Indole derivative as well as synthesis method and application thereof

A synthesis method and technology of application, applied in the field of chemistry, to achieve the effect of inhibiting proliferation and inhibiting the proliferation of cancer cells

Active Publication Date: 2022-03-29
深圳市乐土生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, almost all patients on these three classes

Method used

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  • Indole derivative as well as synthesis method and application thereof
  • Indole derivative as well as synthesis method and application thereof
  • Indole derivative as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0069] Example 1: 4- (5- (4-aminopiperidine-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indole-1-yl) benzonitrile

[0070]

[0071] Step 1: Synthesis 4-ethynyl-2-fluoro-1-methoxybenzene

[0072]

[0073] 3-fluoro-4-methoxybenzaldehyde (1.0eq), MeOH (1-Net nitrogen-2-oxo-propanol) -phoninic acid dimethyl (2.2 eq), K 2 CO 3 (2.2eq), the reaction was stirred at room temperature overnight. After the reaction is complete, the carnation solvent, column chromatography purification (according to volume gauge, PE: EA = 10: 1, PE means petroleum ether, EA refers to ethyl acetate, the meaning of the following: The compound is a pale yellow oily liquid.

[0074] Step 2: Synthesis 4-bromine-2 - ((4-methoxy-3-methylphenyl) ethynyl) aniline

[0075]

[0076]4-ethynyl-2-fluoro-1-methoxyenzene (1.2eq), 4-bromo-2-iodine aniline (1.0 eq), DMA (dimethylacetamide, CAS login number: 127-19-5), PD (PPH 3 ) 2 CL 2 (0.2eq), Cui (0.2eq), ET 2 N (1.5 eq, ET refers to the ether), and after nitrogen protec...

Example Embodiment

[0087] Example 2: 4- (2- (3-fluoro-4-methoxyphenyl) -5- (4- (methyl amino) piperidine-1-yl) -1H-indole-1-group) Benzonitrile (ie, compound I-2)

[0088]

[0089] Step 1: Synthesis (1- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indole-5-yl) piperidine-4-yl (Meth) urethane tert-butyl ester

[0090]

[0091] Add 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-hydrazine-1-yl-1-yl-1-yl), tert-butyl methyl (piperidine) -4-yl) urethane (1.0eq), PD 2 (DBA) 3 (0.11 EQ), cesium carbonate (2.0 eq), X-PhOS (0.22 eq), Dioxane, nitrogen protected, heated to 110 ° C, TLC monitors the reaction process. After the reaction is complete, the reaction solution is filtered, the carnoff, the residual column chromatography purification (PE: EA = 3: 2), resulting in a yellow solid. MS-ES: (ESI, POS.ION) M / Z: 499.30 [M + H] +.

[0092] Step 2: 4- (2- (3-fluoro-4-methoxyphenyl) -5- (4- (methyl amino) piperidine-1-yl) -1H-indole-1-yl) benzyl Nitrile

[0093]

[0094] Add (1- (4-cyanobipheny...

Example Embodiment

[0095] Example 3: 4- (5- (4-aminopiperidine-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indole-1-yl) -2-hydroxyl group Benzonitrile

[0096]

[0097] Step 1: Synthesis 5-bromo-2-cyanobenzyl tert-butyl carbonate

[0098]

[0099] 4-bromo-2-hydroxybenzonitrile (1.0eq), THF (10V), DMAP (0.2 eq), BOC acid anhydride (1.3 eq, tert-tert-butyl di-tert-butyl die ester), TEA (1.5 eq, three) Ethanolamine), incorporate, stirred at room temperature, TLC monitors the reaction process. After the reaction was complete, ethyl acetate (10V) was added to the reaction bottle, and then the 1N dilute hydrochloric acid tuning system pH = 3, the liquid washed, and the organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate. Purification (PE: E: E: E: E: E: E: E: E: E: E A = 3: 1) obtained the title compound as a colorless oil.

[0100] Step 2: Synthesis 5- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indole-1-yl) -2-cyanobenzyl tert-butyl carbonate

[0101]

[0102] 4-bro...

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Abstract

The invention discloses an indole derivative as well as a synthesis method and application thereof. The compound has a structure as shown in a formula (I). The compound can effectively inhibit cancer cell proliferation, especially has a remarkable inhibiting effect on proliferation of non-small cell lung cancer cells, and can be used for preparing drugs for treating and/or preventing cancers.

Description

technical field [0001] The invention relates to the field of chemistry, in particular to an indole derivative and its synthesis method and application. Background technique [0002] Lung cancer is one of the most common malignant tumors in the world. With the growth of the global population and the increase of population aging, the incidence of lung cancer continues to increase, and it has become the most lethal tumor. Non-small cell lung cancer (NSCLC, non-small celllung cancer) is a common lung cancer, accounting for about 80-85% of the total number of lung cancers. It is a heterogeneous tumor that can be further divided into squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Most patients are diagnosed at an advanced stage. Patients with locally advanced NSCLC in good health can achieve a disease-free survival period of 8 months after a series of chemotherapy, radiotherapy and (or) surgery, and the 5-year survival rate is less than 15%. [0003] Therefo...

Claims

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Application Information

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IPC IPC(8): C07D209/12C07D401/04C07D471/10C07D403/12C07D401/12C07D401/14A61K31/454A61K31/4545A61K31/438A61K31/496A61K31/404A61P35/00
CPCC07D209/12C07D401/04C07D471/10C07D403/12C07D401/12C07D401/14A61P35/00
Inventor 邢青峰朱锡祯王波于方彩姜孝明
Owner 深圳市乐土生物医药有限公司
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