Preparation method and application of carbon-14 labeled aniline

Abstract

The invention relates to a preparation method and application of carbon-14 labeled aniline, and the preparation method of carbon-14 labeled aniline comprises the following steps: carrying out a reaction on 14C-BaCO3 and concentrated H2SO4 to prepare 14CO2; the 14CO2 and Ba are subjected to a reaction, and Ba14C2 is prepared; the Ba14C2 and H2O are subjected to a reaction, and 14CH14CH is prepared; the 14CH14CH is subjected to a heating reaction under the action of a molecular sieve catalyst to which potassium dichromate is attached, and 14C6H6 is prepared; the preparation method comprises the following steps: carrying out a reaction on the 14C6H6 and NaNO3, so as to prepare 14C6H5NO2; the 4C6H5NO2 is subjected to a reaction under the action of a catalyst Pd / C, and 14C6H5NH2 is prepared. The scheme has the following advantages: (1) the synthesis steps are short, and an intermediate product does not need post-treatment; (2) the utilization efficiency of carbon isotopes is high, and the reaction yield is high; (3) the product is easy to separate and high in purity; and (4) the reaction reagent is simple, and the abundance of the carbon isotope cannot be diluted.

Description

Technical Field

[0001] The invention relates to the technical field of synthesis of carbon isotope labeled substances, in particular to a preparation method and application of carbon-14 labeled aniline. Background Art

[0002] Carbon is the basic element of life, and all plants and animals are carbon-based. The metabolic process of plants and animals in nature involves the transformation of carbon, so carbon isotope labeled compounds play an important role in studying the metabolic process of plants and animals. Among them, carbon-14 labeled compounds have become the most common tracers in new drug metabolism research due to their easy detection and high sensitivity.

[0003] Aniline (also known as aniline, aniline oil or aminobenzene, with a molecular formula of C6H7N) is an important intermediate in the synthesis of organic small molecule drugs and is widely used in the manufacture of drugs, dyes and resins. In addition, aniline is also an important raw material for the production of pesticides and can be used to synthesize a variety of pesticides. Therefore, carbon-14 labeled aniline has important application value in scientific research, new drug metabolism research and pesticide metabolism research.

[0004] However, the existing conventional industrial production method of aniline cannot be applied to the synthesis of carbon-14 aniline, mainly because the raw materials required for the synthesis of carbon-14 markers (such as carbon-14 barium carbonate) are from a single and scarce source. This limits the widespread use of carbon-14 labeled aniline in research and industrial applications.

[0005] Therefore, it is particularly important to develop an efficient method for synthesizing carbon-14 aniline to overcome the limitations of existing technologies, improve the utilization of carbon-14 isotopes, and meet the needs of scientific research and related industries. Summary of the invention

[0006] Based on this, it is necessary to provide an efficient carbon-14 aniline synthesis method and application to overcome the limitations of existing technologies, improve the utilization rate of carbon-14 isotopes, and meet the needs of scientific research and related industries.

[0007] To achieve the above object, the present invention provides a technical solution:

[0008] A method for preparing carbon-14 labeled aniline, the method comprising the steps of:

[0009] S100, 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 CO2:

[0010] Under vacuum conditions, the concentrated H2SO4 was dripped into the 14 C-BaCO3 reaction to obtain 14CO2; the concentrated H2SO4 and the 14 The mass ratio of C-BaCO3 is (8~11):1.

[0011] S200, the 14 CO2 reacts with Ba to produce Ba 14 C2:

[0012] placing Ba in a metal acetylene reactor, and evacuating the metal acetylene reactor;

[0013] Into the metal acetylene reactor 14 CO2, heat the bottom of the acetylene reactor until Ba melts into liquid, 14 CO2 is completely absorbed and cooled to room temperature to obtain the Ba 14 C2.

[0014] The temperature of heating the acetylene reactor is 900°C to 1100°C.

[0015] S300, the Ba 14 C2 reacts with H2O to obtain 14 CH 14 CH:

[0016] To the Ba 14 Add H2O dropwise to C2 to obtain 14 CH 14 CH, the H2O and 14 CH 14 The mass ratio of CH is (50-100):1.

[0017] S400, the 14 CH 14 CH is heated and reacted under the action of a molecular sieve catalyst attached with potassium dichromate to obtain 14 C6H6:

[0018] Add the activated molecular sieve catalyst to which potassium dichromate is attached 14 CH 14 CH reacts at room temperature for 1 to 3 hours, and then the reaction temperature is raised to 220°C to 280°C until the reaction is complete. 14 C6H6.

[0019] Furthermore, the molecular sieve catalyst attached with potassium dichromate is activated by K2CrO7.

[0020] S500, the 14 C6H6 and NaNO3 react to produce 14 C6H5NO2;

[0021] Dissolve NaNO3 in a solvent to obtain a NaNO3 solution;

[0022] Add the NaNO3 solution 14 C6H6, then 14 C6H5NO2.

[0023] S600: 4 C6H5NO2 reacts under the action of catalyst Pd / C to obtain 14 C6H5NH2:

[0024] Under vacuum conditions, 4 The catalyst Pd / C is added to C6H5NO2, and hydrogen is introduced to react to obtain 14 C6H5NH2.

[0025] The present invention also provides an application of carbon-14 labeled aniline in scientific research, new drug metabolism research and pesticide metabolism.

[0026] Beneficial effects of the present invention:

[0027] (1) The synthesis steps are short and the intermediate products do not require post-treatment;

[0028] (2) High carbon isotope utilization efficiency and high reaction yield;

[0029] (3) The product is easy to separate and has high purity;

[0030] (4) The reaction reagents are simple and the abundance of carbon isotopes will not be diluted. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of carbon-14 aniline;

[0032] Figure 2 is the gas chromatogram of carbon-14 aniline;

[0033] Figure 3 This is the radioactive liquid chromatogram of carbon-14 aniline. DETAILED DESCRIPTION

[0034] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0035] In the examples, the test methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used are all commercially available unless otherwise specified.

[0036] A method for preparing carbon-14 labeled aniline, the method comprising the steps of:

[0037] S100, 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 CO2:

[0038] Under vacuum conditions, the concentrated H2SO4 was dripped into the 14 C-BaCO3 reaction to obtain 14 CO2; the concentrated H2SO4 and the 14 The mass ratio of C-BaCO3 is (8~11):1.

[0039] S200, the 14 CO2 reacts with Ba to produce Ba 14 C2:

[0040] placing Ba in a metal acetylene reactor, and evacuating the metal acetylene reactor;

[0041] Into the metal acetylene reactor 14 CO2, heat the bottom of the acetylene reactor until Ba melts into liquid, 14 CO2 is completely absorbed and cooled to room temperature to obtain the Ba 14 C2.

[0042] The temperature of heating the acetylene reactor is 900°C to 1100°C.

[0043] S300, the Ba 14 C2 reacts with H2O to obtain 14 CH 14 CH;

[0044] To the Ba 14 Add H2O dropwise to C2 to obtain 14 CH 14 CH, the H2O and 14 CH 14 The mass ratio of CH is (50-100):1.

[0045] S400, the 14 CH 14 CH is heated and reacted under the action of a molecular sieve catalyst attached with potassium dichromate to obtain 14 C6H6;

[0046] Add the activated molecular sieve catalyst to which potassium dichromate is attached 14 CH 14 CH reacts at room temperature for h, and then the reaction temperature is raised to 220℃~280℃ until the reaction is complete, and the obtained 14 C6H6.

[0047] In some embodiments, the molecular sieve catalyst attached with potassium dichromate is activated by K2CrO7.

[0048] In some embodiments, the molecular sieve catalyst attached with potassium dichromate is activated by heating at a temperature of 180° C. to 200° C. for a heating time of 1 to 2 hours.

[0049] S500, the 14 C6H6 and NaNO3 react to produce 14 C6H5NO2;

[0050] NaNO3 is dissolved in a solvent to obtain a NaNO3 solution; in some embodiments, the solvent is CF3COOH.

[0051] Add the NaNO3 solution 14 C6H6, then 14 C6H5NO2.

[0052] S600: 4 C6H5NO2 reacts under the action of catalyst Pd / C to obtain 14 C6H5NH2.

[0053] Under vacuum conditions, 4 The catalyst Pd / C is added to C6H5NO2, and hydrogen is introduced to react to obtain 14 C6H5NH2.

[0054] The present invention also provides an application of carbon-14 labeled aniline in scientific research, new drug metabolism research and pesticide metabolism.

[0055] Example 1

[0056] S100, 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 CO2:

[0057] Will 14 C-BaCO3 (1.97 g, 10.0 mmol) was placed in a dry 100 ml round-bottom flask, which was connected to a constant-pressure separatory funnel. 20 ml of concentrated H2SO4 (98 wt.%) was placed in the constant-pressure separatory funnel. Under vacuum conditions, the constant-pressure separatory funnel was opened and concentrated H2SO4 was added dropwise to react to obtain 14 CO2, collect carefully 14 CO2 is kept in the vacuum system's spiral assembly for standby use;

[0058] S200, the 14 CO2 reacts with Ba to produce Ba 14 C2:

[0059] Cut Ba into pieces and place them in a metal acetylene reactor. Use liquid nitrogen to evacuate the metal acetylene reactor, remove the liquid nitrogen, and introduce 14 CO2, heat the bottom of the acetylene reactor until it turns purple-red and Ba melts into liquid (the temperature of heating the acetylene reactor is 900℃), shake the acetylene reactor until 14 CO2 is completely absorbed, cooled to room temperature, and protected by argon to obtain the Ba 14 C2.

[0060] S300, the Ba 14 C2 reacts with H2O to obtain 14 CH 14 CH;

[0061] The upper end of the acetylene reactor was replaced with a double-necked joint, one neck was connected to vacuum through a cold finger, and the other neck was connected to a constant pressure separatory funnel. Under vacuum, purified H2O and Ba in the acetylene reactor were added dropwise through the constant pressure separatory funnel. 14 C2 reaction, the reaction is 14 CH 14 CH, and a large amount of H2 is produced at the same time, so collect it carefully 14 CH 14 CH is in the serpentine condenser, after removing H2 and other impurity gases, 14 CH 14 CH is dried with P2O5 for later use, and H2O and 14 CH 14 The mass ratio of CH is 60:1.

[0062] S400, the 14 CH 14 CH is heated and reacted under the action of a molecular sieve catalyst attached with potassium dichromate to obtain 14 C6H6:

[0063] The molecular sieve catalyst attached with potassium dichromate was placed in a 50 ml double-necked bottle, one neck of which was equipped with a thermometer, and the mercury of the thermometer was immersed in the molecular sieve catalyst attached with potassium dichromate. Under vacuum, the molecular sieve catalyst attached with potassium dichromate was heated to 200°C, heated for 1 hour, cooled to room temperature, and 14 CH 14 Transfer CH liquid nitrogen to the reaction bottle, heat to room temperature for reaction, and then heat to 250°C until the reaction is complete;

[0064] S500, the 14 C6H6 and NaNO3 react to produce 14 C6H5NO2:

[0065] Take NaNO3 (510 mg, 6 mmol), put it in a 50 ml double-necked bottle, add 10 ml CF3COOH, cool with liquid nitrogen, and evacuate. Vacuum transfer 5 mmol C6H6 to the reaction bottle, warm to room temperature, stir and react for 8 hours to obtain 14 C6H5NO2.

[0066] The progress of the reaction was monitored by thin layer chromatography (TLC), and a 1:2 mixture of dichloromethane (DCM) and hexane (Hex) was used as a developing solvent. Under this condition, the Rf value of the target product was 0.45. The Rf value indicates the relative movement distance of the target compound in the developing solvent system, which is convenient for confirming whether the reaction of the reaction product is complete.

[0067] S600: 4 C6H5NO2 reacts under the action of catalyst Pd / C to obtain 14 C6H5NH2:

[0068] Take 100 mg Pd / C (where the mass percentage of Pd is 5%) and add it to 14 The temperature of the double-necked bottle containing C6H5NO2 was cooled to -100°C using liquid nitrogen, and the double-necked bottle was evacuated. Hydrogen was introduced into the double-necked bottle to cause a hydrogenation reaction. At room temperature, the hydrogenation reaction was carried out for 10 hours to obtain 14 The reaction was monitored by TLC.

[0069] Use liquid nitrogen cooling under vacuum conditions to gradually remove the 14 Trifluoroacetic acid (CF3COOH) in a mixture of C6H5NH2:

[0070] In containing 14 3 ml of purified water was added to the mixture of C6H5NH2 and stirred slowly to make the solution uniform. Subsequently, 30% NaOH solution was added dropwise to gradually alkalize the solution to ensure that 14 The free state of C6H5NH2 precipitates;

[0071] Add a small amount of ether to the alkalized mixture and perform liquid-liquid extraction. Take an equal amount of ether each time and perform 2-3 extractions to fully extract the free 14 C6H5NH2, the extracts were combined, dried with anhydrous sodium sulfate to remove the moisture in the organic phase, filtered to remove the sodium sulfate, and concentrated and dried by rotary evaporation to obtain pure 14 C6H5NH2 product, mass 0.50 g.

[0072] According to the initial use of the experiment 14 The reaction yield of C-BaCO3 was calculated and the results showed that the yield of the reaction was 56%.

[0073] The hydrogen nuclear magnetic resonance spectrum of carbon-14 aniline prepared in this example is as follows: Figure 1 As shown, the gas chromatogram of carbon-14 aniline is as follows Figure 2 As shown, the radioactive liquid chromatogram of carbon-14 aniline is as follows Figure 3 shown.

[0074] It should be noted that the specific parameters or some reagents in the above embodiments are specific embodiments or preferred embodiments of the present invention, rather than limiting the present invention; those skilled in the art can make adaptive adjustments within the scope of the present invention.

Claims

1. A method for preparing carbon-14 labeled aniline, characterized in that: The preparation method comprises the steps of: Will 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 CO2; The 14 CO2 reacts with Ba to produce Ba 14 C2; The Ba 14 C2 reacts with H2O to obtain 14 CH 14 CH; The 14 CH 14 CH is heated to react under the action of a molecular sieve with potassium dichromate attached as a catalyst to obtain 14 C6H6; The 14 C6H6 and NaNO3 react to produce 14 C6H5NO2; The 4 C6H5NO2 reacts under the action of catalyst Pd / C to obtain 14 C6H5NH2.

2. The method for preparing carbon-14 labeled aniline according to claim 1, characterized in that: Will 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 The specific steps for CO2 include: Under vacuum conditions, the concentrated H2SO4 was dripped into the 14 C-BaCO3 reaction to obtain 14 CO2; the concentrated H2SO4 and the 14 The mass ratio of C-BaCO3 is (8~11):

1.

3. The method for preparing carbon-14 labeled aniline according to claim 1, characterized in that: The 14 CO2 reacts with Ba to produce Ba 14 The specific steps of C2 include: placing Ba in a metal acetylene reactor, and evacuating the metal acetylene reactor; Into the metal acetylene reactor 14 CO2, heat the bottom of the acetylene reactor until Ba melts into liquid, 14 CO2 is completely absorbed and cooled to room temperature to obtain the Ba 14 C2.

4. The method for preparing carbon-14 labeled aniline according to claim 3, characterized in that: The temperature of heating the acetylene reactor is 900°C to 1100°C.

5. The method for preparing carbon-14 labeled aniline according to claim 1, characterized in that: The Ba 14 C2 reacts with H2O to obtain 14 CH 14 The specific steps of CH include: To the Ba 14 Add H2O dropwise to C2 to obtain 14 CH 14 CH, the H2O and 14 CH 14 The mass ratio of CH is (50-100):

1.

6. The method for preparing carbon-14 labeled aniline according to claim 1, characterized in that: The 14 CH 14 CH is heated and reacted under the action of a molecular sieve catalyst attached with potassium dichromate to obtain 14 The specific steps of C6H6 include: Add the activated molecular sieve catalyst to which potassium dichromate is attached 14 CH 14 CH reacts at room temperature for 1 to 3 hours, and then the reaction temperature is raised to 220°C to 280°C until the reaction is complete. 14 C6H6.

7. The method for preparing carbon-14 labeled aniline according to claim 1, characterized in that: The molecular sieve catalyst attached with potassium dichromate is activated by K2CrO7.

8. The method for preparing carbon-14 labeled aniline according to claim 1, characterized in that: The 14 C6H6 and NaNO3 react to produce 14 The specific steps of C6H5NO2 include: Dissolve NaNO3 in a solvent to obtain a NaNO3 solution; Add the NaNO3 solution 14 C6H6, then 14 C6H5NO2.

9. The method for preparing carbon-14 labeled aniline according to claim 7, characterized in that: The 4 C6H5NO2 reacts under the action of catalyst Pd / C to obtain 14 The specific steps of C6H5NH2 include: Under vacuum conditions, 4 The catalyst Pd / C is added to C6H5NO2, and hydrogen is introduced to react to obtain 14 C6H5NH2.

10. Use of carbon-14 labeled aniline obtained by the preparation method according to any one of claims 1 to 9 in scientific research, new drug metabolism research and pesticide metabolism.

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