Method for preparing deuterated azaarene through heterogeneous photocatalytic hydrogen-deuterium exchange

Abstract

The invention discloses a method for preparing deuterated aza-arene by heterogeneous photocatalytic hydrogen-deuterium exchange, which comprises the following steps: by taking an aza-arene compound as a substrate and an inorganic semiconductor nanomaterial loaded with metal Pd as a photocatalyst, adding a deuterium source, introducing argon for protection, stirring and reacting under the conditions of room temperature and visible light illumination, and synthesizing the deuterated aza-arene. The invention provides a method for preparing deuterated aza-aromatic hydrocarbon by heterogeneous photocatalysis hydrogen-deuterium exchange, which can realize direct hydrogen-deuterium exchange reaction of a series of aza-aromatic hydrocarbon molecules under the driving of visible light at room temperature and normal pressure by taking relatively cheap D2O as a deuterium source, avoids harsh reaction conditions of high temperature and high pressure, is simple and feasible, has mild conditions, and is suitable for industrial production. The method is safe to operate, simple in product separation and easy to realize large-scale production, and provides possibility for large-scale production of deuterated chemicals.

Description

Technical Field

[0001] The invention relates to a method for preparing deuterated nitrogen heteroaromatics by heterogeneous photocatalytic hydrogen-deuterium exchange, belonging to the technical field of photocatalytic organic conversion. Background Art

[0002] Deuterated compounds, as a class of high value-added compounds, have a wide range of applications in organic synthesis, mechanism research, drug metabolism, drug modification and material science. In recent years, the development of new mild, efficient and universal deuteration methods has attracted much attention from chemists. In specific applications, practical and site-selective deuteration is very desirable. The deuteration methods currently developed are mainly divided into three types: hydrogen isotope exchange (HIE), reductive deuteration and dehalogenation; among these three methods, hydrogen isotope exchange reactions allow direct incorporation of deuterium without pre-functionalization of the starting material or substantial changes in the structure of the molecule, which has aroused considerable research interest among researchers.

[0003] Nitrogen-containing heterocycles are the core structures for building bioactive molecules. Among the latest FDA-approved small molecule drugs, 82% of them contain at least one nitrogen-containing heterocycle. Therefore, developing deuterated methods for nitrogen heteroaromatics may have greater potential for drug application research. So far, heterogeneous and homogeneous noble metal catalysts have helped to label nitrogen heteroaromatics by HIE. In these methods, harsh reaction conditions such as high temperature (≥120°C) and high pressure (≥10bar H2 / D2), expensive deuterium sources (D2, C6D6, CD3OD, DMSO-d6, etc.) and complex metal complex catalysts are more common strategies. In addition, there are methods that use stoichiometric strong bases such as sodium hydroxide and potassium tert-butoxide to promote the reaction. These situations may lead to poor functional group tolerance and safety risks, especially in larger scales. Therefore, the existing technology needs to be improved and developed. Summary of the invention

[0004] The purpose of the present invention is to provide a method for preparing deuterated nitrogen heteroaromatics by heterogeneous photocatalytic hydrogen-deuterium exchange.

[0005] The technical solution adopted by the present invention is:

[0006] A method for preparing deuterated nitrogen heteroaromatics by heterogeneous photocatalytic hydrogen-deuterium exchange, using nitrogen heteroaromatic compounds as substrates, using inorganic semiconductor nanomaterials loaded with metal Pd as photocatalysts, adding a deuterium source, passing argon gas for protection, stirring the reaction at room temperature and visible light illumination conditions, and synthesizing deuterated nitrogen heteroaromatics. The reaction formula is shown below:

[0007]

[0008] For substrates with poor solubility, one of the organic solvents acetone, isopropanol, and acetonitrile can be added as a co-solvent to complete the reaction faster.

[0009] Preferably, the inorganic semiconductor nanomaterial is TiO2, and the loading rate of Pd is 0.5wt.% to 2.0wt.%.

[0010] Preferably, the wavelength of the light source used for illumination is 365 to 600 nm, more preferably 365 to 410 nm.

[0011] Preferably, the wavelength of the light source used for illumination is 410 nm.

[0012] Preferably, the preparation method of the inorganic semiconductor nanomaterial is: tetrabutyl titanate and anhydrous ethanol are stirred and mixed evenly, then deionized water is added dropwise until a large amount of white precipitate is precipitated, and then stirred at room temperature for a period of time. The obtained white precipitate is dried after centrifugation and calcined at 400-550°C in an air atmosphere to obtain TiO2 powder.

[0013] Preferably, the volume ratio of tetrabutyl titanate to anhydrous ethanol is 1:5.

[0014] Preferably, the method for loading metal Pd adopts one of the photodeposition reduction method, chemical reduction method, and calcination reduction method. For example, take TiO2, add K2PdCl4 and deionized water, carry out photodeposition loading in an argon atmosphere under 410nm visible light illumination conditions, and then centrifuge and dry to obtain a photocatalyst Pd / TiO2.

[0015] Preferably, the azaaromatic compounds include aminopyrimidine and its derivatives, N-methylpyrrole and its derivatives, pyrazine and its derivatives, doxofylline or ribavirin.

[0016] Preferably, the mass ratio of the added amount of the photocatalyst to the deuterium source is above 1:40; the deuterium source is D2O.

[0017] Preferably, the synthesis reaction is directly centrifuged after completion, and the supernatant is rotary evaporated to obtain deuterated nitrogen heteroaromatic hydrocarbons without the need for column chromatography separation and purification.

[0018] The principle of the present invention is as follows: first, the nitrogen heteroaromatic compounds are coordinated and complexed with metal Pd, then visible light is irradiated on the surface of the semiconductor material to generate electrons and holes, and after the metal Pd obtains the electrons, it undergoes oxidative addition with the nitrogen heteroaromatics, and then further undergoes hydrogen-deuterium exchange with heavy water, and finally undergoes reduction elimination to obtain a deuterated product with high selectivity.

[0019] The preparation method of the present invention has the following advantages and beneficial effects:

[0020] (1) The synthesis method of the present invention is the first example of heterogeneous photocatalysis for direct hydrogen-deuterium exchange of nitrogen-arene, and is highly innovative;

[0021] (2) The synthesis method of the present invention uses relatively cheap D2O as a deuterium source, avoiding the use of expensive deuterium sources such as D2, has high economic value, and D2O can be recycled;

[0022] (3) The synthesis method of the present invention is carried out at room temperature and normal pressure, which solves the defects of the existing HIE reaction that requires high temperature, high pressure, expensive deuterium source and complex metal complex catalyst. The method is simple and easy to operate, with mild conditions, safe operation, simple product separation and can be easily scaled up, providing the possibility for large-scale production of deuterated chemicals;

[0023] (4) The catalyst has high selectivity, is easy to obtain, has good stability, and can be reused. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the X-ray diffraction data (XRD) of TiO2 and the photocatalyst in Example 1 of the present invention.

[0025] Figure 2 This is a scanning electron microscope (SEM) image of TiO2 and the photocatalyst in Example 1 of the present invention, wherein A: TiO2; B: Pd / TiO2.

[0026] Figure 3 The transmission electron microscope and elemental analysis (STEM-EDS elemental mapping) picture of the photocatalyst in Example 1 of the present invention.

[0027] Figure 4 This is a performance diagram of Example 2 of the present invention under different photocatalysts (different precious metals and carriers).

[0028] Figure 5 This is a performance diagram of the photocatalyst in Example 2 of the present invention under different light wavelengths.

[0029] Figure 6 This is a performance diagram of the photocatalyst in Example 2 of the present invention at different reaction times.

[0030] Figure 7 This is a performance diagram of the photocatalyst containing different metal Pd loadings in Example 2 of the present invention.

[0031] Figure 8 This is a physical picture of the 250 mL photoreactor used in Example 7 of the present invention, wherein A: 250 mL Shrek bottle; B: 250 mL homemade photoreactor.

[0032] Fig. 9The NMR hydrogen spectrum of the raw material in Example 2 of the present invention ( 1 1H NMR).

[0033] Fig.10 The H NMR spectrum of the product in Example 2 of the present invention ( 1 1H NMR).

[0034] Fig.11 The NMR hydrogen spectrum of the raw material in Example 3 of the present invention ( 1 1H NMR).

[0035] Fig.12 The H NMR spectrum of the product in Example 3 of the present invention is ( 1 1H NMR).

[0036] Fig.13 The NMR hydrogen spectrum of the raw material in Example 4 of the present invention ( 1 1H NMR).

[0037] Fig.14 The H NMR spectrum of the product in Example 4 of the present invention ( 1 1H NMR).

[0038] Fig.15 The NMR hydrogen spectrum of the raw material in Example 5 of the present invention ( 1 1H NMR).

[0039] Fig.16 The H NMR spectrum of the product in Example 5 of the present invention is ( 1 1H NMR).

[0040] Fig.17 The NMR hydrogen spectrum of the raw material in Example 6 of the present invention ( 1 1H NMR).

[0041] Fig.18 The H NMR spectrum of the product in Example 6 of the present invention ( 1 1H NMR). DETAILED DESCRIPTION

[0042] The present invention is further illustrated by examples below, but is not intended to be limiting of the present invention. The specific materials used in the embodiments of the present invention and their sources are provided below. However, it should be understood that these are merely exemplary and are not intended to limit the present invention, and materials identical or similar to the types, models, qualities, properties or functions of the following reagents and instruments can be used to implement the present invention. The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial sources.

[0043] Example 1: Preparation of photocatalyst

[0044] 1. Preparation of TiO2:

[0045] (1) Tetrabutyl titanate and anhydrous ethanol were stirred and mixed in a volume ratio of 1:5, and then deionized water was added dropwise until a large amount of white precipitate was precipitated, and then stirred at room temperature for 1 hour;

[0046] (2) The white precipitate obtained in step (1) is centrifuged and then dried, and the temperature is increased to 500° C. at 10° C. / min in a muffle furnace under air atmosphere and kept at this temperature for 2 h to obtain white powder TiO2.

[0047] 2. Preparation of Pd / TiO2:

[0048] Take an appropriate amount of TiO2 obtained in the above steps, add K2PdCl4 and deionized water, irradiate the reaction solution with 410nm wavelength visible light for photodeposition loading at room temperature and in an argon atmosphere, and after the reaction solution turns gray-brown, centrifuge and dry it to obtain the photocatalyst Pd / TiO2. The obtained TiO2 and Pd / TiO2 are subjected to X-ray diffraction analysis, electron microscopy scanning, transmission electron microscopy and elemental analysis. The results are as follows: Figure 1-3 shown.

[0049] The photocatalysts containing different precious metals and carriers were also prepared by the photodeposition method in Example 1.

[0050] Example 2: Preparation of deuterated 2-aminopyrimidine (2-aminopyrimidine-d2)

[0051]

[0052] In a cillin bottle equipped with a stirring magnet, 0.1mmol (9.5mg) of 2-aminopyrimidine, 50mg of photocatalyst (0.5wt.% Pd / TiO2) and 2mL of D2O were added; it was placed in a stainless steel reactor with a glass lens on top, flushed with argon for 3-5 times, and then stirred for reaction for 24h under irradiation of a 410nm wavelength LED light. The reaction solution was transferred to a 10mL centrifuge tube and centrifuged to obtain a supernatant, which could be directly subjected to nuclear magnetic resonance detection, and the deuterium substitution rate was measured to be 99%.

[0053] The H NMR spectrum of the raw material is Fig. 9 Shown: 1 H NMR (400MHz, D2O) δ8.30 (d, J = 8Hz, 2H), 6.50 (t, J = 8Hz, 1H).

[0054] The H NMR spectrum of the product is Fig.10 Shown: 1H NMR (400MHz, D2O) δ8.30 (d, J = 4Hz, 0.02H), 6.78 (s, 1H).

[0055] When Example 2 is used as a model reaction, different noble metals (Pt, Ru, Rh, Ir, Au, Ni, Cu) are changed while other conditions remain unchanged, or inorganic semiconductor nanocarriers (commercial TiO2 (P25), In2O3, Nb2O5, SrTiO3, SiC, BiOCl, BiVO4, Bi2WO6) are changed while other conditions remain unchanged, the deuteration rate is as follows: Figure 4 shown.

[0056] When Example 2 is used as a model reaction, the deuterium substitution rate is as follows when the wavelength of light (365-600 nm) is changed while other conditions remain unchanged: Figure 5 shown.

[0057] When Example 2 is used as a model reaction, the reaction time (0-24h) is changed under the condition that other conditions remain unchanged, and the deuteration rate is as follows: Figure 6 It can be seen that the preferred reaction time is more than 8 hours, at which time the deuteration rate can reach more than 84%, and the more preferred reaction time is more than 16 hours, at which time the deuteration rate can reach more than 94%.

[0058] When Example 2 is used as a model reaction, the metal Pd loading (0-2.0%) is changed under the same other conditions, and the deuteration rate is as follows: Figure 7 shown.

[0059] Example 3: Preparation of deuterated N-methylpyrrole (N-Methyl pyrrole-d4)

[0060]

[0061] In a cillin bottle equipped with a stirring magnet, 0.1mmol (8.1mg) of N-methylpyrrole, 50mg of photocatalyst (0.5wt.% Pd / TiO2) and 2mL of D2O were added; the reaction vessel was placed in a stainless steel reactor with a glass lens on top, flushed with argon for 3-5 times, and then stirred for reaction for 24h under irradiation of a 410nm wavelength LED lamp. The reaction solution was transferred to a 10mL centrifuge tube and centrifuged to obtain a supernatant, which could be directly subjected to nuclear magnetic resonance detection, and the deuteration rates were measured to be 95% and 93%, respectively.

[0062] The H NMR spectrum of the raw material is Fig.11 Shown: 1 H NMR (400MHz, D2O) δ6.76 (t, J = 4Hz, 2H), 6.17 (t, J = 4Hz, 2H), 3.66 (s, 3H).

[0063] The H NMR spectrum of the product is Fig.12 Shown: 1 H NMR (400MHz, D2O) δ6.76 (s, 0.10H), 6.16 (s, 0.12H), 3.66 (s, 3H).

[0064] Example 4: Preparation of deuterated pyrazine (Pyrazine-d4)

[0065]

[0066] In a penicillin bottle equipped with a stirring magnet, 0.1mmol (8.0mg) of pyrazine, 50mg of photocatalyst (1.0wt.% Pd / TiO2) and 2mL of D2O were added; it was placed in a stainless steel reactor with a glass lens on top, flushed with argon for 3-5 times, and then stirred for reaction for 48h under irradiation of a 410nm wavelength LED light. The reaction solution was transferred to a 10mL centrifuge tube and centrifuged to obtain a supernatant, which could be directly subjected to nuclear magnetic resonance detection, and the deuteration rate was measured to be 98% (with 1,4-Dioxane as an internal standard).

[0067] The H NMR spectrum of the raw material is Fig.13 Shown: 1 H NMR(400MHz,D2O)δ8.62(s,4H).

[0068] The H NMR spectrum of the product is Fig.14 Shown: 1 H NMR(400MHz,D2O)δ8.62(s,0.09H).

[0069] Example 5: Preparation of deuterated doxofylline (Doxofylline-d1)

[0070]

[0071] 0.1 mmol (26.6 mg) of doxofylline, 50 mg of photocatalyst (0.5 wt.% Pd / TiO2) and 2 mL of D2O were added to a cillin bottle equipped with a stirring magnet; the flask was placed in a stainless steel reactor with a glass lens on top, flushed with argon for 3-5 times, and then stirred for reaction for 24 hours under irradiation of a 410 nm wavelength LED lamp, and the reaction solution was transferred to a 10 mL centrifuge tube and centrifuged to obtain a supernatant, which could be directly subjected to nuclear magnetic resonance detection, and the deuterium substitution rate was measured to be 99%.

[0072] The H NMR spectrum of the raw material is Fig.15 Shown: 1H NMR (400MHz, D2O) δ8.00 (s, 1H), 5.34 (t, J = 4Hz, 1H), 4.60 (d, J = 4Hz, 2H), 3.92–3.89 (m, 2H), 3.78–3.74 (m, 2H), 3.53 (s, 3H), 3.34 (s, 3H).

[0073] The H NMR spectrum of the product is Fig.16 Shown: 1 H NMR (400MHz, D2O) δ7.98 (s, 0.00H), 5.32 (t, J = 4Hz, 1H), 4.58 (d, J = 4Hz, 2H), 3.91–3.87 (m, 2H), 3.76–3.73 (m, 2H), 3.51 (s, 3H), 3.32 (s, 3H).

[0074] Example 6: Preparation of deuterated ribavirin (Ribavirin-d1)

[0075]

[0076] In a penicillin bottle equipped with a stirring magnet, 0.1mmol (24.4mg) of ribavirin, 50mg of photocatalyst (0.5wt.% Pd / TiO2) and 2mL of D2O were added; it was placed in a stainless steel reactor with a glass lens on top, flushed with argon for 3-5 times, and then stirred for reaction for 24h under irradiation of a 410nm wavelength LED light. The reaction solution was transferred to a 10mL centrifuge tube and centrifuged to obtain a supernatant, which could be directly subjected to nuclear magnetic resonance detection, and the deuterium substitution rate was measured to be 88%.

[0077] The H NMR spectrum of the raw material is Fig.17 Shown: 1 H NMR(400MHz,D2O)δ8.76(s,1H),6.08(d,J=4Hz,1H),4.67(dd,J=8,4Hz,1H),4.51(t, J=4Hz,1H),4.24(td,J=8,4Hz,1H),3.89(dd,J=12,4Hz,1H),3.78(dd,J=16,8Hz,1H).

[0078] The H NMR spectrum of the product is Fig.18 Shown: 1H NMR(400MHz,D2O)δ8.78(s,0.11H),6.10(d,J=4Hz,1H),4.69(dd,J=8,4Hz,1H),4.53(t ,J=8Hz,1H),4.26(td,J=8,4Hz,1H),3.91(dd,J=12,8Hz,1H),3.80(dd,J=12,8Hz,1H).

[0079] Example 7: Recycling and amplification of D2O

[0080]

[0081] By using a self-built 250 mL glass photoreactor ( Figure 8 ), the reaction can be easily amplified 1580 times (from 0.1mmol to 158mmol), and the deuteration rate of the obtained product is 95%. Then the reaction solution is centrifuged, the catalyst precipitate is washed with deionized water and dried for the next round of reaction, and the reaction solution is evaporated to remove D2O to obtain a solid product; the catalyst and D2O recovered in the previous round can be used in the second round of reaction, and the deuteration rate of the obtained product is 91%; considering that the D content in D2O decreases as the reaction proceeds, in the third round, the amplification factor is reduced to 1050 times, and the deuterated product can be obtained with a deuteration rate of 90%. Therefore, we use 150mL D2O (8276mmol) to achieve the deuteration of 40g reactants (421mmol), and the average deuteration rate is >90%.

[0082] In summary, the present invention provides a method for preparing deuterated nitrogen-arene by heterogeneous photocatalytic hydrogen-deuterium exchange, which can realize direct hydrogen-deuterium exchange reactions of a series of nitrogen-arene molecules at room temperature and normal pressure using relatively cheap D2O as a deuterium source and driven by visible light, thus avoiding the harsh reaction conditions of high temperature and high pressure. The method is simple and easy, the conditions are mild, the operation is safe, the product separation is simple, and scale-up production can be easily achieved, thus providing the possibility for large-scale production of deuterated chemicals.

Claims

1. A method for preparing deuterated nitrogen aromatics by heterogeneous photocatalytic hydrogen-deuterium exchange, characterized in that: Using nitrogen heteroaromatic compounds as substrates and inorganic semiconductor nanomaterials loaded with metal Pd as photocatalysts, adding a deuterium source, introducing argon gas for protection, stirring and reacting at room temperature and visible light irradiation conditions, deuterated nitrogen heteroaromatics are synthesized. The reaction formula is shown below:

2. The method according to claim 1, characterized in that: The inorganic semiconductor nanomaterial is TiO2, and the loading rate of Pd is 0.5wt.% to 2.0wt.%.

3. The method according to claim 2, characterized in that: The wavelength of the light source used for illumination is 365-600nm.

4. The method according to claim 3, characterized in that: The wavelength of the light source used for illumination is 410nm.

5. The method according to any one of claims 2 to 4, characterized in that: The preparation method of inorganic semiconductor nanomaterials is as follows: tetrabutyl titanate and anhydrous ethanol are stirred and mixed evenly, and then deionized water is added dropwise until a large amount of white precipitate is precipitated, and then stirred at room temperature for a period of time. The obtained white precipitate is dried after centrifugation, and calcined at 400-550°C in an air atmosphere to obtain TiO2 powder.

6. The method according to claim 5, characterized in that: The volume ratio of tetrabutyl titanate to anhydrous ethanol is 1:

5.

7. The method according to claim 5, characterized in that: The method for loading metal Pd is one of a photodeposition reduction method, a chemical reduction method, and a calcination reduction method.

8. The method according to any one of claims 1 to 4, characterized in that: The azaaromatic compounds include aminopyrimidine and its derivatives, N-methylpyrrole and its derivatives, pyrazine and its derivatives, doxofylline or ribavirin.

9. The method according to any one of claims 1 to 4, characterized in that: The mass ratio of the added amount of the photocatalyst to the deuterium source is above 1:40; the deuterium source is D2O.

10. The method according to any one of claims 1 to 4, characterized in that: After the synthesis reaction is completed, the mixture is directly centrifuged and the supernatant is rotary evaporated to obtain deuterated nitrogen aromatics.

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