HK1193409B - Novel method for synthesising 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile, and use for synthesising ivabradine and the added salts thereof with a pharmaceutically acceptable acid - Google Patents

Description

The present invention relates to a process for the synthesis of (3- ((2-bromo-4,5-dimethoxyphenyl) propanetryl of formula (I): - What? and its application to the synthesis of ivabradine and its additive salts to a pharmaceutically acceptable acid.

The compound of formula (I) obtained by the process of the invention is useful in the synthesis of formula (II) ivabradine: - What? or 3-{3-[[[[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl]methyl}(methyl) amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzapine-2-one, which can be transformed into one of its salts of addition to a pharmaceutically acceptable acid, selected from hydrochloric, bromic, sulphuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, benzensulfonic and camphoric acids and into one of their hydrates.

Ivabradine, together with its salts of addition to a pharmaceutically acceptable acid, and in particular its hydrochloride, have very interesting pharmacological and therapeutic properties, in particular bradycardising properties, which make these compounds useful in the treatment or prevention of various clinical conditions of myocardial ischemia such as angina, myocardial infarction and associated arrhythmia, as well as in various pathologies involving arrhythmia, in particular supra-ventricular arrhythmia, and heart failure.

The additive salt of a pharmaceutically acceptable acid of ivabradine may be prepared from an acid selected from hydrochloric, bromic, sulphuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, benzensulfonic and camphoric acids.

The preparation and therapeutic use of ivabradine and its salts of addition to a pharmaceutically acceptable acid, and in particular its hydrochloride, are described in European patent EP 0 534 859.

This patent describes the preparation of ivabradine from 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile of formula (III): - What? which is transformed into a compound of formula (IV): - What? which is split to lead to the compound of formula (V): - What? which is reacted with the compound of formula (VI): - What? for use in the manufacture of compounds of formula (VII): - What? The catalytic hydrogenation leads to ivabradine, which is then converted to its hydrochloride.

The preparation of the compound of formula (III) from the compound of formula (I) is described in Tetrahedron 1973, 29, pp. 73-76.

The same document also describes a pathway for synthesis of the compound of formula (I) from 2-bromo-4,5-dimethoxybenzaldehyde in three steps with an overall yield of 65%.

The preparation of the compound of formula (I) by a bromination reaction of 3- (3,4-dimethoxyphenyl) propanetryl in the presence of dibrom in acetic acid is described in J. Org. Chem 1972, vol. 37, no. 21, pp. 3374-3376 with a yield of 48%.

More recently, Zhao et al. have described a synthesis of the compound of formula (I) from 3,4-dimethoxybenzaldehyde in three steps with 51% overall yield (CN101 407 474 A and J. Chem. Res. 2009, 7, pp. 420-422).

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

Given the industrial interest of ivabradine and its salts, it was imperative to find a high-performance process to obtain formula (I) (3-(2-bromo-4,5-dimethoxyphenyl) propanetryl with excellent yield.

The present invention relates to a process for synthesis of the compound of formula (I): - What? characterised by the compound formula (VIII): - What? is subjected to the action of N-bromosuccinimide in the presence of an organic solvent to lead to the compound of formula (I).

Organic solvents that can be used to transform the compound of formula (VIII) into compound of formula (I) include, but are not limited to N,N-dimethylformamide, tetrahydrofuran, acetonitrile, acetic acid, methanol, dichloromethane and toluene.

The solvent preferentially used to transform the compound of formula (VIII) into compound of formula (I) is N,N-dimethylformamide.

The transformation of the compound of formula (VIII) into compound of formula (I) is carried out at a temperature preferably between - 10°C and 30°C.

The present invention also relates to a process for synthesis of the compound of formula (I) from the compound of formula (VIII), characterized by the fact that the compound of formula (VIII) is prepared from the compound of formula (IX): - What? which is converted into a compound of formula (X): - What? in the presence of a phosphorus hyllure and a base in an organic solvent, which is transformed into a compound of formula (VIII): - What? by a reduction reaction in the presence of a hydride donor agent in an organic solvent or mixture of organic solvents, which is processed into a product of formula (I): - What? in accordance with the procedure described above.

Phosphorus yulies that can be used to transform the compound of formula (IX) into compound of formula (X) include but are not limited to diethylcyanomethylphosphonate and acetonitrile (triphenylphosphoranylidene).

The phosphorus ilure preferentially used to transform the compound of formula (IX) into compound of formula (X) is diethylcyanamethylphosphonate.

The bases that can be used to transform the compound of formula (IX) into compound of formula (X) include but are not limited to potassium tert-butylate, sodium hydride, triethylamine and potassium hydrogen carbonate.

The base preferentially used to perform the transformation of the compound of formula (IX) into compound of formula (X) is potassium tert-butylate.

Organic solvents that can be used to transform the compound of formula (IX) into compound of formula (X) include but are not limited to tetrahydrofuran, acetonitrile and toluene.

The organic solvent preferentially used to transform the compound of formula (IX) into compound of formula (X) is tetrahydrofuran.

The transformation of the compound of formula (IX) into compound of formula (X) is preferably carried out at a temperature between - 5°C and 120°C.

Hydride donors that can be used to transform the compound of formula (X) into compound of formula (VIII) include but are not limited to sodium tetraborohydride, ammonium formate in the presence of Pd/C and formic acid in the presence of Pd ((OAc) 2.

The hydride donor agent preferentially used to perform the transformation of the compound from formula (X) to formula (VIII) is sodium tetraborohydride. Organic solvents that can be used to perform the transformation of the compound from formula (X) to formula (VIII) include but are not limited to alcoholic solvents, such as methanol and ethanol, tetrahydrofuran.

A mixture of organic solvents may also be used to transform the compound of formula (X) into a compound of formula (VIII), preferably the pyridine/methanol mixture.

The transformation of the compound of formula (X) into compound of formula (VIII) is preferably carried out at a temperature between 25°C and 110°C.

The present invention also relates to a process for synthesis of ivabradine from the compound of formula (I) prepared in the process of the invention and transformed into compound of formula (III) by means of the method described in the previous art (Tetrahedron 1973, 29, pp. 73-76) by an intramolecular cycling reaction in a basic medium; the compound of formula (III) is then transformed into ivabradine in the process described in EP 0 534 859.

The following examples illustrate the invention.

The melting points were measured with BÜCHI Melting Point B-545 (Volt. 230VAC, Frequency 50/60 Hz, Power max. 220W).

List of abbreviations used

The chemical composition of the product is determined by the following equation:

Preparation A: (2E) -3- (3,4-dimethoxyphenyle) prop-2-enitrile

7 g of 3,4-dimethoxybenzaldehyde (42.1 mO) is dissolved in 84 mL of THF and the solution is cooled to 0°C. 8,2 g of diethylcyanomethylphosphonate (7,5 mL, 46,3 mO, 1,1 eq.) and then 5,2 g of potassium tert-butoxide (46,3 mO, 1,1 eq.) are added gradually. The mixture is stirred for one hour at 0°C and then overnight at room temperature. The reaction medium is hydrolysed by 175 mL of water and extracted with dichloromethane. The yield is 96.5% The temperature of the water is 93-98°C.

Preparation B: 3- (3,4-dimethoxyphenyle) propanetryl

To a 1 g (5.3 mmoles) solution of (2E)-3-(3,4-dimethoxyphenyl) prop-2-enenitrile in 9.3 mL of pyridine and 2.8 mL of methanol, 0.24 g of NaBH4 (6.3 mmol, 1.2 eq.) is added gradually. The reaction medium is heated at reflux (100 °C) for 9 hours. After cooling to room temperature, the reaction medium is added to a 9 mL solution of 37% hydrochloric acid in 24 g of ice. The solution is reduced twice to dichloromethane. The yield is 82% The temperature of the water is 45-48 °C.

The following is the list of active substances in the feed additive:

A 1 g (5.3 mL) solution of 3-(3,4-dimethoxyphenyl) propanetryl in 42 mL DMF is cooled to 0 °C. To this solution 0.93 g of NBS (5.2 mL, 1 equ) is added gradually. After 30 minutes of agitation at 0 °C, the reaction medium is brought back to room temperature and agitated for two hours. It is then hydrolyzed by 170 mL water and extracted with 2 times 130 mL ethyl acetate. The yield is 98% Purity (HPLC): 96.8% The temperature is 78-80 °C.

Example 2 : 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile According to Tetrahedron1973, 29, pp. 73-76

To a solution of NaNH2, prepared from 200 mL of liquid NH3 and 1 g of Na (catalyst FeCl3), 5,4 g portions of 3-(2-bromo-4,5-dimethoxyphenyle) propanethylene are added and the reaction mixture is stirred at room temperature for 2 hours. After evaporation of excess NH3, 2 g of NH4Cl and 200 mL of water are added in portions. The formed grey crystals are collected and recrystallized in ethanol to lead to 2,38 g of the expected product The yield is 74% The temperature of the water is 84-85 °C.

Example 3 : 3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-amine According to EP 0 534 859

Stage 1: 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-amine hydrochloride Add 312 mL of a borane molar solution complex with THF to a 25 g solution of 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile in 250 mL of THF, drip and stir at room temperature. Leave in contact for 12 hours, then add 200 mL of ethanol and stir for 1 hour. Add 100 mL of 3,3N hydrochloride ether, drip, to obtain 27.7 g of the expected product. Efficiency = 90% The temperature of the water is 205 °C.

Stage 2 : (3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl) ethyl carbamate 1.5 mL of ethyl chloroformate is poured on a 3.4 g suspension of the stage 1 compound of 4.5 mL triethylamine and 50 mL dichloromethane. It is stirred overnight at room temperature and then washed with water and 1N hydrochloric acid. The solvent is dried and evaporated dry. 3.2 g of oil corresponding to the desired product is obtained. The yield is 80%

Stage 3 is 3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-amine 3.2 g of the stage 2 compound in solution in 30 mL THF is added to a suspension of 0.9 g LiAlH4 in 20 mL THF. It is brought to the back flow for 1 hour 30 minutes, then hydrolysed by 0.6 ml of water and 0.5 mL of 20% soda, and finally by 2.3 mL of water. The mineral salts are then filtered, rinsed in THF and then the resulting filtrate is evaporated dry. 2.3 g of the expected compound is obtained. The yield is 92%

Example 4 : (7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-amine According to EP 0 534 859

The amine obtained in example 3 is reacted with an equimolar amount of camphosulfonic acid (d) in ethanol. After evaporation of the solvent in a vacuum, the salt is recrystallized first in ethyl acetate and then in acetonitrile until the target enantiomer is obtained with an optical purity of more than 99% (HPLC assessment on Chiralcel® OD column).

The following is a list of the substances which are to be used in the preparation of the product:

The salt solution of (d) camphosulfonate obtained in Example 4 in ethyl acetate is brought to basic pH by sodium hydroxide and then the organic phase is separated, washed, dried in Na2SO4 and evaporated.

A mixture of 5.6 g of potassium carbonate, 2.2 g of the above amine in 100 ml of acetone and 4 g of 3-(3-iodopropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzabopine-2-one is then brought to the reflux for 18 hours.

The solvent is evaporated in a vacuum, the residue is taken up in ethyl acetate, and then extracted in 3N hydrochloric acid.

The settled aqueous phase is brought to basic pH by sodium hydroxide and then extracted with ethyl acetate. After washing to neutral and drying on MgSO4, 4.5 g of oil is evaporated under vacuum to obtain 4.5 g which is purified on a silica column using a dichloromethane/methanol (90/10) mixture as an electrolyte. The yield is 64%

The following is a list of the substances which are to be used in the preparation of the product:

5 g of the compound obtained in example 5 in 50 mL of glacial acetic acid are hydrogenated in a Parr apparatus, under pressure of 4.9 bar of hydrogen at room temperature for 24 hours, in the presence of 1 g of palladium hydroxide at 10%. The catalyst is filtered, the solvent is evaporated, then the dry residue is re-used in water and ethyl acetate. The organic phase is dried on anhydrous magnesium sulphate, the purified residue is concentrated under vacuum and is placed on a silica column using a dichloromethane/ethanol mixture (95/5). The yield is 40% The temperature of the water is approximately 101-103°C.

Claims (18)

1. Process for the synthesis of the compound of formula (I): characterised in that the compound of formula (VIII): is subjected to the action of N-bromosuccinimide in the presence of an organic solvent to yield the compound of formula (I).
2. Process according to claim 1, characterised in that the organic solvent used to carry out the conversion of the compound of formula (VIII) into the compound of formula (I) is selected from N,N-dimethylformamide, tetrahydrofuran, acetonitrile, acetic acid, methanol, dichloromethane and toluene.
3. Process according to claim 2, characterised in that the organic solvent used to carry out the conversion of the compound of formula (VIII) into the compound of formula (I) is N,N-dimethylformamide.
4. Process according to any one of claims 1 to 3, characterised in that the conversion of the compound of formula (VIII) into the compound of formula (I) is carried out at a temperature between -10°C and 30°C, inclusive.
5. Process according to claim 1, characterised in that the compound of formula (VIII) is prepared starting from the compound of formula (IX): which is converted into the compound of formula (X): in the presence of a phosphorus ylide and a base in an organic solvent, which is converted into the compound of formula (VIII): by a reduction reaction in the presence of a hydride donor agent in an organic solvent or mixture of organic solvents.
6. Process according to claim 5, characterised in that the phosphorus ylide used to carry out the conversion of the compound of formula (IX) into the compound of formula (X) is diethyl cyanomethyl phosphonate or (triphenylphosphoranylidene)acetonitrile.
7. Process according to claim 6, characterised in that the phosphorus ylide used to carry out the conversion of the compound of formula (IX) into the compound of formula (X) is diethyl cyanomethyl phosphonate.
8. Process according to any one of claims 5 to 7, characterised in that the base used to carry out the conversion of the compound of formula (IX) into the compound of formula (X) is selected from potassium tert-butoxide, sodium hydride, triethylamine and potassium hydrogen carbonate.
9. Process according to claim 8, characterised in that the base used to carry out the conversion of the compound of formula (IX) into the compound of formula (X) is potassium tert-butoxide.
10. Process according to any one of claims 5 to 9, characterised in that the organic solvent used to carry out the conversion of the compound of formula (IX) into the compound of formula (X) is selected from tetrahydrofuran, acetonitrile and toluene.
11. Process according to claim 10, characterised in that the organic solvent used to carry out the conversion of the compound of formula (IX) into the compound of formula (X) is tetrahydrofuran.
12. Process according to any one of claims 5 to 11, characterised in that the conversion of the compound of formula (IX) into the compound of formula (X) is carried out at a temperature between -5°C and 120°C, inclusive.
13. Process according to any one of claims 5 to 12, characterised in that the hydride donor agent used to carry out the conversion of the compound of formula (X) into the compound of formula (VIII) is selected from sodium borohydride, ammonium formate in the presence of Pd/C, and formic acid in the presence of Pd(OAc)₂.
14. Synthesis process according to claim 13, characterised in that the hydride donor agent used to carry out the conversion of the compound of formula (X) into the compound of formula (VIII) is sodium borohydride.
15. Process according to any one of claims 5 to 14, characterised in that the organic solvent used to carry out the conversion of the compound of formula (X) into the compound of formula (VIII) is selected from methanol, ethanol, tetrahydrofuran and the mixture pyridine/methanol.
16. Process according to claim 15, characterised in that the organic solvent used to carry out the conversion of the compound of formula (X) into the compound of formula (VIII) is the mixture pyridine/methanol.
17. Process according to any one of claims 5 to 16, characterised in that the conversion of the compound of formula (X) into the compound of formula (VIII) is carried out at a temperature between 25°C and 110°C, inclusive.
18. Process for the synthesis of ivabradine, pharmaceutically acceptable salts thereof and hydrates thereof, characterised in that the compound of formula (VIII) is converted into the intermediate of formula (I) according to the process of claim 1, and then the intermediate of formula (I) is converted into ivabradine, which may be converted into addition salts thereof with a pharmaceutically acceptable acid selected from 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 into hydrates thereof.