Preparation method of deuterated furan
By using sodium hydride catalyst and DMSO-d6 deuterium source, deuterated reaction is carried out under normal pressure, the problems of expensive catalysts and complex post-treatment in the prior art are solved, and the efficient all deuterated furan is achieved, with good operability and commercial prospects.
Patent Information
- Application Number
- CN202411597427.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-11
- Publication Date
- 2025-03-04
AI Technical Summary
The existing deuterated furan preparation methods rely on transition metal catalysis, which have disadvantages such as expensive catalysts, residual drug metals, complex post-treatment procedures, and difficult to amplify production.
Sodium hydride is used as the catalyst and DMSO-d6 as the deuterium source, and deuterated reaction is carried out under normal pressure system. The reaction conditions are 25-80°C and the reaction time is 12 hours.
The total deuterated furan is achieved, with small catalyst usage, simple reaction operation, high deuteratedness and yield, simple separation, safe, green and cheap, and is suitable for deuterated fusion of a variety of furan compounds.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of deuterated synthesis, and in particular to a method for preparing deuterated furan. Background Art
[0002] Among all the aromatic heterocycles, furan is undoubtedly still the most valuable and widely used intermediate. Furan is the most prominent class of heterocyclic compounds, is the molecular skeleton of many natural drugs, and is also a commercially important drug skeleton. Furan drugs (furans) were used as chemotherapeutic drugs in the early 1940s. They can act on the enzyme system of bacteria, interfere with the sugar metabolism of bacteria and have antibacterial effects. There are more than 10 furan drugs in use, and the more commonly used ones are furantoin, furazolidone, etc. In addition, furan substances are also considered to be important synthetic intermediates for the preparation of many cyclic and acyclic compounds. Substituted furans and their derivatives are important chemical intermediates derived from biomass, which can be hydrogenated into various special chemicals, solvents and alternative fuels. In particular, two hemicellulose and cellulose-derived molecules, 2-methylfuran and 2,5-dimethylfuran, have very promising physical and chemical properties for use as alternative fuels. Generally, the aromatic furan ring is hydrogenated and opened by hydrogenolysis, which can be further converted into valuable chemicals such as substituted tetrahydrofurans (THF), mixtures of ketones and alcohols.
[0003] Deuterated furan compounds have significant commercial value due to their wide application in different fields. They play an important role in drug development, material science, catalyst development, and medical imaging. The introduction of deuterated technology not only improves the performance of compounds, but also creates new market opportunities for the pharmaceutical, chemical, electronic, and medical industries. Deuterated-2,5-dimethylfuran is mainly used in drug metabolism and toxicology research. As a stable isotope labeled compound, it is used to analyze the metabolic pathways of drugs and help determine the metabolites and mechanisms of action of drugs in the human body. Deuterated furan-3-methanol is used to explore the metabolic transformation of drugs, especially in the study of the metabolic pathways of anticancer drugs. It can help researchers track the distribution and degradation of drugs in cells and tissues, and analyze the effects of their metabolites on cells. In addition, it can improve the accuracy and safety of anticancer drug development and help pharmaceutical companies develop more targeted treatment plans. Deuterated furan-3-carboxylic acid is mainly used in the development of organic electronic materials, especially organic solar cells and OLED materials. Because deuteration helps to improve the stability of materials, it can provide longer life and higher efficiency in electronic materials. The use of these deuterated compounds in organic solar cells and OLED display technology can help electronics companies develop longer-lasting and more efficient products. This property brings important commercial value to the development of a new generation of green energy devices and displays.
[0004] At present, there are not many studies on the deuteration of furan and its derivatives. Most of them are prepared by catalyzing hydrogen-deuterium exchange with metal catalysts. The catalysts mainly include iron, palladium, iridium, nickel, etc. Paul J. Chirik et al. described an iron-catalyzed method, using deuterium gas as a deuterium source to directly isotope-label heterocyclic drugs such as furan through hydrogen isotope exchange (Nature 529, 195–199 (2016)). Thomas et al. metallated heteroaromatic C–H with iron (II) hydride species, and used non-reducing CD3OD as a deuterium source to achieve α-selective deuteration of electron-rich furan under photocatalytic conditions (Chem. Sci., 2022, 13, 1 0 2 9 1). Kyoko Nozaki et al. independently designed a cyclopentadienone iridium complex, which showed certain activity for the cleavage of CH bonds. Based on this, the authors used deuterated benzene as a deuterium source to achieve the deuteration of heterocyclic compounds such as furan at 80°C (J.Am.Chem.Soc.2021,143,12999-13004). Van Gemmeren developed a multi-substrate screening method to determine the optimal reaction conditions for furan from a minimum number of screening reactions, and finally completed the unguided full deuteration of furan using metal palladium as a catalyst, deuterated HFIP and D2O as a deuterium source, with a deuteration degree of up to 99% (Angew.Chem.Int.Ed.2024,63,e202404421). The furan deuteration methods currently reported mainly rely on transition metal catalysis, and no other methods have been reported. These metal catalysis have the disadvantages of expensive catalysts, drug metal residues, complex post-processing processes, and difficulty in scale-up production. Summary of the invention
[0005] The object of the present invention is to provide a method for preparing deuterated furan, which can use a lower catalyst dosage to achieve full deuteration of furan.
[0006] The technical solution adopted by the present invention to solve the technical problem is: A method for preparing deuterated furan, The furan substance shown in formula I is used as a raw material, and a deuterium source reagent undergoes a deuteration reaction under a normal pressure system and in the presence of a catalyst. The reaction product is separated and purified to obtain a deuterated product of a furan compound; the catalyst is sodium hydride, and the deuterium source reagent is DMSO-d6.
[0007] The sodium hydride catalyst used in the present invention is commercially available and used in small amounts. The developed deuteration method has the characteristics of good operability and stability, high catalytic efficiency, wide substrate application range, simple post-treatment, easy reaction scale expansion, etc., and has potential commercial prospects.
[0008] Compared with the prior art, the present invention uses sodium hydride with high activity and small equivalent as a catalyst; at the same time, DMSO-d6 is used as a deuterium source and also as a solvent to carry out deuteration of furan substrates at room temperature, with simple operation, high deuteration degree and yield, simple separation, and environmentally friendly reagents.
[0009] The furan substance is selected from one of 2-methylfuran, 3-methylfuran, 2-ethylfuran, 2,4-dimethylfuran, 3,4-dimethylfuran, 2,3-dimethylfuran, 2,5-dimethylfuran, 2-methoxyfuran, 3-methoxyfuran, 3-chlorofuran, 2-ethyl-5-methylfuran, 3-acetylfuran, 2-nitrofuran, furazolidone and furazolidone.
[0010] The R 1 One or more selected from methyl, ethyl, isopropyl, n-propyl, acetyl, methoxy, chlorine atom and nitro.
[0011] The dosage ratio of each substance in the reaction is furan substance: catalyst: deuterium source reagent = 1 mol: 0.05-0.2 mol: 1.0-2.0 L.
[0012] The deuteration reaction temperature is 25-80°C and the reaction time is 12 hours.
[0013] The deuteration reaction was carried out under an inert atmosphere.
[0014] The beneficial effects of the present invention are: it can be completed under conventional conditions, the one-pot reaction does not require the replacement of solvents in the middle, and the reaction operability is high and the deuteration effect is good; the process method has good universality and can be used for the preparation of deuterated products of various furan compounds; it has the characteristics of being safe, green and inexpensive. DETAILED DESCRIPTION
[0015] The technical solution of the present invention is further described in detail below through specific embodiments.
[0016] In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the art. The methods in the following embodiments, unless otherwise specified, are all conventional methods in the art.
[0017] Example 1 Synthesis of deuterated 2-ethylfuran In a 15 mL dry sealed tube, 1.0 mmol (96 mg) of 2-ethylfuran, catalyst sodium hydride (0.2 mmol, 5.0 mg), and 1.0 mL of DMSO-d6 were added in sequence, stirred at room temperature, and reacted for 12 hours under a nitrogen atmosphere.
[0018] After the reaction was completed, stirring was stopped, dichloromethane was added, and then DMSO-d6 was continuously removed with distilled water. The liquid was separated with a separatory funnel, and the lower layer of liquid was retained. It was then dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 92 mg of the target compound with a yield of 91% and a deuteration degree of 4.5D. MS . 1 H NMR (400MHz, DMSO-d6) δ7.25 (s, 0.02H), 6.32 (dd, J = 4.9, 1.5Hz, 0.07H), 6.10 (dd, J = 4.8, 1.7Hz, 0.08H), 2.76 (q, J = 7.4Hz, 0.80H), 1.25 (t, J = 7.4Hz, 3H).
[0019] Example 2 Synthesis of deuterated 3-methylfuran In a 15 mL dry sealed tube, 1.0 mmol (82 mg) of 3-methylfuran, catalyst sodium hydride (0.2 mmol, 5.0 mg), and 1.0 mL of DMSO-d6 were added in sequence, stirred at room temperature, and reacted for 12 hours under a nitrogen atmosphere.
[0020] After the reaction was completed, stirring was stopped, dichloromethane was added, and then DMSO-d6 was continuously removed with distilled water. The liquid was separated with a separatory funnel, and the lower layer of liquid was retained. It was then dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 82 mg of the target compound with a yield of 93% and a deuteration degree of 4.2D. MS . 1 H NMR (400MHz, DMSO-d6) δ7.32 (s, 0.03H), 7.28 (t, J = 1.4Hz, 0.06H), 6.02 (t, J = 0.9Hz, 0.09H), 2.21 (s, 1.50H).
[0021] Example 3 Synthesis of deuterated 2-methylfuran In a 15 mL dry sealed tube, 1 mmol (82 mg) of 2-methylfuran, catalyst sodium hydride (0.2 mmol, 5.0 mg), and 1.0 mL of DMSO-d6 were added in sequence, stirred at room temperature, and reacted for 12 hours under a nitrogen atmosphere.
[0022] After the reaction was completed, stirring was stopped, dichloromethane was added, and then DMSO-d6 was continuously removed with distilled water. The liquid was separated with a separatory funnel, and the lower layer of liquid was retained. It was then dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 84 mg of the target compound with a yield of 95% and a deuteration degree of 4.5D. MS . 1H NMR (400MHz, DMSO-d6) δ7.31 (t, J = 1.4 Hz, 0.02H), 6.25 (dd, J = 4.8, 1.2 Hz, 0.05H), 6.04 (ddt, J = 5.5, 1.5, 0.8 Hz, 0.08H), 2.27 (d, J = 0.7 Hz, 1.60H).
[0023] Deuterated furan products were obtained from different furan derivatives under the conditions of Example 1, and the results are shown in the following table: project Compound No. <![CDATA[Degree of deuteration (D MS )]]> Yield (%) Example 4 4-[d] 5.3 92 Example 5 5-[d] 5.0 94 Example 6 6-[d] 5.1 95 Example 7 7-[d] 6.0 90 Example 8 8-[d] 2.9 88 Example 9 9-[d] 2.9 85 Example 10 10-[d] 3.0 89 Embodiment 11 11-[d] 5.5 94 Example 12 12-[d] 3.0 97 Example 13 13-[d] 4.6 85 Embodiment 14 14-[d] 2.7 83 .
[0024] Deuterated 2,4-dimethylfuran (4-[d]). 1 H NMR (400MHz, DMSO-d6) δ7.13–7.09(m,0.05H),6.26–6.22(m,0.07H),2.28(s,1.30H).2.16(s,1.60H).
[0025] Deuterated 3,4-Dimethylfuran (5-[d]) 1 H NMR (400MHz, DMSO-d6) δ7.25 (d, J=0.7Hz, 0.04H), 2.11 (s, 1.0H).
[0026] Deuterated 2,3-Dimethylfuran (6-[d]) 1 H NMR (400MHz, DMSO-d6) δ7.42 (d, J = 2.0Hz, 0.04H), 6.08 (dq, J = 1.5, 0.8Hz, 0.07H), 2.31 (s, 1.30H), 2.12 (d, J = 0.7Hz, 1.50H).
[0027] Deuterated 2,5-Dimethylfuran (7-[d]) 1 H NMR (400MHz, DMSO-d6) δ6.06 (d, J = 0.8Hz, 0.06H), 2.29 (d, J = 0.7Hz, 1.40H).
[0028] Deuterated 2-methoxyfuran (8-[d]). 1H NMR (400MHz, DMSO-d6) δ7.43 (t, J = 1.5 Hz, 0.04H), 6.27 (dd, J = 5.0, 1.4 Hz, 0.08H), 5.65 (dd, J = 5.1, 1.6 Hz, 0.12H), 3.83 (s, 3H).
[0029] Deuterated 3-methoxyfuran (9-[d]). 1 H NMR (400MHz, DMSO-d6) δ7.46 (t, J = 1.7 Hz, 0.04H), 7.10 (t, J = 1.7 Hz, 0.10H), 6.21 (t, J = 1.6 Hz, 0.14H), 3.75 (s, 3H).
[0030] Deuterated 3-chlorofuran (10-[d]). 1 H NMR (400MHz, DMSO-d6) δ7.59 (s, 0.03H), 7.37 (d, J = 1.8Hz, 0.04H), 6.60 (d, J = 1.7Hz, 0.07H).
[0031] Deuterated 1-(3-Furyl)-1-ethanone (11-[d]). 1 H NMR (400MHz, DMSO-d6) δ8.05 (s, 0.02H), 7.55 (t, J = 1.6Hz, 0.02H), 7.01 (t, J = 1.6Hz, 0.05H), 2.64 (s, 0.08H).
[0032] Deuterated 2-nitrofuran (12-[d]). 1 H NMR (400MHz, DMSO-d6) δ7.49–7.43 (m, 0.02H), 6.95 (dd, J=5.7, 1.3Hz, 0.03H).
[0033] Deuterated Nitrofurantoin (13-[d]). 1 H NMR (400MHz, DMSO-d6) δ7.85 (s, 0.04H), 7.68 (d, J = 4.9Hz, 0.02H), 7.24 (d, J = 4.9Hz, 0.02H), 4.61 (s, 0.12H).
[0034] Deuterated Furazolidone (14-[d]). 1 H NMR (400MHz, DMSO-d6) δ7.93 (s, 0.03H), 7.68 (d, J = 4.9Hz, 0.03H), 7.24 (d, J = 4. 9Hz, 0.03H), 4.29 (q, J = 13.4, 4.9, 2.9Hz, 2H), 4.03 ( q, J = 25.6, 4.8, 2.9Hz, 2H).
[0035] Under the same substrate as in Example 1, the dosage and reaction conditions were changed: project Substrate / mmol NaH / mmol <![CDATA[DMSO-d6(mL)]]> T / ℃ Time / h <![CDATA[D MS ]]> Yield / % 1 1 0.20 1 25 12 4.5 91 2 1 0.20 1 40 12 4.6 89 3 1 0.20 2 50 12 4.8 85 4 1 0.05 1 80 12 4.0 93 .
[0036] The above-described embodiment is only a preferred solution of the present invention and does not limit the present invention in any form. There are other variations and modifications without exceeding the technical solution described in the claims.
Claims
1. A method for preparing deuterated furan, characterized in that: The furan substance shown in formula I is used as a raw material, and a deuterium source reagent undergoes a deuteration reaction under a normal pressure system and in the presence of a catalyst. The reaction product is separated and purified to obtain a deuterated product of a furan compound; the catalyst is sodium hydride, and the deuterium source reagent is DMSO-d6.
2. The preparation method according to claim 1, characterized in that: The furan substance is selected from one of 2-methylfuran, 3-methylfuran, 2-ethylfuran, 2,4-dimethylfuran, 3,4-dimethylfuran, 2,3-dimethylfuran, 2,5-dimethylfuran, 2-methoxyfuran, 3-methoxyfuran, 3-chlorofuran, 2-ethyl-5-methylfuran, 3-acetylfuran, 2-nitrofuran, furazolidone and furazolidone.
3. The preparation method according to claim 1, characterized in that: The R 1 One or more selected from methyl, ethyl, isopropyl, n-propyl, acetyl, methoxy, chlorine atom and nitro.
4. The preparation method according to claim 1, characterized in that: The dosage ratio of each substance in the reaction is furan substance: catalyst: deuterium source reagent = 1 mol: 0.05-0.2 mol: 1.0-2.0 L.
5. The preparation method according to claim 1, characterized in that: The deuteration reaction temperature is 25-80°C and the reaction time is 12 hours.
6. The preparation method according to claim 1, characterized in that: The deuteration reaction was carried out under an inert atmosphere.