Synthesis method of < 18 > F labeled alkyl sulfonyl fluoride molecule based on hypervalent iodine (III) carboxylate

Abstract

The invention discloses a synthesis method of 18F-labeled alkyl sulfonyl fluoride molecules based on hypervalent iodine (III) carboxylate, which comprises the following steps: in a solvent, in the presence of an 18F-fluorination reagent, a sulfur dioxide source and copper salt, carrying out a reaction shown as follows on a compound shown as a formula II to obtain a compound shown as a formula I, namely the 18F-labeled alkyl sulfonyl fluoride molecules # imgabs0, in which R is # imgabs1 # imgabs2 #, R1 is phenyl or cyano, R2 is phenyl or cyano, and R3 is phenyl or cyano; r1 is methyl, methoxy, nitro, methyl formate and bromine; and R2 is phenyl. The problem of limitation of an existing < 18 > F sulfonyl fluoride labeling method is solved, a novel method which is simple in reaction condition, efficient and good in substrate applicability is developed, synthesis of < 18 > F labeled alkyl sulfonyl fluoride is achieved, raw materials are easy to obtain, and operation is easy.

Description

Technical Field

[0001] The invention belongs to the technical fields of organic synthesis, radiochemistry and nuclear medicine molecular imaging, and particularly relates to a method for preparing a high-valent iodine (III) carboxylate-based 18 Synthesis of F-labeled alkylsulfonyl fluoride molecules. Background Art

[0002] Sulfonyl functional groups, including sulfones, sulfinic acids and sulfonamides, are widely used in many fields, such as as active ingredients of drugs and pesticides ([1] Y. Harrak et al. J. Med. Chem. 2010, 53, 6560; [2] W.-M. Xue et al. J. Agric. Food Chem. 2012, 60, 1036.), playing a key role as intermediates in complex chemical syntheses ([1] P. Vogel et al. Acc. Chem. Res. 2007, 40, 931; [2] A. El-Awa et al. Chem. Rev. 2009, 109, 2315.), and as specialty materials and food additives (DJ Ager et al. Angew. Chem. Int. Edit. 1998, 37, 1802.). In general, the synthesis of these functional groups is based on the classical reaction mode of sulfide (N.-W.Liu et al.Synthesis 2016,48,1939.). The SO2 group connects all functional groups derived from the sulfonyl fragment. This shows that the direct introduction of the SO2 group is a common method for generating these molecules, such as using SO2 substitutes (such as K2S2O5, Na2S2O5 and 1,4-diazabicyclo [2.2.2] octane-1,4-diacation-1,4-disulfate (DABSO)) (H.Woolven et al.Org.Lett.2011,13,4876.). These SO2 sources have been widely used to introduce SO2 groups by metal catalysis. In the synthesis of (hetero)arylsulfonyl fluorides, DABSO is used as the SO2 source, and the related (hetero)aryl bromides are used as precursors (ATDavies et al.Chem.Sci.2017,8,1233.). There are also a variety of synthetic methods using SO2 substitutes to convert electrophiles (such as aryl iodides, olefin trifluoromethanesulfonates or aryl diazonium salts) into the corresponding aryl sulfonyl fluoride. Aryl nucleophiles can also be used as aromatic sources in catalytic reactions, for example, aryl sulfonyl fluoride is synthesized from DABSO and aryl boronic acid under Cu(I) or Ni(II) catalysis ([1] Y. Chen et al. Chem. Sci. 2017, 8, 3249; [2] PKT Lo et al. ACS Catal. 2019, 9, 10668.); SO2 gas and (hetero)aryl boronic acid are reacted under Bi catalysis (M. Magre et al. J. Am. Chem. Soc. 2021, 143, 21497.).In addition, electrochemical methods can be used to directly convert traditional thiol precursors into sulfonyl fluorides using KF as an economical, safe, and readily available fluorine source (G. Laudadio et al. J. Am. Chem. Soc. 2019, 141, 11832.).

[0003] In radiochemistry, 18 F-labeled arylsulfonyl fluoride is usually synthesized from a sulfonyl chloride precursor (as shown below). 18 F Marked 18 F-fluoromethylsulfonyl fluoride and 18 F-fluoromethyl-d2sulfonyl fluoride process, there are by-products 18 F-toluenesulfonyl fluoride is generated ([1] TR Neal et al. J. Labelled Compd. Rad. 2005, 48, 557; [2] J. Wang et al J. Med. Chem. 2020, 63, 3381.). The sulfonyl chloride precursor can be obtained by direct chlorosulfonylation with chlorosulfonic acid (R. Cremlyn et al. Phosphorus Sulfur 1987, 31, 245.), or by sulfonylation with cyanuric acid chloride followed by chlorination (G. Blotny et al. Tetrahedron Lett. 2003, 44, 1499.).

[0004]

[0005] Using the Advion NanoTek microfluidic synthesis system, 18 F-labeled arylsulfonyl fluoride (as shown below) (L. Matesic et al. J. Org. Chem. 2013, 78, 11262.). Another microfluidic platform, called magnetic droplet microfluidics (MDM), synthesizes 18 F-labeled arylsulfonyl fluoride (SAFiel et al. ACS Appl. Mater. Interfaces 2015, 7, 12923.). Although these methods can shorten the reaction time and synthesize with excellent radiochemical yield (RCY) and specific activity (MA), 18 F product, sulfonyl chloride is still used as a labeling precursor, and the reaction is usually carried out by 18 F-fluoride anion is nucleophilic substitution. Few reports have been reported using readily available precursors to obtain 18 A new method for labeling arylsulfonyl fluoride with F. 18 The preparation of complex drug derivatives of F is difficult, which limits the use of SO2 18 F fragment probe for PET study.

[0006]

[0007] By using SO2 sources (DABSO) and 18 F-fluoride anion, directly construct C-SO2- from aromatic diazonium salts 18 F (X. Deng et al. Org. Lett. 2023, 25, 1969.). This method is compatible with a wide range of substrates, making it possible to 18 F fluorination synthesis and drug-related 18 F-labeled compounds, such as the anti-androgen drug flutamide, the anti-cancer drug neratinib intermediate, the anti-cancer drug cabozantinib intermediate and the antibacterial drug sulfadiazine. 18 F-labeled synthesis yielded two cysteine ​​residues 18 F labels the biomolecule.

[0008]

[0009] Contains bifunctional groups 18 F-labeled arylsulfonyl fluoride can successfully bind to biological molecules that are difficult to directly label. 18 F-labeled arylsulfonyl fluoride can react with 9-amino acid bombesin analog (BBN-ONH2) to generate [ 18 F]BBN-OX-MESIT-SO2F (JAH Inkster, et al. Chem.-Eur. J. 2012, 18, 11079.). In PBS (10% DMSO), this radiolabeled biomolecule has good stability at 37°C. However, in mouse serum, a large amount of it is converted into radiolabeled metabolites in less than 15 minutes. Therefore, in the construction of SO2 as a labeled synthon, 18 F compound, should be considered to contain SO2 18 Stability of biomolecules with F groups.

[0010]

[0011] also, 18 F-labeled sulfonyl fluoride can also be used as 18 F fluorination reagent. 2-Pyridinesulfonyl chloride and [ 18 F]KF / K 222 The reaction generates a fluorination reagent [ 18 F] PyFluor, using this SO2 18 F compounds can achieve alkyl C- 18Formation of F bonds (MK Nielsen, et al. J. Am. Chem. Soc. 2015, 137, 9571.).

[0012]

[0013] and 18 F-labeled arylsulfonyl fluorides are different. 18 F-labeled olefin sulfonyl fluorides show good reactivity and do not require additional highly reactive functional groups. 18 After F-labeled ethylenesulfonyl fluoride was first synthesized, it can be coupled to amino acids and proteins through Michael addition (B. Zhang, et al. J. Labelled Compd. Rad. 2018, 61, 847.). The synthesis was carried out in a microfluidic reactor system by 18 F / 19 The F isotope exchange method can be used to obtain 18 F-ethylenesulfonyl fluoride. Through Michael addition, 18 F-ethylenesulfonyl fluoride reacts with amino-containing compounds to produce 18 F-labeled alkylsulfonyl fluoride. 18 F-ethylenesulfonyl fluoride can also be used in 18 F shows good reactivity in fluorination reactions (B. Zhang, et al. Chem. - Eur. J. 2019, 25, 7613.). 18 The F fluorination strategy can be applied to a wide variety of substrates, including aromatic chlorine, nitro, ammonium, boronic acid, and iodonium salt compounds, as well as aliphatic sulfonate, p-nitrobenzenesulfonate, and triflate precursors. 18 The radiochemical yields are similar when compared to the F fluoride source. Although this method can indirectly obtain 18 F-labeled alkylsulfonyl fluoride, but needs to be prepared in advance 18 F's olefinsulfonyl fluoride is not directly 18 The preparation process of the PCR product obtained by F labeling is cumbersome and complicated, and the substrate range is greatly limited.

[0014]

[0015] Apart from 18 F-ethylenesulfonyl fluoride, another one is synthesized by three steps 18 A method for preparing F-labeled olefin sulfonyl fluoride (W. Zhang, et al. Org. Lett. 2022, 24, 4992.), comprising copper-catalyzed addition of Cl / SO2OCF2H to olefins, dechlorination and reaction of SO2OCF2H precursors 18 F mark.

[0016]

[0017] In summary, 18 F-labeled arylsulfonyl fluorides and alkenylsulfonyl fluorides have corresponding synthesis methods and are widely used. 18 There is no report on the alkyl fluoride sulfonylation method of F. Therefore, it is necessary to find a synthetic method with easy-to-obtain raw materials, simple preparation, and easy operation, and to develop a simple and efficient reaction condition and good substrate universality. 18 A new method for the labeling of alkylsulfonyl fluorides with F 18 F Application of alkylsulfonyl fluoride. Summary of the invention

[0018] The present invention aims to solve the existing 18 The limitation of F sulfonyl fluoride labeling method is that the current method can only synthesize 18 F-labeled aryl and alkenyl sulfonyl fluorides cannot be directly 18 F-labeled alkylsulfonyl fluoride. The object of the present invention is to provide a 18 F-labeled alkylsulfonyl fluoride compound and its synthesis method, which has simple reaction conditions, high efficiency and good substrate applicability, realizes 18 The synthesis of F-labeled alkylsulfonyl fluorides has readily available raw materials and simple operation.

[0019] In order to achieve the above purpose, this application adopts the following technical solutions:

[0020] The present invention provides a method based on a high-valent iodine (III) carboxylate. 18 The synthesis method of F-labeled alkylsulfonyl fluoride molecules in a solvent 18 In the presence of a F-fluorinating agent, a sulfur dioxide source and a copper salt, the compound shown in formula II is subjected to the following reaction to obtain a compound shown in formula I, which is the 18 F marks the alkylsulfonyl fluoride molecule;

[0021]

[0022] Among them, R is R 1 is phenyl, cyano, methoxy, nitro, methyl formate, bromine; R 2 It is phenyl.

[0023] In the above technical scheme, the compound shown in formula I is any of the following compounds:

[0024]

[0025] In the above technical solution, the 18The F-fluorination reagent is selected from 18 F-labeled tetrabutylammonium fluoride, K 18 F and 18 One or more of tetraethylammonium fluoride labeled with F.

[0026] In the above technical solution, the solvent is one or more of an alcohol solvent, an amide solvent, a sulfoxide solvent and a nitrile solvent.

[0027] In the above technical solution, the sulfur dioxide source is 1,4-diazabicyclo[2.2.2]octane-1,4-diacation-1,4-disulfate (DABSO) or sodium pyrosulfite.

[0028] In the above technical solution, the copper salt is cupric chloride, cupric acetate, cupric bromide, cuprous iodide or cuprous bromide.

[0029] In the above technical scheme, the compound shown in formula II and the 18 The molar ratio of F fluorination reagent is 200:1 to 3000:1;

[0030] The molar ratio of the compound represented by formula II to the sulfur dioxide source is 1:5 to 1:1;

[0031] The molar ratio of the compound shown in Formula II to the copper salt is 1:2 to 1:0.5.

[0032] In the above technical solution, the 18 The preparation method of F fluorination reagent is as follows: in water, H 18 F and base generation 18 F fluorination reagent, the base is one or more of tetra-n-butylammonium methanesulfonate, tetra-n-butylammonium trifluoromethanesulfonate, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, tetraethylammonium bicarbonate or potassium carbonate / 4,7,13,16,21,24-hexaoxo-1,10-diazabicyclo[8.8.8]hexacosane; the H 18 The radioactivity of F in water is 1 to 10 mCi.

[0033] The beneficial effects of the present invention are: the present invention solves the existing 18 In order to overcome the limitations of the F-sulfonyl fluoride labeling method, a new method with simple reaction conditions, high efficiency and good substrate applicability was developed to achieve the preparation of high-valent iodine (III) carboxylates. 18 F-labeled alkylsulfonyl fluoride has readily available raw materials and is simple to operate. DETAILED DESCRIPTION

[0034] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments. The present invention can be implemented in many different forms and should not be construed as being limited to the embodiments set forth herein. On the contrary, these embodiments are provided so that this disclosure will be thorough and complete, and the concept of the present invention will be fully conveyed to those skilled in the art, and the present invention will only be limited by the claims.

[0035] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0036] The term "pharmaceutically acceptable" means that salts, solvents, etc. are generally non-toxic, safe, and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.

[0037] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes an inorganic acid, and the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al. Pharmaceutical Salts, Journal of Pharmaceutical Science. 1977, 66, 1-19 or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0038] The term "alkyl" refers to a saturated, straight or branched, monovalent hydrocarbon radical having from one to twelve carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, and 1-octyl.

[0039] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms having at least one unsaturated site, i.e., a carbon-carbon sp2 double bond, and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples include, but are not limited to, vinyl, allyl.

[0040] The term "aryl" refers to any stable monocyclic or bicyclic carbon ring having up to 10 atoms in each ring, wherein the monocyclic or bicyclic ring is aromatic. Examples of the above aryl units include phenyl or naphthyl.

[0041] The present invention provides a method based on a high-valent iodine (III) carboxylate. 18 The synthesis method of F-labeled alkylsulfonyl fluoride molecules in a solvent 18 In the presence of a F-fluorinating agent, a sulfur dioxide source and a copper salt, the compound shown in formula II is subjected to the following reaction to obtain a compound shown in formula I, which is the compound of the present invention. 18 F marks the alkylsulfonyl fluoride molecule.

[0042]

[0043] Among them, R is R 1 is phenyl, cyano, methoxy, nitro, methyl formate, bromine; R 2 It is phenyl.

[0044] In the above technical scheme, the compound shown in formula I is any of the following compounds:

[0045]

[0046] As one example, 18 The F-fluorination reagent may be selected from 18 F-labeled tetrabutylammonium fluoride, K 18 F and 18 One or more of tetraethylammonium fluoride labeled with F.

[0047] As one embodiment, the solvent of the reaction can be one or more of an alcohol solvent, an amide solvent, a sulfoxide solvent and a nitrile solvent, such as an amide solvent, an amide solvent and an alcohol solvent, a nitrile solvent and an alcohol solvent, a sulfoxide solvent and an alcohol solvent, preferably a nitrile solvent. The amide solvent is, for example, N,N-dimethylformamide; the alcohol solvent is, for example, ethanol, tert-butyl alcohol or tri-amyl alcohol; the nitrile solvent is, for example, acetonitrile; the sulfoxide solvent is, for example, dimethyl sulfoxide.

[0048] As one example, the sulfur dioxide source may be 1,4-diazabicyclo[2.2.2]octane-1,4-diacation-1,4-disulfate (DABSO) or sodium pyrosulfite.

[0049] As one embodiment, the copper salt may be cupric chloride, cupric acetate, cupric bromide, cuprous iodide or cuprous bromide.

[0050] As one embodiment, when the reaction solvent is an amide solvent and an alcohol solvent, the volume ratio of the amide solvent to the alcohol solvent may be 1:0.33 to 1:3, preferably 1:3.

[0051] As one embodiment, when the reaction solvent is a nitrile solvent and an amide solvent, the volume ratio of the nitrile solvent to the amide solvent may be 1:0.33 to 1:3, preferably 1:3.

[0052] As one embodiment, when the reaction solvent is a sulfoxide solvent and an amide solvent, the volume ratio of the sulfoxide solvent to the amide solvent may be 1:0.33 to 1:3, preferably 1:3.

[0053] As one example, the compound shown in formula II and 18 The molar ratio of the F fluorinating agent may be 200:1 to 3000:1, for example 300:1, 600:1, 640:1, 700:1, 850:1, 1200:1, 1250:1 or 2500:1.

[0054] As one embodiment, the molar ratio of the compound shown in Formula II to the sulfur dioxide source can be 1:5 to 1:1, for example, 1:5, 1:4, 1:3, 1:2 or 1:1.

[0055] As one embodiment, the molar ratio of the compound shown in Formula II to the copper salt may be 1:2 to 1:0.5, for example, 1:2, 1:1.5, 1:1 or 1:0.5.

[0056] As one example, the concentration of the compound represented by Formula II in the solvent may be a conventional concentration for this type of reaction in the art, such as 0.005 mol / L to 0.1 mol / L, such as 0.033 mol / L or 0.066 mol / L.

[0057] As one embodiment, the reaction temperature can be a conventional temperature for such substitution reactions in the art, such as 50°C to 120°C, for example 60°C, 80°C, 90°C, 100°C, 110°C or 120°C.

[0058] As one embodiment, the reaction time may be a conventional time for such reactions in the art, such as 5 to 20 minutes, for example, 5 minutes, 10 minutes, 15 minutes or 20 minutes.

[0059] As one example, 18 The preparation method of F fluorination reagent is as follows: in water, H 18 F and base generation 18 F fluorination reagent.

[0060] Wherein: the base is one or more of tetra-n-butylammonium methanesulfonate, tetra-n-butylammonium trifluoromethanesulfonate, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, tetraethylammonium bicarbonate or potassium carbonate / 4,7,13,16,21,24-hexaoxo-1,10-diazabicyclo[8.8.8]hexacosane; the base is preferably tetra-n-butylammonium methanesulfonate. 18 The radioactivity of F in water may be 1 to 10 mCi, such as 2 mCi, 4 mCi, 6 mCi or 8 mCi.

[0061] Experimental Procedure

[0062] Using high-valent iodine (III) carboxylate (1a) as a substrate, it is converted to generate a compound of formula [ 18 The reaction conditions of the compound shown in F]2a were optimized. 18 The F anions are H produced by the cyclotron. 18 F aqueous solution (radioactivity intensity of 1 to 10 mCi), the type of base, the type of sulfur dioxide source, the type of copper salt, the reaction temperature and other reaction conditions are screened as shown in Table 1; the product is confirmed by radio-HPLC; RCC is the radiochemical conversion rate (the data shown are the average of three experiments), determined by radio-TLC.

[0063]

[0064] Table 1

[0065]

[0066]

[0067] The preparation of high-valent iodine (III) carboxylate 1 is as follows: 18 F]2 shown 18 F-labeled alkylsulfonyl fluoride, the specific operating conditions are as follows:

[0068]

[0069] The H generated by the cyclotron 18 The F aqueous solution (radioactivity intensity of 1-10 mCi) was eluted with tetrabutylmethanesulfonic acid (TBAOMs) acetonitrile / water solution in a reaction tube, and the water was removed to obtain dry 18 F-labeled tetrabutylammonium fluoride (TBA 18 F); then, trivalent iodine compound 1 (0.01 mmol), DABSO (0.02 mmol), copper chloride (0.01 mmol) and acetonitrile (0.3 mL) were added to the reaction tube in sequence. The reaction system was reacted at 110°C for 15 min, and then the reaction was terminated; the reaction liquid in the reaction tube was taken, and the product was confirmed by radioactive HPLC, and the product conversion rate was determined by radioactive TLC (the average value of three experiments was taken).

[0070] Example 1 18 Preparation of F-labeled 2-([1,1'-biphenyl]-4-yl)ethane-1-sulfonyl fluoride (Compound [ 18 F]2a)

[0071]

[0072] 18 F-labeled 2-([1,1'-biphenyl]-4-yl)ethane-1-sulfonyl fluoride 18 F): Radiochemical conversion rate determined by radioactive TCL was 80±2% (n=3). HPLC conditions: chromatographic column, Waters Symmetry C18 Column (4.6 mm×250 mm, 5 μm); mobile phase, 80% CH3CN, 20% H2O; flow rate, 1.0 mL / min, t R =5.1min. (Using the internal standard method for testing, compound [ 18 F]2a has the same peak position as compound 2a. The following compounds [ 18 F]2 also has the same peak position as its corresponding compound 2)

[0073] Example 2 18 Preparation of F-labeled 2-(4-cyanophenyl)ethane-1-sulfonyl fluoride (compound [ 18 F]2b)

[0074]

[0075] 18 F-labeled 2-(4-cyanophenyl)ethane-1-sulfonyl fluoride 18 F): Radioactive chemical conversion rate determined by radioactive TCL was 70±5% (n=3). HPLC conditions: chromatographic column, Waters Symmetry C18 Column (4.6 mm×250 mm, 5 μm); mobile phase, 60% CH3CN, 40% H2O; flow rate, 1.0 mL / min, t R =5.3min.

[0076] Example 3 18 Preparation of F-labeled 2-(4-methoxyphenyl)ethane-1-sulfonyl fluoride (compound [ 18 F]2c)

[0077]

[0078] 18 F-labeled 2-(4-methoxyphenyl)ethane-1-sulfonyl fluoride 18 F): Radioactive chemical conversion rate determined by radioactive TCL was 84±9% (n=3). HPLC conditions: chromatographic column, Waters Symmetry C18 Column (4.6 mm×250 mm, 5 μm); mobile phase, 70% CH3CN, 30% H2O; flow rate, 1.0 mL / min, t R =4.6min.

[0079] Example 4 18 Preparation of F-labeled 2-(4-nitrophenyl)ethane-1-sulfonyl fluoride (compound [ 18 F]2d)

[0080]

[0081] 18 F-labeled 2-(4-nitrophenyl)ethane-1-sulfonyl fluoride 18F): Radioactive chemical conversion rate determined by radioactive TCL was 36±7% (n=3). HPLC conditions: chromatographic column, Waters Symmetry C18 Column (4.6 mm×250 mm, 5 μm); mobile phase, 60% CH3CN, 40% H2O; flow rate, 1.0 mL / min, t R =5.8min.

[0082] Example 5 18 Preparation of F-labeled methyl 4-(2-((fluoro-18F)sulfonyl)ethyl)benzoate (Compound [ 18 F]2e)

[0083]

[0084] 18 F-labeled methyl 4-(2-((fluoro-18F)sulfonyl)ethyl)benzoate 18 F)sulfonyl)ethyl)benzoate): Radioactive chemical conversion rate determined by radioactive TCL was 34±5% (n=3). HPLC conditions: chromatographic column, Waters Symmetry C18 Column (4.6mm×250mm, 5μm); mobile phase, 60% CH3CN, 40% H2O; flow rate, 1.0mL / min, t R =5.8min.

[0085] Example 6 18 Preparation of F-labeled 2-(4-bromophenyl)ethane-1-sulfonyl fluoride (compound [ 18 F]2f)

[0086]

[0087] 18 F-labeled 2-(4-bromophenyl)ethane-1-sulfonylfluoride 18 F): Radioactive chemical conversion rate determined by radioactive TCL was 50±8% (n=3). HPLC conditions: chromatographic column, Waters Symmetry C18 Column (4.6 mm×250 mm, 5 μm); mobile phase, 70% CH3CN, 30% H2O; flow rate, 1.0 mL / min, t R =5.9min.

[0088] Example 7 18Preparation of F-labeled 3-([1,1'-biphenyl]-4-yl)propane-1-sulfonyl fluoride (Compound [ 18 F]2g)

[0089]

[0090] 18 F-labeled 3-([1,1'-biphenyl]-4-yl)propane-1-sulfonyl fluoride 18 F): Radioactive chemical conversion rate determined by radioactive TCL was 48±6% (n=3). HPLC conditions: chromatographic column, Waters Symmetry C18 Column (4.6 mm×250 mm, 5 μm); mobile phase, 80% CH3CN, 20% H2O; flow rate, 1.0 mL / min, t R =5.8min.

[0091] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A method based on a high-valent iodine (III) carboxylate 18 A method for synthesizing F-labeled alkylsulfonyl fluoride molecules, characterized in that: In solvent, 18 In the presence of a F-fluorinating agent, a sulfur dioxide source and a copper salt, the compound shown in formula II is subjected to the following reaction to obtain a compound shown in formula I, which is the 8 F marks the alkylsulfonyl fluoride molecule, Among them, R is R 1 is phenyl, cyano, methoxy, nitro, methyl formate, bromine; R 2 It is phenyl.

2. The synthesis method according to claim 1, characterized in that: The compound shown in formula I is any of the following compounds:

3. The synthesis method according to claim 1, characterized in that: Said 18 The F-fluorination reagent is selected from 18 F-labeled tetrabutylammonium fluoride, K 18 F and 18 One or more of tetraethylammonium fluoride labeled with F.

4. The synthesis method according to claim 1, characterized in that: The solvent is one or more of an alcohol solvent, an amide solvent, a sulfoxide solvent and a nitrile solvent.

5. The synthesis method according to claim 1, characterized in that: The sulfur dioxide source is 1,4-diazabicyclo[2.2.2]octane-1,4-diacation-1,4-disulfate (DABSO) or sodium pyrosulfite.

6. The synthesis method according to claim 1, characterized in that: The copper salt is cupric chloride, cupric acetate, cupric bromide, cuprous iodide or cuprous bromide.

7. The synthesis method according to claim 1, characterized in that: The compound as shown in formula II and 18 The molar ratio of F fluorination reagent is 200:1 to 3000:1; The molar ratio of the compound represented by formula II to the sulfur dioxide source is 1:5 to 1:1; The molar ratio of the compound shown in Formula II to the copper salt is 1:2 to 1:0.

5.

8. The synthesis method according to claim 1, characterized in that: Said 18 The preparation method of F fluorination reagent is as follows: in water, H 18 F and base generation 18 F fluorination reagent, the base is one or more of tetra-n-butylammonium methanesulfonate, tetra-n-butylammonium trifluoromethanesulfonate, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, tetraethylammonium bicarbonate or potassium carbonate / 4,7,13,16,21,24-hexaoxo-1,10-diazabicyclo[8.8.8]hexacosane; the H 18 The radioactivity of F in water is 1 to 10 mCi.

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