is selected from chloro, bromo or iodo and R is selected from unsubstituted or fluorinated Cl-C4-alkyl or unsubstituted or substituted phenyl; and

wherein for the nucleophilic substitution reaction the amine compound is preferably in a molar excess relative to the compound with the leaving group, wherein the molar excess of the amine compound is more preferably from 1.1- to 10-fold, and the reaction is optionally performed in the presence of a solvent, which is preferably selected from dimethyl sulfoxide, amides, nitriles, cyclic ethers, haloalkanes, aromatic hydrocarbons and esters, more preferably from tetrahydrofuran, and a base, which is preferably selected from alkali metal hydroxides, carbonates, and C1-C5- alkoxides, more preferably from carbonates, such as potassium carbonate; and

wherein for the reductive amination reaction a suitable reductive agent is used, preferably selected from H^Pd/C, sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.

16. The method according to item 15, wherein the method comprises the work-up steps of:

(b') optionally washing the reaction mixture, which is obtained after reacting the compounds A and B, with an alkaline aqueous phase, if the compound which has been derived from the leaving group is extractable by an organic phase, wherein the alkaline aqueous phase is preferably selected from an aqueous solution of alkali hydrogen carbonates, carbonates, phosphates or hydroxides, preferably from sodium or potassium carbonate; and/or

(c') removing the volatile compounds by evaporation; and/or (d') adding to the residue an aqueous solution of inorganic salt(s), preferably a sodium chloride solution, more preferably from 10 % (w/w) to the saturated concentration (brine), and preferably hydrochloric acid in order to obtain the compound according to the formula 5, which is preferably used as 0.5 to 10 molar aqueous solution; and/or

(e') extracting the product with a water immiscible solvent, which is preferably selected from haloalkanes and esters, or brine immiscible solvents, such as C4-C5-alcohols, tetrahydrofuran, acetonitrile, ethyl methyl ketone or methyl acetate, wherein dichloromethane is the most preferable extracting solvent; and/or

(f) removing the solvent; and/or

(g') suspending the residue, preferably in acetone or isopropyl acetate; and/or

(h') isolating the solid product, wherein the isolation of a product is performed by any solid-liquid separation technics, preferably selected from filtration or centrifugation.

17. The method according to item 16, comprising any of steps (c') to (h') and optionally (b')-

18. The method according to any of items 15 to 17, wherein the leaving group is bromo.

19. The method according to any of items 15 to 17, wherein the leaving group is -OS0 ₂ R, which may optionally be prepared by reacting the corresponding alcohol with sulfonyl chloride RS0 ₂ CI or anhydride (RS0 ₂ ) ₂ 0, wherein R is the same as defined above, in the presence of a base, and wherein it is preferred that the resultant 4-chlorophenethyl sulfonate (formula A') or the resultant allyl sulfonate (formula B') are not isolated but used in the step of preparing the compound according to the formula 4, or a salt thereof, preferably the compound according to the formula 5, in an one pot procedure or in situ.

20. The method according to item 19, wherein a 4-chlorophenethyl sulfonate according to the formula A', with R preferably being methyl or 4-methylphenyl, is produced from reacting phenethyl alcohol according to the formula 7 with the corresponding sulfonyl chloride: in the presence of an inorganic or organic base, which is preferably selected from tertiary amines, such as triethylamine, diisopropylethylamine and/or 4-dimethylaminopyridine, in a solvent, which is preferably selected from chlorinated hydrocarbons, aromatic hydrocarbons or pyridine, wherein no further organic base is required if the solvent is pyridine.

21. The method according to item 19, wherein an allyl sulfonate according to the formula B', with R preferably being methyl or 4-methylphenyl, is produced from reacting allyl alcohol with the corresponding sulfonyl chloride:

B' in the presence of an inorganic or organic base, which is preferably selected from tertiary amines, such as triethylamine, diisopropylethylamine and/or 4-dimethylaminopyridine, in a solvent, which is preferably selected from chlorinated hydrocarbons, aromatic hydrocarbons or pyridine, wherein no further organic base is required if the solvent is pyridine.

22. The method according to any of items 15 to 18, wherein

4-chlorophenethyl bromide is reacted with an at least 5-fold molar excess of allylamine without the presence of a solvent and of an additional base, to give, preferably following the treatment of at least steps (c') to (h') and using HCI in step (d'), the compound according to the formula 5.

23. The method according to any of items 15 to 18, wherein a slight excess of 4-chlorophenethyl amine is reacted with allyl bromide in tetrahydrofuran as a solvent and potassium carbonate as a base, to give, preferably following the treatment of at least steps (d') to (h') and using HCI in step (d'), the compound according to the formula 5.

24. The method according to any of items 15 to 17, wherein allyl amine is reacted with (4-chlorophenyl)acetaldehyde in a reductive amination reaction upon reduction, preferably by means of h Pd/C.

25. The method according to any of items 15 to 21 and 24, wherein the compound according to the formula 4 is prepared following the procedure of step (Α') including at least steps (b') to (f) not using HCI in step (d')-

26. Method for preparing essentially enantiopure or enantiopure lorcaserin hydrochloride according to the formula 1 :

following the steps of:

(Α') reacting compounds A and B

B to obtain in a nucleophilic substitution reaction or in a reductive amination reaction the compound according to the formula 4, or a salt thereof; wherein if -X is -NH ₂ , then -Y is a leaving group, which is preferably selected from a halogen or -OS0 ₂ R, or if -X is a carbonyl (=0; i.e. A = (4- chlorophenyl)acetaldehyde) or a leaving group, which is preferably selected from a halogen or -OS0 ₂ R, then -Y is -NH ₂ ;

wherein the halogen is selected from chloro, bromo or iodo and R is selected from unsubstituted or fluorinated Cl-C4-alkyl or unsubstituted or substituted phenyl; and

wherein for the nucleophilic substitution reaction the amine compound is preferably in a molar excess relative to the compound with the leaving group, wherein the molar excess of the amine compound is more preferably from 1.1- to 10-fold, and the reaction is optionally performed in the presence of a solvent, which is preferably selected from dimethyl sulfoxide, amides, nitriles, cyclic ethers, haloalkanes, aromatic hydrocarbons and esters, more preferably from tetrahydrofuran, and a base, which is preferably selected from alkali metal hydroxides, carbonates, and C1-C5- alkoxides, more preferably from carbonates, such as potassium carbonate; and

wherein for the reductive amination reaction a suitable reductive agent is used, preferably selected from H^Pd/C, sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride;

(b') optionally washing the reaction mixture with an alkaline

aqueous phase;

(c') removing the volatile compounds by evaporation;

(d') adding to the residue an aqueous solution inorganic salt(s), preferably a sodium chloride solution, more preferably from 10 % (w/w) to the saturated concentration (brine), and hydrochloric acid, which is preferably used as 0.5 to 10 molar aqueous solution;

(e') extracting the product with an water immiscible solvent,

preferably with dichloromethane;

(f) removing the solvent;

(g') suspending the residue preferably in acetone or isopropyl acetate; (η') isolating the solid compound according to the formula 5;

(A) reacting the compound according to the formula 5 under neat conditions (without the presence of solvents) in the presence of a Friedel Crafts Lewis acid reagent, which is preferably an aluminium or zinc salt, most preferably aluminium chloride;

(b) quenching the reaction mixture by adding the reaction mixture to an aqueous sodium chloride solution with a concentration from 10 % (w/w) to the saturated concentration (brine);

(c) extracting the product from the aqueous phase preferably to dichloromethane;

(d) isolating the compound according to the formula 6;

(e) transforming the compound according to the formula 6 to essentially enantiopure or enantiopure lorcaserin hydrochloride according to the formula 1 by chiral resolution via selective crystallization of diastereoisomeric salt with a resolving agent, preferably tartaric acid, followed by anion exchange.

27. Method for preparing essentially enantiopure or enantiopure lorcaserin hydrochloride according to the formula 1 :

following the steps of:

(Α') reacting compounds A and B

B to obtain in a nucleophilic substitution reaction or in a reductive amination reaction the compound according to the formula 4, or a salt thereof; wherein if -X is -NH ₂ , then -Y is a leaving group, which is preferably selected from a halogen or -OS0 ₂ R, or if -X is a carbonyl (=0; i.e. A = (4- chlorophenyl)acetaldehyde) or a leaving group, which is preferably selected from a halogen or -OS0 ₂ R, then -Y is -NH ₂ ;

wherein the halogen is selected from chloro, bromo or iodo and R is selected from unsubstituted or fluorinated Cl-C4-alkyl or unsubstituted or substituted phenyl; and

wherein for the nucleophilic substitution reaction the amine compound is preferably in a molar excess relative to the compound with the leaving group, wherein the molar excess of the amine compound is more preferably from 1.1- to 10-fold, and the reaction is optionally performed in the presence of a solvent, which is preferably selected from dimethyl sulfoxide, amides, nitriles, cyclic ethers, haloalkanes, aromatic hydrocarbons and esters, more preferably from tetrahydrofuran, and a base, which is preferably selected from alkali metal hydroxides, carbonates, and C1-C5- alkoxides, more preferably from carbonates, such as potassium carbonate; and

wherein for the reductive amination reaction a suitable reductive agent is used, preferably selected from H^Pd/C, sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride;

(b') optionally washing the reaction mixture with an alkaline aqueous phase;

(c') removing the volatile compounds by evaporation;

(d') adding to the residue an aqueous solution of inorganic salt(s), preferably a sodium chloride solution, more preferably from 10 % (w/w) to the saturated concentration (brine), and hydrochloric acid, which is preferably used as 0.5 to 10 molar aqueous solution;

(e') extracting the product with a water immiscible solvent, preferably with dichloromethane;

(f) removing the solvent to isolate the crude compound according to the formula 5; (A) reacting the crude compound according to the formula 5 under neat conditions (without the presence of solvents) in the presence of a Friedel Crafts Lewis acid reagent, which is preferably an aluminium or zinc salt, most preferably aluminium chloride;

(b) quenching the reaction mixture by adding the reaction mixture to an aqueous sodium chloride solution with a concentration from 10 % (w/w) to the saturated concentration (brine);

(c) extracting the product from the aqueous phase to preferably dichloromethane;

(d) isolating the compound according to the formula 6;

(e) transforming the compound according to the formula 6 to essentially enantiopure or enantiopure lorcaserin hydrochloride according to the formula 1 by chiral resolution via selective crystallization of diastereoisomeric salt with tartaric acid, followed by anion exchange.

28. Method for preparing essentially enantiopure or enantiopure lorcaserin hydrochloride according to the formula 1 :

in a one pot synthesis following the steps of: (Α') reacting compounds A and B

B to obtain in a nucleophilic substitution reaction or in a reductive amination reaction the compound according to the formula 4, or a salt thereof;

wherein if -X is -NH ₂ , then -Y is a leaving group, which is preferably selected from a halogen or -OS0 ₂ R, or if -X is a carbonyl (=0; i.e. A = (4- chlorophenyl)acetaldehyde) or a leaving group, which is preferably selected from a halogen or -OS0 ₂ R, then -Y is -NH ₂ ;

wherein the halogen is selected from chloro, bromo or iodo and R is selected from unsubstituted or fluorinated Cl-C4-alkyl or unsubstituted or substituted phenyl; and

wherein for the nucleophilic substitution reaction the amine compound is preferably in a molar excess relative to the compound with the leaving group, wherein the molar excess of the amine compound is more preferably from 1.1- to 10-fold, and the reaction is optionally performed in the presence of a solvent, which is preferably selected from dimethyl sulfoxide, amides, nitriles, cyclic ethers, haloalkanes, aromatic hydrocarbons and esters, more preferably from tetrahydrofuran, and a base, which is preferably selected from alkali metal hydroxides, carbonates, and C1-C5- alkoxides, more preferably from carbonates, such as potassium carbonate; and

wherein for the reductive amination reaction a suitable reductive agent is used, preferably selected from H^Pd/C, sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride;

(c') removing the volatile compounds by evaporation to obtain a residue including the crude compound according to the formula 4, or a salt thereof;

(A) reacting the residue under neat conditions (without the presence of solvents) in the presence of a Friedel Crafts Lewis acid reagent, which is preferably an aluminium or zinc salt, most preferably aluminium chloride;

(b) quenching the reaction mixture by adding the reaction mixture to an aqueous sodium chloride solution with a concentration from 10 % (w/w) to the saturated concentration (brine);

(c) extracting the product from the aqueous phase to preferably dichloromethane;

(d) isolating the compound according to the formula 6;

(e) transforming the compound according to the formula 6 to essentially enantiopure or enantiopure lorcaserin hydrochloride according to the formula 1 by chiral resolution via selective crystallization of diastereoisomeric salt with a resolving agent, preferably tartaric acid, followed by anion exchange.

29. The method according to any of items 26 to 28, wherein the compound B is represented by allyl amine and wherein the compound A is represented by 4-chlorophenethyl bromide.

30. The method according to any of items 26 to 28, wherein the compound B is represented by allyl bromide and wherein the compound A is represented by 4-chlorophenethyl amine.

31. The hydrochloride salt of N-allyl-N-(4-chlorophenethyl)amine according to the formula 5 :

32. Use of N-allyl-N-(4-chlorophenethyl)amine according to the formula 4 or a salt thereof, preferably the hydrochloride salt of N-allyl-N-(4- chlorophenethyl)amine according to the formula 5, for the preparation of racemic 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[c/] azepine according to the formula 9, or a salt thereof, more preferably for the preparation of essentially enantiopure or enantiopure lorcaserin, or its salt, most preferably for the preparation of the essentially enantiopure or enantiopure hydrochloride salt of lorcaserin according to the formula 1.

33. Method for preparing the hydrochloride salt of N-allyl-N-(4- chlorophenethyl)amine according to the formula 5 :

the method comprising the step of: (Α') reacting the compounds A and B:

B to obtain in a nucleophilic substitution reaction or in a reductive amination reaction the compound according to the formula 5;

wherein if -X is -NH ₂ , then -Y is a leaving group, which is preferably selected from a halogen or -OS0 ₂ R, or if -X is a carbonyl (=0; i.e. A = (4- chlorophenyl)acetaldehyde) or a leaving group, which is preferably selected from a halogen or -OS0 ₂ R, then -Y is -NH ₂ ;

wherein the halogen is selected from chloro, bromo or iodo and R is selected from unsubstituted or fluorinated Cl-C4-alkyl or unsubstituted or substituted phenyl; and

wherein for the nucleophilic substitution reaction the amine compound is preferably in a molar excess relative to the compound with the leaving group, wherein the molar excess of the amine compound is more preferably from 1.1- to 10-fold, and the reaction is optionally performed in the presence of a solvent, which is preferably selected from dimethyl sulfoxide, amides, nitriles, cyclic ethers, haloalkanes, aromatic hydrocarbons and esters, more preferably from tetrahydrofuran, and a base, which is preferably selected from alkali metal hydroxides, carbonates, and C1-C5- alkoxides, more preferably from carbonates, such as potassium carbonate; and

wherein for the reductive amination reaction a suitable reductive agent is used, preferably selected from H^Pd/C, sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.

34. The method according to item 33, wherein the method comprises the work-up steps of: (b') optionally washing the reaction mixture, which is obtained after reacting the compounds A and B, with an alkaline aqueous phase, if the compound which has been derived from the leaving group is extractable by an organic phase, wherein the alkaline aqueous phase is preferably selected from an aqueous solution of alkali hydrogen carbonates, carbonates, phosphates or hydroxides, preferably from sodium or potassium carbonate; and/or

(c') removing the volatile compounds by evaporation; and/or (d') adding to the residue an aqueous solution of inorganic salt(s), preferably a sodium chloride solution, more preferably from 10 % (w/w) to the saturated concentration (brine), and hydrochloric acid, which is preferably used as 0.5 to 10 molar aqueous solution; and/or

(e') extracting the product with a water immiscible solvent, which is preferably selected from haloalkanes and esters, or brine immiscible solvents, such as C4-C5-alcohols, tetrahydrofuran, acetonitrile, ethyl methyl ketone or methyl acetate, wherein dichloromethane is the most preferable extracting solvent; and/or

(f) removing the solvent; and/or

(g') suspending the residue, preferably in acetone or isopropyl

acetate; and/or

(h') isolating the solid product, wherein the isolation of a product is performed by any solid-liquid separation technics, preferably selected from filtration or centrifugation.

35. The method according to item 34, comprising any of steps (c') to (h') and optionally (b')-

36. The method according to any of items 33 to 35, wherein the leaving group is bromo. 37. The method according to any of items 33 to 35, wherein the leaving group is -OS0 ₂ R, which may optionally be prepared by reacting the corresponding alcohol with sulfonyl chloride RS0 ₂ CI or anhydride (RS0 ₂ ) ₂ 0, wherein R is the same as defined above, in the presence of a base, and wherein it is preferred that the resultant 4-chlorophenethyl sulfonate

(formula A') or the resultant allyl sulfonate (formula B') are not isolated but used in the step of preparing the compound according to the formula 5 in an one pot procedure or in situ.

38. The method according to item 37, wherein a 4-chlorophenethyl sulfonate according to the formula A', with R preferably being methyl or 4-methylphenyl, is produced from reacting phenethyl alcohol according to the formula 7 with the corresponding sulfonyl chloride:

in the presence of an inorganic or organic base, which is preferably selected from tertiary amines, such as triethylamine, diisopropylethylamine and/or 4-dimethylaminopyridine, in a solvent, which is preferably selected from chlorinated hydrocarbons, aromatic hydrocarbons or pyridine, wherein no further organic base is required if the solvent is pyridine.

39. The method according to item 37, wherein an allyl sulfonate according to the formula B', with R preferably being methyl or 4-methylphenyl, is produced from reacting allyl alcohol with the corresponding sulfonyl chloride:

B' in the presence of an inorganic or organic base, which is preferably selected from tertiary amines, such as triethylamine, diisopropylethylamine and/or 4-dimethylaminopyridine, in a solvent, which is preferably selected from chlorinated hydrocarbons, aromatic hydrocarbons or pyridine, wherein no further organic base is required if the solvent is pyridine.

40. The method according to any of items 33 to 36, wherein

4-chlorophenethyl bromide is reacted with an at least 5-fold molar excess of allylamine without the presence of a solvent and of an additional base, to give, preferably following the treatment of at least steps (c') to (h') and using HCI in step (d'), the compound according to the formula 5.

41. The method according to any of items 33 to 36, wherein a slight excess of 4-chlorophenethyl amine is reacted with allyl bromide in tetrahydrofuran as a solvent and potassium carbonate as a base, to give, preferably following the treatment of at least steps (d') to (h') and using HCI in step (d'), the compound according to the formula 5.

42. The method according to any of items 33 to 35, wherein allyl amine is reacted with (4-chlorophenyl)acetaldehyde in a reductive amination reaction upon reduction preferably by means of H2/Pd/C.

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 shall not be understood as being limiting .

The present invention provides an industrially applicable, economical and simple process for the preparation of the serotonin antagonizing 8-chloro-l- methyl-benzo[c/]azepine, or its salts, particularly lorcaserin, as well as a novel key intermediate for the synthesis thereof. Lorcaserin is a selective 5- HT _2C receptor agonist, and in vitro testing of the drug showed reasonable selectivity for 5-HT _2c over other related targets. The activation of 5-HT _2c receptors in the hypothalamus is supposed to activate proopiomelanocortin (POMC) production and consequently promote weight loss through satiety. For 8-chloro-l-methyl-benzo[c/]azepine, or its salts, particularly lorcaserin, the synthetic route described herein benefits from simple reactions, a reduced amount of sequence steps, rather mild reaction conditions and readily available chemicals.

For the purposes of interpreting the terms used in the description of the invention, the following definitions apply. All other terms as used herein are to be interpreted in accordance with their everyday meaning to the person of ordinary skill in the art.

As used herein, the term "immiscible solvent" represents a solvent which forms with another liquid phase two separated phases with a clearly identifiable intermediate border.

As used herein, the term "one pot" synthesis or process represents two or more reactions, wherein the product(s) of the previous reaction(s) is/are not transferred to the second technical equipment in order to start the next chemical reaction, but some technical manipulations can be carried out in the mother vessel in order to remove impurities, solvents or to concentrate the mixture.

As used herein, the term "in situ" process represents two or more reactions, wherein the product(s) of the previous reaction(s) is/are hold in the previous reaction mixture and the procedure continues further with adding new reagents, solvents and/or additives.

As used herein, the term "essentially enantiopure" means an enantiomeric excess of 70 %ee or more, preferably 80 %ee or more, more preferably 90 %ee or more, most preferably 97 %ee or more.

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

According to a first aspect, the present invention provides a method for preparing 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[c/] azepine according to the formula 9 :

or a salt thereof, wherein * in the formulae denotes an asymmetric C atom, in the form of a racemate, essentially enantiopure or enantiopure, by:

(A) reacting the compound according to the formula 4:

or salt thereof, under neat conditions (without the presence of solvents) in the presence of a Friedel Crafts reagent.

By means of employing this reaction step (A), it is possible to reduce the overall synthesis steps for preparing the compound according to the formula 6, or its salt, preferably lorcaserin, compared with the prior art. The synthesis avoids unfavourable reagents such as trifluoroacetic acid, iodine and palladium catalysts as applied by the intramolecular Heck cyclization as shown in Scheme 1. The present invention takes advantage of easy accessible starting material 4 or 5, which can be converted to the desired product in a straight and facile manner, thereby overcoming the obstacle of the final ring closing procedure.

So far, there is only little description about electrophylic substitution of olefins in Friedel-Crafts conditions. For instance, Wang J. et al. (Eur. J. Org. Chem. 2011, 264-270) reported the cyclization of l-methoxy-2-(3-methyl- 2-butenyl)benzene in biphasic conditions using AICI ₃ . However, the obtained mixture of the desired product contained many side products. Xie et al. (Tetrahedron Lett. 2010, 51 , 4466-4469) reported cyclization of olefins in the presence of FeCI ₃ in nitromethane (Scheme 6). Another olefin Friedel- Crafts cyclization of styrene derivatives using exotic catalysts (Mo(CO) ₆ , Bi(OTf) ₃ or InCI ₃ , was also reported (Beilstein J. Org. Chem. 2010, 6, 6). Friedel-Crafts reactions were also done in ionic liquids (MeImEtCI-AICI3) on alkyl chlorides (J. Org. Chem. 1986, 51 , 480-483). However, no method for the cyclization of olefins under neat Friedel-Crafts conditions has been described in literature.

18 19

Scheme 6. Examples of FC cyclization of olefins (Xie et al.)

The present inventors surprisingly found that using neat conditions for the Friedel-Crafts cyclisation of olefins, the Friedel-Crafts cyclisation gives industrially acceptable yields and purity. On the other hand it is worth mentioning that some methods of cyclizing olefins in solvents, as those described in the literature, such as FeCI ₃ /MeN0 ₂ , FeCI ₃ /AcOH did not yield the desired product.

By means of the new synthesis approach applying the reaction step (A), the present invention attains the following additional benefits:

- Friedel-Crafts reaction (cyclization of olefin precursor) done in molten phase under neat conditions is safer than the prior art equivalent, because no HCI is released during the reaction;

- at higher temperature, Friedel-Crafts reactions very often need

hazardous and toxic solvent, such as chlorobenzene, 1,2- dichlorobenzene, 1,2-dichloroethane, nitromethane, nitrobenzene, while neat conditions allow high temperature by not using such hazardous solvents and as such enable more environmental benign process;

- the absence of solvents makes the very exothermic quenching of the reaction with water in higher temperature safer without risk of ignition;

- there is no need to remove high boiling point solvents;

- less of gaseous hydrogen chloride is released, especially with zinc chloride; - lower reaction volumes allow batches with higher mass gain per equipment;

- the use of simple and commercially available reagents and catalysts;

- no need for special laboratory equipment and techniques.

Usual Friedel Crafts reagents can be applied in the method of the present invention, such as those described in WO 2005/019179. For the purpose of the present invention, preferably a Lewis acid is used. The Lewis acid is preferably selected from transition metal and aluminium compounds, which are more preferably selected from zinc or aluminium salts, preferably chloride salts. The most preferred Lewis acid is aluminium chloride.

The Friedel Crafts reagent is preferably used in excess molar amounts, preferably from 1.1- to 10-fold molar excess, more preferably from 1.25- to 2-fold molar excess.

The reaction is usually carried out at the temperature, at which the mixture is liquid, preferably at the temperature higher than 60 °C, more preferably higher than 90 °C, most preferably at the temperature of 110 - 130 °C. The reaction can be carried out until no further consumption of the starting material can be detected. The reaction is usually carried out for at least 2 hours, preferably for 2 to 24 hour, more preferably for 4 to 10 hours, most preferably for 6 hours.

After the reaction is complete, the present invention preferably comprises the work-up according to above steps (b) to (d).

For the work-up according to step (b), the reaction mixture is preferably cooled down to the temperature at which it is still liquid . More preferably, it is cooled down to 80-100 °C, more preferably to 85-95 °C, most preferably to 90 °C. Thereafter, the reaction mixture is quenched with an aqueous medium, wherein the quenching mixture is preferably an aqueous solution of inorganic salts, preferably an aqueous solution of sodium chloride in a concentration of at least 5 % (w/w), preferably from 10 % (w/w) to saturation (brine). The product is preferably extracted according to step (c) from the quenched aqueous phase to a water immiscible solvent. Thereby, it is possible to purify the crude product from water soluble side products, such as salts, in a straight forward manner. The water immiscible solvent is preferably selected from ethers, esters, haloalkanes, aromatic or aliphatic

hydrocarbons or a mixture thereof. More preferably, it is selected from haloalkanes and esters. If brine is used, also a solvent can be used, which is miscible with pure water, but immiscible with brine, such as C ₄ -C ₅ -alcohols, tetrahydrofuran and acetonitrile. Dichloromethane as the water immiscible solvent is specifically preferred, which is surprisingly even polar enough to extract the hydrochloride salt of the desired product from aqueous phase.

Finally, the product is preferably isolated according to the step (d). This isolation is usually done by evaporating the water immiscible solvent.

Optionally, if the compound according the formula 6 is in the form of a salt, preferably represented by the compound according to the formula 9, the residue obtained after evaporation can optionally be re-suspended or recrystallized from a suitable solvent to obtain a crystalline and purified product. The solvent can suitable be selected by a skilled person and can be represented by one as descried in the reference prior art (e.g.

WO2005/019179).

For obtaining the product according to the formula 9, the quenched aqueous mixture is preferably neutralized and the product is then extracted with a water immiscible solvent, preferably selected from ethers, esters, haloalkanes, aromatic or aliphatic hydrocarbons or a mixture thereof.

Preferably, dichloromethane is used.

For obtaining the product according to the formula 6, the compound according to the formula 9 can be transformed to the hydrochloride salt according to the formula 6 by treating it with HCI in a solvent such as acetone or ether. As described above, the thus obtained residue can optionally be re-suspended or recrystallized from a suitable solvent to obtain a crystalline and purified product. Alternatively, according to a especially preferred embodiment, the compound according to the formula 6 can be obtained by using brine for quenching the reaction mixture and wherein the quenched reaction mixture is not neutralised, but the product is extracted by a water immiscible solvent, preferably dichloromethane, to extract the product according to the formula 6.

By means of the above reaction step (A), the present invention can yield the desired compound according to the formula 9, or a salt thereof which is preferably the compound according to the formula 6, in the form of a racemate.

Preferably, the compound according to the formula 9, or a salt thereof, which is preferably the compound according to the formula 6, can be transferred according to the step (e) to essentially enantiopure or

enantiopure lorcaserin hydrochloride according to the formula 1 :

by performing a chiral resolution via selective crystallization of

diastereoisomeric salt with a resolving agent, preferably tartaric acid, followed by anion exchange.

The racemic compound according to the formula 6, or its salt, can for instance be transformed to enantiopure lorcaserin hydrochloride according to the formula 1 by using the tartaric acid protocol of WO 05/019179.

Preferably, the compound according to the formula 4 employed in the above reaction step (A) is in the form of a solid salt, preferably selected from the bromide or the chloride salt. Most preferably, the compound is the hydrochloride according to the formula 5.

The compound according to the formula 5 is a suitable novel intermediate compound to be applied in the synthesis of the present invention. It has superior physical properties in reactivity in the Friedel-Crafts reaction in molten phase and is able to shortcut in the synthesis of 3-benzo[d]azepine in comparison to the prior art compound in the form of oily base.

According to a further aspect, the present invention teaches the suitability for using N-allyl-N-(4-chlorophenethyl)amine according to the formula 4 or a salt thereof, preferably the hydrochloride salt of N-allyl-N-(4- chlorophenethyl)amine according to the formula 5, for the preparation of racemic 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[c/] azepine according to the formula 9, or a salt thereof, more preferably for the preparation of essentially enantiopure or enantiopure lorcaserin, or its salt, most preferably for the preparation of the essentially enantiopure or enantiopure hydrochloride salt of lorcaserin according to the formula 1.

In a second aspect of the present invention, there is provided a method according the above step (Α') for producing the intermediate compound according to the formula 4, or a salt thereof, which is preferably the compound according to the formula 5, which can suitable be applied for producing the starting material according the first aspect.

In the method of the second aspect, the compounds A and B:

A B are reacted in step (Α') to obtain in a nucleophilic substitution reaction or in a reductive amination reacting reaction the compound according to the formula 4, or a salt thereof, which is preferably the compound according to the formula 5. One of -X and -Y is represented by an amino group (-NH ₂ ). If -X is -NH ₂ , then -Y is a leaving group, which is preferably selected from a halogen or -OS0 ₂ R. Alternatively, if Y is -NH ₂ , then -X is a carbonyl (=0; i.e. A = (4-chlorophenyl)acetaldehyde) or a leaving group, which is preferably selected from a halogen or -OS0 ₂ R.

The leaving group can be represented by any conventional leaving group applicable for a nucleophilic substitution reaction with a primary amine. For the purpose of the present invention and due to the easy accessibility and good reactivity, the leaving group is preferably selected from a halogen or -OS0 ₂ R. The halogen is selected from chloro, bromo or iodo and R is selected from unsubstituted or fluorinated Cl-C4-alkyl or unsubstituted or substituted phenyl. Preferably, R is methyl or 4-methylphenyl, i.e. the group -OS0 ₂ R is represented by a mesylate or tosylate.

For the nucleophilic substitution reaction, the amine compound is preferably in a molar excess relative to the compound with the leaving group, wherein the molar excess of the amine compound is more preferably from 1.1- to 10-fold .

The reaction is optionally performed in the presence of a solvent, which is preferably selected from dimethyl sulfoxide, amides, nitriles, cyclic ethers, haloalkanes, aromatic hydrocarbons and esters, more preferably from tetrahydrofuran, and in the presence of an inorganic or organic base, which is preferably selected from alkali metal hydroxides, carbonates, and C1-C5- alkoxides, more preferably from carbonates, such as potassium carbonate or preferably selected from tertiary amines, such as triethylamine, diisopropylethylamine and/or 4-dimethylaminopyridine.

For the reductive amination reaction, a suitable reductive agent is used . Preferably, the reductive agent is selected from H^Pd/C, sodium

borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.

According to the embodiment of the reductive amination, the commercially available (4-chlorophenyl)acetaldehyde is reacted with allyl amine in a reductive amination reaction upon reduction by means of H^Pd/C. Thereby, all starting materials are readily accessible leading to the key step intermediate 4 or 5 in a straight forward manner.

According to the embodiment of the nucleophilic substitution, the leaving group is represented by a halogen or alternatively by the group -S0 ₂ R.

If the leaving group is represented by a halogen, the halogen is most preferably bromo. Thus, the present invention preferably takes advantage of commercially available and ready accessible 4-chlorophenethyl bromide or allyl bromide to be reacted with the corresponding amine compound . Thereby, all starting materials are readily accessible leading to the key step intermediate 4 or 5 in a straight forward manner.

In an especially preferred embodiment, 4-chlorophenethyl bromide is reacted with an at least 5-fold molar excess of allylamine without the presence of a solvent and of an additional base. The synthesis preferably comprises the work-up by at least steps (c') to (h') and using HCI in step (d'), to give the compound according to the formula 5.

In another embodiment, a slight excess of 4-chlorophenethyl amine is reacted with allyl bromide in tetrahydrofuran as a solvent and potassium carbonate as a base. The synthesis preferably comprises the work-up of at least steps (d') to (h') and using HCI in step (d'), to give the compound according to the formula 5.

If the leaving group is represented by a -OS0 ₂ R, this group can be prepared from the corresponding alcohols and sulfonyl chlorides RS0 ₂ CI or anhydrides (RS0 ₂ ) ₂ 0, wherein R is the same as defined above, in the presence of a base. It is preferred that the resultant 4-chlorophenethyl sulfonate (formula A') or the resultant allyl sulfonate (formula B') are not isolated but are used in the step of preparing the compound according to the formula 4, or a salt thereof, preferably the compound according to the formula 5, in an one pot procedure or in situ. According to one embodiment, a 4-chlorophenethyl sulfonate according to the formula A', with R preferably being methyl or 4-methylphenyl, is produced from reacting phenethyl alcohol according to the formula 7 with the corresponding sulfonyl chloride in the presence of an inorganic or organic base in a solvent:

The base is preferably selected from tertiary amines, such as triethylamlne, diisopropylethylamine and/or 4-dimethylaminopyridine. The solvent is preferably selected from chlorinated hydrocarbons, aromatic hydrocarbons or pyridine, wherein no further organic base is required if the solvent is pyridine.

According to another embodiment, an allyl sulfonate according to the formula B', with R preferably being methyl or 4-methylphenyl, is produced from reacting allyl alcohol with the corresponding sulfonyl chloride in the presence of an inorganic or organic base in a solvent:

B'

The base is preferably selected from tertiary amines, such as triethylamlne, diisopropylethylamine and/or 4-dimethylaminopyridine. The solvent is preferably selected from chlorinated hydrocarbons, aromatic hydrocarbons or pyridine, wherein no further organic base is required if the solvent is pyridine.

After the reaction is complete, the method optionally and preferably comprises the work-up according to above steps (b') to (h').

According to the optional work-up step (b'), the reaction mixture, which is obtained after reacting the compounds A and B, can be washed with an alkaline aqueous phase, if the compound which has been derived from the leaving group is extractable by an organic phase. The alkaline aqueous phase is preferably selected from an aqueous solution of alkali hydrogen carbonates, carbonates, phosphates or hydroxides, preferably from sodium or potassium carbonate.

According to the work-up step (c'), the volatile compounds are removed by evaporation.

According to the work-up step (d'), an aqueous solution of inorganic salt(s) is added to the residue, preferably a sodium chloride solution, more preferably from 10 % (w/w) to the saturated concentration (brine), and preferably hydrochloric acid in order to obtain the compound according to the formula 5, wherein the hydrochloric acid is preferably used as 0.5 to 10 molar aqueous solution. If only an aqueous solution of inorganic salt(s) and no hydrochloric acid is used in the step (d'), the reaction leads to the compound according to the formula 4 (free base). Thereby, the desired product is purified from water soluble impurities.

According to the work-up step (e'), the product is extracted with a water immiscible solvent, which is preferably selected from haloalkanes and esters, or brine immiscible solvents, such as C4-C5-alcohols,

tetrahydrofuran, acetonitrile, ethyl methyl ketone or methyl acetate, wherein dichloromethane is the most preferable extracting solvent.

According to the work-up step (f), the solvent is removed to give the desired crude product. If the method desirably yields the compound according to the formula 4, the work-up is finished with the step (f) to give the oily product according to the formula 4. If the method desirably yields the compound according to the formula 4 in the form of a solid salt, which is preferably represented by the compound according to the formula 5, the work-up may continue with the steps (g') and (h'). The purity of the crude product obtained by step (f) can be sufficient for using it as a starting material in the step (A) according to the method of the first aspect of the present invention. If the purity of the solid product should be increased, the work-up may therefore continued by the steps (g') and (h'). If the purity of the oily compound according to the formula 4 should be increased, usual purification technology can be applied .

According to the work-up step (g'), the crude product is suspended in a suitable solvent. The solvent is preferably acetone or isopropyl acetate.

According to the work-up step (h'), the solid product is isolated . The isolation of the product can be performed by any solid-liquid separation technics, preferably selected from filtration or centrifugation.

According to one embodiment, the method may employ any of steps (c') to (h') and optionally (b')-

In the following, an illustrative overview of the method of the present invention will be given on the basis of preferred and non-limiting

experimental details (Scheme 7) :

Scheme 7. Illustrative synthetic route to racemic 8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-benzo[d] azepine (6) The preparation of racemic lorcaserin hydrochloride according to the formula 6 from phenethyl intermediates according to the formula 2 or 3 according to the present invention is two steps shorter compared to the prior art procedures shown in schemes 2, 4, and 5. A skilled person may select, which embodiment of this invention lead to the most economical route of preparation of a pharmaceutically acceptable product, starting from compounds 2 or 3 and using either purified or crude compound of formula 5 or even choosing the shortest one pot procedure if the process is optimised by such way that the final purification does not essentially lower the overall yield .

In the following the present invention will be described in further detail by illustrative, non-limiting examples.

Experimental Procedures

Example 1: Synthesis of A/-(4-chlorophenethyl)prop-2-en-l-aminium chloride (5) from l-(2-bromoethyl)-4-chlorobenzene (3) :

3 5

Into a flask equipped with magnetic stir bar was placed allylamine (31.0 ml_, 410 mmol) and it was heated to reflux. Starting material (3, 15 g, 68 mmol) was added slowly in 60 minutes The reaction mixture was stirred overnight at reflux. The solution was then cooled down to room temperature and concentrated to an oil. Oil was partitioned between dichloromethane (100 ml_) and HCI IN (200 ml_) plus brine (200 ml_). Phases were separated and water phase was re-extracted with dichloromethane (100 mL). The combined dichloromethane fractions were dried over sodium sulfate, filtered and concentrated. The solid obtained was suspended in isopropyl acetate (25 mL), stirred for 5 minutes and filtered . The solid was dried under vacuum to give the white solid product 5 (12.6 g, 80% yield) which was characterized with H, and IR analysis.

*H NMR (500 MHz, CDCI ₃ , ppm) δ 9.89 (bs, NH), 7.28 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.11 (m, 1H), 5.51 (d, J = 17.0 Hz, 1 H), 5.48 (d, J = 10.2 Hz, 1 H), 3.63 (d, J = 7.0 Hz, 2H), 3.23 (m, 2H), 3.13 (m, 2H); IR (neat) : v = 3436, 2979, 2942, 2801, 2765, 2710, 2641, 2431, 1495, 1446, 1425, 1409, 1339, 1090, 1016, 994, 944, 835, 806 cm ^"1 .

Example 2: Synthesis of A/-(4-chlorophenethyl)prop-2-en-l-aminium chloride (5) from l-(2-aminoethyl)-4-chlorobenzene (2) :

2 5

Into a flask equipped with a magnetic stir bar was placed the starting material (2, 0.28 mL, 2 mmol) which was dissolved in tetrahydrofuran (10 mL). Potassium carbonate (0.55 g, 4 mmol) and allyl bromide (0.165 mL, 1.9 mmol) were added and the reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with water (20 mL) and dichloromethane (30 mL). The phases were separated and the water phase was re-extracted with dichloromethane (20 mL). The combined

dichloromethane fractions were washed with a 2/1 mixture of brine and HCI 1M (2 x 30 mL). The combined acid phases were re-extracted with dichloromethane (20 mL). Then, the combined dichloromethane fractions were dried over sodium sulfate, filtered and concentrated to a solid. The solid was suspended in acetone (5 mL) and was filtered to give product 5 (35% of yield).

Example 3: Synthesis of A/-(4-chlorophenethyl)prop-2-en-l-aminium chloride (5) from l-(2-hydroxyethyl)-4-chlorobenzene (7) :

Into a flask equipped with magnetic stir bar was placed the starting material (7, 2 mL, 11 mmol) which was dissolved in dichloromethane (20 mL).

Triethylamine (1.84 mL, 1.2 eq), 4-dimethylaminopyridine (134 mg, 0.1 eq) and para-toluenesulfonyl chloride (2.3 g, 1.1 eq) were added successively. The solution was stirred for 4 hours after allylamine (3.3 mL, 4 eq) was added and reaction was stirred at reflux overnight. The reaction was washed with saturated Na ₂ C0 ₃ solution (30 mL). The dichloromethane phase was concentrated and the residue was re-dissolved in

dichloromethane (30 mL) and the solution was washed with a 2/1 mixture of brine/HCI IN (40 mL). The water phase was re-extracted with

dichloromethane (20 mL). The combined dichloromethane fractions were dried over Na ₂ S0 ₄ and concentrated. The solid was suspended in isopropyl acetate (30 mL) to give pure product 5 (60% of yield)

Example 4: Synthesis of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[d]azepin-3-ium chloride (6) from A/-(4-chlorophenethyl)prop-2-en-l- aminium chloride (5)

Into a flask equipped with magnetic stir bar was placed the starting material (5, 232 mg, 1 mmol). Aluminum chloride (234 mg, 1.75 mmol) was added and the reaction was stirred. The solid mixture was heated to 125 °C in 25 min and was then stirred as molten phase at this temperature for 6 hours. Solution was cooled down to 90 °C and was diluted with brine (15 mL). The solution was further cooled down and was extracted with dichloromethane (2 x 20 mL). The combined dichloromethane fractions were dried over sodium sulfate, filtered and concentrated to give solid racemic lorcaserin hydrochloride (6, 230 mg ; >99% chromatographic purity) which was anaysed and confirmed with H NM R spectroscopy.

Ή NMR (500 MHz, CDCb) δ 10.2-9.80 (broad s, 2H), 7.26-7.19 (m, 2ArH), 7.08 (m, ArH), 3.82-3.45 (m, 4H), 3.15-2.80 (m, 3H), 1.45 (d, J = 7.0 Hz, 3H) .

Example 5: Synthesis of 8-chloro- l-methyl-2,3,4,5-tetrahydro- lH- benzo[d]azepin-3-ium chloride (6) from A/-(4-chlorophenethyl)prop-2-en- l- aminium chloride (5)

Into a flask equipped with magnetic stir bar was placed the starting material (5, 232 mg, 1 mmol) . Fine powdered zinc chloride (238 mg, 1.75 mmol) was added and the reaction system was stirred . The solid mixture was heated to 125 °C in 25 min and was then stirred as a molten phase at this temperature for 6 hours. The solution was cooled down to 90 °C and was diluted with brine ( 15 ml_). The solution was further cooled down and was extracted with dichloromethane (2 x 20 ml_) . The combined

dichloromethane fractions were dried over sodium sulfate, filtered and concentrated to give solid racemic lorcaserin hydrochloride (6, 230 mg ; >99.5% chromatographic purity) which corresponded to the known compound as confirmed by ¹ H NM R spectroscopy.

Example 6: Synthesis of 8-chloro- l-methyl-2,3,4,5-tetrahydro- lH- benzo[d]azepin-3-ium chloride (6) from A/-(4-chlorophenethyl)prop-2-en- l- amine (4)

Into a flask equipped with magnetic stir bar was placed the starting material (4, 224 mg, 1.15 mmol) . Anhydrous aluminum chloride (268 mg, 2.0 mmol) was added and the reaction system was stirred . The solid mixture was heated to 125 °C in 25 min and was then stirred as a molten phase at this temperature for 6 hours. The solution was cooled down to 90 °C and was diluted with brine ( 15 mL) . The solution was further cooled down and was extracted with dichloromethane (2 x 20 mL) . The combined

dichloromethane fractions were dried over sodium sulfate, filtered and concentrated to give solid racemic lorcaserin hydrochloride (6, 230 mg ; > 99% chromatographic purity) which corresponded to the known compound as confirmed by ¹ H NM R spectroscopy.