CN104530065A - 1-N acyl substituent indolone derivative application - Google Patents

Abstract

The invention belongs to the technical field of drug synthesis and relates to the application of novel 1-N acyl substituted indolinone derivatives. The present invention uses 4-bromoaniline as a starting material to obtain 1-N acyl substituted indolinone derivatives with potential biological activity for the first time through oxime formation, cyclization, acetal protection and N-alkylation reactions. It has good prospects in the field of anti-tumor.

Description

Application of 1-N acyl substituted indolinone derivatives

technical field

The invention belongs to the field of compound synthesis, and in particular relates to indolinone derivatives and their synthesis methods and applications.

technical background

Isatin (isatin), also known as indole quinone, indole quinone has various good biological activities, such as anticonvulsant activity, antiepileptic activity, antidepressant activity, anxiolytic activity, antiaging activity, antitumor activity, antibacterial activity etc., which are widely studied in the research, improvement and optimization of various drugs. It is an important natural product widely distributed in animals, plants and human body. Isatin and its derivatives have a variety of biological activities. Isatin can be synthesized as an industrial product in large quantities at present, and is a relatively cheap raw material. Its 1, 2, 3 positions and benzene ring can undergo various types of chemical reactions, which provide a broad space for the synthesis of its derivatives. Therefore, the current organic synthesis of isatin or isatin and its derivatives The research on the synthesis and activity of is very active.

Contents of the invention

The invention provides a 1-N acyl substituted indolinone derivative and its synthesis method and application.

The specific technical scheme is as follows:

1-N acyl substituted indolinone derivatives, the structure is as follows: X represents any of acyl groups.

X is any of 4-chlorobenzoyl, benzoyl, 4-trifluoromethylbenzoyl, 4-methylbenzoyl, 4-fluorobenzoyl, and 2-naphthoyl; R is hydrogen or bromine.

The corresponding compounds are:

a) 1-(4-chlorobenzoyl)-(3,3-acetal)-5 bromoindolinone

b) 1-benzoyl-(3,3-acetal)-5 bromoindolinone

c) 1-(4-trifluoromethylbenzoyl)-(3,3-acetal)-5 bromoindolinone

d) 1-(4-methylbenzoyl)-(3,3-acetal)-5 bromoindolinone

e) 1-(4-fluorobenzoyl)-(3,3-acetal)-5 bromoindolinone

f) 1-(2-naphthoyl)-(3,3-acetal)-5 bromoindolinone

The synthesis method of the above-mentioned 1-N acyl substituted indolinone derivatives comprises the following steps: using 4-bromoaniline as a starting material, through oxime formation, cyclization, acetal protection, and N-alkylation to obtain the final product 1 -N acyl substituted indolinone derivatives.

The specific synthetic technical route is as follows:

The present invention also relates to the application of the aforementioned 1-N acyl substituted indolinone derivatives in the preparation of antitumor, antiviral, or neuroprotective drugs.

The invention provides 1-N acyl substituted indolinone derivatives and their synthesis method and application. The synthesis method is reliable and simple.

Description of drawings

Fig. 1 Example 1 result figure.

Fig. 2 embodiment 2 result figure.

Fig. 3 embodiment 3 result figure.

Fig. 4 embodiment 4 result figure.

Fig. 5 embodiment 5 result figure.

Fig. 6 embodiment 6 result figure.

Fig. 7 embodiment 7 result figure.

Fig. 8 embodiment 8 result figure.

Detailed ways

Example 1

5-Bromoindoledione

Take 10g (0.058mol) of 4-bromoaniline into a 500mL round bottom flask, add 250 mL of water, add 63.56g (0.452mol) of anhydrous sodium sulfate and 13.24g (0.191mol) of hydroxylamine hydrochloride under stirring, and then add 10 mL of 2 mol/L hydrochloric acid solution, stirred at room temperature for 5 minutes, and finally added 10.6 g (0.116 mol) of chloral hydrate. The reaction mixture was stirred at room temperature for 15 minutes, and then reacted at 90° C. for 2 hours. After 2 hours of reaction, TLC detected that the starting material disappeared, then cooled at room temperature, filtered with suction, and dried in vacuo to obtain 13.4 g of a yellow solid.

Take 40mL of concentrated sulfuric acid and add it to a 100mL round bottom flask, slowly add 13.4g of yellow solid into the concentrated sulfuric acid at 50°C, and react at 65°C for 30min after complete addition. After the reaction was completed, it was cooled to room temperature, and then the reaction mixture was poured into an ice-water mixture, stirred for 30 minutes, filtered with suction to obtain a red solid, and dried in a vacuum oven to obtain 11.4 g of 5-bromoindoledione 84%. It is a red solid.

¹ H NMR (DMSO 400 MHz) δ: 11.137 (1H, s), 7.757-7.730 (1H, t), 7.666-7.661 (1H, d), 6.891-6.870 (1H, d).

See Figure 1 for the specific spectrum.

Example 2

(3,3-Acetal)-5-bromoindolinone

Take 10.0g (0.044mol) of 5-bromoindoledione and put it into a 250mL round bottom flask, add 125mL toluene, then add 13.36g (0.221mol) of ethylene glycol and 1.26g (0.07mol) of p-toluenesulfonic acid ). Use a water separator to react at 130°C for 6 hours. After 6 hours of reaction, TLC detects that the raw materials disappear, cool to room temperature, add 50mL of water, then extract with ethyl acetate (100mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and reduce pressure Rotate off the solvent, petroleum ether: ethyl acetate = 10:1 200-300 mesh silica gel column purification. Obtain (3,3-acetal)-5-bromoindolinone 11.0g 91.6%.

¹ H-NMR(CDCl ₃ 400 MHz)δ : 8.126(1H,s),7.190-7.125(2H,t),6.776-6.754(1H,t),4.587-4.554(2H,t),4.460-4.27( 2H, t).

The specific spectrum is shown in Figure 2.

Example 3

1-(4-Chlorobenzoyl)-(3,3-acetal)-5-bromoindolinone

Dissolve 0.50 g (1.85 mmol) of (3,3-dialdehyde)-5-bromoindolinone in dry dichloromethane, add 0.37 g (7.40 mmol) of triethylamine under ice cooling, and stir for 5 min Finally, 0.38 g (2.20 mmol) of p-chlorobenzoyl chloride was added dropwise, reacted at room temperature for 4 h, and after TLC detected that the reaction was complete, 15 mL of water was added to the reaction mixture, extracted 3 times with dichloromethane, and the combined organic phases were dried. Use petroleum ether: ethyl acetate = 10:1, 200 mesh silica gel column chromatography to obtain 1-(4-chlorobenzoyl)-(3,3-acetal)-5 bromoindolinone, which is white Solid, yield 54%.

¹ H NMR (CDCl ₃ 400 MHz): δ/ppm 4.390-4.356(m, 2H), 4.534-4.501 (m, 2H), 7.490-7.468 (d, 2H), 7.683-7.632 (m, 4H), 7.837 -7.814 (d, 1H).

See Figure 3 for the specific spectrum.

Example 4

1-Benzoyl-(3,3-acetal)-5-bromoindolinone

Dissolve 0.50 g (1.85 mmol) of (3,3-dialdehyde)-5-bromoindolinone in dry dichloromethane, add 0.37 g (7.40 mmol) of triethylamine under ice cooling, and stir for 5 min Finally, 0.31 g (2.20 mmol) of benzoyl chloride was added dropwise, and reacted at room temperature for 4 h. After TLC detected that the reaction was complete, 15 mL of water was added to the reaction mixture, extracted 3 times with dichloromethane, and the combined organic phases were dried and washed with petroleum Ether: ethyl acetate = 10:1, purified by 200 mesh silica gel column chromatography to obtain 1-benzoyl-(3,3-acetal)-5 bromoindolinone as a white solid with a yield of 60%.

¹ H NMR (CDCl ₃ 400 MHz): δ/ppm 4.387-4.365 (m, 2H), 4.539-4.517 (m, 2H), 7.528-7.502 (t, 2H), 7.655-7.632 (m, 3H), 7.749 -7.735 (t, 2H),7.850-7.835 (d, 1H).

The specific spectrum is shown in Figure 4.

Example 5

1-(4-Trifluoromethylbenzoyl)-(3,3-acetal)-5-bromoindolinone

Dissolve 0.50 g (1.85 mmol) of (3,3-dialdehyde)-5-bromoindolinone in dry dichloromethane, add 0.37 g (7.4 mmol) of triethylamine under ice-cooling, and stir for 5 min Finally, 0.46 g (2.2 mmol) of 4-trifluoromethylbenzoyl chloride was added dropwise, and reacted at room temperature for 4 h. After TLC detected that the reaction was complete, 15 mL of water was added to the reaction mixture, extracted 3 times with dichloromethane, and combined The organic phase was dried, purified by petroleum ether:ethyl acetate=10:1, 200 mesh silica gel column chromatography to obtain 1-(4-trifluoromethylbenzoyl)-(3,3-acetal)-5 Bromoindolinone is a white solid with a yield of 55%.

¹ H NMR (CDCl ₃ 400 MHz): δ/ppm 4.385-4.351(m, 2H), 4.512-4.479 (m, 2H), 7.665-7.642 (t, 2H), 7.812-7.748 (m, 4H), 7.926 -7.902 (m, 1H).

The specific spectrum is shown in Figure 5.

Example 6

1-(4-methylbenzoyl)-(3,3-acetal)-5 bromoindolinone

Dissolve 0.50 g (1.85 mmol) of (3,3-dialdehyde)-5-bromoindolinone in dry dichloromethane, add 0.37 g (7.40 mmol) of triethylamine under ice cooling, and stir for 5 min Finally, 0.34 g (2.20 mmol) of p-toluyl chloride was added dropwise, and reacted at room temperature for 4 h. After TLC detected that the reaction was complete, 15 mL of water was added to the reaction mixture, extracted 3 times with dichloromethane, and the combined organic phases were dried. , with petroleum ether: ethyl acetate=10:1, 200 mesh silica gel column chromatography purification, obtain 1-(4-methylbenzoyl)-(3,3-acetal)-5 bromoindolinone, It is a white solid with a yield of 65%.

¹ H NMR (CDCl ₃ 400 MHz): δ/ppm 2.482 (s, 2H), 4.382-4.349 (m, 2H), 4.545-4.512 (m, 2H), 7.316-7.295(d, 2H), 7.666-7.609 (m, 4H), 7.787-7.764(d, 1H).

The specific spectrum is shown in Figure 6.

Example 7

1-(4-fluorobenzoyl)-(3,3-acetal)-5 bromoindolinone

Dissolve 0.50 g (1.85 mmol) of (3,3-dialdehyde)-5-bromoindolinone in dry dichloromethane, add 0.37 g (7.40 mmol) of triethylamine under ice cooling, and stir for 5 min Finally, 0.35 g (2.2 mmol) of 4-fluorobenzoyl chloride was added dropwise, and reacted at room temperature for 4 h. After TLC detected that the reaction was complete, 15 mL of water was added to the reaction mixture, extracted 3 times with dichloromethane, and the organic phases were combined and dried. , with petroleum ether: ethyl acetate=10:1, 200 mesh silica gel column chromatography purification, get 1-(4-fluorobenzoyl)-(3,3-acetal)-5 bromoindolone, as White solid, yield 67%.

¹ H NMR (CDCl ₃ 400 MHz): δ/ppm 4.330-4.364(m, 2H), 4.458-4.492 (m, 2H), 7.623-7.648 (t, 2H), 7.725-7.788 (m, 4H), 7.886 -7.909 (d, 1H).

The specific spectrum is shown in Figure 7.

Example 8

1-(2-Naphthoyl)-(3,3-acetal)-5-bromoindolinone

Dissolve 0.50 g (1.85 mmol) of (3,3-dialdehyde)-5-bromoindolinone in dry dichloromethane, add 0.37 g (7.40 mmol) of triethylamine under ice cooling, and stir for 5 min Then add 0.43 g (2.20 mmol) of 2-naphthoyl chloride dropwise, react at room temperature for 4 h, after TLC detects that the reaction is complete, add 15 mL of water to the reaction mixture, extract 3 times with dichloromethane, combine the organic phases to dry, Purified by petroleum ether:ethyl acetate=10:1, 200 mesh silica gel column chromatography to obtain 1-(2-naphthoyl)-(3,3-acetal)-5 bromoindolone as a white solid , yield 51%.

¹ H NMR (CDCl ₃ 400 MHz): δ/ppm 4.230-4.258(m, 2H), 4.289-4.347 (m, 2H), 7.239-7.242 (d, 3H), 7.497-7.535 (m, 3H), 7.592 -7.677 (m, 1H), 7.894-7.914(m, 2H), 7.985-8.157 (m, 1H).

The specific spectrum is shown in Figure 8.

Embodiment 9 This test of inhibiting tumor cell growth activity

IC50 is the half-inhibition rate, and the standard curve is an S-shaped curve. IC50 is the 50% inhibitory concentration, that is, the concentration corresponding to when the cell viability is half of the control sample. The lower the half inhibition, the higher the toxicity of the drug to the cells.

Take the following compound solutions:

a) 1-(4-chlorobenzoyl)-(3,3-acetal)-5 bromoindolinone; b) 1-benzoyl-(3,3-acetal)-5 bromoindolinone Indolinone; c) 1-(4-trifluoromethylbenzoyl)-(3,3-acetal)-5 bromoindolinone; d) 1-(4-methylbenzoyl)-( 3,3-Acetal)-5-bromoindolinone; e) 1-(4-Fluorobenzoyl)-(3,3-Acetal)-5-bromoindolinone; f) 1-(2 -naphthoyl)-(3,3-acetal)-5 bromoindolinone; , adjusted to an appropriate concentration for later use.

K562 and HePG2 were taken as cells to be tested, and the above compound solution was added to determine the IC ₅₀ value of the cells according to conventional methods. The result is as follows:

The results show that the 1-N acyl substituted indolinone derivatives of the present invention have a good effect of inhibiting the growth of human liver cancer cells HePG2 and K562 cells.

Example 9

Will a) 1-(4-chlorobenzoyl)-(3,3-acetal)-5-bromoindolinone; b) 1-benzoyl-(3,3-acetal)-5-bromoindolinone; Indolinone; c) 1-(4-trifluoromethylbenzoyl)-(3,3-acetal)-5 bromoindolinone; d) 1-(4-methylbenzoyl)- (3,3-Acetal)-5-Bromoindolinone; e) 1-(4-Fluorobenzoyl)-(3,3-Acetal)-5-Bromoindolinone; f) 1-( 2-naphthoyl)-(3,3-acetal)-5 bromoindolinone;

Commonly used drug excipients are added respectively to make conventional drug tablets.

Claims (1)

1. The application of 1-N acyl substituted indolinone derivatives in the preparation of antitumor drugs; the structure of the 1-N acyl substituted indolinone derivatives is as follows: , X represents any one of 4-chlorobenzoyl, benzoyl, 4-trifluoromethylbenzoyl, 4-methylbenzoyl, 4-fluorobenzoyl, or 2-naphthoyl.