A method for the selective synthesis of quinazolin-2-one sulfonyl fluorides and benzoxazinimine sulfonyl fluorides

Abstract

The application discloses a method for selectively synthesizing quinazolin-2-one sulfonyl fluoride and benzoxazin imine sulfonyl fluoride compounds, and belongs to the field of organic fluorine chemical synthesis. The method uses cheap and easily obtained 2-ethynyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride or 2-vinyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride as raw materials, has wide substrate applicability, the raw materials are simple and easy to obtain, and the economic cost is low. In addition, the method can realize the synthesis of target products, and quinazolin-2-one sulfonyl fluoride and benzoxazin imine sulfonyl fluoride compounds can be synthesized at room temperature and obtained in a good yield. These fluorine-containing building block compounds have wide application in the fields of medicine, pesticide and click chemistry.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for selectively synthesizing quinazolin-2-one sulfonyl fluoride and benzoxazin imine sulfonyl fluoride compounds, and belongs to the field of organic fluorine chemical synthesis. BACKGROUND

[0002] Since the 1950s, when it was discovered that introducing fluorine atoms into specific positions of drug molecules could improve their biological activity, a large number of fluorine-containing drugs have emerged like mushrooms after rain. From 1970, only 2% of the pharmaceutical market, to now about 20%. In 2019, the U.S. Food and Drug Administration (FDA) approved 35 chemical drugs for marketing, of which 14 contained fluorine atoms.

[0003] In the past two decades, the core focus of click chemistry has been to find excellent reactions that meet the strict standards of modular synthesis, including easy operation, environmental friendliness, and high selectivity and efficiency. Such reactions play an important role in the fields of material science, chemical biology, and pharmaceutical chemistry. In the process, the "SO2F" group can be effectively transferred to the target substrate to facilitate further chemical connection. In addition, the substrate modules involved include alcohols, phenols, and amines, which have rich structural diversity, bringing more development space to the field of synthetic chemistry. Wang and his colleagues developed the same imidazole sulfonyl fluoride salt for radical fluorosulfonation reactions. Under optimized conditions, the photocatalytic reaction can synthesize a variety of alkenyl sulfonyl fluoride compounds and alkyl sulfonyl fluoride compounds, which can tolerate different functional groups and have moderate to good yields, high regioselectivity and stereoselectivity. Almost at the same time, the Liao group used the same fluorosulfonyl benzimidazolium triflate as a fluorosulfonyl radical precursor to develop a method for radical hydrofluorosulfonylation of alkenes under metal-free conditions, hydrogen donor and photocatalyst conditions. This method constructs aliphatic sulfonyl fluoride under mild and metal-free conditions, and is a new efficient and environmentally friendly way to synthesize fluorine-containing compounds. The further application of this method in the late-stage modification of natural products, peptides and drugs has also been demonstrated, providing a powerful tool for the development of natural products and drugs, and helping to discover and develop new and more effective compounds in these fields.

[0004] Therefore, it is of great significance to develop a new type of fluorosulfonation reagent and the corresponding preparation method in the field of fluorine-containing drugs. SUMMARY

[0005]

Technical problem

[0006] To provide a new type of fluorosulfonation reagent and the corresponding preparation method.

[0007] TECHNICAL SCHEME

[0008] The present application provides an intermediate compound, having the following structure:

[0009]

[0010] R1 is vinyl or ethynyl; R is selected from H, C 1-4 alkyl, halogen (F, Cl, Br, I), cyano, C 1-4 alkoxy, acyl, amido, aryl.

[0011] In one embodiment of the present application, the acyl is -COR a , R a is selected from C 1-6 alkyl.

[0012] In one embodiment of the present application, the amido is -NR b COR c , R b is selected from H, C 1-6 alkyl, R c is selected from C 1-6 alkyl.

[0013] In one embodiment of the present application, the aryl includes benzene ring or naphthalene ring.

[0014] A method for selectively synthesizing quinazolin-2-one sulfonyl fluoride and benzoxazinimine sulfonyl fluoride compounds is to use the above intermediate compound and electrophilic reagent as a substrate, and to selectively react to obtain benzoxazinimine sulfonyl fluoride compound shown in formula (2) and quinazolin-2-one sulfonyl fluoride compound shown in formula (3) by controlling reaction conditions; including the following processes:

[0015]

[0016] R1 and R are defined as above, Y is CHCH2X, or C=CH2; Z is CHCH2X; X is halogen (Cl, Br, I).

[0017] In reaction condition A, silver salt is used as a catalyst, with or without electrophilic reagent; in reaction condition B, base is used as a catalyst, with or without electrophilic reagent.

[0018] In one embodiment of the present application, in reaction condition A or reaction condition B, the electrophilic reagent is selected from any one or more of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide.

[0019] In one embodiment of the present application, no electrophile is added in reaction condition A or reaction condition B, or the molar ratio of the compound of formula (1) to the electrophile is 1:(1.5-3).

[0020] In one embodiment of the present application, the amount of the silver salt used in reaction condition A is 0.1-1.0 equiv (molar equivalent) relative to the compound of formula (1).

[0021] In one embodiment of the present application, the silver salt used in reaction condition A is silver trifluoromethanesulfonate.

[0022] In one embodiment of the present application, the reaction in reaction condition A is carried out in a solvent, and the solvent is acetonitrile.

[0023] In one embodiment of the present application, the reaction in reaction condition B is carried out in a solvent, and the solvent is methanol.

[0024] In one embodiment of the present application, the reaction temperature in reaction condition A or reaction condition B is room temperature (20-30°C), and the reaction time is 6-24 h.

[0025] In one embodiment of the present application, the base used in reaction condition B is sodium tert-butoxide.

[0026] In one embodiment of the present application, the amount of the base used in reaction condition B is 3-6 equiv (molar equivalent) relative to the compound of formula (1).

[0027] In one embodiment of the present application, the present application realizes the cyclization reaction of 2-ethynyl-N-[(phenylamino)carbonyl] sulfamoyl fluoride and 2-vinyl-N-[(phenylamino)carbonyl] sulfamoyl fluoride by selecting 2-ethynyl-N-[(phenylamino)carbonyl] sulfamoyl fluoride and 2-vinyl-N-[(phenylamino)carbonyl] sulfamoyl fluoride to react with N-iodosuccinimide in the presence of a silver salt to synthesize quinazolin-2-one sulfamoyl fluoride and benzoxazinimine sulfamoyl fluoride compounds.

[0028] The present application also provides a preparation method of benzoxazinimine sulfamoyl fluoride compounds, and the reaction route is shown as follows:

[0029] wherein R is as defined above.

[0030] In one embodiment of the present application, a preparation method of β-chlorobenzoxazinimine sulfamoyl fluoride compounds,

[0031] wherein R and X are as defined above.

[0032] In one embodiment of the present application, a method for preparing a quinazolin-2-one sulfonyl fluoride compound,

[0033] wherein R, X are defined as above.

[0034] In one embodiment of the present application, a benzoxazinimine sulfonyl fluoride compound is obtained, and then the pure benzoxazinimine sulfonyl fluoride compound is obtained by filtration, washing, distillation under reduced pressure and column chromatography separation.

[0035] In the above method, the main separation method is fast column chromatography separation, and the final product benzoxazinimine sulfonyl fluoride compound is obtained.

[0036] In one embodiment of the present application, the method is preferably carried out by the following steps: 2-ethynyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride, silver trifluoromethanesulfonate and potassium carbonate are added into a reaction container containing dichloromethane in a molar ratio of 1:0.5:2, stirring at 25-85℃ for 8-24 hours, and then separating and purifying to obtain the target product.

[0037] The present application also provides a fluorosulfonation reagent, which has the following structure:

[0038]

[0039] Y is CHCH2X, or C=CH2; Z is CHCH2X; X is halogen.

[0040] The present application also provides the use of the above fluorosulfonation reagent in the preparation of sulfonyl fluoride reactions.

[0041] Advantages:

[0042] In the present application, 2-ethynyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride and 2-vinyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride compounds are used as substrates, and silver trifluoromethanesulfonate is used as a catalyst, and the cyclization reaction of 2-ethynyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride and 2-vinyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride can be realized in one step to obtain the target compound. The reaction mechanism of the present application is as follows: the silver ion in silver trifluoromethanesulfonate attacks the double bond or triple bond to generate an alpha carbon cation, and then the lone pair of electrons on the oxygen and nitrogen atoms attacks the carbon cation to form a cyclic sulfonyl fluoride compound.

[0043] In the present application, inexpensive and readily available N-chlorosuccinimide is used as a chlorine source, and silver trifluoromethanesulfonate is used as a catalyst, and the substrate has wide applicability, the raw materials are simple and easy to obtain, and the economic cost is low. In addition, the synthesis of the target product in the present application only needs 6-24 hours of reaction to obtain the target product in a good yield, which is faster and more efficient.

[0044] The synthetic method of the present application synthesizes 2-ethynyl-N-[(phenylamino)carbonyl] sulfamoyl fluoride and 2-vinyl-N-[(phenylamino)carbonyl] sulfamoyl fluoride under relatively simple conditions to synthesize quinazolin-2-one sulfamoyl fluoride and benzoxazinimine sulfamoyl fluoride compounds, which are fluorine-containing building block compounds widely used in the fields of medicine, pesticide and click chemistry. BRIEF DESCRIPTION OF DRAWINGS

[0045] Figure 1 The synthetic route map of the method of the present application. DETAILED DESCRIPTION

[0046] The following is a detailed description of the present application.

[0047] The synthetic route map of the present application is shown in Figure 1 .

[0048] 2-ethynyl-N-[(phenylamino)carbonyl] sulfamoyl fluoride and 2-vinyl-N-[(phenylamino)carbonyl] sulfamoyl fluoride are used as raw materials, silver trifluoromethanesulfonate is used as a catalyst, and N-chlorosuccinimide is added as a chlorine source to a reaction bottle containing acetonitrile, after which the reaction bottle is placed in a 25-85°C oil bath for 8-24 hours of full reaction. The reaction expression is Figure 1 .

[0049] Example 1

[0050] Preparation of 2-ethynyl-N-[(phenylamino)carbonyl] sulfamoyl fluoride:

[0051]

[0052] At 0°C under a nitrogen atmosphere, 2-ethynylaniline (1.0 mmol, 1.0 equiv) was added to DCM (5.0 mL) and stirred for 10 min, after which a mixture of fluorosulfonylisocyanate (FSI) (1.2 mmol, 1.2 equiv) and DCM (5.0 mL) was slowly added dropwise to the mixture using a syringe. After the dropwise addition was completed, stirring was continued at room temperature for 2 h, and the progress of the reaction was monitored using thin layer chromatography (TLC). Once it was confirmed that the 2-ethynylaniline had been completely reacted, stirring was stopped. Concentration was performed under reduced pressure at room temperature, and the crude product was separated and purified by silica gel flash column chromatography to obtain the desired product.

[0053] 1 H NMR (400 MHz, CD3OD) δ 8.08 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 3.31 (s, 1H). 19F NMR (376 MHz, CD3OD) δ 49.14 (s, 1F).

[0054] Preparation of 2-vinyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride:

[0055]

[0056] At 0 °C, under a nitrogen atmosphere, 2-vinyl aniline (1.0 mmol, 1.0 equiv) was added to DCM (5.0 mL) and stirred for 10 min, then a mixture of FSI (1.2 mmol, 1.2 equiv) and DCM (5.0 mL) was slowly added dropwise to the mixture using a syringe. After the addition was complete, stirring was continued at room temperature for 2 h, and the progress of the reaction was monitored by thin layer chromatography (TLC). Once it was confirmed that the 2-vinyl aniline had reacted completely, stirring was stopped. Concentration under reduced pressure at room temperature gave the crude product, which was isolated and purified by flash column chromatography on silica gel to give the desired product.

[0057] Preparation of 5-fluoro-2-vinyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride:

[0058]

[0059] At 0 °C, under a nitrogen atmosphere, 5-fluoro-2-vinyl aniline (1.0 mmol, 1.0 equiv) was added to DCM (5.0 mL) and stirred for 10 min, then a mixture of FSI (1.2 mmol, 1.2 equiv) and DCM (5.0 mL) was slowly added dropwise to the mixture using a syringe. After the addition was complete, stirring was continued at room temperature for 2 h, and the progress of the reaction was monitored by thin layer chromatography (TLC). Once it was confirmed that the 2-vinyl aniline had reacted completely, stirring was stopped. Concentration under reduced pressure at room temperature gave the crude product, which was isolated and purified by flash column chromatography on silica gel to give the desired product.

[0060] 1 H NMR (400 MHz, CD3OD) δ 1H), 5.39-5.29 (m, 1H), 5.62 (dd, J = 17.3, 1.2 Hz, 1H), 6.76 (td, J = 8.4, 2.7 Hz, 1H), 6.85 (dd, J = 17.4, 11.0 Hz, 1H), 7.41 (dd, J = 8.6, 6.5 Hz, 1H), 7.65 (dd, J = 11.5, 2.7 Hz. 19 F NMR (376 MHz, CD3OD) δ 48.35 (s, 1F), -115.52 (s, 1F).

[0061] Example 2: Selective synthesis of benzoxazinone sulfamoyl fluoride using 2-ethynyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride

[0062]

[0063] In a 25 ml reaction tube with a rotor, 2-ethynyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride (242 mg, 1 mmol), silver trifluoromethanesulfonate (51.2 mg, 0.2 mmol) were added in 10 ml acetonitrile, and reacted at 30°C for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, washed with distilled water and saturated sodium chloride solution, respectively, concentrated under vacuum, dried with anhydrous magnesium sulfate, re-concentrated, and the target product was separated and purified by column chromatography to obtain 128 mg of the target product with a yield of 53%.

[0064] 1 H NMR (400 MHz, CD3OD) δ 7.64 (dd, J = 8.0, 1.5 Hz, 1H), 7.44-7.37 (m, 1H), 7.22 (td, J = 7.6, 1.2 Hz, 1H), 6.99 (d, J = 6.8 Hz, 1H), 4.99 (d, J = 3.6 Hz, 1H), 4.81 (s, 1H). 19 F NMR (376 MHz, CD3OD) δ 51.00 (s).

[0065] Example 3: Effect of silver salt on the synthesis of benzoxazinone sulfamoyl fluoride

[0066] Referring to Example 2, silver trifluoromethanesulfonate was replaced by silver nitrate, silver methanesulfonate, and silver sulfate, respectively, and a group of experiments without any silver salt was added, and the other conditions were unchanged, and the corresponding benzoxazinone sulfamoyl fluoride was prepared. The specific yield results are shown in Table 1.

[0067] Table 1: Effect of different silver salts on the synthesis of benzoxazinone sulfamoyl fluoride

[0068] Silver salt Yield (%) - 0 AgNO3 34 AgOSO2CH3 39 Ag2SO4 0

[0069] It was found that: without silver salt and using silver nitrate, silver methanesulfonate, and silver sulfate to replace silver trifluoromethanesulfonate in Example 1 as catalyst, the yield of the product was lower than that of Example 1, and the yield was not more than 40%.

[0070] Example 4: Effect of solvent on the synthesis of benzoxazinone sulfamoyl fluoride

[0071] Referring to Example 2, the solvent was replaced by THF, DCM, and methanol, respectively, and the other conditions were unchanged, and the corresponding benzoxazinone sulfamoyl fluoride was prepared. The specific yield results are shown in Table 2.

[0072] Table 2: Effect of different solvents on the synthesis of benzoxazinone sulfamoyl fluoride

[0073]

[0074]

[0075] It is found that the yield is less than 40% when THF, DCM or methanol is used as the solvent of the reaction system, and other conditions are unchanged.

[0076] Example 5: Effect of reaction temperature on synthesis of benzoxazinone sulfonyl fluoride

[0077] Referring to Example 2, the reaction temperature is replaced by 60°C, 80°C and 100°C respectively, and other conditions are unchanged, to prepare the corresponding benzoxazinone sulfonyl fluoride.

[0078] The specific yield results are shown in Table 3.

[0079] Table 3: Effect of different reaction temperatures on synthesis of benzoxazinone sulfonyl fluoride

[0080] Temperature (°C) Yield (%) 60 35 80 20 100 0

[0081] It is found that the yield is less than 40% when 60°C, 80°C or 100°C is used to replace 30°C in Example 1.

[0082] Example 6: Selective synthesis of β-chlorobenzoxazinone sulfonyl fluoride by using 2-vinyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride

[0083]

[0084] In a 25 ml reaction tube with a rotor, 2-vinyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride (244 mg, 1 mmol), silver trifluoromethanesulfonate (51.2 mg, 0.2 mmol) and N-chlorosuccinimide (266 mg, 2 mmol) were added respectively, and after nitrogen replacement, they were fully reacted at 30°C in 10 ml acetonitrile for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate and washed with distilled water and saturated sodium chloride solution respectively, concentrated under vacuum and dried with anhydrous magnesium sulfate, and the target product was separated and purified by column chromatography again, to obtain 247 mg of the target product with a yield of 67%.

[0085] 1H NMR (400 MHz, CD3OD) δ 3.85-3.71 (m, 2H), 5.88 (t, J = 4.3 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 7.24 (td, J = 7.6, 1.0 Hz, 1H), 7.29 (d, J = 6.4 Hz, 1H), 7.40 (td, J = 7.7, 1.4 Hz, 1H). 19 FNMR (376 MHz, CD3OD) δ 51.79 (s).

[0086] Example 7: Influence of catalyst on synthesis of β-chlorobenzoxazinone sulfonyl fluoride

[0087] Referring to Example 6, the silver salt was replaced by silver nitrate, silver methane sulfonate, silver sulfate respectively, in addition, a group of experiments without any silver salt was added, other conditions were unchanged, and the corresponding benzoxazinone sulfonyl fluoride was prepared. The specific yield results are shown in Table 4.

[0088] Table 4 Influence of different catalysts on synthesis of β-chlorobenzoxazinone sulfonyl fluoride

[0089] Catalyst Yield (%) - AgNO3 0 AgOSO2CH3 35 Ag2SO4 30

[0090] It was found that: when the silver salt was replaced by silver nitrate, silver methane sulfonate, silver sulfate, and no silver salt was added, the yield was less than 35%.

[0091] Example 8: Influence of solvent on synthesis of β-chlorobenzoxazinone sulfonyl fluoride

[0092] Referring to Example 6, the solvent was replaced by 1,4-dioxane, DCM, methanol, DMF, DMSO respectively, other conditions were unchanged, and the corresponding benzoxazinone sulfonyl fluoride was prepared. The specific yield results are shown in Table 5.

[0093] Table 5 Influence of different solvents on synthesis of benzoxazinone sulfonyl fluoride

[0094] Solvent Yield (%) 1,4-dioxane 38 DCM 35 Methanol 20 DMF 0 DMSO 0

[0095] It was found that: the yield in other solvent environments was significantly reduced, and was not more than 40%.

[0096] Example 9: Selective synthesis of quinazolin-2-one sulfonyl fluoride by using 2-vinyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride

[0097]

[0098] In a 25 ml reaction tube with a rotor, 2-vinyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride (244 mg, 1 mmol), N-chlorosuccinimide (266 mg, 2 mmol), sodium tert-butoxide (480 mg, 5 mmol) were added respectively, and reacted at 30°C in 10 ml of methanol for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate and washed with distilled water and saturated sodium chloride solution respectively, concentrated under vacuum and dried with anhydrous magnesium sulfate, concentrated again and purified by column chromatography to obtain the target product 155 mg, yield 42%.

[0099] 1 H NMR (400 MHz, CD3OD) δ 7.34 (d, J = 7.7 Hz, 2H), 7.13 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 5.60 (t, J = 4.8 Hz, 1H), 3.65 (d, J = 5.4 Hz, 1H), 3.57 (d, J = 3.5 Hz, 1H). 19 F NMR (376 MHz, CD3OD) δ 56.94 (s).

[0100] Example 10: Influence of base on the synthesis of quinazolin-2-one sulfonyl fluoride

[0101] Referring to Example 9, the base was replaced by potassium carbonate, potassium tert-butoxide, sodium carbonate, sodium hydride respectively, and other conditions remained unchanged, to prepare the corresponding quinazolin-2-one sulfonyl fluoride. The specific yield results are shown in Table 6.

[0102] Table 6: Influence of different bases on the synthesis of quinazolin-2-one sulfonyl fluoride

[0103] Base Yield (%) Potassium tert-butoxide 35 Potassium carbonate 20 Sodium carbonate 10 Sodium hydride 0

[0104] It was found that when the base was replaced by potassium carbonate, potassium tert-butoxide, sodium carbonate, sodium hydride respectively, and other conditions remained unchanged, the yield was less than 35%.

[0105] Example 11: Influence of solvent on the synthesis of quinazolin-2-one sulfonyl fluoride

[0106] Referring to Example 9, the solvent was replaced by DMSO, DMF, acetonitrile, dichloromethane respectively, and other conditions remained unchanged, to prepare the corresponding quinazolin-2-one sulfonyl fluoride. The specific yield results are shown in Table 5.

[0107] Table 5: Influence of different solvents on the synthesis of quinazolin-2-one sulfonyl fluoride

[0108] Solvent Yield (%) DMSO 10 DMF 15 Acetonitrile 25 Dichloromethane 0

[0109] The results show that when the solvent is replaced by DMSO, DMF, acetonitrile, dichloromethane, respectively, and other conditions remain unchanged, the yield is less than 25%.

[0110] Application Example

[0111] Application 1, using benzoxazinone sulfonyl fluoride and β-chlorobenzoxazinone sulfonyl fluoride as intermediates to prepare peptide sulfonyl fluorides related to medicinal chemistry.

[0112]

[0113] In a 10 ml Schlenk, benzoxazinone sulfonyl fluoride or β-chlorobenzoxazinone sulfonyl fluoride (1.5 mmol, 1.5 eq) and thioxanthone (0.05 mmol, 0.05 eq) were added. The Schlenk tube was then evacuated and backfilled with argon three times, then dry dimethyl carbonate (4 mL) and 2-(hex-5-en-1-phenyl)isoindoline-1,3-dione (1 mmol, 1.0 eq) were added. The Schlenk tube was placed under argon and irradiated at 405 nm for 24 hours at room temperature. After completion, the crude reaction mixture was filtered over basic alumina if a solid had formed, and washed with EtOAc. The volatiles were removed in vacuo. Purification by basic silica gel column chromatography gave the desired product.

[0114] The resulting product is a class of peptide sulfonyl fluoride compounds with potential for drug use, which can be found in the existing literature EnT-Mediated N-S Bond Homolysis of a Bifunctional Reagent Leading to Aliphatic Sulfonyl Fluorides. J. Am. Chem. Soc. 2023, 145, 2364-2374.

[0115]

[0116] Referring to the above process, if benzoxazinone sulfonyl fluoride or β-chlorobenzoxazinone sulfonyl fluoride is replaced by equimolar 2-ethynyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride or 2-vinyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride, it is found that essentially no target product is generated.

[0117] Application 2, using quinazolin-2-one sulfonyl fluoride as an intermediate to prepare alkenyl sulfonyl fluoride, which can be further applied to the late-stage modification of natural products and polypeptides.

[0118]

[0119] ODA (0.05 mmol, 0.05 eq) and quinazolin-2-one sulfonyl fluoride (1 mmol, 1.0 eq) were added to an oven-dried Schlenk tube under a nitrogen atmosphere, followed by the addition of anhydrous 1,4-dioxane (5.0 ml), phenylacetylene (1 mmol, 1 eq), and 1,4-CHD (3 mmol, 3.0 eq). The reaction mixture was stirred at room temperature under irradiation with a blue LED (6 w, 460 nm) for 24 h. Purification by column chromatography or silica gel preparative thin-layer chromatography afforded the desired pure product.

[0120] The resulting product is a class of alkenyl sulfonyl fluorides that can be used for the late-stage modification of natural products and polypeptides, as described in the existing literature Radical Hydro-Fluorosulfonylation of Unactivated Alkenes and Alkynes. Angew. Chem. Int. Ed. 2022, 61, e20220768.

[0121]

[0122] Referring to the above process, if quinazolin-2-one sulfonyl fluoride is replaced with equimolar amounts of 2-vinyl-N-[(phenylamino)carbonyl] sulfamoyl fluoride, it is found that essentially no target product is generated.

Claims

1. An intermediate compound, characterized in that, It has the following structure: ， R1 is vinyl or ethynyl; R is selected from H, C 1-4 Alkyl, aryl, halogen, cyano, C 1-4 The alkoxy group, wherein the aryl group is a benzene ring or a naphthalene ring.

2. A method for selectively synthesizing quinazolin-2-one sulfonyl fluoride and benzoxazine imine sulfonyl fluoride compounds, characterized in that, Using the intermediate compound described in claim 1 as a substrate, and by controlling the reaction conditions, the benzoxazine imine sulfonyl fluoride compound shown in formula (2) and the quinazoline-2-one sulfonyl fluoride compound shown in formula (3) are selectively reacted; the process includes the following steps: ， R1 and R are defined as in claim 1, Y is CHCH2X or C=CH2; Z is CHCH2X; X is a halogen; In reaction condition A, a silver salt is used as a catalyst, with or without an electrophilic reagent; In reaction condition B, a base is used as a catalyst, and an electrophilic reagent is added; In reaction condition A or reaction condition B, the electrophilic reagent is selected from... N -Chlorosuccinimide, N -bromosuccinimide, N -Iodosuccinimide, any one or more of the following; In reaction condition A, the silver salt is silver trifluoromethanesulfonate; In reaction condition B, the base is sodium tert-butoxide.

3. The method according to claim 2, characterized in that, In reaction conditions A or B, no electrophilic reagent is added, or the molar ratio of the compound of formula (1) to the electrophilic reagent is 1:(1.5~3).

4. The method according to claim 2, characterized in that, In reaction condition A, the amount of the silver salt relative to the compound of formula (1) is 0.1 - 1.0 equiv.

5. The method according to claim 2, characterized in that, In reaction condition A, the reaction is carried out in a solvent, namely acetonitrile; in reaction condition B, the reaction is carried out in a solvent, namely methanol.

6. The method according to claim 2, characterized in that, In both reaction conditions A and B, the reaction temperature is room temperature.

7. The method according to claim 2, characterized in that, In reaction condition B, the amount of base relative to compound (1) is 3-6 equiv.

8. The method according to claim 2, characterized in that, The method includes the following reaction pathway: Where R is defined as in claim 2; or, Where R and X are defined as in claim 2; or, Where R and X are defined as in claim 2.

9. A fluorosulfonating agent, characterized in that, The structure is as follows: or , Y is CHCH2X or C=CH2; Z is CHCH2X; X is a halogen; R is selected from H and C. 1-4 Alkyl, aryl, halogen, cyano, C 1-4 The alkoxy group, wherein the aryl group is a benzene ring or a naphthalene ring.

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