WO2022032879A1 - 杂芳基胺类化合物的光化学合成方法 - Google Patents

杂芳基胺类化合物的光化学合成方法 Download PDF

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WO2022032879A1
WO2022032879A1 PCT/CN2020/124467 CN2020124467W WO2022032879A1 WO 2022032879 A1 WO2022032879 A1 WO 2022032879A1 CN 2020124467 W CN2020124467 W CN 2020124467W WO 2022032879 A1 WO2022032879 A1 WO 2022032879A1
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synthesis method
photochemical synthesis
titanium dioxide
nano
photochemical
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French (fr)
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张恩选
刘志清
肖毅
卢江平
侯庆龙
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天津凯莱英制药有限公司
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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
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms

Definitions

  • the invention relates to the technical field of organic synthesis, in particular to a photochemical synthesis method of a heteroarylamine compound.
  • aromatic amines plays an important role in organic synthesis unit reactions. It is widely used in the fields of dyes, agricultural chemicals, surfactants, chelating agents and pharmaceutical synthesis, such as aromatic amine drugs: benzocaine, procaine hydrochloride and other local anesthetics.
  • aromatic amine drugs benzocaine, procaine hydrochloride and other local anesthetics.
  • the reduction of aromatic nitro compounds is currently a common method for preparing aromatic amines in chemical production.
  • the reduction of aromatic nitro compounds to prepare aromatic amines mainly includes the following methods: active metal reduction method; metal hydride reduction method; catalytic hydrogenation method; electrochemical reduction method.
  • the active metal reduction method is the most classic method for reducing nitro compounds, such as the metal iron/hydrochloric acid reduction method adopted by Lih-Chu in the US patent application with the publication number of US2018134698A1.
  • Forma et al. adopted the tin chloride/ethanol heating reduction method. Due to the existence of metal salts, the post-treatment steps of such methods are cumbersome and easy to generate a large amount of waste water. The addition of tin chloride catalysts is even more harmful to the environment.
  • the metal hydride reduction method usually uses sodium borohydride or lithium tetrahydroaluminum as the reducing agent. This kind of method is not only expensive for the reagents, but also very easy to react in the presence of moisture, and has a great potential safety hazard.
  • the most commonly used catalytic hydrogenation methods are the palladium-carbon hydrogenation method (MedChemComm, 2016, vol.7.11, 2159-2166) and the Raney nickel hydrogenation method (WO2008143674), which have high requirements on equipment and high safety risks.
  • precious metals such as palladium, rhodium, platinum, etc. are selected, and the production cost is relatively high.
  • the electroreduction method such as Ravichandran C, etc., uses Ti/TiO 2 as the electrode to realize the electroreduction of nitro compounds under the action of sulfuric acid (Journal of Applied Electrochemistry, 1994, 24, 1256-1261), but the system is generally in an acidic environment. Substrate structure requirements are high.
  • the Chinese patent application with publication number CN201110006899.4 discloses a method for catalytic reduction of nitro compounds using platinum nanowires as catalysts.
  • High temperature and high pressure, simple reaction device, is a very promising reduction method.
  • the large-scale preparation and cost control of catalysts still face huge challenges.
  • the main purpose of the present invention is to provide a photochemical synthesis method of heteroaryl amine compounds, so as to solve the large environmental pressure, high safety hazard and preparation of catalysts in the traditional reduction method of aromatic nitro compounds existing in the prior art. high cost issue.
  • a photochemical synthesis method of a heteroarylamine compound comprising: step S1, comprising a heteroarylnitro compound, a solvent, a photocatalyst
  • step S1 comprising a heteroarylnitro compound, a solvent, a photocatalyst
  • step S2 comprising a photocatalytic reduction reaction under illumination conditions to obtain a product system containing a heteroarylamine compound.
  • n and m are each independently 0 or 1
  • Y and Z are each independently selected from any one of chemically acceptable CR 7 , N, NR 8 , O and S, and Y and Z at least have One is any one of N, NR 8 , O, S, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently selected from H, substituted or unsubstituted C 1 -C 20 alkyl, substituted or unsubstituted C 1 -C 20 alkoxy, substituted or unsubstituted C 6 -C 20 aryl, halogen, ester, hydroxyl, amide, nitro One of base, -CF 3 , -CHF 2 .
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently selected from substituted or unsubstituted C 1 -C 10 linear alkyl, substituted or Any of unsubstituted C 3 -C 10 branched alkyl, substituted or unsubstituted C 1 -C 10 alkoxy, and substituted or unsubstituted C 6 -C 10 aryl.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from any one of methoxy, -Cl, and -CHF 2 .
  • the above solvent is selected from C 1 -C 6 alcohol or an aqueous solution of C 1 -C 6 alcohol, preferably the C 1 -C 6 alcohol is selected from methanol, ethanol, ethylene glycol, isopropanol, n-butanol , one or more of tert-butanol and cyclohexanol, preferably the volume ratio of alcohol to water in the aqueous solution of C 1 -C 6 alcohol is 10:1 - 50:1.
  • the active component of the above-mentioned photocatalyst is nano-titanium dioxide, preferably the mass ratio of the heteroaryl nitro compound and the nano-titanium dioxide is 1:1 to 1:5, and the preferred particle size of the nano-titanium dioxide is 15 to 200 nm, preferably 30 nm. ⁇ 60nm, and further preferably, the nano-titanium dioxide is selected from one or more of rutile-type nano-titanium dioxide, anatase-type nano-titanium dioxide, and nano-titanium dioxide-loaded microspheres.
  • the temperature of the photocatalytic reduction reaction is 30-40° C., preferably the time of the photocatalytic reduction reaction is 2-15 h, and the wavelength of light in the illumination condition is preferably 310-400 nm, preferably 340-385 nm.
  • the light source of the light condition is preferably an LED lamp or a laser.
  • the above-mentioned raw materials also include a solubilizing agent, preferably, the solubilizing agent is selected from one or more of tetrahydrofuran, acetone, ethyl acetate, and polyethylene glycol-400.
  • the above-mentioned raw materials also include additives, preferably the additives are selected from one or more of triethylamine, triethanolamine, sodium sulfite, sodium sulfide, EDTA, formic acid, and ascorbic acid.
  • additives are selected from one or more of triethylamine, triethanolamine, sodium sulfite, sodium sulfide, EDTA, formic acid, and ascorbic acid.
  • the above-mentioned photochemical synthesis method also includes: centrifuging the product system to obtain a clear liquid and a solid; subjecting the clear liquid to a vacuum concentration treatment to obtain a heteroarylamine compound and a recovery solvent; washing and drying the solid to obtain a Recover the photocatalyst; preferably, the recovered solvent is returned to step S1 for use as a solvent, and the recovered photocatalyst is preferably returned to step S1 for use as a photocatalyst.
  • the above-mentioned photochemical synthesis method of the present application uses a photocatalyst. Under the condition of illumination, photogenerated holes and photogenerated electrons will be formed on the surface of the catalyst, and the photogenerated electrons and water can generate active hydrogen and further reduce nitrate. That is, the photocatalytic reduction of various heteroaryl nitro compounds is realized under illumination conditions, and the heteroaryl amine compounds with higher yields are obtained.
  • Photocatalysts are currently commonly used catalysts, which do not have strict requirements on equipment, are easy to recycle, and reduce the safety risk and catalyst cost of heteroarylamine compounds. The whole reaction process of the photocatalysis does not need to add any metal reagents and reducing agents, and the conversion rate of the reaction is high, and the post-treatment is simple and easy to operate, therefore, it is more safe and environmentally friendly.
  • the catalysts of the traditional reduction method of aromatic nitro compounds have the problems of high environmental protection pressure, high safety hazard and high preparation cost.
  • the present invention provides a Photochemical synthesis of heteroarylamines.
  • a photochemical synthesis method of a heteroarylamine compound includes: step S1, which includes a heteroarylnitro compound, a solvent, and a photocatalyst.
  • step S1 which includes a heteroarylnitro compound, a solvent, and a photocatalyst.
  • the raw materials are mixed to obtain a mixture; in step S2, the mixture is subjected to a photocatalytic reduction reaction under illumination conditions to obtain a product system containing a heteroarylamine compound.
  • the above-mentioned photochemical synthesis method of the present application uses a photocatalyst. Under illumination conditions, photo-generated holes and photo-generated electrons are formed on the surface of the catalyst, and the photo-generated electrons interact with water to generate active hydrogen and further reduce nitro groups; that is, under illumination conditions The photocatalytic reduction of various heteroaryl nitro compounds was achieved, and the heteroaryl amine compounds with higher yields were obtained.
  • Photocatalysts are currently commonly used catalysts, which do not have strict requirements on equipment, are easy to recycle, and reduce the safety risk and catalyst cost of heteroarylamine compounds.
  • the whole reaction process of the photocatalysis does not need to add any metal reagents and reducing agents, and the conversion rate of the reaction is high, and the post-treatment is simple and easy to operate, therefore, it is more safe and environmentally friendly.
  • the general structural formula of the above-mentioned heteroaryl nitro compounds is I or II:
  • n and m are each independently 0 or 1
  • Y and Z are each independently selected from any one of chemically acceptable CR 7 , N, NR 8 , O and S, and Y and Z at least have One is any one of N, NR 8 , O, S, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently selected from H, substituted or unsubstituted C 1 -C 20 alkyl, substituted or unsubstituted C 1 -C 20 alkoxy, substituted or unsubstituted C 6 -C 20 aryl, halogen, ester, hydroxyl, amide, nitro One of base, -CF 3 , -CHF 2 .
  • heteroaryl nitro compounds conforming to the above-mentioned general structural formulas I and II have better reaction effects under the photocatalytic reduction reaction conditions of the present application, and are more widely used in the fields of chemical industry and medicine.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Each is independently selected from substituted or unsubstituted C 1 -C 10 straight-chain alkyl, substituted or unsubstituted C 3 -C 10 branched alkyl, substituted or unsubstituted C 1 -C 10 alkoxy any one of aryl groups, substituted or unsubstituted C 6 -C 10 aryl groups.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently selected from methoxy, -Cl, -CHF 2 any of the .
  • heteroaryl nitro compounds with the above-mentioned substituent groups are more helpful to obtain the corresponding heteroaryl amine compounds with high yield and high practicability.
  • the above-mentioned solvent is selected from C 1 -C 6 alcohol or an aqueous solution of C 1 -C 6 alcohol
  • the C 1 -C 6 alcohol is selected from methanol , one or more of ethanol, ethylene glycol, isopropanol, n-butanol, tert-butanol, cyclohexanol, the volume ratio of alcohol to water in the aqueous solution of preferably C 1 to C 6 alcohol is 10: 1 to 50:1.
  • the active component of the above-mentioned photocatalyst is nano-titanium dioxide, preferably the mass ratio of the heteroaryl nitro compound to the nano-titanium dioxide is 1:1 to 1:5, and preferably the particle size of the nano-titanium dioxide is 15-200 nm, preferably 30-60 nm, further preferably, the nano-titanium dioxide is selected from one or more of rutile-type nano-titanium dioxide, anatase-type nano-titanium dioxide, and nano-titanium dioxide-loaded microspheres.
  • the particle size of the above-mentioned preferred nano-titania catalyst and the mass ratio of the heteroaryl nitro compound to the nano-titania help to further improve the efficiency of the photocatalytic reduction reaction.
  • the temperature of the photocatalytic reduction reaction is 30-40 °C
  • the preferably time of the photocatalytic reduction reaction is 2-15 h
  • the light wavelength in the light condition is preferably 310°C. ⁇ 400 nm, preferably 340 to 385 nm
  • the light source for the illumination conditions is preferably an LED lamp or a laser.
  • the above-mentioned raw materials also include a solubilizing agent, and preferably the solubilizing agent is selected from one of tetrahydrofuran, acetone, ethyl acetate, ethylene glycol, diethylene glycol, and polyethylene glycol-400. one or more.
  • Nitrogen base material has poor solubility in isopropanol solvent, which is not conducive to the further amplification and industrial application of the reaction. Solubility in the medium, reduce the amount of solvent, and improve the reaction efficiency of raw materials.
  • the above-mentioned raw materials also include additives, preferably the additives are selected from one or more of triethylamine, triethanolamine, sodium sulfite, sodium sulfide, EDTA, formic acid, and ascorbic acid.
  • additives are selected from one or more of triethylamine, triethanolamine, sodium sulfite, sodium sulfide, EDTA, formic acid, and ascorbic acid.
  • the above-mentioned additives can be coordinated with the photocatalyst, so as to facilitate the progress of the photocatalytic reduction reaction and improve the efficiency of the photocatalytic reduction reaction.
  • the catalyst generates photogenerated holes and electrons under illumination, and holes and electrons are easy to combine with themselves, reducing the efficiency of electrons.
  • the addition of additives can combine with photogenerated holes, prolong the life of photogenerated electrons, and improve the reaction rate; acidic substrates are preferably used. Acidic additives, basic substrates are preferably basic additives.
  • the above-mentioned photochemical synthesis method further includes: centrifuging the product system to obtain clear liquid and solid; subjecting the clear liquid to reduced pressure concentration treatment to obtain heteroarylamine compounds and recovery solvent; The solid is washed and dried to recover the photocatalyst; preferably, the recovered solvent is returned to step S1 for use as a solvent, and the recovered photocatalyst is preferably returned to step S1 for use as a photocatalyst.
  • the present application recovers the solvent and the nano-titania catalyst by the above method, and returns them to the photocatalytic reduction reaction for recycling, wherein the recovered photocatalyst is preferably returned to step S1 to be used as a photocatalyst for 1-10 times.
  • the recovered photocatalyst is preferably returned to step S1 to be used as a photocatalyst for 1-10 times.
  • the structural formula of the above-mentioned heteroarylamine compound is:
  • heteroarylamine compounds with the above-mentioned structures can be widely used in the fields of chemical industry and medicine.
  • Example 2 The difference between Example 2 and Example 1 is that 0.1 g of rutile nano-titanium dioxide with a particle size of 30 nm was added, and a 365 nm LED lamp was used as the light source to illuminate for 15 h. 63 mg of 5-aminopyridine, the isolated yield was 78.2%.
  • Example 3 The difference between Example 3 and Example 1 is that 0.2 g of rutile nano-titanium dioxide with a particle size of 30 nm was added, and a 365 nm LED lamp was used as the light source to illuminate for 10 h. Oxy-5-aminopyridine was 68 mg, and its isolated yield was 85.2%.
  • Example 4 The difference between Example 4 and Example 2 is that 0.05 g of rutile nano-titanium dioxide with a particle size of 30 nm was added, and the upper organic phase was concentrated under reduced pressure to obtain 57 mg of reddish-brown liquid 2-methoxy-5-aminopyridine, which was The isolated yield was 70.8%.
  • Example 5 The difference between Example 5 and Example 1 is that 0.5g of anatase type nano-titanium dioxide was added as a catalyst, and at a temperature of 40°C, a 365nm LED lamp was used as a light source to illuminate for 9h, and the upper organic phase was concentrated under reduced pressure to obtain a red color.
  • the brown liquid 2-methoxy-5-aminopyridine was 70 mg, and its isolated yield was 86.7%.
  • Example 6 The difference between Example 6 and Example 1 is that the particle size of the rutile nano-titanium dioxide is 15nm, and the 365nm LED lamp is used as a light source to irradiate for 6.5h, and the upper organic phase is concentrated under reduced pressure column chromatography to obtain a reddish-brown liquid 2-methoxy- 73 mg of 5-aminopyridine, the isolated yield was 90.2%.
  • Example 7 The difference between Example 7 and Example 1 is that the particle size of the rutile nano-titanium dioxide is 200nm, and the 365nm LED lamp is used as a light source to irradiate for 6.5h, and the upper organic phase is concentrated under reduced pressure to obtain a reddish-brown liquid 2-methoxy- 68 mg of 5-aminopyridine, the isolated yield was 84.2%.
  • Example 8 The difference between Example 8 and Example 1 is that the particle size of the rutile nano-titanium dioxide is 45 nm, and the upper organic phase is concentrated under reduced pressure to obtain 75 mg of reddish-brown liquid 2-methoxy-5-aminopyridine, and the isolated yield is 75 mg. was 93.2%.
  • Example 9 The difference between Example 9 and Example 1 is that the particle size of the rutile nano-titanium dioxide is 60 nm, and the upper organic phase obtains 74 mg of reddish-brown liquid 2-methoxy-5-aminopyridine through decompression concentration column chromatography, which is separated and collected. The rate was 91.9%.
  • Example 10 The difference between Example 10 and Example 1 is that 1.0 mL of purified water was added, and a 365nm LED lamp was used as a light source to illuminate for 8h, and the upper organic phase was concentrated under reduced pressure to obtain a reddish-brown liquid 2-methoxy-5-aminopyridine. 73 mg, the isolated yield was 90.2%.
  • Example 11 The difference between Example 11 and Example 1 is that 0.2 mL of purified water was added, and a 365 nm LED lamp was used as a light source to illuminate for 8 h, and the upper organic phase was concentrated under reduced pressure to obtain a reddish-brown liquid 2-methoxy-5-aminopyridine. 70mg, its isolated yield was 86.9%.
  • Example 12 The difference between Example 12 and Example 1 is that 0.15 mL of purified water was added, and a 365 nm LED lamp was used as a light source to illuminate for 8 h, and the upper organic phase was concentrated under reduced pressure to obtain a reddish-brown liquid 2-methoxy-5-aminopyridine. 66 mg, the isolated yield was 81.9%.
  • Example 13 The difference between Example 13 and Example 10 is that 2-methoxy-5-nitropyridine (0.1 g, 0.65 mmol) was dissolved in 10 mL of methanol, irradiated for 2 h with a 365 nm LED lamp as a light source, and the upper organic phase was reduced. 56 mg of red-brown liquid 2-methoxy-5-aminopyridine was obtained by pressure concentration column chromatography, and the isolated yield was 69.5%.
  • 2-methoxy-5-nitropyridine 0.1 g, 0.65 mmol
  • Example 14 The difference between Example 14 and Example 10 is that 2-methoxy-5-nitropyridine (0.1 g, 0.65 mmol) was dissolved in 10 mL of ethanol, irradiated with a 365 nm LED lamp for 3.5 h, and the upper organic phase was Column chromatography was concentrated under reduced pressure to obtain 59 mg of 2-methoxy-5-aminopyridine as a reddish-brown liquid with an isolated yield of 73.3%.
  • Example 15 The difference between Example 15 and Example 10 is that 2-methoxy-5-nitropyridine (0.1 g, 0.65 mmol) was dissolved in 10 mL of ethylene glycol, and irradiated for 8 h with a 365 nm LED lamp as a light source. 61 mg of 2-methoxy-5-aminopyridine as a reddish-brown liquid was obtained by concentrating under reduced pressure column chromatography, and the isolated yield was 75.4%.
  • 2-methoxy-5-nitropyridine 0.1 g, 0.65 mmol
  • Example 16 The difference between Example 16 and Example 10 is that 2-methoxy-5-nitropyridine (0.1 g, 0.65 mmol) was dissolved in 10 mL of tert-butanol, and irradiated for 8 h with a 365 nm LED lamp as a light source, and the upper organic phase was irradiated for 8 h. 69 mg of 2-methoxy-5-aminopyridine as a reddish-brown liquid was obtained by concentrating under reduced pressure column chromatography, and the isolated yield was 86.1%.
  • 2-methoxy-5-nitropyridine 0.1 g, 0.65 mmol
  • Example 17 The difference between Example 17 and Example 16 is that 0.2 ml of purified water was added, HPLC showed that the content of 2-methoxy-5-aminopyridine in the product system was 89.8%, and the upper organic phase was concentrated under reduced pressure by column chromatography. 70 mg of red-brown liquid 2-methoxy-5-aminopyridine, the isolated yield was 86.9%.
  • Example 18 The difference between Example 18 and Example 2 is that 1mL of triethylamine was added as an additive, and a 365nm LED lamp was used as a light source to illuminate for 2h, the reaction system was placed in a centrifuge for centrifugation, and the upper organic phase was concentrated under reduced pressure and subjected to column chromatography. 57 mg of red-brown liquid 2-methoxy-5-aminopyridine was obtained, and the isolated yield was 71.1%.
  • Example 19 The difference between Example 19 and Example 18 is that 1 mL of triethanolamine was added as an additive, and a 365 nm LED lamp was used as a light source to illuminate for 2.5 h, and the reaction system was placed in a centrifuge for centrifugal separation, and the upper organic phase was concentrated under reduced pressure and then subjected to column chromatography. 77 mg of reddish-brown liquid 2-methoxy-5-aminopyridine was obtained, and the isolated yield was 95.6%.
  • Example 22 The difference between Example 22 and Example 1 is that the wavelength of the LED lamp is 310 nm, the light is illuminated for 20 h, and the upper organic phase is concentrated under reduced pressure to obtain 22.3 mg of red-brown liquid 2-methoxy-5-aminopyridine by column chromatography, which is The isolated yield was 28%.
  • Example 23 The difference between Example 23 and Example 1 is that the wavelength of the LED lamp is 400 nm, the light is illuminated for 20 h, and the upper organic phase is concentrated under reduced pressure to obtain 24 mg of reddish-brown liquid 2-methoxy-5-aminopyridine by column chromatography, which is separated The yield was 30%.
  • Example 24 The difference between Example 24 and Example 1 is that the wavelength of the LED lamp is 385 nm, the light is illuminated for 12 h, and the upper organic phase is concentrated under reduced pressure to obtain 64 mg of red-brown liquid 2-methoxy-5-aminopyridine by column chromatography, which is separated The yield was 79.5%.
  • Example 25 The difference between Example 25 and Example 1 is that the wavelength of the LED lamp is 340 nm, the light is illuminated for 12 h, and the upper organic phase is concentrated under reduced pressure to obtain 65.2 mg of red-brown liquid 2-methoxy-5-aminopyridine by column chromatography, which is The isolated yield was 81%.
  • Example 26 The difference between Example 26 and Example 1 is that the wavelength of the LED lamp is 450 nm, the light is illuminated for 24 hours, and the upper organic phase is concentrated under reduced pressure, and no 2-methoxy-5-aminopyridine is formed by column chromatography.
  • Example 30 The difference between Example 30 and Example 18 is that when 365nm laser was used as a light source to illuminate for 3h, HPLC showed that the content of 2-methoxy-5-aminopyridine in the product system was 96.8%, and the upper organic phase was concentrated under reduced pressure to obtain a reddish-brown color.
  • the liquid 2-methoxy-5-aminopyridine was 73 mg, and the isolated yield was 90.7%.
  • 2,4-Dichloro-6-methyl-5-nitropyrimidine (1 g, 4.8 mmol) was dissolved in isopropanol (100 mL) and stirred to clarify, then 10 mL of purified water and 10 mL of triethanolamine were added, followed by 1 g of rutile Nano-titanium dioxide is used as a catalyst, the system is a white suspension, stirred for 0.5h, and then placed in a photochemical reactor, irradiated with a 365nm LED lamp for 6.5h, monitored by TLC or HPLC, and the disappearance of the raw material was stopped to obtain the product system, which was placed in the product system.
  • the catalyst in the above-mentioned embodiment is recovered and reused for the above-mentioned catalytic reaction. As the number of times of reuse of the recovered catalyst increases, its catalytic activity decreases, but the reuse of the recovered catalyst can maximize the utilization of the catalyst and reduce the Three waste volumes and production costs.
  • the catalyst was repeatedly recovered and utilized 10 times, and the specific reaction conditions for the recovery and utilization of the catalyst were as in the present embodiment, and the separation yield data of the IPC (HPLC content) and the heteroaromatic amine compound of the 10 times of illumination reaction are shown in Table 1 below.
  • the above-mentioned photochemical synthesis method of the present application uses a photocatalyst. Under illumination conditions, photo-generated holes and photo-generated electrons are formed on the surface of the catalyst, and the photo-generated electrons interact with water to generate active hydrogen and further reduce nitro groups; that is, under illumination conditions The photocatalytic reduction of various heteroaryl nitro compounds was achieved, and the heteroaryl amine compounds with higher yields were obtained.
  • Photocatalysts are currently commonly used catalysts, which do not have strict requirements on equipment, are easy to recycle, and reduce the safety risk and catalyst cost of heteroarylamine compounds.
  • the whole reaction process of the photocatalysis does not need to add any metal reagents and reducing agents, and the conversion rate of the reaction is high, and the post-treatment is simple and easy to operate, therefore, it is more safe and environmentally friendly.

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Abstract

提供了一种杂芳基胺类化合物的光化学合成方法。该光化学合成方法包括：步骤S1，将包括杂芳基硝基类化合物、溶剂、光催化剂的原料进行混合，得到混合物；步骤S2，将混合物在光照条件下进行光催化还原反应，得到含杂芳基胺类化合物的产物体系。上述光化学合成方法在光照条件下实现对各种不同的杂芳基硝基类化合物的光催化还原，获得了较高产率的杂芳基胺类化合物。光催化剂为现有常用的催化剂，其对设备没有严格要求，易于回收，降低了杂芳基胺类化合物的安全风险和催化剂成本。该光催化的整个反应过程无需加入任何金属试剂和还原剂，且反应的转化率较高，后处理简单易操作，因此，其更加安全环保。

Description

杂芳基胺类化合物的光化学合成方法 技术领域
本发明涉及有机合成技术领域，具体而言，涉及一种杂芳基胺类化合物的光化学合成方法。
背景技术
芳胺类化合物的合成在有机合成单元反应中占有重要地位。被广泛用于染料、农业化学品、表面活性剂、螯合剂以及医药合成等领域，如芳胺类药物：苯佐卡因、盐酸普鲁卡因等局部麻醉药。芳香族硝基化合物还原是目前化工生产制备芳香胺的常用方法。
芳香族硝基化合物还原制备芳香胺主要有以下几种方法：活泼金属还原法；金属氢化物还原法；催化加氢法；电化学还原法等。活泼金属还原法是最经典的硝基化合物还原方法，比如专利申请公开号为US2018134698A1的美国专利申请中Lih-Chu等采用的金属铁/盐酸还原法，专利申请公开号为WO2016171755 A1的专利申请中Forma等采用氯化锡/乙醇加热还原法，此类方法由于金属盐的存在，后处理步骤繁琐，易产生大量废水，氯化锡催化剂的加入更是对环境带来巨大的危害。金属氢化物还原法通常以硼氢化钠或四氢铝锂为还原剂，该类方法不仅试剂价格昂贵，而且遇湿极易反应，安全隐患大。催化加氢法最常用的就是钯碳加氢法(MedChemComm,2016,vol.7.11,2159-2166)和雷尼镍加氢法(WO2008143674)，该方法对设备要求较高，安全风险大，因生产过程中选用了贵金属钯、铑、铂等，生产成本较高。电解还原法，如Ravichandran C等以Ti/TiO 2为电极在硫酸作用下实现了硝基化合物的电还原(Journal of Applied Electrochemistry,1994,24,1256-1261)，但是体系普遍为酸性环境，对底物结构要求较高。
在公开号为CN201110006899.4的中国专利申请中公开了一种以铂纳米线为催化剂催化还原硝基化合物的方法，该方法需要在0～100℃，0.1～1.0个大气压条件下进行，避免了高温高压，反应装置简单，是一种非常有前途的还原方法。但催化剂的规模化制备及成本控制仍面临巨大挑战。
发明内容
本发明的主要目的在于提供一种杂芳基胺类化合物的光化学合成方法，以解决现有技术中存在的芳香族硝基化合物的传统还原方法的催化剂导致的环保压力大、安全隐患大以及制备成本高的问题。
为了实现上述目的，根据本发明的一个方面，提供了一种杂芳基胺类化合物的光化学合成方法，该光化学合成方法包括：步骤S1，将包括杂芳基硝基类化合物、溶剂、光催化剂的 原料进行混合，得到混合物；步骤S2，将混合物在光照条件下进行光催化还原反应，得到含杂芳基胺类化合物的产物体系。
进一步地，上述杂芳基硝基类化合物的结构通式为I或II：
Figure PCTCN2020124467-appb-000001
其中，n与m各自独立地为0或1，Y、Z各自独立地选自化学上可接受的CR 7、N、NR 8、O、S中的任意一种，且Y、Z中至少有一个为N、NR 8、O、S中的任意一种，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8各自独立地选自H、取代或非取代的C 1～C 20的烷基、取代或非取代的C 1～C 20的烷氧基、取代或非取代的C 6～C 20的芳基、卤素、酯基、羟基、酰胺基、硝基、-CF 3、-CHF 2中的一种。
进一步地，上述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8各自独立地选自取代或非取代的C 1～C 10的直链烷基、取代或非取代的C 3～C 10的支链烷基、取代或非取代的C 1～C 10的烷氧基、取代或非取代的C 6～C 10的芳基中的任意一种。
进一步地，上述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8各自独立地选自甲氧基、-Cl、-CHF 2中的任意一种。
进一步地，上述溶剂选自C 1～C 6的醇或C 1～C 6的醇的水溶液，优选C 1～C 6的醇选自甲醇、乙醇、乙二醇、异丙醇、正丁醇、叔丁醇、环己醇中的一种或多种，优选C 1～C 6的醇的水溶液中醇与水的体积比为10:1～50:1。
进一步地，上述光催化剂的活性成分为纳米二氧化钛，优选杂芳基硝基类化合物与纳米二氧化钛的质量比为1:1～1:5，优选纳米二氧化钛的粒径为15～200nm，优选为30～60nm，进一步优选纳米二氧化钛选自金红石型纳米二氧化钛、锐钛矿型纳米二氧化钛、负载纳米二氧化钛的微球中的一种或多种。
进一步地，在上述步骤S2中，光催化还原反应的温度为30～40℃，优选光催化还原反应的时间为2～15h，优选光照条件中的光波长为310～400nm，优选为340～385nm，优选光照条件的光源为LED灯或激光。
进一步地，上述原料还包括助溶试剂，优选助溶试剂选自四氢呋喃、丙酮、乙酸乙酯、聚乙二醇-400中的一种或多种。
进一步地，上述原料还包括添加剂，优选添加剂选自三乙胺、三乙醇胺、亚硫酸钠、硫化钠、EDTA、甲酸、抗坏血酸中的一种或多种。
进一步地，上述光化学合成方法还包括：将产物体系进行离心分离，得到清液和固体；将清液进行减压浓缩处理，得杂芳基胺类化合物和回收溶剂；将固体进行清洗、干燥以回收光催化剂；优选将回收溶剂返回步骤S1作为溶剂使用，优选将回收的光催化剂返回步骤S1作为光催化剂使用。
进一步地，上述杂芳基胺类化合物的结构式为：
Figure PCTCN2020124467-appb-000002
Figure PCTCN2020124467-appb-000003
中的任意一种。
应用本发明的技术方案，本申请的上述光化学合成方法通过使用光催化剂，在光照条件下，催化剂表面会形成光生空穴和光生电子，其中的光生电子与水作用可生成活泼氢进而进一步还原硝基；即在光照条件下实现对各种不同的杂芳基硝基类化合物的光催化还原，获得了较高产率的杂芳基胺类化合物。光催化剂为现有常用的催化剂，其对设备没有严格要求，易于回收，降低了杂芳基胺类化合物的安全风险和催化剂成本。该光催化的整个反应过程无需加入任何金属试剂和还原剂，且反应的转化率较高，后处理简单易操作，因此，其更加安全环保。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。
如背景技术所分析的，现有技术中存在芳香族硝基化合物的传统还原方法的催化剂导致的环保压力大、安全隐患大以及制备成本高的问题，为解决该问题，本发明提供了一种杂芳基胺类化合物的光化学合成方法。
在本申请的一种典型的实施方式中，提供了一种杂芳基胺类化合物的光化学合成方法，该光化学合成方法包括：步骤S1，将包括杂芳基硝基类化合物、溶剂、光催化剂的原料进行混合，得到混合物；步骤S2，将混合物在光照条件下进行光催化还原反应，得到含杂芳基胺类化合物的产物体系。
本申请的上述光化学合成方法通过使用光催化剂，在光照条件下，催化剂表面会形成光生空穴和光生电子，其中的光生电子与水作用可生成活泼氢进而进一步还原硝基；即在光照条件下实现对各种不同的杂芳基硝基类化合物的光催化还原，获得了较高产率的杂芳基胺类化合物。光催化剂为现有常用的催化剂，其对设备没有严格要求，易于回收，降低了杂芳基胺类化合物的安全风险和催化剂成本。该光催化的整个反应过程无需加入任何金属试剂和还原剂，且反应的转化率较高，后处理简单易操作，因此，其更加安全环保。
在本申请的一种实施例中，上述杂芳基硝基类化合物的结构通式为I或II：
Figure PCTCN2020124467-appb-000004
其中，n与m各自独立地为0或1，Y、Z各自独立地选自化学上可接受的CR 7、N、NR 8、O、S中的任意一种，且Y、Z中至少有一个为N、NR 8、O、S中的任意一种，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8各自独立地选自H、取代或非取代的C 1～C 20的烷基、取代或非取代的C 1～C 20的烷氧基、取代或非取代的C 6～C 20的芳基、卤素、酯基、羟基、酰胺基、硝基、-CF 3、-CHF 2中的一种。
符合上述结构通式I和II的杂芳基硝基类化合物在本申请的光催化还原反应条件下具有更好的反应效果，且在化工与医药领域的应用更具广泛性。
为进一步提高上述杂芳基硝基类化合物在本申请的光催化还原反应条件下的反应性，优选上述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8各自独立地选自取代或非取代的C 1～C 10的直链烷基、取代或非取代的C 3～C 10的支链烷基、取代或非取代的C 1～C 10的烷氧基、取代或非取代的C 6～C 10的芳基中的任意一种。
在本申请的一种实施例中，上述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8各自独立地选自甲氧基、-Cl、-CHF 2中的任意一种。
具有上述取代基团的杂芳基硝基类化合物，更有助于得到高产率和高实用性的相应杂芳基胺类化合物。
为进一步提高上述反应原料的溶解性，并提高反应的效率，优选上述溶剂选自C 1～C 6的醇或C 1～C 6的醇的水溶液，优选C 1～C 6的醇选自甲醇、乙醇、乙二醇、异丙醇、正丁醇、叔丁醇、环己醇中的一种或多种，优选C 1～C 6的醇的水溶液中醇与水的体积比为10:1～50:1。
在本申请的一种实施例中，上述光催化剂的活性成分为纳米二氧化钛，优选杂芳基硝基类化合物与纳米二氧化钛的质量比为1:1～1:5，优选纳米二氧化钛的粒径为15～200nm，优选为 30～60nm，进一步优选纳米二氧化钛选自金红石型纳米二氧化钛、锐钛矿型纳米二氧化钛、负载纳米二氧化钛的微球中的一种或多种。
上述优选的纳米二氧化钛催化剂的粒径、杂芳基硝基类化合物与纳米二氧化钛的质量比有助于进一步地提高光催化还原反应的效率。
为提高上述光催化还原反应的效率，优选在上述步骤S2中，光催化还原反应的温度为30～40℃，优选光催化还原反应的时间为2～15h，优选光照条件中的光波长为310～400nm，优选为340～385nm，优选光照条件的光源为LED灯或激光。
在本申请的一种实施例中，上述原料还包括助溶试剂，优选助溶试剂选自四氢呋喃、丙酮、乙酸乙酯、乙二醇、二乙二醇、聚乙二醇-400中的一种或多种。
硝基底物在异丙醇溶剂内溶解性较差，不利于反应的进一步放大与工业化应用，加入上述助溶试剂可在不影响反应进程的前体下，有助于进一步地提高反应原料在溶剂中的溶解度，降低溶剂的用量，并提高原料的反应效率。
在本申请的一种实施例中，上述原料还包括添加剂，优选添加剂选自三乙胺、三乙醇胺、亚硫酸钠、硫化钠、EDTA、甲酸、抗坏血酸中的一种或多种。
上述添加剂可与光催化剂进行配合，从而有利于促进光催化还原反应的进行，提高光催化还原反应的效率。催化剂在光照下产生光生空穴和电子，而空穴和电子容易自身发生结合，降低电子的效率，添加剂的加入可与光生空穴结合，延长光生电子寿命，提高反应速率；酸性底物优选用酸性添加剂，碱性底物优选用碱性添加剂。
本申请的一种实施例中，上述光化学合成方法还包括：将产物体系进行离心分离，得到清液和固体；将清液进行减压浓缩处理，得杂芳基胺类化合物和回收溶剂；将固体进行清洗、干燥以回收光催化剂；优选将回收溶剂返回步骤S1作为溶剂使用，优选将回收的光催化剂返回步骤S1作为光催化剂使用。
本申请通过上述方法将溶剂与纳米二氧化钛催化剂进行回收，并将其返回光催化还原反应循环使用，其中优选将回收的光催化剂返回步骤S1作为光催化剂使用1～10次。一方面减少了环境污染，另一方面降低了生产成本，提高了经济效益。
在本申请的一种实施例中，上述杂芳基胺类化合物的结构式为：
Figure PCTCN2020124467-appb-000005
Figure PCTCN2020124467-appb-000006
中的任意一种。
具有上述结构的杂芳基胺类化合物可以被广泛应用于化工领域以及医药领域。
以下将结合具体实施例，对本申请的有益效果进行说明。
实施例1
将2-甲氧基-5-硝基吡啶(0.1g，0.65mmol)溶解在异丙醇(10mL)中搅拌澄清后，加入0.5mL纯化水，随后加入0.5g粒径为30nm的金红石纳米二氧化钛，形成的混合液为白色悬浊液，搅拌0.5h后置于光化学反应器中，在温度为30℃下，以365nm的LED灯为光源照射6h，HPLC监测原料消失后停止光照得到产物体系，将产物体系置于离心机内进行离心分离，将上层有机相进行减压浓缩，柱层析得到红棕色液体2-甲氧基-5-氨基吡啶7.52g，其分离收率为93.4％，其核磁氢谱数据为： 1H-NMR(400MHz，CDCl 3)：δ3.39(br s,2H),3.84(s,3H),6.58(d,J＝8.8Hz,1H),7.01(d,J＝8.9Hz,1H),7.64(d,J＝2.4Hz,1H)。
实施例2
实施例2与实施例1的区别在于，加入0.1g粒径为30nm的金红石纳米二氧化钛，以365nm的LED灯为光源照射15h，上层有机相经减压浓缩柱层析得2-甲氧基-5-氨基吡啶63mg，其分离收率为78.2％。
实施例3
实施例3与实施例1的区别在于，加入0.2g粒径为30nm的金红石纳米二氧化钛，以365nm的LED灯为光源照射10h，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶68mg，其分离收率为85.2％。
实施例4
实施例4与实施例2的区别在于，加入0.05g粒径为30nm的金红石纳米二氧化钛，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶57mg，其分离收率为70.8％。
实施例5
实施例5与实施例1的区别在于，加入0.5g锐钛型纳米二氧化钛做催化剂，在温度为40℃下，以365nm LED灯为光源照射9h，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶70mg，其分离收率为86.7％。
实施例6
实施例6与实施例1的区别在于，金红石纳米二氧化钛的粒径为15nm，以365nm LED灯为光源照射6.5h，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-胺基吡啶73mg，其分离收率为90.2％。
实施例7
实施例7与实施例1的区别在于，金红石纳米二氧化钛的粒径为200nm，以365nm LED灯为光源照射6.5h，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶68mg，其分离收率为84.2％。
实施例8
实施例8与实施例1的区别在于，金红石纳米二氧化钛的粒径为45nm，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶75mg，其分离收率为93.2％。
实施例9
实施例9与实施例1的区别在于，金红石纳米二氧化钛的粒径为60nm，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶74m g，其分离收率为91.9％。
实施例10
实施例10与实施例1的区别在于，加入1.0mL纯化水，以365nm LED灯为光源照射8h，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶73mg，其分离收率为90.2％。
实施例11
实施例11与实施例1的区别在于，加入0.2mL纯化水，以365nm LED灯为光源照射8h，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶70mg，其分离收率为86.9％。
实施例12
实施例12与实施例1的区别在于，加入0.15mL纯化水，以365nm LED灯为光源照射8h，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶66mg，其分离收率为81.9％。
实施例13
实施例13与实施例10的区别在于，将2-甲氧基-5-硝基吡啶(0.1g，0.65mmol)溶解在10mL甲醇中，以365nm LED灯为光源照射2h，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶56mg，其分离收率为69.5％。
实施例14
实施例14与实施例10的区别在于，将2-甲氧基-5-硝基吡啶(0.1g，0.65mmol)溶解在10mL乙醇中，以365nm LED灯为光源照射3.5h，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶59mg，其分离收率为73.3％。
实施例15
实施例15与实施例10的区别在于，将2-甲氧基-5-硝基吡啶(0.1g，0.65mmol)溶解在10mL乙二醇中，以365nm LED灯为光源照射8h，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶61mg，其分离收率为75.4％。
实施例16
实施例16与实施例10的区别在于，将2-甲氧基-5-硝基吡啶(0.1g，0.65mmol)溶解在10mL叔丁醇中，以365nm LED灯为光源照射8h，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶69mg，其分离收率为86.1％。
实施例17
实施例17与实施例16的区别在于，加入0.2ml纯化水，HPLC显示产物体系中2-甲氧基-5-胺基吡啶的含量为89.8％，上层有机相经减压浓缩柱层析得红棕色液体2-甲氧基-5-氨基吡啶70mg，其分离收率为86.9％。
实施例18
实施例18与实施例2的区别在于，添加1mL三乙胺作为添加剂，以365nm LED灯为光源照射2h，将反应体系置于离心机内离心分离，上层有机相经减压浓缩后柱层析得红棕色液体2-甲氧基-5-氨基吡啶57mg，其分离收率为71.1％。
实施例19
实施例19与实施例18的区别在于，添加1mL三乙醇胺作为添加剂，以365nm LED灯为光源照射2.5h，将反应体系置于离心机内离心分离，上层有机相经减压浓缩后柱层析得红棕色液体2-甲氧基-5-氨基吡啶77mg，其分离收率为95.6％。
实施例20
将2-甲氧基-5-硝基吡啶(0.1g，0.65mmol)加至异丙醇和四氢呋喃混合溶剂(异丙醇：四氢呋喃＝5:5，10ml)中搅拌澄清后，加入0.5ml纯化水，随后加入0.5g金红石纳米二氧化钛做催化剂，体系为白色悬浊液，搅拌0.5h后置于光化学反应器中，以365nm LED灯为光 源照射6h，TLC或HPLC监测原料消失停止光照得到产物体系，将反应体系置于离心机内离心分离，上层有机相经减压浓缩后柱层析得红棕色液体70mg，分离收率为86.9％。
实施例21
将2-甲氧基-5-硝基吡啶(0.1g，0.65mmol)加至异丙醇和PEG-400混合溶剂(异丙醇：PEG-400＝5:5，10ml)中搅拌澄清后，加入0.5ml纯化水，随后加入0.5g金红石纳米二氧化钛做催化剂，体系为白色悬浊液，搅拌0.5h后置于光化学反应器中，以365nm LED灯为光源照射7.5h，TLC或HPLC监测原料消失停止光照得到产物体系，将反应体系置于离心机内离心分离，上层有机相经减压浓缩后柱层析得红棕色液体2-甲氧基-5-氨基吡啶66mg，分离收率为82.7％。
实施例22
实施例22与实施例1的区别在于，LED灯的波长为310nm，光照20h，上层有机相经减压浓缩后柱层析得红棕色液体2-甲氧基-5-氨基吡啶22.3mg，其分离收率为28％。
实施例23
实施例23与实施例1的区别在于，LED灯的波长为400nm，光照20h，上层有机相经减压浓缩后柱层析得红棕色液体2-甲氧基-5-氨基吡啶24mg，其分离收率为30％。
实施例24
实施例24与实施例1的区别在于，LED灯的波长为385nm，光照12h，上层有机相经减压浓缩后柱层析得红棕色液体2-甲氧基-5-氨基吡啶64mg，其分离收率为79.5％。
实施例25
实施例25与实施例1的区别在于，LED灯的波长为340nm，光照12h，上层有机相经减压浓缩后柱层析得红棕色液体2-甲氧基-5-氨基吡啶65.2mg，其分离收率为81％。
实施例26
实施例26与实施例1的区别在于，LED灯的波长为450nm，光照24h，上层有机相经减压浓缩后柱层析无2-甲氧基-5-氨基吡啶生成。
实施例27
将1-(二氟甲基)-4-硝基吡唑(1g，6.1mmol)溶解在异丙醇(100mL)中搅拌澄清后，加入5mL纯化水和10mL三乙醇胺，随后加入1g金红石纳米二氧化钛做催化剂，体系为白色悬浊液，搅拌0.5h后置于光化学反应器中，以365nm LED灯为光源照射6.5h，HPLC监测原料消失停止光照得到产物体系，将产物体系置于离心机内离心分离，上层有机相经减压浓缩，得1-(二氟甲基)-4-氨基吡唑656mg，其分离收率为80.4％。其核磁氢谱数据为： 1H-NMR(400MHz，CDCl 3)：δ7.31(s,2H)，7.05(t,J＝60Hz 1H)，3.30-2.94(hr,s,2H)。
实施例28
将2-氯-3-硝基吡啶(1g，6.3mmol)溶解在异丙醇(100mL)中搅拌澄清后，加入5mL纯化水和10mL三乙醇胺，随后加入1g金红石纳米二氧化钛做催化剂，体系为白色悬浊液，搅拌0.5h后置于光化学反应器中，以365nm LED灯为光源照射7.5h，TLC或HPLC监测原料消失停止光照得到产物体系，将产物体系置于离心机内离心分离，上层有机相经减压浓缩，得2-氯-3-氨基吡啶646mg，其分离收率为82.3％。其核磁氢谱数据为： 1H-NMR(400MHz，CDCl 3)：δ7.80(dd,J＝3.5,0.72Hz,1H)，7.06-7.02(m,2H)，4.09(s,2H)。
实施例29
将4,6-二氯-5-硝基嘧啶(1g，5.2mmol)溶解在异丙醇(100mL)中搅拌澄清后，加入5mL纯化水和10mL三乙醇胺，随后加入1g金红石纳米二氧化钛做催化剂，体系为白色悬浊液，搅拌0.5h后置于光化学反应器中，以365nm LED灯为光源照射5h，TLC或HPLC监测原料消失停止光照得到产物体系，将产物体系置于离心机内离心分离，上层有机相经减压浓缩，得4,6-二氯-5-氨基嘧啶732mg，分离收率为86.6％。其核磁氢谱数据为： 1H NMR(400MHz，CDCl3)：δ3.60(br s,2H)，8.21(s,1H)。
实施例30
实施例30与实施例18的区别在于，以365nm激光为光源照射3h，HPLC显示产物体系中2-甲氧基-5-氨基吡啶的含量为96.8％，上层有机相经减压浓缩得红棕色液体2-甲氧基-5-胺基吡啶73mg，其分离收率为90.7％。
实施例31
将3-硝基噻吩(1g，7.74mmol)溶解在异丙醇(100mL)中搅拌澄清后，加入10mL纯化水和10mL三乙醇胺，随后加入1g金红石纳米二氧化钛做催化剂，体系为白色悬浊液，搅拌0.5h后置于光化学反应器中，以365nm LED灯为光源照射7.5h，TLC或HPLC监测原料消失停止光照得到产物体系，将产物体系置于离心机内离心分离，上层有机相经减压浓缩，得3-氨基噻吩，614mg，其分离收率为80.1％。其核磁氢谱数据为： 1H NMR(400MHz，CDCl3)：δ4.50(br s,2H)，6.17(d J＝3.0Hz,1H),6.65(d J＝5.2Hz,1H),7.13(d J＝5.2Hz,1H)。
实施例32
将2-((2,6-二氯-5-硝基嘧啶-4-基)氧基)苯甲酸乙酯(1g，2.79mmol)溶解在异丙醇(100mL)中搅拌澄清后，加入10mL纯化水和10mL三乙醇胺，随后加入1g金红石纳米二氧化钛做催化剂，体系为白色悬浊液，搅拌0.5h后置于光化学反应器中，以365nm LED灯为光源照射2h，TLC或HPLC监测原料消失停止光照得到产物体系，将产物体系置于离心机内离心分离，上层有机相经减压浓缩，得2-((2,6-二氯-5-氨基嘧啶-4-基)氧基)苯甲酸乙酯970mg，其分离收率为95％。其核磁氢谱数据为： 1H NMR(300MHz,acetone-d6):δ＝8.12(d,J＝7.6Hz, 1H),7.81(dd,J＝7.2Hz,1H),7.57(dd,J＝7.7Hz,1H),7.46(d,J＝8.4Hz,1H),4.24(q,J＝6.9Hz,2H),1.20(t,J＝6.9Hz,3H)。
实施例33
将2-甲氧基-5-硝基嘧啶(1g，6.45mmol)溶解在异丙醇(100mL)中搅拌澄清后，加入10mL纯化水和10mL三乙醇胺，随后加入1g金红石纳米二氧化钛做催化剂，体系为白色悬浊液，搅拌0.5h后置于光化学反应器中，以365nm LED灯为光源照射5.5h，TLC或HPLC监测原料消失停止光照得到产物体系，将产物体系置于离心机内离心分离，上层有机相经减压浓缩，得2-甲氧基-5-氨基嘧啶716mg，其分离收率为88.8％。其核磁氢谱数据为： 1H NMR(400MHz,DMSO-d6)δ8.05(s,2H),3.94(s,3H)。
实施例34
将N-(5-硝基嘧啶-2-基)乙酰胺(1g，5.49mmol)溶解在异丙醇(100mL)中搅拌澄清后，加入10mL纯化水和10mL三乙醇胺，随后加入1g金红石纳米二氧化钛做催化剂，体系为白色悬浊液，搅拌0.5h后置于光化学反应器中，以365nm LED灯为光源照射6.5h，TLC或HPLC监测原料消失停止光照得到产物体系，将产物体系置于离心机内离心分离，上层有机相经减压浓缩，得N-(5-氨基嘧啶-2-基)乙酰胺705mg，其分离收率为84.4％。其核磁氢谱数据为： 1H NMR(400MHz,DMSO-d6)δ2.03(s,3H),2.86(br s,1H)，5.28(s,2H),7.99(s,2H)。
实施例35
将2,4-二氯-6-甲基-5-硝基嘧啶(1g，4.8mmol)溶解在异丙醇(100mL)中搅拌澄清后，加入10mL纯化水和10mL三乙醇胺，随后加入1g金红石纳米二氧化钛做催化剂，体系为白色悬浊液，搅拌0.5h后置于光化学反应器中，以365nm LED灯为光源照射6.5h，TLC或HPLC监测原料消失停止光照得到产物体系，将产物体系置于离心机内离心分离，上层有机相经减压浓缩，得2,4-二氯-6-甲基嘧啶-5-胺735mg，其分离收率为86％。其核磁氢谱数据为： 1H NMR(CDCl 3):δ2.32(s,3H,CH 3),6.08(s,2H,NH 2,D 2O exchangeable)。
回收上述实施例中的催化剂，并重复用于上述催化反应，随着回收的催化剂重复利用次数的增加，其催化活性有所下降，但重复利用回收的催化剂可以使催化剂的利用最大化，并降低三废量和生产成本。
以下为利用回收催化剂的实施例：
将2-甲氧基-5-硝基吡啶(20g，130mmol)溶解在异丙醇(2000mL)中搅拌澄清后，加入100mL纯化水和200mL三乙醇胺添加剂，随后加入20g回收的金红石纳米二氧化钛做催化剂，体系为白色悬浊液，搅拌0.5h后置于光化学反应器中，以365nm LED灯为光源照射4h，HPLC监测原料消失停止光照得到产物体系。催化剂重复回收并利用10次，回收利用催化剂的具体反应条件如本实施例，10次光照反应IPC(HPLC含量)及杂芳胺类化合物的分离收率数据见下表1。
表1
Figure PCTCN2020124467-appb-000007
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：
本申请的上述光化学合成方法通过使用光催化剂，在光照条件下，催化剂表面会形成光生空穴和光生电子，其中的光生电子与水作用可生成活泼氢进而进一步还原硝基；即在光照条件下实现对各种不同的杂芳基硝基类化合物的光催化还原，获得了较高产率的杂芳基胺类化合物。光催化剂为现有常用的催化剂，其对设备没有严格要求，易于回收，降低了杂芳基胺类化合物的安全风险和催化剂成本。该光催化的整个反应过程无需加入任何金属试剂和还原剂，且反应的转化率较高，后处理简单易操作，因此，其更加安全环保。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (15)

  1. 一种杂芳基胺类化合物的光化学合成方法，其特征在于，所述光化学合成方法包括：
    步骤S1，将包括杂芳基硝基类化合物、溶剂、光催化剂的原料进行混合，得到混合物；
    步骤S2，将所述混合物在光照条件下进行光催化还原反应，得到含所述杂芳基胺类化合物的产物体系。
  2. 根据权利要求1所述的光化学合成方法，其特征在于，所述杂芳基硝基类化合物的结构通式为I或II：
    Figure PCTCN2020124467-appb-100001
    其中，n与m各自独立地为0或1，Y、Z各自独立地选自化学上可接受的CR 7、N、NR 8、O、S中的任意一种，且Y、Z中至少有一个为N、NR 8、O、S中的任意一种，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8各自独立地选自H、取代或非取代的C 1～C 20的烷基、取代或非取代的C 1～C 20的烷氧基、取代或非取代的C 6～C 20的芳基、卤素、酯基、羟基、酰胺基、硝基、-CF 3、-CHF 2中的一种，优选所述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8各自独立地选自取代或非取代的C 1～C 10的直链烷基、取代或非取代的C 3～C 10的支链烷基、取代或非取代的C 1～C 10的烷氧基、取代或非取代的C 6～C 10的芳基中的任意一种，更优选所述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8各自独立地选自甲氧基、-Cl、-CHF 2中的任意一种。
  3. 根据权利要求1所述的光化学合成方法，其特征在于，所述溶剂选自C 1～C 6的醇或C 1～C 6的醇的水溶液，优选所述C 1～C 6的醇选自甲醇、乙醇、乙二醇、异丙醇、正丁醇、叔丁醇、环己醇中的一种或多种，优选所述C 1～C 6的醇的水溶液中醇与水的体积比为10:1～50:1。
  4. 根据权利要求1所述的光化学合成方法，其特征在于，所述光催化剂的活性成分为纳米二氧化钛，优选所述纳米二氧化钛的粒径为15～200nm，更优选所述纳米二氧化钛的粒径为30～60nm，优选所述纳米二氧化钛选自金红石型纳米二氧化钛、锐钛矿型纳米二氧化钛、负载纳米二氧化钛的微球中的一种或多种。
  5. 根据权利要求4所述的光化学合成方法，其特征在于，所述杂芳基硝基类化合物与所述纳米二氧化钛的质量比为1:1～1:5。
  6. 根据权利要求1所述的光化学合成方法，其特征在于，在所述步骤S2中，所述光催化还原反应的温度为30～40℃。
  7. 根据权利要求1所述的光化学合成方法，其特征在于，所述光催化还原反应的时间为2～15h。
  8. 根据权利要求1所述的光化学合成方法，其特征在于，所述光照条件中的光波长为310～400nm，优选所述光照条件中的光波长为340～385nm。
  9. 根据权利要求1所述的光化学合成方法，其特征在于，所述光照条件的光源为LED灯或激光。
  10. 根据权利要求1至9中任一项所述的光化学合成方法，其特征在于，所述原料还包括助溶试剂，优选所述助溶试剂选自四氢呋喃、丙酮、乙酸乙酯、聚乙二醇-400中的一种或多种。
  11. 根据权利要求1至9中任一项所述的光化学合成方法，其特征在于，所述原料还包括添加剂，优选所述添加剂选自三乙胺、三乙醇胺、亚硫酸钠、硫化钠、EDTA、甲酸、抗坏血酸中的一种或多种。
  12. 根据权利要求1所述的光化学合成方法，其特征在于，所述光化学合成方法还包括：
    将所述产物体系进行离心分离，得到清液和固体；
    将所述清液进行减压浓缩处理，得杂芳基胺类化合物和回收溶剂；
    将所述固体进行清洗、干燥以回收光催化剂。
  13. 根据权利要求12所述的光化学合成方法，其特征在于，将所述回收溶剂返回所述步骤S1作为所述溶剂使用。
  14. 根据权利要求12所述的光化学合成方法，其特征在于，将回收的所述光催化剂返回所述步骤S1作为所述光催化剂使用。
  15. 根据权利要求1所述的光化学合成方法，其特征在于，所述杂芳基胺类化合物的结构式为：
    Figure PCTCN2020124467-appb-100002
    Figure PCTCN2020124467-appb-100003
    中的任意一种。
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