Indacaterol hydrate and methods of preparation and use thereof

Abstract

The present application relates to a new solid form of indacaterol, which has not only good impurity removal effect and stability, but also simple preparation method, is easy to operate and store, and is suitable for industrial application. The present application also relates to a preparation method of the new solid form of indacaterol, and a use for preparing a high-purity indacaterol pharmaceutical salt.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemistry and the field of pharmacy, in particular to a kind of indacaterol hydrate and preparation method thereof, and the use of the hydrate for preparing high-purity indacaterol maleate or other pharmaceutically acceptable salt. BACKGROUND

[0002] Indacaterol maleate, CAS No. 753498-25-8, chemical name: (R)-5-[2-(5,6-diethylindene-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-ketone maleate, the chemical structural formula is shown as formula I:

[0003]

[0004] Indacaterol maleate is a new type of long-acting β2 receptor agonist developed by Novartis for the treatment of chronic obstructive pulmonary disease (COPD). COPD is a disease characterized by airflow limitation, which has become the fourth leading cause of death in patients, and the incidence and mortality are still on the rise. Actively controlling patient symptoms and improving lung function has always been an important goal of COPD treatment. As a new type of long-acting β2 receptor agonist, indacaterol has rapid onset and long-lasting effect, and can well control patient symptoms by taking it only once a day, with few systemic adverse reactions and mild degree, which can quickly, durably and stably control the asthma symptoms of COPD patients and improve their lung function, making it an ideal new choice for COPD treatment. Indacaterol maleate single inhalation powder and compound inhalation powder with glycopyrronium bromide have been marketed in the United States, the European Union, China and other countries.

[0005] Document CN1156451C (application date: June 2, 2000) first discloses the synthesis route of indacaterol maleate, as follows:

[0006]

[0007] This route is a classic synthesis route for preparing indacaterol maleate, but the main technical problem is that when 5,6-diethyl-2,3-dihydro-1H-inden-2-amine (formula II) and (R)-8-benzyloxy-5-(2-oxiranyl)quinolin-2(1H)-one (formula III) are reacted to prepare formula IV compound, two main impurities, regioisomer impurity (formula IV-a) and disubstituted impurity (formula IV-b), are produced, which makes it difficult to purify intermediate IV, and increases the risk of exceeding the standard of these impurities in the final product indacaterol maleate, or reduces the yield of indacaterol maleate meeting the pharmaceutical requirements.

[0008] The literature CN100363349C (application date: 2004.2.27), CN1774423A (application date: 2004.4.1), CN1968927B (application date: 2005.6.21) and WO 2016 / 161956 (application date: 2016.4.8) reported that the above-mentioned regioisomeric impurities (formula IV-a) and disubstituted impurities (formula IV-b) can be effectively removed by the method of salifying intermediate IV with acid and then recrystallizing. But these methods all directly remove the protecting group of (R)-8-(benzyloxy)-5-[2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]quinolin-2(1H)-one corresponding salt (formula IV corresponding salt) to obtain the salt of formula V compound, and then directly salify the salt of formula V compound with maleic acid to obtain the product indacaterol maleate. The product indacaterol maleate prepared by these methods inevitably contains other salts. In order to remove other salts, even if other impurities (such as the impurities shown in formula IV-a and formula IV-b above) have been qualified, the product still needs to be further purified by additional purification steps such as recrystallization, which reduces the preparation yield of the product. These methods do not free purify the salt of the obtained formula V compound, and the literature CN100363349C explains that the reason is that the formula V compound (indacaterol free base) is unstable in solution.

[0009] According to the reaction mechanism, the main reasons for forming the two main impurities, the regioisomer impurity (Formula IV-a) and the double-substituted impurity (Formula IV-b), in the reaction of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine (Formula II) with (R)-8-benzyloxy-5-(2-oxiranyl)quinolin-2(1H)-one (Formula III) to prepare the compound of Formula IV are as follows: on the one hand, the epoxide structure in the structure of (R)-8-benzyloxy-5-(2-oxiranyl)quinolin-2(1H)-one (Formula III) has two reactive sites, thus being prone to form the regioisomer impurity (Formula IV-a); on the other hand, the amino group in the structure of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine (Formula II) has two N-H bonds, thus being prone to form the double-substituted impurity (Formula IV-b). In order to completely prevent the formation of the two impurities, various new routes for synthesis are reported in the literature, which can be roughly divided into three types. The first type, as reported in the literature CN104379566B (filing date: July 11, 2012), WO 2014 / 008639 (filing date: July 11, 2012), WO 2013 / 132514 (filing date: January 24, 2013) and WO 2014 / 139485 (filing date: March 3, 2014), cancels the epoxide structure in the structure of (R)-8-benzyloxy-5-(2-oxiranyl)quinolin-2(1H)-one (Formula III) and replaces it with a quinolone analogue with a carbonyl group at the 5-position as a starting material for reaction, which can effectively prevent the formation of the regioisomer impurity (Formula IV-a); the second type, as reported in the literature WO 2014 / 044288 (September 21, 2012), WO 2014 / 044566 (September 9, 2013), WO 2014 / 154841 (March 27, 2014), CN104744360B (December 26, 2013) and WO 2015 / 104718 (December 27, 2014), cancels the epoxide structure in the structure of (R)-8-benzyloxy-5-(2-oxiranyl)quinolin-2(1H)-one (Formula III) and replaces it with a quinolone analogue with a hydroxyl group protected by an alcohol hydroxyl protecting group at the 5-position as a starting material for reaction, which can effectively prevent the formation of the regioisomer impurity (Formula IV-a); and the third type, as reported in the literature CN104379566B (filing date: July 11, 2012), WO 2014 / 008639 (filing date: July 11, 2012), CN104744360B (filing date: December 26, 2013) and WO 2015 / 104718 (filing date: December 27, 2014), protects one of the N-H bonds in the amino group in the structure of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine (Formula II) to obtain an indamine analogue as a starting material for reaction, which can effectively prevent the formation of the double-substituted impurity (Formula IV-b).This new route by modifying the structure of the starting material of the reaction can be summarized as follows:

[0010]

[0011] Although these routes can well prevent the generation of two major impurities, regioisomer impurity (Formula IV-a) and disubstituted impurity (Formula IV-b) (even for the removal of isomer impurities, there are relatively good results), and satisfactory yield is also obtained, these routes involve either chiral reduction or removal of multiple protecting groups, so the reaction steps are generally longer than the classical route. In addition, the corresponding starting materials of these routes are often more difficult to obtain than the starting materials used in the classical route.

[0012] In addition, in the above prior art, the compound of Formula V needs to be deprotected by catalytic hydrogenation, so that over-hydrogenated impurities (Formula V-a) are inevitably generated. According to the literature (Bioorg. Med. Chem. Lett., 2012, 6280-6285), the over-hydrogenated impurity (Formula V-a) belongs to 3,4-dihydroquinolone derivatives, and such substances may have some potential side effects. For example, WO2017055506 (filing date: September 29, 2016) reports that the over-hydrogenated impurity (Formula V-a) is more obvious and persistent than indacaterol (Formula V) in terms of the side effect of increasing heart rate. The over-hydrogenated impurity (Formula V-a) has a very similar chemical structure to indacaterol (Formula V), and its chemical properties may also be very close to indacaterol, so it is difficult to purify itself or its salt by common chemical purification / separation techniques.

[0013]

[0014] Therefore, in order to overcome the deficiencies of the prior art, it is necessary to further study the purification process of indacaterol.

[0015] After in-depth research on the purification process of indacaterol, through a large number of experiments, the present application surprisingly found an indacaterol hydrate, which not only has high purity, is not easy to carry impurities (can effectively remove over-hydrogenated impurities and other salt-type impurities), but also has good stability, simple preparation method, high yield, and can be effectively used for industrial production of high-purity indacaterol pharmaceutical salt. SUMMARY

[0016] An object of the present application is to provide a new solid form of indacaterol, which not only has high purity, is not easy to carry impurities (can effectively remove over-hydrogenated impurities and other salt-type impurities), but also has good stability, simple preparation method, high yield, and can be effectively used for industrial production of high-purity indacaterol pharmaceutical salt.

[0017] Another object of the present application is to provide a method for preparing the new solid state form of indacaterol.

[0018] Still another object of the present application is to provide the use of the new solid state form of indacaterol for preparing high-purity pharmaceutical salts of indacaterol.

[0019] The above objects of the present application are achieved by the following solutions:

[0020] According to the objects of the present application, the present application first provides a kind of indacaterol monohydrate shown in formula VI, i.e. (R)-5-[2-(5,6-diethylindene-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one monohydrate.

[0021]

[0022] The molar ratio of indacaterol (compound of formula IV) to water in the indacaterol monohydrate of formula VI according to the present application is 1:1, which can be determined by Karl Fischer's water determination method and other conventional methods. Due to the influence of testing errors, process fluctuations and other factors, the measured molar ratio of indacaterol to water in the indacaterol monohydrate of formula VI may not be exactly 1:1, and an error of ±0.2 can be allowed. Therefore, "H2O" in the structural formula of the compound of formula VI can be understood as "1±0.2H2O", preferably "1±0.15H2O", "1±0.1H2O", "1±0.5H2O" or "H2O".

[0023] In one embodiment, the indacaterol monohydrate of formula VI provided by the present application is in a crystalline state, and the crystal form is Form A, which has a powder X-ray diffraction pattern using Cu-Kα radiation characterized by characteristic diffraction peaks at 2θ values of 6.1°±0.2°, 12.6°±0.2°, 20.4°±0.2°, 22.2°±0.2° and 24.7°±0.2°.

[0024] Furthermore, the powder X-ray diffraction pattern of the indacaterol monohydrate form A represented by formula VI provided by the present invention using Cu-Kα radiation is characterized by: at 2θ values ​​of 6.1°±0.2°, 11.0°±0.2°, 11.6°±0.2°, 12.6°±0.2°, 13.6°±0.2°, 14.2°±0.2°, 14.7°±0.2°, 15.3°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 18. There are characteristic diffraction peaks at positions corresponding to 31.0°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 20.4°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 23.5°±0.2°, 24.3°±0.2°, 24.7°±0.2°, 25.4°±0.2°, 25.8°±0.2°, 26.7°±0.2°, 27.9°±0.2°, 31.0°±0.2° and 31.7°±0.2°.

[0025] Furthermore, the powder X-ray diffraction pattern of the indacaterol monohydrate crystalline form A represented by formula VI provided by the present invention using Cu-Kα radiation has characteristic diffraction peaks and corresponding relative intensities at the following 2θ angle positions:

[0026] 2 theta Relative intensity 6.1°±0.2° 69.30％ 12.6°±0.2° 100.00％ 20.4°±0.2° 33.47％ 22.2°±0.2° 37.65％ 24.7°±0.2° 31.04％

[0027] Furthermore, the powder X-ray diffraction pattern of the indacaterol monohydrate crystalline form A represented by formula VI provided by the present invention using Cu-Kα radiation has characteristic diffraction peaks and corresponding relative intensities at the following 2θ angle positions:

[0028] 2 theta Relative intensity 2 theta Relative intensity 6.1°±0.2° 69.30％ 20.4°±0.2° 33.47％ 11.0°±0.2° 17.11％ 21.0°±0.2° 7.63％ 11.6°±0.2° 8.60％ 22.2°±0.2° 37.65％ 12.6°±0.2° 100.00％ 23.5°±0.2° 7.26％ 13.6°±0.2° 7.92％ 24.3°±0.2° 15.87％ 14.2°±0.2° 16.39％ 24.7°±0.2° 31.04％ 14.7°±0.2° 16.90％ 25.4°±0.2° 10.09％ 15.3°±0.2° 15.50％ 25.8°±0.2° 10.79％ 15.6°±0.2° 6.61％ 26.7°±0.2° 5.99％ 17.8°±0.2° 10.71％ 27.9°±0.2° 4.62％ 18.4°±0.2° 10.10％ 31.0°±0.2° 5.86％ 19.0°±0.2° 4.36％ 31.7°±0.2° 5.31％

[0029] Furthermore, the powder X-ray diffraction pattern of the indacaterol monohydrate crystalline form A of formula VI provided by the present invention using Cu-Kα radiation is substantially as follows: Figure 1 The representative powder X-ray diffraction pattern of the indacaterol monohydrate crystalline form A represented by formula VI provided by the present invention is shown in the accompanying drawings (see Figure 1 , i.e., the powder X-ray diffraction pattern of the indacaterol monohydrate crystalline form A represented by formula VI is substantially as follows Figure 1 The term "representative powder X-ray diffraction pattern" or "substantially" means that the powder X-ray diffraction characteristics of the present crystalline form conform to the overall morphology shown in the pattern. It is understood that during the testing process, due to the influence of various factors (such as the particle size of the test sample, the sample processing method during the test, the instrument, the test parameters, the test operation, etc.), the position or intensity of the characteristic diffraction peaks in the powder X-ray diffraction pattern measured for the same crystalline form may vary to a certain extent.

[0030] In one embodiment, the present application provides a differential scanning calorimetry (DSC) pattern (heating rate: 10°C / min) of the indacaterol monohydrate Form A of Formula VI with a melting point of 177°C.

[0031] According to the purposes of the present application, the present application provides a method for preparing the indacaterol monohydrate of Formula VI or the crystal Form A thereof, which comprises:

[0032] (1) dissolving the compound of Formula IV in a mixed solvent comprising an alcohol and an acid, adding a palladium catalyst, and performing a hydrogenation reaction;

[0033] (2) filtering to remove the catalyst;

[0034] (3) adding an aqueous base solution to the filtrate obtained in step (2) to adjust the pH to 6-8, and precipitating a solid;

[0035] (4) filtering to separate the solid precipitated in step (3);

[0036] (5) optionally, drying the separated solid of step (4), or further purifying and then drying.

[0037]

[0038] In one embodiment, the indacaterol monohydrate of Formula VI and the crystal Form A thereof are prepared by dissolving the compound of Formula IV in a mixed solvent formed by an alcohol and an acid, adding a palladium catalyst, and performing a hydrogenation reaction by introducing hydrogen; filtering to remove the catalyst; adding an aqueous base solution to the obtained filtrate to adjust the pH to alkaline, and precipitating a solid; filtering to separate the precipitated solid; and optionally, drying the separated solid, or further purifying and then drying.

[0039] In one embodiment, the indacaterol monohydrate of Formula VI and the crystal Form A thereof are prepared by dissolving the compound of Formula IV in a mixed solvent formed by an alcohol, an acid and water, adding a palladium catalyst, and performing a hydrogenation reaction by introducing hydrogen; filtering to remove the catalyst; adding an aqueous base solution to the obtained filtrate to adjust the pH to alkaline, and precipitating a solid; filtering to separate the precipitated solid; and optionally, drying the separated solid, or further purifying and then drying.

[0040] In step (1) of the above preparation method, the compound of Formula IV can be prepared according to the method disclosed in CN1156451C, or first prepared into a salt of Formula IV according to the method disclosed in CN100363349C, and then prepared by a conventional method in the art, such as adding a base to free.

[0041] In step (1) of the above preparation method, the alcohol is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, n-pentanol, etc., and is preferably methanol, ethanol or isopropanol.

[0042] In step (1) of the above preparation method, the acid is selected from one or more of formic acid, acetic acid, propionic acid, hydrochloric acid, sulfuric acid, phosphoric acid, preferably formic acid or acetic acid.

[0043] In step (1) of the above preparation method, the palladium catalyst is selected from one or more of palladium, palladium on carbon, and palladium hydroxide, preferably palladium on carbon or palladium hydroxide.

[0044] In step (1) of the above preparation method, the dissolving method can be a conventional method in the art. In one embodiment, the dissolving method is heating, and the heating temperature is selected from -12 to 40°C, preferably 0 to 30°C.

[0045] In step (1) of the above preparation method, the mixed solvent containing alcohol and acid can further contain water, and the molar ratio of the water to the compound of formula IV is generally not less than 3, preferably 3.0 to 15.0.

[0046] In step (1) of the above preparation method, the molar ratio of the acid to the compound of formula IV is generally not less than 3, preferably 3.0 to 5.0.

[0047] In step (1) of the above preparation method, the volume ratio of the alcohol to the acid is generally not less than 27, preferably 27.0 to 37.0.

[0048] In step (1) of the above preparation method, the volume ratio of the alcohol to the water is generally not less than 22, preferably 22.0 to 33.0.

[0049] In step (1) of the above preparation method, the mass ratio of the palladium catalyst to the compound of formula IV is generally 0.05 to 0.30, preferably 0.10 to 0.20.

[0050] In step (1) of the above preparation method, the reaction temperature is generally -10 to 40°C, preferably 10 to 30°C.

[0051] In step (1) of the above preparation method, the hydrogen pressure is generally 0.1 to 0.5 MPa, preferably 0.1 to 0.4 MPa,

[0052] In step (2) of the above preparation method, the filtration is a conventional operation in the technical field, and pressure filtration is preferred. Optionally, the collected solid can be washed with a suitable solvent.

[0053] In step (3) of the above preparation method, the base is selected from one or more of sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, and ammonia water, preferably sodium bicarbonate or potassium bicarbonate.

[0054] In step (4) of the above preparation method, the filtration is a routine operation in the art. Optionally, the collected solid can be washed with a suitable solvent.

[0055] In step (5) of the above preparation method, the drying method includes normal pressure drying, reduced pressure drying or a combination thereof, preferably reduced pressure drying. The drying temperature is generally 40-90°C, preferably 50-80°C.

[0056] In step (5) of the above preparation method, the further purification method includes recrystallization, slurry, washing and the like, preferably slurry. In one embodiment, the purification is performed by slurry, and the solvent used in the slurry is a ketone solvent selected from one or more of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, preferably acetone.

[0057] According to the purpose of the present application, the present application provides the use of indacaterol monohydrate represented by Formula VI or its crystal form A for preparing a high-purity indacaterol pharmaceutical salt.

[0058] In one embodiment, the present application provides a method for preparing a high-chemical / optical purity indacaterol pharmaceutical salt from indacaterol monohydrate represented by Formula VI or its crystal form A, which comprises:

[0059] (a) dissolving a pharmaceutical acid and indacaterol monohydrate represented by Formula VI or its crystal form A in an alcoholic solvent;

[0060] (b) precipitating a solid;

[0061] (c) separating the solid precipitated in step (b);

[0062] (d) optionally, drying the separated solid of step (c), or drying after further purification, to obtain the indacaterol pharmaceutical salt.

[0063] In step (a) of the above preparation method, the pharmaceutical acid is preferably maleic acid or acetic acid.

[0064] In step (a) of the above preparation method, the alcoholic solvent is selected from methanol, ethanol, isopropanol.

[0065] In step (b) of the above preparation method, the method for precipitating the solid is a routine method in the art, such as cooling.

[0066] In step (c) of the above preparation method, the separation is a routine method in the art, such as filtration.

[0067] In step (d) of the above preparation method, the purification method includes recrystallization, slurry, washing and the like. In one embodiment, the purification is performed by recrystallization, and the solvent used for recrystallization is a mixture of alcohol and water. The alcohol solvent is selected from methanol, ethanol or isopropanol.

[0068] In one embodiment, the present application provides a determination result of indacaterol maleate (compound of formula I) prepared by the above method from the indacaterol monohydrate crystal form A of formula VI, wherein the total impurities are less than 0.5%, the single impurities are less than 0.1%, and the salt formation ratio (molar ratio of indacaterol to maleic acid) is 1: (1.00 ± 0.03). The salt formation ratio can be used to determine whether there are other salt type impurities in the product; wherein the maleic acid content determination method is HPLC method calculated by external standard method, and the indacaterol content determination method is non-aqueous titration method. The test result shows that high-purity indacaterol pharmaceutical salt can be prepared from the indacaterol monohydrate crystal form A of formula VI.

[0069] The indacaterol monohydrate of formula VI provided by the present application is a new solid form of indacaterol. The indacaterol solids prepared by the similar preparation methods disclosed in the prior art are not the indacaterol monohydrate, and the following is a summary of the indacaterol solid forms prepared by the similar preparation methods in the prior art.

[0070]

[0071]

[0072] The indacaterol monohydrate of formula VI provided by the present application has the following advantages compared with the prior art:

[0073] (1) It can effectively remove impurities and other salt types, thereby facilitating the preparation of high-purity indacaterol pharmaceutical salt.

[0074] (2) It is in a crystalline state, which is convenient for industrialized operation such as separation and drying.

[0075] (3) It has good stability and is beneficial to storage.

[0076] (4) The preparation method is simple and has good yield. BRIEF DESCRIPTION OF DRAWINGS

[0077] Figure 1 The figure is the powder X-ray diffraction pattern of indacaterol monohydrate crystal form A.

[0078] Figure 2 The figure is the powder X-ray diffraction pattern of indacaterol anhydrate. DETAILED DESCRIPTION

[0079] The following is a further detailed description of the above-mentioned invention contents of the present invention through specific implementation methods in the form of embodiments, but it should not be understood that the invention contents of the present invention are limited to the following embodiments. All inventions made based on the above-mentioned invention contents belong to the scope of the present invention.

[0080] In the following examples, powder X-ray diffraction was measured by a PANalytical X'Pert PRO powder X-ray diffractometer in the Netherlands, with the test conditions being a continuous scan in the θ-θ configuration. The test light source was a copper target Kα (Cu-Kα) radiation (wavelength ), PIXcel detector; voltage and current were 40 kV and 40 mA, respectively. Sample preparation method: Under ambient conditions, use a medicine spoon to place an appropriate amount of sample into the groove of a glass slide. Use the glass slide to gently roll the sample until it is evenly distributed within the groove, and then use the glass slide to smooth the sample surface.

[0081] Differential Scanning Calorimetry (DSC) analysis in the following examples was carried out in the temperature range of 30°C to 200°C at a heating rate of 10°C / min using a NETZSCH DSC 214 differential scanning calorimeter.

[0082] The NMR measurements in the following examples were performed using a BRUKER AVANCE III HD 400 nuclear magnetic resonance spectrometer.

[0083] Example 1: Preparation of Indacaterol Monohydrate (Formula VI) and Its Crystalline Form A

[0084] Add 190g of purified water and 21.5g of potassium carbonate to a reaction flask. After stirring at room temperature to dissolve, add 13g of the fumarate salt of the compound of formula IV (which can be prepared according to the method disclosed in patent CN109721534A, application date: September 25, 2018) and 160g of 2-methyltetrahydrofuran. Stir the reaction for about 1 hour, let it stand to separate the liquids, and wash the resulting organic phase with 200g of saturated sodium chloride aqueous solution and let it stand to separate the liquids. The resulting organic phase solution is concentrated under reduced pressure at 40-50°C to obtain the compound of formula IV. Add 122g of methanol to the resulting compound of formula IV and stir to dissolve at room temperature. Add 6g of acetic acid and transfer to a hydrogenation reactor. After nitrogen displacement, add 2.3g of 10% palladium on carbon. First, replace the atmosphere with nitrogen three times, then with hydrogen three times. Pass hydrogen (hydrogen pressure 0.15-0.25MPa) and control the temperature at 20-30°C until the reaction is complete as monitored by TLC. The filtrate was filtered, the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution, filtered, and the filter cake was washed with an appropriate amount of purified water. The resulting filter cake was dried at 70-80°C to obtain 8.1 g of indacaterol monohydrate (compound of formula VI), with a yield of 86%.

[0085] The measured HPLC purity was 99.4% (the content of the over-hydrogenated impurity Va was 0.06%).

[0086] The measured NMR results are: 1 H NMR (400 MHz, d6-DMSO) ppm 8.196 (d, 1 H), 7.096 (d, 1 H), 6.918 - 6.938 (t, 3 H), 6.500 - 6.524 (t, 1 H), 5.025 - 5.056 (m, 1 H), 3.511 - 3.578 (m, 1 H), 2.951 - 3.037 (m, 2 H), 2.768 - 2.789 (m, 2 H), 2.505 - 2.641 (m, 6 H), 1.100 - 1-137 (t, 6 H).

[0087] 13 C NMR (400 MHz, d6-DMSO) ppm 160.72, 143.13, 139.19, 139.13, 138.97, 136.96, 130.82, 128.52, 124.16, 124.12, 121.37, 119.73, 116.99, 113.91, 68.98, 59.15, 55.53, 24.83, 15.60.

[0088] The measured (+)ESI-MS m / z = 393.2 [M+1] (M is the free base moiety).

[0089] The measured powder X-ray diffraction pattern is shown in Figure 1. Figure 1 The measured values are as follows (the measured values of the diffraction peaks corresponding to relative intensity greater than 0.5% are taken):

[0090]

[0091]

[0092] The measured moisture is 4.47% (Karl Fischer method, the theoretical moisture is about 4.38%).

[0093] The measured differential scanning calorimetry (DSC) melting point is 177°C.

[0094] The above crystal form is named as "crystal form A" of the compound of formula VI.

[0095] Example 2: Preparation of indacaterol monohydrate (compound of formula VI) and its crystal form A

[0096] In a reaction flask, add purified water 190 g and potassium carbonate 21.5 g, stir and dissolve at room temperature, then add the fumarate salt of the compound of formula IV (which can be prepared according to the method disclosed in patent CN109721534A, application date: 2018.9.25) 13 g and 2-methyltetrahydrofuran 160 g. Stir the reaction for about 1 hour, and let it stand to separate. The obtained organic phase is washed with saturated sodium chloride aqueous solution 200 g, and let it stand to separate. The obtained organic phase solution is concentrated under reduced pressure at 40-50℃, and about 122 g of methanol is added to the concentrated residue, which is stirred and dissolved at room temperature. Add glacial acetic acid 6 g and purified water 5.7 g, and transfer to a hydrogenation kettle. After nitrogen replacement, add palladium hydroxide 2.3 g, replace with nitrogen for 3 times, and then replace with hydrogen for 3 times. Control the temperature at 25-35℃ and react until the reaction is completed by TLC monitoring. Filter, adjust the pH to 6-7 with saturated potassium bicarbonate aqueous solution, filter, and wash the filter cake with appropriate amount of purified water. The filter cake is slurried with acetone 70 g for about 2 h, then the temperature is lowered to about 30℃, filtered, and the filter cake is washed with appropriate amount of acetone. The obtained filter cake is dried under reduced pressure at 50-60℃ to obtain indacaterol monohydrate (compound of formula VI) crystal form A 7.7 g, with a yield of 82%.

[0097] The measured HPLC purity is 99.5% (of which the content of over-hydrogenated impurity V-a is 0.04%).

[0098] The measured moisture content is 4.41% (determined by Karl Fischer method, and the theoretical moisture content is about 4.38%).

[0099] The measured powder X-ray diffraction pattern is basically consistent with the attached Figure 1 .

[0100] Example 3: Preparation of maleic acid indacaterol (compound of formula I)

[0101] In a reaction flask, add methanol 60 g and maleic acid 5.8 g, and heat to 50-60℃. After dissolving, add indacaterol monohydrate 8 g prepared according to the method of Example 1, and stir at reflux for about 2 hours. Cool to 20-30℃, filter, and wash the filter cake with appropriate amount of methanol. Dry the obtained filter cake under reduced pressure at 55-65℃ to obtain maleic acid indacaterol 7.7 g.

[0102] The measured HPLC purity is 99.8% (the maximum single impurity is 0.046%, and the HPLC method can effectively detect impurities such as over-hydrogenated impurity V-a).

[0103] The measured salt formation ratio (molar ratio of indacaterol to maleic acid) is 1:1.00.

[0104] Example 4: Stability of indacaterol monohydrate (compound of formula VI) and its crystal form A

[0105] The indacaterol monohydrate (compound of formula VI) crystalline form A obtained in example 2 was dried in a dry oven preheated to 60 °C and 80 °C respectively for 24 hours and above. The samples were taken out and the related substances were determined as follows:

[0106] Temperature Purity Maximum single impurity Powder X-ray diffraction pattern Moisture Before drying 99.5％ 0.072％ With attached Figure 1 basically the same 4.41％ 60℃ 99.5％ 0.074％ With attached Figure 1 basically the same 4.40％ 80℃ 99.5％ 0.072％ With attached Figure 1 basically the same 4.38％

[0107] The above results prove that the indacaterol monohydrate (compound of formula VI) is thermally stable, easy to store and operate in industrial production.

[0108] Preparation of indacaterol (compound of formula V) anhydrate

[0109] In a reaction flask, purified water 13 g and potassium carbonate 1.49 g were added. After stirring and dissolving at room temperature, fumarate salt of compound of formula IV 0.90 g (same batch as used in example 1) and 2-methyltetrahydrofuran 11 g were added. The reaction was stirred for about 1 hour, and then allowed to stand to separate the phases. The obtained organic phase was washed with saturated aqueous sodium chloride solution 14 g, and then allowed to stand to separate the phases. The obtained organic phase solution was concentrated under reduced pressure at 40-50 °C to obtain the compound of formula IV.

[0110] Indacaterol anhydrate was prepared according to the method disclosed in patent WO 2014 / 044288: the compound of formula IV obtained above was dissolved in about 15 mL of methanol and transferred to a hydrogenation autoclave. It was replaced with nitrogen 3 times and then with hydrogen 3 times. 10% palladium on carbon 0.15 g was added and hydrogenated at room temperature (hydrogen pressure 3 atm) until the reaction was completed as monitored by TLC. The palladium on carbon was filtered off and the methanol was removed by rotary evaporation. The residue was exchanged with isopropyl alcohol 5 times and then concentrated to about 8 mL of a suspension. Crystallization was induced by cooling to 0-5 °C, the precipitate was filtered and the obtained filter cake was washed with isopropyl alcohol and then dried to obtain indacaterol anhydrate (compound of formula V) 0.42 g, yield 68%. HPLC: 98.50% (of which the content of over-hydrogenated impurity V-a is 0.37%).

[0111] The powder X-ray diffraction pattern measured is shown in the following figure: Figure 2 .

[0112] The water content measured was 0.25%.

[0113] Preparation of indacaterol (compound of formula V) acetate salt

[0114] In a reaction flask, purified water 172 g and potassium carbonate 19.5 g were added. After stirring and dissolving at room temperature, fumarate salt of compound of formula IV (same batch as used in example 1) 11.80 g and 2-methyltetrahydrofuran 145 g were added. The reaction was stirred for about 1 hour, and then allowed to stand to separate the phases. The obtained organic phase was washed with saturated aqueous sodium chloride solution 181 g, and then allowed to stand to separate the phases. The obtained organic phase solution was concentrated under reduced pressure at 40-50 °C to obtain the compound of formula IV free base.

[0115] The compound of formula IV was dissolved in methanol 100 ml and glacial acetic acid 50 ml and transferred to a hydrogenation flask. The flask was purged with nitrogen for 3 times and then purged with hydrogen for 3 times. 10% Pd-C 1.00 g was added and the reaction was carried out at 25-30 °C under hydrogen pressure 3-4 atm until the reaction was completed by TLC monitoring. The Pd-C was filtered off and the methanol and acetic acid were removed by rotary evaporation. The residue was dispersed in ethyl acetate 50 ml and stirred for about 10 minutes. The ethyl acetate was then concentrated to dryness to give indacaterol acetate (compound of formula V) 6.99 g in 75% yield. HPLC: 98.9% (with the content of over-hydrogenated impurity V-a being 0.29%).

[0116] The measured 1H NMR showed that it was a mono-acetate salt of indacaterol.

[0117] The measured moisture was 0.22%.

[0118] Comparative Example 3: Comparison of the impurity removal effect of indacaterol monohydrate (compound of formula VI) of the present application and existing indacaterol anhydrous or acetate

[0119] The present application compared the impurity removal effect of indacaterol monohydrate (compound of formula VI) and existing indacaterol anhydrous or acetate.

[0120]

[0121]

[0122] The above experiments showed that the indacaterol monohydrate (compound of formula VI) of the present application had better impurity removal effect than the indacaterol acetate and anhydrous of the prior art, and significantly improved the removal effect of over-hydrogenated impurity V-a and other salt-type impurities which were difficult to remove in the subsequent salt formation process.

[0123] The above is only a specific embodiment of the present application, but the protection scope of the present application is not limited thereto, any person skilled in the art can think of changes or substitutions within the technical range disclosed by the present application without creative labor, which should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be limited by the protection scope defined in the claims.

Claims

1. An indacaterol monohydrate crystalline form A represented by formula VI, The powder X-ray diffraction pattern thereof using Cu-Kα radiation is characterized by characteristic diffraction peaks corresponding to positions of 2θ values ​​of 6.1°±0.2°, 12.6°±0.2°, 20.4°±0.2°, 22.2°±0.2° and 24.7°±0.2°.

2. The indacaterol monohydrate crystalline form A according to claim 1, wherein the powder X-ray diffraction pattern using Cu-Kα radiation is characterized by: 2θ values ​​of 6.1°±0.2°, 11.0°±0.2°, 11.6°±0.2°, 12.6°±0.2°, 13.6°±0.2°, 14.2°±0.2°, 14.7°±0.2°, 15.3°±0.2°, 15.6°±0.2°, 17.8°±0.2°, There are characteristic diffraction peaks at positions 18.4°±0.2°, 19.0°±0.2°, 20.4°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 23.5°±0.2°, 24.3°±0.2°, 24.7°±0.2°, 25.4°±0.2°, 25.8°±0.2°, 26.7°±0.2°, 27.9°±0.2°, 31.0°±0.2° and 31.7°±0.2°.

3. The indacaterol monohydrate crystalline form A according to claim 2, which has a powder X-ray diffraction pattern using Cu-Kα radiation as shown in Figure 1.

4. A method for preparing the indacaterol monohydrate crystalline form A according to any one of claims 1 to 3, which is any one of the following two methods: Method 1: Add 190 g of purified water and 21.5 g of potassium carbonate to a reaction flask, stir at room temperature to dissolve, then add 13 g of the fumarate salt of the compound of formula IV and 160 g of 2-methyltetrahydrofuran; stir and react for 1 hour, let stand and separate the liquids, wash the resulting organic phase with 200 g of saturated sodium chloride aqueous solution, let stand and separate the liquids; the resulting organic phase solution is concentrated under reduced pressure at 40-50° C. to obtain the compound of formula IV; add 122 g of methanol to the obtained compound of formula IV, stir at room temperature Dissolve, add 6 g of acetic acid, transfer to a hydrogenation kettle, replace with nitrogen, add 2.3 g of 10% palladium carbon, replace with nitrogen three times, then replace with hydrogen three times, pass hydrogen, the hydrogen pressure is 0.15-0.25 MPa, control the temperature at 20-30°C, and react until the reaction is completed as monitored by TLC; filter, adjust the pH of the filtrate to 8 with saturated sodium bicarbonate aqueous solution, filter, and wash the filter cake with an appropriate amount of purified water; the resulting filter cake is dried at 70-80°C to obtain indacaterol monohydrate crystalline form A; Method 2: 190 g of purified water and 21.5 g of potassium carbonate were added to the reaction flask, stirred at room temperature to dissolve, and then 13 g of the fumarate of the compound of formula IV and 160 g of 2-methyltetrahydrofuran were added; the reaction was stirred for 1 hour, and the liquid was separated by standing; the obtained organic phase was washed with 200 g of saturated sodium chloride aqueous solution, and the liquid was separated by standing; the obtained organic phase solution was concentrated under reduced pressure at 40-50 ° C, 122 g of methanol was added to the concentrated residue, stirred at room temperature to dissolve, 6 g of glacial acetic acid and 5.7 g of purified water were added, and the mixture was transferred to a hydrogenation kettle and nitrogen was placed After replacement, 2.3 g of palladium hydroxide was added, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times, and hydrogen was passed through at a hydrogen pressure of 0.3 to 0.4 MPa. The temperature was controlled at 25 to 35 ° C. and the reaction was completed by TLC monitoring; the filtrate was filtered, and the pH of the filtrate was adjusted to 6 to 7 with a saturated potassium bicarbonate aqueous solution, filtered, and the filter cake was washed with an appropriate amount of purified water; the filter cake was refluxed with 70 g of acetone for 2 hours, then cooled to 30 ° C., filtered, and the filter cake was washed with an appropriate amount of acetone. The resulting filter cake was dried under reduced pressure at 50 to 60 ° C. to obtain indacaterol monohydrate crystal form A; The structural formula of the compound of formula IV is:

5. A method for preparing indacaterol maleate represented by formula I, The method comprises the following steps: adding 60 g of methanol and 5.8 g of maleic acid into a reaction flask, heating the reaction flask to 50-60° C., and after dissolving, adding 8 g of the indacaterol monohydrate crystalline form A described in any one of claims 1-3, heating the reaction flask under reflux and stirring for 2 hours; cooling the reaction flask to 20-30° C., filtering the reaction flask, and washing the filter cake with an appropriate amount of methanol; and drying the filter cake under reduced pressure at 55-65° C. to obtain indacaterol maleate.

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