Preparation method of photo-crosslinking agent compound
By using xanthotoxin as a starting material and combining mild reactions such as etherification, hydrolysis, amide condensation, and deBoc, the problem of low yield in the synthesis route of photocrosslinking agent compounds was solved, and high-purity and high-yield compound preparation was achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202410622280.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-05-20
- Publication Date
- 2025-11-21
AI Technical Summary
Existing synthetic routes for photocrosslinking agents suffer from low reaction yields and difficulty in achieving industrial-scale production.
Using xanthotoxin as the starting material, a high-purity photocrosslinking agent compound was prepared through mild reactions such as etherification, hydrolysis, amide condensation, and deBoc, using a reaction system of DMF, potassium iodide, and a refined solvent system.
This study achieved the preparation of photocrosslinking agent compounds with high yield and high purity, making them suitable for industrial production, reducing costs and improving the commercial prospects of the products.
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Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the field of medicine and chemical industry, and particularly relates to a preparation method of a photocrosslinking agent compound (N-(19-(3-(but-3-yn-1-yl)-3H-diazirine-3-yl)-4,16-dioxo-7,10,13-trioxo-3,17-diazadecyl)-4-(7-oxo-7H-furo[3,2-g]benzopyran-9-yl)oxy)butanamide). BACKGROUND
[0002] With the application of mass spectrometry and bioinformatics in chemical probes, scientists have found that more and more biological targets play a crucial role in medical research and drug discovery. PAL (photoaffinity labeling) is a powerful tool for identifying targets or binding sites in biological systems, which includes four commonly used photo-reactive groups, namely aryl azides (AZs), benzophenones (BPs), diazirines (DAs) and 2-aryl-5-carboxy tetrazoles (ACTs). Under the excitation of ultraviolet light of a specific wavelength, the corresponding intermediates are nitrene, diradical, carbene and carboxy nitrile imine, respectively. Among them, carbene-mediated photoaffinity labeling is widely used for drug target identification.
[0003] Crosslinking refers to the process of chemically binding two or more molecules through covalent bonds. Crosslinking agents contain reactive ends that can react with specific functional groups on proteins or other molecules, such as primary amines and sulfhydryl groups. Proteins and polypeptides have multiple chemical groups that can be used for crosslinking, so proteins and polypeptides can serve as coupling targets for research using crosslinking methods.
[0004] Crosslinking agents are used to determine the relationship between adjacent proteins and ligand-receptor interactions. Homologous crosslinking agents with amino reactivity: succinimidyl or imidate, and heterologous crosslinking agents with amino reactivity and photoactivated azide benzene compounds are the most commonly used crosslinking agents in these applications.
[0005] The process route of the photocrosslinking agent compound of the application uses zanthotoxin alcohol as the starting material, all materials are stable and easy to obtain, the reaction is mild and controllable, there are no harsh conditions, the yield is high, the post-treatment is simple, it is suitable for industrial production and scale-up, has good commercialization prospects, and has considerable economic benefits.
[0006] The inventors compared two different synthesis routes and found that the comparative synthesis route has a lower reaction yield and it is difficult to achieve industrial production through column chromatography purification.
[0007] Therefore, it is of great significance to develop a preparation process of a photocrosslinking agent compound that can achieve industrial production. SUMMARY
[0008] A small molecule compound developed by the present application is a photocrosslinking probe and a technology for covalently capturing protein-nucleic acid complexes in cells, which can enter cells, bind to DNA and / or RNA, and form covalent bonds between DNA or RNA and the proteins bound thereto after activation under long-wavelength (330-370 nm) ultraviolet light irradiation.
[0009] The purpose of the technology is to provide a powerful and effective method for labeling, capturing and identifying protein-nucleic acid complexes in cells. Compared with traditional formaldehyde crosslinking technology, it has the advantages of high specific binding, high binding time selectivity, etc.
[0010] The technology will have wide biomedical applications in mechanism research, disease diagnosis and management, and drug development, including determining new drug targets and determining drug responses.
[0011] The purpose of the present application is to provide an effective and feasible preparation method for the industrial production of a photocrosslinking agent compound. The method has mild reaction conditions, high yield for each reaction, simple operation, high total yield of reaction products, and high purity of the obtained product.
[0012] In the first aspect of the present application, a preparation method of a compound shown as formula 1 is provided. According to an embodiment of the present application, the method comprises:
[0013] 1. condensing zizyphus jujuba mill with a compound shown as formula 2 to obtain a compound shown as formula 3; 2. hydrolyzing the compound shown as formula 3 in an alkaline environment to obtain a compound shown as formula 4;
[0014] 3. condensing the compound shown as formula 4 with a compound shown as formula 5 to obtain a compound shown as formula 6;
[0015] 4. de-BOC of the compound shown as formula 6 in an acidic environment to obtain a compound shown as formula 7; 5. condensing the compound shown as formula 7 with a compound shown as formula 8 to obtain a compound shown as formula 9;
[0016] 6. condensing the compound shown as formula 9 with a compound shown as formula 10 to obtain a compound shown as formula 1.
[0017]
[0018] Using the preparation method of the present application, the compound shown as formula 1 is obtained through etherification, hydrolysis, amide condensation, de-BOC, and the last two steps of amide condensation, and the purity of the final compound shown as formula 1 is as high as 99.0%.
[0019] In the present text, the term "1N NaOH" stands for a 1 mol / L sodium hydroxide solution, "1N HCl" stands for a 1 mol / L hydrochloric acid solution, "HUTA" stands for 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate; "DIEA" stands for N,N-diisopropylethylamine; "N-Boc-ethylenediamine" stands for N-tert-butoxycarbonyl-1,2-ethylenediamine, "DMF" stands for N,N-dimethylformamide, "DCM" stands for dichloromethane. The materials to be reacted can be mixed under stirring as required, and the type of stirring is not particularly limited, and can be, for example, mechanical stirring or magnetic stirring.
[0020] According to the embodiments of the present application, the above-mentioned method for preparing the compound of formula 3, the compound of formula 4, the compound of formula 6, the compound of formula 7, the compound of formula 9, the compound of formula 1 can further have at least one of the following additional technical features:
[0021] According to the embodiments of the present application, the chemical reactions described in the present application can be carried out according to any method known in the art, and the sources of the raw materials for preparing the compound of formula 3, the compound of formula 4, the compound of formula 6, the compound of formula 7, the compound of formula 9, the compound of formula 1 are not particularly limited, and can be prepared by any known method or obtained commercially. The existing xanthotoxol, the compound of formula 2, the compound of formula 5, the compound of formula 8, the compound of formula 10 are all existing compounds, wherein the CAS number of xanthotoxol is 2009-24-7, the CAS number of the compound of formula 2 is 3153-37-5, the CAS number of the compound of formula 5 is 57260-73-8, the CAS number of the compound of formula 8 is 96517-92-9, and the CAS number of the compound of formula 10 is 1450752-97-2.
[0022] According to the embodiments of the present application, in step (1), the following steps are included: dissolving xanthotoxol in DMF, and then adding the compound of formula 2, potassium carbonate and potassium iodide; preferably, the solvent of the reaction is selected from DMF, and the reaction promoter potassium iodide is added to accelerate the reaction speed and further improve the efficiency of preparing the compound of formula 3 by the method.
[0023] According to the embodiments of the present application, in step (1), the molar ratio of xanthotoxol, the compound of formula 2, potassium carbonate and potassium iodide is 1.0:(1.05-1.7):(1.4-2.5):(0.1-0.25), and preferably the molar ratio of xanthotoxol, the compound of formula 2, potassium carbonate and potassium iodide is 1.0:1.05:1.4:0.1. In this way, the utilization rate of the reactants is high, and the raw materials are not wasted, and the yield of the target compound is high.
[0024] According to the embodiment of the present application, in step 1, the mixture of xanthoxal, compound of formula 2, potassium carbonate and potassium iodide is stirred at 80-110°C for 3-8 hours.
[0025] According to the embodiment of the present application, in step 1, the mixture of xanthoxal, compound of formula 2, potassium carbonate and potassium iodide is stirred at 90°C for 5 hours.
[0026] According to the embodiment of the present application, in step 2, the molar ratio of compound of formula 3 to the base solution is 1: (3.0-7.5), preferably 1:3.0. Thus, the reactant utilization rate is high, and the target compound yield is high.
[0027] According to the embodiment of the present application, in step 6, the compound of formula 4, compound of formula 5, HATU and DIEA are dissolved in DMF respectively, and stirred until the reaction is complete. The solvent is removed by concentration, water and ethyl acetate are added, and the mixture is stirred and extracted. The mixture is concentrated, and the compound of formula 6 is obtained by purification with an alcohol / ether system. Thus, the efficiency of preparing the compound of formula 6 is further improved.
[0028] According to the embodiment of the present application, in step 6, the purification mixed solvent is an alcohol / ether system, preferably a methanol / methyl tert-butyl ether system, which can effectively remove impurities, so that the purity and yield of the compound of formula 6 are good, and the efficiency of preparing the compound of formula 6 is further improved.
[0029] According to the embodiment of the present application, in step 8, the compound of formula 8 is dissolved in DMF, and HATU and DIEA are added and stirred until the reaction is complete. Then, the compound of formula 7 is added, and the mixture is stirred at room temperature. The solvent is removed by concentration, and the compound of formula 9 is obtained by purification with a mixed solvent. Thus, the efficiency of preparing the compound of formula 9 is further improved.
[0030] According to the embodiment of the present application, in step 8, the purification mixed solvent is a hydrocarbon / ether system, preferably a dichloromethane / petroleum ether system, which can effectively remove impurities with small polarity, ensure that the next reaction is not disturbed, and ensure that the purity and yield of the compound of formula 9 are good.
[0031] According to the embodiment of the present application, in step 9, the compound of formula 9 is dissolved in DMF, and HATU and DIEA are added and stirred until the reaction is complete. Then, the compound of formula 10 is added, and the mixture is stirred at room temperature. The solvent is removed by concentration, and the compound of formula 1 is obtained by purification with a mixed solvent. Thus, the efficiency of preparing the compound of formula 1 is further improved.
[0032] According to the embodiment of the present application, in step ⑹, the molar ratio of the compound shown as formula 9, the compound shown as formula 10, HATU and DIEA is 1.0:(1.2-2.0):(1.5-3.25):(1.8-3.3); preferably, the molar ratio of the compound shown as formula 9, the compound shown as formula 10, HATU and DIEA is 1.0:1.2:1.5:2.2; thus, the utilization rate of the reactants is high, the raw materials are not wasted, and the yield of the target compound is high.
[0033] According to the embodiment of the present application, in step ⑹, the refined mixed solvent is an alcohol / ether system, preferably an isopropyl alcohol / n-hexane system, which can effectively remove impurities, so that the purity of the compound shown as formula 1 is good, the yield is good, and the efficiency of preparing the compound shown as formula 1 is further improved.
[0034] The beneficial effects achieved by the present application are as follows:
[0035] 1. The route of the present application uses existing commercially available reagents or molecular fragments (Zanthoxylum bungeanum seed oil, the compound shown as formula 2, the compound shown as formula 5, the compound shown as formula 8, the compound shown as formula 10) to obtain the compound shown as formula 1 through etherification, hydrolysis, amide condensation, Boc removal, and finally two-step amide condensation reactions, and the purity of the final compound shown as formula 1 is as high as 99.0%.
[0036] 2. The preparation method of the present application uses a DMF reaction system and a reaction promoter potassium iodide in step one, which greatly improves the reaction conversion rate, the post-treatment is simple, and the yield and purity are good.
[0037] 3. The preparation method of the present application uses an alcohol / ether system for refining in step three, which ingeniously improves the purity of compound 6 and solves the problem of compound 7 which is difficult to purify due to its high polarity, so that compound 1 can be directly subjected to the next step reaction without being affected after Boc removal.
[0038] 4. The preparation method of the present application uses acid-base salt formation to remove impurities in step five, which preliminarily removes most of the impurities of compound 9, and then combines with the hydrocarbon / ether system for refining to ensure the purity of compound 9 without the need for reverse phase preparation purification treatment. This greatly reduces the cost and the purification pressure of the final compound 1.
[0039] 5. The preparation method of the present application uses an alcohol / ether system for refining treatment of compound 1 in step six, which ensures the purity of compound 1 without the need for reverse phase preparation purification treatment. This greatly reduces the cost, thereby providing a solid foundation for the future commercial production of compound 1. BRIEF DESCRIPTION OF DRAWINGS
[0040] Figure 1 The hydrogen spectrum of compound 1 is shown. DETAILED DESCRIPTION
[0041] The following examples are illustrative of the application. The examples are not intended to limit the application, which is defined by the claims. Unless otherwise indicated, the following examples were prepared according to the procedures described in the literature or according to the product instructions. All reagents or instruments not otherwise specified are commercially available and conventional.
[0042] Example 1
[0043] (1) Preparation of the compound shown in formula 3
[0044] Zanthoxylum alantum 45 g was dissolved in DMF 600 mL. Methyl 4-chlorobutyrate 33.75 g, potassium carbonate 43.9 g, potassium iodide 4.23 g were added and reacted at 90°C for 5 hours. The reaction was monitored by TLC and was complete. After concentration and rotary evaporation, water was added to remove the residual DMF. Water and ethyl acetate were added to dissolve and extract the organic phase. The organic phase was washed with water and saturated brine. The organic phase was collected and the solvent was removed by concentration to obtain the compound shown in formula 3 as a white solid 54.8 g with a yield of 81.5%. LC-MS: m / z = 303.1 (M+1).
[0045] (2) Preparation of the compound shown in formula 3
[0046] Zanthoxylum alantum 45.5 g was dissolved in DMF 600 mL. Methyl 4-chlorobutyrate 52.2 g, potassium carbonate 76.5 g, potassium iodide 4.05 g were added and reacted at 90°C for 5 hours. The reaction was monitored by TLC and was complete. After concentration and rotary evaporation, water was added to remove the residual DMF. Water and ethyl acetate were added to dissolve and extract the organic phase. The organic phase was washed with water and saturated brine. The organic phase was collected and the solvent was removed by concentration to obtain the compound shown in formula 3 as a white solid 53.6 g with a yield of 78.8%.
[0047] (3) Preparation of the compound shown in formula 3
[0048] Zanthoxylum alantum 45.2 g was dissolved in DMF 600 mL. Methyl 4-chlorobutyrate 37.8 g, potassium carbonate 52.2 g, potassium iodide 4.08 g were added and reacted at 90°C for 5 hours. The reaction was monitored by TLC and was complete. After concentration and rotary evaporation, water was added to remove the residual DMF. Water and ethyl acetate were added to dissolve and extract the organic phase. The organic phase was washed with water and saturated brine. The organic phase was collected and the solvent was removed by concentration to obtain the compound shown in formula 3 as a white solid 54.3 g with a yield of 80.3%.
[0049] Example 2
[0050] Preparation of the compound shown in formula 4
[0051] Compound 3 30.8 g was dissolved in methanol 450 ml, 1 N sodium hydroxide 300 ml was added dropwise under ice bath. The reaction was stirred at room temperature for 3-5 hours. TLC was used to monitor the completion of the reaction. Most of the methanol was removed by reduced pressure concentration. The residue was adjusted to pH 2-3 with 1 N HCl. Ethyl acetate 600 ml was used to extract the reaction. The organic phase was washed with water and saturated brine. The organic phase was collected and concentrated to remove the solvent to obtain compound 4 as a solid 35.6 g with a yield of 90.9%. LC-MS: m / z = 289.2 (M+1).
[0052] Example 3
[0053] Preparation of compound 6
[0054] Compound 4 24.2 g was dissolved in DMF 240 ml. N-Boc-ethylenediamine 19.1 g, HATU 47.5 g, and DIEA 23.8 g were added. The reaction was stirred at room temperature for 2-3 hours. TLC was used to monitor the completion of the reaction. The solvent was removed by concentration. Water and ethyl acetate were added to extract the reaction. The solvent was concentrated to dryness. Methanol / methyl tert-butyl ether was used to refine the product to obtain compound 6 as a white solid 26.9 g with a yield of 74.5%. LC-MS: m / z = 431.4 (M+1).
[0055] Preparation of compound 6
[0056] Compound 4 22.5 g was dissolved in DMF 240 ml. N-Boc-ethylenediamine 18.3 g, HATU 45.4 g, and DIEA 21.7 g were added. The reaction was stirred at room temperature for 2-3 hours. TLC was used to monitor the completion of the reaction. The solvent was removed by concentration. Water and ethyl acetate were added to extract the reaction. The solvent was concentrated to dryness. Isopropanol / isopropyl ether was used to refine the product to obtain compound 6 as a white solid 24.3 g with a yield of 72.2%.
[0057] Preparation of compound 6
[0058] Compound 4 20.5 g was dissolved in DMF 240 ml. N-Boc-ethylenediamine 16.3 g, HATU 41.8 g, and DIEA 20.6 g were added. The reaction was stirred at room temperature for 2-3 hours. TLC was used to monitor the completion of the reaction. The solvent was removed by concentration. Water and ethyl acetate were added to extract the reaction. The solvent was concentrated to dryness. Isopropanol / methyl tert-butyl ether was used to refine the product to obtain compound 6 as a white solid 22.4 g with a yield of 73.2%.
[0059] Example 4
[0060] Preparation of compound 7
[0061] Compound 6 20 g was added into DCM 300 mL and concentrated hydrochloric acid 100 mL, the reaction was stirred at room temperature for 3-5 hours, and TLC was used to monitor the completion of the reaction. The reaction solution was concentrated to remove the solvent to obtain compound 7 in the form of white solid about 22.8 g with a yield of 98%, which was directly used in the next step.
[0062] Example 5
[0063] Preparation of compound 9
[0064] Compound 8 15.5 g was dissolved in DMF 150 mL, and then HATU 29.5 g and DIEA 10.2 g were added. The reaction was stirred at room temperature for 1 hour, and then compound 7 (about 11.4 g in DMF 100 ml solution) was added. The reaction was stirred at room temperature for 24 hours, and TLC was used to monitor the completion of the reaction. The residue was concentrated to remove the solvent, and then 1N sodium hydroxide solution was added to adjust the pH value to 11-12. The aqueous phase was collected and extracted with dichloromethane 150 ml twice. The pH value of the aqueous phase was adjusted to 2-3 with 1N hydrochloric acid solution, and then extracted with dichloromethane. The organic phase was collected, concentrated to remove the solvent under reduced pressure to obtain yellow solid 12.4 g. Dichloromethane / petroleum ether was used for further purification to obtain compound 9 in the form of white solid about 10 g with a yield of 57.5%. LC-MS: m / z = 562.5 (M+1)
[0065] Example 6
[0066] Preparation of compound 1
[0067] Compound 9 12.1 g was dissolved in DMF 180 ml, and then HATU 12.3 g, DIEA 6.1 g were added successively, stirred and dissolved, and stirred at room temperature for 1 hour. Then 3.54 g of compound 10 was added, and stirred for 24 hours. The reaction was monitored by TLC, and the reaction was completed. The solvent was removed by concentration to obtain a residue. The residue was treated with dichloromethane and water, and the solvent was concentrated. The compound 1 was obtained as a white solid by purification with isopropyl alcohol / n-hexane mixture solvent, and the yield was 8.7 g (59.3 %). LC-MS: m / z = 681.8 (M+1)+; 1H NMR (600 MHz, CDCl3) δ 1.641 ~ 1.697 (m, 4H), δ 2.015 ~ 2.026 (m, 3H), δ 2.189 (m, 2H), δ 2.465 ~ 2.506 (dt, 4H), δ 2.633 ~ 2.645 (t, 2H), δ 3.127 ~ 3.138 (m, 2H), δ 3.402 (m, 2H), δ 3.439 (m, 2H), δ 3.647 ~ 3.666 (m, 8H), δ 3.724 ~ 3.769 (m, 4H), δ 4.473 ~ 4.491 (t, 2H), δ 6.404 ~ 6.420 (d, 1H), δ 6.860 ~ 6.864 (m, 4H), δ 7.442 (s, 1H), δ 7.741 ~ 7.745 (s, 1H), δ 7.837 ~ 7.853 (d, 1H), and the hydrogen spectrum is shown in Figure 1
[0068] Comparative Example 1
[0069] Preparation of Compound 3
[0070]
[0071] Peperonin (45.5 g) was dissolved in acetonitrile (600 ml). Then, ethyl 4-chlorobutyrate 36.4 g and potassium carbonate 52.3 g were added, and the reaction was performed at 90°C for 8 hours. The reaction was concentrated and dried by rotation. Then, water and ethyl acetate were added, and the reaction was stirred and dissolved. The organic phase was washed with water and saturated brine, and the organic phase was collected. The solvent was removed by concentration, and the compound 3 was obtained as a white solid by column chromatography (n-hexane: ethyl acetate = 8:1), and the yield was 27.4 g (40.2 %).
[0072] Comparative Example 2
[0073] Preparation of Compound 4
[0074]
[0075] Compound 3 30.6 g was dissolved in methanol 450 ml, 1 N sodium hydroxide 300 ml was added dropwise under ice bath. The reaction was stirred at room temperature for 3-5 hours. TLC was used to monitor the completion of the reaction. Most of the methanol was removed by reduced pressure concentration. The residue was adjusted to pH 2-3 with 1 N HCl. Ethyl acetate 600 ml was used to extract the reaction. The organic phase was washed with water and saturated brine. The organic phase was collected and concentrated to remove the solvent to obtain compound 4 as a solid 35.4 g with a yield of 90.7%.
[0076] Comparative Example 3
[0077] Preparation of compound 5
[0078]
[0079] Compound 4 28.5 g was dissolved in dichloromethane 300 ml. N-hydroxysuccinimide (NHS) 17.4 g and N,N'-dicyclohexylcarbodiimide (DCC) 45.6 g were added. The reaction was stirred at room temperature for 24 hours. The reaction was washed with water and saturated brine. The organic phase was collected and concentrated to remove the solvent to obtain compound 5 as a solid 27.4 g with a yield of 71%.
[0080] Comparative Example 4
[0081] Preparation of compound 6
[0082]
[0083] Compound 4 20.6 g was dissolved in DCM 240 ml. Ethylenediamine 16.6 g, HATU 41.8 g and DIEA 20.8 g were added. The reaction was stirred at room temperature for 2-3 hours. TLC was used to monitor the completion of the reaction. The solvent was removed by concentration. Water and ethyl acetate were added to extract the reaction. The solvent was concentrated to dryness. The compound 6 was obtained as a yellow solid 9.39 g with a yield of 53.2%.
[0084] Comparative Example 5
[0085] Preparation of compound 7
[0086]
[0087] Compound 3 30.6 g was dissolved in methanol 450 ml, 1 N sodium hydroxide 300 ml was added dropwise under ice bath. The reaction was stirred at room temperature for 3-5 hours. TLC was used to monitor the completion of the reaction. Most of the methanol was removed by reduced pressure concentration. The residue was adjusted to pH 2-3 with 1 N HCl. Ethyl acetate 600 ml was used to extract the reaction. The organic phase was washed with water and saturated brine. The organic phase was collected and concentrated to remove the solvent to obtain compound 4 as a solid 35.4 g with a yield of 90.7%.
[0088] Comparative Example 6
[0089] Preparation of compound 8
[0090]
[0091] Compound 6 6.62 g was dissolved in 60 ml of dimethyl sulfoxide, and then diisopropyl ethylamine 3.87 g was added dropwise thereto, and stirred until clear. Compound 7 8.9 g was added at room temperature, and the reaction was stirred for 2 hours in the dark. After the completion of the reaction, the reaction solution was added to 1 L of water, and then extracted with dichloromethane. The organic phase was washed with water and saturated brine, and then concentrated to dryness to obtain compound 8 6.9 g in a yield of 52.3%.
[0092] Comparative Example 7
[0093] Preparation of compound 1
[0094]
[0095] Compound 9 0.82 g was dissolved in 30 ml of DMF, and then diisopropyl ethylamine 1.1 g was added dropwise thereto, and stirred until dissolved. Compound 8 2.64 g was added at room temperature, and the reaction was stirred for 2 hours in the dark. After the completion of the reaction, the solvent was removed by concentration, and then purified by reverse phase C-18 column chromatography (eluted with acetonitrile / water) to obtain compound 1 2 g in a yield of 73.4%.
Claims
1. A method for preparing a photo-crosslinker compound, chemical name: N-(19-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)-4,16-dioxo-7,10,13-trioxa-3,17-diazanonadecyl)-4-((7-oxo-7H-furo[3,2-g]chromen-9-yl)oxy)butanamide The synthetic route is as follows: A method for preparing a compound shown in formula 1, characterized in that, comprising: (1) condensation reaction of zanthoxylum alantum alcohol and a compound shown in formula 2 to obtain a compound shown in formula 3; (2) hydrolysis of the compound shown in formula 3 in an alkaline environment to obtain a compound shown in formula 4; (3) condensation of the compound shown in formula 4 with a compound shown in formula 5 to obtain a compound shown in formula 6; (4) BOC removal of the compound shown in formula 6 in an acidic environment to obtain a compound shown in formula 7; (5) condensation of the compound shown in formula 7 with a compound shown in formula 8 to obtain a compound shown in formula 9; (6) condensation of the compound shown in formula 9 with a compound shown in formula 10 to obtain a compound shown in formula 1.
2. The method of claim 1, wherein, In step (1), zanthoxylum alantum alcohol is dissolved in DMF, then the compound shown in formula 2, potassium carbonate and potassium iodide are added; the above mixed solution is stirred and reacted under temperature control, the solvent is concentrated and removed, water is added and concentrated, ethyl ester is dissolved and extracted, the organic phase is washed with water and saturated brine, and the organic phase is concentrated to obtain the compound shown in formula 3.
3. The method of claim 2, wherein, In step (1), the molar ratio of zanthoxylum alantum alcohol, the compound shown in formula 2, potassium carbonate and potassium iodide is 1.0:(1.05-1.7):(1.4-2.5):(0.1-0.25), preferably the molar ratio of zanthoxylum alantum alcohol, the compound shown in formula 2, potassium carbonate and potassium iodide is 1.0:1.05:1.4:0.1, optionally, in step (1), zanthoxylum alantum alcohol, the compound shown in formula 2, potassium carbonate and potassium iodide are mixed and stirred at 80-110°C for 3-8 hours, preferably zanthoxylum alantum alcohol, the compound shown in formula 2, potassium carbonate and potassium iodide are mixed and stirred at 90°C for 5 hours.
4. The method of claim 1, wherein, In step (2), the compound shown in formula 3 is hydrolyzed after treatment in an alcohol / dilute alkali solution to obtain the compound shown in formula 4.
5. The method of claim 4, wherein, In step (2), the molar ratio of the compound shown in formula 3 to the alkali solution is 1:(3.0-7.5), preferably the molar ratio of the compound shown in formula 3 to the alkali solution is 1:3.
0.
6. The method of claim 1, wherein, In step (3), the compound of formula 4, the compound of formula 5, HATU and DIEA are dissolved in DMF respectively, and stirred until the reaction is completed, then the solvent is removed by concentration, water and ethyl acetate are added, and the mixture is stirred and extracted, and then concentrated, and the compound of formula 6 is obtained by purification with an alcohol / ether system.
7. The method of claim 6, wherein, In step (3), the molar ratio of the compound of formula 4, the compound of formula 5, HATU and DIEA is 1.0:(1.2-2.0):(1.5-2.5):(1.8-3.0); preferably, the molar ratio of the compound of formula 4, the compound of formula 5, HATU and DIEA is 1.0:1.4:1.5:2.
3.
8. The method of claim 6, wherein, In step (3), the mixed solvent for purification is an alcohol / ether system, the alcohol is one or more of methanol, ethanol and isopropanol, and the ether is one or more of isopropyl ether, methyl tert-butyl ether, tetrahydrofuran and 1,4-dioxane.
9. The method of claim 1, wherein, In step (5), the compound of formula 8 is dissolved in DMF, HATU and DIEA are added, and the mixture is stirred until the reaction is completed, then the compound of formula 7 is added, and the mixture is stirred at room temperature, and then the solvent is removed by concentration, and the compound of formula 9 is obtained by purification with an acid and a base.
10. The method of claim 9, wherein, In step (5), the molar ratio of the compound of formula 7, the compound of formula 8, HATU and DIEA is 1.0:(1.2-2.0):(1.5-2.5):(1.8-3.0); preferably, the molar ratio of the compound of formula 7, the compound of formula 8, HATU and DIEA is 1.0:2.0:2.5:2.
5.
11. The method of claim 9, wherein, In step (5), the mixed solvent for purification is a hydrocarbon / ether system, the alcohol is one or more of chloroform, dichloromethane and toluene, and the ether is one or more of isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, petroleum ether and n-hexane.
12. The method of claim 1, wherein, In step (6), the compound of formula 9 is dissolved in DMF, HATU and DIEA are added, and the mixture is stirred until the reaction is completed, then the compound of formula 10 is added, and the mixture is stirred at room temperature, and then the solvent is removed by concentration, and the mixture is treated with dichloromethane and water, and then purified with a mixed solvent.
13. The method of claim 12, wherein, In step (6), the molar ratio of the compound of formula 9, the compound of formula 10, HATU and DIEA is 1.0:(1.2-2.0):(1.5-3.25):(1.8-3.3); preferably, the molar ratio of the compound of formula 9, the compound of formula 10, HATU and DIEA is 1.0:1.2:1.5:2.
2.
14. The method of claim 12, wherein, In step (6), the mixed solvent for purification is an alcohol / ether system, the alcohol is one or more of methanol, ethanol, isopropanol and tert-butanol, and the ether is one or more of isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, petroleum ether and n-hexane.