Condensing agent and use thereof in preparation of isothiocyanate

Abstract

The present application relates to the field of organic synthesis. Provided is a condensing agent. The condensing agent has formula 1, wherein R1 and R2 are each independently selected from the same or different electron-withdrawing groups. Compared with thiophosgene or carbon disulfide used in a traditional solution, the condensing agent provided in the embodiments of the present application has lower toxicity, and the condensing agent is a solid, such that the diffusion of pollution is easily controlled. Therefore, the condensing agent provided in the embodiments of the present application can be used for environmentally friendly synthesis of an isothiocyanate compound and has relatively small influence on the environment. Moreover, the condensing agent provided in the embodiments of the present application comprises electron-withdrawing groups, such that the yield of the isothiocyanate compound can be increased.

Description

Condensation agent and use thereof in preparing isothiocyanate

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on August 4, 2023, with application number 202310983898.8 and application name “Condensation agent and its use in the preparation of isothiocyanate”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present application relates to the field of organic synthesis, and more particularly, to a condensing agent and use thereof in preparing isothiocyanate. Background Art

[0003] Isothiocyanates (ITCs) have a wide range of applications. For example, ITCs can be used to synthesize anti-gastric cancer drugs, pesticides, and antiviral drugs. In another example, ITCs themselves can be used as pharmaceuticals, showing promising applications in anti-tumor and type 2 diabetes treatment. Furthermore, ITCs can be used as liquid crystal media in applications such as optical communications, wireless communications, microwave scanning antennas, variable focus lenses, gratings, LiDAR, beam tracking, projection, flat-panel displays, and holographic displays.

[0004] Currently, the synthesis of isothiocyanates often requires the introduction of highly toxic substances, which has a significant impact on the environment. Therefore, how to synthesize isothiocyanates in an environmentally friendly way is an urgent problem to be solved.

[0005] Summary of the Invention

[0006] The present application provides a condensing agent that can synthesize isothiocyanate in a green manner and reduce the impact on the environment.

[0007] In a first aspect, a condensing agent is provided, wherein the condensing agent has Formula 1, which is as follows:

[0008] Among them, R 1 and R 2 Each is independently selected from the same or different electron withdrawing groups.

[0009] The condensing agent provided by the embodiment of the present application is less toxic than the thiophosgene or carbon disulfide adopted by 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 in a green way, and the impact on the environment is less. On the other hand, the condensing agent provided by the embodiment of the present application includes an electron-withdrawing group, which can improve the productive rate of isothiocyanate compounds.

[0010] 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 sulfo group, an ester group, an acyl group, a carboxyl group, a monochloromethyl group, a trichloromethyl group, or a trifluoromethyl group.

[0011] 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:

[0012] In conjunction with the first aspect, in certain implementations of the first aspect, R 1 Connected to the para-carbon or meta-carbon of pyridine nitrogen, and / or R 2 Attached to the para 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] In a second aspect, a use of the condensing agent according to the first aspect or any implementation of the first aspect in preparing isothiocyanate is provided.

[0015] The condensing agent provided by the embodiment of the present application is less toxic than the thiophosgene or carbon disulfide adopted by 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 in a green way, and the impact on the environment is less. On the other hand, the condensing agent provided by the embodiment of the present application includes an electron-withdrawing group, which can improve the productive rate of isothiocyanate compounds.

[0016] 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, and reacting the amine and the condensing agent to obtain an isothiocyanate; wherein Formula 1 is as follows:

[0017] 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.

[0018] The condensing agent provided in the embodiments of the present application is less toxic than thiophosgene or carbon disulfide used in conventional solutions, and the condensing agent is solid, making it easy to control the spread of pollution. Therefore, the condensing agent provided in the embodiments of the present application can synthesize isothiocyanate compounds in a green manner with minimal impact on the environment.

[0019] In conjunction with the third aspect, in certain implementations of the third aspect, the amine includes an arylamine or an alkylamine.

[0020] In combination with the third aspect, in certain implementations of the third aspect, the arylamine includes an aromatic heterocyclic amine.

[0021] In conjunction with the third aspect, in certain implementations of the third aspect, the aromatic heterocyclic amine includes 2-methyl-4-aminopyridine.

[0022] In conjunction with the third aspect, in certain implementations of the third aspect, the arylamine includes 2,6-difluoroaniline.

[0023] In combination with the third aspect, in certain implementations of the third aspect, the alkylamine includes phenethylamine.

[0024] In conjunction with the third aspect, in certain implementations of the third aspect, the arylamine includes 2,6-difluoroaniline.

[0025] 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.

[0026] In combination with the third aspect, in certain implementations of the third aspect, the organic solvent is dichloromethane.

[0027] 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; and washing, drying, and purifying the organic reagent after the reaction to obtain the isothiocyanate.

[0028] 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 a washed organic reagent; drying the washed organic reagent with anhydrous sodium sulfate; and purifying the dried organic reagent to obtain an isothiocyanate.

[0029] In conjunction 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.

[0030] 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; and if the reaction is complete, stopping heating the organic reagent.

[0031] 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

[0032] FIG1 is a schematic structural diagram of a liquid crystal on silicon wavelength selective switch. DETAILED DESCRIPTION

[0033] The technical solution in this application is described below.

[0034] In the embodiments of this application, words such as "exemplary" and "for example" are used to indicate examples, illustrations, or descriptions. Any embodiment or design described as "exemplary" in this application should not be construed as preferred or advantageous over other embodiments or designs. Rather, the use of the word "exemplary" is intended to present concepts in a concrete way.

[0035] 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 will 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.

[0036] References to "one embodiment" or "some embodiments" in this specification mean that a particular feature, structure, or characteristic described in conjunction with that embodiment is included in one or more embodiments of the present application. Thus, phrases such as "in one embodiment," "in some embodiments," "in other embodiments," and "in yet other embodiments" appearing in various places in this specification do not necessarily refer to the same embodiment, but rather mean "one or more, but not all, embodiments," unless otherwise specifically stated. The terms "including," "comprising," "having," and variations thereof mean "including but not limited to," unless otherwise specifically stated.

[0037] Isothiocyanates (ITCs) have a wide range of applications. For example, ITCs can be used to synthesize anti-gastric cancer drugs, pesticides, and antiviral drugs. In another example, ITCs themselves can be used as pharmaceuticals, showing promising applications in anti-tumor and type 2 diabetes treatment. Furthermore, ITCs can be used as liquid crystal media in applications such as optical communications, wireless communications, microwave scanning antennas, variable focus lenses, gratings, LiDAR, beam tracking, projection, flat-panel displays, and holographic displays.

[0038] FIG1 is a schematic structural diagram of a liquid crystal on silicon wavelength selective switch (LCoS-WSS).

[0039] As shown in Figure 1, the LCOS wavelength selective switch 100 includes a cover plate 110, an indium tin oxide (ITO) electrode 120, an alignment 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 utilizes LCOS technology to select optical wavelengths. For example, by directing light of different wavelengths onto different pixels, the orientation of the corresponding liquid crystals is controlled, adjusting the polarization state of the light. A polarization analyzer is then used to control the intensity of the output light. LCOS can be used to control the phase of light at each pixel to generate beam steering, where a large number of pixels allows for near-continuous addressing. 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 polarization imaging optics, which physically separate and align 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 near Littrow incidence, reflecting the light back to the imaging optics, which directs each channel to a different part of the Si liquid crystal. The path of each wavelength is then retraced upon reflection from the Si liquid crystal, and the beam steering pattern applied on the Si liquid crystal directs the light to a specific port of the fiber array. Because the wavelength channels are separated on the Si liquid crystal, the switching of each wavelength is independent of all other wavelengths and can be performed without interfering with the light on other channels.

[0040] Isothiocyanate can be used as a liquid crystal medium in the liquid crystal layer 140. Since isothiocyanate has a greater birefringence, when applied to the liquid crystal layer 140, the liquid crystal layer 140 can support greater phase modulation and dielectric modulation, and the liquid crystal on silicon wavelength selective switch 100 can have faster switching speeds and higher resolution.

[0041] It should be noted that Figure 1 only illustrates one application scenario of isothiocyanates and is not intended to limit the present application. Persons skilled in the art will appreciate that isothiocyanates may also be applied in other scenarios.

[0042] Related technical solutions The methods for synthesizing isothiocyanates are shown in Scheme 1 and Scheme 2:

[0043] Route 1 utilizes carbon disulfide (CS2), a colorless, toxic liquid that is highly volatile, flammable, and explosive. It is cytotoxic, disrupting normal cellular metabolism and interfering with lipoprotein metabolism, leading to vascular and neuropathy and damage to major organs throughout the body. Route 2 utilizes thiophosgene (CSCl2), a highly toxic, volatile liquid that poses a significant threat to the environment.

[0044] As can be seen, the synthesis of isothiocyanates often requires the introduction of highly toxic substances, which has a significant impact on the environment. Therefore, how to synthesize isothiocyanates in an environmentally friendly way is an urgent problem to be solved.

[0045] 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.

[0046] The method comprises: dissolving an amine and a condensing agent having Formula 1 in an organic reagent, and reacting the amine and the condensing agent to obtain an isothiocyanate; wherein Formula 1 is as follows:

[0047] 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.

[0048] For example, the method can adopt route 3 to synthesize isothiocyanate. Route 3 is shown below:

[0049] 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.

[0050] 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.

[0051] The condensing agent provided in the embodiments of the present application is less toxic than thiophosgene or carbon disulfide used in conventional solutions, and the condensing agent is solid, making it easy to control the spread of pollution. Therefore, the condensing agent provided in the embodiments of the present application can synthesize isothiocyanate compounds in a green manner with minimal impact on the environment.

[0052] In some embodiments, the amine comprises an arylamine or an alkylamine.

[0053] In some embodiments, the arylamine may include an aromatic heterocyclic amine, such as 2-methyl-4-aminopyridine, or an aromatic cyclic amine, such as 2,6-difluoroaniline.

[0054] In other embodiments, the alkylamine contains a substituted or unsubstituted alkyl group. For example, the alkylamine may include phenylethylamine.

[0055] 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.

[0056] In some embodiments, an amine and a condensing agent having Formula 1 are dissolved in an organic reagent, and the amine and the condensing agent react to produce an isothiocyanate, comprising: dissolving the amine and the condensing agent having Formula 1 in the organic reagent; heating the organic reagent to 25-60° C. to react; and washing, drying, and purifying the organic reagent after the reaction to produce the isothiocyanate. Generally, the reaction time is approximately 4-20 hours.

[0057] 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 a washed organic reagent; drying the washed organic reagent with anhydrous sodium sulfate; and purifying the dried organic reagent to obtain an isothiocyanate.

[0058] 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. In some embodiments, column chromatography is used for treatment.

[0059] In some embodiments, the method further comprises: using thin-layer chromatography (TLC) technology to determine whether the reaction is complete; if the reaction is complete, stopping heating the organic reagent.

[0060] This application does not limit the monitoring method. For example, thin-layer chromatography (TLC), gas chromatography (GC), gas chromatography-mass spectrometry (GC-MS) or high performance liquid chromatography (HPLC) can be used.

[0061] For example, a sample from the reaction system can be taken and analyzed using TLC technology. If little reactant remains, the reaction is determined to be complete. The reactant includes an amine or a condensing agent.

[0062] The present invention also provides a condensing agent according to the embodiment of the present invention. The condensing agent has a formula 1, which is as follows:

[0063] Among them, R 1 and R 2 Each is independently selected from the same or different electron withdrawing groups.

[0064] For example, isothiocyanate can be prepared via Scheme 3 using a condensing agent having Formula 1.

[0065] The condensing agent provided by the embodiment of the present application is less toxic than the thiophosgene or carbon disulfide adopted by 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 in a green way, and the impact on the environment is less. On the other hand, the condensing agent provided by the embodiment of the present application includes an electron-withdrawing group, which can improve the productive rate of isothiocyanate compounds.

[0066] In some embodiments, the electron-withdrawing group includes a halogen atom, a nitro group (-NO2), a cyano group (-CN), a sulfo 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).

[0067] 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 decreases, the group can be called an electron-withdrawing group.

[0068] For example, the electron-withdrawing group may be a group having a substituent constant σ in the Hammett equation that is greater than 0. The substituent constant σ may characterize the electronic effect of the substituent.

[0069] In some embodiments, the condensing agent has Formula 2, wherein Formula 2 is as follows:

[0070] It should be noted that the structural formula of the condensing agent is not limited to Formula 2, and for example, it may also have the following structure:

[0071] In some embodiments, R 1 Connected to the para-carbon or meta-carbon of pyridine nitrogen, and / or R 2 The condensing agent is connected to the para-carbon or meta-carbon of the pyridine nitrogen. For example, the condensing agent can have the following structure:

[0072] The above three structures are based on R 2 For example, R 1 The examples are similar to the above three structures and will not be repeated here.

[0073] 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 adjacent carbon of pyridine nitrogen, R 2 It can also be linked to the carbon ortho position of pyridine nitrogen.

[0074] In some embodiments, the condensing agent has Formula 3 or Formula 4:

[0075] The present invention also provides a method for preparing an isothiocyanate by using the aforementioned condensing agent. For example, the aforementioned condensing agent can be used to synthesize an isothiocyanate as shown in Scheme 3.

[0076] The condensing agent provided by the embodiment of the present application is less toxic than the thiophosgene or carbon disulfide adopted by 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 in a green way, and the impact on the environment is less. On the other hand, the condensing agent provided by the embodiment of the present application includes an electron-withdrawing group, which can improve the productive rate of isothiocyanate compounds.

[0077] The following describes some examples of the synthetic condensing agent provided by the present application in conjunction with Example A1 and Example A2.

[0078] [Example A1]

[0079] In Example A1, the condensing agent can be synthesized using the following formula.

[0080] Specifically, under nitrogen (N2) protection, 50mmol (6.5g) of 4-chloropyridine-2-ol and 50mmol (7.3mL) of triethylamine (TEA) were dissolved in 80mL of anhydrous dichloromethane (DCM), the system was cooled to 0°C, and then 25mmol (1.9mL) of thiophosgene was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature to start the reaction. 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 phases obtained by the separation and extraction were combined. The mixture was washed twice with saturated ammonium chloride solution and saturated brine in sequence. It was dried over anhydrous sodium sulfate, and after filtering out the anhydrous sodium sulfate solid after absorbing water, it was distilled under reduced pressure to obtain a crude product. After recrystallization with a mixed solvent of dichloromethane and n-hexane, 5.7g of white solid was obtained with a yield of 75%. The white solid is the product of the above equation, bis[(4-chloropyridin-2-yl)oxy]methanethione.

[0081] [Example A2]

[0082] In Example A2, the condensing agent can be synthesized using the following formula.

[0083] Specifically, under N2 protection, 50mmol (8.2g) of 5-(trifluoromethyl)pyridine-2-ol and 50mmol (7.3mL) of TEA were dissolved in 80mL of anhydrous DCM, the system was cooled to 0°C, and then 25mmol (1.9mL) of thiophosgene was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature. After the reaction at room temperature for 2 hours, 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 phases obtained by the separation and extraction were combined. The mixture was washed twice with saturated ammonium chloride solution and saturated brine respectively. The mixture was dried over anhydrous sodium sulfate, the anhydrous sodium sulfate solid after water absorption was filtered out, and the crude product was obtained by vacuum distillation. After recrystallization with a mixed solvent of dichloromethane and n-hexane, 6.45g of a white solid was obtained with a yield of 70%. The white solid is the product of the above equation, i.e., bis[(5-trifluoromethylpyridin-2-yl)oxy]methylthioketone.

[0084] Although thiophosgene is introduced in Examples A1 and A2, those skilled in the art will appreciate that thiophosgene need not be introduced during the synthesis of isothiocyanates. In other words, synthesizing a condensing agent and synthesizing an isothiocyanate using the condensing agent are two separate processes. In the examples of the present application, thiophosgene need not be introduced during the second process; the condensation reaction can be achieved using the condensing agent.

[0085] 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.

[0086] The following describes some examples of synthesizing isothiocyanates provided by the present application in conjunction with Examples B1 to B9.

[0087] [Example B1]

[0088] In Example B1, the condensing agent can be synthesized using the following formula.

[0089] Specifically, at room temperature, 0.5 mmol (64.6 mg) of 2,6-difluoroaniline, 0.8 mmol (240.9 mg) of bis[(4-chloropyridin-2-yl)oxy]methylthioketone and 5 mL of DCM were weighed into the sealed tube. After the sealed tube was sealed, it was moved into a sand bath pot preheated to 60 ° C in advance to start the reaction. The reaction was confirmed to be complete by TLC technology. After the reaction was complete, the substance in the sealed tube was naturally cooled to room temperature. The substance in the sealed tube was poured into a separatory funnel, washed twice with water and saturated sodium chloride solution, the washed organic phases were combined, and the organic phase was dried with anhydrous sodium sulfate. The dried organic phase was separated and purified by column chromatography to obtain 81.3 mg of white solid with a yield of 95%. The reaction time was about 10 hours. Among them, the white solid is the product of this embodiment, i.e., 2,6-difluorophenyl isothiocyanate.

[0090] The condensing agent used in Example B1 is bis[(4-chloropyridin-2-yl)oxy]methylthione, which is the product synthesized in Example A1.

[0091] [Example B2]

[0092] In Example B2, the condensing agent can be synthesized using the following formula.

[0093] Specifically, at room temperature, 0.5 mmol (64.6 mg) of 2,6-difluoroaniline, 0.8 mmol (294.6 mg) of bis[(5-trifluoromethylpyridin-2-yl)oxy]methylthioketone and 5 mL of DCM were weighed into the sealed tube. After the sealed tube was sealed, it was moved into a sand bath pot preheated to 60 ° C in advance to start the reaction. The reaction was confirmed to be complete by TLC technology. After the reaction was complete, the substance in the sealed tube was naturally cooled to room temperature. The substance in the sealed tube was poured into a separatory funnel, washed twice with water and saturated sodium chloride solution, the washed organic phases were combined, and the organic phase was dried with anhydrous sodium sulfate. The dried organic phase was separated and purified by column chromatography to obtain 83.0 mg of a white solid with a yield of 97%. The reaction time was about 10 hours. Among them, the white solid is the product of this embodiment, i.e., 2,6-difluorophenyl isothiocyanate.

[0094] The condensing agent used in Example B2 is bis[(5-trifluoromethylpyridin-2-yl)oxy]methylthione, which is the product synthesized in Example A2.

[0095] [Example B3]

[0096] 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.

[0097] The yield of Example B3 was 98%, and the reaction time was about 4 hours.

[0098] [Example B4]

[0099] 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.

[0100] The yield of Example B4 was 97%, and the reaction time was about 4 hours.

[0101] [Example B5]

[0102] In Example B5, the condensing agent can be synthesized using the following formula.

[0103] 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.

[0104] The synthesis process of Example B5 can be referred to Example B1, except that: bis[(2-pyridyl)oxy]methylthione was used as the condensing agent; the equivalent weight of the condensing agent was 1.0, i.e., 0.5 mmol (116.0 mg) of bis[(2-pyridyl)oxy]methylthione was weighed into the sealed tube; and the reaction temperature was 25°C.

[0105] The yield of Example B5 was 43%, and the reaction time was about 20 hours.

[0106] [Example B6]

[0107] The condensing agent used in Example B6 was the same as that in Example B5, except that the equivalent weight of the condensing agent in Example B6 was 1.6, i.e., 0.8 mmol (185.6 mg) of bis[(2-pyridyl)oxy]methylthione was weighed into the sealed tube.

[0108] The yield of Example B6 was 70%, and the reaction time was about 20 hours.

[0109] [Example B7]

[0110] Example B7 is similar to Example B5, except that the reaction temperature of Example B7 is 60°C.

[0111] The yield of Example B7 was 52%, and the reaction time was about 10 hours.

[0112] [Example B8]

[0113] Example B8 is similar to Example B5, except that the reaction temperature in Example B7 is 60°C. In addition, the condensing agent equivalent in Example B7 is 1.2, i.e., 0.6 mmol (139.2 mg) of bis[(2-pyridyl)oxy]methylthioketone is weighed into the sealed tube.

[0114] The yield of Example B8 was 68%, and the reaction time was about 10 hours.

[0115] [Example B9]

[0116] In Example B9, the condensing agent can be synthesized using the following formula.

[0117] 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.

[0118] The synthesis process of Example B9 can be referred to Example B1, except that bis[(6-methylpyridin-2-yl)oxy]methylthione was used as the condensing agent; the equivalent weight of the condensing agent was 1.2, that is, 0.6 mmol (156.0 mg) of bis[(6-methylpyridin-2-yl)oxy]methylthione was weighed into the sealed tube.

[0119] The yield of Example B9 was 66%, and the reaction time was about 10 hours.

[0120] [Example B10]

[0121] In Example B10, the condensing agent can be synthesized using the following formula.

[0122] 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.

[0123] The synthesis process of Example B10 can be referred to Example B1, except that bis[(5-methoxypyridin-2-yl)oxy]methylthione was used as the condensing agent; the equivalent weight of the condensing agent was 1.2, that is, 0.6 mmol (175.2 mg) of bis[(5-methoxypyridin-2-yl)oxy]methylthione was weighed into the sealed tube.

[0124] The yield of Example B10 was 43%, and the reaction time was about 4 hours.

[0125] [Example B11]

[0126] In Example B11, the condensing agent can be synthesized using the following formula.

[0127] 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.

[0128] The synthesis process of Example B11 can be referred to Example B1, except that: bis[(6-methylpyridin-2-yl)oxy]methanone was used as the condensing agent; the equivalent weight of the condensing agent was 1.2, that is, 0.6 mmol (156.0 mg) of bis[(6-methylpyridin-2-yl)oxy]methanone was weighed into the sealed tube; and the reactant was 0.5 mmol (54.0 mg) of 2-methyl-4-aminopyridine.

[0129] The yield of Example B11 was 76%, and the reaction time was about 16 hours.

[0130] Those skilled in the art will understand 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.

[0131] [Example B12]

[0132] In Example B12, the condensing agent can be synthesized using the following formula.

[0133] 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.

[0134] The synthesis process of Example B12 can be referred to Example B1, except that: bis[(6-methylpyridin-2-yl)oxy]methylthione was used as the condensing agent; the equivalent weight of the condensing agent was 1.2, that is, 0.6 mmol (156.0 mg) of bis[(6-methylpyridin-2-yl)oxy]methylthione was weighed into the sealed tube; and the reactant was 0.5 mmol (60.5 mg) of phenylethylamine.

[0135] The yield of Example B12 was 43%, and the reaction time was about 16 hours.

[0136] Those skilled in the art will understand that Example B12 is merely an example of alkyl isothiocyanate, and the present application is not limited to the synthesis of the above product.

[0137] [Example B13]

[0138] In Example B13, the condensing agent can be synthesized using the following formula.

[0139] The synthesis process of Example B13 can be referred to Example B2, except that the equivalent weight of the condensing agent is 1.2, i.e., 0.6 mmol (221.0 mg) of bis[(5-trifluoromethylpyridin-2-yl)oxy]methanthione is weighed into the sealed tube; and the reactant is 2,6-difluoro-4-{[4-(4-pentylphenyl)phenyl]ethynyl}aniline (hereinafter referred to as reactant B13 for simplicity).

[0140] 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.

[0141] Next, Comparative Example C of the present application will be described.

[0142] [Comparative Example C]

[0143] Comparative Example C uses the following formula to synthesize the condensing agent.

[0144] Specifically, at room temperature, 1.0 mmol (100 mg) of calcium carbonate, 5 mL of ultrapure water, and 5 mL of chloroform (CHCl3) were added to a reaction flask. The reaction flask containing the reactants was transferred to an ice bath. After the temperature in the reaction flask stabilized to 0 ° C, 0.75 mmol (86.2 mg) of thiophosgene was added, and then 0.5 mmol (187.7 mg) of the B13 reactant was dissolved in 5 mL of chloroform and added dropwise to the reaction flask. After maintaining the ice bath and stirring for 2 hours, samples were taken for monitoring by TLC spot plate, gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LCMS). After confirming that the reaction was complete, the ice bath was removed and the contents of the reaction flask were heated to room temperature under stirring. The reaction flask was transferred to a sand bath pot set at 50 ° C and heated with stirring for 5 minutes. Remove the sand bath and wait for the mixed solution in the reaction flask to cool naturally to room temperature. Pour the mixed solution into a separating 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).

[0145] The yield of Comparative Example C was 64%.

[0146] 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 ), condensing agent equivalent, reaction temperature, reaction time and yield. 19 Confirmed by F nuclear magnetic resonance.

[0147] Table 1

[0148] Compared to Comparative Example C, Examples B1 to B13 provided herein do not require the addition of thiophosgene to synthesize isothiocyanates. The condensing agents provided in the examples of the present application are less toxic than thiophosgene, and the condensing agents of Examples B1 to B13 are solid, making it easy to control the spread of pollution. Therefore, the condensing agents provided in the examples of the present application can synthesize isothiocyanates in a green manner with minimal impact on the environment.

[0149] 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.

[0150] Specifically, Examples B8 to B10 use condensing agents whose substituents are electron-donating groups. Compared with Examples B3 and B4, the only difference is the substituents. 1 and R 2 is hydrogen, and R of the condensing agent of Example B9 is 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 in Example B4 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.

[0151] The condensing agent R used in Example B11 and Example B12 is 1 and R 2 is an electron-donating group (methyl). Although both Example B11 and Example B12 use reactants with high reactivity, the yields of Example B11 and Example B12 are still relatively low. However, in the case where the reactivity of the reactants is not high enough, Examples B1, B2, B3, and B4 can 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.

[0152] The reactants and products of Example B13 and Comparative Example C are identical, but the yields differ significantly. It can be seen that the synthesis of isothiocyanates using the condensing agents with electron-withdrawing groups provided in the examples of this application yields higher yields than conventional methods for synthesizing isothiocyanates. Furthermore, the products of Example B13 and Comparative Example C are liquid crystal molecules, demonstrating that the condensing agents provided herein can more efficiently synthesize liquid crystal molecules.

[0153] The yields of Examples B1 to B4 are all above 95%, which is very high. Therefore, a condensing agent equivalent of 1.2 to 1.6 and a reaction temperature of about 60°C have a higher yield.

[0154] Embodiment B5 and B6 have the same condensing agent and reaction temperature, except 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 productive rate. In conjunction with the preparation method of isothiocyanate provided by the application, in addition to having the advantage of green environmental protection, productive rate can also be improved by increasing the condensing agent equivalent, thereby having the advantage of high yield.

[0155] Examples B5 and B7 have the same condensing agent and condensing agent equivalent weight, except that the reaction temperature of Example 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, increasing the reaction temperature from 25°C to 60°C only increased the yield from 43% to 52%, indicating that increasing the reaction temperature has a limited effect on the yield. If you want to further improve the yield, it is more effective to use a condensing agent having Formula 1 substituted with an electron-withdrawing group.

[0156] The above description is merely a specific embodiment of the present application, but the scope of protection of the present application is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in this application should be included in the scope of protection of this application. Therefore, the scope of protection of this application should be based on the scope of protection 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 independently selected from 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, a substituted or unsubstituted heteroaryl group having 5 to 60 ring atoms, a substituted or unsubstituted Any of aryloxy groups having 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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