Carbon-14-labeled benzaldehyde as well as preparation method and application thereof

Abstract

The invention relates to carbon-14 labeled benzaldehyde and a preparation method and application thereof.The preparation method comprises the steps that 14C-BaCO3 is converted into 14C-CO2, then 14C-CO2 and a phenyl Grignard reagent are subjected to an insertion reaction to synthesize 14C-benzoic acid, and 14C-benzaldehyde is synthesized from 14C-benzoic acid through a method that the 14C-benzoic acid is firstly reduced and then oxidized. The carbon-14 labeled benzaldehyde provided by the invention can be used as a radioactive tracer for drug metabolism research, and the provided preparation method has the advantages of high utilization efficiency of a carbon-14 source material and high reaction yield; the product is easy to separate and high in purity; in the reaction process, abundance of carbon isotopes cannot be diluted, the specific activity of the product is high, and the method has high application value.

Description

Technical Field

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

[0002] Benzaldehyde is a simple organic compound with the molecular formula C7H6O. It is a colorless liquid at room temperature and pressure with the smell of bitter almonds. Benzaldehyde is an important chemical raw material and can be used to prepare a variety of important organic compounds.

[0003] Common methods for synthesizing benzaldehyde include the following: (1) Toluene is first chlorinated under light conditions to obtain chlorobenzene, which is then hydrolyzed to synthesize benzaldehyde; (2) Benzyl alcohol is oxidized to obtain benzaldehyde; (3) Toluene is directly oxidized to obtain benzaldehyde; (4) Benzene is used as the raw material and is synthesized by reacting with carbon monoxide under the catalysis of aluminum chloride.

[0004] Due to the problem of the source of the starting material (the carbon-14 source material is carbon-14 barium carbonate), the above methods cannot be directly used for 14 Synthesis of C-benzaldehyde. Given the importance of carbon 14 labeling in drug metabolism research, 14 C-benzaldehyde is the most commonly used marker building block, so it provides a 14 C-benzaldehyde and its preparation method have good application prospects. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a carbon-14 labeled benzaldehyde and a preparation method and application thereof. The carbon-14 labeled benzaldehyde provided by the present invention can be used as a radioactive tracer for drug metabolism research, and the preparation method provided has high carbon-14 source material utilization efficiency and high reaction yield; the product is easy to separate and has high purity; the abundance of carbon isotopes will not be diluted during the reaction process, the product has high specific activity, and has high application value.

[0006] To achieve this object, the present invention adopts the following technical solutions:

[0007] In a first aspect, the present invention provides a carbon-14 labeled benzaldehyde, the structural formula of the benzaldehyde is as follows:

[0008]

[0009] *Indicates the carbon-14 labeling site.

[0010] In a second aspect, the present invention provides a method for preparing carbon-14 labeled benzaldehyde according to the first aspect, the preparation method comprising the following steps:

[0011] (1) 14C-BaCO3 reacts with acid to obtain 14 C-CO2; the reaction formula is as follows:

[0012]

[0013] (2) Phenyl Grignard reagent and 14 C-CO2 reaction to obtain carbon-14 labeled benzoic acid; the reaction formula is as follows:

[0014]

[0015] wherein X is selected from chlorine, bromine or iodine;

[0016] (3) The carbon-14 labeled benzoic acid is subjected to a reduction reaction to obtain carbon-14 labeled benzyl alcohol; the reaction formula is as follows:

[0017]

[0018] (4) The carbon-14 labeled benzyl alcohol is subjected to oxidation reaction to obtain carbon-14 labeled benzaldehyde; the reaction formula is as follows:

[0019]

[0020] Carbon-14 source materials cannot be obtained by enrichment. The current industrial method is to synthesize carbon-14 barium carbonate by irradiating aluminum nitride. 14 C-Benzaldehyde can only be obtained via carbon-14 barium carbonate via a multi-step chemical transformation.

[0021] The preparation method provided by the present invention firstly 14 C-BaCO3 is converted to 14 C-CO2, then 14 Synthesis of C-CO2 via insertion reaction with phenyl Grignard reagent 14 C-benzoic acid, 14 Synthesis of C-benzoic acid by reduction followed by oxidation 14 C-benzaldehyde. The preparation method provided by the invention has high carbon-14 source material utilization efficiency and high reaction yield; the product is easy to separate and has high purity; the abundance of carbon isotopes will not be diluted during the reaction process, the product has high specific activity and has high application value.

[0022] Preferably, the acid in step (1) comprises any one of sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid or perchloric acid, or a combination of at least two thereof.

[0023] Preferably, step (1) 14The molar ratio of C-BaCO3 and acid is 1:(10-100) (for example, it can be 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, etc.).

[0024] Preferably, the reaction in step (1) is carried out under vacuum.

[0025] Preferably, the phenyl grignard reagent in step (2) and 14 The molar ratio of C-CO2 is 1:(0.5~0.8) (for example, it can be 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, etc.).

[0026] Preferably, the reaction in step (2) is carried out in the presence of a solvent.

[0027] Preferably, the solvent comprises any one of tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether, or a combination of at least two thereof.

[0028] Preferably, the material mixing method of the reaction in step (2) comprises: mixing the phenyl grignard reagent and the solvent, degassing, introducing 14 C-CO2 reacts.

[0029] Preferably, the mixing is performed in a protective atmosphere.

[0030] Preferably, the protective atmosphere comprises argon.

[0031] Preferably, the degassing method includes: first freezing with liquid nitrogen and then degassing by vacuuming.

[0032] Preferably, the 14 C-CO2 is introduced into the reaction system using liquid nitrogen.

[0033] Preferably, the reaction temperature in step (2) is -25 to -15°C (for example, -24°C, -22°C, -20°C, -18°C, -16°C, etc.), and the reaction time is 30 to 90 min (for example, 40 min, 50 min, 60 min, 70 min, 80 min, etc.).

[0034] Preferably, the reaction in step (2) further comprises a post-treatment step.

[0035] Preferably, the post-treatment comprises: adding a quenching agent to the reaction system for quenching, adding acid to adjust the pH, and then performing organic solvent extraction, washing and drying to obtain the carbon-14 labeled benzoic acid.

[0036] Preferably, the quencher comprises water.

[0037] Preferably, the pH is adjusted to 0.5-2 (for example, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, etc.).

[0038] Preferably, the organic solvent comprises ethyl acetate.

[0039] Preferably, the washing detergent comprises salt water.

[0040] Preferably, the reduction reaction in step (3) is carried out in the presence of a reducing agent.

[0041] Preferably, the reducing agent comprises any one of lithium aluminum hydride or borane dimethyl sulfide complex or a combination of both.

[0042] Preferably, the molar ratio of the carbon-14 labeled benzoic acid to the reducing agent is 1:(2-10) (for example, it can be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, etc.).

[0043] Preferably, the reduction reaction in step (3) is carried out in the presence of a solvent.

[0044] Preferably, the solvent comprises any one of tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether, or a combination of at least two thereof.

[0045] Preferably, the material mixing method for the reduction reaction in step (3) comprises: adding a solvent to the reducing agent to dissolve it, and then adding a solution of carbon-14 labeled benzoic acid to react.

[0046] Preferably, the dropwise addition of the solvent is performed in a protective atmosphere.

[0047] Preferably, the protective atmosphere comprises argon.

[0048] Preferably, the temperature of the reduction reaction in step (3) is 50-70°C (for example, 52°C, 55°C, 58°C, 60°C, 62°C, 65°C, 68°C, etc.), and the reaction temperature is 2-4h (for example, 2.2h, 2.5h, 2.8h, 3h, 3.2h, 3.5h, 3.8h, etc.).

[0049] Preferably, the reduction reaction in step (3) further includes a post-treatment step.

[0050] Preferably, the post-treatment comprises: adding a quenching agent to the reaction system for quenching, alkali-acid treatment, organic solvent extraction, washing, drying, and column purification of the obtained oil to obtain the carbon-14 labeled benzaldehyde.

[0051] Preferably, the quencher comprises water.

[0052] Preferably, the acid-base treatment includes: adding acid to adjust the pH to 0.5-2 (for example, it can be 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, etc.), and then adding alkali to adjust the pH to 12-13.5 (for example, it can be 12.2, 12.4, 12.6, 12.8, 13, 13.2, 13.4, etc.).

[0053] Preferably, the washing detergent comprises salt water.

[0054] Preferably, the solvent used in the column purification comprises a mixed solvent of ethyl acetate and n-hexane.

[0055] Preferably, the volume ratio of ethyl acetate to n-hexane is 1:(5-7) (for example, it can be 1:5.2, 1:5.5, 1:5.8, 1:6, 1:6.2, 1:6.5, 1:6.8, etc.).

[0056] Preferably, the oxidation reaction in step (4) is carried out in the presence of an oxidant.

[0057] Preferably, the oxidant comprises any one of Dess-Martin reagent, manganese dioxide, pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) or a combination of at least two thereof.

[0058] Preferably, the molar ratio of the carbon-14 labeled benzyl alcohol to the oxidant is 1:(2-10) (for example, it can be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, etc.).

[0059] Preferably, the oxidation reaction in step (4) is carried out in the presence of a base.

[0060] Preferably, the base comprises any one of sodium bicarbonate or sodium carbonate or a combination of both.

[0061] Preferably, the molar ratio of the carbon-14 labeled benzyl alcohol to the base is 1:(2-10) (for example, it can be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, etc.).

[0062] Preferably, the oxidation reaction in step (4) is carried out in the presence of a solvent.

[0063] Preferably, the solvent comprises any one of dichloromethane, tetrahydrofuran or 2-methyltetrahydrofuran, or a combination of at least two thereof.

[0064] Preferably, the temperature of the oxidation reaction in step (4) is 0-40°C (for example, 5°C, 15°C, 20°C, 25°C, 30°C, 35°C, etc.), and the time of the oxidation reaction is 30-90min (for example, 40min, 50min, 60min, 70min, 80min, etc.).

[0065] Preferably, the oxidation reaction in step (4) further includes a post-treatment step.

[0066] Preferably, the post-treatment comprises: filtering through a silica gel column to obtain a filtrate, removing the solvent by rotary evaporation, and then performing column purification to obtain the carbon-14 labeled benzaldehyde.

[0067] Preferably, the solvent used in the column purification comprises a mixed solvent of ethyl acetate and n-hexane.

[0068] Preferably, the volume ratio of ethyl acetate to n-hexane is 1:(5-7), for example, 1:5.2, 1:5.5, 1:5.8, 1:6, 1:6.2, 1:6.5, 1:6.8, etc.).

[0069] Preferably, the preparation method comprises the following steps:

[0070] (1) 14 C-BaCO3 and acid react in a molar ratio of 1:(10-100) to obtain 14 C-CO2;

[0071] (2) Phenyl Grignard reagent, 14 C-CO2 and solvent are mixed and reacted at -15 to -25°C for 30 to 90 minutes to obtain carbon-14 labeled benzoic acid; the phenyl Grignard reagent and 14 The molar ratio of C-CO2 is 1:(0.5-0.8);

[0072] (3) mixing carbon-14 labeled benzoic acid, a reducing agent and a solvent, and performing a reduction reaction at 50 to 70° C. for 2 to 4 hours to obtain carbon-14 labeled benzyl alcohol; the molar ratio of the carbon-14 labeled benzoic acid to the reducing agent is 1:(2 to 10);

[0073] (4) mixing carbon-14 labeled benzyl alcohol, an oxidant, a base and a solvent, and performing an oxidation reaction at 0 to 40° C. for 30 to 90 minutes to obtain carbon-14 labeled benzaldehyde; the molar ratio of the carbon-14 labeled benzyl alcohol, the oxidant and the base is 1:(2 to 10):(2 to 10).

[0074] In a third aspect, the present invention provides a use of the carbon-14 labeled benzaldehyde according to the first aspect in the preparation of a carbon-14 labeled drug.

[0075] Compared with the prior art, the present invention has at least the following beneficial effects:

[0076] (1) The carbon-14 labeled benzaldehyde provided by the present invention can be used as a radioactive tracer in drug metabolism research.

[0077] (2) The preparation method provided by the present invention has high carbon-14 source material utilization efficiency and high reaction yield; the product is easy to separate and has high purity; the abundance of carbon isotopes will not be diluted during the reaction, the product has high specific activity, and has high application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 This is a gas chromatogram of carbon-14 labeled benzaldehyde.

[0079] Figure 2 This is a radioactive liquid chromatogram of carbon-14 labeled benzaldehyde. DETAILED DESCRIPTION

[0080] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and through specific implementation methods. However, the following examples are only simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0081] Example 1

[0082] A carbon-14 labeled benzaldehyde, the structural formula is as follows:

[0083]

[0084] The preparation method of the carbon-14 labeled benzaldehyde comprises the following steps:

[0085] (1) 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 resulting 14 C-CO2, collect carefully 14 C-CO2 is kept in the spiral assembly of the vacuum system for standby use;

[0086] (2) Under argon conditions, 30.0 mmol C6H5MgBr was placed in a 100 mL double-necked round-bottom reaction bottle, diluted with anhydrous tetrahydrofuran to about 0.8 M, frozen with liquid nitrogen, evacuated, heated to 25°C to dissolve, and then frozen with liquid nitrogen and evacuated to remove the gas absorbed in the liquid; liquid nitrogen was used to 14C-CO2 was introduced at -20°C until absorption was complete (about 1 hour); the reaction was killed with 2 mL of purified water, then acidified to pH = 1 with 2 mmol / mL H2SO4, extracted twice with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, the solvent was removed by rotary evaporation, and dried in vacuo to obtain 1.16 g of carbon-14 labeled benzoic acid;

[0087] (3) LiAlH4 (600 mg, 16.0 mmol) was placed in a dry 100 mL round-bottom flask, evacuated, and 20 mL of anhydrous THF was added dropwise under argon. The mixture was stirred and carefully evacuated to dissolve until no bubbles were generated (about 1 hour). Carbon-14 labeled benzoic acid (9.5 mmol) was dissolved in about 10 mL of THF and added dropwise to the above LiAlH4 solution. The mixture was refluxed at 60° C. for about 3 hours. The reaction was monitored by EtOAC:Hexane (1:6, v / v). The benzyl alcohol was confirmed by oxidation color development. After the reaction was completed, about 1 mL of purified water was used to kill the reaction. THF was removed by rotary evaporation. Sulfuric acid was added to adjust the pH to 1, and then sodium hydroxide was added to adjust the pH to 13. The mixture was extracted with ether, washed with salt and dried, the solvent was removed by rotary evaporation, and vacuum dried to obtain an oily product. The oily product was purified by column chromatography using EtOAC:Hexane (1:6, v / v) to obtain 842.3 mg of carbon-14 labeled benzyl alcohol with a yield of 82%.

[0088] (4) C-14 labeled benzyl alcohol (650 mg, 6.0 mmol) was placed in a dry 100 mL round-bottom flask. Under argon, 20 mL of anhydrous dichloromethane was added, followed by Dess-Martin reagent (5.1 g, 12.0 mmol) and NaHCO3 (1.5 g, 18.0 mmol). The mixture was reacted at 25 °C for 1 hour, and the reaction was monitored by DCM:Acetone (1:5, v / v). After the reaction was completed, the solid was filtered out by a short silica gel column, and the solvent was evaporated to obtain the product. The product was purified by column purification with EtOAC:Hexane (1:6, v / v), the solvent was evaporated to obtain the product, and the product was dried in vacuo to obtain a light yellow oily product, i.e., C-14 labeled benzaldehyde, weighing 579.4 mg, with a yield of 91%, a purity of 99%, and a specific activity of 54 Ci / mol.

[0089] Figure 1 This is a gas chromatogram of carbon-14 labeled benzaldehyde.

[0090] Figure 2 This is a radioactive liquid chromatogram of carbon-14 labeled benzaldehyde.

[0091] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A carbon-14 labeled benzaldehyde, characterized in that The structural formula of the benzaldehyde is as follows: *Indicates the carbon-14 labeling site.

2. A method for preparing carbon-14 labeled benzaldehyde according to claim 1, characterized in that: The preparation method comprises the following steps: (1) 14 C-BaCO3 reacts with acid to obtain 14 C-CO2; the reaction formula is as follows: (2) Phenyl Grignard reagent and 14 C-CO2 reaction to obtain carbon-14 labeled benzoic acid; the reaction formula is as follows: wherein X is selected from chlorine, bromine or iodine; (3) The carbon-14 labeled benzoic acid is subjected to a reduction reaction to obtain carbon-14 labeled benzyl alcohol; the reaction formula is as follows: (4) The carbon-14 labeled benzyl alcohol is subjected to oxidation reaction to obtain carbon-14 labeled benzaldehyde; the reaction formula is as follows:

3. The preparation method according to claim 2, characterized in that: The acid in step (1) includes any one of sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid or perchloric acid, or a combination of at least two thereof; Preferably, step (1) 14 The molar ratio of C-BaCO3 to acid is 1:(10-100); Preferably, the reaction in step (1) is carried out under vacuum.

4. The preparation method according to claim 2 or 3, characterized in that: The phenyl grignard reagent of step (2) and 14 The molar ratio of C-CO2 is 1:(0.5-0.8); Preferably, the reaction in step (2) is carried out in the presence of a solvent; Preferably, the solvent comprises any one of tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether or a combination of at least two thereof; Preferably, the material mixing method of the reaction in step (2) comprises: mixing the phenyl grignard reagent and the solvent, degassing, introducing 14 C-CO2 reacts; Preferably, the mixing is carried out in a protective atmosphere; Preferably, the protective atmosphere comprises argon; Preferably, the degassing method includes: first freezing with liquid nitrogen and then degassing by vacuuming; Preferably, the 14 C-CO2 is introduced into the reaction system using liquid nitrogen; Preferably, the reaction temperature in step (2) is -25 to -15°C, and the reaction time is 30 to 90 minutes; Preferably, the reaction in step (2) further comprises a post-treatment step; Preferably, the post-treatment comprises: adding a quenching agent to the reaction system for quenching, adding acid to adjust the pH, and then performing organic solvent extraction, washing and drying to obtain the carbon-14 labeled benzoic acid; Preferably, the pH is adjusted to 0.5-2.

5. The preparation method according to any one of claims 2 to 4, characterized in that: The reduction reaction in step (3) is carried out in the presence of a reducing agent; Preferably, the reducing agent comprises any one or a combination of lithium aluminum hydride or borane dimethyl sulfide complex; Preferably, the molar ratio of the carbon-14 labeled benzoic acid to the reducing agent is 1:(2-10); Preferably, the reduction reaction in step (3) is carried out in the presence of a solvent; Preferably, the solvent comprises any one of tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether, or a combination of at least two thereof.

6. The preparation method according to any one of claims 2 to 5, characterized in that: The material mixing method for the reduction reaction in step (3) comprises: adding a solvent dropwise to the reducing agent to dissolve it, and then adding a solution of carbon-14 labeled benzoic acid dropwise to react; Preferably, the dropwise addition of the solvent is carried out in a protective atmosphere; Preferably, the protective atmosphere comprises argon; Preferably, the temperature of the reduction reaction in step (3) is 50-70° C., and the reaction temperature is 2-4 hours; Preferably, the reduction reaction in step (3) further includes a post-treatment step; Preferably, the post-treatment comprises: adding a quenching agent to the reaction system for quenching, alkali-acid treatment, organic solvent extraction, washing, drying, and column purification of the obtained oil to obtain the carbon-14 labeled benzaldehyde; Preferably, the solvent used in the column purification comprises a mixed solvent of ethyl acetate and n-hexane; Preferably, the volume ratio of ethyl acetate to n-hexane is 1:(5-7).

7. The preparation method according to any one of claims 2 to 6, characterized in that: The oxidation reaction in step (4) is carried out in the presence of an oxidant; Preferably, the oxidant comprises any one or a combination of at least two of Dess-Martin reagent, manganese dioxide, pyridine chlorochromate or pyridine dichromate; Preferably, the molar ratio of the carbon-14 labeled benzyl alcohol to the oxidant is 1:(2-10); Preferably, the oxidation reaction in step (4) is carried out in the presence of a base; Preferably, the base comprises any one or a combination of sodium bicarbonate or sodium carbonate; Preferably, the molar ratio of the carbon-14 labeled benzyl alcohol to the base is 1:(2-10); Preferably, the oxidation reaction in step (4) is carried out in the presence of a solvent; Preferably, the solvent comprises any one of dichloromethane, tetrahydrofuran or 2-methyltetrahydrofuran, or a combination of at least two thereof.

8. The preparation method according to any one of claims 2 to 7, characterized in that: The temperature of the oxidation reaction in step (4) is 0 to 40° C., and the time of the oxidation reaction is 30 to 90 minutes; Preferably, the oxidation reaction in step (4) further comprises a post-treatment step; Preferably, the post-treatment comprises: filtering through a silica gel column to obtain a filtrate, removing the solvent by rotary evaporation, and then performing column purification to obtain the carbon-14 labeled benzaldehyde; Preferably, the solvent used in the column purification comprises a mixed solvent of ethyl acetate and n-hexane; Preferably, the volume ratio of ethyl acetate to n-hexane is 1:(5-7).

9. The preparation method according to any one of claims 2 to 8, characterized in that: The preparation method comprises the following steps: (1) 14 C-BaCO3 and acid react in a molar ratio of 1:(10-100) to obtain 14 C-CO2; (2) Phenyl Grignard reagent, 14 C-CO2 and solvent are mixed and reacted at -25 to -15°C for 30 to 90 minutes to obtain carbon-14 labeled benzoic acid; the phenyl Grignard reagent and 14 The molar ratio of C-CO2 is 1:(0.5-0.8); (3) mixing carbon-14 labeled benzoic acid, a reducing agent and a solvent, and performing a reduction reaction at 50 to 70° C. for 2 to 4 hours to obtain carbon-14 labeled benzyl alcohol; the molar ratio of the carbon-14 labeled benzoic acid to the reducing agent is 1:(2 to 10); (4) mixing carbon-14 labeled benzyl alcohol, an oxidant, a base and a solvent, and performing an oxidation reaction at 0 to 40° C. for 30 to 90 minutes to obtain carbon-14 labeled benzaldehyde; the molar ratio of the carbon-14 labeled benzyl alcohol, the oxidant and the base is 1:(2 to 10):(2 to 10).

10. Use of the carbon-14 labeled benzaldehyde according to claim 1 in the preparation of carbon-14 labeled drugs.

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