Pharmaceutical composition for treating chronic obstructive pulmonary disease and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition for treating chronic obstructive pulmonary diseases and a preparation method thereof. The pharmaceutical composition is prepared from the following components in parts by weight: 1 to 1.5 parts of guaijaverin derivatives, 1.5 to 2 parts of resveratrol and 0.5 to 0.8 part of aureomycin. The components are matched for use, so that the expression level of inflammatory factors IL-6 and TNF-alpha in the alveolar lavage fluid can be remarkably reduced at a relatively low dosage, and the lung function of a mouse is further improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to a pharmaceutical composition for treating chronic obstructive pulmonary disease and its preparation method. Background Technology

[0002] Chronic obstructive pulmonary disease (COPD) is a group of chronic respiratory diseases characterized by a long course and multiple contributing factors. The pathogenesis of COPD is not fully understood and is largely based on hypotheses. These hypotheses include: the protease imbalance hypothesis, the oxidative stress hypothesis, the inflammation hypothesis, and the chlamydia infection hypothesis. Although these four hypotheses are not definitively established, they collectively outline the multi-target, multi-stage pathological profile of COPD, providing a theoretical framework for subsequent drug classification and intervention strategies.

[0003] The main drug treatment options for COPD include β2 receptor agonists, M receptor blockers, glucocorticoids, and traditional Chinese medicine. β2 receptor agonists (terbutaline, salmeterol, formoterol, indacaterol, etc.) rapidly relieve symptoms by relaxing bronchial smooth muscle, but their effects only last 4-24 hours and are prone to causing palpitations, hypokalemia, and rapid tolerance. M receptor blockers (tiotropium bromide, adecyl bromide, glycopyrronium bromide, etc.) have a longer duration of action, but are often accompanied by dry mouth, urinary retention, worsening of glaucoma, and the risk of arrhythmia. Inhaled corticosteroids (beclomethasone, budesonide, triamcinolone, etc.) can rapidly reduce inflammation during acute exacerbations, but long-term use cannot prevent the progressive decline in lung function and instead increases the incidence of oral candidiasis, pneumonia, and osteoporosis. Traditional Chinese medicine (Yu Ping Feng granules, Bai Ling capsules, Liu Jun Zi Tang, etc.) emphasizes "simultaneous tonification of the lungs, spleen, and kidneys," which can improve symptoms such as cough and wheezing and susceptibility to colds during the stable phase, but there are defects such as inconsistent formulation quality and potential liver and kidney toxicity.

[0004] Therefore, there is an urgent need for a pharmaceutical composition for treating chronic obstructive pulmonary disease that can overcome the shortcomings of existing methods. Summary of the Invention

[0005] In order to overcome the shortcomings of the prior art, one of the objectives of the present invention is to provide a pharmaceutical composition for treating chronic obstructive pulmonary disease, wherein the components, when used in combination, can significantly reduce the expression levels of inflammatory factors IL-6 and TNF-α in bronchoalveolar lavage fluid at a low dose, thereby improving lung function in mice.

[0006] One of the objectives of this invention is achieved through the following technical solution: A pharmaceutical composition for treating chronic obstructive pulmonary disease, comprising, by weight, the following components: 1-1.5 parts guava glycoside derivative, 1.5-2 parts resveratrol, and 0.5-0.8 parts aurantium; wherein the structural formula of the guava glycoside derivative is: .

[0007] Preferably, the preparation process of the guavaside derivative includes the following steps: (1) Add guavaside to acetone, then add anhydrous potassium carbonate, stir well, and then add 2,3-dibromo-3-phenylpropionic acid for heating reaction; after the reaction is completed, purify to obtain intermediate 1; The structural formula of intermediate 1 is: (2) Ethyl acetoacetate, 7-hydroxycoumarone-3-carboxaldehyde, p-toluenesulfonic acid and urea were added to ethanol and stirred until homogeneous. The mixture was then reacted at 60-70°C. After the reaction was completed, the mixture was purified to obtain intermediate 2. The structural formula of intermediate 2 is as follows: (3) The intermediate 1, the intermediate 2 and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate were added to anhydrous N,N-dimethylformamide, stirred evenly and then triethylamine was added to react; after the reaction was completed, the guava glycoside derivative was obtained by purification.

[0008] Preferably, the molar ratio of guavaside, anhydrous potassium carbonate, and 2,3-dibromo-3-phenylpropionic acid in step (1) is 1:(1.5~1.8):(1~1.2).

[0009] Preferably, the heating reaction in step (1) is carried out at a temperature of 50~60℃ for 12~16h.

[0010] Preferably, the molar ratio of 7-hydroxycoumarone-3-carboxaldehyde, ethyl acetoacetate, p-toluenesulfonic acid, and urea in step (2) is 1:(1.2~1.5):(0.3~0.5):(1.2~1.5).

[0011] Preferably, the reaction time in step (2) is 3 to 5 hours.

[0012] Preferably, the molar ratio of intermediate 1, intermediate 2, 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate, and triethylamine in step (3) is 1:(1.2~1.5):(1.5~2):(2.5~3.2).

[0013] Preferably, the reaction time in step (3) is 4 to 8 hours.

[0014] The second objective of this invention is to provide a method for preparing a pharmaceutical composition for treating chronic obstructive pulmonary disease, which has a simple preparation process.

[0015] The second objective of this invention is achieved by the following technical solution: The preparation method of the above-mentioned pharmaceutical composition for treating chronic obstructive pulmonary disease includes the following steps: Weigh the specified weight proportions of resveratrol, aurantium, and guavaside derivative, mix them evenly, and the drug composition is obtained.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The pharmaceutical composition for treating chronic obstructive pulmonary disease provided by this invention comprises the following raw materials: resveratrol, aurantium styracin, and guava glycoside derivative. Animal experimental results show that the combination of the above components can significantly reduce the expression levels of inflammatory factors IL-6 and TNF-α in bronchoalveolar lavage fluid at low doses, thereby improving lung function in mice.

[0017] 2. This invention utilizes the nucleophilic substitution of the o-dibromo group of guavaside with the o-dibromo group of 2,3-dibromo-3-phenylpropionic acid to prepare intermediate 1. 7-Hydroxycoumarone-3-carboxaldehyde is reacted with ethyl acetoacetate and urea via a Biginelli reaction to obtain intermediate 2. The carboxyl group of intermediate 1 undergoes nucleophilic substitution with an excess of the phenolic hydroxyl group of intermediate 2 to obtain the guavaside derivative. This derivative exhibits no significant cytotoxicity in BEAS-2B cells at concentrations ranging from 5 to 160 μg / mL. Detailed Implementation

[0018] The present invention will be further described below with reference to specific embodiments. It should be noted that, without conflict, the various embodiments or technical features described below can be arbitrarily combined to form new embodiments. Specific conditions not specified in the embodiments shall be performed according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, all reagents or instruments used are conventional products obtained through commercial channels.

[0019] (a) Preparation example Preparation Example 1 provides a guavaside derivative, and the preparation process is as follows: (1) Guava glycoside (CAS: 22255-13-6, 10 mmol) was added to acetone (50 mL), followed by anhydrous potassium carbonate (16 mmol). After stirring evenly, 2,3-dibromo-3-phenylpropionic acid (CAS: 6286-30-2, 11 mmol) was added, and the mixture was gradually heated to 55 °C and reacted for 14 h. The reaction solution was desolvated and diluted with water, then extracted with ethyl acetate. The ethyl acetate phase was collected, washed with 5 wt% sodium hydroxide solution, dried, concentrated, and purified by column chromatography (ethyl acetate / n-hexane volume ratio of 1:3) to obtain intermediate 1. The NMR and mass spectrometry results of intermediate 1 are as follows: 1 HNMR (C 29 H 24 O 13 ,400MHz,DMSO-d6):16.40(s,1H),13.38(s,1H),10.20(s,1H),7.35-7.28(m,6H),6.95(d,1H),6.86(s,1H),6.03( s,1H),5.96(d,1H),5.81(d,1H),5.62(d,1H),5.46(d,1H),4.75(d,2H),4.52(s,1H),4.00-3.65(m,5H); HRMS(ESI) + ):[M+H] + The calculation yields 581.12, and the value is found to be 581.12.

[0020] The specific reactions are as follows: (2) Ethyl acetoacetate (13 mmol), 7-hydroxycoumarone-3-carboxaldehyde (CAS: 42059-55-2, 10 mmol), p-toluenesulfonic acid (4 mmol) and urea (14 mmol) were added to ethanol (50 mL), stirred until homogeneous, and then heated to 65 °C for 4 h. The reaction solution was cooled to room temperature, then poured into crushed ice, stirred for 8 min, filtered, and the filter cake was washed with ice water. The solution was recrystallized from hot ethanol to obtain intermediate 2. The NMR and mass spectrometry results of intermediate 2 are as follows: 1 HNMR (C 17 H 16 N2O6,400MHz,DMSO-d6):10.35(s,1H),9.11(s,1H),7.85(d,1H),7.58(s,1H),7.08 (s,1H),6.45(d,2H),4.95(s,1H),4.09(q,2H),2.28(s,3H),1.17(t,3H); HRMS(ESI + ):[M+H]+ The calculation yields 345.10, and the result is 345.12.

[0021] The specific reactions are as follows: (3) The above intermediate 1 (8 mmol), the above intermediate 2 (11 mmol), and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP, CAS: 128625-52-5, 12 mmol) were added to anhydrous N,N-dimethylformamide (15 mL), stirred evenly, and then triethylamine (24 mmol) was added. The reaction was carried out at room temperature for 6 h. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate / n-hexane volume ratio of 1:5) to obtain the guava glycoside derivative. The NMR and mass spectrometry results of the guava glycoside derivative are as follows: 1 HNMR (C 46 H 38 N2O 18 ,400MHz,DMSO-d6):16.40(s,1H),10.20(s,1H),9.11(s,1H),8.05(d,1H),7.75(s ,1H),7.58(s,1H),7.42(d,1H),7.35-7.28(m,6H),7.08(s,1H),6.95(d,1H),6.86( s,1H),6.12(d,1H),6.03(s,1H),5.96(d,1H),5.62(d,1H),5.43(d,1H),4.95(s,1H ),4.75(d,2H),4.52(s,1H),4.07-3.65(m,7H),2.28(s,3H),1.17(t,3H); HRMS(ESI + ):[M+H] + The calculation yields 907.21, and the result is 907.22.

[0022] The specific reactions are as follows: Preparation Example 2 provides a guavaside derivative, and the preparation process is as follows: (1) Add 10 mmol of guavaside to acetone (50 mL), then add anhydrous potassium carbonate (15 mmol), stir well, and then add 2,3-dibromo-3-phenylpropionic acid (10 mmol). Gradually raise the temperature to 50 °C and react for 16 h. Remove the solvent from the reaction solution under reduced pressure and dilute with water. Extract with ethyl acetate, collect the ethyl acetate phase and wash with 5 wt% sodium hydroxide solution. Dry, concentrate and then purify by column chromatography (ethyl acetate / n-hexane volume ratio of 1:3) to obtain intermediate 1. The NMR and mass spectrometry results of intermediate 1 are the same as those in preparation example 1. (2) Ethyl acetoacetate (12 mmol), 7-hydroxycoumarone-3-carboxaldehyde (10 mmol), p-toluenesulfonic acid (3 mmol) and urea (12 mmol) were added to ethanol (50 mL), stirred until homogeneous, and then heated to 60 °C for 5 h. The reaction solution was cooled to room temperature and then poured into crushed ice. After stirring for 5 min, the mixture was filtered, the filter cake was washed with ice water, and recrystallized from hot ethanol to obtain intermediate 2. The NMR and mass spectrometry results of intermediate 2 were the same as those in preparation example 1. (3) The above intermediate 1 (8 mmol), the above intermediate 2 (10 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP, 10 mmol) were added to anhydrous N,N-dimethylformamide (15 mL), stirred evenly, and then triethylamine (20 mmol) was added. The reaction was carried out at room temperature for 4 h. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate / n-hexane volume ratio of 1:5) to obtain the guava glycoside derivative. The NMR and mass spectrometry results of the guava glycoside derivative were the same as those in Preparation Example 1.

[0023] Preparation Example 3 provides a guavaside derivative, and the preparation process is as follows: (1) Add 10 mmol of guavaside to 50 mL of acetone, then add 18 mmol of anhydrous potassium carbonate, stir well, and then add 12 mmol of 2,3-dibromo-3-phenylpropionic acid. Gradually raise the temperature to 60 °C and react for 12 h. Remove the solvent from the reaction solution under reduced pressure and dilute with water. Extract with ethyl acetate, collect the ethyl acetate phase and wash with 5 wt% sodium hydroxide solution. Dry, concentrate and then purify by column chromatography (ethyl acetate / n-hexane volume ratio of 1:3) to obtain intermediate 1. The NMR and mass spectrometry results of intermediate 1 are the same as those in preparation example 1. (2) Ethyl acetoacetate (15 mmol), 7-hydroxycoumarone-3-carboxaldehyde (10 mmol), p-toluenesulfonic acid (5 mmol) and urea (15 mmol) were added to ethanol (50 mL), stirred until homogeneous, and then heated to 70 °C for 3 h. The reaction solution was cooled to room temperature and then poured into crushed ice. After stirring for 10 min, the mixture was filtered, the filter cake was washed with ice water, and recrystallized from hot ethanol to obtain intermediate 2. The NMR and mass spectrometry results of intermediate 2 were the same as those in preparation example 1. (3) The above intermediate 1 (8 mmol), the above intermediate 2 (12 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP, 15 mmol) were added to anhydrous N,N-dimethylformamide (15 mL), stirred evenly, and then triethylamine (25 mmol) was added. The reaction was carried out at room temperature for 8 h. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate / n-hexane volume ratio of 1:5) to obtain the guava glycoside derivative. The NMR and mass spectrometry results of the guava glycoside derivative were the same as those in Preparation Example 1.

[0024] (II) Implementation Examples Example 1 This embodiment provides a pharmaceutical composition for treating chronic obstructive pulmonary disease, comprising the following components by weight: 1.2 parts of guava glycoside derivative prepared in Preparation Example 1, 1.8 parts of resveratrol, and 0.6 parts of aurantium.

[0025] This embodiment also provides a method for preparing the above-mentioned pharmaceutical composition for treating chronic obstructive pulmonary disease as follows: According to the above-mentioned weight proportions, resveratrol, aurantium, and the guava glycoside derivative prepared in Example 1 were weighed and mixed evenly to obtain the pharmaceutical composition.

[0026] Example 2 This embodiment provides a pharmaceutical composition for treating chronic obstructive pulmonary disease, comprising the following components by weight: 1 part of the guava glycoside derivative prepared in Preparation Example 2, 1.5 parts of resveratrol, and 0.5 parts of aurantium.

[0027] This embodiment also provides a method for preparing the above-mentioned pharmaceutical composition for treating chronic obstructive pulmonary disease as follows: According to the above-mentioned weight proportions, resveratrol, aurantium, and the guava glycoside derivative prepared in Preparation Example 2 were weighed and mixed evenly to obtain the drug composition.

[0028] Example 3 This embodiment provides a pharmaceutical composition for treating chronic obstructive pulmonary disease, comprising the following components by weight: 1.5 parts of the guava glycoside derivative prepared in Preparation Example 3, 2 parts of resveratrol, and 0.8 parts of aurantium.

[0029] This embodiment also provides a method for preparing the above-mentioned pharmaceutical composition for treating chronic obstructive pulmonary disease as follows: According to the above-mentioned weight proportions, resveratrol, aurantium, and the guava glycoside derivative prepared in Preparation Example 3 were weighed and mixed evenly to obtain the drug composition.

[0030] (III) Comparative Example Comparative Example 1 This comparative example provides a pharmaceutical composition comprising, by weight, the following components: 1.2 parts of the guava glycoside derivative prepared in Preparation Example 1 and 1.8 parts of resveratrol.

[0031] Comparative Example 2 This comparative example provides a pharmaceutical composition comprising, by weight, the following components: 1.2 parts guavaside, 1.8 parts resveratrol, and 0.6 parts aurantium.

[0032] (iv) Test Cases Experimental Example 1 Blank control group: 100 μL of α-MEM complete medium and 100 μL of α-MEM medium containing 0.1% DMSO; Negative control group: 100 μL with a density of 1×10 4 Cell suspension of cells / mL and 100 μL of α-MEM medium containing 0.1% DMSO; Experimental group: 100 μL with a density of 1 × 10 4 Cell suspensions of 100 cells / mL and 100 μL of α-MEM medium containing different concentrations (5, 10, 20, 40, 80, 160 μg / mL) of guava glycoside derivatives and 0.1% DMSO.

[0033] Take 100 μL of BEAS-2B cell suspension of human lung (bronchial) epithelial cells in the logarithmic growth phase (concentration of 1×10⁻⁶). 4 Cells (number of cells / mL) were seeded in 96-well plates and cultured at 37°C with 5% CO2 for 12 h. Drug administration was performed according to grouping, with 3 replicates per group. After co-incubation for 24 h, 20 μL of 5 mg / mL MTT was added to each well, and the plates were cultured at 37°C with 5% CO2 for 4 h. The supernatant was removed, and 150 μL of DMSO was added. After 10 min, the OD value of each well was measured at 570 nm. The cell proliferation rate of each group was calculated as follows: Cell proliferation rate (%) = (Experimental group - Blank control group) / (Negative control group - Blank control group) × 100%. The results are shown in Table 1.

[0034] Table 1 As shown in Table 1, guava glycoside derivatives at concentrations ranging from 5 to 160 μg / mL did not exhibit significant cytotoxicity in BEAS-2B cells.

[0035] Experimental Example 2 1. Laboratory animals Eighty male C57BL / 6J wild-type mice aged 6 weeks and weighing 18-20g were randomly divided into the following eight groups: normal control group, COPD model group, positive control group (dexamethasone), Example 1-3 groups, and Comparative Example 1-2 groups.

[0036] 2. Model Building The control group mice were fed normally, while the other groups of mice were used to establish COPD models through smoke inhalation and LPS inhalation. Except for the control group (which received an equal volume of physiological saline), the other groups of mice were injected intratracheally with 2 mL / kg of 10% chloral hydrate on day 1 and day 14 of the experiment. After anesthesia, 1 mg / kg of lipopolysaccharide (LPS) was injected into the trachea of ​​the mice. On day 2 of LPS inhalation, the mice were exposed to smoke 4 times a day (except day 14), for 45 minutes each time, with a 1-hour interval between exposures. The smoke chamber was 50cm×30cm×35cm in size, and 4 standard 1R6F cigarettes were lit each time. The modeling period lasted for 12 weeks.

[0037] 3. Administration method Drug treatment began on day 1 of week 9 of modeling, and the administration method was as follows: Blank control group and COPD model group: Administered an equal volume of normal saline once a day for 28 consecutive days; Positive control group: Administered 0.2 mg / kg dexamethasone solution once daily for 28 consecutive days; Example 1 group: Administered 30 mg / kg of the composition of Example 1 once daily for 28 consecutive days; Example 2 group: Administered 30 mg / kg of the composition of Example 2 once daily for 28 consecutive days; Group 3 of Example: Administered 30 mg / kg of the composition of Example 3 once daily for 28 consecutive days; Comparative Example 1: 30 mg / kg of the composition of Comparative Example 1 was administered once daily for 28 consecutive days; Comparative Example 2: 30 mg / kg of the composition of Comparative Example 2 was administered once daily for 28 consecutive days.

[0038] 4. Detection indicators 4.1 Lung Respiratory Function Test Thirty minutes after the last administration, mice in each group were anesthetized by intraperitoneal injection of 10% chloral hydrate, and then endotracheal intubation was performed. The mice were then connected to a small animal pulmonary function analyzer to detect airway resistance (RI) and dynamic lung compliance (Cydn) in each group. The results are shown in Table 2.

[0039] 4.2 Detection of inflammatory factors in bronchoalveolar lavage fluid After lung respiratory function testing, mice in each group were sacrificed and bronchoalveolar lavage fluid was collected. The levels of IL-6 and TNF-α in the bronchoalveolar lavage fluid were detected using an ELISA kit. The results are shown in Table 3.

[0040] Table 2 Table 3 As shown in Table 2, compared with the blank control group, the COPD model group mice showed increased RI and decreased Cydn, indicating successful construction of the COPD model. Compared with the model group, the RI of Examples 1-3 and the Cydn of Comparative Examples 1-2 decreased, but the effect of Comparative Examples 1-2 was not as good. The above results indicate that the drug composition obtained in this invention can effectively delay the decline of lung function in COPD model mice.

[0041] As shown in Table 3, compared with the model group, the levels of IL-6 and TNF-α were reduced in mice in Examples 1-3 and Comparative Examples 1-2, but the effect of Comparative Examples 1-2 was not as good. These results indicate that the pharmaceutical composition obtained in this invention can reduce the level of lung inflammation in COPD model mice.

[0042] In summary, the pharmaceutical composition of the present invention can significantly reduce the expression levels of inflammatory factors IL-6 and TNF-α in bronchoalveolar lavage fluid at a low dose, thereby improving lung function in mice.

[0043] The above embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-substantial changes and substitutions made by those skilled in the art based on the present invention shall fall within the scope of protection claimed by the present invention.

Claims

1. A pharmaceutical composition for treating chronic obstructive pulmonary disease, characterized in that, The product comprises, by weight, the following components: 1-1.5 parts puerarin derivative, 1.5-2 parts resveratrol, and 0.5-0.8 parts aurantium; the structural formula of the puerarin derivative is: 。 2. The pharmaceutical composition for treating chronic obstructive pulmonary disease according to claim 1, characterized in that, The preparation process of the guava glycoside derivative includes the following steps: (1) Add guavaside to acetone, then add anhydrous potassium carbonate, stir well, and then add 2,3-dibromo-3-phenylpropionic acid for heating reaction; after the reaction is completed, purify to obtain intermediate 1; The structural formula of intermediate 1 is: (2) Ethyl acetoacetate, 7-hydroxycoumarone-3-carboxaldehyde, p-toluenesulfonic acid and urea were added to ethanol and stirred until homogeneous. The mixture was then reacted at 60-70°C. After the reaction was completed, the mixture was purified to obtain intermediate 2. The structural formula of intermediate 2 is as follows: (3) The intermediate 1, the intermediate 2 and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate were added to anhydrous N,N-dimethylformamide, stirred evenly and then triethylamine was added to react; after the reaction was completed, the guava glycoside derivative was obtained by purification.

3. The pharmaceutical composition for treating chronic obstructive pulmonary disease according to claim 2, characterized in that, The molar ratio of guavaside, anhydrous potassium carbonate, and 2,3-dibromo-3-phenylpropionic acid in step (1) is 1:(1.5~1.8):(1~1.2).

4. The pharmaceutical composition for treating chronic obstructive pulmonary disease according to claim 2, characterized in that, The heating reaction in step (1) is carried out at a temperature of 50~60℃ for 12~16h.

5. The pharmaceutical composition for treating chronic obstructive pulmonary disease according to claim 2, characterized in that, The molar ratio of 7-hydroxycoumarone-3-carboxaldehyde, ethyl acetoacetate, p-toluenesulfonic acid, and urea in step (2) is 1:(1.2~1.5):(0.3~0.5):(1.2~1.5).

6. The pharmaceutical composition for treating chronic obstructive pulmonary disease according to claim 2, characterized in that, The reaction time in step (2) is 3 to 5 hours.

7. The pharmaceutical composition for treating chronic obstructive pulmonary disease according to claim 2, characterized in that, The molar ratio of intermediate 1, intermediate 2, 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate and triethylamine in step (3) is 1:(1.2~1.5):(1.5~2):(2.5~3.2).

8. The pharmaceutical composition for treating chronic obstructive pulmonary disease according to claim 2, characterized in that, The reaction time in step (3) is 4 to 8 hours.

9. A method for preparing a pharmaceutical composition for treating chronic obstructive pulmonary disease according to any one of claims 1 to 8, characterized in that, Includes the following steps: Weigh the specified amounts of resveratrol, aurantium, and guavaside derivative, mix them thoroughly, and the pharmaceutical composition is obtained.

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