Preparation method and application of anilinoquinazoline compound

A technology of aniline quinazolines and compounds, which is applied in the field of aniline quinazoline compounds and their preparation, can solve the problems of low yield, long labeling time, short half-life, etc., achieve high specific activity of radioactivity, simple and convenient separation, Effects with simple synthesis steps

Active Publication Date: 2014-01-01
ZHEJIANG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The application of positron nuclides has been reported 11 C, F-18-labeled PD153035, gefitinib, erlotinib, etc. are used as new PET imaging agents for tumor imaging, but due to 11 The half-life of C (t 1 / 2 =20.4 minutes) is too short, it can only be used in PET centers with positron nuclide accelerators, and cannot be distributed, and the yield is very low, and one production can only meet the needs of one patient's examination, which greatly limits these display methods. The use of F-18-labeled drugs, the labeling steps are cumbersome, the labeling time is too long, and it is not suitable for clinical promotion. The present invention has synthesized a new class of aniline quinazoline compounds, which can be used for radiochemical synthesis of 2-position F-18-labeled aniline-quinazoline positron drugs for tumor imaging. This type of aniline-quinazoline compound is used as a labeling precursor. The labeling method is simple and the labeling yield is high.

Method used

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  • Preparation method and application of anilinoquinazoline compound
  • Preparation method and application of anilinoquinazoline compound
  • Preparation method and application of anilinoquinazoline compound

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Example 1: Preparation of 6,7-dimethoxyquinazoline-4-aniline-2-trimethylamine chloride salt

[0023]

[0024] Dissolve 50 mg of 2-chloro-6,7-dimethoxyquinazoline-4-aniline in a mixed solvent of 3 mL of tetrahydrofuran and 1 mL of DMF, add 0.3 mL of trimethylamine in ethanol, and react under ice-cooling. After 5 days, the reaction was stopped, and a white solid was precipitated, which was filtered to obtain 20 mg. ESI-MS (m / z): 339 (M + ); 1 H NMR (DMSO- d 6 , 400 MHz) δ : 10.52 (1H, s, -NH-), 8.15 (1H, s, -5H), 7.73 (2H, d, J = 8.21 Hz, 2’-H, 6’-H), 7.45 (2H, d, J = 7.43 Hz, 3’-H, 5’-H), 7.26 (1H, s, 8-H), 7.21 (1H, t, J = 7.43 Hz, 5-H), 3.98 (6H, s, 2×OCH 3 ), 3.49 (9H, s, 3×NCH 3 ).

Embodiment 2

[0025] Example 2: Preparation of 6,7-dimethoxyquinazoline-4-(3'-bromo)aniline-2-trimethylamine chloride salt

[0026]

[0027] 63 mg of 2-chloro-6,7-dimethoxyquinazoline-4-(3'-bromo)aniline was dissolved in a mixed solvent of 3 mL of tetrahydrofuran and 1 mL of DMF, and 0.3 mL of trimethylamine in ethanol was added, React under ice bath. After 7 days, the reaction was stopped, and a white solid was precipitated, which was filtered to obtain 32 mg. ESI-MS (m / z): 418 (M + ); 1 H NMR (DMSO- d 6 , 400 MHz) δ : 10.52 (1H, s, -NH-), 8.15 (1H, s, 4’-H), 7.73 (1H, d, J = 8.21 Hz, 6’-H), 7.45 (1H, t, J = 7.43 Hz, 5'-H), 7.26 (1H, s, 8-H), 7.24 (1H, s, 5-H) 7.21 (1H, s, 2'-H), 3.98 (6H, s, 2 ×OCH 3 ), 3.49 (9H, s, 3×NCH 3 ).

Embodiment 3

[0028] Example 3: Preparation of 6,7-dimethoxyquinazoline-4-(3'-ethynyl)aniline-2-trimethylamine chloride salt

[0029]

[0030] 54 mg of 2-chloro-6,7-dimethoxyquinazoline-4-(3'-ethynyl)aniline was dissolved in a mixed solvent of 3 mL of tetrahydrofuran and 1 mL of DMF, and 0.3 mL of trimethylamine in ethanol was added , reacted in an ice bath. After 7 days, the reaction was stopped, and a white solid was precipitated, which was filtered to obtain 30 mg. ESI-MS (m / z): 363 (M + ); 1 H NMR (DMSO-d 6 , 400 MHz) δ : 10.52 (1H, s, -NH-), 8.15 (1H, s, 4’-H), 7.73 (1H, d, J = 8.21 Hz, 6’-H), 7.45 (1H, t, J = 7.43 Hz, 5'-H), 7.26 (1H, s, 8-H), 7.24 (1H, s, 5-H) 7.21 (1H, s, 2'-H), 3.98 (6H, s, 2 ×OCH 3 ), 3.49 (9H, s, 3×NCH 3 ), 3.09 (1H, s, alkyne hydrogen).

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Abstract

The invention provides an anilinoquinazoline compound, namely a quinazolinyl-4-anilino-2-(N,N,N-trialkyl) quaternary ammonium salt derivative, which is synthesized into a 2-[fluorine-18]fluoro substituted derivative through the radiochemistry and used as a fluorine-18 labeled precursor, and can be applied to the preparation of a tumor positron imaging agent; the tumor positron imaging agent adopts an epidermal growth factor as a target spot and can perform imaging of a specific tumor. According to the invention, the preparation method for the derivative has the following advantages: the synthesis steps are simple, and the target compound can be obtained at only one step that the quaternary ammonium salt precursor is labeled by the fluorine-18; the time for radiochemical synthesis is short, and only 20-25 min is required; the separation is simple and convenient without adopting HPLC, the product of which the radiochemical purity is more than 98 percent can be obtained with one Sep-Pak C-18 column, and meanwhile the quaternary ammonium salt precursor is removed; the radiochemical yield is high, the non-correction yield can reach 40-60 percent, and the drug specific radioactivity is high. The structural formula is shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a class of aniline quinazoline compounds and their preparation method and application. This class of compounds can be used to radiochemically synthesize a class of positron imaging agents for tumor imaging. Background technique [0002] Quinazolines are a class of important heterocyclic compounds with a wide range of uses and high biological activity, mainly for EGFR or its tyrosine kinase (EGFR-TK), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth The inhibitory activity of PDGFR, Nerve Growth Factor Receptor (NGFR) and other multiple targets, thus exerting various pharmacological effects such as anticancer, antibacterial, antiviral, etc. In particular, 4-aniline quinazoline compounds are the most active and selective tyrosine kinase inhibitors discovered so far, and the main target of this type of compounds is EGFR. There are several anilinoquina...

Claims

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Application Information

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IPC IPC(8): C07D239/95A61K51/04A61K101/02
CPCA61K51/0459C07D239/95
Inventor 董孟杰刘振锋张倩晋建文王国林赵葵
Owner ZHEJIANG UNIV
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