A method for preparing deuterated p-chloroiodobenzene by hydrogen-deuterium exchange
By combining hydrogen-deuterium exchange with p-nitrobenzenesulfonic acid catalyst and optimized purification steps, the problems of complex and costly synthesis of deuterated p-chloroiodobenzene in existing technologies have been solved, realizing efficient, safe and economical preparation of deuterated p-chloroiodobenzene with significantly improved product purity and yield.
Patent Information
- Application Number
- CN202610915879.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-06-24
- Publication Date
- 2026-11-03
AI Technical Summary
In the existing technology, the synthesis method of deuterated p-chloroiodobenzene is complicated, the reaction conditions are harsh, the yield is low and the cost is high, and there is a lack of economically applicable preparation methods.
A hydrogen-deuterium exchange method was adopted, using p-nitrobenzenesulfonic acid as a catalyst. p-chloroiodobenzene, deuterated benzene and the catalyst were added to a reactor to carry out the hydrogen-deuterium exchange reaction. By optimizing the reaction conditions and purification steps, including neutralization, separation, distillation and recrystallization, high-purity deuterated p-chloroiodobenzene was prepared.
This method enables the preparation of deuterated p-chloroiodobenzene, which is simple to operate, highly safe, has a high yield, and is economically applicable. The deuteration rate can reach 98.5%, the chemical purity is as high as 99%, the product quality is excellent, and it is suitable for industrial production.
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Figure CN123026488A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of fine chemical technology, specifically relating to a method for preparing deuterated p-chloroiodobenzene by hydrogen-deuterium exchange. Background Technology
[0002] Hydrogen has three isotopes: protium (H), deuterium (D), and tritium (T). Protium, consisting of one proton and one electron, is the predominant form of hydrogen. Deuterium is another important isotope of hydrogen. Because its atomic mass is twice that of protium, the carbon-deuterium (CD) bond has a lower ground-state energy and a higher activation energy for cleavage than the carbon-hydrogen (CH) bond, making the CD bond more stable. Utilizing this property, deuteration modification of drug molecules has become an important strategy in drug development.
[0003] Deuteration modification can alter the pharmacokinetic properties of drugs. By introducing deuterium atoms into specific metabolic sites of drug molecules, the metabolic rate of drugs can be significantly slowed, thereby prolonging the drug's half-life in vivo, reducing the dosage and frequency of administration, and improving the drug's efficacy and safety. For example, AUSTEDO (deuterated bubenazine), the world's first approved deuterated drug, and Donafenib, China's first approved deuterated drug, have both demonstrated significant advantages over their non-deuterated counterparts in clinical practice. A head-to-head comparative study of Donafenib and Sorafenib showed statistical advantages in pharmacokinetics, efficacy, and safety.
[0004] Besides their applications in the pharmaceutical field, deuterated compounds also show broad application prospects in areas such as nuclear magnetic resonance (NMR) solvents, organic light-emitting diode (OLED) materials, biological metabolic analysis, intermediate labeling, and environmental pollution source tracking. With the increasing demand for deuterated compounds, developing efficient, economical, and safe novel synthetic methods has become a research hotspot in the field of chemical synthesis.
[0005] p-Chloroiodobenzene is an important chemical intermediate, and its deuterated derivatives are valuable in the synthesis of deuterated molecules with specific functions. Current deuteration methods for such aromatic compounds suffer from problems such as complex operation, harsh reaction conditions, low yields, or high costs. Therefore, developing a simple, mild, high-yield, and economical method for preparing deuterated p-chloroiodobenzene is of significant practical importance. Summary of the Invention
[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a simple, safe, high-yield, and economically applicable method for preparing deuterated p-chloroiodobenzene by hydrogen-deuterium exchange.
[0007] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing deuterated p-chloroiodobenzene by hydrogen-deuterium exchange includes the following steps: p-chloroiodobenzene, p-nitrobenzenesulfonic acid as a catalyst, and deuterated benzene as a deuterium source were added to a reaction vessel, and then a hydrogen-deuterium exchange reaction was carried out to obtain a reaction solution containing the target product. After the reaction was completed, the reaction solution was purified to finally prepare deuterated p-chloroiodobenzene with high purity and high deuteration rate.
[0008] Studies have found that p-nitrobenzenesulfonic acid, as a catalyst, has a key impact on the above reaction. If other acids are used as catalysts, there are disadvantages such as long reaction time, low deuteration rate, and many by-products.
[0009] The reaction formula is as follows: .
[0010] In a preferred embodiment of the present invention, the mass-to-volume ratio of p-chloroiodobenzene to p-nitrobenzenesulfonic acid is (40-55) g: 5 mL. Within this ratio range, the catalytic effect is good and the reaction conversion rate is high.
[0011] In a preferred embodiment of the present invention, the mass ratio of p-chloroiodobenzene to deuterated benzene is (40-55):300. This ratio ensures sufficient deuterium source, which is beneficial for the hydrogen-deuterium exchange reaction to proceed in the direction of generating the target product.
[0012] In a preferred embodiment of the present invention, the hydrogen-deuterium exchange reaction is carried out at a temperature of 115-125°C for 26-30 hours. Under these conditions, the reaction rate is moderate, side reactions are few, and a high product yield and deuteration rate can be obtained.
[0013] As a preferred embodiment of the present invention, the specific steps of the purification process are as follows: The resulting reaction solution was allowed to cool to room temperature. A saturated aqueous solution of sodium bicarbonate was added to the cooled reaction solution to neutralize the acid acting as a catalyst in the reaction system. Then, the organic phase was separated by liquid-liquid separation. The obtained organic phase was transferred to an evaporator for distillation to recover the deuterated benzene solvent and preliminarily purify the product; Finally, the distilled product was purified by recrystallization to prepare high-purity deuterated p-chloroiodobenzene.
[0014] The beneficial effects of this invention are at least as follows: 1) Simple operation and high safety: This invention adopts a one-step hydrogen-deuterium exchange method. The reaction process is simple and does not require high-pressure equipment or highly dangerous reagents. The entire process is safe. 2) High yield and good product purity: Through optimized reaction conditions and purification steps, the deuteration rate of deuterated p-chloroiodobenzene prepared by this method can reach 98.5%, the chemical purity is as high as 99%, and the product quality is excellent. 3) Good economic applicability: The raw materials used in this invention are easy to obtain, the amount of catalyst used is small, and the deuterated benzene used as a deuterium source can be recovered and reused through distillation, which reduces the production cost and has good economic applicability and industrial production prospects. 4) Easy purification: The designed purification process includes neutralization, separation, distillation and recrystallization, all of which are conventional chemical operation units. The operation is simple and can effectively remove impurities and ensure the quality of the final product. Attached Figure Description
[0015] Figure 1 This is the liquid chromatogram (HPLC) of the deuterated p-chloroiodobenzene prepared in Example 1.
[0016] Figure 2 This is the nuclear magnetic resonance (NMR) spectrum of the deuterated p-chloroiodobenzene prepared in Example 1. Detailed Implementation
[0017] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of the present invention. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in the art, or in accordance with the product manual.
[0018] Example 1: Preparation of deuterated p-chloroiodobenzene In a reaction vessel equipped with a stirrer and a thermometer, 47.69 g of ordinary p-chloroiodobenzene, 5 mL of p-nitrobenzenesulfonic acid, and 300 g of deuterated benzene were added sequentially. The stirrer was turned on, and the temperature of the reaction system was raised to 120°C and maintained at this temperature for 28 hours.
[0019] After the reaction is complete, stop heating and allow the reaction solution to cool. Once the reaction solution has cooled to room temperature, slowly add a saturated aqueous solution of sodium bicarbonate until no more bubbles are produced, thus completely neutralizing the p-nitrobenzenesulfonic acid. Transfer the mixture to a separatory funnel, allow it to stand and separate into layers, and then separate the lower organic phase.
[0020] The collected organic phase was transferred to an evaporator for atmospheric distillation to recover most of the deuterated benzene solvent. Distillation was stopped when only a small amount of liquid remained in the evaporator. The residue in the evaporator was recrystallized and purified to finally obtain the deuterated p-chloroiodobenzene solid product.
[0021] See Figure 1 and Figure 2Analysis by ¹H NMR spectroscopy showed that the product had a deuteration rate of 98.5%; analysis by HPLC showed that the product had a chemical purity of 99.1%.
[0022] Comparative Example 1: Preparation of Deuterated p-chloroiodobenzene
[0023] In a reaction vessel equipped with a stirrer and a thermometer, 47.69 g of ordinary p-chloroiodobenzene, 4.8 mL of p-toluenesulfonic acid, and 300 g of deuterated benzene were added sequentially. The stirring was started, and the temperature of the reaction system was raised to 120°C and maintained at this temperature for 28 hours.
[0024] After the reaction is complete, stop heating and allow the reaction solution to cool. Once the reaction solution has cooled to room temperature, slowly add a saturated aqueous solution of sodium bicarbonate until no more bubbles are produced, thus completely neutralizing the p-toluenesulfonic acid. Transfer the mixture to a separatory funnel, allow it to stand and separate into layers, and then separate the lower organic phase.
[0025] The collected organic phase was transferred to an evaporator for atmospheric distillation to recover most of the deuterated benzene solvent. Distillation was stopped when only a small amount of liquid remained in the evaporator. The residue in the evaporator was recrystallized and purified to finally obtain the deuterated p-chloroiodobenzene solid product. ¹H NMR analysis showed that the deuteration rate of the product was 75.4%; high performance liquid chromatography (HPLC) analysis showed that the chemical purity of the product was 87.6%.
[0026] Comparative Example 2: Preparation of Deuterated p-chloroiodobenzene
[0027] In a reaction vessel equipped with a stirrer and a thermometer, 47.69 g of ordinary p-chloroiodobenzene, 4.6 mL of benzenesulfonic acid, and 300 g of deuterated benzene were added sequentially. The stirrer was turned on, and the temperature of the reaction system was raised to 120°C and maintained at this temperature for 28 hours.
[0028] After the reaction is complete, stop heating and allow the reaction solution to cool. Once the reaction solution has cooled to room temperature, slowly add a saturated aqueous solution of sodium bicarbonate until no more bubbles are produced, thus completely neutralizing the benzenesulfonic acid. Transfer the mixture to a separatory funnel, allow it to stand and separate into layers, and then separate the lower organic phase.
[0029] The collected organic phase was transferred to an evaporator for atmospheric distillation to recover most of the deuterated benzene solvent. Distillation was stopped when only a small amount of liquid remained in the evaporator. The residue in the evaporator was recrystallized and purified to finally obtain the deuterated p-chloroiodobenzene solid product. ¹H NMR analysis showed that the deuteration rate of the product was 86.3%; high performance liquid chromatography (HPLC) analysis showed that the chemical purity of the product was 88.1%.
[0030] Comparative Example 3: Preparation of Deuterated p-chloroiodobenzene
[0031] In a reaction vessel equipped with a stirrer and a thermometer, 47.69 g of ordinary p-chloroiodobenzene, 3.1 mL of trifluoromethanesulfonic acid, and 300 g of deuterated benzene were added sequentially. The stirrer was turned on, and the temperature of the reaction system was raised to 120°C and maintained at this temperature for 28 hours.
[0032] After the reaction is complete, stop heating and allow the reaction solution to cool. Once the reaction solution has cooled to room temperature, slowly add a saturated aqueous solution of sodium bicarbonate until no more bubbles are produced, thus completely neutralizing the trifluoromethanesulfonic acid. Transfer the mixture to a separatory funnel, allow it to stand and separate into layers, and then separate the lower organic phase.
[0033] The collected organic phase was transferred to an evaporator for atmospheric distillation to recover most of the deuterated benzene solvent. Distillation was stopped when only a small amount of liquid remained in the evaporator. The residue in the evaporator was recrystallized and purified to obtain deuterated p-chloroiodobenzene 86 solid product. ¹H NMR analysis showed a deuteration rate of 86.1% and a chemical purity of 93.9% according to high performance liquid chromatography (HPLC).
[0034] Comparative Example 4: Preparation of Deuterated p-chloroiodobenzene
[0035] In a reaction vessel equipped with a stirrer and a thermometer, 47.69 g of ordinary p-chloroiodobenzene, 2.6 mL of trifluoroacetic acid, and 300 g of deuterated benzene were added sequentially. The stirring was started, and the temperature of the reaction system was raised to 120°C and maintained at this temperature for 28 hours.
[0036] After the reaction is complete, stop heating and allow the reaction solution to cool. Once the reaction solution has cooled to room temperature, slowly add a saturated aqueous solution of sodium bicarbonate until no more bubbles are produced, thus completely neutralizing the trifluoroacetic acid. Transfer the mixture to a separatory funnel, allow it to stand and separate into layers, and then separate the lower organic phase.
[0037] The collected organic phase was transferred to an evaporator for atmospheric distillation to recover most of the deuterated benzene solvent. Distillation was stopped when only a small amount of liquid remained in the evaporator. The residue in the evaporator was recrystallized and purified to finally obtain the deuterated p-chloroiodobenzene solid product. ¹H NMR analysis showed that the deuteration rate of the product was 67.1%; high performance liquid chromatography (HPLC) analysis showed that the chemical purity of the product was 92.4%.
[0038] Example 2: Preparation of deuterated p-chloroiodobenzene
[0039] In a reaction vessel equipped with a stirrer and a thermometer, 47.69 g of ordinary p-chloroiodobenzene, 5 mL of p-nitrobenzenesulfonic acid, and 300 g of deuterated benzene were added sequentially. The stirrer was turned on, and the temperature of the reaction system was raised to 120°C and maintained at this temperature for 22 hours.
[0040] After the reaction is complete, stop heating and allow the reaction solution to cool. Once the reaction solution has cooled to room temperature, slowly add a saturated aqueous solution of sodium bicarbonate until no more bubbles are produced, thus completely neutralizing the p-nitrobenzenesulfonic acid. Transfer the mixture to a separatory funnel, allow it to stand and separate into layers, and then separate the lower organic phase.
[0041] The collected organic phase was transferred to an evaporator for atmospheric distillation to recover most of the deuterated benzene solvent. Distillation was stopped when only a small amount of liquid remained in the evaporator. The residue in the evaporator was recrystallized and purified to finally obtain the deuterated p-chloroiodobenzene solid product.
[0042] Analysis by ¹H NMR spectroscopy showed that the product had a deuteration rate of 97.5%; analysis by HPLC showed that the product had a chemical purity of 97.2%.
[0043] Example 3: Preparation of deuterated p-chloroiodobenzene
[0044] In a reaction vessel equipped with a stirrer and a thermometer, 47.69 g of ordinary p-chloroiodobenzene, 5 mL of p-nitrobenzenesulfonic acid, and 300 g of deuterated benzene were added sequentially. The stirrer was turned on, and the temperature of the reaction system was raised to 120°C and maintained at this temperature for 34 hours.
[0045] After the reaction is complete, stop heating and allow the reaction solution to cool. Once the reaction solution has cooled to room temperature, slowly add a saturated aqueous solution of sodium bicarbonate until no more bubbles are produced, thus completely neutralizing the p-nitrobenzenesulfonic acid. Transfer the mixture to a separatory funnel, allow it to stand and separate into layers, and then separate the lower organic phase.
[0046] The collected organic phase was transferred to an evaporator for atmospheric distillation to recover most of the deuterated benzene solvent. Distillation was stopped when only a small amount of liquid remained in the evaporator. The residue in the evaporator was recrystallized and purified to finally obtain the deuterated p-chloroiodobenzene solid product.
[0047] Analysis by ¹H NMR spectroscopy showed that the product had a deuteration rate of 98.1%; analysis by HPLC showed that the product had a chemical purity of 98.3%.
[0048] Example 4: Preparation of deuterated p-chloroiodobenzene
[0049] In a reaction vessel equipped with a stirrer and a thermometer, 47.69 g of ordinary p-chloroiodobenzene, 5 mL of p-nitrobenzenesulfonic acid, and 300 g of deuterated benzene were added sequentially. The stirring was started, and the temperature of the reaction system was raised to 110°C and maintained at this temperature for 28 hours.
[0050] After the reaction is complete, stop heating and allow the reaction solution to cool. Once the reaction solution has cooled to room temperature, slowly add a saturated aqueous solution of sodium bicarbonate until no more bubbles are produced, thus completely neutralizing the p-nitrobenzenesulfonic acid. Transfer the mixture to a separatory funnel, allow it to stand and separate into layers, and then separate the lower organic phase.
[0051] The collected organic phase was transferred to an evaporator for atmospheric distillation to recover most of the deuterated benzene solvent. Distillation was stopped when only a small amount of liquid remained in the evaporator. The residue in the evaporator was recrystallized and purified to finally obtain the deuterated p-chloroiodobenzene solid product.
[0052] Analysis by ¹H NMR spectroscopy showed that the product had a deuteration rate of 96.5%; analysis by HPLC showed that the product had a chemical purity of 96.2%.
[0053] Example 5: Preparation of deuterated p-chloroiodobenzene
[0054] In a reaction vessel equipped with a stirrer and a thermometer, 47.69 g of ordinary p-chloroiodobenzene, 5 mL of p-nitrobenzenesulfonic acid, and 300 g of deuterated benzene were added sequentially. The stirrer was turned on, and the temperature of the reaction system was raised to 130°C and maintained at this temperature for 28 hours.
[0055] After the reaction is complete, stop heating and allow the reaction solution to cool. Once the reaction solution has cooled to room temperature, slowly add a saturated aqueous solution of sodium bicarbonate until no more bubbles are produced, thus completely neutralizing the p-nitrobenzenesulfonic acid. Transfer the mixture to a separatory funnel, allow it to stand and separate into layers, and then separate the lower organic phase.
[0056] The collected organic phase was transferred to an evaporator for atmospheric distillation to recover most of the deuterated benzene solvent. Distillation was stopped when only a small amount of liquid remained in the evaporator. The residue in the evaporator was recrystallized and purified to finally obtain the deuterated p-chloroiodobenzene solid product.
[0057] Analysis by ¹H NMR spectroscopy showed that the product had a deuteration rate of 97.8%; analysis by HPLC showed that the product had a chemical purity of 96.8%.
[0058] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for preparing deuterated p-chloroiodobenzene by hydrogen-deuterium exchange, characterized in that, Includes the following steps: p-chloroiodobenzene, p-nitrobenzenesulfonic acid as a catalyst, and deuterated benzene as a deuterium source were added to a reaction vessel, and then a hydrogen-deuterium exchange reaction was carried out to obtain a reaction solution containing the target product. After the reaction was completed, the reaction solution was purified to finally prepare deuterated p-chloroiodobenzene.
2. The preparation method according to claim 1, characterized in that: The mass-to-volume ratio of p-chloroiodobenzene to p-nitrobenzenesulfonic acid is (40-55) g: 5 mL.
3. The preparation method according to claim 1 or 2, characterized in that: The mass ratio of p-chloroiodobenzene to deuterated benzene is (40-55):
300.
4. The preparation method according to claim 1 or 2, characterized in that: The temperature for the hydrogen-deuterium exchange reaction is 115-125℃.
5. The preparation method according to claim 4, characterized in that: The hydrogen-deuterium exchange reaction takes 26-30 hours.
6. The preparation method according to claim 1 or 2, characterized in that: The specific steps of the purification process are as follows: The resulting reaction solution was allowed to cool to room temperature. A saturated aqueous solution of sodium bicarbonate was added to the cooled reaction solution to neutralize the acid acting as a catalyst in the reaction system. Then, the organic phase was separated by liquid-liquid separation. The obtained organic phase was transferred to an evaporator for distillation to recover the deuterated benzene solvent and preliminarily purify the product; Finally, the distilled product was purified by recrystallization to prepare deuterated p-chloroiodobenzene.