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WO2025030970A1 - Agent de condensation et son utilisation dans la préparation d'isothiocyanate - Google Patents

Agent de condensation et son utilisation dans la préparation d'isothiocyanate Download PDF

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Publication number
WO2025030970A1
WO2025030970A1 PCT/CN2024/093624 CN2024093624W WO2025030970A1 WO 2025030970 A1 WO2025030970 A1 WO 2025030970A1 CN 2024093624 W CN2024093624 W CN 2024093624W WO 2025030970 A1 WO2025030970 A1 WO 2025030970A1
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Prior art keywords
group
condensing agent
isothiocyanate
formula
substituted
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English (en)
Chinese (zh)
Inventor
思晓佳
陈�全
雷爱文
易红
陈宜鸿
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Huawei Technologies Co Ltd
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Huawei Technologies Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
    • C07C331/16—Isothiocyanates
    • C07C331/28—Isothiocyanates having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms

Definitions

  • the present application relates to the field of organic synthesis, and more specifically, to a condensing agent and use thereof in preparing isothiocyanate.
  • ITCs Isothiocyanates
  • isothiocyanates can be used to synthesize anti-gastric cancer drugs, pesticides, and antiviral drugs.
  • isothiocyanates themselves can be used as drugs, and have good application prospects in anti-tumor and treatment of type II diabetes.
  • 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.
  • the present application provides a condensing agent that can synthesize isothiocyanate in a green manner and reduce the impact on the environment.
  • a condensing agent is provided, wherein the condensing agent has Formula 1, which is as follows:
  • R1 and R2 are each independently selected from the same or different electron withdrawing groups.
  • 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.
  • 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.
  • R1 is connected to the para-carbon or meta-carbon of the pyridine nitrogen
  • R2 is connected to the para-carbon or meta-carbon of the pyridine nitrogen
  • the condensing agent has Formula 3 or Formula 4:
  • 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.
  • a method for preparing an isothiocyanate 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:
  • R1 and R2 are each 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
  • 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.
  • the amine includes an arylamine or an alkylamine.
  • the aromatic amine includes an aromatic heterocyclic amine.
  • the aromatic heterocyclic amine includes 2-methyl-4-aminopyridine.
  • the arylamine includes 2,6-difluoroaniline.
  • the alkylamine includes phenethylamine.
  • the arylamine includes 2,6-difluoroaniline.
  • the organic solvent includes at least one of chloroform, 1,4-dioxane, 1,4-dichlorobutane and dichloromethane.
  • the organic solvent is dichloromethane.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG. 1 is a schematic diagram of the structure of a liquid crystal on silicon wavelength selective switch.
  • 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.
  • 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.
  • ITCs Isothiocyanates
  • isothiocyanates can be used to synthesize anti-gastric cancer drugs, pesticides, and antiviral drugs.
  • isothiocyanates themselves can be used as drugs, and have good application prospects in anti-tumor and treatment of type II diabetes.
  • 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.
  • FIG1 is a schematic diagram of the structure of a liquid crystal on silicon wavelength selective switch (LCoS-WSS).
  • 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.
  • 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 polarization imaging optics, 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 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 light on other channels.
  • 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.
  • Figure 1 only shows one 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 in other scenarios.
  • route 1 uses carbon disulfide (CS 2 ), 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.
  • CS 2 carbon disulfide
  • Route 2 uses thiophosgene (CSCl 2 ), which is a highly toxic volatile liquid that is extremely harmful to the environment.
  • 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.
  • 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:
  • R1 and R2 are each 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
  • the method can adopt route 3 to synthesize isothiocyanate.
  • Route 3 is as follows:
  • the isothiocyanate may be an aryl isothiocyanate or an alkyl isothiocyanate.
  • 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.
  • the amine comprises an arylamine or an alkylamine.
  • 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.
  • the alkylamine contains a substituted or unsubstituted alkyl group, for example, the alkylamine may include phenethylamine.
  • the organic solvent may include at least one of chloroform, 1,4-dioxane, 1,4-dichlorobutane and dichloromethane.
  • the organic solvent is dichloromethane.
  • 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.
  • the reaction time is approximately 4 to 20 hours.
  • 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.
  • the dried organic reagent can be treated by column chromatography, distillation, rectification or recrystallization, and other purification methods can also be used for treatment.
  • column chromatography is used for treatment.
  • the above method also includes: using monitoring means such as thin-layer chromatography (TLC) technology to determine whether the reaction is complete; when the reaction is complete, stopping heating the organic reagent.
  • monitoring means such as thin-layer chromatography (TLC) technology to determine whether the reaction is complete; when the reaction is complete, stopping heating the organic reagent.
  • TLC thin-layer chromatography
  • TLC thin-layer chromatography
  • GC gas chromatography
  • GC-MS gas chromatography-mass spectrometry
  • HPLC high performance liquid chromatography
  • 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.
  • the present application also provides a condensing agent, which has Formula 1, which is as follows:
  • R1 and R2 are each independently selected from the same or different electron withdrawing groups.
  • isothiocyanate can be prepared via Scheme 3 using a condensing agent having Formula 1.
  • 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.
  • 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 ).
  • the electron-withdrawing groups in the embodiments of the present application are not limited to the above examples.
  • 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.
  • the electron withdrawing group may be a group whose substituent constant ⁇ in the Hammett equation is greater than 0.
  • the substituent constant ⁇ may characterize the electronic effect of the substituent.
  • the condensing agent has Formula 2, wherein Formula 2 is as follows:
  • R 1 is connected to the para carbon or meta carbon of the pyridine nitrogen
  • R 2 is connected to the para carbon or meta carbon of the pyridine nitrogen.
  • the condensing agent can have the following structure:
  • R1 and R2 can be symmetrical or asymmetrical based on the thiol group, and this application does not limit this.
  • R1 can also be connected to the ortho carbon of the pyridine nitrogen
  • R2 can also be connected to the ortho carbon of the pyridine nitrogen.
  • the condensing agent has Formula 3 or Formula 4:
  • the present application also provides a use of the aforementioned condensing agent in the preparation of isothiocyanate.
  • the aforementioned condensing agent can be used to synthesize isothiocyanate as shown in Scheme 3.
  • 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.
  • Example A1 the condensing agent can be synthesized using the following formula.
  • the organic phase obtained by the separation and extraction was combined. It was washed twice with a saturated ammonium chloride solution and a saturated saline solution in turn. It was dried with 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, 5.7 g of a 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]methylthione.
  • Example A2 the condensing agent can be synthesized using the following formula.
  • 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.
  • 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.
  • 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 the present application is not limited to the selection of the above two R1 and R2 . By introducing different substituents on the aromatic ring of 2-pyridinol, the selection of any R1 and R2 in the condensing agent can be achieved.
  • Example B1 the condensation agent can be synthesized using the following formula.
  • 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.
  • the white solid is the product of this embodiment, i.e., 2,6-difluorophenyl isothiocyanate.
  • the condensing agent used in Example B1 is bis[(4-chloropyridin-2-yl)oxy]methylthione, which is the product synthesized in Example A1.
  • Example B2 the condensing agent can be synthesized using the following formula.
  • 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.
  • the white solid is the product of this embodiment, i.e., 2,6-difluorophenyl isothiocyanate.
  • the condensing agent used in Example B2 is bis[(5-trifluoromethylpyridin-2-yl)oxy]methylthione, which is the product synthesized in Example A2.
  • 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.
  • Example B3 The yield of Example B3 was 98% and the reaction time was about 4 hours.
  • 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.
  • Example B4 The yield of Example B4 was 97% and the reaction time was about 4 hours.
  • Example B5 the condensing agent can be synthesized using the following formula.
  • 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.
  • Example B5 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.
  • 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.
  • Example B5 The yield of Example B5 was 43% and the reaction time was about 20 hours.
  • Example B6 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.
  • Example B6 The yield of Example B6 was 70% and the reaction time was about 20 hours.
  • Example B7 is similar to Example B5, except that the reaction temperature of Example B7 is 60°C.
  • Example B7 The yield of Example B7 was 52% and the reaction time was about 10 hours.
  • 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.
  • Example B8 The yield of Example B8 was 68% and the reaction time was about 10 hours.
  • Example B9 the condensation agent can be synthesized using the following formula.
  • 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.
  • Example B9 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.
  • 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.
  • Example B9 The yield of Example B9 was 66% and the reaction time was about 10 hours.
  • Example B10 the condensation agent can be synthesized using the following formula.
  • 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.
  • Example B10 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.
  • Example B10 The yield of Example B10 was 43% and the reaction time was about 4 hours.
  • Example B11 the condensing agent can be synthesized using the following formula.
  • 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.
  • Example B11 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.
  • 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.
  • Example B11 The yield of Example B11 was 76% and the reaction time was about 16 hours.
  • Example B11 is merely an example of aromatic heterocyclic isothiocyanate, and the present application is not limited to the synthesis of the above product.
  • Example B12 the condensing agent can be synthesized using the following formula.
  • 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.
  • Example B12 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.
  • 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.
  • Example B12 The yield of Example B12 was 43% and the reaction time was about 16 hours.
  • Example B12 is merely an example of alkyl isothiocyanate, and the present application is not limited to the synthesis of the above product.
  • Example B13 the condensing agent can be synthesized using the following formula.
  • Example B13 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).
  • 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 (herein
  • 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.
  • Comparative Example C uses the following formula to synthesize the condensation agent.
  • Table 1 shows the condensing agent substituents (R 1 and R 2 ), condensing agent equivalents, reaction temperatures, reaction times and yields of Examples B1 to B13 and Comparative Example C. The yields were determined by 19 F nuclear magnetic resonance.
  • 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.
  • 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.
  • 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.
  • R 1 and R 2 of the condensing agent of Example B8 are hydrogen
  • R 1 and R 2 of the condensing agent of Example B9 are methyl
  • R 1 and R 2 of the condensing agent of Example B10 are methoxy
  • R 1 and R 2 of Example B3 are chlorine atoms
  • R 1 and R 2 of Example B4 are trifluoromethyl.
  • the yields of Examples B3 and B4 are much higher than those of Examples B8 to B10, indicating that R 1 and R 2 of the condensing agent are electron-withdrawing groups, which is beneficial to improving the yield of isothiocyanate.
  • the R1 and R2 of the condensing agent used in Example B11 and Example B12 are electron-donating groups (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 in Examples B1, B2, B3, and B4 is not high enough, they can still have a relatively high yield. This further illustrates that the R1 and R2 of the condensing agent are electron-withdrawing groups, which are beneficial to improving the yield of isothiocyanate.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente demande relève du domaine de la synthèse organique. L'invention concerne un agent de condensation. L'agent de condensation a la formule 1, dans laquelle R1 et R2 sont chacun indépendamment choisis parmi les mêmes ou différents groupes attracteurs d'électrons. Par comparaison avec le thiophosgène ou le disulfure de carbone utilisé dans une solution classique, l'agent de condensation selon des modes de réalisation de la présente demande a une toxicité inférieure, et l'agent de condensation est un solide, de telle sorte que la diffusion de la pollution est facilement contrôlée. Par conséquent, l'agent de condensation selon des modes de réalisation de la présente demande peut être utilisé pour la synthèse écologique d'un composé isothiocyanate et a une influence relativement faible sur l'environnement. De plus, l'agent de condensation selon des modes de réalisation de la présente demande comprend des groupes attracteurs d'électrons, de telle sorte que le rendement du composé isothiocyanate peut être augmenté.
PCT/CN2024/093624 2023-08-04 2024-05-16 Agent de condensation et son utilisation dans la préparation d'isothiocyanate Pending WO2025030970A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1065465A (zh) * 1991-03-25 1992-10-21 霍夫曼-拉罗奇有限公司 聚乙二醇蛋白质结合物
US20130079542A1 (en) * 2011-09-22 2013-03-28 National Chung Hsing University Processes for producing aryl carbamates, isocynates and polyureas using diaryl carbonate
CN103159691A (zh) * 2011-12-19 2013-06-19 天津市国际生物医药联合研究院 异硫氰酸酯类化合物的制备及应用
CN104211986A (zh) * 2014-08-25 2014-12-17 华东理工大学 一种交联含异氰尿酸酯大分子阻燃成炭剂及其制备方法
WO2016014522A1 (fr) * 2014-07-21 2016-01-28 Brandeis University Inhibiteurs de protéases de désubiquitination
CN106349110A (zh) * 2015-07-17 2017-01-25 大东树脂化学股份有限公司 制备脂肪族二异氰酸酯的二步法及一锅化合成法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1065465A (zh) * 1991-03-25 1992-10-21 霍夫曼-拉罗奇有限公司 聚乙二醇蛋白质结合物
US20130079542A1 (en) * 2011-09-22 2013-03-28 National Chung Hsing University Processes for producing aryl carbamates, isocynates and polyureas using diaryl carbonate
CN103159691A (zh) * 2011-12-19 2013-06-19 天津市国际生物医药联合研究院 异硫氰酸酯类化合物的制备及应用
WO2016014522A1 (fr) * 2014-07-21 2016-01-28 Brandeis University Inhibiteurs de protéases de désubiquitination
CN104211986A (zh) * 2014-08-25 2014-12-17 华东理工大学 一种交联含异氰尿酸酯大分子阻燃成炭剂及其制备方法
CN106349110A (zh) * 2015-07-17 2017-01-25 大东树脂化学股份有限公司 制备脂肪族二异氰酸酯的二步法及一锅化合成法

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