CN117820344A - Fluorinated aza-BODIPY derivative and synthetic method and application thereof - Google Patents
Fluorinated aza-BODIPY derivative and synthetic method and application thereof Download PDFInfo
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- CN117820344A CN117820344A CN202311780497.9A CN202311780497A CN117820344A CN 117820344 A CN117820344 A CN 117820344A CN 202311780497 A CN202311780497 A CN 202311780497A CN 117820344 A CN117820344 A CN 117820344A
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- 238000010189 synthetic method Methods 0.000 title description 2
- 238000000799 fluorescence microscopy Methods 0.000 claims abstract description 19
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- 238000001308 synthesis method Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 127
- 238000006243 chemical reaction Methods 0.000 claims description 88
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 26
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 22
- 230000002194 synthesizing effect Effects 0.000 claims description 13
- 230000035484 reaction time Effects 0.000 claims description 12
- XZNOAVNRSFURIR-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-ol Chemical compound FC(F)(F)C(O)(C(F)(F)F)C(F)(F)F XZNOAVNRSFURIR-UHFFFAOYSA-N 0.000 claims description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001424 substituent group Chemical group 0.000 claims description 6
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- 239000002872 contrast media Substances 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
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- 238000006482 condensation reaction Methods 0.000 claims description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 4
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
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Abstract
The invention discloses a fluorinated aza-BODIPY derivative, a synthesis method and application thereof, which are symmetrically introduced into aza-BODIPY moleculesPerfluoro-t-butoxy (PFTBO) groups having 9 equivalent fluorine atoms, can be performed not only with high sensitivity 19 F MRI imaging, and the large-volume PFTBO group can effectively relieve aggregation of fluorinated aza-BODIPY molecules and improve photodynamic therapy (PDT) and fluorescence imaging (FLI) capabilities. In addition, by virtue of the strong hydrophobicity and lipophobicity of PFTBO, fluorinated aza-BODIPY is easily anchored on the cell membrane during cell uptake, thus realizing cell membrane targeting. Therefore, the PFTBO group is introduced into the aza-BODIPY molecule, thereby effectively realizing the targeting of tumor cell membranes 19 Fmri and NIR FLI bimodal imaging guided photothermal and photodynamic therapy.
Description
Technical Field
The invention belongs to the technical field of magnetic resonance imaging technology and molecular diagnosis and treatment agents, and particularly relates to a fluorinated aza-BODIPY derivative, and a synthesis method and application thereof.
Background
Today, where modern medicine is highly developed, cancer is still one of the major diseases seriously endangering human life and health, but treatment means for cancer are limited, and common cancer treatment methods mainly comprise: surgery, radiation therapy, chemotherapy, and the like. However, the above methods have obvious drawbacks, such as difficulty in completely resecting all lesions and influence on the functions of the patient's physical organs when resecting the lesions; the radiotherapy method is only effective on part of tumors with high radiotherapy sensitivity; chemotherapy is not specific and has serious toxic side effects (Miller, K.D.; nogueira, L.; devasia, T.et al.2022CA: cancer J.Clin.2022,72, 409-436). Therefore, the development of the new technology and method for diagnosing and treating cancer in time, accurately and efficiently is particularly important.
In recent years, as research is advanced, many innovative methods such as immunotherapy, phototherapy, and chemo-kinetic treatment have been greatly advanced in the treatment of tumors. Among them, phototherapy of tumors is receiving increasing attention due to advantages of high temporal-spatial selectivity, negligible invasiveness, no drug resistance, and the like. As an emerging treatment approach, PDT delivers and accumulates Photosensitizers (PSs) to in vivo tumor tissue by active or passive targeting strategies, locally irradiating tumor tissue with light of specific wavelengths to excite PSs with in vivo O 2 A photochemical reaction occurs, generating reactive oxygen species (ROS, e.g. singlet oxygen 1 O2, superoxide anion O 2– And hydroxyl radical OH, etc.), thereby destroying tumor cells to induce cell death (phar, t.c.; nguyen, V.—N.; choi, y.et al chem.Rev.2021,121, 13454-13619). Thus, the absorption and emission wavelengths of PSs and the efficiency of ROS production will greatly affect the effectiveness of PDT, and designing and synthesizing PSs with excellent properties plays a significant role in enhancing PDT effectiveness.
However, the lack of high performance and functionalized PSs severely hampers the development of PDT: on the one hand, in solid tumors, oxygen supply in the tissue is insufficient due to rapid growth of tumor tissue, and oxygen consumption process of PDT further worsens the hypoxic condition of the tumor, thereby limiting the efficacy of PDT (Du, J.; shi, T.; long, S.et al Coord. Chem. Rev.2021,427, 213604); on the other hand, complex Tumor Microenvironments (TMEs), abnormal vasculature and extracellular matrix also prevent the delivery of PSs to cancer cells (Junttila, m.r.; de Sauvage, f.j. Nature 2013,501,346-354). In addition, in the case of the optical fiber, 1 O 2 shorter half-lives (0.03-0.18 ms) and diffusion distances (10-20 nm) require more accurate delivery of PSs to target cancer cells, maximizing the efficacy of space-time controlled PDT (Niede, M.; patterson, M.S.; wilson, B.C.Photohem.Photobiol. 2002,75, 382-391). Therefore, various PSs targeting different organelles such as mitochondria, cell membranes, endoplasmic reticulum and the like are applied to PDT, and the curative effect of PDT is obviously improved while the dosage of a drug is reduced (Wang, R.; li, X.; yoon, J.ACS appl. Mater. Interfaces 2021,13,19543-19571). Among them, since cell membrane plays an important role in maintaining cell integrity and regulating the exchange of substances inside and outside the cell, development of PSs targeting cell membranes can directly oxidize phospholipids to destroy cell membranes, can avoid complex endocytic processes and inefficient PDT processes in tumor cells, and is an effective measure for inducing cell death. In particular, PSs with near infrared absorption and emission wavelengths sensitively realize the diagnosis and treatment integrated process of tumors through fluorescence imaging (FLI), and are paid attention to.
Although FLI is a disease diagnostic modality with many advantages of high sensitivity, multiple markers, high stability, real-time feedback, and low cost, the difference in tissue penetration depth greatly limits its clinical application. In contrast, magnetic Resonance Imaging (MRI) techniques without ionizing radiation and tissue depth limitations can not only accommodate imagingThe parameters are multiple, the imaging mode is flexible, the resolution of soft tissues is high, rich information can be provided, and excellent advantage complementation is formed with FLI. In particular, without background interference 19 FMRI is well suited for in vivo tracking and quantitative investigation of specific molecular, cellular and physiological pathological processes, etc.
A great deal of research shows that the perfluorocarbon compound (PFC) not only has excellent oxygen carrying capacity, but also can effectively relieve the hypoxia state of tumor cells (Yang, Y.; liu, Y.; jiang, Y.mol. Pharmaceuticals 2023,20,3254-3277), and the special property of the perfluorocarbon compound also obviously prolongs the dissolution of the perfluorocarbon compound 1 The half-life of O2 is very beneficial for improving the efficacy of PDT (Cheng, Y.; cheng, H.; jiang, C.et al Nat. Commun.2015,6,8785). Recently, it has been reported that the use of fluorinated PSs achieves quantifiable deep tumor tissue 19 F MRI in vivo tracer and visualization self-oxygen-supplying PDT procedure (Li, Y.; zhang, J.; zhu, L.et al adv. Healthcare Mater.2023, 2300941). Therefore, the development of novel fluorinated PSs with near infrared absorption and emission capabilities, cell membrane targeting capabilities, and capable of alleviating tumor hypoxia conditions has become an important direction to achieve efficient tumor PDT treatments.
Disclosure of Invention
Based on the prior art, the invention provides a fluorinated aza-BODIPY derivative, a synthesis method and application thereof, and the invention introduces perfluoro-tert-butoxy (PFTBO) groups with 9 equivalent fluorine into aza-BODIPY molecules, thereby not only effectively performing high sensitivity 19 F MRI imaging, and the large volume of PFTBO groups can effectively relieve aggregation of fluorinated aza-BODIPY molecules, thereby improving PDT and FLI capabilities. In addition, by virtue of the strong hydrophobicity and lipophobicity of PFTBO, fluorinated aza-BODIPY is easily anchored on the cell membrane during cell uptake, thus realizing cell membrane targeting. Thus, the PFTBO group is introduced into the aza-BODIPY molecule to realize the cell membrane targeting capability, NIR FLI and NIR FLI on tumor cells 19 FMRI bimodal imaging guided photothermal and photodynamic therapy can effectively improve PDT efficacy of cancer.
The technical scheme adopted for achieving the purposes of the invention is as follows:
a fluorinated aza-BODIPY derivative has the following structural formula:
wherein R is 1 、R 2 Methoxy, trifluoromethyl or (CH) 2 ) n OC(CF 3 ) 3 Equal substituent, R 1 、R 2 The number of (2) is not less than 1, and R 1 、R 2 At least one of them is (CH 2 ) n OC(CF 3 ) 3 N is a natural number of not more than 20, and F is fluorine-19.
A synthesis method of fluorinated aza-BODIPY derivative comprises the following steps:
s1, a structural general formula of the compound shown in the formula (I) is as follows:
wherein R is 2 Is methoxy, trifluoromethyl or (CH) 2 ) n OC(CF 3 ) 3 Equal substituent, R 2 Not less than 1, n is a natural number not greater than 20;
when R is 2 Is (CH) 2 ) n OC(CF 3 ) 3 In this case, the method for synthesizing the compound of formula (I) is as follows:
in the presence of a catalyst, the compound of the formula (II) and a brominating reagent undergo bromination reaction to generate a compound of the formula (III), wherein the reaction formula is as follows:
nucleophilic substitution reaction of the compound of formula (III) with a metal salt of perfluoro-tert-butanol under nitrogen atmosphere to produce a compound of formula (I) having the following reaction formula:
s2, the structural general formula of the compound shown in the formula (IV) is as follows:
wherein R is 1 Is methoxy or (CH) 2 ) n OC(CF 3 ) 3 Equal substituent, R 1 Not less than 1, n is a natural number not greater than 20;
when R is 1 Is (CH) 2 ) n OC(CF 3 ) 3 In this case, the method for synthesizing the compound of formula (IV) is as follows:
nucleophilic substitution reaction of the compound of formula (V) with a metal salt of perfluoro-tert-butanol under nitrogen atmosphere to produce a compound of formula (IV) having the following reaction formula:
s3, under alkaline conditions, carrying out aldol condensation reaction on the compound of the formula (I) and the compound of the formula (IV) to generate a compound of the formula (VI), wherein the reaction formula is as follows:
s4, carrying out Michael addition reaction on the compound of the formula (VI) and nitromethane under alkaline conditions to generate a compound of the formula (VII), wherein the reaction formula is as follows:
s5, carrying out condensation reaction on the compound of the formula (VII) in the presence of ammonium acetate and in the dark to generate the compound of the formula (VIII), wherein the reaction formula is as follows:
s6, under the condition of nitrogen atmosphere and in the presence of alkali, the compound of the formula (VIII) is directly subjected to complexation reaction with boron trifluoride diethyl ether to generate the fluorinated aza-BODIPY derivative, wherein the reaction formula is as follows:
further, the brominating reagent is N-bromosuccinimide, and the catalyst is azodiisobutyronitrile.
Further, in the bromination reaction, the reaction temperature is 80-100 ℃, the reaction time is 4-24h, and the mol ratio of the compound of the formula (II), the brominating reagent and the catalyst is 1.0:1.0-2.0:0.2.
Further, the perfluoro-tert-butanol metal salt is potassium salt or sodium salt of perfluoro-tert-butanol, in the nucleophilic substitution reaction of the steps S1 and S2, the reaction temperature is normal temperature, the reaction time is 12-24h, and the molar ratio of the compound of the formula (III) or the compound of the formula (V) to perfluoro-tert-butoxide is 1.0:1.0-2.0.
Further, the base used in the steps S3 and S4 is sodium hydroxide or potassium hydroxide, and the base used in the step S6 is N, N-diisopropylethylamine.
Further, in the aldol condensation reaction, the reaction temperature is normal temperature, the reaction time is 0.5-24h, and the molar ratio of the compound of the formula (I), the compound of the formula (IV) and the alkali is 1.0:1.0:2.0-3.0.
Further, in the Michael addition reaction, the reaction temperature is 80-100 ℃, the reaction time is 4-12h, and the molar ratio of the compound of the formula (VI), nitromethane and alkali is 1.0:20.0-30.0:0.2.
Further, in the condensation reaction, the reaction temperature is 115-120 ℃, the reaction time is 4-12h, and the molar ratio of the (VII) compound to the ammonium acetate is 1.0:20.0-40.0.
Further, in the complexing reaction, the reaction temperature is 25-50 ℃, the reaction time is 12-24 hours, and the molar ratio of the compound of the formula (VIII), the alkali and the boron trifluoride diethyl etherate is 1.0:20.0-30.0:20.0-30.0.
Use of fluorinated aza-BODIPY derivatives for the preparation of bimodal contrast agents.
Further, the bimodal imaging agent is a fluorescence imaging contrast agent and a fluorine-19 magnetic resonance imaging contrast agent.
Use of fluorinated aza-BODIPY derivatives for the preparation of photothermal and photodynamic therapeutic drugs targeting tumor cell membranes. Compared with the prior art, the invention has the advantages that:
1. the aza-BODIPY derivative of the invention consists of two parts: the first part is an aza-BODIPY molecule, the second part is a PFTBO group serving as a fluorine signal source, and the derivative not only maintains the excellent fluorescence, photo-thermal and ROS generating capacity of the aza-BODIPY, can realize excellent fluorescence imaging capacity, but also is connected with the PFTBO serving as the fluorine-19 signal source through a stable covalent bond to realize excellent fluorescence imaging capacity 19 F MRI imaging capability.
2. The aza-BODIPY derivative provided by the invention contains 18 or 36 magnetically equivalent fluorine-19, can generate a single and strong stable fluorine signal, avoids the problems of fluorine signal splitting or low fluorine atom utilization rate and the like, and can obtain a fluorine-19 magnetic resonance spectrum or imaging with higher sensitivity.
3. The aza-BODIPY derivative has better biocompatibility and provides guarantee for higher dose use safety in organisms.
4. The aza-BODIPY derivative of the invention has excellent FLI and FLI 19 Fmri bimodal imaging capability, photothermal and ROS generating capability (photosensitizers) to achieve FLI and targeting of tumor cell membranes 19 Fmri bimodal imaging guided PTT and PDT capabilities.
5. The aza-BODIPY derivative of the invention has the capability of selectively targeting cell membranes, and can improve PDT curative effect of cancer to a greater extent.
6. The synthesis route of the aza-BODIPY derivative is reasonable in design, mild in synthesis condition and simple in operation.
7. In the concentration range of 2.2mM-0.07mM, the fluorine signal of the aza-BODIPY derivative of the invention has good linear relation with the concentration, and the linear relation is convenient for realizing quantitative monitoring of the distribution of the derivative in a living body.
Drawings
FIG. 1 is a graph of the photothermal conversion of the aza-BODIPY derivatives prepared in examples 1-9.
FIG. 2 is a graph of the active oxygen generating capacity of the aza-BODIPY derivatives prepared in examples 1-9.
FIG. 3 shows the aza-BODIPY derivatives prepared in example 8 19 F NMR spectrum.
FIG. 4 shows the concentration of fluorine in the aza-BODIPY derivatives prepared in example 8 19 F MRI imaging map.
FIG. 5 is a graph of fluorine concentration versus imaging intensity for the aza-BODIPY derivatives prepared in example 8.
FIG. 6 is a fluorescence imaging of the aza-BODIPY derivatives prepared in example 8.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1 (Compound 9 a)
1. Synthesis of compound 4 a:
4-bromomethylbenzaldehyde (4.42 g,22.21 mmol) and KOC (CF) were reacted under nitrogen 3 ) 3 (7.31 g,26.66 mmol) in anhydrous DMF at room temperature for 24 hours, after completion of the reaction, water quench reaction was added, then DMF was removed by washing with copious amounts of water, and the organic phase was extracted with anhydrous Na 2 SO 4 After drying and distillation under reduced pressure, the residue was purified by column chromatography (eluent PE and EA) to give 4a (9.98 g) as a white solid in 91% yield.
1 H NMR(400MHz,CDCl 3 )δ10.03(s,1H),7.91(d,J＝8.2Hz,2H),7.51(d,J＝8.0Hz,2H),5.12(s,2H).
19 F NMR(376MHz,CDCl 3 )δ–70.25.
13 C NMR(101MHz,CDCl 3 )δ191.7,141.3,136.5,130.0,127.6,120.3(q,J＝293.7,Hz),80.9–78.9(m),70.4.
The structural formula of compound 4a is as follows:
2. synthesis of compound 6 a:
p-methoxyacetophenone (1.27 g,8.47 mmol) and KOH (1.42 g,25.41 mmol) were dissolved in 90mL of ethanol, after stirring for 5min, compound 4a (3.00 g,8.47 mmol) was added, and after completion of the reaction, the system was neutralized to neutrality by addition of 2M dilute hydrochloric acid, a large amount of pale yellow solid was precipitated, after completion of the precipitation, the precipitate was filtered, collected, and recrystallized from a mixed solution of EA and EtOH to give pale yellow solid 6a (3.77 g) in 91% yield.
1 H NMR(400MHz,CDCl 3 )δ8.09–7.99(m,2H),7.79(d,J＝15.7Hz,1H),7.66(d,J＝8.3Hz,2H),7.56(d,J＝15.6Hz,1H),7.39(d,J＝8.3Hz,2H),7.04–6.95(m,2H),5.07(s,2H),3.89(s,3H)。
19 F NMR(376MHz,CDCl 3 )δ–73.33。
13 C NMR(151MHz,CDCl 3 )δ188.5,163.6,143.0,136.9,135.6,131.0,130.9,128.6,128.1,122.6,120.4(q,J＝293.3Hz),113.9,81.3–78.8(m),70.8,55.5。
The structural formula of compound 6a is as follows:
3. synthesis of compound 7 a:
compound 6a (3.77 g,7.75 mmol), meNO 2 (9.46 g,155.03 mmol) and KOH (87 mg,1.55 mmol) were dissolved in a suitable amount of EtOH and reacted at 80℃for 5h, after which the reaction was completed, cooled to room temperature, the system was then neutralized to neutrality by the addition of 2M dilute hydrochloric acid, followed by extraction with DCM and the organic phase was taken up in anhydrous Na 2 SO 4 Drying, distilling off the solvent under reduced pressure, separating the residue by column chromatography (eluent PE and EA) to give compound 7a (4.02 g) as a pale yellow oil,the yield was 94%.
1 H NMR(400MHz,CDCl 3 )δ7.94–7.86(m,2H),7.32(s,4H),6.96–6.88(m,2H),5.00(s,2H),4.84(dd,J＝12.6,6.4Hz,1H),4.68(dd,J＝12.6,8.3Hz,1H),4.20–4.27(m,1H),3.86(s,3H),3.47–3.31(m,2H)。
19 F NMR(376MHz,CDCl 3 )δ–73.30.
13 C NMR(151MHz,CDCl 3 )δ195.2,164.0,140.2,134.5,130.5,129.5,128.4,128.0,120.4(q,J＝292.9Hz),114.0,80.6–79.7(m),79.6,70.9,55.6,41.2,39.2。
The structural formula of compound 7a is as follows:
4. synthesis of compound 8 a:
under dark conditions, compound 7a (0.96 g,1.75 mmol) and NH were taken up 4 OAc (5.40 g,70.05 mmol) is reacted at 120℃for 5h, after the reaction is completed, a large amount of water is added to wash out excess NH 4 OAc followed by three extractions with DCM and combining the organic phases with anhydrous Na 2 SO 4 After drying and spin-evaporation of the solvent, recrystallization from a mixed solvent of DCM and methanol afforded dark purple intermediate 8a (50 mg) which was used directly in the next reaction.
5. Synthesis of compound 9 a:
black-violet intermediate 8a (50 mg) and DIPEA (105.4 mg,0.82 mmol) were added to anhydrous DCM under nitrogen, stirred for 20 min, followed by the addition of BF 3 ·Et 2 O (173.6 mg,1.22 mmol) was reacted at room temperature for 24h, quenched with water after completion of the reaction and extracted three times with DCM, the organic phases were combined and the organic phase was taken up in anhydrous Na 2 SO 4 After drying, DCM was distilled off and purified by column chromatography (eluent PE and EA) to give black compound 9a (51 mg) in 82% yield.
1 H NMR(500MHz,CDCl 3 )δ8.12–8.04(m,8H),7.42(d,J＝7.9Hz,4H),7.08–7.00(m,6H),5.10(s,4H),3.90(s,6H).
19 F NMR(376MHz,CDCl 3 )δ–73.42,–135.28(dd,J＝64.4,32.2Hz)。
13 C NMR(126MHz,CDCl 3 )δ162.1,158.4,145.4,142.4,135.8,133.0,131.7(t,J＝4.8Hz),129.6,127.8,124.0,120.5(q,J＝293.6Hz),118.9,114.4,80.57–79.04(m),71.0,55.5。
The structural formula of compound 9a is as follows:
example 2 (Compound 9 b)
1. Synthesis of compound 3 b:
under nitrogen atmosphere, 4-methylacetophenone (10.00 g,74.53 mmol), NBS (16.58 g,93.16 mmol) and AIBN (2.45 g,14.92 mmol) are dissolved in anhydrous acetonitrile and reacted for 4h at 90 ℃, after the reaction is completed, a proper amount of water is added for quenching reaction, after DCM extraction is carried out three times, the organic phases are combined, and the organic phases are quenched with anhydrous Na 2 SO 4 Drying, distillation under reduced pressure, and separation of the solvent by column chromatography (eluent PE and EA) gave 3b (15.46 g) as a white solid in 97% yield.
1 H NMR(400MHz,CDCl 3 )δ7.95–7.90(m,2H),7.50–7.45(m,2H),4.50(s,2H),2.60(s,3H).
The structural formula of compound 3b is as follows:
2. synthesis of Compound 1 b:
compound 3b (8.85 g,41.54 mmol) and KOC (CF) were reacted under nitrogen 3 ) 3 (12.53 g,45.71 mmol) was dissolved in anhydrous DMF and reacted at room temperature for 24 hours, after the completion of the reaction, water was added to quench the reaction, then DMF was removed by washing with a large amount of water, and after the organic phase was extracted with anhydrous Na 2 SO 4 The EA was removed by distillation under reduced pressure, and the residue was purified by column chromatography (washingThe stripping agent was PE and EA) to give 1b (9.98 g) as a white solid in 65% yield.
1 H NMR(400MHz,CDCl 3 )δ7.98(d,J＝8.3Hz,2H),7.44(d,J＝8.2Hz,2H),5.10(s,2H),2.61(s,3H).
19 F NMR(376MHz,CDCl 3 )δ–73.33.
13 C NMR(126MHz,CDCl 3 )δ197.6,139.9,137.5,128.9,127.5,120.5(q,J＝293.6,Hz),80.9–79.0(m),70.6,26.8.
The structural formula of compound 1b is as follows:
3. synthesis of compound 6 b:
compound 1b (4.10 g,10.76 mmol) and NaOH (1.33 g,33,25 mmol) were added to 100mL of ethanol, stirred for 5min, then 4-methoxybenzaldehyde (1.81 g,13.29 mmol) was added, reacted at room temperature for 24h, after the reaction was completed, 2M diluted hydrochloric acid was added to neutralize the system to neutrality, a large amount of pale yellow solid was precipitated, after the precipitation was completed, the filtration was carried out, the precipitate was collected, and the precipitate was recrystallized from a mixed solution of EA and ethanol to give pale yellow solid 6b (3.96 g) in 53% yield.
1 H NMR(400MHz,CDCl 3 )δ8.03(d,J＝8.3Hz,2H),7.79(d,J＝15.6Hz,1H),7.60(d,J＝8.3Hz,2H),7.47(d,J＝8.1Hz,2H),7.39(d,J＝15.6Hz,1H),6.93(d,J＝7.7Hz,2H),5.12(s,2H),3.84(s,3H).
19 F NMR(376MHz,CDCl 3 )δ–73.34.
13 C NMR(151MHz,CDCl 3 )δ190.1,162.0,145.2,139.3,138.9,130.4,128.9,127.6,127.6,120.5(q,J＝293.0Hz),119.7,114.6,81.2–79.3(m),70.7,55.5.
The structural formula of compound 6b is as follows:
4. synthesis of compound 7 b:
compound 6b (3.81 g,7.83 mmol), meNO 2 (4.78 g,78.31 mmol) and KOH (88 mg,1.57 mmol) were dissolved in EtOH and reacted at 80℃for 5h, after which the reaction was completed, cooled to room temperature, then the system was neutralized to neutrality by the addition of 2M dilute hydrochloric acid, then extracted with DCM and the organic phase was taken up in anhydrous Na 2 SO 4 Drying, distillation under reduced pressure, and separation of the solvent by column chromatography (PE and EA as eluent) gave 7b (4.02 g) as a pale yellow oil in 93% yield.
1 H NMR(400MHz,CDCl 3 )δ7.93(d,J＝8.3Hz,2H),7.42(d,J＝8.1Hz,2H),7.20(d,J＝8.5Hz,2H),6.85(d,J＝8.6Hz,2H),5.10(s,2H),4.79(dd,J＝12.4,6.6Hz,1H),4.64(dd,J＝12.4,8.1Hz,1H),4.24–4.10(m,1H),3.74(s,3H),3.50–3.33(m,2H).
19 F NMR(376MHz,CDCl 3 )δ–73.35.
13 C NMR(101MHz,CDCl 3 )δ196.5,159.1,140.3,136.6,131.0,128.6,128.5,127.5,120.4(q,J＝292.8Hz),114.4,81.4–78.7(m),79.9,70.5,55.1,41.7,38.6.
The structural formula of compound 7b is as follows:
5. synthesis of compound 8 b:
under dark conditions, compound 7b (1.61 g,2.94 mmol) and NH were taken up 4 OAc (7.92 g,102.75 mmol) is reacted at 120℃for 5h, after the reaction is completed, a large amount of water is added to wash out excess NH 4 OAc followed by three extractions with DCM and combining the organic phases, the organic phases were extracted with anhydrous Na 2 SO 4 The solvent was removed by rotary evaporation, and the residue was recrystallized from a mixed solvent of DCM and methanol to give dark purple intermediate 8b (201 mg) which was used directly in the next reaction.
6. Synthesis of compound 9 b:
black purple intermediate 8b (201 mg) and DIPEA (0) were combined under nitrogen.26mg,2.01 mmol) was added to anhydrous DCM and stirred for 20 min, followed by the addition of BF 3 ·Et 2 O (0.39 mg,2.75 mmol) was reacted at room temperature for 24h, quenched with water after completion of the reaction, and the organic phases were combined after three extractions with DCM, the organic phases were taken up in anhydrous Na 2 SO 4 The DCM was dried, distilled off, and the residue was purified by column chromatography (eluent PE and EA) to give 9b (57.4 mg) as a black solid in 27% yield.
1 H NMR(400MHz,CDCl 3 )δ8.10–8.01(m,8H),7.45(d,J＝8.3Hz,4H),7.05–6.97(m,4H),6.93(s,2H),5.10(s,4H),3.91(s,6H).
19 F NMR(376MHz,CDCl 3 )δ–73.31,–133.94(dd,J＝63.5,31.6Hz).
13 C NMR(126MHz,THF–d 8 )δ161.4,158.3,145.6,143.8,137.3,132.3,130.8,129.8(t,J＝4.5Hz),127.4,125.1,120.6(q,J＝293.6Hz),117.6,114.1,80.9–79.8(m),79.9,71.2,54.7.
The structural formula of compound 9b is as follows:
example 3 (Compound 9 c)
1. Synthesis of Compound 6 c:
acetophenone (0.62 g,5.15 mmol) and KOH (0.58 g,10.36 mmol) were dissolved in 90mL ethanol, compound 4a (1.82 g,5.15 mmol) was added after stirring for 5min, reacted at room temperature for 24h, after the reaction was complete, 2M dilute hydrochloric acid was added to neutralize the system to neutrality, a large amount of pale yellow solid was precipitated, after complete precipitation, filtration was performed, the precipitate was collected, and the precipitate was recrystallized in a mixed solution of EA and EtOH to give pale yellow solid 6c (2.02 g) in 86% yield.
1 H NMR(400MHz,CDCl 3 )δ8.06–7.99(m,2H),7.81(d,J＝15.7Hz,1H),7.67(d,J＝8.2Hz,2H),7.63–7.48(m,5H),7.40(d,J＝8.2Hz,2H),5.07(s,2H).
19 F NMR(376MHz,CDCl 3 δ–73.30.
13 C NMR(101MHz,CDCl 3 )δ190.5,144.0,138.2,137.2,135.5,133.1,128.8,128.8,128.6,128.2,122.8,120.5(q,J＝292.9Hz),82.2–78.8(m),70.9.
The structural formula of compound 6c is as follows:
2. synthesis of Compound 7 c:
compound 6c (1.66 g,3.64 mmol), meNO 2 (2.22 g,36.36 mmol) and KOH (41 mg,0.72 mmol) were dissolved in EtOH and reacted at 80℃for 5h, after which the reaction was completed, cooled to room temperature, then the system was neutralized to neutrality by the addition of 2M dilute hydrochloric acid, then extracted with DCM and the organic phase was taken up in anhydrous Na 2 SO 4 After drying and distilling off the solvent under reduced pressure, the mixture was separated by column chromatography (eluent PE and EA) to give 7c (1.77 g) as a pale yellow oil in 94% yield.
1 H NMR(500MHz,CDCl 3 )δ7.92(d,J＝7.4Hz,2H),7.58(t,J＝7.4Hz,1H),7.46(t,J＝7.7Hz,2H),7.32(s,4H),5.00(s,2H),4.84(dd,J＝12.6,6.5Hz,1H),4.70(dd,J＝12.6,8.1Hz,1H),4.30–4.21(m,1H),3.53–3.39(m,2H).
19 F NMR(376MHz,CDCl 3 )δ–73.27.
13 C NMR(126MHz,CDCl 3 )δ196.8,140.0,136.4,134.6,133.8,128.9,128.5,128.1,128.0,120.5(q,J＝293.1Hz),80.7–79.6(m),79.5,70.9,41.5,39.1.
The structural formula of compound 7c is as follows:
4. synthesis of Compound 8 c:
under dark conditions, compound 8c (0.65 g,1.26 mmol) and NH were taken up 4 OAc (3.40 g,44.13 mmol) is reacted for 5h at 120℃and after the reaction is completed, a large amount of water is added to wash out excess NH 4 OAcThe organic phases were combined after three subsequent extractions with DCM and extracted with anhydrous Na 2 SO 4 After drying and spin-evaporation of the solvent, recrystallization from a mixed solvent of DCM and methanol afforded dark purple intermediate 8c (98 mg) which was used directly in the next reaction.
5. Synthesis of compound 9 c:
black-violet intermediate 8c (98 mg) and DIPEA (142.2 mg,1.10 mmol) were added to anhydrous DCM under nitrogen, stirred for 20 min, followed by BF 3 ·Et 2 O (218.6 mg,1.54 mmol) was reacted at room temperature for 24h, quenched with water after completion of the reaction and extracted three times with DCM, the organic phases were combined and the organic phase was taken up in anhydrous Na 2 SO 4 The DCM was dried, distilled off by rotary evaporation and the residue was purified by column chromatography (eluent PE and EA) to give 7c (66 mg) as a black solid in 64% yield.
1 H NMR(500MHz,CDCl 3 )δ8.09–8.02(m,8H),7.52–7.48(m,6H),7.44(d,J＝8.1Hz,4H),7.06(s,2H),5.11(s,4H).
19 F NMR(471MHz,CDCl 3 )δ–73.36,–134.64(dd,J＝64.8,33.1Hz).
13 C NMR(126MHz,CDCl 3 )δ160.0,145.8,143.6,136.2,132.8,131.6,131.2,129.8,128.8,128.0,120.6(q,J＝291.6Hz),119.4,80.8–79.4(m),71.1,60.6.
The structural formula of compound 9c is as follows:
example 4 (Compound 9 d)
1. Synthesis of Compound 6 d:
1b (3.03 g,8.23 mmol) and NaOH (0.66 g,16.46 mmol) were dissolved in 100mL of ethanol, benzaldehyde (960.7 mg,9.05 mmol) was added after stirring for 5min, the reaction was carried out at room temperature for 24h, after completion of the reaction, 2M diluted hydrochloric acid was added to neutralize the system to neutrality, a large amount of pale yellow solid was precipitated, after completion of the precipitation, filtration was carried out, the precipitate was collected, and the precipitate was recrystallized in a mixed solution of EA and EtOH to give 6d (2.93 g) as a pale yellow solid in 78% yield.
1 H NMR(400MHz,Chloroform–d)δ8.05(d,J＝8.1Hz,2H),7.83(d,J＝15.7Hz,1H),7.65(m,2H),7.57–7.38(m,6H),5.13(s,2H).
19 F NMR(376MHz,Chloroform–d)δ–73.31.
13 C NMR(101MHz,Chloroform–d)δ190.0,145.3,139.6,138.5,134.8,130.8,129.1,129.0,128.6,127.6,121.9,117.6(q,J＝293.2Hz),80.7–79.3(m),70.6.
The structural formula of compound 6d is as follows:
2. synthesis of Compound 7 d:
compound 6d (3.45 g,7.56 mmol), meNO 2 (4.61 g,155.03 mmol) and KOH (84 mg,1.51 mmol) were dissolved in EtOH and reacted at 80℃for 5h, after which the reaction was completed, cooled to room temperature, then the system was neutralized to neutrality by the addition of 2M dilute hydrochloric acid, then extracted with DCM and the organic phase was taken up in anhydrous Na 2 SO 4 Drying, distillation under reduced pressure, and separation of the solvent by column chromatography (PE and EA as eluent) gave 7d (3.69 g) as a pale yellow oil in 94% yield.
1 H NMR(400MHz,CDCl 3 )δ7.94(d,J＝8.3Hz,2H),7.43(d,J＝8.1Hz,2H),7.38–7.24(m,5H),5.10(s,2H),4.83(dd,J＝12.5,6.7Hz,1H),4.69(dd,J＝12.5,7.9Hz,1H),4.27–4.20(m,1H),3.54–3.38(m,2H).
19 F NMR(376MHz,CDCl 3 )δ–73.34.
13 C NMR(151MHz,CDCl 3 )δ140.4,139.1,136.7,129.2,128.6,128.1,127.6,120.5(q,J＝295.0Hz),80.1–79.6(m),79.7,70.5,41.7,39.4.
The structural formula of compound 7d is as follows:
4. synthesis of Compound 8 d:
under dark conditions, compound 7d (2.00 g,3.86 mmol) and NH were taken up 4 OAc (10.41 g,135.12 mmol) is reacted for 5h at 120℃and after the reaction is completed, a large amount of water is added to wash out excess NH 4 OAc followed by three extractions with DCM and combining the organic phases, the organic phases were extracted with anhydrous Na 2 SO 4 The solvent was removed by rotary evaporation, and the residue was recrystallized from a mixed solvent of DCM and methanol to give dark purple intermediate 8d (190.7 mg) which was used directly in the next reaction.
5. Synthesis of Compound 9 d:
black-violet intermediate 8d (190.7 mg) and DIPEA (286.2 mg,2.02 mmol) were added to anhydrous DCM under nitrogen, stirred for 20 min, followed by BF 3 ·Et 2 O (400.7 mg,2.82 mmol) was reacted at room temperature for 24h, quenched with water after completion of the reaction and extracted three times with DCM, the organic phases were combined and the organic phase was taken up in anhydrous Na 2 SO 4 The DCM was dried, distilled off, and the residue was purified by column chromatography (eluent PE and EA) to give 9d (44.3 mg) as a black solid in 22% yield.
1 H NMR(400MHz,CDCl 3 )δ8.12–8.03(m,8H),7.51–7.43(m,10H),7.05(s,2H),5.11(s,4H).
19 F NMR(376MHz,CDCl 3 )δ–73.28,–134.45(dd,J＝63.0,31.4Hz).
13 C NMR(151MHz,CDCl 3 )δ158.9,145.8,144.6,137.6,132.2,131.9,129.9(t,J＝4.3Hz),129.7,129.4,128.7,127.5,120.4(q,J＝292.8Hz)119.1,80.6–79.2(m),70.7.
The structural formula of compound 9d is as follows:
example 5 (Compound 9 e)
1. Synthesis of Compound 4e
3-bromomethylbenzene was reacted under nitrogen atmosphereFormaldehyde (2.50 g,12.56 mmol) and KOC (CF 3 ) 3 (6.7 g,24.44 mmol) was dissolved in anhydrous DMF and reacted at room temperature for 24 hours, after the completion of the reaction, water was added to quench the reaction, then DMF was removed by washing with a large amount of water, and after the organic phase was extracted with anhydrous Na 2 SO 4 The EA was dried, distilled off under reduced pressure and the residue was purified by column chromatography (eluent PE and EA) to give 4e (4.24 g) as a white solid in 95% yield.
1 H NMR(500MHz,CDCl 3 )δ10.04(s,1H),7.92–7.82(m,2H),7.67–7.55(m,2H),5.12(s,2H).
19 F NMR(471MHz,CDCl 3 )δ–73.31.
13 C NMR(126MHz,CDCl 3 )δ191.8,136.8,136.0,133.5,130.2,129.6,128.6,120.4(q,J＝294.1,Hz),81.9–78.2(m),70.5.
The structural formula of compound 4e is as follows:
2. synthesis of compound 6 e:
under ice bath, acetophenone (0.68 g,5.65 mmol) and NaOH (451.7 mg,11.29 mmol) were added to 90mL of ethanol, stirred for 5min, then compound 4e (2.00 g,5.65 mmol) was added, reacted at room temperature for 24h, after the reaction was completed, 2M of dilute hydrochloric acid was added to neutralize the system, after three extractions with DCM was added, the organic phases were combined, and the organic phases were quenched with anhydrous Na 2 SO 4 Drying, rotary evaporation to remove the solvent, and column chromatography separation and purification of the residue (eluent PE and EA) gave 6e (1.80 g) as a pale yellow solid in 70% yield.
1 H NMR(500MHz,CDCl 3 )δ8.05–8.00(m,2H),7.81(d,J＝15.7Hz,1H),7.68–7.38(m,8H),5.09(s,2H).
19 F NMR(471MHz,Chloroform–d)δ–73.23.
13 C NMR(126MHz,Chloroform–d)δ190.4,144.0,138.1,135.7,135.4,132.9,129.6,129.4,128.7,128.6,128.5,127.6,122.8,123.9–116.9(q,J＝292.9Hz),82.4–78.2(m),70.9.
The structural formula of compound 6e is as follows:
3. synthesis of compound 7 e:
compound 6e (1.06 g,2.32 mmol), meNO 2 (1.36 g,22.35 mmol) and KOH (26 mg,0.46 mmol) were dissolved in EtOH and reacted at 80℃for 5h, after which the reaction was completed, cooled to room temperature, then the system was neutralized to neutrality by the addition of 2M dilute hydrochloric acid, then extracted with DCM and the organic phase was taken up in anhydrous Na 2 SO 4 After drying and distilling off the solvent under reduced pressure, the mixture was separated by column chromatography (eluent PE and EA) to give 7e (1.08 g) as a pale yellow oil in 90% yield.
1 H NMR(600MHz,CDCl 3 )δ7.89(d,J＝7.65Hz,2H),7.58–7.53(m,1H),7.46–7.40(m,2H),7.38–7.32(m,1H),7.29–7.20(m,4H),5.00(s,2H),4.85–4.78(m,1H),4.71–4.64(m,1H),4.25–4.20(m,1H),3.49–3.37(m,2H).
19 F NMR(471MHz,CDCl 3 )δ–73.28.
13 C NMR(126MHz,CDCl 3 )δ196.7,139.8,136.3,135.8,133.7,129.6,128.8,128.1,127.9,127.2,126.7,123.9–116.9(q,J＝293.2Hz),80.5–79.5(m),79.4,71.0,41.5,39.2.
The structural formula of compound 7e is as follows:
4. synthesis of compound 8 e:
under dark conditions, compound 7e (1.06 g,2.05 mmol) was reacted with NH 4 OAc (5.51 g,71.52 mmol) is reacted at 120℃for 5h, after the reaction is completed, a large amount of water is added to wash out excess NH 4 OAc followed by three extractions with DCM and combining the organic phases, the organic phases were extracted with anhydrous Na 2 SO 4 DryingThe solvent was removed by rotary evaporation, and the residue was recrystallized from a mixed solvent of DCM and methanol to give blue-black intermediate 8e (330 mg) which was used directly in the next reaction.
5. Synthesis of compound 9 e:
blue-black intermediate 8e (170 mg,0.18 mmol) and DIPEA (222.6 mg,1.72 mmol) were added to anhydrous DCM under nitrogen, stirred for 20 min, followed by BF 3 ·Et 2 O (336.4 mg,2.36 mmol), at 40℃for 24h, quenched with water, extracted three times with DCM, the organic phases combined, and the organic phase quenched with anhydrous Na 2 SO 4 The DCM was dried, distilled off, and the residue was purified by column chromatography (eluent PE and EA) to give black compound 9e (137.6 mg) in 77% yield.
1 H NMR(500MHz,CDCl 3 )δ8.06–8.04(m,6H),7.90(s,2H),7.57–7.41(m,9H),7.05(s,2H),5.08(s,4H).
19 F NMR(471MHz,CDCl 3 )δ–73.29,–134.71(dd,J＝61.2,31.0Hz).
13 C NMR(151MHz,CDCl 3 )δ159.8,145.6,143.5,135.4,132.7,131.4,131.2,129.9,129.7(t,J＝4.2Hz),129.0,128.7,128.6,128.3,123.3–117.5(q,J＝293.0Hz)119.5,80.8–79.0(m),71.1.
The structural formula of compound 9e is as follows:
example 6 (Compound 9 f)
1. Synthesis of compound 3 f:
3-methylacetophenone (200.00 mg,1.49 mmol), NBS (331.6 mg,1.86 mmol) and AIBN (122.3 mg,0.74 mmol) were dissolved in anhydrous acetonitrile under nitrogen atmosphere and reacted at 90℃for 4h. After the reaction was completed, an appropriate amount of water was added to quench the reaction, the organic phases were combined after three extractions with DCM, and the organic phases were quenched with anhydrous Na 2 SO 4 Drying, distilling off the solvent under reduced pressure, and separating the residue by column chromatography (eluent PE and EA) to give 3f (220.3 mg) as a white solid in the yield of69％。
1 H NMR(500MHz,CDCl 3 )δ7.96(t,J＝1.9Hz,1H),7.86(dt,J＝7.7,1.5Hz,1H),7.58(dt,J＝7.6,1.5Hz,1H),7.43(t,J＝7.7Hz,1H),4.51(s,2H),2.59(s,3H).
The structural formula of compound 3f is as follows:
2. synthesis of Compound 1 f:
under nitrogen, compound 3f (4.14 g,19.43 mmol) and KOC (CF) 3 ) 3 (7.99 g,29.15 mmol) in anhydrous DMF at room temperature for 24 hours, after completion of the reaction, water quench reaction was added, then DMF was removed by washing with a large amount of water, and after extraction of the organic phase with anhydrous Na 2 SO 4 The EA was dried, distilled off under reduced pressure and the residue was purified by column chromatography (eluent PE and EA) to give 1f (4.71 g) as a white solid in 66% yield.
1 H NMR(500MHz,CDCl 3 )δ7.98–7.90(m,2H),7.59–7.49(m,2H),5.10(s,2H),2.62(s,3H).
19 F NMR(471MHz,CDCl 3 )δ–73.27.
13 C NMR(126MHz,CDCl 3 )δ197.6,137.6,135.5,132.2,129.2,128.8,127.5,120.4(q,J＝293.5Hz),80.4–79.3(m),70.8,26.7.
The structural formula of compound 1f is as follows:
3. synthesis of compound 6 f:
compound 1f (3.06 g,8.15 mmol) and KOH (932.6 mg,16.62 mmol) were added to 110mL of ethanol, after stirring for 5min, benzaldehyde (1.06 g,9.98 mmol) was added, and after completion of the reaction, the system was neutralized to neutrality by adding 2M of diluted hydrochloric acid, a large amount of pale yellow solid was precipitated, after completion of the precipitation, filtration was carried out, the precipitate was collected, and the precipitate was recrystallized from a mixed solution of EA and ethanol to give pale yellow solid 6f (1.71 g) in 44% yield.
1 H NMR(500MHz,CDCl 3 )δ8.04–7.95(m,2H),7.83(d,J＝15.7Hz,1H),7.70–7.41(m,8H),5.13(s,2H).
19 F NMR(471MHz,CDCl 3 )δ–73.25.
13 C NMR(126MHz,CDCl 3 )δ190.1,145.4,138.7,135.6,134.8,131.9,130.8,129.2,129.1,128.9,128.5,127.7,121.9,120.5(q,J＝292.83Hz),80.0–79.9(d,J＝29.86Hz),70.9.
4. Synthesis of compound 7 f:
compound 6f (1.71 g,3.75 mmol), meNO 2 (2.84 g,46.52 mmol) and KOH (52.1 mg,0.93 mmol) were dissolved in a suitable amount of EtOH and reacted at 80℃for 5h, after which the reaction was completed, cooled to room temperature, then the system was neutralized to neutrality by the addition of 2M dilute hydrochloric acid, then extracted with DCM and the organic phase was taken up in anhydrous Na 2 SO 4 Drying, distillation under reduced pressure, and separation of the solvent by column chromatography (PE and EA as eluent) gave 7f (1.48 g) as a pale yellow oil in 76% yield.
1 H NMR(500MHz,CDCl 3 )δ7.99–7.82(m,2H),7.61–7.56(m,1H),7.51(t,J＝7.7Hz,1H),7.38–7.26(m,5H),5.08(s,2H),4.83(dd,J＝12.5,6.8Hz,1H),4.70(dd,J＝12.5,7.8Hz,1H),4.24–4.22(m,1H),3.53–3.39(m,2H).
19 F NMR(471MHz,CDCl 3 )δ–73.28.
13 C NMR(126MHz,CDCl 3 )δ196.4,139.0,136.8,135.7,132.7,129.3,129.2,128.5,128.0,127.5,127.2,120.4(q,J＝292.9Hz),80.8–79.2(m),79.6,70.7,41.6,39.3.
The structural formula of compound 7f is as follows:
5. synthesis of compound 8 f:
under dark conditions, compound 7f (1.20 g,2.32 mmol) and NH 4 OAc (6.25 g,81.12 mmol) is reacted for 5h at 120℃and after the reaction is completed, a large amount of water is added to wash out excess NH 4 OAc followed by three extractions with DCM and combining the organic phases, the organic phases were extracted with anhydrous Na 2 SO 4 The solvent was removed by rotary evaporation, and the residue was recrystallized from a mixed solvent of DCM and methanol to give dark purple intermediate 8f (400 mg) which was used directly in the next reaction.
6. Synthesis of compound 9 f:
black-violet intermediate 8f (400 mg) and DIPEA (549 mg,4.24 mmol) were added to anhydrous DCM under nitrogen, stirred for 20 min, followed by the addition of BF 3 ·Et 2 O (840 mg,5.92 mmol) was reacted at room temperature for 24h, quenched with water after completion of the reaction and extracted three times with DCM, the organic phases were combined and the organic phase was taken up in anhydrous Na 2 SO 4 The DCM was dried, distilled off, and the residue was purified by column chromatography (eluent PE and EA) to give 9f (171.4 mg) as a black solid in 41% yield.
1 H NMR(500MHz,CDCl 3 )δ8.12–7.94(m,8H),7.55–7.41(m,10H),7.02(s,2H),5.11(s,4H).
19 F NMR(471MHz,CDCl 3 )δ–73.27,–134.50(dd,J＝64.9,33.3Hz).
13 C NMR(126MHz,CDCl 3 )δ159.1,145.8,144.7,135.3,132.2,132.1,130.0,129.8,129.5,129.1,128.7,128.7–128.6,120.5(q,J＝293.1Hz),119.1,80.6–79.4(m),71.0.
The structural formula of compound 9f is as follows:
example 7 (Compound 9 g)
1. Synthesis of Compound 6 g:
3, 5-Ditrifluoromethyl acetophenone (1.90 g,7.42 mmol) and Compound 4a (2.63 g,7.42 mmol) were dissolved in ethanol, naOH (593.4 mg,14.83 mmol) was dissolved in water, aqueous NaOH solution was poured into the above ethanol solution, reacted at room temperature for 40min, 2M diluted hydrochloric acid was added to neutralize the system, DCM was then added to extract three times and the organic phase was combined, and the organic phase was taken up with anhydrous Na 2 SO 4 The mixture was dried, the solvent was removed by rotary evaporation, and the residue was purified by chromatography on a column (eluent PE and EA) to give 6g (1.62 g) of a pale yellow oily compound in 37% yield.
1 H NMR(500MHz,CDCl 3 )δ8.44(d,J＝1.8Hz,2H),8.10(s,1H),7.91(d,J＝15.6Hz,1H),7.72(d,J＝8.2Hz,2H),7.55–7.41(m,3H),5.10(s,2H).
19 F NMR(376MHz,CDCl 3 )δ–66.02,–73.28.
13 C NMR(126MHz,CDCl 3 )δ187.3,146.5,139.7,138.1,134.6,132.5(q,J＝34.0Hz),129.1,128.5(d,J＝3.9Hz),128.2,126.1–126.0(m),123.0(q,J＝272.9Hz),120.9,120.4(d,J＝292.4Hz),80.9–79.1(m),70.7(d,J＝3.8Hz).
The structural formula of compound 6g is as follows:
2. synthesis of Compound 7 g:
6g (2.69 g,4.54 mmol) of the compound, meNO 2 (2.77 g,45.42 mmol) and KOH (51 mg,0.91 mmol) were dissolved in EtOH and reacted at 80℃for 5h, after which the reaction was completed, cooled to room temperature, then the system was neutralized to neutrality by the addition of 2M dilute hydrochloric acid, then extracted with DCM and the organic phase was taken up in anhydrous Na 2 SO 4 Drying, distillation under reduced pressure and removal of the solvent gave 7g (2.04 g) as a pale yellow oily liquid in 69% yield, which was purified by separation through a column chromatography (eluent PE and EA).
1 H NMR(400MHz,CDCl 3 )δ8.32(s,2H),8.08(s,1H),7.34(s,4H),5.00(s,2H),4.83(dd,J＝12.7,7.2Hz,1H),4.73(dd,J＝12.7,7.4Hz,1H),4.32–4.25(m,1H),3.59–3.48(m,2H).
19 F NMR(376MHz,CDCl 3 )δ–66.14,–73.29.
13 C NMR(151MHz,CDCl 3 )δ194.2,139.2,137.8,135.1,132.7(q,J＝34.1Hz),128.6,128.2,128.0,126.9–127.0(m),122.9(q,J＝273.0Hz),120.5(q,J＝293.0Hz),80.1–70.6(m),79.1,70.8,41.9,39.0.
The structural formula of compound 7g is as follows:
3. synthesis of Compound 8 g:
under light-shielding conditions, 7g (2.04 g,3.44 mmo) of the compound was reacted with NH 4 OAc (8.42 g,109.28 mmol) is reacted at 120℃for 5h, after the reaction is completed, a large amount of water is added to wash out excess NH 4 OAc, followed by three extractions with DCM and combining the organic phases, the organic phases were extracted with anhydrous Na 2 SO 4 The solvent was removed by rotary evaporation, and the residue was recrystallized from a mixed solvent of DCM and methanol to give 8g (110 mg) of the purple-black intermediate which was used directly in the next reaction.
4. Synthesis of Compound 9 g:
violet intermediate 8g (110 mg,0.09 mmol) and DIPEA (116.3 mg,0.90 mmol) were added to anhydrous DCM under nitrogen, stirred for 20 min, followed by BF 3 ·Et 2 O (178.8 mg,1.26 mmol), at 40℃for 24h, quenched with water, extracted three times with DCM and the organic phases combined, dried Na 2 SO 4 The DCM was dried, distilled off by rotary evaporation and the residue was purified by chromatography (eluent PE and EA) to give 9g (60 mg) of a purplish black solid in 53% yield.
1 H NMR(500MHz,CDCl 3 )δ8.54(s,4H),8.09(d,J＝8.0Hz,4H),8.00(s,2H),7.47(d,J＝7.9Hz,4H),7.15(s,2H),5.14(s,4H).
19 F NMR(471MHz,CDCl 3 )δ–66.36,–73.38,–133.59(dd,J＝63.00,31.87Hz).
13 C NMR(151MHz,CDCl 3 )δ157.0,146.3,145.6,137.2,132.8,132.4(q,J＝33.9Hz),131.9,130.0,129.6,128.0,124.5,123.0(q,J＝272.9Hz),120.5(q,J＝293.2Hz),118.9,80.4–79.7(m),70.8.
The structural formula of compound 9g is as follows:
example 8 (Compound 9 h)
1. Synthesis of Compound 3 h:
the compound 3, 5-dimethyl acetophenone (5.00 g,33.74 mmol), NBS (15.01 g,84.33 mmol), AIBN (3.32 g,20.22 mmol) was dissolved in anhydrous acetonitrile under nitrogen atmosphere and reacted for 4h at 90℃after the reaction was completed, quenched with appropriate amount of water, extracted three times with DCM and the organic phases were combined, the organic phases were quenched with anhydrous Na 2 SO 4 Drying, distilling off the solvent under reduced pressure, and separating and purifying the residue by chromatography column (eluent PE and EA) to obtain white solid (5.01 g) with a yield of 48%.
1 H NMR(500MHz,CDCl 3 )δ7.89(d,J＝1.7Hz,2H),7.62(t,J＝1.8Hz,1H),4.51(s,4H),2.61(s,3H).
The structural formula of compound 3h is as follows:
2. synthesis of Compound 1 h:
compound 3h (4.09 g,13.37 mmol) and KOC (CF) were reacted under nitrogen 3 ) 3 (10.78 g,39.32 mmol) was dissolved in anhydrous DMF and reacted at room temperature for 24 hours, after the completion of the reaction, water was added to quench the reaction, then DMF was removed by washing with a large amount of water, then the organic phase was collected by extraction with EA, and the organic phase was taken up in anhydrous Na 2 SO 4 Drying, distilling under reduced pressure to remove EA, separating and purifying the residue with chromatography column (eluting with PE and EA),a white solid was obtained in 1h (7.00 g) with a yield of 85%.
1 H NMR(600MHz,CDCl 3 )δ7.89(s,2H),7.59(s,1H),5.13(s,4H),2.62(s,3H).
19 F NMR(471MHz,CDCl 3 )δ–73.31.
13 C NMR(126MHz,CDCl 3 )δ197.0,138.0,136.4,130.6,127.4,126.5–115.4(q,J＝293.6Hz),80.0–79.4(m),70.4,26.6.
The structural formula of compound 1h is as follows:
3. synthesis of Compound 6 h:
under ice bath conditions, compound 1h (4.00 g,6.49 mmol) and KOH (728.4 mg,12.98 mmol) were added to 90mL ethanol, benzaldehyde (0.83 g,7.82 mmol) was added after stirring for 5min, reacted at room temperature for 24h, after the reaction was complete, 2M diluted hydrochloric acid was added to neutralize the system, the organic phase was combined after three extractions with DCM, and the organic phase was taken up in anhydrous Na 2 SO 4 Drying, rotary evaporation to remove the solvent, and separation and purification of the residue by chromatography column (eluting with PE and EA) gave a pale yellow solid (1.05 g) in 22% yield.
1 H NMR(500MHz,CDCl 3 )δ7.94(s,2H),7.83(d,J＝15.7Hz,1H),7.68–7.60(m,3H),7.53–7.40(m,4H),5.16(s,4H).
19 F NMR(471MHz,CDCl 3 )δ–73.28.
13 C NMR(126MHz,CDCl 3 )δ189.6,146.0,139.1,136.4,134.6,131.0,130.2,129.1,128.6,127.6,121.5,123.9–116.7(q,J＝291.2Hz),80.0–79.7(m),70.4.
The structural formula of compound 6h is as follows:
4. synthesis of Compound 7 h:
compound 6h (1.05 g,1.49 mmol), meNO 2 (0.91 g,14.91 mmol) and KOH (17 mg,0.30 mmol) were dissolved in EtOH and reacted at 80℃for 5h, after which the reaction was completed, cooled to room temperature, then the system was neutralized to neutrality by the addition of 2M dilute hydrochloric acid, then extracted with DCM and the organic phase was taken up in anhydrous Na 2 SO 4 Drying, distilling under reduced pressure to remove the solvent, and separating and purifying the residue by chromatography column (eluting with PE and EA) to obtain pale yellow oily liquid (0.92 g) with a yield of 81%.
1 H NMR(500MHz,CDCl 3 )δ7.83(d,J＝1.6Hz,2H),7.62(s,1H),7.37–7.26(m,5H),5.11(s,4H),4.82(dd,J＝12.5,6.9Hz,1H),4.70(dd,J＝12.5,7.6Hz,1H),4.23(p,J＝7.1Hz,1H),3.53–3.39(m,2H).
19 F NMR(471MHz,CDCl 3 )δ–73.27.
13 C NMR(126MHz,CDCl 3 )δ195.9,138.8,137.2,136.6,131.0,129.2,128.1,127.5,127.1,120.4(q,J＝292.6Hz),81.0–79.5(m),79.5,70.3,41.6,39.3.
The structural formula of compound 7h is as follows:
5. synthesis of Compound 8 h:
under dark conditions, the compound was taken up in water for 7h (861 mg,1.12 mmol) and NH 4 OAc (3.03 g,39.33 mmol) is reacted at 120℃for 5h, after the reaction is completed, a large amount of water is added to wash out excess NH 4 OAc, followed by three extractions with DCM and combining the organic phases, the organic phases were extracted with anhydrous Na 2 SO 4 The solvent was removed by rotary evaporation and the residue was recrystallized from a mixed solvent of DCM and methanol to give the dark purple intermediate 8h (170 mg) which was used directly in the next reaction.
6. Synthesis of Compound 9 h:
black-violet intermediate 8h (170 mg) and DIPEA (155.82 mg,1.20 mmol) were added to anhydrous DCM under nitrogen, stirred for 20 min, followed by BF addition 3 ·Et 2 O (235.2 mg,1.66 mmol), at 40℃for 24h, quenched with water, extracted three times with DCM and the organic phases combined, dried Na 2 SO 4 The DCM was dried, distilled off, and the residue was purified by chromatography column (eluent PE and EA) to give a black solid 9h (101.4 mg) in 58% yield.
1 H NMR(600MHz,CDCl 3 )δ8.09–8.04(m,4H),7.91(s,4H),7.54–7.43(m,8H),7.00(d,J＝1.3Hz,2H),5.13(s,8H).
19 F NMR(471MHz,CDCl 3 )δ–73.41,–134.33(dd,J＝61.34,31.05Hz).
13 C NMR(126MHz,CDCl 3 )δ158.7,145.9,145.2,136.2,132.5,132.0,130.0,129.5,128.8,128.5,128.3,123.9–116.9(q,J＝294.5Hz),119.2,80.0–79.7(m),70.5.
The structural formula of compound 9h is as follows:
example 9 (Compound 9 i)
1. Synthesis of compound 6 i:
under ice bath, compound 1f (2.38 g,6.46 mmol) and NaOH (517mg, 9.21 mmol) were dissolved in 90mL ethanol, stirred for 5min, then compound 4e (2.28 g,6.44 mmol) was added, reacted at room temperature for 24h, after the reaction was complete, 2M diluted hydrochloric acid was added to neutralize the system, after three extractions with DCM was added, the organic phases were combined, and the organic phases were quenched with anhydrous Na 2 SO 4 Drying, rotary evaporation to remove the solvent, and separation and purification of the residue by chromatography column (eluent PE and EA) gave 6i (2.59 g) as a pale yellow solid in 57% yield.
1 H NMR(500MHz,CDCl 3 )δ8.05–7.95(m,2H),7.82(d,J＝15.7Hz,1H),7.67–7.40(m,7H),5.13(s,2H),5.09(s,2H).
19 F NMR(471MHz,CDCl 3 )δ–73.26.
13 C NMR(126MHz,CDCl 3 )δ189.9,144.6,138.5,135.8,135.6,135.3,132.0,129.8,129.5,129.3,128.9,128.8,127.7,127.5,122.5,124.0–117.0(d,J＝293.1Hz),80.6–79.4(m),70.9.
The structural formula of compound 6i is as follows:
2. synthesis of compound 7 i:
compound 6i (2.55 g,3.62 mmol), meNO 2 (2.27 g,37.18 mmol) and KOH (41 mg,0.73 mmol) were dissolved in EtOH and reacted at 80℃for 5h, after which the reaction was completed, cooled to room temperature, then the system was neutralized to neutrality by the addition of 2M dilute hydrochloric acid, then extracted with DCM and the organic phase was taken up in anhydrous Na 2 SO 4 Drying, distilling off the solvent under reduced pressure, and separating and purifying the residue by chromatography column (eluent PE and EA) to give 7i (1.99 g) as pale yellow oily liquid in 72% yield.
1 H NMR(500MHz,CDCl 3 )δ7.93–7.84(m,2H),7.58(d,J＝7.6Hz,1H),7.51(t,J＝7.7Hz,1H),7.38(t,J＝7.6Hz,1H),7.32–7.26(m,3H),7.24(d,J＝2.2Hz,1H),5.07(s,2H),5.02(s,2H),4.84(dd,J＝12.6,6.7Hz,1H),4.71(dd,J＝12.6,7.8Hz,1H),4.28–4.23(m,1H),3.53–3.40(m,2H).
19 F NMR(471MHz,CDCl 3 )δ–73.30.
13 C NMR(126MHz,CDCl 3 )δ196.2,139.6,136.7,135.9,135.7,132.7,129.6,129.4,128.4,127.9,127.2,127.1,126.6,120.4(q,J＝293.4Hz),80.9–79.1(m),79.3,70.9,70.6,41.5,39.1.
The structural formula of compound 7i is as follows:
3. synthesis of compound 8 i:
under dark conditions, compound 7i (1.98 g,2.58 mmol) was reacted with NH 4 OAc (6.97 g,90.47 mmol) is placed at 120 ℃The reaction was carried out for 5 hours. After the reaction is finished, adding a large amount of water to wash out excessive NH 4 OAc, followed by three extractions with DCM and combining the organic phases, the organic phases were extracted with anhydrous Na 2 SO 4 The solvent was removed by rotary evaporation and the residue was recrystallized from a mixed solvent of DCM and methanol to give purple-black intermediate 8i (150 mg) which was used directly in the next reaction.
4. Synthesis of compound 9 i:
violet intermediate 8i (150 mg,0.10 mmol) and DIPEA (133.56 mg,1.03 mmol) were added to anhydrous DCM under nitrogen, stirred for 20 min, followed by BF 3 ·Et 2 O (201.6 mg,1.42 mmol), at 40℃for 24h, quenched with water, extracted three times with DCM and the organic phases combined, dried Na 2 SO 4 The DCM was dried, distilled off, and the residue was purified by chromatography column (eluent PE and EA) to give 9i (97 mg) as a black solid in 63% yield.
1 H NMR(500MHz,CDCl 3 )δ8.08–7.87(m,8H),7.50(tt,J＝16.4,7.7Hz,8H),7.03(s,2H),5.11(s,4H),5.08(s,4H).
19 F NMR(471MHz,CDCl 3 )δ–73.30,–134.62(dd,J＝64.5,32.0Hz).
13 C NMR(151MHz,CDCl 3 )δ159.3,145.7,144.0,135.5,135.4,132.5,131.8,130.2,129.9,129.2,129.0,128.8,128.6,128.3,120.4(q,J＝292.39Hz),80.4–79.6(m),71.0,70.9.
The structural formula of compound 9i is as follows:
test one, photo-thermal Effect test of fluorinated aza-BODIPY derivatives of the invention
The test method comprises the following steps:
1. an appropriate amount of the compound 9a prepared in example 1 was weighed and dissolved in chloroform to prepare a sample solution having a final concentration of 20. Mu.M of the compound 9 a. The sample solution was subjected to a treatment of 0.5W/cm 2 660nm laser irradiation, usingThe infrared camera records the temperature change of the sample, the numerical value is recorded every 30 seconds, the temperature change after 6 minutes is smooth, and the laser irradiation is stopped. Three replicates were averaged.
2. Compounds 9b-9i were tested according to the procedure of step 1.
Test results:
the temperature change with time of the compounds 9a to 9i under laser irradiation is shown in FIG. 1, and it can be seen from FIG. 1 that the temperature change value (. DELTA.T) of the compounds 9a to 9i under laser irradiation is 13.9℃to 20.2 ℃. Compared with many photothermal agents based on aza-BODIPY, the compounds 9a-9i show moderate photothermal conversion capacity, thus indicating that the invention introduces perfluoro-tert-butyl based on aza-BODIPY without significantly changing the photothermal conversion capacity of aza-BODIPY.
Test II, test of the Activity of the fluorinated aza-BODIPY derivative of the invention
The test method comprises the following steps:
1. an appropriate amount of the compound 9a and DPBF prepared in example 1 was weighed and dissolved in chloroform to prepare a sample solution in which the final concentration of the compound 9a was 1 μm and the final concentration of 1, 3-diphenyl isobenzofuran (DPBF) was 40 μm. The sample solution was treated with 660nm, 0.5W/cm 2 The absorbance values of DPBF at 415nm were recorded at different times by laser irradiation. Three replicates were averaged.
2. The compounds 9b to 9i were tested according to the procedure of step 1, using DPBF as an active oxygen indicator, and the active oxygen formation of the compounds 9a to 9i was studied, and the characteristic absorption peak of DPBF at 415nm was gradually decreased with the formation of active oxygen.
Test results:
in the presence of laser irradiation and fluorinated aza-BODIPY derivatives, the ultraviolet-visible absorption spectrum of DPBF over time is shown in FIG. 2, and it is clear from FIG. 2 that the DPBF can be consumed within 1min of laser irradiation with the compound 9a-9i, wherein the consumption rate is the fastest with the compound 9 h. However, the compound 9a having an electron-donating methoxy group at the lower end requires 5 minutes of irradiation after DPBF is consumed, indicating that the methoxy group having an electron-donating group at the lower end is unfavorable for the generation of active oxygen. Compounds with perfluoro-tert-butyl at the lower end consume DPBF more rapidly, whether perfluoro-tert-butyl is in the para-or meta-position, indicating that perfluoro-tert-butyl contributes to reactive oxygen species at the lower end.
Test III in vitro fluorinated aza-BODIPY derivatives of the invention 19 F MRI test
The test method comprises the following steps:
an appropriate amount of the compound 9h prepared in example 8 was weighed and dissolved in chloroform to prepare 4mL of 80mM mother liquor. The stock solutions were diluted with chloroform to give a series of test solutions of 80mM, 40mM, 20mM, 10mM, 5mM and 2.5mM, respectively. The solution to be tested of each concentration is carried out on a 400MHz Bruker BioSpec imaging system 19 F imaging and testing the magnetic room temperature was maintained at 24 ℃ throughout the MRI experiment. Imaging results were obtained using a gradient echo (GRE) pulse sequence, method = re, matrix size = 32 x 32, si = 20mm, fov = 3.0cm, tr = 4000ms, te = 3ms, scan time = 256s.
Test results:
compound 9h 19 As shown in FIG. 3, the F NMR spectrum of the compound 9h showed that it contained 36 symmetrical fluorine atoms, resulting in a strong and single at-77.41 ppm 19 F NMR peak, indicated by 19 F NMR gave a sensitive monitoring of compound 9 h. This is strong and unitary 19 The F NMR peak allows compound 9h to be 19 F MRI contrast agents without chemical shift induced imaging artifacts allow for 100% imaging utilization of fluorine atoms.
Solutions of compounds 9h at different concentrations 19 FMRI is shown in FIG. 4, and as can be seen from FIG. 4, compound 9h shows a higher level 19 F MRI sensitivity can be performed even at a low concentration of 0.14mmol of the compound 19 F MRI analysis.
Taking the concentration of the compound 9h solution as the abscissa, taking the compound 9h solutions with different concentrations 19 The logarithmic value of the signal intensity of the F MRI is plotted according to the detected data to obtain a standard curve after fitting, the standard curve is shown in figure 5, and the standard curve is shown in figure 5， 19 Logarithmic value of F MRI signal intensity 19 F concentration is proportional, indicating that it can be utilized 19 Fmri signal intensity accurate quantification 19 F sample concentration.
The above experimental results show that the fluorinated aza-BODIPY derivatives of the present invention have the following properties as 19 Potential of F MRI contrast agents.
Test IV cell uptake assay of fluorinated aza-BODIPY derivatives of the invention
The test method comprises the following steps:
a549 cells were cultured using DMEM-high sugar medium containing 10% fetal bovine serum and 1% penicillin-streptomycin and containing 5% CO at 37 °c 2 Is cultured in an incubator of (a) 549 cells (1×10) 5 Individual cells, 1 mL) were inoculated in confocal dishes and placed in an incubator for 24h incubation. After the cells were sufficiently attached, the original culture solution was removed, and fresh medium containing the compound 9h (8. Mu.M) prepared in example 8 was added thereto, and incubated for 0.5, 2,4, 6, and 12h, respectively. After each incubation was completed, 3 washes with ice PBS followed by fixation with 1mL of 4% paraformaldehyde for 15min, blotting off 4% paraformaldehyde, 3 washes with ice PBS, further incubation with 200 μl of DAPI staining solution for 10min, blotting off DAPI staining solution, 3 washes with ice PBS, and finally adding 1mL of PBS in a petri dish, and cell images were collected using a nikon confocal laser scanning microscope 60-fold oil microscope.
Test results:
as shown in fig. 6, the fluorescence imaging chart of the compound 9h after incubation with the a549 cells for different time is shown in fig. 6, and as the incubation time is prolonged, the fluorescence intensity of the intracellular compound 9h gradually increases, and the fluorescence intensity reaches the maximum value at 6h, thereby showing that the fluorinated aza-BODIPY derivative has excellent cell membrane targeting capability, and the maximum uptake time point is 6h.
Claims (13)
1. A fluorinated aza-BODIPY derivative is characterized by having the following structural general formula:
wherein R is 1 、R 2 Methoxy, trifluoromethyl or (CH) 2 ) n OC(CF 3 ) 3 Equal substituent, R 1 、R 2 The number of (2) is not less than 1, and R 1 、R 2 At least one of them is (CH 2 ) n OC(CF 3 ) 3 N is a natural number of not more than 20, and F is fluorine-19.
2. A synthesis method of fluorinated aza-BODIPY derivatives is characterized by comprising the following steps:
s1, a structural general formula of the compound shown in the formula (I) is as follows:
wherein R is 2 Is methoxy, trifluoromethyl or (CH) 2 ) n OC(CF 3 ) 3 Equal substituent, R 2 Not less than 1, n is a natural number not greater than 20;
when R is 2 Is (CH) 2 ) n OC(CF 3 ) 3 In this case, the method for synthesizing the compound of formula (I) is as follows:
in the presence of a catalyst, the compound of the formula (II) and a brominating reagent undergo bromination reaction to generate a compound of the formula (III), wherein the reaction formula is as follows:
nucleophilic substitution reaction of the compound of formula (III) with a metal salt of perfluoro-tert-butanol under nitrogen atmosphere to produce a compound of formula (I) having the following reaction formula:
s2, the structural general formula of the compound shown in the formula (IV) is as follows:
wherein R is 1 Is methoxy or (CH) 2 ) n OC(CF 3 ) 3 Equal substituent, R 1 Not less than 1, n is a natural number not greater than 20;
when R is 1 Is (CH) 2 ) n OC(CF 3 ) 3 In this case, the method for synthesizing the compound of formula (IV) is as follows:
nucleophilic substitution reaction of the compound of formula (V) with a metal salt of perfluoro-tert-butanol under nitrogen atmosphere to produce a compound of formula (IV) having the following reaction formula:
s3, under alkaline conditions, carrying out aldol condensation reaction on the compound of the formula (I) and the compound of the formula (IV) to generate a compound of the formula (VI), wherein the reaction formula is as follows:
s4, carrying out Michael addition reaction on the compound of the formula (VI) and nitromethane under alkaline conditions to generate a compound of the formula (VII), wherein the reaction formula is as follows:
s5, carrying out condensation reaction on the compound of the formula (VII) in the presence of ammonium acetate and in the dark to generate the compound of the formula (VIII), wherein the reaction formula is as follows:
s6, under the condition of nitrogen atmosphere and alkali, the compound of the formula (VIII) is directly subjected to complexation reaction with boron trifluoride diethyl etherate to generate the fluorinated aza-BODIPY derivative, wherein the reaction formula is as follows:
3. the method for synthesizing a fluorinated aza-BODIPY derivative according to claim 2, wherein: the brominating reagent is N-bromosuccinimide, and the catalyst is azodiisobutyronitrile.
4. The method for synthesizing a fluorinated aza-BODIPY derivative according to claim 2, wherein: in the bromination reaction, the reaction temperature is 80-100 ℃, the reaction time is 4-24h, and the mol ratio of the compound shown in the formula (II), the brominating reagent and the catalyst is 1.0:1.0-2.0:0.2.
5. The method for synthesizing a fluorinated aza-BODIPY derivative according to claim 2, wherein: the metal salt of perfluoro-tert-butanol is potassium salt or sodium salt of perfluoro-tert-butanol, the reaction temperature is normal temperature, the reaction time is 12-24h, and the molar ratio of the compound of formula (III) or the compound of formula (V) to perfluoro-tert-butoxide is 1.0:1.0-2.0 in the nucleophilic substitution reaction of the steps S1 and S2.
6. The method for synthesizing a fluorinated aza-BODIPY derivative according to claim 2, wherein: the alkali used in the steps S3 and S4 is sodium hydroxide or potassium hydroxide, and the alkali used in the step S6 is N, N-diisopropylethylamine.
7. The method for synthesizing a fluorinated aza-BODIPY derivative according to claim 2, wherein: in the aldol condensation reaction, the reaction temperature is normal temperature, the reaction time is 0.5-24h, and the molar ratio of the compound of the formula (I), the compound of the formula (IV) and the alkali is 1.0:1.0:2.0-3.0.
8. The method for synthesizing a fluorinated aza-BODIPY derivative according to claim 2, wherein: in the Michael addition reaction, the reaction temperature is 80-100 ℃, the reaction time is 4-12h, and the molar ratio of the compound of the formula (VI), nitromethane and alkali is 1.0:20.0-30.0:0.2.
9. The method for synthesizing a fluorinated aza-BODIPY derivative according to claim 2, wherein: in the condensation reaction, the reaction temperature is 115-120 ℃, the reaction time is 4-12h, and the molar ratio of the (VII) compound to the ammonium acetate is 1.0:20.0-40.0.
10. The method for synthesizing a fluorinated aza-BODIPY derivative according to claim 2, wherein: in the complexing reaction, the reaction temperature is 25-50 ℃, the reaction time is 12-24h, and the molar ratio of the compound of the formula (VIII), the alkali and the boron trifluoride diethyl ether is 1.0:20.0-30.0:20.0-30.0.
11. Use of a fluorinated aza-BODIPY derivative according to claim 1 for the preparation of a bimodal contrast agent.
12. Use of a fluorinated aza-BODIPY derivative according to claim 11, characterized in that: the bimodal contrast agent is a fluorescence imaging contrast agent and a fluorine-19 magnetic resonance imaging contrast agent.
13. Use of a fluorinated aza-BODIPY derivative according to claim 1 for the preparation of a photothermal and photodynamic therapeutic drug targeting the cell membrane of a tumour cell.
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