Synthesis method of 4-SCF3 substituted isoquinoline diketone compound

Abstract

The invention discloses a synthesis method of a 4-SCF3 substituted isoquinoline diketone compound, and belongs to the technical field of organic synthesis. The method comprises the following steps: in a mixed solvent of water and DMSO (dimethylsulfoxide), N-methacryloyl-N-methyl benzamide and silver trifluoromethylthio react under the action of an oxidizing agent to obtain 2, 4-dimethyl-4-(((trifluoromethyl) thio) methyl) isoquinoline-1, 3 (2H, 4H)-diketone; the molar ratio of N-methacryloyl-N-methyl benzamide to silver trifluoromethylthio to the oxidizing agent is 1: (1.0-2.0): (1.0-2.0), the reaction temperature is 60-80 DEG C, the volume ratio of DMSO to water is (2-4): 1 or 1: 2, and the oxidizing agent is selected from potassium persulfate or sodium persulfate. According to the method, the synthesis steps are simplified, the synthesis efficiency is improved, and a new way is provided for preparing the 4-SCF3 isoquinoline diketone derivative with potential biological activity.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing a 4-SCF3-substituted isoquinolinedione compound. Background Art

[0002] Isoquinolinediones are a very important class of N-heterocyclic compounds that play an important role in natural products and a variety of key pharmaceutical molecules. Figure 1 As shown (the red portion represents the isoquinolinedione group), compounds A and B are highly selective CDK4 inhibitors, effectively inhibiting cancer cell proliferation. Compound C has been identified as a scaffold capable of inhibiting HIV-1 integrase. Compound D, an inhibitor of IGF-1R kinase activity, has demonstrated significant inhibition of human tumor growth. Furthermore, isoquinolinediones can be used as fluorescent sensors and pesticides. Consequently, the synthesis of isoquinolinediones has attracted widespread attention among chemists.

[0003] Free radical cascade reactions have attracted much attention in the chemical community due to their high efficiency and simplicity. In particular, in the synthesis of isoquinolinedione derivatives, free radical cascade reactions via acrylamide have become a research hotspot. Various free radicals, including carbon, nitrogen, and sulfur, have been introduced into acrylamide to obtain various 4-substituted isoquinolinedione compounds (such as Figure 2 On the other hand, the trifluoromethylthio (SCF3) group, due to its exceptional lipophilicity and electron-withdrawing properties, plays a crucial role in drug design. The introduction of this group can significantly enhance the biostability and solubility of drug molecules. Therefore, its integration into the isoquinolinedione structure holds promise for the development of novel bioactive drug molecules. While free radical trifluoromethylthiolation reactions have been extensively studied in recent years, the construction of 4-SCF3-substituted isoquinolinediones via a cascade reaction of acrylamide radicals directly initiated by SCF3 radicals remains unreported.

[0004] Shi Tang , Qing-Lan Li , Dong Zhou , et al. Palladium-CatalyzedOxidative Carboacetoxylation of Activated Alkynes with Amino Acids[J],Synthetic Communications . 2014, 1, 689–696. Yu-Jue Chen, Yan-Hong He, ZhiGuan.Metal-free visible-light-promoted thiocyanation / cyclization cascade forthe synthesis of thiocyanato-containing isoquinolinediones.Tetrahedron.Volume 75, Issue 22, 31 May 2019, Pages 3053-3061 discloses a preparation process of isoquinolinediones, which is as follows: Figure 3 As shown, the 4-SCN-substituted isoquinolinedione is first prepared through a thiocyanate-initiated acrylamide radical cascade reaction, and then trifluoromethylated to obtain the target product. This process is relatively tedious and not economical. Summary of the Invention

[0005] This patent provides a method for synthesizing 4-SCF3-substituted isoquinolinedione compounds. This method uses trifluoromethylthiosilver (AgSCF3) as a SCF3 free radical source and potassium persulfate or sodium persulfate as an oxidant. Through the free radical addition / cyclization reaction of acrylamide, 4-SCF3 isoquinolinedione can be generated in one step. Under optimized conditions, the yield reaches more than 50%.

[0006] The reaction equation of this method is as follows:

[0007] The method comprises reacting N-methacryloyl-N-methylbenzamide (compound 1) and trifluoromethylthiosilver (compound 2) in a mixed solvent of water and DMSO under the action of an oxidant to obtain 2,4-dimethyl-4-(((trifluoromethyl)thio)methyl)isoquinoline-1,3(2H,4H)-dione (compound 3). The molar ratio of N-methacryloyl-N-methylbenzamide, trifluoromethylthiosilver, and oxidant is 1:1.0-2.0:1.0-2.0, the reaction temperature is 60-80°C, and the volume ratio of DMSO to water is 2-4:1 or 1:2. The oxidant is selected from potassium persulfate or sodium persulfate.

[0008] Preferably, the molar ratio of N-methacryloyl-N-methylbenzamide, silver trifluoromethylthio and potassium persulfate is 1:1.5:1.5-2.0.

[0009] Preferably, the reaction temperature is 70°C.

[0010] The reaction time is 10-16 hours, preferably 12 hours.

[0011] Preferably, the oxidizing agent is potassium persulfate.

[0012] Preferably, the volume ratio of DMSO to water is 3:1.

[0013] Most preferably, the synthesis method provided by the present invention comprises: reacting N-methacryloyl-N-methylbenzamide and trifluoromethylthiosilver in the presence of potassium persulfate in a mixed solvent of water and DMSO to obtain 2,4-dimethyl-4-(((trifluoromethyl)thio)methyl)isoquinoline-1,3(2H,4H)-dione. The molar ratio of N-methacryloyl-N-methylbenzamide, trifluoromethylthiosilver, and potassium persulfate is 1:1.5:1.5-2.0, the reaction temperature is 70°C, the reaction time is 12 hours, and the volume ratio of DMSO to water is 3:1.

[0014] Furthermore, after the reaction is completed, the product is purified. The purification process is as follows: after the reaction is completed, water is added to the reaction solution, and then an extractant is added to extract multiple times, and the organic phase is evaporated to obtain a crude product; the crude product is extracted multiple times with an extractant and water, the organic phase is dried, and purified by chromatography to obtain a fine product.

[0015] Specifically, the purification process is as follows: after the reaction is completed, water is added to the reaction solution, and each extraction is performed three times with ethyl acetate. The resulting organic phases are combined and dried on a rotary evaporator to obtain a crude product. Water and ethyl acetate are added to the crude product for extraction, and the organic phase is collected and extracted three times in the same manner. The organic phases are combined and dried over anhydrous magnesium sulfate. After removing the organic solvent in a vacuum, the resulting crude product is further separated and purified by column chromatography. The mobile phase for separation and purification is a developing solvent of ethyl acetate:petroleum ether in a ratio of 1:10, and the stationary phase is silica gel. Chromatographic purification yields a fine product.

[0016] The applicant speculates that the possible reaction mechanism of this patent is as follows Figure 3 As shown: AgSCF3 is initially oxidized by K2S2O8 to generate the SCF3 radical. The SCF3 radical undergoes intermolecular regioselective addition across the double bond of compound 1 to provide the alkyl radical intermediate A, which then undergoes cyclization to provide the aryl radical intermediate B. Finally, another single electron transfer reaction with the Ag(II) species and a β-H elimination affords the desired compound 3.

[0017] Under the optimized conditions of this patent: the reaction solvent is DMSO and H2O (volume ratio 3:1), the oxidant is K2S2O8 (1.5 equiv.), the amount of N-methylacryloyl-N-methylbenzamide and trifluoromethylthiosilver n(1):n(2) is 1:1.5, the reaction time is 12h, the reaction temperature is 70℃, and the yield is 54%. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is the molecular formula of various isoquinolinedione compounds.

[0019] Figure 2 This is a reaction flow diagram of a free radical cascade reaction.

[0020] Figure 3 The present invention is a roadmap for synthesizing 4-SCF3-substituted isoquinolinediones in the prior art.

[0021] Figure 4 This is the possible reaction mechanism of the present synthesis method speculated by the applicant.

[0022] Figure 5 The target product 1 HNMR spectrum.

[0023] Figure 6 The target product 3 CNMR spectrum.

[0024] Figure 7 The target product 19 FNMR spectrum. DETAILED DESCRIPTION

[0025] In order to make the objectives, technical solutions and advantages of the present invention more clear, the present invention will be described in further detail below with reference to the accompanying drawings.

[0026] The embodiment of the present invention provides a method for synthesizing a 4-SCF3-substituted isoquinolinedione compound, and the process is as follows: 1. Synthesis Experiment 1.1 Reagents and Instruments All reagents and solvents were commercially available unless otherwise specified; column chromatography silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant; and a Bruker ADVANCE 400 MHz NMR spectrometer (CDCl3 as solvent, TMS as internal standard) was purchased from Bruker, Germany. 1.2 Synthesis Method In order, 0.2mmol N -Methacryloyl- N4-Methylbenzamide (Compound 1), 0.3 mmol silver trifluoromethylthiosulfate (Compound 2), 0.3 mmol potassium persulfate, and 2 mL of a mixture of water and DMSO (DMSO:water, volume ratio 3:1) were added, along with a No. 5 magnetic stirrer (stirring rate 600 r / s). After passing condensed water through a condenser tube from bottom to top, the reactor was placed in a 70°C oil bath and heated with stirring for 12 hours. After the reaction, 15 mL of water was added to the reaction mixture, and the mixture was extracted three times with 10 mL of ethyl acetate each time. The resulting organic phases were combined and dried on a rotary evaporator to obtain the crude product. 15 mL of water and 10 mL of ethyl acetate were added to the crude product for extraction, and the organic phase was collected. The same extraction procedure was repeated three times, and the organic phases were combined and dried over anhydrous magnesium sulfate. After removing the organic solvent in vacuo, the crude product was further separated and purified by column chromatography. The mobile phase for separation and purification was a developing solvent of ethyl acetate:petroleum ether = 1:10, and the stationary phase was column chromatography silica gel. The chromatography reaction was carried out using a 300 mL column. The by-products were separated from the target product during the column chromatography separation process, and 32.7 mg of a white oily liquid (Rf = 0.3) was obtained, with a yield of 54%.

[0027] 1 HNMR (400 MHz, CDCl3): δ 8.28 (dd, J = 7.9, 1.5Hz, 1H), 7.68(td, J = 7.6,1.5 Hz, 1H), 7.50 (td, J = 7.5, 1.1 Hz, 1H), 7.41 (dd, J = 8.0, 1.1Hz, 1H), 3.80(d, J = 12.8 Hz, 1H), 3.44( d , J = 12.9 Hz, 1H), 3.40 (s, 3H), 1.73 (s, 3H).

[0028] 13 CNMR (100 MHz, CDCl3): δ173.3, 162.8, 139.3, 133.3, 129.1 (q, J =306Hz), 128.3, 127.4, 124.2, 124.1, 46.7, 39.2 (q, J = 2.09 Hz), 28.7, 26.3.

[0029] 19 FNMR (376MHz, CDCl3): δ -41.02 (s).

[0030] The fluorine spectrum reveals a single fluorine signal at δ -41.02, with a chemical shift similar to that of the SCF3 group, indicating the presence of the SCF3 group. The proton spectrum reveals four hydrogen atoms in the aromatic region. Two singlets at δ 3.4 and 1.7, with an integral of 3, are attributed to the two methyl CH3 groups. The remaining two hydrogen atoms are located in the aliphatic region, chemically shifted downfield at 3.88 ppm and 3.4 ppm due to the presence of electron-withdrawing groups. The integrated number of hydrogen atoms is consistent with the structure, indicating 12 hydrogen atoms. The carbon spectrum reveals two peaks at δ 173 and 168, attributed to the two carbonyl groups in the compound's structure. In addition, the characteristic quartet of carbon peaks of SCF3 is also visible. The spectral data are consistent with those reported in the literature.

[0031] 2. Exploration of reaction optimization conditions Based on the existing literature reports on free radical trifluoromethylsulfonation / cyclization, the effects of reaction conditions (solvent type, oxidant type, reactant ratio n(1):n(2), oxidant equivalent, reaction time and temperature) on the yield of the final compound 3 were investigated. The results are shown in Table 1. The applicant also conducted a large number of other experiments, but the yields were much lower than those in Table 1, so they are not listed one by one.

[0032] Table 1

[0033] First, we investigated the effect of solvent on the reaction (Nos. 1-9). We found that no single solvent could yield target product 3 in high yield. Water and DMSO performed best as single solvents. We then tried a mixture of water and DMSO, ultimately achieving a 54% yield of target product 3 using a 3:1 volume ratio of DMSO to water. This is likely due to the fact that the addition of water properly solubilizes the potassium salt of the oxidant, thereby promoting the reaction. We then further screened oxidants and found that none performed as well as potassium persulfate (Nos. 10, 11). Finally, we extensively screened the reaction molar ratio, equivalent ratio of the oxidant, reaction temperature, and time, finding no other conditions superior to those in No. 8. Selected data are shown in Table 1. The maximum yield of the target product in this reaction was only 54%, primarily due to the fact that compound 1 decomposes into an amide under the reaction conditions when the reaction temperature is too high, while the reaction does not initiate at too low a temperature. Furthermore, a non-cyclized trifluoromethylthioation byproduct is present during the reaction. Therefore, it was finally determined that the optimal reaction solvent was DMSO and H2O (volume ratio 3:1), the oxidant was K2S2O8 (1.5 equiv.), the dosage n(1):n(2) was 1:1.5, the reaction time was 12 h, and the reaction temperature was 70 °C (No. 8). The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. 4-SCF3 substituted isoquinolinedione compound synthesis method, characterized in that, The method comprises: in a mixed solvent of water and DMSO, reacting N-methacryloyl-N-methylbenzamide and trifluoromethylthiosilver under the action of an oxidant to obtain 2,4-dimethyl-4-(((trifluoromethyl)thio)methyl)isoquinoline-1,3(2H,4H)-dione; the molar ratio of the N-methacryloyl-N-methylbenzamide, trifluoromethylthiosilver and the oxidant is 1:1.0-2.0:1.0-2.0, the reaction temperature is 60-80°C, the volume ratio of the DMSO to water is 2-4:1 or 1:2, and the oxidant is selected from potassium persulfate or sodium persulfate.

2. The synthesis method according to claim 1, wherein The molar ratio of the N-methylacryloyl-N-methylbenzamide, silver trifluoromethylthio and potassium persulfate is 1:1.5:1.5-2.

0.

3. The synthesis method according to claim 1, wherein The reaction temperature was 70°C.

4. The synthesis method according to claim 1, characterized in that The reaction time is 10-16 hours.

5. The synthesis method according to claim 1, characterized in that The reaction time is 12 hours.

6. The synthesis method according to claim 1, characterized in that The oxidant is potassium persulfate.

7. The synthesis method according to claim 1, characterized in that The volume ratio of DMSO to water is 3:

1.

8. The synthesis method according to claim 1, characterized in that The method comprises: in a mixed solvent of water and DMSO, reacting N-methylacryloyl-N-methylbenzamide and trifluoromethylthiosilver under the action of potassium persulfate to obtain 2,4-dimethyl-4-(((trifluoromethyl)thio)methyl)isoquinoline-1,3(2H,4H)-dione; the molar ratio of the N-methylacryloyl-N-methylbenzamide, trifluoromethylthiosilver and potassium persulfate is 1:1.5:1.5-2.0, the reaction temperature is 70°C, the reaction time is 12 hours, and the volume ratio of the DMSO to water is 3:

1.

9. The synthesis method according to claim 1 or 8, characterized in that After the reaction is completed, water is added to the reaction solution, and then an extractant is added to extract multiple times, and the organic phase is evaporated to dryness to obtain a crude product; the crude product is extracted multiple times with an extractant and water, the organic phase is dried, and purified by chromatography to obtain a fine product.

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