CN115960085A - Preparation method of fluoro-oxindole heterocyclic compound - Google Patents

Abstract

The invention relates to a preparation method of a fluorooxindole heterocyclic compound, which adopts a cheap and small-dose cerium catalyst to synthesize a series of fluorooxindole heterocyclic compounds by a mild and efficient photo-promoted cerium catalytic method. Compared with the traditional process for synthesizing the 3-fluorooxoindole heterocyclic ring, the process has the advantages that the cerium chloride and the N-fluorobisbenzenesulfonamide which are cheap and efficient are used as the catalyst and the fluorination reagent, so that the use of precious metals is avoided, the metal consumption is reduced, the reaction condition is milder, economic and efficient, and the industrialization possibility of a reaction system is promoted; the coupling reaction is promoted by utilizing visible light, so that the use of strong acid in the traditional coupling reaction is avoided, and the method is more environment-friendly; 3- (3-fluoro-2-oxoindol-3-yl) -quinolinone compounds with different substituents are efficiently expanded, a reaction system has better functional group compatibility and provides higher yield, and the yield of a target product can reach more than 90%.

Description

A kind of preparation method of fluorooxindole heterocyclic compound

technical field

The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of fluorinated oxindole heterocyclic compounds.

Background technique

Oxindole heterocyclic compounds widely exist in natural products and important drug molecular structures. Their unique biological properties have attracted much attention in the field of medicinal chemistry and have been widely used in the treatment of diseases, such as anti-neurological disorders, anti-stroke and Drugs such as progesterone receptor modulators.

The traditional methods for preparing 3-fluoroindole derivatives can be mainly divided into two types. One is to perform fluorine oxidation or nucleophilic fluorination on indole or oxindole derivatives respectively. This method requires relatively difficult to obtain Substrates such as 2-hydroxymethylindole and spirocyclic epoxyindole are used as substrates, and dangerous fluorinated reagents such as ammonium hydrofluoride are used as fluorine sources, and even additional oxidants and bases are added to promote the reaction , the reaction conditions are relatively harsh and the steps are complicated; another commonly used method uses malonamide or diazoacetamide which is difficult to obtain as a cyclization substrate, and adds expensive organometallic complexes and other additives to promote cyclization reaction, thus increasing the preparation cost and environmental burden, it is not suitable for industrialization. The above traditional preparation methods have significantly reduced their practicability due to their higher preparation costs, cumbersome synthesis steps, lower safety and more waste. Therefore, it is necessary to develop an efficient, environmentally friendly and economical fluorinated The preparation method of oxindole heterocyclic compounds, especially 3-fluorooxindole derivatives, is better applicable to the field of practical application.

Contents of the invention

In order to overcome the deficiencies in the prior art, the present invention provides a kind of fluorooxindole heterocyclic compound (3-(3-fluoro-2-oxoindol-3-yl) with simple and convenient operation and high efficiency - the preparation method of quinolinone derivatives).

The technical scheme adopted in the present invention is:

A preparation method of fluoroindole heterocyclic compound, the structural formula of the fluoroindole heterocyclic compound is as shown in (I):

Wherein, R ₁ is any one of H, methyl, cyclohexylmethyl, propargyl; R ₂ is selected from any one of the following groups: H, bromine substituted at the 5-position of indole, cyano And an ester group substituted at the 6-position of indole; _R3 is selected from any one of the following groups: H, methyl, benzyl; _R4 is any one of chlorine and bromine substituted at the 6-position of H, quinolinone kind;

The preparation method of the fluorooxindole heterocyclic compound comprises the following steps:

(1) preparation of structural formula such as compounds shown in (II);

(2) preparation of structural formula such as compounds shown in (III);

(3) Add the compound shown in the structural formula (II), the compound shown in the structural formula (III), and the cerium catalyst into the reaction vessel, add the solvent, and stir the reaction under blue light irradiation at room temperature; then add N-fluorobisbenzenesulfonate Amide, continue stirring and reacting under the condition of 35～65 ℃; Obtain the product shown in structural formula (I).

The present invention prepares fluorinated oxindole heterocyclic compound (3-(3-fluoro-2-oxoindol-3-yl)-quinolinone derivatives) with light-promoted cerium catalysis, and the reaction process is as follows: :

Preferably, R ₁ is methyl or cyclohexylmethyl; R ₂ is H or bromine substituted at the 5-position of indole; R ₃ is methyl; R ₄ is H or bromine substituted at the 6-position of quinolinone.

Preferably, the cerium catalyst is anhydrous cerium chloride.

Preferably, the solvent is acetonitrile or dichloroethane.

Preferably, the molar ratio of the compound represented by the structural formula (II), the compound represented by the structural formula (III), N-fluorobisbenzenesulfonamide, and the cerium catalyst is 1:1.1:1.5:0.005-0.01.

Preferably, the temperature for continuing to stir the reaction is 50°C.

Preferably, after the reaction is completed, the solvent is spin-dried, recrystallized with a mixed solution of ethanol and water, then suction filtered, washed three times with a mixed solution of petroleum ether/ethyl acetate as a detergent, and vacuum-dried to obtain the product.

The preparation method of 3-(3-fluoro-2-oxoindol-3-yl)-quinolinone derivatives provided by the present invention is scientific and reasonable, adopts cheap and low-dose cerium catalyst, and is mild and efficient A series of 3-(3-fluoro-2-oxoindol-3-yl)-quinolinone derivatives were synthesized by light-promoted cerium-catalyzed method.

The beneficial effects of the present invention are:

(1) Using cheap and efficient cerium chloride and N-fluorobisbenzenesulfonamide as catalysts and fluorinating reagents, compared with the traditional synthesis of 3-fluoroindole heterocycles, the use of noble metals is avoided, and The amount of metal used is reduced, the reaction conditions are milder, economical and efficient, and the possibility of industrialization of the reaction system is promoted;

(2) Using visible light to promote the coupling reaction, avoiding the use of strong acid in the traditional coupling reaction, and being more environmentally friendly;

(3) Efficiently expanded 3-(3-fluoro-2-oxoindol-3-yl)-quinolinone compounds with different substituents, the reaction system has better functional group compatibility and provides higher Yield, the yield of the target product can be as high as more than 90%.

Description of drawings

Fig. 1 is the NMR of 3-(3-fluoro-1-cyclohexylmethyl-2-oxoindol-3-yl)-1-methylquinolin-2(1H)-one prepared in Example 1 Hydrogen Spectrum.

Detailed ways

The present invention will be further described below in conjunction with specific examples, but the protection scope of the present invention is not limited thereto. Those skilled in the art can and should know that any simple changes or substitutions based on the essence and spirit of the present invention shall fall within the scope of protection required by the present invention.

Example 1

Preparation of N-cyclohexylmethylindole (R in structural formula (II) ₁ is cyclohexylmethyl, R ₂ is H)

Add respectively indole (13.2mmol, 1.55g) in 50mL round bottom flask, potassium hydroxide (46.2mmol, 2.60g), 15mL N,N-dimethylformamide (DMF), stir under ice bath, then A DMF solution of (bromomethyl)cyclohexane (15.84 mmol, 2.80 g) was added dropwise to the round bottom flask, and after the addition was completed, the reaction was continued at room temperature for 3 hours, and the reaction was detected by TLC. After the reaction was completed, the reaction solution was washed with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with brine, the organic phase was separated, dried, spin-dried, and extracted with petroleum ether and ethyl acetate (80:1 ) ratio is that the eluent is purified through the column, and N-cyclohexylmethylindole is obtained after drying.

Preparation of N-methylquinoxalinone ( _R in structural formula (III) for methyl, _R for H)

Add respectively 2-hydroxyquinoxalinone (12mmol, 1.75g), potassium carbonate (24mmol, 3.31g), 15mL N,N-dimethylformamide (DMF) in 100mL round bottom flask, stir under ice bath , then dropwise the DMF solution of iodomethane (14.4mmol, 2g) in the round bottom flask, continue to react at room temperature for 6 hours after the dropwise addition, and the reaction is detected by TLC. After the reaction was completed, the reaction solution was washed with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was washed with brine, the organic phase was separated, and spin-dried to obtain the crude product, which was then washed with ethyl acetate/petroleum ether (1 : 4) carry out recrystallization to obtain purer N-methylquinoxalinone.

The preparation of 3-(3-fluoro-1-cyclohexylmethyl-2-oxoindol-3-yl)-1-methylquinolin-2(1H)-ketone ( _R in the structural formula (I) is Cyclohexylmethyl, _R2 is H, _R3 is methyl, _R4 is H)

N-cyclohexylmethylindole (0.2mmol, 42.7mg), N-methylquinoxalinone (0.22mmol, 35.2mg), anhydrous cerium chloride (0.001mmol, 0.25mg ), 3mL of acetonitrile, and reacted for 1 hour at room temperature under blue light irradiation; then slowly added N-fluorobisbenzenesulfonamide (0.3mmol, 94.6mg) into the reaction system, and continued the reaction at 50°C for 3h, and the reaction was performed by TLC detection. After the reaction is complete, spin dry the acetonitrile, add ethanol to dissolve the mixture, slowly add water dropwise until the reaction solution is gradually cloudy, cool down to 0°C and continue stirring for 20 minutes to separate the material, filter, and use a mixture of petroleum ether/ethyl acetate (3/1) The filter cake was washed three times with the solution, and vacuum-dried to obtain the target product 3-(3-fluoro-1-cyclohexylmethyl-2-oxoindol-3-yl)-1-methylquinolin-2(1H)-one , the yield was 95%.

The structural characterization of 3-(3-fluoro-1-cyclohexylmethyl-2-oxoindol-3-yl)-1-methylquinolin-2(1H)-one NMR data is shown in Figure 1 : ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.04 (dd, J = 8.1, 1.5Hz, 1H), 7.76 (ddd, J = 8.6, 7.3, 1.6Hz, 1H), 7.64 (d, J = 8.5Hz, 1H), 7.54–7.45(m, 2H), 7.27–7.21(m, 2H), 7.02(t, J＝7.5Hz, 1H), 3.61(dd, J＝7.0, 2.0Hz, 2H), 3.57(s,3H),1.87(dt,J＝12.4,3.5Hz,2H),1.80–1.69(m,3H),1.66–1.60(m,1H),1.26–1.17(m,3H),1.08( tt, J=11.9, 6.4Hz, 2H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ152.12, 146.32, 133.70, 132.56, 132.24, 132.13, 130.41, 125.04, 124.70, 124.32, 123.07, 115.6 9,110.48,46.43 , 36.41, 30.69, 29.40, 26.39, 25.81; ¹⁹ F NMR (471MHz, DMSO-d ₆ ) δ-159.67.

The analysis results showed that the obtained target product was correct.

Example 2

Using dichloroethane instead of acetonitrile, the yield of the target product was 90%.

Example 3

Using N,N-dimethylformamide (DMF) instead of acetonitrile, the yield of the target product was 72%.

Example 4

Preparation of 5-bromo-1-methyl-1H-indole (R in structural formula (II) ₁ is a methyl group, R ₂ is bromine substituted at the 5-position of indole)

Add 5-bromo-1H-indole (13.2mmol, 2.6g), potassium hydroxide (46.2mmol, 2.60g), 15mL N,N-dimethylformamide (DMF) respectively in 50mL round bottom flask, in After stirring in an ice bath, a DMF solution of iodomethane (15.84 mmol, 2.2 g) was added dropwise to the round bottom flask. After the dropwise addition, the reaction was continued at room temperature for 3 hours, and the reaction was detected by TLC. After the reaction was completed, the reaction solution was washed with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with brine, the organic phase was separated, dried, spin-dried, and extracted with petroleum ether and ethyl acetate (80:1 ) ratio is that the eluent is purified through the column, and 5-bromo-1-methyl-1H-indole is obtained after drying.

The preparation of 3-(5-bromo-3-fluoro-1-methyl-2-oxoindoline-3-yl)-1-methylquinolin-2(1H)-ketone (in structural formula (I) R ₁ is methyl, R ₂ is bromine substituted at the 5-position of indole, R ₃ is methyl, R ₄ is H)

Add 5-bromo-1-methyl-1H-indole (0.2mmol, 42mg), N-methylquinoxalinone (0.22mmol, 35.2mg), anhydrous cerium chloride (0.002 mmol, 0.25 mg), 3 mL of acetonitrile, and react under blue light irradiation at room temperature for 3 hours; then slowly add N-fluorobisbenzenesulfonamide (0.3 mmol, 94.6 mg) into the reaction system, and continue the reaction at 50 ° C for 3 h , the reaction was detected by TLC. After the reaction is complete, spin dry the acetonitrile, add ethanol to dissolve the mixture, slowly add water dropwise until the reaction solution is gradually cloudy, cool down to 0°C and continue to stir for 20 minutes to separate the material, filter, and use a mixture of petroleum ether/ethyl acetate (3/1) The filter cake was washed three times with the solution, and vacuum-dried to obtain the target product 3-(5-bromo-3-fluoro-1-methyl-2-oxoindoline-3-yl)-1-methylquinoline-2(1H )-ketone, the yield is 92%.

Structural characterization of 3-(5-bromo-3-fluoro-1-methyl-2-oxoindolin-3-yl)-1-methylquinolin-2(1H)-one NMR data: ¹ H NMR (400MHz, Chloroform-d) δ8.14 (dd, J = 8.0, 1.5Hz, 1H), 7.69 (ddd, J = 8.6, 7.2, 1.5Hz, 1H), 7.57 (dt, J = 8.3, 2.0 Hz,1H),7.53–7.46(m,1H),7.43–7.36(m,2H),6.86(dd,J＝8.3,1.2Hz,1H),3.64(d,J＝1.6Hz,3H),3.37 (s,3H); ¹³ C NMR(101MHz,Chloroform-d)δ169.64,152.36,151.51,145.18,145.13,134.82,134.79,133.37,132.56,131.85,131.16,127.95,125.95,124. 51,115.43,115.39,113.91, 110.53, 90.34, 29.09, 26.79; ¹⁹ F NMR (376MHz, Chloroform-d) δ-163.51.

The analysis results showed that the obtained target product was correct.

Example 5

The preparation of N-methylindole (R in structural formula (II) ₁ is a methyl group, R ₂ is H)

Add respectively indole (13.2mmol, 1.55g) in 50mL round bottom flask, potassium hydroxide (46.2mmol, 2.60g), 15mL N,N-dimethylformamide (DMF), stir under ice bath, then A DMF solution of iodomethane (15.84 mmol, 2.25 g) was added dropwise to the round bottom flask, and after the dropwise addition was completed, the reaction was continued at room temperature for 3 hours, and the reaction was detected by TLC. After the reaction was completed, the reaction solution was washed with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with brine, the organic phase was separated, dried, spin-dried, and extracted with petroleum ether and ethyl acetate (80:1 ) ratio is that the eluent is purified through the column, and N-methylindole is obtained after drying.

Preparation of 6-bromo-1-methylquinolin-2(1H)-one (R in structural formula (III) ₃ is methyl, R ₄ is bromine substituted at the 6-position of quinolinone)

Add 6-bromoquinolin-2 (1H)-ketone (12mmol, 2.7g) respectively in 100mL round bottom flask, potassium carbonate (24mmol, 3.31g), 15mL N,N-dimethylformamide (DMF), After stirring in an ice bath, a DMF solution of iodomethane (14.4 mmol, 2 g) was added dropwise to the round bottom flask. After the dropwise addition, the reaction was continued at room temperature for 6 hours, and the reaction was detected by TLC. After the reaction was completed, the reaction solution was washed with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was washed with brine, the organic phase was separated, and spin-dried to obtain the crude product, which was then washed with ethyl acetate/petroleum ether (1 :3) recrystallization is carried out to obtain relatively pure 6-bromo-1-methylquinolin-2 (1H)-one.

The preparation of 6-bromo-3-(3-fluoro-1-methyl-2-oxoindoline-3-yl)-1-methylquinolin-2(1H)-ketone (in structural formula (I) R ₁ is methyl, R ₂ is H, R ₃ is methyl, R ₄ is bromine substituted at the 6-position of quinolinone)

Add N-methylindole (0.2mmol, 26.2mg), 6-bromo-1-methylquinolin-2(1H)-one (0.22mmol, 52.6mg) into a 25mL reaction flask, anhydrous chlorination Cerium (0.002mmol, 0.25mg), 3mL of acetonitrile, reacted at room temperature under blue light irradiation for 3 hours; then slowly added N-fluorobisbenzenesulfonamide (0.3mmol, 94.6mg) into the reaction system, at 50°C The reaction was continued for 3h, and the reaction was detected by TLC. After the reaction is complete, spin dry the acetonitrile, add ethanol to dissolve the mixture, slowly add water dropwise until the reaction solution is gradually cloudy, cool down to 0°C and continue stirring for 20 minutes to separate the material, filter, and use a mixture of petroleum ether/ethyl acetate (3/1) The filter cake was washed three times with the solution, and vacuum-dried to obtain the target product 6-bromo-3-(3-fluoro-1-methyl-2-oxoindoline-3-yl)-1-methylquinoline-2(1H )-ketone, the yield is 93%.

Structural characterization of 6-bromo-3-(3-fluoro-1-methyl-2-oxoindolin-3-yl)-1-methylquinolin-2(1H)-one NMR data: ¹ H NMR (400MHz, Chloroform-d) δ8.30(s, 1H), 7.76(d, J=8.8Hz, 1H), 7.46(t, J=7.7Hz, 1H), 7.25(d, J=8.9Hz , 2H), 7.05(t, J=7.5Hz, 1H), 6.97(d, J=7.8Hz, 1H), 3.60(s, 3H), 3.38(s, 3H); ¹³ C NMR (101MHz, Chloroform- d) δ153.78, 152.05, 134.32, 133.40, 133.26, 132.51, 132.28, 132.25, 124.79, 123.90, 123.72, 123.07, 123.04, 116.97, 115.29, 109.13, 92.75, 2 9.20, 26.70; ¹⁹ F NMR (376MHz, Chloroform-d) δ-163.49.

The analysis results showed that the obtained target product was correct.

Example 6

The preparation of N-propargylquinoxalinone (in the structural formula (II) _{, R1} is propargyl, _R2 is H)

Add respectively 2-hydroxyquinoxalinone (12mmol, 1.75g), potassium carbonate (24mmol, 3.31g), 15mL N,N-dimethylformamide (DMF) in 100mL round bottom flask, stir under ice bath , Then in the round bottom flask, dropwise add the DMF solution of 3-bromopropyne (14.4mmol, 1.71g), continue to react at room temperature for 6 hours after the dropwise addition, and the reaction is detected by TLC. After the reaction is completed, the reaction solution is washed with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase is washed with brine, the organic phase is separated, dried, and spin-dried to obtain the crude product, which is then washed with ethyl acetate/petroleum Ether (1:4) was recrystallized to obtain relatively pure N-propargylquinoxalinone.

The preparation of 3-(3-fluoro-1-methyl-2-oxoindol-3-yl)-1-propargylquinoxaline-2(1H)-ketone ( _R in the structural formula (I) is propargyl, _R2 is H, _R3 is methyl, _R4 is H)

Add N-methylindole (0.2mmol, 26.2mg), N-propargylquinoxalinone (0.22mmol, 40.5mg) and anhydrous cerium chloride (0.001mmol, 0.25mg) respectively in a 25mL reaction tube , 3mL acetonitrile, reacted under blue light irradiation at room temperature for 1 hour; then slowly added N-fluorobisbenzenesulfonamide (0.3mmol, 94.6mg) into the reaction system, and continued the reaction at 50°C for 3h, and the reaction was detected by TLC . After the reaction is complete, spin dry the acetonitrile, add ethanol to dissolve the mixture, slowly add water dropwise until the reaction solution is gradually cloudy, cool down to 0°C and continue stirring for 20 minutes to separate the material, filter, and use a mixture of petroleum ether/ethyl acetate (3/1) The filter cake was washed three times with the solution, and vacuum-dried to obtain the target product 3-(3-fluoro-1-methyl-2-oxoindol-3-yl)-1-propargylquinoxaline-2(1H)-one , the yield was 92%.

The structural characterization of 3-(3-fluoro-1-methyl-2-oxoindol-3-yl)-1-propargylquinoxaline-2(1H)-one The NMR data are as follows: ¹ H NMR (400MHz, Chloroform-d) δ8.16(d, J=8.0Hz, 1H), 7.64(t, J=7.8Hz, 1H), 7.49–7.43(m, 2H), 7.38–7.31(m, 2H), 7.05(t, J＝7.5Hz, 1H), 6.97(d, J＝7.8Hz, 1H), 5.90–5.79(m, 1H), 4.85–4.79(m, 2H), 3.39(s, 3H ).

The analysis results showed that the obtained target product was correct.

It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present application, and these all belong to the protection scope of the present application.

Claims (7)

1. a preparation method of fluoroindole heterocyclic compound, characterized in that: the structural formula of said fluoroindole heterocyclic compound is as shown in (1):

Wherein, R ₁ is any one of H, methyl, cyclohexylmethyl, propargyl; R ₂ is selected from any one of the following groups: H, bromine substituted at the 5-position of indole, cyano And an ester group substituted at the 6-position of indole; _R3 is selected from any one of the following groups: H, methyl, benzyl; _R4 is any one of chlorine and bromine substituted at the 6-position of H, quinolinone kind; The preparation method of the fluorooxindole heterocyclic compound comprises the following steps: (1) preparation of structural formula such as compounds shown in (II);

(2) preparation of structural formula such as compounds shown in (III);

(3) Add the compound shown in the structural formula (II), the compound shown in the structural formula (III), and the cerium catalyst into the reaction vessel, add the solvent, and stir the reaction under blue light irradiation at room temperature; then add N-fluorobisbenzenesulfonate Amide, continue stirring and reacting under the condition of 35～65 ℃; Obtain the product shown in structural formula (I). 2. according to the preparation method of the described fluorinated oxygen indole heterocyclic compound of claim 1, it is characterized in that: R ₁ is methyl or cyclohexylmethyl; R ₂ is the bromine that H or indole 5 positions replace; R ₃ is methyl; R ₄ is H or bromine substituted at the 6-position of quinolinone. 3. The preparation method of fluoroindole heterocyclic compound according to claim 1, characterized in that: the cerium catalyst is anhydrous cerium chloride. 4. The preparation method of the fluorinated indole heterocyclic compound according to claim 1, characterized in that: the solvent is acetonitrile or dichloroethane. 5. according to the preparation method of the described fluorinated indole heterocyclic compound of claim 1, it is characterized in that: the compound shown in (II) of structural formula, the compound shown in (III) of structural formula, N-fluorobisbenzenesulfonic acid The molar ratio of the amide and the cerium catalyst is 1:1.1:1.5:0.005-0.01. 6. The method for preparing fluoroindole heterocyclic compounds according to claim 1, characterized in that: the temperature for continuing to stir and react is 50°C. 7. according to the preparation method of the described fluorinated oxindole heterocyclic compound of claim 1, it is characterized in that: after reaction is finished, spin dry solvent, carry out recrystallization with the mixed solution of ethanol and water, suction filtration subsequently, detergent Select the mixed solution of petroleum ether/ethyl acetate to wash three times, and vacuum-dry to obtain the product.

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