Preparation method and application of carbon-14 labeled iodomethane

Abstract

The invention relates to a preparation method and application of carbon-14 labeled iodomethane, and the preparation method of carbon-14 labeled iodomethane comprises the following steps: carrying out a reaction on 14C-BaCO3 and concentrated H2SO4 to prepare 14CO2; the preparation method comprises the following steps: carrying out reaction on < 14 > CO2 and LiAlH4 to prepare < 14 > CH3OH; the 14CH3OH and HI are subjected to a reaction, and the 14CH3I is prepared. The scheme has the following advantages: (1) the synthesized intermediate product does not need post-treatment; (2) the utilization efficiency of the carbon-14 source material is high, and the reaction yield is high; (3) the product is easy to separate and high in purity; and (4) the abundance of carbon isotope in the reaction process is not diluted, and the specific activity of the product is high.

Description

Technical Field

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

[0002] Methyl iodide (CH3I) is a common halogenated hydrocarbon, which is widely used as a methylating agent in the pharmaceutical industry, especially in the synthesis of various drugs. As a methylating agent, methyl iodide can effectively introduce methyl groups into compounds, so it is widely used in drug synthesis, pesticide synthesis and organic synthesis reactions.

[0003] At present, the common methods for synthesizing methyl iodide include the following:

[0004] (1) Producing methyl iodide by disproportionation reaction of dimethyl sulfate (DMS);

[0005] (2) synthesizing methyl iodide by reacting potassium iodide, calcium carbonate, water and dimethyl sulfate;

[0006] (3) Methyl iodide is synthesized from red phosphorus and methanol under halogenation conditions.

[0007] However, these methods are limited in the starting materials used and cannot be directly used to synthesize carbon-14 labeled methyl iodide ( 14 C-iodomethane).

[0008] 14 C-labeled compounds are of great significance in drug metabolism research, especially in the quantitative analysis and tracking of drug metabolism in vivo. The application of carbon-14 labeled methyl iodide as a methylating agent in drug research is particularly critical. Summary of the invention

[0009] Based on this, it is necessary to provide an effective and reliable 14C-iodomethane synthesis method and application to overcome the limitations of existing synthesis methods.

[0010] To achieve the above object, the present invention provides a technical solution:

[0011] A method for preparing carbon-14 labeled methyl iodide, the method comprising the steps of:

[0012] Will 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 CO2;

[0013] Will 14 CO2 reacts with a reducing agent to produce 14 CH3OH;

[0014] Will 14CH3OH reacts with HI to obtain 14 CH3I.

[0015] Preferably, 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 The specific steps for CO2 include:

[0016] Under vacuum conditions, the concentrated H2SO4 was dripped into the 14 C-BaCO3 reaction to obtain 14 CO2; the volume of the concentrated H2SO4 and the 14 The mass ratio of C-BaCO3 is (8~11)ml:1g.

[0017] Preferably, 14 In the step of reacting CO 2 and LiAlH 4 , the LiAlH 4 is dissolved in a solvent.

[0018] Preferably, the solvent comprises 2-(tetrahydrofurfuryloxy)tetrahydropyran (THFA).

[0019] Preferably, the HI is prepared by reacting elemental iodine and red phosphorus.

[0020] Preferably, the molar ratio of the iodine element to the red phosphorus is (1:0.5-3).

[0021] Preferably, the reducing agent comprises at least one of NaBH4 and NaBH4.

[0022] Preferably, 14 The mass ratio of CO2 and LiAlH4 is 1:(2~5).

[0023] Preferably, 14 The mass ratio of CH3OH and HI is 1:(10~20).

[0024] The present invention also provides an application of carbon-14 labeled methyl iodide in scientific research, new drug metabolism research and pesticide metabolism.

[0025] Beneficial effects of the present invention:

[0026] (1) No post-treatment is required for the synthetic intermediates;

[0027] (2) High utilization efficiency of carbon-14 source materials and high reaction yield;

[0028] (3) The product is easy to separate and has high purity;

[0029] (4) The abundance of carbon isotopes will not be diluted during the reaction, and the specific activity of the product is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 is the H NMR spectrum of 14C-iodomethane;

[0031] Figure 2 This is the gas chromatogram of 14C-iodomethane. DETAILED DESCRIPTION

[0032] 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.

[0033] 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.

[0034] A method for preparing carbon-14 labeled methyl iodide, the method comprising the steps of:

[0035] Will 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 CO2;

[0036] Will 14 CO2 reacts with a reducing agent to produce 14 CH3OH;

[0037] Will 14 CH3OH reacts with HI to obtain 14 CH3I.

[0038] Preferably, 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 The specific steps for CO2 include:

[0039] Under vacuum conditions, the concentrated H2SO4 was dripped into the 14 C-BaCO3 reaction to obtain 14 CO2; the volume of the concentrated H2SO4 and the 14 The mass ratio of C-BaCO3 is (8~11)ml:1g.

[0040] Preferably, 14 In the step of reacting CO 2 and LiAlH 4 , the LiAlH 4 is dissolved in a solvent.

[0041] Preferably, the solvent comprises 2-(tetrahydrofurfuryloxy)tetrahydropyran (THFA).

[0042] Preferably, the HI is prepared by reacting elemental iodine and red phosphorus.

[0043] Preferably, the molar ratio of the iodine element to the red phosphorus is (1:0.5-3).

[0044] Preferably, the reducing agent comprises at least one of NaBH4 and NaBH4.

[0045] Preferably, 14 The mass ratio of CO2 and LiAlH4 is 1:(2~5).

[0046] Preferably, 14 The mass ratio of CH3OH and HI is 1:(10~20).

[0047] The present invention also provides an application of carbon-14 labeled methyl iodide in scientific research, new drug metabolism research and pesticide metabolism.

[0048] Example 1

[0049] S100, 14 C-BaCO3 (1.97 g, 10.0 mmol) was placed in a dry 100 ml round-bottom flask, 20 ml of concentrated H2SO4 was placed in a constant pressure separatory funnel, and the mixture was added to the round-bottom flask under vacuum. 14 C-BaCO3 is added dropwise to concentrated H2SO4, and the reaction produces 14 CO2, collect carefully 14 CO2 is kept in the vacuum system's spiral assembly for standby use;

[0050] S200, 14 CO2 reacts with a reducing agent to produce 14 CH3OH:

[0051] 20.0 mmol of reducing agent (LiAlH4) was transferred to a 100 ml double-necked round-bottomed reaction bottle, and the double-necked round-bottomed reaction bottle was evacuated. 40 ml of solvent THFA (2-(tetrahydrofurfuryloxy)tetrahydropyran) was added dropwise to the double-necked round-bottomed reaction bottle, and vacuumed and stirred to dissolve for 2 hours until no bubbles were generated. The double-necked round-bottomed reaction bottle was placed in an ice-water bath (temperature was 0° C.), and the product prepared in step S100 was added. 14 CO2 was introduced into the double-necked round-bottomed reaction flask for reaction. 14 The time for CO2 is 1 hour;

[0052] Under the condition of ice water bath (temperature is 0℃), 120mmol THFA-OH tetrahydrofurfuryl alcohol) was added dropwise to react to generate H2 to remove unreacted LiAlH4. After the generated H2 was completely removed, the system was heated to 120℃ and cold finger refluxed (temperature is -20℃) to distill out methanol ( 14 CH3OH), and the mass of the liquid methanol obtained by weighing was 0.22g.

[0053] S300, 14CH3OH reacts with HI to obtain 14 CH3I:

[0054] 21 mmol of 55 wt.% hydroiodic acid (HI) aqueous solution was placed in a vacuum bottle, liquid nitrogen was introduced to cool the hydroiodic acid aqueous solution, and the vacuum bottle was evacuated to remove the methanol ( 14 CH3OH) was vacuum transferred into a vacuum bottle, and the temperature in the vacuum bottle was gradually raised to 80°C for reaction for 3 hours, and N-trap was used for separation and purification 14 C-iodomethane ( 14 CH3I), 14 The volume of CH3I is 0.35 mL, and barium carbonate ( 14 C-BaCO3) as the raw material, the total yield of the reaction is 56%, and the specific activity of the product is 54.5mCi / mmol.

[0055] Note: "N-trap" separation and purification is a term in chromatography technology, which refers to a trap column or trap technology used in the chromatography process to separate certain unwanted components or impurities from the sample before sample analysis. This technology is particularly suitable for liquid chromatography (LC) and gas chromatography (GC) to improve the sensitivity and selectivity of the analysis.

[0056] Example 2

[0057] S100, 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 CO2:

[0058] Will 14 C-BaCO3 (1.97 g, 10.0 mmol) was placed in a dry 100 ml round-bottom flask, and 20 ml of concentrated H2SO4 was placed in a constant pressure separatory funnel connected to the round-bottom flask. Under vacuum conditions, 14 C-BaCO3 is added dropwise to concentrated H2SO4, and the reaction produces 14 CO2, collect carefully 14 CO2 is kept in the vacuum system's spiral assembly for standby use;

[0059] S200, 14 CO2 reacts with a reducing agent to produce 14 CH3OH:

[0060] 20.0 mmol of reducing agent (NaBH4) was transferred to a 100 ml double-necked round-bottomed reaction bottle, and the double-necked round-bottomed reaction bottle was evacuated. 30 mmol of solvent THFA (2-(tetrahydrofurfuryloxy)tetrahydropyran) was added dropwise to the double-necked round-bottomed reaction bottle, and the mixture was stirred and dissolved for 2 hours while evacuating and stirring, until no bubbles were generated. The double-necked round-bottomed reaction bottle was placed in an ice-water bath (temperature was 0° C.), and the prepared product in step S100 was added. 14 CO2 was introduced into the double-necked round-bottomed reaction flask for reaction. 14 The time for CO2 is 1 hour;

[0061] Under the condition of ice water bath (temperature is 0℃), 120mmol THFA-OH (ml, tetrahydrofurfuryl alcohol) is added dropwise to generate H2 to remove the unreacted NaBH4. After the generated H2 is completely removed, the system is heated to 120℃ and cold finger reflux (temperature is -20℃) is used to distill out methanol ( 14 CH3OH), and the mass of the liquid methanol obtained by weighing was 0.22g.

[0062] S300, 14 CH3OH reacts with HI to obtain 14 CH3I:

[0063] 21 mmol of 60 wt.% hydroiodic acid (HI) aqueous solution was placed in a vacuum bottle, liquid nitrogen was introduced to cool the hydroiodic acid aqueous solution, and the vacuum bottle was evacuated to remove the methanol ( 14 CH3OH) was vacuum transferred into a vacuum bottle, and the temperature in the vacuum bottle was gradually raised to 80°C for reaction for 3 hours, and N-trap was used for separation and purification 14 C-iodomethane ( 14 CH3I), 14 The volume of CH3I is 0.33 mL, and barium carbonate ( 14 C-BaCO3) as the raw material, the total yield of the reaction is 54%, and the specific activity of the product is 56.1mCi / mmol.

[0064] Example 3

[0065] S100, 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 CO2:

[0066] Will 14 C-BaCO3 (1.97 g, 10.0 mmol) was placed in a dry 100 ml round-bottom flask, 20 ml of concentrated H2SO4 was placed in a constant pressure separatory funnel, and the mixture was added to the round-bottom flask under vacuum. 14 C-BaCO3 is added dropwise to concentrated H2SO4, and the reaction produces 14CO2, collect carefully 14 CO2 is kept in the vacuum system's spiral assembly for standby use;

[0067] S200, 14 CO2 reacts with a reducing agent to produce 14 CH3OH:

[0068] 20.0 mmol of reducing agent (NaBH4) was transferred to a 100 ml double-necked round-bottomed reaction bottle, and the double-necked round-bottomed reaction bottle was evacuated. 335 ml of THFA (2-(tetrahydrofurfuryloxy)tetrahydropyran) was added dropwise to the double-necked round-bottomed reaction bottle, and the mixture was stirred and dissolved for about 1 hour until no bubbles were generated. The double-necked round-bottomed reaction bottle was placed in an ice-water bath (temperature was 0° C.), and the CO2 prepared in step S100 was introduced into the double-necked round-bottomed reaction bottle for reaction, and then the mixture was introduced into the reaction bottle. 14 The time for CO2 is 1 hour;

[0069] Under the condition of ice water bath (temperature is 0℃), 120mmol THFA-OH (ml, tetrahydrofurfuryl alcohol) was added dropwise to remove the unreacted NaBH4. After the generated H2 was completely removed, the system was heated to 120℃ and cold finger refluxed (temperature is -20℃) to distill out methanol ( 14 CH3OH), and the mass of the liquid methanol obtained by weighing was 0.22g.

[0070] S300, 14 CH3OH reacts with HI to obtain 14 CH3I:

[0071] 21 mmol of iodine and 0.1 g of red phosphorus were placed in a vacuum bottle to react and generate hydroiodic acid (HI). Liquid nitrogen was introduced to cool the hydroiodic acid. The vacuum bottle was evacuated and the methanol ( 14 CH3OH) was vacuum transferred to a vacuum bottle, and the temperature in the vacuum bottle was gradually raised to 80°C for reaction for 3 hours, and N-trap was used for separation and purification 14 C-iodomethane ( 14 CH3I), 14 The volume of CH3I is 0.37 mL, and barium carbonate ( 14 C-BaCO3) as the raw material, the total yield of the reaction is 58%, and the specific activity of the product is 53.4 mCi / mmol.

[0072] Comparative Example 1

[0073] The other steps of this comparative example are the same as those of Example 1, except that:

[0074] In step S200, 14In the CH3OH step, the solvent THFA was replaced with ether. Due to the poor solubility of ether, the product 14 The yield of CH3OH was only 30%.

[0075] 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 methyl iodide, characterized in that: The preparation method comprises the steps of: Will 14 C-BaCO3 reacts with concentrated H2SO4 to obtain 14 CO2; Will 14 CO2 reacts with a reducing agent to produce 14 CH3OH; Will 14 CH3OH reacts with HI to obtain 14 CH3I.

2. The method for preparing carbon-14 labeled methyl iodide 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 volume of the concentrated H2SO4 and the 14 The mass ratio of C-BaCO3 is (8~11)ml:1g.

3. The method for preparing carbon-14 labeled methyl iodide according to claim 1, characterized in that: Will 14 In the step of reacting CO 2 and LiAlH 4 , the LiAlH 4 is dissolved in a solvent.

4. The method for preparing carbon-14 labeled methyl iodide according to claim 3, characterized in that: The solvent includes 2-(tetrahydrofurfuryloxy)tetrahydropyran.

5. The method for preparing carbon-14 labeled methyl iodide according to claim 1, characterized in that: The HI is prepared by reacting elemental iodine with red phosphorus.

6. The method for preparing carbon-14 labeled methyl iodide according to claim 5, characterized in that: The molar ratio of the iodine element to the red phosphorus is (1:0.5-3).

7. The method for preparing carbon-14 labeled methyl iodide according to claim 1, characterized in that: The reducing agent includes at least one of NaBH4 and NaBH4.

8. The method for preparing carbon-14 labeled methyl iodide according to claim 1, characterized in that: 14 The mass ratio of CO2 and LiAlH4 is 1:(2~5).

9. The method for preparing carbon-14 labeled methyl iodide according to claim 1, characterized in that: 14 The mass ratio of CH3OH and HI is 1:(10~20).

10. Use of carbon-14 labeled methyl iodide 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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