Preparation method of 7-fluoro-2-oxoindoline-4-carboxylic acid

An indoline and oxo technology, applied in the direction of organic chemistry, etc., can solve the problems of large-scale production danger, hazardous waste liquid environment, and high risk coefficient, and achieves easy industrialization amplification, improved safety, and high reaction yield. Effect

Pending Publication Date: 2021-12-17
上海皓鸿生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The above route uses bromine as a reagent, bromine has strong volatility and strong sensitization, large-scale production is dangerous, and pollutes the environment; using metal zinc reagent, activated metal zinc has strong spontaneous combustion , the risk factor is high in industrial production; the zinc salt produced is difficult to handle, and the waste liquid is harmful to the environment and needs special treatment

Method used

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  • Preparation method of 7-fluoro-2-oxoindoline-4-carboxylic acid
  • Preparation method of 7-fluoro-2-oxoindoline-4-carboxylic acid
  • Preparation method of 7-fluoro-2-oxoindoline-4-carboxylic acid

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Effect test

Embodiment 1

[0048] Add 250ml of ethylene glycol into a 500ml three-necked flask, add 50g (205mmol) of the compound shown in formula (II) and 15.4g (250mmol) of hydrazine hydrate (80%), stir for 30min, control the internal temperature at 55-65°C, and react 2 -6h, the central control raw material disappeared, and the reaction was completed. Cool down to room temperature and filter to obtain 60 g of the crude product represented by formula (III) (the next reaction can be directly carried out without further treatment).

Embodiment 2

[0050] Add 500ml of ethylene glycol into a 500ml three-necked flask, add 60g of the crude product shown in (III) obtained above, add 1.7g (20.5mmol) of sodium acetate, and raise the reaction temperature to 135-145°C, react for 8-16h, and control The reaction is complete. Concentrate under reduced pressure to 1 / 3 of the original volume, cool down to 0-10°C, filter, rinse with 100ml of water, and vacuum-dry to obtain 40g of the compound represented by formula (IV), with a purity of ≥98%.

Embodiment 3

[0052] In the pressure reactor of 500ml, add methanol 300ml, add the compound 30g shown in (IV) obtained above, add triethylamine 27ml, (dppf)PdCl 2 1.55g, replace with CO three times, control the pressure of CO in the reactor to 0.5MPa; control the reaction temperature at 115-125°C, react for 10h, cool down to room temperature, concentrate the solvent, add DMF and DCM, stir for 30min, and filter to obtain formula (V) The compound shown is 23g, with a purity≥98%.

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Abstract

The invention provides a preparation method of 7-fluoro-2-oxoindoline-4-carboxylic acid, wherein the method adopts a synthetic route as shown in the specification and specifically comprises the steps: step 1, adding a compound (IV) into a solvent, adding a catalyst and alkali, introducing carbon monoxide gas, and reacting to prepare a compound (V); and step 2, hydrolyzing the compound (V) under the condition of alkali to obtain a compound (I) 7-fluoro-2-oxoindoline-4-carboxylic acid. According to the preparation method provided by the invention, 4-bromo-7-fluoroindoline-2,3-diketone is taken as a raw material, the raw material is easy to obtain, and the related reaction has the characteristics of high safety, high yield, simplicity and convenience in operation, easiness in industrial production and the like.

Description

technical field [0001] The invention relates to the field of organic chemical synthesis, in particular to a method for preparing 7-fluoro-2-oxoindoline-4-carboxylic acid. Background technique [0002] Benzo[b]pyrrole ring derivatives are the most common heterocyclic motifs in natural products The indole family includes many notable representatives such as the essential α-amino acid tryptophan, its spoilage products, the plant growth factor 3-indole Indoleacetic acid (heterologous auxin), neurotransmitter serotonin, pineal hormone melatonin, Rauwolfia alkaloids, reserpine and yohimbine, ranunculus alkaloids, ellipsomycin, strychnium alkaloids, Ning, ergotamine and vinca alkaloids, vincristine. However, many natural plants have very large toxic and side effects. Later, by optimizing the structure of this large class of indole family compounds, their toxicity can be significantly reduced and their efficacy can be improved, and anti-hypertensive, anti-proliferation, anti-virus,...

Claims

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Application Information

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IPC IPC(8): C07D209/34
CPCC07D209/34Y02P20/55
Inventor 彭东杰路化雷苏岭岭何玉林李硕梁杨绍波高强郑保富
Owner 上海皓鸿生物医药科技有限公司
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