阅读说明：本技术 茚达特罗及其盐的制备方法 (Preparation method of indacaterol and salt thereof ) 是由 黄才古 孙辉 聂秋朋 于 2019-04-10 设计创作，主要内容包括：本发明涉及茚达特罗及其盐的制备方法,其包括如下步骤：在溶剂中,将含有式I化合物的混合物与间氯苯甲酸反应制得式II-1化合物；将所得式II-1化合物反应转化茚达特罗及其盐。本发明的茚达特罗及其盐制备方法具有收率更高、纯度高、易精制且操作简便,适合于工业化。(The invention relates to a preparation method of indacaterol and salts thereof, which comprises the following steps: reacting a mixture containing a compound shown in a formula I with m-chlorobenzoic acid in a solvent to obtain a compound shown in a formula II-1; the resulting compound of formula II-1 is reacted to convert indacaterol and salts thereof. The preparation method of indacaterol and the salt thereof has the advantages of higher yield, high purity, easy refining and simple and convenient operation, and is suitable for industrialization.)

1. A process for the preparation of indacaterol and salts thereof comprising the steps of:

(a) reacting a mixture containing a compound of formula I with m-chlorobenzoic acid in a solvent to obtain a compound of formula II, wherein the mixture contains a compound of formula III, formula IV and/or formula V;

r in the compounds of formula I-V is a hydroxyl protecting group;

HX in the compound of the formula II is m-chlorobenzoic acid;

(b) and (3) reacting the compound of the formula II obtained in the previous step to convert the indacaterol and salts thereof.

2. The process according to claim 1, wherein the solvent in the step (a) is capable of dissolving the mixture and the m-chlorobenzoic acid; the solvent comprises C_1-6One or more of alkyl alcohol, tetrahydrofuran, dichloromethane, ethyl acetate and N, N-dimethylformamide.

3. The process according to claim 1, wherein the solvent is ethanol and/or isopropanol.

4. The method of claim 1, wherein the acid is used in an amount of 1 to 10 times the molar equivalent (relative to the compound of formula I).

5. The method of claim 1, wherein the reaction temperature in step (a) is 0 ℃ to 100 ℃.

6. The process according to claim 1, wherein the protecting group R comprises an aryl group, an alkyl group, an aralkyl group or a substituted silyl group.

7. The method according to claim 1 to 5, wherein the mixture is prepared by: carrying out substitution reaction on the compounds of the formula VI and the formula VII in a solvent to obtain a mixture;

the protecting group R in formula VI is structurally identical to R in claims 1 and 5.

8. The process of claim 1, wherein step (a) comprises isolation and/or crystallization of intermediate formula II, and the crystallization solvent comprises C_1-6One or more of alkyl alcohol, tetrahydrofuran, dichloromethane, ethyl acetate and N, N-dimethylformamide.

9. The method of claim 1, comprising the steps of:

(i) carrying out substitution reaction on the compounds of the formula VI and the formula VII in a solvent to obtain a mixture containing the compound of the formula I;

(ii) (ii) treating the mixture of step (i) with m-chlorobenzoic acid;

(iii) crystallizing and isolating the compound of formula II;

(iv) removing the protecting group R of the compound of the formula II to obtain a compound of a formula VIII;

(v) treatment of the compound of formula VIII with an acid gives the salt of the compound of formula IX, indacaterol, wherein the more preferred acid is an organic acid, such as maleic acid.

Wherein the protecting group R of formula I, II or VI comprises an aryl, alkyl, aralkyl or substituted silyl group, more preferably R is benzyl; HX in the compound of the formula II is m-chlorobenzoic acid; HY in the compound of the formula IX is an acid for forming the salt of indacaterol, and a preferred acid is maleic acid;

the material ratio of the compound of the formula VII to the compound of the formula VI in the step (i) is 1.1: 1.0-1.5: 1.0 (mol), and the reaction temperature is 80-120 ℃;

the amount of the acid used in the step (ii) is 1-10 times of the molar equivalent (relative to the compound of formula I), and the reaction temperature is 0-100 ℃, preferably 50-90 ℃.

10. The method of claim 1, wherein step (b) comprises the steps of: removing the protecting group R of the compound shown in the formula II to prepare a compound VIII; neutralizing the free base with a base, converting the compound VIII into indacaterol free base and then into a salt thereof or treating the compound VIII with an acid to directly convert into an indacaterol salt.

11. The method of claim 1, wherein step (b) comprises the steps of: neutralizing and dissociating with alkali, and converting refined salt compound II into free alkali compound I; removing the protecting group R of the compound shown in the formula I to obtain indacaterol free alkali, and directly converting the indacaterol free alkali into indacaterol salt by acid treatment.

12. The method of claim 1, wherein the intermediate of formula II comprises a structure of formula II-1:

13. the crystalline solid of compound II-1 in the intermediate as claimed in claim 11, characterized by an absorption peak at diffraction angle 2 θ at 6.82, 10.44, 11.87, 12.42, 12.82, 15.38, 16.17, 16.78, 18.32, 19.19, 20.92, 21.56, 22.58, 22.87, 23.87, 24.58, 24.92, 25.60, 29.51, 31.13, 39.23 ° in an X-ray powder diffraction pattern using a radiation source Cu — K α; or an X-ray powder diffraction pattern thereof, wherein the diffraction angle 2 theta has absorption peaks at 6.82 degrees, 10.44 degrees, 11.87 degrees, 12.42 degrees, 12.82 degrees, 13.68 degrees, 15.38 degrees, 16.17 degrees, 16.78 degrees, 18.32 degrees, 19.19 degrees, 20.92 degrees, 21.56 degrees, 22.58 degrees, 22.87 degrees, 23.87 degrees, 24.58 degrees, 24.92 degrees, 25.60 degrees, 27.46 degrees, 28.57 degrees, 29.51 degrees, 31.13 degrees, 32.34 degrees, 32.68 degrees, 34.74 degrees, 34.96 degrees, 35.71 degrees, 38.96 degrees and 39.23 degrees, and the error range of the 2 theta is +/-0.2 degrees.

Technical Field

The invention particularly relates to a preparation method of indacaterol and salts thereof.

Background

Long acting beta₂The adrenergic agonist drug Indacaterol Maleate (Indacaterol Maleate), chemical name of which is (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one maleate having the formula: c₂₄H₂₈N₂O₃·C₄H₄O₄Molecular weight: 508.56, developed by nova, for the maintenance treatment of adult Chronic Obstructive Pulmonary Disease (COPD) patients, having the following structural formula:

Disclosure of Invention

The invention provides a novel preparation method of indacaterol, a salt thereof or an intermediate (formula II) thereof, aiming at overcoming the defects of high cost, low yield and low purity of the preparation method of indacaterol, a salt thereof or an intermediate (formula II) thereof in the prior art. The preparation process of the indacaterol and the salt or intermediate (formula II) thereof has the advantages of simple operation, low cost, high yield and high quality, is suitable for industrial production, and ensures the cost and quality of the raw material medicaments.

The invention provides a preparation method of indacaterol and salts thereof, which comprises the following steps:

(a) reacting a mixture containing a compound of formula I with m-chlorobenzoic acid in a solvent to obtain a compound of formula II, wherein the mixture contains a compound of formula III, formula IV and/or formula V;

r in the compounds of formula I-V is a hydroxyl protecting group;

HX in the compound of the formula II is m-chlorobenzoic acid;

(b) and (3) reacting the compound of the formula II obtained in the previous step to convert the indacaterol and salts thereof.

In the preparation method of indacaterol and salts thereof according to the present invention, the solvent described in step (a) is capable of dissolving the mixture and the m-chlorobenzoic acid; more preferred solvents include C_1-6One or more of alkyl alcohol, tetrahydrofuran, dichloromethane, ethyl acetate and N, N-dimethylformamide; more preferred solvents are ethanol and or isopropanol.

In the preparation method of indacaterol and salts thereof, the amount of the acid in the step (a) is 1-10 times of molar equivalent (relative to the compound of formula I), and preferably 2 times of molar equivalent; the reaction temperature is 0-100 ℃, and preferably 50-90 ℃; the protecting group R includes aryl, alkyl, aralkyl or substituted silyl, and more preferably R is benzyl.

In the preparation method of the invention, the preparation method of the mixture comprises the following steps: carrying out substitution reaction on the compounds of the formula VI and the formula VII in a solvent to obtain a mixture;

the protecting group R in formula VI is structurally identical to R in claims 1 and 5.

In the preparation method, the step (a) comprises the separation and/or crystallization of an intermediate shown as a formula II, and a crystallization solvent comprises C_1-6One or more of alkyl alcohol, tetrahydrofuran, dichloromethane, ethyl acetate and N, N-dimethylformamide. .

The preparation method of the indacaterol and the salt thereof comprises the following steps:

(i) carrying out substitution reaction on the compounds of the formula VI and the formula VII in a solvent to obtain a mixture containing the compound of the formula I;

(ii) (ii) treating the mixture of step (i) with m-chlorobenzoic acid;

(iii) crystallizing and isolating the compound of formula II;

(iv) removing the protecting group R of the compound of the formula II to obtain a compound of a formula VIII;

(v) treatment of the compound of formula VIII with an acid gives the salt of the compound of formula IX, indacaterol, wherein the more preferred acid is an organic acid, such as maleic acid.

Wherein the protecting group R of formula I, II or VI comprises an aryl, alkyl, aralkyl or substituted silyl group, more preferably R is benzyl; HX in the compound of the formula II is m-chlorobenzoic acid; HY in the compound of formula IX is indacaterol salifying acid, and the preferred acid is maleic acid.

The material ratio of the compound of the formula VII and the compound of the formula VI in the step (i) is 1.1: 1.0-1.5: 1.0 (mol), and the reaction temperature is 80-120 ℃.

The amount of the acid used in the step (ii) is 1-10 times of the molar equivalent (relative to the compound of formula I), and the reaction temperature is 0-100 ℃, preferably 50-90 ℃.

The method for removing the protecting group in the step (iv) is preferably catalytic hydrogenation, preferably the catalyst comprises palladium, palladium hydroxide, palladium carbon, platinum or Raney nickel, and more preferably palladium carbon as the catalyst; the reaction temperature is preferably 0 ℃ to 80 ℃, more preferably 30 ℃ to 60 ℃; preferred reaction solvents include C_1-6One or more of alkyl alcohols; more preferred solvents are methanol and or ethanol.

In the preparation method of indacaterol and salts thereof, step (b) comprises the following steps: removing the protecting group R of the compound shown in the formula II to prepare a compound VIII; neutralizing the free base with a base to convert compound VIII into indacaterol free base and then into a salt thereof, or treating compound VIII with an acid to directly convert into indacaterol salt.

In the preparation method of indacaterol and salts thereof, step (b) comprises the following steps: neutralizing and dissociating with alkali, and converting refined salt compound II into free alkali compound I; removing the protecting group R of the compound shown in the formula I to obtain indacaterol free alkali, and directly converting the indacaterol free alkali into indacaterol salt by acid treatment.

The intermediate formula II of the indacaterol and the salt thereof comprises a structure shown in a formula II-1:

the invention provides a crystalline solid of an intermediate compound formula II-1, which is characterized in that in an X-ray powder diffraction pattern using a radiation source Cu-Kalpha, the diffraction angle 2 theta has absorption peaks at 6.82, 10.44, 11.87, 12.42, 12.82, 15.38, 16.17, 16.78, 18.32, 19.19, 20.92, 21.56, 22.58, 22.87, 23.87, 24.58, 24.92, 25.60, 29.51, 31.13 and 39.23 degrees; preferably, the diffraction angle 2 theta in the X-ray powder diffraction pattern has absorption peaks at 6.82 degrees, 10.44 degrees, 11.87 degrees, 12.42 degrees, 12.82 degrees, 13.68 degrees, 15.38 degrees, 16.17 degrees, 16.78 degrees, 18.32 degrees, 19.19 degrees, 20.92 degrees, 21.56 degrees, 22.58 degrees, 22.87 degrees, 23.87 degrees, 24.58 degrees, 24.92 degrees, 25.60 degrees, 27.46 degrees, 28.57 degrees, 29.51 degrees, 31.13 degrees, 32.34 degrees, 32.68 degrees, 34.74 degrees, 34.96 degrees, 35.71 degrees, 38.96 degrees and 39.23 degrees, and the error range of the 2 theta is +/-0.2 degrees; more preferably, the XPRD spectrum of the crystalline solid of II-1 is shown in FIG. 1.

The room temperature in the invention means that the ambient temperature is 10-30 ℃.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the preparation method of indacaterol and the salt thereof has the advantages of simple operation, high yield, low cost, high quality and suitability for industrial production, and ensures the cost and quality of the raw material medicaments.

Drawings

FIG. 1 is a powder diffraction pattern of (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl ] -8-benzyloxy-2 one m-chlorobenzoate.

Detailed Description

The technical solutions of the present invention will be described below with reference to the embodiments and the accompanying drawings to better understand the technical features, objects and advantages of the present invention, but the present invention is not limited to the scope of the embodiments. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.