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

AI Technical Summary

Problems solved by technology

However, almost all patients on these three classes of drugs will inevitably develop acquired resistance

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

Embodiment 1

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

[0070]

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

[0072]

[0073] Add 3-fluoro-4-methoxybenzaldehyde (1.0eq), MeOH, (1-diazo-2-oxo-propanol)-phosphonic acid dimethyl ester (2.2eq), K 2 CO 3 (2.2eq), the addition was completed, and the reaction was stirred overnight at room temperature. After the reaction was complete, the solvent was spin-dried and purified by column chromatography (by volume, PE:EA=10:1, PE refers to petroleum ether, EA refers to ethyl acetate, and the following meanings are the same), and the title The compound is light yellow oily liquid.

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

[0075]

[0076]Add 4-ethynyl-2-fluoro-1-methoxybenzene (1.2 eq), 4-bromo-2-iodoaniline (1.0 eq), DMA (dimethylacetamide, CAS accession number: 127-19-5), Pd(PPh 3 ) 2 Cl 2 (0.2eq), CuI(0.2eq), E...

Embodiment 2

[0087] Example 2: 4-(2-(3-fluoro-4-methoxyphenyl)-5-(4-(methylamino)piperidin-1-yl)-1H-indol-1-yl) Benzonitrile (i.e. compound I-2)

[0088]

[0089] Step 1: Synthesis of (1-(1-(4-cyanophenyl)-2-(3-fluoro-4-methoxyphenyl)-1H-indol-5-yl)piperidin-4-yl )(methyl)carbamate tert-butyl ester

[0090]

[0091] Add 4-(5-bromo-2-(3-fluoro-4-methoxyphenyl)-1H-indol-1-yl)benzonitrile (1.0 eq), tert-butylmethyl (piperidine -4-yl) carbamate (1.0eq), Pd 2 (dba) 3 (0.11eq), cesium carbonate (2.0eq), X-phos (0.22eq), dioxane, under nitrogen protection, heated to 110°C to react, TLC to monitor the reaction progress. After the reaction was complete, the reaction solution was filtered with a membrane filter, the filtrate was spin-dried, and the residue was purified by column chromatography (PE:EA=3:2) to obtain the title compound as 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-(methylamino)piperidin-1-yl)-1H-indol-1-y...

Embodiment 3

[0095] Example 3: 4-(5-(4-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)-1H-indol-1-yl)-2-hydroxy Benzonitrile

[0096]

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

[0098]

[0099] Add 4-bromo-2-hydroxybenzonitrile (1.0eq), THF (10V), DMAP (0.2eq), BOC anhydride (1.3eq, di-tert-butyl dicarbonate), TEA (1.5eq, tris ethanolamine), the addition was completed, the reaction was stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction is complete, add ethyl acetate (10V) to the reaction flask, then use 1N dilute hydrochloric acid to adjust the pH of the system to 3, separate the liquids, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and spin to dry the solvent, and the residual The product was purified by column (PE:E A=3:1) to obtain the title compound as a colorless oil.

[0100] Step 2: Synthesis of 5-(5-bromo-2-(3-fluoro-4-methoxyphenyl)-1H-indol-1-yl)-2-cyan...

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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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