WO2025108293A1 - Dual-function tracheodilator and crystallization and preparation methods therefor - Google Patents

Abstract

The main purpose of the present invention is to provide a quaternary ammonium salt structural compound having both an M₃ receptor antagonist function and a β₂ receptor agonist function, namely (R)-(-)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-{2-[4-((R)2-{(R)-[2-hydroxy-2-(3-formamido-4-hydroxy)phenyl]ethylamino}propyl)phenoxy]propyl}-1-azabicyclo[2,2,2]octylonium hydrochloride chloride, as well as crystallization and preparation methods therefor, and a use thereof. The compound can form a crystalline solid, has better stability and solubility in water, has a faster onset time for airway relaxation, and is more suitable for drug preparation.

Description

A dual-function tracheodilator and its crystallization and preparation method Technical Field

The present invention belongs to the field of medical technology, and specifically relates to a quaternary ammonium salt structure compound having both _M3 (muscarinic receptor, ₃ -subtype abbreviated as M3) receptor antagonism and _β2 (adrenaline receptor, 2-subtype receptor abbreviated as _β2 ) receptor agonism, namely, (R)-(-)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-{2-[4-((R)2-{(R)-[2-hydroxy-2-(3-formamido-4-hydroxy)phenyl]ethylamino}propyl)phenoxy]propyl}-1-azabicyclo[2,2,2]octanium chloride hydrochloride and a preparation method thereof; the present invention also relates to a crystalline form of the quaternary ammonium salt compound suitable for practical application and application thereof in the preparation of pharmaceutical preparations.

Background Art

Asthma and chronic obstructive pulmonary disease (COPD) are the most common epidemic diseases. Bronchodilators are the first choice for the treatment of asthma and COPD. Commonly used bronchodilators include M receptor antagonists such as ipratropium bromide, tiotropium bromide and _β2 receptor agonists such as salbutamol, formoterol, and vilanterol. The combination of M receptor antagonists and _β2 receptor agonists shows better efficacy in the treatment of moderate to severe asthma and COPD than single M receptor antagonists or _β2 receptor agonists. For example, ipratropium bromide and salbutamol form a compound inhalation solution, which has a stronger efficacy than the two single drugs through synergistic effects; the compound inhalation powder of umeclidinium bromide and vilanterol has better efficacy than umeclidinium bromide or vilanterol alone; the tiotropium bromide/olodaterol compound inhalation powder was approved by the FDA for marketing in 2015, and its efficacy is better than the two single drugs.

In addition, compounds with both _β2 adrenergic receptor agonist activity and M receptor antagonist activity (MABA for short) have been reported in many literatures for the treatment of asthma and COPD. MABA can produce bronchodilator effects through two independent modes of action. Because it is a single molecule with a single pharmacokinetics, its efficacy is even better than that of compound preparations, which will bring good news to patients with moderate to severe asthma and COPD.

WO2018108089A1 discloses a class of long-acting MABA compounds, among which Example 93-R bromide (R)-(-)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-{2-[4-((R)-2-{(R)-[2-hydroxy-2-(3-formamido-4-hydroxy)phenyl]ethylamino}propyl)phenoxy]propyl}-1-azabicyclo[2,2,2]octanium salt (compound of formula (1)) is a preferred compound. Its receptor binding experiment shows that the compound has both _β2 adrenal receptor agonist activity and _M3 receptor antagonist activity, and the two functions have a good match. Compared with the prior art, it has the characteristics of rapid onset and low toxic side effects in the treatment of asthma and COPD.

The method disclosed in WO2018108089A1 shows that the bromide ions of all compounds (including the compound of formula (1)) can be replaced by other acid radicals in a molar ratio of 1:1, and there is no mention of the product obtained by the salification of the amine group with the acid. We found that after the above compounds were dissolved in a benign solvent and the solvent was removed under vacuum decompression conditions, a solid substance was obtained, but a crystalline solid could not be obtained, and the stability was poor, the solubility in water was low, and a qualified pharmaceutical preparation could not be made. Such solids were detected by liquid chromatography, and the content of 5 single impurities exceeded 0.1% (Figure 1, HPLC diagram of the compound of formula (1)). Therefore, a crystallization purification method must be found to solve this technical problem and provide technical guarantee for its commercial application. The inventors tried to crystallize and purify the compound of formula (1) through a variety of single solvents and mixed solvents, but all failed, such as methanol, ethanol, isopropanol, isobutanol, 2-butanone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, water, toluene, ethyl acetate, isopropyl acetate, n-heptane and other single solvents and mixed solvents composed of the above solvents. In view of this, without changing the free base structure of the compound of formula (1), the bromide ion of the compound of formula (1) is replaced by other anions to change the physical and chemical properties of the product, so that the product formed by the compound has stable and consistent crystals and controllable quality, which can be truly put into commercial application. In the continuous experimental process, the product crystal generated by the base of the compound of formula (1): HCl = 1:2 was obtained by chance and luck (Figure 2, HPLC chart of the compound of formula (2)), which greatly reduced the impurity level of the product and improved the quality of the product. The crystal was dissolved in ethanol for single crystal preparation to obtain a single crystal of the compound of formula (2). X-ray diffraction results showed the structural formula of the single crystal, and the chemical name was (R)-(-)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-{2-[4-((R)-2-{(R)-[2-hydroxy-2-(3-formamido-4-hydroxy)phenyl]ethylamino}propyl)phenoxy]propyl}-1-azabicyclo[2,2,2]octanium chloride hydrochloride. More unexpectedly, the use of other anions such as bromine, iodine, sulfate, nitrate in different proportions and various but not limited to organic acids such as acetic acid, propionic acid, tartaric acid, citric acid, methanesulfonic acid, furoic acid, etc. did not obtain the corresponding crystalline product, and even the product generated by using the base of the compound of formula (1) with HCl = 1:1 could not obtain crystals. The difference between the compound of formula (2) and the compound of formula (1) is that the bromide ion of formula (1) is replaced by chloride ion, and the amine group in the compound structure forms a hydrochloride. That is, the free base of the compound of formula (1) can only be crystallized when it is chloride hydrochloride (the compound of formula (2)), which proves the particularity of the structure of this compound. The crystal form I, crystal form II and amorphous form of the compound of formula (2) show more stable physical and chemical properties and higher water solubility than the compound of formula (1). The three crystals of the compound of formula (1) and the compound of formula (2) have strong airway dilation effects, but the crystal form I, crystal form II and amorphous form of the compound of formula (2) take effect when The reaction time is significantly faster than that of the compound of formula (1), which lays a solid foundation for improving the quality of the compound and broadening its practical application range.

The compound production process disclosed in WO2018108089A1 is as follows: (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-azabicyclo[2,2,2]octane free base is reacted with 3-[4-(2-oxopropyl)phenoxy]propane bromide to generate brominated (R)-(-)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-[3-(4-acetonylphenoxy)propyl]-1- Azabicyclo[2,2,2]octanium salt, which reacts with (R)-2-amino-1-[(4-hydroxy-3-formamido)phenyl]ethanol to generate bromide (R)-(-)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-{2-[4-(2-{(R)-[2-hydroxy-2-(3-formamido-4-hydroxy)phenyl]ethylamino}propyl)phenoxy]propyl}-1-azabicyclo[2,2,2]octanium salt. The target product obtained in the above process is a pair of diastereomers. To obtain a single stereoisomer sample, it is necessary to separate and prepare it using preparative HPLC.

After continuous research by the inventors, the process route in synthetic route 1 is adopted, that is, intermediate I is subjected to nucleophilic substitution reaction with 1,3-dibromopropane to generate intermediate II, intermediate II is subjected to quaternization reaction with (2R,3R)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-azabicyclo[2,2,2]octane free base to obtain intermediate III, the nitro group in the structure of intermediate III is reduced to amino group by iron powder and ammonium chloride solution, and then the bromine ion in the structure is replaced by intermediate IV by treatment with 20% sodium chloride aqueous solution, intermediate IV is then reacted with mixed acid anhydride in dichloromethane to formylate the amino group in the structure to prepare intermediate V, and finally intermediate V is subjected to hydrogenation reduction to prepare target compound VI, i.e., compound of formula (2).

In the synthesis route of the compound of formula (2), the same effect can be achieved by using a chloride anion resin exchange process for ion exchange. However, the method of synthesis route 1 is used to wash with a 20% sodium chloride aqueous solution for ion replacement, which is conducive to large-scale commercial production and greatly reduces the production cost. At the same time, the solvent anhydrous formic acid in the mixed anhydride formylation method reported in the literature is replaced with dichloromethane. Only a small amount of anhydrous formic acid and acetic anhydride (mixed anhydride method) is added to perform formylation, which greatly reduces the content of impurities in the final product, is conducive to the recrystallization and purification of the product, is also conducive to the safety and environmental protection of production, and reduces the production cost; it is more conducive to commercial production, which is both economical and environmentally friendly.

The inventors have successfully solved the above problems after extensive creative research.

The reaction formula is as follows:

Synthetic route 1

Summary of the invention

One of the purposes of the present invention is to provide a compound as shown in formula (2):

Another object of the present invention is to provide a method for preparing the compound of formula (2), such as synthetic route 1, comprising the following steps:

Step 1, preparing intermediate II by reacting intermediate I with 1,3-dibromopropane;

The reaction solvent is selected from methanol, ethanol, N, N-dimethylformamide and N, N-dimethylacetamide, etc., preferably methanol, ethanol, etc.; the molar ratio of 1,3-dibromopropane to intermediate I is 5-10:1, preferably 8-10:1; the base used in the reaction is hydroxide Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. The molar ratio of the base to the intermediate I is 2-5:1, preferably 3:1.

Step 2, intermediate II reacts with (R)-(-)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-azabicyclo[2,2,2]octane to prepare intermediate III:

The molar ratio of intermediate II to (R)-(-)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-azabicyclo[2,2,2]octane (prepared according to the "Preparation 2" method in the specific implementation method of WO2018108089) is 1-3:1, preferably 1.1:1; the reaction solvent is selected from methanol, ethanol, N,N-dimethylformamide and N,N-dimethylacetamide, etc., preferably methanol, ethanol, etc.

Step 3, using iron powder to reduce the nitro group of intermediate III to amine group, the molar ratio of intermediate III to iron powder is 1:3-8, preferably 1:5; the solvent used for the reaction is selected from 5%-10% aqueous solution of methanol, ethanol, tetrahydrofuran and acetone, preferably ethanol and methanol aqueous solution.

Step 4, intermediate IV reacts with mixed acid anhydride for formylation, and then is treated with hydrochloric acid to prepare intermediate V. The molar ratio of intermediate IV to formic acid and acetic anhydride is 1:1-3:3-8, preferably 1:1.2:6. The solvent is selected from formic acid and dichloromethane, preferably dichloromethane.

Step 5. The intermediate V is hydrogenated under Pd-C catalysis to remove the benzyl protecting groups on the amine and hydroxyl groups to obtain the target product, (R)-(-)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-{2-[4-((R)-2-{(R)-[2-hydroxy-2-(3-formamido-4-hydroxy)phenyl]ethylamino}propyl)phenoxy]propyl}-1-azabicyclo[2,2,2]octanium chloride hydrochloride. The reaction solvent is selected from formic acid, acetic acid, methanol and ethanol, and formic acid is preferred.

Another object of the present invention is to provide three different crystal forms of the compound of formula (2) and a method for preparing the same.

The crystal form analysis method for studying the crystal of the present invention is as follows:

X-ray powder diffraction (XRPD)

The solid samples obtained in the experiment were analyzed by powder X-ray diffraction analyzer (Bruker D8 advance), which was equipped with LynxEye detector. The 2θ scanning angle of the sample was from 3° to 40°, the scanning step was 0.02°, the tube voltage and tube current were 40KV and 40mA respectively. The sample pan used for sample measurement was a zero background sample pan.

The pharmaceutical compositions of the present invention usually contain a therapeutically effective dose of the compound of the present invention. Usually, such pharmaceutical compositions contain about 0.001% to 100% by weight of the active ingredient.

Any conventional carrier or excipient can be used in the present invention, and the selection of a specific carrier or excipient, or a combination of carrier and excipient depends on the mode of administration or the medical condition or disease type of the particular patient being treated. The preparation techniques for the pharmaceutical composition of a specific mode are within the knowledge of those skilled in the art. In addition, carriers or excipients or a combination of carrier and excipients can be purchased commercially.

Representative examples of pharmaceutically acceptable carriers include, but are not limited to, the following: (1) sugars, such as glucose, lactose, sucrose, etc.; (2) starches, such as corn starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, cellulose acetate, etc.; (4) talc; (5) excipients, such as cocoa butter, waxes; (6) oils, such as olive oil, soybean oil, etc.; (7) alcohols, such as ethanol, propylene glycol, glycerol, sorbitol, polyethylene glycol, mannitol, etc.; (8) esters, such as ethyl oleate, ethyl laurate; (9) pyrogen-free water; (10) isotonic saline; (11) phosphate buffer; (12) compressed propellant gases, such as chlorofluorocarbons, hydrofluorocarbons, etc.; (13) other non-toxic miscible substances used in pharmaceutical compositions.

The compositions of the present invention are usually prepared by thoroughly mixing the compounds of the present invention with one or more optional carriers. If necessary, the homogeneous mixture obtained in the present invention can be shaped or loaded into tablets, capsules, pills, cans or cartridges using conventional equipment and methods.

Pharmaceutical composition of the present invention is suitable for administration by inhalation. Compositions for administration by inhalation are usually in the form of atomized inhalation, aerosol or powder spray. Such compositions are usually administered with known administration devices, such as atomizers, metered dose inhalers (MDI) or dry powder inhalers (DPI) or other similar administration devices.

The composition of the present invention containing the active ingredient is administered by atomization through a nebulizer. The nebulizer can usually generate a high-speed airflow to atomize the pharmaceutical composition containing the active ingredient and inhale it into the respiratory tract of the patient. Therefore, the active ingredient is usually dissolved in a suitable solvent to form a solution and placed in the nebulizer. Alternatively, the active ingredient is micronized and combined with a suitable carrier to form a micronized particle suspension suitable for inhalation. Micronization is usually defined as making more than 90% of the solid particles less than 10 μm in diameter. Suitable nebulizers are commercially available.

Representative pharmaceutical compositions for use with a nebulizer inhaler include 5 μg/ml to 10 mg/ml of the compound of formula (2) or a pharmaceutically acceptable solvate thereof.

The present invention includes pharmaceutical compositions for administration by inhalation using a dry powder inhaler. The dry powder inhaler administration method generally forms a free-flowing powder in the patient's airflow during inhalation. Therefore, the active ingredient is generally formulated with a suitable excipient to obtain a free-flowing powder, such as lactose as an excipient.

A representative pharmaceutical composition for use in a dry powder inhaler comprises micronized particles of dry lactose having a particle size between about 1 μm and about 100 μm and a compound of formula (2).

Dry powder formulations can be prepared by dry mixing the active ingredient with or without excipients and then loading the pharmaceutical composition into a dry powder dispenser, or into an inhalation cartridge or capsule for use with a dry powder delivery device. Dry powder delivery devices are commercially available.

The composition of the present invention comprising the compound of formula (2) is administered by inhalation using a metered dose inhaler. This metered dose inhaler utilizes compressed propellant gas to release a measured amount of the compound of formula (2). Therefore, the pharmaceutical composition administered by the metered dose inhaler is contained in a liquefied propellant solution or suspension.

A representative pharmaceutical composition for use in a metered dose inhaler comprises 0.001% to about 3% by weight of a compound of formula (2) or a pharmaceutically acceptable solvate thereof; about 0% to about 40% of a co-solvent ethanol or glycol, preferably 5% to about 30%; about 0% to 3% by weight of a surfactant; and the remainder being a hydrofluoroalkane (HFA) propellant.

Such compositions are generally prepared by adding ice-cold or pressurized hydrofluorocarbons to a suitable container containing the active ingredient, ethanol (if present) and a surfactant (if present). To prepare a suspension, the active ingredient is micronized and then mixed with a propellant. The formulation is then placed in an aerosol canister to form part of a metered dose inhaler device.

Methods for preparing inhalable particles and other examples of formulations suitable for administration by inhalation are described in the literature.

The present invention relates to a method for treating a patient's pulmonary disease such as COPD or asthma, comprising administering to the patient a compound of formula (2), or a combination thereof and a steroidal anti-inflammatory agent.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 HPLC spectrum of the pure compound of formula (1)

Figure 2 HPLC spectrum of the pure product of the compound of formula (2)

Figure 3 XRPD spectrum of the compound of Example 2 (Form I)

FIG4 XRPD spectrum of the compound of Example 3 (crystal form II)

FIG5 XRPD spectrum of the sample of the compound of Example 4 (crystal form III)

Specific implementation method:

Preparation Example

Intermediate I: 4-((R)-2-(Benzyl((R)-2-(4-(Benzyloxy)-3-nitrophenyl)-2-hydroxyethyl)amine)propyl)phenol

In a 500mL reactor, add (R)-4-(2-(benzylamino)propyl)phenol 128.0g (0.530mol) (prepared by referring to the method of US9029421), (R)-2-(4-(benzyloxy)-3-nitrophenyl)oxirane 146.0g (0.538mol) (prepared by referring to the method of US6268533), 1,4-dioxane 250mL, stir, heat to reflux (about 114°C), and react for 8h. After the reaction is completed, cool to an internal temperature of about 55°C, and the reaction mixture is evaporated at 55°C under reduced pressure until no liquid is distilled out. The residue is dissolved in 300mL of ethyl acetate and washed with water 3 times (3X50mL). The organic phase is dried over anhydrous magnesium sulfate, the desiccant is filtered, and the solution is evaporated under reduced pressure to dryness to obtain 258.1g of light reddish brown oil, with a yield of 95.0%.

Example 1

Preparation of (R)-(-)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-{2-[4-((R)-2-{(R)-[2-hydroxy-2-(3-formamido-4-hydroxy)phenyl]ethylamino}propyl)phenoxy]propyl}-1-azabicyclo[2,2,2]octanium chloride hydrochloride (steps described in synthetic route 1)

Step 1: Preparation of Intermediate II

Add 148.1g (0.289mol) of intermediate I to a 5L reactor, add 1000mL of methanol in portions, heat to about 55°C and stir to dissolve, then add 583.2g (2.889mol) of 1,3-dibromopropane, 0.613kg (0.5784mol) of anhydrous sodium carbonate, and 200mL of purified water in sequence. After the addition is complete, continue stirring, heat to reflux, and continue stirring to react for 10h. Take a sample and detect the end point of the reaction by HPLC. The residue of intermediate I shall not exceed 2%. After the reaction is completed, the reaction mixture is cooled to an internal temperature of 25°C, 500mL of ethyl acetate is added, and the inorganic salt is filtered out. The solid is rinsed with 1000mL of ethyl acetate for 3 times, the filtrate is combined, and the solvent is removed under reduced pressure to dryness. The residue is dissolved with 900mL of dichloromethane, and washed with 200mL of purified water for 3 times by stirring, and the organic phase is dried with 60g of anhydrous magnesium sulfate. Filter, add 2500 mL of n-heptane to the filtrate, stir well, pour out the upper solvent, remove the excess 1,3-dibromopropane, dissolve the residue in 500 mL, remove the solvent under reduced pressure to dryness, and obtain 145.3 g of light yellow oil (Intermediate II), which is directly used in the next step reaction, yield: 79.4%. m/z 632.48, 634.49 (M-1), ¹ HNMR (DMSO-d ₆ ) δppm 8.228 (d, 1H, J＝3.9Hz), 7.672 (d, 1H, J＝7.6Hz), 7.484 (m, 2H), 7.403 (m, 2H), 7.324 (m, 1H), 7.293 (m, 1H), 7.13-7.25 (m, 7H), 6.865 (d, J＝7.8Hz, 2H), 5.5 74(s,1H),5.158(s,2H),4.872(m,1H),4.082(m,2H),3.621(m,2H),3.508( m, 2H), 3.118 (m, 1H), 2.711 (m, 2H), 2.511 (m, 1H), 2.13 (m, 2H), 1.11 (d, 3H).

Step 2: Preparation of Intermediate III

In a 2L reaction bottle, add 145.1g (0.229mol) of intermediate II, 66.3g (0.210mol) of (R)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-azabicyclo[2,2,2]octane, and 500mL of anhydrous ethanol, heat and stir to dissolve, raise the temperature to reflux, and stir to react for 3h. After the reaction is completed, TLC detection of (R)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-azabicyclo[2,2,2]octane is less than 1%, and the mixture is evaporated to dryness under reduced pressure. The residue was dissolved with 300 mL of dichloromethane, and 300 mL of isopropyl ether was added under stirring. The stirring was continued for 15 min, and the mixture was allowed to stand. The supernatant was discarded, and the lower layer of oil was dissolved with 700 mL of dichloromethane, and the mixture was washed with 300 mL of purified water for 3 times by stirring. The mixture was allowed to stand for stratification, and the organic phase was separated. 100.00 g of anhydrous magnesium sulfate was added, and the mixture was allowed to stand for drying. The desiccant was removed by filtration under reduced pressure, and the desiccant was rinsed with 200 ml of dichloromethane for 3 times. The filtrate was transferred to a rotary evaporator in portions, and the mixture was rotary evaporated under reduced pressure at 37 ° C until no liquid was distilled out. The mixture was heated to 50 ° C and rotary evaporated for 1 h. The mixture was rotary evaporated under reduced pressure using an oil pump (the rotary evaporation speed was 100 r/min) until a foamy solid was obtained, and 179.29 g of yellow foamy solid, namely intermediate III, was obtained with a yield of 90.0%.

m/z 869.01(M ⁺ -Br), ¹ HNMR(DMSO-d ₆ )δppm 8.218 (d, 1H, J = 3.9Hz), 7.66 (d, 1H, J = 7.6Hz), 7.540 (m, 2H), 7.491 (m, 2H), 7.4 03(m,2H),7.324(m,1H),7.293(m,3H),7.13-7.25(m,8H),6.865(d,J＝7.8Hz,2H ), 5.574 (s, 1H), 5.520 (s, 1H), 5.149 (s, 2H), 4.807 (m, 1H), 4.050 (m, 2H), 3.793 (m, 1H), 3.611 (m, 2H), 3.222 (m, 4H), 3.102 (m, 1H), 2.711 (m, 2H), 2.601 (m, 1H), 2.511(m,1H),2.47(m,1H),2.310(m,2H),2.26(m,2H),2.15(m,2H),1.902(m,2H),1.770- 1.790 (m, 3H), 1.731 (m, 2H), 1.602-1.682 (m, 3H), 1.561 (m, 2H), 1.44 (m, 2H), 1.11 (d, 3H).

Step 3, preparation of intermediate IV

In a 5L reactor, add 177.6g (0.1871mol) of intermediate III and 1500mL of anhydrous ethanol, heat and stir to dissolve, then add 41.7g (0.747mol) of activated iron powder and rinse it into the reactor with 400mL of purified water for several times, then add 40g (0.749mol) of ammonium chloride and 260g of purified water, stir and heat to reflux for 8h. After the reaction is completed, the reaction mixture is cooled to the internal temperature, filtered under reduced pressure to remove iron mud, and the filtrate is concentrated to dryness under reduced pressure. The residue was dissolved in 1000 mL of dichloromethane, washed with 300 mL of purified water, and the organic phase was separated. The organic phase was washed with 400 mL of 20% sodium chloride aqueous solution × 3, separated, and dried with 60 g of anhydrous magnesium sulfate. The filtrate was concentrated to dryness to a foamy solid, and the solid was dissolved in 400 mL of anhydrous ethanol, and the pH value was adjusted to about 5 with an appropriate amount of hydrochloric acid. Activated carbon was added for decolorization, and the filtrate was concentrated to dryness to obtain 163.3 g of a light brown solid of intermediate IV, with a yield of 96.5%. m/z 839.1 (M-Cl), ¹ HNMR (DMSO-d ₆ )δppm 7.393-7.601(m,6H),7.290-7.324(m,5H),7.13-7.25(m,6H)6.991(s,1H), 6.930(m,1H),6.859(m,2H),6.674(m,1H),5.674(s,1H),5.510(s,1H),5.27 1(s,2H),5.161(s,1H),4.868(m,1H),4.048(m,3H),3.920(m,1H),3.793(m, 2H), 3.721 (m, 2H), 3.665 (m, 1H), 3.620 (m, 2H), 3.481 (m, 1H), 3.35 (m, 1H), 3 .272(m,4H),3.223(m,5H),3.112(m,1H),2.961(m,1H),2.770(m,1H),2.84 3(m,1H),2.715(m,1H),2.601(m,1H),2.640(m,1H),2.515(m,1H),2.47(m,1 H),2.310(m,2H),2.261(m,2H),2.15(m,2H),1.891(m,2H),1.770(m,2H),1. 729 (m, 2H), 1.602-1.682 (m, 8H), 1.525 (m, 2H), 1.441 (m, 2H), 1.120 (d, 3H).

Step 4. Preparation of Intermediate V

In a 5L three-necked flask, add 437g (0.95mol) of anhydrous formic acid, stir, cool to 0-5℃, add 311.0g (0.305mol) of acetic anhydride dropwise below 15℃, and keep the reaction below 15℃ for 30min. Add a solution containing 162.8g (0.179mol) of intermediate IV dissolved in 2000mL of dichloromethane dropwise under stirring, keep the internal temperature at 0-10℃, and after the addition is complete, control the internal temperature at 10-15℃ and continue stirring the reaction for 6h. After the reaction is completed, add 2000mL of dichloromethane to dilute the reaction mixture, wash the reaction mixture with 800mL×5 of 10% sodium chloride aqueous solution, add 160g of anhydrous magnesium sulfate, and stir and dry for 2h. Filter under reduced pressure to remove the desiccant, and concentrate the filtrate under reduced pressure to a foamy solid to obtain 155.8g of light brown foamy solid of intermediate V, with a yield of 93.3%. m/z 839.1 (M-Cl), ¹ HNMR (DMSO-d ₆ ) δppm 8.56(s,1H),7.393-7.541(m,6H),7.290-7.324(m,5H),7.13-7.25(m,8H),6.860(m,2H ), 6.674(m,1H), 5.674(s, 1H), 5.510(s, 1H), 5.158(s,1H), 4.862(m, 1H), 4.050(m, 3H), 3.923(m,1H), 3.790(m,2H), 3.720(m,2H), 3.656(m,1H), 3.618(m,2H), 3.480(m,1H), 3.347(m,1H), 3.271 (m, 4H), 3.220 (m, 5H), 3.110 (m, 1H), 2.959 (m, 1H), 2.768 (m, 1H), 2.840 (m, 1H), 2.695 (m, 1H), 2 .629(m,1H),2.60(m,1H),2.512(m,1H),2.468(m,1H),2.308(m,2H),2.260(m,2H),2.15(m,2H),1.88 0 (m, 2H), 1.770 (m, 2H), 1.726 (m, 2H), 1.60-1.680 (m, 8H), 1.515 (m, 2H), 1.438 (m, 2H), 1.110 (d, 3H).

Step 5: Preparation of target compound

In a 5L hydrogenation kettle, add 1300mL of methanol and 155.6g (0.166mol) of intermediate V, control the temperature at about 25°C and stir for 10min, add 35.1g of 10% palladium carbon (pre-washed with purified water) and 1800mL of purified water, introduce nitrogen to an internal pressure of about 0.4MPa, replace the air, repeat this operation twice, introduce hydrogen to an internal pressure of about 0.4MPa, replace the nitrogen, repeat this operation twice, introduce hydrogen to an internal pressure of about 0.4MPa, maintain the internal temperature at 25°C and react for 5h. After the reaction is completed, release the pressure and discharge the materials, rinse the reactor with 1300mL of methanol, and add the reaction solution, filter the reaction solution under reduced pressure (0.45um filter membrane) to remove palladium carbon, and rinse the palladium carbon with 300mL of methanol × 4 times. The filtrate was transferred to a rotary evaporator, and vacuum-evaporated at 50°C until no liquid was distilled out, and then vacuum-evaporated to dryness, and then vacuum-evaporated with an oil pump (evaporation speed of about 100 r/min) until a foamy solid was obtained, to obtain 116.3 kg of a crude product of the compound of formula (2) as a pale yellow solid, with a yield of 92.5%. Samples were taken to test the water content, and the water content was controlled to be no more than 1.5%.

Example 2. Preparation of Crystalline Form I of Compound of Formula (2)

In a 10mL reaction bottle, add 1.311g of the crude compound of formula (2) and 3mL of anhydrous methanol, stir, heat to 50℃ to dissolve, add 7mL of isobutyl acetate, continue stirring for 5 minutes, cool to 5℃, stir and crystallize, after a large amount of solid precipitates, maintain about 25℃ for continuous crystallization for 1.5h, cool to 5±2℃, stir and crystallize for 3.5h. Filter under reduced pressure, rinse the filter cake with 0.159kg×3 of a 50% anhydrous ethanol and isopropanol mixture, and vacuum dry the solid at 80～85℃ for 4h to obtain 0.817g of off-white powdery solid, yield: 62.3%. Elemental analysis: C ₂₉ H ₄₀ BrNO ₃ , calculated value: C65.65, H7.60, Br15.06, N2.64; measured value: C65.60, H7.58, Br15.0, N2.62. m/z 687.5 (M-Cl-HCl), elemental analysis 1HNMR (DMSO-d6) δppm 10.197 (1H), 9.644 (s, 1H), 9.498 (m, 1H), 8.758 (m, 1H), 8.292 (d, 1H), 8.145 (s, 1H), 7.484 (d, J = 7.6 Hz, 2H), 7.283 (t, J = 7.6 Hz, 2H), 7.13-7.22 (m, 3H), 6.92-6.99 (m, 2H), 6.895 ( d, 2H), 6.084 (s, 1H), 4.938 (m, 1H), 4.802 (s, 1H), 3.988 (t, 2H), 3.795 (m, 1H), 3.718 (d, 1H), 3.653 (m, 1H), 3.4 80 (d, 1H), 3.07-3.16 (m, 7H), 2.91-3.07 (m, 2H), 2.611 (t, 1H), 2.399 (m, 1H), 2.217 (m, 1H), 2.065 (m, 2H), 1.893 (m, 1H), 1.65-1.77 (m, 2H), 1.57-1.65 (m, 3H), 1.44-1.57 (m, 2H), 1.29-1.44 (m, 2H), 1.231 (m, 1H), 1.087 (m, 4H).

The results showed that the product did not contain water of crystallization or other crystallization solvents, and was consistent with the molecular formula of the compound of formula (2); the XRPD results showed that the product was crystalline, named Form I, and its X-ray powder diffraction pattern was shown in Figure 3, and the data were shown in Table 1.

Table 1. Characteristic X-ray powder diffraction data of target compound crystal form I

The crystal characteristics of the compound crystalline form I are as follows: X-ray powder diffraction pattern (CuKα, at about 25° C.), and can also be characterized by the following data: including 2θ values selected from the following: 9.4±0.3, 14.7±0.3, 15.3±0.3, 18.6±0.3, 19.8±0.3, 20.8±0.3, 25.1±0.3.

Example 3: Preparation of Crystalline Form II of the Compound of Formula (2)

In a 5L reactor, add 1.50g of the crude compound of formula (2) and 3mL of anhydrous ethanol, stir, heat to about 50°C to dissolve, cool to about 25°C, stir and crystallize, and after a large amount of solid is precipitated, maintain about 25°C for continuous crystallization for 1.5h, cool to 5±2°C, and stir and crystallize for 3.5h. Filter under reduced pressure, rinse the filter cake with 3mL×3 of a 50% anhydrous ethanol and isopropanol mixture, and dry the solid in vacuum at 80-85°C for 4h to obtain 1.17g of off-white powder solid, named Form II, with a yield of 78.0%. The X-ray powder diffraction pattern of Form II is shown in Figure 4, and the X-ray powder diffraction data of the target compound are shown in Table 2.

Table 2 Characteristic X-ray powder diffraction data of target compound crystal form II

The crystal characteristics of the compound form II are as follows: X-ray powder diffraction pattern (CuKα, At about 25° C.), it can also be characterized by the following data: including 2θ values selected from the following: 3.5±0.3, 7.1±0.3, 10.7±0.3, 17.1±0.3, 18.8±0.3.

Example 4: Preparation of amorphous crystals of the compound of formula (2)

In a 50 ml single-mouth bottle, add 2.00 g of the compound of formula (2) (crystal form I) and 20.00 g of isopropyl acetate containing 1.0% water, maintain the internal temperature at about 35°C, stir magnetically for 1 hour, then filter out the solid, repeat the above process once, and dry the solid in vacuum at 80-85°C for 4 hours to obtain an amorphous sample. The appearance of the sample is a loose solid of off-white color. The X-ray powder diffraction pattern of this product is shown in Figure 5.

Preparation Example 1

The dry powder formulation for inhalation administration was prepared by the following method

Components and dosages of each dose in the composition

Example 2 Compound 1.0 mg

Lactose 25mg

The compound of Example 3 of the present invention was micronized to an average particle size of 1 to 10 μm, and mixed thoroughly with lactose. The mixture was put into capsules and administered using a powder inhaler.

Preparation Example 2

The dry powder formulation for inhalation administration was prepared by the following method

Components and dosages of each dose in the composition

Example 3 compound 0.30 mg

Lactose 25mg

Magnesium stearate 0.04mg

1.19% by weight of the compound of Example 4 of the present invention was micronized to an average particle size of 1-10 μm, mixed evenly with 0.16% by weight of micronized magnesium stearate, and then mixed evenly with 98.65% by weight of lactose to prepare a capsule preparation of 25.34 mg/capsule, which was administered using a powder inhaler.

Preparation Example 3

The dry powder formulation for inhalation administration was prepared by the following method.

Components and dosages of each dose in the composition

Example 4 Compound 0.05 mg

Lactose 25mg

The compound of Example 4 of the present invention was micronized to an average particle size of 1 to 10 μm, and mixed thoroughly with lactose. The mixture was put into capsules and administered using a powder inhaler.

Preparation Example 4

The inhalation solution is contained in a low-density polyethylene ampoule for inhalation solution and is administered by atomization inhalation.

Components and dosages of each dose in the composition

Preparation Example 5

The inhalation solution is contained in a low-density polyethylene ampoule for inhalation solution and is administered by atomization inhalation.

Components and dosages of each dose in the composition

Preparation Example 6

The aerosol medicine liquid is contained in a pressure-resistant container consisting of an aluminum can and a metered-dose valve; it is sprayed out in a mist-like state by an actuator and inhaled through the mouth.

Specification: 20 μg/press (calculated as anhydrous substance of formula (2), 60 presses/bottle (actual dosage is 150%). The formula composition of the unit dose product is as follows:

Preparation Example 7

The aerosol medicine liquid is contained in a pressure-resistant container consisting of an aluminum can and a metered-dose valve; it is sprayed out in a mist-like state by an actuator and inhaled through the mouth.

Specification: 200 μg/press (calculated as anhydrous substance according to formula (2)), 60 presses/bottle (actual dosage is 150%). The formula composition of the unit dose product is as follows:

Experimental Example 1: Impurity Removal Effect of Recrystallization

The impurity removal effect of the recrystallization process of the crystal of the present invention was determined using the following high performance phase chromatography conditions.

Instrument: High performance liquid chromatograph equipped with UV detector

Solvent: Mobile phase A

First, the purity (%) of the crude product of the compound of formula (2), the three crystals and the compound of formula (1) was calculated according to the following formula based on the HPLC chromatogram: Purity of the main drug (%) = (peak area of the main drug) / (sum of all peak areas) × 100%. The impurity removal rate (%) in the solid is based on the solid of the compound of formula (2) = [{(the main drug purity in each crystal) - (the main drug purity of the compound of formula (2))} / {100% - (the main drug purity of the crude compound of formula (2))}] × 100%

The results are shown in Table 3:

Table 3. Results of Recrystallization to Remove Impurities from API

The results show that compared with the crude product of the compound of formula (2), the crystalline form I, crystalline form II and amorphous form of the compound of formula (2) of the present invention can remove most of the impurities in the raw material. The purity of the crystalline form I, crystalline form II and amorphous form of the compound of formula (2) is not much different. In addition, the impurity content in the crude product of the compound of formula (1) and the compound of formula (2) is relatively close, which fully illustrates the important role of the crystallization process in removing impurities.

Experimental Example 2: Influencing Factor Destruction Test (HPLC method see Experimental Example 1)

The crude product of the compound of formula (1), the compound of formula (2), and the crystal form I, crystal form II, and amorphous form were subjected to high temperature, high humidity, and light damage tests, respectively. The main peak content (stability), total impurities (total impurity %), and main peak purity of each test sample were analyzed.

(1) Take 10 mg of each undamaged test sample, accurately weigh it, place it in a 20 ml volumetric flask, add solvent to dissolve and dilute to the scale, and shake well.

(2) Samples damaged by high temperature: Take 10 mg of each sample, weigh accurately, place in a 20 ml volumetric flask, place at 80°C for 12 days, add solvent to dissolve and dilute to the scale, and shake well.

(3) Samples damaged by high temperature: Take 10 mg of each sample, weigh accurately, place in a 20 ml volumetric flask, place at 105°C for 24 hours, add solvent to dissolve and make up to the mark, shake well.

(4) Samples damaged by high humidity: Take 10 mg of each sample, weigh accurately, and place in a weighing bottle. After leaving it open at a humidity of 75% for 24 hours, add solvent to dissolve it and transfer it to a 20 ml volumetric bottle, dilute to the mark, and shake well.

(5) Light-damaged samples: Take 10 mg of each sample, weigh accurately, and place in a 20 ml transparent volumetric bottle. After placing at 4500 Lx ± 500 Lx for 12 days, add solvent to dissolve and dilute to the scale, and shake well.

Take the above test solution and inject it into the liquid chromatograph respectively, and record the chromatogram.

The test results are shown in Table 4:

Table 4. Results of relevant material inspection and destruction test

Result analysis: When the compound of formula (1) was placed at high temperature of 80°C for 12 days, 0.3% of single impurity was generated in 5.4 min; when the crude compound of formula (2) was placed at high temperature of 80°C for 12 days, 0.21% of single impurity was generated in 5.4 min; the crystal form I, crystal form II and amorphous form of the compound of formula (2) did not generate more than 0.2% of impurities, and the stability was good; when placed at high temperature of 105°C for 24 hours, each of the test samples generated impurities in 5.4 min and 42.5 min, but the total impurities and single impurities of the compound of formula (1) were significantly higher than those of the crude compound of formula (2), and the crude compound of formula (2) was higher than the three crystals; in the stability test under high humidity and light conditions, each test sample did not generate more than 0.2% of single impurity, but the total impurities and single impurities of the compound of formula (1) were significantly higher than those of the crude compound of formula (2), and the crude compound of formula (2) was higher than the three crystals of the compound of formula (2).

Conclusion: Under high temperature, light and high humidity conditions, the stability of the compound of formula (1) is worse than that of the crude compound of formula (2), and the crude compound of formula (2) is worse than the three crystals of the compound of formula (2). The stability of the three crystals of the compound of formula (2) under the above conditions is basically the same, with no obvious difference.

Experimental Example 3: Solubility of the crude product of the compound of formula (2), three crystals and the compound of formula (1)

According to the determination method under the general rules of Part IV of the Chinese Pharmacopoeia: shake vigorously for 30 seconds every 5 minutes in water at 25°C ± 2°C; observe the dissolution within 30 minutes: Results: The crude product of the compound of formula (2) and the three crystalline forms are easily soluble in water, with a solubility of more than 700 mg per 1 ml of water; the compound of formula (1) is slightly soluble in water, with a solubility of less than 1.0 mg per 1 ml of water. The results are shown in Table 5.

Table 5. Solubility results of three crystal forms of the compound of formula (1) and the compound of formula (2)

Conclusion: The solubility of the crude product and three kinds of crystals of the compound of formula (1) and formula (2) in water is very different. The solubility of the compound of formula (1) in water is slightly soluble, which is not conducive to the preparation of aqueous solution preparations (such as inhalation solutions). However, the solubility of the crude product and three kinds of crystals of the compound of formula (2) in water is freely soluble.

Experimental Example 4: Relaxation effect of three crystals of the compound of formula (1) and the compound of formula (2) on the contraction reaction of isolated guinea pig tracheal smooth muscle induced by carbachol (CCh)

Preparation of isolated tracheal smooth muscle specimens of guinea pigs: guinea pigs were anesthetized by intraperitoneal injection of 1.5 g/kg of ulanose (15% ulanose, intraperitoneal injection of 10 mL/kg). After anesthesia, the trachea between the larynx and the carina was quickly removed and placed in a KH solution containing a mixture of 5% CO ₂ and 95% O _2. The loose connective tissue around the trachea was separated and cut into tracheal rings with a width of about 3 mm. The cartilage was cut open and the two ends were tied with thread. The specimens were placed in a McArthur bath containing 5 mL of KH solution. The water bath temperature was 37°C and a mixture of 5% CO ₂ and 95% O ₂ was continuously introduced. The upper end was connected to a muscle tension transducer, and the initial resting tension of the tracheal piece was set to 1.0 g. The changes in muscle tension were recorded. The KH solution (5 mL) was changed once every 15 to 30 minutes. The experiment was started after the muscle tension of the tracheal piece was stable.

Dosing method: After the muscle tension of the tracheal piece is stabilized, add CCh with a final concentration of 3× ^10-6 M to the McLean bath. After the contraction tension of the tracheal piece reaches the plateau, add three crystals ( ^crystal I, crystal II and amorphous form) of the compound of formula (1) and the compound of formula (2) with final concentrations of 10-11, ^10-10 , ^10-9 , 3× ^10-9 , ^10-8 , 3× ^10-8 , ^10-7 , ^10-6 , ^10-5 and ^10-4 M respectively by cumulative dosing method. The positive control is a mixture of ipratropium bromide (IPR) and salbutamol (SAL). The mixture IPR:SAL=1:6, and the concentration is calculated in IPR. The highest concentration is only added to ^10-5 M. The blank control group is added with solvent. The tension of the tracheal piece is recorded by the MedLab biological signal acquisition system. If there is no reaction (subthreshold concentration), continue to add the next dose in sequence. If a reaction occurs, wait until the relaxation plateau is reached before adding the next dose. Finally, add isoproterenol (Iso) at a final concentration of 3×10 ^-5 M to achieve maximum relaxation and record the curve, with the relaxation effect of Iso being considered 100% relaxation.

Data entry and statistical analysis: Excel and SPSS (Version 20) software packages were used for statistical processing, and EC ₅₀ was calculated and expressed as mean ± standard error. Each data was tested for homogeneity of variance. If the variance was homogeneous (P>0.05), a one-way analysis of variance was performed, and a Dunnet test was performed between each dose group and the control group. If the variance was unequal (P≤0.05), a nonparametric test was performed, and a Mann-Whitney U test was performed between each dose group and the control group. Compared with the control group, P<0.05 was considered to be statistically significant. When comparing the two groups, an independent sample t test was performed, and P<0.05 was considered to be statistically significant.

Experimental results: The EC ₅₀ (95% confidence interval) results of the relaxation effect of the compound of formula (1), the crystal I of the compound of formula (2), the crystal II of the compound of formula (2), the amorphous form of the compound of formula (2), and the IPR+SAL mixture on tracheal smooth muscle are shown in Table 6.

Table 6 EC ₅₀ of the relaxing effect of the example compounds on isolated tracheal smooth muscle

Conclusion: The compound of formula (1), three crystals of the compound of formula (2) (crystal I, crystal II and amorphous form) and IPR+SAL (mixture) all have strong diastolic effects on the contraction of tracheal smooth muscle induced by CCh. There is no significant difference in the intensity of the effects of the compound of formula (1) and three crystals of the compound of formula (2) (crystal I, crystal II and amorphous form), and all are stronger than the positive control drug IPR+SAL mixture.

Experimental Example 5: Start-up time of the relaxation effect of the compound of formula (1), three crystals of the compound of formula (2) (crystal I, crystal II and amorphous form) and the IPR+SAL mixture on the contractile response of isolated guinea pig tracheal smooth muscle induced by CCh

See Experimental Example 4 for the preparation of isolated guinea pig tracheal smooth muscle.

Dosing method: The prepared guinea pig isolated tracheal smooth muscle samples were used to record the changes in muscle tension using the MedLab biological signal acquisition system. After the tracheal muscle tension was stable, the tracheal smooth muscle samples were induced to contract with a final concentration of 3× ^10-6 M CCh. After the contraction tension of the tracheal slice reached a plateau, the EC 80 concentrations of the compound of formula (1), three crystals of the compound of formula (2) (crystal I, crystal II and amorphous) and the IPR+SAL mixture (in terms of IPR) obtained in reference to Experimental Example ₄ were 1.73× ^10-8 , 1.69× ^10-8 , 1.72× ^10-8 , 1.75× ^10-8 and 1.01× ^10-8 M, respectively. The trachea was induced with a final concentration of 3× ^10-6 M CCh. After the smooth muscle samples contracted and the tension reached the plateau phase, the test drug was added to each test group to a concentration of EC ₈₀ , and the control group was added with KH solution. The tension of the tracheal piece was recorded by the MedLab biological signal acquisition system, the plateau phase of the maximum relaxation was taken as 100% relaxation, and the time of 10% relaxation was recorded and calculated as the start-up time.

For data entry and statistical analysis, see Experimental Example 4.

The test results are shown in Table 7.

Table 7. Onset of relaxation time of the example compounds on isolated tracheal smooth muscle

Conclusion: The compound of formula (1), three crystals of the compound of formula (2) (crystal I, crystal II and amorphous form) and the IPR+SAL mixture all have a strong relaxing effect on the contraction of tracheal smooth muscle caused by CCh. The onset time of the compound of formula (1), three crystals of the compound of formula (2) (crystal I, crystal II and amorphous form) and the positive control drug IPR+SAL mixture is relatively fast, less than 5 minutes. There is no significant difference between the compound of formula (2) and the IPR+SAL mixture, but both are significantly faster than the compound of formula (1) (P < 0.05).

Claims (7)

A compound represented by the structure of formula (2):
The method for preparing the compound of claim 1, comprising the following steps:
(1) The reaction solvent in step 1 is selected from methanol, ethanol, N,N-dimethylformamide and N,N-dimethylacetamide, etc., preferably methanol, ethanol, etc.; the molar ratio of 1,3-dibromopropane to intermediate I is 5-10:1, preferably 8-10:1; the base used in the reaction is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, etc., and the molar ratio of the base to intermediate I is 2-5:1, preferably 3:1; (2) The molar ratio of intermediate II in step 2 to (R)-(-)-3-[(R)-2-hydroxy-2-cyclopentyl-2-phenyl]ethoxy-1-azabicyclo[2,2,2]octane is 1-3:1, preferably 1.1:1; the reaction solvent is selected from methanol, ethanol, N,N- Dimethylformamide and N,N-dimethylacetamide, etc., preferably methanol, ethanol, etc.; (3) The molar ratio of intermediate III in step 3 to iron powder is 1:3-8, preferably 1:5; the solvent used in the reaction is selected from a 5%-10% aqueous solution of methanol, ethanol, tetrahydrofuran and acetone, preferably an aqueous solution of ethanol and methanol; (4) The molar ratio of the intermediate IV in step 4 to formic acid and acetic anhydride is 1:1-3:3-8, preferably 1:1.2:6, and the solvent is selected from formic acid and dichloromethane, preferably dichloromethane; (5) The reaction solvent in step 5 is selected from formic acid, acetic acid, methanol and ethanol, preferably formic acid. The crystalline form I of the compound shown in claim 1 is characterized in that, in the X-ray powder diffraction pattern, it has diffraction peaks at 2θ values of 9.4±0.3, 14.7±0.3, 15.3±0.3, 18.6±0.3, 19.8±0.3, 20.8±0.3, and 25.1±0.3. The crystalline form II of the compound shown in claim 1 is characterized in that in the X-ray powder diffraction pattern, it has diffraction peaks at 2θ values of 3.5±0.3, 7.1±0.3, 10.7±0.3, 17.1±0.3, and 18.8±0.3. The amorphous form of the compound of claim 1 is characterized by having the X-ray powder diffraction pattern characteristics shown in Figure 5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 as an active ingredient. Use of any one of the compounds of claims 1 to 5 or any one of the pharmaceutical compositions of claim 6 in the preparation of a medicament as a bronchodilator.