A method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a C1 source and solvent

Abstract

The present invention provides a method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a C1 source and solvent, and relates to the technical field of organic synthesis. The synthesis method provided by the present invention uses cyclohexanecarboxylate, CH2Cl2, and a nucleophilic reagent as reaction substrates, and a continuous nucleophilic substitution reaction occurs under base catalysis to obtain the 1,4,2-dioxazole compound; the cyclohexanecarboxylate is an aryl-substituted cyclohexanecarboxylate, a heteroaryl-substituted cyclohexanecarboxylate, or an alkyl-substituted cyclohexanecarboxylate; the nucleophilic reagent includes an oxygen nucleophile, a nitrogen nucleophile, a nitrogen heterocyclic nucleophile, or a sulfur nucleophile. The present invention provides a new path for the synthesis of 1,4,2-dioxazole compounds. The synthetic route of the present invention is used to prepare 1,4,2-dioxazole compounds, with mild conditions, green and environmental protection, low cost, and high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 1,4,2-dioxazole compounds by using dichloromethane as a Cl source and a solvent. Background Art

[0002] CH2Cl2 is one of the most frequently used solvents in organic synthesis. Its specific characteristics are as follows: (1) CH2Cl2 is relatively cheap, easy to purchase and store, and has relatively good hydrophobicity. (2) CH2Cl2 is a halogenated hydrocarbon with two chlorine atoms attached to the same carbon. Therefore, it has many properties of halogenated hydrocarbons, such as the ability to undergo MX exchange, oxidative addition, nucleophilic substitution, etc. (3) CH2Cl2 has good solubility, a relatively low boiling point and toxicity. It is a basic chemical in organic synthesis in the chemical industry and laboratories. It is usually used as an organic solvent to mediate organic reactions, separation and purification, or sample analysis, but rarely participates in reactions as a reactant. Therefore, there is an urgent need to develop new organic transformations to use the bulk chemical CH2Cl2 as a C1 source for the synthesis of high-value-added drugs and fine chemicals.

[0003] 1,4,2-dioxazoles are widely found in pharmaceuticals and bioactive molecules, such as those with anti-amoebic activity (European Journal of Medicinal Chemistry. 2011, 46, 4742-4752) and moderate central nervous system depressant activity (J. Pharm. Sci. 1977, 66, 772-775). Furthermore, 1,4,2-dioxazoles are also important building blocks for organic synthesis, serving as nitrene transfer reagents (J. Am. Chem. Soc. 2024, 146, 1001-1008), nitrene precursors (Angew. Chem. Int. Ed. 2014, 53, 5639), and amide reagents (Angew. Chem. Int. Ed. 2015, 54, 14103-14107). However, currently, only three methods have been reported for the synthesis of 1,4,2-dioxazoles. The first method is the 1,3-dipolar cycloaddition reaction of nitrile oxide and acyl derivative reported by Professors Velo and Polat-Cakir respectively (Phosphorus Sulfur Silicon Relat.Elem.2021,196,461-467; Tetrahedron Lett.1967,4,331-334.); the second method is the addition reaction of acyl azide and ketone under the irradiation of Hg lamp (Tetrahedron 1995,51,7181-7192); the third method is the addition reaction of phenhydroxamic acid with alkyne or ketal (J.Org.Chem.2023,88,433-441;Org.Lett.2019,21,22-26). These methods face several limitations, such as the difficulty in obtaining raw materials, a limited substrate range, harsh reaction conditions, and the requirement for multiple steps and complex purification processes for some reactions. These factors severely restrict the practicality of these methods. Therefore, developing new, broad-spectrum, and efficient catalytic modes and reaction systems to achieve green, sustainable, and chemoselective construction of 1,4,2-dioxazole compounds has practical scientific significance and application value. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for synthesizing 1,4,2-dioxazole compounds using the bulk chemical dichloromethane (CH2Cl2) as a Cl source and solvent under the action of heating. The present invention provides a new path for the synthesis of 1,4,2-dioxazole compounds. The synthetic route of the present invention is used to prepare 1,4,2-dioxazole compounds under mild conditions and high yield.

[0005] To achieve the above objectives, the present invention proposes the following technical solution: a method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a C1 source and solvent, comprising the following steps: cyclohexanecarboxylates, nucleophilic reagents, and CH2Cl2 are used as reaction substrates, and the 1,4,2-dioxazole compounds are obtained by a one-pot reaction under base-catalyzed conditions.

[0006] Furthermore, the cyclohexanecarboxylate includes cyclohexanecarboxylate substituted with an aryl group, cyclohexanecarboxylate substituted with a heteroaryl group, or cyclohexanecarboxylate substituted with an alkyl group.

[0007] Furthermore, the nucleophilic reagent includes an oxygen nucleophilic reagent, a nitrogen nucleophilic reagent, a nitrogen heterocyclic nucleophilic reagent or a sulfur nucleophilic reagent.

[0008] Furthermore, the base includes at least one of 4-dimethylaminopyridine (DMAP), pyridine, triethylamine, 1,4-diazabicyclo[2,2,2]octane (DABCO), N,N-diisopropylethylamine (DIPEA), cesium carbonate, tetramethylguanidine (TMG), and potassium tert-butoxide.

[0009] Furthermore, the reaction temperature is 20-100°C.

[0010] Furthermore, the reaction time is 12 to 60 hours.

[0011] Furthermore, the molar ratio of the cyclohexanecarboxylate to the nucleophilic reagent is 1:(1-5).

[0012] Furthermore, for every 1 mmol of the cyclohexanecarboxylate, the volume of CH2Cl2 corresponds to 0.3 to 3.0 mL.

[0013] Furthermore, the molar ratio of the cyclohexanecarboxylate to the base is 1:(1-4).

[0014] In the present invention, when the cyclohexanecarboxylate is an aryl cyclohexanecarboxylate (e.g., 1,3-dioxoisoindolin-2-yl cyclohexanecarboxylate), the chemical equation for synthesizing the 1,4,2-dioxazole compound is shown in the following formula (I):

[0015]

[0016] The base is at least one of 4-dimethylaminopyridine (DMAP), pyridine, triethylamine, 1,4-diazabicyclo[2,2,2]octane (DABCO), N,N-diisopropylethylamine (DIPEA), cesium carbonate, tetramethylguanidine (TMG), and potassium tert-butoxide.

[0017] Further, according to R 1The groups are different, and the cyclohexanecarboxylate compounds are selected from:

[0018]

[0019] Furthermore, among the nucleophilic compounds, Nu compounds include the following categories depending on the type of nucleophilic reagent:

[0020] a) Oxygen nucleophile compounds

[0021]

[0022] b) Nitrogen nucleophile compounds

[0023]

[0024] c) Nitrogen heterocyclic nucleophilic compounds

[0025]

[0026] d) Sulfur nucleophile compounds

[0027]

[0028] The raw materials selected in the synthesis process are different, and accordingly, the substituent groups in the structure of the synthesized 1,4,2-dioxazole compounds change accordingly.

[0029] Furthermore, the molar ratio of the cyclohexanecarboxylate to the nucleophilic reagent and the base is 1:

[0030] (1~5):(1~4).

[0031] Furthermore, the cyclohexanecarboxylate is an aromatic substituted cyclohexanecarboxylate, and the molar ratio of the nucleophile to the cyclohexanecarboxylate is (2-3):1.

[0032] Furthermore, the base is tetramethylguanidine, and the reaction temperature is 60-80°C.

[0033] Furthermore, the method further comprises purification: adding 300-400 mesh silica gel to the column chromatography column, and purifying the column using petroleum ether:ethyl acetate with a polarity of 2:1 to 10:1.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] The present invention provides a method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a C1 source and solvent, providing a new path for the synthesis of 1,4,2-dioxazole compounds. The synthetic route of the present invention is used to prepare 1,4,2-dioxazole compounds under mild conditions, is environmentally friendly, has low cost, and has a high yield. DETAILED DESCRIPTION

[0036] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below through specific embodiments.

[0037] Unless otherwise specified, the specific experimental methods and equipment involved in the following examples are all conventional methods or carried out according to the conditions recommended by the manufacturer's instructions; the reagents involved are all commercially available.

[0038] The yield of the synthesized 1,4,2-dioxazole compounds was investigated in the examples of the present invention. The yield was calculated as follows:

[0039] Yield = (actual yield / theoretical yield) * 100%

[0040] Theoretical yield = the number of moles of raw materials added multiplied by the relative molecular mass of the target product.

[0041] Example 1 (Synthesis of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate)

[0042] The structural formula of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate is:

[0043]

[0044] 1,3-Dioxoisoindolin-2-ylcyclohexanecarboxylate (54.7 mg, 0.20 mmol, 1.0 equiv.), CH2Cl2 (2 mL), 2-methoxyphenol (44.0 μL, 0.40 mmol, 2.0 equiv.), and Et3N (69.5 μL, 0.50 mmol, 2.5 equiv.) were added sequentially to a Schlenk tube under an argon atmosphere. The reaction mixture was stirred at 60°C for 24 h. After completion of the reaction, the reaction mixture was washed with ethyl acetate, and the washings were removed by rotary evaporation under vacuum. Finally, the residue was purified by column chromatography using 300-400 mesh silica gel and a 10:1 ratio of petroleum ether to ethyl acetate to obtain a colorless oily product.

[0045] 1H NMR(600MHz, CDCl3)δ:8.10–8.08(m,1H),7.70–7.69(m,1H),7.60–7.58(m,2H),7.19–7.16(m, 1H),7.12(dd,J=7.8,1.5Hz,1H),6.95–6.91(m,2H),5.78(s,2H),3.76(s,3H); HRMS(ESI):m / z calcd for C 16 H 14 NO5Na[M+Na] + :322.0686,found:322.0683.

[0046] The colorless oily product was 1 H NMR and 13 C NMR analysis confirmed that the colorless oily product was 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate. Calculations indicate that the yield of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate in this example was 21%.

[0047] Example 2 (Synthesis of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate)

[0048] The structural formula of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate is:

[0049]

[0050] 1,3-Dioxoisoindolin-2-ylcyclohexanecarboxylate (54.7 mg, 0.20 mmol, 1.0 equiv.), CH2Cl2 (2 mL), 2-methoxyphenol (44.0 μL, 0.40 mmol, 2.0 equiv.), and TMG (62.7 μL, 0.50 mmol, 2.5 equiv.) were added sequentially to a Schlenk tube under an argon atmosphere. The reaction mixture was stirred at 60°C for 24 h. After completion of the reaction, the reaction mixture was washed with ethyl acetate, and the washings were removed by rotary evaporation under vacuum. Finally, the residue was purified by column chromatography using 300-400 mesh silica gel and a 10:1 ratio of petroleum ether to ethyl acetate to obtain a colorless oily product.

[0051] The colorless oily product was 1 H NMR and 13C NMR analysis confirmed that the colorless oily product was 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate. Calculations indicate that the yield of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate in this example was 82%.

[0052] Example 3 (Synthesis of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate)

[0053] The structural formula of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate is:

[0054]

[0055] 1,3-Dioxoisoindolin-2-ylcyclohexanecarboxylate (54.7 mg, 0.20 mmol, 1.0 equiv.), CH2Cl2 (2 mL), and 2-methoxyphenol (44.0 μL, 0.40 mmol, 2.0 equiv.) were added sequentially to a Schlenk tube under an argon atmosphere. The reaction mixture was stirred at 60°C for 24 hours. After completion of the reaction, the reaction mixture was washed with ethyl acetate, and the washings were removed using a rotary evaporator under vacuum. Finally, the residue was purified by column chromatography using 300-400 mesh silica gel and a 10:1 ratio of petroleum ether to ethyl acetate to obtain a colorless oily product.

[0056] The colorless oily product was 1 H NMR and 13 C NMR analysis confirmed that the colorless oily product was 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate. Calculations showed that the yield of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate in this example was undetectable.

[0057] Example 4 (Synthesis of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate)

[0058] The structural formula of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate is:

[0059]

[0060] 1,3-Dioxoisoindolin-2-ylcyclohexanecarboxylate (54.7 mg, 0.20 mmol, 1.0 equiv.), CHCl (2 mL), 2-methoxyphenol (44.0 μL, 0.40 mmol, 2.0 equiv.), and TMG (62.7 μL, 0.50 mmol, 2.5 equiv.) were added sequentially to a Schlenk tube under an argon atmosphere. The reaction mixture was stirred at 20°C for 24 h. After completion of the reaction, the reaction mixture was washed with ethyl acetate, and the washings were removed by rotary evaporation under vacuum. Finally, the residue was purified by column chromatography using 300-400 mesh silica gel and a 10:1 ratio of petroleum ether to ethyl acetate to obtain a colorless oily product.

[0061] The colorless oily product was 1 H NMR and 13 C NMR analysis confirmed that the colorless oily product was 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate. Calculations indicate that the yield of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate in this example was 45%.

[0062] Example 5 (Synthesis of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate)

[0063] The structural formula of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate is:

[0064]

[0065] 1,3-Dioxoisoindolin-2-ylcyclohexanecarboxylate (54.7 mg, 0.20 mmol, 1.0 equiv.), CH2Cl2 (2 mL), 2-methoxyphenol (44.0 μL, 0.40 mmol, 2.0 equiv.), and TMG (25.1 μL, 0.20 mmol, 1.0 equiv.) were added sequentially to a Schlenk tube under an argon atmosphere. The reaction mixture was stirred at 60°C for 24 h. After completion of the reaction, the reaction mixture was washed with ethyl acetate, and the washings were removed using a rotary evaporator under vacuum. Finally, the residue was purified by column chromatography using 300-400 mesh silica gel and a 10:1 ratio of petroleum ether to ethyl acetate to obtain a colorless oily product.

[0066] The colorless oily product was 1 H NMR and 13C NMR analysis confirmed that the colorless oily product was 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate. Calculations indicate that the yield of 2-methoxyphenyl-2-(1,4,2-dioxazol-3-yl)benzoate in this example was 48%.

[0067] Example 6 (Synthesis of 2-methoxyphenyl-3-(1,4,2-dioxazol-3-yl)propionate)

[0068] The structural formula of 2-methoxyphenyl-3-(1,4,2-dioxazol-3-yl) propionate is:

[0069]

[0070] 2,5-Dioxopyrrolidin-1-ylcyclohexanecarboxylate (45.0 mg, 0.20 mmol, 1.0 equiv.), CHCl (2 mL), 2-methoxyphenol (44.0 μL, 0.40 mmol, 2.0 equiv.), and TMG (37.6 μL, 0.30 mmol, 1.5 equiv.) were added sequentially to a Schlenk tube under an argon atmosphere. The reaction mixture was stirred at 60°C for 24 h. After completion of the reaction, the reaction mixture was washed with ethyl acetate, and the washings were removed using a rotary evaporator under vacuum. Finally, the residue was purified by column chromatography using 300-400 mesh silica gel and a 10:1 ratio of petroleum ether to ethyl acetate to obtain a colorless oily product.

[0071] 1 H NMR(600MHz, CDCl3)δ:7.22–7.19(m,1H),7.04(dd,J=7.8,1.8Hz,1H),6.98– 6.93(m,2H),5.69(s,2H),3.82(s,3H),2.98–2.96(m,2H),2.86–2.83(m,2H); 13 C NMR (150MHz, CDCl3) δ: 169.5, 160.3, 150.9, 139.5, 127.0, 122.6, 120.7, 112.4, 98.1, 55.8, 29.5, 19.3; HRMS (ESI): m / z calcd for C 12 H 13 NO5[M+Na] + :274.0686,found:274.0686.

[0072] The colorless oily product was 1 H NMR and 13C NMR analysis confirmed that the colorless oily product was 2-methoxyphenyl-3-(1,4,2-dioxazol-3-yl) propionate. Calculations indicate that the yield of 2-methoxyphenyl-3-(1,4,2-dioxazol-3-yl) propionate in this example was 60%.

[0073] Example 7 (Synthesis of 2-(1,4,2-dioxazol-3-yl)-N-methyl-N-(methylsulfonyl)benzamide)

[0074] The structural formula of 2-(1,4,2-dioxazol-3-yl)-N-methyl-N-(methylsulfonyl)benzamide is:

[0075]

[0076] 1,3-Dioxoisoindolin-2-ylcyclohexanecarboxylate (54.7 mg, 0.20 mmol, 1.0 equiv.), CH2Cl2 (2 mL), N-methylmethanesulfonamide (54.8 μL, 0.60 mmol, 3.0 equiv.), and TMG (62.7 μL, 0.50 mmol, 2.5 equiv.) were added sequentially to a Schlenk tube under an argon atmosphere. The reaction mixture was stirred at 60°C for 24 h. After completion of the reaction, the reaction mixture was washed with ethyl acetate, and the washings were removed by rotary evaporation under vacuum. Finally, the residue was purified by column chromatography using 300-400 mesh silica gel and a 2:1 ratio of petroleum ether to ethyl acetate to obtain a colorless oily product.

[0077] 1 H NMR(600MHz, CDCl3)δ:7.82(d,J=7.8Hz,1H),7.61(t,J=7.5Hz,1H),7.55(t, J=7.5Hz,1H),7.41(d,J=7.8Hz,1H),5.84(s,2H),3.38(s,3H),3.14(s,3H); 13 C NMR (150MHz, CDCl3) δ: 169.9, 157.7, 135.0, 132.1, 130.0, 128.3, 126.6, 118.5, 98.6, 40.2, 34.0; HRMS (ESI): m / z calcd for C 11 H 12 N2O5SNa[M+Na] + :307.0359,found:307.0357.

[0078] The colorless oily product was 1 H NMR and13 C NMR analysis confirmed that the colorless oily product was 2-(1,4,2-dioxazol-3-yl)-N-methyl-N-(methylsulfonyl)benzamide. Calculated, in this example, the yield of 2-(1,4,2-dioxazol-3-yl)-N-methyl-N-(methylsulfonyl)benzamide was 60%.

[0079] Example 8 (Synthesis of S-isopropyl-2-(1,4,2-dioxazol-3-yl)benzothioester)

[0080] The structural formula of S-isopropyl-2-(1,4,2-dioxazol-3-yl)benzothioate is:

[0081]

[0082] 1,3-Dioxoisoindolin-2-ylcyclohexanecarboxylate (54.7 mg, 0.20 mmol, 1.0 equiv.), CHCl (2 mL), isopropyl mercaptan (37.2 μL, 0.40 mmol, 2.0 equiv.), and TMG (62.7 μL, 0.50 mmol, 2.5 equiv.) were added sequentially to a Schlenk tube under an argon atmosphere. The reaction mixture was stirred at 60°C for 24 h. After completion of the reaction, the reaction mixture was washed with ethyl acetate, and the washings were removed using a rotary evaporator under vacuum. Finally, the residue was purified by column chromatography using 300-400 mesh silica gel and a 10:1 ratio of petroleum ether to ethyl acetate to obtain a colorless oily product.

[0083] 1 H NMR(600MHz, CDCl3)δ:7.76–7.75(m,1H),7.70–7.68(m,1H),7.57–7.53(m,2H),5.83(s,2H),3.87–3.82(m,1H),1.40(d,J=6.6Hz,6H); 13 CNMR(150MHz, CDCl3)δ:193.1,159.3,139.3,131.5,131.2,130.2,128.1,119.9,98.7,35.9,22.7; HRMS(ESI):m / z calcdfor C 12 H 13 NO3SNa[M+Na] + :274.0508,found:274.0506.

[0084] The colorless oily product was 1 H NMR and 13C NMR analysis confirmed that the colorless oily product was S-isopropyl-2-(1,4,2-dioxazol-3-yl)benzothioate. Calculations indicate that the yield of S-isopropyl-2-(1,4,2-dioxazol-3-yl)benzothioate in this example was 88%.

[0085] Example 9 (Synthesis of 2-(1,4,2-dioxazol-3-yl)phenyl)(1H-indazol-1-yl)methanone)

[0086] The structural formula of 2-(1,4,2-dioxazol-3-yl)phenyl)(1H-indazol-1-yl)methanone is:

[0087]

[0088] 1,3-Dioxoisoindolin-2-ylcyclohexanecarboxylate (54.7 mg, 0.20 mmol, 1.0 equiv.), CH2Cl2 (2 mL), indazole (70.9 mg, 0.60 mmol, 3.0 equiv.), and TMG (62.7 μL, 0.50 mmol, 2.5 equiv.) were added sequentially to a Schlenk tube under an argon atmosphere. The reaction mixture was stirred at 60°C for 24 h. After completion of the reaction, the reaction mixture was washed with ethyl acetate, and the washings were removed using a rotary evaporator under vacuum. Finally, the residue was purified by column chromatography using 300-400 mesh silica gel and a 5:1 ratio of petroleum ether to ethyl acetate to obtain a colorless oily product.

[0089] 1 H NMR(600MHz, CDCl3)δ:8.60(d,J=8.4Hz,1H),8.11(s,1H),7.95(d,J=7.8Hz,1H ),7.76(d,J=7.8Hz,1H),7.67–7.61(m,4H),7.43(t,J=7.5Hz,1H),5.50(s,2H); 13 C NMR (150MHz, CDCl3) δ: 168.3, 158.6, 140.9, 139.4, 134.7, 131.4, 130.4, 129.8, 128.8, 128.3, 126.3, 125.1, 121.0, 120.8, 115.7, 98.5. HRMS(ESI):m / z calcd for C 17 H 13 N3O3Na[M+Na] + :330.0849,found:330.0847.

[0090] The colorless oily product was1 H NMR and 13 C NMR analysis confirmed that the colorless oily product was 2-(1,4,2-dioxazol-3-yl)phenyl)(1H-indazol-1-yl)methanone. Calculated, in this example, the yield of 2-(1,4,2-dioxazol-3-yl)phenyl)(1H-indazol-1-yl)methanone was 68%.

[0091] Example 10 (Synthesis of estrone-2-(1,4,2-dioxazol-3-yl)benzoate)

[0092] The structural formula of estrone-2-(1,4,2-dioxazol-3-yl)benzoate is:

[0093]

[0094] 1,3-Dioxoisoindolin-2-ylcyclohexanecarboxylate (54.7 mg, 0.20 mmol, 1.0 equiv.), CH2Cl2 (2 mL), estrone (135.2 mg, 0.50 mmol, 2.5 equiv.), and TMG (87.8 μL, 0.70 mmol, 3.5 equiv.) were added sequentially to a Schlenk tube under an argon atmosphere. The reaction mixture was stirred at 60°C for 24 hours. After completion of the reaction, the reaction mixture was washed with ethyl acetate, and the washings were removed using a rotary evaporator under vacuum. Finally, the residue was purified by column chromatography using 300-400 mesh silica gel and a 5:1 ratio of petroleum ether to ethyl acetate to obtain a colorless oily product.

[0095] 1 H NMR(600MHz, CDCl3)δ:7.60(dd,J=7.8,0.6Hz,1H),7.50–7.48(m,1H),7.33(t,J=7.8Hz,1H),7.29– 7.28(m,1H),7.23(d,J=7.8Hz,1H),7.12(d,J=8.4Hz,1H),6.95(t,J=7.8Hz,1H),6.72–6.69(m,2H) ,6.56(d,J=8.4Hz,1H),5.87(d,J=3.6Hz,1H),5.80(d,J=3.0Hz,1H),4.49(s,1H),3.13–3.07(m,2H ),3.00–2.95(m,1H),2.86(dd,J=15.6,8.4Hz,1H),2.31–2.26(m,3H),2.15(dd,J=19.8,9.6Hz,1H), 13C NMR(150MHz, CDCl3)δ:164.0,159.7,152.4,147.0,146.6,145.3,138.3,133.3,131.8,131.2,130.3,130.2, 130.1,129.0,128.4,123.1,122.6,121.0,117.2,114.6,98.8,58.5,38.1,37.6,31.2,31.1; HRMS(ESI):m / z calcd for C 26 H 21 NO5Na[M+Na] + :450.1312,found:450.1309.

[0096] The colorless oily product was 1 H NMR and 13 C NMR analysis confirmed that the colorless oily product was estrone-2-(1,4,2-dioxazol-3-yl)benzoate. Calculations indicate that the yield of estrone-2-(1,4,2-dioxazol-3-yl)benzoate in this example was 65%.

[0097] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a C1 source and solvent, characterized in that: The following steps are involved: Cyclohexanecarboxylate, CH2Cl2, and a nucleophilic reagent are used as reaction substrates, and continuous nucleophilic substitution reactions occur under base-catalyzed conditions to obtain the 1,4,2-dioxazole compound; the nucleophilic reagent is selected from 2-methoxyphenol, N-methylmethanesulfonamide, isopropyl mercaptan, indazole, or estrone; the chemical formula for synthesizing the 1,4,2-dioxazole compound is as follows: ; R 1 Selected from 、 、 、 、 、 、 、 、 or .

2. The method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a Cl source and solvent according to claim 1, characterized in that: The base includes at least one of 4-dimethylaminopyridine, pyridine, triethylamine, 1,4-diazabicyclo[2,2,2]octane, N,N-diisopropylethylamine, cesium carbonate, tetramethylguanidine, and potassium tert-butoxide.

3. The method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a Cl source and solvent according to claim 1, characterized in that: The reaction temperature is 20~100℃.

4. The method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a Cl source and solvent according to claim 3, characterized in that: The reaction time is 12~60h.

5. The method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a Cl source and solvent according to claim 1, characterized in that: For every 1 mmol of cyclohexanecarboxylate, use 0.3-3.0 mL of CH2Cl2.

6. The method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a Cl source and solvent according to claim 1, characterized in that: The molar ratio of cyclohexanecarboxylate to nucleophile is 1:(1~5).

7. The method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a Cl source and solvent according to claim 1, characterized in that: The molar ratio of the cyclohexanecarboxylate to the base is 1:(1-4).

8. The method for synthesizing 1,4,2-dioxazole compounds using dichloromethane as a Cl source and solvent according to claim 1, characterized in that: The method further comprises purification: adding 300-400 mesh silica gel to a column chromatography column and purifying the product by column chromatography using petroleum ether:ethyl acetate with a polarity ratio of 2:1 to 10:1.

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