Method for synthesizing ivabradine key intermediate

Abstract

The invention relates to a method for synthesizing an ivabradine key intermediate (S)-4,5-dimethoxy-1-(methylamino)methyl-benzocyclobutane hydrochloride. The method comprises the following steps: performing chiral resolution on 4,5-dimethoxy-1-methylamino-benzocyclobutane to obtain an S configuration of the 4,5-dimethoxy-1-methylamino-benzocyclobutane; preparing formamide from amino group; and reducing with zinc powder to prepare the ivabradine key intermediate in the formula (I). Compared with a traditional method for preparing methylamine by reducing ethyl chloroformate, lithium aluminium hydride or sodium di-aluminum hydride, the method is simple in operation, high in product purity, little in side effect, mild and easily controllable in condition, convenience in post-treatment, environment-friendly, and higher in total yield, and is a brand-new method for synthesizing (S)- 4,5-dimethoxy-1-(methylamino)methyl-benzocyclobutane hydrochloride.

Description

technical field

[0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing (S)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane, a key intermediate of ivabradine. Background technique

[0002] Ivabradine and its pharmaceutically acceptable acid addition salts, especially the hydrochloride, have very important pharmacological and therapeutic properties, especially heart rate slowing properties, which allow these compounds to be used in the treatment or prophylaxis of Various clinical myocardial ischemic conditions such as angina, myocardial infarction and associated rhythm disturbances.

[0003] Generally, ivabradine of formula (V) and its pharmaceutically acceptable acid addition salt can be obtained according to the present invention. The key intermediate compound of formula (I) (S)-4,5-dimethoxy-1-(form Aminomethyl)-benzocyclobutane was prepared.

[0004]

[0005] And in the existing synthetic method, ivabradine key int...

Examples

Embodiment 1

[0046]96.5g (0.5mol) of 4,5-dimethoxy-1-aminomethyl-benzocyclobutane was heated and dissolved in 500ml of ethanol, and 94.5g (0.5mol) of N-acetyl-L-glutamic acid was added , after the reaction is finished, cool to about 20°C, let it stand for 12 hours, crystals are precipitated, and the salt of formula (III) is obtained by suction filtration.

[0047] Dissolve the above salt in 200ml of pure water, adjust the pH to 10 with 16g (0.4mol) of 40% sodium hydroxide, add 200mol*3 dichloromethane to extract 3 times, combine the organic layer, add 50g of anhydrous sodium sulfate to dry 6-8 Hours, the desiccant was filtered off, and the solvent was spin-dried in vacuo to obtain a yellow oil, 33.78g, with a yield of 70%.

Embodiment 2

[0049] 96.5g (0.5mol) of 4,5-dimethoxy-1-aminomethyl-benzocyclobutane was heated and dissolved in 500ml of methanol, and 94.5g (0.5mol) of N-acetyl-L-glutamic acid was added , after the reaction was completed, cooled to about 20°C, stood still for 12 hours, crystals were precipitated, and filtered with suction to obtain the salt of (S)-4,5-dimethoxy-1-aminomethyl-benzocyclobutane, such as Salts of formula (III).

[0050] Dissolve the above salt in 200ml of pure water, adjust the pH to 10 with 16g (0.4mol) of 40% sodium hydroxide, add 200mol*3 dichloromethane to extract 3 times, combine the organic layer, add 50g of anhydrous sodium sulfate to dry 6-8 hour, filter off the desiccant, and spin dry the solvent in vacuo to obtain a yellow oil, i.e. (S)-4,5-dimethoxy-1-aminomethyl-benzocyclobutane, 30.45g, yield 63.21% .

Embodiment 3

[0052] Formula (III) compound (S)-4,5-dimethoxy-1-aminomethyl-benzocyclobutane, 33.78g, dissolved in 100ml formic acid, added ZnCl 2 , 5g, the reaction temperature is about 65°C, stir the reaction for 5 hours, after the reaction, the temperature of the reaction solution is lowered to below zero, add 500ml of water dropwise, add 300ml of dichloromethane*2 for extraction twice, wash once with 100ml of saturated sodium chloride solution, 200ml *2 Washed twice with water, dried with anhydrous sodium sulfate and then spin-dried to obtain (S)-4,5-dimethoxy-1-formamidomethyl-benzocyclobutane, such as formula (II), shallow Yellow oil, 33.65g, yield 87%.

technical field

[0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing (S)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane, a key intermediate of ivabradine. Background technique

[0002] Ivabradine and its pharmaceutically acceptable acid addition salts, especially the hydrochloride, have very important pharmacological and therapeutic properties, especially heart rate slowing properties, which allow these compounds to be used in the treatment or prophylaxis of Various clinical myocardial ischemic conditions such as angina, myocardial infarction and associated rhythm disturbances.

[0003] Generally, ivabradine of formula (V) and its pharmaceutically acceptable acid addition salt can be obtained according to the present invention. The key intermediate compound of formula (I) (S)-4,5-dimethoxy-1-(form Aminomethyl)-benzocyclobutane was prepared.

[0004]

[0005] And in the existing synthetic method, ivabradine key int...

Examples

Embodiment 1

[0046]96.5g (0.5mol) of 4,5-dimethoxy-1-aminomethyl-benzocyclobutane was heated and dissolved in 500ml of ethanol, and 94.5g (0.5mol) of N-acetyl-L-glutamic acid was added , after the reaction is finished, cool to about 20°C, let it stand for 12 hours, crystals are precipitated, and the salt of formula (III) is obtained by suction filtration.

[0047] Dissolve the above salt in 200ml of pure water, adjust the pH to 10 with 16g (0.4mol) of 40% sodium hydroxide, add 200mol*3 dichloromethane to extract 3 times, combine the organic layer, add 50g of anhydrous sodium sulfate to dry 6-8 Hours, the desiccant was filtered off, and the solvent was spin-dried in vacuo to obtain a yellow oil, 33.78g, with a yield of 70%.

Embodiment 2

[0049] 96.5g (0.5mol) of 4,5-dimethoxy-1-aminomethyl-benzocyclobutane was heated and dissolved in 500ml of methanol, and 94.5g (0.5mol) of N-acetyl-L-glutamic acid was added , after the reaction was completed, cooled to about 20°C, stood still for 12 hours, crystals were precipitated, and filtered with suction to obtain the salt of (S)-4,5-dimethoxy-1-aminomethyl-benzocyclobutane, such as Salts of formula (III).

[0050] Dissolve the above salt in 200ml of pure water, adjust the pH to 10 with 16g (0.4mol) of 40% sodium hydroxide, add 200mol*3 dichloromethane to extract 3 times, combine the organic layer, add 50g of anhydrous sodium sulfate to dry 6-8 hour, filter off the desiccant, and spin dry the solvent in vacuo to obtain a yellow oil, i.e. (S)-4,5-dimethoxy-1-aminomethyl-benzocyclobutane, 30.45g, yield 63.21% .

Embodiment 3

[0052] Formula (III) compound (S)-4,5-dimethoxy-1-aminomethyl-benzocyclobutane, 33.78g, dissolved in 100ml formic acid, added ZnCl 2 , 5g, the reaction temperature is about 65°C, stir the reaction for 5 hours, after the reaction, the temperature of the reaction solution is lowered to below zero, add 500ml of water dropwise, add 300ml of dichloromethane*2 for extraction twice, wash once with 100ml of saturated sodium chloride solution, 200ml *2 Washed twice with water, dried with anhydrous sodium sulfate and then spin-dried to obtain (S)-4,5-dimethoxy-1-formamidomethyl-benzocyclobutane, such as formula (II), shallow Yellow oil, 33.65g, yield 87%.

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