A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole

Abstract

The application discloses a synthesis method of 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole. 1,2-dihydro-3H-pyrazol-3-one is used as raw material, and is converted into 1-acetyl-1H-pyrazol-3(2H)-one through N-acetylation reaction, and is then converted into 1-{3-[(2-bromoethyl)oxy]-2,3-dihydro-1H-pyrazol-1-yl}ethan-1-one, and is then converted into 2,3-dihydropyrazolo[5,1-b]oxazole through cyclization reaction, and is finally converted into the target compound 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole through bromination reaction. The synthesis route is simple in post-treatment and purification, ideal in each step yield, suitable for industrial amplification, and provides a potential route for large-scale production of the target compound 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole. Background Technology

[0002] 7-Bromo-2,3-dihydropyrazolo[5,1-b]oxazole is an important class of organic compounds, primarily used as pharmaceutical intermediates and building blocks. This compound, as a "molecular building block" or "pharmaceutical intermediate," is used to synthesize more complex active pharmaceutical ingredients (APIs). Its core value lies in its pyrazoloxazole ring structure and the bromine atom at position 7; these structural features make it a key starting material or intermediate for constructing new compounds with specific biological activities (such as potential anticancer or antiviral activities). For example, 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is used as an important building block in the synthesis of sulfonylimine amide compounds as inhibitors of interleukin-1 activity in patent WO2020 / 018975; in the synthesis of aryl ether compounds as regulators of TEAD in patent WO2022 / 177869; and in the synthesis of O-linked thiadiazole compounds as inhibitors of DNA polymerase THETA in patent WO2022 / 259204.

[0003] In existing technologies, the synthesis of 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole mainly focuses on two strategies: selective bromination of the pyrazolo[5,1-b]oxazole core or cyclization using a bromine-containing precursor. The main challenges in its synthesis lie in controlling regioselectivity, avoiding side reactions under harsh conditions, obtaining ideal yields and high-purity products, and the potential stability issues of the product. These shortcomings need to be optimized and addressed during process development and scale-up production. Summary of the Invention

[0004] To address the aforementioned problems in the existing technology, the present invention aims to provide a method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole, which has low synthesis cost, mild reaction conditions, low safety risks, and ideal yield.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: This invention provides a method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole, and the synthetic route of the method is as follows: .

[0006] Specifically, it includes the following steps: (1) Compound 1, namely 1,2-dihydro-3H-pyrazole-3-one, was added to organic solvent I, and then base A was added. The temperature was lowered to -5℃~5℃, and acetic anhydride was added dropwise. After the addition was completed, the reaction was carried out at 15~40℃ for 8~20 hours. After the reaction was completed, the resulting reaction solution was post-treated to obtain compound 2.

[0007] (2) Add compound 2 to organic solvent II, then add triphenylphosphine, cool to -5℃~5℃, add diisopropyl azodicarbonate and 2-bromoethanol dropwise, after the addition is complete, react at 15~40℃ for 8~20 hours, after the reaction is complete, the resulting reaction solution is post-treated to obtain compound 3.

[0008] (3) Add compound 3 to organic solvent III, then add base B, heat to 60~150℃, stir for 8~20 hours, and after the reaction is completed, the resulting reaction solution is post-treated to obtain compound 4.

[0009] (4) Add compound 4 to organic solvent IV, then add pyridine tribromide, heat to 60~150℃, and stir for 8~20 hours. After the reaction is complete, the resulting reaction solution is post-treated to obtain compound 5.

[0010] Preferably, in step (1), the base A is selected from one or more of triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,5-diazabicyclo[4.3.0]non-5-ene.

[0011] Preferably, in step (1), the organic solvent I is selected from one or more of dichloromethane, dichloroethane, dichloropropane, chloroform, trichloroethane, acetonitrile, and 2-methyltetrahydrofuran.

[0012] Preferably, in step (1), the molar ratio of compound 1 to acetic anhydride is 1:1.05~1.5.

[0013] Preferably, in step (1), the molar ratio of compound 1 to base A is 1:1.1~3.0.

[0014] Preferably, in step (1), the mass-to-volume ratio of compound 1 to organic solvent I is 1:5g ~40mL.

[0015] Preferably, in step (1), the post-processing includes: after the reaction is complete, the reaction solution is evaporated to dryness, organic solvent V is added, and then the solution is concentrated under reduced pressure until a large amount of solid precipitates out. The solid is collected to obtain the crude product. The crude product is purified to obtain compound 2, namely 1-acetyl-1H-pyrazole-3(2H)-one.

[0016] Preferably, in step (1), the organic solvent V is selected from one or more of ethyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, ethyl propionate, and ethyl butyrate.

[0017] Preferably, in step (1), the purification method is selected from one or more of pulping, column chromatography, recrystallization or distillation.

[0018] Preferably, in step (2), the organic solvent II is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, and methyl tert-butyl ether.

[0019] Preferably, in step (2), the molar ratio of compound 2 and 2-bromoethanol is 1:1.1~2.0.

[0020] Preferably, in step (2), the molar ratio of compound 2 to triphenylphosphine is 1:1.2~3.0.

[0021] Preferably, in step (2), the molar ratio of compound 2 and diisopropyl azodicarbonate is 1:1.2~3.0.

[0022] Preferably, in step (2), the mass-to-volume ratio of compound 2 to organic solvent II is 1:5g ~40mL.

[0023] Preferably, in step (2), the post-processing includes: after the reaction is completed, the reaction solution is evaporated to dryness to obtain a crude product, and the crude product is purified to obtain compound 3, namely 1-{3-[(2-bromoethyl)oxy]-2,3-dihydro-1H-pyrazol-1-yl}ethyl-1-one.

[0024] Preferably, in step (2), the purification method is selected from one or more of pulping, column chromatography, recrystallization or distillation.

[0025] Preferably, in step (3), the base B is selected from one or more of potassium carbonate, sodium carbonate, and cesium carbonate.

[0026] Preferably, in step (3), the organic solvent III is selected from one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, and dimethylformamide.

[0027] Preferably, in step (3), the molar ratio of compound 3 to base B is 1:1.1~3.0.

[0028] Preferably, in step (3), the mass-to-volume ratio of compound 3 to organic solvent III is 1:5g~40mL.

[0029] Preferably, in step (3), the post-processing includes: after the reaction is completed, the reaction solution is cooled to room temperature, filtered, the filtrate is dried by rotary evaporation to obtain the crude product, and the crude product is purified to obtain compound 4, namely 2,3-dihydropyrazolo[5,1-b]oxazole.

[0030] Preferably, in step (3), the purification method is selected from one or more of pulping, column chromatography, recrystallization or distillation.

[0031] Preferably, in step (4), the organic solvent IV is selected from one or more of methanol, acetonitrile, and 1,2-dichloroethane.

[0032] Preferably, in step (4), the molar ratio of compound 4 to pyridine tribromide is 1:1.8~3.0.

[0033] Preferably, in step (4), the mass-to-volume ratio of compound 4 to organic solvent IV is 1:5g~40mL.

[0034] Preferably, in step (4), the post-processing includes: after the reaction is complete, cooling the reaction solution to room temperature, adding ice water to the reaction solution, extracting with organic solvent VI, combining the organic phases, washing the organic phases, drying them, concentrating them under reduced pressure to obtain the crude product. The crude product is purified to obtain compound 5, namely 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole.

[0035] Preferably, in step (4), the organic solvent VI is selected from one or more of ethyl acetate, butyl acetate, toluene, dichloromethane, dichloroethane, and chloroform.

[0036] Preferably, in step (4), the purification method is selected from one or more of pulping, column chromatography, recrystallization or distillation.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention provides a method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole. Using 1,2-dihydro-3H-pyrazol-3-one as a starting material, the method involves N-acetylation to convert it to 1-acetyl-1H-pyrazol-3(2H)-one, then to 1-{3-[(2-bromoethyl)oxy]-2,3-dihydro-1H-pyrazol-1-yl}ethyl-1-one, followed by intramolecular nucleophilic substitution cyclization to convert it to 2,3-dihydropyrazolo[5,1-b]oxazole, and finally bromination to convert it to the target compound 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole. This synthetic route for the preparation of 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole offers significant advantages: simple post-processing and purification, with each step involving simple slurry purification (eliminating the need for column chromatography), significantly reducing purification costs; ideal yields at each step, suitable for industrial scale-up; precise regioselectivity, with the bromination step using pyridine tribromide, selectively targeting the 7-position bromination of the pyrazole ring, resulting in fewer byproducts compared to traditional electrophilic bromination (such as NBS); and optimized atom economy, achieving one-step oxyalkylation to construct the side chain in the second step, avoiding multi-step protection / deprotection operations; and the third cyclization step using intramolecular SN2 cyclization, requiring no additional condensing agent. In summary, this route, through an efficient cyclization strategy and precise bromination control, provides a low-risk, high-efficiency pathway to obtain the target molecule, offering a potential route for the large-scale production of the target compound 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole. Attached Figure Description

[0038] Figure 1 The image shows the 1H NMR spectrum of compound 2 from Example 1.

[0039] Figure 2 The image shows the 1H NMR spectrum of compound 4 from Example 1.

[0040] Figure 3 The image shows the 1H NMR spectrum of compound 5 from Example 1. Detailed Implementation

[0041] To more fully understand and demonstrate the technical solutions, objectives, and advantages of the present invention, the technical effects produced by the present invention will be further described in detail and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. It should be noted that other embodiments obtained by those skilled in the art without departing from the concept of the present invention are all within the protection scope of the present invention.

[0042] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0043] Example 1

[0044] This embodiment provides a method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole, and the synthetic route is as follows: The specific steps are as follows: (1) Compound 1, namely 1,2-dihydro-3H-pyrazole-3-one (500.00 g, 5.95 mol, 1.00 eq), was added to dichloromethane (5.0 L), followed by triethylamine (782.31 g, 7.73 mol, 1.30 eq). The mixture was cooled to 0 °C, and acetic anhydride (667.82 g, 6.54 mol, 1.10 eq) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 12 hours. After the reaction was complete, the reaction solution was evaporated to dryness at 45 °C, and ethyl acetate (2.0 L) was added. The mixture was then concentrated under reduced pressure until a large amount of solid precipitated. The solid was collected to obtain the crude product. The crude product was pulped in an organic mixture of ethyl acetate and petroleum ether in a volume ratio of 1:3, filtered, and the resulting solid was dried to obtain compound 2, namely 1-acetyl-1H-pyrazole-3(2H)-one (off-white solid, weight 709.00 g, purity 98%, yield 93%).

[0045] The 1H NMR spectrum of compound 2 is as follows Figure 1 As shown, the obtained characterization data are as follows: 1 H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.13 (d, J = 2.9 Hz, 1H), 6.01 (d, J = 2.9 Hz, 1H), 2.48 (s, 3H). (2) Compound 2 (700.00 g, 5.55 mol, 1.00 eq) was added to tetrahydrofuran (7.0 L), followed by triphenylphosphine (2.18 kg, 8.33 mol, 1.50 eq). The mixture was cooled to 0 °C, and diisopropyl azodicarbonate (1.68 kg, 8.33 mol, 1.50 eq) and 2-bromoethanol (832.34 g, 6.66 mol, 1.20 eq) were added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 12 hours. After the reaction was completed, the reaction solution was evaporated at 45°C to obtain a crude product. The crude product was then slurried in an organic mixture of ethyl acetate and petroleum ether at a volume ratio of 1:10 (3.0 L), filtered, and the resulting solid was dried to obtain compound 3, namely 1-{3-[(2-bromoethyl)oxy]-2,3-dihydro-1H-pyrazol-1-yl}ethyl-1-one (white solid, weight 1.29 kg, purity 96%, yield 95%).

[0046] (3) Compound 3 (1.00 kg, 4.25 mol, 1.00 eq) was added to a mixed organic solvent of acetonitrile (10.0 L), followed by potassium carbonate (1.18 kg, 8.51 mol, 2.00 eq). The mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was slurried in a mixed organic solution of ethyl acetate and petroleum ether at a volume ratio of 1:10 (3.0 L), filtered, and the resulting solid was dried to obtain compound 4, namely 2,3-dihydropyrazolo[5,1-b]oxazole (a white solid, 459.00 g, 98% purity, 96% yield).

[0047] The 1H NMR spectrum of compound 4 is as follows: Figure 2 As shown, the obtained characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 5.36 (s, 1H), 5.09 – 5.01 (m, 2H), 4.33 – 4.26 (m, 2H). (4) Compound 4 (400.00 g, 3.63 mol, 1.00 eq) was added to methanol (4.0 L), followed by pyridine tribromide (2.32 kg, 7.27 mol, 2.00 eq). The mixture was heated to 80 °C and stirred for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and ice water (4.0 L) was added to the reaction solution. The mixture was extracted three times with ethyl acetate (2.0 L × 3). The organic phases were combined, washed with saturated sodium thiosulfate solution, then washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was slurried with petroleum ether (2.0 L), filtered, and the resulting solid was dried to obtain compound 5, namely 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole (white solid, weight 679.59 g, purity 98%, yield 97%).

[0048] The 1H NMR spectrum of compound 5 is as follows: Figure 3 As shown, the obtained characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 5.10 (t, J = 7.9 Hz, 2H), 4.34(t, J = 8.0 Hz, 2H). Example

[0049] A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that triethylamine (782.31 g, 7.73 mol, 1.30 eq) in step (1) is replaced with diisopropylethylamine (999.20 g, 7.73 mol, 1.30 eq), and the yield of compound 2 is 92%.

[0050] Example 3 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that triethylamine (782.31 g, 7.73 mol, 1.30 eq) in step (1) is replaced with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.09 kg, 7.14 mol, 1.20 eq), and the yield of compound 2 is 91%.

[0051] Example 4 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that dichloromethane (5.0 L) in step (1) is replaced with acetonitrile (5.0 L), and the yield of compound 2 is 90%.

[0052] Example 5 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that dichloromethane (5.0 L) in step (1) is replaced with 2-methyltetrahydrofuran (5.0 L), and the yield of compound 2 is 92%.

[0053] Example 6 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the acetic anhydride (667.82 g, 6.54 mol, 1.10 eq) in step (1) is replaced with acetic anhydride (637.46 g, 6.24 mol, 1.05 eq), and the yield of compound 2 is 91%.

[0054] Example 7 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the acetic anhydride (667.82 g, 6.54 mol, 1.10 eq) in step (1) is replaced with acetic anhydride (910.66 g, 8.92 mol, 1.50 eq), and the yield of compound 2 is 92%.

[0055] Example 8 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the triethylamine (782.31 g, 7.73 mol, 1.30 eq) in step (1) is replaced with triethylamine (661.96 g, 6.54 mol, 1.10 eq), and the yield of compound 2 is 90%.

[0056] Example 9 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the triethylamine (782.31 g, 7.73 mol, 1.30 eq) in step (1) is replaced with triethylamine (1.81 kg, 17.84 mol, 3.00 eq), and the yield of compound 2 is 93%.

[0057] Example 10 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that tetrahydrofuran (7.0 L) in step (2) is replaced with toluene (7.0 L), and the yield of compound 3 is 94%.

[0058] Example 11 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that tetrahydrofuran (7.0 L) in step (2) is replaced with methyl tert-butyl ether (7.0 L), and the yield of compound 3 is 93%.

[0059] Example 12 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that 2-bromoethanol (832.34 g, 6.66 mol, 1.20 eq) in step (2) is replaced with 2-bromoethanol (762.98 g, 6.11 mol, 1.10 eq), and the yield of compound 3 is 93%.

[0060] Example 13 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that 2-bromoethanol (832.34 g, 6.66 mol, 1.20 eq) in step (2) is replaced with 2-bromoethanol (1.39 kg, 11.10 mol, 2.00 eq), and the yield of compound 3 is 94%.

[0061] Example 14 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the triphenylphosphine (2.18 kg, 8.33 mol, 1.50 eq) in step (2) is replaced with triphenylphosphine (1.75 kg, 6.66 mol, 1.20 eq), and the yield of compound 3 is 91%.

[0062] Example 15 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the triphenylphosphine (2.18 kg, 8.33 mol, 1.50 eq) in step (2) is replaced with triphenylphosphine (4.37 kg, 16.65 mol, 3.00 eq), and the yield of compound 3 is 95%.

[0063] Example 16 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that diisopropyl azodicarbonate (1.68 kg, 8.33 mol, 1.50 eq) in step (2) is replaced with diisopropyl azodicarbonate (1.35 kg, 6.66 mol, 1.20 eq), and the yield of compound 3 is 90%.

[0064] Example 17 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that diisopropyl azodicarbonate (1.68 kg, 8.33 mol, 1.50 eq) in step (2) is replaced with diisopropyl azodicarbonate (3.37 kg, 16.65 mol, 3.00 eq), and the yield of compound 3 is 95%.

[0065] Example 18 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that potassium carbonate (1.18 kg, 8.51 mol, 2.00 eq) in step (3) is replaced with sodium carbonate (901.71 g, 8.51 mol, 2.00 eq), and the yield of compound 4 is 95%.

[0066] Example 19 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that potassium carbonate (1.18 kg, 8.51 mol, 2.00 eq) in step (3) is replaced with cesium carbonate (2.77 kg, 8.51 mol, 2.00 eq), and the yield of compound 4 is 96%.

[0067] Example 20 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that acetonitrile (10.0 L) in step (3) is replaced with tetrahydrofuran (10.0 L), and the yield of compound 4 is 94%.

[0068] Example 21 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that acetonitrile (10.0 L) in step (3) is replaced with dimethylformamide (10.0 L), and the yield of compound 4 is 90%.

[0069] Example 22 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the potassium carbonate (1.18 kg, 8.51 mol, 2.00 eq) in step (3) is replaced with potassium carbonate (646.69 g, 4.68 mol, 1.10 eq), and the yield of compound 4 is 91%.

[0070] Example 23 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the potassium carbonate (1.18 kg, 8.51 mol, 2.00 eq) in step (3) is replaced with potassium carbonate (1.76 kg, 12.76 mol, 3.00 eq), and the yield of compound 4 is 96%.

[0071] Example 24 The method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the 80°C in step (3) is replaced with 60°C and the yield of compound 4 is 92%.

[0072] Example 25 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the 80°C in step (3) is replaced with 120°C and the yield of compound 4 is 95%.

[0073] Example 26 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the 12 hours in step (3) are replaced with 8 hours, and the yield of compound 4 is 91%.

[0074] Example 27 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the 12 hours in step (3) are replaced with 20 hours, and the yield of compound 4 is 96%.

[0075] Example 28 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that methanol (4.0 L) in step (4) is replaced with acetonitrile (4.0 L), and the yield of compound 5 is 95%.

[0076] Example 29 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the pyridine tribromide (2.32 kg, 7.27 mol, 2.00 eq) in step (4) is replaced with pyridine tribromide (2.09 kg, 6.54 mol, 1.80 eq), and the yield of compound 5 is 93%.

[0077] Example 30 A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole is basically the same as that in Example 1, except that the pyridine tribromide (2.32 kg, 7.27 mol, 2.00 eq) in step (4) is replaced with pyridine tribromide (3.49 kg, 10.90 mol, 3.00 eq), and the yield of compound 5 is 96%.

[0078] Comparative Example 1 Using compound 4, prepared in the same manner as in Example 1, as a starting material, the reaction was carried out according to the following steps: Compound 4 (400.00 g, 3.63 mol, 1.00 eq) was added to acetonitrile (4.0 L), followed by N-bromosuccinimide (NBS) (775.84 g, 4.36 mol, 1.20 eq). The mixture was stirred at room temperature (25 °C) for 24 hours. After the reaction was complete, the reaction solution was post-processed to obtain a crude product, which was purified by column chromatography. The yield of compound 5 was 64%.

[0079] As can be seen from Examples 1-3, in step (1), triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene were used as bases for the reaction, and the reaction proceeded smoothly. The yield of compound 2 was high and not less than 90%. Among them, the reaction yield was the highest when triethylamine was used as the base.

[0080] As can be seen from Examples 1 and 4-5, in step (1), dichloromethane, acetonitrile, and 2-methyltetrahydrofuran were used as solvents for the reaction, and the reaction proceeded smoothly. The yield of compound 2 was high in all cases. Among them, the reaction yield was the highest when dichloromethane was used as the solvent.

[0081] As can be seen from Examples 1 and 6-7, in step (1), when the molar ratio of compound 1 to acetic anhydride is 1.0:(1.05~1.50), the yield of compound 2 is relatively high. Among them, when the molar ratio of compound 1 to acetic anhydride is 1.0:1.1, the reaction effect is even better.

[0082] As can be seen from Examples 1 and 8-9, in step (1), when the molar ratio of compound 1 to base is 1.0:(1.1~3.0), the yield of compound 2 is relatively high. Among them, the product yields when the molar ratio of compound 1 to base is 1.0:1.3 and 1.0:3.0 are basically the same.

[0083] As can be seen from Examples 1 and 10-11, in step (2), tetrahydrofuran, toluene, and methyl tert-butyl ether were used as solvents for the reaction, and the reaction proceeded smoothly. The yield of compound 3 was high in all cases. Among them, the reaction yield was the highest when tetrahydrofuran was used as the solvent.

[0084] As can be seen from Examples 1 and 12-13, in step (2), when the molar ratio of compound 2 to 2-bromoethanol is 1.0:(1.10~2.00), the yield of compound 3 is relatively high. Among them, when the molar ratio of compound 2 to 2-bromoethanol is 1.0:1.2, the reaction effect is better.

[0085] As can be seen from Examples 1 and 14-15, in step (2), when the molar ratio of compound 2 to triphenylphosphine is 1.0:(1.2~3.0), the yield of compound 3 is relatively high. Among them, the product yields when the molar ratio of compound 2 to triphenylphosphine is 1.0:1.5 and 1.0:3.0 are basically the same.

[0086] As can be seen from Examples 1 and 16-17, in step (2), when the molar ratio of compound 2 to diisopropyl azodicarbonate is 1.0:(1.2~3.0), the yield of compound 3 is relatively high. Among them, the product yields when the molar ratio of compound 2 to diisopropyl azodicarbonate is 1.0:1.5 and 1.0:3.0 are basically the same.

[0087] In conjunction with Examples 1 and 18-19, in step (3), potassium carbonate, sodium carbonate, and cesium carbonate were used as bases for the reaction, respectively. The reaction proceeded smoothly, and the yield of compound 4 was high, not less than 90%. Among them, the reaction yield was the highest when potassium carbonate or cesium carbonate was used for the reaction.

[0088] As can be seen from Examples 1 and 20-21, in step (3), acetonitrile, tetrahydrofuran, and dimethylformamide were used as solvents for the reaction, and the reaction proceeded smoothly. The yield of compound 4 was high in all cases. Among them, the reaction yield was the highest when acetonitrile was used as the solvent.

[0089] As can be seen from Examples 1 and 22-23, in step (3), when the molar ratio of compound 3 to base is 1.0:(1.1~3.0), the yield of compound 4 is relatively high. Among them, the product yields when the molar ratio of compound 3 to base is 1.0:2.0 and 1.0:3.0 are basically the same.

[0090] As can be seen from Examples 1 and 24-25, in step (3), when the reaction temperature is in the range of 80 to 120°C, the reaction yield first increases and then decreases as the temperature increases, with the reaction yield being higher at 80°C.

[0091] As can be seen from Examples 1 and 26-27, in step (3), the reaction yield is basically optimal when the reaction time is 12 hours.

[0092] As can be seen from Examples 1 and 28, in step (4), methanol and acetonitrile were used as solvents for the reaction, and the reaction proceeded smoothly. The yield of compound 5 was high in both cases. Among them, the reaction yield was the highest when methanol was used as the solvent.

[0093] As can be seen from Examples 1 and 29-30, in step (4), when the molar ratio of compound 4 to pyridine tribromide is 1.0:(1.8~3.0), the yield of compound 5 is relatively high. Among them, when the molar ratio of compound 4 to pyridine tribromide is 1.0:2.0, the reaction effect is even better.

[0094] As can be seen from Example 1 and Comparative Example 1, in step (4), compared with NBS as the brominating agent, pyridine tribromide has a better reaction effect in this bromination reaction.

[0095] The above are merely preferred embodiments of the present invention and are not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole, characterized in that, Its synthetic route is as follows: 。 2. The method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole according to claim 1, characterized in that, Includes the following steps: (1) Compound 1, namely 1,2-dihydro-3H-pyrazole-3-one, was added to organic solvent I, and then base A was added. The temperature was lowered to -5℃~5℃, and acetic anhydride was added dropwise. After the addition was completed, the reaction was carried out at 15~40℃ for 8~20 hours. After the reaction was completed, the resulting reaction solution was post-treated to obtain compound 2. (2) Add compound 2 to organic solvent II, then add triphenylphosphine, cool to -5℃~5℃, add diisopropyl azodicarbonate and 2-bromoethanol dropwise, after the addition is complete, react at 15~40℃ for 8~20 hours, after the reaction is complete, the resulting reaction solution is post-treated to obtain compound 3; (3) Add compound 3 to organic solvent III, then add base B, heat to 60~150℃, stir for 8~20 hours, and after the reaction is completed, the resulting reaction solution is post-treated to obtain compound 4; (4) Add compound 4 to organic solvent IV, then add pyridine tribromide, heat to 60~150℃, and stir for 8~20 hours; after the reaction is completed, the resulting reaction solution is post-treated to obtain compound 5.

3. The method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole according to claim 2, characterized in that, In step (1), The base A is selected from one or more of triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,5-diazabicyclo[4.3.0]non-5-ene; The organic solvent I is selected from one or more of dichloromethane, dichloroethane, dichloropropane, chloroform, trichloroethane, acetonitrile, and 2-methyltetrahydrofuran; The molar ratio of compound 1 to acetic anhydride is 1:1.05~1.5; The molar ratio of compound 1 to base A is 1:1.1~3.0; The mass-to-volume ratio of compound 1 to organic solvent I is 1:5g ~40mL.

4. The method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole according to claim 2, characterized in that, In step (1), The post-processing process includes: after the reaction is completed, the reaction solution is evaporated to dryness, organic solvent V is added, and then the solution is concentrated under reduced pressure until a large amount of solid precipitates out. The solid is collected to obtain a crude product. The crude product is purified to obtain compound 2, namely 1-acetyl-1H-pyrazole-3(2H)-one. The organic solvent V is selected from one or more of ethyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, ethyl propionate, and ethyl butyrate. The purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

5. The method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole according to claim 2, characterized in that, In step (2), The organic solvent II is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, and methyl tert-butyl ether; The molar ratio of compound 2 to 2-bromoethanol is 1:1.1~2.0; The molar ratio of compound 2 to triphenylphosphine is 1:1.2~3.0; The molar ratio of compound 2 to diisopropyl azodicarbonate is 1:1.2~3.0; The mass-to-volume ratio of compound 2 to organic solvent II is 1:5g ~40mL.

6. The method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole according to claim 2, characterized in that, In step (2), The post-processing includes: after the reaction is completed, the reaction solution is evaporated to dryness to obtain a crude product, and the crude product is purified to obtain compound 3, namely 1-{3-[(2-bromoethyl)oxy]-2,3-dihydro-1H-pyrazol-1-yl}ethyl-1-one; The purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

7. The method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole according to claim 2, characterized in that, In step (3), The base B is selected from one or more of potassium carbonate, sodium carbonate, and cesium carbonate; The organic solvent III is selected from one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, and dimethylformamide; The molar ratio of compound 3 to base B is 1:1.1~3.0; The mass-to-volume ratio of compound 3 to organic solvent III is 1:5g~40mL.

8. The method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole according to claim 2, characterized in that, In step (3), The post-processing includes: after the reaction is completed, the reaction solution is cooled to room temperature, filtered, the filtrate is evaporated to dryness to obtain crude product, the crude product is purified to obtain compound 4, namely 2,3-dihydropyrazolo[5,1-b]oxazole; The purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

9. The method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole according to claim 2, characterized in that, In step (4), The organic solvent IV is selected from one or more of methanol, acetonitrile, and 1,2-dichloroethane; The molar ratio of compound 4 to pyridine tribromide is 1:1.8~3.0; The mass-to-volume ratio of compound 4 to organic solvent IV is 1:5g~40mL.

10. The method for synthesizing 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole according to claim 2, characterized in that, In step (4), The post-processing includes: after the reaction is completed, the reaction solution is cooled to room temperature, ice water is added to the reaction solution, and the solution is extracted with organic solvent VI. The organic phases are combined, washed, dried, and concentrated under reduced pressure to obtain a crude product. The crude product is purified to obtain compound 5, namely 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole. The organic solvent VI is selected from one or more of ethyl acetate, butyl acetate, toluene, dichloromethane, dichloroethane, and chloroform; The purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

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