Method for preparing beta-trifluoromethyl enamine compound from trifluoromethyl thianthrene salt

Abstract

The invention discloses a method for preparing a beta-trifluoromethyl substituted enamine compound from trifluoromethyl thianthrene salt, which comprises the following steps: by taking the trifluoromethyl thianthrene salt as a trifluoromethyl source, synthesizing enamine ester or 4-amino coumarin from a first component amine and an electron-deficient terminal alkyne compound; and synthesizing the beta-trifluoromethyl substituted enamine compound from the first component and a second component trifluoromethyl thianthrene salt in two steps. According to the method for preparing the beta-trifluoromethyl substituted enamine compound through two steps, the synthesis method is mild in reaction condition, free of inert gas protection, capable of being carried out at the room temperature in the air atmosphere, good in functional group tolerance and wide in substrate universality, the separation and purification process is easy to operate, and the method is suitable for industrial production. And a target product with high site selectivity can be generated at a good to excellent yield. According to the synthesis strategy, the reaction steps are effectively shortened, the atom economy is greatly improved, meanwhile, the cost required by the preparation process is remarkably reduced, and large-scale industrial production can be achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis of small organic molecules, and specifically relates to a method for preparing a beta-trifluoromethyl enamine compound from a trifluoromethyl thianthrene salt. Background Art

[0002] Enamine compounds play an indispensable role in the field of organic synthesis. In particular, they exhibit a rich variety of chemical reactivity due to their unique nucleophilic enamine type and electrophilic enamine functionalities. This reactivity not only promotes in-depth research on their application in cascade or cyclization reactions, but also makes them key intermediates for the synthesis of a variety of valuable organic molecules. 2 Enamine compounds are widely used to achieve complex chemical transformations under transition metal catalysis, such as the activation / functionalization of )-H, the cleavage of CC double bonds and CN bonds, etc.

[0003] Enamides in particular have shown great potential in the synthesis of diverse organic molecules, with applications including, but not limited to, double bond hydrogenation, catalytic ethylene CH functionalization, amino elimination reactions, and the construction of complex aromatic structures. In addition, they can also generate non-aromatic ring compounds and structures such as nucleophilic transformed β-carbon centers through asymmetric and racemization cascade reactions. Enaminones and enaminoesters, as powerful synthons with trinucleophilicity and mixed electrophilicity, are widely used in synthesis. They not only play a role in the synthesis of compounds with antiviral and anticancer biological activities, but also can cope with diverse organic synthesis challenges.

[0004] Under appropriate reaction conditions, enamines have been shown to be versatile vehicles for the synthesis of carbocyclic, heterocyclic, and acyclic compounds, demonstrating their broad applicability and flexibility in organic synthesis. With the increasing demand for environmentally friendly synthetic methods, visible light-mediated reactions have attracted much attention due to their ability to efficiently promote chemical reactions under mild conditions. Such photocatalytic reactions not only support the principles of green chemistry, but also open up new pathways for the chemical transformation of enamines, further expanding the application prospects of such compounds in the field of sustainable organic synthesis.

[0005] Fluorinated compounds play an indispensable role in drug development, pesticide manufacturing and materials science. Notably, according to research, nearly one-third of pesticide molecules incorporate fluorine. The fact that more than half of newly launched agrochemicals in the past two decades contain fluorine atoms highlights the importance of fluorine compounds in modern agriculture. A series of organofluorine compounds with a wide range of medicinal activities have been developed, covering a variety of therapeutic properties such as anticancer, antibacterial, antidepressant, anticonvulsant, antipsychotic and antiemetic. In particular, the unique properties of trifluoromethyl - including electronic effects, hydrogen-like mimetic effects and increased lipid solubility - significantly enhance the conformational stability of the compound, the affinity of biomolecules and metabolic properties, thereby giving the molecule a new biological activity. The excellent electron absorption and excellent hydrophobicity of these molecules (manifested as good lipophilicity and metabolic stability) make them the preferred additives in drug design, and many trifluoromethyl-containing drugs have been approved internationally. In particular, more than 40% of small molecule drugs approved by the FDA in 2018 and 2019 contained fluorine atoms, and drugs such as fluvoxamine and paxlovid played a decisive role in the antiviral treatment of COVID-19. These examples further demonstrate the key role of fluorine compounds in addressing global medical challenges.

[0006] As the structural design trend of fluorinated molecules increasingly relies on advances in synthetic methods, the number of newly introduced trifluoromethyl-containing molecules has shown an upward trend since 2019, despite the limited variety of organic fluorine compounds in nature. This shows that in medicinal chemistry, the precise integration of trifluoromethyl units into specific positions in drug molecules has become a key strategy for lead compound optimization. The design of fluorinated drugs not only aims to improve their absorption, distribution, metabolism and excretion properties, but also emphasizes the importance of developing methods to introduce fluorine atoms or fluorinated units into diverse organic frameworks in a simple, efficient and selective manner. This demand has spawned new synthetic strategies and technologies to meet the growing medical and agricultural needs, while also promoting cutting-edge advances in the fields of organic chemistry and medicinal chemistry.

[0007] At present, although methods for synthesizing and preparing β-trifluoromethyl substituted enamine compounds have been reported, the process is relatively complicated or the application scope is relatively narrow. Developing a simple, economical, green and efficient method to synthesize potentially active β-trifluoromethyl substituted enamine compounds is still an inventive work of great significance. Summary of the invention

[0008] Purpose of the invention: In view of the problems existing in the prior art, the present invention aims to provide a method for preparing β-trifluoromethyl substituted enamine compounds from novel trifluoromethyl thianthrene salts in two steps, so as to introduce a trifluoromethyl skeleton structure into the enamine compound. According to the principles of splicing and activity superposition in drug design, the present invention integrates active units with specific structures together to exhibit special biological activity. The present invention adopts a specific method to connect specific enamine compounds and trifluoromethyl skeleton fragments together to synthesize β-trifluoromethyl substituted enamine compounds, which exhibit better biological activity and pharmacological activity.

[0009] The invention also provides a prepared beta-trifluoromethyl substituted enamine compound and application thereof.

[0010] Technical solution: In order to achieve the above-mentioned purpose, the present invention discloses a method for preparing β-trifluoromethyl substituted enamine compounds using trifluoromethyl thianthrene salt as a trifluoromethyl source, using trifluoromethyl thianthrene salt as a trifluoromethyl source and an organic solvent as a solvent, and synthesizing β-trifluoromethyl substituted enamine compounds in two steps through a first component amine, an enamine ester or 4-aminocoumarin synthesized from an electron-deficient terminal acetylene compound, and a second component trifluoromethyl thianthrene salt.

[0011] The invention discloses a method for preparing a β-trifluoromethyl substituted enamine compound from a novel trifluoromethyl thianthrene salt in two steps. The method uses a novel trifluoromethyl thianthrene salt as a fluorine source, dimethyl sulfoxide as a solvent, and uses cheap and readily available organic small molecule amines and electron-deficient terminal alkynes, or 4-aminocoumarin as raw materials. Under air atmosphere, room temperature and normal pressure, the β-trifluoromethyl substituted enamine compound is synthesized in two steps by using a first component, an amine, an enamine ester or 4-aminocoumarin synthesized from an electron-deficient terminal alkyne compound, and a second component, the trifluoromethyl thianthrene salt.

[0012] Wherein, the method for preparing a β-trifluoromethyl substituted enamine compound using a trifluoromethyl thianthrene salt as a trifluoromethyl source comprises the following steps:

[0013] Step 1, reacting the first component amine and the electron-deficient terminal alkyne with stirring at room temperature to obtain reactant A, or reacting 4-hydroxycoumarin and tetrabutylammonium bromide at high temperature to prepare 4-bromocoumarin, and then reacting with amine to prepare 4-aminocoumarin as reactant A;

[0014] Step 2, dissolving reactant A and trifluoromethylthianthrene salt in dimethyl sulfoxide solvent and adding sodium bicarbonate, and stirring the reaction system under blue light;

[0015] Step 3: After the reaction is completed, add saturated sodium bicarbonate solution to the reaction solution and mix evenly, separate and collect the organic phase, perform liquid phase separation and extraction on the aqueous phase, combine the organic phases and dry, filter, collect the filtrate and remove the solvent under reduced pressure; the crude product is purified to obtain a β-trifluoromethyl substituted enamine compound.

[0016] Wherein, the structure of the first component amine compound is preferably any one of the following structures:

[0017]

[0018] Wherein, the structure of the electron-deficient terminal alkyne compound is any one of the following structures:

[0019]

[0020] Wherein, the amine reagent is selected from any one of the following:

[0021]

[0022] Wherein, the amount of the first component amine substance is 1 to 1.5 times that of the electron-deficient terminal acetylene compound;

[0023] The amount of tetrabutylammonium bromide is 1.2 to 2.0 times that of 4-hydroxycoumarin. 2 O 5 The amount of the substance is 1.8 to 2.5 times that of 4-hydroxycoumarin; the amount of the amine reagent substance is 1 to 1.5 times that of 4-bromocoumarin;

[0024] The amount of the trifluoromethylthianthrene salt substance is 1.0 to 2 times that of the electron-deficient terminal alkyne compound;

[0025] The amount of the sodium bicarbonate substance is 1.0 to 2 times that of the electron-deficient terminal alkyne compound.

[0026] Preferably, the amount of the first component amine substance is 1 to 1.5 times that of the electron-deficient terminal acetylene compound; the amount of the tetrabutylammonium bromide substance is 1.5 times that of 4-hydroxycoumarin, 2 O 5 The amount of the substance is 2 times that of 4-hydroxycoumarin; the amount of the amine reagent substance is 1.2 times that of 4-bromocoumarin; the amount of the trifluoromethylthianthrene salt substance is 1.0 times that of the electron-deficient terminal alkyne compound; and the amount of the sodium bicarbonate substance is 1.0 times that of the electron-deficient terminal alkyne compound.

[0027] The reaction in step (2) is carried out at room temperature, under normal pressure and air atmosphere, and for a reaction time of 15-20 hours.

[0028] Preferably, the reaction temperature of the reaction in step (2) is room temperature, the reaction is carried out under normal pressure and air atmosphere, and the reaction time is 18 hours.

[0029] Preferably, the reaction in step (2) is carried out under 20W 465nm blue light.

[0030] Wherein, the organic solvent is dimethyl sulfoxide, and the amount of dimethyl sulfoxide used is not particularly limited, as long as it can allow the reaction to proceed smoothly.

[0031] Preferably, the method for preparing a β-trifluoromethyl substituted enamine compound using a trifluoromethyl thianthrene salt as a trifluoromethyl source comprises the following steps:

[0032] Step 1: Add amine and electron-deficient terminal alkyne to a reaction tube and stir at room temperature for 30 minutes to obtain a crude reactant A. The crude product is purified to obtain a pure substance A; or add 4-hydroxycoumarin and toluene to a flask, and then add tetrabutylammonium bromide and P under an argon atmosphere. 2 O 5 After refluxing for 3 hours, the cooled toluene layer was washed with 5% NaHCO, water and saturated brine in sequence. The organic layer was washed with anhydrous NaSO 4 The mixture was dried and concentrated in vacuo to obtain 4-bromocoumarin. Then 4-bromocoumarin, potassium carbonate and dimethylpyridinamine were added to DMF and heated to 80°C for 3 hours. The reaction mixture was successively treated with 5% NaHCO 3 , water and saturated brine. Then, the organic layer was added to anhydrous Na2SO4 4 The residue was dried on ice, concentrated in vacuo, and purified by column chromatography to obtain the corresponding compound A;

[0033] Step 2: Add reactant A and trifluoromethylthianthrene salt to the reaction solvent at room temperature, normal pressure and air atmosphere, add sodium bicarbonate to the tube, and then place it under a 20W 465nm blue light LED lamp and a magnetic stirrer to stir the reaction (500 rpm) for 18 hours to stop the reaction;

[0034] Step 3: After the reaction in step (2) is completed, the reaction solution is diluted with ethyl acetate, then transferred to a separatory funnel and saturated with NaHCO 3 The organic phase was collected and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and washed with anhydrous Na 2 SO 4 Dry, filter, and collect the filtrate into a round-bottom flask. Then, use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine derivatives, that is, a mixture of β-trifluoromethyl substituted enamine compounds and reaction by-products;

[0035] Step 4: Using a mixed solvent of petroleum ether and ethyl acetate as an eluent, separating and purifying the obtained crude product containing β-trifluoromethyl substituted enamine derivatives through a liquid chromatography column, collecting the solution containing pure β-trifluoromethyl substituted enamine derivatives and transferring it to a round-bottom flask, removing the eluent, i.e., the mixed solvent of petroleum ether and ethyl acetate, using a rotary evaporator, and then drying and weighing the purified β-trifluoromethyl substituted enamine derivatives to finally obtain a yellow oily or solid β-trifluoromethyl substituted enamine compound, which is the method for preparing β-trifluoromethyl substituted enamine compounds from a novel trifluoromethyl thianthrene salt in two steps.

[0036] Preferably, the polytetrafluoroethylene magnetic stirrer described in step 1 is in the shape of a spindle, and its measurement unit size is 6*10mm.

[0037] More preferably, the method does not require the participation of heating, catalysts, or oxidants.

[0038] The method for preparing a β-trifluoromethyl substituted enamine compound from a trifluoromethyl thianthrene salt as a trifluoromethyl source of the present invention has a structure as shown in the following formula I:

[0039]

[0040] Among them, the R 1 , R 2 Each is independently selected from any one of aryl, alkyl, benzyl and derivatives thereof;

[0041] The EWG is any one of an ester group, a ketone group, an amide group, a cyano group and a derivative group thereof.

[0042] The application of the compound synthesized by the method of preparing β-trifluoromethyl substituted enamine compounds using trifluoromethyl thianthrene salt as a trifluoromethyl source described in the present invention is that the compound is used to synthesize lead compounds for screening antiviral, tumor or fungal biopharmaceuticals; or the compound is used to synthesize herbicides, insect repellents and fungicides in agricultural chemicals; or the compound is used to synthesize probes for detecting metal ions.

[0043] The compound is used to synthesize a probe for detecting copper ions.

[0044] The present invention uses trifluoromethyl thianthrene salt as a trifluoromethyl source, dimethyl sulfoxide as a solvent, and synthesizes β-trifluoromethyl enamine compounds in two steps by β-enamine ester or 4-aminocoumarin and a trifluoromethyl source under air atmosphere and room temperature. The reaction conditions of the synthesis method of the present invention are mild, no inert gas protection is required, room temperature and air atmosphere can be carried out, and it has good functional group tolerance and a wide range of substrate universality, and the separation and purification process is simple to operate, and a target product with high site selectivity can be generated with a good to excellent yield. The substrate raw materials used in the present invention are cheap and easy to obtain, widely available, and the solvent is environmentally friendly and green. The synthesis strategy effectively shortens the reaction steps, greatly improves the atom economy, and significantly reduces the cost required for the preparation process, which is conducive to realizing large-scale industrial production.

[0045] Specifically, the present invention uses the following raw materials:

[0046] 1. Organic amines: Organic amine compounds are widely distributed in nature, and most of them are produced by decarboxylation of amino acids. The industrial method of preparing amines is mostly to react ammonia with alcohols or alkyl halides, or to catalytically reduce aldehydes and ketones in the presence of ammonia to obtain the corresponding amines. In addition, amine compounds are often prepared by catalytic reduction of nitro compounds, nitriles, amides or nitrogen-containing heterocyclic compounds. Amines have a wide range of uses. Some amines are necessary to maintain life activities. At the same time, the early dye industry was developed based on aniline.

[0047] 2. Electron-deficient terminal alkynes: Electron-deficient terminal alkynes are important organic chemical raw materials and pharmaceutical intermediates, and are used in the synthesis of many flavors or pyridine anti-inflammatory drugs. Among them, terminal acetylene esters are valuable drugs themselves, such as pyrethroids, which are highly effective and low-toxic insecticides widely used in agriculture and household pest control, and antibiotics such as erythromycin.

[0048] 3. Trifluoromethylthianthrene trifluoromethanesulfonate is a new type of trifluoromethyl source reagent, with the chemical formula of TT + -CF 3 OTf - At room temperature and pressure, trifluoromethylthianthrene salt is a light yellow solid with a slight aromatic odor. The pure trifluoromethylthianthrene salt used in the laboratory is white crystals, and is slightly yellow when there are impurities.

[0049] Based on the special physical and chemical properties of trifluoromethyl and enamine, the present invention introduces a trifluoromethyl skeleton into an enamine compound to construct a β-trifluoromethyl substituted enamine skeleton for screening, research and development of drug molecules.

[0050] The present invention provides a method for preparing β-trifluoromethyl substituted enamine compounds by two steps from a novel trifluoromethyl thianthrene salt ( Figure 1 ), and conducted a methodological study on this method, which shows that the method has high universality.

[0051] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0052] (1) The present invention adopts a new trifluoromethyl source, and the entire synthesis process is simple to operate. The process can be simplified from a two-step method to a three-step "one-pot method", which greatly shortens the synthesis steps required for the trifluoromethylation reaction, thereby showing excellent atom economy and significantly reducing the cost required for the reaction. The synthesis process is simple to operate and easy to automate.

[0053] (2) The reaction conditions are mild and green, without the need for transition metals, oxidants, and heating, using green solvent water as the solvent, and is insensitive to air.

[0054] (3) The raw materials used in the reaction are widely available and cheap.

[0055] (4) At the same time, this method has a wide substrate range and good functional group tolerance. The product is easy to separate and purify, and a series of target products (Z-type structure) with high chemical regioselectivity are obtained in moderate to good yields. In addition, the target product also retains the carbon-carbon unsaturated double bond, which makes the β-trifluoromethyl substituted enamine compound have great potential in further functionalization modification in the later stage.

[0056] (5) The β-trifluoromethylformylamine compounds synthesized by the present invention can perform fluorescence determination on copper ions, and have broad application prospects in the field of metal ion detection. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 It is a technical scheme diagram of the synthesis method of the trifluoromethylthianthrene salt in two steps to prepare β-trifluoromethyl substituted enamine compounds;

[0058] Figure 2 The probe of β-trifluoromethyl substituted enamine compound (10 μM) was used for the detection of Cu 2+ Effect of fluorescence intensity (excitation wavelength λ = 304 nm, emission wavelength λ = 418 nm, slit width 4 nm);

[0059] Figure 3 β-trifluoromethyl substituted enamine compound probe for Cu 2+ Determination of response time (excitation wavelength λ = 304 nm, emission wavelength λ = 418 nm, slit width 4 nm);

[0060] Figure 4 β-trifluoromethyl substituted enamine compound probe for Cu 2+ Selectivity (excitation wavelength λ = 304nm, emission wavelength λ = 418nm, slit width 4nm);

[0061] Figure 5 β-trifluoromethyl substituted enamine compound probe for Cu 2+ competitiveness (excitation wavelength λ = 304 nm, emission wavelength λ = 418 nm, slit width 4 nm);

[0062] Figure 6 For the scale-up production and modular synthesis of β-trifluoromethyl substituted enamine compounds. DETAILED DESCRIPTION

[0063] The present invention is further described below in conjunction with embodiments and drawings.

[0064] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0065] The preparation of trifluoromethylthianthrene salt is prepared according to the existing literature method, as follows:

[0066] Under air atmosphere, thianthrene (17.3 g, 80.0 mmol) and dichloromethane (200.0 mL, c = 0.4 M) were added to a 500 mL double-necked round-bottom flask equipped with a polytetrafluoroethylene magnetic stirrer. Subsequently, trifluoromethanesulfonic anhydride (24.8 g, 14.8 mL, 88.0 mmol) was added at room temperature in one portion. After the addition of trifluoromethanesulfonic anhydride, the reaction mixture quickly turned light purple and gradually deepened, and suspended particles were formed. Subsequently, saturated NaHCO was carefully added. 3 The suspension was poured into a 500 mL separation funnel, the aqueous layer was discarded, and the suspension was washed with anhydrous Na 2 SO 4 The DCM layer was dried. Ether (100.0 mL) was added to the residue and the suspension was stirred vigorously at room temperature for 30 minutes. The mixture was allowed to stand for 5 minutes and then the solvent was carefully decanted. In order to obtain analytically pure compounds, the decantation process was repeated four times with ether. The resulting yellow slurry was concentrated to dryness under reduced pressure to obtain 21.1 grams (63%) of light yellow solid trifluoromethylthianthrene salt. In most cases, the trifluoromethylthianthrene salt can be used directly for subsequent conversions without chromatographic purification or recrystallization.

[0067]

[0068] The preparation of compound A was prepared according to the existing literature method, as follows:

[0069] A mixture of amine (0.5 mmol) and distilled water (0.1 mL) was placed in a 10 mL reaction tube, and the electron-deficient terminal alkyne compound (0.6 mmol) was slowly added under stirring and cooled in a water bath at room temperature, and then the mixture was stirred at the same temperature for 10 minutes. The reaction was quenched with saturated aqueous NaCl solution (0.5 mL), and the resulting mixture was extracted with AcOEt (3 × 1 mL) using a dropper in the same vial. The organic layers were combined and precipitated with Na 2 SO 4 The residue was purified by silica gel column chromatography to obtain the corresponding compound A.

[0070]

[0071] R1 and R2 and EWG in the above reactant A correspond to those in the claims or examples.

[0072] Example 1

[0073] β-Trifluoromethyl substituted enamine compounds

[0074] Synthesis of Ethyl(E)-3-(benzyl(methyl)amino)-2-(trifluoromethyl)acrylate:

[0075]

[0076] Prepare a 10.0 mL boron glass reaction tube, and place a polytetrafluoroethylene magnetic stirrer in each tube, then add reactant A (109.6 mg, 0.5 mmol, 1.0 equiv.) and trifluoromethylthianthrene salt (216.9 mg, 0.5 mmol, 1.0 equiv.) and dimethyl sulfoxide (2 ml) as solvent to obtain reaction solution A, and add sodium bicarbonate (42.0 mg, 0.5 mmol, 1.0 equiv). Place the reaction mixture on a magnetic stirrer and stir (500 rpm) at room temperature and 20 W 465 nm blue light to stop the reaction after 18 hours;

[0077] The mixture after the reaction was diluted with ethyl acetate (10.0 mL╳3), then transferred to a separatory funnel and washed with saturated sodium bicarbonate solution (20.0 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10.0 mL╳2), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dry, filter, and collect the filtrate into a round-bottom flask. Then use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine;

[0078] Then, a mixed solvent of petroleum ether and ethyl acetate (V石油醚 :V 乙酸乙酯 =32:1) as an eluent, the obtained crude product containing the β-trifluoromethyl substituted enamine compound is separated and purified by a liquid chromatography column, the solution containing the pure β-trifluoromethyl substituted enamine compound is collected and transferred to a round-bottom flask, and the eluent, i.e., a mixed solvent of petroleum ether and ethyl acetate, is removed by a rotary evaporator, and then the purified β-trifluoromethyl substituted enamine compound is dried and weighed to finally obtain a yellow oily β-trifluoromethyl substituted enamine compound with a yield of 75%.

[0079] Identification data of the product of this example:

[0080] 1 H NMR (400MHz, Chloroform-d, Major isomer) δ7.43-7.28(m,3H),7.25-7.14(m,3H),4.49(s,2H),4.20(q,J=7.1Hz,2H),2.89(s,3H),1.28(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d,Major isomer) δ 163.83, 150.97 (q, J = 6.4Hz), 135.74, 129.09, 128.25, 127.21, 125.20 (q, J = 268.7Hz), 89.55 (q, J = 30.3Hz), 62.99, 60.23, 41.01, 14.33. 19 F NMR(376MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ-57.50(s,3F).HR-MS(ESI),m / z(%):Calculated for C 24 H 42 N 2 NaO 2 S 2 + [M+Na] + :477.2585,Found:477.2593.

[0081] Example 2

[0082] β-Trifluoromethyl substituted enamine compounds

[0083] Synthesis of Hexyl(E)-3-((4-methylbenzyl)amino)-2-(trifluoromethyl)acrylate:

[0084]

[0085] Prepare a 10.0 mL boron glass reaction tube, and place a polytetrafluoroethylene magnetic stirrer in each tube, then add reactant A (137.6 mg, 0.5 mmol, 1.0 equiv.) and trifluoromethylthianthrene salt (216.9 mg, 0.5 mmol, 1.0 equiv.) and dimethyl sulfoxide (2 ml) as solvent to obtain reaction solution A, and add sodium bicarbonate (42.0 mg, 0.5 mmol, 1.0 equiv). Place the reaction mixture on a magnetic stirrer and stir (500 rpm) at room temperature and 20 W 465 nm blue light to stop the reaction after 18 hours;

[0086] The mixture after the reaction was diluted with ethyl acetate (10.0 mL╳3), then transferred to a separatory funnel and washed with saturated sodium bicarbonate solution (20.0 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10.0 mL╳2), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dry, filter, and collect the filtrate into a round-bottom flask. Then, use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine;

[0087] Then, the obtained crude product containing the β-trifluoromethyl substituted enamine compound is separated and purified by a liquid chromatography column using pure petroleum ether solvent as an eluent, the solution containing the pure β-trifluoromethyl substituted enamine compound is collected and transferred to a round-bottom flask, and the eluent, i.e., a mixed solvent of petroleum ether and ethyl acetate, is removed using a rotary evaporator. Subsequently, the purified β-trifluoromethyl substituted enamine compound is dried and weighed to finally obtain a yellow oily β-trifluoromethyl substituted enamine compound with a yield of 67%.

[0088] Identification data of the product of this example:

[0089] 1 H NMR(400MHz,Chloroform-d)δ8.82(s,1H),7.32(d,J=13.6Hz,1H),7.19-7.10(m,4H),4.39(d,J=5.9 Hz,2H),4.14(t,J=6.6Hz,2H),2.34(s,3H),1.71-1.55(m,2H),1.36-1.23(m,6H),0.90-0.86(m,3H). 13C NMR (101MHz, Chloroform-d) δ 167.44, 152.71 (q, J = 6.0Hz), 138.01, 133.98, 129.74, 127.35, 125. 19(q,J=268.7Hz),88.09(q,J=33.3Hz),64.08,52.82,31.46,28.71,25.58,22.62,21.20,14.07. 19 F NMR(376MHz,Chloroform-d)δ-58.98(s,3F).HR-MS(ESI),m / z(%):Calculated for C 27 H 36 N 2 NaO 2 S 2 + [M+Na] + :507.2116,Found:507.2123.

[0090] Example 3

[0091] β-Trifluoromethyl substituted enamine compounds

[0092] Synthesis of Ethyl(E)-3-((1R,7R)-5-oxo-2-azabicyclo[5.1.0]octan-2-yl)-2-(trifluoromethyl)acr ylate:

[0093]

[0094] Prepare a 10.0 mL boron glass reaction tube, and place a polytetrafluoroethylene magnetic stirrer in each tube, then add reactant A (111.6 mg, 0.5 mmol, 1.0 equiv.) and trifluoromethylthianthrene salt (216.9 mg, 0.5 mmol, 1.0 equiv.) and solvent dimethyl sulfoxide (2 ml) to obtain reaction solution A, and add sodium bicarbonate (42.0 mg, 0.5 mmol, 1.0 equiv). Place the reaction mixture on a magnetic stirrer (500 rpm) at room temperature and 20 W 465 nm blue light to stop the reaction after 18 hours;

[0095] The mixture after the reaction was diluted with ethyl acetate (10.0 mL╳3), then transferred to a separatory funnel and washed with saturated sodium bicarbonate solution (20.0 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10.0 mL╳2), the organic phases were combined and washed with anhydrous Na 2 SO 4Dry, filter, and collect the filtrate into a round-bottom flask. Then use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine;

[0096] Then, a mixed solvent of petroleum ether and ethyl acetate (V 石油醚 :V 乙酸乙酯 =15:1) as eluent, the obtained crude product containing the β-trifluoromethyl substituted enamine compound was separated and purified by a liquid chromatography column, the solution containing the pure β-trifluoromethyl substituted enamine compound was collected and transferred to a round-bottom flask, and the eluent, i.e., the mixed solvent of petroleum ether and ethyl acetate, was removed by a rotary evaporator, and then the purified β-trifluoromethyl substituted enamine compound was dried and weighed to finally obtain a yellow oily β-trifluoromethyl substituted enamine compound with a yield of 72%.

[0097] Identification data of the product of this example:

[0098] 1 H NMR(400MHz,Chloroform-d,Major isomer)δ7.17(d,J=1.8Hz,1H),4.62-4.30(m,2H),4.19(q,J=7.1Hz,2H),3.04-2.62(m,2H), 2.45(dt,J=15.6,1.7Hz,2H),2.29-2.02(m,2H),1.75(q,J=7.3Hz,2H),1.28(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d,Major isomer)δ206.85,164.43,147.85,145.26(q,J=6.7Hz),125.63(q,J=270.7Hz),89.85(q,J=30.3Hz),60.24,49.73,28.61,14.28. 19 F NMR(376MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ-57.69(s,3F).HR-MS(ESI),m / z(%):Calculated for C 21 H 30 N 2 NaO 5 S 2 + [M+Na] + :477.1494,Found:477.1497.

[0099] Example 4

[0100] β-Trifluoromethyl substituted enamine compounds

[0101] Synthesis of Tert-butyl(E)-(2-(ethoxycarbonyl)-3,3,3-trifluoroprop-1-en-1-yl)-L-prolinate

[0102]

[0103] Prepare a 10.0 mL boron glass reaction tube, and place a polytetrafluoroethylene magnetic stirrer in each tube, then add reactant A (134.6 mg, 0.5 mmol, 1.0 equiv.) and trifluoromethylthianthrene salt (216.9 mg, 0.5 mmol, 1.0 equiv.) and dimethyl sulfoxide (2 ml) as solvent to obtain reaction solution A, and add sodium bicarbonate (42.0 mg, 0.5 mmol, 1.0 equiv). Place the reaction mixture on a magnetic stirrer (500 rpm) at room temperature and 20 W 465 nm blue light to stop the reaction after 18 hours;

[0104] The mixture after the reaction was diluted with ethyl acetate (10.0 mL╳3), then transferred to a separatory funnel and washed with saturated sodium bicarbonate solution (20.0 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10.0 mL╳2), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dry, filter, and collect the filtrate into a round-bottom flask. Then use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine;

[0105] Then, a mixed solvent of petroleum ether and ethyl acetate (V 石油醚 :V 乙酸乙酯 =8:1) as an eluent, the obtained crude product containing the β-trifluoromethyl substituted enamine compound is separated and purified by a liquid chromatography column, the solution containing the pure β-trifluoromethyl substituted enamine compound is collected and transferred to a round-bottom flask, and the eluent, i.e., a mixed solvent of petroleum ether and ethyl acetate, is removed by a rotary evaporator, and then the purified β-trifluoromethyl substituted enamine compound is dried and weighed to finally obtain a yellow oily β-trifluoromethyl substituted enamine compound with a yield of 74%.

[0106] Identification data of the product of this example:

[0107] 1H NMR (400MHz, Chloroform-d, Major isomer) δ7.13 (s, 1H), 4.17 (q, J = 7.0Hz, 2H), 3.51 (m, 2H), 2.31-1.80 (m, 4H), 1.43 (s, 9H), 1.25 (t, J = 7.1Hz, 3H). 13 C NMR(101MHz,Chloroform-d,Major isomer)δ170.41,163.48,147.11,125.63(q,J=270.7Hz),90.9(q,J=30.3Hz),82.69,67.13,60.11,29.13,27.93,24.75,14.29. 19 F NMR(376MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ-57.92(s,3F).HR-MS(ESI),m / z(%):Calculated forC 18 H 29 N 2 O 5 S 2 + [M+H] + :417.1518,Found:417.1522.

[0108] Example 5

[0109] β-Trifluoromethyl substituted enamine

[0110] Synthesis of Ethyl(Z)-3-((3S,4R)-3-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidin-1-yl)-2-(trifluoromethyl)acrylate

[0111]

[0112] Prepare a 10.0 mL boron glass reaction tube, and place a polytetrafluoroethylene magnetic stirrer in each tube, then add reactant A (206.6 mg, 0.5 mmol, 1.0 equiv.) and trifluoromethylthianthrene salt (216.9 mg, 0.5 mmol, 1.0 equiv.) and dimethyl sulfoxide (2 ml) as solvent to obtain reaction solution A, and add sodium bicarbonate (42.0 mg, 0.5 mmol, 1.0 equiv). Place the reaction mixture on a magnetic stirrer and stir (500 rpm) at room temperature and 20 W 465 nm blue light to stop the reaction after 18 hours;

[0113] The mixture after the reaction was diluted with ethyl acetate (10.0 mL╳3), then transferred to a separatory funnel and washed with saturated sodium bicarbonate solution (20.0 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10.0 mL╳2), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dry, filter, and collect the filtrate into a round-bottom flask. Then, use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine;

[0114] Then, a mixed solvent of petroleum ether and ethyl acetate (V 石油醚 :V 乙酸乙酯 =8:1) as an eluent, the obtained crude product containing the β-trifluoromethyl substituted enamine compound is separated and purified by a liquid chromatography column, the solution containing the pure β-trifluoromethyl substituted enamine compound is collected and transferred to a round-bottom flask, and the eluent, i.e., a mixed solvent of petroleum ether and ethyl acetate, is removed by a rotary evaporator, and then the purified β-trifluoromethyl substituted enamine compound is dried and weighed to finally obtain a yellow oily β-trifluoromethyl substituted enamine compound with a yield of 45%.

[0115] Identification data of the product of this example:

[0116] 1H NMR (400MHz, DMSO-d6) δ7.40 (s, 1H), 7.31 (ddd, J=8.7, 5.8, 3.1Hz, 2H), 7.11 (td, J=8.9, 1.9 Hz,2H),6.73(dd,J=8.5,1.4Hz,1H),6.45(dd,J=4.9,2.4Hz,1H),6.17(dt,J=8.5,2.6Hz,1H) ,5.92(s,2H),4.10(q,J=7.1Hz,2H),4.00-3.67(m,2H),3.64-3.44(m,2H),3.34-3.10(m,2H ),2.82(td,J=11.6,3.9Hz,1H),2.36-2.15(m,1H),2.02-1.69(m,2H),1.17(t,J=7.1Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ163.85,171.47(d,J=243.4Hz),154.36,151.20(dd,J=6.3Hz),148.38,141.79,139.75,129.75(d,J=7.7Hz),128.38(q,J =270.7Hz),115.79(d,J=21.0Hz),108.47,106.05,101.52,98.27,85.91 (q,J=30.3Hz),69.06,59.79,55.43,49.11,42.57,41.91,33.91,14.75. 19 F NMR (376MHz, DMSO-d6, Majorisomer, E / Z≈3 / 1)δ-54.92(s,3F),-116.18(s,1F).

[0117] HR-MS(ESI),m / z(%):Calculated for C 22 H 38 N 2 NaO 4 S 2 + [M+Na] + :481.2171,Found:481.2178.

[0118] Example 6

[0119] β-Trifluoromethyl substituted enamine

[0120] Synthesis of Ethyl(E)-3-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-2-(trifluoromethyl)acrylate e

[0121]

[0122] Prepare a 10.0 mL boron glass reaction tube, and place a polytetrafluoroethylene magnetic stirrer in each tube, then add reactant A (158.7 mg, 0.5 mmol, 1.0 equiv.) and trifluoromethylthianthrene salt (216.9 mg, 0.5 mmol, 1.0 equiv.) and dimethyl sulfoxide (2 ml) as solvent to obtain reaction solution A, and add sodium bicarbonate (42.0 mg, 0.5 mmol, 1.0 equiv). Place the reaction mixture under room temperature and 20 W 465 nm blue light under a magnetic stirrer (500 rpm) for 18 hours to stop the reaction;

[0123] The mixture after the reaction was diluted with ethyl acetate (10.0 mL╳3), then transferred to a separatory funnel and washed with saturated sodium bicarbonate solution (20.0 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10.0 mL╳2), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dry, filter, and collect the filtrate into a round-bottom flask. Then, use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine;

[0124] Then, a mixed solvent of petroleum ether and ethyl acetate (V 石油醚 :V 乙酸乙酯 =8:1) as eluent, the obtained crude product containing the β-trifluoromethyl substituted enamine compound was separated and purified by a liquid chromatography column, the solution containing the pure β-trifluoromethyl substituted enamine compound was collected and transferred to a round-bottom flask, and the eluent, i.e., the mixed solvent of petroleum ether and ethyl acetate, was removed by a rotary evaporator, and then the purified β-trifluoromethyl substituted enamine compound was dried and weighed to finally obtain a yellow oily β-trifluoromethyl substituted enamine compound with a yield of 70%.

[0125] Identification data of the product of this example:

[0126] 1H NMR(400MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ7.84(ddt,J=20.3,8.2,0.9Hz,2H),7.56-7.32(m,2H),7.08( d,J=1.2Hz,1H),4.21(q,J=7.1Hz,2H),3.78-3.50(m,8H),1.29(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ164.20,163.05,152.98,150.05(q,J=6.4Hz),127.95,127.76,125.81( q,J=271.7Hz),124.35,123.59,120.81,89.08(q,J=30.3Hz),60.33,51.98,50.02,14.36. 19 FNMR(376MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ-57.54(s,3F).HR-MS(ESI),m / z(%):Calculated for C 20 H 34 N 2 NaO 4 S 2 + [M+Na] + :453.1858,Found:453.1865.

[0127] Example 7

[0128] β-Trifluoromethyl substituted enamine

[0129] Synthesis of Ethyl(E)-3-((3-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-ylidene)propyl)(met hyl)amino)-2-(trifluoromethyl)acrylate

[0130]

[0131] Prepare a 10.0 mL boron glass reaction tube, and place a polytetrafluoroethylene magnetic stirrer in each tube, then add reactant A (180.7 mg, 0.5 mmol, 1.0 equiv.) and trifluoromethylthianthrene salt (216.9 mg, 0.5 mmol, 1.0 equiv.) and solvent dimethyl sulfoxide (2 ml), prepare reaction solution A at 465 nm, and add sodium bicarbonate (42.0 mg, 0.5 mmol, 1.0 equiv), place in a magnetic stirrer and stir the reaction (500 rpm) at room temperature and 20 W blue light to stop the reaction after 18 hours;

[0132] The mixture after the reaction was diluted with ethyl acetate (10.0 mL╳3), then transferred to a separatory funnel and washed with saturated sodium bicarbonate solution (20.0 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10.0 mL╳2), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dry, filter, and collect the filtrate into a round-bottom flask. Then use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine;

[0133] Then, a mixed solvent of petroleum ether and ethyl acetate (V 石油醚 :V 乙酸乙酯 =16:1) as eluent, the obtained crude product containing the β-trifluoromethyl substituted enamine compound was separated and purified by a liquid chromatography column, the solution containing the pure β-trifluoromethyl substituted enamine compound was collected and transferred to a round-bottom flask, and the eluent, i.e., the mixed solvent of petroleum ether and ethyl acetate, was removed by a rotary evaporator, and then the purified β-trifluoromethyl substituted enamine compound was dried and weighed to finally obtain a yellow oily β-trifluoromethyl substituted enamine compound with a yield of 56%.

[0134] Identification data of the product of this example:

[0135] 1 H NMR(400MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ7.69-7.40(m,1H),7.25-7.00(m,8H),5.78(t,J=7.5Hz,1H),4.20(q,J=7.1Hz,2H),3.45-3.22(m,4H),2 .96(t,J=15.0Hz,1H),2.87(t,J=3.4Hz,1H),2.85(s,2H),2.78(d,J=13.1Hz,1H),2.64-2.28(m,2H),1.28(t,J=7.1Hz,3H). 13C NMR(101MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ163.73,150.39(q,J=6.4Hz),146.33,140.69,139.54,139.42,137.20,130.23,128.55,128.34,127.91(d ,J=3.2Hz),127.51,126.23,126.04,125.17(q,J=265.6Hz),88.86(q,J=30.3Hz),60.11,41.31,33.77,32.03,28.56,14.39. 19 F NMR(376MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ-57.33(s,3F).HR-MS(ESI),m / z(%):Calculated for C 21 H 28 N 2 NaO 4 S 2 + [M+Na] + :459.1388,Found:459.1389.

[0136] Example 8

[0137] β-Trifluoromethyl substituted enamine

[0138] Synthesis of Ethyl(E)-3-(((1S,4R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)amino)-2-(trifluoromethyl)acrylatee

[0139]

[0140] Prepare a 10.0 mL boron glass reaction tube, and place a polytetrafluoroethylene magnetic stirrer in each tube, then add reactant A (202.1 mg, 0.5 mmol, 1.0 equiv.) and trifluoromethylthianthrene salt (216.9 mg, 0.5 mmol, 1.0 equiv.) and dimethyl sulfoxide (2 ml) as solvent to obtain reaction solution A, and add sodium bicarbonate (42.0 mg, 0.5 mmol, 1.0 equiv). Place the reaction mixture on a magnetic stirrer and stir (500 rpm) at room temperature and 20 W 465 nm blue light to stop the reaction after 18 hours;

[0141] The mixture after the reaction was diluted with ethyl acetate (10.0 mL╳3), then transferred to a separatory funnel and washed with saturated sodium bicarbonate solution (20.0 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10.0 mL╳2), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dry, filter, and collect the filtrate into a round-bottom flask. Then, use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine;

[0142] Then, a mixed solvent of petroleum ether and ethyl acetate (V 石油醚 :V 乙酸乙酯 =16:1) as an eluent, the obtained crude product containing the β-trifluoromethyl substituted enamine compound is separated and purified by a liquid chromatography column, the solution containing the pure β-trifluoromethyl substituted enamine compound is collected and transferred to a round-bottom flask, and the eluent, i.e., a mixed solvent of petroleum ether and ethyl acetate, is removed by a rotary evaporator, and then the purified β-trifluoromethyl substituted enamine compound is dried and weighed to finally obtain a yellow oily β-trifluoromethyl substituted enamine compound with a yield of 71%.

[0143] Identification data of the product of this example:

[0144] 1 H NMR(400MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ7.33(d,J=8.3Hz,1H),7.30(dt,J=6.7,1.6Hz,1H),7.27–7.17(m,3H),7.12(d,J=19.3Hz,1H),7.03–6.92(m ,1H),6.83(dd,J=8.4,2.1Hz,1H),4.77–4.47(m,1H),4.25–4.10(m,3H),2.83(s,3H),2.34-1.74(m,4H),1.28(t,J=7.1Hz,3H). 13 CNMR(101MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ163.84,153.52,150.19,146.46,138.73,134.18,132.63,130.95,130.66,130.47,128.78,128. 74,128.00,127.96,125,90(q,J=271.69Hz),89.50(q,J=30.3Hz),67.06,60.29,43.48,38.13,29.37,24.21,14.37. 19F NMR(376MHz,Chloroform-d,Majorisomer,E / Z≈3 / 1)δ-57.42(s,3F).HRMS-ESI,m / z(%):Calculated for C 29 H 41 N 4 O 2 S 3 + ,[M+H] + :573.2392, found 573.2389.

[0145] Example 9

[0146] β-Trifluoromethyl substituted enamine

[0147] Synthesis of 2-chlorobenzyl(E)-3-(benzylamino)-2-(trifluoromethyl)acrylate

[0148]

[0149] Prepare a 10.0 mL boron glass reaction tube, and place a polytetrafluoroethylene magnetic stirrer in each tube, then add reactant A (150.9 mg, 0.5 mmol, 1.0 equiv.) and trifluoromethylthianthrene salt (216.9 mg, 0.5 mmol, 1.0 equiv.) and dimethyl sulfoxide (2 ml) as solvent to obtain reaction solution A, and add sodium bicarbonate (42.0 mg, 0.5 mmol, 1.0 equiv). Place the reaction mixture on a magnetic stirrer and stir (500 rpm) at room temperature and 20 W 465 nm blue light to stop the reaction after 18 hours;

[0150] The mixture after the reaction was diluted with ethyl acetate (10.0 mL╳3), then transferred to a separatory funnel and washed with saturated sodium bicarbonate solution (20.0 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10.0 mL╳2), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dry, filter, and collect the filtrate into a round-bottom flask. Then, use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine;

[0151] Then, the obtained crude product containing the β-trifluoromethyl substituted enamine compound is separated and purified by a liquid chromatography column using pure petroleum ether solvent as an eluent, and the solution containing the pure β-trifluoromethyl substituted enamine compound is collected and transferred to a round-bottom flask. The eluent, i.e., a mixed solvent of petroleum ether and ethyl acetate, is removed using a rotary evaporator. Subsequently, the purified β-trifluoromethyl substituted enamine compound is dried and weighed to finally obtain a yellow oily β-trifluoromethyl substituted enamine compound with a yield of 46%.

[0152] Identification data of the product of this example: 1 H NMR (400MHz, Chloroform-d) δ8.87 (s, 1H), 7.52-7.47 (m, 1H), 7.44-7.19 (m, 9H), 5.34 (s, 2H), 4.45 (d, J = 6.0Hz, 2H). 13 C NMR(101MHz,Chloroform-d)δ166.70,153.32(q,J=5.9Hz),136.76,134.21,132.50,129.36,129.15, 128.97,128.40,128.33,127.39,127.08,125.17(q,J=268.7Hz),87.82(q,J=32.3Hz),62.72,53.19. 19 F NMR(376MHz,Chloroform-d)δ-58.67(s,3F).HR-MS(ESI),m / z(%):Calculated for C 29 H 37 F 3 N 2 NaO 3 S 2 + [M+Na] + :605.2095,Found:605.2099.

[0153] Example 10

[0154] β-Trifluoromethyl substituted enamine

[0155] Preparation of 4-(bis(pyridin-2-ylmethyl)amino)-3-(trifluoromethyl)-2H-chromen-2-one

[0156]

[0157] Prepare a 10.0 mL boron glass reaction tube, and place a polytetrafluoroethylene magnetic stirrer in each tube, then add reactant A (171.7 mg, 0.5 mmol, 1.0 equiv.) and trifluoromethylthianthrene salt (216.9 mg, 0.5 mmol, 1.0 equiv.) and solvent dimethyl sulfoxide (2 ml) to obtain reaction solution A, and add sodium bicarbonate (42.0 mg, 0.5 mmol, 1.0 equiv). Place the reaction mixture on a magnetic stirrer (500 rpm) at room temperature and 20 W 465 nm blue light to stop the reaction after 18 hours;

[0158] The mixture after the reaction was diluted with ethyl acetate (10.0 mL╳3), then transferred to a separatory funnel and washed with saturated sodium bicarbonate solution (20.0 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (10.0 mL╳2), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dry, filter, and collect the filtrate into a round-bottom flask. Then use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine;

[0159] Then, the crude product containing the β-trifluoromethyl substituted enamine compound is separated and purified by a liquid chromatography column using a mixed solvent of petroleum ether and ethyl acetate as an eluent, and the solution containing the pure β-trifluoromethyl substituted enamine compound is collected and transferred to a round-bottom flask. The eluent, i.e., the mixed solvent of petroleum ether and ethyl acetate, is removed by a rotary evaporator. Subsequently, the purified β-trifluoromethyl substituted enamine compound is dried and weighed to finally obtain a yellow oily β-trifluoromethyl substituted enamine compound with a yield of 48%.

[0160] Identification data of the product of this example: 1 H NMR (400 MHz, DMSO-d 6 )δ8.59-8.47(m,2H),7.96(dd,J=8.3,1.6Hz,1H),7.81(td,J=7.6,1.8Hz,2H),7.72(ddd,J=8.5,7.2,1. 5Hz,1H),7.47(dd,J=8.3,1.2Hz,1H),7.45-7.36(m,3H),7.33(ddd,J=7.5,4.8,1.2Hz,2H),4.48(s,4H). 13 C NMR (101 MHz, DMSO-d 6)δ161.99,158.73,156.35,153.87,149.86,137.39,134.33,128.72,124.89,124. 24,123.53,123.16(q,J=270.7Hz),118.18,117.73,104.59(q,J=30.3Hz),59.18. 19 F NMR (376 MHz, DMSO-d 6 )δ-58.80(s,3F).HRMS-ESI(m / z)[M+H] + calculated for C 22 H 17 F 3 N 3 O 2 + 412.1267, found 412.1270.

[0161] The synthesis of compound A in this example was prepared according to the existing literature method, as follows:

[0162] Under argon atmosphere, 4-hydroxycoumarin (1 g, 6.2 mmol) was added to toluene (12.4 mL) and heated to 100°C. Bu was then added. 4 NBr (3.0 g, 9.3 mmol), continue heating until Bu 4 NBr is dissolved, then P is added 2 O 5 (1.8 g, 12.4 mmol), and the mixture was refluxed for 3 hours. The combined toluene layers were successively treated with 5% NaHCO 3 (2×30.0 mL), water (50.0 mL) and saturated brine (50.0 mL). 2 SO 4 (10.0 g) and dried and concentrated in vacuo to give 4-bromocoumarin (1.4 g, 96%).

[0163] 4-Bromocoumarin (225.0 mg, 1 mmol), potassium carbonate (138.2 mg, 1 mmol) and dimethylpyridinamine (239.1 mg, 1.2 mmol) were added to DMF (0.25 M) and heated to 80°C for 3 hours. The reaction was successively treated with 5% NaHCO 3 (2×30.0 mL), water (50 mL) and saturated brine (50.0 mL). 2 SO 4 (10.0 g), and concentrated in vacuo to give the corresponding compound A (171.1 mg, 50%).

[0164]

[0165] Embodiment 11

[0166] The fluorescence determination experiment of copper ions using the β-trifluoromethyl substituted enamine compound probe synthesized in Example 10 was carried out.

[0167] 1. Probe and Determination of Copper Ion Concentration

[0168] In order to determine the relationship between the change in fluorescence intensity and different concentrations of copper ions, 11 centrifuge tubes (4 mL each) were prepared. 3 mL of V DMF :V PBS (1:9) buffer solution. Then, the prepared copper ion stock solution (1mM) was added to the centrifuge tubes in the following amounts: 0μL, 3μL, 6μL, 9μL, 12μL, 15μL, 18μL, 21μL, 24μL, 27μL and 30μL. Then, 30μL of the probe stock solution (1mM) was added to each test tube. Shake the mixture and let it stand for 20 minutes. After the incubation period, measure the fluorescence emission spectrum. The results are shown in Figure 2 As shown, at the emission wavelength of 418 nm, the fluorescence intensity of the probe shows a gradient decrease with the increasing concentration of copper ions, and the probe forms an ion complex with copper ions with a complex ratio of 1:1.

[0169] 2. Effect of reaction time on the fluorescence emission spectrum of the probe

[0170] In order to study the relationship between the change in fluorescence intensity and time after the probe reacted with copper ions, 3 mL of V DMF :V PBS (1:9) buffer solution. Then add 30μL probe stock solution (1mM) and 30μL copper ion stock solution (1mM). Shake the mixture and let it stand. Measure the fluorescence intensity at the following time intervals: 0 min, 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 21 min, 22 min, 23 min. The results are shown in Figure 3 The results show that after adding copper ions (30 μM), the fluorescence intensity of the probe decreases rapidly and stabilizes in about 20 minutes. This indicates that the reaction time is relatively short, and the probe and copper ions react almost completely within about 20 minutes after mixing, proving that the compound synthesized by the present invention can quickly detect the concentration of copper ions.

[0171] 3. Selectivity and Competitiveness Test of Copper Ion Probe

[0172] In order to test the selectivity of the probe for copper ions, a series of comparisons with traditional competing ions were performed. 16 centrifuge tubes (3 mL each) were prepared, and 3 mL of V DMF :V PBS (1:9) buffer solution and 30 μL probe stock solution (1 mM). Each centrifuge tube was injected with 30 μL of different ion stock solutions (concentration of 1 mM): Mg 2+ , Fe 3+ , Fe 2+ 、Al 3+ 、Zn 2+ 、Ni 2+ 、Na + 、Co 2+ , K + 、F - 、Cd 2+ ,I - , Cu + , Cu 2+ , Ca 2+ and Mn 2+ The mixture was shaken and allowed to stand for 20 minutes. The fluorescence emission spectrum was then measured. Figure 4 As shown, the fluorescence intensity of the probe does not change except for copper ions, which proves that the probe has good selectivity and only detects copper ions.

[0173] In order to test the competitiveness of the probe for copper ions, a series of comparisons with traditional competitive ions were performed. 15 centrifuge tubes (3 mL each) were prepared, and 3 mL of V DMF :V PBS (1:9) buffer solution and 30 μL probe stock solution (1 mM). Each centrifuge tube was injected with 30 μL of different ion stock solutions (concentration of 1 mM) and 30 μL of copper ion stock solution (concentration of 1 mM): Mg 2+ , Fe 3+ , Fe 2+ 、Al 3+ 、Zn 2+ 、Ni 2+ 、Na + 、Co 2+ , K + 、F - 、Cd 2+ ,I - , Cu + , Ca 2+ and Mn 2+ The mixture was shaken and allowed to stand for 20 minutes. The fluorescence emission spectrum was then measured. Figure 5As shown, when other ions and copper ions are added, the fluorescence intensity of the probe decreases, which is the same as the result of detecting only copper ions, proving that the fluorescence performance of the probe is good and will not be affected by other ions.

[0174] Example 12

[0175] Scale-up and modular synthesis of β-trifluoromethyl substituted enamine compounds ( Figure 6 )

[0176] Can easily achieve gram-scale amplification synthesis

[0177]

[0178] In air, reactant A (4 mmol, 1.0 equiv) and trifluoromethylthianthrene salt (1735.8 mg, 4 mmol, 1.0 equiv) were slowly added to a 50 ml covered quartz tube, and then anhydrous dimethyl sulfoxide (16 ml) was added as a solvent to dissolve them to form a solution. Then, NaHCO was added to the reaction mixture. 3 (336.0 mg, 4 mmol, 1.0 equiv), placed in a magnetic stirrer under room temperature and 20W 465nm blue light conditions to stir the reaction (500 rpm) for 18 hours and then stop the reaction;

[0179] The mixture after the reaction was diluted with ethyl acetate (50.0 mL╳3), then transferred to a separatory funnel and washed with saturated sodium bicarbonate solution (50.0 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (50.0 mL╳2), the organic phases were combined and washed with anhydrous Na 2 SO 4 Dry, filter, and collect the filtrate into a round-bottom flask. Then, use a rotary evaporator to remove ethyl acetate under reduced pressure to obtain a crude product mainly composed of β-trifluoromethyl substituted enamine;

[0180] Then, the obtained crude product containing the β-trifluoromethyl substituted enamine compound is separated and purified by a liquid chromatography column using pure petroleum ether solvent as an eluent, the solution containing the pure β-trifluoromethyl substituted enamine compound is collected and transferred to a round-bottom flask, and the eluent, i.e., a mixed solvent of petroleum ether and ethyl acetate, is removed using a rotary evaporator. Subsequently, the purified β-trifluoromethyl substituted enamine compound is dried and weighed to finally obtain a yellow oily β-trifluoromethyl substituted enamine compound with a yield of 63%.

[0181] Identification data of the product of this example:

[0182] 1H NMR (400MHz, Chloroform-d) δ7.42-7.29(m,7H),7.22-7.11(m,4H),4.45(s,4H),4.16(q,J=7.1Hz,2H),1.23(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ164.11,150.38(q,J=6.9Hz),135.71,128.97,12 8.14,127.91125.87(q,J=271.7Hz),90.84(q,J=30.3Hz),60.36,57.49,14.28. 19 F NMR(376MHz,Chloroform-d,Major isomer,E / Z≈3 / 1)δ-57.52(s,3F).HRMS-ESI(m / z)[M+H] + calculated for C 20 H 21 F 3 NO 2 + 364.1519, found 364.1516.

[0183] The implementation of the above experiments can prove that the new synthesis method developed by the present invention has the potential to be applied to a large number of industrial productions, and can also be used in the synthesis of biologically active compounds.

[0184] The substrate comparison experiment is as follows:

[0185] (1) Based on the above reaction conditions in Example 12, the amount of reactant 1 was selected as 0.5 mmol as the standard reaction method, the two were in an equimolar ratio, and the proportions of other steps remained unchanged. The base and solvent were adjusted for comparative experiments

[0186]

[0187]

[0188] (2) Based on the reaction conditions in Example 12, the amount of reactant 1 was selected as 0.5 mmol as the standard reaction method, and the other steps and proportions remained unchanged. The proportion of the reaction substrate was adjusted to compare the experiment.

[0189]

[0190] (3) Based on the reaction conditions in Example 12, the amount of reactant 1 was selected as 0.5 mmol as the standard reaction method, and the other steps and proportions remained unchanged. The reaction base equivalent, time and light source were adjusted for comparative experiments

[0191]

[0192]

[0193] In summary, the standard preparation method is adopted, except that: when other bases are selected to replace sodium bicarbonate, such as potassium phosphate, sodium carbonate, sodium hydroxide, etc., the target product yield is not as good as the present invention. When the reaction solvent is a common organic solvent, the target product yield is lower than the yield when dimethyl sulfoxide is used as the solvent. When the ratio of the reaction substrate in the reaction process is screened, it is found that when any substrate ratio is inconsistent with the present invention, the reaction effect is not as good as the present invention, and the yield of the target product is lower than the present invention. In addition, the reaction conditions of the present invention in terms of light source and time are also the optimal reaction conditions.

Claims

1. A method for preparing a β-trifluoromethyl substituted enamine compound using a trifluoromethyl thianthrene salt as a trifluoromethyl source, characterized in that: Using trifluoromethylthianthrene salt as a trifluoromethyl source and an organic solvent as a solvent, a β-trifluoromethyl substituted enamine compound is synthesized in two steps by using an amine as a first component, an enamine ester or 4-aminocoumarin synthesized from an electron-deficient terminal acetylenic compound, and trifluoromethylthianthrene salt as a second component.

2. The method for preparing a β-trifluoromethyl substituted enamine compound using a trifluoromethyl thianthrene salt as a trifluoromethyl source according to claim 1, characterized in that: The steps include: Step 1, stirring the first component amine and the electron-deficient terminal alkyne at room temperature, or reacting 4-hydroxycoumarin and tetrabutylammonium bromide at high temperature to prepare 4-bromocoumarin and reacting it with an amine reagent to obtain a reaction product A; Step 2, dissolving reactant A and trifluoromethylthianthrene salt in dimethyl sulfoxide solvent and adding sodium bicarbonate, stirring the reaction system under blue light; Step 3: After the reaction is completed, add saturated sodium bicarbonate solution to the reaction solution and mix evenly, separate and collect the organic phase, perform liquid phase separation and extraction on the aqueous phase, combine the organic phases and dry, filter, collect the filtrate and remove the solvent under reduced pressure; the crude product is purified to obtain a β-trifluoromethyl substituted enamine compound.

3. The method for preparing β-trifluoromethyl substituted enamine compounds from trifluoromethyl thianthrene salt as a trifluoromethyl source according to claim 1, characterized in that: The structure of the first component amine compound is preferably any one of the following structures: The structure of the electron-deficient terminal alkyne compound is any one of the following structures:

4. The method for preparing β-trifluoromethyl substituted enamine compounds from trifluoromethyl thianthrene salt as a trifluoromethyl source according to claim 1, characterized in that: The amine reagent is selected from any one of the following: NH3 5. The method for preparing β-trifluoromethyl substituted enamine compounds from trifluoromethyl thianthrene salt as a trifluoromethyl source according to claim 2, characterized in that: The amount of the first component amine substance is 1 to 1.5 times that of the electron-deficient terminal acetylene compound; The amount of the tetrabutylammonium bromide substance is 1.2 to 2.0 times that of 4-hydroxycoumarin; the amount of the amine reagent substance is 1 to 1.5 times that of 4-bromocoumarin; The amount of the trifluoromethylthianthrene salt substance is 1.0 to 2 times that of the electron-deficient terminal alkyne compound; The amount of the sodium bicarbonate substance is 1.0 to 2 times that of the electron-deficient terminal alkyne compound.

6. The method for preparing β-trifluoromethyl substituted enamine compounds from trifluoromethyl thianthrene salt as a trifluoromethyl source according to claim 1, characterized in that: The reaction temperature of step (2) is room temperature, normal pressure and air atmosphere, and the reaction time is 15-20h.

7. The method for preparing β-trifluoromethyl substituted enamine compounds from trifluoromethyl thianthrene salt as a trifluoromethyl source according to claim 1, characterized in that: The organic solvent is dimethyl sulfoxide, and the amount of the solvent used is such that the reaction can be smoothly converted.

8. A method for preparing a β-trifluoromethyl substituted enamine compound using a trifluoromethyl thianthrene salt as a trifluoromethyl source as claimed in claim 1, characterized in that: The structure of the β-trifluoromethyl substituted enamine compound is shown in the following formula I: Among them, the R 1 , R 2 Each is independently selected from any one of aryl, alkyl, benzyl and derivatives thereof; The EWG is any one of an ester group, a ketone group, an amide group, a cyano group and a derivative group thereof.

9. An application of a compound synthesized by the method for preparing a β-trifluoromethyl substituted enamine compound using a trifluoromethyl thianthrene salt as a trifluoromethyl source according to claim 1, characterized in that: The compound is used for synthesizing a lead compound for screening antiviral, tumor or fungal biomedicine; or the compound is used for synthesizing herbicides, insect repellents and fungicides in agricultural chemicals; or the compound is used for synthesizing a probe for detecting metal ions.

10. The use according to claim 9, characterized in that: The compound is used for synthesizing a probe for detecting copper ions.

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