Novel method for directional deuteration of heterocyclic compound
Deuterated heterocyclic compounds are achieved by using acidic zeolite HBeta catalyst and D2O, which solves the problems of complex reaction systems and difficult catalyst recovery in the prior art, and achieves efficient and non-toxic deuterated reactions, which are suitable for industrial production.
Patent Information
- Application Number
- CN202411370288.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-29
- Publication Date
- 2025-01-03
AI Technical Summary
The prior art requires silver salt catalysts and additional phosphine ligands in the deuterated process of heterocyclic compounds, resulting in complex reaction systems and are not conducive to the recovery and industrial production of catalysts, which violates the concept of green and sustainable development.
The acidic zeolite HBeta is used as the catalyst and D2O is used as the deuterium source to achieve deuterated hydrogen at the alpha position in heterocyclic compounds and deuterated deuterated at the beta position of the partial benzoheterocyclic system without the need for additional additives.
The reaction system is simplified, and the hydrogen-deuterium exchange is achieved with high efficiency and non-toxic hydrogen-deuterium exchange, and excellent yield and deuterated rate are obtained. It is suitable for industrial production and meets the requirements of green and sustainable development.
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Abstract
Description
Technical Field
[0001] The invention belongs to the field of heterogeneous catalytic organic synthesis and discloses a new method for realizing directional deuteration of heterocyclic compounds by utilizing a heterogeneous catalyst. Background Art
[0002] Deuterium is an isotope of hydrogen. Since the bond energy of CD bonds is higher than that of CH bonds, converting CH bonds in compounds into CD bonds can enhance their stability. Therefore, deuterium-labeled compounds are widely used in many fields such as materials, chemistry, biomedicine, and analytical science. In particular, the introduction of deuterium into specific positions of drug molecules can change their absorption, distribution, metabolism, and excretion characteristics, thereby enhancing drug activity.
[0003] There are two main ways to synthesize deuterium-labeled compounds: one is a multi-step synthesis method, which is to gradually prepare the deuterium-labeled target compound by chemical synthesis starting from a deuterium-labeled precursor. The other is the hydrogen isotope exchange method (HIE), which is to exchange hydrogen and deuterium between the H atoms in the compound molecule and the D atoms in the deuterium source to obtain the deuterium-labeled target compound. Since the multi-step synthesis method may produce deuteration and deuterium transfer in the process of synthesizing deuterated compounds, the hydrogen isotope exchange method has been more widely used due to its simplicity and effectiveness.
[0004] Heterocyclic compounds are widely used in the medical field and can be used to prepare anticancer drugs, antiviral drugs, etc. In recent years, many researchers have made great efforts to achieve the deuteration of heterocyclic compounds. For example, (1) Wei Huang et al. used Ag 2 CO 3 As a catalyst, 2-(di-tert-butylphosphino)biphenyl was used as a ligand, K 2 CO 3 As base, DMSO as solvent, D 2 O as a deuterium source, achieving hydrogen-deuterium exchange at the α-position of a five-membered heterocyclic compound at room temperature; (Org. Lett. 2019, 21, 6745-6749) (2) Hartwig et al. used silver salt Ag 2 CO 3 as catalyst, JohnPhos as ligand, CH 3 OD was used as a deuterium source to achieve hydrogen-deuterium exchange at the α position of the five-membered heterocyclic compound; (ACS Catal. 2021, 11, 1119-1127) (3) Hong-Hai Zhang's group used Ag 2 CO 3 as catalyst, MePhos as ligand, toluene as solvent, D 2 O is a deuterium source, achieving full deuteration of thiophene compounds. (Org.Biomol.Chem.2022,20,1176-1180)
[0005] In the above reaction system, silver salt Ag is required 2 CO 3 As a catalyst, it is necessary to add additional phosphine-containing ligands, which makes the reaction system complicated, is not conducive to the separation and purification of subsequent products, and the catalyst is difficult to recycle and reuse. These shortcomings hinder large-scale industrial production and are not in line with the concept of green and sustainable development. Summary of the invention
[0006] In order to solve the problems in the background technology, the present invention uses acidic zeolite HBeta as a catalyst. 2 O is a deuterium source, which can realize the deuteration of hydrogen at the α position of heteroatoms in heterocyclic compounds and the deuteration of β position of some benzoheterocyclic systems without the need for additional additives.
[0007] The technical solution of the present invention is as follows:
[0008] The set amount of HBeta zeolite, D 2 O. Add the heterocyclic compound into a glass reaction tube and react at a set reaction temperature for a period of time. After the reaction is completed, the reaction solution is centrifuged, filtered, extracted, rotary evaporated and dried to obtain the target product.
[0009]
[0010] X is selected from N; Y is selected from S; Z is selected from O; R is selected from phenyl; R 1 are independently selected from phenyl, methyl or H; R 2 Independently selected from bromine and chlorine.
[0011] Furthermore, the reaction temperature in the present invention is 60-100°C, preferably 80°C.
[0012] Furthermore, the reaction time in the present invention is 4 to 12 hours, preferably 6 hours.
[0013] Further, the heterocyclic compound and D 2 The molar ratio of O is 1:(10 to 50), preferably 1:(15 to 45), and more preferably 1:(20 to 40).
[0014] Furthermore, in the present invention, the molar ratio of the mass of the HBeta zeolite catalyst to the heterocyclic compound is (20-80) mg:1 mmol, preferably (25-75) mg:1 mmol, and more preferably (30-70) mg:1 mmol.
[0015] Furthermore, HBeta zeolite is first prepared by conventional hydrothermal synthesis to obtain Beta zeolite, and Beta zeolite is then subjected to two ammonium exchanges to obtain HBeta zeolite.
[0016] That is, silica sol, sodium aluminate, sodium hydroxide, tetraethylammonium hydroxide, and cationic copolymer (RCC) containing quaternary ammonium salt are mixed and stirred evenly, and then placed in a reaction kettle for crystallization. After the crystallization is completed, Beta zeolite is obtained through filtration, washing, drying, and calcination. The composition of the gel system is Al 2 O 3 :32SiO 2 :2Na 2 O:0.01RCC:2.6TPAOH:296H 2 O.
[0017] The obtained Beta zeolite is exchanged with an aqueous solution of ammonium nitrate of a certain concentration at a set temperature for a period of time. After the exchange is completed, it is filtered, washed, dried, and calcined. The same steps are repeated twice to obtain the HBeta zeolite catalyst.
[0018] Compared with the prior art, the present invention has the following advantages:
[0019] (1) The reaction system is simple and does not require the use of additional additives. The common acid-catalyzed hydrogen-deuterium exchange strategy and metal-catalyzed hydrogen-deuterium exchange strategy will generate industrial pollution and metal pollution to a certain extent during the production process. The present invention uses zeolite as a catalyst to achieve simple, efficient and non-toxic hydrogen-deuterium exchange.
[0020] (2) The catalyst has excellent catalytic activity and can obtain excellent yield and deuteration rate. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 is the deuterated benzothiazole of Example 1 1 HNMR spectrum.
[0022] Figure 2 Example 2 deuterated benzothiophene 1 HNMR spectrum.
[0023] Figure 3 Example 3 deuterated 2,3-benzofuran 1 H NMR spectrum.
[0024] Figure 4 Example 4 deuterated 2-bromothiophene 1 HNMR spectrum.
[0025] Figure 5 Example 5 deuterated 2-chloro-3-methylthiophene 1 H NMR spectrum.
[0026] Figure 6 Example 6 deuterated 3,4-dimethylthiophene1 H NMR spectrum. DETAILED DESCRIPTION
[0027] The present invention will be further described below in conjunction with embodiments, but is not limited thereto.
[0028] The preparation method of the HBeta zeolite catalyst in the embodiment is as follows:
[0029] The synthesis of HBeta zeolite can be obtained by referring to the method in (ACS Catal. 2018, 8, 9043-9055), and the specific process is as follows:
[0030] First, 0.34 kg of NaOH was dissolved in 19 L of deionized water and stirred for 1 h. Then, 0.73 kg of NaAlO 2 and 6L of 25wt.% tetraethylammonium hydroxide (TPAOH), stirred at room temperature for 1h, added 8.5kg of silica gel, continued stirring for 1h, and added 4.5L of cationic copolymer (RCC) containing quaternary ammonium salt groups. After the addition was completed, stirred for 2h to obtain a gel. The composition of the gel system was Al 2 O 3 :32SiO 2 :2Na 2 O:0.01RCC:2.6TPAOH:296H 2 O. The obtained gel system was transferred to a 50L autoclave and crystallized at 140°C for 6 days. The dehydrated crude product was obtained by filtration and drying, and then calcined at 550°C for 6h to remove the organic template, and the obtained sample was Beta.
[0031] The Beta sample and the ammonium nitrate aqueous solution (1M) were mixed in a mass ratio of 1:10 and placed in a water bath at 80°C for 4 hours. After the water bath, the sample was obtained by filtration, washing, and drying, and then calcined at 550°C for 4 hours. The above operation was repeated twice, and the obtained sample was the HBeta zeolite catalyst.
[0032] The texture parameters of the synthesized HBeta zeolite are as follows:
[0033]
[0034] a Specific surface area; b External surface area; c Micropore volume; d Mesopore volume
[0035] Example 1
[0036]
[0037] Weigh 50 mg of HBeta zeolite into a reaction tube, add 135 mg of benzothiazole, 500 mg of D 2 O, in an air atmosphere, reacted on a heating plate at 80°C for 6 hours. After the reaction system cooled to room temperature, the reaction solution was centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 130 mg of the target product, deuterated benzothiazole, with a yield of 95%. The deuteration rate of the product was determined by 1 H NMR analysis showed that the deuterium substitution rate of benzothiazole was 95%. Figure 1 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1 H NMR (400 MHz, DMSO-d 6 )δ9.36(s,0.05H),8.13(dd,J=25.0,8.0Hz,2H),7.51(dt,J=24.9,7.5Hz,2H).
[0038] The deuterium substitution rate is calculated after measuring the hydrogen nuclear magnetic resonance spectrum.
[0039] Specifically, it is calculated by integrating the peaks of the chemical shift corresponding to the hydrogen at the target deuterated position in the compound on the NMR spectrum. The calculation formula is:
[0040]
[0041] Where D% represents the deuterium substitution rate;
[0042] Sp represents the integrated peak area of the chemical shift corresponding to the hydrogen at the target deuterated position in the deuterated product in the H NMR spectrum;
[0043] S R It represents the integrated peak area of the chemical shift corresponding to the undeuterated hydrogen in the substrate in the H NMR spectrum.
[0044] Example 2
[0045]
[0046] Weigh 50 mg of HBeta zeolite into a reaction tube, add 134 mg of benzothiophene, 500 mg of D 2 O, in an air atmosphere, reacted on a heating plate at 80°C for 6 hours. After the reaction system cooled to room temperature, the reaction solution was centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 131 mg of the target product, deuterated benzothiophene, with a yield of 96%. The deuteration rate of the product was determined by 1 H NMR analysis showed that the deuterium substitution rate of benzothiophene at the α position was 97% and that at the β position was 96%. Figure 2 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1H NMR (400MHz, DMSO-d6) δ8.02-7.98(m,1H),7.91-7.85(m,1H),7.46(s,0.04H),7.43-7.31(m,2.03H).
[0047] Example 3
[0048]
[0049] Weigh 50 mg of HBeta zeolite into a reaction tube, add 118 mg of 2,3-benzofuran, 500 mg of D 2 O, in an air atmosphere, reacted on a heating plate at 80°C for 6 hours. After the reaction system cooled to room temperature, the reaction solution was centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 113 mg of the target product, deuterated 2,3-benzofuran, with a yield of 94%. The deuteration rate of the product was determined by 1 H NMR analysis showed that the deuterium substitution rate of 2,3-benzofuran at the α position was 80% and that at the β position was 51%. Figure 3 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1 H NMR (400MHz, DMSO-d6) δ7.99 (s, 0.49H), 7.62 (dd, J = 27.4, 7.6Hz, 2H), 7.38-7.17 (m, 2H), 6.95 (s, 0.20H).
[0050] Example 4
[0051]
[0052] Weigh 50 mg of HBeta zeolite into a reaction tube, add 163 mg of 2-bromothiophene, 500 mg of D 2 O, in an air atmosphere, reacted on a heating plate at 80°C for 6 hours. After the reaction system cooled to room temperature, the reaction solution was centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 154 mg of the target product, deuterated 2-bromothiophene, with a yield of 94%. The deuteration rate of the product was determined by 1 H NMR analysis showed that the deuterium substitution rate of 2-bromothiophene was 96%. Figure 4 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.14 (d, J = 5.6 Hz, 0.04H), 6.97 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.7 Hz, 1H).
[0053] Example 5
[0054]
[0055] Weigh 50 mg of HBeta zeolite into a reaction tube, add 132 mg of 2-chloro-3-methylthiophene, 500 mg of D 2 O, in an air atmosphere, reacted on a heating plate at 80°C for 6 hours. After the reaction system cooled to room temperature, the reaction solution was centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 121 mg of the target product, deuterated 2-chloro-3-methylthiophene, with a yield of 91%. The deuteration rate of the product was determined by 1 H NMR analysis showed that the deuterium substitution rate of 2-chloro-3-methylthiophene was 92%. Figure 5 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1 H NMR (400MHz, Chloroform-d) δ6.88 (d, J = 5.6Hz, 0.08H), 6.65 (s, 1H), 2.08 (s, 3H).
[0056] Example 6
[0057]
[0058] Weigh 50 mg of HBeta zeolite into a reaction tube, add 112 mg of 3,4-dimethylthiophene, 500 mg of D 2 O, in an air atmosphere, reacted on a heating plate at 80°C for 6 hours. After the reaction system cooled to room temperature, the reaction solution was centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 108 mg of the target product, deuterated 3,4-dimethylthiophene, with a yield of 95%. The deuteration rate of the product was determined by 1 H NMR analysis showed that the deuterium substitution rate of 3,4-dimethylthiophene was 93%. Figure 6 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1 H NMR (400MHz, Chloroform-d) δ6.86 (s, 0.14H), 2.15 (s, 6H).
[0059] Example 7
[0060] Weigh 50 mg of HBeta zeolite into a reaction tube, add 135 mg of benzothiazole, 500 mg of D 2 O, in an air atmosphere, reacted on a 100°C heating plate for 12 hours. After the reaction system cooled to room temperature, the reaction solution was centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 131 mg of the target product, deuterated benzothiazole, with a yield of 96%. The deuteration rate of the product was determined by 1 H NMR analysis revealed that the deuteration rate of benzothiazole was 96%.
[0061] Example 8
[0062] Weigh 30 mg of HBeta zeolite into a reaction tube, add 135 mg of benzothiazole, 300 mg of D 2 O, in an air atmosphere, reacted on a heating plate at 80°C for 6 hours. After the reaction system cooled to room temperature, the reaction solution was centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 121 mg of the target product, deuterated benzothiazole, with a yield of 89%. The deuteration rate of the product was determined by 1 H NMR analysis revealed that the deuteration rate of benzothiazole was 83%.
[0063] Comparative Example 1
[0064] Weigh 50 mg of ETS-10 zeolite into a reaction tube, add 135 mg of benzothiazole, 500 mg of D 2 O, in an air atmosphere, react in a heating plate at 80 ° C for 6 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried. 1 HNMR analysis revealed no deuterated product.
[0065] Comparative Example 2
[0066] Weigh 50 mg of TS-1 zeolite into a reaction tube, add 135 mg of benzothiazole, 500 mg of D 2 O, in an air atmosphere, react in a heating plate at 80 ° C for 6 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried. 1 HNMR analysis revealed no deuterated product.
[0067] Comparative Example 3
[0068] Weigh 50 mg of Beta zeolite into a reaction tube, add 135 mg of benzothiazole, 500 mg of D 2 O, in an air atmosphere, reacted on a heating plate at 80°C for 6 hours. After the reaction system cooled to room temperature, the reaction solution was centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 113 mg of the target product, deuterated benzothiazole, with a yield of 83%. The deuteration rate of the product was determined by 1 HNMR analysis revealed that the deuteration rate of benzothiazole was 22%.
[0069] The embodiments are preferred implementations of the present invention, but the present invention is not limited to the above-mentioned implementations. Any obvious improvements, substitutions or modifications that can be made by those skilled in the art without departing from the essential content of the present invention belong to the protection scope of the present invention.
Claims
1. A novel method for directed deuteration of heterocyclic compounds, characterized in that: A heterocyclic compound, a deuterated reagent and an HBeta zeolite catalyst are mixed and reacted at a set temperature for a period of time to deuterate at least the ortho-position CH of the heteroatom in the heterocyclic compound. After the reaction is completed, the reaction solution is cooled to room temperature, and the reaction solution is centrifuged, filtered, extracted, rotary evaporated and dried to obtain a deuterated heterocyclic compound; the heterocyclic structure in the heterocyclic compound is one of furan, thiophene and thiazole.
2. The novel method for directed deuteration of heterocyclic compounds according to claim 1, characterized in that: The deuterated reagent is D2O.
3. The novel method for directed deuteration of heterocyclic compounds according to claim 1, characterized in that: The molar ratio of the heterocyclic compound to the deuterated reagent is 1:(10-50).
4. The novel method for directed deuteration of heterocyclic compounds according to claim 1, characterized in that: The molar ratio of the mass of the HBeta zeolite catalyst to the heterocyclic compound is (20-80) mg:1 mmol.
5. The novel method for directed deuteration of heterocyclic compounds according to claim 1, characterized in that: The reaction temperature is 60-100°C.
6. The novel method for directed deuteration of heterocyclic compounds according to claim 1, characterized in that: The reaction time is 4 to 12 hours.
7. The novel method for directed deuteration of heterocyclic compounds according to claim 1, characterized in that: The structural formula of the heterocyclic compound is: The structural formula of the corresponding deuterated heterocyclic compound obtained is as follows: