CN106866621B - Radiofluorination reagent, preparation and application - Google Patents
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Abstract
The invention relates to a radiofluorination reagent, a preparation method and an application thereof in synthesizing fluorinated oxazolidinone compounds. The prepared novel image diagnosis and treatment reagent can be used for carrying out nondestructive examination and disease treatment research on organisms, including nondestructive research on the metabolic process of the organisms and chemical and radiation treatment on diseases. We selected representative radioactive oxazolidinones to be injected into mice for PET imaging experiments and no bone resorption signal was observed due to defluorination of the tracer.
Description
Technical Field
The invention relates to the technical field of positron emission tomography, in particular to a radiofluorination reagent, a preparation method and an application thereof in synthesis of radiofluorination oxazolidinone compounds.
Background
Chemical, biological and physical properties of organic molecules can be significantly changed by introducing fluorine atoms, and thus organofluorine compounds are widely used in chemical industries such as medicine, agriculture and materials. In addition, 18F-labeled organic compounds are widely used as Positron Emission Tomography (PET) reagents in diagnostic medical and clinical pharmaceutical research. Therefore, there is an urgent need to develop new synthetic strategies that can facilitate the preparation of complex fluorochemicals. From a radiological point of view, the late fluorination strategy will greatly simplify the synthesis of complex radiotracers due to the short half-life of 18F.
The intramolecular fluorinated cyclization reaction of the compound containing the olefin structure can construct a ring structure with a plurality of new bonds including C-F bonds in one step, and the ring structure can be used as a general structural unit for constructing the aliphatic fluorine-containing bioactive compound. Among the reported synthetic methods, fluorinated cyclization using electrophilic fluorinating reagents is one of the most important methods. However, electrophilic fluorinating reagents are generally prepared from fluorine gas, which is costly to prepare, which limits their use in industry and laboratories, particularly in 18F radiolabelling. In addition, electrophilic fluorination reactions generally have a low specific activity, which limits their use in radiofluorination reactions. Recently, in the research of the fluorocyclization reaction, high-valent iodine reagents have been attracting much attention as a fluorine source because they exhibit unique reactivity and can be easily obtained from inexpensive fluorides. Although the reaction mechanism of such reactions is not well defined, most reports suggest ionic reaction pathways. In these reactions, alkyl-substituted olefins and styrene derivatives are used as effective nucleophiles, and fluorocyclization of substrates with electron-poor double bonds is not reported in the literature.
Disclosure of Invention
The object of the present invention is to develop a radiofluorination reagent and to apply this reagent to a silver-promoted cyclization/1, 2- (hetero) aryl migration/fluorination cascade for the preparation of radiofluorooxazolidinone compounds.
In order to achieve the purpose, the technical scheme provided by the invention is as follows:
the present invention provides a radiofluorination reagent based on a high-valence iodine compound, which comprises a high-valence iodine-chlorine compound and radioactivity18F]-TBAF reaction, which introduces radioactive fluorine atoms into high-valent iodofluoride compounds to produce novel radiofluorination reagents of the formula:
the invention also provides a preparation method of the radiofluorination reagent, which comprises the following steps: mixing a solution of a high-valent chloroiodine compound in acetonitrile with the solution of [ 2 ]18F]-TBAF in acetonitrile and reacting the reaction mixture at 60 ℃ for 10 minutes to make the novel radiofluorination reagent;
the reaction formula is as follows:
the invention uses the radioactive fluoridation reagent as an intermediate to carry out fluoridation reaction to obtain the radioactive fluoro oxazolidone compound, and the structural formula of the compound is as follows:
the concrete are the following eight compounds:
the invention adopts a one-pot method to realize radioactive fluorine cyclization reaction to obtain radioactive fluoro oxazolidinone compounds, and specifically comprises the following steps:
the method comprises the following steps: preparation of radioiodine fluoride intermediate 2
The higher chloroiodine compound 1 (6. mu. mol) was mixed in 25. mu.L of anhydrous MeCN, and the resulting solution was then mixed with [ [ solution ], [ solution ] ]18F]-TBAF was combined in MeCN and the reaction mixture was reacted at 60 ℃ for 10 minutes to give a radioiodinofluoride intermediate18F-2 is a radiofluorination reagent and is directly subjected to the next reaction without further purification;
step two: synthesis of radioactive fluoro-oxazolidinone compounds by fluorine cyclization reaction
An acetonitrile solution of an olefin precursor styrene or acrylamide-based compound 2 (6. mu. mol) and AgOTf salt (6. mu. mol) was added to the above reaction mixture, reacted at 80 ℃ for 10 minutes, and reacted with 1mL of 1:1(v/v) water: quenching MeCN, filtering by a Sep-Pak light alumina N column, and separating by HPLC to obtain corresponding radioactive fluoro oxazolidinone compounds;
the reaction formula is as follows:
the synthetic product comprises:
further, the HPLC conditions were: the amount of the Phenomenex is that the amount of the Phenomenex is less than the amount of the Phenomenex,5μm EVO C18a 250X 4.6mm liquid phase column; solvent A: 0.1% TFA/water; solvent B: 0.1% TFA/acetonitrile; 0 to 2 minutes: isocratic elution at 50% solvent B, 2 to 12 minutes, 50% to 95% solvent B; flow rate: 1mL/min, column temperature: 19 to 21 ℃.
The invention being aimed at verifying the synthesis18F-oxazolidin-2-one18F]-3a stability, for which we have performed in vivo and in vitro experiments, respectively. Will 218F]-3a was added to a phosphoric acid buffer solution having a pH of 7.5, and after 3 hours, analysis was conducted to find [ 2 ], [ 2 ]18F]-3a has little decomposition. Subsequently, we will use [ 2 ]18F]-3a was injected into the mice, and after 1h, PET/CT images of nude mice were obtained, and no bone resorption signal due to tracer defluorination was observed (see FIG. 1, FIG. 1 is PET/CT image of nude mice (PET image acquisition, injection of 0.1mCi of [18F ] 18F into nude mice via tail vein in 1 XPBS pH 7.5(300 μ L))]-3 a. At the post-injection time point, mice were anesthetized with isoflurane (2% oxygen) and then placed on an imaging stent and maintained at body temperature. Static PET/CT acquisitions are then achieved and reconstructed for analysis. ). These conclusions can be drawn to this class18F-labeled radioactive fluoro oxazolidinone compounds can be applied to the field of in vivo biomedical research.
Although fluorination reactions have been reported in a large number of documents, successful conversion of these methods to practical radiofluorination syntheses remains a challenge. Efficient radiofluorination synthesis presents the following difficulties: 1) only a few are available18A fluoride of F; 2) due to the fact that18The half-life of the F-radioisotope is 110 minutes, so the reaction must be completed quickly; 3) there is an increasing interest in nuclear radiation. Encouraged by the above experimental results, we attempted to radiofluorinate the olefin precursors (2a-c) by a one-pot synthesis method so as to be able to complete the reaction in the shortest time. However, the solution has not been successful in obtaining a composition containing18F-labeled cyclic compounds. This is probably because compound 10 and AgOTf generated AgCl, thereby inhibiting the progress of the radiofluorination reaction.
To solve this problem, we decided to use a one-pot two-step method for radiofluorination labeling, and to obtain appropriate reaction conditions by varying a range of reaction parameters. The radiofluorination reaction comprises two reaction processes, i.e.18Atomic exchange of F with Cl and fluorination process. We first varied the reaction temperature of the two processes and found that the fluorination temperature had an effect on the radiochemical yield (RCY) of the product18The F-Cl exchange temperature had little effect on the radiochemical yield (RCY). Therefore, the temperature of the molten metal is controlled,18F-Cl exchange temperature and18the F-fluorination temperatures were set to 60 ℃ and 80 ℃ respectively. In addition to the reaction temperature, the reaction solution concentration, the solvent and the silver salt species have a large influence on the reaction. In terms of the kind of solvent and the concentration of the reaction solution, it was successfully obtained only in an acetonitrile solution of the compound 10 (0.24. mu.M) at a high concentration18F-labeled cyclic compounds. When a reaction solution of low concentration or a DMSO/DMF mixed solvent system is used, the reaction cannot be successfully carried out. In addition, Ag salt is indispensable in the reaction, and AgSbF is found by optimizing conditions6Is the best silver salt and can obtain the highest radioactive yield. However, when AgSbF6When the amount of (A) is reduced to 0.5 or 0.05 equivalents, the fluorination reaction fails. To avoid additional introduction of the reaction19F, we replace AgSbF with AgOTf6As a catalyst for the reactionPrepared from various kinds of high radioactive purity18F-oxazolidin-2-one, the results are shown in Table 1.
Has the advantages that:
the present invention relates to a high-valence iodochlorine compound and a radioactive [ alpha ], [ beta18F]The method comprises the following steps of-TBAF reaction, introducing radioactive fluorine atoms into high-valence iodine fluorine compounds to prepare novel radioactive fluorine reagents, using the radioactive fluorine reagents as reaction intermediates and adopting a one-pot two-step method to quickly obtain unreported radioactive fluoro oxazolidone compounds, and using the compounds as PET tracers to perform nondestructive examination and disease treatment research on organisms, including nondestructive research on the metabolic process of the organisms and chemical and radiation treatment on diseases.
Drawings
FIG. 1 is a decay-corrected micro PET/CT image of a nude mouse vein scan 1 hour after injection of [18F ] -3 a. A: coronal image, B: sagittal image);
FIG. 2 shows purified [ 2 ] coinjected with the standard sample (3a) in the absence of a corresponding structure18F]-HPLC UV-chromatogram (upper panel) and radiochromatogram (lower panel) of the solution of 3 a;
FIG. 3 is the purified [ 2 ] coinjected with the standard sample (3b)18F]-HPLC UV-chromatogram (upper panel) and radiochromatogram (lower panel) of the 3b solution;
FIG. 4 is the purified [ 2 ] coinjected with the standard sample (3c)18F]-HPLC UV-chromatogram (upper panel) and radiochromatograms (lower panel) of the 3c solution;
FIG. 5 is the purified [ 2 ] coinjected with the standard sample (3d)18F]-HPLC UV-chromatogram (upper panel) and radiochromatogram (lower panel) of the 3d solution;
FIG. 6 is the purified [ 2 ] coinjected with the standard sample (3e)18F]-HPLC UV-chromatogram (upper panel) and radiochromatogram (lower panel) of the 3e solution;
FIG. 7 is the purified [ 2 ] coinjected with the standard sample (3f)18F]-HPLC UV-chromatogram (upper panel) and radiochromatogram (lower panel) of the 3f solution;
FIG. 8 is the purified [ 2 ] coinjected with the standard sample (3g)18F]-HPLC UV-chromatogram (upper panel) and radiochromatogram (lower panel) of 3g of solution.
Detailed Description
The present invention will be further described with reference to the following specific examples.
Example 1
Preparation of a standard sample: synthesis of fluoro-oxazolidone compounds by catalyzing fluorine cyclization reaction
Substrate 2, the desired amount of Compound 1(1.5 equiv.), AgSbF6(0.1 eq) and DCM were charged into the reaction flask. The mixture was stirred at 20-60 ℃ and the progress of the reaction was monitored by TLC. When the reaction is observed to be finished, the reaction mixture is concentrated to be dry, and oxazolidinone compounds 3 are obtained by extraction and separation through column chromatography, wherein the oxazolidinone compounds are eight compounds in the following 3 a-3 h.
5-benzyl-5-fluoro-3- (4-methoxyphenyl) oxazolidine-2-one (3a)
NMR(376MHz,CDCl3)δ-92.52ppm.13C NMR(101MHz,CDCl3)δ156.96,152.32(d,J＝1.7Hz),132.23(d,J＝4.2Hz),130.37,130.20,128.95,128.03,120.68,114.49,112.31(d,J＝233.1Hz),55.58,54.10(d,J＝30.6Hz),42.03(d,J＝29.1Hz)ppm.IR(KBr)ν3005,2990,1771,1515,1456,1339,1275,1360,1080,828,764,750,704.HRMS(ESI)m/z calcd.forC17H16FNNaO3 +(M+Na+):324.1006,Found:324.1002.
5-benzyl-5-fluoro-3- (p-tolyl) oxazolidine-2-one (3b)
152.13,134.70,132.25(d,J＝4.3Hz),130.42,129.86,129.04,128.11,118.69,112.31(d,J＝233.1Hz),53.77(d,J＝30.7Hz),42.15(d,J＝29.1Hz),20.90ppm.IR(KBr)ν3033,3006,2986,2921,2851,1774,1517,1468,1404,1335,1275,1261,1080,976,810,764,750,702.HRMS(ESI)m/z calcd.for C17H16FNNaO2 +(M+Na+):308.1057,Found:308.1045.
5-benzyl-3- (4-chlorophenyl) -5-fluorooxazolidine-2-one (3c)
130.39,130.18,129.36,129.08,128.20,119.66,112.24(d,J＝233.9Hz),53.51(d,J＝30.8Hz),42.03(d,J＝28.9Hz)ppm.IR(KBr)ν3005,2986,1771,1496,1338,1275,1261,1094,1080,978,826,764,750,704.HRMS(ESI)m/z calcd.for C16H14ClFNO2 +(M+H+):306.0692,Found:306.0688.
2- (5-benzyl-5-fluoro-2-oxooxazolidin-3-yl) -3-phenylpropionic acid ethyl ester (3d)
(3H)]ppm.19F NMR(376MHz,CDCl3)δ-92.12,-94.35ppm.13C NMR(101MHz,CDCl3)δ169.95,169.81,155.15(d,J＝1.5Hz),154.92(d,J＝1.4Hz),135.71,135.63,132.33(d,J＝3.2Hz),132.31(d,J＝4.7Hz),130.38,130.30,128.92,128.89,128.85,128.81,128.69,128.54,127.89,127.85,127.36,127.29,113.42(d,J＝234.4Hz),113.38(d,J＝234.5Hz),61.92,61.83,56.63,56.54,50.60(d,J＝29.6Hz),50.48(d,J＝30.7Hz),42.18(d,J＝28.9Hz),42.06(d,J＝29.5Hz),35.48,35.18,14.14ppm.IR(KBr)ν3005,2989,1779,1738,1456,1275,1261,1031,897,765,750,703.HRMS(ESI)m/z calcd.for C21H22FNNaO4 +(M+Na+):394.1425,Found:394.1425.
5-fluoro-5- (4-fluorobenzyl) -3- (4-methoxyphenyl) oxazolidine-2-one (3e)
Hz),130.13,127.96(t,J＝3.7Hz),120.72,115.93(d,J＝21.4Hz),114.56,112.07(dd,J＝233.0,1.2Hz),55.63,54.19(d,J＝30.6Hz),41.32(d,J＝29.6Hz)ppm.IR(KBr)ν3008,2992,2920,2845,1771,1760,1512,1275,1258,1080,826,764,750.HRMS(ESI)m/zcalcd.for C17H16F2NO3 +(M+H+):320.1093,Found:320.1091.
5-fluoro-5- (4-methoxybenzyl) -3- (4-methoxyphenyl) oxazolidine-2-one (3f)
157.00,152.40,131.46,130.31,124.19(d,J＝4.6Hz),120.69,114.55,114.43,112.49(d,J＝232.9Hz),55.64,55.41,54.04(d,J＝30.6Hz),41.23(d,J＝29.4Hz)ppm.IR(KBr)ν3005,2984,1771,1515,1456,1339,1275,1260,764,750.HRMS(ESI)m/z calcd.forC18H18FNNaO4 +(M+Na+):354.1112,Found:354.1104.
5-fluoro-3- (4-methoxyphenyl) -5- (thiophen-3-ylmethyl) oxazolidine-2-one (3g)
7.38–7.29(m,3H),7.23(d,J＝1.8Hz,1H),7.08(d,J＝4.9Hz,1H),6.91–6.83(m,2H),4.01,3.92(ABq,J＝10.9Hz,1H),3.93,3.87(ABq,J＝10.9Hz,1H),3.78(s,3H),3.49–3.32(m,2H)ppm.19F NMR(376MHz,CDCl3)δ-92.91ppm.13C NMR(101MHz,CDCl3)δ157.00,152.27,132.24(d,J＝4.4Hz),130.18,128.99,126.64,124.68,120.72,114.53,112.05(d,J＝232.9Hz),55.62,54.19(d,J＝30.5Hz),36.79(d,J＝30.7Hz)ppm.IR(KBr)ν2920,2849,1771,1646,1515,1469,1338,1276,1255,1090,1060,830,764,750.HRMS(ESI)m/z calcd.forC15H15FNO3S+(M+H+):308.0751,Found:308.0742.
5-fluoro-3- (4-methoxyphenyl) -5- (thiophen-2-ylmethyl) oxazolidine-2-one (3h)
MHz,CDCl3)δ-93.23ppm.13C NMR(101MHz,CDCl3)δ157.10,152.14,133.14(d,J＝5.2Hz),130.17,128.56,127.47,126.20,120.82,114.59,111.68(d,J＝233.3Hz),55.65,54.00(d,J＝30.4Hz),36.57(d,J＝32.4Hz)ppm.IR(KBr)ν3006,2920,2849,1775,1646,1515,1469,1338,1275,1257,975,829,764,750.HRMS(ESI)m/z calcd.for C15H15FNO3S+(M+H+):308.0751,Found:308.0747.
Example 2
The preparation of the radiofluorination reagent and the radiofluorooxazolidinone compound comprises the following steps:
the radioactive fluorine cyclization reaction is realized by adopting a one-pot method to obtain the radioactive fluoro oxazolidinone compound
Step one, the higher chloro-iodine compound 1 (6. mu. mol) is mixed in 25. mu.L of anhydrous MeCN, and the resulting solution is then mixed with 218F]-TBAF was combined in MeCN and the reaction mixture was reacted at 60 ℃ for 10 minutes to give a radioiodinofluoride intermediate18F-2, the radiofluorinating reagent, was carried on to the next reaction without further purification.
Step two, an acetonitrile solution of an olefin precursor styrene or acrylamide-based compound 2 (6. mu. mol) and AgOTf salt (6. mu. mol) was added to the above reaction mixture, reacted at 80 ℃ for 10 minutes, and reacted with 1mL of 1:1(v/v) water: MeCN quenching, through Sep-Pak light alumina N column filtration. Then by HPLC conditions: the amount of the Phenomenex is that the amount of the Phenomenex is less than the amount of the Phenomenex,5μm EVO C18250X 4.6mm liquid phase column. Solvent A: 0.1% TFA/water; solvent B: 0.1% TFA/acetonitrile; 0 to 2 minutes: isocratic elution at 50% solvent B, 2 to 12 minutes, 50% to 95% solvent B. Flow rate: 1mL/min, column temperature: 19 to 21 ℃) to obtain the corresponding radioactive fluoro oxazolidinone compounds. Product identification was judged by comparing the retention time of the control standards in the HPLC. (see fig. 2 to 8)
Claims (3)
1. A preparation method of radiofluorination reagent based on high-valence iodine compounds is characterized in that: mixing a solution of a high-valent chloroiodine compound in acetonitrile with the solution of [ 2 ]18F]-TBAF in acetonitrile and reacting the reaction mixture at 60 ℃ for 10 minutes to make the novel radiofluorination reagent;
the reaction formula is as follows:
2. a method of preparing a class of radiofluoro-oxazolidinone compounds using the radiofluorination reagent of claim 1, wherein the compound has the formula:
the concrete are the following eight compounds:
the preparation method adopts a one-pot method to realize radioactive fluorine cyclization reaction to obtain the radioactive fluoro oxazolidinone compound, and specifically comprises the following steps:
the method comprises the following steps: preparation of radioiodine fluoride intermediate 2
The higher chloro-iodine compound 1 was mixed in anhydrous MeCN, and the resulting solution was then mixed with [18F ]]-TBAF was combined in MeCN and the reaction mixture was reacted at 60 ℃ for 10 minutes to give a radioiodinofluoride intermediate18F-2 is a radiofluorination reagent and is directly subjected to the next reaction without further purification;
step two: synthesis of radioactive fluoro-oxazolidinone compounds by fluorine cyclization reaction
Olefin precursor styrene or acrylamide compound 2 and an acetonitrile solution of AgOTf salt are added to the above reaction mixture, reacted at 80 ℃ for 10 minutes, and reacted with 1mL of water in a volume ratio of 1: quenching MeCN, filtering by a Sep-Pak light alumina N column, and separating by HPLC to obtain corresponding radioactive fluoro oxazolidinone compounds; the reaction formula is as follows:
wherein, the structural general formula of the compound 2 is as follows:
3. the process for preparing a class of radiofluorooxazolidinones according to claim 2, wherein: the HPLC conditions are as follows: the amount of the Phenomenex is that the amount of the Phenomenex is less than the amount of the Phenomenex,5μm EVO C18a 250X 4.6mm liquid phase column; solvent A: 0.1% TFA/water; solvent B: 0.1% TFA/acetonitrile; 0 to 2 minutes: isocratic elution at 50% solvent B, 2 to 12 minutes, 50% to 95% solvent B; flow rate: 1mL/min, column temperature: 19 to 21 ℃.
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| One-Pot Synthesis of Hypervalent Iodine Reagents for Electrophilic Trifluoromethylation;Matousek, Vaclav;等，;《Journal of Organic Chemistry》;20130604;第78卷(第13期);第6763-6768页 * |
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