Method for preparing 3,3',4,4'-tetrachlorobiphenyl-d 6

Abstract

A method for preparing 3,3',4,4'-tetrachlorobiphenyl-d6, comprising: step 1, mixing deuterated o-dichlorobenzene, methoxy(cyclooctadiene)iridium dimer, 4,4'-di-tert-butyl-2,2'-dipyridine, and bis(pinacolato)diboron to prepare 3,4-dichlorophenylboronic acid pinacol ester-d3; step 2, mixing the 3,4-dichlorophenylboronic acid pinacol ester-d3, cuprous iodide, 1,10-phenanthroline, and potassium iodide to prepare 3,4-dichloroiodobenzene-d3; and step 3, mixing the 3,4-dichloroiodobenzene-d3, a palladium catalyst, an alkaline solution, and the 3,4-dichlorophenylboronic acid pinacol ester-d3 to prepare the 3,3',4,4'-tetrachlorobiphenyl-d6.

Description

Preparation method of 3,3',4,4'-tetrachlorobiphenyl-d6 TECHNICAL FIELD

[0001] The present application relates to the technical field of preparation of isotopically labeled compounds, and particularly relates to a preparation method of 3,3',4,4'-tetrachlorobiphenyl-d6. BACKGROUND

[0002] In the field of environmental science and technology, polychlorinated biphenyls (PCBs) as a class of highly stable and highly toxic chlorinated aromatic compounds have serious environmental pollution problems, which pose a long-term and profound impact on the ecological system and human health. In view of the persistence, bioaccumulation and toxicity (i.e. "three effects": teratogenic, carcinogenic and mutagenic) of PCBs, the United Nations Environment Programme explicitly included them in the 12 persistent organic pollutants listed in the Stockholm Convention in 2001, emphasizing the urgency of global monitoring and management.

[0003] Currently, one of the major challenges in the field of PCBs monitoring in China is the lack of high-quality isotopic standard samples, especially for precise quantitative analysis of PCBs. This shortcoming limits the development pace of environmental monitoring technology in China. In recent years, although scholars such as Zheng et al. explored the direct hydrogen / deuterium exchange strategy catalyzed by base to synthesize deuterated polychlorinated biphenyls in their 2022 research, the deuterium enrichment of the obtained products was uneven (deuterium isotope abundance ranged from 12% to 99%), which could not fully meet the demand of high-precision internal standards, especially in high-standard analysis applications requiring isotopic purity and labeling rate of more than 98.0%.

[0004] In view of the above technical limitations and urgent needs, it is particularly important to develop a preparation method of 3,3',4,4'-tetrachlorobiphenyl-d6, aiming to improve its applicability and accuracy as an analysis internal standard, to fill the gap in this field in China and even internationally, and to promote the progress of environmental monitoring technology and the implementation of pollution control strategies.

[0005] SUMMARY

[0006] The purpose of the present application is to overcome the deficiencies in the prior art and provide a preparation method of 3,3',4,4'-tetrachlorobiphenyl-d6.

[0007] To achieve the above purpose, the technical solution adopted by the present application is:

[0008] A preparation method of 3,3',4,4'-tetrachlorobiphenyl-d6 is provided, comprising the following steps:

[0009] Step one, mixing deuterated o-dichlorobenzene, methoxy(cyclooctadiene)iridium dimer, 4,4'-di-tert-butyl-2,2'-bipyridine, and bis(pinacolato)diboron, and providing a first reaction environment to prepare pinacol 3,4-dichlorophenylboronic acid-d3;

[0010] Step two, mixing the pinacol 3,4-dichlorophenylboronic acid-d3, cuprous iodide, 1,10-phenanthroline, and potassium iodide, and providing a second reaction environment to prepare 3,4-dichloroiodobenzene-d3.

[0011] Step three, mixing the 3,4-dichloroiodobenzene-d3, a palladium catalyst, a basic solution, and the pinacol 3,4-dichlorophenylboronic acid-d3, and providing a third reaction environment to prepare the 3,3',4,4'-tetrachlorobiphenyl-d6.

[0012] Preferably, the step one comprises:

[0013] dissolving and mixing the deuterated o-dichlorobenzene, the methoxy(cyclooctadiene)iridium dimer, the 4,4'-di-tert-butyl-2,2'-bipyridine, and the bis(pinacolato)diboron in a first reaction solvent, reacting for a first reaction time at a first reaction temperature under protection of an inert gas to prepare the pinacol 3,4-dichlorophenylboronic acid-d3.

[0014] Preferably, the molar ratio of the deuterated o-dichlorobenzene to the methoxy(cyclooctadiene)iridium dimer to the 4,4'-di-tert-butyl-2,2'-bipyridine to the bis(pinacolato)diboron is 2:(0.001-0.005):(0.002-0.005):1.

[0015] Preferably, the first reaction solvent is anhydrous tetrahydrofuran.

[0016] Preferably, the first reaction temperature is 80-100°C.

[0017] Preferably, the first reaction time is 36-60h.

[0018] Preferably, the step two comprises:

[0019] dissolving and mixing the pinacol 3,4-dichlorophenylboronic acid-d3, the cuprous iodide, the 1,10-phenanthroline, and the potassium iodide in a second reaction solvent, reacting for a second reaction time at a second reaction temperature under a sealed environment to prepare the 3,4-dichloroiodobenzene-d3.

[0020] Preferably, the molar ratio of the 3,4-dichlorophenylboronic acid pinacol ester-d3 to the copper iodide to the 1,10-phenanthroline to the potassium iodide is 1:(0.1-0.4):(0.2-0.8):(1.5-4.0).

[0021] Preferably, the second reaction solvent is methanol or / and water.

[0022] Preferably, the second reaction temperature is 60℃-100℃.

[0023] Preferably, the second reaction time is 4h-8h.

[0024] Preferably, the step three comprises:

[0025] dissolving the 3,4-dichlorophenylboronic acid pinacol ester-d3 in a third reaction solvent to obtain a solution of the 3,4-dichlorophenylboronic acid pinacol ester-d3;

[0026] dissolving and mixing the 3,4-dichloroiodobenzene-d3, a palladium catalyst, and a basic solution in a fourth reaction solvent under the protection of an inert gas, adding the solution of the 3,4-dichlorophenylboronic acid pinacol ester-d3 drop by drop at a third dropping rate after the third reaction temperature, and reacting for a third reaction time to prepare the 3,3',4,4'-tetrachlorobiphenyl-d6.

[0027] Preferably, the molar ratio of the 3,4-dichloroiodobenzene-d3 to the palladium catalyst to the basic solution to the 3,4-dichlorophenylboronic acid pinacol ester-d3 is 1:(0.03-0.1):(1.5-3):(1-2).

[0028] Preferably, the palladium catalyst is at least one of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, or palladium acetate.

[0029] Preferably, the basic solution is at least one of an aqueous solution of sodium carbonate, an aqueous solution of potassium carbonate, or an aqueous solution of cesium carbonate.

[0030] Preferably, the third reaction solvent is ethanol.

[0031] Preferably, the fourth reaction solvent is 1,4-dioxane or / and toluene.

[0032] Preferably, the third reaction temperature is 90℃-110℃.

[0033] Preferably, the third dropping rate is 1 drop / second-2 drops / second.

[0034] Preferably, the third reaction time is 4h-24h.

[0035] The present application adopts the above technical solutions, and has the following technical effects compared with the prior art:

[0036] The preparation method of the present application significantly improves the synthesis efficiency and product quality, including:

[0037] (1) The product 3,3',4,4'-tetrachlorobiphenyl-d6 has extremely high chemical purity, more than 98.0%, ensuring the accuracy and reliability of the analysis results; the deuterium isotope abundance of the product 3,3',4,4'-tetrachlorobiphenyl-d6 also reaches more than 98.0%, which is a significant leap compared with the isotope abundance level of about 92% in the prior art. This breakthrough makes the product of the present application an ideal high-precision isotope internal standard reagent in polychlorinated biphenyl analysis, greatly enhancing the accuracy and reliability of environmental monitoring and scientific research;

[0038] (2) The synthesis path significantly simplifies the complexity of the traditional synthesis process, is simple and fast to operate, and greatly reduces the production cost; at the same time, through the optimized separation and purification steps, not only the overall yield is improved, but also the high purity and stability of the product are ensured, laying a solid foundation for large-scale production and wide application.

[0039] (3) Attention is paid to the atomic utilization rate in the synthesis process, effectively reducing the generation of by-products, reducing resource consumption and environmental pollution, embodying the concept of green chemistry. In addition to its significant effect on cost control, the method ensures environmental friendliness while also taking into account economic benefits, providing a sustainable solution for related fields. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 is the nuclear magnetic hydrogen spectrum of 3,3',4,4'-tetrachlorobiphenyl-d6 prepared by the preparation method in Example 1 of the present application;

[0041] Figure 2 is the gas-mass spectrum of 3,3',4,4'-tetrachlorobiphenyl-d6 prepared by the preparation method in Example 1 of the present application;

[0042] Figure 3 is the gas phase purity chromatogram of 3,3',4,4'-tetrachlorobiphenyl-d6 prepared by the preparation method in Example 1 of the present application. DETAILED DESCRIPTION

[0043] The specific embodiments of the present application will be described in detail below.

[0044] Unless otherwise defined, the technical terms or scientific terms used in the claims and the specification should be understood as the usual meaning understood by a person with ordinary skills in the art to which the present application belongs.

[0045] The word "comprising" or similar terms used in the specification and claims of this patent application mean that the objects preceding "comprising" include the objects listed after "comprising" or their equivalents, and do not exclude other objects.

[0046] The numerical values ​​mentioned in this invention include all values ​​increasing one unit at a time from low to high, assuming that there is at least a two-unit interval between any lower and higher value. For example, if it is said that a component quantity or a physical quantity is better from 1 to 100, 10 to 90, and 20 to 80, it means that values ​​such as 5 to 95, 14 to 76, 23 to 67, 32 to 58, and 41 to 49 are clearly listed in this specification; for values ​​less than 1, 0.0001, 0.001, 0.01, or 0.1 are considered to be a suitable unit. The foregoing examples are for illustrative purposes only; in practice, all combinations of values ​​between the lowest and highest listed values ​​are considered to be clearly listed in this specification in a similar manner.

[0047] Example 1

[0048] This embodiment provides a method for preparing 3,3',4,4'-tetrachlorobiphenyl-d6, the steps of which include:

[0049] Step 1: Provide a 100 mL sealing tube and dissolve and mix deuterated o-dichlorobenzene (5 g, 2.0 eq.), methoxy(cyclooctadiene) iridium dimer (10.97 mg, 0.001 eq.), 4,4'-di-tert-butyl-2,2'-dipyridine (8.89 mg, 0.002 eq.), and bis(pinacol)diboron (4.20 g, 1.0 eq.) in anhydrous tetrahydrofuran (15 mL). Under nitrogen protection, the reaction is carried out at 80 °C for 48 h to prepare 3,4-dichlorophenylboronic acid pinacol ester-d3;

[0050] The reaction was monitored by TLC (using n-hexane as the eluent). After cooling to room temperature, the mixture was successively diluted with ethyl acetate, filtered, concentrated, and subjected to column chromatography (using n-hexane and ethyl acetate as eluents, V... 正己烷 V 乙酸乙酯 =50:1), and evaporated to dryness to obtain 7.49 g of colorless oily product, namely 3,4-dichlorophenylboronic acid pinacol ester-d3, with a yield of 82%;

[0051] Step two, provide a 100 mL sealed tube, dissolve the 3,4-dichlorobenzene pinacol borate-d3(3 g) in methanol, add cuprous iodide (414.06 mg, 0.2 eq.), 1,10-phenanthroline (783.58 mg, 0.4 eq.), potassium iodide (5.41 g, 3.0 eq.), and water (7 mL), mix, and react at 80 °C for 6 h under a sealed environment to prepare 3,4-dichloroiodobenzene-d3;

[0052] Monitor the reaction by TLC (eluent: n-hexane), after cooling to room temperature, sequentially perform suction filtration, ethyl acetate washing of the filter cake, spinning off the organic solvent, ethyl acetate extraction, anhydrous sodium sulfate drying, and concentration to obtain 3,4-dichloroiodobenzene-d3;

[0053] Step three, dissolve the 3,4-dichlorobenzene pinacol borate-d3(3.6 g, 1.2 eq.) in ethanol (20 mL) to obtain a 3,4-dichlorobenzene pinacol borate-d3 solution;

[0054] Provide a three-necked flask, dissolve the 3,4-dichloroiodobenzene-d3, [1,1’-bis(diphenylphosphino)ferrocene]palladium dichloride (397.79 mg, 0.05 eq.) in 1,4-dioxane (100 mL) under the protection of nitrogen, mix with an aqueous solution (2 mol / L) of sodium carbonate (2 eq.), after adding the 3,4-dichlorobenzene pinacol borate-d3 solution dropwise at 1 drop / sec-2 drops / sec under reflux at 105 °C for 4 h to prepare the 3,3’,4,4’-tetrachlorobiphenyl-d6;

[0055] Monitor the reaction by TLC (eluent: n-hexane), after cooling to room temperature, sequentially perform ethyl acetate dilution, reduced-pressure filtration, three times of water washing of the filtrate, ethyl acetate extraction of the aqueous layer, combination of the organic layers, anhydrous sodium sulfate drying, filtration, concentration, addition of silica gel and spinning drying, and column chromatography (eluent: n-hexane) to obtain 2.88 g of the product, i.e., 3,3’,4,4’-tetrachlorobiphenyl-d6, with a yield of 89%, 1H NMR as shown in FIG. 1, GC-MS as shown in FIG. 2, and gas phase purity chromatogram as shown in FIG. 3, with a gas chromatographic purity of 100.00%, and calculated isotopic abundance of 98.38 atom% D, without obvious isotopic abundance dilution.

[0056] Example 2

[0057] The present example provides a preparation method of 3,3’,4,4’-tetrachlorobiphenyl-d6, including the following steps:

[0058] Step 1, provide a 100 mL sealed tube, dissolve and mix deuterated o-dichlorobenzene (5 g, 2.0 eq.), methoxy (cyclooctadiene) iridium dimer (21.95 mg, 0.002 eq.), 4,4'-di-tert-butyl-2,2'-bipyridine (17.77 mg, 0.004 eq.), and bis(pinacolato)diboron (4.20 g, 1.0 eq.) in anhydrous tetrahydrofuran (15 mL), and react at 100 °C for 36 h under the protection of nitrogen to prepare pinacol 3,4-dichlorophenylboronic acid-d3;

[0059] Monitor the reaction by TLC (eluent: n-hexane), after cooling to room temperature, sequentially dilute with ethyl acetate, filter, concentrate, column chromatography (eluent: n-hexane and ethyl acetate, V 正己烷 :V 乙酸乙酯 = 50:1), and rotary evaporation to obtain 7.30 g of colorless oily product, i.e., pinacol 3,4-dichlorophenylboronic acid-d3, with a yield of 80%;

[0060] Step 2, provide a 100 mL sealed tube, dissolve the pinacol 3,4-dichlorophenylboronic acid-d3 (3 g) in methanol, add copper iodide (207.03 mg, 0.1 eq.), 1,10-phenanthroline (391.79 mg, 0.2 eq.), potassium iodide (2.71 g, 1.5 eq.), and water (7 mL) to mix, and react at 80 °C for 4 h under a sealed environment to prepare 3,4-dichloroiodobenzene-d3;

[0061] Monitor the reaction by TLC (eluent: n-hexane), after cooling to room temperature, sequentially perform suction filtration, ethyl acetate washing of the filter cake, rotary evaporation of the organic solvent, ethyl acetate extraction, anhydrous sodium sulfate drying, and concentration to obtain 3,4-dichloroiodobenzene-d3;

[0062] Step 3, dissolve the pinacol 3,4-dichlorophenylboronic acid-d3 (4.20 g, 1.4 eq.) in ethanol (20 mL) to obtain a solution of pinacol 3,4-dichlorophenylboronic acid-d3;

[0063] Provide a three-necked flask, dissolve the 3,4-dichloroiodobenzene-d3 and tetrakis(triphenylphosphine)palladium (1.26 g, 0.1 eq.) in toluene (100 mL) under the protection of nitrogen, add an aqueous solution (2 mol / L) of cesium carbonate (3 eq.) to mix, after adding the solution of pinacol 3,4-dichlorophenylboronic acid-d3 dropwise at 1 drop / s-2 drops / s under reflux at 110 °C for 12 h to prepare the 3,3',4,4'-tetrachlorobiphenyl-d6;

[0064] TLC (eluent: n-hexane) was used to monitor the reaction. After cooling to room temperature, ethyl acetate dilution, vacuum filtration, three times of water washing of the filtrate, ethyl acetate extraction of the water layer, combined organic layer, anhydrous sodium sulfate drying, filtration, concentration, addition of silica gel and spin-drying, and column chromatography (eluent: n-hexane) were sequentially performed to obtain 2.63 g of the product, i.e., 3,3',4,4'-tetrachlorobiphenyl-d6, with a yield of 81%, a gas chromatography purity of 99.52%, and an isotopic abundance of 98.22 atom% D, and no significant isotopic abundance dilution was observed.

[0065] Comparative Example

[0066] A 25 mL sealed tube was provided, 3,3',4,4'-tetrachlorobiphenyl (100 mg) and potassium tert-butoxide (11.53 mg, 0.3 eq.) were dissolved and mixed in DMSO-d6 (3 mL), deuterium source heavy water (0.13 mL, 20.0 eq.) was added and mixed, and the reaction was performed at 100°C for 24 h.

[0067] After cooling to room temperature, ethyl acetate dilution, three times of water washing of the organic layer, anhydrous sodium sulfate drying, filtration, concentration, addition of silica gel and spin-drying, and column chromatography (eluent: n-hexane) were sequentially performed to obtain the product 3,3',4,4'-tetrachlorobiphenyl-d6 with an isotopic abundance of 77.57 atom% D.

[0068] In summary, the preparation method of the present application significantly improves the synthesis efficiency and product quality, including:

[0069] (1) The product 3,3',4,4'-tetrachlorobiphenyl-d6 has extremely high chemical purity, more than 98.0%, ensuring the accuracy and reliability of the analysis results; the deuterium isotopic abundance of the product 3,3',4,4'-tetrachlorobiphenyl-d6 also reaches more than 98.0%, which is a significant leap compared to the isotopic abundance level of about 92% in the prior art. This breakthrough makes the product of the present application an ideal high-precision isotopic internal standard reagent in polychlorinated biphenyl analysis, greatly enhancing the accuracy and reliability of environmental monitoring and scientific research;

[0070] (2) The synthesis path significantly simplifies the complexity of the traditional synthesis process, is simple and fast to operate, and greatly reduces the production cost; at the same time, through the optimized separation and purification steps, not only the overall yield is improved, but also the high purity and stability of the product are ensured, laying a solid foundation for large-scale production and wide application.

[0071] (3) Pay attention to the atomic utilization rate in the synthesis process, effectively reduce the generation of by-products, reduce resource consumption and environmental pollution, embody the concept of green chemistry. In addition to its significant effect on cost control, the method ensures environmental friendliness while also taking into account economic benefits, providing a sustainable solution for related fields.

[0072] The above only describes the preferred embodiments of the present application, and does not limit the implementation and protection scope of the present application. Those skilled in the art should realize that any equivalent replacement and obvious change made by applying the content of the present application description and drawings should be included in the protection scope of the present application.

Claims

1. A process for the preparation of 3,3',4,4'-tetrachlorobiphenyl-d6, characterized in that the steps Comprising: Step one, mixing deuterated o-dichlorobenzene, methoxy(cyclooctadiene)iridium dimer, 4,4'-di-tert-butyl-2,2'-bipyridine, and bis(pinacolato)diboron, and providing a first reaction environment to prepare pinacol 3,4-dichlorophenylboronic acid-d3; Step two, mixing the pinacol 3,4-dichlorophenylboronic acid-d3, cuprous iodide, 1,10-phenanthroline, and potassium iodide, and providing a second reaction environment to prepare 3,4-dichloroiodobenzene-d3; Step three, mixing the 3,4-dichloroiodobenzene-d3, a palladium catalyst, a basic solution, and the pinacol 3,4-dichlorophenylboronic acid-d3, and providing a third reaction environment to prepare the 3,3',4,4'-tetrachlorobiphenyl-d6.

2. The production method according to claim 1, characterized by, The step one comprises: dissolving and mixing deuterated o-dichlorobenzene, methoxy(cyclooctadiene)iridium dimer, 4,4'-di-tert-butyl-2,2'-bipyridine, and bis(pinacolato)diboron in a first reaction solvent, under the protection of an inert gas, and reacting at a first reaction temperature for a first reaction time to prepare pinacol 3,4-dichlorophenylboronic acid-d3.

3. The production method according to claim 1 or 2, characterized by, The molar ratio of the deuterated o-dichlorobenzene to the methoxy(cyclooctadiene)iridium dimer to the 4,4'-di-tert-butyl-2,2'-bipyridine to the bis(pinacolato)diboron is 2:(0.001-0.005):(0.002-0.005):

1.

4. The production method according to claim 2, characterized by, The first reaction solvent is anhydrous tetrahydrofuran; the first reaction temperature is 80-100℃; and the first reaction time is 36-60h.

5. The preparation method according to claim 1, characterized in that, The step two comprises: dissolving and mixing the pinacol 3,4-dichlorophenylboronic acid-d3, cuprous iodide, 1,10-phenanthroline, and potassium iodide in a second reaction solvent, under a sealed environment, and reacting at a second reaction temperature for a second reaction time to prepare 3,4-dichloroiodobenzene-d3.

6. The production method according to claim 1 or 5, characterized by, The molar ratio of the pinacol 3,4-dichlorophenylboronic acid-d3 to the cuprous iodide to the 1,10-phenanthroline to the potassium iodide is 1:(0.1-0.4):(0.2-0.8):(1.5-4.0).

7. The preparation method according to claim 5, characterized in that, The second reaction solvent is methanol or / and water; the second reaction temperature is 60-100℃; and the second reaction time is 4-8h.

8. The method of claim 1, wherein, The step three comprises: dissolving the pinacol 3,4-dichlorophenylboronic acid-d3 in a third reaction solvent to obtain a solution of the pinacol 3,4-dichlorophenylboronic acid-d3; under the protection of an inert gas, dissolving and mixing the 3,4-dichloroiodobenzene-d3, a palladium catalyst, and a basic solution in a fourth reaction solvent, adding the solution of the pinacol 3,4-dichlorophenylboronic acid-d3 drop by drop at a third dropping rate after the third reaction temperature, and reacting for a third reaction time to prepare the 3,3',4,4'-tetrachlorobiphenyl-d6.

9. The production method according to claim 1 or 8, characterized by, The molar ratio of the 3,4-dichloroiodobenzene-d3 to the palladium catalyst to the basic solution to the 3,4-dichlorobenzeneboronic acid pinacol ester-d3 is 1:(0.03-0.1):(1.5-3):(1-2); the palladium catalyst is at least one of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, or palladium acetate; the basic solution is at least one of an aqueous sodium carbonate solution, an aqueous potassium carbonate solution, or an aqueous cesium carbonate solution.

10. The preparation method according to claim 8, characterized in that, The third reaction solvent is ethanol; the fourth reaction solvent is 1,4-dioxane or / and toluene; the third reaction temperature is 90-110°C; the third dropwise adding rate is 1-2 drops per second; the third reaction time is 4-24 hours.

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