Method for selectively synthesizing quinazoline-2-ketone sulfonyl fluoride and benzoxazine imine sulfonyl fluoride compounds

Abstract

The invention discloses a method for selectively synthesizing quinazoline-2-ketone sulfonyl fluoride and benzoxazine imine sulfonyl fluoride compounds, and belongs to the field of chemical synthesis of organic fluorine. According to the method, 2-ethynyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride or 2-vinyl-N-[(phenylamino) carbonyl] sulfamoyl fluoride which is low in price and easy to obtain is adopted as the raw materials, the substrate applicability is wide, the raw materials are simple and easy to obtain, and the economic cost is low; in addition, the quinazoline-2-ketone sulfonyl fluoride and benzoxazine imine sulfonyl fluoride compounds can be synthesized in a relatively high yield only in a room temperature environment according to the method disclosed by the invention, and the fluorine-containing building block compounds are widely applied to the fields of medicines, pesticides and click chemistry.

Description

Technical Field

[0001] The invention specifically relates to a method for selectively synthesizing quinazoline-2-one sulfonyl fluoride and benzoxazine imine sulfonyl fluoride compounds, and belongs to the field of organic fluorine chemical synthesis. Background Art

[0002] Since the discovery in the 1950s that introducing fluorine atoms into specific sites of drug molecules can improve their biological activity, a large number of fluorine-containing drugs have sprung up. From only 2% of the pharmaceutical market in 1970, it has reached about 20% today. In 2019, the U.S. Food and Drug Administration (FDA) approved a total of 35 chemical drugs for marketing, 14 of which contain fluorine atoms.

[0003] Over 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, environmentally friendly, highly selective and efficient. This type of reaction has played a wide and important role in research fields such as materials science, chemical biology, and medicinal chemistry. In this process, the "SO2F" group can be effectively transferred to the target substrate, thereby facilitating further chemical connection. In addition, the substrate modules involved include alcohols, phenols, and amines, which have rich structural diversity and bring broader development space to the field of synthetic chemistry. Wang and his colleagues developed the same imidazolesulfonyl fluoride salt for free radical fluorination reaction. Under optimized conditions, the photocatalytic reaction can synthesize a variety of olefinsulfonyl fluoride compounds and alkylsulfonyl fluoride compounds, can tolerate different functional groups, and have moderate to good yields, with high regioselectivity and stereoselectivity. Almost at the same time, Liao's research group used the same fluorosulfonylbenzimidazolium trifluorosulfonate as a fluorosulfonyl radical precursor and developed a method for free radical hydrofluorosulfonylation of olefins under metal-free conditions, hydrogen donors and photocatalysts. This method constructs aliphatic sulfonyl fluorides under mild and metal-free conditions, and is a new efficient and environmentally friendly way to synthesize fluorinated compounds. The further application of this method in the post-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, providing and developing a new type of fluorinated sulfonated reagent and a corresponding preparation method is of great significance to the field of fluorinated drugs. Summary of the invention

[0005]

Technical issues

[0006] Provided are a novel fluorinated sulfonating agent and a corresponding preparation method.

[0007]

Technical solution

[0008] The present invention 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, amide, aryl.

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

[0012] In one embodiment of the present invention, the amide group is -NR b COR c , R b Selected from H, C 1-6 Alkyl, R c Selected from C 1-6 alkyl.

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

[0014] A method for selectively synthesizing quinazoline-2-one sulfonyl fluoride and benzoxazine imine sulfonyl fluoride compounds, which uses the above intermediate compound and electrophilic reagent as substrates, and selectively reacts to obtain benzoxazine imine sulfonyl fluoride compounds shown in formula (2) and quinazoline-2-one sulfonyl fluoride compounds shown in formula (3) by controlling reaction conditions; and comprises the following steps:

[0015]

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

[0017] Reaction condition A uses silver salt as catalyst with or without electrophilic reagent; reaction condition B uses base as catalyst with or without electrophilic reagent.

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

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

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

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

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

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

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

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

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

[0027] In one embodiment of the present invention, the present invention selects 2-ethynyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride and 2-vinyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride to react with N-iodosuccinimide under the catalysis of silver salt to synthesize quinazoline-2-onesulfonyl fluoride and benzoxazine iminesulfonyl fluoride compounds, thereby achieving the cyclization reaction of 2-ethynyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride and 2-vinyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride.

[0028] The present invention also provides a method for preparing a benzoxazine imine sulfonyl fluoride compound, and the reaction scheme thereof is as follows:

[0029] Wherein R is defined as above.

[0030] In one embodiment of the present invention, a method for preparing β-chlorobenzoxazine imine sulfonyl fluoride compounds is provided.

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

[0032] In one embodiment of the present invention, a method for preparing a quinazoline-2-one sulfonyl fluoride compound is provided.

[0033] Wherein R and X are as defined above.

[0034] In one embodiment of the present invention, a crude benzoxazine imine sulfonyl fluoride compound is obtained, and then a pure benzoxazine imine sulfonyl fluoride compound is obtained by filtering, washing, vacuum distillation and column chromatography separation.

[0035] In the above method, the main separation method is rapid column chromatography separation to obtain the final product benzoxazine imine sulfonyl fluoride compound.

[0036] In one embodiment of the present invention, the method is preferably carried out as follows: 2-ethynyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride, silver trifluoromethanesulfonate, and potassium carbonate are added to a reaction vessel containing dichloromethane in a molar ratio of 1:0.5:2, stirred at 25°C-85°C for 8-24 hours, separated and purified to obtain the target product.

[0037] The present invention also provides a fluorinated sulfonation reagent, the structure of which is shown below:

[0038]

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

[0040] The present invention also provides application of the fluorinated sulfonating agent in the reaction of preparing sulfonyl fluorides.

[0041] Beneficial effects:

[0042] The method of the present invention uses 2-ethynyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride and 2-vinyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride compounds as substrates and silver trifluoromethanesulfonate as a catalyst in an air atmosphere, and can achieve a cyclization reaction of 2-ethynyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride and 2-vinyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride in one step to obtain a target compound. The reaction mechanism of the present invention is as follows: silver ions in silver trifluoromethanesulfonate attack double bonds or triple bonds to generate α-position carbon cations, and then lone pairs of electrons on oxygen and nitrogen atoms attack the carbon cations to form cyclic sulfonyl fluoride compounds.

[0043] The method of the invention uses cheap and easily available N-chlorosuccinimide as a chlorine source and silver trifluoromethanesulfonate as a catalyst, and has wide substrate applicability, simple and easily available raw materials, and low economic cost. In addition, the method of the invention only needs 6-24 hours of reaction to achieve the synthesis of the target product, and the target product can be obtained with a good yield, which is faster and more efficient.

[0044] The synthesis method of the invention uses 2-ethynyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride and 2-vinyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride which are easily available to synthesize quinazoline-2-onesulfonyl fluoride and benzoxazine iminesulfonyl fluoride compounds under relatively simple conditions, and the fluorine-containing building block compounds are widely used in the fields of medicine, pesticides and click chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The synthetic route diagram of the method of the present invention is shown in FIG. DETAILED DESCRIPTION

[0046] The following are specific embodiments of the present invention.

[0047] The synthetic route diagram of the embodiment of the present invention is as follows: Figure 1 As shown:

[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 used as a chlorine source. The reaction bottle is then placed in an oil bath at 25°C-85°C for a full reaction of 8-24 hours. 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 nitrogen atmosphere, 2-ethynylaniline (1.0 mmol, 1.0 equiv) was added to DCM (5.0 mL) and stirred for 10 min. Then, a mixture of fluorosulfonyl isocyanate (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 reaction progress was monitored by thin layer chromatography (TLC). Once it was confirmed that 2-ethynylaniline had reacted completely, stirring was stopped. The mixture was concentrated 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 (400MHz, CD3OD) δ8.08(d,J=8.3Hz,1H),7.45(d,J=7.7Hz,1H),7.36(t,J=8.1Hz,1H),7.08(t,J=7.6Hz,1H),3.31(s,1H). 19F NMR (376MHz, CD3OD) δ49.14 (s, 1F).

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

[0055]

[0056] At 0°C, under nitrogen atmosphere, 2-vinylaniline (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 reaction progress was monitored by thin layer chromatography (TLC). Once it was confirmed that 2-vinylaniline had reacted completely, stirring was stopped. The mixture was concentrated 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.

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

[0058]

[0059] At 0°C, under nitrogen atmosphere, 5-fluoro-2-vinylaniline (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 reaction progress was monitored by thin layer chromatography (TLC). Once it was confirmed that 2-vinylaniline had reacted completely, stirring was stopped. The mixture was concentrated 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.

[0060] 1 H NMR(400MHz,CD3OD)δ1H),5.39-5.29(m,1H),5.62(dd,J=17.3,1.2Hz,1H),6.76(td,J=8.4,2. 7Hz, 1H), 6.85 (dd, J=17.4, 11.0Hz, 1H), 7.41 (dd, J=8.6, 6.5Hz, 1H), 7.65 (dd, J=11.5, 2.7Hz. 19 F NMR (376MHz, CD3OD) δ48.35 (s, 1F), -115.52 (s, 1F).

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

[0062]

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

[0064] 1 H NMR (400MHz, CD3OD) δ7.64 (dd, J=8.0, 1.5Hz, 1H), 7.44-7.37 (m, 1H), 7.22 (td ,J=7.6,1.2Hz,1H),6.99(d,J=6.8Hz,1H),4.99(d,J=3.6Hz,1H),4.81(s,1H). 19 F NMR(376MHz,CD3OD)δ51.00(s).

[0065] Example 3 Investigating the effect of silver salt on the synthesis of benzoxazine imine sulfonyl fluoride

[0066] Referring to Example 2, the silver salt was replaced by silver nitrate, silver methanesulfonate, and silver sulfate respectively from silver trifluoromethanesulfonate, and a group of experiments without adding any silver salt was added, and other conditions remained unchanged to obtain the corresponding benzoxazine imine sulfonyl fluoride. The specific yield results are shown in Table 1.

[0067] Table 1 Effect of different silver salts on the synthesis of benzoxazine imine sulfonyl fluoride

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

[0069] The results show that: without adding silver salt and using silver nitrate, silver methanesulfonate, or silver sulfate to replace the silver trifluoromethanesulfonate in Example 1 as the catalyst, the yield of the obtained product is worse than that in Example 1, and the yield does not exceed 40%.

[0070] Example 4 Investigating the effect of solvent on the synthesis of benzoxazine imine sulfonyl fluoride

[0071] Referring to Example 2, the solvent was replaced by THF, DCM, and methanol respectively from acetonitrile, and other conditions remained unchanged to obtain the corresponding benzoxazine imine sulfonyl fluoride. The specific yield results are shown in Table 2.

[0072] Table 2 Effect of different solvents on the synthesis of benzoxazine imine sulfonyl fluoride

[0073]

[0074]

[0075] The results show that when THF, DCM and methanol are used as the solvents of the reaction system and other conditions remain unchanged, the yield is worse than that of Example 1 and does not exceed 40%.

[0076] Example 5 Investigating the effect of reaction temperature on the synthesis of benzoxazine imine sulfonyl fluoride

[0077] Referring to Example 2, the reaction temperature was replaced from 30°C to 60°C, 80°C, and 100°C, respectively, and other conditions remained unchanged to obtain the corresponding benzoxazine imine sulfonyl fluoride.

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

[0079] Table 3 Effect of different reaction temperatures on the synthesis of benzoxazine imine sulfonyl fluoride

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

[0081] The results showed that when 60°C, 80°C, and 100°C were used instead of 30°C in Example 1, the yield of the product obtained was worse than that in Example 1, and the yield did not exceed 40%.

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

[0083]

[0084] 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 to a 25 ml reaction tube equipped with a rotor, and after nitrogen substitution, the mixture was fully reacted in 10 ml acetonitrile at 30°C for 12 hours. After the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, washed with distilled water and saturated sodium chloride solution, concentrated in vacuo, dried with anhydrous magnesium sulfate, concentrated again, and purified by column chromatography to obtain 247 mg of the target product with a yield of 67%.

[0085] 1H NMR (400MHz, CD3OD) δ3.85-3.71(m,2H),5.88(t,J=4.3Hz,1H),7.01(d,J=7.9Hz,1 H),7.24(td,J=7.6,1.0Hz,1H),7.29(d,J=6.4Hz,1H),7.40(td,J=7.7,1.4Hz,1H). 19 FNMR (376MHz, CD3OD)δ51.79(s).

[0086] Example 7 Investigating the effect of catalyst on the synthesis of β-chlorobenzoxazine imine sulfonyl fluoride

[0087] Referring to Example 6, the silver salt was replaced by silver nitrate, silver methanesulfonate, and silver sulfate respectively from silver trifluoromethanesulfonate, and a group of experiments without adding any silver salt was added, and other conditions remained unchanged to obtain the corresponding benzoxazine imine sulfonyl fluoride. The specific yield results are shown in Table 4.

[0088] Table 4 Effect of different catalysts on the synthesis of β-chlorobenzoxazine imine sulfonyl fluoride

[0089] catalyst Yield (%) - <![CDATA[AgNO3]]> 0 <![CDATA[AgOSO2CH3]]> 35 <![CDATA[Ag2SO4]]> 30

[0090] The results showed that the yields of the silver salts were all lower than 35% when silver trifluoromethanesulfonate was replaced by silver nitrate, silver methanesulfonate, silver sulfate, or no silver salt was added.

[0091] Example 8 Investigating the Effect of Solvent on the Synthesis of β-Chlorobenzoxazine Sulfonyl Fluoride

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

[0093] Table 5 Effect of different solvents on the synthesis of benzoxazine imine sulfonyl fluoride

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

[0095] The results showed that the yields in other solvent environments were significantly reduced and did not exceed 40%.

[0096] Example 9: Selective synthesis of quinazoline-2-onesulfonyl fluoride using 2-vinyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride

[0097]

[0098] 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 to a 25 ml reaction tube equipped with a rotor, and the mixture was fully reacted in 10 ml methanol at 30°C for 12 hours. After the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, washed with distilled water and saturated sodium chloride solution, concentrated in vacuo, dried with anhydrous magnesium sulfate, concentrated again, and purified by column chromatography to obtain 155 mg of the target product with a yield of 42%.

[0099] 1 H NMR (400MHz, CD3OD) δ7.34(d,J=7.7Hz,2H),7.13(t,J=7.6Hz,1H),6.95(d,J=7 .7Hz,1H),5.60(t,J=4.8Hz,1H),3.65(d,J=5.4Hz,1H),3.57(d,J=3.5Hz,1H). 19 FNMR (376MHz, CD3OD)δ56.94(s).

[0100] Example 10 Investigating the effect of base on the synthesis of quinazoline-2-one sulfonyl fluoride

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

[0102] Table 6 Effect of different bases on the synthesis of quinazoline-2-one sulfonyl fluoride

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

[0104] The results showed that when the base was replaced by potassium carbonate, potassium tert-butoxide, sodium carbonate, and sodium hydride respectively, while other conditions remained unchanged, the yield was lower than 35%.

[0105] Example 11 Investigating the Effect of Solvent on the Synthesis of Quinazoline-2-One Sulfonyl Fluoride

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

[0107] Table 5 Effect of different solvents on the synthesis of quinazoline-2-one sulfonyl fluoride

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

[0109] The results showed that when the solvent was replaced from methanol to DMSO, DMF, acetonitrile, and dichloromethane respectively, while other conditions remained unchanged, the yields were all lower than 25%.

[0110] Application Examples

[0111] Application 1: using benzoxazine imine sulfonyl fluoride and β-chlorobenzoxazine imine sulfonyl fluoride as intermediates to prepare peptide sulfonyl fluoride related to medicinal chemistry.

[0112]

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

[0114] The obtained product is a class of peptide sulfonyl fluoride compounds with medicinal potential, which can be found in the existing literature EnT-MediatedN-SBond 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 benzoxazine imine sulfonyl fluoride or β-chlorobenzoxazine imine sulfonyl fluoride is replaced by an equimolar amount of 2-ethynyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride or 2-vinyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride, it is found that substantially no target product is generated.

[0117] Application 2: Using quinazoline-2-onesulfonyl fluoride as an intermediate to prepare olefinsulfonyl fluoride, which can be further applied to the later modification of natural products and peptides.

[0118]

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

[0120] The obtained product is a class of olefin sulfonyl fluoride compounds that can be used for the later modification of natural products and peptides. See 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-onesulfonyl fluoride is replaced by an equal molar amount of 2-vinyl-N-[(phenylamino)carbonyl]sulfamoyl fluoride, it is found that substantially 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 (F, Cl, Br, I), cyano, C 1-4 Alkoxy, acyl and amide groups.

2. A method for selectively synthesizing quinazoline-2-one sulfonyl fluoride and benzoxazine imine sulfonyl fluoride compounds, characterized in that: The method uses the intermediate compound described in claim 1 as a substrate, and selectively reacts to obtain the benzoxazine imine sulfonyl fluoride compound shown in formula (2) and the quinazoline-2-one sulfonyl fluoride compound shown in formula (3) by controlling the reaction conditions; and comprises the following steps: R1 and R are as defined in claim 1, Y is CHCH2X, or C=CH2; Z is CHCH2X; X is halogen; Reaction conditions: Type A uses silver salt as catalyst with or without electrophilic reagent; In reaction condition B, a base is used as a catalyst with or without the addition of an electrophilic reagent.

3. The method according to claim 2, characterized in that In reaction condition A or reaction condition B, the electrophilic reagent is selected from any one or more of N-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide.

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

5. 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, and the silver salt is silver trifluoromethanesulfonate.

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

7. The method according to claim 2, characterized in that: In reaction condition A or reaction condition B, the reaction temperature is room temperature (20-30°C).

8. The method according to claim 2, characterized in that: In reaction condition B, the base is sodium tert-butoxide; the amount of the base relative to the compound of formula (1) is 3-6 equiv.

9. The method according to claim 2, characterized in that: The method comprises the following reaction scheme: wherein R is as defined in claim 2; or Wherein R and X are as defined in claim 2; or Wherein R and X are defined as in claim 2.

10. A fluorinated sulfonating agent, characterized in that: The structure is as follows: Y is CHCH2X, or C=CH2; Z is CHCH2X; X is halogen.

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