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

Abstract

The invention discloses a synthesis method of an N-trifluoromethylthio isochromene-1-imine compound, and belongs to the field of organic chemistry. According to the method disclosed by the invention, a 2-alkynyl aromatic amide compound and N-trifluoromethylthio saccharin are taken as raw materials, and the polysubstituted N-trifluoromethylthio isochromene-1-imine compound can be synthesized in one step under the condition of not adding any metal catalyst and organic ligand. The method has the advantages of wide substrate applicability, simple and easily available raw materials and low economic cost; besides, the synthesis of the target product is realized by the method, the target product can be obtained at a relatively high yield only by reacting for 12-14 hours at room temperature, and the target compound has wide application in the fields of medicines, pesticides, functional materials and the like.

Description

Technical Field

[0001] The invention specifically relates to a method for synthesizing an N-trifluoromethylthioisochromene-1-imine compound, and belongs to the field of organic chemistry. Background Art

[0002] The trifluoromethylsulfide group is an important fluorine-containing functional group with excellent lipid solubility, strong electron absorption and biological activity. It is widely used in organic synthesis, medicinal chemistry, materials science and other fields. The stability of the trifluoromethylsulfide group and its relatively easy chemical properties make it one of the most popular groups. In addition, isochromene is a stable lipophilic compound of orthophenols. Polyphenolic isochromene can inhibit stimulant-induced platelet aggregation and coagulation, activate platelets, and activate microglia. However, there are few reports on the methods of introducing N-SCF3 into the isochromene skeleton.

[0003] In the prior art, when introducing trifluoro groups into compounds, catalysts are mostly used. For example, the catalysts used in patent CN117865869A are various metal compounds; when synthesizing heterochromatic olefin compounds, noble metal catalysts are mostly used. For example, CN 110204533A uses silver as a catalyst. Since the catalyst itself has defects such as high cost, toxicity, and environmental damage during recycling, and by-products are easily generated during the catalytic reaction, the two are difficult to separate during the subsequent separation and purification of the product, which will affect the product quality.

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

[0005] The present invention develops a new method for synthesizing N-trifluoromethylthioisochromene-1-imine. The N-trifluoromethylthioisochromene-1-imine compound is obtained by N-trifluoromethylthio / cyclization of 2-alkynyl aromatic amide compounds and N-trifluoromethylthio saccharin, thereby realizing the synthesis of N-trifluoromethylthioisochromene-1-imine derivatives quickly and conveniently.

[0006] The first object of the present invention is to provide a method for synthesizing N-trifluoromethylthioisochromene-1-imine compounds, comprising the following steps: in an organic solvent, a 2-alkynyl aromatic amide compound represented by formula (1) and trifluoromethylthiosaccharin are used as reactants, and a cyclization reaction is carried out in the absence of a catalyst and a ligand to synthesize an N-trifluoromethylthioisochromene-1-imine compound represented by formula (2);

[0007]

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

[0009] In one embodiment of the present invention, the aryl group includes a substituted or unsubstituted benzene ring or a naphthalene ring; the substitution may be one to three substitutions; the substituted group is 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 It is H, C1-8 alkyl.

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

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

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

[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), preferably CH2Cl2.

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

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

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

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

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

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

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

[0022] In one embodiment of the present invention, the separation and purification method is to use rapid 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 in the following steps: adding 2-alkynyl aromatic amide compounds and N-trifluoromethylthiosaccharin in a molar ratio of 1:2.8 to a reaction vessel containing a dichloromethane solvent, stirring at 25°C-30°C for 12-14 hours, separating and purifying 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, and then the intermediate undergoes an isomerization similar to an enol tautomerization, and the oxygen anion undergoes nucleophilic addition / cyclization with the alkynyl group at the ortho position of the aromatic ring, accompanied by hydrogen electron transfer to generate a multi-substituted N-trifluoromethylthioisochromene-1-imine compound.

[0025] The third object of the present invention is to provide a method for preparing an isocoumarin derivative that can be used as an important component of a natural product, the preparation method comprising:

[0026] (1) First, the method of the present invention is used to prepare and synthesize N-trifluoromethylthioisochromene-1-imine compounds, specifically:

[0027] In an organic solvent, a 2-alkynyl aromatic amide compound represented by formula (1) and trifluoromethylthiosaccharin are used as reactants, and a cyclization reaction is carried out in the absence of a catalyst and a ligand to synthesize an N-trifluoromethylthioisochromene-1-imine compound represented by formula (2);

[0028]

[0029] Among them, R 1is selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, C1-C8 alkoxy, acyl and amide, and heterocycle; R 2 Selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocyclic rings.

[0030] (2) Using the N-trifluoromethylthioisochromene-1-imine compound obtained in step (1) as a reactant to prepare isocoumarin derivatives.

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

[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 N-trifluoromethylthioisochromene-1-imine compounds, or isocoumarin derivatives that can be obtained by further reaction using N-trifluoromethylthioisochromene-1-imine compounds as raw materials.

[0034] The fifth object of the present invention is to provide a method for synthesizing an isocoumarin derivative, the structure of which is as follows: The reaction route of the method is:

[0035]

[0036] Among them, R 1 , R 2 The definition is the same as above, R 1 is selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, C1-C8 alkoxy, acyl and amide, and heterocycle; R 2 Selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocyclic rings.

[0037] In one embodiment of the present invention, R 1 Specific options: H, R 2 Specifically, methylphenyl can be selected.

[0038] In one embodiment of the present invention, the method for synthesizing the isocoumarin drug intermediate comprises the following steps:

[0039] (1) In an organic solvent, 2-alkynyl aromatic amide compounds and N-trifluoromethylthio saccharin are used as reactants to carry out a one-pot cyclization reaction to synthesize N-trifluoromethylthio isochromene-1-imine compounds;

[0040] (2) The obtained N-trifluoromethylthioisochromene-1-imine compound is alkalized and then acid hydrolyzed to obtain an isocoumarin drug intermediate.

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

[0042] In one embodiment of the present invention, the acidic hydrolysis after alkalization in step (2) is to dissolve the N-trifluoromethylthioisochromene-1-imine compound in methanol, then add potassium carbonate, stir at room temperature for a period of time, and then add hydrochloric acid aqueous solution to 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) The method of the present invention uses 2-alkynyl aromatic amide and N-trifluoromethylthio saccharin as reactants in a nitrogen atmosphere to achieve the construction of N-trifluoromethylthio isochromene-1-imine skeleton through 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, and the raw materials are simple and easy to obtain, and the economic cost is low. In addition, the method of the present invention only requires 12-14 hours of reaction at room temperature to achieve the synthesis of the target product, and the target product can be obtained in a high yield. The method is fast and efficient. Moreover, the present invention does not require any catalyst, ligand or base for catalysis, and the reaction method is simple and efficient.

[0047] (3) The synthetic method of the present invention converts the readily available 2-alkynyl aromatic amide into the corresponding N-trifluoromethylthioisochromene-1-imine compound under relatively simple conditions, thereby realizing the synthesis of multi-substituted N-trifluoromethylthioisochromene-1-imine derivatives in one step. The target compound has a wide range of applications in the fields of medicine, pesticides and functional materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 The synthetic route diagram of the method of the present invention is shown in FIG. DETAILED DESCRIPTION

[0049] The following are 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-fluorophenylethynylbenzamide (CAS: 1839028-54-4), 2-(2-methylphenylethynyl)benzamide (CAS: 1260150-35-3), 2-octynylbenzamide (CAS: 124394-20-3), 2-phenylethynyl-5-methylbenzamide (CAS: 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-trifluoromethylthiophthalimide (CAS: 719-98-2), and N-trifluoromethylthiobisbenzenesulfonimide (CAS: 1902154-93-1) were synthesized according to existing literature reports.

[0051] Dichloromethane, ethyl acetate, potassium carbonate, and MeOH were 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 embodiment of the present invention is as follows: Figure 1 As shown, specifically:

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

[0055] Example 1: Synthesis of N-trifluoromethylthio-3-phenyl-1-hydrogen-isochromene-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 added to a 25 ml reaction tube equipped with a stirrer, and the mixture was reacted at 25 ° C and 800 rpm for 12 hours. After the reaction, 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 vacuum distillation, and 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 (400MHz, CDCl3) δ8.14(d,J=9.3Hz,1H),7.78(d,J=6.7Hz,2H),7.55–7.40(m,4H),7.39–7.34(m,1H),7.30(d,J=7.8Hz,1H),6.68(s,1H). 19 F NMR (376MHz, CDCl3) δ-50.24 (s, 3F). 13 C NMR(101MHz, CDCl3)δ151.91(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-1-hydrogen-isochromene-1-imine

[0061]

[0062] Under nitrogen protection, 2-fluorophenylethynylbenzamide (120 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were added to a 25 ml reaction tube equipped with a stirrer, and reacted at 25 ° C and 800 rpm for 12 hours. After the reaction, 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 distilled off 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] 1H NMR (400MHz, CDCl3) δ8.12(d,J=9.1Hz,1H),7.75(dd,J=8.9,5.2Hz,2H),7.50(t,J=7.6H z,1H),7.37(t,J=7.6Hz,1H),7.29(d,J=7.8Hz,1H),7.15(t,J=8.6Hz,2H),6.61(s,1H). 19 F NMR(376MHz, CDCl3)δ-50.22(s,3F),-110.13(s,1F). 13 C NMR(101MHz, CDCl3)δ165.12(s),162.62(s),151.22(d,J=1.5Hz),151.06(s),132.66(s),132.00(s),128.82(s),128.70(q),1 28.20(d,J=3.3Hz),127.14(s),126.86(d,J=8.4Hz),126.03(s),122.81(s),116.37(s),116.15(s),101.41(s).HRMS(ESI)m / z calcd.for C 16 H9F4NOSH(M+H) + :340.0419; found:340.0401.

[0065] Example 3: Synthesis of N-trifluoromethylthio-3-o-methylphenyl-1-hydrogen-isochromene-1-imine

[0066]

[0067] Under nitrogen protection, 2-methylphenylethynylbenzamide (118 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were added to a 25 ml reaction tube equipped with a stirrer, and reacted at 25 ° C and 800 rpm for 12 hours. After the reaction, 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 distilled off under reduced pressure, and the crude product was separated and 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] 1H NMR (400MHz, CDCl3) δ8.18(d,J=8.2Hz,1H),7.51(q,2H),7.43–7.33(m,2H),7.29(d,J=9.1Hz,3H),6.34(s,1H),2.52(s,3H).19F NMR(376MHz, CDCl3)δ-50.40(s,3F).13C NMR(101MHz, CDCl3)δ154.24(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.forC 17 H 12 F3NOSH(M+H) + :336.0670; found:336.0650.

[0070] Example 4: Synthesis of N-trifluoromethylthio-3-n-hexyl-1-hydrogen-isochromene-1-imine

[0071]

[0072] Under nitrogen protection, 2-octynylbenzamide (115 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were added to a 25 ml reaction tube equipped with a stirrer, and reacted at 25 ° C and 800 rpm for 12 hours. After the reaction, 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 vacuum distillation, and the crude product was separated and 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] 1H NMR (400MHz, CDCl3) δ8.09(d,J=7.9Hz,1H),7.45(t,J=7.6Hz,1H),7.32(t,J=7.7Hz,1H),7.15(d,J=6 .6Hz,1H),5.96(s,1H),2.44(t,J=7.5Hz,2H),1.67(p,J=7.4Hz,2H),1.47–1.19(m,6H),0.91(t,3H). 19 F NMR (376MHz, CDCl3) δ-50.45 (s, 3F). 13 CNMR(101MHz, CDCl3)δ156.58(s),152.11(s),132.39(s),132.24(s),130.39(q,J=305.8Hz),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-isochromene-1-imine

[0076]

[0077] Under nitrogen protection, 2-phenylethynyl-5-methylbenzamide (118 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were added to a 25 ml reaction tube equipped with a stirrer, and reacted at 25 ° C and 800 rpm for 12 hours. After the reaction, 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 vacuum distillation, and the crude product was separated and 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] 1H NMR (400MHz, CDCl3) δ7.93 (s, 1H), 7.76 (d, J = 7.5Hz, 2H), 7.45 (d, J = 7.4Hz, 3H), 7.31 (d, J = 7.9Hz, 1H), 7.20 (d, J = 7.9Hz, 1H), 6.66 (s, 1H), 2.41 (s, 3H). 19 F NMR(376MHz, CDCl3)δ-50.18(s,3F). 13 C NMR(101MHz, CDCl3)δ151.65(s),151.16(s),139.13(s),133.82(s),132.08(s),130.38(q,J=306.1Hz),129.87(s),1 29.64(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 / zcalcd.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-trifluoromethylthiosaccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were added to a 25 ml reaction tube equipped with a stirrer, and reacted at 25 ° C and 800 rpm for 12 hours. After the reaction, 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 distilled off under reduced pressure, and the crude product was separated and 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 H NMR (400MHz, CDCl3) δ7.84–7.66(m,3H),7.52–7.33(m,3H),7.29(dd,J=8.6,5.2Hz,1H),7.20(td,J=8.4,2.7Hz,1H),6.64(s,1H). 19F NMR(376MHz, CDCl3)δ-50.20(s,3F),-110.34(s,1F). 13 C NMR (101MHz, CDCl3) δ163.72 (s), 161.24 (s), 151.50 (d, J = 3.0Hz), 131.66 (s), 130.16 (s), 130.11 (q, J = 306.2Hz), 129.11 (s), 128.56 (d, J=2.8Hz),128.16(d,J=8.1Hz),124.75(s),124.51(d,J=8.9Hz),120.65(d,J=23.1Hz),113.15(d,J=24.3Hz),100.67(s).HRMS(ESI)m / z calcd.for C 16 H9F4NOSH(M+H) + :340.0419; found:340.0402.

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

[0086]

[0087] Under nitrogen protection, 2-(thiophene-2-ethynyl)-5-methylbenzamide (114 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (396 mg, 1.4 mmol) and dichloromethane (5 mL) were added to a 25 ml reaction tube equipped with a stirrer, and reacted at 25 ° C and 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 distilled off under reduced pressure, and the crude product was separated and 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 H NMR (400MHz, CDCl3) δ8.10 (d, J = 8.5Hz, 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 F NMR (376MHz, CDCl3) δ-50.27 (s, 3F). 13C NMR(101MHz, CDCl3)δ150.80(s),147.95(s),135.55(s),132.61(s),131.92(s),130.25(q,J=306.2Hz),12 8.55(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 H8F3NOS2H(M+H) + :328.0078; found:328.0062.

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

[0091] Example 8: Effect of different solvents on the synthesis of N-trifluoromethylthioisochromene-1-imine compounds

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

[0093] Table 1 Effect of different solvents on the synthesis of N-trifluoromethylthioisochromene-1-imine

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

[0095] The results show that: except for water, acetonitrile, tetrahydrofuran, methanol, water, or dichloromethane in Example 1 can be used as the solvent to obtain the target product, but the product yield is worse than that 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 changed from 25°C to 50°C, 75°C, and 90°C, the reaction solvent was changed to acetonitrile, and other conditions were kept unchanged to synthesize N-trifluoromethylthioisochromene-1-imine. The specific yield results are shown in Table 2.

[0098] Table 2 Effect of different reaction temperatures on the synthesis of N-trifluoromethylthioisochromene-1-imine

[0099] Temperature(℃) Isolation yield (%) 25 65 50 59 75 45 90 30

[0100] The results show that when acetonitrile is used to replace the dichloromethane in Example 1 and the reaction temperature is replaced from 25°C in Example 1 to 25°C, 50°C, and 75°C, respectively, the target product can be obtained, but the product yield is worse than that in Example 1. When the temperature reaches 90°C, the yield decreases significantly.

[0101] Example 10: Synthesis of N-trifluoromethylsulfonylisochromene-1-imine compounds from different trifluoromethylsulfide sources

[0102] Referring to Example 1, the trifluoromethylsulfide source was replaced by N-trifluoromethylsulfonyl saccharin with N-trifluoromethylsulfonyl phthalimide, N-trifluoromethylsulfonyl bisbenzenesulfonimide, and trifluoromethylsulfonyl silver, respectively, and other conditions remained unchanged to synthesize N-trifluoromethylsulfonyl isochromene-1-imide compounds. The specific yield results are shown in Table 3.

[0103] Table 3 Effect of different trifluoromethylsulfide sources on the synthesis of N-trifluoromethylsulfide isochromene-1-imine

[0104] Methyl trifluorosulfide source Isolation yield (%) N-trifluoromethylthiosaccharin (Example 1) 76 N-Trifluoromethylthiophthalimide trace N-Trifluoromethylthiobisbenzenesulfonimide 70 Silver trifluoromethylthiothionate NR

[0105] The results showed that: when N-trifluoromethylthiophthalimide, N-trifluoromethylthiobisbenzenesulfonimide and silver trifluoromethylthiodide were used to replace N-trifluoromethylthiosaccharin in Example 1 as the trifluoromethyl sulfide source, except when the trifluoromethyl sulfide source was silver trifluoromethylthiodide, the target product could be obtained, but the product yield was worse than that in Example 1. When N-trifluoromethylthiobisbenzenesulfonimide was used as the trifluoromethyl sulfide source, the product yield was 6% lower than that in Example 1.

[0106] Example 11: Different molar ratios of 2-alkynyl aromatic amide compounds and N-trifluoromethylthiosaccharin

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

[0108] Table 4 Effect of the molar ratio of 2-alkynyl aromatic amide compounds and N-trifluoromethylthiosaccharin on the synthesis of N-trifluoromethylthioisochromene-1-imine compounds

[0109]

[0110] The results showed that the target product could be obtained by replacing 1:2.8 in Example 1 with a molar ratio of 1:1, 1:2, 1:2.5, or 1:3.0 of 2-alkynyl aromatic amide compounds to N-trifluoromethylthio saccharin, but the yields were worse than those in Example 1. Among them, the yield obtained with a molar ratio of 1:3.0 of 2-alkynyl aromatic amide compounds to N-trifluoromethylthio saccharin 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 concentrations of the 2-alkynyl aromatic amide compound were adjusted to 0.05, 0.5, and 1 mmol / mL, and other conditions were kept unchanged to synthesize N-trifluoromethylthioisochromene-1-imine compounds. The specific yield results are shown in Table 5.

[0113] Table 5 Effect of different 2-alkynyl aromatic amide reaction concentrations on the synthesis of N-trifluoromethylthioisochromene-1-imine compounds

[0114]

[0115] The results showed that the target product could be obtained by using 2-alkynyl aromatic amide compounds at reaction concentrations of 0.05, 0.5, and 1 mmol / ml to replace 0.1 mmol / ml in Example 1, but the yields were worse than those in Example 1.

[0116] Example 13: Different reaction times

[0117] Referring to Example 1, the reaction time was adjusted to 11 h, 13 h, and 14 h, and other conditions were kept unchanged to synthesize N-trifluoromethylthioisochromene-1-imine. The specific yield results are shown in Table 6.

[0118] Table 6 Effect of different reaction times on the synthesis of N-trifluoromethylthioisochromene-1-imine

[0119] Reaction time (h) Isolation yield (%) 11 70 13 75 14 75

[0120] The results showed that the target product could be obtained by replacing the 12 h in Example 1 with a reaction time of 11 h, 13 h, or 14 h, but the yield was worse than that in Example 1 and extending the reaction time had no significant effect on the yield of the reaction.

[0121] Example 14: Synthesis of an isocoumarin derivative (taking an isocoumarin drug intermediate as an example)

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

[0123] Therefore, this embodiment provides a method for preparing an isocoumarin derivative, the preparation method comprising:

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

[0125] In an organic solvent, a 2-alkynyl aromatic amide compound represented by formula (1) and trifluoromethylthiosaccharin are used as reactants, and a cyclization reaction is carried out in the absence of a catalyst and a ligand to synthesize an N-trifluoromethylthioisochromene-1-imine compound represented by formula (2);

[0126]

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

[0128] (2) Using the N-trifluoromethylthioisochromene-1-imine compound obtained in step (1) as a reactant to prepare isocoumarin derivatives.

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

[0130]

[0131] Therefore, the synthetic reaction route of the isocoumarin derivatives can be carried out as follows:

[0132]

[0133] Specifically:

[0134] First, N-trifluoromethylthio-3-o-methylphenyl-1-hydrogen-isochromene-1-imine was prepared according to the method of Example 1, and then N-trifluoromethylthio-3-o-methylphenyl-1-hydrogen-isochromene-1-imine (0.5 mmol) prepared in Example 1 and potassium carbonate (207 mg) were added to MeOH (5 mL), and the reaction mixture was stirred at room temperature and 800 rpm for 8 h, and then 10 mL of 12M hydrochloric acid aqueous solution was added dropwise and continued to stir for 12 h. After the reaction was completed, 3x10 mL of ethyl acetate was used for extraction three times, and the organic phases were combined and dried over anhydrous MgSO4, filtered, and the filtrate was collected. The solvent was distilled off 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 (400MHz, CDCl3) δ8.30(d,J=8.2Hz,1H),7.78(d,J=8.1Hz,2H),7.71(t,J=7 .5Hz,1H),7.48(dt,J=7.3,3.2Hz,2H),7.28(s,1H),6.91(s,1H),2.41(s,3H).

[0137] Further, You can also use R 1 , R 2 Make more substitution expansions to obtain more analogues and provide corresponding synthetic methods for exploring more isocoumarin derivatives.

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

[0139] Comparative Example 1

[0140] Referring to Example 1, sodium bicarbonate was added, and the rest remained unchanged.

[0141] The results showed that the yield dropped to 45% with the addition of sodium bicarbonate and there were by-products.

[0142] Comparative Example 2

[0143] Referring to Example 1, potassium carbonate was added, and the rest remained unchanged.

[0144] The results showed that the yield dropped to 33% with the addition of potassium carbonate, and there were by-products.

[0145] Comparative Example 3

[0146] Referring to Example 1, potassium tert-butoxide was added, and the rest remained unchanged.

[0147] The results showed that the yield dropped to 28% and there were by-products when potassium tert-butoxide was added.

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, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, C1-C8 alkoxy, acyl and amide, and heterocycle; R 2 Selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocyclic rings.

2. The method according to claim 1, characterized in that The organic solvent includes 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. Application of the method according to any one of claims 1 to 6 in the fields of medicine, pesticide and functional material preparation.

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, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, C1-C8 alkoxy, acyl and amide, and heterocycle; R 2 Selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocyclic rings.

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