Indian Patents. 260761:"NEW PROCESS FOR THE SYNTHESIS OF 7,8-DIMETHOXY-1,3-DIHYDRO-2H-3-BENZAZEPIN-2-ONE, AND APPLICATION IN THE SYNTHESIS OF IVABRADINE AND ADDITION SALTS THEREOF WITH A PHARMACEUTICALLY ACCEPTABLE ACID"

Title of Invention	"NEW PROCESS FOR THE SYNTHESIS OF 7,8-DIMETHOXY-1,3-DIHYDRO-2H-3-BENZAZEPIN-2-ONE, AND APPLICATION IN THE SYNTHESIS OF IVABRADINE AND ADDITION SALTS THEREOF WITH A PHARMACEUTICALLY ACCEPTABLE ACID"
Abstract	NEW PROCESS FOR THE SYNTHESIS OF 7,8-DIMETHOXY-1,3-DIHYDRO-2H- 3-BENZAZEPIN-2-ONE, AND APPLICATION IN THE SYNTHESIS OF IVABRADINE AND ADDITION SALTS THEREOF WITH A PHARMACEUTICALLY ACCEPTABLE ACID Process for the synthesis of the compound of formula (I): Application in the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof.

Full Text	The present invention relates to a process for the synthesis of 7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-one of formula (I), and to the application thereof in the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof (Formula Removed) The compound of formula (I) obtained according to the process of the invention is useful in the synthesis of ivabradine of formula (II) (Formula Removed) or 3-{3-[{[(75)-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7-yl]methyl}(methyl)amino]-propyl} -7,8 -dimethoxy-1,3,4,5 -tetrahydro-2H-3 -benzazepin-2-one, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof. Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure. The preparation and therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent specification EP 0 534 859. That patent specification describes the synthesis of ivabradine hydrochloride starting from the compound of formula (III): (Formula Removed) and makes reference to the publication J. Med. Chem 1990, Vol. 33 (5), 1496-1504 for the preparation of that compound. The synthesis route described in that publication for the compound of formula (III) uses an alkylation reaction on the compound of formula (I): (Formula Removed) The afore-mentioned publication describes the preparation of the compound of formula (I) by using, as intermediate, Ar-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide obtained starting from (3,4-dimethoxyphenyl)acetic acid. Cyclisation of the phenylacetamide obtained is carried out in the presence of hydrochloric acid in acetic acid to yield the compound of formula (I) in an overall yield of 58 % relative to the (3,4-dimethoxyphenyl)acetic acid. In view of the value of ivabradine and its salts to industry, it has been imperative to find an effective process that especially makes it possible to obtain 7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-one of formula (I) in an excellent yield. The Applicant has now found, surprisingly, that by using specific operating conditions it is possible to obtain the compound of formula (I) on an industrial scale in a yield greater than 92 % and with a chemical purity greater than 99.5 %. More specifically, the present invention relates to a process for the synthesis of the compound of formula (I): (Formula Removed) characterised in that (3,4-dimethoxyphenyl)acetic acid of formula (IV): (Formula Removed) is converted into the compound of formula (V): (Formula Removed) wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepanering, which is subjected to a cyclisation reaction in an acid medium to yield, after isolation, the compound of formula (I). In one of the preferred embodiments of the invention, the conversion of the compound of formula (IV) into the compound of formula (V) is carried out by means of preliminary conversion of the compound of formula (IV) into the compound of formula (VI): (Formula Removed) wherein X represents a halogen atom or a group OCOR3 wherein R3 is a linear or branched (C1-C6)alkyl group, a phenyl group, a benzyl group or an imidazole group, in an organic solvent, and then the compound of formula (VI) is subjected to a condensation reaction with a compound of formula (VII): (Formula Removed) wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepanering, in the presence of a base in an organic solvent, to yield the compound of formula (V): (Formula Removed) In another preferred embodiment of the invention, the conversion of the compound of formula (IV) into the compound of formula (V) is carried out by reaction with a compound of formula (VII): (Formula Removed) wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepane ring, in the presence of a coupling agent in an organic solvent, to yield the compound of formula (V): (Formula Removed) Among the coupling agents that may be used for the condensation reaction of the compound of formula (VII) with the compound formula (IV), there may be mentioned, without implying any limitation, the following reagents or pairs of reagents: EDCI, EDCI/HOBT, EDCI/HOAT, EDCI/NHS, DCC, DCC/HOBT, DCC/HOAT, DCC/NHS, HATU, HBTU, TBTU, BOP, PyBOP, CDI, T3P. Among the organic solvents that may be used for the condensation reaction of the compound of formula (VII) with the compound of formula (IV) in the presence of a coupling agent, there may be mentioned, without implying any limitation, toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1,2-dichloroethane, chloroform and dioxane. In one of the preferred embodiments of the invention, the compound of formula (V) is not isolated. In one of the preferred embodiments of the invention, the compound of formula (VI) is not isolated. The group X in the compound of formula (VI) preferably represents a chlorine atom. Among the organic solvents that may be used for the reaction for conversion of the compound of formula (IV) into the compound of formula (VI), there may be mentioned, without implying any limitation, toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1,2-dichloroethane, chloroform and dioxane. The preferred organic solvent for the reaction for conversion of the compound of formula (IV) into the compound of formula (VI) is dichloromethane. The temperature of the reaction for conversion of the compound of formula (IV) into the compound of formula (VI) is preferably from 20 to 40°C. The reagent preferably used for carrying out conversion of the compound of formula (IV) into the compound of formula (VI) wherein X represents a chlorine atom is thionyl chloride. The amount of thionyl chloride used in the reaction for conversion of the compound of formula (IV) into the compound of formula (VI) is preferably from 1 to 1.3 moles per mole of compound of formula (IV). Among the organic solvents that may be used for the reaction between the compound of formula (VI) and the compound of formula (VII), there may be mentioned, without implying any limitation, toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1,2-dichloroethane, chloroform and dioxane. The preferred organic solvent for the reaction between the compound of formula (VI) and the compound of formula (VII) is dichloromethane. The temperature of the reaction between the compound of formula (VI) and the compound of formula (VII) is preferably from 0 to 40°C. The amount of compound of formula (VII) used in the reaction with the compound of formula (VI) is preferably from 1 to 1.2 moles per mole of compound of formula (VI). The amount of base used in the reaction between the compound of formula (VI) and the compound of formula (VII) is preferably from 1 to 1.3 moles per mole of compound of formula (VI). Among the bases that may be used for the reaction between the compound of formula (VI) and the compound of formula (VII), there may be mentioned, without implying any limitation, pyridine, DMAP and tertiary amines, for example triethylamine, DIEA, N-methylpiperidine, DBU, DABCO, DBN and N-methylmorpholine. The base preferably used for the reaction between the compound of formula (VI) and the compound of formula (VII) is triethylamine. Among the acids that may be used to carry out cyclisation of the compound of formula (V) to form the compound of formula (I), there may be mentioned, without implying any limitation, concentrated sulphuric acid, polyphosphoric acid, concentrated hydrochloric acid in aqueous solution, concentrated hydrochloric acid in solution in acetic acid, concentrated hydrobromic acid in solution in acetic acid, and methanesulphonic acid. The amount of acid used in the reaction for cyclisation of the compound of formula (V) to form the compound of formula (I) is preferably from 5 to 15 moles per mole of compound of formula (V). The temperature of the reaction for cyclisation of the compound of formula (V) in an acid medium is preferably from 0 to 40°C. The acid preferably used for carrying out cyclisation of the compound of formula (V) to form the compound of formula (I) is concentrated sulphuric acid. When the reaction intermediates are not isolated in the course of the process, the amount of concentrated sulphuric acid used in the reaction for cyclisation of the compound of formula (V) is preferably from 1.5 to 3 millilitres per gram of (3,4-dimethoxyphenyl)acetic acid of formula (IV). The compound of formula (I) obtained according to the process of the present invention is especially useful as synthesis intermediate in the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof. By way of example, alkylation of the compound of formula (I) with a compound of formula (VIII): (Formula Removed) wherein R4 and R5, which may be the same or different, each represent a linear or branched (C1-C6)alkoxy group or, together with the carbon atom carrying them, form a 1,3-dioxane or 1,3-dioxolane ring, and Y represents a halogen atom, preferably a bromine atom, or a tosylate, mesylate or triflate group, yields the compound of formula (IX) (Formula Removed) catalytic hydrogenation of which yields the corresponding hydrogenated compound of formula (X): wherein R4 and R5 are as defined for formula (VIII), deprotection of the diacetal moiety of which yields the aldehyde of formula (XI): (Formula Removed) which is reacted with (7S)-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7-yl]-N-methyl-methanamine under conditions of reductive amination to yield ivabradine, which may optionally be converted into its addition salts with a pharmaceutically acceptable acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid and camphoric acid, and into hydrates thereof. Key to the abbreviations used: BOP: benzotriazol-1 -yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate CDI: carbonyldiimidazole DABCO: l,4-diazabicyclo[2.2.2]octane DBN: l,5-diazabicyclo[4.3.0]non-5-ene DBU: l,8-diazabicyclo[5.4.0]undec-7-ene DCC: dicyclohexylcarbodiimide DIEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine EDCI: 1 -(3 -dimethylaminopropyl)-3 -ethyl-carbodiimide hydrochloride HATU: O-(7-azabenzotriazol-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HBTU: O(benzotriazol-1 -yl)-1,l,3,3-tetramethyluronium hexafluorophosphate HO AT: 1 -hydroxy-7 -azabenzotriazole HOBT: 1-hydroxybenzotriazole NHS: N-hydroxysuccinimide NMP: N-methylpyrrolidone PyBOP: (9-(benzotriazol-1 -yl)-oxytripyrrolidinophosphonium hexafluorophosphate TBTU: O(benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium tetrafluoroborate T3P: n-propane phosphonic anhydride The Example hereinbelow illustrates the invention. Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one Step A : (3,4-Dimethoxyphenyl)acetic acid chloride Load into a reactor 135 g of (3,4-dimethoxyphenyl)acetic acid and 270 ml of dichloromethane and then bring the temperature of the reaction mixture to reflux and add, dropwise, 90 g of thionyl chloride. Stir the mixture at reflux for 3 hours. The solution obtained is used as such in the following Step. Step B: N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide Load into a reactor 225 ml of dichloromethane, 44.15 g of 2,2-dimethoxyethylamine and 44.35 g of triethylamine and then cool the mixture to 10°C and add, dropwise, 237.4 g of the solution obtained in the preceding Step (corresponding to 75 g of (3,4- dimethoxyphenyl)acetic acid) whilst maintaining the mass temperature at 10°C. Stir the mixture for 2 hours at 15°C. The solution obtained is used as such in the following Step. Step C: 7,8-Dimethoxy-l,3-dihydro-2H-3-benzazepin-2-one In a reactor containing the solution obtained in the preceding Step and cooled to 10°C, add 150 ml of 36N sulphuric acid, whilst maintaining the temperature below 20°C. Stir the mixture at 15-20°C for 10 hours, then allow the reaction mixture to separate and collect the product-containing sulphuric acid phase. The product is obtained by precipitation from a water/NMP mixture (4/1), filtration and drying, in a yield of 92.9 % relative to the (3,4-dimethoxyphenyl)acetic acid and with a chemical purity greater than 99.5 %. CLAIMS 1. Process for the synthesis of the compound of formula (I): (Formula Removed) characterised in that (3,4-dimethoxyphenyl)acetic acid of formula (IV): (Formula Removed) is converted into the compound of formula (V): (Formula Removed) wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepanering, which is subjected to a cyclisation reaction in an acid medium to yield, after isolation, the compound of formula (I). 2. Synthesis process according to claim 1, characterised in that the conversion of the compound of formula (IV) into the compound of formula (V) is carried out by means of preliminary conversion of the compound of formula (IV) into the compound of formula (VI): (Formula Removed) wherein X represents a halogen atom or a group OCOR3 wherein R3 is a linear or branched (Ci-C6)alkyl group, a phenyl group, a benzyl group or an imidazolyl group, in an organic solvent, and then the compound of formula (VI) is subjected to a condensation reaction with a compound of formula (VII): (Formula Removed) wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepanering, in the presence of a base in an organic solvent, to yield the compound of formula (V): (Formula Removed) 3. Synthesis process according to claim 1, characterised in that the conversion of the compound of formula (IV) into a compound of formula (V) is carried out by reaction with a compound of formula (VII): (Formula Removed) wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepane ring, in the presence of a coupling agent in an organic solvent, to yield the compound of formula (V): (Formula Removed) Synthesis process according to claim 2, characterised in that the compounds of formulae (V) and (VI) are not isolated. 5. Synthesis process according to claim 3, characterised in that the compound of formula (V) is not isolated. 6. Synthesis process according to either claim 2 or claim 4, characterised in that, in the compound of formula (VI), X represents a chlorine atom. 7. Synthesis process according to any one of claims 2, 4 or 6, characterised in that the solvent used for conversion of the compound of formula (IV) into the compound of formula (VI) is dichloromethane. 8. Synthesis process according to any one of claims 2, 4, 6 or 7, characterised in that the temperature of the reaction for conversion of the compound of formula (IV) into the compound of formula (VI) is from 20 to 40°C. 9. Synthesis process according to any one of claims 2, 4 or 6 to 8, characterised in that the reagent used for conversion of the compound of formula (IV) into the compound of formula (VI) is thionyl chloride. 10. Synthesis process according to claim 9, characterised in that the amount of thionyl chloride used in the reaction for conversion of the compound of formula (IV) into the compound of formula (VI) is from 1 to 1.3 moles per mole of compound of formula (IV). 11. Synthesis process according to any one of claims 2, 4 or 6 to 10, characterised in that the solvent for the reaction between the compounds of formulae (VI) and (VII) is dichloromethane. 12. Synthesis process according to any one of claims 2, 4 or 6 to 11, characterised in that the temperature of the reaction between the compounds of formulae (VI) and (VII) is from 0 to 40°C. 13. Synthesis process according to any one of claims 2, 4 or 6 to 12, characterised in that the amount of compound (VII) used in the reaction with the compound of formula (VI) is from 1 to 1.2 moles per mole of compound of formula (VI). 14. Synthesis process according to any one of claims 2, 4 or 6 to 13, characterised in that the amount of base used in the reaction between the compounds of formulae (VI) and (VII) is from 1 to 1.3 moles per mole of compound (VI). 15. Synthesis process according to any one of claims 2, 4 or 6 to 14, characterised in that the base used in the reaction between the compounds of formulae (VI) and (VII) is pyridine, DMAP or a tertiary amine. 16. Synthesis process according to claim 15, characterised in that the base used in the reaction between the compounds of formulae (VI) and (VII) is triethylamine. 17. Synthesis process according to any one of claims 1 to 16, characterised in that the amount of acid used in the reaction for cyclisation of the compound of formula (V) is from 5 to 15 moles per mole of compound of formula (V). 18. Synthesis process according to any one of claims 1 to 17, characterised in that the temperature of the reaction for cyclisation of the compound of formula (V) in an acid medium is from 0 to 40°C. 19. Synthesis process according to any one of claims 1 to 18, characterised in that the acid used for cyclisation of the compound of formula (V) is concentrated sulphuric acid. 20. Synthesis process according to claims 4 or 5 and 19, characterised in that the amount of concentrated sulphuric acid used in the reaction for cyclisation of the compound of formula (V) is from 1.5 to 3 millilitres per gram of (3,4-dimethoxyphenyl)acetic acid of formula (IV). 21. Process for the synthesis of ivabradine and pharmaceutically acceptable salts thereof, wherein the compound of formula (IV) is converted into the compound of formula (I) in accordance with the process of claim 1 and then the compound of formula (I) is converted into ivabradine, which may optionally be converted into its addition salts with a pharmaceutically acceptable acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid and camphoric acid, and into hydrates thereof.

Full Text

The present invention relates to a process for the synthesis of 7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-one of formula (I), and to the application thereof in the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof
(Formula Removed)
The compound of formula (I) obtained according to the process of the invention is useful in the synthesis of ivabradine of formula (II)
(Formula Removed)
or 3-{3-[{[(75)-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7-yl]methyl}(methyl)amino]-propyl} -7,8 -dimethoxy-1,3,4,5 -tetrahydro-2H-3 -benzazepin-2-one,
addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof.
Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.

The preparation and therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent specification EP 0 534 859.
That patent specification describes the synthesis of ivabradine hydrochloride starting from the compound of formula (III):
(Formula Removed)
and makes reference to the publication J. Med. Chem 1990, Vol. 33 (5), 1496-1504 for the preparation of that compound.
The synthesis route described in that publication for the compound of formula (III) uses an alkylation reaction on the compound of formula (I):
(Formula Removed)
The afore-mentioned publication describes the preparation of the compound of formula (I) by using, as intermediate, Ar-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide obtained starting from (3,4-dimethoxyphenyl)acetic acid. Cyclisation of the phenylacetamide obtained is carried out in the presence of hydrochloric acid in acetic acid to yield the compound of formula (I) in an overall yield of 58 % relative to the (3,4-dimethoxyphenyl)acetic acid.
In view of the value of ivabradine and its salts to industry, it has been imperative to find an effective process that especially makes it possible to obtain 7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-one of formula (I) in an excellent yield.

The Applicant has now found, surprisingly, that by using specific operating conditions it is possible to obtain the compound of formula (I) on an industrial scale in a yield greater than 92 % and with a chemical purity greater than 99.5 %.
More specifically, the present invention relates to a process for the synthesis of the compound of formula (I):
(Formula Removed)
characterised in that (3,4-dimethoxyphenyl)acetic acid of formula (IV):
(Formula Removed)
is converted into the compound of formula (V):

(Formula Removed)
wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepanering,
which is subjected to a cyclisation reaction in an acid medium to yield, after isolation, the compound of formula (I).

In one of the preferred embodiments of the invention, the conversion of the compound of formula (IV) into the compound of formula (V) is carried out by means of preliminary conversion of the compound of formula (IV) into the compound of formula (VI):
(Formula Removed)
wherein X represents a halogen atom or a group OCOR3 wherein R3 is a linear or branched (C1-C6)alkyl group, a phenyl group, a benzyl group or an imidazole group,
in an organic solvent,
and then the compound of formula (VI) is subjected to a condensation reaction with a compound of formula (VII):
(Formula Removed)
wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepanering,
in the presence of a base in an organic solvent,
to yield the compound of formula (V):
(Formula Removed)
In another preferred embodiment of the invention, the conversion of the compound of formula (IV) into the compound of formula (V) is carried out by reaction with a compound of formula (VII):
(Formula Removed)
wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepane ring,
in the presence of a coupling agent in an organic solvent,
to yield the compound of formula (V):
(Formula Removed)
Among the coupling agents that may be used for the condensation reaction of the compound of formula (VII) with the compound formula (IV), there may be mentioned, without implying any limitation, the following reagents or pairs of reagents: EDCI, EDCI/HOBT, EDCI/HOAT, EDCI/NHS, DCC, DCC/HOBT, DCC/HOAT, DCC/NHS, HATU, HBTU, TBTU, BOP, PyBOP, CDI, T3P.
Among the organic solvents that may be used for the condensation reaction of the compound of formula (VII) with the compound of formula (IV) in the presence of a coupling agent, there may be mentioned, without implying any limitation, toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1,2-dichloroethane, chloroform and dioxane.
In one of the preferred embodiments of the invention, the compound of formula (V) is not isolated.
In one of the preferred embodiments of the invention, the compound of formula (VI) is not isolated.
The group X in the compound of formula (VI) preferably represents a chlorine atom.
Among the organic solvents that may be used for the reaction for conversion of the compound of formula (IV) into the compound of formula (VI), there may be mentioned, without implying any limitation, toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1,2-dichloroethane, chloroform and dioxane.
The preferred organic solvent for the reaction for conversion of the compound of formula (IV) into the compound of formula (VI) is dichloromethane.
The temperature of the reaction for conversion of the compound of formula (IV) into the compound of formula (VI) is preferably from 20 to 40°C.
The reagent preferably used for carrying out conversion of the compound of formula (IV) into the compound of formula (VI) wherein X represents a chlorine atom is thionyl chloride.
The amount of thionyl chloride used in the reaction for conversion of the compound of formula (IV) into the compound of formula (VI) is preferably from 1 to 1.3 moles per mole of compound of formula (IV).
Among the organic solvents that may be used for the reaction between the compound of formula (VI) and the compound of formula (VII), there may be mentioned, without implying any limitation, toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1,2-dichloroethane, chloroform and dioxane.
The preferred organic solvent for the reaction between the compound of formula (VI) and the compound of formula (VII) is dichloromethane.
The temperature of the reaction between the compound of formula (VI) and the compound of formula (VII) is preferably from 0 to 40°C.
The amount of compound of formula (VII) used in the reaction with the compound of formula (VI) is preferably from 1 to 1.2 moles per mole of compound of formula (VI).
The amount of base used in the reaction between the compound of formula (VI) and the compound of formula (VII) is preferably from 1 to 1.3 moles per mole of compound of formula (VI).
Among the bases that may be used for the reaction between the compound of formula (VI) and the compound of formula (VII), there may be mentioned, without implying any limitation, pyridine, DMAP and tertiary amines, for example triethylamine, DIEA, N-methylpiperidine, DBU, DABCO, DBN and N-methylmorpholine.
The base preferably used for the reaction between the compound of formula (VI) and the compound of formula (VII) is triethylamine.
Among the acids that may be used to carry out cyclisation of the compound of formula (V) to form the compound of formula (I), there may be mentioned, without implying any limitation, concentrated sulphuric acid, polyphosphoric acid, concentrated hydrochloric acid in aqueous solution, concentrated hydrochloric acid in solution in acetic acid, concentrated hydrobromic acid in solution in acetic acid, and methanesulphonic acid.
The amount of acid used in the reaction for cyclisation of the compound of formula (V) to form the compound of formula (I) is preferably from 5 to 15 moles per mole of compound of formula (V).

The temperature of the reaction for cyclisation of the compound of formula (V) in an acid medium is preferably from 0 to 40°C.
The acid preferably used for carrying out cyclisation of the compound of formula (V) to form the compound of formula (I) is concentrated sulphuric acid.
When the reaction intermediates are not isolated in the course of the process, the amount of concentrated sulphuric acid used in the reaction for cyclisation of the compound of formula (V) is preferably from 1.5 to 3 millilitres per gram of (3,4-dimethoxyphenyl)acetic acid of formula (IV).
The compound of formula (I) obtained according to the process of the present invention is especially useful as synthesis intermediate in the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof.
By way of example, alkylation of the compound of formula (I) with a compound of formula (VIII):
(Formula Removed)
wherein R4 and R5, which may be the same or different, each represent a linear or branched (C1-C6)alkoxy group or, together with the carbon atom carrying them, form a 1,3-dioxane or 1,3-dioxolane ring, and Y represents a halogen atom, preferably a bromine atom, or a tosylate, mesylate or triflate group,
yields the compound of formula (IX)
(Formula Removed)

catalytic hydrogenation of which yields the corresponding hydrogenated compound of formula (X):
wherein R4 and R5 are as defined for formula (VIII),
deprotection of the diacetal moiety of which yields the aldehyde of formula (XI):
(Formula Removed)
which is reacted with (7S)-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7-yl]-N-methyl-methanamine under conditions of reductive amination to yield ivabradine, which may optionally be converted into its addition salts with a pharmaceutically acceptable acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid and camphoric acid, and into hydrates thereof.
Key to the abbreviations used:
BOP: benzotriazol-1 -yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate
CDI: carbonyldiimidazole
DABCO: l,4-diazabicyclo[2.2.2]octane
DBN: l,5-diazabicyclo[4.3.0]non-5-ene
DBU: l,8-diazabicyclo[5.4.0]undec-7-ene
DCC: dicyclohexylcarbodiimide
DIEA: N,N-diisopropylethylamine
DMAP: 4-dimethylaminopyridine
EDCI: 1 -(3 -dimethylaminopropyl)-3 -ethyl-carbodiimide hydrochloride
HATU: O-(7-azabenzotriazol-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
HBTU: O(benzotriazol-1 -yl)-1,l,3,3-tetramethyluronium hexafluorophosphate
HO AT: 1 -hydroxy-7 -azabenzotriazole
HOBT: 1-hydroxybenzotriazole
NHS: N-hydroxysuccinimide
NMP: N-methylpyrrolidone
PyBOP: (9-(benzotriazol-1 -yl)-oxytripyrrolidinophosphonium hexafluorophosphate
TBTU: O(benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
T3P: n-propane phosphonic anhydride
The Example hereinbelow illustrates the invention.
Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one
Step A : (3,4-Dimethoxyphenyl)acetic acid chloride
Load into a reactor 135 g of (3,4-dimethoxyphenyl)acetic acid and 270 ml of dichloromethane and then bring the temperature of the reaction mixture to reflux and add, dropwise, 90 g of thionyl chloride. Stir the mixture at reflux for 3 hours. The solution obtained is used as such in the following Step.
Step B: N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide
Load into a reactor 225 ml of dichloromethane, 44.15 g of 2,2-dimethoxyethylamine and 44.35 g of triethylamine and then cool the mixture to 10°C and add, dropwise, 237.4 g of the solution obtained in the preceding Step (corresponding to 75 g of (3,4-

dimethoxyphenyl)acetic acid) whilst maintaining the mass temperature at 10°C. Stir the mixture for 2 hours at 15°C. The solution obtained is used as such in the following Step.
Step C: 7,8-Dimethoxy-l,3-dihydro-2H-3-benzazepin-2-one
In a reactor containing the solution obtained in the preceding Step and cooled to 10°C, add 150 ml of 36N sulphuric acid, whilst maintaining the temperature below 20°C. Stir the mixture at 15-20°C for 10 hours, then allow the reaction mixture to separate and collect the product-containing sulphuric acid phase.
The product is obtained by precipitation from a water/NMP mixture (4/1), filtration and drying, in a yield of 92.9 % relative to the (3,4-dimethoxyphenyl)acetic acid and with a chemical purity greater than 99.5 %.

CLAIMS
1. Process for the synthesis of the compound of formula (I):
(Formula Removed)
characterised in that (3,4-dimethoxyphenyl)acetic acid of formula (IV):
(Formula Removed)
is converted into the compound of formula (V):
(Formula Removed)
wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepanering,
which is subjected to a cyclisation reaction in an acid medium to yield, after isolation, the compound of formula (I).
2. Synthesis process according to claim 1, characterised in that the conversion of the compound of formula (IV) into the compound of formula (V) is carried out by means of preliminary conversion of the compound of formula (IV) into the compound of formula (VI):

(Formula Removed)
wherein X represents a halogen atom or a group OCOR3 wherein R3 is a linear or branched (Ci-C6)alkyl group, a phenyl group, a benzyl group or an imidazolyl group,
in an organic solvent,
and then the compound of formula (VI) is subjected to a condensation reaction with a compound of formula (VII):
(Formula Removed)
wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepanering,
in the presence of a base in an organic solvent,
to yield the compound of formula (V):

(Formula Removed)
3. Synthesis process according to claim 1, characterised in that the conversion of the compound of formula (IV) into a compound of formula (V) is carried out by reaction with a compound of formula (VII):

(Formula Removed)
wherein the groups R1 and R2, which may be the same or different, represent linear or branched (C1-C6)alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepane ring,
in the presence of a coupling agent in an organic solvent,
to yield the compound of formula (V):

(Formula Removed)
Synthesis process according to claim 2, characterised in that the compounds of formulae (V) and (VI) are not isolated.
5. Synthesis process according to claim 3, characterised in that the compound of formula (V) is not isolated.
6. Synthesis process according to either claim 2 or claim 4, characterised in that, in the compound of formula (VI), X represents a chlorine atom.
7. Synthesis process according to any one of claims 2, 4 or 6, characterised in that the solvent used for conversion of the compound of formula (IV) into the compound of formula (VI) is dichloromethane.

8. Synthesis process according to any one of claims 2, 4, 6 or 7, characterised in that the temperature of the reaction for conversion of the compound of formula (IV) into the compound of formula (VI) is from 20 to 40°C.
9. Synthesis process according to any one of claims 2, 4 or 6 to 8, characterised in that the reagent used for conversion of the compound of formula (IV) into the compound of formula (VI) is thionyl chloride.
10. Synthesis process according to claim 9, characterised in that the amount of thionyl chloride used in the reaction for conversion of the compound of formula (IV) into the compound of formula (VI) is from 1 to 1.3 moles per mole of compound of formula (IV).
11. Synthesis process according to any one of claims 2, 4 or 6 to 10, characterised in that the solvent for the reaction between the compounds of formulae (VI) and (VII) is dichloromethane.
12. Synthesis process according to any one of claims 2, 4 or 6 to 11, characterised in that the temperature of the reaction between the compounds of formulae (VI) and (VII) is from 0 to 40°C.
13. Synthesis process according to any one of claims 2, 4 or 6 to 12, characterised in that the amount of compound (VII) used in the reaction with the compound of formula (VI) is from 1 to 1.2 moles per mole of compound of formula (VI).
14. Synthesis process according to any one of claims 2, 4 or 6 to 13, characterised in that the amount of base used in the reaction between the compounds of formulae (VI) and (VII) is from 1 to 1.3 moles per mole of compound (VI).
15. Synthesis process according to any one of claims 2, 4 or 6 to 14, characterised in that the base used in the reaction between the compounds of formulae (VI) and (VII) is pyridine, DMAP or a tertiary amine.

16. Synthesis process according to claim 15, characterised in that the base used in the reaction between the compounds of formulae (VI) and (VII) is triethylamine.
17. Synthesis process according to any one of claims 1 to 16, characterised in that the amount of acid used in the reaction for cyclisation of the compound of formula (V) is from 5 to 15 moles per mole of compound of formula (V).
18. Synthesis process according to any one of claims 1 to 17, characterised in that the temperature of the reaction for cyclisation of the compound of formula (V) in an acid medium is from 0 to 40°C.
19. Synthesis process according to any one of claims 1 to 18, characterised in that the acid used for cyclisation of the compound of formula (V) is concentrated sulphuric acid.
20. Synthesis process according to claims 4 or 5 and 19, characterised in that the amount of concentrated sulphuric acid used in the reaction for cyclisation of the compound of formula (V) is from 1.5 to 3 millilitres per gram of (3,4-dimethoxyphenyl)acetic acid of formula (IV).
21. Process for the synthesis of ivabradine and pharmaceutically acceptable salts thereof, wherein the compound of formula (IV) is converted into the compound of formula (I) in accordance with the process of claim 1 and then the compound of formula (I) is converted into ivabradine, which may optionally be converted into its addition salts with a pharmaceutically acceptable acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid and camphoric acid, and into hydrates thereof.

Documents:

1205-del-2009-Abstract-(07-10-2013).pdf

1205-del-2009-abstract.pdf

1205-del-2009-Claims-(07-10-2013).pdf

1205-del-2009-claims.pdf

1205-del-2009-Correspondence Others-(07-10-2013).pdf

1205-DEL-2009-Correspondence-Others-(10-09-2009).pdf

1205-DEL-2009-Correspondence-Others-(29-09-2010).pdf

1205-del-2009-correspondence-others.pdf

1205-del-2009-description (complete).pdf

1205-del-2009-form-1.pdf

1205-del-2009-form-18.pdf

1205-del-2009-form-2.pdf

1205-del-2009-Form-3-(07-10-2013).pdf

1205-DEL-2009-Form-3-(29-09-2010).pdf

1205-del-2009-form-3.pdf

1205-del-2009-Form-5-(07-10-2013).pdf

1205-del-2009-form-5.pdf

1205-del-2009-GPA-(07-10-2013).pdf

1205-DEL-2009-GPA-(10-09-2009).pdf

1205-del-2009-Petition-137-(07-10-2013).pdf

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Patent Number

260761

Indian Patent Application Number

1205/DEL/2009

PG Journal Number

21/2014

Publication Date

23-May-2014

Grant Date

21-May-2014

Date of Filing

12-Jun-2009

Name of Patentee

LES LABORATOIRES SERVIER

Applicant Address

35 RUE DE VERDUN, F-92284 SURESNES, FRANCE

Inventors:

#	Inventor's Name	Inventor's Address
1	JEAN-MICHEL LERESTIF	27, BIS, RUE DE LA BRIQUETERIE 76190 YVETOT, FRANCE
2	JEAN-PIERRE LECOUVE	93, RUE DU DR VIGNE 76600 LE HAVRE, FRANCE
3	DANIEL BRIGOT	74, RUE DES PEUPLIERS 76190 STE MARIE DES CHAMPS, FRANCE

PCT International Classification Number

C07D

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	08.03452	2008-06-20	France