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Synthesis method of radioisotope carbon-14 double-labeled furmonertinib mesylate

A technology of radioisotope and synthesis method, applied in the field of radiochemical synthesis, can solve problems such as difficulty in reaching detection limit, inability to increase the dosage of fumetinib mesylate, failure of tracer test and the like

Pending Publication Date: 2022-01-07
浙江爱索拓科技有限公司
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Problems solved by technology

It should be pointed out that this marker is a carbon-14 single-site marker, and its theoretical maximum specific activity is 62.4mCi / mmol[Atzrodt J, Allen J: Synthesis of Radiolabeled Compounds for Clinical Studies[M] / / Vogel H G , MaasJ, Gebauer A, editor, Drug Discovery and Evaluation: Methods in Clinical Pharmacology: Springer Berlin Heidelberg, 2011: 105-118]; for the dosage of fometinib mesylate is very small and cannot be increased, and the system composition is complex In the tracer test, the carbon-14 single-site marker (its specific activity is usually about 50mCi / mmol) is often difficult to reach the detection limit of the radioactive measuring instrument, which leads to the failure of the tracer test

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  • Synthesis method of radioisotope carbon-14 double-labeled furmonertinib mesylate
  • Synthesis method of radioisotope carbon-14 double-labeled furmonertinib mesylate
  • Synthesis method of radioisotope carbon-14 double-labeled furmonertinib mesylate

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preparation example Construction

[0036] refer to Figure 2 to Figure 9 , specifically, the synthesis method of the radioactive isotope carbon-14 double-labeled vormetinib mesylate comprises the following steps:

[0037] S1: Under inert gas protection and 90-130°C, [2,3- 14 C 2 ] propiolic acid (1) React with urea in polyphosphoric acid (PPA).

[0038] After the reaction, dilute with water, adjust pH with alkali and filter to obtain [5,6- 14 C 2 ] uracil (2) ;

[0039] S2: Under inert gas protection and 90-130°C, the intermediate [5,6- 14 C 2 ] uracil (2) React with phosphorus oxychloride under the catalysis of diisopropylethylamine (DIPEA). After the reaction, the reaction mixture was purified by conventional post-processing and column chromatography to obtain 2,4-dichloro[5,6- 14 C 2 ] pyrimidine (3) ;

[0040] S3: Under inert gas protection and 70-90 °C, the intermediate 2,4-dichloro[5,6- 14 C 2 ] pyrimidine (3) , N-methylindole and Lewis acid in an aprotic organic solvent. After the react...

Embodiment 1

[0052] Under argon protection and 50°C, urea (50 mg) and polyphosphoric acid (1.5 mL) were stirred and dissolved, and [2,3- 14 C 2 ] propiolic acid (1,80.4 μCi, 750 μmol). After the addition, the temperature was raised to 90°C, and the reaction was completed after stirring for 16 hours. 1 mL of water was added to the reaction liquid to quench the reaction, the pH was adjusted to about 7 with ammonia water (28-30% wt), and the crystallization was carried out by stirring at 5° C. for 4 h. Filtration, the obtained solid was rinsed with 1mL water and 5mL methanol successively, and after drying, the solid [5,6- 14 C 2 ] Uracil (2, 65.2 μCi, 81%). 1 H NMR (400MHz, DMSO-d 6 )δ10.87(s,2H),7.38(d,J=7.6Hz,1H),5.45(d,J=7.6Hz,1H).ESI-MS(m / z):135,139[M+H] + .

[0053] Under the protection of argon, the [5,6- 14 C 2 ]Uracil (2,63.2μCi) and 2 drops of diisopropylethylamine were added in turn to phosphorus oxychloride (3mL), heated to 90°C and stirred for 2.5h. The reaction solution...

Embodiment 2

[0060] Under argon protection and 50°C, urea (50 mg) and polyphosphoric acid (1.5 mL) were stirred and dissolved, and [2,3- 14 C 2 ] propiolic acid (1,80.4 μCi, 750 μmol). After the addition, the temperature was raised to 110°C, and the reaction was completed after stirring for 13 hours. Add 1 mL of water to the reaction liquid to quench, add dropwise a saturated aqueous solution of sodium bicarbonate to adjust the pH to about 7, stir at 5°C for 4 h to crystallize, filter, and rinse the solid with 1 mL of water and 5 mL of methanol in sequence. Dried to a solid [5,6- 14 C 2 ] Uracil (2, 64.2 μCi, 80%). ESI-MS(m / z):135,139[M+H] + .

[0061] Under the protection of argon, the [5,6- 14 C 2 ]Uracil (2,63.2μCi) and 2 drops of diisopropylethylamine were added in turn to phosphorus oxychloride (3mL), heated to 110°C, and stirred for 1.5h. The reaction solution was cooled to room temperature, and after conventional treatment (same as in Example 1), 2,4-dichloro[5,6- 14 C 2 ...

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Abstract

The invention provides a synthesis method of radioisotope carbon-14 double-labeled furmonertinib mesylate (N-(2-((2-(dimethylamino) ethyl) methylamino)-5-((4-(1-methyl-1H-indole-3-yl)-2-[5, 6-<14>C2] pyrimidyl) amino)-6-(2, 2, 2-trifluoroethoxy) pyridine-3-yl) acrylamide mesylate, wherein the asterisks represent carbon-14 marker sites). The method provides a feasible, safe and economical method for synthesis of carbon-14 double-labeled furmonertinib mesylate, and is characterized in that the carbon-14 double-labeled furmonertinib mesylate is obtained with carbon-14 double-labeled propiolic acid ([2, 3-<14>C2] propiolic acid) as an isotope raw material through ring closing, hydroxyl chlorination, coupling, substitution, reduction, condensation, salification and other radioactive reactions, and the specific activity of the marker is two times that of a corresponding carbon-14 single marker. The target carbon-14 double-labeled furmonertinib mesylate disclosed by the invention can be used as a radioactive tracer, and can meet the requirements on a high-specific-activity carbon-14 marker in basic researches such as a radioactive isotope tracer test related to furmonertinib mesylate.

Description

technical field [0001] The invention belongs to the field of radiochemical synthesis, and in particular relates to a radioactive isotope carbon-14 double-labeled fometinib mesylate (N-(2-((2-(dimethylamino)ethyl)methylamino)- 5-((4-(1-methyl-1H-indol-3-yl)[5,6- 14 C 2 ] pyrimidin-2-yl) amino)-6-(2,2,2-trifluoroethoxy) pyridin-3-yl) acrylamide) synthetic method. Background technique [0002] The sensitive mutation rate of epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) in my country is about 50%, and the first and second epidermal growth factor receptor tyrosine kinase inhibitors (EGFR- TKI) treatment. However, most patients acquire drug resistance after 9-13 months of treatment, and about 60% of patients have EGFR T790M mutation, and the appearance of T790M mutation means that the median survival period of patients is less than 2 years [Third-generation inhibitor targeting EGFR T790M mutation in advanced non-small cell lung canc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14C07B2200/05
Inventor 杨征敏徐凌锋宋明钰李梦雪李明明周兵
Owner 浙江爱索拓科技有限公司
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