HK1174616B - Process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid - Google Patents

Description

Process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid

The invention relates to ivabradine or 3- {3- [ { [ (7S) -3, 4-dimethoxybicyclo [4.2.0] of formula (I)]Oct-1, 3, 5-trien-7-yl]Methyl } (methyl) amino]Propyl } -7, 8-dimethoxy-1, 3, 4, 5-tetrahydro-2H-3-benzazepineProcess for the synthesis of (E) -2-ketones, their addition salts with pharmaceutically acceptable acids and their hydrates

Ivabradine and its addition salts with a pharmaceutically acceptable acid, more particularly its hydrochloride, have very valuable pharmacological and therapeutic properties, in particular a property of slowing down the heart rate, which makes the compound useful for the treatment or prevention of various clinical manifestations of myocardial ischemia, such as angina pectoris, myocardial infarction and the accompanying rhythm disorders, and also for conditions associated with rhythm disorders, in particular supraventricular rhythm disorders, and for heart failure.

The preparation and therapeutic use of ivabradine and its addition salts with a pharmaceutically acceptable acid (and more particularly its hydrochloride) have been described in european patent specification EP 0534859.

Said patent specification describes the synthesis of ivabradine hydrochloride starting from the compound of formula (II):

resolving the compound of formula (II) to give a compound of formula (III):

reacting a compound of formula (III) with a compound of formula (IV),

to obtain a compound of formula (V):

the compound of formula (V) is catalytically hydrogenated to ivabradine, which is then converted to its hydrochloride salt.

The disadvantage of said synthetic route is that it gives ivabradine in a yield of only 1%.

In view of the pharmaceutical value of said compounds, it is important to be able to obtain ivabradine by an efficient synthetic process which gives ivabradine in good yield.

The invention relates to a method for synthesizing ivabradine of formula (I):

the method is characterized in that: reacting a compound of formula (VI) in an organic solvent, a mixture of organic solvents or a mixture of an organic solvent and water in the presence of a reducing agent

Wherein R is₁And R₂Are identical or different and represent a linear or branched (C)₁-C₆) Alkoxy groups forming either, together with the carbon atom bearing them, a 1, 3-dioxane, 1, 3-dioxolane or 1, 3-dioxepane ring,

carrying out a reductive amination reaction together with a compound of formula (VII),

to obtain a compound of formula (VIII):

wherein R is₁And R₂As defined above;

condensing a compound of formula (VIII) with a compound of formula (IX) in an organic solvent in the presence of a base,

to obtain a compound of formula (X):

wherein R is₁And R₂As defined above;

subjecting the compound of formula (X) to a cyclisation reaction in an acidic medium to obtain a compound of formula (V):

subjecting the compound of formula (V) to a hydrogenation reaction to obtain ivabradine of formula (I), optionally converting ivabradine to an addition salt thereof with a pharmaceutically acceptable acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric 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, methanesulfonic acid, benzenesulfonic acid and camphoric acid, and optionally converting ivabradine to a hydrate thereof.

A series of reducing agents useful for carrying out reductive amination reactions can be found in the reference works: comprehensive Organic Transformations (Richard C. Larock, VCH publishers 1989, pages 421-.

Among the reducing agents which can be used to carry out the reductive amination of the compound of formula (VI) with the compound of formula (VII), mention may be made, without implying any limitation, of sodium triacetoxyborohydride, sodium cyanoborohydride, and hydrogen (H) in the presence of a catalyst such as palladium, platinum, nickel, ruthenium, rhodium and compounds thereof, in particular on a support or in the form of oxides₂)。

Is preferably used forThe reducing agent which effects the reductive amination of the compound of formula (VI) with the compound of formula (VII) is H in the presence of palladium on carbon₂。

The reductive amination of a compound of the formula (VI) with a compound of the formula (VII) is preferably carried out at 0.5 to 1.5bar of H₂Under pressure.

Among the solvents that can be used to carry out the reductive amination of the compound of formula (VI) with the compound of formula (VII) there may be mentioned, without implying any limitation, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, acetates, alcohols (preferably ethanol, methanol or isopropanol), toluene and xylenes.

The solvent used to effect the reductive amination reaction of the compound of formula (VI) with the compound of formula (VII) preferably comprises a mixture of ethanol and water.

The reductive amination of the compound of formula (VI) with the compound of formula (VII) is preferably carried out at a temperature of from 0 ℃ to 40 ℃.

Among the organic solvents that can be used in the reaction between the compound of formula (VIII) and the compound of formula (IX), mention may be made, without implying any limitation, of toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1, 2-dichloroethane, chloroform and dioxane.

The organic solvent used in the reaction between the compound of formula (VIII) and the compound of formula (IX) is preferably dichloromethane.

The reaction between the compound of formula (VIII) and the compound of formula (IX) is preferably carried out at a temperature of from 0 ℃ to 40 ℃.

Among the bases that can be used in the reaction between the compound of formula (VIII) and the compound of formula (IX), mention may be made, without implying any limitation, of pyridine, DMAP and tertiary amines, such as triethylamine, DIEA, N-methylpiperidine, DBU, DABCO, DBN and N-methylmorpholine.

The base used in the reaction between the compound of formula (VIII) and the compound of formula (IX) is preferably triethylamine.

Among the acids which can be used for the cyclisation of the compound of formula (X) to form the compound of formula (V), mention may be made, without implying any limitation, of concentrated sulfuric acid, polyphosphoric acid, aqueous solutions of concentrated hydrochloric acid, solutions of concentrated hydrochloric acid in acetic acid, solutions of concentrated hydrobromic acid in acetic acid and methanesulfonic acid.

The acid used to cyclize the compound of formula (X) to form the compound of formula (V) is preferably a solution of concentrated hydrochloric acid in acetic acid.

The cyclisation reaction of the compound of formula (X) to form the compound of formula (V) in an acidic medium is preferably carried out at a temperature of from 0 ℃ to 40 ℃.

The compounds of formula (VIII) and of formula (X) are novel products which are useful as synthesis intermediates in the chemical or pharmaceutical industry, in particular for the synthesis of ivabradine, its addition salts with a pharmaceutically acceptable acid and its hydrates, and thus they form an integral part of the present invention.

List of abbreviations used：

DABCO: 1, 4-diazabicyclo [2.2.2] octane

DBN: 1, 5-diazabicyclo [4.3.0] non-5-ene

DBU: 1, 8-diazabicyclo [5.4.0] undec-7-ene

DIEA: n, N-diisopropylethylamine

DMAP: 4-dimethylaminopyridine

IR: infrared ray

The following examples illustrate the invention.

The infrared spectra were recorded on a Bruker sensor 27 infrared instrument with a Golden Gate ATR fitting. The material was placed in pure form on the plate.

Example 1: 2- {3- [ { [ (7S) -3, 4-Dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl]Methyl } (methyl) amino]Propyl } -1H-isoindole-1, 3(2H) -dione

5.3g (25.5mmol) of 1- [ (7S) -3, 4-dimethoxybicyclo [4.2.0]Oct-1, 3, 5-trien-7-yl]-N-methylmethylamine and 6.8g (25.5mmol)2- (3-bromopropyl) -1H-isoindole-1, 3(2H) -dione are dissolved in 230mL of acetone. To the resulting solution was added 13g (95mmol, 3.7 equivalents) of potassium carbonate. Then, the mixture was heated under reflux for 24 hours. After cooling to ambient temperature, the potassium carbonate was removed by filtration and the filtrate was evaporated to dryness. The residue was taken up in water and extracted with dichloromethane. The organic phase was washed with MgSO₄Dried, filtered and evaporated to dryness. 9.7g of the expected product are obtained in the form of a pale yellow oil.

The yield is 97%

IR：v＝2782，1770，1704，1206，836，718cm^-1。

Example 2: n- { [ (7S) -3, 4-Dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl]Methyl } -N-methylpropane-1, 3-diamine

9.7g (24.58mmol) of the phthalimide compound obtained in the previous step was dissolved in 100mL of ethanol. 2.7mL (36.87mmol, 1.5 equiv.) of hydrazine hydrate are added and heated under reflux for 4 hours. After cooling to ambient temperature, 100mL of aqueous hydrochloric acid (4N) was added; the mixture was stirred at ambient temperature for 1 hour and filtered through a frit (frat). The filtrate was then evaporated (ethanol removed). The aqueous phase is then washed twice with diethyl ether and adjusted to pH 9 by addition of cold concentrated sodium hydroxide solution. Extracted 3 times with dichloromethane, then the combined organic phases are washed with water, over MgSO₄Dried, filtered and evaporated to dryness. 4.9g of the expected product are obtained in the form of a pale yellow oil.

The yield is 75%

IR：v＝3366，3302，1591cm^-1。

Examples3: n- { [ (7S) -3, 4-Dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl]Methyl } -N' - (2, 2-dimethoxyethyl) -N-methylpropane-1, 3-diamine

1g (3.7mmol) of N- { [ (7S) -3, 4-dimethoxybicyclo [4.2.0] oct-1, 3, 5-trien-7-yl ] methyl } -N-methylpropane-1, 3-diamine was dissolved in 20mL of ethanol. 520mg (0.45mL) of a 60% aqueous solution of glyoxal 1, 1-dimethylacetal was added, followed by 100mg of 10% Pd/C. The reaction mixture was hydrogenated at atmospheric pressure and ambient temperature for 12 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness. 1.2g of the expected product are obtained in the form of an oil.

The yield is 90 percent

IR：v＝1207，1508，834cm^-1。

Example 4: n- {3- [ { [ (7S) -3, 4-Dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl]Methyl } (methyl) amino]Propyl } -N- (2, 2-dimethoxyethyl) -2- (3, 4-dimethoxyphenyl) acetamide

Preparation of 6.3g (17.9mmol) of the acetal obtained in the preceding step in 80mL of CH₂Cl₂And (3) solution. To the resulting solution was added 5mL triethylamine (35.8mmol, 2 equiv.), which was then cooled to 0 ℃. Subsequently, a solution of 3.8g (17.9mmol) of 3, 4-dimethoxyphenylacetyl chloride in 40mL of methylene chloride was added dropwise thereto. Then stirred at ambient temperature for 3 hours. The mixture was diluted with water and extracted with dichloromethane. The organic phase is over MgSO₄Dried, filtered and evaporated to dryness. 10g of oil are obtained which is purified over 500g of silica gel (eluent ═ CH)₂Cl₂EtOH: 90/10). 8.5g of the expected product are obtained in the form of a brown oil.

The yield is 90 percent

IR：v＝1627，1207，1124，1071，1049，1027cm^-1。

Example 5: 3- {3- [ { [ (7S) -3, 4-Dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl]Methyl } (methyl) amino]Propyl } -7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepine-2-ketones

To a mixture of 10mL of acetic acid and 10mL of concentrated hydrochloric acid at ambient temperature was added 1g (1.9mmol) of the acetal obtained in the previous step. Stirring was carried out at 25 ℃ for 1 hour. The solution was adjusted to pH 9 by the addition of ice and aqueous sodium hydroxide (20%). Then, the mixture was extracted with dichloromethane. The organic phase is washed with water and over MgSO₄Dried, filtered and evaporated to dryness. 1g of oil are obtained which is purified by flash chromatography on 40g of silica gel (Merck)^TMColumn, eluent ═ CH₂Cl₂EtOH: 95/5). 270mg of the expected product are obtained in the form of an oil with an optical purity of more than 99%.

The yield is 31%

IR：v＝1656，836，760cm^-1。

Example 6: 3- {3- [ { [ (7S) -3, 4-Dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl]Methyl } (methyl) amino]Propyl } -7, 8-dimethoxy-1, 3, 4, 5-tetrahydro-2H-3-benzazepine-2-ketones

The title compound was obtained from the compound of example 5 above by repeating step D of example 1 of patent specification EP 0534859.

Claims (20)

1. A process for the synthesis of ivabradine of formula (I) or an addition salt thereof,

is characterized in that: reacting a compound of formula (VI) in an organic solvent, a mixture of organic solvents or a mixture of an organic solvent and water in the presence of a reducing agent

Wherein R is₁And R₂Are identical or different and represent a linear or branched (C)₁-C₆) Alkoxy groups forming either, together with the carbon atom bearing them, a 1, 3-dioxane, 1, 3-dioxolane or 1, 3-dioxepane ring,

carrying out a reductive amination reaction together with a compound of formula (VII),

to obtain a compound of formula (VIII):

wherein R is₁And R₂As defined above;

condensing a compound of formula (VIII) with a compound of formula (IX) in an organic solvent in the presence of a base,

to obtain a compound of formula (X):

wherein R is₁And R₂As defined above;

subjecting the compound of formula (X) to a cyclisation reaction in an acidic medium to obtain a compound of formula (V):

subjecting the compound of formula (V) to a hydrogenation reaction to obtain ivabradine of formula (I), optionally converting ivabradine to an addition salt thereof with a pharmaceutically acceptable acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric 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, methanesulfonic acid, benzenesulfonic acid and camphoric acid.

2. The synthesis process according to claim 1, characterized in that the reducing agent used to effect the reductive amination of the compound of formula (VI) with the compound of formula (VII) is selected from sodium triacetoxyborohydride, sodium cyanoborohydride, and H in the presence of a catalyst₂。

3. The synthesis process according to claim 2, characterized in that the catalyst is chosen from palladium, platinum, nickel, ruthenium, rhodium and compounds thereof.

4. The synthesis process according to claim 2, characterized in that the catalyst is on a support or in the form of an oxide.

5. The synthesis process according to claim 2, characterized in that the reducing agent used to effect the reductive amination of the compound of formula (VI) with the compound of formula (VII) is H in the presence of palladium on carbon₂。

6. Synthesis process according to claim 5, characterized in that the reductive amination of the compound of formula (VI) with the compound of formula (VII) is carried out at 0.5-1.5bar of H₂Under pressure.

7. The synthesis process according to any one of claims 1 to 6, characterized in that the solvent used to effect the reductive amination of the compound of formula (VI) with the compound of formula (VII) is selected from tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, acetates, alcohols, toluene and xylenes.

8. The synthesis according to claim 7, characterized in that the alcohol is selected from ethanol, methanol or isopropanol.

9. The synthesis according to any one of claims 1 to 6, characterized in that the solvent used to effect the reductive amination of the compound of formula (VI) with the compound of formula (VII) comprises a mixture of ethanol and water.

10. Process according to any one of claims 1 to 6, characterized in that the reductive amination of the compound of formula (VI) with the compound of formula (VII) is carried out at a temperature of between 0 ℃ and 40 ℃.

11. The synthesis process according to any one of claims 1 to 6, characterized in that the organic solvent used in the reaction between the compound of formula (VIII) and the compound of formula (IX) is selected from toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1, 2-dichloroethane, chloroform and dioxane.

12. A synthesis according to claim 11, characterized in that the organic solvent used in the reaction between the compound of formula (VIII) and the compound of formula (IX) is dichloromethane.

13. A synthesis according to any one of claims 1 to 6, characterized in that the reaction between the compound of formula (VIII) and the compound of formula (IX) is carried out at a temperature ranging from 0 ℃ to 40 ℃.

14. The synthesis according to any one of claims 1 to 6, characterized in that the base used in the reaction between the compound of formula (VIII) and the compound of formula (IX) is selected from pyridine, 4-Dimethylaminopyridine (DMAP) and tertiary amines.

15. A synthesis according to claim 14, characterized in that the base used in the reaction between the compound of formula (VIII) and the compound of formula (IX) is triethylamine.

16. The synthesis according to any one of claims 1 to 6, characterized in that the acid used for cyclizing the compound of formula (X) to form the compound of formula (V) is selected from concentrated sulfuric acid, polyphosphoric acid, aqueous solution of concentrated hydrochloric acid, solution of concentrated hydrochloric acid in acetic acid, solution of concentrated hydrobromic acid in acetic acid and methanesulfonic acid.

17. The synthesis according to claim 16, characterized in that the acid used for cyclizing the compound of formula (X) to form the compound of formula (V) is a solution of concentrated hydrochloric acid in acetic acid.

18. A synthesis according to any one of claims 1 to 6, characterized in that the cyclisation of the compound of formula (X) to form the compound of formula (V) is carried out at a temperature of between 0 ℃ and 40 ℃.

19. A compound of formula (VIII):

wherein R is₁And R₂Are identical or different and represent a linear or branched (C)₁-C₆) Alkoxy radicals either together with the carbon atom bearing them form 1, 3-dioxane, 1, 3-dioxolane or 1,3-dioxepane ring.

20. A compound of formula (X):

wherein R is₁And R₂As defined in claim 19.