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Method for preparing indolone derivative

A derivative, indolinone technology, applied in the field of medicinal chemistry synthesis, can solve the problems of unsuitability for scale-up production, low yield, reduced production efficiency, etc., and achieve the effects of low toxicity, high total yield and high production efficiency

Active Publication Date: 2018-10-16
烟台药物研究所
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The yield of each step of this method is all relatively low (for example: step 1 yield 62%, step 2 yield 65%, step 3 yield 62%, the 4th step yield 70%), and the purification of each step needs column Chromatographic purification, not suitable for scale-up production, and greatly reduces production efficiency

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  • Method for preparing indolone derivative
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  • Method for preparing indolone derivative

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preparation example Construction

[0042] In a preferred embodiment, the preparation method of YLF466D provided by the invention comprises the following steps:

[0043]

[0044] (1) Phenylpropiolic acid and aniline undergo a condensation reaction under the action of a condensing agent to obtain an amide intermediate I (compound of formula I). Phenylpropiolic acid and aniline react in a suitable solvent under the action of a condensing agent to obtain the amide intermediate I conveniently. The condensing agent used is a condensing agent such as DCC, EDC, DIC or BDDC.

[0045] (2) At an appropriate temperature, the intermediate I obtained in step (1) and methyl 3-bromomethylbenzoate carry out a nucleophilic substitution reaction in an appropriate solvent under the action of a base to obtain intermediate II (formula II compound).

[0046] Specifically, the temperature of the substitution reaction is 30°C to 120°C, preferably 40°C to 60°C; the base can be sodium hydride, K 2 CO 3 、Na 2 CO 3 , Li 2 CO 3 , ...

Embodiment 11

[0059] The preparation of formula I compound

[0060]

[0061] Phenylpropiolic acid (2000g, 13.7mol) and aniline (1911g, 20.5mol) were dissolved in dichloromethane (15L), then EDCI (5252.6g, 27.4mol) was added in batches, and the reaction temperature was controlled below 30°C. After the addition is complete, the reaction takes about 20 hours at room temperature.

[0062] The reaction solution was washed with 8L of 2.5mol / L dilute hydrochloric acid and 5L of 1mol / L dilute hydrochloric acid, respectively. The organic phase was washed once with 8L saturated sodium bicarbonate and once with 8L saturated brine, and methylene chloride was recovered to obtain a yellow-white solid powder, which was dissolved in 6600mL of anhydrous methanol, and 1 volume (10000ml) of purified water was added dropwise for crystallization. After filtering, the solid was washed with purified water, and air-dried at 40°C to obtain 2885.4 g of the compound of formula I, which was an off-white solid powd...

Embodiment 12

[0065] The preparation of formula I compound

[0066] Phenylpropiolic acid (20.0g, 0.14mol) and aniline (19.11g, 0.21mol) were dissolved in dichloromethane (150mL), then DIC (1,3-diisopropylcarbodiimide , 34.0g, 0.27mol), the reaction temperature is controlled below 30°C. After the addition is complete, the reaction takes about 20 hours at room temperature. The reaction solution was washed with 80 mL of 2.5 mol / L dilute hydrochloric acid and 50 mL of 1 mol / L dilute hydrochloric acid, respectively. The organic phase was washed once with 80mL of saturated sodium bicarbonate and once with 80mL of saturated brine, and dichloromethane was recovered to obtain a yellow-white solid powder, which was dissolved in 67mL of anhydrous methanol, and 100mL of purified water was added dropwise for crystallization, filtered, and the solid was purified with After washing with water, air-drying at 40°C gave 26.6 g of the compound of formula I, off-white solid powder. Yield: 86.0%.

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Abstract

The invention discloses a method for preparing an indolone derivative. The method disclosed by the invention comprises the step of subjecting phenylpropiolic acid and aniline, which serve as startingraw materials, to four steps, i.e., condensation, nucleophilic substitution, palladium catalyzing coupling and hydrolyzing sequentially, thereby obtaining the indolone derivative. According to the method disclosed by the invention, the raw materials are readily available, the operation is simple and convenient, the production efficiency is high, enlarged production is facilitated, and the productis high in total yield and easy to purify.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and relates to a 4-{3-[1-(4-chloro-phenyl)-1-phenyl-methyl-(E)-ylidene]-2-oxo-2,3 - Process for the preparation of dihydro-indol-1-yl-methyl}-benzoic acid. Background technique [0002] In recent years, the incidence of ischemic heart disease has been increasing, which seriously threatens human health. Decreased blood flow in the coronary arteries, leading to myocardial cell damage and even death, is the main cause of ischemic heart disease. Current treatment measures mainly include arterial bypass surgery, thrombolytic therapy, percutaneous transluminal coronary angioplasty and other modern technologies to reperfuse the heart with blood. However, myocardial ischemia-reperfusion itself can also lead to myocardial injury, even after the blood vessel is opened, it will cause more serious acute myocardial injury than that of blood vessel occlusion, leading to severe arrhythmia, myo...

Claims

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Application Information

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IPC IPC(8): C07D209/34C07C231/08C07C233/51
CPCC07C231/08C07D209/34C07C233/51
Inventor 南发俊张仰明尹建朋战得胜马辉刘桦楠时圣杰
Owner 烟台药物研究所
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