A kind of preparation method of dehydroivabradine oxalate
A technology of oxalate and dehydrogenation, applied in the direction of organic chemistry, etc., can solve the problems of high impurity content of dehydro-ivabradine and cumbersome treatment process, so as to improve the purity of reaction liquid, avoid complicated operations, and increase product yield Effect
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Embodiment 1
[0035] Embodiment 1 The preparation of dehydroivabradine and its oxalate
[0036] Method A
[0037] 24.6 g of compound (II) and 20 g of compound (III) hydrochloride were added to 200 mL of toluene, and 80 g of sodium carbonate, 4 g of sodium iodide and 2 g of tetrabutylammonium bromide were added. Raise the temperature to 98-102°C and react for 10 hours. The purity of the reaction solution is greater than 85%, and the impurity (A) content is less than 1% (HPLC, area normalization method).
[0038] Cool down to 40-60°C, add 200g of drinking water, stir evenly, stand still, and separate the liquids to obtain a toluene solution of dehydroivabradine (concentrate under reduced pressure below 80°C to obtain dehydroivabradine).
[0039] Add 12g of oxalic acid dihydrate dropwise to the toluene solution of dehydroivabradine at 40-60°C (dissolve in 50mL of ethanol and add dropwise). Then raise the temperature to 80-100°C to dissolve and clarify the reaction liquid, then slowly cool d...
Embodiment 2
[0061] Example 2 Preparation of ivabradine hydrochloride impurity (A)
[0062] Take 1.0 g of compound (II) and add it to 20 mL of NMP (N-methylpyrrolidone), add 10 mL of drinking water and 5 g of potassium carbonate, and raise the temperature to 70-80 ° C for 12 hours. Distill and remove NMP under high vacuum pressure, add 20mL of drinking water and 50mL of dichloromethane, stir evenly, let stand, and separate liquids. The organic layer was anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain ivabradine hydrochloride impurity (A). Ivabradine hydrochloride impurity (A) can be purified by silica gel column chromatography, the eluent is dichloromethane: methanol (10:1).
[0063] 1 H-NMR: 400MHz, d 6 -DMSO, δ6.90~6.92 (2 single peaks, 2 hydrogens), δ6.35~6.40 (overlapping peaks, 2 hydrogens), δ3.75~3.77 (overlapping peaks, 6 hydrogens), δ3.51 ~3.55 (triplet, 2 hydrogens), δ3.34 (singlet, 2 hydrogens), δ3.27~3.30 (triplet, 2 hydrogens), δ1.50~1....
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