Claims:
1. A process for the preparation of compound of formula I

or any pharmaceutically acceptable salt, hydrate or solvate thereof
wherein the configuration at the stereogenic centre marked as (*) is either (R)-, (S)- or mixture of both isomers in any ratio;
n equals to 0, 1, 2, 3, 4 or 5;
R is alkyl, alkenyl, alkynyl or alkoxy group wherein chain group is either straight or branched with 1 to 15 carbon atoms;
and A may be an aromatic or heteroaromatic ring, wherein an aromatic ring is a C6-18 aromatic group, formed by one or more rings, and a heterocyclic ring is an aromatic ring as defined above, which contains one or more heteroatoms, each of which may be optionally substituted with one or more substituents selected from the following groups:
i) alkyl group, wherein alkyl means a monovalent straight or branched chain group of the formula CmH2m+1 or a cyclic group of the formula CmH2m-1, with m being 1 to 15 carbon atoms;
ii) haloalkyl group, wherein haloalkyl means alkyl groups substituted with one or more halogen atoms in one or more positions of the alkyl chain;
iii) alkenyl group, wherein alkenyl means monovalent straight or branched chain moieties containing one or more carbon-carbon double bonds and at least 2 carbon atoms, which moieties conform to the formula CmH(2m-1), with m being 1 to 15 carbon atoms present;
iv) alkynyl group, wherein alkynyl means monovalent straight or branched chain moieties containing one or more carbon-carbon triple bonds and at least 2 carbon atoms, which moieties conform to the formula CmH(2m-3), with m being 1 to 15carbon atoms present;
v) aryl group, wherein aryl means aromatic ring, as defined above;
vi) halogen atom
vii) hydroxyl group
viii) substituted hydroxyl group, wherein substituted hydroxyl means -O-alkyl, -O-aryl, -O-C(O)-alkyl, -O-C(O)-aryl, -O-SO2-O-alkyl, -O-SO2-O-haloalkyl, -O-SO-2-O-aryl;
ix) amino group;
x) aminoalkyl groups, wherein aminoalkyl means an amino group substituted with one or two of the same or different alkyl groups;
xi) nitro group;
xii) cyano group;
xiii) formyl group;
xiv) alkyl carbonyl group, wherein alkyl carbonyl means alkyl-C(O)-;
xv) alkoxycarbonyl group, wherein alkoxycarbonyl means alkyl-O-C(O)- groups;
xvi) carboxyl group;
comprising the steps of :
a) selective reduction of cyano group of compound of formula II to form compound of formula IIIa

b) optional transimination using non racemic amine RcNH2 to enrich the formation of (S)-enantiomer

wherein compound of formula IIIb is a mixture of geometric isomers (syn/anti) in any ratio;
and the configuration at the stereogenic center marked as (*) is (S)- or mixture of both isomers in any ratio;
c) transimination to prepare compound of formula IV from compound of formula III

wherein R’ is either an hydrogen atom or Rc;
R is as defined above;
the configuration at the stereogonic centre marked as (*) is either (S)- or mixture of both isomers in any ratio;
and compound of formula IV is a mixture of geometric isomers (syn/anti) in any ratio;
d) reduction of the imine double bond to form compound of formula I

wherein the configuration at the stereogenic centre marked as (*) is (S)- or mixture of both isomers in any ratio.

2. A process for the preparation of compound of formula Ias according to claim 1

or any pharmaceutically acceptable salt, hydrate or solvate thereof;
wherein the configuration at the stereogenic centre marked as (*) is (S)-;
n equals to 1;
R is a methyl group;
and A is an C6 aromatic ring substituted in positions 3- and 4- with a methoxy group.
comprising the steps a), b), c) and d).

3. A process for the preparation of compound of formula Ia according to claim 1

or any pharmaceutical acceptable salt, hydrate or solvate thereof;
wherein the configuration at the stereogonic centre marked as (*) is a mixture of both isomers in any ratio;
n equals to 1;
R is a methyl group;
and A is an C6 aromatic ring substituted in positions 3- and 4- with a methoxy group.
comprising the steps a), c) and d).

4. A process for preparation of compound of formula VI

or any pharmaceutically acceptable salt, hydrate or solvate thereof;
comprising the steps of
a) resolving compound of formula Ia as prepared in claim 3 using an optical active acid to form compound of formula VII

b) converting compound of formula VII to compound of formula Ias or any pharmaceutically acceptable salt, hydrate or solvate thereof

c) reaction of compound of formula Ias or any pharmaceutically acceptable salt, hydrate or solvate thereof as prepared in step (a), (b) or as prepared in claim 2 with compound of formula V

wherein Hal is selected from chloro, bromo and iodo preferably bromo;
to form compound of formula IX or any pharmaceutically acceptable salt, hydrate or solvate thereof

d) reduction of double bond of compound of formula IX or any pharmaceutically acceptable salt, hydrate or solvate thereof to form compound of formula VI

e) optionally converting compound of formula VI to any pharmaceutically acceptable salt, hydrate and solvate thereof.

5. A process according to claims 1, 2 and 3 wherein in step (a) the reduction of the cyano group is performed in the presence of a reducing agent or in the presence of hydrogen and Lindlaar’s catalyst.

6. A process according to claim 5 wherein the reducing agent in step (a) is selected from DIBAL-H, a borane agent.

7. A process according to claim 6 wherein the reducing agent in step (a) is DIBAL-H.

8. A process according to claims 1 and 2 wherein in step (b) RcNH2 is a non-racemic amine, such as (S)- or (R)-α-methylbenzylamine, (S)- or (R)-α-methyl-4-nitrobenzylamine, (S)- or (R)-phenylglycine amide, (R)- or (S)-1-(1-naphthyl)ethylamine, (R)- or (S)-1-aminoindane, trans-(1R, 2R)-1-aminoindan-2-ol, trans-(1S, 2R)-1-aminoindan-2-ol, trans-(1R, 2S)-1-aminoindan-2-ol, trans-(1S, 2S)-1-aminoindan-2-ol, trans-(1R,2R)-6-nitro-1-aminoindan-2-ol, trans-(1S,2R)-6-nitro-1-aminoindan-2-ol, trans-(1R,2S)-6-nitro-1-aminoindan-2-ol, trans-(1S,2S)-6-nitro-1-aminoindan-2-ol, or enantiomeric pure amine of general formula A

wherein ring B may be a β-naphthol ring and Ar a phenyl ring which are independently optionally substituted.

9. A process according to claim 8 wherein in step (b) the non-racemic amine is trans-(1R,2R)-6-nitro-1-aminoindan-2-ol.

10. A process according to claim 8 wherein in step (b) the non-racemic amine is an enantiomeric pure amine of general formula A

wherein ring B may be a β-naphthol ring and Ar is a phenyl group which are independently optionally substituted.

11. A process according to claim 10 wherein in step (b) the non-racemic amine is compound of formula A1.

12. A process according to claims 1, 2 and 3 wherein the reduction of the imine double bond in step (d) is performed in the presence of a reducing agent selected from LiAlH4, LiBH4, NaBH4, NaBH3CN, NaB(OAc)3H, Red-Al.

13. A process according to claim 12 wherein the reducing agent is NaBH4.

14. A process according to claim 4 wherein in step (a) the resolution is performed in the presence of an optical active carboxylic acid such as CSA, glutaminic acid.

15. A process according to claim 14 wherein the optical active acid is CSA.

16. A process according to claim 4 wherein in step (c) the nucleophilic substitution is performed in the presence of a base.

17. A process according to claim 16 wherein base is selected from alkali metal carbonates, bicarbonates and hydroxides.

18. A process according to claim 17 wherein the base is potassium carbonate.

19. A process according to claim 4 wherein in step (d) the hydrogenation of the double bond of compound of formula IX is performed in the presence of a suitable catalytic system in a suitable solvent.

20. A process according to claim 19 wherein the hydrogenation of the double bond in step (d) is performed in the presence of hydrogen and palladium on charcoal.

21. A process for the preparation of compound of formula Va or any pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Hal is a chloro atom comprising the steps of:

a) dissolving compound of formula X in N, N’-dimethylformamide
b) adding under stirring 1-bromo-3-chloropropane
c) adding potassium hydroxide at a temperature between -5oC to 20oC, preferably between 0oC to 5oC.
, Description:
TECHNICAL FIELD OF THE INVENTION

The present invention relates to a novel preparation method for (S)-1-(3,4-dimethoxy bicyclo [4.2.0] octa - 1, 3, 5 - trien - 7 - yl) - N - methylmethanamine, key intermediate for the preparation of Ivabradine or any pharmaceutically acceptable salt, hydrate or solvate thereof.

BACKGROUND OF THE INVENTION

Ivabradine of formula (I) is an alternative drug for the treatment of stable angina pectoris in case of intolerance or contraindication for beta receptor blockers. Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated.
The first reported synthesis of Ivabradine of formula I is disclosed in EP0534859B by Adir Company as described in scheme below.

N-methylation of the amine derivative was performed using chloroformate followed by reduction of the corresponding amide. Resolution of the methylamine derivative was performed in the presence CSA to enrich the formation of the (S)-enantiomer. Nucleophilic substitution reaction with N-iodo-propyl benzazepinone fragment and subsequent hydrogenation of the double bond in the benzazepinone moiety led to the formation of Ivabradine (I).

Servier, in EP1598333B, proposed an alternative pathway for the preparation of key intermediate of formula V according to the following scheme where the resolution was made before the N-methylation.

Servier Laboratories in another patent application -WO2010023383- perform the resolution in the racemic carbon of the cyclobutano ring moiety in the first step prior to the reduction of the cyano group.

In WO2011183625, Richter Gedeon describes a novel process for the preparation of key intermediate VII. Propionyl nitrile derivative of formula I reacted with an alkali alkyl amide to form cyclobutano nitrile derivative of formula II. Hydrolysis of compound of formula II resulted carboxylic acid derivative of formula III wherein resolution with the use of optically active tertiary amine led to the formation of the enriched (S)-carboxylic acid derivative of formula V. The carboxylic acid moiety is activated to the corresponding acyl chloride where reaction with methylamine led to the formation of the methyl amide derivative of formula VI. Reduction of the amide carbonyl group formed the methyl amine of formula VII.

In 1317/MUM/20120 application, Unichem followed a different route for the formation of the methyl amine salt of formula V comprising formylation of the amine derivative of formula I, subsequent methylation and hydrolysis.

For the resolution of the methylamine of formula IV mandelic acid was employed to form the corresponding salt of formula V.

Process for the preparation of key intermediate of formula VII is also disclosed in CN101857549 by MENOVO according to the scheme below.

In the Chinese patent application the formation of the methyl amine key intermediate of formula VII is formed via nucleophilic substitution of N-Boc methyl amine to the compound of formula IV followed by Boc-deprotection and resolution of the racemic methylamine derivative of formula VI.

In CN103524360 patent application, Anteng Pharmaceutical demonstrated a new process for the preparation of compound of formula I. Initially they perform resolution of the amine derivative of formula IV followed by formylation. Finally they performed reduction of the resulting carboxamide derivative of formula II using zinc and hydrochloric acid.

It is obvious that in all above mentioned processes Ivabradine’s precursor is formed in a lot of steps which are leading to low overall yields. Furthermore, the resolution in order to yield (S)-enantiomer is performed in a separate step. Thus, it was really challenging in finding a new short and cheap process for its production wherein the resolution could happen in a one-pot synthesis.

SUMMARY OF THE INVENTION

The present invention discloses a novel process for the preparation of compound of formula I or any pharmaceutically acceptable salt, hydrate or solvate thereof, from a compound of formula II,

wherein ring A may be an aromatic or heteroaromatic ring, each of which may be optionally substituted and the configuration at the stereogenic center marked as (*) is either (S)- or a mixture of both enantiomers.

The present invention discloses a new method for the preparation of compound of formula I comprising a one-pot formation of the alkylamine having the appropriate stereochemistry.

The present invention discloses a novel process comprising a transimination reaction followed by reductive amination.

The present invention discloses a novel process for the preparation of compound of formula I or any pharmaceutically acceptable salt, hydrate or solvate thereof, and its use for preparation of Ivabradine or any pharmaceutically acceptable salt, solvate or hydrate thereof.

The novel process for the preparation of the compound of formula I or any pharmaceutically acceptable salt, hydrate or solvate thereof, from compound of formula II comprises the steps of:
a) selective reduction of cyano group of compound of formula II to form compound of formula IIIa

b) optional transimination using non racemic amine RcNH2 to enrich the formation of (S)-enantiomer

wherein RcNH2 is an non racemic amine such as (S)- or (R)-α-methylbenzylamine, (S)- or (R)-α-methyl-4-nitrobenzylamine, (S)- or (R)-phenylglycine amide, (R)- or (S)-1-(1-naphthyl)ethylamine, (R)- or (S)-1-aminoindane, trans-(1R, 2R)-1-aminoindan-2-ol, trans-(1S, 2R)-1-aminoindan-2-ol, trans-(1R, 2S)-1-aminoindan-2-ol, trans-(1S, 2S)-1-aminoindan-2-ol and trans-(1R,2R)-6-nitro-1-aminoindan-2-ol, trans-(1S,2R)-6-nitro-1-aminoindan-2-ol, trans-(1R,2S)-6-nitro-1-aminoindan-2-ol, trans-(1S,2S)-6-nitro-1-aminoindan-2-ol, or enantiomeric pure amine of general formula A;

wherein ring B may be a β-naphthol ring and Ar is a phenyl ring which are independently optionally substituted with one or more substituents from the following groups:
i) alkyl group, wherein alkyl means a monovalent straight or branched chain group of the formula CmH2m+1 or a cyclic group of the formula CmH2m-1, with m being 1 to 15 carbon atoms;
ii) haloalkyl group, wherein haloalkyl means alkyl groups substituted with one or more halogen atoms in one or more positions of the alkyl chain;
iii) alkenyl group, wherein alkenyl means monovalent straight or branched chain moieties containing one or more carbon-carbon double bonds and at least 2 carbon atoms, which moieties conform to the formula CmH(2m-1), with m being 1 to 15 carbon atoms present;
iv) alkynyl group, wherein alkynyl means monovalent straight or branched chain moieties containing one or more carbon-carbon triple bonds and at least 2 carbon atoms, which moieties conform to the formula CmH(2m-3), with m being 1 to 15carbon atoms present;
v) aryl group, wherein aryl means aromatic ring, as defined above;
vi) halogen atom
vii) hydroxyl group
viii) substituted hydroxyl group, wherein substituted hydroxyl means -O-alkyl, -O-aryl, -O-C(O)-alkyl, -O-C(O)-aryl, -O-SO2-O-alkyl, -O-SO2-O-haloalkyl, -O-SO-2-O-aryl;
ix) amino group;
x) aminoalkyl groups, wherein aminoalkyl means an amino group substituted with one or two of the same or different alkyl groups;
xi) nitro group;
xii) cyano group;
xiii) formyl group;
xiv) alkyl carbonyl group, wherein alkyl carbonyl means alkyl-C(O)-;
xv) alkoxycarbonyl group, wherein alkoxycarbonyl means alkyl-O-C(O)- groups;
xvi) carboxyl group;
the configuration at the stereogenic center marked as (*) is either (S)- or mixture of both isomers in any ratio;
and compound of formula IIIb is a mixture of geometric isomers (syn/anti) in any ratio;
c) transimination to prepare compound of formula IV from compound of formula III

wherein R’ is either H or Rc as defined in step (b);
R is alkyl, alkenyl, alkynyl or alkoxy group wherein chain group is either straight or branched with 1 to 15 carbon atoms;
the configuration at the stereogenic center marked as (*) is (S)- or mixture of both isomers in any ratio;
and both compounds of formulae III and IV is are mixture of geometric isomers (syn/anti) in any ratio;
d) reduction of the imine double bond to form compound of formula I

wherein R is alkyl, alkenyl, alkynyl or alkoxy group wherein chain group is either straight or branched with 1 to 15 carbon atoms;
and the configuration at the stereogenic center marked as (*) is (S)- or mixture of both isomers in any ratio;
e) optionally converting compound of formula I to any pharmaceutically acceptable salt, hydrate or solvate thereof.

A particular object of the present invention is a previously undisclosed transimination followed by reductive amination, in order to convert a cyano group to the corresponding alkylamino group.

A further object of the present invention is the preparation of compound of formula IV from compound of formula III via transimination reaction.

Another embodiment in the present invention is the enrichment of (S)-enantiomer by dynamic kinetic resolution.

According to another object of the invention, steps a), b), c) and d) of the process described above are performed without isolation of any intermediate compound in the same solvent.

Another object of the present invention is the use of compound of formula I prepared by this process for the preparation of analogous derivatives i.e ivabradine.

A particular embodiment of the present application is the straightforward recovery of the non-racemic amine using a resin such as Dowex 50WX8-100.

In particular, the present invention discloses the preparation of compound of formula Ias or any pharmaceutically acceptable salt, hydrate or solvate thereof,

wherein the configuration at the stereogenic center marked as (*) is either (S)- or mixture of both enantiomers where the percentage of (R)-enantiomer is less than 20%;
n equals to 1;
R is a methyl group;
and A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions,
exhibiting improved yield, safe reagents and industrially applicable techniques.

The present invention discloses a novel process for the preparation of compound of formula Ias or any pharmaceutically acceptable salt, hydrate or solvate thereof, comprising a transimination reaction followed by reductive amination.

The novel process for the preparation of compound of formula Ias or any pharmaceutically acceptable salt, hydrate or solvate thereof, comprises the following steps:
a) selective reduction of compound of formula IIa wherein n equals to 1, and A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions to form compound of formula IIIa wherein n equals to 1, and A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions

wherein the configuration at the stereogenic center marked as (*) is a mixture of both isomers in any ratio;
b) transimination using a non-racemic amine RcNH2 and formation of compound of formula IIIb wherein n equals to 1, and A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions and RcNH2 is an non racemic amine such as (S)- or (R)-α-methylbenzylamine, (S)- or (R)-α-methyl-4-nitrobenzylamine, (S)- or (R)-phenylglycine amide, (R)- or (S)-1-(1-naphthyl)ethylamine, (R)- or (S)-1-aminoindane, trans-(1R, 2R)-1-aminoindan-2-ol, trans-(1S, 2R)-1-aminoindan-2-ol, trans-(1R, 2S)-1-aminoindan-2-ol, trans-(1S, 2S)-1-aminoindan-2-ol, trans-(1R,2R)-6-nitro-1-aminoindan-2-ol, trans-(1S,2R)-6-nitro-1-aminoindan-2-ol, trans-(1R,2S)-6-nitro-1-aminoindan-2-ol, trans-(1S,2S)-6-nitro-1-aminoindan-2-ol or enantiomeric pure amine of general formula A;

wherein ring B may be a β-naphthol ring and Ar is a phenyl ring which are independently may be optionally substituted as defined above;

wherein the compound of formula IIIb is a mixture of geometric isomers (syn, anti) in any ratio;
and the configuration at the stereogenic center marked as (*) is (S)- or mixture of both isomers where the percentage of (R)-enantiomer is less than 20%; ;
c) transimination reaction in compound of formula IIIb to form compound of formula IVa wherein n equals to 1, A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions, R is a methyl group

and compound of formula IVa is a mixture of geometric isomers (syn/anti) in any ratio and the configuration at the stereogenic center marked as (*) is (S)- or mixture of both isomers where the percentage of (R)-enantiomer is less than 20%;
d) reduction of compound of formula IVa to compound of formula Ia

wherein the configuration at the stereogenic center marked as (*) is (S)- or mixture of both isomers as defined above.

A particular object of the present invention is a previously undisclosed transimination followed by reductive amination, in order to convert a cyano group to the corresponding methylamino group.

A further object of the present invention is the preparation of compound of formula IIIb from compound of formula IIIa using a non-racemic amine via transimination reaction in order to enrich the formation of (S)-enantiomer.

According to another object of the invention, steps a), b), c) and d) of the process described above are performed without isolation of any intermediate compound in the same solvent.

A further embodiment of the present invention the resolution of the racemic carbon can be achieved prior to the reductive amination via dynamic kinetic resolution using a non-racemic amine.

A particular embodiment of the present application is the straightforward recovery of the non racemic amine using a resin such as Dowex 50WX8-100.

Another object of the present invention is the preparation of compound of formula Ia in its racemic form without employing transamination using a non racemic amine.

The process for the preparation of racemic compound of formula Ia

or any pharmaceutically acceptable salt, hydrate or solvate thereof, comprises the following steps of:
a) selective reduction of compound of formula IIa wherein n equals to 1, and A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions, to form compound of formula IIIa wherein n equals to 1, and A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions and the configuration at the stereogenic center marked as (*) is a mixture of both isomers in any ratio;

b) transimination reaction in compound of formula IIIa to form compound of formula IVa wherein n equals to 1, A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions, R is a methyl group, the configuration at the stereogenic center marked as (*) is a mixture of both isomers in any ratio and compound of formula IVa is a mixture of geometric isomers (syn/anti) in any ratio

c) reduction of the imine bond of compound of formula IVa to form compound of formula Ia

wherein the configuration at the stereogenic center marked as (*) is a mixture of both isomers in any ratio.

A further object of the present invention is the preparation of compound of formula IVa from compound of formula IIIa via transimination reaction.

A particular object of the present invention is a previously undisclosed transimination of compound of formula IIIa to form compound of formula IVa, followed by reductive amination, in order to convert a cyano group to the corresponding methylamino group of compound of formula Ia.

According to another object of the invention, steps a), b) and c) of the process described above are performed without isolation of any intermediate compound in the same solvent.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention a novel process for the conversion of the cyano group of compound of formula II to the alkylamino group of compound of formula I or any pharmaceutically acceptable salt, hydrate or solvate thereof, is described, where A may be an aromatic or heteroaromatic ring, each of which may be optionally substituted, n represents number of carbon atoms between 1 to 5 and R is an alkyl, alkenyl, alkynyl, or alkoxy group.

The novel process disclosed in the present invention comprising the following steps:
a) selective reduction of cyano group of compound of formula II to form compound of formula IIIa

b) optional transimination using non racemic amine RcNH¬2 to enrich the formation of (S)-enantiomer

wherein RcNH2 is an non racemic amine such as (S)- or (R)-α-methylbenzylamine, (S)- or (R)-α-methyl-4-nitrobenzylamine, (S)- or (R)-phenylglycine amide, (R)- or (S)-1-(1-naphthyl)ethylamine, (R)- or (S)-1-aminoindane, trans-(1R, 2R)-1-aminoindan-2-ol, trans-(1S, 2R)-1-aminoindan-2-ol, trans-(1R, 2S)-1-aminoindan-2-ol, trans-(1S, 2S)-1-aminoindan-2-ol and trans-(1R,2R)-6-nitro-1-aminoindan-2-ol, trans-(1S,2R)-6-nitro-1-aminoindan-2-ol, trans-(1R,2S)-6-nitro-1-aminoindan-2-ol, trans-(1S,2S)-6-nitro-1-aminoindan-2-ol, or enantiomeric pure amines of general formula A;

wherein ring B may be a β-naphthol ring and Ar is a phenyl ring which are independently optionally substituted;
compound of formula IIIb is a mixture of geometric isomers (syn/anti) in any ratio;
and the configuration at the stereogenic center marked as (*) is (S)- or mixture of both isomers in any ratio;
c) transimination to prepare compound of formula IV from compound of formula III

wherein R’ is either an hydrogen atom or Rc as defined above;
R is as defined above;
the configuration at the stereogenic center marked as (*) is either (S)- or mixture of both isomers in any ratio;
and compound of formula IV is a mixture of geometric isomers (syn/anti) in any ratio;

d) reduction of the imine double bond to form compound of formula I

wherein the configuration at the stereogenic center marked as (*) is either (S)- or mixture of both isomers in any ratio;

e) optionally converting compound of formula I to any pharmaceutically acceptable salt, hydrate or solvate thereof.

In another embodiment of the present invention, the above described process may be performed excluding step b), performing the transimination using an amine after the selective reduction of the cyano group.

In step a), the selective reduction of the cyano group to the corresponding imine is performed using various mild reductive reagents or under hydrogen atmosphere with a suitable catalytic system.

The selective reduction of the cyano group can take place using typical mild reductive reagents such as diisobutylaluminium hydride (DIBAl-H), sodium cyanoboronhydride, lithium diisobutylpiperidinohydroaluminate (LDBPA) or similar mild reductive reagents.

The reaction can take place in typical organic solvents such us ethers, for example diethylether, tert¬-butylmethylether, tetrahydrofuran or similar ethers, aromatic hydrocarbons, for example benzene, toluene, xylene or similar, or halogenated solvents, for example dichloromethane, chloroform or similar. The temperature of the reduction can vary from about -78oC to ambient temperature. Compound of formula IIIa is not isolated and used in the next step without further purification.

In step b), the transimination is performed using a non-racemic amine, such as (S)- or (R)-α-methylbenzylamine, (S)- or (R)-α-methyl-4-nitrobenzylamine, (S)- or (R)-phenylglycine amide, (R)- or (S)-1-(1-naphthyl)ethylamine, (R)- or (S)-1-aminoindane, trans-(1R, 2R)-1-aminoindan-2-ol, trans-(1S, 2R)-1-aminoindan-2-ol, trans-(1R, 2S)-1-aminoindan-2-ol, trans-(1S, 2S)-1-aminoindan-2-ol, trans-(1R,2R)-6-nitro-1-aminoindan-2-ol, trans-(1S,2R)-6-nitro-1-aminoindan-2-ol, trans-(1R,2S)-6-nitro-1-aminoindan-2-ol, trans-(1S,2S)-6-nitro-1-aminoindan-2-ol or enantiomeric pure amines of general formula A;

wherein ring B may be a β-naphthol ring and Ar is a phenyl ring which are independently may be optionally substituted, is employed in order to enrich the formation of (S)-enantiomer.

The reaction can run in typical organic solvents such as ethers, for example tetrahydrofuran (THF), diethylether, diethylene glycol dimethylether (diglyme), tert¬-butylmethylether or similar ethers, alcohols such as methanol, ethanol, isopropyl alcohol (IPA), n-butanol or similar alcohols, hydrocarbons such as pentane, hexane, heptane, cyclohexane or similar hydrocarbons, halogenated solvents such as dichloromethane, chloroform or similar halogenated solvents, esters such as ethyl acetate, triethyl orthoformate, or similar ester, nitriles such as acetonitrile or similar nitriles, ketones such as acetone, butanone, methyl ¬iso-butyl ketone or similar ketones. The temperature of the reaction varies from -20oC to the boiling point of the solvent employed.

In step c), the second transimination takes place using a substituted amine such as methylamine, ethylamine, propylamine, isopropylamine or similar amines, an urethane derivative such as BocNH2, CbzNH2 or similar.

The reaction can take place in typical organic solvents such us ethers, for example diethylether, tert¬-butylmethylether, tetrahydrofuran or similar ethers, aromatic hydrocarbons such us benzene, toluene, xylene or similar, or halogenated solvents such us dichloromethane, chloroform or similar. The temperature of the reaction can vary from about -78oC to ambient temperature.

In step d), the reduction of the imine double bond is carried out with typical reductive reagents such as sodium borohydride, sodium cyanoborohydride.

The reaction can take place in typical organic solvents such us ethers, for example diethylether, tert¬-butylmethylether, tetrahydrofuran or similar ethers, aromatic hydrocarbons such as benzene, toluene, xylene or similar, or halogenated solvents such as dichloromethane, chloroform or similar. The temperature of the reduction can vary from about -78oC to ambient temperature.

A further embodiment of the present invention is that all steps can be performed in the same solvent without purification of the intermediates.

Another embodiment of the present invention is the use of compound of formula I or any pharmaceutically acceptable salt, hydrate or solvate thereof, for the production of pharmaceutical compounds i.e. ivabradine.

In particular the present invention discloses a novel pathway for the preparation of compound of formula Ias or any pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n equals to 1, R is a methyl group and A is a C6 aromatic ring bearing two methoxy groups at 3- and 4- positions, exhibiting improved yield, safe reagents and industrially applicable techniques.

The novel process for the preparation of compound of formula Ias or any pharmaceutically acceptable salt, hydrate or solvate thereof, comprises the following steps:

a) selective reduction of compound of formula IIa wherein n equals to 1, and A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions to form compound of formula IIIa wherein n equals to 1, and A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions, the configuration at the stereogenic center marked as (*) is a mixture of both isomers in any ratio;

b) transimination using a non-racemic amine RcNH2 and formation of compound of formula IIIb wherein n equals to 1, and A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions and RcNH2 is a non racemic amine such as (S)- or (R)-α-methylbenzylamine, (S)- or (R)-α-methyl-4-nitrobenzylamine, (S)- or (R)-phenylglycine amide, (R)- or (S)-1-(1-naphthyl)ethylamine, (R)- or (S)-1-aminoindane, trans-(1R, 2R)-1-aminoindan-2-ol, trans-(1S, 2R)-1-aminoindan-2-ol, trans-(1R, 2S)-1-aminoindan-2-ol, trans-(1S, 2S)-1-aminoindan-2-ol, trans-(1R,2R)-6-nitro-1-aminoindan-2-ol, trans-(1S,2R)-6-nitro-1-aminoindan-2-ol, trans-(1R,2S)-6-nitro-1-aminoindan-2-ol, trans-(1S,2S)-6-nitro-1-aminoindan-2-ol, or enantiomeric pure amine of general formula A

wherein ring B may be a β-naphthol ring and Ar is a phenyl ring which are independently may be optionally substituted;

wherein the compound of formula IIIb is a mixture of geometric isomers (syn, anti) in any ratio
and the configuration at the stereogenic center marked as (*) in compound of formula IIIb is (S)- or mixture of both isomers where the percentage of the (R)-enantiomer is less than 20%;
c) transimination reaction in compound of formula IIIb to form compound of formula IVa wherein n equals to 1, A is an C6 aromatic ring bearing two methoxy groups at 3- and 4- positions, R is a methyl group, the configuration at the stereogenic center marked as (*) is (S)- or mixture of both isomers where the percentage of the (R)-enantiomer is less than 20% and compound of formula IVa is a mixture of geometric isomers (syn/anti) in any ratio

d) reduction of compound of formula IVa to compound of formula Ia

wherein the configuration at the stereogenic center marked as (*) is (S)- or a mixture of both enantiomers as defined above.

A further embodiment of the present invention is that all steps can be performed one pot without any purification in the same solvent.

In another embodiment of the present invention is the use of compound of formula Ias or any pharmaceutically acceptable salt, hydrate or solvate thereof, for the production of Ivabradine.

Another embodiment of the present invention is the preparation of compound of formula Ia or any pharmaceutically acceptable salt, hydrate or solvate thereof, following steps, a), c) and d) wherein the configuration at stereogenic center marked as (*) is a mixture of both enantiomers in any ratio.

A further embodiment of the present invention is the use of the racemic compound of formula Ia or any pharmaceutically acceptable salt, hydrate or solvate thereof, for the preparation of Ivabradine.

Another embodiment of the present invention is the use of the (S)-enantiomer of compound of formula Ias or any pharmaceutically acceptable salt, hydrate or solvate thereof, for the preparation of Ivabradine.

A particular embodiment of the present application is the straightforward recovery of the non-racemic amine using a resin such as Dowex 50WX8-100.

EXPERIMENTAL

EXAMPLE 1: Preparation of compound of formula Ia

Add 1.0 gr 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile under argon to 10.0 ml Toluene. Cool the resulting solution down to 70oC and add a solution DIBAL-H (1.0 M in Hexane, 6.6 ml, 1.25 equiv) under stirring over a period of 15-30 min. After the completion of the addition, the reaction mixture is stirred for 1 h further keeping the temperature <-55 oC, before 2.0 ml MeOH is added dropwise at -55oC. Leave the reaction mixture to slowly warm up under stirring for 30 min. Add MeNH2 (33% wt in EtOH, 3.2 ml, 4.9 equiv) in one portion when temperature reaches -40oC. Stir the reaction mixture for 45 min and then cool reaction mixture in an ice bath. Add NaBH4 (400 mg, 2.0 equiv) when internal temperature reaches 0oC, in 3 portions over 15 min. Stir reaction mixture for 30 min longer and then quench with 10 ml aq. K Na tartrate (25% w/v). Stir the biphasic system for 10-15 min. Collect organic phase, while aqueous one is extracted twice with 2× 10 ml ethyl acetate. The combined organic phases are dried over anh. Na2SO4, filtered and evaporated down to give 1.81 g of crude 1-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N-methylmethanamine (Formula Ia).

1H NMR (500 MHz, DMSO) δ: 9.11 (s, 2H), 6.98 (s, 1H), 6.80 (s, 1H), 3.70 (bs, 7H), 3.26 – 3.19 (m, 2H), 3.07 (dd, J = 13.4, 6.3 Hz, 1H), 2.93 (dd, J = 13.4, 1.7 Hz, 1H), 2.58 (t, J = 5.4 Hz, 3H).
EXAMPLE 2: Preparation of compound of formula Va

7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one of formula X (100 g) is mixed with in N,N-Dimethylformamide (300 ml) into 3 neck RBF equipped with mechanical stirrer, thermometer pocket and septum at 25-35°C under nitrogen atmosphere. 1-Bromo-3-chloropropane is added to the reaction mixture followed by N,N-Dimethylformamide (200 ml). Potassium hydroxide (51.17 g) is added to the reaction mixture in 4 lots at 0-5°C.The reaction mixture is stirred for 2-6 hours 0-5°C. Process water (700 ml) was added to the reaction mixture and stirred for 60-120 minutes at 0-5°C. Solid material was filtered and wet cake was washed with process water (100 ml X 3) and dried in hot air oven 60-65°C.

EXAMPLE 3: Preparation of compound of formula IX

N,N-Dimethylformamide (600 ml), (3-Chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (100 g) (formula Va), potassium carbonate powder (140 g) are mixed into a 3 neck RBF under nitrogen atmosphere at 25-30°C followed by addition of N-[[(7S)-3,4-Dimethoxybicyclo[4,2,0]octa-1,3,5-trien-7-yl]methyl]-N-methylamine hydrochloride (74 g) (formula Ia), sodium iodide (71 g) into the RBF under nitrogen atmosphere at 25-30°C. The reaction mixture is heated and stirred at 50-55°C. After completion of the reaction, the reaction mass is cooled to 15-25° and process water (600 ml) is added to the reaction mass; pH of the reaction mass is adjusted to 1-2 using hydrochloric acid and washed with in toluene (300 ml X 3); pH of the aqueous layer is adjusted to 9.0-9.5 with aqueous sodium hydroxide solution and the product extracted with ethyl acetate (500 ml X 3). Ethyl acetate is distilled out completely under vacuum to get residue of Unreduce Ivabradine (formula IX).

EXAMPLE 4: Preparation of compound of formula VI

The residual mass is dissolved in ethanol solvent (1200 ml) and charged into a 2 lit hydrogenator followed by 10% Pd/C (50% wet) (21 g). The reaction mass is stirred under hydrogen pressure (7-8 Kg/cm2) at 60-65°C. After completion of reaction distills off the solvents and methanol (150 ml) is added to the reaction mass. Methanolic solution of hydrochloric acid is added slowly to adjust the pH of the reaction mass to 1-2. Solvent is distilled out completely under vacuum and acetonitrile (400 ml) is added to the reaction mass and stirred for 1-2 hours at 15-20°C. Solid material is filtered and dried under vacuum at 60-65°C to get Crude Ivabradine HCl.

EXAMPLE 5: Preparation of compound of formula IX

Crude Ivabradine Hydrochloride (100 g) is dissolved in ethanol (500 ml) at 75-80°C and maintained for 1 hour; added activated carbon (10 g) at 75-80°C and maintained for 30 minutes and filter through the hyflo bed and wash with ethanol (100 ml), further heat the reaction mass is heated to get the clear solution and then cooled to 25-35°C and stirred at for 15 hours followed by cooling the reaction mass to 10-15°C. Solid material is filtered and washed with chilled ethanol (50 ml) and dried under vacuum oven at 70-75°C to get Ivabradine HCl API.