WO2014060575A2

WO2014060575A2 - Process for the enantioselective synthesis of a tetrahydrobenzazepine compound

Info

Publication number: WO2014060575A2
Application number: PCT/EP2013/071832
Authority: WO
Inventors: Ernesto DURAN LÓPEZ
Original assignee: Medichem SA
Current assignee: Medichem SA
Priority date: 2012-10-19
Filing date: 2013-10-18
Publication date: 2014-04-24
Anticipated expiration: 2015-04-19
Also published as: WO2014060575A3

Abstract

This invention relates to an improved process for the enantioselective synthesis of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Description

PROCESS FOR THE E ANTIO SELECTIVE SYNTHESIS OF A

TE TRAH YDROBENZ AZEPINE COMPOUND

BACKGROUND OF THE INVENTION

[0001 ] Lorcaserin (compound I) is the international commonly accepted non- proprietary name (INN) for (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine, and has an empirical formula of CnH₁₄NCl and a molecular weight of 195.69.

(I)

[0002] The hydrochloride salt of lorcaserin is known to be therapeutically useful and is commercially marketed as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m² or greater (obese), or 27 kg/m² or greater (overweight) in the presence of at least one weight related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes). In the United States, lorcaserin hydrochloride (as hemihydrate) is marketed under the name Belviq™.

[0003] Lorcaserin was first described in U.S. Patent No. 6,953,787. Specifically, Example 55 of said patent discloses the separation of a trifluoroacetamide derivative of racemic lorcaserin into their respective enantiomers using a semi-preparative HPLC chiral system, followed by the subsequent hydrolysis of the desired enantiomer to give lorcaserin (see Scheme 1).

Scheme 1

[0004] U.S. Patent Application No. 2008/045502 Al describes a different process for the synthesis of lorcaserin. Specifically, Example 4 of said patent application discloses the treatment of racemic lorcaserin (0.06 mol) with L-(+)-tartaric acid (0.015 mol) to give the L-(+)-tartaric acid salt of lorcaserin having an enantiomeric excess higher than 98.9% after recrystallization in only 23.6% yield from the starting amount of racemic lorcaserin. Additionally, Example 13 of the same patent application discloses a similar process at a larger scale, i.e. 0.686 mol of racemic lorcaserin and 0.140 mol of L-(+)-tartaric acid, to give the L-(+)-tartaric acid salt of lorcaserin having an enantiomeric excess of 98.7% after two recrystallizations in only 14.7% yield from the starting amount of racemic lorcaserin. Subsequently, the isolated L-(+)-tartaric acid salt of lorcaserin is treated with sodium hydroxide to give lorcaserin, as disclosed in Example 5. Finally, Example 14 also discloses the preparation of lorcaserin hydrochloride by treatment of lorcaserin (as free base) with 1M HC1 in ether, in methylene chloride as solvent.

[0005] However, the processes for the synthesis of lorcaserin described in the prior art suffer from a number of drawbacks and are not suitable for an industrial synthesis of said compound. For example, both the process described in U.S. Patent No. 6,953,787 as well as the process described in U.S. Patent Application No. 2008/045502 Al involve the enantiomeric resolution of a racemic compound at a very late step of the process, which means that at least 50% of the intermediate material (i.e. the undesired enantiomer) is discarded. Additionally, the process described in U.S. Patent No. 6,953,787 involves a chromatographic resolution of the desired enantiomer, which is not feasible at industrial scale due to the need of special equipments and to the use of large amounts of solvent. Furthermore, the process described in U.S. Patent Application No. 2008/045502 Al involves the need of successive crystallization steps to improve the enantiomeric excess of the isolated lorcaserin L-(+)-tartrate, thus yielding the desired enantiomer in a very low overall yield.

[0006] In view of the foregoing, there is an unmet need for a reproducible, high atom efficient process for preparing lorcaserin or a salt and/or a hydrate thereof, wherein said process is suitable for preparing lorcaserin in a large scale and with good yields.

BRIEF SUMMARY OF THE INVENTION

[0007] It is an object of the present invention to provide simple processes for preparing lorcaserin at an industrial scale which overcome the drawbacks of the processes disclosed in the prior art. Additional advantages of the processes as herein disclosed are that lorcaserin is obtained in high atom efficiency and stereoselectivity.

DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention provides processes for preparing lorcaserin and for preparing the intermediates used therein. The present invention further provides the intermediates as such as well as in an enantiomerically enriched form.

[0009] The first aspect of the present invention is to provide a process for the preparation of an enantiomerically enriched compound of formula (III),

or a salt thereof, the process comprising an enantio selective transformation of a compound of formula (II),

wherein R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl; and i) A and B taken together are methylene and X and Y taken together are carbonyl ii) A and B are each independently hydrogen and X and Y taken together are carbonyl

iii) A and B taken together are methylene and X and Y are each independently hydrogen

iv) A is methyl, B and X taken together and together with the bond linking the carbon atoms to which B and X are attached form a double bond and Y is hydrogen.

[0010] With the process according to the present invention, a high atom efficiency is achieved. Further, this inventive process is feasible on an industrial scale with good yields. A further advantage lies in the fact that no chromatographic resolutions are necessary.

[0011 ] Within the scope of the present invention, an amino protecting moiety is defined to be the N-bonded group resulting from the protection of the nitrogen atom of compounds of formula (II) and (III) through the formation of a suitable amino protecting group. A suitable amino protecting group is preferably a group selected from a suitable carbamate-type protecting group, such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluorenylmethyl carbamate, 17-tetrabenzo[a,c,g,z]fluorenylmethyl carbamate (Tbfmoc), 2-chloro-3-indenylmethyl carbamate (Climoc), benz[ ]inden-3-ylmethyl carbamate (Bimoc), 2,7-di-tert-butyl[9-( 10, 10-dioxo-l 0, 10,10, 10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), l , l-dioxobenzo[¾]thiophene-2- ylmethyl carbamate (Bsmoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l- methylethyl carbamate (Adpoc), 2-chloroethyl carbamate, l , l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2- trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-tert-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'-pyridyl)ethyl carbamate (Pyoc), 2-(4'-pyridyl)ethyl carbamate (Pyoc), 2,2-bis(4'-nitrophenyl)ethyl carbamate (Bnpeoc), N-(2-pivaloylamino)-l,l-dimethylethyl carbamate, 2-[(2- nitrophenyl)dithio]-l-phenylethyl carbamate (NpSSPeoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, tert-butyl carbamate (BOC), 1-adamantyl carbamate (1-Adoc), 2-adamantyl carbamate (2-Adoc), vinyl carbamate (Voc), allyl carbamate (Aloe or Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 3-(3'-pyridyl)prop-2-enyl carbamate (Paloc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz or Z), /?-methoxybenzyl carbamate (Moz), /?-nitrobenzyl carbamate (PNZ), /?-bromobenzyl carbamate, /?-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-( ?-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 1 -methyl- l-(triphenylphosphonio)ethyl (2-triphenylphosphonioisopropyl) carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, 2-dansylethyl carbamate (Dnseoc), 2-(4-nitrophenyl)ethyl carbamate (Npeoc), 4-phenylacetoxybenzyl carbamate (PbAcOZ), 4-azidobenzyl carbamate (ACBZ), 4-azidomethoxybenzyl carbamate, m-chloro-/?-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate (Dobz), 5-benzisoxazolylmethyl carbamate (Bic), 2- (trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5- dimethoxybenzyl carbamate, l-methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate (Ddz), a-methylnitropiperonyl carbamate (Menpoc), o-nitrobenzyl carbamate, 3,4-dimethoxy- 6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate (Npeoc), 2-(2- nitrophenyl)ethyl carbamate, 6-nitroveratryl carbamate (Nvoc), 4-methoxyphenacyl carbamate (Phenoc), 3',5'-dimethoxybenzoin carbamate (DMBOCO), tert-amyl carbamate, S-benzyl thiocarbamate, butynyl carbamate, /?-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, /?-decyloxybenzyl carbamate, diisopropylmethyl carbamate, 2,2- dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1 , 1 -dimethyl-3 -(N,N-dimethylcarboxamido) propyl carbamate, 1 , 1 -dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-ip'- methoxyphenylazo)benzyl carbamate, 1-methylcyclo butyl carbamate, 1- methylcyclohexyl carbamate, 1 -methyl- 1-cyclopropylmethyl carbamate, 1 -methyl- l-(p- phenylazophenyl)ethyl carbamate, 1 -methyl- 1-phenylethyl carbamate, 1 -methyl- 1 -(4' - pyridyl)ethyl carbamate, phenyl carbamate, /?-(phenylazo)benzyl carbamate, 2,4,6-tri- tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6- trimethylbenzyl carbamate; suitable urea-type derivative, such as phenothiazinyl-(lO)- carbonyl derivative, N'-/?-toluenesulfonylaminocarbonyl derivative and N'- phenylaminothiocarbonyl derivative; suitable amides, such as formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide (TFA), phenylacetamide, 3- phenylpropanamide, pent-4-enamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivative, benzamide, /?-phenylbenzamide, o- nitrophenylacetamide, o-nitrophenoxyacetamide, 3-(o-nitrophenyl)propanamide, 2- methyl-2-(o-nitrophenoxy)propanamide, 3 -methyl-3 -nitrobutanamide, o- nitrocinnamide, o-nitrobenzamide, 3-(4-tert-butyl-2,6-dinitrophenyl)-2,2- dimethylpropanamide, o-(benzoyloxymethyl)benzamide (BMB), 2- (acetoxymethyl)benzamide (AMB), 2-[(tert-butyldiphenylsiloxy)methyl]benzamide (SiOMB), 3-(3 ' ,6 '-dioxo-2 ' ,4 ' ,5 ' -trimethylcyclohexa- 1 ' ,4 '-diene)-3 ,3- dimethylpropionamide, o-hydroxy-trans-cinnamide, 2-methyl-2-(o-phenylazophenoxy) propanamide, 4-chlorobutanamide, acetoacetamide, 3-(/?-hydroxyphenyl) propanamide, and (N'-dithiobenzyloxycarbonylamino)acetamide; suitable N-alkyl or N-aryl amine, such as N-methylamine, N-tert-butylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N- cyanomethylamine, N-2,4-dimethoxybenzylamine (Dmb), N-2,4-dinitrophenylamine, N- benzylamine; N-4-methoxybenzylamine (MPM), N-2,4-dimethoxybenzylamine (DMPM), N-2-hydroxybenzylamine (HBn), N-(diphenylmethyl)amine (DPM), N-bis(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine (DBS), N- triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9- phenylfluorenylamine (Pf), N-ferrocenylmethylamine (Fcm) and N-2-picolylamine N'- oxide; a suitable enamine derivative such as N-(5,5-dimethyl-3-oxo-l- cyclohexenyl)amine, N-2,7-dichloro-9-fluorenylmethyleneamine, N-2-(4,4-dimethyl- 2,6-dioxocyclohexylidene)-ethylamine (Dde), N-4,4,4-trifiuoro-3-oxo-l-butenylamine (Tfav) and N-(l-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine; a suitable N-N derivative such as N-nitroamine and N-nitrosoamine; a suitable N-P derivative such as diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphmamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, and diphenyl phosphoramidate; a suitable N-Si derivative; and a suitable N-S derivative such benzenesulfenamide, 2-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, N- 1 -(2,2,2-trifluoro- 1,1- diphenyl)ethylsulfenamide (TDE), 3-nitro-2-pyridinesulfenamide (Npys), p- toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Mds), pentamethylbenzene-sulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide ( te), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- dimethoxy-4-methylbenzenesulfonamide (iMds), 3-methoxy-4-tert- butylbenzenesulfonamide, 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), 2- nitrobenzenesulfonamide (Nosyl or Ns), 4-nitrobenzenesulfonamide (Nosyl or Ns), 2,4- dinitrobenzenesulfonamide (DNs), benzothiazole-2-sulfonamide (Betsyl or Bts), pyridine-2-sulfonamide, methanesulfonamide (Ms), 2-(trimethylsilyl)ethane- sulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)- benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, phenacylsulfonamide and tert-butylsulfonamide (Bus).

[0012] In an embodiment of the above process the compound of formula (III) is obtained with an enantiomeric excess higher than 30%, preferably higher than 50%, preferably higher than 70%, more preferably higher than 90%, even more preferably higher than 95%, and yet even more preferably higher than 99%. [0013] Enantiomeric excess (ee or e.e.), most often expressed as a percentage enantiomeric excess, ee(%>) or e.e.(%>), is defined as 100(x^*-x)/(x^*+x), where x^* is the mole fraction of the majority enantiomer and x is the mole fraction of the minority enantiomer. An equimolar mixture of enantiomers (referred to as a racemic mixture or a racemate) has an enantiomeric excess (e.e.) of zero. A pure enantiomer has an enantiomeric excess (e.e.) of 100%.

[0014] In the context of the present invention the term "enantiomerically enriched" when applied to a product designates either anyone of the product's two enantiomers or mixtures of the product's two enantiomers where one of the enantiomers predominates over the other enantiomer. [0015] In the context of the present invention the term "enantioselective" when applied to a transformation or reaction {i.e. an hydrogenation reaction or a methylation reaction) indicates that the reaction yields an "enantiomerically enriched" product, more preferably that the product is obtained with an enantiomeric excess higher than 30%, preferably higher than 50%, preferably higher than 70%, more preferably higher than 90%, even more preferably higher than 95%, and yet even more preferably higher than

99%.

[0016] In the context of the present invention when a group, such as a Ci-C₆ alkyl group or a benzyl group, is said to be "optionally substituted" it is meant that 1, 2 or 3 of the group's hydrogen atoms may be replaced correspondingly with 1, 2 or 3 atoms or groups selected from halogen atoms, hydroxyl, cyano, nitro, C₁-C₃ alkyl, trifluomethyl, amino, mono C₁-C₃ alkyl amino, di C₁-C₃ alkyl amino, C₁-C₃ alkyl oxy and C₁-C3 alkyl thio. [0017] In a preferred embodiment of the present invention, a specific example of a compound of formula (III) is the compound of formula (Illb).

(Illb)

[0018] In a more preferred embodiment of the present invention, a specific example of a compound of formula (Illb) is (i?)-8-chloro-l,3-dimethyl-2,3,4,5-tetrahydro-lH-3- benzazepine (compound Illb- 1 ) .

[0019] In another embodiment of the present invention, A and B taken together are methylene.

[0020] In an embodiment of the above process X and Y are each independently hydrogen.

[0021] In a further embodiment of the above process, the compound of formula (II) is the compound (He):

(lie) [0022] In another embodiment of the present invention, A is methyl, B and X taken together and together with the bond linking the carbon atoms to which B and X are attached form a double bond and Y is hydrogen.

[0023] In a further embodiment of the above process, the compound of formula (II) is the compound (lid):

(lid)

[0024] Compounds (lie) and (lid) can be interconverted by tautomerization, and therefore they are considered as a different tautomers of the same chemical compound. In solutions in which tautomerization is possible, a chemical equilibrium between (lie) and (lid) tautomers is reached, being the exact ratio of the tautomers depending on several factors including temperature, solvent and pH.

[0025] The compound of formula (Illb) is for example prepared by enantioselective hydrogenation of the compound of formula (He),

[0026] In a preferred embodiment of the present invention, the compound of formula (Illb) is preferably (i?)-8-chloro-l ,3-dimethyl-2,3,4,5-tetrahydro-lH-3- benzazepine (compound Illb- 1) which can be prepared by enantioselective hydrogenation of a compound of formula (lie) which is preferably 8-chloro-3-methyl-l- methylidene-2,3 ,4,5-tetrahydro- lH-3-benzazepine (compound lie- 1 ). [0027] The compound of formula (Illb) is also prepared for example by enantioselective hydrogenation of the compound of formula (lid),

[0028] In a prefered embodiment of the present invention, the compound of formula (Illb) is preferably (i?)-8-chloro-l,3-dimethyl-2,3,4,5-tetrahydro-lH-3-benzazepine (compound IIIb-1) which can be prepared by enantio selective hydrogenation of a compound of formula (lid) which is preferably 7-chloro-3,5-dimethyl-2,3-dihydro-lH- 3-benzazepine (compound IId-1).

[0029] The enantio selective hydrogenation of the compounds of formula (lie) and of formula (lid) is preferably carried out by a hydrogen donor reagent, in the presence of a chiral catalyst. Non-limiting examples of suitable hydrogen donor reagents can be selected from the group comprising molecular hydrogen, tetralin, hydrazine, diimide, cyclohexene, cyclohexadiene, dihydronaphthalene, dihydroanthracene, isopropanol, combinations of metals and alcohols such as for example magnesium and methanol, Hantzsch esters, formic acid, phosphoric acid, and mixtures thereof. The enantio selective hydrogenation of compounds (lie) or (lid) is preferably carried out by molecular hydrogen, which can be present in the reaction mixture at partial pressures ranging from 0.1 to 1000 bar, preferably from 0.5 to 100 bar, more preferably from 0.6 to lO bar.

[0030] Non-limiting examples of chiral catalysts suitable for the enantioselective hydrogenation of compounds (lie) and (lid) are rhodium, ruthenium and iridium complexes containing chiral ligands such as chiral biphosphine ligands. Non-limiting examples of chiral biphosphine ligands can be selected from the group comprising JosiPhos ligands, Butiphane ligands, MeoBIPHEP ligands, MandyPhos ligands, TaniaPhos ligands, WalPhos ligands, RoPhos ligands, Ubaphox ligands, BINAP ligands, TunePhos ligands, TangPhos ligands, BINAPINE ligands, BINAPHANE ligands, DuanPhos ligands, DuPhos ligands, SiPhos ligands, MonoPhos ligands, ChiraPhos ligands, 2,4-bis(diphenylphosphino)pentane (BDPP), and mixtures thereof. The term "ligand" as used herein refers to an ion or molecule that binds to a central metal atom to form a coordination complex, the bonding between metal and ligand generally involving formal donation of one or more of the ligand's electron pairs. [0031] The chiral configuration of the chiral ligand is selected in order to obtain compound (Illb) with the desired chiral configuration. Thus, if a specific chiral ligand gives predominantly the opposite enantiomer of compound (Illb), the enantiomer of the same chiral ligand is expected to give predominantly compound (Illb). [0032] The enantio selective hydrogenation of the compounds of formula (lie) or of formula (lid) preferably takes place in the presence of a solvent. Non limiting examples of suitable solvents for the hydrogenation process described above include, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec- butanol, tert-butanol, 1,3-butanediol, 1,4-butanediol, n-pentanol, sec-pentanol, 3- methylbutanol (isopentanol), 2-methylbutanol, 2,2-dimethyl-l-propanol (neopentanol), 3-pentanol, 3-methyl-2-butanol, 2-methyl-2-butanol, cyclopentanol, n-hexanol, 2- hexanol, 3-hexanol, cyclohexanol, n-heptanol, 2-heptanol, 3-heptanol, 4-heptanol, cycloheptanol, n-octanol, 2-octanol, 3-octanol, 4-octanol, cyclooctanol, n-nonanol, 2- nonanol, n-decanol, 2-butoxyethanol, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 2-ethoxy ethanol, 2-methoxyethanol, and glycerol; ketones such as acetone, cyclohexanone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone, diisobutyl ketone, and 3-pentanone; esters such as ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, pentyl acetate, 2-methoxyethyl acetate, methyl formate, and ethyl formate; ethers such as diethyl ether, diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, 1,4-dioxane, methyl tert-butyl ether, tetrahydroiuran, 2-methyltetrahydrofuran, dimethoxymethane, diethoxymethane, 1 ,2-dimethoxyethane, 1,1-diethoxypropane, 2,2-dimethoxypropane, ethylene glycol diethyl ether, diethylene glycol diethyl ether, and propylene oxide; alkanes such as n-hexane, n-heptane, n-pentane, isooctane, petroleum ether, cyclohexane, methylcyclohexane, and cyclopentane; aromatic compounds such as toluene, xylene, benzene, cumene, ethylbenzene, bromobenzene, chlorobenzene, 1,2- dichlorobenzene, nitrobenzene, pyridine, tetralin and anisole; halogenated alkanes such as chloroform, 1 ,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, dichloromethane, tetrachloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethene, carbon tetrachloride and trichloroethylene; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, formamide, 2-pyrrolidone, and N-methyl-2-pyrrolidone; carboxylic acids such as acetic acid, formic acid, trichloroacetic acid and trifluoroacetic acid; acetonitrile, dimethylsulfoxide, sulfolane, nitromethane, propylene carbonate, water, and mixtures thereof. [0033] The compound of formula (Illb) is obtained with an enantiomeric excess higher than 30%, preferably higher than 50%, preferably higher than 70%, more preferably higher than 90%, even more preferably higher than 95%, and yet even more preferably higher than 99%. [0034] Compounds of formula (lie) and (lid) are preferably prepared from compounds of formula (lib), more preferably from 8-chloro-3-methyl-l-methylidene- l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (compound IIb-1), by means of reducing agents as disclosed hereinbefore. The preferred reducing agent is an aluminium hydride such as aluminium hydride (alane), lithium aluminium hydride, diisobutylaluminium hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al) or lithium trimethoxy aluminium hydride.

[0035] Compounds of formula (lib) are preferably prepared from compounds of formula (Ila), preferably 8-chloro-3-methyl-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (compound IIa-1), by means of an aldol condensation with formaldehyde or a synthetic equivalent thereof such as trioxane or paraformaldehyde, in the presence of a base.

[0036] In another embodiment of the present invention, A and B taken together are methylene and X and Y taken together form a carbonyl.

[0037] In a further embodiment of the above process, the compound of formula (II) is the compound (lib):

[0038] In another embodiment of the present invention, the above process comprises an enantioselective hydrogenation of the compound of formula (lib).

[0039] In a preferred embodiment of the present invention, a specific example of a compound of formula (III) is a compound of formula (Ilia), preferably (i?)-8-chloro-l,3- dimethyl-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (compound IIIa-1).

[0040] The compound of formula (Ilia) is preferably prepared by enantioselective hydrogenation of the compound of formula (lib) [0041] In a preferred embodiment of the present invention, the compound of formula (Ilia) is preferably (i?)-8-chloro-l,3-dimethyl-l,3,4,5-tetrahydro-2H-3- benzazepin-2-one (compound IIIa-1) and is prepared by enantioselective hydrogenation of a compound of formula (lib) which is preferably 8-chloro-3-methyl-l-methylidene- l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (compound IIb-1). [0042] The enantioselective hydrogenation of the compound of formula (lib) is preferably carried out by a hydrogen donor reagent, in the presence of a chiral catalyst. Non-limiting examples of suitable hydrogen donor reagents can be selected from the group comprising molecular hydrogen, tetralin, hydrazine, diimide, cyclohexene, cyclohexadiene, dihydronaphthalene, dihydroanthracene, isopropanol, combinations of metals and alcohols such as for example magnesium and methanol, Hantzsch esters, formic acid, phosphoric acid, and mixtures thereof. The enantioselective hydrogenation of compound (lib) is preferably carried out by molecular hydrogen, which can be present in the reaction mixture at partial pressures ranging from 0.1 to 1000 bar, preferably from 0.5 to 100 bar, more preferably from 0.6 to 10 bar. [0043] Non-limiting examples of chiral catalysts suitable for the enantioselective hydrogenation of compound (lib) are rhodium, ruthenium and iridium complexes containing chiral ligands such as chiral biphosphine ligands. Non-limiting examples of chiral biphosphine ligands can be selected from the group comprising JosiPhos ligands, Butiphane ligands, MeoBIPHEP ligands, MandyPhos ligands, TaniaPhos ligands, WalPhos ligands, RoPhos ligands, Ubaphox ligands, BINAP ligands, TunePhos ligands, TangPhos ligands, BINAPINE ligands, BINAPHANE ligands, DuanPhos ligands, DuPhos ligands, SiPhos ligands, MonoPhos ligands, ChiraPhos ligands, 2,4- bis(diphenylphosphino)pentane (BDPP), and mixtures thereof. The term "ligand" as used herein refers to an ion or molecule that binds to a central metal atom to form a coordination complex, the bonding between metal and ligand generally involving formal donation of one or more of the ligand' s electron pairs.

[0044] The chiral configuration of the chiral ligand is selected in order to obtain compound (Ilia) with the desired chiral configuration. Thus, if a specific chiral ligand gives predominantly the opposite enantiomer of compound (Ilia), the enantiomer of the same chiral ligand is expected to give predominantly compound (Ilia).

[0045] The enantioselective hydrogenation of the compound of formula (lib) preferably takes place in the presence of a solvent. Non limiting examples of suitable solvents for the hydrogenation process described above include, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, 1,3-butanediol, 1,4-butanediol, n-pentanol, sec-pentanol, 3-methylbutanol (isopentanol), 2-methylbutanol, 2,2-dimethyl-l-propanol (neopentanol), 3-pentanol, 3- methyl-2-butanol, 2-methyl-2-butanol, cyclopentanol, n-hexanol, 2-hexanol, 3-hexanol, cyclohexanol, n-heptanol, 2-heptanol, 3-heptanol, 4-heptanol, cycloheptanol, n-octanol, 2-octanol, 3-octanol, 4-octanol, cyclooctanol, n-nonanol, 2-nonanol, n-decanol, 2- butoxyethanol, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 2-ethoxyethanol, 2-methoxyethanol, and glycerol; ketones such as acetone, cyclohexanone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone, diisobutyl ketone, and 3-pentanone; esters such as ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, /? -butyl acetate, isobutyl acetate, pentyl acetate, 2- methoxyethyl acetate, methyl formate, and ethyl formate; ethers such as diethyl ether, diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, 1 ,4-dioxane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxymethane, diethoxymethane, 1 ,2-dimethoxyethane, 1,1-diethoxypropane, 2,2-dimethoxypropane, ethylene glycol diethyl ether, diethylene glycol diethyl ether, and propylene oxide; alkanes such as n- hexane, n-heptane, n-pentane, isooctane, petroleum ether, cyclohexane, methylcyclohexane, and cyclopentane; aromatic compounds such as toluene, xylene, benzene, cumene, ethylbenzene, bromobenzene, chlorobenzene, 1 ,2-dichlorobenzene, nitrobenzene, pyridine, tetralin and anisole; halogenated alkanes such as chloroform, 1 ,2-dichloroethane, 1,1-dichloroethene, 1 ,2-dichloroethene, dichloromethane, tetrachloroethylene, 1,1,1-trichloroethane, 1 , 1 ,2-trichloroethene, carbon tetrachloride and trichloroethylene; amides such as N,N-dimethylacetamide, N,N- dimethylformamide, formamide, 2-pyrrolidone, and N-methyl-2-pyrrolidone; carboxylic acids such as acetic acid, formic acid, trichloroacetic acid and trifluoroacetic acid; acetonitrile, dimethylsulfoxide, sulfolane, nitromethane, propylene carbonate, water, and mixtures thereof.

[0046] The compound of formula (Ilia) is obtained with an enantiomeric excess higher than 30%, preferably higher than 50%, preferably higher than 70%, more preferably higher than 90%, even more preferably higher than 95%, and yet even more preferably higher than 99%.

[0047] The enantioselective hydrogenation of the compound of formula (lib), preferably 8-chloro-3-methyl-l-methylidene-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (compound IIb-1), to give the compound (Ilia), preferably (i?)-8-chloro-l,3-dimethyl- l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (compound IIIa-1), can further comprise the reduction of the compound (Ilia) to obtain the compound (Illb), preferably (i?)-8- chloro -1,3 -dimethy 1-2 ,3,4,5 -tetrahydro - 1 H-3 -benzazepine (compound Illb- 1 ) .

(Illb)

[0048] The reduction of the compound of formula (Ilia) into the compound of formula (Illb) is preferably carried out by using reducing agents. As used herein, the term "reducing agents" refers to reagents used for the reduction of an amide functionality to the corresponding amine. Examples of reducing agents and methods include, but are not limited to: silanes such as triethylsilane, diphenylsilane or trichlorosilane, optionally in the presence of one or more Lewis acids, such as trifluoroborane, titanium chloride, aluminium chloride, zinc iodide or trifluoroacetic acid, also in form of complexes with ethers, such as boron trifluoride diethyl etherate; borohydrides such as sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, lithium cyanoborohydride or mixtures thereof, also in the presence of suitable additives such as sulfuric acid, methanesulfonic acid, acetic acid, titanium chloride, cobalt (II) chloride, aluminium chloride, tin chloride, phosphorus oxychloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, pyridine, trifluoroethanol or 1,2-ethanedithiol; boranes such as borane, diborane or catechol borane, also in the form of complexes with ethers, sulfides or amines such as BH₃ SMe₂, BH₃ Et₂0, BH₃ THF or BH₃ di- ethylaniline; aluminium hydrides such as aluminium hydride (alane), lithium aluminium hydride, diisobutylaluminium hydride (DIBAL), sodium bis(2- methoxyethoxy)aluminium hydride (Red-Al) or lithium trimethoxyaluminium hydride, optionally in the presence of one or more Lewis acids, such as trifluoroborane, titanium chloride, aluminium chloride, zinc iodide or trifluoro acetic acid. The preferred reducing agent is an aluminium hydride such as aluminium hydride (alane), lithium aluminium hydride, diisobutylaluminium hydride (DIBAL), sodium bis(2- methoxyethoxy)aluminium hydride (Red-Al) or lithium trimethoxyaluminium hydride, optionally in the presence of one or more Lewis acids, such as trifluoroborane, titanium chloride, aluminium chloride, zinc iodide or trifluoroacetic acid. [0049] The reduction of the compound of formula (Ilia) into the compound of formula (Illb) as disclosed herein preferably takes place in the presence of an organic solvent. Non-limiting examples of suitable organic solvents which can be used are: ethers such as diethyl ether, diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, 1,4-dioxane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxymethane, diethoxymethane, 1,2-dimethoxyethane, 1,1-diethoxypropane, 2,2- dimethoxypropane, ethylene glycol diethyl ether, diethylene glycol diethyl ether, and propylene oxide; alkanes such as n-hexane, n-heptane, n-pentane, isooctane, petroleum ether, cyclohexane, methylcyclohexane, and cyclopentane; aromatic compounds such as toluene, xylene, benzene, cumene, ethylbenzene, bromobenzene, chlorobenzene, 1,2- dichlorobenzene, nitrobenzene, pyridine, tetralin and anisole; halogenated alkanes such as chloroform, 1 ,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, dichloromethane, tetrachloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethene, carbon tetrachloride and trichloroethylene, and mixtures thereof.

[0050] The compound of formula (Illb) is obtained with an enantiomeric excess higher than 30%, preferably higher than 50%, preferably higher than 70%, more preferably higher than 90%, even more preferably higher than 95%, and yet even more preferably higher than 99%.

[0051 ] In another embodiment of the present invention, A and B are independently hydrogen, and X and Y of the compound of formula (II) taken together form a carbonyl. [0052] In an embodiment of the above process, the compound of formula (II) is the compound (Ila):

[0053] In another embodiment of the present invention, the above process comprises an enantio selective methylation of the compound of formula (Ila). [0054] In a further embodiment of the above process, the compound of formula (Ilia) is obtained by enantio selective methylation of the compound of formula (Ila).

(Ilia)

[0055] The compound of formula (Ilia) can be prepared by enantioselective methylation of the compound of formula (Ila), preferably 8-chloro-3-methyl-l , 3,4,5- tetrahydro-2H-3-benzazepin-2-one (compound Ila- 1).

[0056] The enantioselective methylation of the compound of formula (Ila) is preferably carried out by using a methylating agent in the presence of a chiral auxiliary. Preferably, the enantioselective methylation of the compound of formula (Ila) is carried out in the presence of a base. [0057] Non-limiting examples of suitable methylating agents which can be used are dimethyl sulfate, dimethyl carbonate, methyl iodide, methyl bromide, methyl triflate, a methyl sulfonate such as, for example, methyl methanesulfonate, methyl benzenesulfonate, methyl /?-toluenesulfonate or methyl fluorosulfonate, and mixtures thereof. Preferred methylating agents are dimethyl sulfate, dimethyl carbonate, methyl iodide, and mixtures thereof. Preferred methylating agents are dimethyl sulfate, dimethyl carbonate, methyl iodide, and mixtures thereof. [0058] The term "chiral auxiliary" as used herein refers to an optically active chemical compound that is temporally incorporated into the process so the reaction can be carried out asymmetrically with the selective formation of one of the two enantiomers. Chiral auxiliaries can be used in any equivalent amount with respect to compound (Ha), preferably in a catalytical amount (i.e. less than one molar equivalent amount) with respect to compound (Ha). Non-limiting examples of suitable chiral auxiliaries which can be used are ephedrine derivatives; cinchona derivatives such as cinchonine derivatives, cinchonidine derivatives, quinine derivatives and quinidine derivatives; Maruoka's derivatives; and mixtures thereof. Particular examples of suitable chiral auxiliaries which can be used are N-benzyl quininium salts, N-[p- (trifluoromethyl)benzyl]cinchoninium salts, O-allyl-N-(9-anthracenylmethyl)- cinchonidinium salts, (1 lbi?)-(-)-4,4-dibutyl-4,5-dihydro-2,6-bis(3,4,5-trifluorophenyl)- 3H-dinaphth[2,l-c: l\2'-e]azepinium salts, (1 lb5)-(+)-4,4-dibutyl-4,5-dihydro-2,6- bis(3,4,5-trifluorophenyl)-3H-dinaphth[2,l-c: ,2'-e]azepinium salts, and mixtures thereof, preferably in the form of their chloride, bromide, iodide or hydrogensulfate salts.

[0059] The chiral configuration of the chiral auxiliary is selected in order to obtain compound (Ilia) with the desired chiral configuration. Thus, if a specific chiral auxiliary gives predominantly the opposite enantiomer of compound (Ilia), the enantiomer of the same chiral auxiliary is expected to give predominantly compound (Ilia). [0060] The term "in the presence of a base" as used herein means that there is at least one base with a pK_a value above 7. Non-limiting examples of suitable bases are hydroxides such as lithium, sodium or potassium hydroxide; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; hydrides such as sodium hydride or potassium hydride; alkoxides such as lithium, sodium, potassium or cesium methoxides, ethoxides, propoxides, isopropoxides, tert-butoxides or tert- pentoxides; amides such as lithium diisopropylamide; alkyl lithium; Grignard reagents, and mixtures thereof. The pK_a is a measurement of the strength of an acid. The lower the pK_a, the stronger the acidity. The higher the pK_a, the weaker the acid. The p¾, is a related measurement and is a measurement of the strength of a base; the lower the pK_b, the stronger the base, and the higher the K_b, the weaker the base. Although it is not strictly accurate, often the pK_a of a base's conjugated acid is provided as the pIQ of the base. In this application the term pIQ of a base is used to designate the pIQ of the base's conjugated acid. In this application the pK_a values refer to the pK_a in water as determined at room temperature and atmospheric pressure.

[0061 ] The enantio selective methylation of the compound of formula (Ila) preferably takes place in the presence of a solvent. Non-limiting examples of suitable solvents which can be used are for example, ethers such as diethyl ether, diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, 1,4-dioxane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxymethane, diethoxymethane, 1,2- dimethoxyethane, 1,1-diethoxypropane, 2,2-dimethoxypropane, ethylene glycol diethyl ether, diethylene glycol diethyl ether, and propylene oxide; alkanes such as n-hexane, n- heptane, n-pentane, isooctane, petroleum ether, cyclohexane, methylcyclohexane, and cyclopentane; aromatic compounds such as toluene, xylene, benzene, cumene, ethylbenzene, bromobenzene, chlorobenzene, 1 ,2-dichlorobenzene, nitrobenzene, pyridine, tetralin and anisole; halogenated alkanes such as chloroform, 1,2- dichloroethane, 1,1-dichloroethene, 1 ,2-dichloroethene, dichloromethane, tetrachloroethylene, 1,1,1-trichloroethane, 1 , 1 ,2-trichloroethene, carbon tetrachloride and trichloroethylene; water, and mixtures thereof. Preferably the enantio selective methylation of compound (Ila) is carried out in the presence of a mixture of a water non-miscible organic solvent and water, so that the chiral auxiliary can act as a phase transfer catalyst. Preferred water non-miscible organic solvents are those having water solubility values (w/w) of less than 50%, more preferably less than 10%, even more preferably less than 1%. [0062] The compound of formula (Ilia) is obtained with an enantiomeric excess higher than 30%, preferably higher than 50%, preferably higher than 70%, more preferably higher than 90%, even more preferably higher than 95%, and yet even more preferably higher than 99%.

[0063] The enantioselective methylation of the compound of formula (Ila), preferably 8-chloro-3-methyl-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (compound IIa-1), to give the compound (Ilia), preferably (i?)-8-chloro-l,3-dimethyl-l, 3,4,5- tetrahydro-2H-3-benzazepin-2-one (compound IIIa-1), can further comprise the reduction of the compound (Ilia) to obtain the compound (Illb), preferably (i?)-8- chloro -1,3 -dimethy 1-2 ,3,4,5 -tetrahydro - 1 H-3 -benzazepine (compound Illb- 1 ) . [0064] The reduction of the compound of formula (Ilia) into the compound of formula (Illb) is preferably carried out by using reducing agents. As used herein, the term "reducing agents" refers to reagents used for the reduction of an amide functionality to the corresponding amine. Examples of reducing agents and methods include, but are not limited to: silanes such as triethylsilane, diphenylsilane or trichlorosilane, optionally in the presence of one or more Lewis acids, such as trifluoroborane, titanium chloride, aluminium chloride, zinc iodide or trifluoroacetic acid, also in form of complexes with ethers, such as boron trifluoride diethyl etherate; borohydrides such as sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, lithium cyanoborohydride or mixtures thereof, also in the presence of suitable additives such as sulfuric acid, methanesulfonic acid, acetic acid, titanium chloride, cobalt (II) chloride, aluminium chloride, tin chloride, phosphorus oxychloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, pyridine, trifluoroethanol or 1,2-ethanedithiol; boranes such as borane, diborane or catechol borane, also in the form of complexes with ethers, sulfides or amines such as BH₃ SMe₂, BH₃ Et₂0, BH₃ THF or BH₃ di- ethylaniline; aluminium hydrides such as aluminium hydride (alane), lithium aluminium hydride, diisobutylaluminium hydride (DIBAL), sodium bis(2- methoxyethoxy)aluminium hydride (Red-Al) or lithium trimethoxyaluminium hydride, optionally in the presence of one or more Lewis acids, such as trifluoroborane, titanium chloride, aluminium chloride, zinc iodide or trifluoroacetic acid. The preferred reducing agent is an aluminium hydride such as aluminium hydride (alane), lithium aluminium hydride, diisobutylaluminium hydride (DIBAL), sodium bis(2- methoxyethoxy)aluminium hydride (Red-Al) or lithium trimethoxyaluminium hydride. [0065] The reduction of the compound of formula (Ilia) into the compound of formula (Illb) as disclosed herein preferably takes place in the presence of an organic solvent. Non-limiting examples of suitable organic solvents which can be used are: ethers such as diethyl ether, diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, 1,4-dioxane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxymethane, diethoxymethane, 1,2-dimethoxyethane, 1,1-diethoxypropane, 2,2- dimethoxypropane, ethylene glycol diethyl ether, diethylene glycol diethyl ether, and propylene oxide; alkanes such as n-hexane, n-heptane, n-pentane, isooctane, petroleum ether, cyclohexane, methylcyclohexane, and cyclopentane; aromatic compounds such as toluene, xylene, benzene, cumene, ethylbenzene, bromobenzene, chlorobenzene, 1,2- dichlorobenzene, nitrobenzene, pyridine, tetralin and anisole; halogenated alkanes such as chloroform, 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, dichloromethane, tetrachloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethene, carbon tetrachloride and trichloroethylene, and mixtures thereof.

[0066] The compound of formula (Illb) is obtained with an enantiomeric excess higher than 30%, preferably higher than 50%, preferably higher than 70%, more preferably higher than 90%, even more preferably higher than 95%, and yet even more preferably higher than 99%.

[0067] In another aspect of the present invention, the compound of formula (Ila) is preferably prepared by ring-closing of a compound of formula (IV), preferably 2- chloro-N- [2-(4-chlorophenyl)ethyl] -N-methylacetamide (compound IV- 1 ) .

[0068] The ring-closing of the compound of formula (IV) to give the compound of formula (Ila) is preferably carried out by means of a Friedel- Crafts alkylation reaction, using a strong Lewis acid catalyst. Non-limiting examples of strong Lewis acids for the Friedel- Crafts alkylation are aluminium bromide, aluminium chloride, iron (III) chloride, boron trifluoride, tin chloride, zinc chloride, titanium tetrachloride, and mixtures thereof.

[0069] In another embodiment of the present invention, enantiomerically enriched compound (III) is transformed into lorcaserin or a salt and/or a hydrate thereof.

[0070] In a particular embodiment of the present invention, the transformation of enantiomerically compound (III) into lorcaserin comprises the cleavage of the suitable amino protecting moiety.

[0071] In a preferred embodiment of the present invention, the compound of formula (Illb), preferably (i?)-8-chloro-l,3-dimethyl-2,3,4,5-tetrahydro-lH-3- benzazepine (compound IIIb-1), is N-demethylated to give lorcaserin or a salt and/or a hydrate thereof. [0072] N-Demethylation of the compound of formula (IIIb-1) is preferably carried out in the presence of 1-chloroethyl chloro formate, thus forming intermediate 1- chloroethyl 8-chloro- 1 -methyl- 1 ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate, compound (V) which can be treated with methanol to give lorcaserin hydrochloride (see Scheme 2).

Scheme 2

[0073] Lorcaserin is obtained with an enantiomeric excess higher than 30%, preferably higher than 50%, preferably higher than 70%, more preferably higher than 90%, even more preferably higher than 95%, and yet even more preferably higher than 99%.

[0074] In another embodiment of the present invention, Lorcaserin is obtained in form of its hydrochloride acid salt or a hydrate thereof.

[0075] Anhydrous lorcaserin hydrochloride is preferably obtained by a process comprising the addition of methanol to 1-chloroethyl 8-chloro- 1 -methyl- 1,2,4, 5- tetrahydro-3H-3-benzazepine-3-carboxylate, compound of formula (V). Said process avoids the use of highly corrosive hydrogen chloride gas or hydrogen chloride solutions in organic solvents for the preparation of anhydrous lorcaserin hydrochloride from lorcaserin base at industrial scale, as it is disclosed in the prior art processes. [0076] In another embodiment of the present invention, R is methyl. [0077] Another aspect of the present invention is a compound of formula (II)

wherein:

R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl; and i) A and B taken together are methylene and X and Y taken together are carbonyl ii) A and B are each independently hydrogen and X and Y taken together are carbonyl

[0078] In an embodiment, the compound of formula (II) is compound (Ha).

wherein R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl. [0079] In another embodiment, the compound of formula (II) is compound (lib).

(lib) wherein R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl. [0080] In a further embodiment, the compound of formula (II) is compound (lie).

(lie) wherein R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl. [0081 ] In a further embodiment, the compound of formula (II) is compound (lid).

(lid) wherein R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl. [0082] Another aspect of the present invention is the (R) enantiomer of the compound of formula (III),

wherein:

X and Y are independently hydrogen or X and Y taken together are carbonyl; and

R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl.

[0083] Another aspect of the present invention is a compound of formula (IV)

wherein R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl.

[0084] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

SPECIFIC EXAMPLES

General Experimental Conditions

HPLC Method 1

[0085] The chromatographic separation was carried out in a Phenomenex Lux Cellulose-2, 5 μιη, 4.6 mm x 150 mm column. [0086] The mobile phase was a 95:5 (v/v) mixture of hexane and isopropanol.

[0087] The chromatograph was equipped with a 215 nm detector and the flow rate was 1.0 mL/min at 30 °C.

HPLC Method 2 [0088] The chromatographic separation was carried out in a Daicel Chiralpak AY- 3R, 3 μιη, 4.6 x 150 mm column.

[0089] The mobile phase was a 70:30 (v/v) mixture of a 0.020M ammonium bicarbonate buffer (pH 9.0) and acetonitrile. The 0.020M ammonium bicarbonate buffer (pH 9.0) was prepared from 1.58 g of NH₄HCO₃ dissolved in 1000 mL of water, adjusting pH to 9.0 with diethylamine, and filtered through a 0.22 μιη nylon membrane.

[0090] The chromatograph was equipped with a 215 nm detector and the flow rate was 0.7 mL/min at 20 °C.

Reference Example 1. Preparation of 2-chloro- V-[2-(4-chlorophenyl)ethyl]- V- methylacetamide (IV-1) a) Preparation of tert-butyl [2-(4-chlorophenyl)ethyl] carbamate

[0091] 215 g (1.38 mol) of 2-(4-chlorophenyl)ethanamine were dissolved in 1 L of tetrahydrofuran, under a nitrogen atmosphere. A solution of 301 g (1.38 mol) of άι-tert- butyl dicarbonate in 500 mL of tetrahydrofuran was added drop wise, and the resulting mixture was stirred at 30 °C for 1 hour. The solvent was evaporated and the residue was dissolved in a mixture of 800 mL of water and 800 mL of dichloromethane. The organic layer was extracted, and the aqueous phase was washed with 500 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give 319 g of tert-butyl [2-(4- chlorophenyl)ethyl]carbamate. b) Preparation of 2-(4-chlorophenyl)- V-methylethanamine

[0092] 319 g (1.25 mol) of tert-butyl [2-(4-chlorophenyl)ethyl]carbamate were dissolved in 700 mL of tetrahydrofuran, under a nitrogen atmosphere. The solution was added over a suspension of 200 g (5.27 mol) of lithium aluminium hydride in 1.5 L of tetrahydrofuran at 50 °C, and the resulting mixture was stirred at 50 °C for 8 hours. After cooling to 20 °C, 600 mL of water were added. The resulting suspension was filtered, and the cake was washed with 500 mL of tetrahydrofuran. The filtrate was evaporated, and the residue was dissolved in a mixture of 1.5 L of water and 1.5 L of dichloromethane. The organic layer was extracted, and the aqueous phase was washed with 800 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by vacuum distillation, to give 150 g of 2-(4-chlorophenyl)-N-methylethanamine as a colorless oil. c) Preparation of 2-chloro- V-[2-(4-chlorophenyl)ethyl]- V-methylacetamide (IV- 1)

[0093] 50 g (295 mmol) of 2-(4-chlorophenyl)-N-methylethanamine were dissolved in 500 mL of dichloromethane, under a nitrogen atmosphere. A solution of 31.2 g (371 mmol) of sodium bicarbonate in 300 mL of water was added while keeping the reaction temperature at 5 °C. Subsequently, a solution of 34.9 g (309 mmol) of chloroacetyl chloride in 500 mL of dichloromethane was added dropwise, while keeping the reaction temperature at 5 °C. The resulting mixture was stirred at 5 °C for 30 minutes. The organic layer was extracted, and the aqueous phase was washed with 500 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give 72 g of 2-chloro-N-[2-(4- chlorophenyl)ethyl]-N-methylacetamide (compound IV- 1).

Example 1. Preparation of 8-chloro-3-methyl-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-one (IIa-1) [0094] A mixture of 75 g (305 mmol) of 2-chloro-N-[2-(4-chlorophenyl)ethyl]-N- methylacetamide (compound IV-1) and 122 g (914 mmol) of aluminium trichloride was stirred at 150 °C for 6 hours, under a nitrogen atmosphere. The reaction mixture was poured into a mixture of 500 mL of water and 500 mL of dichloromethane, at 0 °C. The organic layer was extracted, and the aqueous phase was washed with 400 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was recrystallized from a mixture of 120 mL of petroleum ether and 30 mL of ethyl acetate, to give 29 g of 8-chloro-3- methyl-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (compound IIa-1). Example 2. Preparation of 8-chloro-3-methyl-l-methylidene-l,3,4,5-tetrahydro- 2H-3-benzazepin-2-one (IIb-1)

[0095] 51 g (243 mmol) of 8-chloro-3-methyl-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-one (compound IIa-1), 237 g (727 mmol) of cesium carbonate, 18 g (599 mmol) of paraformaldehyde and 19.5 g (60 mmol) of tetrabutylammonium bromide were suspended in 370 mL of N,N-dimethylformamide, under a nitrogen atmosphere, and the resulting mixture was stirred at 80 °C for 16 hours. After cooling to 25 °C, 1 L of water and 1 L of ethyl acetate were added. The organic layer was extracted, and the aqueous phase was washed with 500 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography to give 25 g of 8-chloro-3-methyl-l-methylidene- l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (compound IIb-1).

Example 3. Preparation of 7-chloro-3,5-dimethyl-2,3-dihydro-lH-3-benzazepine (IId-1) [0096] 16.1 g (72.6 mmol) of 8-chloro-3-methyl-l-methylidene-l,3,4,5-tetrahydro- 2H-3-benzazepin-2-one (compound IIb-1) were suspended in 300 mL of anhydrous toluene, under a nitrogen atmosphere. 123 mL (123 mmol) of a 1 M solution of diisobutylaluminium hydride in hexanes were added, and the resulting mixture was stirred at 25 °C for 16 hours. 100 mL of water were added. The organic layer was extracted and evaporated to dryness. The residue was purified by column chromatography to give 3.5 g of 7-chloro-3,5-dimethyl-2,3-dihydro-lH-3-benzazepine (compound IId-1).

Example 4. Preparation of enantiomerically enriched 8-chloro-l,3-dimethyl- l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (IIIa-1) [0097] 111.1 mg (0.501 mmol) of 8-chloro-3-methyl-l-methylidene-l,3,4,5- tetrahydro-2H-3-benzazepin-2-one (compound (IIb-1)), 8.0 mg (0.020 mmol) of bis(l,5-cyclooctadien)rhodium(I) tetrafluoroborate, Rh(COD)₂BF₄, and 9.1 mg (0.021 mmol) of (5',5)-2,4-bis(diphenylphosphino)pentane (BDPP) were suspended in 5 mL of degassed methanol. The mixture was stirred under a hydrogen pressure of 20 psi (137.9 kPa) at 25°C for 46 hours. The resulting mixture was analyzed by HPLC (method 1), showing a 92.3% conversion into 8-chloro-l,3-dimethyl-l,3,4,5-tetrahydro-2H-3- benzazepin-2-one having an enantiomeric excess of 53.2%. Example 5. Preparation of enantiomerically enriched 8-chloro-l,3-dimethyl- l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (IIIa-1)

[0098] 110.7 mg (0.500 mmol) of 8-chloro-3-methyl-l-methylidene-l,3,4,5- tetrahydro-2H-3-benzazepin-2-one (compound (IIb-1)), 8.4 mg (0.021 mmol) of bis(l,5-cyclooctadien)rhodium(I) tetrafluoroborate, Rh(COD)₂BF₄, and 8.8 mg (0.020 mmol) of (5',5)-2,4-bis(diphenylphosphino)pentane (BDPP) were suspended in 6 mL of degassed methanol. The mixture was stirred under a hydrogen pressure of 10 psi (68.9 kPa) at 50°C for 46 hours. The resulting mixture was analyzed by HPLC (method 1), showing a complete conversion into 8-chloro-l,3-dimethyl-l,3,4,5-tetrahydro-2H-3- benzazepin-2-one having an enantiomeric excess of 49.9%.

Example 6. Preparation of enantiomerically enriched 8-chloro-l,3-dimethyl- 2,3,4,5-tetrahydro-lH-3-benzazepine (IIIb-1)

[0099] 104.2 mg (0.502 mmol) of 7-chloro-3,5-dimethyl-2,3-dihydro-lH-3- benzazepine (compound IId-1), 5.2 mg (0.011 mmol) of chloro(l ,5- cyclooctadiene)rhodium (I) dimer, [Rh(COD)Cl]₂, and 19.0 mg (0.020 mmol) of (i?)-l- {(i?p)-2-[2-(diphenylphosphino)phenyl]ferrocenyl}ethylbis[3,5-bis-(trifluoromethyl) phenyl]phosphine, Walphos SL-WOOl-1 (CAS 387868-06-6), were suspended in 4 mL of degassed methanol. The mixture was stirred under a hydrogen pressure of 75 psi (517.1 kPa) at 20°C for 22 hours. The resulting mixture was analyzed by HPLC (method 2), showing a complete conversion into 8-chloro-l,3-dimethyl-2,3,4,5-tetrahydro-lH-3- benzazepine.

Example 7. Preparation of enantiomerically enriched 8-chloro-l,3-dimethyl- 2,3,4,5-tetrahydro-lH-3-benzazepine (IIIb-1)

[00100] 107.0 mg (0.515 mmol) of 7-chloro-3,5-dimethyl-2,3-dihydro-lH-3- benzazepine (compound IId-1), 6.0 mg (0.012 mmol) of chloro(l ,5- cyclooctadiene)rhodium (I) dimer, [Rh(COD)Cl]₂, and 18.8 mg (0.020 mmol) of (i?)-l- {(i?p)-2-[2-(dicyclohexylphosphino)phenyl]ferrocenyl}ethylbis[3,5-bis(trifluorome- thyl)phenyl]phosphine, Walphos SL-W008-1 (CAS 494227-32-6), were suspended in 4 mL of degassed methanol. The mixture was stirred under a hydrogen pressure of 75 psi (517.1 kPa) at 20°C for 70 hours. The resulting mixture was analyzed by HPLC (method 2), showing a complete conversion into 8-chloro-l,3-dimethyl-2,3,4,5-tetrahydro-lH-3- benzazepine. Example 8. Preparation of enantiomerically enriched 8-chloro-l,3-dimethyl- 2,3,4,5-tetrahydro-lH-3-benzazepine (IIIb-1)

[00101] 104.0 mg (0.501 mmol) of 7-chloro-3,5-dimethyl-2,3-dihydro-lH-3- benzazepine (compound IId-1) and 8.4 mg (0.005 mmol) of 1,5- cyclooctadiene{[dibenzyl((4i?,5i?)-5-methyl-2-phenyl-4,5-dihydro-4-oxazolyl)methyl] diphenylphosphinite K_N:K_P}iridium(I) tetrakis(3,5-bis(trifluoro-methyl)phenyl)borate, Ubaphox catalyst (CAS 880262-16-8), were suspended in 4 mL of degassed, anhydrous dichloromethane. The mixture was stirred under a hydrogen pressure of 75 psi (517.1 kPa) at 20°C for 22 hours. The resulting mixture was analyzed by HPLC (method 2), showing a 87.5% conversion into 8-chloro-l,3-dimethyl-2,3,4,5-tetrahydro-lH-3- benzazepine.

Example 9. Preparation of 8-chloro-l,3-dimethyl-2,3,4,5-tetrahydro-lH-3- benzazepine

[00102] 2.35 g (10.5 mmol) of 8-chloro-l,3-dimethyl-l,3,4,5-tetrahydro-2H-3- benzazepin-2-one were dissolved in 50 mL of diethyl ether at 25 °C, under nitrogen atmosphere. 0.80 g (21 mmol) of lithium aluminium hydride were added, and the resulting suspension was stirred at reflux temperature for 3 hours. After cooling to room temperature, 3 mL of water were added. The resulting suspension was filtered, and the filtrate was evaporated to dryness to give 2.12 g of 8-chloro-l,3-dimethyl-2, 3,4,5- tetrahydro-lH-3-benzazepine.

Example 10. Preparation of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3- benzazepine hydrochloride

[00103] 8.4 g (40.0 mmol) of 8-chloro-l,3-dimethyl-2,3,4,5-tetrahydro-lH-3- benzazepine are suspended in 70 mL of toluene, and water is azeotropically removed. After cooling to 25 °C, 0.68 mL (4.0 mmol) of N,N-diisopropylethylamine and subsequently 5.19 mL (48.0 mmol) of 1-chloroethyl chloroformate are added while keeping the reaction temperature at 25 °C. The reaction mixture is heated to 50 °C and stirred at this temperature for 3 hours. After cooling to 25 °C, 12 mL of a 10% (w/w) aqueous solution of ammonia are added. The organic layer is extracted and washed with 10 mL of deionized water. 60 mL of methanol are added to the resulting organic phase, and the mixture is stirred at 50 °C for 6 hours. The solvent is evaporated to dryness to give 8-chloro- 1 -methyl-2,3 ,4,5-tetrahydro- lH-3-benzazepine hydrochloride. Example 11. Preparation of Lorcaserin hydrochloride

[00104] 2-chloro-N-[2-(4-chlorophenyl)ethyl]-N-methylacetamide (compound IV- 1) is mixed with aluminium chloride to give 8-chloro-3-methyl-l,3,4,5-tetrahydro-2H-3- benzazepin-2-one (compound IIa-1) which is reacted with formaldehyde and potassium hydroxide to yield 8-chloro-3-methyl-l-methylidene-l,3,4,5-tetrahydro-2H-3- benzazepin-2-one (compound (IIb-1)). Afterwards, compound (IIb-1) is mixed with DIBAL to obtain 8-chloro-3-methyl-l-methylidene-2,3,4,5-tetrahydro-lH-3- benzazepine (compound IIc-1). Furthermore, an asymmetric hydrogenation is carried out with molecular hydrogen and [Rh(COD)Cl]₂ and a chiral phosphine such as Solvias' Walphos in the presence of methanol to yield (i?)-8-chloro-l,3-dimethyl-2, 3,4,5- tetrahydro-lH-3-benzazepine (compound (IIIb-1)). In addition, compound (IIIb-1) is mixed with 1-chloroethyl chloro formate, thus forming intermediate 1-chloroethyl 8- chloro- 1 -methyl- 1 ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate, compound (V) which can be treated with methanol to give lorcaserin hydrochloride. Example 12. Preparation of Lorcaserin hydrochloride

[00105] 2-chloro-N-[2-(4-chlorophenyl)ethyl]-N-methylacetamide (compound IV- 1) is mixed with aluminium chloride to give 8-chloro-3-methyl-l,3,4,5-tetrahydro-2H-3- benzazepin-2-one (compound IIa-1) which is reacted with formaldehyde and potassium hydroxide to yield 8-chloro-3-methyl-l-methylidene-l,3,4,5-tetrahydro-2H-3- benzazepin-2-one (compound (IIb-1)). Afterwards, an asymmetric hydrogenation is carried out with molecular hydrogen and Rh(COD)₂BF₄ and a chiral phosphine such as 2,4-bis(diphenylphosphino)pentane (BDPP) in the presence of methanol to yield (i?)-8- chloro-l,3-dimethyl-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (compound (IIIa-1)), which is mixed with lithium aluminium hydride to obtain (i?)-8-chloro-l,3-dimethyl- 2,3,4,5-tetrahydro-lH-3-benzazepine (compound (IIIb-1)). In addition, compound (Illb- 1) is mixed with 1-chloroethyl chloro formate, thus forming intermediate 1-chloroethyl 8-chloro- 1 -methyl- 1 ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate, compound (V) which can be treated with methanol to give lorcaserin hydrochloride.

[00106] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. [00107] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those ordinary skilled in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above- described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

1 . A process for the preparation of an enantiomerically enriched compound of formula (III),

or a salt thereof, the process comprising an enantioselective transformation of a compound of formula (II),

wherein:

R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl; and

A and B taken together are methylene and X and Y taken together are carbonyl

A and B are each independently hydrogen and X and Y taken together are carbonyl

A and B taken together are methylene and X and Y are each independently hydrogen

A is methyl, B and X taken together and together with the bond linking the carbon atoms to which B and X are attached form a double bond and Y is hydrogen.

2. The process according to claim 1 , wherein the enantiomerically enriched compound of formula (III) is enriched in the (R) enantiomer of formula (Illb):

The process according to any one of claims 1 or 2, wherein compound (II) compound (He):

The process according to any one of claims 1 or 2, wherein compound (II) compound (lid):

5. The process according to any one of claims 1 or 2, wherein compound (II) is compound (lib):

The process according to any of claims 1 to 5, wherein the step of enantio selectively transforming a compound of formula (II) into a compound of formula (III) comprises an enantioselective hydrogenation. The process according to any one of claims 1 or 2, wherein compound (II) compound (Ila):

(Ila)

The process according to claim 7, wherein the process comprises enantio selective methylation of the compound of formula (Ila).

The process according to any one of claims 5 to 8, further comprising reduction step of compound (Ilia):

to obtain a compound of formula (Illb)

( b).

The process according to any one of the preceding claims, further comprising deprotection of compound (Illb):

(nib) to obtain compound (I) or a salt thereof:

(I).

1 1 . The process according to claim 10, wherein compound (I) is obtained with an enantiomeric excess higher than 30%, preferably higher than 50%, preferably higher than 70%, more preferably higher than 90%, even more preferably higher than 95%, and yet even more preferably higher than 99%.

12. The process according to claims 10 or 11, wherein compound (I) is obtained in form of its hydrochloric acid salt or a hydrate thereof.

13. A process for the preparation of the compound of formula (Ila), comprising the ring-closing of compound (IV),

to give compound (Ila);

A process for the preparation of a compound of formula (lie) or a compound of formula (lid) comprising:

(a) reacting compound (Ila) with formaldehyde to give compound (lib);

reducing compound (lib) to give compound (lie) or compound (lid)

15. The process according to any one of the preceding claims, wherein R is methyl. 16. A compound of formula (II),

wherein:

R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl, or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl; and

A and B taken together are methylene and X and Y taken together are carbonyl

A and B are each independently hydrogen and X and Y taken together are carbonyl

A and B taken together are methylene and X and Y are each independently hydrogen A is methyl, B and X taken together and together with the bond linking the carbon atoms to which B and X are attached form a double bond and Y is hydrogen

17. A compound as defined in claim 16, having formula (Ila)

18. A compound as defined in claim 16, having formula (lib)

19. A compound as defined in claim 16, having formula (lie)

A compound as defined in claim 16, having formula (lid)

21 . A compound of formula (III) in the form of the (i?)-enantiomer,

wherein:

X and Y are independently hydrogen or X and Y taken together are carbonyl; and

R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl provided that X, Y and R are not simultaneously hydrogen atoms.

A compound as defined in claim 21, having formula (Ilia)

(Ilia)

A compound as defined in claim 21, having formula (Illb)

(nib)

24. A compound of formula (IV)

wherein R is hydrogen, an optionally substituted Ci-C₆ alkyl, an optionally substituted benzyl or a suitable amino protecting moiety; preferably R is an optionally substituted Ci-C₆ alkyl; and more preferably R is methyl. 25. The compound according to any one of claims 16 to 24, wherein R is methyl.