阅读说明：本技术 一种茚达特罗乙酸盐的制备方法 (Preparation method of indacaterol acetate ) 是由 俞雄 戴德明 张袁伟 于 2019-09-12 设计创作，主要内容包括：本发明提供了一种茚达特罗乙酸盐的制备方法,其制备工艺简洁,三废排放量小,制备成本低、收率及产品纯度均较高,有利于大规模商业化生产,具有较高的经济价值,所得到的目标产物的晶型与文献报道一致,该晶型以其X射线衍射图特征吸收峰表征。(The invention provides a preparation method of indacaterol acetate, which has the advantages of simple preparation process, small three-waste discharge amount, low preparation cost, high yield and high product purity, is beneficial to large-scale commercial production, and has high economic value, the crystal form of the obtained target product is consistent with the report of a document, and the crystal form is characterized by an X-ray diffraction pattern characteristic absorption peak.)

1. A preparation method of indacaterol acetate comprises the steps of dissolving acetic acid in a halogenated hydrocarbon solution of indacaterol alkali shown in formula I, adding a proper amount of mixed solvent of alcohol and ester, and crystallizing to obtain the indacaterol acetate shown in formula II;

2. the method of claim 1, wherein,

the halogenated hydrocarbon solution is selected from one or more of dichloromethane, trichloromethane and 1, 2-dichloroethane, preferably dichloromethane;

the mixed solvent of the alcohol and the ester is a mixture of an alcohol solvent and an ester solvent, preferably the alcohol solvent is selected from one or more of ethanol, isopropanol and tert-butanol, and is more preferably isopropanol;

the ester solvent is selected from one or more of butyl acetate, ethyl formate, isobutyl acetate, methyl acetate and propyl acetate, more preferably ethyl acetate.

3. The process according to claim 1 or 2, wherein the volume ratio of the halogenated hydrocarbon solution to the alcohol solvent is 1:1 to 1:5, preferably 1:2 to 1: 3.5.

4. A process according to any one of claims 1 to 3, wherein the volume ratio of ester solvent to alcohol solvent is from 0 to 1.5:1, preferably 1: 1.

5. The process according to any one of claims 1 to 4, wherein the concentration of indacaterol base in the halocarbon solution is from 0.1 to 0.5g/mL, preferably from 0.3 to 0.4g/mL, based on the indacaterol base.

6. The process according to any one of claims 1 to 5, wherein the molar ratio of indacaterol base to acetic acid is from 1:2 to 1:5, preferably from 1:2.5 to 1: 3.5.

7. The method according to any one of claims 1 to 6, wherein after dissolving acetic acid in the halogenated hydrocarbon solution of indacaterol base represented by formula I, before adding a proper amount of the mixed solvent of alcohol and ester, the method further comprises the step of heating the reaction system to a reaction temperature of 10 to 45 ℃, preferably 30 to 40 ℃;

preferably, after adding a proper amount of mixed solvent of alcohol and ester, the method also comprises a heat preservation step; more preferably, the heat preservation time is 0.5-4 hours, and further preferably 1-2 hours;

preferably, the crystallization is carried out for 5-10 hours at 5-10 ℃;

preferably, all operations of the process are carried out under stirring.

8. The process according to any one of claims 1 to 7, wherein the indacaterol base of formula I is prepared by: carrying out a neutralization reaction on the indacaterol salt in an alcohol solution of alkali metal hydroxide to obtain the indacaterol alkali shown in the formula I;

preferably, the indacaterol base represented by formula I can be prepared by the following method: adding indacaterol maleate into an alcohol solution of alkali metal hydroxide by stirring, adding a proper amount of water to quench the reaction after the reaction is finished by stirring at a certain temperature, filtering and drying the product.

9. The process according to claim 8, wherein the indacaterol salt is selected from indacaterol maleate, indacaterol tartrate, indacaterol benzoate or indacaterol mesylate, preferably indacaterol maleate;

preferably, the alkali metal hydroxide is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, more preferably sodium hydroxide;

preferably, the alcohol solution is selected from one or more of methanol, ethanol, propanol and isopropanol, which are completely miscible with water, preferably methanol.

10. The process according to claim 8 or 9, wherein the molar ratio of indacaterol salt to alkali metal hydroxide is from 1:1 to 1: 5; preferably, the reaction concentration is 0.2-2.0 mmol/mL calculated by the indacaterol salt; preferably, the reaction temperature is 10-45 ℃ and the reaction time is 0.5-4 hours.

Technical Field

The invention belongs to the field of medicines, and particularly relates to a preparation method of indacaterol acetate.

Background

Indacaterol acetate, systematic name: (R) -5- [2- (5, 6-Diethylindan-2-ylamino) -1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one acetate having the formula: c₂₆H₃₂N₂O₅Molecular weight: 452.55, CAS number: 1000160-96-2, the structural formula is shown as follows:

indacaterol acetate is a long-acting beta 2 receptor agonist, suitable for patients with Chronic Obstructive Pulmonary Disease (COPD), currently in the third clinical stage. In 2019, the phase III QUARTZ study of norhua announced its inhaled combination therapy drug QMF149 (the major ingredients indacaterol acetate and mometasone furoate) had reached a major and key secondary endpoint in patients with poor asthma control. Once daily fixed doses showed significant improvement in lung function and asthma control compared to Inhaled Corticosteroids (ICS).

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a novel preparation method of indacaterol acetate, which avoids the defect that a mixed substance of indacaterol acetate and indacaterol alkali is easy to generate in large-scale preparation due to poor solubility of indacaterol alkali and indacaterol acetate in a single solvent such as isopropanol and the like. In addition, the method has mild reaction conditions, no high-temperature step is needed, the using amount of the solvent is small, the obtained product is easy to filter, and the method is more suitable for large-scale commercial production.

In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:

in one aspect, the invention provides a preparation method of indacaterol acetate, wherein the method comprises the steps of dissolving acetic acid in a halogenated hydrocarbon solution of indacaterol alkali shown in formula I, adding a proper amount of mixed solvent of alcohol and ester, and crystallizing to obtain the indacaterol acetate shown in formula II;

the halogenated hydrocarbon solution is selected from one or more of dichloromethane, trichloromethane and 1, 2-dichloroethane, preferably dichloromethane;

the mixed solvent of alcohol and ester is a mixture of an alcohol solvent and an ester solvent, preferably the alcohol solvent is selected from one or more of ethanol, isopropanol and tert-butanol, and more preferably isopropanol;

preferably the ester solvent is selected from one or more of butyl acetate, ethyl formate, isobutyl acetate, methyl acetate and propyl acetate, more preferably ethyl acetate;

in the method provided by the invention, the volume ratio of the halogenated hydrocarbon solution to the alcohol solvent is 1: 1-1: 5, preferably 1: 2-1: 3.5, and most preferably 1:2.

In the method provided by the invention, the volume ratio of the ester solvent to the alcohol solvent is 0-1.5: 1, preferably 1: 1.

In the method provided by the invention, the concentration of the indacaterol alkali in the halogenated hydrocarbon solution is 0.1-0.5 g/mL, preferably 0.3-0.4 g/mL, and more preferably 0.3g/mL, calculated as the indacaterol alkali.

In the method provided by the invention, the molar ratio of the indacaterol base to the acetic acid is 1: 2-1: 5, preferably 1: 2.5-1: 3.5, and more preferably 1: 3.5.

In the method provided by the invention, after the acetic acid is dissolved in the halogenated hydrocarbon solution of the indacaterol base shown in the formula I, before a proper amount of mixed solvent of alcohol and ester is added, the method further comprises the step of heating the reaction system to the reaction temperature; preferably, the reaction temperature is 10-45 ℃, more preferably 30-40 ℃, and further preferably 35 ℃;

in the method provided by the invention, after a proper amount of mixed solvent of alcohol and ester is added, the method also comprises a heat preservation step; preferably, the heat preservation time is 0.5-4 hours, more preferably 1-2 hours, and further preferably 1 hour;

in the method provided by the invention, the crystallization is carried out for 5-10 hours at 5-10 ℃; preferably, the crystallization is carried out at 5-10 ℃ for 10 hours.

In the process provided by the invention, all operations are carried out with stirring.

In a specific embodiment of the present invention, the present invention provides a process for the preparation of indacaterol acetate, wherein the process comprises: dissolving acetic acid in a dichloromethane solution of indacaterol alkali shown in formula I, dropwise adding acetic acid, stirring for dissolving, heating to a reaction temperature of 35 ℃, adding a mixed solvent of isopropanol and ethyl acetate, keeping the temperature, stirring for 1 hour, cooling to 5-10 ℃, stirring for 10 hours, and crystallizing to obtain the indacaterol acetate shown in formula II;

the volume ratio of the dichloromethane to the isopropanol is 1:2, the volume ratio of the ethyl acetate to the isopropanol is 1:1, the concentration of the indacaterol base in the halogenated hydrocarbon solution is 0.3g/mL, and the molar ratio of the indacaterol base to the acetic acid is 1: 3.5.

In another aspect, the present invention also provides a method for preparing indacaterol base represented by formula I, which comprises:

carrying out a neutralization reaction on the indacaterol salt in an alcohol solution of alkali metal hydroxide to obtain the indacaterol alkali shown in the formula I;

preferably, the present invention also provides a preparation method of the indacaterol base shown in formula I, which comprises: adding indacaterol maleate into an alcohol solution of alkali metal hydroxide by stirring, stirring at a certain temperature to react, adding a proper amount of water to quench the reaction, filtering and drying the product.

Preferably, the indacaterol salt is indacaterol maleate, indacaterol tartrate, indacaterol benzoate or indacaterol mesylate, more preferably indacaterol maleate.

Preferably, the alkali metal hydroxide is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, more preferably sodium hydroxide.

Preferably, the alcohol solution is selected from one or more of methanol, ethanol, propanol and isopropanol, which are completely miscible with water, preferably methanol.

Preferably, the molar ratio of the indacaterol salt to the alkali metal hydroxide is 1: 1-1: 5; preferably, the reaction concentration is 0.2-2.0 mmol/mL calculated by the indacaterol salt; preferably, the reaction temperature is 10-45 ℃ and the reaction time is 0.5-4 hours.

The inventor tries to search for a solvent system capable of completely dissolving indacaterol base, and finds that common solvents such as methanol, ethanol, isopropanol, butanol, tert-butanol, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether, dichloromethane and the like have extremely poor solubility on indacaterol base, and dimethyl sulfoxide and N, N-dimethylformamide have better solubility on indacaterol base. For comparison, the indacaterol base is respectively dissolved in two solvent systems of dimethyl sulfoxide and N, N-dimethylformamide, an isopropanol solution of acetic acid is added, and the mixture is stirred for crystallization, but the yield of the target product is generally low. In addition, the indacaterol acetate is prepared by selecting high-boiling-point solvents such as dimethyl sulfoxide, N-dimethylformamide and the like, and the solvent residue is obviously higher and difficult to remove, so that the method is not beneficial to the production of subsequent pharmaceutical preparations.

The invention provides a novel preparation method of indacaterol acetate, which has the advantages of simple preparation process, high yield and high product purity, is beneficial to industrial production, and the obtained specific crystal form is consistent with the literature report and has high economic value. In addition, the invention also provides a method for preparing the solid indacaterol alkali, so that the solid indacaterol alkali with better properties can be obtained and can be used for preparing other salts of indacaterol.

Drawings

The invention will be further described with reference to the accompanying drawings.

FIG. 1 is a nuclear magnetic spectrum of indacaterol acetate prepared in example 7;

FIG. 2 is an X-ray diffraction pattern of indacaterol acetate prepared in example 7.

Detailed Description

The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teachings herein, and such equivalents may fall within the scope of the invention as defined in the appended claims.

The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagents used in the following examples are all commercially available products unless otherwise specified.

In the following examples and comparative examples, the detection conditions for X-ray diffraction were:

the instrument model is as follows: bruker D8 Advance

And (3) testing conditions are as follows: x-ray source: Cu-K

Working current: 40mA

Working voltage: 40KV

A detector: PSD

Initial angle: 4 ° (2 θ)

End angle: 40 ° (2 θ)

Increment: 0.05 degree/step

Scanning speed: 1 second/step