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Radioactive fluorine labeled Larotrectinib compound and preparation method thereof

A compound and labeling technology, which can be used in radioactive carriers, chemical instruments and methods, compounds of Group 4/14 elements of the periodic table, etc., and can solve problems such as no more effective technical means.

Active Publication Date: 2019-05-03
SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a small molecule inhibitor of tropomyosin receptor kinase (TRK), Larotrectinib has strong selectivity to TRK and can be used as a PET imaging molecule to accurately locate Larotrectinib for in vivo evaluation Tumor status, realize online tracing of the distribution of Larotrectinib molecules in animals or humans and the status of solid tumors, intuitively judge the physiological function and pharmacological process of Larotrectinib in animals, humans and tumors, and evaluate its curative effect and prognosis , there is no more effective technical means

Method used

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  • Radioactive fluorine labeled Larotrectinib compound and preparation method thereof
  • Radioactive fluorine labeled Larotrectinib compound and preparation method thereof
  • Radioactive fluorine labeled Larotrectinib compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Esterification of benzoyl chloride to prepare I-Bz-2-Larotrectinib or I-Bz-5-Larotrectinib

[0109] In a 2000ml reaction flask, add 400mL of chloroform, compound I-2-Larotrectinib (80mmol, 42.9g), stir at room temperature until dissolved, add pyridine (240mmol, 18.98g), and simultaneously add benzoyl chloride (80mmol, 11.4g) , the mixture was stirred and reacted at room temperature for 3 hours, and controlled by TLC. After the reaction was completed, the mixture was poured into water, and the organic layer was separated, followed by dilute HCl (to remove pyridine; at the same time, let the unreacted acid chloride become acid), and then dilute NaOH (preferably saturated sodium bicarbonate, 100 mL) to remove acid, saturated sodium chloride to neutrality, and remove most of the water in the organic layer. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was crystallized with ethanol-methyl...

Embodiment 2

[0112] Esterification of benzoyl chloride to prepare I-Bz-5-Larotrectinib

[0113] The preparation method was the same as in Example 1, and the compound I-5-Larotrectinib was used as the raw material to obtain the product I-Bz-5-Larotrectinib as a white solid with a yield of 88% (70.4 mmol, 45.1 g). The route is as follows:

[0114]

Embodiment 3

[0116] Esterification of pivaloyl chloride to prepare I-Piv-2-Larotrectinib

[0117] In a 2000 ml reaction flask, add 400 mL of chloroform, compound I-2-Larotrectinib (80 mmol, 42.9 g), stir at room temperature until dissolved, and simultaneously add saturated sodium bicarbonate solution (23 g) and pivaloyl chloride (80 mmol, 9.64 g) , the mixture was stirred and reacted at room temperature for 24 hours, and controlled by TLC. After the reaction was completed, the mixture was poured into water, and the organic layer was separated, washed with 1N sodium hydroxide (100mL), washed with saturated brine (100mL), dried over anhydrous magnesium sulfate, and reduced Concentrated under reduced pressure to remove the solvent, and the residue was crystallized from methanol-isopropyl ether (7:3, 150 mL) to obtain the product I-Piv-2-Larotrectinib as a white solid with a yield of 85% (68 mmol, 42.2 g). The route is as follows:

[0118]

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Abstract

The invention relates to a radioactive fluorine labeled Larotrectinib compound and a preparation method thereof, in particular, an in vivo imaging agent for Trk receptor subtype in refractory solid tumors, the present invention provides a radiofluorocompound 18F-Larotrectinib and 18F-Larotorectinib analogues based on a novel inhibitor Larotrectinib for tyrosine receptor kinase (TRK), and more particularly a preparation method of the Larotrectinib and its analogue radioactive fluorine-18 labeled compound 18F-Larotdirectinib and its 18F-Larotorectinib analogue. Compared with the prior art, the invention has the advantages of fast reaction speed, relatively mild condition, simple operation, short reaction time and simple post-treatment, and the prepared carrier-free radioactive label compounds have high radiochemical purity and positron emission characteristics, and PET-CT positron emission tomography can be used, so as to visually display the distribution of Larotrectinib compounds and their analogues in vivo and tumors, and a new imaging agent for early diagnosis of tumors is provided.

Description

technical field [0001] The invention relates to the field of chemical drug synthesis, especially in vivo imaging agents of Trk receptor subtypes in refractory solid tumors, in particular to a radioactive fluoride based on a novel inhibitor of tyrosine receptor kinase (TRK), Larotrectinib compound 18 F-Larotrectinib and its 18 F-Larotrectinib analogue, more particularly to a kind of Larotrectinib and its analogue radioactive fluorine-18 labeled compound 18 F-Larotrectinib and its 18 Process for the preparation of F-Larotrectinib analogues. 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 a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07F7/10C07F7/18A61K51/04A61P35/00A61K101/02
CPCC07D487/04C07F7/18A61P35/00A61K51/04C07F7/10
Inventor 黄钢李斌
Owner SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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