Method for synthesizing 2-hydroxy diaryl urea

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses a method for synthesizing a 2-hydroxyl diaryl urea derivative. According to the method, benzoxazole compounds and aryl iso (thio) cyanate are used as raw materials and react in a methanol solvent at 60 DEG C under the synergistic catalysis of PIFA and protonated aluminum oxide, and an o-hydroxyl-ureido structure is constructed in one step. According to the method, highly toxic phosgene / isocyanate and noble metal catalysts are thoroughly avoided, the problems of low yield and more byproducts of a traditional route are solved, and the highest yield of 87% is achieved under normal-pressure mild conditions. 100% regioselectivity is achieved through a ring opening / coupling mechanism, derivatives containing 24 substituent groups such as halogen, trifluoromethoxy and naphthyl are successfully synthesized, and the bottleneck of asymmetric urea selective synthesis is broken through.

Description

Technical Field

[0001] The present invention relates to the field of organic synthetic chemistry, and in particular to a method for synthesizing 2-hydroxydiaryl urea. Background Art

[0002] Urea building blocks are ubiquitous and predominant building blocks in functional materials, bioactive compounds, and natural products. They form the active cores of numerous therapeutic agents, including anti-tumor drugs, natural receptor antagonists, allosteric modulators, enzyme inhibitors, anti-HIV drugs, and anticonvulsants. Urea compounds are also used as efficient and stable organocatalysts or transition metal ligands. Beyond medicinal chemistry, urea derivatives also have important applications in organic materials.

[0003] Among functionalized urea compounds, 2-hydroxydiaryl urea derivatives represent an important subclass with wide applications in drug synthesis, organic materials and catalysis. The unique ortho-position arrangement of the hydroxyl group and the urea group enables it to form a complex hydrogen bond network. This property is crucial for specific interactions with biological targets, making it a key skeleton for the design of anti-tumor agents, enzyme inhibitors and antiviral drugs. For example, in anti-HIV and anticonvulsant therapies, the 2-hydroxydiaryl urea structure enhances the binding efficiency of drugs to targets by regulating molecular polarity and hydrogen bonding ability. In the development of kinase inhibitors (for example, targeting SRPK3), this structural unit acts as a key pharmacophore, utilizing hydrophobic interactions and hydrogen bonding to bind to the hydrophobic pocket within the kinase domain, highlighting its potential in anti-cancer drug discovery.

[0004] The strong hydrogen bond donor ability of 2-hydroxydiarylurea has also promoted its application in materials science. They can be used to design self-assembled structures, fluorescent probes and functional polymers. Intermolecular hydrogen bonds can guide orderly assembly, play a role in optoelectronic materials or serve as signal transduction units in sensors. In the design of fluorescent probes (for example, for Hg 2+ The introduction of hydroxyl groups and aromatic ring structures can adjust the conjugated system to achieve selective recognition and fluorescence response of metal ions, which is applied to environmental monitoring and biological imaging.

[0005] Given the importance of functionalized ureas in the aforementioned fields, the development of efficient synthetic methods is crucial. Traditional urea synthesis methods typically rely on reagents such as phosgene, isocyanates, azides, carbamates, or carbonyldiimidazoles, which have disadvantages such as high toxicity, instability, and operational difficulties. Alternative strategies such as oxidative carbonylation of amines using carbon monoxide (CO) or direct carbonylation of amines using carbon dioxide (CO2) have been explored; however, these methods typically require expensive metal catalysts and high-pressure conditions. In addition, these methods are often limited in the synthesis of asymmetric urea derivatives, and the synthesis of a specific type of 2-hydroxydiaryl urea is particularly challenging.

[0006] Currently, the primary route for synthesizing 2-hydroxydiarylureas is the reaction of o-aminophenol with isocyanates. Unfortunately, this approach often suffers from complex reaction mixtures, low yields, and difficult purification, severely hindering access to these valuable compounds. Therefore, there is an urgent need to develop novel synthetic strategies that can efficiently and selectively prepare asymmetric 2-hydroxydiarylureas under mild conditions. Summary of the Invention

[0007] To solve the above-mentioned technical problems in the prior art, the present invention provides a method for synthesizing 2-hydroxydiaryl urea derivatives, wherein a benzoxazole compound and an aryl iso(thio)cyanate are used as raw materials, and a ring-opening coupling reaction occurs under the action of bis(trifluoroacetyl)iodobenzene and an additive to produce a 2-hydroxydiaryl urea derivative.

[0008] The general formula for synthesizing 2-hydroxydiaryl urea derivatives according to the method is:

[0009]

[0010] wherein X is selected from S or O;

[0011] R 1 Selected from alkyl, alkoxy, halogen, trifluoromethoxy, naphthyl, polyhaloalkyl;

[0012] R 2 Selected from alkyl, alkoxy, halogen.

[0013] The additive is protonated alumina.

[0014] The molar ratio of the additive to benzoxazole is 0.8-1.2:1

[0015] The amount of bis(trifluoroacetyl)iodobenzene used is 0.5-1.0 equivalents of the molar amount of benzoxazole.

[0016] The solvent of the method is methanol, the reaction temperature is 55-65° C., and the reaction time is 1-3 hours.

[0017] The molar ratio of the benzoxazole compound to the aryl iso(thio)cyanate is 1:0.8-1:1.2.

[0018] In another aspect, the present invention provides a 2-hydroxydiaryl urea or thiourea derivative, wherein the 2-hydroxydiaryl urea derivative is prepared by the method and comprises the following structure:

[0019]

[0020] The method of the present invention is used in the preparation of anti-tumor drugs, anti-HIV drugs or kinase inhibitors, and the 2-hydroxydiaryl urea derivative is used as an active ingredient in a pharmaceutical composition.

[0021] The method of the present invention is used in the preparation of fluorescent probes or functional polymer materials, wherein the 2-hydroxydiaryl urea derivative serves as a hydrogen bond-directed self-assembly unit.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The present invention provides a method for synthesizing 2-hydroxydiarylurea. Compared with traditional methods that rely on highly toxic phosgene, isocyanate or precious metal catalytic systems (such as CO / CO2 high-pressure carbonylation), the present invention utilizes a new ring-opening / coupling mechanism mediated by bis(trifluoroacetyl)iodobenzene (PIFA). The reaction is highly efficient in a methanol solvent at normal pressure and mild temperature (60-80°C), completely avoiding highly hazardous reagents and precious metal catalysts. The yield of the target product is increased to 75-92%, by-products are extremely low, and no complex purification is required. This solves the problems of high operational risk, low yield and difficult post-processing commonly encountered in the background art.

[0024] Secondly, in response to the shortcomings of existing carbonylation strategies, such as poor selectivity control over asymmetric ureas (especially ortho-hydroxyl substituted types) and difficulty in separating regioisomers, the present invention directly generates a single-structure 2-hydroxydiaryl urea by precisely opening the benzoxazole ring to construct a C (urea)-N (aromatic amine) bond, achieving 100% regioselectivity and successfully synthesizing derivatives containing 24 types of substituents such as methyl, halogen, and trifluoromethoxy, providing a universal synthesis platform for the fields of medicine and materials.

[0025] On the other hand, the present invention replaces high-risk raw materials with stable commercial reagents, and the reaction can be completed in an air atmosphere and under normal pressure conditions, without the need for high-pressure / corrosion-resistant equipment, significantly reducing the safety risks and equipment costs of industrial scale-up. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Single crystal X-ray diffraction molecular structure diagram and bond length / bond angle data of compound 3i synthesized by the method described in the present invention;

[0027] Figure 2 Crystallographic parameters and structure refinement data of compound 3i synthesized by the method described in the present invention;

[0028] Figure 3 Single crystal X-ray diffraction molecular structure diagram and bond length / bond angle data of compound 3j synthesized by the method described in the present invention;

[0029] Figure 4 Crystallographic parameters and structure refinement data table of compound 3j synthesized by the method described in the present invention;

[0030] Figure 5 H NMR spectrum (400 MHz, DMSO-d6) of compound 3a synthesized by the method of the present invention;

[0031] Figure 6 C NMR spectrum (101 MHz, DMSO-d6) of compound 3a synthesized by the method of the present invention;

[0032] Figure 7 H NMR spectrum (400 MHz, DMSO-d6) of compound 3b synthesized by the method of the present invention;

[0033] Figure 8 C NMR spectrum (101 MHz, DMSO-d6) of compound 3b synthesized by the method of the present invention;

[0034] Figure 9 H NMR spectrum (400 MHz, DMSO-d6) of compound 3c synthesized by the method of the present invention;

[0035] Figure 10 C NMR spectrum (101 MHz, DMSO-d6) of compound 3c synthesized by the method of the present invention;

[0036] Figure 11 H NMR spectrum (400 MHz, DMSO-d6) of compound 3d synthesized by the method of the present invention;

[0037] Figure 12 C NMR spectrum (101 MHz, DMSO-d6) of compound 3d synthesized by the method of the present invention;

[0038] Figure 13 H NMR spectrum (400 MHz, DMSO-d6) of compound 3h synthesized by the method of the present invention;

[0039] Figure 14 C NMR spectrum (101 MHz, DMSO-d6) of compound 3h synthesized by the method of the present invention;

[0040] Figure 15 H NMR spectrum (400 MHz, Acetone-d6) of compound 3i synthesized by the method of the present invention;

[0041] Figure 16 C NMR spectrum (101 MHz, Acetone-d6) of compound 3i synthesized by the method of the present invention;

[0042] Figure 17H NMR spectrum (400 MHz, DMSO-d6) of compound 3q synthesized by the method of the present invention;

[0043] Figure 18 C NMR spectrum (101 MHz, DMSO-d6) of compound 3q synthesized by the method of the present invention;

[0044] Figure 19 Reaction mechanism diagram of the present invention DETAILED DESCRIPTION

[0045] To make the objectives, technical solutions, and advantages of the present invention more clearly apparent, the present invention is described below using specific embodiments shown in the accompanying drawings. However, it should be understood that these descriptions are merely illustrative and are not intended to limit the scope of the present invention. In addition, in the following description, descriptions of well-known structures and technologies are omitted to avoid unnecessary confusion of the concepts of the present invention.

[0046] Example 1

[0047] Benzoxazole 1a (12 mg, 0.1 mmol, 1.0 equiv), 3-methylisocyanatophenyl 2a (15 mg, 0.1 mmol, 1.0 equiv), and bis(trifluoroacetyl)iodobenzene (44 mg, 0.1 mmol, 1.0 equiv) (Table 1) were added to a 10 mL reaction tube. Using acetonitrile as the solvent and stirring at 80°C for 2 hours, the target product, 1-(2-hydroxyphenyl)-3-(3-methylphenyl)urea 3a, was obtained in an isolated yield of 56%. Next, comparing Examples 1-9, no target product was produced using DMF and DMSO. Other commonly used solvents, such as dioxane, THF, DCM, Toluene, and Acetone, yielded low target product yields. However, using CH3OH as the solvent, the target product 3a was obtained with the highest isolated yield of 73%. Therefore, the present invention determined that CH3OH was the optimal reaction solvent for this application. Then, under the conditions of CH3OH as solvent and reaction temperature of 60°C, the present invention conducted comparative experiments with a series of different oxidants, such as diacetyl iodobenzene (DIPA), dichloroiodobenzene, 2-iodobenzoic acid (IBX), di-tert-butyl peroxide (DTBP), and tert-butyl peroxide (TBHP). The reaction results showed that the yield of the target product was low (Comparative Examples 10-14). Finally, we screened a series of different additives (Comparative Examples 15-20). When adding CS2CO3, t BuOK, NaOH, CF3COOH, DBU and DABCO, the target product yield is good, when adding Al2O3 / H +*(Example 2) The yield is the highest. The present invention determines the optimal reaction conditions through a series of condition screening, using CH3OH as solvent, Al2O3 / H + As additives, 0.5 equivalents of PIFA, 0.2 mmol of benzoxazole 1a, and 0.2 mmol of 3-methylisocyanate phenyl 2a were reacted at 60°C for 2 hours. After completion of the reaction, the mixture was stripped of the solvent under vacuum distillation. The residue was extracted three times with appropriate amounts of saturated NaCl solution and ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The crude product was isolated and purified by silica gel column chromatography to obtain the desired product 3a in 87% yield.

[0048] Table 1 a

[0049]

[0050]

[0051] The reaction conditions of Example 2 were adopted, and the additive Al2O3 / H + Dosage: When Al2O3 / H + The yield of product 3a is 82% (Example 3). + The yield of product 3a was 87%. + The amount of the reaction mixture was 1.2 equivalents, and the yield of product 3a was 83% (Example 4).

[0052] The reaction conditions of Example 2 were used, but the amount of PIFA was varied: when PIFA was used at 0.5 equivalents, the yield of product 3a was 82% (Example 5). When PIFA was used at 0.8 equivalents, the yield of product 3a was 84% ​​(Example 6). When PIFA was used at 1.0 equivalents, the yield of product 3a was 87%.

[0053] Using the reaction conditions of Example 2, when the molar ratio of the benzoxazole compound to the aryl iso(thio)cyanate was 1:1, the yield of product 3a was 87%. When the molar ratio of the benzoxazole compound to the aryl iso(thio)cyanate was 1:0.8, the yield of product 3a was 83% (Example 7). When the molar ratio of the benzoxazole compound to the aryl iso(thio)cyanate was 1:1.2, the yield of product 3a was 82% (Example 8).

[0054] The reaction scale was expanded 20-fold (Example 9). Benzoxazole 1a (2.4 mmol, 288 mg), 3-methylphenylisocyanate 2a (2.4 mmol, 300 mg), PIFA (1.2 mmol, 528 mg), Al2O3 / H +The product (2.4 mmol, 240 mg) was added to methanol (20 mL) and stirred at 60°C for 2.5 hours. The product was then processed as in Example 2 to afford 520 mg of 3a in 85% yield, demonstrating the potential for scalability of this method.

[0055] The present invention explores the substrate universality of different substituted phenyl isocyanates or phenyl isosulfates and aryl oxazoles for the preparation of 1-(2-hydroxyphenyl)-3-(phenyl)urea 3 derivatives (Table 2).

[0056] Benzoxazole 5 (0.2 mmol, 1.0 equiv), aryl isocyanate or aryl isosulfate 6 (0.2 mmol, 1.0 equiv), bis(trifluoroacetyl)iodobenzene (0.1 mmol, 1.0 equiv), Al2O3 / H + (1.0 equiv) and CH3OH (1 mL). The mixture reaction tube was placed in an oil bath and stirred at 60°C for 2 hours. After the reaction, the mixture was distilled under vacuum to remove the solvent, and the residue was extracted three times with an appropriate amount of saturated NaCl solution and ethyl acetate (30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The crude product was separated and purified by silica gel column chromatography (PE / EtOAc=6:1) to obtain products 7a-7t with yields of 71%-95%. The products were identified by nuclear magnetic resonance spectroscopy (NMR), HRMS, and FTIR.

[0057] The present invention discloses the reaction of phenyl isocyanate substrates bearing various substituents, such as methyl, methoxy, halogen, and trifluoromethoxy (Tables 2, 3a-3h, yields of 75-92%), to produce the corresponding 1-(2-hydroxyphenyl)-3-(phenyl)urea derivatives in good to excellent yields. The electronic effects of the substituents on the phenyl isocyanate ring have no significant effect on the yield of the target compound, nor does the position of the substituent on the phenyl isocyanate ring. For example, 3c, o-Cl, yielded 89%, 3d, m-Cl, yielded 87%, and 3e, p-Cl, yielded 92%. Phenyl isosulfate and benzoxazole also react in this manner, yielding 1-(2-hydroxyphenyl)-3-(phenyl)thiourea in good to excellent yields with unsubstituted, methyl, tert-butyl, and naphthalene rings (Tables 2, 3i-3l). Polysubstituted phenyl isocyanates can also provide the target compound in high yields (Table 2, 3m, 84% yield). The present invention studied the reaction of phenyl isocyanates with different substituents and substituted benzoxazoles in the preparation of target product 3. It can be seen that all are equally suitable for the reaction, producing the corresponding target product 3 in good yields (Table 2, 3p-3r, 75%-84%), indicating that the reaction has good substrate universality.

[0058] Table 2

[0059]

[0060]

[0061] The present invention proposes a mechanism for synthesizing asymmetric urea derivatives by ring-opening coupling reaction of benzoxazole under the action of bis(trifluoroacetyl)iodobenzene (see attached) Figure 19 The starting material benzoxazole 1a undergoes a ring-opening reaction with bis(trifluoroacetyl)iodobenzene to produce intermediate Int-1. Intermediate Int-1 then undergoes a coupling reaction with the raw material 3-methylphenylisocyanate 2a to produce intermediate II. Finally, intermediate II is catalyzed by acidic Al2O3 to remove iodobenzene and acetic acid to obtain the target compound 3a.

[0062] This invention pioneered the development of the first PIFA-mediated benzoxazole ring-opening / coupling method to synthesize 2-hydroxydiarylureas, demonstrating breakthrough innovations in the following three aspects:

[0063] Firstly, the technical route of the present invention is innovative. For the first time, the benzoxazole ring-opening strategy is applied to the synthesis of ureas, and the benzoxazole ring-opening strategy is applied to the synthesis of ureas by PIFA, Al2O3 / H + A synergistic catalytic system (Example 2) enables the precise construction of ortho-hydroxy-urea structures. This design completely avoids the highly toxic phosgene / isocyanate and precious metal catalysts, completing the reaction with an 87% yield in methanol at atmospheric pressure and 60°C (Table 1), addressing the core drawbacks of traditional methods, such as low yield (<50%) and high operational risks.

[0064] Secondly, the present invention has achieved significant breakthroughs in selectivity and universality. The present invention achieves 100% regioselectivity through a ring-opening / coupling mechanism, completely avoiding the difficulty of isomer separation of asymmetric urea. 24 substituted derivatives containing halogen, trifluoromethoxy, naphthyl, etc. (Table 2, 3a-3r) were successfully synthesized with yields of 75–92%, and the electronic effect / substitution site did not affect the efficiency (for example, the yields of 3c (o-chloro) and 3e (para-chloro) were both >87%), breaking through the limitations of existing methods for sensitive substituents.

[0065] Finally, the present invention achieves a key advancement in industrial application. Gram-scale scale-up experiments (Example 9) maintain an 85% yield, demonstrating the need for high-pressure / corrosion-resistant equipment (compared to CO / CO2 carbonylation). The hydrogen bond network of the synthesized compound was confirmed by single crystal diffraction ( Figure 1-4 ), directly supporting its role in anti-tumor drugs (3a inhibits SRPK3 IC 50 =0.38 μM) and fluorescent probes (3i for Hg 2+ Fluorescence enhancement 15 times) in the application value.

[0066] In summary, the method of the present invention achieves efficient synthesis of high-value-added molecules with simple raw materials, mild conditions and green processes, providing an irreplaceable technical platform for drug development and materials science.

[0067] All chemicals and reagents were of commercial grade and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) on silica gel GF254. Chromatography was performed on a 200-300 mesh silica gel column. All yields were obtained from the purified isolated products. Synthetic intermediates and products were characterized by spectroscopic data. Nuclear magnetic resonance spectra were recorded on a Bruker DRX-600 (1H: 600 MHz, 13C: 151 MHz) using DMSO-d6 as the solvent. The following abbreviations are used to indicate multiplicity: (s) = singlet, (d) = doublet, (t) = triplet, (q) = quartet, (sept) = septet, (dd) = doublet, (dt) = double triplet, (dq) = double quartet, (ddd) = double doublet, and (m) = multiplet. Chemical shifts (δ) are expressed in parts per million (ppm), and J values ​​are expressed in Hertz (Hz). Infrared spectra were recorded on a Thermo Fisher Scientific AVATAR 360 FT-IR instrument using KBr pellets. HRMS was performed on an Agilent LC / MSD TOF instrument. Melting points were determined using an XT-4A melting point instrument without correction.

[0068] The spectral data of the compound prepared in the present invention are as follows:

[0069] 3a:

[0070] Brown solid; 42 mg, yield: 87%; Mp: 125.3-126.6°C; IR (KBr): 3551, 3369, 2549, 1931, 1745, 1247, 1043, 943, 854, 786, 762 cm -1 ; 1 H NMR (400MHz, DMSO-d6) δ10.01(s,1H,OH),9.29(s,1H,NH),8.22(s,1H,NH),8.10(dd,J=7.8,1.8Hz,1H,ArH),7.35(d ,J=2.4Hz,1H,ArH),7.28(d,J=8.1Hz,1H,ArH),7.20(t,J=7.7Hz,1H,ArH),6.91–6.78(m,4H,ArH),2.33(s,3H,CH3). 13C NMR(101MHz,DMSO-d6)δ153.0,146.0,144.4,140.3,138.4,136.9,129.1,128.3,122.8,1 22.1,119.9,119.6,119.0,118.8,116.8,115.5,114.9,114.8,21.7.HRMS(ESI-TOF):m / z calcd for C 14 H 15 N2O3[M+H] + ,259.1004;found,259.1005.

[0071] 3b:

[0072] Brown solid; 47 mg, yield: 91%; Mp: 136.2-137.6°C; IR (KBr): 3553, 3374, 2546, 1926, 1742, 1246, 1041, 940, 855, 784, 766, 755 cm -1 ; 1 H NMR(400MHz,DMSO-d6)δ9.96(s,1H,OH),9.32(s,1H,NH),8.16(s,1H,NH),8.04(dd,J=7.8,1.8Hz,1H,ArH),7.2 1–7.16(m,2H,ArH),6.93–6.90(m,1H,ArH),6.84–6.73(m,3H,ArH),6.56–6.52(m,1H,ArH),3.73(s,3H,OCH3). 13 C NMR(101MHz,DMSO-d6)δ159.3,154.2,147.5,137.3,129.1,125.4,124.4,121.8,119.7,117.90,112.9,109.5,106.6,54.3.HRMS(ESI-TOF):m / z calcdfor C 14 H 15 N2O3

[0073] [M+H] + ,259.1004;found,259.1005.

[0074] 3c:

[0075] Brown solid; 47 mg, yield: 89%; Mp: 170.4-171.3°C; IR (KBr): 3567, 3376, 1742, 1245, 1048, 883, 764, 741, 637, 607; 1 H NMR (400MHz, DMSO-d6) δ9.89(s,1H,OH),8.97(s,1H,NH),8.94(s,1H,NH),8.10(dd,J=8.3,1.6Hz,1H,ArH),8.00(dd,J=8.0,1.6Hz,1H,ArH),7.44(dd,J=8. 0,1.5Hz,1H,ArH),7.29(ddd,J=8.5,7.4,1.5Hz,1H,ArH),7.03(td,J=7.6,1. 6Hz,1H,ArH),6.89–6.79(m,2H,ArH),6.75(ddd,J=8.9,7.1,1.9Hz,1H,ArH). 13 C NMR(101MHz,DMSO-d6)δ152.9,146.6,136.7,129.7,127.9,127.8,123.7,122.9,122.7,122.6,119.9,119.5,115.0.HRMS(ESI-TOF):m / z calcd for C 12 H 12 ClN2O2

[0076] [M+H] + ,263.0509;found,263.0511.

[0077] 3d:

[0078] Brown solid; 46 mg, yield: 87%; Mp: 136.4-137.5°C; IR (KBr): 3542, 3338, 1741, 1724, 1249, 1050, 880, 780, 740, 646, 603; 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H,OH),9.46(s,1H,NH),8.16(s,1H,NH),7.98(dd,J=7.8,1.8Hz,1H,ArH),7.68(t,J=2 .1Hz,1H,ArH),7.25–7.14(m,2H,ArH),6.95–6.91(m,1H,ArH),6.81–6.73(m,2H,ArH),6.69(td,J=7.6,1.8Hz,1H,ArH). 13CNMR(101MHz,DMSO-d6)δ152.7,146.1,141.9,133.7,130.8,127.9,122.4,121.6,119.6,119.1,117.6,116.6,114.8.HRMS(ESI-TOF):m / z calcd for C 12 H 12 ClN2O2[M+H] + ,263.0509;found,263.0511.

[0079] 3e:

[0080] Brown solid; 48 mg, yield: 92%; Mp: 88.4-89.6°C; IR (KBr): 3573, 3363, 1732, 1250, 754, 757, 720, 683, 657; 1 H NMR (600MHz, DMSO-d6) δ9.98(s,1H,OH),9.43(s,1H,NH),8.17(s,1H,NH),8.02(dd,J=7.9,1.6Hz,1H,ArH),7.48(dt,J=8.7,1.8Hz,2 H,ArH),7.33–7.30(m,2H,ArH),6.84(dt,J=7.8,1.5Hz,1H,ArH),6.80(tt,J=7.8,1.5Hz,1H,ArH),6.75(td,J=7.6,1.5Hz,1H,ArH). 13 CNMR(151MHz,DMSO-d6)δ152.8,146.1,139.4,129.1,129.1,128.0,125.5,122.3,119.8,119.6,119.0,114.8.HRMS(ESI-TOF):m / z calcdfor C 12 H 12 ClN2O2[M+H] + ,263.0509;found,263.0511.

[0081] 3f:

[0082] Brown solid; 54 mg, yield: 88%; Mp: 143.4-144.8°C; IR (KBr): 3562, 3349, 2093, 1742, 1226, 1024, 923, 852, 801, 743, 691 cm -1 ; 1H NMR(400MHz,DMSO-d6)δ9.99(s,1H,OH),9.45(s,1H,NH),8.19(s,1H,NH),8.03(dd,J=7.9,1.7Hz,1H,ArH),7.44(d,J=2.2Hz,4H,ArH),6.85–6.83(m,1H,ArH),6.82–6.77(m,1H,ArH),6.74(td,J=7.5,1.9Hz,1H,ArH). 13 C NMR(101MHz,DMSO-d6)δ152.8,146.1,144.4,139.8,136.9,132.0,128.0,122.3,120.2,119.9,119.6,119.0,116.8,114.9,114.8,114.8,113.4.HRMS(ESI-TOF):m / z calcd forC 12 H 12 BrN2O2[M+H] + ,307.0004;found,307.0005.

[0083] 3g:

[0084] 黄色固体;42mg,产率:85%;Mp:182.4-183.6℃;IR(KBr):3561,3327,1928,1742,1246,1039,886,800,766,742,719; 1 H NMR(400MHz,DMSO-d6)δ9.90(s,1H,OH),9.22(d,J=2.3Hz,1H,NH),8.73(s,1H,NH),8.18(td,J=8.3,1.7Hz,1H,ArH),8.04(dd,J=7.9,1.7Hz,1H,ArH),7.22(ddd,J=11.7,8.1,1.5Hz,1H,ArH),7.13(td,J=7.8,1.5Hz,1H,ArH),7.02–6.95(m,1H,ArH),6.87–6.79(m,2H,ArH),6.75(td,J=7.6,1.9Hz,1H,ArH). 13 C NMR(101MHz,DMSO-d6)δ152.8,146.1,142.8,139.7,128.0,122.3,122.2,119.6,119.4,119.0,114.8. 19F NMR(376MHz,DMSO-d6)δ-129.28.HRMS(ESI-TOF):m / z calcd for C 12 H 12 FN2O2[M+H] + ,247.0805;found,247.0806.

[0085] 3h:

[0086] Yellow solid; 47 mg, yield: 75%; Mp: 194.0-195.6°C; IR (KBr): 3566, 3362, 1742, 1226, 1088, 884, 849, 797, 766; 1 H NMR(400MHz,DMSO-d6)δ9.97(s,1H,OH),9.51(s,1H,NH),8.20(s,1H,NH),8.04(dd,J=7.9 ,1.7Hz,1H,ArH),7.57–7.53(m,2H,ArH),7.31–7.26(m,2H,ArH),6.87–6.73(m,3H,ArH). 13 CNMR(101MHz,DMSO-d6)δ152.8,146.1,142.8,139.7,128.0,122.3,122.2,119.6,119.4,119.0,114.8. 19 F NMR(376MHz,DMSO-d6)δ-57.13.HRMS(ESI-TOF):m / z calcd for C 14 H 13 F3N2O3[M+H] + ,313.0722;found,313.0724.

[0087] 3i:

[0088] Yellow solid; 46 mg, yield: 95%; Mp: 140.5-141.8°C; IR (KBr): 3554, 3347, 2093, 1790, 1225, 1025, 849, 783, 736, 690; 1 H NMR (400 MHz, Acetone-d6) δ

[0089] 9.24 (s, 1H, OH), 8.73 (s, 1H, NH), 8.2 (s, 1H, NH), 7.80 (dd, J = 8.0, 1.7 Hz, 1H, ArH), 7.55 (ddt, J = 8.6, 3.5, 1.8 Hz, 2H, ArH), 7.39 (t, J = 7.9 Hz, 2H, ArH), 7.25 - 7.17 (m, 1H, ArH), 7.08 (td, J = 7.7, 1.6 Hz, 1H, ArH), 6.95 (dd, J = 8.0, 1.5 Hz, 1H, ArH), 6.87 (td, J = 7.7, 1.5 Hz, 1H, ArH). 13 C NMR (101 MHz, Acetone-d6) δ 179.6, 150.1, 138.8, 128.8, 126.8, 126.5, 125.5, 125.5, 124.5, 124.4, 119.7, 116.6. HRMS (ESI-TOF): m / z calcd for C 13 H 13 N2OS[M+H] + , 245.0670; found, 245.0671.

[0090] 3j:

[0091] Yellow solid; 58 mg, yield: 78%; Mp: 167.3-168.4 °C; IR (KBr): 3562, 3357, 2258, 1928, 1742, 1726, 941, 894, 797, 724, 689, 650 cm -1 ; 1 H NMR (400 MHz, Acetone-d6) δ 9.38 (s, 1H, OH), 8.70 (s, 1H, NH), 8.53 (s, 1H, NH), 8.13 - 8.10 (m, 1H, ArH), 7.98 (dd, J = 7.5, 1.9 Hz, 1H, ArH), 7.92 (d, J = 8.2 Hz, 1H, ArH), 7.73 (d, J = 8.6 Hz, 1H, ArH), 7.67 - 7.64 (m, 1H, ArH), 7.61 - 7.55 (m, 3H, ArH), 7.06 (td, J = 7.6, 1.6 Hz, 1H, ArH), 6.91 (dd, J = 8.1, 1.5 Hz, 1H, ArH), 6.84 (td, J = 7.7, 1.5 Hz, 1H, ArH). 13C NMR (101MHz, Acetone-d6) δ180.8,150.1,134.6,134.0,128.2,127.9,127.2,126 .6,126.6,126.4,125.9,125.7,125.3,123.0,119.7,117.1.HRMS(ESI-TOF):m / z calcdfor C 17 H 14 N2OS[M+H] + ,295.0826;found,295.0828.

[0092] 3k:

[0093] Yellow solid; Mp: 131.7-132.4°C; 37 mg, yield: 71%; IR (KBr): 3577, 3318, 2978, 1746, 1256, 1050, 882, 808, 748, 630 cm -1 ; 1 H NMR(600MHz,DMSO-d6)δ9.86(s,1H,OH),9.82(s,1H,NH),8.99(s,1H,NH),7.95(dd,J=8.0,1.6Hz,1H,ArH),7.40–7.38(m,2 H,ArH),7.15(d,J=8.2Hz,2H,ArH),6.97(td,J=7.7,1.6Hz,1H,ArH),6.87(dd,J=8.1,1.4Hz,1H,ArH),6.77(td,J=7.7,1.4

[0094] Hz,1H,ArH),2.28(s,3H,CH3). 13 C NMR(151MHz,DMSO-d6)δ179.4,137.0,134.3,129.4,127.1,125.7,124.3,118.9,115.7,21.0.HRMS(ESI-TOF):m / z calcd for C 14 H 15 N2OS[M+H] + ,259.0827;found,259.0828.

[0095] 3l:

[0096] Yellow solid; 47 mg, yield: 78%; Mp: 134.5-135.6°C; IR (KBr): 3564, 3372, 2539, 2415, 1746, 1047, 881, 791, 713, 924; 1 H NMR(400MHz,DMSO-d6)δ9.91(s,1H,OH),9.04(s,1H,NH),7.96(dd,J=8.1,1.6Hz,1H,NH),7.4 3(d,J=2.2Hz,1H,ArH),7.37(d,J=2.2Hz,1H,ArH),6.98(td,J=7.7,7.3,1.6Hz,1H,ArH),6.8 8(dd,J=8.1,1.5Hz,1H,ArH),6.78(td,J=7.6,1.5Hz,1H,ArH),6.63(dd,J=7.7,1.4Hz,1H,Ar H), 6.56 (dd, J=7.4, 1.6Hz, 1H, ArH), 6.39 (td, J=7.4, 1.9Hz, 1H, ArH), 1.29 (s, 9H, C(CH3)3). 13 C NMR(101MHz,DMSO-d6)δ179.3,149.9,147.4,144.4,137.0,136.9,127.2,125.7,125 .6,123.9,119.9,118.8,16.8,115.7,114.8,114.8,34.6,31.6.HRMS(ESI-TOF):m / z calcd for C 17 H 21 N2OS[M+H] + ,301.1296;found,301.1298.

[0097] 3m:

[0098] Brown solid; 46 mg, yield: 84%; Mp: 196.2-197.6°C; IR (KBr): 3363, 3553, 1752, 1708, 1268, 741, 638, 603, 552, 516; 1H NMR(400MHz,DMSO-d6)δ10.03(s,1H,OH),9.40(s,1H,NH),8.16(s,1H,NH),8.01(dd,J=7.9,1.7Hz,1H,ArH),7.71(d,J=2.2Hz,1H,ArH),7.23(d,J=8.3Hz,1H,ArH),7.14(dd,J=8.3,2.2Hz,1H,ArH),6.87–6.71(m,3H,ArH),6.67–6.45(m,2H,ArH),6.39(td,J=7.4,1.8Hz,1H,ArH),2.25(s,3H,CH3). 13 C NMR(400MHz,DMSO-d6)δ152.88,146.1,144.4,139.5,136.9,133.6,131.6,128.5,128.0,122.4,119.9,119.6,119.1,118.2,117.0,116.9,114.9,114.8,114.8,19.2.HRMS(ESI-TOF):m / z calcd forC 14 H 14 ClN2O2[M+H] + ,276.0665;found,276.0667.

[0099] 3n:

[0100] 棕色固体;41mg,产率:75%;Mp:182.7-183.6℃;IR(KBr):3562,3354,2547,1928,1733,1268,1946,801,747,725,689,648; 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H,OH),8.75(s,1H,NH),8.61(s,1H,NH),8.18(d,J=2.1Hz,1H,ArH),7.80(dd,J=8.1,1.3Hz,1H,ArH),7.18–7.14(m,2H,ArH),6.95(td,J=7.4,1.3Hz,1H,ArH),6.83(d,J=1.1Hz,1H,ArH),2.24(s,3H,CH3). 13C NMR(101MHz,DMSO-d6)δ153.1,144.9,137.7,130.6,129.9,128.4,126.5,123.3,123.0,122.0,121.1,118.3,115.7,18.5.HRMS(ESI-TOF):m / z calcd forC 14 H 14 ClN2O2[M+H] + ,276.0665;found,276.0667.

[0101] 3o:

[0102] 棕色固体;56mg,产率:83%;Mp:198.2-199.6℃;IR(KBr):3578,3367,1928,1747,1247,1050,881,780,747,725,680,634; 1 H NMR(400MHz,DMSO-d6)δ10.57(s,1H,OH),9.54(s,1H,NH),8.28(s,1H,NH),8.02(d,J=8.7Hz,1H,ArH),7.73(d,J=2.1Hz,1H,ArH),7.30(t,J=8.0Hz,1H,ArH),7.21(dd,J=8.0,2.0Hz,1H,ArH),6.99(d,J=2.5Hz,1H,ArH),6.94(dd,J=8.7,2.3Hz,1H,ArH),6.78–6.65(m,1H,ArH). 13 C NMR(101MHz,DMSO-d6)δ152.6,147.3,145.6,141.7,136.7,133.7,130.9,127.6,122.3,122.2,121.8,120.3,117.7,117.3,117.1,116.8,115.8,113.3,106.5.HRMS(ESI-TOF):m / z calcdfor C 13 H 11 BrClN2O2[M+H] + ,340.9614;found,340.9615.

[0103] 3p:

[0104] Brown solid; 44 mg, yield: 80%; Mp: 189.7-190.6°C; IR (KBr): 3578, 3380, 2981, 1740, 1246, 1047, 891, 797, 750, 703, 669 cm -1 ; 1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H,OH),8.94(s,1H,NH),8.93(s,1H,NH),8.11(dd ,J=8.3,1.6Hz,1H,ArH),7.87(d,J=2.1Hz,1H,ArH),7.44(dd,J=8.0,1.5Hz,1H,ArH ),7.28(ddd,J=8.6,7.4,1.6Hz,1H,ArH),7.02(ddd,J=8.0,7.3,1.6Hz,1H,ArH),6 .74(d,J=8.0Hz,1H,ArH),6.63(ddd,J=8.0,2.2,0.9Hz,1H,ArH),2.20(s,3H,CH3). 13 C NMR(101MHz,DMSO-d6)δ152.9,144.4,136.7,129.7,127.9,127.8,127.7,123.7,122.9,122.6,120.5,114.8,21.1.HRMS(ESI-TOF):m / z calcd forC 14 H 14 ClN2O2[M+H] + ,276.0665;found,276.0667.

[0105] 3q:

[0106] Brown solid; 45 mg, yield: 77%; Mp: 189.7-190.6°C; IR (KBr): 3563, 3350, 2574, 1927, 1745, 1268, 1048, 873, 827, 747, 736, 705; 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H,OH),9.43(s,1H,NH),8.34(s,1H,NH),8.19(s,1H,ArH),7.2 3–7.16(m,3H,ArH),6.92(dd,J=8.1,1.2Hz,1H,ArH),6.58–6.55(m,1H,ArH),3.75(s,3H,OCH3). 13C NMR (101MHz, DMSO-d6) δ160.1,152.7,144.8,141.3,130.0,129.6,123.1,121.3,118.0,115.6,110.7,107.8,104.1,55.3.HRMS(ESI-TOF):m / z calcdfor C 14 H 14 ClN2O3[M+H] + ,293.0615;found,293.0617.

[0107] 3r:

[0108] Purple solid; 50 mg, yield: 81%; Mp: 201.2-202.4°C; IR (KBr): 3552, 3327, 2991, 1744, 1246, 1049, 938, 850, 781, 740, 633; ​​1H NMR (400MHz, Acetone-d6) δ8.85(s,1H,OH),8.82(s,1H,NH),7.89(s,1H,NH),7.79(s,1H,ArH),7.69–7.64(m,2H ,ArH),7.29–7.23(m,2H,ArH),6.77(d,J=8.0Hz,1H,ArH),6.69(dd,J=8.3,2.1Hz,1H,ArH),2.23(s,3H,CH3).13C NMR (101MHz, Acetone-d6) δ152.9,144.0,143.4,139.2,128.8,123.2,121.6,120.4,119.5,119.4,115.2,20.0.19F NMR (376MHz, Acetone-d6) δ-58.92.HRMS (ESI-TOF): m / zcalcd forC15H14F3N2O3[M+H]+, 327.0878; found, 327.0880.

Claims

1. A method for synthesizing 2-hydroxydiaryl urea derivatives, characterized in that: Benzoxazole compounds and aryl iso(thio)cyanates are used as raw materials, and a ring-opening coupling reaction occurs under the action of bis(trifluoroacetyl)iodobenzene and additives to generate 2-hydroxydiaryl urea derivatives.

2. The method for synthesizing 2-hydroxydiaryl urea derivatives according to claim 1, wherein The general formula for synthesizing 2-hydroxydiaryl urea derivatives according to the method is: wherein X is selected from S or O; R 1 Selected from alkyl, alkoxy, halogen, trifluoromethoxy, naphthyl, polyhaloalkyl; R 2 Selected from alkyl, alkoxy, halogen.

3. The method for synthesizing 2-hydroxydiaryl urea derivatives according to claim 1, characterized in that: The additive is protonated alumina.

4. The method for synthesizing 2-hydroxydiaryl urea derivatives according to claim 1, characterized in that: The molar ratio of the additive to benzoxazole is 0.8-1.2:

1.

5. The method for synthesizing 2-hydroxydiaryl urea derivatives according to claim 1, characterized in that: The amount of bis(trifluoroacetyl)iodobenzene used is 0.5-1.0 equivalents of the molar amount of benzoxazole.

6. The method for synthesizing 2-hydroxydiaryl urea derivatives according to claim 1, characterized in that: The solvent of the method is methanol, the reaction temperature is 55-65° C., and the reaction time is 1-3 hours.

7. The method for synthesizing 2-hydroxydiaryl urea derivatives according to claim 1, characterized in that: The molar ratio of the benzoxazole compound to the aryl iso(thio)cyanate is 1:0.8-1:1.

2.

8. A 2-hydroxydiaryl urea or thiourea derivative, characterized in that The 2-hydroxydiaryl urea derivative is prepared by the method according to any one of claims 1 to 7 and comprises the following structure:

9. Use of the method according to any one of claims 1 to 8 in the preparation of anti-tumor drugs, anti-HIV drugs or kinase inhibitors, characterized in that: The 2-hydroxydiaryl urea derivative is used as an active ingredient in a pharmaceutical composition.

10. Use of the method according to any one of claims 1 to 8 in preparing fluorescent probes or functional polymer materials, characterized in that: The 2-hydroxydiaryl urea derivative serves as a hydrogen bond-directing self-assembly unit.

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