Clathrate compound of ring-opened cucurbituril and minoxidil as well as preparation method and application of clathrate compound

Abstract

The invention discloses a ring-opened cucurbituril and minoxidil clathrate compound and a preparation method and application thereof.The preparation method comprises the steps that minoxidil is added into a ring-opened cucurbituril aqueous solution, stirring is conducted in a dark place, a clathration reaction is conducted, and a mixture is prepared; and enabling the mixture to pass through a microfiltration membrane, and freeze-drying to obtain the clathrate compound. The preparation method disclosed by the invention is simple in process, mild in condition and suitable for industrial production; the minoxidil is included by specific ring-opening cucurbituril with a more regular cavity structure, so that specific molecules can be identified and combined more accurately, and the interference of impurities on host-guest combination is reduced; the minoxidil is included, so that the water solubility of the minoxidil is improved; the bioavailability of the medicine is enhanced, the transdermal absorption efficiency is improved, the local irritation is reduced, the stability and the uniformity of the preparation are improved, various dosage forms can be conveniently developed, the administration dosage and the side effect are reduced, the use comfort of a patient is improved, the clinical application range is expanded, the production process control is optimized, the medicine storage and transportation convenience is improved, and the application prospect is good.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of supramolecular technology, and relates to a clathrate of open ring cucurbituril and minoxidil, and a preparation method and application thereof. BACKGROUND

[0002] Minoxidil is a drug widely used in hair loss treatment and hypertension management. Initially developed as an oral antihypertensive drug, it was later found that its external use could effectively promote hair growth, gradually becoming a commonly used drug for treating hair loss. Minoxidil can expand blood vessels, increase local blood flow, provide more nutrients for hair follicles, and prolong the growth period of hair, thus stimulating dormant hair follicles to re-enter the growth phase, thereby improving hair loss problems. It is mainly used to treat male pattern hair loss (androgenic alopecia), female pattern hair loss, and alopecia areata and other hair thinning problems. It is usually used in the form of solution or foam, applied daily to the scalp, and significant effects can be seen after several months of continuous use.

[0003] Minoxidil shows significant efficacy in clinical application, but its limitations are also quite obvious, especially the problem of water solubility which limits its more extensive application. Minoxidil has poor water solubility, which directly affects the stability and bioavailability of its preparations. Due to its low water solubility, organic solvents such as ethanol and propylene glycol are needed to increase the solubility when preparing external solutions, but these solvents can cause scalp irritation, dryness or allergic reactions, reducing patient tolerance and compliance. In addition, the poor water solubility of minoxidil also leads to limited permeability when administered topically, making it difficult to effectively penetrate the skin barrier to reach the target site of hair follicles or vascular smooth muscle, thereby affecting its efficacy. In order to improve the water solubility and bioavailability of minoxidil, various strategies have been tried by those skilled in the art, including using nano-carriers (such as liposomes, nano-emulsions and polymer nanoparticles) to encapsulate minoxidil to enhance its solubility and skin permeability; developing prodrug technology to improve its water solubility through chemical modification; and using cyclodextrin inclusion and other solubilization technologies to improve its solubility characteristics. Although these methods have improved the water solubility problem of minoxidil to some extent, they still face the challenges of technical complexity and high cost. In addition, the poor water solubility of minoxidil also limits the diversification of its dosage forms, such as the difficulty in developing high-efficiency water-based preparations or transdermal patches, which further limits its application flexibility in clinical practice. Therefore, the water solubility problem is an important bottleneck in the research and development of minoxidil, and further exploration of more efficient and economical solubilization technologies and new delivery systems is needed in the future to overcome this limitation and fully realize its therapeutic potential.

[0004] Therefore, it is of great practical significance to develop a minoxidil clathrate that can solve the problem of poor water solubility at low cost. SUMMARY

[0005] Due to the above defects of the prior art, the present application provides a low-cost solution to the poor water solubility of minoxidil, specifically a cucurbituril and minoxidil inclusion compound, a preparation method and application thereof, which overcomes the defects of the current technology for solving the poor water solubility of minoxidil, such as complexity, high cost and poor economy.

[0006] In order to achieve the above-mentioned purpose, the present application provides the following technical solutions:

[0007] A preparation method of a cucurbituril and minoxidil inclusion compound, comprising the following steps:

[0008] (1) adding minoxidil into a cucurbituril aqueous solution, stirring under light protection to carry out an inclusion reaction, and preparing a mixture, wherein the cucurbituril is a compound shown in formula I, and the formula I is ;

[0009] (2) filtering the mixture through a microporous filter membrane, and freeze-drying to obtain the cucurbituril and minoxidil inclusion compound.

[0010] The preparation method of the cucurbituril and minoxidil inclusion compound of the present application has simple process and mild conditions, and is suitable for industrial production. The specific cucurbituril is used to include minoxidil, the specific cucurbituril has a more regular cavity structure, can more accurately recognize and combine specific molecules (such as drugs, metal ions, organic dyes, etc.), and reduces the interference of impurities on the host-guest combination. The inclusion of minoxidil greatly improves the water solubility of minoxidil, enhances the drug bioavailability, improves the transdermal absorption efficiency, reduces local irritation, improves the stability and uniformity of the preparation, facilitates the development of various dosage forms (such as solution, gel, microemulsion, etc.), reduces the dosage and side effects, improves the patient's comfort, expands the clinical application range (such as foam or spray), optimizes the production process control, and improves the convenience of drug storage and transportation, which has good application prospect.

[0011] As a preferred technical solution:

[0012] In step (1) of the preparation method, the molar ratio of the cucurbituril to minoxidil is 1:1.2.

[0013] The inclusion reaction is carried out under inert gas protection, the reaction time of the inclusion reaction is 35-37 h, the reaction temperature is 23-27 ℃, and the stirring speed of the stirring is 300-500 rpm.

[0014] In step (2) of the preparation method, the microporous filter membrane refers to that the mixture is filtered through a 0.22 μm polyether sulfone microporous filter membrane under reduced pressure.

[0015] The specific operation of the freeze-drying is: pre-freezing for 4 hours at -50°C, then freeze-drying at a temperature of -80 to -90°C, a vacuum degree of 10 to 30 Pa, and a drying time of 40 to 48 hours.

[0016] The preparation method of the open ring cucurbituril is as follows:

[0017] A1) Compound A is dissolved in a mixed solution of trifluoroacetic acid and acetic anhydride;

[0018] A2) Compound B is added to the mixed solution, and the reaction is carried out at 70 to 80°C for 3 to 5 hours, then the reaction solution is added to a methanol solution, and white solid is precipitated, and stirring is continued for 2 to 4 hours;

[0019] A3) A light yellow solid is obtained by filtration, and the filter cake is added to boiling water and stirred until it is completely dissolved;

[0020] A4) White precipitate is produced after adding acetone dropwise;

[0021] A5) Steps A3 and A4 are repeated multiple times, and then vacuum drying is performed to obtain the open ring cucurbituril;

[0022] The compound A is , and the compound B is .

[0023] The preparation method of the compound A is as follows:

[0024] B1) Compound C is added to anhydrous methane sulfonic acid, and stirring is carried out at 50 to 60°C until it is completely dissolved;

[0025] B2) Etherified methyl glycoluril is added thereto, and the reaction solution is stirred at 50 to 60°C for 3 to 5 hours;

[0026] B3) After the reaction is completed, the reaction solution is cooled to room temperature, and then the reaction solution is slowly added to 3L of acetone, and stirring is continued for 1 to 2 hours;

[0027] B4) The reaction solution in B3 is filtered to obtain filter residue, and the filter residue is dispersed in acetone, and the reaction is continued for 1 to 2 hours;

[0028] B5) The filter residue is obtained by filtration, and vacuum drying is performed on the filter residue to obtain the compound A with a purity of 88%;

[0029] The compound C is .

[0030] The preparation method of the compound B is as follows:

[0031] C1) 1,4-benzenediol is added to a NaOH solution and stirred until it is dissolved;

[0032] C2) adding 1,3-benzenesulfonic acid lactone in the mixture, and reacting at 60-70°C for 12-16h;

[0033] C3) cooling the reaction solution after the reaction is completed, and re-precipitating with proper amount of acetone;

[0034] C4) filtering the white solid precipitated in C3, and washing the filter cake with water for 3 times;

[0035] C5) vacuum drying the filter cake obtained by the last filtering to obtain compound B, with a yield of 75%.

[0036] The preparation method of the etherified methylated glycoluril is as follows:

[0037] D1) dissolving methylated glycoluril in hydrochloric acid solution, and stirring at room temperature until completely dissolved;

[0038] D2) adding paraformaldehyde into the reaction solution, and stirring the reaction solution at room temperature for 24h, with the ratio of methylated glycoluril and paraformaldehyde being 1:5;

[0039] D3) adding deionized water after the reaction is completed, and continuing to stir for 1-3h;

[0040] D4) filtering the reaction solution, and stirring the filter residue in water for 1h;

[0041] D5) filtering the product obtained in step D4, and vacuum drying to obtain etherified methylated glycoluril, with a yield of 68.9%.

[0042] The preparation method of the methylated glycoluril is as follows:

[0043] E1) weighing a mixture of urea and hydrochloric acid solution, and stirring at room temperature until completely dissolved, with the ratio of urea and 2,3-butanedione being 3:1 to ensure efficient reaction, and the ratio can be adjusted appropriately during the reaction to optimize the reaction conditions and improve the yield of the final product;

[0044] E2) adding 2,3-butanedione dropwise into the above reaction solution, and reacting at room temperature for 10-14h;

[0045] E3) filtering the above reaction solution to obtain white solid;

[0046] E4) washing the separated liquid with clean water for multiple times until the aqueous phase is neutral, and drying and filtering;

[0047] E5) vacuum drying to obtain methylated glycoluril (with a purity of 96%).

[0048] The preparation method of the present application significantly improves the purity of the open ring cucurbituril.

[0049] The application provides the inclusion compound of the open-looped cucurbituril and minoxidil prepared by the preparation method, which greatly improves water solubility of the minoxidil, enhances drug bioavailability, improves transdermal absorption efficiency, reduces local irritation, improves preparation stability and uniformity, facilitates development of various dosage forms (such as solution, gel, microemulsion and the like), reduces a drug dose and side effects, improves patient comfort, expands a clinical application range (such as foam or spray), optimizes production process control and improves convenience of drug storage and transportation.

[0050] In addition, the application also provides application of the inclusion compound of the open-looped cucurbituril and minoxidil in hair loss treatment and blood pressure reduction.

[0051] The above technical scheme is only one possible technical scheme of the application, and the protection scope of the application is not limited to this, and a person skilled in the art can reasonably adjust the specific design according to actual needs.

[0052] The above application has the following advantages or beneficial effects:

[0053] (1) The preparation method of the inclusion compound of the open-looped cucurbituril and minoxidil is simple in method process, mild in conditions and suitable for industrial production.

[0054] (2) The preparation method of the inclusion compound of the open-looped cucurbituril and minoxidil uses specific open-looped cucurbituril to include minoxidil, the specific open-looped cucurbituril has a more regular cavity structure, can more accurately identify and combine specific molecules (such as drugs, metal ions, organic dyes and the like), and reduces interference of impurities on host-guest combination.

[0055] (3) The preparation method of the inclusion compound of the open-looped cucurbituril and minoxidil greatly improves water solubility of the minoxidil, enhances drug bioavailability, improves transdermal absorption efficiency, reduces local irritation, improves preparation stability and uniformity, facilitates development of various dosage forms (such as solution, gel, microemulsion and the like), reduces a drug dose and side effects, improves patient comfort, expands a clinical application range (such as foam or spray), optimizes production process control and improves convenience of drug storage and transportation, and has a good application prospect. DETAILED DESCRIPTION

[0056] The application will be further described below in combination with specific examples, but is not limited to the application.

[0057] Example 1

[0058] A preparation method of an inclusion compound of open-looped cucurbituril and minoxidil, comprising the following steps:

[0059] The specific steps of step A are as follows:

[0060] A1, weigh the mixture of urea and hydrochloric acid solution, stir at room temperature until it is completely dissolved;

[0061] Weigh 50.0 g (0.83 mol) of urea and 300 mL of 1 mol / L hydrochloric acid solution into a 500 mL three-necked flask, stir with a magnetic stirrer (speed 300 rpm) at 25±2°C for 30 min until completely dissolved, forming a homogeneous transparent solution.

[0062] A2, add 2,3-butanedione dropwise to the above reaction solution, react at room temperature for 10-14 h;

[0063] Load 75.0 g (0.87 mol) of 2,3-butanedione into a constant pressure dropping funnel, control the dropping rate at 1-2 drops per second (about 2 h to drop), and maintain the reaction system temperature at 25±2°C. After the addition is completed, continue to stir for 12±2 h, and monitor the reaction process by TLC (developing agent V (ethyl acetate): V (petroleum ether)=1:3).

[0064] A3, filter the above reaction solution to obtain white solid;

[0065] Filter the reaction mixture through a Buchner funnel (pore size 10-15 μm) under reduced pressure, collect the white crystalline solid, and rinse the filter cake with 50 mL of pre-cooled deionized water (4°C) three times.

[0066] A4, wash the liquid with water three times until the water phase reaches neutral, and dry and filter;

[0067] Transfer the crude product to a separatory funnel, add 300 mL of deionized water for water washing, and repeat the separation operation three times until the pH value of the water phase reaches 6.5-7.0 (determined by pH test paper). The obtained solid is placed in a watch glass and pre-dried in a 40°C air-drying oven for 2 h.

[0068] A5, finally placed in a vacuum drying oven, and finally obtained the product of methylated glycol with a purity of 96%.

[0069] Transfer the pre-dried product to a vacuum drying oven, set the parameters as follows: temperature 60±5°C, vacuum degree-0.095 MPa, dry for 6 h to obtain white needle-shaped crystals. HPLC analysis (chromatographic column: C18, mobile phase: methanol / water=70 / 30) shows that the product purity is 96.2% (area normalization method).

[0070] The specific steps of step B are as follows:

[0071] B1, dissolve the methylated glycol in hydrochloric acid solution, stir at room temperature until completely dissolved;

[0072] Methylated glycoluril (10.0 g, 0.075 mol) was weighed into a 250 mL three-necked flask, 1 mol / L hydrochloric acid solution (100 mL) was added, and magnetic stirring (speed 300 rpm) was carried out at 25±2°C until complete dissolution, forming a homogeneous transparent solution.

[0073] B2, polyformaldehyde was added to the reaction solution, and the reaction solution was stirred at room temperature for 24 h;

[0074] Polyformaldehyde (4.5 g, 0.15 mol) was added to the above solution in batches, and the feeding rate was controlled to avoid local overheating. After the feeding was completed, the stirring was continued at 25±2°C for 24±1 h, and the reaction process was monitored by TLC (developing agent V (ethyl acetate): V (petroleum ether)=1:2).

[0075] B3, after the reaction was completed, deionized water was added, and stirring was continued for 1-3 h;

[0076] After the reaction was completed, deionized water (100 mL) was slowly added to the system, and the temperature was maintained at 25±2°C to continue stirring for 2±0.5 h to fully dissolve the by-products.

[0077] B4, the reaction solution was filtered, and the filter residue was added to water and stirred for 1 h;

[0078] The reaction mixture was filtered under reduced pressure through a Buchner funnel (pore size 10-15 μm), the filter residue was collected and redispersed with deionized water (50 mL), stirred for 1 h, and then filtered again. This washing step was repeated once.

[0079] B5, the product obtained in step B4 was filtered, and the white solid obtained was placed in a vacuum drying oven to obtain white pure etherified methylated glycoluril, with a yield of 68.9%.

[0080] The white solid obtained was transferred to a vacuum drying oven, and the parameters were set as follows: temperature 50±5°C, vacuum degree -0.09 MPa, and drying time 6 h to obtain white crystalline etherified methylated glycoluril. HPLC analysis (chromatographic column: C18, mobile phase: acetonitrile / water=60 / 40) showed that the product purity was ≥98.0% (area normalization method), and the yield was 68.9%.

[0081] The specific steps of step C are as follows:

[0082] C1, the dimer was weighed into anhydrous methane sulfonic acid, and stirring was carried out at 50°C until complete dissolution;

[0083] The dimer (15.0 g, 0.05 mol) was added into a 500 mL three-necked flask, and anhydrous methane sulfonic acid (150 mL) was injected under nitrogen protection. The temperature was raised to 50±2℃, and mechanical stirring (200 rpm) was applied until complete dissolution, forming a homogeneous solution.

[0084] C2, and then etherified methylated glycoluril was added thereto, and the reaction solution was stirred at 50℃ for 3-5 h;

[0085] The reaction temperature was controlled at 50±2℃, and etherified methylated glycoluril (12.8 g, 0.06 mol) was added in batches within 30 min. After the addition was completed, the temperature was maintained and the reaction was continued for 4±0.5 h, during which the reaction progress was monitored by HPLC (C18 column, acetonitrile / water=70 / 30).

[0086] C3, after the reaction was completed, the reaction solution was cooled to room temperature, and then the reaction solution was slowly added to 3 L of acetone, and stirring was continued for 1-2 h;

[0087] The reaction system was cooled to 25±3℃, and was slowly added dropwise to pre-cooled acetone (3 L, 0-5℃) under stirring (150 rpm), and the dropwise rate was controlled at about 1 mL / min. After the dropwise addition was completed, stirring was continued for 1.5±0.5 h to allow the product to be completely precipitated.

[0088] C4, the reaction solution in C3 was filtered to obtain a filter residue, which was dispersed in acetone and the reaction was continued for 1-2 h;

[0089] The precipitate was collected by vacuum filtration through a Buchner funnel (pore size 5-10 μm), and the filter cake was re-dispersed in fresh acetone (500 mL), and was treated by ultrasonic (40 kHz, 10 min) and then stirred for 1 h, and was filtered again. The washing operation was repeated once.

[0090] C5, the filter residue was filtered, and was placed in a vacuum drying oven to obtain the pure product of the tetramer, with a purity of 88%.

[0091] The final filter cake was transferred to a vacuum drying oven, and was dried at 45±5℃ and -0.095 MPa for 8 h to obtain a white powder of the tetramer. The product was analyzed by nuclear magnetic resonance (1H NMR, DMSO-d6) and HPLC (C18 column, acetonitrile / water gradient elution), and the purity was 88.0% (area normalization method), and the yield was 72.3%.

[0092] The specific steps of Step D are as follows:

[0093] D1, 1,4-benzenediol was added to a NaOH solution, and was stirred until dissolution;

[0094] A mechanical stirrer, thermometer and nitrogen protection device were installed in a 1000 mL three-necked flask. 700 mL of NaOH (2.5 M) solution was added as a reaction solvent. 1,4-benzenediol (50 g, 0.45 mol) was weighed and slowly added to the reaction flask, and stirred to completely dissolve at a temperature below 25°C to form a colorless transparent solution.

[0095] D2, propylsulfone lactone was added to the mixture, and the reaction was stirred and heated;

[0096] The reaction temperature was maintained at 50-60°C, and propylsulfone lactone (1.13 mol) was added in batches, and the feeding rate was controlled to ensure that the temperature did not exceed 60°C. After the addition was completed, the stirring was continued for 12 h to make the system mixed uniformly and fully reacted.

[0097] D3, the reaction solution was cooled, and then the reaction solution was reprecipitated with an appropriate amount of acetone;

[0098] After the addition was completed, the heating was stopped, and the reaction system was naturally lowered to 25±2°C. Re-precipitation was performed with 100 mL of acetone, and the process was repeated three times.

[0099] D4, the white solid precipitated in D3 was filtered, and the filter cake was washed with an aqueous solution three times.

[0100] After the reaction was completed, 200 mL of deionized water was slowly added to the reaction solution to quench the reaction, and the addition rate was controlled to avoid violent exothermic. After the addition was completed, the stirring was continued for 30 min to make the product fully precipitate. The white solid was collected by vacuum filtration through a Buchner funnel (pore size 10-15 μm).

[0101] D5, the filter cake obtained by the last filtration was placed in a vacuum drying oven to obtain Wall-1 white product with a yield of 75%.

[0102] The filter cake was washed with a pre-cooled methanol / water mixed solution (V / V=1 / 1, 300 mL) in three times, each time 100 mL. Finally, the product was transferred to a vacuum drying oven, and dried at 40±2°C, -0.095 MPa for 12 h to obtain white powder Wall-1 product. HPLC analysis (chromatographic column: C18, mobile phase: methanol / water=80 / 20) showed that the product purity was 98.5% (area normalization method), and the yield was 75.2%.

[0103] The reaction equation of step D is as follows:

[0104]

[0105] The specific steps of step F are as follows:

[0106] F1, the product of step C was added to a mixed solution of trifluoroacetic acid and acetic anhydride, and stirred until dissolved;

[0107] In a 1000 mL three-necked flask, add trifluoroacetic acid / acetic anhydride mixed solution (V / V=3 / 1, 300 mL), install mechanical stirrer, thermometer and reflux condenser. Weigh the product of Step C (30.0 g, 0.1 mol) and add it into the mixed solution in batches, control the feeding rate to maintain the temperature at 25±2°C. After the feeding is completed, continue to stir for 30 min until it is completely dissolved to form a homogeneous solution.

[0108] F2, add the product of D into it, and react the solution at 70°C for 3 h, then add the reaction solution into the methanol solution, and white solid is precipitated, continue to stir for 2 h;

[0109] Add the product of Step D (35.2 g, 0.12 mol) into the reaction system in three times with an interval of 15 min. Increase the temperature to 70±1°C in the oil bath, and keep the stirring rate at 400 rpm for 3±0.1 h. The reaction process is monitored by TLC (developing agent: dichloromethane / methanol=10 / 1).

[0110] F3, filter to obtain light yellow solid, and add the filter cake into boiling water and stir until it is completely dissolved;

[0111] After the reaction is completed, cool the system to below 30°C. Slowly drop the reaction solution into the pre-cooled methanol solution (800 mL, 0-5°C) under stirring, and control the dropping speed (about 2 mL / min). After the dropping is completed, continue to stir for 2±0.1 h to make the product precipitate.

[0112] F4, white precipitate is generated after the addition of acetone, repeat the steps of F3 and F4 three times, and place the product in a vacuum drying box to obtain ACB white pure product;

[0113] Collect the light yellow solid by pressure filtration through a Buchner funnel (pore size 5-10 μm). Transfer the filter cake into a 500 mL beaker, add boiling deionized water (300 mL), and stir at 95°C until it is completely dissolved. Filter to remove the insoluble substances while hot, and slowly drop acetone (150 mL) into the filtrate after it is cooled to 50°C, and control the dropping speed (1 drop / s) to make the white crystals slowly precipitate. Repeat the recrystallization operation of Step S604 three times. Filter the final product through a G4 sand core funnel, and wash it with cold acetone (50 mL) three times. Transfer the product into a vacuum drying box, and set the parameters as follows: temperature 60±1°C, vacuum degree -0.098 MPa, and dry for 12 h. Obtain white powder ACB product, which is analyzed by HPLC (C18 column, acetonitrile / water=65 / 35) and has a purity of ≥99.5% and a yield of 78.2%.

[0114] The reaction equation of Step F is as follows:

[0115]

[0116] The specific steps of step G are as follows:

[0117] G1, dissolve the open-ring cucurbitacin in water, add minoxidil, and stir in the dark for 36 h;

[0118] In a 20 mL brown light-protected reaction flask, add 16 mL of ultrapure water and 0.2 g (0.2 mmol) of open-ring cucurbituril. Stir magnetically (300 rpm) at 25 ± 2 °C until completely dissolved. Then add minoxidil (50 mg (0.24 mmol), purge with nitrogen, and stir continuously for 36 ± 1 h in the dark.

[0119] G2, the mixed solution from the previous step is filtered through a microporous membrane and then freeze-dried to obtain the inclusion complex;

[0120] The reaction solution was filtered under reduced pressure through a 0.22 μm microporous membrane (polyethersulfone material), and the clear filtrate was collected. The filtrate was transferred to a lyophilization bottle, pre-frozen at -50℃ for 4 h, and then freeze-dried (cold trap temperature: -80℃, vacuum degree: 10 Pa, drying time: 48 h) to obtain a white, loose inclusion complex powder, i.e., the inclusion complex.

[0121] The inclusion ratio of the host (open-ring cucurbituril) to the guest (minoxidil) was 1:1 as demonstrated by 1H NMR, 2D-ROESY, phase solubility curves, and molecular docking simulation experiments. Furthermore, the water solubility of the minoxidil inclusion complex was increased by 31 times by the internal standard method, which solves the problem of skin allergy caused by the need for a large amount of propylene glycol to dissolve minoxidil.

[0122] Comparative Example 1

[0123] A method for preparing an inclusion complex of open-ring cucurbituril and minoxidil is basically the same as that in Example 1, except that the product of step D in step F is replaced with the product of step E and the molar amount added is the same.

[0124] The reaction equation is as follows:

[0125]

[0126] The specific steps of step E are as follows:

[0127] E1, Weigh out hydroquinone and add it to water, then add sodium hydroxide solution and stir until dissolved;

[0128] In a 500 mL three-necked flask, add 200 mL of deionized water and 22.0 g (0.20 mol) of hydroquinone sequentially. Attach a mechanical stirrer, thermometer, and reflux condenser. Slowly add 40.0 g (0.20 mol) of 20% sodium hydroxide aqueous solution at 25 ± 2 °C, controlling the dropping rate to keep the temperature below 30 °C. After the addition is complete, continue stirring for 30 min until the system becomes a homogeneous, transparent solution.

[0129] E2, add 1,3-propanesulfonic acid lactone to the reaction solution and stir at 50°C for 10-12 hours;

[0130] Add 24.4 g (0.20 mol) of 1,3-propanesulfonate lactone to the above solution in portions over a period of 30 min. Heat the solution to an oil bath at 50 ± 1 °C and maintain a stirring rate of 300 rpm for 11 ± 0.5 h. Monitor the reaction process by HPLC (C18 column, mobile phase: 0.1% phosphoric acid aqueous solution / methanol = 70 / 30).

[0131] E3, after cooling, acetone was added to the reaction solution, stirred for 30-45 min, and filtered to obtain a gray solid;

[0132] After the reaction was complete, the system was allowed to cool naturally to 25±3℃. Acetone (400 mL) was slowly added while stirring, controlling the addition rate (approximately 5 mL / min) to avoid local precipitation. After the addition was complete, stirring was continued for 40±5 min to allow the product to fully precipitate.

[0133] E4, the filter cake obtained from the final filtration was dried in a vacuum drying oven to obtain Wall-2 gray pure product, with a yield of 82%.

[0134] The product was transferred to a vacuum drying oven, and the drying parameters were set as follows: temperature 45±2℃, vacuum degree -0.090 MPa, and drying time 8h. A gray powder of Wall-2 was obtained. Elemental analysis and HPLC detection (chromatographic conditions as above) showed that the product purity was 99.1% (area normalization method), and the yield was 82.3%.

[0135] The reaction equation for step E is as follows:

[0136]

[0137] The result was obtained by internal standard method. The water solubility of the minoxidil inclusion complex was increased by 25 times. Comparative Example 1 and Comparative Example 1 show that... The minoxidil inclusion complex further enhances the water solubility of minoxidil.

[0138] Those skilled in the art should understand that variations can be implemented by combining existing technology with the above embodiments, which will not be elaborated here. Such variations do not affect the essence of the present invention and will not be elaborated here.

[0139] The preferred embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and the devices and structures not described in detail should be understood as being implemented in a conventional manner in the art. Any person skilled in the art can make many possible variations and modifications to the technical solutions of the present invention using the methods and techniques disclosed above, or modify them into equivalent embodiments with equivalent changes, without departing from the scope of the present invention. This does not affect the essential content of the present invention. Therefore, any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the present invention's technical solutions still fall within the protection scope of the present invention.

Claims

1. A method for preparing an inclusion complex of open-ring cucurbituril and minoxidil, characterized in that, Includes the following steps: (1) Minoxidil was added to an aqueous solution of open-ring cucurbituril, and the mixture was stirred in the dark to carry out an inclusion reaction, thereby obtaining a mixture. The open-ring cucurbituril is a compound as shown in Formula I. ; (2) The mixture was filtered through a microporous membrane and freeze-dried to obtain the inclusion complex of open-ring cucurbituril and minoxidil.

2. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of the open-ring cucurbita to minoxidil is 1:1.2; The inclusion reaction is carried out under inert gas protection, with a reaction time of 35-37 h, a reaction temperature of 23-27 ℃, and a stirring speed of 300-500 rpm.

3. The preparation method according to claim 1, characterized in that, In step (2), the microporous filter membrane refers to the mixture being filtered under reduced pressure through a 0.22 μm polyethersulfone microporous filter membrane; The specific freeze-drying operation is as follows: pre-freezing at -50℃ for 4 hours followed by freeze-drying, wherein the freeze-drying temperature is -80 to -90℃, the vacuum degree is 10 to 30 Pa, and the drying time is 40 to 48 hours.

4. The preparation method according to claim 1, characterized in that, The preparation method of the open-ring cucurbituril is as follows: A1) Dissolve compound A in a mixed solution of trifluoroacetic acid and acetic anhydride; A2) Add compound B to the mixed solution and react at 70℃~80℃ for 3~5h. Then add the reaction solution to methanol solution, and a white solid precipitates out. Continue stirring for 2~4h. A3) Filter to obtain a pale yellow solid. Add the filter cake to boiling water and stir until fully dissolved. A4) A white precipitate forms after adding acetone; A5) Repeat steps A3 and A4 multiple times, then vacuum dry to obtain open-ring cucurbita; The compound A is The compound B is .

5. The preparation method according to claim 4, characterized in that, The preparation method of compound A is as follows: B1) Add compound C to anhydrous methanesulfonic acid and stir at 50-60°C until it is completely dissolved; B2) Add etherified methylated urea to it, and stir the reaction solution at 50-60°C for 3-5 hours; B3) After the reaction is complete, cool the reaction solution to room temperature, then slowly add the reaction solution to 3L of acetone and continue stirring for 1-2 hours; B4) Filter the reaction solution in B3 to obtain filter residue, disperse the filter residue in acetone, and continue the reaction for 1-2 hours; B5) The filter residue is obtained by filtration and vacuum drying to obtain compound A; The compound C is .

6. The preparation method according to claim 4, characterized in that, The preparation method of compound B is as follows: C1) Add 1,4-benzenediol to the NaOH solution and stir until dissolved; C2) Add 1,3-benzenesulfonate lactone to the mixture and react fully at 60-70°C for 12-16 hours; C3) After the reaction is complete, cool the reaction solution and use an appropriate amount of acetone for back precipitation; C4) Filter the white solid precipitated from C3, and wash the filter cake with water three times; C5) The filter cake obtained from the final filtration was vacuum dried to obtain compound B.

7. The preparation method according to claim 5, characterized in that, The preparation method of the etherified methylated glycourea is as follows: D1) Dissolve methylated glycyrrhizin in hydrochloric acid solution and stir at room temperature until completely dissolved; D2) Add paraformaldehyde to the reaction solution and stir the reaction solution at room temperature for 24 hours; D3) After the reaction is complete, add deionized water and continue stirring for 1-3 hours; D4) Filter the reaction solution and add the filter residue to water and stir for 1 hour; D5) The product obtained in step D4 is filtered and then vacuum dried to obtain etherified methylated glycourea.

8. The preparation method according to claim 7, characterized in that, The method for preparing the methylated glycourea is as follows: E1) Weigh the mixture of urea and hydrochloric acid solution and stir at room temperature until it is completely dissolved; E2) Add 2,3-butanedione dropwise to the above reaction solution and react at room temperature for 10-14 h; E3) The above reaction solution was filtered to obtain a white solid; E4) Wash the separated liquid multiple times with clean water until the aqueous phase reaches neutrality, and then dry and filter. E5) Vacuum drying yields methylated glycourea.

9. The inclusion complex of open-ring cucurbituril and minoxidil prepared by the preparation method according to any one of claims 1 to 8.

10. The application of the inclusion complex of open-ring cucurbituril and minoxidil according to claim 9 in the treatment of hair loss and in lowering blood pressure.

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