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A technology for procaterol hydrochloride and impurities is applied in the field of preparation of procaterol hydrochloride impurities, which can solve the problems of difficulty in obtaining and high cost, and achieve the effects of improving selectivity, reducing synthesis cost and saving preparation time.
Inactive Publication Date: 2021-04-13
SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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Problems solved by technology
[0004] The invention provides a method for preparing procaterol hydrochloride impurities, which solves the problem of difficulty in obtaining and high cost
Method used
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Embodiment 1
[0029] The preparation of embodiment 1 intermediate 1
[0030]
[0031] Sodium hydroxide (1.3g, 32.1mmol), 16ml of water, and 30ml of methanol were added to a 100ml single-necked flask, cooled to 0°C, procaterol hydrochloride (5.0g, 17.2mmol) was added, and then benzyl chloride (2.51g, 19.8mmol), heated to reflux to 80°C, after 4 hours of reaction, the reaction was complete, the reaction was stopped, and the temperature was lowered. Methanol was removed by rotary evaporation under reduced pressure, 150 ml of water was added, extracted twice with dichloromethane, dried and concentrated to obtain 4.70 g of a light yellow solid with a yield of 80.8%.
Embodiment 2
[0032] The preparation of embodiment 2 intermediate 2
[0033]
[0034] Intermediate 1 (4.0g, 10.5mmol) was added to 40ml of DMF, heated to 60°C, 150ml of sodium periodate aqueous solution (concentration: 0.1mol / L) was quickly added at one time, and reacted at 60°C for 15 minutes. After the reaction was complete, the reaction solution was poured into 400 ml of ice water, and a solid was precipitated, which was filtered and dried to obtain 2.4 g of a light yellow solid, with a yield of 82%.
Embodiment 3
[0035] The preparation of embodiment 3 Procaterol hydrochloride impurity
[0036]
[0037] Intermediate 2 (3.0g, 10.6mmol) and 90ml of dichloromethane were mixed and stirred, and the temperature was lowered to -5-0°C; boron trichloride (30ml, 30mmol) was slowly added dropwise, and reacted at -5-0°C for 2 hours until the reaction is complete. The reaction solution was poured into ice water, and a white solid was precipitated. The dichloromethane was removed by rotary evaporation, and the white solid was obtained by filtration, that is, Procaterol impurity I (1.95 g, 97.5%), and the HPLC purity was 99.65%.
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Abstract
The invention discloses a procaterol hydrochloride impurity preparation method, which comprises: 1, adding procaterol hydrochloride to an organic solvent under an alkaline condition, adding an appropriate amount of benzyl halide, carrying out heating reflux until the reaction is complete, and carrying out post-treatment to obtain an intermediate 1; step 2, adding the intermediate 1 into a reaction bottle, then adding an organic solvent, raising the temperature, adding an oxidant aqueous solution, pouring into ice water after heating reaction is completed, and separating out a solid to obtain an intermediate 2; and step 3, adding the intermediate 2 into a reaction bottle, then adding an organic solvent, cooling to a low temperature, slowly adding boron trichloride, keeping the low temperature until the reaction is complete, pouring into ice water, separating out solids, and filtering to obtain the procaterol impurity. Procaterol hydrochloride which is easy to obtain is used as an initial raw material to prepare the procaterol hydrochloride impurity, the synthesis cost of the procaterol hydrochloride impurity is reduced, the preparation steps of the procaterol hydrochloride impurity are simplified, and the selectivity is improved, so that the preparation time is saved, and the preparation efficiency is improved. The total yield of the reaction is 50-70%.
Description
technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of procaterol hydrochloride impurity. Background technique [0002] Procaterol hydrochloride was invented and manufactured by Otsuka Pharmaceutical Co., Ltd., Japan, and is a bronchodilator. It is suitable for bronchial asthma, asthmatic bronchitis, acute bronchitis with increased bronchial reactivity, and chronic obstructive pulmonary disease. [0003] There are few published patent documents about the preparation of this product. The original Japanese Otsuka patent US4026897 describes the use of 8-dihydroxyquinoline as a starting material to prepare Procaterol hydrochloride through rearrangement, condensation, hydrogenation reduction, and salification. Various types of impurities often appear in pharmaceutical research, and the present invention is prepared by a relatively simple method. Contents of the invention [0004] The inve...
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