CN111057062A

CN111057062A - Preparation method and application of furan and indole-based aryloxy bifunctional synthesis spiro indolone

Info

Publication number: CN111057062A
Application number: CN201911342069.1A
Authority: CN
Inventors: 黄新祥
Original assignee: Jiangsu Innovo Biotechnology Co ltd
Current assignee: Jiangsu Innovo Biotechnology Co ltd
Priority date: 2019-12-24
Filing date: 2019-12-24
Publication date: 2020-04-24

Abstract

The invention discloses a preparation method for synthesizing spiro indolone by aryloxy bifunctional synthesis based on furan and indole, which uses simple and easily synthesized indole derivative (N- (o-bromophenyl) -3-indole carboxamide) to generate stereospecific spiro indoline-3, 3' -oxoindole and 5, 11-dihydro-6H-indole [3,2-C ] quinoline-6-ketone by controlling different reaction conditions and regioselectively generating intramolecular direct C3 and C2 arylation. The invention takes simple furan and indole derivatives as raw materials, and constructs the spiro furan and indole indolone compounds while dearomatizing furan and indole through Heck reaction.

Description

Preparation method and application of furan and indole-based aryloxy bifunctional synthesis spiro indolone

Technical Field

The invention relates to a preparation method and application of aromatic double-functionalization synthesis spiro indolone based on furan and indole.

Background

Furan and indole are two aromatic compounds that occur widely in nature. Chemists take advantage of their low aromaticity to dearomatize them and convert them into a series of structurally complex organic compounds. There are a lot of reports on dearomatization conversion of furan and indole and application thereof, however, development of new catalytic means for efficiently realizing dearomatization conversion of furan and indole and application of the new catalytic means for synthesizing heterocyclic compounds with potential biological activity still deserves attention.

Spirocyclic indoles are a class of basic frameworks for the construction of biologically active compounds, and many substances containing such structural units exist in nature. At present, the method for effectively synthesizing the spiro indole compound mainly comprises the oxidation/lactonization reaction of indole propionic acid, the series Michael ring expansion conversion reaction of hydroxy indolone and the like. However, the main problems of these reactions are the following:

the oxidation/lactonization of the indole propionic acid has the problems of complicated steps, need of transition metal catalysis, harsh conditions, low yield and the like; on the other hand, the spiro indole compound synthesized by methods such as series Michael ring expansion conversion reaction of oxindole has the problem of regioselectivity. More importantly, few methods relate to direct synthesis of compounds with spiro indole frameworks, and no report on a method for directly constructing spiro indole frameworks by adopting an oxidation rearrangement reaction appears. The green high-efficiency synthesis method without transition metal catalysis is only mentioned in individual documents, and the raw material synthesis is complex. Therefore, it is necessary to develop a method for efficiently and environmentally synthesizing the spiro indole compound.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects of the prior art and provide a preparation method for synthesizing spiro indolone by aryloxy double functionalization based on furan and indole.

In order to solve the technical problems, the invention provides the following technical scheme:

the invention provides a preparation method for synthesizing spiro indolone based on furan and indole aryloxy bifunctional synthesis, which comprises the following steps:

(1) putting indole-3-carboxylic acid, a quantitative catalyst and o-bromoaniline into a pre-reaction kettle, starting a condenser to cool water, starting stirring, starting steam to heat to 50 ℃, stopping heating, keeping the temperature at 60 +/-3 ℃, refluxing and stirring for 30 minutes, and stopping stirring to finish the pre-reaction; the reaction is as follows:

(2) conveying the prepared materials to a synthesis reaction kettle through a feed valve, increasing the pressure in the kettle to 0.20Mpa while heating the synthesis kettle, adjusting a heat conduction oil valve, opening an exhaust valve of a flowmeter, and continuously and slowly heating the synthesis reaction kettle after checking whether the temperature of the synthesis reaction kettle is normal;

(3) adding indole-3-methyl formate into a dry anhydrous round-bottom flask with magnetons, adding 25mL anhydrous DMF, slowly adding NaH under an ice bath condition, reacting for 1h at room temperature, adding alkyl iodide or alkyl bromide, reacting until the raw materials completely disappear, adding water for quenching under the ice bath condition, adding ethyl acetate for extraction, combining organic phases, drying by using anhydrous sodium sulfate, concentrating to obtain a crude product, and directly performing subsequent conversion without separation and purification;

(4) adding N-alkyl o-bromoaniline, magnetons and DMAP into a 100mL dry and anhydrous round-bottom flask, protecting with N2, adding 25mL anhydrous dichloromethane and anhydrous triethylamine, slowly dropwise adding indole-3-formyl chloride under the ice bath condition, stirring at room temperature for 12H, extracting the reaction with H2O (30mL) to obtain quenched CH2Cl2 (3 × 10mL), combining organic phases, drying anhydrous Na2SO4, filtering, concentrating to obtain a crude product, and performing column chromatography separation and purification (using petroleum ether and ethyl acetate ═ 14:1 as an eluent) to obtain a target raw material;

(4) distilling, sucking the material into a distillation intermediate kettle after desolventizing, opening an emptying valve of the distillation intermediate kettle, and adjusting a heating valve of the intermediate kettle to control the material temperature of the intermediate kettle to be about 145 ℃; controlling the temperature of the rectifying kettle to be less than or equal to 215 ℃, the temperature of the tower top to be less than or equal to 195 ℃, and the vacuum degree to be-0.1 Mpa, when the temperature of the tower top needs to be reduced, starting cooling water at the tower top, and controlling the temperature of a hot water tank at the tower top to be 55-60 ℃; observing the receiving and liquid level conditions of the finished product receiving kettle, controlling the temperature of the finished product receiving kettle material to be between 55 and 65 ℃, and preparing for feeding the slag kettle when the content in the distillation kettle is low; and when the shift is switched, slowly opening a vacuum valve of the standby receiving kettle, after the vacuum balance is realized, opening a material receiving valve of the standby receiving kettle, and closing the vacuum valve and the material receiving valve of the in-use kettle.

Further, the catalyst in the step (1) is phosphotungstic acid.

The function of the spiro indolone in treating lung cancer is synthesized by double functionalization of furan and indole-based aryloxy.

The invention has the following beneficial effects:

the invention takes simple furan and indole derivatives as raw materials, and constructs the spiro furan and indole indolone compounds while dearomatizing furan and indole through Heck reaction. The invention adopts the phosphotungstic acid as the catalyst, improves the selectivity of the reaction, simplifies the treatment after the reaction, improves the reaction yield, can recycle the phosphotungstic acid, saves the cost and is more beneficial to the industrial production.

Detailed Description

The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention.

(1) putting indole-3-carboxylic acid, a quantitative phosphotungstic acid catalyst and o-bromoaniline into a pre-reaction kettle, starting a condenser to cool water, starting stirring, starting steam to heat to 50 ℃, stopping heating, keeping the temperature at 60 +/-3 ℃, refluxing and stirring for 30 minutes, and stopping stirring to finish the pre-reaction; the reaction is as follows:

Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes in the embodiments and modifications can be made, and equivalents can be substituted for elements thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. based on the preparation method of the aryloxy bifunctionalization of furan and indole to synthesize spirocyclic indolone, it is characterized in that, comprise the following steps:

(1) indole-3-carboxylic acid, quantitative catalyzer and o-bromoaniline are dropped into pre-reaction kettle, open condenser cooling water, open stirring, open steam and be warmed up to 50 ℃ and stop heating, keep 60 ± 3 ℃ of reflux stirring 30 minutes, stop stirring and pre-reaction ends; The reaction is:

(2) Transfer the prepared material to the synthesis reaction kettle through the feed valve. When the synthesis kettle heats up, the pressure in the kettle will increase accordingly. When the pressure rises to 0.20Mpa, adjust the heat transfer oil valve, and open the flow meter exhaust valve. After the device checks that everything is normal, continue to heat up slowly;

(3) Add methyl indole-3-carboxylate to a dry anhydrous round-bottomed flask with magnets, add 25 mL of anhydrous DMF, slowly add NaH under ice bath conditions, react at room temperature for 1 h, add The alkyl iodide or alkyl bromide is reacted until the raw material disappears completely. Under ice bath conditions, add water to quench, add ethyl acetate for extraction, combine the organic phases, then dry with anhydrous sodium sulfate and concentrate to obtain the crude product. It needs to be separated and purified for direct subsequent transformation;

(4) In a 100mL dry anhydrous round-bottomed flask, add N-alkyl o-bromoaniline, magneton and DMAP, N2 protection, add 25mL anhydrous dichloromethane, anhydrous triethylamine, under ice bath conditions , indole-3-carbonyl chloride was slowly added dropwise, stirred at room temperature for 12 h, and the reaction was quenched with H2O (30 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to obtain the crude product. Chromatographic separation and purification (using petroleum ether:ethyl acetate=14:1 as eluent) to obtain the target raw material;

(4) Distillation, after desolvation, the material is sucked into the intermediate still of distillation, the vent valve of the intermediate still of distillation is opened, and the heating valve of the intermediate still is adjusted, so that the temperature of the material in the intermediate still is controlled at about 145 °C; The temperature at the top of the tower is ≤195℃, and the vacuum degree reaches -0.1Mpa. When it is necessary to reduce the temperature at the top of the tower, turn on the cooling water at the top of the tower, and control the temperature of the hot water tank on the top to be 55-60℃; observe the reception and liquid level of the finished product receiving kettle, Control the temperature of the finished product receiving kettle material between 55 and 65 °C. When the content in the distillation kettle is low, make preparations for feeding the slag kettle; when the shift is handed over, slowly open the vacuum valve of the standby receiving kettle until the vacuum balances. After that, open the material receiving valve of the standby receiving kettle, and close the vacuum valve and material receiving valve of the in-use kettle.

2. the preparation method of a kind of benzophenone according to claim 1, is characterized in that: described step (1) catalyst is phosphotungstic acid.

3. The role of spirocyclic indolones in the treatment of lung cancer based on aryloxy bifunctionalization of furan and indole.