Condensing agent and use thereof in production of isothiocyanates

Abstract

The invention provides a condensing agent, and relates to the field of organic synthesis. The condensing agent has a formula 1: # imgabs0 #, wherein R1 and R2 are independently selected from the same or different electron withdrawing groups. Compared with sulfur phosgene or carbon disulfide adopted in a traditional scheme, the condensing agent provided by the embodiment of the invention is low in toxicity, and the condensing agent is solid, so that pollution diffusion is easy to control. Therefore, the condensing agent provided by the embodiment of the invention can be used for green synthesis of the isothiocyanate compound, and has small influence on the environment. On the other hand, the condensing agent provided by the embodiment of the invention comprises an electron withdrawing group, so that the yield of the isothiocyanate compound can be improved.

Description

Technical Field

[0001] The present application relates to the field of organic synthesis, and more specifically, to a condensing agent and use thereof in preparing isothiocyanate. Background Art

[0002] Isothiocyanates (ITCs) are widely used. For example, isothiocyanates can be used to synthesize anti-gastric cancer drugs, pesticides, and antiviral drugs. For another example, isothiocyanates themselves can be used as drugs, and have good application prospects in anti-tumor and treatment of type II diabetes. For another example, isothiocyanates can be used as liquid crystal media and applied to optical communications, wireless communications, microwave scanning antennas, variable focus lenses, gratings, lidar, beam tracking, projection, flat panel displays, and holographic displays.

[0003] At present, the synthesis of isothiocyanates often requires the introduction of highly toxic substances, which has a greater impact on the environment. Therefore, how to synthesize isothiocyanates in an environmentally friendly way is an urgent problem to be solved. Summary of the invention

[0004] The present application provides a condensing agent that can synthesize isothiocyanate in a green manner and reduce the impact on the environment.

[0005] In a first aspect, a condensing agent is provided, wherein the condensing agent has Formula 1, which is as follows:

[0006]

[0007] Among them, R 1 and R 2 Each is independently selected from the same or different electron withdrawing groups.

[0008] The condensing agent provided by the embodiment of the present application is less toxic than the thiophosgene or carbon disulfide used in the conventional scheme, and the condensing agent is solid, and the diffusion of pollution is easily controlled. Therefore, the condensing agent provided by the embodiment of the present application can synthesize isothiocyanate compounds greenly, and the impact on the environment is small. On the other hand, the condensing agent provided by the embodiment of the present application includes an electron-withdrawing group, which can improve the yield of isothiocyanate compounds.

[0009] In combination with the first aspect, in certain implementations of the first aspect, the electron withdrawing group includes a halogen atom, a nitro group, a cyano group, a sulfonyl group, an ester group, an acyl group, a carboxyl group, a monochloromethyl group, a trichloromethyl group, or a trifluoromethyl group.

[0010] In conjunction with the first aspect, in certain implementations of the first aspect, the condensing agent has Formula 2, wherein Formula 2 is as follows:

[0011]

[0012] In conjunction with the first aspect, in some implementations of the first aspect, R 1 is connected to the para-carbon or meta-carbon of the pyridine nitrogen, and / or R 2 Attached to the para-carbon or meta-carbon of pyridine nitrogen

[0013] In conjunction with the first aspect, in certain implementations of the first aspect, the condensing agent has Formula 3 or Formula 4:

[0014]

[0015]

[0016] In a second aspect, there is provided a use of the condensing agent according to the first aspect or any implementation of the first aspect in the preparation of isothiocyanate.

[0017] The condensing agent provided by the embodiment of the present application is less toxic than the thiophosgene or carbon disulfide used in the conventional scheme, and the condensing agent is solid, and the diffusion of pollution is easily controlled. Therefore, the condensing agent provided by the embodiment of the present application can synthesize isothiocyanate compounds greenly, and the impact on the environment is small. On the other hand, the condensing agent provided by the embodiment of the present application includes an electron-withdrawing group, which can improve the yield of isothiocyanate compounds.

[0018] In a third aspect, a method for preparing an isothiocyanate is provided, comprising: dissolving an amine and a condensing agent having Formula 1 in an organic reagent, so that the amine and the condensing agent react to obtain an isothiocyanate; wherein Formula 1 is as follows:

[0019]

[0020] Among them, R 1 and R 2 Each is independently selected from any one of a deuterium atom, a tritium atom, a halogen atom, a cyano group, an isocyano group, an isocyanate group, a thiocyanate group, an isothiocyanate group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted thioalkoxy group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted aryloxycarbonyl group, a substituted or unsubstituted aryl group having 5 to 60 ring atoms, a substituted or unsubstituted heteroaryl group having 5 to 60 ring atoms, and a substituted or unsubstituted aryloxy group having 5 to 60 ring atoms.

[0021] The condensing agent provided in the embodiment of the present application is less toxic than thiophosgene or carbon disulfide used in the traditional solution, and the condensing agent is solid, which makes it easy to control the spread of pollution. Therefore, the condensing agent provided in the embodiment of the present application can synthesize isothiocyanate compounds in a green way, with less impact on the environment.

[0022] In combination with the third aspect, in certain implementations of the third aspect, the amine includes an arylamine or an alkylamine.

[0023] In combination with the third aspect, in certain implementations of the third aspect, the aromatic amine includes an aromatic heterocyclic amine.

[0024] In combination with the third aspect, in certain implementations of the third aspect, the aromatic heterocyclic amine includes 2-methyl-4-aminopyridine.

[0025] In combination with the third aspect, in certain implementations of the third aspect, the arylamine includes 2,6-difluoroaniline.

[0026] In combination with the third aspect, in certain implementations of the third aspect, the alkylamine includes phenethylamine.

[0027] In combination with the third aspect, in certain implementations of the third aspect, the arylamine includes 2,6-difluoroaniline.

[0028] In combination with the third aspect, in certain implementations of the third aspect, the organic solvent includes at least one of chloroform, 1,4-dioxane, 1,4-dichlorobutane and dichloromethane.

[0029] In combination with the third aspect, in certain implementations of the third aspect, the organic solvent is dichloromethane.

[0030] In combination with the third aspect, in certain implementations of the third aspect, an amine and a condensing agent having formula 1 are dissolved in an organic reagent so that the amine and the condensing agent react to obtain an isothiocyanate, comprising: dissolving the amine and the condensing agent having formula 1 in an organic reagent; heating the organic reagent to 25 to 60° C. for reaction; washing, drying, and purifying the organic reagent after the reaction to obtain the isothiocyanate.

[0031] In combination with the third aspect, in certain implementations of the third aspect, the organic reagent after the reaction is washed, dried, and purified, including: washing with water or a saturated sodium chloride solution to obtain the washed organic reagent; drying the washed organic reagent with anhydrous sodium sulfate; purifying the dried organic reagent to obtain isothiocyanate.

[0032] In combination with the third aspect, in certain implementations of the third aspect, purifying the dried organic reagent to obtain the isothiocyanate includes: treating the dried organic reagent by column chromatography, distillation, rectification or recrystallization to obtain the isothiocyanate.

[0033] In combination with the third aspect, in certain implementations of the third aspect, the method further includes: using a monitoring means to determine whether the reaction is complete; if the reaction is complete, stopping heating the organic reagent.

[0034] In combination with the third aspect, in certain implementations of the third aspect, a monitoring method is used to determine whether the reaction is complete, including: using thin layer chromatography, gas chromatography, gas chromatography-mass spectrometry or high performance liquid chromatography to determine whether the reaction is complete. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 It is a schematic diagram of the structure of a silicon-based liquid crystal wavelength selective switch. DETAILED DESCRIPTION

[0036] The technical solution in this application is described below.

[0037] In the embodiments of the present application, words such as "exemplary" and "for example" are used to indicate examples, illustrations or descriptions. Any embodiment or design described as "exemplary" in the present application should not be interpreted as being more preferred or more advantageous than other embodiments or designs. Specifically, the use of the word "exemplary" is intended to present concepts in a concrete way.

[0038] The business scenarios described in the embodiments of the present application are intended to more clearly illustrate the technical solutions of the embodiments of the present application, and do not constitute a limitation on the technical solutions provided in the embodiments of the present application. Ordinary technicians in this field can know that with the emergence of new business scenarios, the technical solutions provided in the embodiments of the present application are also applicable to similar technical problems.

[0039] References to "one embodiment" or "some embodiments" etc. described in this specification mean that a particular feature, structure or characteristic described in conjunction with the embodiment is included in one or more embodiments of the present application. Thus, the phrases "in one embodiment", "in some embodiments", "in some other embodiments", "in some other embodiments", etc. appearing in different places in this specification do not necessarily refer to the same embodiment, but mean "one or more but not all embodiments", unless otherwise specifically emphasized in other ways. The terms "including", "comprising", "having" and their variations all mean "including but not limited to", unless otherwise specifically emphasized in other ways.

[0040] Isothiocyanates (ITCs) are widely used. For example, isothiocyanates can be used to synthesize anti-gastric cancer drugs, pesticides, and antiviral drugs. For another example, isothiocyanates themselves can be used as drugs, and have good application prospects in anti-tumor and treatment of type II diabetes. For another example, isothiocyanates can be used as liquid crystal media and applied to optical communications, wireless communications, microwave scanning antennas, variable focus lenses, gratings, lidar, beam tracking, projection, flat panel displays, and holographic displays.

[0041] Figure 1The present invention is a schematic diagram of the structure of a liquid crystal on silicon wavelength selective switch (LCoS-WSS).

[0042] like Figure 1 As shown, the LCOS wavelength selective switch 100 includes: a cover plate 110, an indium tin oxide (ITO) electrode 120, an orientation layer 130, a liquid crystal layer 140, a passivation layer 150, a backplane electrode 160, and a substrate 170. The LCOS wavelength selective switch 100 performs optical wavelength selection based on LCOS technology, for example, by irradiating light of different wavelengths on different pixels, thereby controlling the orientation of the corresponding pixel liquid crystal, adjusting the polarization state change of the light, and then using a polarizer to control the intensity of the output light. Among them, LCOS can be used to control the phase of light at each pixel to produce beam steering, where a large number of pixels allow nearly continuous addressing capabilities. Typically, a large number of phase steps are used to create the high-efficiency, low-insertion loss switch shown. This simple optical design combines polarization diversity, mode size control, and 4-f wavelength optical imaging on the LCOS dispersion axis to provide integrated switching and optical power control. In operation, light passes from the fiber array through a polarization imaging optical device, which physically separates and aligns orthogonal polarization states to the efficient s-polarization state of the diffraction grating. Input light from a selected fiber in the array reflects from the imaging mirror and is then angularly dispersed by a grating close to the Littrow incidence, reflecting the light back to the imaging optics, which directs each channel to a different part of the LCOS. The path of each wavelength is then retraced upon reflection from the LCOS, and the beam steering pattern applied on the LCOS directs the light to a specific port of the fiber array. Because the wavelength channels are separated on the LCOS, the switching of each wavelength is independent of all other wavelengths and can be performed without interfering with the light on other channels.

[0043] Isothiocyanate can be applied to the liquid crystal layer 140 as a liquid crystal medium. Since isothiocyanate has a larger birefringence, after being applied to the liquid crystal layer 140, the liquid crystal layer 140 can support a larger phase modulation and dielectric modulation, and the silicon-based liquid crystal wavelength selective switch 100 can have a faster switching speed and a higher resolution.

[0044] It should be noted that Figure 1 This is only an example of an application scenario of isothiocyanate, and is not intended to limit the present application. A person skilled in the art can understand that isothiocyanate can also be applied to other scenarios.

[0045] Related technical solutions The method for synthesizing isothiocyanate is shown in Route 1 and Route 2:

[0046]

[0047]

[0048] Among them, route 1 uses carbon disulfide (CS2), which is a colorless toxic liquid with strong volatility, flammability and explosiveness. It has cytotoxic effects and can destroy the normal metabolism of cells and interfere with lipoprotein metabolism, causing vascular lesions, neuropathy and damage to major organs of the body. Route 2 uses thiophosgene (CSCl2), which is a highly toxic volatile liquid that is extremely harmful to the environment.

[0049] It can be seen that the synthesis of isothiocyanates often requires the introduction of highly toxic substances, which has a greater impact on the environment. Therefore, how to synthesize isothiocyanates in an environmentally friendly way is an urgent problem to be solved.

[0050] Based on this, the embodiments of the present application provide a method for preparing isothiocyanate, which can synthesize isothiocyanate in a green way and reduce the impact on the environment.

[0051] The method comprises: dissolving an amine and a condensing agent having a formula 1 in an organic reagent, so that the amine and the condensing agent react to obtain an isothiocyanate; wherein the formula 1 is as follows:

[0052]

[0053] Among them, R 1 and R 2 Each is independently selected from any one of a deuterium atom, a tritium atom, a halogen atom, a cyano group, an isocyano group, an isocyanate group, a thiocyanate group, an isothiocyanate group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted thioalkoxy group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted aryloxycarbonyl group, a substituted or unsubstituted aryl group having 5 to 60 ring atoms, a substituted or unsubstituted heteroaryl group having 5 to 60 ring atoms, and a substituted or unsubstituted aryloxy group having 5 to 60 ring atoms.

[0054] For example, the method can adopt route 3 to synthesize isothiocyanate. Route 3 is as follows:

[0055]

[0056] It can be seen that compared with Route 1 and Route 2, the embodiment of the present application does not need to use highly toxic CS2 or CSCl2 to synthesize isothiocyanate, thereby reducing the toxicity of the reactants.

[0057] The present application does not limit the specific structure of the isothiocyanate. For example, the isothiocyanate may be an aryl isothiocyanate or an alkyl isothiocyanate.

[0058] The condensing agent provided in the embodiment of the present application is less toxic than thiophosgene or carbon disulfide used in the traditional solution, and the condensing agent is solid, which makes it easy to control the spread of pollution. Therefore, the condensing agent provided in the embodiment of the present application can synthesize isothiocyanate compounds in a green way, with less impact on the environment.

[0059] In some embodiments, the amine comprises an arylamine or an alkylamine.

[0060] In some embodiments, the arylamine may include an aromatic heterocyclic amine, for example, 2-methyl-4-aminopyridine. The arylamine may also include an aromatic ring amine, for example, 2,6-difluoroaniline.

[0061] In other embodiments, the alkylamine contains a substituted or unsubstituted alkyl group, for example, the alkylamine may include phenethylamine.

[0062] The present application does not limit the organic solvent, and for example, the organic solvent may include at least one of chloroform, 1,4-dioxane, 1,4-dichlorobutane and dichloromethane. In some embodiments, the organic solvent is dichloromethane.

[0063] In some embodiments, an amine and a condensing agent having Formula 1 are dissolved in an organic reagent, so that the amine and the condensing agent react to obtain an isothiocyanate, comprising: dissolving the amine and the condensing agent having Formula 1 in an organic reagent; heating the organic reagent to 25 to 60° C. for reaction; washing, drying, and purifying the organic reagent after the reaction to obtain the isothiocyanate. Generally speaking, the reaction time is approximately 4 to 20 hours.

[0064] In some embodiments, the organic reagent after the reaction is washed, dried, and purified, including: washing with water or a saturated sodium chloride solution to obtain the washed organic reagent; drying the washed organic reagent with anhydrous sodium sulfate; purifying the dried organic reagent to obtain isothiocyanate.

[0065] The present application does not limit the purification method, for example, the dried organic reagent can be treated by column chromatography, distillation, rectification or recrystallization, and other purification methods can also be used for treatment. In some embodiments, column chromatography is used for treatment.

[0066] In some embodiments, the method further comprises: using a monitoring means, thin-layer chromatography (TLC) technology, to determine whether the reaction is complete; if the reaction is complete, stopping heating the organic reagent.

[0067] The present application does not limit the monitoring means, for example, thin-layer chromatography (TLC), gas chromatography (GC), gas chromatography-mass spectrometry (GC-MS) or high performance liquid chromatography (HPLC) can be used.

[0068] For example, a sample from the reaction system can be taken and analyzed using TLC technology, and when there is less reactant residue, it is determined that the reaction is complete. The reactant includes an amine or a condensing agent.

[0069] The present application also provides a condensing agent, which has Formula 1, which is as follows:

[0070]

[0071] Among them, R 1 and R 2 Each is independently selected from the same or different electron withdrawing groups.

[0072] For example, isothiocyanate can be prepared via Scheme 3 using a condensing agent having Formula 1.

[0073] The condensing agent provided by the embodiment of the present application is less toxic than the thiophosgene or carbon disulfide used in the conventional scheme, and the condensing agent is solid, and the diffusion of pollution is easily controlled. Therefore, the condensing agent provided by the embodiment of the present application can synthesize isothiocyanate compounds greenly, and the impact on the environment is small. On the other hand, the condensing agent provided by the embodiment of the present application includes an electron-withdrawing group, which can improve the yield of isothiocyanate compounds.

[0074] In some embodiments, the electron withdrawing group includes a halogen atom, a nitro group (-NO2), a cyano group (-CN), a sulfone group (-SO3H), an ester group (-COOR), an acyl group (-COR), a carboxyl group (-COOH), a monochloromethyl group (-CH2Cl), a trichloromethyl group (-CCl3), or a trifluoromethyl group (-CF3).

[0075] It should be noted that the electron-withdrawing groups in the embodiments of the present application are not limited to the above examples. When a group replaces hydrogen (H) on an aromatic ring, if the electron density on the aromatic ring is reduced, the group can be called an electron-withdrawing group.

[0076] For example, the electron withdrawing group may be a group having a substituent constant σ in the Hammett equation greater than 0. The substituent constant σ may characterize the electronic effect of the substituent.

[0077] In some embodiments, the condensing agent has Formula 2, wherein Formula 2 is as follows:

[0078]

[0079] It should be noted that the structural formula of the condensing agent is not limited to Formula 2, and for example, may also have the following structure:

[0080]

[0081]

[0082] In some embodiments, R 1 is connected to the para-carbon or meta-carbon of the pyridine nitrogen, and / or R 2 Attached to the para-carbon or meta-carbon of the pyridine nitrogen.

[0083] For example, the condensing agent may have the following structure:

[0084]

[0085] The above three structures are based on R 2 For example, R 1 The example is similar to the above three structures and will not be repeated here.

[0086] It should be noted that R 1 With R 2 It can be symmetrical or asymmetrical based on the thiol group, which is not limited in this application. 1 It can also be connected to the ortho carbon of pyridine nitrogen, R 2 It can also be linked to the ortho-carbon of pyridine nitrogen.

[0087] In some embodiments, the condensing agent has Formula 3 or Formula 4:

[0088]

[0089] The present application also provides a use of the aforementioned condensing agent in the preparation of isothiocyanate. For example, the aforementioned condensing agent can be used to synthesize isothiocyanate as shown in Scheme 3.

[0090] The condensing agent provided by the embodiment of the present application is less toxic than the thiophosgene or carbon disulfide used in the conventional scheme, and the condensing agent is solid, and the diffusion of pollution is easily controlled. Therefore, the condensing agent provided by the embodiment of the present application can synthesize isothiocyanate compounds greenly, and the impact on the environment is small. On the other hand, the condensing agent provided by the embodiment of the present application includes an electron-withdrawing group, which can improve the yield of isothiocyanate compounds.

[0091] In the following, some embodiments of the synthetic condensing agent provided by the present application are introduced in combination with Example A1 and Example A2.

[0092] [Example A1]

[0093] In Example A1, the condensing agent can be synthesized using the following formula.

[0094]

[0095] Specifically, 50mmol (6.5g) of 4-chloropyridine-2-ol and 50mmol (7.3mL) of triethylamine (TEA) were dissolved in 80mL of anhydrous dichloromethane (DCM) under nitrogen (N2) protection, the system was cooled to 0°C, and then 25mmol (1.9mL) of thiophosgene was slowly added dropwise. After the addition was completed, it was slowly warmed to room temperature and the reaction was started. The TLC technology was used to confirm whether the reaction was complete. After the reaction was complete, 80mL of saturated sodium carbonate aqueous solution was added to quench the reaction. After the substances in the reaction system were separated and extracted, the organic phase obtained by the separation and extraction was combined. Washed twice with saturated ammonium chloride solution and saturated brine in turn. Drying with anhydrous sodium sulfate, filtering out the anhydrous sodium sulfate solid after absorbing water, and distilling under reduced pressure to obtain a crude product. Recrystallization with a mixed solvent of dichloromethane and n-hexane gave 5.7g of a white solid with a yield of 75%. The white solid is the product of the above equation, bis[(4-chloropyridin-2-yl)oxy]methylthione.

[0096] [Example A2]

[0097] In Example A2, the condensing agent can be synthesized using the following formula.

[0098]

[0099] Specifically, 50mmol (8.2g) of 5-(trifluoromethyl)pyridine-2-ol and 50mmol (7.3mL) of TEA were dissolved in 80mL of anhydrous DCM under N2 protection, the system was cooled to 0°C, and then 25mmol (1.9mL) of thiophosgene was slowly added dropwise. After the addition was completed, it was slowly warmed to room temperature. After 2 hours of reaction at room temperature, the reaction was confirmed to be complete by TLC technology. After the reaction was complete, 80mL of saturated sodium carbonate aqueous solution was added to quench the reaction. After the substances in the reaction system were separated and extracted, the organic phase obtained by separation and extraction was combined. Washed twice with saturated ammonium chloride solution and saturated brine in turn. Drying with anhydrous sodium sulfate, filtering out the anhydrous sodium sulfate solid after absorbing water, and distilling under reduced pressure to obtain a crude product. Recrystallization with a mixed solvent of dichloromethane and n-hexane gave 6.45g of a white solid with a yield of 70%. The white solid is the product of the above equation, i.e., bis[(5-trifluoromethylpyridin-2-yl)oxy]methylthioketone.

[0100] Although thiophosgene is introduced in Examples A1 and A2, those skilled in the art will appreciate that, in the process of synthesizing isothiocyanate, thiophosgene does not need to be introduced. In other words, synthesizing a condensing agent and synthesizing isothiocyanate using a condensing agent are two processes, and in the second process of the present application, thiophosgene does not need to be introduced, and a condensation reaction can be achieved using a condensing agent.

[0101] Example A1 and Example A2 describe the synthesis of bis[(5-trifluoromethylpyridin-2-yl)oxy]methylthione and bis[(5-trifluoromethylpyridin-2-yl)oxy]methylthione, respectively. It will be appreciated by those skilled in the art that this application is not limited to the above two R 1 and R 2 By introducing different substituents on the aromatic ring of 2-pyridinol, any R 1 and R 2 choice.

[0102] In the following, some examples of synthesizing isothiocyanates provided by the present application are introduced in conjunction with Examples B1 to B9.

[0103] [Example B1]

[0104] In Example B1, the condensation agent can be synthesized using the following formula.

[0105]

[0106] Specifically, at room temperature, 0.5mmol (64.6mg) of 2,6-difluoroaniline, 0.8mmol (240.9mg) of bis[(4-chloropyridin-2-yl)oxy]methylthione and 5mL of DCM were weighed into the sealed tube, and the sealed tube was moved into a sand bath pot preheated to 60°C to start the reaction. The TLC technique was used to confirm whether the reaction was complete, and the substance in the sealed tube was naturally cooled to room temperature after the reaction was complete. The substance in the sealed tube was poured into a separatory funnel, washed twice with water and saturated sodium chloride solution, and the organic phases after washing were combined and dried with anhydrous sodium sulfate. The dried organic phase was separated and purified by column chromatography to obtain 81.3mg of white solid with a yield of 95% and a reaction time of about 10 hours. Among them, the white solid is the product of this embodiment, i.e., 2,6-difluorophenyl isothiocyanate.

[0107] The condensing agent used in Example B1 is bis[(4-chloropyridin-2-yl)oxy]methylthione, which is the product synthesized in Example A1.

[0108] [Example B2]

[0109] In Example B2, the condensing agent can be synthesized using the following formula.

[0110]

[0111] Specifically, at room temperature, 0.5mmol (64.6mg) of 2,6-difluoroaniline, 0.8mmol (294.6mg) of bis[(5-trifluoromethylpyridin-2-yl)oxy]methylthione and 5mL of DCM were weighed into the sealed tube, and the sealed tube was moved into a sand bath pot preheated to 60°C to start the reaction. The TLC technique was used to confirm whether the reaction was complete, and the substance in the sealed tube was naturally cooled to room temperature after the reaction was complete. The substance in the sealed tube was poured into a separatory funnel, washed twice with water and saturated sodium chloride solution, and the organic phases after washing were combined and dried with anhydrous sodium sulfate. The dried organic phase was separated and purified by column chromatography to obtain 83.0mg of white solid with a yield of 97% and a reaction time of about 10 hours. Among them, the white solid is the product of this embodiment, i.e., 2,6-difluorophenyl isothiocyanate.

[0112] The condensing agent used in Example B2 is bis[(5-trifluoromethylpyridin-2-yl)oxy]methylthione, which is the product synthesized in Example A2.

[0113] [Example B3]

[0114] Example B3 is similar to Example B1, except that the condensing agent equivalent of Example B3 is 1.2, that is, 0.6 mmol (180.7 mg) of bis[(4-chloropyridin-2-yl)oxy]methylthione is weighed into the sealed tube.

[0115] The yield of Example B3 was 98% and the reaction time was about 4 hours.

[0116] [Example B4]

[0117] Example B4 is similar to Example B2, except that the condensing agent equivalent of Example B4 is 1.2, that is, 0.6 mmol (221.0 mg) of bis[(5-trifluoromethylpyridin-2-yl)oxy]methylthione is weighed into the sealed tube.

[0118] The yield of Example B4 was 97% and the reaction time was about 4 hours.

[0119] [Example B5]

[0120] In Example B5, the condensation agent can be synthesized using the following formula.

[0121]

[0122] Wherein, bis[(2-pyridyl)oxy]methylthione can be synthesized from 2-pyridinol and thiophosgene. The synthesis process can be referred to Example A1 or Example A2, which will not be described in detail here.

[0123] The synthesis process of Example B5 can refer to Example B1, which is different from Example B1 in that: the condensing agent used is bis[(2-pyridyl)oxy]methylthione; the equivalent of the condensing agent is 1.0, that is, 0.5 mmol (116.0 mg) of bis[(2-pyridyl)oxy]methylthione is weighed into the sealed tube; and the reaction temperature is 25°C.

[0124] The yield of Example B5 was 43% and the reaction time was about 20 hours.

[0125] [Example B6]

[0126] The condensing agent used in Example B6 is the same as that in Example B5, except that the condensing agent equivalent in Example B6 is 1.6, that is, 0.8 mmol (185.6 mg) of bis[(2-pyridyl)oxy]methylthioketone is weighed into the sealed tube.

[0127] The yield of Example B6 was 70% and the reaction time was about 20 hours.

[0128] [Example B7]

[0129] Example B7 is similar to Example B5, except that the reaction temperature of Example B7 is 60°C.

[0130] The yield of Example B7 was 52% and the reaction time was about 10 hours.

[0131] [Example B8]

[0132] Example B8 is similar to Example B5, except that the reaction temperature of Example B7 is 60° C. and the condensing agent equivalent of Example B7 is 1.2, that is, 0.6 mmol (139.2 mg) of bis[(2-pyridyl)oxy]methylthioketone is weighed into the sealed tube.

[0133] The yield of Example B8 was 68% and the reaction time was about 10 hours.

[0134] [Example B9]

[0135] In Example B9, the condensation agent can be synthesized using the following formula.

[0136]

[0137] Wherein, bis[(6-methylpyridin-2-yl)oxy]methanthione can be synthesized from 6-methylpyridin-2-ol and thiophosgene. The synthesis process can be referred to Example A1 or Example A2, which will not be described in detail here.

[0138] The synthesis process of Example B9 can refer to Example B1, which is different from Example B1 in that: the condensing agent used is bis[(6-methylpyridin-2-yl)oxy]methylthione; the equivalent of the condensing agent is 1.2, that is, 0.6 mmol (156.0 mg) of bis[(6-methylpyridin-2-yl)oxy]methylthione is weighed into the sealed tube.

[0139] The yield of Example B9 was 66% and the reaction time was about 10 hours.

[0140] [Example B10]

[0141] In Example B10, the condensation agent can be synthesized using the following formula.

[0142]

[0143] Wherein, bis[(5-methoxypyridin-2-yl)oxy]methanthione can be synthesized from 5-methoxypyridin-2-ol and thiophosgene. The synthesis process can be referred to Example A1 or Example A2, which will not be described in detail here.

[0144] The synthesis process of Example B10 can refer to Example B1, which is different from Example B1 in that: the condensing agent used is bis[(5-methoxypyridin-2-yl)oxy]methylthione; the equivalent of the condensing agent is 1.2, that is, 0.6 mmol (175.2 mg) of bis[(5-methoxypyridin-2-yl)oxy]methylthione is weighed into the sealed tube.

[0145] The yield of Example B10 was 43% and the reaction time was about 4 hours.

[0146] [Example B11]

[0147] In Example B11, the condensing agent can be synthesized using the following formula.

[0148]

[0149] Wherein, bis[(6-methylpyridin-2-yl)oxy]methanthione can be synthesized from 6-methylpyridin-2-ol and thiophosgene. The synthesis process can be referred to Example A1 or Example A2, which will not be described in detail here.

[0150] The synthesis process of Example B11 can refer to Example B1, which is different from Example B1 in that: the condensing agent used is bis[(6-methylpyridin-2-yl)oxy]methylthione; the equivalent of the condensing agent is 1.2, that is, 0.6 mmol (156.0 mg) of bis[(6-methylpyridin-2-yl)oxy]methylthione is weighed into the sealed tube; the reactant is 0.5 mmol (54.0 mg) of 2-methyl-4-aminopyridine.

[0151] The yield of Example B11 was 76% and the reaction time was about 16 hours.

[0152] Those skilled in the art will appreciate that Example B11 is merely an example of aromatic heterocyclic isothiocyanate, and the present application is not limited to the synthesis of the above product.

[0153] [Example B12]

[0154] In Example B12, the condensing agent can be synthesized using the following formula.

[0155]

[0156] Wherein, bis[(6-methylpyridin-2-yl)oxy]methanthione can be synthesized from 6-methylpyridin-2-ol and thiophosgene. The synthesis process can be referred to Example A1 or Example A2, which will not be described in detail here.

[0157] The synthesis process of Example B12 can refer to Example B1, which is different from Example B1 in that: the condensing agent used is bis[(6-methylpyridin-2-yl)oxy]methylthione; the equivalent of the condensing agent is 1.2, that is, 0.6 mmol (156.0 mg) of bis[(6-methylpyridin-2-yl)oxy]methylthione is weighed into the sealed tube; and the reactant is 0.5 mmol (60.5 mg) of phenethylamine.

[0158] The yield of Example B12 was 43% and the reaction time was about 16 hours.

[0159] Those skilled in the art will appreciate that Example B12 is merely an example of alkyl isothiocyanate, and the present application is not limited to the synthesis of the above product.

[0160] [Example B13]

[0161] In Example B13, the condensing agent can be synthesized using the following formula.

[0162]

[0163] The synthesis process of Example B13 can refer to Example B2, which is different from Example B2 in that: the equivalent of the condensing agent is 1.2, that is, 0.6 mmol (221.0 mg) of bis[(5-trifluoromethylpyridin-2-yl)oxy]methanethione is weighed into the sealed tube; the reactant is 2,6-difluoro-4-{[4-(4-pentylphenyl)phenyl]ethynyl}aniline (hereinafter referred to as B13 reactant for brevity).

[0164] Example B13 obtained 194.2 mg of a white solid, which was the product [(2,6-difluoro-4-{[4-(4-pentylphenyl)phenyl]ethynyl}phenyl isothiocyanate. The yield of Example B13 was 43%, and the reaction time was about 24 hours.

[0165] Next, Comparative Example C of the present application will be described.

[0166] [Comparative Example C]

[0167] Comparative Example C uses the following formula to synthesize the condensation agent.

[0168]

[0169] Specifically, at room temperature, 1.0mmol (100mg) of calcium carbonate, 5mL ultrapure water and 5mL chloroform (CHCl3) were added to the reaction bottle. The reaction bottle containing the reactants was transferred to an ice bath. After the temperature in the reaction bottle stabilized to 0°C, 0.75mmol (86.2mg) of thiophosgene was added, and then 0.5mmol (187.7mg) of the B13 reactant of the compound was dissolved with 5mL chloroform and added dropwise to the reaction bottle. After maintaining the ice bath and stirring for 2h, sampling was performed for TLC spot plate, gas chromatography-mass spectrometer (GC-MS) or liquid chromatography-mass spectrometer (LCMS) and other monitoring. After confirming that the reaction was complete, the ice bath was removed and the substance in the reaction bottle was heated to room temperature under stirring. The reaction bottle was transferred to a sand bath pot set at 50°C and heated and stirred for 5 minutes. Remove the sand bath and wait for the mixed solution in the reaction bottle to cool naturally to room temperature. Pour the mixed solution into a separatory funnel, wash twice with DCM after separation, and combine the washed organic phases. Wash twice with water, dilute hydrochloric acid, and saturated sodium chloride solution in sequence, and combine the washed organic phases. Dry the washed organic phase with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography, wherein n-hexane is used as the elution phase. 133.6 mg of white solid is finally obtained, and the white solid is [(2,6-difluoro-4-{[4-(4-pentylphenyl)phenyl]ethynyl}phenylisothiocyanate (consistent with the product of Example B13).

[0170] The yield of Comparative Example C was 64%.

[0171] The following is described in conjunction with Examples B1 to B13 and Comparative Example C. Table 1 shows the condensing agent substituents (R 1 and R 2 ), condensation agent equivalent, reaction temperature, reaction time and yield. Among them, the yield is 19 Determined by F NMR.

[0172] Table 1

[0173] name Reactants Condensation agent (substituent) Condensation agent equivalent Reaction temperature / ℃ Yield Example B1 2,6-Difluoroaniline -Cl 1.6 60 95％ Example B2 2,6-Difluoroaniline <![CDATA[-CF3]]> 1.6 60 97％ Example B3 2,6-Difluoroaniline -Cl 1.2 60 98％ Example B4 2,6-Difluoroaniline <![CDATA[-CF3]]> 1.2 60 97％ Example B5 2,6-Difluoroaniline -H 1.0 25 43％ Example B6 2,6-Difluoroaniline -H 1.6 25 70％ Example B7 2,6-Difluoroaniline -H 1.0 60 52％ Example B8 2,6-Difluoroaniline -H 1.2 60 68％ Example B9 2,6-Difluoroaniline <![CDATA[-CH3]]> 1.2 60 66％ Example B10 2,6-Difluoroaniline -OMe 1.2 60 43％ Example B11 2-Methyl-4-aminopyridine <![CDATA[-CH3]]> 1.2 60 76％ Example B12 Phenylethylamine <![CDATA[-CH3]]> 1.2 60 43％ Example B13 B13 Reactant <![CDATA[-CF3]]> 1.2 60 93％ Comparative Example C B13 Reactant Thiophosgene 1.5 60 64％

[0174] Compared with Comparative Example C, Examples B1 to B13 provided herein do not require the addition of thiophosgene to the synthesis of isothiocyanates. The condensing agent provided in the embodiments of the present application is less toxic than thiophosgene, and the condensing agents of Examples B1 to B13 are solid, which is easy to control the spread of pollution. Therefore, the condensing agent provided in the embodiments of the present application can synthesize isothiocyanates in a green manner, with less impact on the environment.

[0175] The substituents of the condensing agents used in Examples B1, B2, B3, B4 and B13 are electron-withdrawing groups, while the substituents of the condensing agents used in Examples B5 to B12 are not electron-withdrawing groups. It can be seen that the use of condensing agents with electron-withdrawing groups can improve the yield.

[0176] Specifically, Examples B8 to B10 use condensing agents whose substituents are electron-donating groups, which are different from Examples B3 and B4 only in the substituents. 1 and R 2 is hydrogen, and R of the condensing agent of Example B9 1 and R 2 is methyl, and R of the condensing agent of Example B10 is 1 and R 2 is methoxy; and R in Example B3 1 and R 2 is a chlorine atom, R 1 and R 2 The yields of Examples B3 and B4 far exceed those of Examples B8 to B10, indicating that the R 1 and R 2 The electron-withdrawing group is beneficial to increase the yield of isothiocyanate.

[0177] The condensing agent used in Example B11 and Example B12 has a R 1 and R 2 is an electron donating group (methyl). Although both Example B11 and Example B12 use highly reactive reactants, the yields of Example B11 and Example B12 are still relatively low. However, when the reactive activity of the reactants of Examples B1, B2, B3, and B4 is not high enough, they still have relatively high yields. This further illustrates that the R 1 and R 2 The electron-withdrawing group is beneficial to increase the yield of isothiocyanate.

[0178] The reactants and products of Example B13 and Comparative Example C are the same, but the yields are very different. It can be seen that the yield of synthesizing isothiocyanates using the condensing agent with an electron-withdrawing group provided in the embodiment of the present application is higher than that of the traditional method for synthesizing isothiocyanates. In addition, the products of Example B13 and Comparative Example C are liquid crystal molecules, which shows that the condensing agent provided in the present application can synthesize liquid crystal molecules more efficiently.

[0179] The yields of Examples B1 to B4 are all above 95%, which is very high. Therefore, the condensing agent equivalent is 1.2 to 1.6 and the reaction temperature is around 60°C, which has a higher yield.

[0180] Embodiment B5 and B6 have the same condensing agent and reaction temperature, and the difference is that the condensing agent equivalent of embodiment B6 is higher.Therefore, it can be seen that for the condensing agent without electron-withdrawing group, increasing the condensing agent equivalent can also improve the yield.In conjunction with the preparation method of isothiocyanate provided in the application, in addition to having the advantage of green environmental protection, the yield can also be improved by increasing the condensing agent equivalent, thereby having the advantage of high yield.

[0181] Embodiment B5 and B7 have the same condensing agent and condensing agent equivalent, except that the reaction temperature of embodiment B7 is higher. Therefore, it can be seen that for condensing agents without electron withdrawing groups, increasing the reaction temperature can also increase the yield. However, when the reaction temperature is increased from 25°C to 60°C, the yield is only increased from 43% to 52%, which shows that increasing the reaction temperature has limited effect on the yield. If you want to further increase the yield, it is more effective to use a condensing agent having formula 1 substituted with an electron withdrawing group.

[0182] The above is only a specific implementation of the present application, but the protection scope of the present application is not limited thereto. Any person skilled in the art who is familiar with the present technical field can easily think of changes or substitutions within the technical scope disclosed in the present application, which should be included in the protection scope of the present application. Therefore, the protection scope of the present application should be based on the protection scope of the claims.

Claims

1. A condensation agent, characterized in that The condensing agent has Formula 1, which is as follows: Among them, R 1 and R 2 Each is independently selected from the same or different electron withdrawing groups.

2. The condensing agent according to claim 1, characterized in that The electron withdrawing group includes a halogen atom, a nitro group, a cyano group, a sulfo group, an ester group, an acyl group, a carboxyl group, a monochloromethyl group, a trichloromethyl group or a trifluoromethyl group.

3. The condensing agent according to claim 1 or 2, characterized in that The condensing agent has Formula 2, wherein the Formula 2 is as follows:

4. The condensation agent according to any one of claims 1 to 3, characterized in that R 1 is connected to the para-carbon or meta-carbon of the pyridine nitrogen, and / or R 2 Attached to the para-carbon or meta-carbon of the pyridine nitrogen.

5. The condensation agent according to any one of claims 1 to 4, characterized in that The condensing agent has Formula 3 or Formula 4:

6. Use of the condensing agent according to any one of claims 1 to 5 in the preparation of isothiocyanate.

7. A method for preparing an isothiocyanate, characterized in that: include: dissolving an amine and a condensing agent having Formula 1 in an organic reagent so that the amine and the condensing agent react to obtain an isothiocyanate; Wherein, the formula 1 is as follows: Among them, R 1 and R 2 Each is independently selected from any one of a deuterium atom, a tritium atom, a halogen atom, a cyano group, an isocyano group, an isocyanate group, a thiocyanate group, an isothiocyanate group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted thioalkoxy group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted aryloxycarbonyl group, a substituted or unsubstituted aryl group having 5 to 60 ring atoms, a substituted or unsubstituted heteroaryl group having 5 to 60 ring atoms, and a substituted or unsubstituted aryloxy group having 5 to 60 ring atoms.

8. The method according to claim 7, characterized in that The amine includes an arylamine or an alkylamine.

9. The method according to claim 8, characterized in that The arylamines include aromatic heterocyclic amines.

10. The method according to claim 9, characterized in that The aromatic heterocyclic amines include 2-methyl-4-aminopyridine.

11. The method according to claim 8, characterized in that The arylamine includes 2,6-difluoroaniline.

12. The method according to claim 8, characterized in that The alkylamines include phenethylamine.

13. The method according to any one of claims 7 to 12, characterized in that The organic solvent includes at least one of chloroform, 1,4-dioxane, 1,4-dichlorobutane and dichloromethane.

14. The method according to claim 13, characterized in that The organic solvent is dichloromethane.

15. The method according to any one of claims 7 to 14, characterized in that The step of dissolving an amine and a condensing agent having Formula 1 in an organic reagent so that the amine and the condensing agent react to obtain an isothiocyanate comprises: dissolving an amine and a condensing agent having Formula 1 in an organic reagent; Heating the organic reagent to 25-60° C. to react; The organic reagent after the reaction is washed, dried and purified to obtain the isothiocyanate.

16. The method according to claim 15, characterized in that The step of washing, drying and purifying the organic reagent after the reaction comprises: washing with water or a saturated sodium chloride solution to obtain a washed organic reagent; Drying the washed organic reagent with anhydrous sodium sulfate; The dried organic reagent is purified to afford the isothiocyanate.

17. The method according to claim 16, characterized in that: The purified dried organic reagent to obtain the isothiocyanate comprises: The dried organic reagent is treated by column chromatography, distillation, rectification or recrystallization to obtain the isothiocyanate.

18. The method according to any one of claims 15 to 17, characterized in that Also includes: Use monitoring methods to determine whether the reaction is complete; In case the reaction is complete, heating of the organic reagent is stopped.

19. The method according to claim 18, characterized in that The monitoring means used to determine whether the reaction is complete includes: The completion of the reaction is determined by thin layer chromatography, gas chromatography, gas chromatography-mass spectrometry or high performance liquid chromatography.

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