Naphthalene ring carbon-14 labeled 2, 6-diisopropyl naphthalene and synthesis method thereof
The lack of effective radiotracers in existing studies has been addressed by the synthesis of naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene, providing an efficient tool for studying pesticide behavior to help in-depth understanding of the metabolic and environmental behavior of 2,6-diisopropylnaphthalene.
Patent Information
- Application Number
- CN202510143854.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-10
- Publication Date
- 2025-04-29
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
The lack of effective radiotracers in existing studies and insufficient research on the metabolic processes and environmental behavior of 2,6-diisopropylnaphthalene has led to insufficient understanding of its transformation and influence mechanisms in ecosystems.
By synthesizing naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene, using 14C-sodium cyanide to undergo substitution reaction with homemade iodine aromatic hydrocarbons, a series of steps include ester formation, hydrolysis, ring closing and reduction, and finally a marker is obtained, and the naphthalene ring is selected as the marking position.
It provides an efficient radiotracer that can be used to study the behavior of insecticides in plants, soil and water bodies, fills the gaps in related research, helps to deeply explore the metabolic processes and environmental behavior of 2,6-diisopropylnaphthalene, and ensures the accuracy and reliability of experimental results.
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Figure CN119899079A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of radiochemistry, and particularly relates to naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene and a synthesis method thereof. Background Art
[0002] As a vital organic chemical raw material, 2,6-diisopropylnaphthalene occupies an important position in the chemical industry. In addition, its biological activity makes it a potential application value in environmentally friendly insecticides, plant growth regulators, and preservatives for stored vegetables, and its importance in the field of pesticides is becoming increasingly prominent.
[0003] However, current research on 2,6-diisopropylnaphthalene faces many limitations. In terms of its behavior in plants, it is limited to the detection of parent compounds using chromatography or chromatography-mass spectrometry, and there is a serious lack of research on metabolism and degradation products. This situation directly leads to our extremely superficial understanding of its metabolic process and environmental behavior, and we cannot deeply understand its transformation and impact mechanism in the ecosystem.
[0004] In the process of creating new pesticides internationally, radioactive isotope tracing technology is indispensable for the research of new drugs. As for 2,6-diisopropylnaphthalene, from the perspective of chemical stability, its chemical transformation process in complex environments and organisms is still unclear, and labeling with carbon-14 helps to accurately track its structural changes; in terms of metabolic stability, due to the lack of research on metabolism and degradation products, it is impossible to accurately evaluate its persistence and transformation characteristics in organisms, and radioactive labeling can provide direct evidence; from the perspective of toxicological significance, in-depth exploration of its metabolic pathways, mechanisms of action, etc. is the key to evaluating its impact on the ecological environment and biosafety, and carbon-14 labeling of 2,6-diisopropylnaphthalene is a necessary means to carry out these studies.
[0005] Therefore, there is an urgent need to conduct research on carbon-14 labeled 2,6-diisopropylnaphthalene to fill the existing research gaps and promote the comprehensive understanding and rational application of this compound. Summary of the invention
[0006] The purpose of the present invention is to provide a naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene and a synthesis method thereof, and to successfully synthesize the naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene by taking the naphthalene ring as the labeling position. The naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene can be used as a tracer for the tracing of pesticides in plants, soil and water bodies and other researches, so as to solve the problems of lack of effective radioactive tracers and insufficient research on its metabolic process and environmental behavior in existing researches.
[0007] To achieve the above objectives, in a first aspect, the present technical solution provides a method for synthesizing 2,6-diisopropylnaphthalene labeled with 14 carbon atoms of the naphthalene ring, comprising the following steps: S1: Synthesis of 1-{2-[(1- 14 C) cyanomethyl]-3-methylbutyl}-4-isopropylbenzene; Under the protection of inert gas, 1-[2-(iodomethyl)-3-methylbutyl]-4-isopropylbenzene and 14 C-sodium cyanide is dissolved in an aprotic solvent and an inorganic base is added to stir the reaction. After the reaction is completed, the organic phase is extracted and combined, and the organic phase is washed, dried, filtered and concentrated, and then rapidly column chromatographed to obtain 1-{2-[(1- 14 C) cyanomethyl]-3-methylbutyl}-4-isopropylbenzene; S2: Synthesis of 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] ethyl valerate; Under the protection of inert gas, 1-{2-[(1- 14 C) 3-[(4-isopropylphenyl)methyl]-4-methyl[1-[(4-isopropylphenyl)methyl]-3-methylbutyl]-4-isopropylbenzene was dissolved in an alcohol solvent and an acid solvent was added to stir the reaction. After the reaction was completed, the mixture was concentrated to dryness and flash column chromatography was performed to obtain 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] ethyl valerate; S3: Synthesis of 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] valeric acid; Under the protection of inert gas, 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] ethyl valerate was dissolved in a polar solvent and an inorganic base was added to stir the reaction. After the reaction, dilute hydrochloric acid was added to extract and backwash, and then dried, filtered and concentrated to obtain 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] valeric acid; S4: Synthesis of 3,7-diisopropyl-[1- 14 C]-tetralone; Under the protection of inert gas, 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] valeric acid was dissolved in an acid solution and dehydrated, stirred and reacted at high temperature, and after the reaction was completed, the organic phase was extracted and combined, and the organic phase was washed with an alkaline solution and saturated brine, dried, filtered and concentrated, and then rapidly column chromatographed to obtain 3,7-diisopropyl-[1- 14 C]-tetralone; S5: Synthesis of 3,7-diisopropyl-[1- 14 C]-Tetrahydronaphthol: Under the protection of inert gas, 3,7-diisopropyl-[1- 14C]-tetralone was dissolved in an aprotic solvent and a reducing agent was added, and the reaction was stirred at low temperature. After the reaction was completed, the mixture was quenched with water and acid was added to adjust the acidity before extraction. The organic phases were combined and washed with saturated brine, dried, filtered and concentrated, and then rapidly column chromatographed to obtain 3,7-diisopropyl-[1- 14 C]-tetrahydronaphthol; S6: Synthesis of 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthone; Under the protection of inert gas, 3,7-diisopropyl-[1- 14 C]-tetrahydronaphthol is dissolved in an aprotic solvent, an acid solution is added to catalyze and dehydrate, and the reaction is stirred at a high temperature. After the reaction is completed, the organic phase is extracted and combined, and the organic phase is washed, dried, filtered and concentrated, and then rapidly column chromatographed to obtain 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthone; S7: Synthesis 14 C-2,6-Diisopropylnaphthalene: Under the protection of inert gas, 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthone is dissolved in an aprotic solvent, an oxidant is added for oxidation, and the reaction is stirred at high temperature. After the reaction is completed, the organic phases are combined, washed, dried, filtered, concentrated, and then rapidly column chromatographed to obtain 14 C-2,6-Diisopropylnaphthalene.
[0008] This program will 14 C-sodium cyanide is substituted with self-made iodinated aromatic hydrocarbons to obtain 14 The C-cyano substituted product is reacted with thionyl chloride methanol to form an ester, which is then hydrolyzed to obtain a carboxylic acid, which is then cyclized to form a naphthone under the action of PPA, which is then reduced and eliminated by LAH to obtain a crude product, which is purified by preparative HPLC to obtain the target product of the present invention, naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene. The specific activity range of the labeled product of this scheme is 1.0-300 mCi / mmol; the chemical purity and radiochemical purity are both greater than 98%, and the synthesized 14 C-2,6-diisopropylnaphthalene selects the naphthalene ring as the labeling position and can be used as a tracer for tracing pesticides in plants, soil and water and other studies.
[0009] In step S1, 14 C-Sodium cyanide dissociates in an alkaline environment 14 C-cyanide ion, 4The C-cyanide ion acts as a nucleophile to attack the carbon atom with a leaving group on 1-[2-(iodomethyl)-3-methylbutyl]-4-isopropylbenzene, thereby causing a nucleophilic substitution reaction. The leaving group leaves 1-[2-(iodomethyl)-3-methylbutyl]-4-isopropylbenzene with a pair of electrons to generate 14 C-cyano substituent: 1-{2-[(1- 14 C) Cyanomethyl]-3-methylbutyl}-4-isopropylbenzene.
[0010] In addition, in step S1, the aprotic solvent is selected from one or any combination of DMSO, DMF, and THF. Preferably, the aprotic solvent is selected from DMSO.
[0011] In step S1, the inorganic base is selected from one or any combination of LiOH, NaOH, and KOH. Preferably, the inorganic base is NaOH.
[0012] In step S1, 1-[2-(iodomethyl)-3-methylbutyl]-4-isopropylbenzene and 14 C-sodium cyanide was dissolved in an aprotic solvent and an inorganic base was added and stirred, and the mixture was placed at 0-25°C and stirred for 2-12 hours. After the reaction was completed, water and ethyl acetate were added for extraction, and the organic phases were combined, washed with saturated brine, dried, filtered, concentrated, and flash column chromatography was used to obtain 1-{2-[(1- 14 C) Cyanomethyl]-3-methylbutyl}-4-isopropylbenzene.
[0013] In some specific embodiments, the reaction equation of step S1 is as follows: .
[0014] The chemical formula of 1-[2-(iodomethyl)-3-methylbutyl]-4-isopropylbenzene involved in step S1 is shown in the following formula (II): .
[0015] Regarding 1-{2-[(1- 14 C) The chemical formula of cyanomethyl]-3-methylbutyl}-4-isopropylbenzene is shown in the following formula (III): .
[0016] In step S2, an acid solvent and an alcohol solvent undergo a nucleophilic addition reaction to obtain an active intermediate, and the active intermediate and 1-{2-[(1- 14 C) Cyanomethyl]-3-methylbutyl}-4-isopropylbenzene undergoes a nucleophilic substitution reaction, thereby making 1-{2-[(1- 14 C) Cyanomethyl]-3-methylbutyl}-4-isopropylbenzene 14The carbon atom adjacent to the C-cyano group is attracted by the active intermediate and undergoes a nucleophilic attack to form an ester bond, generating 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] ethyl valerate.
[0017] In step S2, the alcohol solvent is selected from one or any combination of MeOH, EtOH, and n-BuOH. Preferably, the alcohol solvent is selected from EtOH.
[0018] In step S2, the acid solvent is selected from one or any combination of SOCl2, H2SO4, and HCl. Preferably, the acid solvent is selected from SOCl2.
[0019] In step S2, 1-{2-[(1- 14 C) Dissolve [(4-isopropylphenyl)methyl]-3-methylbutyl]-4-isopropylbenzene in an alcohol solvent and add an acid solvent to stir the reaction. Stir the reaction at 0-80°C for 1-12 hours. After the reaction is completed, concentrate to dryness and perform rapid column chromatography to obtain 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] ethyl valerate.
[0020] In a specific embodiment, the reaction equation involved in step S2 is as follows: .
[0021] Regarding the 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] The structural formula of ethyl valerate is shown in the following formula (IV): .
[0022] In step S3, 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] Ethyl valerate undergoes hydrolysis in a polar solvent under the action of an inorganic base to form a carboxylate, which is then acidified and converted into a carboxylic acid under the action of dilute hydrochloric acid to obtain 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] Valeric acid.
[0023] In step S3, the polar solvent is selected from one or any combination of MeOH, EtOH, H2O, THF, and dioxane. Preferably, the polar solvent is selected from EtOH and H2O.
[0024] In step S3, the inorganic base is selected from one or any combination of LiOH, NaOH, and KOH. Preferably, the inorganic base is selected from KOH.
[0025] In step S3, 3-[(4-isopropylphenyl)methyl]-4-methyl[1-14 C] ethyl pentanoate was dissolved in a polar solvent and an inorganic base was added, and the mixture was stirred at 0-80°C for 2-12 hours. After the reaction was completed, dilute hydrochloric acid was added to adjust the acidity, and the mixture was extracted twice with DCM and backwashed once with saturated brine, and then dried, filtered and concentrated to obtain 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] Valeric acid.
[0026] In one specific embodiment, the reaction equation involved in step S3 is as follows: .
[0027] Regarding the 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 The chemical formula of valeric acid is shown in the following formula (V): .
[0028] In step S4, under the catalytic action of the acid solution, 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] Valeric acid undergoes an intramolecular dehydration reaction, in which the acid provides a proton to protonate the oxygen atom on the carboxyl group, and an electrophilic substitution reaction occurs within the molecule. While the carboxyl group is leaving, a new carbon-carbon bond is formed with the carbon atom at the adjacent position on the benzene ring to form a product e containing a naphthalene ring structure.
[0029] In step S4, the acid solution is selected from one or any combination of H2SO4, PPA, and TsOH. Preferably, the acid solution is selected from PPA.
[0030] In step S4, 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] valeric acid was dissolved in an acid solution and dehydrated, stirred at 50-120°C for 2-12h, and after the reaction was completed, water and ethyl acetate were added to the reaction system for extraction, and the organic phases were combined, washed with 20% NaOH solution and saturated brine, dried, filtered, concentrated, and flash column chromatography was performed to obtain the product 3,7-diisopropyl-[1- 14 C]-tetralone.
[0031] In one specific embodiment, the reaction equation of step S4 is as follows: .
[0032] Regarding the 3,7-diisopropyl-[1- 14 The chemical formula of [C]-tetralone is shown in the following formula (VI): .
[0033] In step S5, 3,7-diisopropyl-[1- 14 The carbonyl group in tetralone undergoes carbonyl reduction reaction with a reducing agent in an aprotic solvent, opening the carbonyl double bond, and the oxygen atom accepts an electron pair to form an oxygen anion, which is then protonated to obtain a hydroxyl group, thereby reducing the carbonyl group to a hydroxyl group to generate 3,7-diisopropyl-[1- 14 C]-tetrahydronaphthol.
[0034] In step S5, the aprotic solvent is selected from one or any combination of Et2O, THF, and 2-Me-THF. Preferably, the aprotic solvent is selected from THF.
[0035] In step S5, the reducing agent is selected from one or any combination of LiBHEt3, NaBH4, and LiAlH4. Preferably, the reducing agent is selected from LiAlH4.
[0036] In step S5, 3,7-diisopropyl-[1- 14 C]-tetralone was dissolved in an aprotic solvent and a reducing agent was added. The reaction was stirred at -10-30°C for 1-12 hours. After the reaction was completed, the mixture was quenched with water and diluted hydrochloric acid was added to adjust the acidity. The mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried, filtered and concentrated, and then rapidly column chromatographed to obtain 3,7-diisopropyl-[1- 14 C]-tetrahydronaphthol.
[0037] In one specific embodiment, the reaction equation of step S5 is as follows: .
[0038] Regarding the 3,7-diisopropyl-[1- 14 The chemical formula of [C]-tetrahydronaphthol is shown in formula (VII): .
[0039] In step S6, 3,7-diisopropyl-[1- 14 The hydroxyl group in [1-(2-(4-nitro-1-ol)]-tetrahydronaphthol undergoes an intramolecular dehydration elimination reaction under the catalysis of acid. The hydrogen atoms on the adjacent carbon atoms are removed in the form of protons under the catalysis of acid. At the same time, the carbon-oxygen bond is broken, and a double bond is formed between the two adjacent carbon atoms to generate a product containing an unsaturated bond, 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthone.
[0040] In step S6, the aprotic solvent is selected from one or any combination of Toluene, THF, and 2-Me-THF. Preferably, the aprotic solvent is selected from Toluene.
[0041] In step S6, the acid solution is selected from one or any combination of H2SO4, PPA, and TsOH. Preferably, the acid solution is selected from TsOH.
[0042] In step S6, 3,7-diisopropyl-[1- 14 C]-tetrahydronaphthol was dissolved in an aprotic solvent, an acid solution was added to catalyze and dehydrate, and the reaction was stirred at 50-120°C for 1-12 hours. After the reaction, water and ethyl acetate were added to the reaction system for extraction. After the organic phases were combined, the organic phases were washed with saturated brine, dried, filtered and concentrated, and then rapidly column chromatographed to obtain 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthone.
[0043] In one specific embodiment, the reaction equation of step S6 is as follows: .
[0044] Regarding the 3,7-diisopropyl-[1- 14 The chemical formula of [C]-3,4-2H-naphthone is shown in the following formula (VIII): .
[0045] In step S7, 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthalenone is oxidized by an oxidizing agent to obtain 3,7-diisopropyl-[1- 14 The electrons in C]-3,4-2H-naphthone cause the partial structure of the indene ring to undergo oxidation transformation to form a naphthalene ring structure, generating 14 C-2,6-Diisopropylnaphthalene.
[0046] In step S7, the aprotic solvent is selected from one or any combination of Toluene, Benzene and DCE. Preferably, the aprotic solvent is selected from Benzene.
[0047] In step S7, the oxidant is selected from one or any combination of anthraquinone-2-sulfonate sodium, chloranil, and 4-phenylpyridine-N-oxide. Preferably, the oxidant is selected from chloranil.
[0048] In step S7, 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthone is dissolved in an aprotic solvent, an oxidant is added for oxidation, and the reaction is stirred at 60-120°C for 2-12 hours. After the reaction is completed, water and ethyl acetate are added to the reaction system for extraction, and the organic phases are combined. The organic phases are washed with saturated brine, dried, filtered, concentrated, and then rapidly column chromatographed to obtain 14 C-2,6-Diisopropylnaphthalene.
[0049] In one specific embodiment, the reaction equation of step S7 is as follows: .
[0050] Regarding the step S7 14 C-2,6-diisopropylnaphthalene is represented by the following formula (I): .
[0051] In a second aspect, the present invention provides a naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene, which is synthesized according to the above-mentioned naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene synthesis method, and the chemical formula is shown in the following formula (I): .
[0052] The naphthyl ring carbon-14 labeled 2,6-diisopropylnaphthalene synthesized in this scheme selects the naphthalene ring as the labeling position, and the specific activity range of the labeled product is 1.0~300 mCi / mmol; the chemical purity and radiochemical purity are both greater than 98%.
[0053] Compared with the prior art, this technical solution has the following characteristics and beneficial effects: This scheme successfully synthesized 2,6-diisopropylnaphthalene labeled with carbon-14 on the naphthalene ring, filling the gap in radioactive tracers in related research. It can be used for tracing of pesticides in plants, soil and water and other studies, helping to deeply explore their metabolic processes and environmental behaviors. The specific activity range is 1.0~300 mCi / mmol, and the chemical purity and radiochemical purity are both greater than 98%. The label is firm and not easy to fall off, which can meet the requirements of biological and environmental tracing experiments and ensure the accuracy and reliability of the experimental results. BRIEF DESCRIPTION OF THE DRAWINGS
[0054] Figure 1 is a reaction equation according to a specific embodiment of the present invention, wherein the asterisk indicates the labeling position of carbon-14.
[0055] Figure 2 It is the nuclear magnetic hydrogen spectrum of 2,6-diisopropylnaphthalene labeled with carbon-14 of the naphthalene ring in the present invention.
[0056] Figure 3 It is a high performance liquid chromatogram of 2,6-diisopropylnaphthalene labeled with carbon-14 of the naphthalene ring in the present invention. DETAILED DESCRIPTION
[0057] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.
[0058] The following examples are provided to illustrate the present invention. The examples are only used to further illustrate the present invention and do not represent the protection scope of the present invention. Non-essential modifications and adjustments made by others based on the present invention still fall within the protection scope of the present invention.
[0059] S1: Under nitrogen atmosphere, 14 C-sodium cyanide (196.0 mg, 4 mmol, 55 mCi / mmol) was dissolved in anhydrous DMSO (14 mL), and NaOH (176.4 mg, 4.4 mmol) was added. The substrate 1-[2-(iodomethyl)-3-methylbutyl]-4-isopropylbenzene (1.4432 g, 4.4 mmol) was added and stirred vigorously at 25 °C for 12 h. After the reaction was completed, water (20 mL) and ethyl acetate (15 mLx3) were added to the reaction system for extraction. The organic phases were combined, washed with saturated brine (8 mLx2), dried over anhydrous sodium sulfate, filtered, concentrated, and flash column chromatography PE / EA=40:1~20:1 was used to obtain a light yellow oily product 1-{2-[(1- 14 C) Cyanomethyl]-3-methylbutyl}-4-isopropylbenzene (670.6 mg, 2.90 mmol, 72% yield): .
[0060] S2: Under nitrogen atmosphere, the product 1-{2-[(1- 14 C) Dissolve 3-methylbutyl]-4-isopropylbenzene (670.6 mg, 2.90 mmol) in EtOH (10 mL), add SOCl2 (1.7250 g, 14.5 mmol) dropwise at 0-5 °C, then heat to 78 °C and stir for 12 h. After the reaction, concentrate the reaction solution to dryness and perform flash column chromatography with PE / EA = 20:1-10:1 to obtain a light yellow oily substance 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C]Ethyl valerate (589.4 mg, 2.12 mmol, 73% yield): .
[0061] S3: The product obtained in the previous step, 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14C] Ethyl valerate (589.4 mg, 2.12 mmol) was dissolved in EtOH (4 mL), and KOH (594.8 mg, 10.6 mmol) in water (4 mL) was added. The mixture was heated to 80 °C and stirred for 12 h. After the reaction, dilute hydrochloric acid (2 N) was added to the reaction solution to adjust the pH to 3-4, and then extracted with DCM (12 mL x5), backwashed once with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C]Valeric acid (487.5 mg, 1.95 mmol, 92% yield): .
[0062] S4: Under nitrogen atmosphere, the product obtained in the previous step, 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C]valeric acid (487.5 mg, 1.95 mmol) was added to PPA (10 mL), and then the temperature was raised to 100 °C and stirred for 3 h. After the reaction was completed, water (15 mL) and ethyl acetate (10 mL x3) were added to the reaction system for extraction. The organic phases were combined, washed with 20% NaOH solution (15 mLx2) and saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, concentrated, and flash column chromatography PE / EA=15:1~10:1 was used to obtain a light yellow oily product 3,7-diisopropyl-[1- 14 C]-Tetralone (320.1 mg, 1.38 mmol, 71% yield): .
[0063] S5: Under nitrogen atmosphere, the product obtained in the previous step, 3,7-diisopropyl-[1- 14 C]-tetralone (320.1 mg, 1.38 mmol) was dissolved in THF (5 mL), and LiAlH4 (1.2 mL, 1.2 mmol, 1.0 M in THF) was added dropwise at 0-5 °C, and then the temperature was raised to 25 °C and stirred for 2 h. After the reaction was completed, it was quenched with water (10 mL), and the pH was adjusted to 5-6 with dilute hydrochloric acid (2 N), and extracted with ethyl acetate (10 mLx5). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow oily substance 3,7-diisopropyl-[1- 14 C]-Tetrahydronaphthol (320.6 mg, 1.37 mmol, 99% yield): .
[0064] S6: Under nitrogen atmosphere, the product obtained in the previous step, 3,7-diisopropyl-[1- 14 C]-tetrahydronaphthol (320.6 mg, 1.37 mmol) was dissolved in Toluene (6 mL), TsOH (260.0 mg, 1.51 mmol) was added, and the temperature was raised to 110 °C and stirred for 12 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mLx3) were added to the reaction system for extraction. The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and flash column chromatography PE / EA=20:1~10:1 was used to obtain a light yellow oily substance 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthone (248.4 mg, 1.15 mmol, 84% yield): .
[0065] S7: Under nitrogen atmosphere, the product obtained in the previous step, 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthone (248.4 mg, 1.15 mmol) was dissolved in Benzene (5 mL), and tetrachlorobenzoquinone (309.8 mg, 1.26 mmol) was added, and the temperature was raised to 80 °C and stirred for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mLx5) were added to the reaction system for extraction. The organic phases were combined, washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and flash column chromatography PE / EA=100:1~20:1 was used to obtain a white solid. 14 C-2,6-Diisopropylnaphthalene (111.2 mg, 0.52 mmol, 45% yield): .
[0066] The synthesized 14 C-2,6-diisopropylnaphthalene was tested to obtain the NMR hydrogen spectrum of 2,6-diisopropylnaphthalene labeled with naphthalene ring carbon-14 as shown below Figure 2 As shown, we get 14 The HPLC chromatogram of C-2,6-diisopropylnaphthalene is as follows Figure 3 As shown, the test conditions of the HPLC chromatogram are: detection wavelength: 254nm, injection volume 10μL, and it can be seen that its chemical purity is 98.67%.
[0067] The explanation of the HPLC chromatogram is shown in Table 1 below: Table 1 Peak results table .
[0068] It is to be understood that the term "one" should be understood as "at least one" or "one or more", that is, in one embodiment, the number of an element may be one, while in another embodiment, the number of the element may be multiple, and the term "one" should not be understood as a limitation on the quantity.
[0069] The present invention is not limited to the above-mentioned optimal implementation mode. Anyone can derive other various forms of products under the inspiration of the present invention. However, no matter what changes are made in the shape or structure, all technical solutions that are the same or similar to those of the present application fall within the protection scope of the present invention.
Claims
1. A method for synthesizing 2,6-diisopropylnaphthalene labeled with 14 carbon atoms of the naphthalene ring, characterized in that: The following steps are involved: S1: Synthesis of 1-{2-[(1- 14 C) cyanomethyl]-3-methylbutyl}-4-isopropylbenzene; Under the protection of inert gas, 1-[2-(iodomethyl)-3-methylbutyl]-4-isopropylbenzene and 14 C-sodium cyanide is dissolved in an aprotic solvent and an inorganic base is added to react with stirring to obtain 1-{2-[(1- 14 C) cyanomethyl]-3-methylbutyl}-4-isopropylbenzene; S2: Synthesis of 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] ethyl valerate; Under the protection of inert gas, 1-{2-[(1- 14 C) Dissolve 3-[(4-isopropylphenyl)methyl]-4-methyl[1-[(4-isopropylphenyl)methyl]-3-methylbutyl]-4-isopropylbenzene in an alcohol solvent and add an acid solvent to stir the reaction to obtain 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] ethyl valerate; S3: Synthesis of 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] valeric acid; Under the protection of inert gas, 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] ethyl valerate was dissolved in a polar solvent and an inorganic base was added and stirred to obtain 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] valeric acid; S4: Synthesis of 3,7-diisopropyl-[1- 14 C]-tetralone; Under the protection of inert gas, 3-[(4-isopropylphenyl)methyl]-4-methyl[1- 14 C] valeric acid is dissolved in an acid solution and dehydrated, and stirred at high temperature to react to obtain 3,7-diisopropyl-[1- 14 C]-tetralone; S5: Synthesis of 3,7-diisopropyl-[1- 14 C]-Tetrahydronaphthol: Under the protection of inert gas, 3,7-diisopropyl-[1- 14 C]-tetralone is dissolved in an aprotic solvent and a reducing agent is added, and the reaction is stirred at low temperature to obtain 3,7-diisopropyl-[1- 14 C]-tetrahydronaphthol; S6: Synthesis of 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthone; Under the protection of inert gas, 3,7-diisopropyl-[1- 14 C]-tetrahydronaphthol is dissolved in an aprotic solvent, an acid solution is added to catalyze and dehydrate, and the reaction is stirred at high temperature to obtain 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthone; S7: Synthesis 14 C-2,6-Diisopropylnaphthalene: Under the protection of inert gas, 3,7-diisopropyl-[1- 14 C]-3,4-2H-naphthone is dissolved in an aprotic solvent, an oxidant is added for oxidation, and the reaction is stirred at high temperature to obtain 14 C-2,6-Diisopropylnaphthalene.
2. The synthetic method of naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene according to claim 1, characterized in that, In step S1, the aprotic solvent is selected from DMSO, DMF, THF or any combination thereof.
3. The synthetic method of naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene according to claim 1, characterized in that, In step S1, the inorganic base is selected from one or any combination of LiOH, NaOH, and KOH.
4. The synthetic method of naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene according to claim 1, characterized in that, In step S2, the alcohol solvent is selected from one or any combination of MeOH, EtOH, and n-BuOH, and the acid solvent is selected from one or any combination of SOCl2, H2SO4, and HCl.
5. The method for synthesizing naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene according to claim 1, characterized in that, In step S3, the polar solvent is selected from one or any combination of MeOH, EtOH, H2O, THF, and dioxane, and the inorganic base is selected from one or any combination of LiOH, NaOH, and KOH.
6. The method for synthesizing naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene according to claim 1, characterized in that, In step S4, the acid solution is selected from one or any combination of H2SO4, PPA, and TsOH.
7. The method for synthesizing naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene according to claim 1, characterized in that, In step S5, the aprotic solvent is selected from one or any combination of Et2O, THF, and 2-Me-THF, and the reducing agent is selected from one or any combination of LiBHEt3, NaBH4, and LiAlH4.
8. The method for synthesizing naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene according to claim 1, characterized in that, In step S6, the aprotic solvent is selected from one or any combination of Toluene, THF, and 2-Me-THF, and the acid solution is selected from one or any combination of H2SO4, PPA, and TsOH.
9. The method for synthesizing naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene according to claim 1, characterized in that, In step S7, the aprotic solvent is selected from one or any combination of Toluene, Benzene, and DCE, and the oxidant is selected from one or any combination of anthraquinone-2-sulfonate sodium, tetrachlorobenzoquinone, and 4-phenylpyridine-N-oxide.
10. A naphthalene ring carbon-14 labeled 2,6-diisopropylnaphthalene, characterized in that: According to the synthesis method of any one of claims 1 to 9, 2,6-diisopropylnaphthalene labeled with carbon-14 of the naphthalene ring is synthesized, and the structural formula is shown in the following formula (I): 。