Radioactive iodine marked Larotrectinib compound, and preparation method and application thereof
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A technology of radioactive iodine and compounds, applied in the direction of in vivo radioactive preparations, radioactive carriers, organic chemical methods, etc., can solve problems such as lack of technical means
Active Publication Date: 2019-04-12
SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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How to track the distribution of larotrectinib in the human body and the status of solid tumors online in vivo, intuitively judge the physiological function of larotrectinib in tumors, evaluate its curative effect and its prognosis, there is still a lack of more effective technical means
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Embodiment 1
[0193] Embodiment one: the synthesis of key intermediate 4: the synthesis of 2-(5-fluoro-2-iodophenyl)pyrrolidine
Embodiment 1a
[0194] Embodiment 1a, the synthesis of (E)-4-(5-fluoro-2-iodophenyl)-4-oxobut-2-enoic acid
[0195]
[0196] In a 500mL reactor, add 5-fluoro-2-iodoacetophenone (39.6g, 150mmol), glyoxylic acid monohydrate (13.9g, 151mmol), heat the reaction and evaporate water under reduced pressure (95 degrees, 0.1Mpa ), reacted for 3 hours, cooled the reaction mixture to room temperature, added 5% potassium carbonate aqueous solution (300mL), extracted 2 times with ethyl acetate, 200mL each time, after the aqueous layer was acidified (10% hydrochloric acid, 300mL), extracted with ethyl acetate 2 times, 200 mL each time, combined the organic phases, washed with brine, dried over anhydrous sodium sulfate, and removed the solvent under reduced pressure to obtain an orange solid. The solid was dissolved in glacial acetic acid (50mL), concentrated hydrochloric acid (36%, 5mL), the mixture was heated to reflux for 4 hours, the acetic acid was removed under reduced pressure, the residue was ext...
Embodiment 1b
[0199] Synthesis of embodiment 1b, 4-(5-fluoro-2-iodophenyl)-4-oxobutanoic acid
[0200]
[0201] In a 500mL reaction flask, add 210mL of acetic acid, 75mL of water, starting material (47.1g, 147mmol), and under stirring, add zinc powder (10.9g, 166mmol) in batches to the reaction mixture, add it in about 1 hour, and the mixture Stirring was continued for 3 hours, the reactant was filtered, the filter cake was rinsed with ethyl acetate (300mL), the organic phase was washed 3 times with brine, each 100mL, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the target product (29.8g, 63%). M.P.152 degrees.
[0202] 1 H NMR (400MHz, CDCl 3 )12.00(1H,brs),7.91-7.71(3H,m),3.23(2H,t,J=6.26),2.57(2H,t,J=6.24).
[0203] MS (EI) m / z 322 (M+).
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Abstract
The invention relates to a radioactive iodine marked Larotrectinib compound, and a preparation method and application thereof. The provided compounds comprise the radioactive iodine marked Larotrectinib compound with the following structural formula and analogues of the compound, wherein R1 and R2 are selected from a group consisting of H, F, Cl, Br, 123I, 124I, 125I, 130I and 131I, and at least one of R1 and R2 is a radioactive iodine element. The invention provides the preparation method of the radioactive iodo-pyrazolo[1,5-a]pyrimidine compound and a preparation method thereof. A long half-life period and different ray energy of the radioactive iodo-pyrazolo[1,5-a]pyrimidine compound can be used for positron emission tomography (PET) development, and can also be applied to clinical diagnosis research of single-photon emission computed tomography (SPECT). Meanwhile, the high-energy radioactive iodo-pyrazolo[1,5-a]pyrimidine can be used as a TrK receptor ligand to inhibit activity ofTRK kinase to kill tumor cells, high-energy iodine-131-ray energy carried by the high-energy radioactive iodo-pyrazolo[1,5-a]pyrimidine can synergistically shoot tumor cells, and an accurate radiotherapy effect is achieved.
Description
technical field [0001] The invention relates to the field of chemical drug synthesis, in particular to an in vivo imaging agent for Trk receptor subtypes in refractory solid tumors, and more particularly to a preparation method of Larotrectinib radioactive iodine-labeled compound and a synthesis method of its intermediate. The present invention provides radioactive iodine compounds and intermediates based on a novel inhibitor of tyrosine receptor kinase (TRK), Larotrectinib. Background technique [0002] Larotrectinib was developed by Loxo Oncology as a broad-spectrum tumor drug for all tumor patients expressing tropomyosin receptor kinase (TRK). With strong selectivity, larotrectinib can inhibit tumor growth by inhibiting the TRK signaling pathway. Larotrectinib is an oral potent TRK inhibitor with consistent and durable antitumor activity in TRK fusion tumors, applicable to a wide range of patient ages and tumor types, its indications are distributed in 13 different tumor...
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