阅读说明：本技术 一种盐酸丙卡特罗杂质的制备方法 (Preparation method of procaterol hydrochloride impurity ) 是由 唐田 黄汉敏 栾升霖 严悦梅 冯汉林 于琳 于 2020-12-09 设计创作，主要内容包括：本发明公开了一种盐酸丙卡特罗杂质的制备方法,包括以下步骤：步骤1,在碱性条件下,在有机溶剂中加入盐酸丙卡特罗,然后再加入适量的卤化苄,加热回流至反应完全,经后处理后得到中间体1；步骤2,将中间体1加入反应瓶中,然后加入有机溶剂,升高温度,加入氧化剂水溶液,加热反应完全后,倒入冰水中,析出固体,得到中间体2；步骤3,将中间体2加入反应瓶中,然后加入有机溶剂,降至低温,缓慢加入三氯化硼,保持低温至反应完全后,倒入冰水中,析出固体,过滤,得到丙卡特罗杂质。以易于获得的盐酸丙卡特罗为起始原料来制备盐酸丙卡特罗杂质,降低了盐酸丙卡特罗杂质的合成成本,而且简化了盐酸丙卡特罗杂质的制备步骤,提高了选择性,从而节省了制备时间,提高了制备效率。本发明反应的总收率50-70％。(The invention discloses a preparation method of procaterol hydrochloride impurity, which comprises the following steps: step 1, adding procaterol hydrochloride into an organic solvent under an alkaline condition, then adding a proper amount of benzyl halide, heating and refluxing until the reaction is complete, and carrying out aftertreatment to obtain an intermediate 1; step 2, adding the intermediate 1 into a reaction bottle, adding an organic solvent, raising the temperature, adding an oxidant aqueous solution, heating to react completely, pouring into ice water, and separating out a solid to obtain an intermediate 2; and 3, adding the intermediate 2 into a reaction bottle, adding an organic solvent, cooling to a low temperature, slowly adding boron trichloride, keeping the low temperature till the reaction is complete, pouring into ice water, separating out a solid, and filtering to obtain procaterol impurities. The procaterol hydrochloride impurity is prepared by taking easily obtained procaterol hydrochloride as a starting raw material, so that the synthesis cost of the procaterol hydrochloride impurity is reduced, the preparation steps of the procaterol hydrochloride impurity are simplified, the selectivity is improved, the preparation time is saved, and the preparation efficiency is improved. The total yield of the reaction of the invention is 50-70%.)

1. A preparation method of procaterol hydrochloride impurity comprises the following steps:

step 1, adding procaterol hydrochloride into an organic solvent under an alkaline condition, then adding a proper amount of benzyl halide, heating and refluxing until the reaction is complete, and carrying out aftertreatment to obtain an intermediate 1; wherein the weight g/volume ml ratio of procaterol hydrochloride to the organic solvent is 1: 20-1: 25, the molar ratio of procaterol hydrochloride to benzyl halide is 1: 1-3, the heating reflux temperature is 60-100 ℃, and the reaction time is 3-8 hours;

step 2, adding the intermediate 1 into a reaction bottle, adding an organic solvent, raising the temperature, rapidly adding an oxidant aqueous solution at one time, heating to react completely, pouring into ice water, and separating out solids to obtain an intermediate 2; wherein the weight g/volume ml of the intermediate 1 and the organic solvent is 1: 8-1: 15, intermediate 1 to oxidant ratio of 1: 1-3, the heating temperature is 40-80 ℃, and the reaction time is 0.10-1 hour;

step 3, adding the intermediate 2 into a reaction bottle, adding an organic solvent, cooling to a low temperature, slowly adding boron trichloride, keeping the low temperature till the reaction is complete, pouring into ice water, separating out a solid, and filtering to obtain procaterol impurities; wherein the weight g/volume ml ratio of the intermediate 2 to the organic solvent is 1: 25-1: 35, the molar ratio of the intermediate 2 to the boron trichloride is 1: 1-6, the low temperature is-10-15 ℃, and the reaction time is 1-4 hours.

2. The process according to claim 1 for the preparation of procaterol hydrochloride impurity,

in the step 1, the weight g/volume ml ratio of procaterol hydrochloride to the organic solvent is 1:23, the molar ratio of procaterol hydrochloride to benzyl halide is 1:1.2, and the heating reflux temperature is 80 ℃, preferably 4 hours;

in the step 2, the weight g/volume ml of the intermediate 1 and the organic solvent is 1: 10, the ratio of the intermediate 1 to the oxidant is 1:1.5, the heating temperature is 60 ℃, and the reaction time is selected to be 0.25 hour;

in the step 3, the weight g/volume ml ratio of the intermediate 2 to the organic solvent is 1: 30, the molar ratio of the intermediate 2 to the boron trichloride is 1:3, the low temperature is-5-0 ℃, and the reaction time is 2 hours.

3. The process for the preparation of procaterol hydrochloride impurity according to claim 1 or 2,

in the step 1, the alkaline condition is selected from sodium hydroxide, potassium tert-butoxide and triethylamine, and the benzyl halide is benzyl chloride or benzyl bromide; the organic solvent is ethyl acetate, tetrahydrofuran, ethanol and methanol;

in the step 2, the oxidant is sodium periodate or m-chlorobenzoic acid chloride, and the organic solvent is N, N-dimethylformamide, dioxane, dimethyl sulfoxide, dichloromethane, ethyl acetate, tetrahydrofuran, ethanol and methanol;

the organic solvent in the step 3 is dichloromethane, ethyl acetate, tetrahydrofuran, ethanol and methanol.

4. The method for preparing procaterol hydrochloride impurity according to claim 3, wherein the organic solvent in step 1 is methanol, the alkaline condition is sodium hydroxide, the benzyl halide is benzyl chloride,

the organic solvent in the step 2 is N, N-dimethylformamide;

the organic solvent in step 3 is dichloromethane.

5. The process according to claim 4 for the preparation of procaterol hydrochloride impurity,

step 1, adding sodium hydroxide, water and methanol into a reaction bottle, cooling to 0 ℃, adding procaterol hydrochloride, then adding benzyl chloride according to the molar ratio of the procaterol hydrochloride to the benzyl halide of 1:1.2, heating and refluxing for 4 hours at 80 ℃, and obtaining an intermediate 1 after post-treatment;

and 2, adding the intermediate 1 into a reaction bottle, adding an organic solvent N, N-dimethylformamide, quickly adding a sodium periodate aqueous solution at one time according to the ratio of the intermediate 1 to an oxidant N sodium periodate of 1:1.5, and reacting for 15 minutes at 60 ℃. Slowly adding an oxidant aqueous solution, heating to react completely, pouring into ice water, and separating out solids to obtain an intermediate 2;

and 3, adding the intermediate 2 into a reaction bottle, adding dichloromethane, reacting for 2 hours at the temperature of-5-0 ℃ until the reaction is complete, slowly adding boron trichloride according to the molar ratio of 1:3 of the intermediate 2 to the boron trichloride, keeping the temperature low until the reaction is complete, pouring into ice water, separating out solids, and filtering to obtain procaterol impurities.

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a procaterol hydrochloride impurity.

Background

Procaterol hydrochloride was invented and manufactured by tsukamur pharmaceutical corporation of japan as a bronchodilator. It is suitable for treating bronchial asthma, asthmatic bronchitis, acute bronchitis complicated with bronchial reactivity increase, and chronic obstructive pulmonary disease.

The patent literature about the preparation of the product is less, and originally developed tsukamur japanese patent US4026897 describes that procaterol hydrochloride is prepared by using 8-dihydroxyquinoline as a starting material through rearrangement, condensation, hydrogenation reduction and salt formation, while various impurities often appear in pharmaceutical research.

Disclosure of Invention

The invention provides a preparation method of procaterol hydrochloride impurity, which solves the problems of difficult acquisition and high cost.

The specific technical scheme is as follows:

a preparation method of procaterol hydrochloride impurity comprises the following steps:

the preparation method comprises the following steps of 1, taking procaterol hydrochloride as a starting raw material, adding procaterol hydrochloride into an organic solvent under an alkaline condition, then adding a proper amount of benzyl halide, heating and refluxing until the reaction is complete, and carrying out aftertreatment to obtain an intermediate;

the alkaline condition is selected from sodium hydroxide, potassium tert-butoxide and triethylamine, preferably sodium hydroxide;

the organic solvent is selected from methanol, ethanol, tetrahydrofuran, ethyl acetate, etc., preferably methanol; the weight g/volume ml ratio of procaterol hydrochloride to the organic solvent is 1: 20-1: 25, preferably 1: 23;

the benzyl halide is benzyl chloride or benzyl bromide, and is preferably benzyl chloride; the molar ratio of procaterol hydrochloride to benzyl halide is as follows: 1: 1-3, preferably 1: 1.2;

the heating reflux temperature is 60-100 ℃, and preferably 80 ℃;

the reaction time in step 1 is 3 to 8 hours, preferably 4 hours.

In the step 2 of the invention, the intermediate 1 is added into a reaction bottle, then an organic solvent is added, the temperature is raised, an oxidant aqueous solution is rapidly added at one time, after the reaction is completely heated, the mixture is poured into ice water, and a solid is separated out to obtain an intermediate 2;

the organic solvent is N, N-dimethylformamide, dioxane, dimethyl sulfoxide, dichloromethane, ethyl acetate, tetrahydrofuran, ethanol and methanol, and preferably N, N-dimethylformamide; the weight g/volume ml of the intermediate 1 and the organic solvent is 1: 8-1: 15, preferably 1: 10;

the oxidant is sodium periodate or m-chloroperoxybenzoic acid, and the ratio of the intermediate 1 to the oxidant is 1:1 to 3, preferably 1: 1.5.

The heating temperature is 40-80 ℃, and preferably 60 ℃;

the reaction time in step 2 is 0.10 to 1 hour, preferably 0.25 hour.

In the step 3, adding the intermediate 2 into a reaction bottle, adding an organic solvent, cooling to a low temperature, rapidly adding boron trichloride at one time, keeping the low temperature till the reaction is complete, pouring into ice water, separating out a solid, and filtering to obtain procaterol impurity I;

the organic solvent is dichloromethane, ethyl acetate, tetrahydrofuran, ethanol and methanol, preferably dichloromethane; the weight g/volume ml ratio of the intermediate 2 to the organic solvent is 1: 25-1: 35, preferably 1: 30, of a nitrogen-containing gas;

the low temperature is-10-15 ℃, preferably-5-0 ℃;

the reaction time in step 3 is 1 to 4 hours, preferably 2 hours.

According to the technical scheme, the invention has the following advantages:

the invention provides a preparation method of procaterol hydrochloride impurities, which comprises the steps of reacting procaterol hydrochloride with benzyl halide to protect hydroxyl on a benzene ring, and then obtaining a target compound under the action of boron halide. According to the preparation method of the procaterol hydrochloride impurity, the procaterol hydrochloride impurity is prepared by taking the easily obtained procaterol hydrochloride as a starting material, so that the synthesis cost of the procaterol hydrochloride impurity is reduced, the preparation steps of the procaterol hydrochloride impurity are simplified, the selectivity is improved, the preparation time is saved, and the preparation efficiency is improved. The total yield of the reaction of the invention is 50-70%.

The embodiment of the invention provides a preparation method of procaterol hydrochloride, which is used for solving the problem that the existing procaterol hydrochloride impurity is difficult to synthesize. Particularly, benzyl halide reacts with procaterol in the step 1, so that the hydrogenation risk is avoided, the operation is simple, the reaction yield is high, and the product purity is high.

In order to make the objects, features and advantages of the present invention more obvious and understandable, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the embodiments described below are only a part of the present invention.

Detailed Description

Examples, but not all examples. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

EXAMPLE 1 preparation of intermediate 1

Sodium hydroxide (1.3g,32.1mmol), water (16 ml) and methanol (30 ml) are added into a 100ml single-neck flask, cooled to 0 ℃, added with procaterol hydrochloride (5.0g,17.2mmol) and then benzyl chloride (2.51g,19.8mmol), heated to reflux to 80 ℃, reacted for 4 hours, completely reacted, stopped, and cooled. Methanol was removed by rotary evaporation under reduced pressure, 150ml of water was added, extraction was performed twice with methylene chloride, and after drying, concentration was performed to obtain 4.70g of a pale yellow solid with a yield of 80.8%.

Example 2 preparation of intermediate 2

Intermediate 1(4.0g,10.5mmol) was added to DMF40ml, heated to 60 ℃ and 150ml of aqueous sodium periodate (0.1 mol/L) was added rapidly in one portion and reacted at 60 ℃ for 15 minutes. After the reaction was completed, the reaction solution was poured into 400ml of ice water to precipitate a solid, which was then filtered and dried to obtain 2.4g of a pale yellow solid with a yield of 82%.

EXAMPLE 3 preparation of procaterol hydrochloride impurity

Mixing and stirring the intermediate 2(3.0g,10.6mmol) and 90ml of dichloromethane, and cooling to-5-0 ℃; slowly dropwise adding boron trichloride (30ml,30mmol), and reacting for 2 hours at-5-0 ℃ until the reaction is complete. The reaction was poured into ice water to precipitate a white solid, dichloromethane was removed by rotary evaporation, and the filtrate was filtered to give a white solid, procaterol impurity I (1.95g, 97.5%), HPLC purity 99.65%.

1H NMR(DMSO-d6,400MHz):δ6.71(d,J＝9.91Hz,1H,＝CH),9.00(d,J＝9.91Hz,1H,＝CH),7.11(d,J＝8.15Hz,1H,ArH),7.65(d,J＝8.15Hz,1H,ArH),10.03(s,1H,-CHO),10.88(s,1H,-OH),11.73(s,1H,-NH)。

In summary, the above embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.