Carbon-14-labeled epinephrine and preparation method thereof, carbon-14-labeled noradrenaline and preparation method thereof

Abstract

The invention provides carbon-14-labeled epinephrine and a preparation method thereof, carbon-14-labeled noradrenaline and a preparation method thereof, and belongs to the field of radioactive chemistry. The invention provides a carbon-14 labeled epinephrine or a carbon-14 labeled noradrenaline, wherein the carbon-14 label is located at the a position of the benzene ring of the epinephrine or the noradrenaline. According to the present invention, the epinephrine and the noradrenaline are subjected to carbon-14 labeling, such that the metabolite ratio can be quantitatively analyzed, the dynamic conversion rule of the metabolite in the human body can be revealed, the drug administration scheme can be easily optimized, the toxicological mechanism can be easily clarified, the theoretical basis can be provided for the clinical safety application, and the scientific development of the first-aid drug can be promoted.

Description

Technical Field

[0001] This invention relates to the field of radiochemistry, specifically to a carbon-14 labeled adrenaline and its preparation method, and a carbon-14 labeled norepinephrine and its preparation method. Background Technology

[0002] Epinephrine is a key drug in clinical emergency care, possessing both α and β receptor agonist effects. It is widely used in the emergency treatment of anaphylactic shock, bronchospasm, and cardiac arrest. Its synthesis begins in the adrenal medulla chromaffin cells, produced through the methylation of norepinephrine catalyzed by PNMT enzyme. Furthermore, norepinephrine is also a vasoactive drug, suitable for the treatment of acute hypotension and shock.

[0003] Precise analysis is still needed to further study the metabolism of adrenaline and noradrenaline. Summary of the Invention

[0004] This invention provides carbon-14 labeled adrenaline and its preparation method, as well as carbon-14 labeled norepinephrine and its preparation method. The carbon-14 labeled adrenaline and carbon-14 labeled norepinephrine of this invention can provide precise analysis for metabolic research.

[0005] The present invention provides a carbon-14 labeled adrenaline or carbon-14 labeled norepinephrine, wherein the carbon-14 is labeled at the a-position of the benzene ring of the adrenaline or norepinephrine.

[0006] This invention also provides a method for preparing carbon-14 labeled adrenaline or carbon-14 labeled norepinephrine as described in the above technical solution, comprising the following steps: Under anhydrous and oxygen-free sealed conditions, 14 CO2 is passed into a solution of alkyl Grignard reagent to carry out an addition reaction, yielding carbon-14 labeled acetic acid; The carbon-14 labeled acetic acid, the first acid anhydride, and the first organic solvent are mixed to carry out a first acid anhydride reaction to generate acetic anhydride, thus obtaining the first acid anhydride reaction system. The first anhydride reaction system was mixed with liquid bromine to carry out a bromination reaction, yielding carbon-14 labeled bromoacetic acid; The carbon-14 labeled bromoacetic acid, the second acid anhydride, and the second organic solvent are mixed to carry out a second acid anhydridation reaction to obtain a second acid anhydridation reaction system. The second anhydride reaction system was mixed with a catechol solution and subjected to a Friedel-Crafts acylation reaction to obtain 2-bromo-1-(3,4-dihydroxyphenyl) ethyl ketone; Dibenzylamine or N-methylbenzylamine is mixed with the 2-bromo-1-(3,4-dihydroxyphenyl) ethyl ketone, a base, and a third organic solvent to carry out a substitution reaction, yielding 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl) ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl) ethyl ketone; The 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl)ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl)ethyl ketone is mixed with an alcohol solvent and a palladium-containing catalyst and subjected to hydrogenation and debenzylation in a hydrogen atmosphere to obtain carbon-14 labeled adrenaline or carbon-14 labeled norenaline.

[0007] Preferably, the concentration of the alkyl Grignard reagent in the solution is 0.3~3 mmol / mL; The alkyl-Gernature reagents include lithium methyl and / or magnesium methyl bromide; The solvent for the solution of the alkyl Grignard reagent includes one or more of diethyl ether, tetrahydrofuran, and dimethyltetrahydrofuran; The addition reaction is carried out at a temperature of -20 to 20°C for a time of 0.5 to 5 hours. The 14 The CO2 introduction rate is 1~3 cm. 3 / min.

[0008] Preferably, the molar ratio of the carbon-14 labeled acetic acid to the first acid anhydride is 1:1 to 3; The first acid anhydride includes one or more of methanesulfonic anhydride, trifluoroacetic anhydride, and Boc anhydride; The ratio of carbon-14 labeled acetic acid to the first organic solvent is 1 mmol: 1~5 mL; the first organic solvent includes dichloromethane; The temperature of the first anhydride reaction is -20~100℃, and the time is 1~5h; the first anhydride reaction is carried out in a protective atmosphere.

[0009] Preferably, the molar ratio of acetic anhydride to liquid bromine is 1:1~2; The bromination reaction is carried out at a temperature of -20 to 100°C for 5 to 20 hours, and is conducted in a protective atmosphere.

[0010] Preferably, the molar ratio of the carbon-14 labeled bromoacetic acid to the second acid anhydride is 1:1~2; The second acid anhydride includes one or more of acetic anhydride, Tf2O, and Boc anhydride; The mass ratio of the carbon-14 labeled bromoacetic acid to the volume of the second organic solvent is 410 mg: 1 mL; the second organic solvent comprises nitromethane. The second anhydride reaction is carried out at a temperature of -20 to 100°C for a time of 10 to 30 minutes, and is conducted in a protective atmosphere.

[0011] Preferably, the volume ratio of the second anhydride reaction system to the catechol solution is 1:1 to 3; The ratio of the mass of catechol to the volume of solvent in the catechol solution is 220 mg: 1~5 mL; The Friedel-Crafts acylation reaction is carried out at a temperature of 20~100℃ for a time of 10~30 min.

[0012] Preferably, the molar ratio of the dibenzylamine or N-methylbenzylamine to 2-bromo-1-(3,4-dihydroxyphenyl)ethyl ketone is 1 to 3:1; The molar ratio of 2-bromo-1-(3,4-dihydroxyphenyl)ethyl ketone to the base is 1:1 to 3, and the base includes one or more of DBU, potassium carbonate, sodium carbonate, triethylamine and diethylmethylamine; The mass ratio of the 2-bromo-1-(3,4-dihydroxyphenyl)ethyl ketone to the volume ratio of the third organic solvent is 231 mg: 1~3 mL, and the third organic solvent includes methanol; The substitution reaction is carried out at a temperature of 0~100℃ for a time of 0.5~5h in a protective atmosphere.

[0013] Preferably, the ratio of 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl)ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl)ethyl ketone to the alcohol solvent is 1 mmol: 2~8 mL, and the alcohol solvent includes methanol; The molar ratio of 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl)ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl)ethyl ketone to the palladium catalyst is 1:0.03~0.3, and the palladium-containing catalyst includes palladium on carbon and / or palladium hydroxide on carbon; The hydrogenation debenzylation is carried out at a temperature of 30-70°C for 12-24 hours.

[0014] Preferably, after the hydrogenation and debenzylation, the process further includes: adjusting the pH of the product obtained by hydrogenation and debenzylation to 1-3 with acid, then removing the palladium-containing catalyst, and then adjusting the pH to 10-13 with alkali before precipitation to obtain the carbon-14 labeled adrenaline or carbon-14 labeled norepinephrine.

[0015] This invention uses carbon-14 labeling of adrenaline and noradrenaline, which not only allows for quantitative analysis of the proportion of metabolites but also reveals their dynamic transformation patterns in the human body. This helps optimize dosing regimens, elucidate toxicological mechanisms, provide a theoretical basis for safe clinical applications, and promote the scientific development of emergency drugs.

[0016] The preparation method of this invention is simple and low-cost. The boiling point of C-14 bromoacetic acid is higher than that of chloroacetyl chloride, making it less volatile. Friedel-Crafts acylation avoids the use of phosphorus oxychloride. The synthesized adrenaline and noradrenaline precursors are easy to purify, reducing the difficulty of purifying the final product. Attached Figure Description

[0017] Figure 1 The diagram shows the structures of carbon-14 labeled adrenaline and noradrenaline in the examples; Figure 2 The example illustrates the synthetic route for -14-adrenaline and noradrenaline. Detailed Implementation

[0018] The present invention provides a carbon-14 labeled adrenaline or carbon-14 labeled norepinephrine, wherein the carbon-14 is labeled at the a-position of the benzene ring of the adrenaline or norepinephrine.

[0019] In this invention, the structural formulas of the carbon-14 labeled adrenaline and carbon-14 labeled norepinephrine are shown below, wherein, " "Indicates carbon-14: .

[0020] This invention also provides a method for preparing carbon-14 labeled adrenaline or carbon-14 labeled norepinephrine as described in the above technical solution, comprising the following steps: Under anhydrous and oxygen-free sealed conditions, 14 CO2 is passed into a solution of alkyl Grignard reagent to carry out an addition reaction, yielding carbon-14 labeled acetic acid; The carbon-14 labeled acetic acid, the first acid anhydride, and the first organic solvent are mixed to carry out a first acid anhydride reaction to generate acetic anhydride, thus obtaining the first acid anhydride reaction system. The first anhydride reaction system was mixed with liquid bromine to carry out a bromination reaction, yielding carbon-14 labeled bromoacetic acid; The carbon-14 labeled bromoacetic acid, the second acid anhydride, and the second organic solvent are mixed to carry out a second acid anhydridation reaction to obtain a second acid anhydridation reaction system. The second anhydride reaction system was mixed with a catechol solution and subjected to a Friedel-Crafts acylation reaction to obtain 2-bromo-1-(3,4-dihydroxyphenyl) ethyl ketone; Dibenzylamine or N-methylbenzylamine is mixed with the 2-bromo-1-(3,4-dihydroxyphenyl) ethyl ketone, a base, and a third organic solvent to carry out a substitution reaction, yielding 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl) ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl) ethyl ketone; The 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl)ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl)ethyl ketone is mixed with an alcohol solvent and a palladium-containing catalyst and subjected to hydrogenation and debenzylation in a hydrogen atmosphere to obtain carbon-14 labeled adrenaline or carbon-14 labeled norenaline.

[0021] This invention, under anhydrous and oxygen-free sealed conditions, will... 14 CO2 is passed into a solution of an alkyl Grignard reagent to carry out an addition reaction, yielding carbon-14 labeled acetic acid.

[0022] In this invention, the concentration of the alkyl Grignard reagent in the solution is preferably 0.3~3 mmol / mL; the alkyl Grignard reagent preferably includes lithium methyl and / or magnesium methyl bromide; the solvent of the solution of the alkyl Grignard reagent preferably includes one or more of diethyl ether, tetrahydrofuran and dimethyltetrahydrofuran.

[0023] In this invention, the 14 The optimal CO2 introduction rate is 1~3 cm. 3 / min, in a specific embodiment of the present invention, can be 1.5cm. 3 / min, 2cm 3 / min or 2.5cm 3 / min.

[0024] In this invention, the temperature of the addition reaction is preferably -20~20℃, and the time is preferably 0.5~5h. In specific embodiments of this invention, the temperature of the addition reaction can be -15℃, -10℃, -5℃, 0℃, 5℃, 10℃ or 15℃, and the time can be 1h, 2h, 3h or 4h.

[0025] Following the addition reaction, the present invention preferably further includes: subjecting the product obtained from the addition reaction to a first post-treatment.

[0026] In this invention, the first post-processing preferably includes: mixing the product obtained from the addition reaction with a strong alkaline solution to quench the reaction, then removing part of the solvent from the obtained product, and then adjusting the pH value of the remaining product to 1-2 with acid to obtain a crude product; extracting the crude product, and then concentrating the obtained organic phase until no liquid flows out to obtain the carbon-14 labeled acetic acid.

[0027] After obtaining carbon-14 labeled acetic acid, the present invention mixes the carbon-14 labeled acetic acid, a first acid anhydride, and a first organic solvent to carry out a first anhydride reaction to generate acetic anhydride, thus obtaining the first anhydride reaction system. In this invention, the molar ratio of the carbon-14 labeled acetic acid to the first acid anhydride is preferably 1:1 to 3, and in specific embodiments of this invention, it can be 1:1.5, 1:2, or 1:2.5; the first acid anhydride preferably includes one or more of methanesulfonic anhydride, trifluoroacetic anhydride, and Boc anhydride. When the first acid anhydride is trifluoroacetic anhydride, the acetic anhydride is acetic acid trifluoroacetic anhydride.

[0028] In this invention, the preferred ratio of carbon-14 labeled acetic acid to the first organic solvent is 1 mmol: 1~5 mL, and in specific embodiments of this invention, it can be 1 mmol: 2 mL, 1 mmol: 3 mL or 1 mmol: 4 mL; the first organic solvent preferably includes dichloromethane.

[0029] In this invention, the temperature of the first anhydride reaction is preferably -20 to 100°C, and the time is preferably 1 to 5 hours. In specific embodiments of this invention, the temperature of the first anhydride reaction can be -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, or 90°C, and the time can be 2 hours, 3 hours, or 4 hours. The first anhydride reaction is preferably carried out in a protective atmosphere.

[0030] After obtaining the first anhydride reaction system, the present invention mixes the first anhydride reaction system with liquid bromine to carry out a bromination reaction to obtain carbon-14 labeled bromoacetic acid.

[0031] In this invention, the molar ratio of acetic anhydride to liquid bromine is preferably 1:1 to 2, and in specific embodiments of this invention it can be 1:1.2, 1:1.5 or 1:1.8.

[0032] The bromination reaction is carried out at a temperature of -20 to 100°C for a time of 5 to 20 hours. In specific embodiments of the present invention, the temperature of the bromination reaction can be -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, or 90°C, and the time can be 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, or 19 hours. The bromination reaction is preferably carried out in a protective atmosphere.

[0033] Following the bromination reaction, the present invention preferably further includes: subjecting the product obtained from the bromination reaction to a second post-treatment.

[0034] In this invention, the second post-processing preferably includes: quenching the bromination product with water under ice bath conditions, then mixing it with DCM to obtain a mixture; drying and separating the mixture with a desiccant; washing the separated desiccant; and then concentrating the resulting liquid phase and the resulting washing liquid to dryness to obtain the carbon-14 labeled bromoacetic acid.

[0035] After obtaining carbon-14 labeled bromoacetic acid, the present invention mixes the carbon-14 labeled bromoacetic acid, a second acid anhydride, and a second organic solvent to carry out a second acid anhydride reaction to obtain a second acid anhydride reaction system.

[0036] In this invention, the molar ratio of the carbon-14 labeled bromoacetic acid to the second anhydride is preferably 1:1 to 2, and in specific embodiments of this invention it can be 1:1.2, 1:1.5 or 1:1.8; the second anhydride preferably includes one or more of acetic anhydride, Tf2O and Boc anhydride.

[0037] In this invention, the mass ratio of the carbon-14 labeled bromoacetic acid to the volume ratio of the second organic solvent is preferably 410 mg: 1~3 mL; the second organic solvent preferably includes nitromethane.

[0038] In this invention, the temperature of the second anhydride reaction is preferably -20 to 100°C, and the time is preferably 10 to 30 minutes. In specific embodiments of this invention, the temperature of the second anhydride reaction can be -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, or 90°C, and the time can be 15 minutes, 20 minutes, or 25 minutes. The second anhydride reaction is preferably carried out in a protective atmosphere.

[0039] After obtaining the second anhydride reaction system, the present invention mixes the second anhydride reaction system with a catechol solution to carry out a Friedel-Crafts acylation reaction to obtain 2-bromo-1-(3,4-dihydroxyphenyl)ethyl ketone.

[0040] In this invention, the volume ratio of the second anhydride reaction system to the catechol solution is preferably 1:1 to 3, and in specific embodiments of this invention, it can be 1:1.5, 1:2, or 1:2.5; the mass ratio of catechol to solvent volume in the catechol solution is preferably 220 mg: 1 to 5 mL, and in specific embodiments of this invention, it can be 220 mg: 2 mL, 220 mg: 3 mL, or 220 mg: 4 mL; the solvent preferably includes nitromethane.

[0041] In this invention, the preferred temperature for the Friedel-Crafts acylation reaction is 20~100℃, and the preferred time is 10~30min. In specific embodiments of this invention, the preferred temperature for the Friedel-Crafts acylation reaction is 30℃, 40℃, 50℃, 60℃, 70℃, 80℃ or 90℃, and the preferred time is 15min, 20min or 25min.

[0042] Following the Friedel-Crafts acylation reaction, the present invention preferably further includes: subjecting the product obtained from the Friedel-Crafts acylation reaction to a third post-treatment.

[0043] In this invention, the third post-processing preferably includes: mixing the product obtained from the Friedel-Crafts acylation reaction with a saturated sodium carbonate solution to quench the reaction, then extracting the obtained reaction product to obtain an organic phase; drying, concentrating, and column chromatography of the organic phase to obtain the 2-bromo-1-(3,4-dihydroxyphenyl)ethyl ketone.

[0044] After obtaining 2-bromo-1-(3,4-dihydroxyphenyl) ethyl ketone, the present invention performs a substitution reaction by mixing dibenzylamine or N-methylbenzylamine with the 2-bromo-1-(3,4-dihydroxyphenyl) ethyl ketone, a base, and a third organic solvent to obtain 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl) ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl) ethyl ketone; In this invention, the molar ratio of dibenzylamine or N-methylbenzylamine to 2-bromo-1-(3,4-dihydroxyphenyl)ethyl ketone is preferably 1 to 3:1, and in specific embodiments of this invention, it can be 1.5:1, 2:1 or 2.5:1.

[0045] In this invention, the molar ratio of 2-bromo-1-(3,4-dihydroxyphenyl)ethyl ketone to the base is preferably 1:1 to 3, and in specific embodiments of this invention it can be 1:1.5, 1:2 or 1:2.5. The base preferably includes one or more of DBU, potassium carbonate, sodium carbonate, triethylamine and diethylmethylamine.

[0046] In this invention, the mass ratio of 2-bromo-1-(3,4-dihydroxyphenyl)ethyl ketone to the volume ratio of the third organic solvent is preferably 231 mg: 1~5 mL, and the third organic solvent preferably includes methanol.

[0047] In this invention, the temperature of the substitution reaction is preferably 0~100℃, and the time is preferably 0.5~5h. In specific embodiments of this invention, the temperature of the substitution reaction is preferably 10℃, 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃ or 90℃, and the time is preferably 1h, 2h, 3h or 4h. The substitution reaction is preferably carried out in a protective atmosphere.

[0048] Following the substitution reaction, the present invention preferably further includes: subjecting the product obtained from the substitution reaction to a third post-treatment.

[0049] In this invention, the third post-processing preferably includes: concentrating the product obtained from the substitution reaction and then performing column chromatography to obtain 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl) ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl) ethyl ketone.

[0050] After obtaining 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl) ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl) ethyl ketone, the present invention mixes the 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl) ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl) ethyl ketone with an alcohol solvent and a palladium-containing catalyst in a hydrogen atmosphere for hydrogenation and debenzylation to obtain carbon-14 labeled adrenaline or carbon-14 labeled norepinephrine.

[0051] In this invention, the preferred ratio of 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl)ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl)ethyl ketone to the alcohol solvent is 1 mmol: 2-8 mL. In specific embodiments of this invention, the ratio can be 1 mmol: 2.5 mL, 1 mmol: 3 mL, 1 mmol: 3.5 mL, 1 mmol: 4 mL, 1 mmol: 4.5 mL, 1 mmol: 5 mL, 1 mmol: 5.5 mL, 1 mmol: 6 mL, 1 mmol: 6.5 mL, 1 mmol: 7 mL, or 1 mmol: 7.5 mL. The alcohol solvent preferably includes methanol.

[0052] In this invention, the molar ratio of 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl)ethyl ketone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl)ethyl ketone to palladium in the palladium catalyst is preferably 1:0.03~0.3. In specific embodiments of this invention, it can be 1:0.05, 1:0.1 or 1:0.2. The palladium-containing catalyst preferably includes palladium on carbon and / or palladium hydroxide on carbon.

[0053] In this invention, the preferred temperature for hydrogenation debenzylation is 30~70℃, and the preferred time is 12~24h. In specific embodiments of this invention, the preferred temperature for hydrogenation debenzylation is 40℃, 50℃ or 60℃, and the preferred time is 15h, 18h, 20h or 22h.

[0054] In this invention, the pressure of the hydrogenation debenzylation is preferably five atmospheres.

[0055] After the hydrogenation and debenzylation, the present invention preferably further includes: adjusting the pH value of the product obtained by hydrogenation and debenzylation to 1-3 with acid, then removing the palladium-containing catalyst, and then adjusting the pH value to 10-13 with alkali before precipitation to obtain the carbon-14 labeled adrenaline or carbon-14 labeled norepinephrine.

[0056] In this invention, the acid preferably includes one or more of hydrochloric acid, nitric acid, sulfuric acid, acetic acid, formic acid, and maleic acid; the base preferably includes one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, ammonia, sodium methoxide, and sodium ethoxide.

[0057] The following detailed descriptions, in conjunction with embodiments, illustrate the carbon-14 labeled adrenaline and its preparation method, as well as the carbon-14 labeled norepinephrine and its preparation method. However, these descriptions should not be construed as limiting the scope of protection of this invention.

[0058] Figure 1 The following are structural diagrams of carbon-14 labeled adrenaline and noradrenaline in the examples; (asterisk) (Represents the marked position) Figure 2 The synthetic route of -14-adrenaline and noradrenaline in the examples is shown in the asterisks. This indicates the location of the marker.

[0059] Example 1 Under an ice-water bath and nitrogen atmosphere, concentrated sulfuric acid (98% by mass, 5 mL) was added to barium [14C] carbonate (400 mg, 2 mmol, 1 mCi / mmol). The resulting carbon dioxide was released at a rate of 1 cm⁻¹. 3 The reaction mixture of methyl magnesium bromide and tetrahydrofuran (6.4 mL, 2.4 mmol of methyl magnesium bromide) was introduced at a rate of 0 °C and stirred vigorously for 3 h. After the reaction was completed, sodium hydroxide aqueous solution (1 M, 2 mL) was added to quench the reaction, and the mixture was transferred to a 100 mL round-bottom flask and concentrated to 2 mL. The pH was adjusted to 1-2 with dilute hydrochloric acid (2 M, 2.5 mL), and the mixture was extracted with diethyl ether (9 mL). 8) Combine the organic phases, dry them, and concentrate them until no liquid flows out, to obtain the crude product acetic acid ( ).14 C) No further purification is required; it can be used directly in the next reaction. Dissolve acetic acid in 2 mL of dichloromethane under an ice-water bath and nitrogen atmosphere. 14 C) (2 mmol), carefully add TFAA (1270 mg, 6 mmol, the pale yellow liquid turns pale orange) dropwise, stir for 5 min, remove from ice bath and stir for 30 min, place the reaction solution back in an ice-water bath, slowly add bromine (360 mg, 2 mmol, the solution turns dark brown), transfer to an oil bath at 28 °C and react for 17 h. After the reaction is complete, the solution is orange-yellow, monitored by TLC (10% DCM / MeOH, Rf=0.3). Quench the reaction by adding 1 mL of water in an ice bath and stirring for 30 min, add 10 mL of DCM to dilute, dry with anhydrous sodium sulfate for 1 h, wash the dried sodium sulfate with DCM, combine the washings and organic phase, concentrate under reduced pressure to dryness, and obtain 410 mg of pale yellow solid.

[0060] 410 mg of bromoacetic acid was transferred to a 10 mL sealed tube with 1 mL of nitromethane. Tf₂O (370 mg, 2.05 mmol) was carefully added and reacted at 25 °C for 10 min. Catechol (220 mg, 2 mmol) was weighed, dissolved in 1 mL of nitromethane, and added to the reaction system. The reaction was carried out at 60 °C for 10 min, and monitored by TLC (PE / EA = 3:1, Rf = 0.2). After the reaction was completed, the reaction was quenched with 3 mL of saturated sodium bicarbonate, extracted with EA, dried, concentrated, and subjected to rapid column chromatography to obtain 231 mg of brown solid. The three-step yield was 50%.

[0061] The substrate (231 mg, 1 mmol) was dissolved in 5 mL of methanol, and N-methylbenzylamine (133 mg, 1.1 mmol) and triethylamine (123 mg, 1.2 mmol) were added. Under nitrogen protection, the mixture was reacted in an oil bath at 46 °C for 1 h. The reaction was monitored by TLC (DCM / MeOH / NH4OH = 10:1:0.1, Rf = 0.15). The mixture was directly concentrated and subjected to rapid column chromatography to give 176 mg of brown solid, with a yield of 64.9%.

[0062] The substrate (0.649 mmol) was dissolved in 5 mL of ethanol and transferred to a high-temperature and high-pressure reactor. 35 mg of palladium hydroxide on carbon (10% by mass) was added. The reactor was stirred at 50 °C for 5 atmospheres of hydrogen for 18 h. After TLC monitoring showed no raw material, 3 mL of 1 M hydrochloric acid was added and stirred for 30 min. Then, 2 g of activated carbon was added to adsorb the palladium catalyst. The mixture was filtered through diatomaceous earth and washed with water for three volumes. The pH was adjusted to 12 with 10% ammonia and the mixture was placed in a 4 °C refrigerator to precipitate the solid, yielding 20 mg of adrenaline with a yield of 16.8% and a purity of 95%.

[0063] Example 2 The substrate (231 mg, 1 mmol) was dissolved in 5 mL of methanol, and dibenzylamine (217 mg, 1.1 mmol) and triethylamine (123 mg, 1.2 mmol) were added. Under nitrogen protection, the mixture was reacted in an oil bath at 46 °C for 1 h. The reaction was monitored by TLC (DCM / MeOH / NH4OH = 10:1:0.1, Rf = 0.15). The mixture was directly concentrated and subjected to rapid column chromatography to give 173 mg of brown solid, with a yield of 49.8%.

[0064] The substrate (0.49 mmol) was dissolved in 5 mL of ethanol and transferred to a high-temperature and high-pressure reactor. Palladium on carbon (36 mg) with a mass fraction of 10% palladium was added. The reactor was stirred at 50 °C for 5 atmospheres of hydrogen for 18 h. After TLC monitoring showed no raw material, 3 mL of 1 M hydrochloric acid was added and stirred for 30 min. Then, 2 g of activated carbon was added to adsorb the palladium catalyst. The mixture was filtered through diatomaceous earth and washed with water for three volumes. The pH was adjusted to 12 with 10% ammonia and the mixture was placed in a 4 °C refrigerator to precipitate the solid, yielding 10 mg of norepinephrine with a yield of 12% and a purity of 96%.

[0065] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A carbon-14 labeled epinephrine or a carbon-14 labeled norepinephrine, characterized in that, The carbon-14 label is at the a position of the benzene ring of the epinephrine or norepinephrine.

2. The process for the preparation of carbon-14 labeled epinephrine or carbon-14 labeled norepinephrine according to claim 1, characterized in that, The method comprises the following steps: The addition reaction is carried out by bubbling CO2 into a solution of the alkyl grignard reagent under anhydrous and anaerobic conditions. 14 The addition reaction is carried out by bubbling CO2 into a solution of the alkyl grignard reagent under anhydrous and anaerobic conditions. The carbon-14 labeled acetic acid, the first acid anhydride and the first organic solvent are mixed to perform a first acid anhydride reaction to generate acetic anhydride, thereby obtaining a first acid anhydride reaction system; The first acid anhydride reaction system and liquid bromine are mixed to perform a bromination reaction, thereby obtaining carbon-14 labeled bromoacetic acid; The carbon-14 labeled bromoacetic acid, the second acid anhydride and the second organic solvent are mixed to perform a second acid anhydride reaction, thereby obtaining a second acid anhydride reaction system; The second acid anhydride reaction system and a catechol solution are mixed to perform a Friedel-Crafts acylation reaction, thereby obtaining 2-bromo-1-(3,4-dihydroxyphenyl)ethanone; Dibenzylamine or N-methylbenzylamine is mixed with the 2-bromo-1-(3,4-dihydroxyphenyl)ethanone, a base and a third organic solvent to perform a substitution reaction, thereby obtaining 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl)ethanone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl)ethanone; The 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl)ethanone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl)ethanone is mixed with an alcohol solvent and a catalyst containing palladium to perform a hydrogenation debenzylization in a hydrogen atmosphere, thereby obtaining carbon-14 labeled epinephrine or carbon-14 labeled norepinephrine.

3. The preparation method according to claim 2, characterized in that, The concentration of the alkyl Grignard reagent in the solution of the alkyl Grignard reagent is 0.3-3 mmol / mL; The alkyl Grignard reagent comprises methyl lithium and or methyl magnesium bromide; The solvent of the solution of the alkyl Grignard reagent comprises one or more of diethyl ether, tetrahydrofuran and dimethyl tetrahydrofuran; The temperature of the addition reaction is -20-20 ℃, and the time is 0.5-5 h; The 14 The speed of CO2inflow is 1~3cm 3 / min.

4. The preparation method according to claim 2, characterized in that, The molar ratio of the carbon-14 labeled acetic acid to the first acid anhydride is 1:1-3; The first acid anhydride comprises one or more of methanesulfonic acid anhydride, trifluoroacetic anhydride and Boc anhydride; The use amount ratio of the carbon-14 labeled acetic acid to the first organic solvent is 1 mmol:1-5 mL; and the first organic solvent comprises dichloromethane; The temperature of the first acid anhydride reaction is -20-100 ℃, and the time is 1-5 h; and the first acid anhydride reaction is performed in a protective atmosphere.

5. The preparation method according to claim 2, characterized in that, The molar ratio of the acetic anhydride to the liquid bromine is 1:1-2; The temperature of the bromination reaction is -20-100 ℃, and the time is 5-20 h; and the bromination reaction is performed in a protective atmosphere.

6. The preparation method according to claim 2, characterized in that, The molar ratio of the carbon-14 labeled bromoacetic acid to the second acid anhydride is 1:1-2; The second acid anhydride comprises one or more of acetic anhydride, Tf2O and Boc anhydride; The ratio of the mass of the carbon-14 labeled bromoacetic acid to the volume of the second organic solvent is 410 mg:1 mL; and the second organic solvent comprises nitromethane; The temperature of the second acid anhydride reaction is -20-100 ℃, and the time is 10-30 min; and the second acid anhydride reaction is performed in a protective atmosphere.

7. The preparation method according to claim 2, characterized in that, The volume ratio of the second acid anhydride reaction system to the catechol solution is 1:1-3; The mass of catechol to the volume of solvent in the catechol solution is 220 mg:1-5 mL; The temperature of the Friedel-Crafts acylation reaction is 20-100 DEG C, and the time is 10-30 min.

8. The preparation method according to claim 2, characterized in that, The molar ratio of the dibenzylamine or N-methylbenzylamine to 2-bromo-1-(3,4-dihydroxyphenyl)ethanone is 1-3:1; The molar ratio of the 2-bromo-1-(3,4-dihydroxyphenyl)ethanone to the base is 1:1-3, and the base includes one or more of DBU, potassium carbonate, sodium carbonate, triethylamine and diethylmethylamine; The mass of the 2-bromo-1-(3,4-dihydroxyphenyl)ethanone to the volume of the third organic solvent is 231 mg:1-3 mL, and the third organic solvent includes methanol; The temperature of the substitution reaction is 0-100 DEG C, and the time is 0.5-5 h, and the substitution reaction is carried out in a protective atmosphere.

9. The preparation method according to claim 2, characterized in that, The use amount ratio of the 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl)ethanone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl)ethanone to the alcoholic solvent is 1 mmol:2-8 mL, and the alcoholic solvent includes methanol; The molar ratio of the 2-[bis(benzyl)amino]-1-(3,4-dihydroxyphenyl)ethanone or 2-(benzylmethylamino)-1-(3,4-dihydroxyphenyl)ethanone to the palladium catalyst is 1:0.03-0.3, and the palladium-containing catalyst includes palladium on carbon and / or palladium hydroxide on carbon; The temperature of the hydrogenative debenzylization is 30-70 DEG C, and the time is 12-24 h.

10. The production method according to claim 2 or 9, characterized by, After the hydrogenative debenzylization, the method further comprises: adjusting the pH value of the product obtained by the hydrogenative debenzylization to 1-3 by using an acid, then removing the palladium-containing catalyst, and then adjusting the pH value to 10-13 by using a base to carry out precipitation, so as to obtain the carbon-14 labeled adrenaline or the carbon-14 labeled norepinephrine.

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