Synthesis method of an N-trifluoromethylthio isochromene-1-imine compound

Abstract

The invention discloses a method for synthesizing N-trifluoromethylthioisochromene-1-imine compounds, belonging to the field of organic chemistry. The method of the invention uses 2-alkynyl aromatic amide compounds and N-trifluoromethylthiosaccharin as raw materials, and can realize the one-step synthesis of polysubstituted N-trifluoromethylthioisochromene-1-imine compounds without adding any metal catalysts and organic ligands. This method has a wide substrate applicability, simple and easily available raw materials, and low economic cost; in addition, to realize the synthesis of the target product by the method of the invention, it only needs to react at room temperature for 12-14 hours to obtain the target product in a good yield, and the target compound has wide applications in the fields of medicine, pesticides and functional materials, etc.

Description

Technical Field

[0001] The present invention specifically relates to a method for synthesizing N-trifluoromethylthioisochromene-1-imine compounds, belonging to the field of organic chemistry. Background Art

[0002] The trifluoromethylthio group is an important fluorine-containing functional group, which has excellent liposolubility, strong electron-withdrawing property and the resulting biological activities, etc., and is widely used in the fields of organic synthesis, medicinal chemistry, materials science, etc. The stability and relatively easy introduction chemical properties of the trifluoromethylthio group make it one of the most popular groups. In addition, isochromene is a stable lipophilic compound of o-phenols. Polyphenolic isochromenes can inhibit stimulant-induced platelet aggregation and coagulation, activate platelets, and activate microglia. However, there are few reports on the method of introducing N-SCF3 into the isochromene skeleton at present.

[0003] When the prior art introduces trifluorinated groups into compounds, most of them will use catalysts. For example, the catalyst used in Patent CN117865869A is various metal compounds; when synthesizing isochromene compounds, most of them use noble metal catalysts. For example, CN 110204533A uses silver as the catalyst. Due to the defects of high cost, toxicity, environmental damage during recovery and treatment of the catalyst itself, and the easy generation of by-products during the catalytic reaction process, and the difficulty in separating the two during the subsequent separation and purification of the product, it will affect the product quality.

[0004] Therefore, it is very valuable to directly synthesize N-trifluoromethylthioisochromene-1-imine compounds by a simple and mild method without adding a catalyst. In the field of organic synthesis, the research on N-trifluoromethylthiolation methods has also attracted wide attention. Summary of the Invention

[0005] The present invention has developed a new method for synthesizing N-trifluoromethylthioisochromene-1-imine. Through the N-trifluoromethylthiolation / cyclization of 2-alkynyl aromatic amide compounds and N-trifluoromethylthiosaccharin, the synthesis of N-trifluoromethylthioisochromene-1-imine compounds is realized quickly and conveniently.

[0006] The first object of the present invention is to provide a method for synthesizing N-trifluoromethylthioisochromene-1-imine compounds, which includes the following steps: in an organic solvent, the 2-alkynyl aromatic amide compounds shown in formula (1) and N-trifluoromethylthiosaccharin are used as reactants, and a cyclization reaction is carried out without a catalyst and a ligand to synthesize the N-trifluoromethylthioisochromene-1-imine compounds shown in formula (2);

[0007]

[0008] Among them, R 1 is selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, C1-C8 alkoxy, acyl, amide and heterocycle; R 2 is selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl, amide and heterocycle.

[0009] In one embodiment of the present invention, the aryl includes a substituted or unsubstituted benzene ring or naphthalene ring; the substitution can be mono- to trisubstitution; the substituting groups are selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, ester group, cyano group, nitro group and heterocycle.

[0010] In one embodiment of the present invention, the acyl group is -COR a , R a is H or C1-8 alkyl.

[0011] In one embodiment of the present invention, the amide group is -NHCOR b , R b is H or C1-8 alkyl.

[0012] In one embodiment of the present invention, the heterocycle is a three- to six-membered ring containing 1-3 heteroatoms. The heteroatoms include N, O, and S.

[0013] In one embodiment of the present invention, the ester group is -COOR c , R c is C1-8 alkyl.

[0014] In one embodiment of the present invention, the organic solvent includes any one or more of dichloromethane (CH2Cl2), acetonitrile (CH3CN), tetrahydrofuran (THF), and methanol (CH3OH). CH2Cl2 is preferred.

[0015] In one embodiment of the present invention, the temperature of the reaction is 25°C - 50°C. 25 - 30°C is preferred.

[0016] In one embodiment of the present invention, the reaction time is 8 - 14 h. Specifically, 12 h is preferred.

[0017] In one embodiment of the present invention, the molar ratio of the 2-alkynyl aromatic amide compound to N-trifluoromethylsulfonyl saccharin is 1:(2.0 - 3.0). 1:2.8 is preferred.

[0018] In one embodiment of the present invention, the reaction concentration of the 2-alkynyl aromatic amide compound is 0.05 - 5 mmol / mL. Specifically, 0.1 mmol / mL is preferred.

[0019] In one embodiment of the present invention, the N-trifluoromethylthiolation / cyclization reaction is carried out under an inert atmosphere. For example: a nitrogen atmosphere.

[0020] The second object of the present invention is to provide a synthetic method for a novel green economy N-trifluoromethylthioisochromene-1-imine compound, comprising the following steps:

[0021] Using 2-alkynyl aromatic amide compounds and trifluoromethylthiosaccharin as raw materials, after stirring and reacting at 25 °C - 30 °C for a period of time, a crude product of a polysubstituted N-trifluoromethylthioisochromene-1-imine compound is obtained, and then a pure polysubstituted N-trifluoromethylthioisochromene-1-imine compound is obtained through filtration, washing, vacuum distillation and column chromatography separation.

[0022] In one embodiment of the present invention, the separation and purification method is to use flash column chromatography to obtain the final product, a polysubstituted N-trifluoromethylthioisochromene-1-imine compound.

[0023] In one embodiment of the present invention, the method is preferably carried out as follows: Add 2-alkynyl aromatic amide compounds and N-trifluoromethylthiosaccharin to a reaction vessel containing dichloromethane solvent in a molar ratio of 1:2.8, stir at 25 °C - 30 °C for 12 - 14 hours, separate and purify to obtain the target product.

[0024] In one embodiment of the present invention, the reaction mechanism of the method is as follows: 2-alkynyl aromatic amide compounds react with N-trifluoromethylthiosaccharin to form a -CONHSCF3 reaction intermediate. Subsequently, the intermediate undergoes an isomerization similar to enol tautomerism, and the oxygen anion undergoes nucleophilic addition / cyclization with the alkynyl group adjacent to the aromatic ring, accompanied by hydrogen electron transfer to generate a polysubstituted N-trifluoromethylthioisochromene-1-imine compound.

[0025] The third object of the present invention is to provide a preparation method for isocoumarin derivatives, which can be an important component of natural products. The preparation method includes:

[0026] (1) First, use the method of the present invention to prepare and synthesize N-trifluoromethylthioisochromene-1-imine compounds. Specifically:

[0027] In an organic solvent, 2-alkynyl aromatic amide compounds shown in formula (1) and trifluoromethylthiosaccharin are used as reactants, and a cyclization reaction is carried out without a catalyst and a ligand to synthesize N-trifluoromethylthioisochromene-1-imine compounds shown in formula (2);

[0028]

[0029] Wherein, R 1Selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, C1-C8 alkoxy, acyl, amido and heterocycle; R 2 Selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl, amido and heterocycle.

[0030] (2) The N-trifluoromethylthioisochromene-1-imine compound prepared in step (1) is used as a reactant to prepare isocoumarin derivatives.

[0031] In one embodiment of the present invention, the isocoumarin derivatives use the polysubstituted N-trifluoromethylthioisochromene-1-imine compound as a synthetic intermediate; optionally, the isocoumarin derivatives can be bioactive drug molecules, such as the isocoumarin drug intermediates reported in the patent document WO2015144911Al, etc.

[0032] The fourth object of the present invention is to provide an application of the method in the fields of medicine, pesticide and functional material preparation.

[0033] In one embodiment of the present invention, the application is for preparing the N-trifluoromethylthioisochromene-1-imine compound, or the isocoumarin derivatives that can be further reacted from the N-trifluoromethylthioisochromene-1-imine compound as a raw material.

[0034] The fifth object of the present invention is to provide a synthesis method of isocoumarin derivatives, and the structure of the isocoumarin derivatives is shown as follows: The reaction route of the method is:

[0035]

[0036] Wherein, R 1 , R 2 are as defined above, and R 1 is selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, C1-C8 alkoxy, acyl, amido and heterocycle; R 2 is selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl, amido and heterocycle.

[0037] In one embodiment of the present invention, R 1 is specifically optional as H, and R 2 is specifically optional as methylphenyl.

[0038] In one embodiment of the present invention, the synthesis method of the isocoumarin drug intermediate includes the following steps:

[0039] (1) In an organic solvent, 2-alkynyl aromatic amide compounds and N-trifluoromethylthiosaccharin are used as reactants, and a cyclization reaction is carried out in one pot to synthesize N-trifluoromethylthioisochromene-1-imine compounds;

[0040] (2) The obtained N-trifluoromethylthioisochromene-1-imine compounds are basified and then acid-hydrolyzed to obtain isocoumarin drug intermediates.

[0041] In one embodiment of the present invention, the conditions involved in step (1) are the same as those in the above synthesis method of N-trifluoromethylthioisochromene-1-imine compounds.

[0042] In one embodiment of the present invention, the acid hydrolysis after basification in step (2) is to dissolve the N-trifluoromethylthioisochromene-1-imine compounds in methanol, then add potassium carbonate, stir at room temperature for a period of time, and then add an aqueous hydrochloric acid solution and react at room temperature for a period of time.

[0043] In one embodiment of the present invention, the concentration of the aqueous hydrochloric acid solution is 12M.

[0044] Beneficial effects:

[0045] (1) In the method of the present invention, in a nitrogen atmosphere, 2-alkynyl aromatic amide and N-trifluoromethylthiosaccharin are used as reactants, and the construction of the N-trifluoromethylthioisochromene-1-imine skeleton is achieved by a one-pot reaction to obtain the target compound.

[0046] (2) The method of the present invention uses N-trifluoromethylthiosaccharin as a fluorine source, has a wide substrate applicability, simple and easily available raw materials, and low economic cost; in addition, the method of the present invention only needs to react at room temperature for 12-14 hours to obtain the target product in a relatively high yield, and the method is fast and efficient; moreover, the present invention does not require any catalyst, ligand and base for catalysis, and the reaction method is simple and efficient.

[0047] (3) The synthesis method of the present invention converts easily available 2-alkynyl aromatic amide into the corresponding N-trifluoromethylthioisochromene-imine compounds under relatively simple conditions, and realizes the synthesis of multi-substituted N-trifluoromethylthioisochromene-imine derivatives in one step. The target compounds have wide applications in the fields of medicine, pesticides and functional materials, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 It is a synthesis route diagram of the method of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0049] The following are the specific embodiments of the present invention.

[0050] 1. The o-alkynylbenzamides involved in the following examples include 2-phenylethynylbenzamide (CAS: 80221-08-5), 2-(p-fluorophenylethynyl)benzamide (CAS: 1839028-54-4), 2-(2-methylphenylethynyl)benzamide (CAS: 1260150-35-3), 2-octynylbenzamide (CAS: 124394-20-3), 2-phenylethynyl-5-methylbenzamide (1425605-57-7), 2-phenylethynyl-5-fluorobenzamide (1338797-90-2), 2-[2-(2-thienyl)ethynyl]benzamide (2516418-56-5); N-trifluoromethylthiosaccharin (CAS: 1647073-46-8), N-trifluoromethylthio phthalimide (CAS: 719-98-2), and N-trifluoromethylthio bis(phenylsulfonyl)imide (CAS: 1902154-93-1) were synthesized according to the reported literature respectively.

[0051] Dichloromethane, ethyl acetate, potassium carbonate, and MeOH were all purchased from Adamas.

[0052] 2. The chromatographic separation and purification method involved in the following examples: Column model: G3, stationary phase: silica gel (particle size 200 - 300 mesh), mobile phase: V 石油醚 :V 乙酸乙酯 = 100:1.

[0053] 3. The synthetic route diagram of the examples of the present invention is as Figure 1 shown, specifically:

[0054] Using o-alkynylbenzamide and N-trifluoromethylthiosaccharin as raw materials, dichloromethane as the reaction solvent, reacting at 25°C - 30°C for 12 - 14 hours, the target compound can be obtained. The reaction expression is Figure 1 .

[0055] Example 1: Synthesis of N-trifluoromethylthio-3-phenyl-1H-isoquinoline-1-imine

[0056]

[0057] Under nitrogen protection, 2-phenylethynylbenzamide (111 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (396 mg, 1.4 mmol), and dichloromethane (5 mL) were respectively added to a 25 ml reaction tube equipped with a magnetic stirrer, and reacted at 25°C with a rotation speed of 800 rpm for 12 hours. After the reaction, diatomaceous earth was added for filtration, the filter residue was washed with 30 mL of ethyl acetate, the organic phases were combined and the solvent was removed by distillation under reduced pressure, and then the crude product was separated and purified by column chromatography to obtain 121 mg of the target compound, with a separation yield of 76%.

[0058] The obtained product was analyzed and characterized, and the specific data are as follows:

[0059] 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 9.3 Hz, 1H), 7.78 (d, J = 6.7 Hz, 2H), 7.55–7.40 (m, 4H), 7.39–7.34 (m, 1H), 7.30 (d, J = 7.8 Hz, 1H), 6.68 (s, 1H). 19 F NMR (376 MHz, CDCl3) δ -50.24 (s, 3F). 13 C NMR (101 MHz, CDCl3) δ 151.91 (s), 151.39 (s), 132.58 (s), 132.11 (s), 131.93 (s), 130.10 (s), 129.08 (s), 128.95 (q), 128.74 (s), 127.10 (s), 126.07 (s), 124.85 (s), 122.93 (s), 101.62 (s). HRMS (ESI) m / z calcd. for C 16 H 10 F3NOSH (M + H) + : 322.0513; found: 322.0494.

[0060] Example 2: Synthesis of N-(trifluoromethylthio)-3-(p-fluorophenyl)-1H-isoindene-1-imine

[0061]

[0062] Under nitrogen protection, 2-fluorophenylethynylbenzamide (120 mg, 0.5 mmol), N-(trifluoromethylthio)saccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were respectively added to a 25 ml reaction tube equipped with a magnetic stirrer, and the reaction was carried out at 25 °C with a rotation speed of 800 rpm for 12 hours. After the reaction was completed, diatomaceous earth was added for filtration, the filter residue was washed with 30 mL of ethyl acetate, the organic phases were combined and the solvent was removed by distillation under reduced pressure, and the crude product was separated and purified by column chromatography to obtain 123 mg of the target compound with a separation yield of 73%.

[0063] The obtained product was analyzed and characterized, and the specific data are as follows:

[0064] 11H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 9.1 Hz, 1H), 7.75 (dd, J = 8.9, 5.2 Hz, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 8.6 Hz, 2H), 6.61 (s, 1H). 19 19F NMR (376 MHz, CDCl3) δ -50.22 (s, 3F), -110.13 (s, 1F). 13 13C NMR (101 MHz, CDCl3) δ 165.12 (s), 162.62 (s), 151.22 (d, J = 1.5 Hz), 151.06 (s), 132.66 (s), 132.00 (s), 128.82 (s), 128.70 (q), 128.20 (d, J = 3.3 Hz), 127.14 (s), 126.86 (d, J = 8.4 Hz), 126.03 (s), 122.81 (s), 116.37 (s), 116.15 (s), 101.41 (s). HRMS (ESI) m / z calcd. for C 16 19H9F4NOSH (M + H) + : 340.0419; found: 340.0401.

[0065] Example 3: Synthesis of N-(trifluoromethylthio)-3-o-tolyl-1H-isochromene-1-imine

[0066]

[0067] Under nitrogen protection, 2-methylphenylethynylbenzamide (118 mg, 0.5 mmol), N-(trifluoromethylthio)saccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were added to a 25 ml reaction tube equipped with a magnetic stir bar, and the reaction was carried out at 25 °C with a rotation speed of 800 rpm for 12 hours. After the reaction was completed, diatomaceous earth was added for filtration, and the filter residue was washed with 30 mL of ethyl acetate. The organic phases were combined and the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography to obtain 152 mg of the target compound with a separation yield of 91%.

[0068] The obtained product was analyzed and characterized, and the specific data are as follows:

[0069] 11H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.2 Hz, 1H), 7.51 (q, 2H), 7.43–7.33 (m, 2H), 7.29 (d, J = 9.1 Hz, 3H), 6.34 (s, 1H), 2.52 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -50.40 (s, 3F). 13C NMR (101 MHz, CDCl3) δ 154.24 (s), 151.62 (s), 137.09 (s), 132.64 (s), 132.56 (s), 132.04 (s), 131.37 (s), 130.30 (q, J = 306.2 Hz), 130.07 (s), 129.16 (s), 128.85 (s), 127.14 (s), 126.25 (s), 125.91 (s), 122.80 (s), 105.85 (s), 21.12 (s). HRMS (ESI) m / z calcd. for C 17 H 12 F3NOSH (M + H) + : 336.0670; found: 336.0650.

[0070] Example 4: Synthesis of N-(trifluoromethylthio)-3-n-hexyl-1H-isoindene-1-imine

[0071]

[0072] Under nitrogen protection, 2-octynylbenzamide (115 mg, 0.5 mmol), N-(trifluoromethylthio)saccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were added to a 25 ml reaction tube equipped with a magnetic stir bar, and the reaction was carried out at 25 °C with a rotation speed of 800 rpm for 12 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filter residue was washed with 30 mL of ethyl acetate. The organic phases were combined and the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography to obtain 150 mg of the target compound with a separation yield of 91%.

[0073] The obtained product was analyzed and characterized, and the specific data are as follows:

[0074] 11H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 6.6 Hz, 1H), 5.96 (s, 1H), 2.44 (t, J = 7.5 Hz, 2H), 1.67 (p, J = 7.4 Hz, 2H), 1.47–1.19 (m, 6H), 0.91 (t, 3H). 19 19F NMR (376 MHz, CDCl3) δ -50.45 (s, 3F). 13 13C NMR (101 MHz, CDCl3) δ 156.58 (s), 152.11 (s), 132.39 (s), 132.24 (s), 130.39 (q, J = 305.8 Hz), 128.07 (s), 127.00 (s), 125.07 (s), 122.66 (s), 102.43 (s), 33.08 (s), 31.74 (s), 28.90 (s), 26.66 (s), 22.75 (s), 14.25 (s). HRMS (ESI) m / z calcd. for C 16 H 18 F3NOSH (M + H) + : 330.1140; found: 330.1123.

[0075] Example 5: Synthesis of N-(trifluoromethylthio)-3-phenyl-7-methyl-1H-isoindene-1-imine

[0076]

[0077] Under nitrogen protection, 2-phenylethynyl-5-methylbenzamide (118 mg, 0.5 mmol), N-(trifluoromethylthio)saccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were added to a 25 ml reaction tube equipped with a magnetic stir bar, and the reaction was carried out at 25 °C with a rotation speed of 800 rpm for 12 hours. After the reaction was completed, diatomaceous earth was added for filtration, the filter residue was washed with 30 mL of ethyl acetate, the organic phases were combined and the solvent was removed by distillation under reduced pressure. Then the crude product was purified by column chromatography to obtain 73 mg of the target compound with a separation yield of 44%.

[0078] The obtained product was analyzed and characterized, and the specific data are as follows:

[0079] 11H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.45 (d, J = 7.4 Hz, 3H), 7.31 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.66 (s, 1H), 2.41 (s, 3H). 19 19F NMR (376 MHz, CDCl3) δ -50.18 (s, 3F). 13 13C NMR (101 MHz, CDCl3) δ 151.65 (s), 151.16 (s), 139.13 (s), 133.82 (s), 132.08 (s), 130.38 (q, J = 306.1 Hz), 129.87 (s), 129.64 (s), 129.06 (s), 126.98 (s), 126.04 (s), 124.73 (s), 122.77 (s), 101.61 (s), 21.66 (s). HRMS (ESI) m / z calcd. for C 17 H 12 F3NOSH (M + H) + : 336.0670; found: 336.0663.

[0080] Example 6: Synthesis of N-(trifluoromethylthio)-3-phenyl-7-methyl-1H-isochromene-1-imine

[0081]

[0082] Under nitrogen protection, 2-phenylethynyl-5-fluorobenzamide (120 mg, 0.5 mmol), N-(trifluoromethylthio)saccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were added to a 25 ml reaction tube equipped with a magnetic stir bar, and the reaction was carried out at 25 °C with a rotation speed of 800 rpm for 12 hours. After the reaction was completed, diatomaceous earth was added for filtration, and the filter residue was washed with 30 mL of ethyl acetate. The organic phases were combined and the solvent was removed by distillation under reduced pressure. The crude product was further purified by column chromatography to obtain 94 mg of the target compound with a separation yield of 56%.

[0083] The obtained product was analyzed and characterized, and the specific data are as follows:

[0084] 1 1H NMR (400 MHz, CDCl3) δ 7.84–7.66 (m, 3H), 7.52–7.33 (m, 3H), 7.29 (dd, J = 8.6, 5.2 Hz, 1H), 7.20 (td, J = 8.4, 2.7 Hz, 1H), 6.64 (s, 1H). 1919F NMR (376 MHz, CDCl3) δ -50.20 (s, 3F), -110.34 (s, 1F). 13 13C NMR (101 MHz, CDCl3) δ 163.72 (s), 161.24 (s), 151.50 (d, J = 3.0 Hz), 131.66 (s), 130.16 (s), 130.11 (q, J = 306.2 Hz), 129.11 (s), 128.56 (d, J = 2.8 Hz), 128.16 (d, J = 8.1 Hz), 124.75 (s), 124.51 (d, J = 8.9 Hz), 120.65 (d, J = 23.1 Hz), 113.15 (d, J = 24.3 Hz), 100.67 (s). HRMS (ESI) m / z calcd. for C 16 19H9F4NOSH (M + H) + : 340.0419; found: 340.0402.

[0085] Example 7: Synthesis of N-(trifluoromethylthio)-3-(2-thienyl)-1H-isoindene-1-imine

[0086]

[0087] Under nitrogen protection, 2-(thiophen-2-ylethynyl)-5-methylbenzamide (114 mg, 0.5 mmol), N-(trifluoromethylthio)saccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were added to a 25 ml reaction tube equipped with a magnetic stir bar, and the reaction was carried out at 25 °C with a rotation speed of 800 rpm for 12 hours. After the reaction was completed, diatomaceous earth was added for filtration, the filter residue was washed with 30 mL of ethyl acetate, the organic phases were combined and the solvent was removed by distillation under reduced pressure. Then the crude product was purified by column chromatography to obtain 146 mg of the target compound with a separation yield of 90%.

[0088] The obtained product was analyzed and characterized, and the specific data are as follows:

[0089] 1 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.5 Hz, 1H), 7.50–7.44 (m, 2H), 7.40–7.30 (m, 2H), 7.28–7.21 (m, 1H), 7.13–7.07 (m, 1H), 6.50 (s, 1H). 19 19F NMR (376 MHz, CDCl3) δ -50.27 (s, 3F). 1313C NMR (101 MHz, CDCl3) δ 150.80 (s), 147.95 (s), 135.55 (s), 132.61 (s), 131.92 (s), 130.25 (q, J = 306.2 Hz), 128.55 (s), 128.24 (s), 127.26 (s), 127.19 (s), 125.82 (s), 125.62 (s), 122.74 (s), 100.68 (s). HRMS (ESI) m / z calcd. for C 14 18H8F3NOS2H (M + H) + : 328.0078; found: 328.0062.

[0090] In the present invention, we also replaced 2-[2-(2-thienyl)ethynyl]benzamide with other substitution cases to prepare more corresponding multi-substituted N-trifluoromethylthioisochromene-1-imine target compounds. Through dozens of extended compounds synthesized, we found that the method of the present invention is universal and can effectively prepare the target compounds.

[0091] Example 8: Influence of Different Solvents on the Synthesis of N-Trifluoromethylthioisochromene-1-imine Compounds

[0092] Referring to Example 1, the solvent dichloromethane was replaced with acetonitrile, tetrahydrofuran, methanol, and water respectively, and other conditions remained unchanged to synthesize N-trifluoromethylthioisochromene-1-imine compounds. The specific yield results are shown in Table 1.

[0093] Table 1 Influence of Different Solvents on the Synthesis of N-Trifluoromethylthioisochromene-1-imine

[0094] solvent Separation yield (%) <![CDATA[CH2Cl2 (Example 1)]]> 76 MeCN 65 THF 38 MeOH 45 <![CDATA[H2O]]> 0

[0095] It was found that: when acetonitrile, tetrahydrofuran, methanol, and water were used to replace dichloromethane in Example 1 as the solvent, target products could be obtained except for water, but the product yields were all worse than those in Example 1.

[0096] Example 9: Synthesis of N-Trifluoromethylthioisochromene-1-imine Compounds at Different Reaction Temperatures

[0097] Referring to Example 1, the reaction temperature was replaced with 50 °C, 75 °C, and 90 °C respectively, and the reaction solvent was replaced with acetonitrile, and other conditions remained unchanged to synthesize N-trifluoromethylthioisochromene-1-imine compounds. The specific yield results are shown in Table 2.

[0098] Table 2 Influence of Different Reaction Temperatures on the Synthesis of N-Trifluoromethylthioisochromene-1-imine

[0099] Temperature (°C) Separation yield (%) 25 65 50 59 75 45 90 30

[0100] It was found that when acetonitrile was used to replace dichloromethane in Example 1 and the reaction temperature was replaced by 25°C, 50°C, and 75°C respectively from 25°C in Example 1, the target product could be obtained, but the product yield was worse than that in Example 1. When the temperature reached 90°C, the yield decreased significantly.

[0101] Example 10: Synthesis of N-(trifluoromethylthio)isochromene-1-imine compounds with different trifluoromethylthio sources

[0102] Referring to Example 1, the trifluoromethylthio source was replaced from N-(trifluoromethylthio)saccharin with N-(trifluoromethylthio)phthalimide, N-(trifluoromethylthio)bis(phenylsulfonyl)imide, and silver trifluoromethylthiolate respectively, and other conditions remained unchanged to synthesize N-(trifluoromethylthio)isochromene-1-imine compounds. The specific yield results are shown in Table 3.

[0103] Table 3 Effects of different trifluoromethylthio sources on the synthesis of N-(trifluoromethylthio)isochromene-1-imine

[0104] Trifluoromethylthio source Separation yield (%) N-Trifluoromethylthiosaccharin (Example 1) 76 N-Trifluoromethylthio phthalimide trace N-Trifluoromethylthio bis(phenylsulfonyl)imide 70 Silver trifluoromethylthiolate N.R.

[0105] It was found that when N-(trifluoromethylthio)phthalimide, N-(trifluoromethylthio)bis(phenylsulfonyl)imide, and silver trifluoromethylthiolate were used to replace N-(trifluoromethylthio)saccharin in Example 1 as the trifluoromethylthio source, the target product could be obtained except when the trifluoromethylthio source was silver trifluoromethylthiolate, but the product yields were all worse than that in Example 1. Among them, when N-(trifluoromethylthio)bis(phenylsulfonyl)imide was used as the trifluoromethylthio source, the product yield was 6% lower than that in Example 1.

[0106] Example 11: Different molar ratios of 2-alkynylbenzamides to N-(trifluoromethylthio)saccharin

[0107] Referring to Example 1, the molar ratio of 2-alkynylbenzamides to N-(trifluoromethylthio)saccharin was adjusted to 1:1, 1:2, 1:2.5, and 1:3.0, and other conditions remained unchanged to synthesize N-(trifluoromethylthio)isochromene-1-imine compounds. The specific yield results are shown in Table 4.

[0108] Table 4 Effects of the molar ratio of 2-alkynylbenzamides to N-(trifluoromethylthio)saccharin on the synthesis of N-(trifluoromethylthio)isochromene-1-imine compounds

[0109]

[0110] It was found that when the molar ratios of 2-alkynyl aromatic amide compounds to N-(trifluoromethylthio)saccharin were 1:1, 1:2, 1:2.5, and 1:3.0, replacing 1:2.8 in Example 1, the target product could be obtained, but the yields were all worse than that in Example 1. Among them, the yield obtained with a molar ratio of 2-alkynyl aromatic amide compounds to N-(trifluoromethylthio)saccharin of 1:3.0 was 3% lower than that in Example 1.

[0111] Example 12: Reaction Concentrations of Different 2-Alkynyl Aromatic Amide Compounds

[0112] Referring to Example 1, the reaction concentration of 2-alkynyl aromatic amide compounds was adjusted to 0.05, 0.5, and 1 mmol / mL, and other conditions remained unchanged to synthesize N-(trifluoromethylthio)isochromene-1-imine compounds. The specific yield results are shown in Table 5.

[0113] Table 5 Effects of Reaction Concentrations of Different 2-Alkynyl Aromatic Amide Compounds on the Synthesis of N-(trifluoromethylthio)isochromene-1-imine Compounds

[0114]

[0115] It was found that when the reaction concentrations of 2-alkynyl aromatic amide compounds were 0.05, 0.5, and 1 mmol / mL, replacing 0.1 mmol / mL in Example 1, the target product could be obtained, but the yields were all worse than that in Example 1.

[0116] Example 13: Different Reaction Durations

[0117] Referring to Example 1, the reaction duration was adjusted to 11 h, 13 h, and 14 h, and other conditions remained unchanged to synthesize N-(trifluoromethylthio)isochromene-1-imine compounds. The specific yield results are shown in Table 6.

[0118] Table 6 Effects of Different Reaction Durations on the Synthesis of N-(trifluoromethylthio)isochromene-1-imine

[0119] Reaction duration (h) Isolated yield (%) 11 70 13 75 14 75

[0120] It was found that when the reaction durations were 11 h, 13 h, and 14 h, replacing 12 h in Example 1, the target product could be obtained, but the yields were all worse than that in Example 1, and extending the reaction time had no obvious effect on the reaction yield.

[0121] Example 14: Synthesis of an Isochromene Derivative (Taking an Intermediate of an Isochromene Drug as an Example)

[0122] N-trifluoromethylthioisochromene-1-imine compounds can be used as raw materials or synthetic intermediates to further synthesize isocoumarin derivatives, and thus have wide applications in the fields of medicine, pesticides and functional materials in the direction of functional compounds. For example, N-trifluoromethylthioisochromene-1-imine compounds can be used as raw materials to prepare bioactive drug molecules - isocoumarin derivatives, such as the isocoumarin drug intermediates reported in the patent document WO2015144911Al.

[0123] Therefore, this embodiment provides a method for preparing isocoumarin derivatives, and the preparation method includes:

[0124] (1) First, use the method of the present invention to prepare and synthesize N-trifluoromethylthioisochromene-1-imine compounds, specifically:

[0125] In an organic solvent, 2-alkynyl aromatic amide compounds shown in formula (1) and trifluoromethylthiosaccharin are used as reactants, and a cyclization reaction is carried out under the conditions of no catalyst and ligand to synthesize N-trifluoromethylthioisochromene-1-imine compounds shown in formula (2);

[0126]

[0127] Among them, R 1 is selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, C1-C8 alkoxy, acyl, amide group and heterocycle; R 2 is selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl, amide group and heterocycle;

[0128] (2) The N-trifluoromethylthioisochromene-1-imine compound prepared in step (1) is used as a reactant to prepare isocoumarin derivatives.

[0129] Taking the isocoumarin drug intermediate as an example: The synthesis method of the isocoumarin drug intermediate (intermediate TI 19 disclosed in WO2015144911Al) is as follows:

[0130]

[0131] Therefore, the synthesis reaction route of this isocoumarin derivative can be carried out with reference to the following:

[0132]

[0133] Specifically:

[0134] First, prepare N-trifluoromethylthio-3-o-tolyl-1H-isochromene-1-imine according to the method of Example 1. Then, add N-trifluoromethylthio-3-o-tolyl-1H-isochromene-1-imine (0.5 mmol) and potassium carbonate (207 mg) prepared in Example 1 into MeOH (5 mL). The reaction mixture was stirred at room temperature and 800 rpm for 8 h, and then 10 mL of 12 M hydrochloric acid aqueous solution was added dropwise and stirred for another 12 h. After the reaction, it was extracted three times with 3 x 10 mL of ethyl acetate. The combined organic phases were dried over anhydrous MgSO4, filtered by suction, the filtrate was collected, the solvent was removed by distillation under reduced pressure, and the intermediate TI 19 (51 mg, yield 43%) was obtained by column chromatography.

[0135] The obtained product was analyzed and characterized, and the specific data are as follows:

[0136] 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.48 (dt, J = 7.3, 3.2 Hz, 2H), 7.28 (s, 1H), 6.91 (s, 1H), 2.41 (s, 3H).

[0137] Furthermore, more substitutions can also be made on R 1 and R 2 to obtain more analogues and provide corresponding synthesis methods for exploring more isocoumarin derivatives.

[0138] Furthermore, the isocoumarin derivatives can be prepared with reference to the patent document WO2015144911Al.

[0139] Comparative Example 1

[0140] Refer to Example 1, add sodium bicarbonate, and keep other conditions unchanged.

[0141] It was found that: when sodium bicarbonate was added, the yield decreased to 45%, and there were by-products.

[0142] Comparative Example 2

[0143] Refer to Example 1, add potassium carbonate, and keep other conditions unchanged.

[0144] It was found that: when potassium carbonate was added, the yield decreased to 33%, and there were by-products.

[0145] Comparative Example 3

[0146] Refer to Example 1, add potassium tert-butoxide, and keep other conditions unchanged.

[0147] It was found that: when potassium tert-butoxide was added, the yield decreased to 28%, and there were by-products.

Claims

1. A method for synthesizing an N-trifluoromethylthioisochromene-1-imine compound, characterized in that: The method comprises the following steps: in an organic solvent, a 2-alkynyl aromatic amide compound represented by formula (1) and N-trifluoromethylthiosaccharin are used as reactants, and a cyclization reaction is carried out without adding any catalyst or base to synthesize an N-trifluoromethylthioisochromene-1-imine compound represented by formula (2); Among them, R 1 is selected from H, methyl, F; R 2 Selected from phenyl, F-substituted phenyl, methyl-substituted phenyl, n-hexyl, thiophene.

2. The method according to claim 1, characterized in that: The organic solvent is any one or more of dichloromethane, acetonitrile, tetrahydrofuran and methanol.

3. The method according to claim 1, characterized in that The reaction temperature is 25°C-50°C.

4. The method according to claim 1, characterized in that: The molar ratio of the 2-alkynyl aromatic amide compound to N-trifluoromethylthiosaccharin is 1:(2.0-3.0).

5. The method according to claim 1, characterized in that The reaction concentration of the 2-alkynyl aromatic amide compound is 0.05-5 mmol / mL.

6. The method according to claim 1, characterized in that The N-trifluoromethylation / cyclization reaction is carried out under an inert gas atmosphere.

7. The method according to claim 1, characterized in that The reaction time is 8-14h.

8. Use of the method according to any one of claims 1 to 6 in the preparation of isocoumarin derivatives in the fields of medicine, pesticides and functional materials.

9. A method for preparing an isocoumarin derivative, characterized in that: The preparation method comprises: (1) firstly preparing and synthesizing N-trifluoromethylthioisochromene-1-imine compound by the method described in any one of claims 1 to 6; (2) The N-trifluoromethylthioisochromene-1-imine compound prepared in step (1) is used as a reactant to prepare isocoumarin derivatives.

10. A method for synthesizing isocoumarin derivatives, which are important components of natural products, characterized in that: The structure of the isocoumarin is The reaction route of the method is: Among them, R 1 is selected from H, methyl, F; R 2 Selected from phenyl, F-substituted phenyl, methyl-substituted phenyl, n-hexyl, thiophene.

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