A method for preparing a benzoxatrine derivative

Abstract

The application discloses a preparation method of a benzoxathiazinone derivative and belongs to the technical field of organic synthesis. The method uses benzodisulfone and an epoxide compound as reaction raw materials, and under the action of a catalytic system composed of lanthanum nitrate hexahydrate and tributyl phosphine, potassium carbonate is used as an alkali, acetonitrile is used as a solvent, and the reaction is carried out under heating, and then column chromatography is used for separation and purification, so that the target seven-membered sulfur heterocyclic compound is obtained. The synergistic catalytic mechanism formed between the lanthanum nitrate hexahydrate and the organic phosphine effectively overcomes the problem of the regioselective ring opening of the epoxide compound, and realizes the efficient and high-selectivity cyclization of the benzodisulfone and the epoxide compound. The synthetic route has mild reaction conditions, does not need inert gas protection, is simple in operation, and has good functional group compatibility, and provides an efficient and practical technical path for constructing novel benzoxathiazinone derivatives.

Description

Technical Field

[0001] This invention belongs to the field of organic synthetic chemistry technology, specifically relating to a method for preparing benzoxoxetine derivatives. Background Technology

[0002] Benzo[a]oxazolidinones are important structural units in many natural products and synthetic drug molecules. As a class of heterocyclic compounds that have attracted much attention, they have become a research hotspot in medicinal chemistry and chemical biology due to their diverse and unique biological activities. These compounds widely exhibit multiple pharmacological activities, including anti-inflammatory, antibacterial, analgesic, and anticancer effects. For example, Dibenzepin is a highly effective non-nucleoside HIV-1 reverse transcriptase inhibitor; Amoxapine is a commercially available antidepressant; Loxapine is an important antipsychotic drug; and protohematoxylin A not only has a strong inhibitory effect on various tumor cells but also possesses immunosuppressive effects such as sedation, antibacterial, antiplatelet aggregation, and anti-heart transplant rejection. It is worth noting that although research on benzo[a]oxazolidinone derivatives is quite extensive, there are currently no reports in the literature of sulfur-containing medium-ring molecules in the benzo[a]oxathione class, constructed by introducing a sulfur atom into its parent nucleus.

[0003] Compared to well-established five- or six-membered ring compounds, medium-ring compounds (especially seven-membered rings) generally suffer from unfavorable entropy effects and significant transring strain during synthesis, leading to greater challenges in ring system construction. Furthermore, the large atomic radius, strong nucleophilicity, and susceptibility to metal catalyst poisoning of sulfur atoms result in far fewer efficient synthetic methods for sulfur-containing medium-ring molecules compared to their carbon- or oxygen-containing heterocyclic counterparts. Based on these bottlenecks, there is an urgent need to develop novel and efficient synthetic strategies to construct sulfur-containing medium-ring molecules, particularly to establish a feasible synthetic route for benzoxoxetrazolone derivatives. This will not only promote research on this type of skeleton in interdisciplinary fields such as supramolecular chemistry, biomedicine, and materials science, but also provide a more diverse library of lead compounds for high-throughput screening of sulfur-containing drug molecules.

[0004] Epoxides, as highly reactive electrophiles, readily undergo ring-opening reactions involving CO bond cleavage due to their high ring strain, making them ideal synthons for constructing carbon-heteroatom bonds. However, research on their application in the construction of mesocyclic molecules remains extremely rare. Of particular interest is the regioselective ring-opening / cyclization reaction between benzodisulfonyl ketones and epoxides, which has not been documented in existing literature. Therefore, developing a novel method with mild reaction conditions, high synthetic efficiency, and excellent functional group compatibility to construct sulfur-containing mesocyclic molecules in one step via the cyclization reaction of benzodisulfonyl ketones and epoxides has significant academic research value and broad application prospects. The synthetic strategy proposed in this invention is expected to effectively fill the current technological gap in the construction of benzo(oxothiazophenones), enrich the methodological toolbox of sulfur heterocyclic chemistry, and provide a novel molecular construction paradigm for medicinal chemistry, materials science, and related industrial fields. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing benzoxoxetine derivatives. This method has mild reaction conditions, is easy to operate, does not require inert gas protection, has good functional group tolerance, and has a high yield.

[0006] The technical solution of the present invention is as follows: A method for preparing benzoxoxetrazolone derivatives, using benzodisulfonyl ketone compounds and epoxides as reactants, and lanthanum nitrate hexahydrate as a Lewis acid, in a reaction mixture of potassium carbonate and tributylphosphine (P( n In the presence of Bu)3), using acetonitrile as solvent, the mixture was heated to 85-95℃ and stirred for 10-14 hours. After the reaction was completed, the benzoxoxetine derivative was obtained by separation and purification.

[0007] Furthermore, the Lewis acid is preferably lanthanum nitrate hexahydrate, and the amount used is 20 mol% of the amount of benzodisulfonyl ketone compound, which can effectively promote the ring-opening reaction of the epoxide compound.

[0008] Furthermore, the inorganic base is preferably potassium carbonate, and the molar ratio of benzo[a]sulfonyl ketone compound to potassium carbonate is 1:2, which can effectively promote the ring-opening reaction of the epoxide compound.

[0009] Furthermore, the organophosphorus compound is preferably tributylphosphorus, and the molar ratio of benzodisulfonyl ketone compound to organophosphorus compound is 1:1.5, which can significantly promote the cleavage of SS bonds and improve the reaction yield.

[0010] Furthermore, the molar ratio of the benzodisulfonyl ketone compound to the epoxide compound is 1:1.5 to ensure sufficient reaction of the raw materials and improve the yield of the target sulfur-containing ring.

[0011] Furthermore, the separation and purification steps are as follows: after the reaction is completed, the mixture is cooled to room temperature, and the solvent is removed by rotary evaporation to obtain the crude product. The crude product is then separated by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a high-purity sulfur-containing medium-cyclic target product.

[0012] Further, the epoxy compound is 2-((benzyloxy)methyl)ethylene oxide, 2-[(allyloxy)methyl]ethylene oxide, 2-((ethylene oxide-2-ylmethoxy)methyl)furan, 2-(3-chlorophenyl)ethylene oxide, 2-(4-bromophenyl)ethylene oxide, 2-(ethoxymethyl)ethylene oxide, 1,2-epoxycyclohexane, and 4-(ethylene oxide-2-ylmethoxy)butyl acrylate.

[0013] Furthermore, the benzodisulfonyl ketone compound is an unsubstituted benzodisulfonyl ketone or one with alkyl, alkoxy, or halogen substituents.

[0014] Beneficial effects

[0015] (1) This invention is the first to realize the Lewis acid-catalyzed cyclization reaction of benzodisulfonyl ketones with epoxides. For a long time, the synthesis of sulfur-containing medium-ring molecules has faced significant technical challenges, especially the construction of seven-membered sulfur heterocyclic skeletons. Due to the dual constraints of unfavorable entropy effects and significant transring strain, it has always been a major difficulty in this field. This invention provides a simple and green new synthetic route for the construction of seven-membered sulfur heterocycles—benzo(oxothiazophenone) compounds.

[0016] (2) Overcoming reaction bottlenecks and achieving efficient conversion: Although epoxides are prone to ring opening due to high ring strain, the highly regioselective CO bond formation still requires precise control. This invention, by leveraging the synergistic catalytic effect of Lewis acids and organophosphorus compounds, successfully overcomes the selectivity bottleneck of existing technologies, achieving selective ring opening of epoxides and efficiently coupling it with the SS bond breaking process of benzodisulfonyl ketones, thus constructing benzoxoxetrazolone derivatives in one step.

[0017] (3) This method does not require inert gas protection and is simple to operate. Compared with the harsh conditions such as high temperature, high pressure and strong oxidants required by traditional methods, it significantly reduces energy consumption and production costs. The overall operation process is simple and efficient, and the product separation and purification only requires conventional silica gel column chromatography, which has good potential for large-scale preparation and industrial application value.

[0018] (4) Excellent functional group compatibility, expanding application scenarios: This method exhibits excellent tolerance to a variety of functional groups, including alkyl, alkoxy, halogen, ester, olefin, furan and other structural units, which greatly expands the structural diversity of target molecules and potential application scenarios. Attached Figure Description

[0019] Figure 1 This is a diagram of the reaction mechanism; Figure 2 The 1H NMR spectrum of the product in Example 1; Figure 3 The carbon spectrum of the product in Example 1; Figure 4 The 1H NMR spectrum of the product in Example 2; Figure 5 The carbon spectrum of the product in Example 2; Figure 6 The hydrogen NMR spectrum of the product in Example 3; Figure 7 The carbon spectrum of the product in Example 3; Figure 8 The 1H NMR spectrum of the product in Example 4; Figure 9 The carbon spectrum of the product in Example 4; Figure 10 The hydrogen NMR spectrum of the product in Example 5; Figure 11 The carbon spectrum of the product in Example 5; Figure 12 The hydrogen NMR spectrum of the product in Example 6; Figure 13 The carbon spectrum of the product in Example 6; Figure 14 The hydrogen NMR spectrum of the product in Example 7; Figure 15 The carbon spectrum of the product in Example 7; Figure 16 The 1H NMR spectrum of the product in Example 8; Figure 17 The carbon spectrum of the product in Example 8; Figure 18 The hydrogen NMR spectrum of the product in Example 9; Figure 19 The carbon spectrum of the product in Example 9; Figure 20 The 1H NMR spectrum of the product in Example 10; Figure 21 The carbon spectrum of the product in Example 10 is shown below. Detailed Implementation

[0020] To make the above-mentioned objectives, features, and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to examples. The following content is merely illustrative and explanatory of the concept of the present invention. Those skilled in the art can make various modifications or additions to the described specific embodiments or use similar methods to replace them, as long as they do not deviate from the concept of the invention, they should all fall within the protection scope of the present invention.

[0021] The preparation method of the present invention will be described below through specific embodiments.

[0022] Example 1 Synthesis of 3-((benzyloxy)methyl)-2,3-dihydro-5H-benzo[e][1,4]oxothiazolinone: To a clean 10 mL reaction tube, benzodisulfonic acid ketone (0.2 mmol), lanthanum nitrate hexahydrate (0.04 mmol, 20 mol%), potassium carbonate (0.4 mmol), tributylphosphine (0.3 mmol), and 2-((benzyloxy)methyl)ethylene oxide (0.3 mmol) were added sequentially, followed by acetonitrile (2 mL). The reaction mixture was heated to 90 °C and stirred for 12 hours, with the reaction progress monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a colorless liquid, in 63% yield.

[0023] according to Figure 2 The product's 1H NMR spectrum and Figure 3 The carbon spectrum of the product yields the following structural formula of the target product: ; 1 H NMR (300 MHz, CDCl3) δ 7.71 – 7.64 (m, 1H), 7.53 – 7.48 (m, 1H), 7.46 – 7.42 (m, 1H), 7.38 – 7.24 (m, 5H), 4.58 (s, 2H), 4.35 – 4.28 (m, 1H), 3.72 (qd, J = 10.5, 4.9 Hz, 2H), 3.27 (dd, J = 12.3, 3.4 Hz, 1H), 3.06 (t, J= 12.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 169.5, 137.3, 136.8, 133.7, 132.6,130.7, 129.1, 128.4, 127.9, 127.7, 76.0, 73.7, 70.5, 34.8.

[0024] Example 2 3-((allyloxy)methyl)-2,3-dihydro-5H-benzo[e][1,4]oxothiazolinone-5-one: To a clean 10 mL reaction tube, benzo[2]sulfonyl ketone (0.2 mmol), lanthanum nitrate hexahydrate (0.04 mmol, 20 mol%), potassium carbonate (0.4 mmol), tributylphosphine (0.3 mmol), and 2-[(allyloxy)methyl]ethylene oxide (0.3 mmol) were added sequentially, followed by acetonitrile (2 mL). The reaction mixture was heated to 85 °C and stirred for 10 hours, with the reaction progress monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a yellow liquid, with a yield of 57%.

[0025] according to Figure 4 The product's 1H NMR spectrum and Figure 5 The carbon spectrum of the product yields the following structural formula of the target product: ; 1 H NMR (300 MHz, CDCl3) δ 7.73 – 7.64 (m, 1H), 7.54 – 7.49 (m, 1H), 7.47 – 7.41 (m, 1H), 5.94 – 5.81 (m, 1H), 5.27 (dd, J = 17.2, 1.5 Hz, 1H),5.20 (dd, J = 10.4, 1.3 Hz, 1H), 4.36 – 4.28 (m, 1H), 4.10 – 4.00 (m, 2H),3.70 (qd, J = 10.5, 4.9 Hz, 2H), 3.29 (dd, J = 12.3, 3.4 Hz, 1H), 3.08 (t, J= 12.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 169.5, 136.9, 134.0, 133.7, 132.6,130.7, 129.1, 117.7, 76.07, 72.6, 70.5, 34.8.

[0026] Example 3 Synthesis of 3-((furan-2-ylmethoxy)methyl)-2,3-dihydro-5H-benzo[e][1,4]oxothiazolinone-5-one: To a clean 10 mL reaction tube, benzo[a]sulfonyl ketone (0.2 mmol), lanthanum nitrate hexahydrate (0.04 mmol, 20 mol%), potassium carbonate (0.4 mmol), tributylphosphine (0.3 mmol), and 2-((ethylene oxide-2-ylmethoxy)methyl)furan (0.3 mmol) were added sequentially, followed by acetonitrile (2 mL). The reaction mixture was heated to 95 °C and stirred for 14 hours, with the reaction progress monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a yellow liquid, with a yield of 49%.

[0027] according to Figure 6 The product's 1H NMR spectrum and Figure 7 The carbon spectrum of the product yields the following structural formula: ; 1 H NMR (300 MHz, CDCl3) δ 7.70 – 7.62 (m, 1H), 7.51 – 7.47 (m, 1H), 7.44 (dt, J = 5.4, 3.6 Hz, 2H), 7.40 – 7.34 (m, 1H), 6.32 (s, 2H), 4.51 (s,2H), 4.30 – 4.23 (m, 1H), 3.75 (dd, J = 10.5, 5.5 Hz, 1H), 3.67 (dd, J =10.5, 4.6 Hz, 1H), 3.25 (dd, J = 12.4, 3.4 Hz, 1H), 3.02 (t, J = 12.1 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 169.5, 150.9, 143.0, 136.9, 133.8, 132.6,130.8, 129.1, 110.3, 109.9, 75.9, 70.3, 65.3, 34.8.

[0028] Example 4 Synthesis of 3-(3-chlorophenyl)-2,3-dihydro-5H-benzo[e][1,4]oxothiazolinone: To a clean 10 mL reaction tube, benzo[a]sulfonyl ketone (0.2 mmol), lanthanum nitrate hexahydrate (0.04 mmol, 20 mol%), potassium carbonate (0.4 mmol), tributylphosphine (0.3 mmol), and 2-((ethylene oxide-2-ylmethoxy)methyl)furan (0.3 mmol) were added sequentially, followed by acetonitrile (2 mL). The reaction mixture was heated to 85 °C and stirred for 12 hours, with the reaction progress monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a yellow liquid, in 60% yield.

[0029] according to Figure 8 The product's 1H NMR spectrum and Figure 9 The carbon spectrum of the product yields the following structural formula of the target product: ; 1 H NMR (300 MHz, CDCl3) δ 7.68 (dd, J = 7.1, 1.6 Hz, 1H), 7.61 – 7.56(m, 1H), 7.54 – 7.45 (m, 1H), 7.42 (s, 1H), 7.31 – 7.27 (m, 3H), 5.12 (dd, J = 11.8, 3.4 Hz, 1H), 3.40 (dd, J = 12.5, 3.5 Hz, 1H), 3.19 (t, J = 12.2 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 168.9, 138.8, 136.5, 134.7, 133.9, 132.9,130.8, 130.18, 129.4, 128.9, 128.8, 126.4, 124.3, 77.5, 39.6.

[0030] Example 5 Synthesis of 3-(4-bromophenyl)-2,3-dihydro-5H-benzo[e][1,4]oxothiazolinone: To a clean 10 mL reaction tube, benzo[a]sulfonyl ketone (0.2 mmol), lanthanum nitrate hexahydrate (0.04 mmol, 20 mol%), potassium carbonate (0.4 mmol), tributylphosphine (0.3 mmol), and 2-(4-bromophenyl)ethylene oxide (0.3 mmol) were added sequentially, followed by acetonitrile (2 mL). The reaction mixture was heated to 90 °C and stirred for 14 hours, with the reaction progress monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a yellow liquid, with a yield of 61%.

[0031] according to Figure 10 The product's 1H NMR spectrum and Figure 11 The carbon spectrum of the product yields the following structural formula of the target product: ; 1 H NMR (300 MHz, CDCl3) δ 7.69 (dd, J = 7.1, 1.7 Hz, 1H), 7.62 – 7.56 (m, 1H), 7.56 – 7.42 (m, 4H), 7.27 (d, J = 8.3 Hz, 2H), 5.11 (dd, J = 11.8,3.4 Hz, 1H), 3.38 (dd, J = 12.5, 3.5 Hz, 1H), 3.18 (t, J = 12.2 Hz, 1H). 13 CNMR (75 MHz, CDCl3) δ 168.9, 136.6, 135.9, 133.9, 132.8, 132.0, 130.8, 129.4,128.9, 127.9, 122.8, 77.7, 39.6.

[0032] Example 6 Synthesis of 3-(ethoxymethyl)-2,3-dihydro-5H-benzo[e][1,4]oxothiazolinone: To a clean 10 mL reaction tube, benzo[a]sulfonyl ketone (0.2 mmol), lanthanum nitrate hexahydrate (0.04 mmol, 20 mol%), potassium carbonate (0.4 mmol), tributylphosphine (0.3 mmol), and 2-(ethoxymethyl)ethylene oxide (0.3 mmol) were added sequentially, followed by acetonitrile (2 mL). The reaction mixture was heated to 90 °C and stirred for 10 hours, with the reaction progress monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a white solid, in 72% yield.

[0033] according to Figure 12 The product's 1H NMR spectrum and Figure 13 The carbon spectrum of the product yields the following structural formula of the target product: ; 1 H NMR (300 MHz, CDCl3) δ 7.70 – 7.67 (m, 1H), 7.57 – 7.50 (m, 1H), 7.49 – 7.41 (m, 2H), 4.35 – 4.26 (m, 1H), 3.68 (qd, J = 10.5, 4.9 Hz, 2H), 3.55 (q, J = 7.0 Hz, 2H), 3.29 (dd, J = 12.4, 3.4 Hz, 1H), 3.07 (t, J = 12.1Hz, 1H), 1.19 (t, J = 7.0 Hz, 3H). 13 C NMR (75 MHz, CDCl3) δ 169.6, 136.9,133.7, 132.6, 130.7, 129.2, 129.1, 76.1, 71.0, 67.2, 34.9, 15.0.

[0034] Example 7 Synthesis of 5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]oxothiazo-11-one: To a clean 10 mL reaction tube, benzo[a]sulfonyl ketone (0.2 mmol), lanthanum nitrate hexahydrate (0.04 mmol, 20 mol%), potassium carbonate (0.4 mmol), tributylphosphine (0.3 mmol), and 1,2-epoxycyclohexane (0.3 mmol) were added sequentially, followed by acetonitrile (2 mL). The reaction mixture was heated to 95 °C and stirred for 10 hours, with the reaction progress monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a colorless liquid, with a yield of 78%.

[0035] according to Figure 14 The product's 1H NMR spectrum and Figure 15 The carbon spectrum of the product yields the following structural formula of the target product: ; 1 H NMR (300 MHz, CDCl3) δ 7.72 – 7.61 (m, 1H), 7.52 – 7.35 (m, 3H), 3.86 (td, J = 10.7, 4.1 Hz, 1H), 3.27 – 3.05 (m, 1H), 2.29 – 2.03 (m, 2H),1.90 – 1.76 (m, 1H), 1.74 – 1.68 (m, 2H), 1.53 – 1.39 (m, 1H), 1.35 – 1.13(m, 2H). 13 C NMR (75 MHz, CDCl3) δ 170.1, 137.0, 134.0, 132.4, 130.6, 129.0,128.8, 79.6, 51.2, 35.3, 32.4, 25.7, 24.1.

[0036] Example 8 Synthesis of 4-((7-fluoro-5-oxo-2,3-dihydro-5H-benzo[e][1,4]oxothiazo-3-yl)methoxy)butyl acrylate: To a clean 10 mL reaction tube, 0.2 mmol of a 5-fluorosubstituted benzenesulfonyl ketone compound, 0.04 mmol of lanthanum nitrate hexahydrate (20 mol%), 0.4 mmol of potassium carbonate, 0.3 mmol of tributylphosphine, and 0.3 mmol of 4-(ethylene oxide-2-ylmethoxy)acrylate were added sequentially, followed by 2 mL of acetonitrile. The reaction mixture was heated to 90 °C and stirred for 12 hours, with the reaction progress monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a colorless liquid, in 58% yield.

[0037] according to Figure 16 The product's 1H NMR spectrum and Figure 17 The carbon spectrum of the product yields the following structural formula of the target product: ; 1 H NMR (300 MHz, CDCl3) δ 7.43 (td, J = 8.0, 5.5 Hz, 1H), 7.32 (d, J =7.3 Hz, 1H), 7.17 (t, J = 8.7 Hz, 1H), 6.38 (dd, J = 17.3, 1.4 Hz, 1H), 6.10(dd, J = 17.3, 10.4 Hz, 1H), 5.81 (dd, J = 10.4, 1.4 Hz, 1H), 4.34 – 4.26 (m,1H), 4.15 (t, J = 6.3 Hz, 2H), 3.79 – 3.61 (m, 2H), 3.55 – 3.50 (m, 2H), 3.24(dd, J = 12.4, 3.5 Hz, 1H), 3.05 (t, J = 12.1 Hz, 1H), 1.75 – 1.62 (m, 4H). 13 C NMR (75 MHz, CDCl3) δ 166.2, 163.8, 160.2 (d, J = 257.7 Hz), 133.3, 133.2,130.6, 129.5 (d, J = 3.4 Hz), 128.4, 124.6 (d, J = 13.7 Hz), 117.3 (d, J =20.9 Hz), 75.7, 71.4, 71.0, 64.2, 34.9, 26.1, 25.3.

[0038] Example 9 Synthesis of 3-((7-methoxy-5-oxo-2,3-dihydro-5H-benzo[e][1,4]oxothiazo-3-yl)methoxy)butyl acrylate: To a clean 10 mL reaction tube, 0.2 mmol of a 5-methoxy-substituted benzenesulfonyl ketone compound, 0.04 mmol of lanthanum nitrate hexahydrate (20 mol%), 0.4 mmol of potassium carbonate, 0.3 mmol of tributylphosphine, and 0.3 mmol of 4-(ethylene oxide-2-ylmethoxy)acrylate were added sequentially, followed by 2 mL of acetonitrile. The reaction mixture was heated to 90 °C and stirred for 12 hours, with the reaction progress monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a yellow liquid, in 68% yield.

[0039] according to Figure 18 The product's 1H NMR spectrum and Figure 19 The carbon spectrum of the product yields the following structural formula of the target product: ; 1 H NMR (300 MHz, CDCl3) δ 7.41 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 2.8Hz, 1H), 6.97 (dd, J = 8.5, 2.9 Hz, 1H), 6.38 (dd, J = 17.3, 1.4 Hz, 1H),6.15 – 6.10 (m, 1H), 5.81 (dd, J = 10.4, 1.4 Hz, 1H), 4.29 – 4.21 (m, 1H),4.15 (t, J = 6.3 Hz, 2H), 3.83 (s, 3H), 3.66 (qd, J = 10.6, 4.9 Hz, 2H), 3.51(t, J = 6.0 Hz, 2H), 3.22 (dd, J = 12.4, 3.5 Hz, 1H), 2.98 (t, J = 12.1 Hz, 1H), 1.77 – 1.59 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 169.4, 166.2, 160.4,138.3, 135.2, 130.6, 128.5, 119.5, 118.6, 115.7, 76.2, 71.3, 64.2, 55.6,35.0, 29.6, 26.1, 25.4.

[0040] Example 10 Synthesis of 3-((furan-2-ylmethoxy)methyl)-8-methyl-2,3-dihydro-5H-benzo[e][1,4]oxothiazolinone: To a clean 10 mL reaction tube, 0.2 mmol of a 4-methyl-substituted benzenesulfonyl ketone compound, 0.04 mmol of lanthanum nitrate hexahydrate (20 mol%), 0.4 mmol of potassium carbonate, 0.3 mmol of tributylphosphine, and 0.3 mmol of 2-((ethylene oxide-2-ylmethoxy)methyl)furan were added sequentially, followed by 2 mL of acetonitrile. The reaction mixture was heated to 90 °C and stirred for 12 hours, with the reaction progress monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a yellow liquid, in 61% yield.

[0041] according to Figure 20 The product's 1H NMR spectrum and Figure 21 The carbon spectrum of the product yields the following structural formula of the target product: ; 1 H NMR (300 MHz, CDCl3) δ 8.20 (d, J = 8.1 Hz, 1H), 7.90 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 6.31 (d, J = 1.2 Hz, 2H), 4.67 – 4.59 (m,1H), 4.54– 4.51 (m, 2H), 4.35 – 4.23 (m, 1H), 3.67 – 3.56 (m, 2H), 3.21 (d, J= 5.8 Hz, 1H), 2.58 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 156.5, 151.2 146.3,144.3, 142.9, 133.9, 127.8, 124.9, 117.2, 110.2, 109.6, 71.4, 69.4, 65.2,53.0, 21.9.

Claims

1. A method for preparing a benzoxoxetazidine derivative, characterized in that, Using benzodisulfonyl ketone and epoxy compounds as reactants, under the co-catalysis of organophosphorus and lanthanum nitrate hexahydrate, potassium carbonate as base and acetonitrile as solvent, the reaction was heated to 85-95℃ and stirred for 10-14 hours. After the reaction was completed, the benzodisulfonyl ketone derivative was obtained by separation and purification. The amount of lanthanum nitrate hexahydrate used is 20 mol% of the amount of benzodisulfonate compound. The organophosphine is tributylphosphine, and the molar ratio of benzodisulfonyl ketone to tributylphosphine is 1:1.5; The molar ratio of potassium carbonate to benzo[a]sulfonyl ketone compound is 1:

2. The molar ratio of the benzodisulfonone compound to the epoxide compound is 1:1.5; The epoxy compounds are 2-((benzyloxy)methyl)ethylene oxide, 2-[(allyloxy)methyl]ethylene oxide, 2-((ethylene oxide-2-ylmethoxy)methyl)furan, 2-(3-chlorophenyl)ethylene oxide, 2-(4-bromophenyl)ethylene oxide, 2-(ethoxymethyl)ethylene oxide, 1,2-epoxycyclohexane, and 4-(ethylene oxide-2-ylmethoxy)butyl acrylate.

2. The method according to claim 1, characterized in that, The separation and purification steps are as follows: after the reaction is completed, the mixture is cooled to room temperature, and the solvent is removed by rotary evaporator to obtain the crude product. The crude product is then separated by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain high-purity benzoxoxetidine compounds.

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