HK1165790A - Novel method for the synthesis of ivabradine and the pharmaceutically acceptable acid addition salts thereof - Google Patents

Description

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

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.

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.

The present invention relates to a process for the synthesis of a compound of formula (VI) in its racemic or optically active form:

wherein A represents H₂C-CH₂Or HC is equal to CH or a group of,

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

wherein X represents a halogen atom, a methanesulfonate group or a toluenesulfonate group,

alkylation with a compound of formula (VIII) in an organic solvent in the presence of a base:

wherein A is as defined above.

In a preferred embodiment of the invention, the compound of formula (VII) is in an optically active form, and more particularly in the (S) configuration.

When A represents H₂C-CH₂When the alkylation product of a compound of formula (VII) with a compound of formula (VIII) in (S) configuration is ivabradine of formula (I):

which can optionally be converted into a pharmaceutically acceptable acid addition salt thereof, 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.

When a represents HC ═ CH, the alkylation product of a compound of formula (VII) with a compound of formula (VIII) in the (S) configuration is a compound of formula (V):

which is subjected to catalytic hydrogenation to obtain ivabradine of formula (I):

which can optionally be converted into a pharmaceutically acceptable acid addition salt thereof, 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.

In another preferred embodiment of the invention, the compound of formula (VII) is in racemic form. A step of alkylating a racemic compound of formula (VII) with a compound of formula (VIII), followed by subjecting the resulting compound of formula (VI) to optical resolution.

When A represents H₂C-CH₂When the compound of formula (VI) is subjected to a step of optical resolution, the product obtained is ivabradine of formula (I):

which can optionally be converted into a pharmaceutically acceptable acid addition salt thereof, 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.

When a represents HC ═ CH, the product obtained after the step of subjecting the compound of formula (VI) to optical resolution is a compound of formula (V):

which is subjected to catalytic hydrogenation to obtain ivabradine of formula (I):

which can optionally be converted into a pharmaceutically acceptable acid addition salt thereof, 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.

Among the bases which can be used for carrying out the alkylation reaction of the compound of formula (VII) with the compound of formula (VIII), there may be mentioned, without representing any limitation, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate and sodium bicarbonate.

The base used to carry out the alkylation of the compound of formula (VII) with the compound of formula (VIII) is preferably potassium carbonate.

Among the solvents which can be used for carrying out the alkylation reaction of the compound of formula (VII) with the compound of formula (VIII), mention may be made, without representing any limitation, of acetonitrile, acetone or butan-2-one.

The solvent used to carry out the alkylation of the compound of formula (VII) with the compound of formula (VIII) is preferably acetonitrile.

The compounds of formula (VIIa) in their racemic or optically active form, in which X represents a halogen atom or a mesylate group, as particular aspects of the compounds of formula (VII), are novel products which are useful as synthesis intermediates in the chemical or pharmaceutical industry, in particular for the synthesis of ivabradine and its pharmaceutically acceptable acid addition salts and hydrates thereof, and thus form an integral part of the present invention.

The following examples serve to illustrate the invention.

List of abbreviations used:

DMF: n, N-dimethylformamide

IR: infrared spectroscopy

Melting points (m.p.) were measured using a Kofler block.

Example 1: 7, 8-dimethoxy-3- [3- (methylamino) propyl group]-1, 3, 4, 5-tetrahydro-2H-3-benzazepine-2-ketones

50g (0.18mol) of 3- (7, 8-dimethoxy-2-oxo-1, 2, 4, 5-tetrahydro-benzo [ d ]]Aza derivatives-3-yl) -propionaldehyde was dissolved in 625mL of methanol. The resulting solution was cooled to 0 ℃. 62.5mL (0.81 mol; 4.5 equivalents) of a 40% aqueous methylamine solution were then added. Stirring at 0 ℃ for one hour, followed by addition of 7.5g (0.2 mol; 1.1 eq) of NaBH₄. Stirring was carried out at 0 ℃ for 30 minutes and subsequently at ambient temperature for 12 hours. The methanol was removed by evaporation. The residue was dissolved in aqueous hydrochloric acid (1N) and extracted with ethyl acetateWashing was followed by adjusting the aqueous phase to pH 8 by addition of 20% sodium hydroxide solution and extraction with dichloromethane. The organic phase was washed with water and MgSO₄Dried, filtered and evaporated to dryness to give 52g of oil.

The resulting oil was purified by flash chromatography on 1.5kg of silica gel (eluent: dichloromethane/ethanol/NH)₄OH: 80/20/2). 42g of the expected product are obtained in the form of a white solid.

The yield is 80%

Melting point of 68-70 deg.C

Example 2: 7, 8-dimethoxy-3- [3- (methylamino) propyl group]-1, 3-dihydro-2H-3-benzazepine-2-ketones

Step 1: [3- (7, 8-dimethoxy-2-oxo-1, 2-dihydro-3H-3-benzazepine-3-yl) propyl]Methyl carbamic acid tert-butyl ester

1.7g (7.8mmol) of 7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepine-2-ketone was suspended in 35mL of DMF, followed by addition of 374mg (9.35mmol, 1.2 equiv.) of sodium hydride (60% suspension in oil). A clear pale yellow solution was obtained which was stirred at 25 ℃ for 1 hour. Subsequently, 1.94g (9.35mmol, 1.2 equivalents) of tert-butyl (3-chloropropyl) methylcarbamate dissolved in 10mL of DMF is added dropwise. Heating was carried out at 50 ℃ overnight, followed by evaporation of the solvent to dryness. The residue was dissolved in water and extracted with dichloromethane. The organic phase is MgSO₄Dried, filtered and then evaporated to dryness. 4.2g of an oil are obtained which is purified by flash chromatography on 200g of silica gel (eluent:dichloromethane/ethyl acetate: 80/20). 2.3g of the title product are subsequently obtained in the form of a colorless oil.

The yield was 77%

IR (pure): v ═ 1685, 1659, 1155, 1102, 872, 770cm^-1。

Step 2: 7, 8-dimethoxy-3- [3- (methylamino) propyl group]-1, 3-dihydro-2H-3-benzazepine-2-ketones

1.9g (4.86mmol) of the product obtained in step 1 are dissolved in 30mL of ethanol and 7mL (24.3mmol, 5 equiv.) of HCl in ethanol (3.5N) are added to the solution obtained. The reaction mixture was evaporated to dryness by heating at 60 ℃ overnight. The residue obtained is dissolved in water, and the aqueous phase is subsequently brought to pH 8 by addition of 20% sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and MgSO₄Dried, filtered and then evaporated to dryness. 1.1g of the title product are obtained in the form of a colorless oil.

The yield was 78%

IR (pure): v is 3400, 1651, 1610, 1510, 856, 710cm^-1。

Example 3: (R, S) -7- (iodomethyl) -3, 4-dimethoxybicyclo [4.2.0] octa-1, 3, 5-triene

To 60mL of dichloromethane were added in sequence: 4.8g of P (Ph)3(18.5 mmol; 1.2 equiv.), 1.2g of imidazole (18.5 mmol; 1.2 equiv.) wait until a clear solution is obtained, then add 4.7g of iodine (18.5 mmol; 1.2 equiv.). Good precipitated imidazole iodonium hydrate formation was observed. Then, 3g (15.4mmol) of (3, 4-dimethoxybicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methanol dissolved in 15mL of dichloromethane was added dropwise to the resulting mixture; an exothermic reaction was observed, with a temperature rise from 20 ℃ to 28 ℃. Stir at ambient temperature for 12 hours.

Filtering out insoluble substances; this was then evaporated to dryness to give 15g of an oily residue.

The resulting product is purified by flash chromatography on 500g of silica gel (eluent dichloromethane/cyclohexane: 80/20). 4g of iodo compound are obtained in the form of a green oil, which crystallizes at ambient temperature.

The yield is 85 percent

Melting point of 55-60 deg.C

Example 4: methanesulfonic acid (R, S) - (3, 4-dimethoxybicyclo [4.2.0] octa-1, 3, 5-trien-7-yl) methyl ester

4g (20.6mmol) of (3, 4-dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl) methanol was dissolved in 50mL of dichloromethane. Cooled to 0 deg.C and 4.3mL (31.0mmol, 1.5 equiv.) of triethylamine was added. Then 1.9mL of methanesulfonyl chloride (24.7mmol, 1.2 equiv.) dissolved in 10mL of dichloromethane was added dropwise. Stir at ambient temperature overnight. The organic phase is washed with aqueous HCl (1N), then with water and MgSO₄Drying, filtration and evaporation to dryness gave 4.7g of the title product as a pale brown solid.

The yield was 84%

Melting point of 98-100 deg.C

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

1g (3.28mmol) of 7- (iodomethyl) -3, 4-dimethoxybicyclo [4.2.0]Octane-1, 3, 5-triene was dissolved in 20mL of acetonitrile. 907mg (2 equivalents) of K are added₂CO₃And 959mg (3.28mmol) of 7, 8-dimethoxy-3- [3- (A)Alkylamino) propyl group]-1, 3, 4, 5-tetrahydro-2H-3-benzazepine-2-ketones. The resulting reaction mixture was heated to reflux for 4 hours.

Cooling was carried out, the insoluble material was filtered off and evaporated to dryness to give 2g of an oil which was purified by flash chromatography on 100g of silica gel (eluent ═ dichloromethane/ethanol/NH₄OH: 90/10/1). 780mg of the expected product are obtained as a colorless oil which crystallizes at ambient temperature.

The yield was 51%

Melting point of 98-100 deg.C

Alternative methods:

1g (3.67mmol) of methanesulfonic acid (R, S) - (3, 4-dimethoxybicyclo [4.2.0] obtained in example 4]Oct-1, 3, 5-trien-7-yl) methyl ester was dissolved in 20mL of acetonitrile. 1g (7.34mmol, 2 equiv.) of K are added₂CO₃And 1.07g (3.67mmol) of 7, 8-dimethoxy-3- (3-methylamino-propyl-1, 3, 4, 5-tetrahydro-benzo [ d ]]Aza derivatives-2-ketones. The resulting reaction mixture was heated to reflux for 48 hours. Cooling is carried out, the insoluble is filtered off and evaporated to dryness to give 1.8g of an oil which is first purified by flash chromatography on 100g of silica gel (eluent ═ dichloromethane/ethanol/NH₄OH: 90/10/1) and then purified on 100g of silica gel (eluent dichloromethane/ethanol/NH₄OH: 95/5/0.5) to yield the title product.

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-keto hydrochloride (optical resolution)

2.1g of the racemic compound from example 5 are separated on a 60cmx60mm column packed with 2.1kgAD phase (particle size: 20 μm). The eluent used was a mixture of ethanol/acetonitrile/diethylamine (volume ratio 10/90/0.1) at a flow rate of 50 mL/min. The ultraviolet detector connected in series has a wavelength of 280 nm.

0.95g of the enantiomer in (R) configuration is obtained in the form of a white cake, followed by 0.95g of the enantiomer in (S) configuration, also in the form of a white cake.

The hydrochloride of the enantiomer in the (S) configuration is then obtained according to the method described in patent specification EP 0534859 (example 2, step E).

Example 7: 3- {3- [ [ (3, 4-dimethoxybicyclo [4.2.0] methyl ethyl ester]Octane-1, 3, 5-trien-7-yl) methyl]- (methyl) amino]Propyl } -7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepine-2-ketones

1g (3.28mmol) of 7- (iodomethyl) -3, 4-dimethoxy [4.2.0]Octane-1, 3, 5-triene was dissolved in 20mL of acetonitrile. 907mg (2 equivalents) of K are added₂CO₃And 952mg (3.28mmol) of 7, 8-dimethoxy-3- [3- (methylamino) propyl]-1, 3-dihydro-2H-3-benzazepine-2-ketones. The reaction mixture was heated to reflux for 4 hours. Cooling is carried out, the insoluble is filtered off and evaporated to dryness to give 2g of an oil which is purified by flash chromatography on 100g of silica gel (eluent: dichloromethane/ethanol/NH)₄OH: 90/10/1). 700mg of the title product are obtained as an oil.

The yield was 47%

IR (pure): 1656, 1607, 1511, 1273, 1206, 1101, 836, 760cm^-1。

Alternative methods:

1g (3.67mmol) of methanesulfonic acid (3, 4-dimethoxy [ 4.2.0)]Oct-1, 3, 5-trien-7-yl) methyl ester was dissolved in 20mL of acetonitrile. 1g (7.34mmol, 2 equiv.) of K are added₂CO₃And 1.06g (3.67mmol) of (7, 8-dimethoxy-3- [3- (methylamino) propyl)]-1, 3-dihydro-2H-3-benzazepine-2-ketones. The reaction mixture was heated to reflux for 12 hours. Cooling is carried out, the insoluble is filtered off and evaporated to dryness to give 1.9g of an oil which is first purified by flash chromatography on 100g of silica gel (eluent: dichloromethane/ethanol/NH)₄OH: 90/10/1) and then purified on 100g of silica gel (eluent: dichloromethane/ethanol/NH₄OH: 95/5/0.5) to yield the title product.

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

1.4g of the racemic compound from example 7 are separated on a 60cmx60mm column packed with 3kgT101 phase (particle size: 20 μm). The eluent used was a mixture of ethanol/acetonitrile/diethylamine (volume ratio 10/90/0.1) at a flow rate of 100 mL/min. The ultraviolet detector connected in series has a wavelength of 280 nm.

0.56g of the enantiomer in (R) configuration is obtained as a colorless oil, followed by 0.62g of the enantiomer in (S) configuration, also as a colorless oil.

The hydrogenation was then carried out according to the method described in patent specification EP 0534859 (example 1, step D) to give the compound of configuration (S). The hydrochloride salt of the compound obtained was prepared according to the method described in patent specification EP 0534859 (example 2, step E).

Example 9: 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

Using the procedure described in example 5, starting from (7S) - (iodomethyl) -3, 4-dimethoxybicyclo [4.2.0]Octane-1, 3, 5-triene (or (7S) - (3, 4-dimethoxybicyclo [4.2.0] methanesulfonic acid)]Octa-1, 3, 5-trien-7-yl) methyl ester) and 7, 8-dimethoxy-3- [3- (methylamino) propyl]-1, 3, 4, 5-tetrahydro-2H-3-benzazepine-2-ketone to obtain ivabradine base, which is then converted into its hydrochloride salt according to the method described in patent specification EP 0534859 (example 2, step E).

Example 10: 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

Using the procedure described in example 7, starting from (7S) - (iodomethyl) -3, 4-dimethoxybicyclo [4.2.0]1, 3, 5-tri-octyl-)Alkene (or from methanesulfonic acid (7S) - (3, 4-dimethoxybicyclo [4.2.0]]Octa-1, 3, 5-trien-7-yl) methyl ester) and 7, 8-dimethoxy-3- [3- (methylamino) propyl]-1, 3-dihydro-2H-3-benzazepine-2-ketone, to obtain the compound which is hydrogenated according to the method described in patent specification EP 0534859 (example 1, step D) to obtain ivabradine base, which is then converted into its hydrochloride according to the method described in patent specification EP 0534859 (example 2, step E).

Claims (11)

1. A process for the synthesis of a compound of formula (VI) in its racemic or optically active form:

wherein A represents H₂C-CH₂Or HC is equal to CH or a group of,

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

wherein X represents a halogen atom, a methanesulfonate group or a toluenesulfonate group,

alkylation with a compound of formula (VIII) in an organic solvent in the presence of a base:

wherein A is as defined above.

2. The synthesis according to claim 1, characterized in that the compound of formula (VII) is in an optically active form, and more particularly in the (S) configuration.

3. The synthesis according to claim 2, characterized in that A represents H₂C-CH₂And the product of the alkylation of the compound of formula (VII) with the compound of formula (VIII) is ivabradine of formula (I):

which can optionally be converted into a pharmaceutically acceptable acid addition salt thereof, 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.

4. A process according to claim 2, characterised in that a represents HC ═ CH and the product of the alkylation reaction of the compound of formula (VII) with the compound of formula (VIII) is a compound of formula (V):

which is subjected to catalytic hydrogenation to obtain ivabradine of formula (I):

which can optionally be converted into a pharmaceutically acceptable acid addition salt thereof, 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.

5. A process according to claim 1, characterized in that the compound of formula (VII) is in racemic form and after the alkylation of the compound of formula (VII) with the compound of formula (VIII), the resulting racemic compound of formula (VI) is subjected to a step of optical resolution.

6. The process according to claim 5, wherein A represents H₂C-CH₂And the product obtained after the step of optically resolving the compound of formula (VI) is ivabradine of formula (I):

which can optionally be converted into a pharmaceutically acceptable acid addition salt thereof, 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.

7. The synthesis according to claim 5, characterized in that A represents HC ═ CH and the product obtained after the step of subjecting the compound of formula (VI) to optical resolution is a compound of formula (V):

which is subjected to catalytic hydrogenation to obtain ivabradine of formula (I):

which can optionally be converted into a pharmaceutically acceptable acid addition salt thereof, 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.

8. Process of synthesis according to any one of claims 1 to 7, characterized in that the base used for the alkylation reaction of the compound of formula (VII) with the compound of formula (VIII) is chosen from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate and sodium bicarbonate.

9. A synthesis process according to any one of claims 1 to 8, characterised in that the base used to carry out the alkylation of the compound of formula (VII) with the compound of formula (VIII) is potassium carbonate.

10. Synthesis process according to any one of claims 1 to 9, characterized in that the solvent used for the alkylation reaction of the compound of formula (VII) with the compound of formula (VIII) is chosen from acetonitrile, acetone and butan-2-one.

11. A compound of formula (VIIa), in racemic or optically active form, which is a particular case of compounds of formula (VII):

wherein X represents a halogen atom or a methanesulfonate group.