Method for preparing deuterated 1, 3-dibromobenzene by adopting hydrogen-deuterium exchange method
The invention relates to a novel method for preparing 1,3-dibromobenzene by reacting it with heavy water in the presence of a catalyst and a base through hydrogen-deuterium exchange, combined with temperature and time control, thereby solving the problem of synthesizing 1,3-dibromobenzene with a high deuteration rate and high purity in the prior art, and realizing a simple, safe and efficient preparation method suitable for the preparation of pharmaceutical synthesis intermediates.
Patent Information
- Application Number
- CN202510634519.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-16
- Publication Date
- 2025-09-09
AI Technical Summary
Existing technologies make it difficult to efficiently synthesize 1,3-dibromobenzene with a high deuteration rate and high purity, and the synthesis process is complex and costly, which limits its application in drug synthesis.
The hydrogen-deuterium exchange method is used. In the presence of a catalyst and a base, 1,3-dibromobenzene reacts with heavy water in an organic solvent. By controlling the reaction temperature and time, deuterated 1,3-dibromobenzene is synthesized in one step, and then purified by steam distillation and reduced pressure distillation.
The synthesis of deuterated 1,3-dibromobenzene with high deuteration rate and high purity has been achieved. The operation is simple, safe, economical and applicable. The purification method is simple and the yield is high. It is suitable for the preparation of drug synthesis intermediates.
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Figure CN120607430A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of fine chemicals, and particularly relates to a method for preparing deuterated 1,3-dibromobenzene by adopting a hydrogen-deuterium exchange method. Background Art
[0002] Hydrogen has three different isotopes: protium, deuterium, and tritium. Protium, consisting of one proton and one electron, is the primary form of hydrogen. Deuterium is another important isotope of hydrogen. With the advancement of science and technology, the importance of deuterium is increasingly recognized. From a chemical perspective, the carbon-deuterium bond is shorter than the carbon-hydrogen bond, more stable, and has a higher bond energy. Due to their unique properties, deuterated compounds show promising application prospects in biological metabolic analysis, nuclear magnetic resonance, optoelectronic materials, scientific research testing, intermediate labeling, drug development, and pollution source tracking.
[0003] Currently, most drugs on the market suffer from poor absorption, rapid metabolism, and large excretion volumes, which to some extent limit their application. Deuterium modification is one of the methods to improve drug properties. By replacing one or more deuterium sites on the active sites of drug molecules, drug metabolism time can be significantly prolonged, drug dosage can be reduced, drug efficacy can be increased, safety can be improved, and better therapeutic effects can be achieved.
[0004] In 2017, the U.S. Food and Drug Administration (FDA) approved the world's first deuterated drug, AUSTEDO (deutetrabenazine), for marketing. Several other deuterated drugs are currently in Phase III clinical trials, signaling the FDA's recognition of the distinct role of deuterium in drug design compared to ordinary hydrogen. Currently, demand for deuterated compounds with specialized structures is increasing. 1,3-Dibromobenzene, a key raw material for the synthesis of several drug-related intermediates, necessitates the development of novel methods for synthesizing its deuterated counterparts. Summary of the Invention
[0005] The present invention aims to provide a method for synthesizing deuterated 1,3-dibromobenzene in one step from ordinary 1,3-dibromobenzene by utilizing a hydrogen-deuterium exchange process. The method has the advantages of simple operation, high safety, high yield, good economic applicability, and easy purification.
[0006] Specifically, the present invention provides the following technical solutions:
[0007] A method for preparing deuterated 1,3-dibromobenzene by using a hydrogen-deuterium exchange method comprises the following steps:
[0008] In the presence of a catalyst and a base, 1,3-dibromobenzene undergoes a hydrogen-deuterium exchange reaction with heavy water in an organic solvent, and is further purified to obtain deuterated 1,3-dibromobenzene.
[0009] Preferably, the catalyst is Ni(DME)Cl2 or Ni(dppf)Cl2.
[0010] Preferably, the base is potassium carbonate or potassium hydroxide.
[0011] Preferably, the organic solvent is toluene.
[0012] Preferably, the mass volume ratio of the 1,3-dibromobenzene to heavy water is 1 g:4-20 mL.
[0013] Preferably, the reaction temperature of the hydrogen-deuterium exchange reaction is 105-115° C., and the reaction time is 44-52 h.
[0014] Most preferably, the catalyst is Ni(DME)Cl2, the base is potassium carbonate, the reaction temperature for the hydrogen-deuterium exchange reaction is 105-115°C, and the reaction time is 44-52 hours. Research has found that through the synergistic effect of these reaction conditions, the deuterated 1,3-dibromobenzene produced simultaneously achieves high deuteration rate, high purity, and high yield, showing promising application prospects.
[0015] Preferably, the purification comprises the following steps:
[0016] The reaction system after the hydrogen-deuterium exchange reaction is cooled to room temperature, then poured into an evaporator for steam distillation, and the distillate containing deuterated 1,3-dibromobenzene is collected. Finally, the deuterated 1,3-dibromobenzene product is obtained by vacuum distillation.
[0017] The beneficial effects of the present invention are at least:
[0018] 1) The present invention provides a method for preparing deuterated 1,3-dibromobenzene by a hydrogen-deuterium exchange method, which uses heavy water as a deuterium source and utilizes a hydrogen-deuterium exchange process to synthesize deuterated 1,3-dibromobenzene in one step. The method is simple to operate, highly safe, and economical.
[0019] 2) The present invention provides a method for preparing deuterated 1,3-dibromobenzene using a hydrogen-deuterium exchange method. Through the synergistic effect of catalyst, base, reaction temperature and time, the obtained deuterated 1,3-dibromobenzene product has high deuteration rate, high purity and high yield, and has good application prospects;
[0020] 3) The present invention provides a method for preparing deuterated 1,3-dibromobenzene by hydrogen-deuterium exchange. The purification method is convenient and fast. Deuterated 1,3-dibromobenzene product with a purity of more than 92% can be obtained by simple steam distillation and reduced pressure distillation. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 The deuterated 1,3-dibromobenzene prepared in Example 1 1 H spectrum.
[0022] Figure 2 This is the gas chromatogram of deuterated 1,3-dibromobenzene prepared in Example 1. DETAILED DESCRIPTION
[0023] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention are clearly and completely described below. The following examples are used to illustrate the present invention but are not intended to limit the scope of the present invention. If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions shall be followed.
[0024] Example 1
[0025] Preparation of deuterated 1,3-dibromobenzene: 10g of 1,3-dibromobenzene, 11g of potassium carbonate, 6.2g of Ni(DME)Cl2, 100ml of heavy water, and 25ml of toluene were added to a reactor in sequence. The reaction was carried out at 110°C for 48 hours. After the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire system was poured into an evaporator and purified by steam distillation at 140°C. The distillate containing deuterated 1,3-dibromobenzene was collected and finally, deuterated by reduced pressure distillation at 120°C to prepare deuterated 1,3-dibromobenzene with a deuteration rate of 97.5%, a purity of 98.5%, and a yield of 97%.
[0026] The reaction formula is:
[0027]
[0028] Figure 1 The deuterated 1,3-dibromobenzene prepared in Example 1 1 H spectrum, through Figure 1 It can be calculated that the deuteration rate of deuterated 1,3-dibromobenzene is 97.5%.
[0029] Figure 2 The gas chromatogram of deuterated 1,3-dibromobenzene prepared in Example 1 is shown by Figure 2 The results show that the purity of deuterated 1,3-dibromobenzene is 98.5%.
[0030] Example 2
[0031] Preparation of deuterated 1,3-dibromobenzene: 10g of 1,3-dibromobenzene, 11g of potassium carbonate, 19.2g of Ni(dppf)Cl2, 200ml of heavy water, and 25ml of toluene were added sequentially to a reactor and reacted at 110°C for 48 hours. After completion of the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire system was poured into an evaporator and purified by steam distillation at 140°C. The distillate containing deuterated 1,3-dibromobenzene was collected and finally, vacuum distilled at 120°C to prepare deuterated 1,3-dibromobenzene with a deuteration rate of 81%, a purity of 95.3%, and a yield of 94.5%.
[0032] The reaction formula is:
[0033]
[0034] Example 3
[0035] Preparation of deuterated 1,3-dibromobenzene: 10g of 1,3-dibromobenzene, 11g of potassium carbonate, 15.4g of Ni(dppp)Cl2, 200ml of heavy water, and 25ml of toluene were added to a reactor in sequence. The reaction was carried out at 110°C for 48 hours. After the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire system was poured into an evaporator and purified by steam distillation at 140°C. The distillate containing deuterated 1,3-dibromobenzene was collected and finally, deuterated by reduced pressure distillation at 120°C to prepare deuterated 1,3-dibromobenzene with a deuteration rate of 62%, a purity of 92.3%, and a yield of 91%.
[0036] The reaction formula is:
[0037]
[0038] Example 4
[0039] Preparation of deuterated 1,3-dibromobenzene: 10g of 1,3-dibromobenzene, 11g of potassium carbonate, 6.2g of Ni(DME)Cl2, 75ml of heavy water, and 25ml of toluene were added to a reactor in sequence and reacted at 110°C for 72 hours. After the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire system was poured into an evaporator and purified by steam distillation at 140°C. The distillate containing deuterated 1,3-dibromobenzene was collected and finally, deuterated by reduced pressure distillation at 120°C to prepare deuterated 1,3-dibromobenzene with a deuteration rate of 91%, a purity of 97.3%, and a yield of 72%.
[0040] The reaction formula is:
[0041]
[0042] Example 5
[0043] Preparation of deuterated 1,3-dibromobenzene: 10g of 1,3-dibromobenzene, 11g of potassium carbonate, 6.2g of Ni(DME)Cl2, 625ml of heavy water, and 25ml of toluene were added to a reactor in sequence and reacted at 110°C for 24 hours. After the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire system was poured into an evaporator and purified by steam distillation at 140°C. The distillate containing deuterated 1,3-dibromobenzene was collected and finally, deuterated by reduced pressure distillation at 120°C to prepare deuterated 1,3-dibromobenzene with a deuteration rate of 98.2%, a purity of 98.2%, and a yield of 91%.
[0044] Compared with Example 1, although the deuteration rate of Example 5 is slightly higher, the amount of heavy water used is 6.25 times that of Example 1, and the economic benefit is significantly reduced.
[0045] The reaction formula is:
[0046]
[0047] Example 6
[0048] Preparation of deuterated 1,3-dibromobenzene: 10g of 1,3-dibromobenzene, 11g of potassium carbonate, 6.2g of Ni(DME)Cl2, 100ml of heavy water, and 25ml of toluene were added to a reactor in sequence. The reaction was carried out at 130°C for 48 hours. After the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire system was poured into an evaporator and purified by steam distillation at 140°C. The distillate containing deuterated 1,3-dibromobenzene was collected and finally, deuterated by reduced pressure distillation at 120°C to prepare deuterated 1,3-dibromobenzene with a deuteration rate of 97.1%, a purity of 98.4%, and a yield of 87%.
[0049] The reaction formula is:
[0050]
[0051] Example 7
[0052] Preparation of deuterated 1,3-dibromobenzene: 10g of 1,3-dibromobenzene, 4.5g of potassium hydroxide, 6.2g of Ni(DME)Cl2, 100ml of heavy water, and 25ml of toluene were added to a reactor in sequence. The reaction was carried out at 110°C for 48 hours. After the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire system was poured into an evaporator and purified by steam distillation at 140°C. The distillate containing deuterated 1,3-dibromobenzene was collected and finally, deuterated 1,3-dibromobenzene was prepared by reduced pressure distillation at 120°C with a deuteration rate of 92.1%, a purity of 95.6%, and a yield of 56%.
[0053] The reaction formula is:
[0054]
[0055] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.
Claims
1. A method for preparing deuterated 1,3-dibromobenzene by hydrogen-deuterium exchange, characterized in that: The following steps are involved: In the presence of a catalyst and a base, 1,3-dibromobenzene undergoes a hydrogen-deuterium exchange reaction with heavy water in an organic solvent, and is further purified to obtain deuterated 1,3-dibromobenzene.
2. The method for preparing deuterated 1,3-dibromobenzene by hydrogen-deuterium exchange according to claim 1, characterized in that: The catalyst is Ni(DME)Cl2 or Ni(dppf)Cl2.
3. The method for preparing deuterated 1,3-dibromobenzene by hydrogen-deuterium exchange according to claim 1 or 2, characterized in that: The base is potassium carbonate or potassium hydroxide.
4. The method for preparing deuterated 1,3-dibromobenzene by hydrogen-deuterium exchange according to claim 1 or 2, characterized in that: The mass volume ratio of the 1,3-dibromobenzene to heavy water is 1 g:4-20 mL.
5. The method for preparing deuterated 1,3-dibromobenzene by hydrogen-deuterium exchange according to claim 1, characterized in that: The catalyst is Ni(DME)Cl2, the base is potassium carbonate, the reaction temperature of the hydrogen-deuterium exchange reaction is 105-115°C, and the reaction time is 44-52h.
6. The method for preparing deuterated 1,3-dibromobenzene by hydrogen-deuterium exchange according to claim 1 or 2, characterized in that: The purification comprises the following steps: The reaction system after the hydrogen-deuterium exchange reaction is cooled to room temperature, then poured into an evaporator for steam distillation, the distillate containing deuterated 1,3-dibromobenzene is collected, and finally vacuum distillation is performed to obtain the deuterated 1,3-dibromobenzene product.