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Preparation method and application of 4-phenoxyphenylpyrazolopyrimidine amide derivative

A technology of phenoxyphenyl and pyrimidine, which is applied in the field of organic compound synthesis and medical application, and can solve problems such as limited effect

Active Publication Date: 2021-03-30
山东康瑞健医疗技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Clinical trials have shown that the application of vorinostat in the treatment of relapsed and refractory MCL has shown a certain therapeutic effect, but the effect of single drug is limited

Method used

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  • Preparation method and application of 4-phenoxyphenylpyrazolopyrimidine amide derivative
  • Preparation method and application of 4-phenoxyphenylpyrazolopyrimidine amide derivative
  • Preparation method and application of 4-phenoxyphenylpyrazolopyrimidine amide derivative

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Experimental program
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Effect test

Embodiment 1

[0115] The preparation of embodiment 1, intermediate 2

[0116] Dissolve 4-aminopyrazolo[3,4-d]pyrimidine (5g, 37mmol) in 30ml DMF, add N-bromosuccinimide (7.9g, 44.4mmol), stir, 80°C oil bath Heating, the color of the solution changed from light yellow to red, reacted for 3 hours, TLC detection, the basic reaction was complete, cooled to room temperature, poured the reaction solution into 300ml ice water, stirred, a large amount of yellow solid was precipitated, filtered, and the filter cake was washed with ice water , and dried to obtain 6.33 g of a light yellow solid with a yield of 79.9%. MP: 270-273°C 1 H NMR (400MHz, DMSO) δ 13.77(s, 1H), 8.18(s, 1H).

Embodiment 2

[0117] Embodiment 2, the preparation of intermediate 3

[0118] Take 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2g, 9.34mmol), 4-phenoxyphenylboronic acid (3.99g, 18.68mmol), tetrakis(triphenylphosphine ) Palladium (531mg, 0.46mmol), K 3 PO 4 ·3H 2 O (7.45g, 28.02mmol), added to a 250ml two-neck bottle, added 100ml of solvent (1,4-dioxane: water = 4:1) to dissolve, nitrogen protection, ultrasonic removal of oxygen in the solution, and nitrogen The air in the replacement device was heated to reflux in an oil bath at 135° C. After 30 hours of reaction, TLC detected that the reaction was basically complete. The reaction solution was cooled to room temperature, filtered with diatomaceous earth, and the filtrate was evaporated under reduced pressure to obtain a yellow solid. Silica gel column chromatography (dichloromethane:methanol=100:1) gave 2.23 g of a light yellow solid with a yield of 78.8 %. MP: 251-254°C 1 H NMR (400MHz, DMSO) δ13.57(s, 1H), 8.22 (s, 1H), 7.67(d, J=...

Embodiment 3

[0119] Embodiment 3, the preparation of intermediate 4

[0120] 1. Preparation of Intermediate 4a

[0121] Take 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (250mg, 0.82mmol), methyl 4-(bromomethyl)benzoate (224mg , 0.98mmol), K 2 CO 3 (170mg, 1.23mmol) and KI (13mg, 0.08mmol) were added to a 50ml reaction bottle, 15ml of DMF was added to dissolve and stirred, and reacted at room temperature for 8 hours, and TLC detected that the reaction was complete. The reaction solution was poured into 100ml of ice water, stirred, and a white solid was precipitated. Added 30ml of ethyl acetate, extracted three times with a separatory funnel, combined the organic phases, washed with saturated brine, evaporated the organic phases under reduced pressure, and performed silica gel column chromatography (dichloro Methane:methanol=200:1), 287 mg of white solid was obtained, and the yield was 77.6%. 1 H NMR (400MHz, DMSO) δ8.28(s, 1H), 7.66(d, J=6.8Hz, 2H), 7.45–7.41(m, 2H), 7.25–7....

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Abstract

The invention provides a preparation method and applications of a 4-phenoxy phenyl pyrazolo pyrimidine amide derivative. The compound has a structure represented by a formula (I), wherein X and Y aretwo linking groups, X is selected from benzyl, substituted benzyl, piperidyl and C1-6 straight-chain or branched-chain alkyl, Y is -(CH2)n-, n is any integer selected from 0-4, R is selected from hydroxyl, hydroxyamino and o-phenylenediamine, and the structure of the formula (I) comprises a racemate and a stereoisomer. The compound has a BTK / HDAC double-target inhibition effect and growth inhibition activity on T cell leukemia cells and mantle cell lymphoma cells, and is used for preparing antitumor drugs.

Description

technical field [0001] The invention relates to the field of organic compound synthesis and medical application, in particular to a preparation method and application of a 4-phenoxyphenylpyrazolopyrimidine amide derivative. Background technique [0002] Mantle cell lymphoma (MCL) is a highly malignant non-Hodgkin lymphoma (NHL) with poor prognosis, characterized by t(11;14)(q13;q32) Chromosomal translocation, resulting in overexpression of cyclin D1. MCL is mostly aggressive clinically and is still an incurable lymphoma so far. At present, there is no standard first-line chemotherapy regimen. Compared with other B-cell lymphomas, it is difficult for MCL to maintain long-term effects through chemotherapy. (See: Zhou Y, Wang H, Fang W, Romaguer JE, Zhang Y, Delasalle KB, Kwak L, Yi Q, DuXL, Wang M: Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004. Cancer 2008, 113( 4):791.) In recent years, with the in-depth research on the pathogenesis of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00A61P35/02A61K31/519
CPCA61P35/00A61P35/02C07D487/04
Inventor 赵桂森禚慧君杨庆滔景永奎冉凡胜包宇
Owner 山东康瑞健医疗技术有限公司
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