CN111808021A - Preparation method of indacaterol and salt thereof - Google Patents
Preparation method of indacaterol and salt thereof Download PDFInfo
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Abstract
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.
Description
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:
the prior art discloses a synthesis process of indacaterol maleate, for example, patents WO2000/075114, WO2004/076422, CN201410682500 and WO2016/161956 disclose indacaterol maleate prepared by ring-opening substitution, debenzylation and salt-forming reactions using 8-phenylmethoxy-5- (R) oxiranyl-1H-quinolin-2-one and 2-amino-5, 6-diethylindan as raw materials, wherein the reaction route is as follows:
the ring-opening substitution reaction in the step 1 in the route has poor selectivity and low yield, and a large amount of isomeric substitution (formula III), disubstituted (formula IV) and deethyl (formula V) byproducts are generated in the reaction process, wherein the content of the isomeric substitution (formula III) and disubstituted (formula IV) byproducts accounts for 7.8 percent and 12.4 percent of the crude product.
The purification and isolation of intermediate formula I includes two methods: one method is that a column chromatography purification process is used in WO2000/075114, and the method has low yield and high cost and cannot realize industrialized production; the other method is a salifying crystallization process, the yield of the benzoate of the formula 1 reported in the patent WO2004/076422 in the original research process is 60%, the purity is 96%, and the yield of the salicylate of the formula 1 reported in the patent CN201410682500 after two crystallization purifications is 59%, and the purity is 99.6%.
In order to better meet the pharmaceutical requirements, the development of a preparation process of the bulk drug with low cost and high yield has higher commercial practical value and better meets the requirements of green chemistry. The preparation process of the invention can lead the yield of the ring-opening substitution reaction (formula II-1) to reach 75 percent, lead the purity to reach 99.8 percent and reduce the content of S isomer to be below 0.1 percent, has stable crystallization process, is suitable for industrial production, overcomes a plurality of defects in the prior art and ensures the high quality of the raw material medicine.
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 C1-6One 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 C1-6One 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 C1-6One 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.
Example 1
2-amino-5, 6-diethylindan (22.7g) and 600ml of n-butanol were added to a 2L reaction flask, stirred to dissolve, and 8-phenylmethoxy-5- (R) -oxiranyl-1H-quinolin-2-one (29.3g, S isomer content 0.5%) was added to the solution, heated to 110 deg.C, stirred for 4 hours, and the reaction was detected by TLC to be complete. Concentrating the reaction solution under reduced pressure to obtain brown oily crude product, adding 800ml of ethanol, stirring for dissolving, adding 200ml of an ethanol solution of m-chlorobenzoic acid (31.3g), stirring for dissolving at 80 ℃, cooling to 30 ℃, stirring for 6 hours, filtering, washing twice with a small amount of ethanol, and drying at 60 ℃ for 8 hours to obtain a white-like solid product (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl]-8-benzyloxy-2-one m-chlorobenzoate (47.9g) in 75.1% yield and 99.8% HPLC purity (area normalization), with less than 0.05% single impurities and 0.06% S isomer. HPLC methods for impurity analysis: mobile phase A (H of pH2.0)3PO4/KH2PO4Gradient elution with buffer solution, water and acetonitrile 2: 7: 1) and mobile phase B (buffer solution and acetonitrile 2: 8); a chromatographic column: c18 column (3.5 μm, 4.6 × 150 mm); detection wavelength: 210 nm; column temperature: 40 ℃; flow rate: 1.0 ml/min; HPLC analysis method for S isomer: mobile phase: phosphate buffer/water/methanol; a chromatographic column: OD-RH chiral columns (5 μm, 4.6 × 250 mm); detection wavelength: 250nm, column temperature: 40 ℃; flow rate: 0.8 ml/min.
1H NMR(400MHz，DMSO-d6)H(ppm)：10.72(s，1H)，8.27(d，J＝10.0Hz，1H)，7.86(d，J＝8.4Hz，2H)，7.58(d，J＝7.2Hz，2H)，7.54(d，J＝7.6Hz，1H)，7.44(t，J＝7.6Hz，1H)，7.39(t，J＝7.6Hz，2H)，7.33(q，J＝14.4Hz，1H)，7.23(t，J＝8.4Hz，2H)，6.98(s，2H)，6.54(d，J＝10.0Hz，1H)，5.34(t，J＝2.8Hz)，5.31(s，2H)，3.84(m，1H)，3.17～3.09(m，2H)，3.02(m，1H)，2.97～2.87(m，3H)，2.55(q，J＝14.8Hz，4H)，1.12(t，J＝7.6Hz，6H)。
TABLE 1 XRD characteristic peaks of crystalline solid of intermediate formula II-1
Example 2
2-amino-5, 6-diethylindan (27.2g) and 600ml of n-butanol were added to a 2L reaction flask, stirred to dissolve, and 8-phenylmethoxy-5- (R) -oxiranyl-1H-quinolin-2-one (29.3g, S isomer content 0.5%) was added to the solution, heated to 80 ℃ and stirred for 8 hours to complete the reaction as detected by TLC. The reaction solution was concentrated under reduced pressure to give a crude brown oil, which was dissolved by stirring with addition of 400ml of tetrahydrofuran, and 200ml of a tetrahydrofuran solution of m-chlorobenzoic acid (78.2g) was added, dissolved by stirring at 50 ℃, cooled to 30 ℃, stirred for 6 hours, filtered, washed twice with a small amount of tetrahydrofuran, and dried at 60 ℃ for 8 hours to give a white-like solid product (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl ] -8-benzyloxy-2-one m-chlorobenzoate (46.3g), yield 72.5%, HPLC purity 99.8% (area normalization), content of single impurities less than 0.05%, and S isomer content 0.07%.
Example 3
2-amino-5, 6-diethylindan (20.8g) and 600ml of n-butanol were added to a 2L reaction flask, stirred to dissolve, and 8-phenylmethoxy-5- (R) -oxiranyl-1H-quinolin-2-one (29.3g, S isomer content 0.5%) was added to the solution, heated to 120 ℃, stirred for 6 hours, and the reaction was detected by TLC to be complete. The reaction solution was concentrated under reduced pressure to give a crude brown oil, which was dissolved by adding 800ml of isopropanol, and then dissolved by stirring, and 200ml of an isopropanol solution of m-chlorobenzoic acid (15.7g) was added, dissolved by stirring at 80 ℃, cooled to 30 ℃, stirred for 6 hours, filtered, washed twice with a small amount of isopropanol, and dried at 60 ℃ for 8 hours to give a white-like solid product (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl ] -8-benzyloxy-2-one m-chlorobenzoate (48.2g), yield 75.5%, HPLC purity 99.7% (area normalization method), single impurity content less than 0.05%, and S isomer content 0.08%.
Example 4
To the hydrogenation kettle were added (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl ] -8-benzyloxy-2-one m-chlorobenzoate (20g) and methanol 200ml, followed by 10% palladium on carbon (2.0g, 50 wt% water) and the reaction was hydrogenated for 2 hours to complete the conversion. Filtering the reaction liquid, concentrating the filtrate under reduced pressure to obtain a light yellow crude product, adding 200ml of ethanol, heating to 60 ℃, adding 25ml of ethanol solution of maleic acid (5.5g), stirring to dissolve, cooling to 10 ℃, stirring for 8 hours, filtering, washing with ethanol to obtain a white solid indacaterol maleate crude product, and refining by ethanol recrystallization to obtain (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxyethyl ] -8-hydroxy-1H-quinolin-2-one maleate, wherein the total amount of white crystalline solids is 10.2g, the yield is 64.1%, the HPLC purity is 99.8% (area normalization method), the content of monoimpurities is less than 0.05%, and the content of S isomers is 0.03%. HPLC analysis method for impurities and S isomer HPLC analysis method as in example 1.
Example 5
2-amino-5, 6-diethylindan (113.5g) and 3000ml of n-butanol were added to a 10L reaction flask, stirred to dissolve, and 8-phenylmethoxy-5- (R) -oxiranyl-1H-quinolin-2-one (146.5g, S isomer content 0.5%) was added to the solution, heated to 110 deg.C, stirred for 4 hours, and the reaction was detected by TLC to be complete. The reaction solution was concentrated under reduced pressure to give a crude brown oil, which was dissolved by adding 4000ml of ethanol, and then dissolved by stirring, 1000ml of an ethanol solution of m-chlorobenzoic acid (156.5g) was added, dissolved by stirring at 80 ℃, cooled to 30 ℃, stirred for 6 hours, filtered, washed twice with a small amount of ethanol, and dried at 60 ℃ for 8 hours to give (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl ] -8-benzyloxy-2-one m-chlorobenzoic acid salt (240.2g) as a white-like solid with a yield of 75.3%, an HPLC purity of 99.8% (area normalization method), a single impurity content of less than 0.05%, and an S isomer content of 0.05%.
Example 6
To the hydrogenation kettle were added (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl ] -8-benzyloxy-2-one m-chlorobenzoate (200g) and 2000ml methanol, followed by 10% palladium on carbon (20.0g, 50 wt% water) and the reaction was hydrogenated for 4 hours to complete the conversion. Filtering the reaction liquid, concentrating the filtrate under reduced pressure to obtain a light yellow crude product, adding 2000ml of ethanol, heating to 60 ℃, adding 250ml of ethanol solution of maleic acid (55g), stirring to dissolve, cooling to 10 ℃, stirring for 8 hours, filtering, washing with ethanol to obtain a white solid indacaterol maleate crude product, and refining by ethanol recrystallization to obtain (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxyethyl ] -8-hydroxy-1H-quinolin-2-one maleate, wherein the total amount of white crystalline solids is 101.2g, the yield is 64.0%, the HPLC purity is 99.9% (area normalization method), the content of monoimpurity is less than 0.03%, and the content of S isomer is 0.02%.
Comparative example 1
2-amino-5, 6-diethylindan (22.7g) and 600ml of n-butanol were added to a 2L reaction flask, stirred to dissolve, and 8-phenylmethoxy-5- (R) -oxiranyl-1H-quinolin-2-one (29.3g, S isomer content 0.5%) was added to the solution, heated to 110 deg.C, stirred for 4 hours, and the reaction was detected by TLC to be complete. The reaction solution was concentrated under reduced pressure to give a crude brown oil, which was dissolved with stirring in 800ml of ethanol, and then 200ml of an ethanol solution of benzoic acid (24.4g) was added, dissolved with stirring at 80 ℃, cooled to 30 ℃, stirred for 6 hours, filtered, washed twice with a small amount of ethanol, and dried at 60 ℃ for 8 hours to give (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl ] -8-benzyloxy-2-one benzoate (32.2g) as a white-like solid in 53.3% yield, with HPLC purity of 98.2% (area normalization), single impurity content of less than 0.3%, and S isomer content of 0.25%.
Comparative example 2
2-amino-5, 6-diethylindan (22.7g) and 600ml of n-butanol were added to a 2L reaction flask, stirred to dissolve, and 8-phenylmethoxy-5- (R) -oxiranyl-1H-quinolin-2-one (29.3g, S isomer content 0.5%) was added to the solution, heated to 110 deg.C, stirred for 4 hours, and the reaction was detected by TLC to be complete. The reaction solution was concentrated under reduced pressure to give a crude brown oil, which was dissolved with stirring in 800ml of ethanol, and then 200ml of an ethanol solution of p-methoxybenzoic acid (30.4g) was added, dissolved with stirring at 80 ℃, cooled to 30 ℃, stirred for 6 hours, filtered, washed twice with a small amount of ethanol, and dried at 60 ℃ for 8 hours to give (R) -5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl ] -8-benzyloxy-2-one p-methoxybenzoate (35.5g) as a white-like solid in 56.0% yield, with HPLC purity of 98.5% (area normalization), single impurity content of less than 0.3%, and S isomer content of 0.22%.
Claims (13)
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 C1-6One 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 C1-6One 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.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20150225346A1 (en) * | 2012-09-21 | 2015-08-13 | Crystal Pharma S.A.U. | Methods for the preparation of indacaterol and pharmaceutically acceptable salts thereof |
| CN105693603A (en) * | 2014-11-24 | 2016-06-22 | 上海医药工业研究院 | Improved indacaterol maleate preparation technology |
| WO2016161956A1 (en) * | 2015-04-09 | 2016-10-13 | 正大天晴药业集团股份有限公司 | Preparation method of indacaterol or salt thereof |
| CN107021921A (en) * | 2016-02-02 | 2017-08-08 | 常州爱诺新睿医药技术有限公司 | A kind of salt of QAB-149 intermediate and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150225346A1 (en) * | 2012-09-21 | 2015-08-13 | Crystal Pharma S.A.U. | Methods for the preparation of indacaterol and pharmaceutically acceptable salts thereof |
| CN105693603A (en) * | 2014-11-24 | 2016-06-22 | 上海医药工业研究院 | Improved indacaterol maleate preparation technology |
| WO2016161956A1 (en) * | 2015-04-09 | 2016-10-13 | 正大天晴药业集团股份有限公司 | Preparation method of indacaterol or salt thereof |
| CN107021921A (en) * | 2016-02-02 | 2017-08-08 | 常州爱诺新睿医药技术有限公司 | A kind of salt of QAB-149 intermediate and preparation method thereof |
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