Preparation method of ivabradine and hydrochloride thereof
An acid binding agent, quaternary ammonium salt technology, applied in chemical instruments and methods, organic compounds/hydrides/coordination complex catalysts, organic chemistry and other directions, can solve heavy metal residues and high process costs, raw materials or intermediates It is difficult to obtain and realize industrialized production and other problems, so as to avoid the column chromatography process, the product quality is good, and the purity is improved.
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Embodiment 1
[0069] Example 1 Research on Phase Transfer Catalysts
[0070] The inventors conducted research on commonly used phase transfer catalysts (as shown in Table 1). The end point of the nucleophilic substitution reaction is monitored by HPLC (high performance liquid chromatography), and the reaction is considered complete when the remaining amount of the compound shown in formula III (wherein the substituent X is Cl) is less than 0.5%. The experimental results are shown in Table 1. It can be seen from Table 1 that when no phase transfer catalyst is used, the nucleophilic substitution reaction time is as long as 22.0h; When quaternary ammonium salts phase-transfer catalyst was used as a single phase-transfer catalyst, it played a certain catalytic effect, and the reaction time was shortened to 18.5~20.5h, but the catalytic effect was still not ideal enough; use catalytic amount (2% of the compound quality shown in formula IV %~10%) polyether phase transfer catalyst as a single ...
Embodiment 2
[0082] Example 2 Preparation of ivabradine
[0083] 1, the preparation of formula III compound
[0084] Dissolve 40.0g of 7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-3-benzazepine-2-one (compound of formula II) in 200mL iso Add 9 g of acetic acid to propanol, transfer to a high-pressure hydrogenation reactor, add 2 g of 10% palladium-carbon catalyst, and perform hydrogenation reaction at 35-40 ° C and 1-4 atm pressure for 18 hours. Filtrate, wash the filter cake with a small amount of isopropanol, recover the palladium carbon catalyst, and evaporate the filtrate to dryness under reduced pressure at 40-45°C to obtain 7,8-dimethoxy-3-(3-chloropropyl)-1, 3,4,5-Tetrahydro-2H-3-benzazepin-2-one acetate (compound of formula III) oil, slowly add methanol to crystallize at room temperature, grow crystal at 5~10℃ for 2h, Filter and dry to obtain 42.2g 7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one Acetate (compound of formula III) has a purity of 9...
Embodiment 3
[0097] Example 3 Preparation of ivabradine
[0098] 1, the preparation of formula III compound
[0099] Dissolve 40.0g of 7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-3-benzazepine-2-one (compound of formula II) in 180mL ethanol 9g of acetic acid was added, transferred to a high-pressure hydrogenation reactor, and 2g of 10% palladium carbon catalyst was added for hydrogenation reaction at 35-40°C and 1-4atm pressure for 18h. Filter, wash the filter cake with a small amount of ethanol, recover the palladium carbon catalyst, and evaporate the filtrate to dryness under reduced pressure at 40-45°C to obtain 7,8-dimethoxy-3-(3-chloropropyl)-1,3, 4,5-Tetrahydro-2H-3-benzazepin-2-one acetate (compound of formula III) oil, add methanol slowly at room temperature for crystallization, crystallize at 5-10°C for 2 hours, filter, Dry to obtain 42.4g7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one acetic acid The salt (compound of formula III) has a purity ...
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