Method for preparing deuterated 4-bromofluorobenzene by adopting hydrogen-deuterium exchange method
Deuterated 4-bromofluorobenzene is prepared through the hydrogen-deuterium exchange method. The synergistic effect of heavy water, reaction ligand and catalyst is utilized to solve the problem of preparing high-purity and high-yield deuterated 4-bromofluorobenzene in the existing technology, and realize the feasibility of industrial production.
Patent Information
- Application Number
- CN202510611648.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-13
- Publication Date
- 2025-09-23
AI Technical Summary
Existing technologies make it difficult to efficiently prepare deuterated 4-bromofluorobenzene with high purity and high yield, and the reaction conditions are relatively harsh, making it unsuitable for industrial production.
The hydrogen-deuterium exchange method is adopted, with heavy water as the deuterated reagent, diphenylcyclohexylphosphine or triphenylphosphine as the reaction ligand, Pd(OAc)2 as the catalyst, and sodium acetate as the base. The hydrogen-deuterium exchange reaction is carried out in an organic solvent, and then purified by steam distillation and reduced pressure distillation.
The preparation of deuterated 4-bromofluorobenzene with high deuteration rate, high purity and high yield was achieved, which is suitable for industrial production and has good application prospects.
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Figure CN120682080A_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 4-bromofluorobenzene 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. 4-Bromofluorobenzene, a key raw material for the synthesis of several drug-related intermediates, is imperative to develop methods for synthesizing its deuterated derivatives. Summary of the Invention
[0005] The present invention aims to provide a method for preparing deuterated 4-bromofluorobenzene by using a hydrogen-deuterium exchange method. The reaction process is simple to operate, the reaction conditions are mild, the deuteration rate, purity and yield of the product are high, and the method is very suitable for industrial production.
[0006] Specifically, the present invention provides the following technical solutions:
[0007] A method for preparing deuterated 4-bromofluorobenzene by a hydrogen-deuterium exchange method comprises the following steps:
[0008] Using heavy water as a deuterated reagent and diphenylcyclohexylphosphine or triphenylphosphine as a reaction ligand, in the presence of a catalyst, a base and an organic solvent, a hydrogen-deuterium exchange reaction of 4-bromofluorobenzene occurs, and further purification is performed to obtain deuterated 4-bromofluorobenzene.
[0009] Preferably, the reaction ligand is diphenylcyclohexylphosphine.
[0010] Preferably, the catalyst is Pd(OAc) 2. Studies have found that Pd(OAc) 2 catalyst is particularly suitable for the present invention. If other catalysts such as silver salt catalysts are used, the effect is not very good due to the presence of fluorine atoms, and the deuteration rate is very low.
[0011] Preferably, the base is sodium acetate.
[0012] Preferably, the mass volume ratio of the 1,3-dibromobenzene to heavy water is 1 g:5 to 30 mL.
[0013] Preferably, the reaction temperature of the hydrogen-deuterium exchange reaction is 120-140° C., and the reaction time is 50-70 h.
[0014] Most preferably, the reaction ligand is diphenylcyclohexylphosphine, the catalyst is Pd(OAc)2, the base is sodium acetate, and the mass volume ratio of 1,3-dibromobenzene to heavy water is 1g:5-30mL;
[0015] The reaction temperature of the hydrogen-deuterium exchange reaction is 120-140° C., and the reaction time is 50-70 hours.
[0016] The study found that through the synergistic effect of the above-mentioned reaction conditions, the deuterated 4-bromofluorobenzene prepared has the excellent effects of high deuteration rate, high purity and high yield, which is very suitable for industrial production and has good application prospects.
[0017] Preferably, the purification comprises the following steps:
[0018] 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 4-bromofluorobenzene is collected. Finally, the deuterated 4-bromofluorobenzene product is obtained by vacuum distillation.
[0019] The beneficial effects of the present invention are at least:
[0020] 1) The present invention provides a method for preparing deuterated 4-bromofluorobenzene by a hydrogen-deuterium exchange method, wherein heavy water is used as a deuteration reagent, diphenylcyclohexylphosphine or triphenylphosphine is used as a reaction ligand, and a hydrogen-deuterium exchange reaction of 4-bromofluorobenzene occurs in the presence of a catalyst, a base, and an organic solvent. The reaction process is simple to operate, the reaction conditions are mild, the safety is high, and the economic applicability is good;
[0021] 2) The present invention provides a method for preparing deuterated 4-bromofluorobenzene by hydrogen-deuterium exchange, wherein the catalyst is preferably Pd(OAc)2, and the deuterated 4-bromofluorobenzene prepared has a high deuteration rate;
[0022] 3) The present invention provides a method for preparing deuterated 4-bromofluorobenzene using a hydrogen-deuterium exchange method. Through the synergistic effect of specific reaction ligands, catalysts, bases, and reaction conditions, the deuterated 4-bromofluorobenzene prepared has a high deuteration rate, high purity, and high yield, making it very suitable for industrial production and having good application prospects.
[0023] 4) The present invention provides a method for preparing deuterated 4-bromofluorobenzene by hydrogen-deuterium exchange. The purification method is convenient and fast, and a deuterated 4-bromofluorobenzene product with a purity of more than 95% can be obtained by simple distillation. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 This is the gas chromatography-mass spectrometry of deuterated 4-bromofluorobenzene prepared in Example 1.
[0025] Figure 2 This is the gas chromatogram of deuterated 4-bromofluorobenzene prepared in Example 1. DETAILED DESCRIPTION
[0026] 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.
[0027] Example 1
[0028] Preparation of deuterated 4-bromofluorobenzene: 7 g of standard 4-bromofluorobenzene, 8 g of sodium acetate, 13.4 g of diphenylcyclohexylphosphine, 24.5 g of Pd(OAc), 100 ml of heavy water, and 20 ml of toluene were added sequentially to a reaction kettle and reacted at 130°C for 60 hours. After completion of the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire solution was poured into an evaporator and purified by steam distillation at 130°C. The distillate containing deuterated 4-bromofluorobenzene was collected and finally subjected to reduced pressure distillation at 80°C to prepare deuterated 4-bromofluorobenzene with a deuteration rate of 98%, a purity of 99.9%, and a yield of 97.7%.
[0029] The reaction formula is:
[0030]
[0031] Figure 1 This is the gas chromatography-mass spectrometer of deuterated 4-bromofluorobenzene prepared in Example 1. The calculated deuteration rate is 98%.
[0032] Figure 2 This is the gas chromatogram of deuterated 4-bromofluorobenzene prepared in Example 1, which shows that the purity of deuterated 4-bromofluorobenzene is 99.9%.
[0033] Example 2
[0034] Preparation of deuterated 4-bromofluorobenzene: 7 g of standard 4-bromofluorobenzene, 8 g of sodium acetate, 13.1 g of triphenylphosphine, 24.5 g of Pd(OAc), 100 ml of heavy water, and 20 ml of toluene were added sequentially to a reaction vessel and reacted at 130°C for 60 hours. After completion of the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire solution was poured into an evaporator and purified by steam distillation at 130°C. The distillate containing deuterated 4-bromofluorobenzene was collected and finally subjected to reduced pressure distillation at 80°C to produce deuterated 4-bromofluorobenzene with a deuteration rate of 84%, a purity of 98.3%, and a yield of 91.3%.
[0035] The reaction formula is:
[0036]
[0037] Example 3
[0038] Preparation of deuterated 4-bromofluorobenzene: 7 g of standard 4-bromofluorobenzene, 5.5 g of potassium hydroxide, 13.4 g of diphenylcyclohexylphosphine, 24.5 g of Pd(OAc), 100 ml of heavy water, and 20 ml of toluene were added sequentially to a reaction vessel and reacted at 130°C for 60 hours. After completion of the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire solution was poured into an evaporator and purified by steam distillation at 130°C. The distillate containing deuterated 4-bromofluorobenzene was collected and finally subjected to reduced pressure distillation at 80°C to prepare deuterated 4-bromofluorobenzene with a deuteration rate of 62%, a purity of 95.8%, and a yield of 81%.
[0039] The reaction formula is:
[0040]
[0041] Example 4
[0042] Preparation of deuterated 4-bromofluorobenzene: 7 g of standard 4-bromofluorobenzene, 13.46 g of potassium carbonate, 13.4 g of diphenylcyclohexylphosphine, 24.5 g of Pd(OAc), 100 ml of heavy water, and 20 ml of toluene were added sequentially to a reaction kettle and reacted at 130°C for 60 hours. After the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire solution was poured into an evaporator and purified by steam distillation at 130°C. The distillate containing deuterated 4-bromofluorobenzene was collected and finally subjected to reduced pressure distillation at 80°C to prepare deuterated 4-bromofluorobenzene with a deuteration rate of 77.2%, a purity of 98.9%, and a yield of 72%.
[0043] The reaction formula is:
[0044]
[0045] Example 5
[0046] Preparation of deuterated 4-bromofluorobenzene: 7 g of standard 4-bromofluorobenzene, 8 g of sodium acetate, 13.4 g of diphenylcyclohexylphosphine, 24.5 g of Pd(OAc), 400 ml of heavy water, and 20 ml of toluene were added sequentially to a reaction vessel and reacted at 130°C for 40 hours. After completion of the reaction, the resulting reaction solution was allowed to cool. After cooling to room temperature, the entire solution was poured into an evaporator and purified by steam distillation at 130°C. The distillate containing deuterated 4-bromofluorobenzene was collected and finally subjected to reduced pressure distillation at 80°C to prepare deuterated 4-bromofluorobenzene with a deuteration rate of 96.2%, a purity of 99.91%, and a yield of 81%.
[0047] The reaction formula is:
[0048]
[0049] 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 4-bromofluorobenzene by hydrogen-deuterium exchange, characterized in that: The following steps are involved: Using heavy water as a deuterated reagent and diphenylcyclohexylphosphine or triphenylphosphine as a reaction ligand, in the presence of a catalyst, a base and an organic solvent, a hydrogen-deuterium exchange reaction of 4-bromofluorobenzene occurs, and further purification is performed to obtain deuterated 4-bromofluorobenzene.
2. The method for preparing deuterated 4-bromofluorobenzene by hydrogen-deuterium exchange according to claim 1, wherein: The reaction ligand is diphenylcyclohexylphosphine.
3. The method for preparing deuterated 4-bromofluorobenzene by hydrogen-deuterium exchange according to claim 1 or 2, characterized in that: The catalyst is Pd(OAc)2.
4. The method for preparing deuterated 4-bromofluorobenzene by hydrogen-deuterium exchange according to claim 1 or 2, characterized in that: The base is sodium acetate.
5. The method for preparing deuterated 4-bromofluorobenzene by hydrogen-deuterium exchange method according to claim 1 or 2, characterized in that: The mass volume ratio of the 1,3-dibromobenzene to heavy water is 1 g:5 to 30 mL.
6. The method for preparing deuterated 4-bromofluorobenzene by hydrogen-deuterium exchange according to claim 1 or 2, characterized in that: The reaction temperature of the hydrogen-deuterium exchange reaction is 120-140° C., and the reaction time is 50-70 hours.
7. The method for preparing deuterated 4-bromofluorobenzene by hydrogen-deuterium exchange according to claim 1, characterized in that: The reaction ligand is diphenylcyclohexylphosphine, the catalyst is Pd(OAc)2, the base is sodium acetate, and the mass volume ratio of 1,3-dibromobenzene to heavy water is 1g:5-30mL; The reaction temperature of the hydrogen-deuterium exchange reaction is 120-140° C., and the reaction time is 50-70 hours.
8. The method for preparing deuterated 4-bromofluorobenzene 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, and the distillate containing deuterated 4-bromofluorobenzene is collected. Finally, the deuterated 4-bromofluorobenzene product is obtained by vacuum distillation.