HK1200028B - Process for the synthesis of carbonitrile and application in the synthesis of ivabradine - Google Patents

Description

Method for synthesizing formonitrile compound and application of formonitrile compound in ivabradine synthesis

Technical Field

The invention relates to the field of drug synthesis. More particularly, the invention relates to a method for synthesizing 3, 4-dimethoxybicyclo [4.2.0] octa-1, 3, 5-triene-7-carbonitrile of formula (I):

and the use of this compound in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid.

The compound of formula (I) obtained by the process of the invention can be used for the synthesis of ivabradine of formula (II), addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof:

namely 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.

Background

Ivabradine and its addition salts with a pharmaceutically acceptable acid, more particularly its hydrochloride, have very valuable pharmacological and therapeutic properties, in particular a heart rate slowing property, which may 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, as well as various pathologies related to arrhythmias (in particular supraventricular arrhythmias) and heart failure.

The preparation and therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, more particularly the hydrochloride salt thereof, are described in the european patent specification (european patent specification) EP 0534859.

This patent specification describes the preparation of ivabradine using 3, 4-dimethoxybicyclo [4.2.0] octa-1, 3, 5-triene-7-carbonitrile of formula (I) as starting material:

converting it into a compound of formula (III):

resolving the compound to obtain a compound of formula (IV):

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

obtaining a compound of formula (VI):

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

In order to achieve the industrial value of ivabradine and salts thereof, it is necessary to find an effective process capable of obtaining the compound of formula (I) in higher yields.

Patent application WO2011/138625 describes a process for the preparation of compounds of formula (I) by intramolecular cyclization of 3- (2-bromo-4, 5-dimethoxyphenyl) propionitrile in the presence of lithium diethylamide or lithium diisopropylamide.

Disclosure of Invention

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

characterized in that a compound of formula (VII):

the compound of formula (I) is obtained by the action of 1- (isocyanomethylsulfonyl) -4-methylbenzene (TosMIC).

The amount of 1- (isocyanomethylsulfonyl) -4-methylbenzene preferably used to convert the compound of formula (VII) to form the compound of formula (I) is 2-5 equivalents.

Among the bases that may be used to convert the compound of formula (VII) to form the compound of formula (I) are, but are not limited to, organic bases of the alkoxide type, such as potassium tert-butoxide, sodium tert-butoxide, potassium ethoxide, sodium ethoxide, potassium methoxide and sodium methoxide.

The preferred base for the conversion of the compound of formula (VII) to form the compound of formula (I) is potassium tert-butoxide.

Among the organic solvents that may be used to convert the compound of formula (VII) to form the compound of formula (I) are alcohols, such as methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran, ethylene glycol, and dimethyl sulfoxide.

The organic solvent used for the conversion of the compound of formula (VII) to form the compound of formula (I) may also consist of a mixture of two solvents selected from the above-mentioned organic solvents.

Preferred solvents for the conversion of the compound of formula (VII) to form the compound of formula (I) are mixtures of tetrahydrofuran and methanol.

The reaction of converting the compound of formula (VII) to form the compound of formula (I) is preferably carried out at a temperature of from-20 ℃ to 50 ℃.

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

converting a compound of formula (VIII) to a compound of formula (IX) in an organic solvent in the presence of 1, 1-dialkoxyethylene, wherein the alkoxy group has 1 to 4 carbon atoms, and an organometallic compound:

wherein R represents (C)₁-C₄) An alkyl group, a carboxyl group,

converting the compound of formula (IX) to a compound of formula (VII) by hydrolysis:

converting the compound of formula (VII) into the product of formula (I) according to the process described hereinabove:

the 1, 1-dialkoxyethylenes preferably used for converting the compounds of formula (VIII) to form compounds of formula (IX) are 1, 1-diethoxyethylenes.

The amount of 1, 1-diethoxyethylene preferably used for converting the compound of formula (VIII) to form the compound of formula (IX) is from 0.8 to 5 equivalents.

Among the organometallic compounds useful for converting the compound of formula (VIII) to form the compound of formula (IX), there are included, but are not limited to, n-butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium, and isopropylmagnesium chloride.

The organometallic compound preferably used for converting the compound of formula (VIII) to form the compound of formula (IX) is n-butyllithium.

The amount of n-butyllithium preferably used to convert the compound of formula (VIII) to form the compound of formula (IX) is from 1 to 3 equivalents.

In organic solvents used to convert the compound of formula (VIII) to form the compound of formula (IX), including but not limited to toluene, tetrahydrofuran, dichloromethane, and chlorobenzene.

The preferred solvent for the conversion of the compound of formula (VIII) to form the compound of formula (IX) is toluene.

The reaction of converting the compound of formula (VIII) to form the compound of formula (IX) is preferably carried out at a temperature of from-20 ℃ to 30 ℃.

The hydrolysis reaction carried out when the compound of formula (IX) forms the compound of formula (VII) may be carried out in an amphiphilic (organoqueous) acidic medium consisting of a mixture of:

an organic solvent, for example tetrahydrofuran, ethyl acetate, toluene or dichloromethane, and

excess aqueous acid, for example hydrochloric acid (1N-12N).

Detailed Description

The following examples illustrate the invention.

Melting points were determined using a capillary melting point instrument of the BuchiB-545 melting point type.

NMR spectra were recorded on a Bruker apparatus at 400MHz mass spectrum and at 100MHz carbon spectrum.

Chemical shift () is expressed in ppm (internal standard: TMS).

The following abbreviations were used to determine peaks: singlet(s), doublet (d), doublet (dd), triplet (t), quartet (q), multiplet (m).

List of abbreviations used:

m.p.: melting Point

THF: tetrahydrofuran (THF)

TosMIC: 1- (isocyanomethylsulfonyl) -4-methylbenzene

Preparation A: 1, 2-dibromo-4, 5-dimethoxybenzene

16.16g of 1, 2-dimethoxybenzene (117mmol) were stirred at 0 ℃ in CCl4(120 mL). 13.2mL of dibromo (2.2 eq; 257.4 mmol; 41.13g) dissolved in CCl4(25mL) were added dropwise (30min) while monitoring the temperature (0-5 ℃ C.) [ equipped with a mouthpiece through which Na was added₂CO₃Solution to facilitate neutralization of the hydrobromic acid formed]. After stirring for 2 hours at 0 ℃ the reaction mixture is poured into an ice-water mixture and the organic phase is treated with 10% NaHSO₃Washed with an aqueous solution and then with a 10% aqueous solution of NaOH. After evaporation and drying, 33.42g of a white solid were obtained as the desired product.

The yield is 97%

m.p.92－93℃

¹HNMR(CDCl3)：＝7.06(s；2H)；3.86(s；6H)。

¹³CNMR(CDCl3)：＝148.8；115.9；114.7；56.2。

Preparation B: 1, 1-diethoxyethylene

The equipment was assembled as follows: a50-ml flask was equipped with a distillation apparatus (column 20 cm; condenser-20 cm, distillation thermometer). To potassium tert-butoxide (102 mmol; 11.4g) cooled in an ice bath was added rapidly 20g of 2-bromo-1, 1-diethoxyethane (101.25mmol) (1 min). A very dense white smoke is formed. When the reaction was complete (5-10 minutes), the reaction mixture was heated to 120 ℃ and 130 ℃ (hotplate readings) and the tert-butanol formed during the reaction was distilled off at atmospheric pressure. When all the tert-butanol is distilled out, a water jet vacuum pump is connected with the distillation device. In this way, the target product was distilled under vacuum for several minutes. 8.5g of a colorless liquid containing traces of tert-butanol are obtained.

The yield is 72%

¹HNMR(CDCl₃)：＝3.78(q；4H)；3.03(s；2H)；1.25(t；6H)。

Example 1: 7, 7-diethoxy-3, 4-dimethoxybicyclo [4.2.0] octa-1, 3, 5-triene

2.55g of 1, 2-dibromo-4, 5-dimethoxybenzene (8.62 mmol; 2eq) and 500mg of 1, 1-diethoxyethylene (4.31 mmol; 1eq) were stirred in 25mL of toluene at 0 ℃ under argon. 3.5mL of n-butyllithium (2.5M in hexane, 8.62 mmol; 2eq) are added dropwise at 0 ℃. When the addition was complete, the reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was then hydrolyzed and extracted 3 times with ethyl acetate. The organic phase is dried and evaporated and the crude product is purified by column chromatography on a column of silica (eluent: heptane/ethyl acetate 90/10). 333mg of a yellow oil are obtained which crystallizes at room temperature.

The yield is 31%

¹HNMR(CDCl₃)：＝6.86(s；1H)；6.79(s；1H)；3.84(s；6H)；3.72(q；4H)；3.30(s；2H)；1.25(t；6H)。

Example 2: 3, 4-Dimethoxybicyclo [4.2.0] octa-1, 3, 5-trien-7-one

Mixing 7, 7-diethoxy-3, 4-dimethoxy bicyclo [4.2.0]]Octane-1, 3, 5-triene (1.76g,6.98mmol) was stirred in a THF/water (6/1) mixture at room temperature. 815mg of 11N HCl aqueous solution (1.1eq,7.7mmol) were then added. The reaction mixture was stirred at room temperature for 2 hours. Adding water to facilitate the use of ethyl acetateEster extraction twice (2 × 30 mL). organic phase was over MgSO₄Dried and then dried. 1.01g of the expected product are obtained as a grey powder.

The yield is 81%

¹HNMR(CDCl₃)：7.02(s；2H)；6.82(s；2H)；3.99(s；3H)；3.87(s；5H).

¹³CNMR(CDCl₃)：185.8；155.9；151.4；146.2；138.7；105.6；102.3；56.4；56.1；51.0。

m.p.＝146℃

Example 3: 3, 4-Dimethoxybicyclo [4.2.0] octa-1, 3, 5-triene-7-carbonitrile

To a solution of potassium tert-butoxide (1.22 g; 10.9 mmol; 5eq) in THF (7.5mL) was added a solution of TosMIC (0.98 g; 4.98 mmol; 2.3eq) in THF (3mL) over 20 minutes and stirred at 0 ℃ under nitrogen. Then 200. mu.L of methanol was added to the mixture and stirring was continued at 0 ℃ for 30 minutes. Simultaneously, 3, 4-dimethoxybicyclo [4.2.0] octa-1, 3, 5-trien-7-one (0.39g,2.17mmol,1eq), lithium bromide (0.19g,2.17mmol,1eq), and THF (2.5mL) were added to a second three-necked flask. After cooling to 0 ℃ under nitrogen, a solution of TosMIC and potassium tert-butoxide was added to the reaction mixture. After returning to room temperature, the solution was heated to 40 ℃ and stirred at this temperature for 16 hours. The mixture was then hydrolyzed with 11N HCl (0.7mL,7.73mmol) in water (2 mL). After evaporation of THF under reduced pressure, the product is extracted with 5mL of dichloromethane. The organic phase is washed twice with 2X 5mL of water and then dried. The crude product was purified by silica gel column chromatography eluting with a binary mixture methylcyclohexane/ethyl acetate 75/25 to give the target product as a cream-white powder.

The yield is 54%

¹HNMR(CDCl₃)：6.76(s；1H)；6.68(s；1H)；4.14(m；1H)；3.83(s；6H)；3.59-3.41(m；2H)。

¹³CNMR(CDCl₃)：151.4；150.4；134.2；129.7；119.9；106.9；106.1；56.2；35.5；22.6。

Example 4: 3, 4-dimethoxy-N-methylbicyclo [4.2.0] octa-1, 3, 5-trien-7-amine

According to EP0534859

Step 1: 3, 4-Dimethoxybicyclo [4.2.0] octa-1, 3, 5-trien-7-amine hydrochloride

To a solution of 25g of 3, 4-dimethoxybicyclo [4.2.0] octa-1, 3, 5-triene-7-carbonitrile in 250mL of THF was added dropwise, with stirring at room temperature, 312mL of a molar solution of borane and THF complex, and the mixture was allowed to contact for 12 hours; then 200mL of ethanol was added and stirring was continued for 1 hour. 100mL of 3.3N ether was added dropwise to make HCl. 27.7g of the expected product are obtained.

The yield is 90 percent

m.p.＝205℃

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

To a suspension of 3.4g of the compound obtained in step 1 in 4.5mL of triethylamine and 50mL of dichloromethane was added 1.5mL of ethyl chloroformate, and the mixture was left overnight while stirring at room temperature; washed with water and then 1N hydrochloric acid. Dry and evaporate the solvent to dryness. 3.2g of the expected product are obtained as an oil.

The yield is 80%

And step 3: 3, 4-dimethoxy-N-methylbicyclo [4.2.0] octa-1, 3, 5-trien-7-amine

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

The yield is 92%

Example 5: (7S) -3, 4-dimethoxy-N-methylbicyclo [4.2.0] octa-1, 3, 5-trien-7-amine

According to EP0534859

The amine obtained in example 4 was reacted with an equimolar amount of (d) camphorsulfonic acid in ethanol. After evaporation of the solvent in vacuo, the salt was recrystallized from ethyl acetate and then acetonitrile until an optical purity of more than 99% was obtained (by HPLC in Chiral)OD column) of the target enantiomer.

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-dihydro-2H-3-benzazepine-2-ketones

According to EP0534859

The ethyl acetate solution of (d) camphorsulfonate obtained in example 5 was adjusted to basic pH with sodium hydroxide, then the organic phase was separated, washed, dried over sodium sulfate and evaporated.

Then, a solution of 5.6g of potassium carbonate, 2.2g of the above amine in 100mL of acetone and 4g of 3- (3-iodopropyl) -7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepineReflux of the mixture of-2-ketones for 18 hours.

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

The separated aqueous phase was adjusted to basic pH with sodium hydroxide and then extracted with ethyl acetate. After washing to neutrality, drying over magnesium sulfate and evaporation in vacuo, 4.5g of an oil were obtained which was purified on a silica gel column using dichloromethane/methanol (90/10) as eluent.

The yield is 64%

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

According to EP0534859

A solution of 5g of the compound obtained in example 6 in 50mL of glacial acetic acid in the presence of 1g of palladium hydroxide 10% is hydrogenated in a Parr apparatus under a hydrogen pressure of 4.9bar at room temperature for 24 hours. The catalyst was filtered, the solvent was evaporated, and the dry residue was then dissolved in water and ethyl acetate. The organic phase was dried over anhydrous magnesium sulphate, concentrated in vacuo and the residue was purified by column chromatography on silica gel using a mixture of dichloromethane/methanol (95/5) as eluent. After recrystallization from ethyl acetate, 2g of the title compound were obtained.

The yield is 40%

m.p.＝101－103℃。

Claims (17)

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

the process is characterized by reacting a compound of formula (VII):

the compound of formula (I) is obtained by the action of 1- (isocyanomethylsulfonyl) -4-methylbenzene in an organic solvent in the presence of a base.

2. Process according to claim 1, characterized in that the amount of 1- (isocyanomethylsulfonyl) -4-methylbenzene used to convert the compound of formula (VII) to the compound of formula (I) is 2-5 equivalents.

3. Process according to claim 1, characterized in that the base used for the conversion of the compound of formula (VII) to form the compound of formula (I) is selected from potassium tert-butoxide, sodium tert-butoxide, potassium ethoxide, sodium ethoxide, potassium methoxide and sodium methoxide.

4. A process according to claim 3, characterized in that the base used for the conversion of the compound of formula (VII) to form the compound of formula (I) is potassium tert-butoxide.

5. The process as claimed in any of claims 1 to 4, characterized in that the organic solvent used for the conversion of the compound of the formula (VII) to form the compound of the formula (I) is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, ethylene glycol and dimethyl sulfoxide and mixtures of two of the aforementioned solvents.

6. The process according to claim 5, characterized in that the organic solvent used for the conversion of the compound of formula (VII) to form the compound of formula (I) is a mixture of tetrahydrofuran and methanol.

7. Process according to any one of claims 1 to 4, characterized in that the reaction for converting the compound of the formula (VII) to form the compound of the formula (I) is carried out at a temperature of from-20 ℃ to 50 ℃.

8. Process according to claim 1, characterized in that the compound of formula (VII) is prepared using the compound of formula (VIII) as starting material:

converting a compound of formula (VIII) to a compound of formula (IX) in an organic solvent in the presence of a 1, 1-dialkoxyethylene and an organometallic compound, wherein the alkoxy group has 1 to 4 carbon atoms:

wherein R represents C₁-C₄An alkyl group, a carboxyl group,

hydrolyzing a compound of formula (IX) in an amphiphilic acidic medium to form a compound of formula (VII):

9. the process according to claim 8, characterized in that the 1, 1-dialkoxyethylene used for converting the compound of formula (VIII) to form the compound of formula (IX) is 1, 1-diethoxyethylene.

10. Process according to claim 9, characterized in that the amount of 1, 1-diethoxyethylene used for converting the compound of formula (VIII) to form the compound of formula (IX) is between 0.8 and 5 equivalents.

11. Process according to any one of claims 8 to 10, characterized in that the organometallic compound used for converting the compound of formula (VIII) to form the compound of formula (IX) is selected from n-butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium and isopropylmagnesium chloride.

12. A process according to claim 11, characterised in that the organometallic compound used to convert the compound of formula (VIII) to form the compound of formula (IX) is n-butyllithium.

13. Process according to claim 12, characterized in that the amount of n-butyllithium used for the conversion of the compound of formula (VIII) to form the compound of formula (IX) is 1 to 3 equivalents.

14. Process according to any one of claims 8 to 10, characterized in that the organic solvent used for the conversion of the compound of formula (VIII) to form the compound of formula (IX) is selected from the group consisting of toluene, tetrahydrofuran, dichloromethane and chlorobenzene.

15. The process according to claim 14, characterized in that the organic solvent used for the conversion of the compound of formula (VIII) to form the compound of formula (IX) is toluene.

16. Process according to any one of claims 1-4 and 8-10, characterized in that the reaction of converting the compound of formula (VIII) to form the compound of formula (IX) is carried out at a temperature of-20 ℃ to 30 ℃.

17. A process for the synthesis of ivabradine, pharmaceutically acceptable salts thereof and hydrates thereof, wherein said compound of formula (VII) is converted into an intermediate of formula (I) according to the process of claim 1, followed by conversion of the intermediate of formula (I) into ivabradine.