A diarylmethylsulfonamide compound and preparation method thereof

Abstract

The present invention belongs to the technical field of compound synthesis, and specifically discloses a diarylmethylsulfonamide compound and a preparation method thereof. The diarylmethylsulfonamide compound provided by the present invention has the following structure: #imgabs0# wherein R1 is selected from #imgabs1##imgabs2# or #imgabs3#R2 is selected from H, #imgabs4# or #imgabs5# The present invention provides a diarylmethylsulfonamide compound with a novel structure, enriches the types of diarylmethylsulfonamide compounds, provides a new compound for the development of anti-tumor drugs, anti-cerebral thrombotic drugs and lipid-lowering drugs, is of great significance for studying the activity of the compound and expanding the application of the compound in the medical field, and provides a basis for studying new drugs with unique physiological activities.

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis, and particularly relates to a diarylmethylsulfonamide compound and a preparation method thereof. Background Art

[0002] Sulfonamide compounds, also known as sulfonamide drugs, are an important class of synthetic antibacterial agents with a p-aminobenzenesulfonamide parent structure. At present, a variety of drugs for clinical use have been successfully developed by chemically modifying the p-aminobenzenesulfonamide parent structure. However, traditional structural modifications of sulfonamide drugs are prone to drug hypersensitivity reactions. Therefore, structural modification of the p-phenylamino group and avoiding drug hypersensitivity reactions have been a research hotspot in recent years.

[0003] Diarylmethyl structure is an important component of organic chemistry and is widely present in chemical molecules such as bioactive molecules, important drugs, and functional chemical materials. In the field of medicine, the introduction of diarylmethyl structure into the parent structure of the drug for modification can increase the lipid solubility of the drug, make it easier to penetrate the cell membrane, improve the activity of the drug, and reduce the effect of drug hypersensitivity. Therefore, the synthesis of diarylmethyl sulfonamide compounds with novel structures is of great significance for the development of anti-tumor drugs, anti-cerebral thrombotic drugs, and lipid-lowering drugs. However, the existing method for synthesizing diarylmethyl sulfonamide compounds is relatively cumbersome and cannot be industrialized. Summary of the invention

[0004] In order to enrich the types of diarylmethylsulfonamide compounds and solve the problem that the method for synthesizing diarylmethylsulfonamide compounds in the prior art is relatively complicated, the present invention provides a diarylmethylsulfonamide compound and a preparation method thereof.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] The present invention provides a diarylmethylsulfonamide compound, the structure of which is shown in formula (III):

[0007]

[0008] Wherein R1 is selected from

[0009] R2 is selected from H,

[0010] Compared with the prior art, the present invention provides a diarylmethylsulfonamide compound with a novel structure, enriches the types of diarylmethylsulfonamide compounds, provides a new compound for the development of anti-tumor drugs, anti-cerebral thrombotic drugs and lipid-lowering drugs, is of great significance for studying the activity of the compound and expanding the application of the compound in the medical field, and provides a basis for studying new drugs with unique physiological activities.

[0011] The present invention also provides a method for preparing the above-mentioned diarylmethylsulfonamide compound, comprising the following steps: subjecting the compound represented by formula I, the compound represented by formula II and Lewis acid to Michael addition reaction under solvent-free physical grinding conditions to obtain the diarylmethylsulfonamide compound;

[0012]

[0013]

[0014] Wherein R1 is selected from

[0015] R2 is selected from H,

[0016] The preparation method of diarylmethylsulfonamide compounds requires the addition of organic solvents to promote sufficient mixing of reactants, thereby improving the purity and yield of the reaction products. However, the use of organic solvents is not only costly, but also causes problems such as solvent volatilization and generation of a large amount of hazardous waste during use, causing environmental pollution and waste of resources.

[0017] The inventor accidentally discovered during the experiment that by screening out specific reaction substrates and catalysts, the reaction substrates can produce diarylmethylsulfonamide compounds of specific structures under solvent-free conditions. Compared with the prior art, the preparation method of diarylmethylsulfonamide compounds provided by the present invention selects the compound shown in formula I and the compound shown in formula II as specific reaction substrates, selects Lewis acid as the catalyst for the reaction, and through solvent-free physical grinding, the compound shown in formula I and the compound shown in formula II can react to produce diarylmethylsulfonamide compounds of specific structures. This method can reduce the operation procedures such as solvent recovery and purification, and eliminate the harm of solvent volatilization and environmental pollution; the preparation method of diarylmethylsulfonamide compounds provided by the present invention is scientific and reasonable, and the raw materials are cheap and easy to obtain, the preparation method is simple to operate, the reaction conditions are green and environmentally friendly, and the yield is as high as 93.7% on the basis of a purity of 99%, which has good practical value and broad application prospects.

[0018] Preferably, the grinding time is 15 min-20 min.

[0019] The preferred grinding time can make the yield of diarylmethylsulfonamide compounds as high as 93.7%.

[0020] Preferably, the grinding speed is 80r / min-110r / min.

[0021] By controlling the grinding rate, the compound represented by formula I and the compound represented by formula II can be promoted to fully react, thereby greatly improving the purity and yield of the reaction.

[0022] Preferably, the Lewis acid is scandium trifluoromethanesulfonate.

[0023] The preferred catalyst can accelerate the reaction rate, shorten the reaction time, and more importantly, improve the selectivity of the reaction, reduce the occurrence of side reactions, and thus improve the purity and yield of the target compound.

[0024] Preferably, the molar ratio of the compound represented by formula I, the compound represented by formula II and Lewis acid is 1:(1-1.2):(0.15-0.3).

[0025] Further preferably, the molar ratio of the compound represented by formula I, the compound represented by formula II and Lewis acid is 1:1:0.2.

[0026] The preferred ratio can improve the purity and yield of the target compound.

[0027] Preferably, the temperature of the Michael addition reaction is 20°C-25°C.

[0028] Preferably, the method further comprises a refining process, wherein the reaction product is extracted, dried, the solvent is removed, and recrystallized to obtain the diarylmethylsulfonamide compound.

[0029] Preferably, the extraction agent is a mixture of dichloromethane and saturated sodium bicarbonate aqueous solution.

[0030] Preferably, the volume ratio of dichloromethane to saturated sodium bicarbonate aqueous solution in the extractant is 1:13-15.

[0031] As a preferred embodiment, the mass volume ratio of the reaction product to the extractant is 1:10-15, the unit of mass is g, and the unit of volume is mL.

[0032] As a preferred embodiment, the extraction is performed 3-5 times.

[0033] As a preferred embodiment, the desiccant used during the drying is anhydrous sodium sulfate.

[0034] As a preferred embodiment, the solvent used in the recrystallization is a mixed solvent of dichloromethane and petroleum ether.

[0035] Preferably, the volume ratio of dichloromethane to petroleum ether is 1:3-5.

[0036] Preferably, the recrystallization process is: adding the dichloromethane to the crude product after the solvent is removed, heating to completely dissolve the crude product, and then filtering to remove insoluble matter to obtain a filtrate; heating the filtrate to near boiling, slowly dripping petroleum ether until turbidity occurs, leaving it to stand, cooling, and crystallizing.

[0037] The preparation method of the diarylmethylsulfonamide compound provided by the invention is scientific and reasonable, and the raw materials are cheap and easily available, the preparation method is simple to operate, the reaction conditions are green and environmentally friendly, the yield is as high as 93.7%, and the compound has good practical value and broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the diarylmethylsulfonamide compound prepared in Example 1 of the present invention;

[0039] Figure 2 This is the carbon NMR spectrum of the diarylmethylsulfonamide compound prepared in Example 1 of the present invention;

[0040] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the diarylmethylsulfonamide compound prepared in Example 2 of the present invention;

[0041] Figure 4 This is the carbon NMR spectrum of the diarylmethylsulfonamide compound prepared in Example 2 of the present invention;

[0042] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of the diarylmethylsulfonamide compound prepared in Example 3 of the present invention;

[0043] Figure 6 This is the carbon NMR spectrum of the diarylmethylsulfonamide compound prepared in Example 3 of the present invention;

[0044] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of the diarylmethylsulfonamide compound prepared in Example 4 of the present invention;

[0045] Figure 8 This is the carbon NMR spectrum of the diarylmethylsulfonamide compound prepared in Example 4 of the present invention;

[0046] Fig. 9 This is the hydrogen nuclear magnetic resonance spectrum of the diarylmethylsulfonamide compound prepared in Example 5 of the present invention;

[0047] Fig.10 This is the carbon NMR spectrum of the diarylmethylsulfonamide compound prepared in Example 5 of the present invention;

[0048] Fig.11 This is the hydrogen nuclear magnetic resonance spectrum of the diarylmethylsulfonamide compound prepared in Example 6 of the present invention;

[0049] Fig.12 This is the carbon NMR spectrum of the diarylmethylsulfonamide compound prepared in Example 6 of the present invention;

[0050] Fig.13 This is the hydrogen nuclear magnetic resonance spectrum of the diarylmethylsulfonamide compound prepared in Example 7 of the present invention;

[0051] Fig.14 This is the carbon NMR spectrum of the diarylmethylsulfonamide compound prepared in Example 7 of the present invention;

[0052] Fig.15 This is the hydrogen nuclear magnetic resonance spectrum of the diarylmethylsulfonamide compound prepared in Example 8 of the present invention;

[0053] Fig.16 This is the carbon nuclear magnetic resonance spectrum of the diarylmethylsulfonamide compound prepared in Example 8 of the present invention. DETAILED DESCRIPTION

[0054] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments and drawings. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0055] The purity of the target product prepared in the examples of the present invention was detected by high performance liquid chromatography through gradient elution, and the specific detection conditions were as follows:

[0056] Chromatographic column: YMC-AQ-C18 (5 μm, 4.6 mm × 250 mm);

[0057] Column temperature: 25-35°C;

[0058] Mobile phase: water-acetonitrile-triethylamine (799:200:1);

[0059] Detection wavelength: 254nm;

[0060] Flow rate: 1.0mL / min.

[0061] Example 1

[0062] This embodiment provides a method for preparing a diarylmethylsulfonamide compound, comprising the following steps:

[0063] Will and scandium trifluoromethanesulfonate (0.2mmol) were mixed evenly, ground at 80r / min for 15min at 20°C to obtain a reactant, which was extracted with a mixed extractant of dichloromethane and saturated sodium bicarbonate aqueous solution in a volume ratio of 1:15, extracted 3 times, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was recrystallized and purified at 40°C-50°C using a mixed solvent of dichloromethane and petroleum ether in a volume ratio of 1:3 as a solvent to obtain The purity is 98% and the yield is 92.24%;

[0064] The mass volume ratio of the reactant to the extractant is 1:15, the unit of mass is g, and the unit of volume is mL.

[0065] Example 2

[0066] This embodiment provides a method for preparing a diarylmethylsulfonamide compound, comprising the following steps:

[0067] Will and scandium trifluoromethanesulfonate (0.3 mmol) were mixed uniformly, ground at 110 r / min for 20 min at 25 ° C to obtain a reactant, which was extracted with a mixed extractant of dichloromethane and saturated sodium bicarbonate aqueous solution in a volume ratio of 1:13, extracted 5 times, combined the organic phases, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was recrystallized and purified at 40 ° C-50 ° C using a mixed solvent of dichloromethane and petroleum ether in a volume ratio of 1:5 as a solvent to obtain The purity is 99% and the yield is 83.93%;

[0068] The mass volume ratio of the reactant to the extractant is 1:10, the unit of mass is g, and the unit of volume is mL.

[0069] Example 3

[0070] This embodiment provides a method for preparing a diarylmethylsulfonamide compound, comprising the following steps:

[0071] Will and scandium trifluoromethanesulfonate (0.15mmol) were mixed evenly, ground at 100r / min for 18min at 22°C to obtain a reactant, which was extracted with a mixed extractant of dichloromethane and saturated sodium bicarbonate aqueous solution in a volume ratio of 1:14, extracted 4 times, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was recrystallized and purified at 40°C-50°C using a mixed solvent of dichloromethane and petroleum ether in a volume ratio of 1:3 as a solvent to obtain The purity is 99% and the yield is 93.7%;

[0072] The mass volume ratio of the reactant to the extractant is 1:12, the unit of mass is g, and the unit of volume is mL.

[0073] Example 4

[0074] Compared with Example 1, the difference between this embodiment and Example 1 is that: Replace with The other steps are the same as those in Example 1; the target compound is The purity is 99% and the yield is 85.23%.

[0075] Example 5

[0076] Compared with Example 1, the difference between this embodiment and Example 1 is that: Replace with Will Replace with The other steps are the same as those in Example 1; the target compound is The purity is 98% and the yield is 84.53%.

[0077] Example 6

[0078] Compared with Example 1, the difference between this embodiment and Example 1 is that: Replace with The other steps are the same as those in Example 1; the target compound is The purity is 99% and the yield is 82.18%.

[0079] Example 7

[0080] Compared with Example 1, the difference between this embodiment and Example 1 is that: Replace with Will Replace with The other steps are the same as those in Example 1; the target compound is The purity is 98% and the yield is 89.22%.

[0081] Example 8

[0082] Compared with Example 1, the difference between this embodiment and Example 1 is that: Replace with Will Replace with The other steps are the same as those in Example 1; the target compound is The purity is 98% and the yield is 93.09%.

[0083] Example 9

[0084] Compared with Example 1, the difference between this comparative example and Example 1 is that scandium trifluoromethanesulfonate is replaced by an equal amount of zinc chloride, and the other operating steps are the same as those in Example 1. The purity of the target compound finally obtained is 98%, and the yield is 64.47%.

[0085] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a diarylmethylsulfonamide compound, characterized in that: The method comprises the following steps: subjecting the compound represented by formula I, the compound represented by formula II and Lewis acid to Michael addition reaction under solvent-free physical grinding conditions to obtain the diarylmethylsulfonamide compound; （Ⅰ）； （Ⅱ）； Wherein R1 is selected from , , , , , , or ; R2 is selected from H, , or ; The structure of the diarylmethylsulfonamide compound is shown in formula (III): （Ⅲ）； The Lewis acid is scandium trifluoromethanesulfonate.

2. The method for preparing a diarylmethylsulfonamide compound according to claim 1, characterized in that: The grinding time is 15min-20min; The grinding speed is 80r / min-110r / min.

3. The method for preparing diarylmethyl sulfonamide compounds according to claim 1, characterized in that: The molar ratio of the compound represented by formula I, the compound represented by formula II and Lewis acid is 1:(1-1.2):(0.15-0.3).

4. The method for preparing diarylmethylsulfonamide compounds according to claim 3, characterized in that: The molar ratio of the compound represented by formula I, the compound represented by formula II and Lewis acid is 1:1:0.

2.

5. The method for preparing diarylmethylsulfonamide compounds according to claim 1, characterized in that: The temperature of the Michael addition reaction is 20°C-25°C.

6. The method for preparing diarylmethylsulfonamide compounds according to claim 1, characterized in that: The process also includes a refining process: extracting, drying, removing the solvent, and recrystallizing the reactants after the reaction is completed to obtain the diarylmethylsulfonamide compound.

7. The method for preparing diarylmethylsulfonamide compounds according to claim 6, characterized in that: The extractant for the extraction is a mixture of dichloromethane and a saturated sodium bicarbonate aqueous solution.

8. The method for preparing diarylmethylsulfonamide compounds according to claim 7, characterized in that: The volume ratio of dichloromethane to saturated sodium bicarbonate aqueous solution in the extractant is 1:13-15.

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