CN114230470A - Synthetic method and application of stable isotope labeled benzidine - Google Patents
Synthetic method and application of stable isotope labeled benzidine Download PDFInfo
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- CN114230470A CN114230470A CN202111557533.6A CN202111557533A CN114230470A CN 114230470 A CN114230470 A CN 114230470A CN 202111557533 A CN202111557533 A CN 202111557533A CN 114230470 A CN114230470 A CN 114230470A
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- HFACYLZERDEVSX-UHFFFAOYSA-N benzidine Chemical compound C1=CC(N)=CC=C1C1=CC=C(N)C=C1 HFACYLZERDEVSX-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000010189 synthetic method Methods 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 29
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000000203 mixture Substances 0.000 claims abstract description 22
- WDFQBORIUYODSI-IDEBNGHGSA-N 4-bromoaniline Chemical compound N[13C]1=[13CH][13CH]=[13C](Br)[13CH]=[13CH]1 WDFQBORIUYODSI-IDEBNGHGSA-N 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- HFACYLZERDEVSX-WCGVKTIYSA-N [13C]1(=[13CH][13CH]=[13C](N)[13CH]=[13CH]1)[13C]1=[13CH][13CH]=[13C](N)[13CH]=[13CH]1 Chemical compound [13C]1(=[13CH][13CH]=[13C](N)[13CH]=[13CH]1)[13C]1=[13CH][13CH]=[13C](N)[13CH]=[13CH]1 HFACYLZERDEVSX-WCGVKTIYSA-N 0.000 claims abstract description 9
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000011056 potassium acetate Nutrition 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000000376 reactant Substances 0.000 claims abstract description 5
- 238000012958 reprocessing Methods 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- 238000004440 column chromatography Methods 0.000 claims description 10
- 239000000284 extract Substances 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical group N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 238000001308 synthesis method Methods 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000011161 development Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000000975 dye Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- HFACYLZERDEVSX-BJLRPUNDSA-N 4-(4-amino-2,3-dideuteriophenyl)-N,N,2,3,5,6-hexadeuterioaniline Chemical group C1(=C(C(=C(N([2H])[2H])C(=C1[2H])[2H])[2H])[2H])C=1C(=C(C(N)=CC=1)[2H])[2H] HFACYLZERDEVSX-BJLRPUNDSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000004750 isotope dilution mass spectroscopy Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 231100000315 carcinogenic Toxicity 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000001948 isotopic labelling Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method and application of stable isotope labeled benzidine, wherein the synthetic method comprises the following steps: placing aniline marked by stable isotope and N-bromosuccinimide into an organic solvent for mixing, adding a catalyst, stirring at room temperature for reaction, and carrying out post-treatment on the mixture after the reaction to obtain 4-bromoaniline-13C6H4(ii) a Under the protection of nitrogen atmosphere, the obtained 4-bromoaniline-13C6H4Adding the mixture into an ethanol solution containing a palladium/carbon catalyst, potassium acetate and bis (pinacolato) diboron, heating and stirring, cooling to room temperature after reaction, and reprocessing the obtained reactant to obtain the stable isotope labeled benzidine. The method provided by the invention has the advantages of simple steps, controllable process, high efficiency and high yield; the stable isotope labeled 4,4' -benzidine-13C12H8The quality of the product is stable, and the product has great development and utilization values.
Description
Technical Field
The invention relates to the technical field of isotope labeling, in particular to a synthetic method of stable isotope labeled benzidine and application thereof.
Background
Benzidine (trivial name), also known as 1, 1 '-biphenyl-4, 4' -diamine (systematic name), is an organic compound having the molecular formula (C)6H4NH2)2White or slightly reddish stable acicular crystal or powder, flammable, darkened when exposed to air and irradiated by light, and commercially available products are often brown or deep purple brown and are insoluble in cold waterSlightly soluble in hot water and ether, and easily soluble in acetic acid, dilute hydrochloric acid and boiling ethanol; as an aromatic amine, the chemical property is similar to that of aniline, diazotization reaction can be carried out with nitrous acid to generate diazonium salt, and the diazonium salt is coupled with aromatic amine or phenol to obtain various benzidine dyes. Benzidine was an important intermediate for dye synthesis, from which more than 300 dyes could be synthesized, but due to its strong toxicity, other less toxic starting materials have been used; benzidine and its salt are toxic and carcinogenic substances, and solid and vapor easily enter into body through skin, cause contact dermatitis, irritate mucous membrane, damage liver and kidney, and cause bladder cancer and pancreatic cancer; as long as the concentration of benzidine reaches 6.7ppb, there is a risk of carcinogenesis in humans.
Benzidine, because of its enormous carcinogenic risk, its use should be banned; to prevent and stop the continued use of benzidine in pigment production, a technique is needed that can detect it quickly, accurately, and very sensitively.
Stable Isotope Dilution Mass Spectrometry (IDMS) uses a stable Isotope labeled compound having the same molecular structure as a substance to be detected as an internal standard substance, and a high resolution liquid chromatography-Mass spectrometer (LC/MS) is used for detection, and the Mass spectrometer is used for measuring the ratio of ions with corresponding Mass numbers and comparing the ratio with a standard ratio to achieve the purpose of accurate quantification. The isotope internal standard can effectively eliminate the recovery rate difference of the sample in the chemical and physical pretreatment steps, thereby avoiding the deviation of the detection result caused by the loss of the sample treatment process.
This property of stable isotope internal standards, combined with the high sensitivity of LC/MS and the ability to process complex samples, makes the chromatography/isotope dilution mass spectrometry technique recognized as a baseline method for measuring trace and trace organics; the successful development of the stable isotope labeled benzidine provides a standard reagent for more accurate quantitative detection of the benzidine, thereby effectively providing residual detection service for the dye industry safety field in China.
The stable isotope labeled benzidine currently available on the market is benzidine-d 8 shown below.
In particular, deuterium of benzidine-d 8 is bonded to a conjugated bond of a benzene ring and is easily replaced by hydrogen in a solvent, so that the deuterium label is lost; the 8 deuterium atoms also easily cause Matrix effect (Matrix effect) of the internal standard, and may cause errors due to non-co-flow between the standard and the analyte during LC-MS analysis.
To overcome the defects of benzidine-d 8, the stable isotope labeled benzidine (4, 4' -benzidine-13C12H8) The synthesis method of (2) is already in need.
In view of this, the invention is particularly proposed.
Disclosure of Invention
In view of this, the invention provides a method for synthesizing stable isotope labeled benzidine and applications thereof.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for synthesizing stable isotope labeled benzidine, wherein the molecular structural formula of the stable isotope labeled benzidine is as follows:
the synthesis method comprises the following steps:
s1, placing aniline marked by stable isotope and N-bromosuccinimide into an organic solvent for mixing, adding a catalyst, stirring at room temperature for reaction, and carrying out post-treatment on the obtained mixture after the reaction is finished to obtain 4-bromoaniline-13C6H4；
S2, under the protection of nitrogen atmosphere, the 4-bromoaniline obtained in the step S113C6H4Adding into ethanol solution containing palladium/carbon catalyst, potassium acetate and bis (pinacolato) diboron, heating and stirring, reacting, and coolingCooling to room temperature, and reprocessing the obtained reactant to obtain the benzidine labeled by the stable isotope.
In the above technical solution, in step S1, the catalyst is ammonium acetate.
In a preferred embodiment of the present invention, in step S1, the catalyst is added in a molar amount of 0.08 to 0.125 times that of the stable isotope-labeled aniline.
In the above technical scheme, in step S1, the stirring reaction time is 10-60 min.
In the above technical solution, in step S1, the molar weight of the N-bromosuccinimide added is 1.0 to 1.15 times that of the stable isotope-labeled aniline.
In the above technical solution, in step S1, the organic solvent is acetonitrile.
Further, in the above technical solution, in step S1, the post-processing includes:
concentrating the mixture obtained after the reaction is finished, then adding saturated sodium bicarbonate solution and extracting with ethyl acetate, separating the obtained extract and collecting an organic phase, drying and concentrating, and finally carrying out column chromatography purification on the residue to obtain 4-bromoaniline-13C6H4。
Specifically, in the above technical solution, in step S1, the mixture obtained after the reaction is completed is concentrated to dryness, and then a saturated sodium bicarbonate solution is added.
Specifically, in the above technical solution, in step S1, the amount of the saturated sodium bicarbonate solution added is 20 to 50mL, corresponding to 10mmol of aniline.
In the above technical solution, in step S2, the molar amount of the palladium/carbon catalyst added in the ethanol solution is 4-bromoaniline-13C6H40.01-0.1 times of the total weight of the composition.
In the above technical scheme, in the step S2, the molar amount of the potassium acetate added in the ethanol solution is 4-bromoaniline-13C6H42.75-3.6 times of the total weight of the powder.
In the above technical solution, in step S2, the molar amount of the bis (pinacolato) diboron added into the ethanol solution is 4-bromoaniline-13C6H41.35-1.8 times of the total weight of the composition.
In the above technical solution, in step S2, the heating and stirring temperature and time are 55-72 ℃ and 7.5-9h, respectively.
Further, in the above technical solution, in step S2, the reprocessing includes:
filtering the obtained reactant, taking the filtrate, concentrating under reduced pressure, adding saturated sodium bicarbonate solution, extracting with dichloromethane, separating the obtained extract, collecting an organic phase, drying, concentrating, and finally performing column chromatography purification on the residue to obtain the benzidine labeled by the stable isotope.
The invention also provides the synthesis method for preparing the stable isotope labeled 4,4' -benzidine-13C12H8The use of (1).
Compared with the prior art, the invention has the following advantages:
(1) the preparation of stable isotope labeled 4,4' -benzidine-13C12H8The method has the advantages of simple steps, controllable process, high efficiency and high yield;
(2) the stable isotope labeled 4,4' -benzidine-13C12H8The quality of the standard is stable, the mass spectrum of the standard as an internal standard is definite, a Matrix effect (Matrix effect) cannot be caused in the LC-MS analysis process, and the phenomenon of non-cocurrent flow cannot occur with the analyte in the LC-MS analysis process, so that the analysis error is avoided, a standard reagent is provided for more accurately and quantitatively detecting the benzidine, and the residual detection service in the dye industry safety field of China is effectively provided; has great development and utilization value.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments.
It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the examples, the means used are conventional in the art unless otherwise specified.
The terms "comprises," "comprising," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Unless otherwise specified, the raw materials used in the examples of the present invention are all commercially available products.
In order to facilitate a further understanding of the present invention, the technical solutions of the present invention will now be described in detail with reference to the preferred embodiments.
Example 1
The embodiment of the invention provides a method for synthesizing stable isotope labeled benzidine, which comprises the following steps:
s1, to a 250mL round bottom flask containing 50mL acetonitrile (AcCN), aniline (991mg, 10.0mmol) was added followed by NH4OAc (77.1mg, 1.0mmol), N-bromosuccinimide (NBS, 1.78g, 10.0mmol) was added, the mixture was stirred at room temperature for 10min, after completion of the reaction, the reaction mixture was concentrated to dryness by a rotary evaporator, 25ml of a saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate (25ml 3 times), the obtained extracts were separated and the organic phase was collected, combined and dried with anhydrous sodium sulfate (30 g) (room temperature, 1-2 hours), then concentrated to dryness by a rotary evaporator, and finally the residue was purified by column chromatography (silica gel, hexane-ethyl acetate, 10: 1) to obtain 1.53 g of light brown solid 4-bromoaniline-13C6H4。
S2, under the protection of nitrogen, loadingA250 ml round bottom flask with 35ml of anhydrous ethanol was charged with 1.62g of 4-bromoaniline-13C6H4And 3.47g bis (pinacolato) diboron, then introducing nitrogen gas into the resulting solution for 5min, then successively adding palladium-carbon (10%, 96.8mg) and potassium acetate (2.68g), continuing to introduce nitrogen gas for 5min, then heating the mixture to 60 ℃, stirring for 8h, cooling the reactor to room temperature, filtering the reaction mixture, concentrating the filtrate under reduced pressure, adding 25ml of saturated sodium bicarbonate solution, extracting the residue with dichloromethane (25 ml. times.3), separating the obtained extracts and collecting the organic phases, combining, drying over magnesium sulfate and vacuum concentrating to dryness, and finally purifying the residue by column chromatography (silica gel, hexane-ethyl acetate, 10: 2) to obtain 1.55g of stable isotope labeled 4,4' -benzidine-13C12H8。
Example 2
The embodiment of the invention provides a method for synthesizing stable isotope labeled benzidine, which comprises the following steps:
s1, to a 250mL round bottom flask containing 50mL acetonitrile (AcCN), aniline (991mg, 10.0mmol) was added followed by NH4OAc (77.1mg, 1.0mmol), N-bromosuccinimide (NBS, 1.87g, 10.5mmol) was added, the mixture was stirred at room temperature for 10min, after completion of the reaction, the reaction mixture was concentrated to dryness by a rotary evaporator, 25ml of a saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate (25ml 3 times), the obtained extracts were separated and the organic phase was collected, combined and dried with anhydrous sodium sulfate (30 g) (room temperature, 1-2 hours), then concentrated to dryness by a rotary evaporator, and finally the residue was purified by column chromatography (silica gel, hexane-ethyl acetate, 10: 1) to obtain 1.71 g of light brown solid 4-bromoaniline-13C6H4。
S2, under the protection of nitrogen, adding 1.62g of 4-bromoaniline into a 250ml round-bottom flask containing 35ml of absolute ethyl alcohol13C6H4And 3.47g bis (pinacolato) diboron, then introducing nitrogen into the resulting solution for 5min, then adding palladium-carbon (10%, 484.0mg) followed by potassium acetate (2.68g), continuing with nitrogen for 5min, and then adding the mixture to a reactorThe mixture was heated to 60 ℃ and stirred for 8h, the reactor was cooled to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, 25ml of saturated sodium bicarbonate solution was added, the residue was extracted with dichloromethane (25ml 3 times), the obtained extracts were separated and the organic phases were collected, combined and dried over magnesium sulfate and concentrated to dryness in vacuo, and finally the residue was purified by column chromatography (silica gel, hexane-ethyl acetate, 10: 2) to give 1.64g of stable isotope-labeled 4,4' -benzidine-13C12H8。
Example 3
The embodiment of the invention provides a method for synthesizing stable isotope labeled benzidine, which comprises the following steps:
s1, to a 250mL round bottom flask containing 50mL acetonitrile (AcCN), aniline (991mg, 10.0mmol) was added followed by NH4OAc (77.1mg, 1.0mmol), N-bromosuccinimide (NBS, 1.96g, 11.0mmol) are added, the mixture is stirred at room temperature for 10min, after the reaction is completed, the reaction mixture is concentrated to dryness by a rotary evaporator, 25ml of saturated sodium bicarbonate solution is added, then ethyl acetate (25ml for 3 times) is used for extraction, the obtained extracts are separated and the organic phase is collected, anhydrous sodium sulfate (30 g) is added after combination for drying (room temperature, 1-2 h), then the mixture is concentrated to dryness by a rotary evaporator, finally the residue is purified by column chromatography (silica gel, hexane-ethyl acetate, 10: 1) to obtain 1.62g of light brown solid 4-bromoaniline-13C6H4。MS:179.6(MH+)；1H NMR(CDCl3)δ: 7.32(m,JC-H＝164Hz,1H),6.90(m,JC-H＝164Hz,1H),6.69(m,JC-H＝ 160,Hz,1H),6.30(m,JC-H＝160Hz,1H)；13C NMR(CDCl3)δ:148.0(dt, J＝7.8,59Hz),131.2(dt,J＝6.5,63Hz),115.7(dt,J＝6.5,63Hz),105.8(dt, J＝9.4,63Hz)。
S2, under the protection of nitrogen, adding 1.62g of 4-bromoaniline into a 250ml round-bottom flask containing 35ml of absolute ethyl alcohol13C6H4And 3.47g bis (pinacolato) diboron, then introducing nitrogen into the resulting solution for 5min, then adding palladium-carbon (10%, 968.0mg) followed by potassium acetate (2.68g), continuing the nitrogen introduction for 5min, and then adding the mixture to the reaction vesselHeating to 60 deg.C, stirring for 8h, cooling the reactor to room temperature, filtering the reaction mixture, concentrating the filtrate under reduced pressure, adding saturated sodium bicarbonate solution 25ml, extracting the residue with dichloromethane (25ml 3 times), separating the obtained extracts and collecting the organic phases, combining, drying over magnesium sulfate and vacuum concentrating to dryness, and purifying the residue by column chromatography (silica gel, hexane-ethyl acetate, 10: 2) to obtain 1.73g of stable isotope labeled 4,4' -benzidine-13C12H8。MS:197.1(MH+)；1H NMR(CD3OD)δ:7.17(4H,ddd,J＝8.6,1.2,0.5Hz),7.78(4H,ddd,J ＝8.6,1.8,0.5Hz)。
It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. The protection scope of the present invention should be subject to the appended claims.
Claims (9)
1. A method for synthesizing stable isotope labeled benzidine is characterized in that,
the molecular structural formula of the stable isotope labeled benzidine is as follows:
the synthesis method comprises the following steps:
s1, placing aniline marked by stable isotope and N-bromosuccinimide into an organic solvent for mixing, adding a catalyst, stirring at room temperature for reaction, and carrying out post-treatment on the obtained mixture after the reaction is finished to obtain 4-bromoaniline-13C6H4；
S2, under the protection of nitrogen atmosphere, the 4-bromoaniline obtained in the step S113C6H4Adding the mixture into an ethanol solution containing a palladium/carbon catalyst, potassium acetate and bis (pinacolato) diboron, heating and stirring, cooling to room temperature after reaction, and reprocessing the obtained reactant to obtain the stable isotope labeled benzidine.
2. The method for synthesizing stable isotope-labeled benzidine according to claim 1,
in the step S1, in the step S,
the catalyst is ammonium acetate, and preferably, the molar amount of the catalyst added is 0.08-0.125 times that of the stable isotope labeled aniline;
and/or the stirring reaction time is 10-60 min.
3. The method for synthesizing stable isotope-labeled benzidine according to claim 1,
in the step S1, in the step S,
the molar weight of the N-bromosuccinimide added is 1.0 to 1.15 times that of the aniline marked by the stable isotope;
and/or the organic solvent is acetonitrile.
4. The method for the synthesis of stable isotope-labeled benzidine according to any one of claims 1 to 3,
in step S1, the post-processing includes:
concentrating the mixture obtained after the reaction is finished, then adding saturated sodium bicarbonate solution and extracting with ethyl acetate, separating the obtained extract and collecting an organic phase, drying and concentrating, and finally carrying out column chromatography purification on the residue to obtain 4-bromoaniline-13C6H4。
5. The method for synthesizing stable isotope-labeled benzidine according to claim 4,
in the step S1, in the step S,
concentrating the mixture obtained after the reaction is finished to be dry, and then adding saturated sodium bicarbonate solution;
and/or, the amount of said saturated sodium bicarbonate solution added is 20-50mL, corresponding to 10mmol of aniline.
6. The method for synthesizing stable isotope-labeled benzidine according to claim 1,
in step S2, in the ethanol solution,
the molar amount of the palladium/carbon catalyst is 4-bromoaniline-13C6H40.01-0.1 times of;
and/or the potassium acetate is added in a molar amount of 4-bromoaniline-13C6H42.75-3.6 times of;
and/or the bis (pinacolato) diboron is added in a molar amount of 4-bromoaniline-13C6H41.35-1.8 times of the total weight of the composition.
7. The method for synthesizing stable isotope-labeled benzidine according to claim 1,
in the step S2, in the step S,
the heating and stirring temperature and time are respectively 55-72 ℃ and 7.5-9 h.
8. The method for the synthesis of stable isotope-labeled benzidine according to claim 1, 6 or 7,
in the step S2, in the step S,
the reprocessing comprises:
filtering the obtained reactant, taking the filtrate, concentrating under reduced pressure, adding saturated sodium bicarbonate solution, extracting with dichloromethane, separating the obtained extract, collecting an organic phase, drying, concentrating, and finally performing column chromatography purification on the residue to obtain the benzidine labeled by the stable isotope.
9. The method of any one of claims 1 to 8 for the preparation of stable isotope-labeled 4,4' -benzidine-13C12H8The use of (1).
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