Novel purine derivative, intermediate thereof and application thereof in preparation of anti-cancer drugs

A technology of derivatives and intermediates, applied in the field of novel purine derivatives and their intermediates, to achieve the effect of low preparation cost, simple structure, and excellent PI3K inhibitory activity

Pending Publication Date: 2021-04-27
张飞 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present invention also uses PI3Kα as the starting point for target research on new drugs, especially in China, there is no PI3Kα inhibitor invented in China for the treatment of malignant tumors

Method used

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  • Novel purine derivative, intermediate thereof and application thereof in preparation of anti-cancer drugs
  • Novel purine derivative, intermediate thereof and application thereof in preparation of anti-cancer drugs
  • Novel purine derivative, intermediate thereof and application thereof in preparation of anti-cancer drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] The preparation of embodiment 1 compound I-1

[0058] Take the following route to synthesize compound I-1:

[0059]

[0060] 1.1. Synthesis of compound 2

[0061] Compound 2: Chinese name is 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane; English name is 2-(4-isocyanatophenyl )-4,4,5,5-tetramethyl-1,3,2-dioxaborolane;

[0062]

[0063] Add 4-aminophenylboronic acid pinacol ester compound 1 (10g, 45.6mmol) and triethylamine (13.8g, 136.8mmol) respectively into 300mL of dichloromethane, cool to zero degree, slowly add triphosgene in batches at zero degree (8.1 g, 27.4 mmol), and then stirred at zero for 50 minutes to obtain a solution of compound 2, which was directly used in the next step.

[0064] 1.2. Synthesis of compound 3

[0065] Compound 3: The Chinese name is 1-(4-(hydroxymethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxin-2- base) phenyl) urea; the English name is:

[0066] 1-(4-(hydroxymethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2...

Embodiment 2

[0085] The preparation of embodiment 2 compound 1-2

[0086] Take the following route to synthesize compound I-2:

[0087]

[0088] 2.1. Synthesis of Compound 9

[0089] Compound 9: The Chinese name is (4-nitro-2-(trifluoromethyl)phenyl)methanol; the English name is:

[0090] (4-nitro-2-(trifluoromethyl)phenyl)methanol;

[0091]

[0092] Compound 8 (25.0g, 106.4mmol) was dissolved in tetrahydrofuran (100mL), sodium borohydride (11.5g, 319.1mmol) was slowly added in an ice bath, and boron trifluoride diethyl ether (20mL) was slowly added dropwise, followed by stirring at room temperature overnight. TLC showed that after the reaction was over, 100 mL of brine was added, extracted with ethyl acetate (300 mL x 3), and the organic phase was dried and concentrated over sodium sulfate to obtain compound 9 (14.5 g, yield = 61%). Measured: ESI- MS m / z=222[M+1] +

[0093] 2.2. Synthesis of compound 10

[0094] Compound 10: The Chinese name is tert-butyldimethyl(4-nitro-...

Embodiment 3

[0115] The preparation of embodiment 3 compound 1-3

[0116] Take the following route to synthesize compound I-3:

[0117]

[0118] 3.1. Synthesis of compound 15

[0119] Compound 15: The Chinese name is 4-(2-(benzyloxy)ethyl)morpholine; the English name is:

[0120] 4-(2-(benzyloxy)ethyl)morpholine;

[0121]

[0122] Compound 14 (32.8g, 0.25mol) was dissolved in DMF (200mL), NaH (10g, 0.25mol) was added in portions under cooling in an ice-water bath, stirred at room temperature for 1.5 hours, benzyl bromide (39.3g, 0.23 mol). The reaction solution was stirred at room temperature for 16 hours, concentrated under reduced pressure, added ethyl acetate (100 mL), washed with water and saturated brine. The organic phase was concentrated under reduced pressure and purified by silica gel column (DCM:MeOH=10:1) to obtain compound 15 (40 g, yield 78%) as a colorless oil. Measured: ESI-MS m / z=222[M+1] +

[0123] 3.2. Synthesis of Compound 16

[0124] Compound 16: Chine...

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PUM

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Abstract

The invention discloses a novel purine derivative shown as a formula (I) or a pharmaceutically acceptable salt thereof, an intermediate of the novel purine derivative, and an application of the novel purine derivative or the pharmaceutically acceptable salt in preparation of drugs for treating or preventing cancers. The compound is a novel PI3K inhibitor, has excellent inhibitory activity and is expected to be used for treating various malignant tumors.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a novel class of novel purine derivatives and intermediates thereof. The novel purine derivatives have phosphoinositide-3-kinase (PI3K) inhibitory activity and can be used to prepare drugs for preventing and treating tumors . Background technique [0002] PI3K is an intracellular phosphatidylinositol kinase. Lewis C. Cantley, professor of cancer biomedicine at Weill Cornell Medical College, discovered the phosphoinositide-3-kinase (PI3K) signaling pathway and elucidated its key role in tumor development. The PI3K signaling pathway is usually activated by receptors on the cell surface, such as receptor tyrosine kinases, GPCRs, and some oncogenes, such as RAS. The activated p110 subunit catalyzes the conversion of PIP2 to PIP3 and activates Akt activity. Akt will further transmit signals to downstream molecules, such as mTORC1, GSK3, and BCL-2, to regulate differen...

Claims

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Application Information

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IPC IPC(8): C07D473/34A61P35/00A61P35/02A61K31/5377
CPCC07D473/34A61P35/00A61P35/02A61K31/5377C07D487/04C07D513/04A61K31/519Y02P20/55C07B2200/13
Inventor 冯子侠张飞
Owner 张飞
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