HK1199013B - Process for the synthesis of 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile, and application in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid - Google Patents

Description

Method for synthesizing 3- (2-bromo-4, 5-dimethoxyphenyl) propionitrile and application of method in synthesizing ivabradine

Technical Field

The invention relates to a method for synthesizing 3- (2-bromo-4, 5-dimethoxyphenyl) propionitrile of formula (I) and the use thereof for synthesizing ivabradine and addition salts thereof with a pharmaceutically acceptable acid:

the compounds 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-2-ketones, which can be converted into addition salts with pharmaceutically acceptable acids 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.

Processes for preparing compounds of formula (III) starting from compounds of formula (I) are described in Tetrahedron1973,29, pp 73-76.

The same document also describes a route to the compound of formula (I) starting from 2-bromo-4, 5-dimethoxybenzaldehyde in 3 steps, with an overall yield of 65%.

More recently, Zhao et al described the synthesis of the compound of formula (I) starting from 3, 4-dimethoxybenzaldehyde in 3 steps, with a total yield of 51% (CN101407474A and j.chem.res.2009,7, pp 420-422).

The compound of formula (I) is a key intermediate for the synthesis of ivabradine.

In view of the industrial value of ivabradine and its salts, there is a continuous need to find an efficient process capable of obtaining 3- (2-bromo-4, 5-dimethoxyphenyl) propionitrile of formula (I) in excellent yields.

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

characterized in that a compound of formula (VIII):

with a base in the presence of propionitrile in an organic solvent to give the compound of the formula (I).

Among the bases which can be used to carry out the conversion of the compound of formula (VIII) into the compound of formula (I), non-limiting examples which may be mentioned are n-butyllithium, lithium diisopropylamide, potassium bis (trimethylsilyl) amide, potassium tert-butoxide and potassium hydroxide.

A preferred base for carrying out the conversion of the compound of formula (VIII) to the compound of formula (I) is n-butyllithium.

Among the solvents which can be used to carry out the conversion of the compound of formula (VIII) into the compound of formula (I), mention may be made, by way of non-limiting example, of tetrahydrofuran and acetonitrile.

The preferred solvent for carrying out the conversion of the compound of formula (VIII) into the compound of formula (I) is tetrahydrofuran.

The reaction for converting the compound of formula (VIII) to the compound of formula (I) is preferably carried out at a temperature of from-65 ℃ to 25 ℃ inclusive.

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

the compound of formula (IX) is converted to a compound of formula (X) by a reduction reaction:

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

it is converted to the product of formula (I) according to the method described above:

the reduction of the compound of formula (IX) can be carried out under the conditions described in the publication org.biomol.chem.2010,8, 539-545.

The bromination reaction on the compound of formula (X) can be carried out under the conditions described in the publication chem. eur. j.2010,16, 9772-9776.

The invention also relates to a process for the synthesis of ivabradine starting from the compound of formula (I) prepared according to the process of the invention and 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) and said compound of formula (III) is then converted into ivabradine according to the process described in EP 0534859.

The invention is illustrated by the following examples.

Melting points were determined using a Buchi CHIB-545 melting point apparatus (voltage 230VAC, frequency 50/60Hz, maximum power 220W).

List of abbreviations used

m.p. melting Point

THF tetrahydrofuran

Detailed Description

Preparation example 13, 4-dimethoxyphenyl-methanol

Reference is made to org.biomol.chem.2010,8,539-545

10g (60.2mmol,1eq.) of 3, 4-dimethoxybenzaldehyde are dissolved in 300mL of methanol and the solution is cooled to 0 ℃. 2.73g (72.2mmol,1.2eq.) of NaBH were added portionwise₄And the reaction mixture was stirred for 20 minutes and then hydrolyzed with 10mL of 1MHCl aqueous solution to a medium of neutral pH. The solvent was removed under reduced pressure and the residue was extracted with 3x50mL dichloromethane. The organic phases were combined and MgSO₄Drying, filtration and concentration under reduced pressure gave 9.88g of a clear oil.

The yield is =98%

Preparation example 21-bromo-2- (bromomethyl) -4, 5-dimethoxybenzene

Reference is made to chem. Eur. J.2010,16,9772-

To a solution of (3, 4-dimethoxyphenyl) methanol (101.5mmol,14.85mL,1eq.) in 80mL of glacial acetic acid was added 6mLBr over 30 minutes at 0 deg.C₂(116.8mmol,1.15eq.) in 18mL of glacial acetic acid. The reaction mixture was stirred for 3 hours and then returned to room temperature. Stirring was stopped to allow 1-bromo-2- (bromomethyl) -4, 5-dimethoxybenzene to precipitate out completely, and the mixture was allowed to stand overnight. The precipitate was filtered off, washed with methanol and recrystallized from methanol to yield 29.9g of a pale yellow powder.

The yield is 95 percent

Example 13- (2-bromo-4, 5-dimethoxyphenyl) propionitrile

To a solution of 0.3mL acetonitrile (5.8mmol,1.8eq.) in 15mL THF was added 1.77mL n-butyllithium (2M in cyclohexane, 3.5mmol,1.1eq.) at-60 ℃. The solution was stirred at-60 ℃ for 15 minutes, then 1g 1-bromo-2- (bromomethyl) -4, 5-dimethoxybenzene (3.2mmol) dissolved in 5ml THF was added. The reaction mixture was stirred for 1 hour, then hydrolyzed with 10mL water and extracted twice with ethyl acetate. The organic phases were combined and then evaporated under reduced pressure. The crude reaction product was purified by chromatography on silica gel (eluent: methylcyclohexane/ethyl acetate (70/30)). Evaporation of the solvent under reduced pressure gave 505mg of an orange oil which crystallized as a beige solid.

The yield is =58%

m.p.=74-81℃

Example 23, 4-dimethoxybicyclo [4.2.0]Octane-1, 3, 5-triene-7-carbonitrile

Reference is made to Tetrahedron1973,29, pp73-76

To NaNH₂From 200mL of liquid NH₃And 1gNa (catalyst: FeCl)₃) Prepared) 5.4g of 3- (2-bromo-4, 5-dimethoxyphenyl) propionitrile were added portionwise and the reaction mixture was stirred at room temperature for 2 hours. Excess NH is distilled off₃Thereafter, 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 33, 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

While stirring at room temperature, 312mL of 1M borane/THF complex solution was added dropwise to a 250mL solution of 3, 4-dimethoxybicyclo [4.2.0] octa-1, 3, 5-triene-7-carbonitrile in THF and allowed to contact for 12 hours, followed by addition of 200mL of 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 then allowed to stand overnight at room temperature with stirring; washed with water and then with 1N hydrochloric acid. Dry and evaporate the solvent to dryness. 3.2g of an oil corresponding to the expected product are obtained.

The yield is 80 percent

Step 33, 4-dimethoxy-N-methylbicyclo [4.2.0]The preparation method comprises the steps of (1) pungent-1,3, 5-trien-7-amines

3.2g of the compound obtained in step 2 dissolved in 30ml of THF were added to 0.9g of LiAlH₄20ml of THF suspension. Reflux for 1 hour 30 minutes, then hydrolysis with 0.6mL water and 0.5mL20% sodium hydroxide, and finally hydrolysis with 2.3mL water. The mineral salts are then filtered off, rinsed with THF and the resulting filtrate is evaporated to dryness. 2.3g of the expected compound are obtained.

The yield is 92%

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

Reference is made to EP0534859

The amine obtained in example 3 was 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 in water)OD on column evaluation).

Example 53- {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 camphorsulfonate (d) obtained in example 4 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-dimethoxyl1, 3-dihydro-2H-3-benzazepine radicalReflux of the mixture of-2-ketones 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 63- {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

A50 mL glacial acetic acid solution of 5g of the compound obtained in example 5 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 (5)

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

characterized in that a compound of formula (IX)

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:

reacting it with a base in the presence of acetonitrile in an organic solvent to obtain the compound of formula (I), the reaction being carried out at a temperature of-65 ℃ to 25 ℃, inclusive.

2. The process as claimed in claim 1, wherein the base used to complete the conversion of the compound of formula (VIII) into the compound of formula (I) is selected from the group consisting of n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium tert-butoxide and potassium hydroxide.

3. A process according to claim 2, characterised in that the base used to effect the conversion of the compound of formula (VIII) to the compound of formula (I) is n-butyllithium.

4. 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 (VIII) into the compound of formula (I) is tetrahydrofuran.

5. A process for the synthesis of ivabradine, pharmaceutically acceptable salts thereof and hydrates thereof, characterized in that a compound of formula (IX) is converted into a compound of formula (I) according to the process of claim 1, followed by the conversion of the compound of formula (I) into ivabradine, 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.