HK1162021B - Process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid - Google Patents

Description

Method for synthesizing ivabradine and pharmaceutically acceptable acid addition salts thereof

Technical Field

The invention relates to the synthesis of ivabradine of formula (I)

Or 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, and the pharmaceutically acceptable acid addition salts thereof and the hydrates thereof.

Background

Ivabradine, and its pharmaceutically acceptable acid addition salts, and more particularly its hydrochloride, have very valuable pharmacological and therapeutic properties, in particular heart rate slowing properties, which make these compounds useful for the treatment or prevention of various clinical manifestations of myocardial ischemia, such as angina pectoris, myocardial infarction and related rhythm disorders, and also for various diseases involving rhythm disorders, in particular supraventricular arrhythmias, and for heart failure.

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

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

resolving it to give a compound of formula (III):

the latter is reacted with a compound of formula (IV):

to give 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 this synthetic route is that it results in only 1% yield of ivabradine.

In view of the pharmaceutical value of the compound, it is important to be able to obtain a good yield of ivabradine by an efficient synthetic method.

Disclosure of Invention

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

the process is characterized in that a compound of formula (VI):

formation of a thiohemiacetal of formula (VII) by the action of a thiol in an organic solvent:

wherein R represents a substituted or unsubstituted, optionally perfluorinated, linear or branched alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted benzyl group, or a group CH₂CO₂Et，

Subjecting it to a cyclisation reaction to give a compound of formula (VIII):

wherein R is as defined above, and wherein,

the compound of formula (VIII) is subjected to a reduction reaction to obtain ivabradine of formula (I), which can optionally be converted into a pharmaceutically acceptable acid addition salt thereof, said pharmaceutically acceptable acid being 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 can be converted into a hydrate thereof.

The solvent used in the reaction to form the thiohemiacetal of formula (VII) is preferably dichloromethane.

The thiol selected for reaction with the compound of formula (VI) is preferably thiophenol.

The solvent used in the cyclisation reaction of the compound of formula (VII) to form the compound of formula (VIII) is preferably dichloromethane.

In a preferred embodiment of the invention, the cyclization reaction of the compound of formula (VII) to form the compound of formula (VIII) is carried out in the presence of a reagent selected from the group consisting of acetic anhydride, trifluoroacetic anhydride and trimethylsilyl triflate.

The cyclisation of the compound of formula (VII) to form the compound of formula (VIII) is more preferably carried out in the presence of trifluoroacetic anhydride.

The cyclisation of the compound of formula (VII) to form the compound of formula (VIII) is even more preferably carried out in the presence of trifluoroacetic anhydride and a Lewis acid selected from BF₃.OEt₂、Sc(OTf)₃And Yb (OTf)₃。

The cyclization of the compound of formula (VII) to form the compound of formula (VIII) is even more preferably carried out in trifluoroacetic anhydride and BF₃.OEt₂In the presence of oxygen.

The reaction for reducing the compound of formula (VIII) is preferably carried out in ethanol in the presence of Raney nickel or in tetrahydrofuran in the presence of samarium (II) iodide.

The compounds of formulae (VI), (VII) and (VIII) are novel products which are useful as synthetic intermediates in the chemical or pharmaceutical industry, in particular in the synthesis of ivabradine and its pharmaceutically acceptable acid addition salts and hydrates, and therefore they form an integral part of the compounds of the invention.

Detailed Description

List of abbreviations used:

DMF: n, N-dimethylformamide

DMSO, DMSO: dimethyl sulfoxide

THF: tetrahydrofuran (THF)

IR: infrared spectroscopy

The following examples illustrate the invention.

Melting Point (MP) was measured using a Kofler Block (KB).

The infrared spectra were recorded on a Bruker Tensor 27 infrared instrument with a Golden Gate ATR accessory. The substance is placed in pure form on the tray.

Example 1: [2- (3, 4-Dimethoxyphenyl) ethyl group]Carbamic acid tert-butyl ester

Di-tert-butyl dicarbonate (12 g; 55.2mmol) is added to a solution of 2- (3, 4-dimethoxyphenyl) ethylamine (10 g; 55.2mmol) in dichloromethane (200 mL). After 1 hour of contact at ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was taken up in pentane (100mL) and after 1 hour of contact at ambient temperature, the suspension was filtered through a frit. 13.2g of the title product are obtained in solid form.

The yield is 85 percent

m.p.＝65±2℃。

Example 2: 3- [ { [ (7S) -3, 4-Dimethoxybicyclo [4.2.0 ]]Oct-1, 3, 5-trien-7-yl]Methyl } (methyl) amino]Propyl- [2- (3, 4-dimethoxyphenyl) ethyl]Carbamic acid tert-butyl ester

NaH (60% in oil) (1.14 g; 28.5mmol) was added in small portions to a solution of the compound obtained in the previous step (7.6 g; 27mmol) in 40mL of DMF at ambient temperatureIn the liquid. After 1 hour of contact at ambient temperature, 3-chloro-N- { [ (7S) -3, 4-dimethoxybicyclo [4.2.0]Oct-1, 3, 5-trien-7-yl]A solution of methyl } -N-methyl-1-propylamine (7.68 g; 27mmol) in 16mL of DMF was added, and the reaction mixture was heated at 80 ℃ for 3 hours. After cooling to ambient temperature, the reaction mixture was poured into a mixture of distilled water and ice. The aqueous phase was extracted with ethyl acetate. The combined organic phases were separated by MgSO₄Dried and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH)₂Cl₂EtOH: 95/5) to yield 9.1g of the title product as an oil.

The yield was 64%

IR：v＝3340，1678，1519，1167cm^-1。

Example 3: n- { [ (7S) -3, 4-Dimethoxybicyclo [4.2.0 ]]Oct-1, 3, 5-trien-7-yl]Methyl } -N' - [2- (3, 4-dimethoxyphenyl) ethyl]-N-methyl-1, 3-propanediamine

9g (17mmol) of the compound obtained in the above step were dissolved in a 2.8N HCl in ethanol solution. After 2 hours of contact at ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was taken up in 1N sodium hydroxide solution and the aqueous phase was extracted with ethyl acetate. Over MgSO₄After drying the organic phase, concentration under reduced pressure gave 6.8g of the title product as an oil.

The yield was 93%

IR：v＝3304，2793，1261，1236，1205，1153cm^-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- (3, 4-dimethoxyphenyl) ethyl]-2-hydroxyacetamide

Step 1: acetic acid 2- { {3- [ { [ (7S) -3, 4-Dimethoxybicyclo [4.2.0 ]]Oct-1, 3, 5-trien-7-yl]Methyl } (methyl) amino]Propyl } - [2- (3, 4-dimethoxyphenyl) ethyl]Amino } -2-oxoethyl ester

To a solution of the compound (6.8 g; 15.8mmol) obtained in the above step in 200mL of dichloromethane was added triethylamine (3.1 g; 22mmol) at 0 ℃ followed by dropwise addition of acetoxyacetyl chloride (2.1 mL; 19 mmol). After 0.5 hour of contact at ambient temperature, the reaction mixture was washed with distilled water, and the organic phase was then washed with MgSO₄And (5) drying. After concentration of the organic phase under reduced pressure, 8g of the title product are obtained as an oil which is used directly in the next step without purification.

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

Will K₂CO₃(8.3 g; 60.4mmol) was added to a solution of the compound obtained in the above step (8g) in 80mL of a water/methanol mixture (2/1). After 1 hour of contact at ambient temperature, the reaction mixture was concentrated under reduced pressure and the residue was taken up in distilled water. After extraction with ethyl acetate, the combined organic phases are over MgSO₄Dried and then concentrated under reduced pressure. 6.2g of the title product are obtained as an oil.

Yield 81% (2 steps)

IR：v＝3406，2794，1641，1261，1236，1205，1153cm^-1。

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

To a solution of oxalyl chloride (0.6 mL; 6.77mmol) in 25mL of dichloromethane was added a solution of DMSO (0.9 mL; 12.32mmol) in 5mL of dichloromethane at-78 ℃. After contacting at-78 ℃ for 1 hour, a solution of the compound (3 g; 6.16mmol) obtained in the above step in 25mL of dichloromethane was added over 0.5 hour. After 1 hour at-78 deg.C, triethylamine (4.3 mL; 30.8mmol) was added; the reaction mixture was then stirred at ambient temperature for 3 hours, then saturated NaHCO was poured in₃In aqueous solution. The organic phase is MgSO₄Dried and then concentrated under reduced pressure. 2.7g of the title product are obtained as an oil.

The yield is 89%

IR：v＝2788，1645，1589，1261，1236，1207，1151cm^-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- (phenylsulfanyl) -1, 3, 4, 5-tetrahydro-2H-3-benzazepine-2-ketones

Thiophenol (0.53 mL; 5.17mmol) was added to a solution of the compound obtained in the above step (2.6 g; 5.17mmol) in 60mL of dichloromethane. After overnight contact at ambient temperature, trifluoroacetic anhydride (6.5 mL; 47mmol) and BF were added successively₃.OEt₂(6.5 mL; 26 mmol). The reaction mixture was stirred at ambient temperature for 3 hours, then saturated NaHCO was poured in₃In aqueous solution. With MgSO₄After drying the organic phase and concentrating under reduced pressure, the residue obtained is chromatographed on silica gel (CH)₂Cl₂/EtOH/NH₄OH 28%: 97/3/0.3). 1.15g of the title product are obtained as an oil.

The yield was 38%

IR：v＝2790，1641，1245，1205，1174cm^-1。

Example 7: 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

Raney nickel (2.5g) (50% in H)₂O) was added the compound obtained in the above step (0.8 g;1.39mmol) in ethanol. After 1 hour of contact at reflux, the suspension was cooled and then filtered through celite. 600mg of the title product are obtained as an oil.

The yield is 94%

IR：v＝2788，1646，1519，1461，1245，1105cm^-1。

Example 8: 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-keto hydrochloride

Starting from the product obtained in the above step, the title product was prepared according to the procedure described in patent specification EP 0534859 (example 2, step E).

Claims (4)

1. A process for the synthesis of ivabradine of formula (I):

characterized in that a compound of formula (VI):

formation of a thiohemiacetal of formula (VII) by the action of thiophenol in dichloromethane:

wherein R represents a phenyl group, and R represents a phenyl group,

subjecting it to a cyclisation reaction to give a compound of formula (VIII):

wherein R is as defined above, and wherein,

subjecting the compound of formula (VIII) to a reduction reaction to obtain ivabradine of formula (I), which may optionally be converted to a pharmaceutically acceptable acid addition salt thereof, said pharmaceutically acceptable acid being selected from the group consisting of 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,

wherein the cyclisation of the compound of formula (VII) to form the compound of formula (VIII) is carried out in the presence of a reagent selected from acetic anhydride, trifluoroacetic anhydride and trimethylsilyl triflate,

and wherein the reaction to reduce the compound of formula (VIII) is carried out in ethanol in the presence of Raney nickel or in tetrahydrofuran in the presence of samarium (II) iodide.

2. The synthesis process according to claim 1, characterized in that the solvent used in the cyclization reaction of the compound of formula (VII) to form the compound of formula (VIII) is dichloromethane.

3. The synthesis process according to claim 1, characterized in that the cyclization reaction of the compound of formula (VII) to form the compound of formula (VIII) is carried out in the presence of trifluoroacetic anhydride and a Lewis acid, said Lewis acid beingThe silicic acid is selected from BF₃.OEt₂、Sc(OTf)₃And Yb (OTf)₃。

4. A synthesis process according to any one of claims 1 to 3, characterized in that the cyclization reaction of the compound of formula (VII) to form the compound of formula (VIII) is carried out between trifluoroacetic anhydride and BF₃.OEt₂In the presence of oxygen.