Novel method for synthesizing bisoprolol importance intermediate
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A technology for bisoprolol and intermediates, which is applied in the field of synthesis of important intermediates of bisoprolol, can solve the problems of consumption of 2-isopropoxyethanol, inability to process and reuse, and high production costs, and achieve easy industrial production, Low-cost, easy-to-operate effect
Inactive Publication Date: 2015-09-02
UNIV OF JINAN
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[0009] A large amount of bromine is used in the reaction process of this method, there are safety and pollution risks such as toxicity damage, and will consume a large amount of 2-is
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Embodiment 1
[0026] Add 12.2g (0.1mol) of p-hydroxybenzaldehyde and 0.3g of concentrated sulfuric acid into a 100ml three-necked flask, slowly add 12.12g (0.12mol) of acetic anhydride dropwise, and heat to reflux. After TLC detects that the reaction is complete, distill off the solvent and add After stirring with 20ml of water, solids were precipitated, cooled to crystallize, separated by suction filtration, and dried to obtain 16.1 g of 4-acetoxybenzaldehyde, with a yield of 98% and a purity of 99.3% by HPLC.
Embodiment 2
[0028] In a 100ml three-neck flask, add 16.1g (0.098mol) 4-acetoxybenzaldehyde and 20ml ethanol, stir to dissolve, add 1.48g sodium borohydride in batches in an ice-water bath, continue stirring, and heat up to 25°C after 1h Reaction, TLC detects that after the reaction is complete, evaporate the solvent, add 30ml of ethyl acetate and 10ml of water to the residue, keep the organic phase, continue to add 10ml of water to the organic phase for washing, remove the water layer, and concentrate the organic phase to obtain 4- Acetoxybenzyl alcohol was 15.8 g, the yield was 97.4%, and the HPLC purity was 99.5%.
Embodiment 3
[0030] In a 100ml three-neck flask, add 16.1g (0.098mol) 4-acetoxybenzaldehyde and 20mlTHF, stir to dissolve, add 2.23g sodium borohydride in ice water bath, continue stirring, after 1h, heat up to 25°C for reaction , after the TLC detection reaction was complete, evaporate the solvent, add 30ml ethyl acetate and 10ml water to the residue, keep the organic phase, continue to add 10ml water to the organic phase for washing, remove the water layer, and evaporate the organic phase to dryness to obtain 4- Acetoxybenzyl alcohol 15.5g, yield rate 95%, HPLC purity 98%.
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Abstract
The invention discloses a novel method for synthesizing a bisoprolol importance intermediate. The novel method has the following steps: carrying out a reaction between hydroxy benzaldehyde which is taken as a raw material and acetic anhydride to obtain 4-acetoxybenzaldehyde; conducting reduction on 4-acetoxybenzaldehyde with sodium borohydride to obtain 4-acetoxyl benzyl alcohol; carrying out a reaction between 4-acetoxyl benzyl alcohol and 2-isopropoxyethanol to obtain 4-[(2-isopropoxyethanol)methyl]phenyl acetic acid, thereby avoiding side reactions such as phenolic hydroxyl etherification; under an alkaline condition, directly hydrolyzing 4-[(2-isopropoxyethanol)methyl]phenyl acetic acid without separation to recover 2-isopropoxyethanol, thereby obtaining the required intermediate, namely 4-isopropoxyethoxymethylphenol. The novel method is mild in reaction and safe to operate; impurities generated due to self-polymerization of raw materials, phenolic hydroxyl etherification and the like are reduced; the product purity and yield are relatively high; as a novel way for obtaining the bisoprolol importance intermediate, the novel method can be applied to large-scale industrialized production.
Description
technical field [0001] The invention belongs to the field of preparation of pharmaceutical intermediates, and in particular relates to a new method for synthesizing an important intermediate of bisoprolol. Background technique [0002] Bisoprolol important intermediate 4-isopropoxyethoxymethylphenol, English name 4-isopropoxyethoxymethylphenol, molecular formula: C 12 h 18 o 3 , Molecular weight: 210, it is a key intermediate in the synthesis of bisoprolol fumarate for the treatment of angina pectoris, arrhythmia and hypertension. [0003] There are not many reports on the synthesis method of 4-isopropoxyethoxymethylphenol, and there are mainly two routes. European patent WO2007069266 discloses a preparation method of 4-isopropoxyethoxymethylphenol, specifically, 4-hydroxybenzaldehyde is used as a starting material, and reduced by potassium borohydride, under the action of a catalyst, and 2 - Isopropoxyethanol is produced by etherification of alcoholic hydroxyl groups. ...
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