HK1198159B

HK1198159B - Process for the synthesis of (2e)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile, and application in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid

Info

Publication number: HK1198159B
Application number: HK14111643.2A
Authority: HK
Inventors: Maria Del Pilar Carranza; Maria Isabel Garcia Aranda; José Lorenzo Gonzalez; Frédéric Sanchez
Original assignee: Les Laboratoires Servier
Priority date: 2012-11-08
Filing date: 2014-11-18
Publication date: 2016-11-25

Description

Method for synthesizing (2E) -3- (3, 4-dimethoxyphenyl) prop-2-enenitrile and application thereof in synthesizing ivabradine and pharmaceutically acceptable acid addition salts thereof

Technical Field

The invention relates to a method for synthesizing (2E) -3- (3, 4-dimethoxyphenyl) prop-2-enenitrile of formula (I) and the application thereof in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid

The compound of formula (I) obtained according to the process of the invention can be used for the synthesis of ivabradine of formula (II),

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-a 2-ketone having a structure represented by formula (I),

which can be converted into addition salts 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 into hydrates thereof.

Background

Ivabradine and its addition salts with a pharmaceutically acceptable acid, in particular 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 conditions of myocardial ischemia, such as angina pectoris, myocardial infarction and related arrhythmias, and also for various diseases involving arrhythmias, in particular supraventricular arrhythmias, and heart failure.

The preparation and therapeutic use of ivabradine and its addition salts with a pharmaceutically acceptable acid, in particular its hydrochloride, are described in european patent specification EP 0534859.

The description of this patent describes the preparation of ivabradine starting from 3, 4-dimethoxybicyclo [4.2.0] octa-1, 3, 5-triene-7-carbonitrile of formula (III):

converting it into a compound of formula (IV):

resolving the compound of formula (IV) to give a compound of formula (V):

reacting a compound of formula (V) with a compound of formula (VI):

to give a compound of formula (VII):

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

The preparation of compounds of formula (III) starting from 3- (2-bromo-4, 5-dimethoxyphenyl) propionitrile of formula (VIII) is described in Tetrahedron1973,29, pp 73-76:

the compound of formula (I) which is a precursor of the compound of formula (VIII) is therefore a key intermediate in the synthesis of ivabradine.

Patent application DE2303919 describes the preparation of the compound of formula (I) in 74% yield starting from 3, 4-dimethoxybenzaldehyde.

In view of the industrial value of ivabradine and its salts, there is a continuous need to find an efficient process capable of obtaining (2E) -3- (3, 4-dimethoxyphenyl) propan-2-enenitrile of formula (I) in excellent yields.

Disclosure of Invention

The present invention relates to a process for the synthesis of a compound of formula (I):

characterized in that a compound of formula (IX):

and acrylonitrile in the presence of a palladium catalyst, a ligand, a base and a phase transfer reagent in an organic solvent to obtain the compound shown in the formula (I).

Among the palladium catalysts which can be used to carry out the conversion of the compound of formula (IX) into the compound of formula (I), mention may be made, by way of non-limiting example, of palladium (II) acetate, palladium on carbon and palladium chloride.

The preferred palladium catalyst for completing the conversion of the compound of formula (IX) to the compound of formula (I) is palladium on carbon.

Among the ligands which can be used to carry out the conversion of the compound of formula (IX) into the compound of formula (I), mention may be made, by way of non-limiting example, of triphenylphosphine and tri (o-tolyl) phosphine.

The preferred ligand for accomplishing the conversion of the compound of formula (IX) to the compound of formula (I) is tri (o-tolyl) phosphine.

Among the bases which can be used to carry out the conversion of the compound of formula (IX) into the compound of formula (I), mention may be made, by way of non-limiting example, of triethylamine, sodium acetate, sodium carbonate and potassium carbonate.

A preferred base for accomplishing the conversion of the compound of formula (IX) to the compound of formula (I) is sodium acetate.

Among the phase transfer reagents which can be used to carry out the conversion of the compound of formula (IX) into the compound of formula (I), mention may be made, by way of non-limiting example, of tetrabutylammonium bromide and tetrabutylammonium chloride.

A preferred phase transfer reagent for accomplishing the conversion of the compound of formula (IX) to the compound of formula (I) is tetrabutylammonium bromide.

Among the organic solvents which can be used to carry out the conversion of the compound of formula (IX) into the compound of formula (I), non-limiting examples which may be mentioned are N, N-dimethylacetamide and N, N-dimethylformamide.

A preferred solvent for accomplishing the conversion of the compound of formula (IX) to the compound of formula (I) is N, N-dimethylacetamide.

The reaction for converting the compound of formula (IX) to the compound of formula (I) is preferably carried out at a temperature of from 100 ℃ to 170 ℃, inclusive.

The invention also relates to a process for the synthesis of a compound of formula (VIII) starting from a compound of formula (I) prepared according to the above process, characterized in that said compound of formula (I):

conversion to a compound of formula (X) by reduction:

the compound of formula (X) is then converted to a compound of formula (VIII) by bromination:

the reduction of the compound of formula (I) can be carried out under the conditions described in patent application CN101407474 and publication j.chem.res.2009(7),420-422 with respect to the corresponding brominated compound.

Bromination of the compounds of formula (X) can be carried out under the conditions described for analogous compounds in the publications J.chem.Soc., PerkinTransI1985,2151-2154 and J.chem.Soc., PerkinTransI1991, 1749-1754.

Furthermore, Br in J.org.Chem1972, vol.37, No.21, pp3374-3376 is described₂The compound of formula (VIII) was prepared in 48% yield by bromination of the compound of formula (X) in acetic acid.

The present invention relates to a process for the synthesis of ivabradine starting from the compound of formula (I) prepared according to the process of the invention, which is converted into the compound of formula (VIII) according to the reaction sequence described above. The compound of formula (VIII) is then converted into the compound of formula (III) by intramolecular cyclization in a basic medium according to the teaching of the prior art (Tetrahedron1973,29, pp73-76), said compound of formula (III) then being converted into ivabradine according to the method described in EP 0534859.

The invention is illustrated by the following examples.

For melting pointB-545 melting point apparatus (voltage 230VAC, frequency 50/60Hz, maximum power 220W).

List of abbreviations used

DMAC N, N-Dimethylacetamide

m.p. melting Point

THF tetrahydrofuran

Examples

Example 1(2E) -3- (3, 4-dimethoxyphenyl) prop-2-enenitrile

A mixture of 5g 4-bromo-1, 2-dimethoxybenzene (3.31mL,23mmol), 3.2g acrylonitrile (3.9mL,60mmol,2.6eq.), 2.3g sodium acetate (27.6mmol,1.2eq.), 7.4g tetrabutylammonium bromide (23mmol,1eq.), 0.7g tri (o-tolyl) phosphine (2.3mmol,0.1eq.), and 4.9g5% palladium on carbon (2.3mmol,0.1eq.) in 25mL dmac was prepared. The black suspension was stirred at reflux for 12 hours. The reaction mixture was allowed to cool to room temperature and filtered. The solid residue was washed twice with toluene. The filtrates were combined and then evaporated under reduced pressure. The crude reaction product is purified on a column of silica gel (eluent: methylcyclohexane: ethyl acetate 6:4) to give 1.4g of the expected product.

The yield is 33%

m.p.=92-99℃

Example 23- (3, 4-dimethoxyphenyl) propionitrile

To a solution of 1g (5.3mmol) of (2E) -3- (3, 4-dimethoxyphenyl) prop-2-enenitrile in 9.3mL of pyridine and 2.8mL of methanol was added 0.24g of NaBH in small portions₄(6.3mmol,1.2 eq.). The reaction mixture was heated to reflux for 9 hours. After cooling to room temperature, the reaction mixture was added to a solution of 9mL37% hydrochloric acid in 24g ice. The solution was extracted twice with dichloromethane. The organic phase was collected and the solvent was distilled off under reduced pressure to give 0.82g of a reddish brown oil which crystallized upon standing.

The yield is =82%

m.p.=47-48℃

Example 33- (2-bromo-4, 5-dimethoxyphenyl) propionitrile

The title compound was prepared according to the procedure described in publication j.chem.soc., perkin transi1985,2151-2154 for the preparation of 3- (2-bromo-5, 6-dimethoxyphenyl) propionitrile:

to a mixture of 3- (3, 4-dimethoxyphenyl) propionitrile, 10.3g sodium acetate and 400mL acetic acid was added 20g Br₂50mL of acetic acid solution. The resulting reaction mixture was stirred overnight then poured into water and extracted with benzene. The organic phase is washed with aqueous sodium thiosulfate solution, then with water, dried over sodium sulfate and concentrated under reduced pressure. The crude reaction product is purified on a column of silica gel (eluent: benzene) and the product obtained is recrystallized from ethanol to yield 19.3g of the expected product.

The yield is 65 percent

m.p.:78-80℃

Example 43, 4-dimethoxybicyclo [4.2.0]Octane-1, 3, 5-triene-7-carbonitrile

Reference is made to Tetrahedron1973,29, pp73-76

To NaNH₂Solution (from 200mL liquid NH)₃And 1 gNa) (catalyst: FeCl₃) 5.4g of 3- (2-bromo-4, 5) are added in several portions-dimethoxyphenyl) propionitrile and the reaction mixture is stirred at room temperature for 2 hours. Distilling off excess NH₃Thereafter, 2gNH was added in portions₄Cl and 200mL of water. The gray crystals formed are collected and recrystallized from ethanol to give 2.38g of the expected product.

The yield is =74%

m.p.=84-85℃

Example 53, 4-dimethoxy-N-methylbicyclo [4.2.0]Octane-1, 3, 5-trien-7-amines

Reference is made to EP0534859

Step 13, 4-dimethoxybicyclo [4.2.0]Octane-1, 3, 5-triene-7-amine hydrochloride

312mL of a 1M borane/THF complex solution were added dropwise to a 250mL THF solution of 25g3, 4-dimethoxybicyclo [4.2.0] octa-1, 3, 5-triene-7-carbonitrile at room temperature with stirring and allowed to contact for 12 hours, followed by addition of 200mL ethanol and stirring for 1 hour. 100ml of 3.3N HCl in ether was added dropwise. 27.7g of the expected product are obtained.

The yield is =90%

m.p.=205℃

Step 2(3, 4-Dimethoxybicyclo [4.2.0]]Octane-1, 3, 5-trien-7-yl) carbamic acid ethyl ester

1.5mL of ethyl chloroformate was poured into a suspension of 3.4g of the compound obtained in step 1 in 4.5mL of triethylamine and 50mL of dichloromethane and left overnight at room temperature with stirring, followed by washing with water and 1N hydrochloric acid. Dry and evaporate the solvent to dryness. 3.2g of the expected product are obtained in the form of an oil. The yield is 80 percent

Step 33, 4-dimethoxy-N-methylbicyclo [4.2.0]Octane-1, 3, 5-trien-7-amines

3.2g of the compound obtained in step 2 were dissolved in 30ml of THF and added to 0.9g of LiAlH₄20ml of THF suspension. Reflux for 1 hour 30 minutes, then use 0.6Water and 0.5mL of 20% sodium hydroxide solution, and finally 2.3mL of water. The inorganic salts were then filtered off, rinsed with THF and the resulting filtrate was evaporated to dryness. 2.3g of the expected compound are obtained.

The yield is 92%

Example 6(7S) -3, 4-dimethoxy-N-methylbicyclo [4.2.0]Octane-1, 3, 5-trien-7-amines

Reference is made to EP0534859

3, 4-dimethoxy-N-methyl bicyclo [4.2.0]]The octa-1, 3, 5-trien-7-amine is reacted with an equimolar amount of (d) camphorsulfonic acid in ethanol. After evaporation of the solvent in vacuo, the salt is first recrystallized from ethyl acetate and then acetonitrile until the optical purity of the target enantiomer obtained is greater than 99% (by HPLC onOn-column evaluation).

Example 73- {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

Reference is made to EP0534859

The ethyl acetate solution of (d) camphorsulfonic acid salt obtained in example 6 was adjusted to alkaline pH with sodium hydroxide, and then the organic phase was separated, washed, and Na was added₂SO₄Dried and evaporated.

A solution of 5.6g of potassium carbonate, 2.2g of the above-mentioned amine in 100mL of acetone and 4g of 3- (3-iodopropyl) -7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepine-2-keto groupThe resulting mixture was refluxed for 18 hours.

The solvent was evaporated in vacuo and the residue was added with ethyl acetate and then extracted with 3N hydrochloric acid.

The separated aqueous phase was adjusted to basic pH with sodium hydroxide and extracted with ethyl acetate. Washing to neutrality with MgSO₄Drying and evaporation in vacuo gave 4.5g of an oil which was purified on a silica gel column using a dichloromethane/methanol (90/10) mixture as eluent.

The yield is 64 percent

Example 83- {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

Reference is made to EP0534859

5g of 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-benzazepineA50 mL solution of the (E) -2-ketone in glacial acetic acid was hydrogenated in a Parr apparatus under a hydrogen pressure of 4.9 bar in the presence of 1g of 10% palladium hydroxide at room temperature for 24 hours. The catalyst was filtered off, the solvent was distilled off, and then water and ethyl acetate were added to the dry residue. The organic phase was dried over anhydrous magnesium sulphate, concentrated in vacuo and the residue was purified on a silica gel column using a mixture of dichloromethane/methanol (95/5) as eluent.

After recrystallization from ethyl acetate, 2g of the expected compound are obtained.

The yield is =40%

m.p.=101-103℃

Claims

1. A method of synthesizing a compound of formula (I):

characterized in that a compound of formula (IX):

2. The process as claimed in claim 1, characterized in that the palladium catalyst used to complete the conversion of the compound of formula (IX) into the compound of formula (I) is selected from palladium (II) acetate, palladium on carbon and palladium chloride.

3. The process according to claim 2, characterized in that the palladium catalyst used to accomplish the conversion of the compound of formula (IX) to the compound of formula (I) is palladium on carbon.

4. A process according to any one of claims 1 to 3, characterized in that the ligand used to accomplish the conversion of the compound of formula (IX) into the compound of formula (I) is selected from triphenylphosphine and tri (o-tolyl) phosphine.

5. The process as claimed in claim 4, characterized in that the ligand for carrying out the conversion of the compound of the formula (IX) into the compound of the formula (I) is tri (o-tolyl) phosphine.

6. A process according to any one of claims 1 to 3, characterized in that the base used to accomplish the conversion of the compound of formula (IX) into the compound of formula (I) is selected from triethylamine, sodium acetate, sodium carbonate and potassium carbonate.

7. The process as claimed in claim 6, characterized in that the base used to carry out the conversion of the compound of the formula (IX) into the compound of the formula (I) is sodium acetate.

8. A process according to any one of claims 1 to 3, characterized in that the phase transfer reagent used to accomplish the conversion of the compound of formula (IX) into the compound of formula (I) is selected from tetrabutylammonium bromide and tetrabutylammonium chloride.

9. The process as claimed in claim 8, characterized in that the phase transfer reagent used to complete the conversion of the compound of the formula (IX) into the compound of the formula (I) is tetrabutylammonium bromide.

10. A process according to any one of claims 1 to 3, characterized in that the organic solvent used to accomplish the conversion of the compound of formula (IX) into the compound of formula (I) is selected from N, N-dimethylacetamide and N, N-dimethylformamide.

11. The process according to claim 10, characterized in that the organic solvent used to accomplish the conversion of the compound of formula (IX) into the compound of formula (I) is N, N-dimethylacetamide.

12. A process according to any one of claims 1 to 3, characterized in that the conversion of the compound of formula (IX) into the compound of formula (I) is carried out at a temperature of from 100 ℃ to 170 ℃.

13. A process for the preparation of a compound of formula (VIII),

reacting a compound of formula (IX):

carrying out coupling reaction with acrylonitrile in the presence of a palladium catalyst, a ligand, alkali and a phase transfer reagent in an organic solvent to obtain a compound shown in a formula (I),

the resulting compound of formula (I) is subsequently converted to a compound of formula (X) by reduction:

14. a process for the synthesis of ivabradine, pharmaceutically acceptable salts thereof and hydrates thereof, characterized in that:

reacting a compound of formula (IX):

the compound of formula (VIII) is subsequently converted to ivabradine, which can be converted to addition salts with a pharmaceutically acceptable acid 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, and to hydrates thereof.