NZ603483B - New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid - Google Patents

Abstract

603483 Disclosed herein is a preparation of (P1) ivabradine (I) involving a reductive amination reaction of 4-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-butyraldehyde (V) with ((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-amine (VI) in the presence of an iron-based catalyst (VII), optionally in the presence of trimethylamine N-oxide, under dihydrogen pressure of 1-20 bars, in an organic solvent or mixture of organic solvents, at 25-100°C iron-based catalyst (VII), optionally in the presence of trimethylamine N-oxide, under dihydrogen pressure of 1-20 bars, in an organic solvent or mixture of organic solvents, at 25-100°C

Description

NEW ZEALAND PATENTS ACT, 1953 TE SPECIFICATION NEW PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ADDITION SALTS THEREOF WITH A PHARMACEUTICALLY ABLE ACID We, LES LABORATOIRES SERVIER, a company of 35, rue de Verdun, 92284 Suresnes Cedex, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention s to a process for the synthesis of ivabradine of formula (I): H3CO 3 N N H3CO or 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trienyl]methyl}(methyl)amino]- propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2Hbenzazepinone, addition salts thereof with a pharmaceutically acceptable acid, and hydrates thereof.

Ivabradine, and its addition salts with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable cological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial mia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in s pathologies involving rhythm disturbances, ally supraventricular rhythm disturbances, and in heart failure.

The preparation and therapeutic use of ivabradine and its addition salts with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the an patent specification EP 0 534 859. Unfortunately, the ivabradine synthesis route described in that patent specification results in the expected product in a yield of only 1 %.

Another ivabradine synthesis route, which is based on a reductive ion reaction, has been described in the European patent ication EP 1 589 005.

Reductive amination is a route that is a favoured approach for preparing amines. As this approach does not require isolation of the intermediate imine formed, this coupling reaction between an aldehyde and an amine in the presence of a reducing agent is widely used for the synthesis of compounds that are of value in the pharmaceutical or emical fields and also in materials science.

The ural protocols conventionally employed for carrying out reductive amination are: • either use of stoichiometric amounts of hydride donors such as drides (NaBH4, NaBH3CN or Ac)3), • or catalytic hydrogenation.

The use of hydride donors generates numerous waste products and the reagents in themselves are toxic.

In the case of catalytic hydrogenation, the fact that the reducing agent is molecular hydrogen is certainly of environmental value. The synthesis described in patent specification EP 1 589 005 follows this second route.

The patent specification EP 1 589 005 namely describes the synthesis of ivabradine hydrochloride starting from the compound of a (II): H CO N O (II) H CO O 3 O which is subjected to a tic hydrogenation reaction in the presence of hydrogen and a palladium catalyst to yield the compound of formula (III): H CO N O (III) H CO O O which, without being isolated, is reacted, in the presence of hydrogen and a palladium catalyst, with the compound of formula (IV): OCH3 . HCl (IV) N OCH3 to yield ivabradine of formula (I), in hydrochloride form.

The antage of that synthesis route is the use of a palladium catalyst.

Palladium, like m, ruthenium or iridium, metals that are likewise used for catalysing reductive ion reactions, is a precious metal, the scarcity - and consequently high price - and also the toxicity of which limit its acceptability.

The present Application describes an ivabradine synthesis route which makes it possible to dispense with the use of a precious metal.

The present invention relates namely to a s for the synthesis of ivabradine of formula (I): H3CO 3 N N H3CO O characterised in that the compound of formula (V): H CO N O (V) H CO 3 O is subjected to a reductive amination reaction with the amine of formula (VI): OCH3 (VI) N OCH3 in the presence of an ased catalyst, in the presence or not of trimethylamine N-oxide, under dihydrogen pressure of from 1 to 20 bars, in an organic solvent or mixture of organic solvents, at a temperature from 25 to 100°C, wherein the ased st has the following general formula: R2 X R3 R4 (VII) 1 L L2 3 wherein R1, R2, R3 and R4 independently represent: • a hydrogen atom, or • a group –SiR5R6R7, wherein R5, R6 and R7 independently ent an optionally substituted, linear or branched (C1-C6)alkyl group or an optionally substituted aromatic or heteroaromatic group, or • an optionally substituted aromatic or heteroaromatic group, or • an ally substituted, linear or branched (C1-C6)alkyl group, or • an electron-attracting group, or • an amine group that is aliphatic, aromatic, heteroaromatic or carrying an electronattracting group, or • an tic, aromatic or aromatic ether group, or the pairs R1 and R2, or R2 and R3, or R3 and R4 form, together with the carbon atoms carrying them, a 3- to 7-membered carbocycle or heterocycle, X represents: • an oxygen atom, or • a –NH group or a nitrogen atom substituted by an aliphatic, aromatic, heteroaromatic or electron-attracting group, or • a –PH group or a phosphorus atom substituted by one or more aliphatic, aromatic or electron-attracting groups, or • a sulphur atom, L1, L2 and L3 independently represent a carbonyl, nitrile, isonitrile, heteroaromatic, phosphine, phosphite, phosphonite, phosphoramidite, phosphinite, phospholane, phospholene, aliphatic amine, aromatic amine, heteroaromatic amine, electron-attracting-group-carrying amine, aliphatic ether, ic ether, heteroaromatic ether, sulphone, sulphoxide or sulphoximine group or an rocyclic carbene group having one of the two following formulae: Y Z R wherein Y and Z independently represent a sulphur or oxygen atom or a group NR8 n R8 represents an optionally substituted alkyl group or an ally substituted aromatic or heteroaromatic group, K represents a carbon or nitrogen atom, R9 and R10 independently represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aromatic or heteroaromatic group, a halogen atom, an aliphatic, aromatic or heteroaromatic ether group, an aliphatic, aromatic or heteroaromatic amine group, or the pair R9 and R10 form, together with the atoms carrying them, a 3- to 7-membered carbocycle or heterocycle, or R11 C R12 N N wherein R11 and R12 independently represent an ally substituted alkyl group or an optionally substituted aromatic or heteroaromatic group and n is 1 or 2 Unlike precious metal compounds, iron compounds are usually non-toxic and iron salts are abundantly present in nature. They are metallic entities which are not harmful to the environment. The present ion proposes using metal complexes which are, in on, easy to handle.

Iron complexes are known to catalyse reductive amination reactions in the presence of silylated hydrides (Enthaler S. ChemCatChem 2010 , 2, 1411-1415) but there are only two examples in the literature which be reductive amination based on catalytic hydrogenation (Bhanage B. M. et al Tet. Lett. 2008 , 49 , 965-969; Beller M. et al. Chem Asian J. 2011 , 6, 2240-2245).

The operating conditions bed by e require the presence of a water-soluble complex composed of an I) salt and EDTA in a medium heated to a high temperature and under a high hydrogen pressure.

Applying the operating conditions described in that publication to the preparation of ivabradine did not enable the expected product to be ed.

The following Table summarises the tests carried out in a 20-mL autoclave in the presence of 4 mL of degassed water, under 30 bars of hydrogen for 18 hours. The reactions were carried out at the scale of 0.5 mmol with an aldehyde/amine ratio of 1/1.5 (except for line 1: aldehyde/amine (1/1) and addition of 1 % p-toluenesulphonic acid). The amounts in mol% are calculated with respect to the aldehyde.

NTf is the abbreviation for trifluoromethanesulphonamide.

Table 1. Results for reductive amination reactions catalysed by iron(II) salts Iron(II) salt Amount (mol%) Temperature Findings (mol%) of EDTANa2 (°C) 1 7 H2O (2) 10 150 0% ivabradine - degradation 2 FeSO4.7 H2O (2) 10 85 0% ivabradine 3 FeCl2.4 H2O (5) 10 85 0% ivabradine 4 FeBr2.4H2O (5) 10 85 0% ivabradine Fe(BF4)2.6H2O (5) 10 85 0% ivabradine 6 Fe(NTf2)2.6H2O (5) 10 85 0% ivabradine The publication by Beller describes the reductive amination of various aldehydes by aniline derivatives in the presence of Fe3(CO)12 in toluene under 50 bars of en at 65°C.

Applying the ing conditions described in that publication to the ation of ivabradine did not enable the expected product to be obtained.

The following Table summarises the tests, which were carried out in the presence of 1.7 mol% Fe3(CO)12 in various solvents at 65°C under 25 bars of hydrogen for 18 hours.

The reactions were carried out in a 20-mL autoclave in the presence of 4 mL of degassed solvent.

The tests were ted at the scale of 1 mmol with an aldehyde/amine ratio of 1/1 with 1 % p-toluenesulphonic acid.

Table 2. Results for ive amination reactions catalysed by Fe3(CO)12 Solvent Findings 1 toluene 0% ivabradine 2 dichloromethane 0% ivabradine 3 tetrahydrofuran 0% ivabradine 4 N-methylpyrrolidone 0% ivabradine The iron-based st used in the reaction for the reductive amination of the compound of formula (V) with the compound of a (VI) has the following general formula: 2 X R (VII) 3 4 1 L L 3 wherein R1, R2, R3 and R4 independently represent: • a en atom, or • a group –SiR5R6R7, wherein R5, R6 and R7 independently represent an optionally substituted, linear or branched (C1-C6)alkyl group or an optionally substituted aromatic or heteroaromatic group, or • an optionally substituted aromatic or heteroaromatic group, or • an optionally substituted, linear or branched (C1-C6)alkyl group, or • an on-attracting group, or • an amine group that is aliphatic, aromatic, heteroaromatic or carrying an electronattracting group, or • an tic, aromatic or heteroaromatic ether group, or the pairs R1 and R2, or R2 and R3, or R3 and R4 form, together with the carbon atoms ng them, a 3- to 7-membered carbocycle or heterocycle, X ents: • an oxygen atom, or • a –NH group or a nitrogen atom tuted by an aliphatic, aromatic, heteroaromatic or electron-attracting group, or • a –PH group or a phosphorus atom substituted by one or more tic, aromatic or electron-attracting groups, preferably forming a phosphine, phosphite, phosphonite, phosphoramidite, phosphinite, phospholane or phospholene group, or • a sulphur atom, L1, L2 and L3 independently represent a carbonyl, nitrile, isonitrile, aromatic, phosphine, phosphite, phosphonite, phosphoramidite, phosphinite, phospholane, phospholene, aliphatic amine, aromatic amine, heteroaromatic amine, electron-attracting-group-carrying amine, aliphatic ether, aromatic ether, heteroaromatic ether, sulphone, sulphoxide or sulphoximine group or an N-heterocyclic carbene group having one of the two following formulae: Y Z R n Y and Z independently represent a sulphur or oxygen atom or a group NR8 wherein R8 represents an optionally substituted alkyl group or an optionally substituted aromatic or heteroaromatic group, K represents a carbon or nitrogen atom, R9 and R10 independently represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aromatic or heteroaromatic group, a halogen atom, an aliphatic, aromatic or heteroaromatic ether group, an aliphatic, aromatic or heteroaromatic amine group, or the pair R9 and R10 form, together with the atoms carrying them, a 3- to ered carbocycle or heterocycle, R11 C R12 N N wherein R11 and R12 independently ent an optionally substituted alkyl group or an optionally substituted aromatic or heteroaromatic group and n is 1 or 2.

An on-attracting group is a group which attracts electrons more than a hydrogen atom occupying the same position in the molecule would.

Among the electron-attracting groups there may be mentioned, without implying any tion, the following : ester, acid, nitrile, aldehyde, ketone, amide, nitro, sulphone, sulphoxide, ximine, sulphonamide or phosphoric diester.

In an embodiment of the invention, the iron-based catalyst used in the reaction for the reductive amination of the compound of formula (V) with the compound of formula (VI) has the following l formula: R O R R4 (VIII) OC CO wherein R2 and R3 each represent a en atom or form, together with the carbon atoms carrying them, a 3- to 7-membered carbocycle or heterocycle, and R1 and R4 independently represent: • either a group –SiR5R6R7, wherein R5, R6 and R7 ndently represent an optionally substituted, linear or branched (C1-C6)alkyl group or an ally substituted aryl group, • or an optionally substituted aromatic or heteroaromatic group, • or an optionally substituted, linear or branched (C1-C6)alkyl group.

The catalyst of formula (VIII) used in the reaction for the reductive amination of the compound of formula (V) with the compound of formula (VI) is preferably ed from the following catalysts: SiMe3 SiMe3 (IX) O (X) SiMe3 S OC Fe SiMe O OC Fe 3 OC CO O OC CO Si(iPr)3 Si(iPr)3 O (XI) O N O (XII) S Si(iPr)3 O OC Fe Si(iPr)3 OC Fe OC CO OC CO In another embodiment of the invention, the iron-based catalyst used in the reaction for the reductive amination of the compound of formula (V) with the compound of formula (VI) has the following general a: R O 2 (XIII) R R 3 4 OC N wherein R2 and R3 each ent a hydrogen atom or form, together with the carbon atoms carrying them, a 3- to 7-membered carbocycle or heterocycle, and R1 and R4 independently represent: • either a group –SiR5R6R7, wherein R5, R6 and R7 independently represent an optionally tuted, linear or branched (C1-C6)alkyl group or an optionally substituted aromatic or heteroaromatic group, • or an optionally substituted aromatic or heteroaromatic group, • or an optionally substituted, linear or branched (C1-C6)alkyl group.

The catalyst of formula (XIII) used in the reaction for the reductive amination of the nd of a (V) with the compound of formula (VI) is preferably selected from the following catalysts: SiMe3 SiMe3 O O (XIV) EtO2C (XV) OC Fe SiMe3 EtO2C SiMe3 OC Fe OC N OC N In r embodiment of the invention, the iron-based catalyst used in the on for the reductive amination of the compound of formula (V) with the compound of formula (VI) has the following formula: SiMe (XVI) OC Fe SiMe3 OC N In another ment of the invention, the iron-based catalyst used in the reaction for the reductive amination of the compound of formula (V) with the compound of a (VI) has the ing formula: (XVII) The amount of catalyst used in the reaction for the ive amination of the compound of formula (V) with the compound of formula (VI) is from 1 mol% to 10 mol% relative to the aldehyde.

The amount of trimethylamine N-oxide used in the reaction for the reductive amination of the compound of formula (V) with the compound of formula (VI) is from 0 to 3 equivalents relative to the catalyst, more preferably from 0.5 to 1.5 equivalents relative to the catalyst.

The ogen pressure in the reaction for the reductive amination of the compound of formula (V) with the compound of formula (VI) is preferably from 1 to 20 bars, more preferably from 1 to 10 bars, and even more ably from 1 to 5 bars.

Among the solvents that may be used for carrying out the reaction for the reductive amination of the compound of formula (V) with the compound of formula (VI) there may be mentioned, without implying any limitation, alcohols, preferably ethanol, isopropanol, trifluoroethanol, utanol or methanol, tetrahydrofuran, ethyl acetate, acetonitrile and dioxane.

The solvent preferably used for carrying out the reaction for the reductive amination of the compound of formula (V) with the compound of formula (VI) is ethanol.

The temperature of the reductive amination reaction between the compound of formula (V) and the compound of formula (VI) is preferably from 25 to 100°C, more preferably from 50 to 100°C, and even more preferably from 80 to 100°C.

The term “comprising” as used in this ication and claims means “consisting at least in part of”. When interpreting statements in this ication and claims which include the term “comprising”, other features besides the features prefaced by this term in each statement can also be present. Related terms such as “comprise” and “comprised” are to be reted in similar manner.

In this specification where reference has been made to patent ications, other external documents, or other sources of information, this is lly for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

In the description in this ication nce may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be y identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.

The es hereinbelow illustrate the invention.

The column chromatography cation procedures are carried out on 70-230 mesh silica gel.

The 1H NMR spectra are recorded at 400 MHz.

The chemical shifts are expressed in ppm (internal reference: TMS).

The following abbreviations have been used to describe the peaks: singlet (s), doublet (d), doublet of doublets (dd), triplet (t), quadruplet (q), multiplet (m).

The catalysts used in the process of the invention can be prepared in accordance with the methods described in the following publications: Synlett 1992 , pp1002-1004, Synlett 1993 , pp924-926 and Advanced Synthesis and Catalysis 2012 , 354 (4), pp597-601.

General pprroocceedduurree AA ffoorr ppaarraattiioonn ooff 33--{{33--[[{{[[((77SS))--33,,44--ddiimmeetthhooxxyybbiiccyycclloo[[44..22..00]]ooccttaa-- 1,3,5-trienyl]methyl}(methyl)amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H benzazepinone 1 mmol of [(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trienyl]-N-methylmethanamine and 1 mmol of 3-(7,8-dimethoxyoxo-1,2,4,5-tetrahydro-3Hbenzazepinyl)propanal are uced into a clean and dry stainless-steel autoclave under an argon atmosphere. The mixture is degassed by three vacuum/argon cycles, and 2 mL of distilled and degassed ethanol are added. The solution is stirred at 85°C for one hour.

A mixture of 5 mol% of iron complex and 5 mol% of trimethylamine e in 1 mL of ethanol is prepared over 30 minutes in a Schlenk tube under an argon atmosphere and then introduced into the autoclave.

The autoclave is then placed under hydrogen pressure (5 bars) and the reaction mixture is stirred at 85°C for 16 hours and the autoclave is then ed to ambient temperature and decompressed.

The reaction mixture is filtered over deactivated neutral alumina (3 % water) using ethyl acetate as solvent.

The crude product is purified on silica gel (eluant: pentane/ethyl acetate (95/5) with 0.5 % ylamine) to obtain the expected product.

General pprroocceedduurree BB ffoorr pprreeppaarraattiioonn ooff 33--[[{{[[((77SS))--33,,44--ddiimmeetthhooxxyybbiiccyycclloo[[44..22..00]]ooccttaa-- 1,3,5-trienyl]methyl}(methyl)amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H benzazepinone 1 mmol of [(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trienyl]-N-methylmethanamine and 1 mmol of 3-(7,8-dimethoxyoxo-1,2,4,5-tetrahydro-3Hbenzazepinyl)propanal are introduced into a clean and dry stainless-steel ave under an argon atmosphere. The mixture is degassed by three vacuum/argon cycles and 3 mL of distilled and degassed ethanol are added. The solution is stirred at 85°C for one hour. The iron complex (5 mol%) is added under argon. The autoclave is then placed under hydrogen re (5 bars) and the reaction mixture is stirred at 85°C for 16 hours and then the autoclave is returned to t temperature and decompressed.

The reaction mixture is filtered over deactivated neutral alumina (3 % water) using ethyl acetate as solvent.

The crude product is purified on silica gel (eluant: pentane/ethyl acetate (95/5) with 0.5 % triethylamine) to obtain the expected t.

EXAMPLE 11 3-{3-[{[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trienyl]methyl}(methyl)amino]- propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2Hbenzazepinone is prepared according to general procedure A in the presence of the iron st of formula (IX).

Yield = 61 % 1H NMR (CDCl 3): δ = 6.67 and 6.64 (2s, 2H); 6.55 and 6.50 (2s, 2H); 3.79 and 3.78 (2s, 12H); 3.76 (s, 2H); 3.67 (m, 2H); 3.45 (m, 3H); 3.17 (dd, 1H); 2.99 (m, 2H); 2.65 (m, 2H); 2.50 (dd, 1H); 2.37 (t, 2H); 2.26 (s, 3H); 1.72 (q, 2H).

EXAMPLE 22 3-{3-[{[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trienyl]methyl}(methyl)amino]- propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2Hbenzazepinone is prepared according to general procedure A in the ce of the iron st of formula (X).

Yield = 63 % EXAMPLE 33 3-{3-[{[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trienyl]methyl}(methyl)amino]- propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2Hbenzazepinone is prepared according to general procedure A in the presence of the iron catalyst of formula (XI).

Yield = 79 % EXAMPLE 44 3-{3-[{[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trienyl]methyl}(methyl)amino]- propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2Hbenzazepinone is prepared according to general ure A in the presence of the iron catalyst of formula (XII).

Yield = 68 % EXAMPLE 55 3-{3-[{[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trienyl]methyl}(methyl)amino]- propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2Hbenzazepinone is ed according to general ure B in the presence of the iron catalyst of formula (XIV).

Yield = 68 % E 66 3-{3-[{[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trienyl]methyl}(methyl)amino]- propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2Hbenzazepinone is prepared according to general procedure B in the ce of the iron catalyst of formula (XV).

Yield = 68 % EXAMPLE 77 3-{3-[{[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trienyl]methyl}(methyl)amino]- propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2Hbenzazepinone is prepared according to general procedure B in the presence of the iron catalyst of formula (XVI).

Yield = 59 % EXAMPLE 88 3-{3-[{[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trienyl]methyl}(methyl)amino]- propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2Hbenzazepinone is prepared according to general procedure B in the presence of the iron catalyst of formula (XVII).

Yield = 48 %

Claims (16)

WHAT WE CLAIM IS::

1. Process for the sis of ivabradine of formula (I): H3CO 3 N N H3CO characterised in that the compound of formula (V): H CO N O (V) H CO 5 O is subjected to a ive amination reaction with the amine of formula (VI): OCH3 (VI) N OCH3 in the presence of an iron-based catalyst, in the presence or not of trimethylamine N-oxide, 10 under dihydrogen pressure of from 1 to 20 bars, in an organic solvent or mixture of organic solvents, at a temperature from 25 to 100°C, wherein the iron-based catalyst has the following general formula: R2 X R3 R4 (VII) 1 L L2 3 wherein R1, R2, R3 and R4 independently represent: • a hydrogen atom, or • a group –SiR5R6R7, wherein R5, R6 and R7 independently represent an ally 5 substituted, linear or branched (C1-C6)alkyl group or an optionally substituted aromatic or heteroaromatic group, or • an optionally substituted ic or heteroaromatic group, or • an ally tuted, linear or branched (C1-C6)alkyl group, or • an electron-attracting group, or 10 • an amine group that is aliphatic, aromatic, heteroaromatic or carrying an electronattracting group, or • an aliphatic, aromatic or heteroaromatic ether group, or the pairs R1 and R2, or R2 and R3, or R3 and R4 form, together with the carbon atoms carrying them, a 3- to 7-membered carbocycle or heterocycle, 15 X represents: • an oxygen atom, or • a –NH group or a nitrogen atom substituted by an aliphatic, aromatic, aromatic or electron-attracting group, or • a –PH group or a orus atom substituted by one or more aliphatic, aromatic or 20 electron-attracting groups, or • a sulphur atom, L1, L2 and L3 independently represent a carbonyl, nitrile, isonitrile, heteroaromatic, phosphine, phosphite, phosphonite, phosphoramidite, phosphinite, phospholane, phospholene, aliphatic amine, aromatic amine, heteroaromatic amine, electron-attracting-group-carrying 25 amine, aliphatic ether, aromatic ether, heteroaromatic ether, sulphone, sulphoxide or sulphoximine group or an rocyclic carbene group having one of the two following formulae: Y Z 10 R wherein Y and Z independently represent a sulphur or oxygen atom or a group NR8 wherein R8 represents an optionally substituted alkyl group or an optionally tuted aromatic or heteroaromatic group, 5 K represents a carbon or en atom, R9 and R10 ndently represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aromatic or heteroaromatic group, a halogen atom, an aliphatic, aromatic or heteroaromatic ether group, an tic, aromatic or heteroaromatic amine group, or the pair R9 and R10 form, together with the atoms carrying them, a 3- to 7-membered 10 carbocycle or cycle, R11 C R12 N N wherein R11 and R12 independently represent an optionally substituted alkyl group or an optionally substituted aromatic or heteroaromatic group and n is 1 or 2. 15

2. sis process according to claim 1, wherein the iron-based catalyst has the following general formula: R2 O R R (VIII) 3 4 OC CO wherein R2 and R3 each represent a hydrogen atom or form, together with the carbon atoms carrying them, a 3- to 7-membered carbocycle or heterocycle, 20 and R1 and R4 independently represent: • either a group –SiR5R6R7, wherein R5, R6 and R7 independently represent an optionally substituted, linear or branched (C1-C6)alkyl group or an ally substituted aryl group, • or an optionally substituted aromatic or heteroaromatic group, 5 • or an optionally substituted, linear or branched (C1-C6)alkyl group.

3. Synthesis process according to claim 2, wherein the iron-based catalyst is selected from: SiMe3 SiMe3 (IX) O (X) Fe SiMe3 S OC SiMe O OC Fe OC OC CO Si(iPr)3 Si(iPr)3 O (XI) O N O (XII) S Si(iPr)3 O OC Fe )3 O OC OC CO OC CO

4. Synthesis process according to claim 1, characterised in that the iron-based catalyst has the following general formula: R O 2 (XIII) R R 3 4 OC N wherein R2 and R3 each represent a hydrogen atom or form, together with the carbon atoms ng them, a 3- to ered ycle or heterocycle, and R1 and R4 independently represent: • either a group –SiR5R6R7, wherein R5, R6 and R7 independently represent an 15 optionally substituted, linear or branched (C1-C6)alkyl group or an optionally tuted aromatic or heteroaromatic group, • or an optionally substituted aromatic or heteroaromatic group, • or an optionally substituted, linear or branched (C1-C6)alkyl group.

5. Synthesis s according to claim 4, terised in that the iron-based catalyst is selected from: SiMe3 SiMe3 O O (XIV) EtO2C (XV) Fe SiMe3 EtO2C SiMe3 OC OC Fe OC N OC N

6. Process according to claim 1, characterised in that the iron-based catalyst has the 5 following formula: SiMe (XVI) OC Fe SiMe3 OC N

7. Process according to claim 1, characterised in that the ased catalyst has the 10 following formula: (XVII)

8. Synthesis process according to any one of claims 1 to 7, characterised in that the amount of catalyst used in the reductive amination reaction is from 1 mol% to 10 mol% relative to the aldehyde. 15

9. Synthesis process according to any one of claims 1 to 8, characterised in that the amount of trimethylamine N-oxide used in the ive amination reaction is from 0 to 3 equivalents relative to the catalyst.

10. Synthesis process according to claim 9, characterised in that the amount of hylamine N-oxide used in the reductive amination reaction is from 0.5 to 1.5 equivalents relative to the catalyst.

11. Synthesis process according to any one of claims 1 to 10, characterised in that the 5 dihydrogen re in the reductive amination on is from 1 to 10 bars.

12. Synthesis process according to any one of claims 1 to 11, characterised in that the solvent in the reductive amination reaction is an alcohol.

13. Synthesis process according to claim 12, characterised in that the solvent in the reductive amination reaction is ethanol. 10

14. Synthesis process according to any one of claims 1 to 13, characterised in that the temperature of the reductive amination reaction is from 50 to 100°C.

15. Ivabradine of formula I as defined in claim 1 when prepared using the s of any one of claims 1-14.

16. A process according to claim 1, substantially as herein described with reference to any e thereof.