Preparation method of methyl-2-phenylbenzoxazole-7-carboxylate

Abstract

The invention discloses a preparation method of methyl-2-phenylbenzoxazole-7-carboxylic ester, which comprises the following steps: step (1), taking 2-fluoro-3-aminobenzoic acid methyl ester and benzoyl chloride as raw materials, and carrying out condensation reaction on the raw materials and an alkaline substance in a solvent to prepare 3-benzamido-2-fluorobenzoic acid methyl ester; and (2) dissolving the 3-benzamido-2-methyl fluorobenzoate in a solvent, and carrying out a cyclization reaction with an alkaline substance, so as to prepare the methyl-2-phenylbenzoxazole-7-carboxylic ester. By optimizing a reaction path and a post-treatment process, a complex purification step of an intermediate is avoided; high yield and high purity are realized by controlling reaction conditions; the solvent can be recycled, and the discharge amount of three wastes is reduced; the method has mild process conditions and is suitable for industrial continuous production.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for preparing methyl-2-phenylbenzoxazole-7-carboxylate. Background Art

[0002] The benzoxazole ring mainly serves as a key structure in anti-inflammatory and anti-rheumatic drug molecules, such as benoxaprofen and benzoxazolamine. The traditional synthesis methods for the benzoxazole moiety are the condensation reaction of 2-aminophenol with carboxylic acid under acidic conditions or the reaction of 2-aminophenol with aldehyde and subsequent oxidative cyclization of the imine intermediate.

[0003] In recent years, Anthony Huxley et al. (SYNLETT 2006, No.16, pp 2658-2660 04.10.2006 Advanced online publication: 22.09.2006 DOI: 10.1055 / s-2006-951489) condensed methyl 2-hydroxy-3-aminobenzoate with benzoyl chloride to form methyl 3-benzamidobenzoate-2-fluorobenzoate, and used a co-solvent with a ratio of acetic acid:trifluoroacetic acid = 1:1, at a temperature of 200 °C for 20 min, with microwave assistance to synthesize methyl-2-phenylbenzoxazole-7-carboxylate. Satoshi Ueda and Hideko Nagasawa (Angew.Chem.Int.Ed. 2008, 47, 6411-6413 DOI: 10.1002 / anie.200801240) directly used methyl 3-benzamidobenzoate with a Cu(OTf)2 / O2 catalytic system and reacted at 140 °C for 48 h. Anthony Huxley et al. used a co-solvent with a ratio of acetic acid:trifluoroacetic acid = 1:1 and a temperature of 200 °C, and the reaction conditions were relatively harsh, which also brought challenges to the treatment of three wastes; in addition, Satoshi Ueda and Hideko Nagasawa directly used methyl 3-benzamidobenzoate with a Cu(OTf)2 / O2 catalytic system, the reaction time was long, increasing the time cost; using a catalyst increased the raw material cost; and the reaction yield was only 61%. Summary of the Invention

[0004] Object of the Invention: The present invention provides a method for preparing methyl-2-phenylbenzoxazole-7-carboxylate with high yield and purity of the target product, mild reaction conditions, simple post-treatment method, low cost, and green and safe.

[0005] Summary of the Invention: The method for preparing methyl-2-phenylbenzoxazole-7-carboxylate according to the present invention comprises the following steps:

[0006] Step (1): Using methyl 2-fluoro-3-aminobenzoate and benzoyl chloride as raw materials, after carrying out a condensation reaction with a basic substance in a solvent, methyl 3-benzamido-2-fluorobenzoate is prepared.

[0007] Step (2): Dissolving methyl 3-benzamido-2-fluorobenzoate in a solvent and carrying out a cyclization reaction with a basic substance to prepare methyl 2-phenylbenzoxazole-7-carboxylate. In the present invention, using methyl 2-fluoro-3-aminobenzoate and benzoyl chloride as raw materials, the reaction path and post-treatment process are optimized, avoiding complex purification steps of intermediates. Compared with directly using existing intermediate products, it is more suitable for the subsequent cyclization reaction. Through the condensation reaction, the yield of methyl 3-benzamido-2-fluorobenzoate reaches 96.82% and the purity is 99.98%; in the cyclization reaction, methyl 3-benzamido-2-fluorobenzoate is directly reacted with a basic substance to generate methyl 2-phenylbenzoxazole-7-carboxylate.

[0008] This process does not require an additional catalyst, and the post-treatment method is simple, efficient, green and safe. The yield of the final product can reach 90.64% and the purity is 99.67%, meeting the requirements of industrial production.

[0009] Preferably, in step (1), the solvent is one or two of water, benzene, toluene, dichloromethane, 1,2-dichloroethane, ethyl acetate, butyl acetate, methanol, ethanol, acetone, methyl isobutyl ketone, cyclohexanone, acetonitrile, and propionitrile.

[0010] Preferably, in step (1), the basic substance includes one or two of trimethylamine, pyridine, diisopropylethylamine, lithium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, and lithium diisopropylamide.

[0011] It has been found through research that in the process of the condensation reaction, the present invention selects a basic substance with relatively strong basicity, which can effectively neutralize HCl generated during the reaction, thereby promoting the reaction to proceed in the forward reaction direction, ensuring the efficient progress and high selectivity of the reaction. This strategy not only improves the conversion rate of the reaction but also reduces the occurrence of side reactions, providing high-quality intermediates for subsequent synthesis steps.

[0012] Preferably, in step (1), the condensation reaction includes recrystallization, and the recrystallization uses n-heptane.

[0013] The present invention selects n - heptane as the recrystallization solvent, which can further separate methyl 3 - benzamido - 2 - fluorobenzoate from impurities, thereby improving the purity and yield of the product. During the recrystallization process, n - heptane does not react with methyl 3 - benzamido - 2 - fluorobenzoate or impurities, avoiding the introduction of new impurities or interfering with the reaction process. After recrystallization is completed, the product is separated from the solvent by suction filtration, facilitating subsequent drying and purification operations and improving efficiency.

[0014] Preferably, in step (1), the molar ratio of methyl 2 - fluoro - 3 - aminobenzoate to benzoyl chloride is 1:1.0 - 1.1.

[0015] Preferably, in step (1), the molar ratio of methyl 2 - fluoro - 3 - aminobenzoate to the basic substance is 1:1.1 - 2.

[0016] Preferably, in step (2), it is one or two of water, benzene, toluene, dichloromethane, 1,2 - dichloroethane, ethyl acetate, butyl acetate, methanol, ethanol, acetone, methyl isobutyl ketone, cyclohexanone, acetonitrile, and propionitrile.

[0017] Preferably, in step (2), the basic substance includes one or two of trimethylamine, pyridine, diisopropylethylamine, lithium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, and lithium diisopropylamide.

[0018] It has been found through research that in the cyclization reaction, the present invention selects a basic substance with relatively strong alkalinity, which can effectively neutralize hydrofluoric acid (HF) generated during the reaction process, thereby promoting the reaction to proceed in the forward reaction direction. In this way, the acidic environment of the reaction system is effectively inhibited, ensuring the efficient progress and high selectivity of the reaction, while reducing the occurrence of side reactions.

[0019] Preferably, in step (2), the molar ratio of methyl 3 - benzamido - 2 - fluorobenzoate to the basic substance is 1:1.2 - 2.

[0020] Preferably, in step (2), the reaction temperature is 90 - 120 °C and the reaction time is 2 - 3 h.

[0021] Beneficial effects: Compared with the prior art, the present invention has remarkable effects:

[0022] The present invention uses methyl 2 - fluoro - 3 - aminobenzoate and benzoyl chloride as raw materials to directly prepare the target product by optimizing the synthesis route, avoiding the use of high - cost intermediates and complex multi - step reactions, thereby significantly reducing the raw material cost;

[0023] In the condensation reaction and the cyclization reaction, the present invention selects appropriate basic substances and solvents to ensure the efficient progress of the reaction. The yield of the intermediate methyl 3-benzamido-2-fluorobenzoate is as high as 96.82%, and it can be directly used in the subsequent reaction without additional purification steps, significantly improving the quality and stability of the product. The yield of the final product methyl 2-phenylbenzoxazole-7-carboxylate reaches 90.64%;

[0024] In addition, the present invention ensures the high purity and high yield of the product by optimizing the reaction temperature, time, and post-treatment method, meeting the strict requirements of industrial production for product quality. The cyclization reaction does not require an additional catalyst, and the post-treatment process is simple and efficient, not only reducing the production cost but also reducing the generation of chemical waste. The green, safe, and efficient synthesis method of the present invention is applicable to large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the reaction route diagram of the present invention;

[0026] Figure 2 is the 1H NMR spectrum of methyl 2-phenylbenzoxazole-7-carboxylate;

[0027] Figure 3 is the 19F NMR spectrum of methyl 2-phenylbenzoxazole-7-carboxylate;

[0028] Figure 4 is the 13C NMR spectrum of methyl 2-phenylbenzoxazole-7-carboxylate;

[0029] Figure 5 is the mass spectrum of methyl 2-phenylbenzoxazole-7-carboxylate. DETAILED DESCRIPTION OF THE INVENTION

[0030] The following further clarifies the present invention in conjunction with the drawings and specific embodiments. The materials, reagents, instruments, etc. used in the embodiments can be obtained from commercial channels without special instructions. It should be understood that the following specific embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

[0031] To investigate the influence of the type of solvent in step (1) on the yield of methyl 3-benzamido-2-fluorobenzoate, the following experiment was designed:

[0032] Example 1

[0033] As Figure 1As shown, 5 g of methyl 2-fluoro-3-aminobenzoate was dissolved in 25 g of DCM. Under nitrogen protection at 25 °C, 3.45 g of sodium carbonate was added, and 4.55 g of benzoyl chloride was added dropwise. The reaction was carried out for 30 min. TLC detection: DCM:EA = 10:1, and the raw materials were completely reacted. DCM was added to dilute the reaction solution. The organic phase was washed twice with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Recrystallization was carried out with n-heptane, and it was dried in a vacuum oven at 60 °C for 9 hours to obtain 7.8 g of methyl 3-benzamido-2-fluorobenzoate.

[0034] 5 g of methyl 3-benzamido-2-fluorobenzoate was dissolved in 50 g of DMF. 3.80 g of potassium carbonate was added, and the temperature was slowly raised to 120 °C. The reaction was carried out for 3 hours. PE:EA = 4:1, and the reaction was complete. The insoluble substances were removed by filtration. At room temperature, the reaction solution was poured into 50 g of water and stirred for crystallization. It was dried in a vacuum oven at 60 °C for 9 hours to obtain 4.2 g of methyl 2-phenylbenzoxazole-7-carboxylate.

[0035] Example 2

[0036] 5 g of methyl 2-fluoro-3-aminobenzoate was dissolved in 25 g of toluene. Under nitrogen protection at 25 °C, 3.45 g of sodium carbonate was added, and 4.55 g of benzoyl chloride was added dropwise. The reaction was carried out for 30 min. TLC detection: DCM:EA = 10:1, and the raw materials were completely reacted. Toluene was added to dilute the reaction solution. The organic phase was washed twice with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Recrystallization was carried out with n-heptane, and it was dried in a vacuum oven at 60 °C for 9 hours to obtain 7.82 g of methyl 3-benzamido-2-fluorobenzoate.

[0037] 5 g of methyl 3-benzamido-2-fluorobenzoate was dissolved in 50 g of DMF. 3.80 g of potassium carbonate was added, and the temperature was slowly raised to 120 °C. The reaction was carried out for 3 hours. PE:EA = 4:1, and the reaction was complete. The insoluble substances were removed by filtration. At room temperature, the reaction solution was poured into 50 g of water and stirred for crystallization. It was dried in a vacuum oven at 60 °C for 9 hours to obtain 4.2 g of methyl 2-phenylbenzoxazole-7-carboxylate.

[0038] Comparative Example 1

[0039] On the basis of Example 1, only the solvent DCM in step (1) was replaced with THF, and the other steps and conditions remained unchanged.

[0040] Comparative Example 2

[0041] On the basis of Example 1, only the solvent DCM in step (1) was replaced with DMF, and the other steps and conditions remained unchanged.

[0042] Table 1 Effects of different solvents on the yield of methyl 3-benzamido-2-fluorobenzoate

[0043]

[0044] From the yield of methyl 3-benzamido-2-fluorobenzoate in Table 1, it can be seen that when toluene is used as the solvent, the yield of methyl 3-benzamido-2-fluorobenzoate is relatively high.

[0045] To investigate the effect of the type of basic substance in step (1) on the yield of methyl 3-benzamido-2-fluorobenzoate, the following experiment was designed:

[0046] Example 3

[0047] Dissolve 5 g of methyl 2-fluoro-3-aminobenzoate in 25 g of toluene. Under nitrogen protection at 25 °C, add 3.45 g of sodium carbonate, and dropwise add 4.55 g of benzoyl chloride. React for 30 min and spot-check. DCM:EA = 10:1, and the raw materials have completely reacted. Add toluene to dilute the reaction solution. Wash the organic phase twice with 20 ml of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Add n-heptane for recrystallization, and dry in a vacuum oven at 60 °C for 9 hours to obtain 7.82 g of methyl 3-benzamido-2-fluorobenzoate.

[0048] Dissolve 5 g of methyl 3-benzamido-2-fluorobenzoate in 50 g of DMF, add 3.80 g of potassium carbonate, and slowly heat to 120 °C. React for 3 hours, and PE:EA = 4:1, and the reaction is complete. Filter to remove insoluble substances. At room temperature, pour the reaction solution into 50 g of water and stir to crystallize. Dry in a vacuum oven at 60 °C for 9 hours to obtain 4.2 g of methyl 2-phenylbenzoxazole-7-carboxylate.

[0049] Example 4

[0050] Dissolve 5 g of methyl 2-fluoro-3-aminobenzoate in 25 g of toluene. Under nitrogen protection at 25 °C, add 2.57 g of pyridine, and dropwise add 4.55 g of benzoyl chloride. React for 30 min and spot-check. DCM:EA = 10:1, and the raw materials have completely reacted. Add toluene to dilute the reaction solution, add 20 ml of 1N HCl to adjust the pH to acidic, and stir for 1 hour to remove pyridine. Separate the liquid. Add 20 ml of toluene to the pyridine phase for extraction, and combine the organic phases. Adjust the pH of the organic phase to basic with 3 ml of saturated sodium carbonate solution. Wash the organic phase twice with 20 ml of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Add n-heptane for recrystallization, and dry in a vacuum oven at 60 °C for 9 hours to obtain 7.48 g of methyl 3-benzamido-2-fluorobenzoate.

[0051] Dissolve 5 g of methyl 3-benzamido-2-fluorobenzoate in 50 g of DMF, add 3.80 g of potassium carbonate, and slowly heat to 120 °C. React for 3 hours, and the reaction is complete when PE:EA = 4:1. Filter to remove insoluble substances. At room temperature, pour the reaction solution into 50 g of water and stir to crystallize. Dry in a vacuum oven at 60 °C for 9 hours to obtain 4.2 g of methyl 2-phenylbenzoxazole-7-carboxylate.

[0052] Comparative Example 3

[0053] On the basis of Example 3, only replace the basic substance sodium carbonate in step (1) with triethylamine, and keep the rest of the steps and conditions unchanged.

[0054] Comparative Example 4

[0055] On the basis of Example 3, only replace the basic substance sodium carbonate in step (1) with dipotassium hydrogen phosphate, and keep the rest of the steps and conditions unchanged.

[0056] Table 2 Effects of different types of basic substances on the yield of methyl 3-benzamido-2-fluorobenzoate

[0057]

[0058] From the yield of methyl 3-benzamido-2-fluorobenzoate in Table 2, it can be seen that when the basic substance is sodium carbonate, the yield of methyl 3-benzamido-2-fluorobenzoate is relatively high. At the same time, sodium carbonate simplifies the post-treatment. While triethylamine and dipotassium hydrogen phosphate have relatively weak alkalinity, resulting in poor reaction effects.

[0059] To investigate the effect of using recrystallization in step (1) on the yield, the following experiment was designed:

[0060] Example 5

[0061] Dissolve 5 g of methyl 2-fluoro-3-aminobenzoate in 25 g of toluene, add 3.45 g of sodium carbonate under nitrogen protection at 25 °C, and dropwise add 4.55 g of benzoyl chloride. React for 30 min and spot-check with DCM:EA = 10:1, and the raw materials react completely. Add toluene to dilute the reaction solution, wash the organic phase twice with 20 ml of saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Add n-heptane for recrystallization, and dry in a vacuum oven at 60 °C for 9 hours to obtain 7.82 g of methyl 3-benzamido-2-fluorobenzoate.

[0062] Dissolve 5 g of methyl 3-benzamido-2-fluorobenzoate in 50 g of DMF, add 3.80 g of potassium carbonate, and slowly heat to 120 °C. React for 3 hours, and the reaction is complete when PE:EA = 4:1. Filter to remove insoluble substances. At room temperature, pour the reaction solution into 50 g of water and stir to crystallize. Dry in a vacuum oven at 60 °C for 9 hours to obtain 4.2 g of methyl 2-phenylbenzoxazole-7-carboxylate.

[0063] Comparative Example 5

[0064] On the basis of Example 5, only step (1) was changed from recrystallization with n-heptane to recrystallization with ethyl acetate, and the remaining steps and conditions remained unchanged.

[0065] Comparative Example 6

[0066] On the basis of Example 5, only step (1) was changed from recrystallization with n-heptane to recrystallization with methyl tert-butyl ether, and the remaining steps and conditions remained unchanged.

[0067] Table 3 Effects of Different Recrystallization Methods on the Yield of Methyl 3-Benzamido-2-fluorobenzoate

[0068]

[0069] From the yield of methyl 3-benzamido-2-fluorobenzoate in Table 3, it can be seen that the yield of methyl 3-benzamido-2-fluorobenzoate is higher when recrystallized with n-heptane.

[0070] The characterization data are as follows, which are the 1H NMR, 13C NMR and mass spectrum of methyl 2-phenylbenzoxazole-7-carboxylate respectively:

[0071] 1HNMR(500MHz,CDCl3)δ8.74(ddd,J=8.6,7.1,1.7Hz,1H),8.20(s,1H),7.96-7.90(m,2H),7.71(ddd,J=8.4,7.0,1.7Hz,1H),7.66-7.59(m,1H),7.59-7.52(m,2H),7.29(td,J=8.1,1.2Hz,1H),3.98(s,3H).

[0072] 13C NMR(126MHz,CDCl3)δ165.58,164.37,152.99,150.94,134.28,132.39,129.00,127.76,127.67,127.15,126.28,125.97,124.28,124.24,118.50,118.43,77.34,77.08,76.83,52.47.

[0073] ESI-MS:m / z274.08[M+H]+

[0074] To investigate the effect of the type of basic substance used in step (2) on the yield, the following experiment was designed:

[0075] Example 6

[0076] Dissolve 5 g of methyl 2-fluoro-3-aminobenzoate in 25 g of toluene. Under nitrogen protection at 25 °C, add 3.45 g of sodium carbonate, and dropwise add 4.55 g of benzoyl chloride. React for 30 min and monitor by TLC (DCM:EA = 10:1). When the raw materials are completely reacted, add toluene to dilute the reaction solution. Wash the organic phase twice with 20 ml of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Recrystallize with n-heptane and dry in a vacuum oven at 60 °C for 9 hours to obtain 7.82 g of methyl 3-benzamido-2-fluorobenzoate.

[0077] Dissolve 5 g of methyl 3-benzamido-2-fluorobenzoate in 50 g of DMF, add 3.80 g of potassium carbonate, and slowly heat to 120 °C. React for 3 hours (PE:EA = 4:1). Filter to remove insoluble substances. At room temperature, pour the reaction solution into 50 g of water and stir to crystallize. Dry in a vacuum oven at 60 °C for 9 hours to obtain 4.2 g of methyl 2-phenylbenzoxazole-7-carboxylate.

[0078] Example 7

[0079] Dissolve 5 g of methyl 2-fluoro-3-aminobenzoate in 25 g of toluene. Under nitrogen protection at 25 °C, add 3.45 g of sodium carbonate, and dropwise add 4.55 g of benzoyl chloride. React for 30 min and monitor by TLC (DCM:EA = 10:1). When the raw materials are completely reacted, add toluene to dilute the reaction solution. Wash the organic phase twice with 20 ml of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Recrystallize with n-heptane and dry in a vacuum oven at 60 °C for 9 hours to obtain 7.82 g of methyl 3-benzamido-2-fluorobenzoate.

[0080] Dissolve 5 g of methyl 3-benzamido-2-fluorobenzoate in 50 g of DMF, add 2.91 g of sodium carbonate, and slowly heat to 120 °C. React for 3 hours (PE:EA = 4:1). Filter to remove insoluble substances. At room temperature, pour the reaction solution into 50 g of water and stir to crystallize. Dry in a vacuum oven at 60 °C for 9 hours to obtain 3.94 g of methyl 2-phenylbenzoxazole-7-carboxylate.

[0081] Comparative Example 7

[0082] On the basis of Example 6, only change the basic substance in step (2) from potassium carbonate to triethylamine, and keep the other steps and conditions unchanged.

[0083] Comparative Example 8

[0084] On the basis of Example 6, only change the basic substance in step (2) from potassium carbonate to sodium acetate, and keep the other steps and conditions unchanged.

[0085] Table 4 Effect of the type of basic substance on the yield of methyl 2-phenylbenzoxazole-7-carboxylate

[0086]

[0087] From the yield of methyl 2-phenylbenzoxazole-7-carboxylate in Table 4, it can be seen that the yield of methyl 2-phenylbenzoxazole-7-carboxylate is the highest when potassium carbonate is used as the basic substance.

[0088] To investigate the effect of the feeding amount of potassium carbonate in step (2) on the yield, the following experiments were designed:

[0089] Example 8

[0090] Dissolve 5 g of methyl 2-fluoro-3-aminobenzoate in 25 g of toluene. Under nitrogen protection at 25 °C, add 3.45 g of sodium carbonate, and dropwise add 4.55 g of benzoyl chloride. React for 30 min and spot-check with DCM:EA = 10:1. The raw materials have completely reacted. Add toluene to dilute the reaction solution. Wash the organic phase twice with 20 ml of saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Add n-heptane for recrystallization and dry in a vacuum oven at 60 °C for 9 hours to obtain 7.82 g of methyl 3-benzamido-2-fluorobenzoate.

[0091] Dissolve 5 g of methyl 3-benzamido-2-fluorobenzoate in 50 g of DMF, add 5.06 g of potassium carbonate, and slowly heat to 120 °C. React for 3 hours until the reaction is complete with PE:EA = 4:1. Filter to remove insoluble substances. At room temperature, pour the reaction solution into 50 g of water and stir to crystallize. Dry in a vacuum oven at 60 °C for 9 hours to obtain 4.17 g of methyl 2-phenylbenzoxazole-7-carboxylate.

[0092] Example 9

[0093] On the basis of Example 8, only change the mass of potassium carbonate as the basic substance in step (2) to 4.05 g, and keep the rest of the steps and conditions unchanged.

[0094] Example 10

[0095] On the basis of Example 8, only change the mass of potassium carbonate as the basic substance in step (2) to 3.80 g, and keep the rest of the steps and conditions unchanged.

[0096] Example 11

[0097] On the basis of Example 8, only change the mass of potassium carbonate as the basic substance in step (2) to 3.04 g, and keep the rest of the steps and conditions unchanged.

[0098] Table 5 Effect of the feeding amount of potassium carbonate on the yield of methyl 2-phenylbenzoxazole-7-carboxylate

[0099]

[0100] From the yield of methyl-2-phenylbenzoxazole-7-carboxylate in Table 5, it can be seen that when 3.80 g (i.e., 1.5 equivalents) of potassium carbonate is used as the basic substance, the yield of methyl-2-phenylbenzoxazole-7-carboxylate is the highest.

[0101] To investigate the effect of the reaction temperature in step (2) on the yield of methyl-2-phenylbenzoxazole-7-carboxylate, the following experiment was designed:

[0102] Example 12

[0103] Dissolve 5 g of methyl 2-fluoro-3-aminobenzoate in 25 g of toluene, add 3.45 g of sodium carbonate under nitrogen protection at 25 °C, and dropwise add 4.55 g of benzoyl chloride. After reacting for 30 min, spot-checking showed that DCM:EA = 10:1 and the raw materials had completely reacted. Dilute the reaction solution with toluene, wash the organic phase twice with 20 ml of saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Recrystallize with n-heptane and dry in a vacuum oven at 60 °C for 9 hours to obtain 7.82 g of methyl 3-benzamido-2-fluorobenzoate.

[0104] Dissolve 5 g of methyl 3-benzamido-2-fluorobenzoate in 50 g of DMF, add 3.80 g of potassium carbonate, and slowly heat to 120 °C. React for 3 hours, and when PE:EA = 4:1, the reaction is complete. Filter to remove insoluble substances. At room temperature, pour the reaction solution into 50 g of water and stir to crystallize. Dry in a vacuum oven at 60 °C for 9 hours to obtain 4.2 g of methyl-2-phenylbenzoxazole-7-carboxylate.

[0105] Example 13

[0106] Dissolve 5 g of methyl 2-fluoro-3-aminobenzoate in 25 g of toluene, add 3.45 g of sodium carbonate under nitrogen protection at 25 °C, and dropwise add 4.55 g of benzoyl chloride. After reacting for 30 min, spot-checking showed that DCM:EA = 10:1 and the raw materials had completely reacted. Dilute the reaction solution with toluene, wash the organic phase twice with 20 ml of saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Recrystallize with n-heptane and dry in a vacuum oven at 60 °C for 9 hours to obtain 7.82 g of methyl 3-benzamido-2-fluorobenzoate.

[0107] Dissolve 5 g of methyl 3-benzamido-2-fluorobenzoate in 50 g of DMF, add 3.80 g of potassium carbonate, and slowly heat to 90 °C. React for 3 hours, when PE:EA = 4:1, filter to remove insoluble substances. At room temperature, pour the reaction solution into 50 g of water and stir to crystallize. Dry in a vacuum oven at 60 °C for 9 hours to obtain 3.73 g of methyl-2-phenylbenzoxazole-7-carboxylate.

[0108] Comparative Example 9

[0109] On the basis of Example 12, only change the reaction temperature in step (2) to 60 °C, and keep the rest of the steps and conditions unchanged.

[0110] Table 6 Influence of reaction temperature on the yield of methyl 2-phenylbenzoxazole-7-carboxylate

[0111]

[0112] From the yield of methyl 2-phenylbenzoxazole-7-carboxylate in Table 6, it can be seen that the yield of methyl 2-phenylbenzoxazole-7-carboxylate is the highest when the reaction temperature is selected as 120 °C.

[0113] To investigate the influence of the reaction time in step (2) on the yield of methyl 2-phenylbenzoxazole-7-carboxylate, the following experiment was designed:

[0114] Example 14

[0115] Take 5 g of methyl 2-fluoro-3-aminobenzoate and dissolve it in 25 g of toluene. Under nitrogen protection at 25 °C, add 3.45 g of sodium carbonate, and dropwise add 4.55 g of benzoyl chloride. React for 30 min and spot-check by TLC (DCM:EA = 10:1). The raw materials have completely reacted. Add toluene to dilute the reaction solution. Wash the organic phase twice with 20 ml of saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Add n-heptane for recrystallization and dry in a vacuum oven at 60 °C for 9 hours to obtain 7.82 g of methyl 3-benzamido-2-fluorobenzoate.

[0116] Take 5 g of methyl 3-benzamido-2-fluorobenzoate and dissolve it in 50 g of DMF. Add 3.80 g of potassium carbonate and slowly raise the temperature to 120 °C. React for 2 hours (PE:EA = 4:1). Filter to remove insoluble substances. At room temperature, pour the reaction solution into 50 g of water and stir to crystallize. Dry in a vacuum oven at 60 °C for 9 hours to obtain 3.71 g of methyl 2-phenylbenzoxazole-7-carboxylate.

[0117] Example 15

[0118] Take 5 g of methyl 2-fluoro-3-aminobenzoate and dissolve it in 25 g of toluene. Under nitrogen protection at 25 °C, add 3.45 g of sodium carbonate, and dropwise add 4.55 g of benzoyl chloride. React for 30 min and spot-check by TLC (DCM:EA = 10:1). The raw materials have completely reacted. Add toluene to dilute the reaction solution. Wash the organic phase twice with 20 ml of saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Add n-heptane for recrystallization and dry in a vacuum oven at 60 °C for 9 hours to obtain 7.82 g of methyl 3-benzamido-2-fluorobenzoate.

[0119] Dissolve 5 g of methyl 3-benzamido-2-fluorobenzoate in 50 g of DMF, add 3.80 g of potassium carbonate, and slowly heat to 120 °C. React for 2.5 hours. PE:EA = 4:1. Filter to remove insoluble substances. At room temperature, pour the reaction solution into 50 g of water and stir to crystallize. Dry in a vacuum oven at 60 °C for 9 hours to obtain 3.97 g of methyl 2-phenylbenzoxazole-7-carboxylate.

[0120] Example 16

[0121] Dissolve 5 g of methyl 2-fluoro-3-aminobenzoate in 25 g of toluene. Under nitrogen protection at 25 °C, add 3.45 g of sodium carbonate, and dropwise add 4.55 g of benzoyl chloride. React for 30 min and spot-check. DCM:EA = 10:1. The raw materials have completely reacted. Add toluene to dilute the reaction solution. Wash the organic phase twice with 20 ml of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Recrystallize with n-heptane and dry in a vacuum oven at 60 °C for 9 hours to obtain 7.82 g of methyl 3-benzamido-2-fluorobenzoate.

[0122] Dissolve 5 g of methyl 3-benzamido-2-fluorobenzoate in 50 g of DMF, add 3.80 g of potassium carbonate, and slowly heat to 120 °C. React for 3 hours. PE:EA = 4:1. Filter to remove insoluble substances. At room temperature, pour the reaction solution into 50 g of water and stir to crystallize. Dry in a vacuum oven at 60 °C for 9 hours to obtain 4.2 g of methyl 2-phenylbenzoxazole-7-carboxylate.

[0123] Table 7 Effect of reaction time on the yield of methyl 2-phenylbenzoxazole-7-carboxylate

[0124]

[0125] From the yield of methyl 2-phenylbenzoxazole-7-carboxylate in Table 7, it can be seen that when the reaction time is selected as 3 h, the yield of methyl 2-phenylbenzoxazole-7-carboxylate is the highest.

[0126] The characterization data are as follows, which are the 1H NMR, 13C NMR, and mass spectrum of methyl 2-phenylbenzoxazole-7-carboxylate respectively:

[0127] 1H NMR(500MHz,CDCl3)δ8.40-8.33(m,2H),8.02(ddd,J=16.4,7.8,1.2Hz,2H),7.64-7.55(m,3H),7.46(t,J=7.9Hz,1H),4.10(s,3H).

[0128] 13C NMR (126 MHz, CDCl3) δ 164.64, 164.07, 149.76, 143.55, 131.94, 128.97, 127.95, 127.13, 126.66, 124.76, 124.32, 114.97, 52.38.

[0129] ESI-MS: m / z 254.08 [M+H]+.

Claims

1. A method for preparing methyl-2-phenylbenzoxazole-7-carboxylate, characterized in that, The preparation method comprises the following steps: Step (1): Using methyl 2-fluoro-3-aminobenzoate and benzoyl chloride as raw materials, after carrying out a condensation reaction with a basic substance in a solvent, methyl 3-benzamido-2-fluorobenzoate is prepared. Step (2): Dissolving methyl 3-benzamido-2-fluorobenzoate in a solvent, and carrying out a cyclization reaction with a basic substance to prepare methyl 2-phenylbenzooxazole-7-carboxylate.

2. The preparation method of methyl-2-phenylbenzoxazole-7-carboxylate according to claim 1, characterized in that, In step (1), the solvent is one or two of water, benzene, toluene, dichloromethane, 1,2-dichloroethane, ethyl acetate, butyl acetate, methanol, ethanol, acetone, methyl isobutyl ketone, cyclohexanone, acetonitrile, and propionitrile.

3. The preparation method of methyl-2-phenylbenzoxazole-7-carboxylate according to claim 1, characterized in that, In step (1), the basic substance includes one or two of trimethylamine, pyridine, diisopropylethylamine, lithium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, and lithium diisopropylamide.

4. The preparation method of methyl-2-phenylbenzoxazole-7-carboxylate according to claim 1, characterized in that, In step (1), the condensation reaction includes recrystallization, and n-heptane is used for recrystallization.

5. The preparation method of methyl-2-phenylbenzoxazole-7-carboxylate according to claim 1, characterized in that, In step (1), the molar ratio of methyl 2-fluoro-3-aminobenzoate to benzoyl chloride is 1:1.0 - 1.

1.

6. The preparation method of methyl-2-phenylbenzoxazole-7-carboxylate according to claim 1, characterized in that, In step (1), the molar ratio of methyl 2-fluoro-3-aminobenzoate to the basic substance is 1:1.1 - 2.

7. The preparation method of methyl-2-phenylbenzoxazole-7-carboxylate according to claim 1, characterized in that, In step (2), the solvent is one or two of water, benzene, toluene, dichloromethane, 1,2-dichloroethane, ethyl acetate, butyl acetate, methanol, ethanol, acetone, methyl isobutyl ketone, cyclohexanone, acetonitrile, and propionitrile.

8. The preparation method of methyl-2-phenylbenzoxazole-7-carboxylate according to claim 1, characterized in that, In step (2), the basic substance includes one or two of trimethylamine, pyridine, diisopropylethylamine, lithium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, and lithium diisopropylamide.

9. The preparation method of methyl-2-phenylbenzoxazole-7-carboxylate according to claim 1, characterized in that, In step (2), the molar ratio of methyl 3-benzamido-2-fluorobenzoate to the basic substance is 1:1.2 - 2.

10. The preparation method of methyl-2-phenylbenzoxazole-7-carboxylate according to claim 1, characterized in that, In step (2), in the cyclization reaction, the reaction temperature is 90 - 120 °C, and the reaction time is 2 - 3 h.

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