Synthesis of Radioisotope 14C Labelled Remdesivir
To prepare the radiotracer for the pharmacokinetics study of Remdesivir, the 14C labelled Remdesivir at 4-C in pyrrolo[2,1-f][1,2,4]triazine moiety was synthesized via ten-step reaction. Firstly, nonradioactive 1H-pyrrole was formylated with N,N-dimethyl[14C]formamide and phosphorus oxychloride in d...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | zho |
| Published: |
Editorial Office of Journal of Nuclear and Radiochemistry
2025-02-01
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| Series: | He huaxue yu fangshe huaxue |
| Subjects: | |
| Online Access: | https://jnrc.xml-journal.net/cn/article/doi/10.7538/hhx.2025.47.01.0093 |
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| Summary: | To prepare the radiotracer for the pharmacokinetics study of Remdesivir, the 14C labelled Remdesivir at 4-C in pyrrolo[2,1-f][1,2,4]triazine moiety was synthesized via ten-step reaction. Firstly, nonradioactive 1H-pyrrole was formylated with N,N-dimethyl[14C]formamide and phosphorus oxychloride in dichloroethane at 0-15 ℃, followed by cyanidation with hydroxylamine in the solution of potassium hydroxide and amination with O-(2,4-dinitrophenyl)hydroxylamine in tetrahydrofuran at 0-15 ℃. The resulting product 5 was cyclized with formamidine acetate in the presence of tribasic potassium phosphate in EtOH at 78 ℃, and then iodinated with N-iodosuccinimide to obtain the key intermediate 7-iodo[4-14C]pyrrolo[2,1-f][1,2,4]triazin-4-amine(compound 7-1) in DMF at 0 ℃. Secondly, the intermediate 7-1 was substituted by the nonradioactive intermediate 7-2 and then cyanided to achieve the intermediate 9 at −65-−60 ℃. The protecting benzyls in intermediate 9 were deprotected with boron trichloride in dichloromethane at −65-−60 ℃, and two secondary hydroxyls of the deprotected product were selectively protected with acetone in the presence of TsOH in 2,2-dimethoxypropane at 25 ℃. Thirdly, the resulting product 11-1 was phosphated with the nonradioactive intermediate 11-2 and tert-butylmagnesium chloride in tetrahydrofuran at 0-20 ℃, and then deprotected with acetic acid at 100 ℃ to obtain the carbon-14 labelled product Remdesivir as racemic mixture 13. Finally, the target product 14C labelled Remdesivir (compound 2b, 2-ethylbutyl N-[({[(2R,3S,4R,5R)-5-(4-amino[4-14C]pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydro-2-furyl]methyl}oxy)(oxo)(phenyloxy)-λ5-phosphanyl]-L-alaninate; 217.7 MBq, optical ee＞99%) was obtained in the ten-step chemical/radiochemical yield of 4.3% after the purification by using preparative RP-HPLC and resolution of the racemic mixture by using chiral semi-preparative HPLC. The product 2b was compared with the standard sample of nonradioactive Remdesivir and charactered by 1H NMR, ESI-MS, and HPLC-FSA. Its technical data(radiochemical/chemical purity ＞98%, specific activity 2 069.8 MBq/mmol, content of radioactive/nonradioactive single impurity ＜1%) was determined by TLC-IIA, HPLC-LSC, HPLC-FSA/PDA/MS, LSC, and HPLC-MS/MS. The following tracing study indicates that the target product can be used as radiotracer in the radiopharmacokinetics study of Remdesivir. |
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| ISSN: | 0253-9950 |