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Preparation method of 5-benzyl-1H-indazole-3-amine compound

A compound, the technology of hydrazine hydrate, which is applied in the field of catalytic synthesis of fine chemical products, can solve the problems of large environmental pollution, harsh reaction conditions, and danger, and achieve the effects of reducing production costs, simple treatment and purification, and reducing pollution

Pending Publication Date: 2022-03-25
海南梵圣生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] This route involves anhydrous and anaerobic Grignard reaction, the reaction conditions are harsh and very dangerous; it also needs to use strong acid to dehydroxylate, and there is a side reaction of cyano hydrolysis, which is relatively polluting to the environment and does not meet the needs of green chemistry and sustainable development. , so this route is not suitable for commercial production

Method used

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  • Preparation method of 5-benzyl-1H-indazole-3-amine compound
  • Preparation method of 5-benzyl-1H-indazole-3-amine compound
  • Preparation method of 5-benzyl-1H-indazole-3-amine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: Preparation of 5-(3,5-difluorobenzyl)-1H-indazol-3-amine

[0054]

[0055] Dissolve 2-fluoro-5-formylbenzenecyanide (20g, 1eq) in 200mL 1,4-dioxane, add p-toluenesulfonyl hydrazide (27.47g, 1eq), stir at room temperature for 3 hours, then add Potassium carbonate (27.8g, 1.5eq), 3,5-difluorophenylboronic acid (23.3g, 1eq), heated to 100°C, and stirred for 12 hours. After TLC monitors raw material to react, filter, filtrate is spin-dried, adds sherwood oil and stirs for half an hour, filters, and filtrate spin-dries obtains 2-fluoro-5-(3,5-difluorobenzyl) benzonitrile 28g (yield is 84%).

[0056]2-Fluoro-5-(3,5-difluorobenzyl)benzonitrile (28g, 1eq) was dissolved in 200mL of tert-butanol, hydrazine hydrate (18.2g, 5eq) was added, and stirred at 120°C for 12 hours. After TLC monitors the reaction of the raw materials, cool down to room temperature, spin the reaction solution to dryness directly, add petroleum ether and stir for half an hour, filter, and dry...

Embodiment 2

[0057] Example 2: Preparation of 5-(3-fluorobenzyl)-1H-indazol-3-amine

[0058]

[0059] Dissolve 2-fluoro-5-formylbenzenecyanide (20g, 1eq) in 200mL 1,4-dioxane, add p-toluenesulfonylhydrazide (27.47g, 1.1eq), stir at room temperature for 3 hours, and then Potassium carbonate (27.8g, 1.5eq) and 3-fluorophenylboronic acid (20.6g, 1.1eq) were added, the temperature was raised to 100°C, and the mixture was stirred for 12 hours. After the reaction of raw materials was monitored by TLC, filter and spin dry the filtrate, add petroleum ether and stir for half an hour, filter and spin dry the filtrate to obtain 26 g of 2-fluoro-5-(3fluorobenzyl)benzonitrile (yield 85%).

[0060] 2-Fluoro-5-(3-fluorobenzyl)benzonitrile (26g, 1eq) was dissolved in 200mL of tert-butanol, hydrazine hydrate (18.17g, 5eq) was added, and stirred at 120°C for 12 hours. After the TLC monitoring of the reaction of the raw materials, it was lowered to room temperature, the reaction solution was directly spi...

Embodiment 3

[0061] Embodiment 3: Preparation of 5-benzyl-1H-indazol-3-amine

[0062]

[0063] Dissolve 2-fluoro-5-formylbenzenecyanide (50g, 1eq) in 500mL 1,4-dioxane, add p-toluenesulfonylhydrazide (68.7g, 1eq), stir at room temperature for 3 hours, then add Potassium carbonate (69.5g, 1.5eq), phenylboronic acid (45g, 1eq), heated to 80°C, and stirred for 8 hours. After the reaction of the raw materials was monitored by TLC, the mixture was filtered, and the filtrate was spin-dried, and petroleum ether was added to stir for half an hour, filtered, and the filtrate was spin-dried to obtain 65 g of 2-fluoro-5-benzylbenzonitrile (91% yield).

[0064] 2-Fluoro-5-benzylbenzonitrile (65g, 1eq) was dissolved in 700mL of tert-butanol, hydrazine hydrate (62g, 5eq) was added, and stirred at 120°C for 12 hours. After TLC monitors raw material to react, drop to room temperature, reaction solution is directly spin-dried, adds sherwood oil and stirs for half an hour, filters, and filter cake is dr...

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Abstract

The invention discloses a method for preparing a 5-benzyl-1H-indazole-3-amine compound and a preparation method of the 5-benzyl-1H-indazole-3-amine compound. According to the method, 2-fluoro-5-formyl cyanophenyl, p-toluenesulfonhydrazide and arylboronic acid are taken as substrates and react in 1, 4-dioxane in the presence of alkali, and the 2-fluoro-5-benzyl cyanophenyl compound is obtained. The preparation method comprises the following steps: dissolving a 2-fluoro-5-benzyl cyanophenyl compound and hydrazine hydrate in tert-butyl alcohol, and reacting to obtain the 5-benzyl-1H-indazole-3-amine compound. The method provided by the invention has the following characteristics: (1) the reaction raw materials are common commercial raw materials, and the used alkali and solvent are cheap and easy to obtain; no noble metal catalyst is used, and the production cost is low; (2) the reaction is insensitive to air and moisture, and the open reaction has no influence on the yield; magnesium powder is not used as a Grignard reagent, water and oxygen removal operation is not needed, and the method is safe, efficient and suitable for industrial production; and (3) treatment and purification after reaction are simple and convenient, and pollution of solvents and silica gel to the environment is reduced.

Description

technical field [0001] The invention belongs to the field of catalytic synthesis of fine chemical products, and relates to a method for preparing 5-benzyl-1H-indazol-3-amine compounds. Background technique [0002] 5-Benzyl-1H-indazol-3-amine compounds are often used to synthesize CNS-active, oral, selective tyrosine kinase inhibitors, which do not target certain A specific cancer type, but for cancer patients with NTRK (NTRK1, NTRK2 and NTRK3), ROS1 or ALK gene fusions, the proteins encoded by these three genes are TRK (TRKA, TRKB, TRKC), ROS1 and ALK protein binding, so as to achieve the purpose of inhibiting cancer. It is suitable for the treatment of central nervous system tumors, neuroendocrine tumors, salivary gland tumors, pancreatic cancer, non-small cell lung cancer, thyroid cancer, sarcoma, colorectal cancer, salivary gland tumors, bile duct cancer, brain tumors, ductal tumors, breast-like secretory tumors, breast Cancer, breast malignant melanoma and other gynec...

Claims

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Application Information

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IPC IPC(8): C07D231/56
CPCC07D231/56
Inventor 粟骥闵鑫欧阳赟王恺之华瑞茂
Owner 海南梵圣生物科技有限公司