CN109020994A - A kind of benzothiophene spiral shell oxoindole derivative and its synthetic method and application - Google Patents

Abstract

The invention discloses a kind of formula (I) benzothiophene spiral shell oxoindole derivative and its synthetic methods, replace ketone as raw material using 3- diazonium Oxoindole, 2- thio-phenyl, withMolecular sieve is water absorbing agent, using rhodium acetate and chirality BINOL phosphoric acid as catalyst, in organic solvent, obtains benzothiophene spiral shell oxoindole derivative shown in formula (I) by single step reaction.Synthetic method of the invention has atom economy, highly selective, high yield advantage, and reaction condition is mild, safety easy to operate.There are two quaternary carbon centers for benzothiophene spiral shell oxoindole derivative tool of the present invention, can be used as important chemical industry and medicine intermediate, are widely applied in field of medicine and chemical technology, have very big application prospect.

Description

A kind of benzothiophene spirooxindole derivative and its synthesis method and application

technical field

The invention relates to the field of synthetic medicine and chemical industry, and mainly relates to a rapid and green benzothiophene spirooxindole derivative and its chemical synthesis method and application.

Background technique

Spirooxindole derivatives are ubiquitous structural units in natural products and pharmaceuticals. In the past few decades, a series of synthetic methods of spiroxindole rings have been developed, such as ring-forming reactions under the action of chiral ligands and metal catalysts, under the action of chiral ligands and metal catalysts [5+1 ] Cycloaddition reaction, Prins series reaction, multi-component reaction. The reported methods for the synthesis of spirooxindole derivatives have disadvantages such as harsh reaction conditions, use of air-sensitive reagents or transition metal catalysts, multi-step reactions, large amounts of chemical waste, time-consuming, and high cost, which are not conducive to spiro-oxindole derivatives. The application of oxindole ring derivatives in organic synthesis and its industrial synthesis, but there is no report on the synthesis method of benzothiophene spiro oxindole derivatives.

Contents of the invention

The present invention overcomes the above-mentioned defects of the prior art, and proposes a synthesis method of benzothiophene spirooxindole derivatives with short route, reliable reaction and simple operation. The invention uses 2-thiophenyl substituted ketone and 3-diazoindole as raw materials, and can prepare the benzothiophene spirooxindole derivative only through one-step reaction. Compared with the reported synthetic method of spirooxindole derivatives, the present invention uses cheap and easy-to-obtain compounds as raw materials, and has the advantages of mild reaction conditions, few reaction steps, fast reaction, low cost, less waste generated, and atom economy With high characteristics, the benzothiophene spirooxindole derivatives of the present invention have broad application prospects in the field of drug synthesis.

The present invention proposes a class of benzothiophene spirooxindole derivatives, the structure of which is shown in the following formula (I):

in,

R1 is hydrogen, alkoxy or halogen ^; R2 is alkyl; ^R3 is ^hydrogen , alkyl, alkoxy or halogen.

Preferably, R ¹ is hydrogen, C1-C10 alkoxy or halogen; R ² is C1-C10 alkyl; R ³ is hydrogen, C1-C10 alkyl, C1-C10 alkoxy or halogen.

Further preferably, R ¹ is hydrogen, methoxy, fluorine, chlorine, bromine; R ² is methyl, n-butyl; R ³ is hydrogen, methyl, methoxy, fluorine, chlorine, bromine.

Further preferably, R ¹ is hydrogen, 5-methoxy, 5-fluoro, 5-chloro, 5-bromo; R ² is methyl, n-butyl; R ³ is hydrogen, 5-methyl, 5-methyl Oxygen, 5-fluoro, 5-chloro, 5-bromo, 7-chloro.

Further preferably, R ¹ is hydrogen, 5-methoxy, 5-fluoro; R ² is methyl, n-butyl; R ³ is hydrogen, 5-methyl, 5-methoxy, 7-chloro.

Further preferably, the benzothiophene spirooxindole derivative includes the following structure:

The present invention also proposes a synthetic method of benzothiophene spirooxindole derivatives, which are substituted with 3-diazoindole shown in formula (2), 2-thiophenyl shown in formula (1) Ketones as raw materials, with Molecular sieve ( MS) is a water absorbing agent, with rhodium acetate and chiral BINOL phosphoric acid as a catalyst, in an organic solvent, the benzothiophene spirooxindole derivatives shown in the formula (I) are obtained through a one-step reaction. The equation of described reaction is as shown in formula (II):

Wherein, R1 is hydrogen, alkoxyl or halogen ^; R2 is alkyl; ^R3 is ^hydrogen , alkoxyl, alkyl or halogen.

Preferably, R ¹ is hydrogen, C1-C10 alkoxy or halogen; R ² is C1-C10 alkyl; R ³ is hydrogen, C1-C10 alkyl, C1-C10 alkoxy or halogen.

Further preferably, R ¹ is hydrogen, methoxy, fluorine, chlorine, bromine; R ² is methyl, n-butyl; R ³ is hydrogen, methyl, methoxy, fluorine, chlorine, bromine.

Further preferably, R ¹ is hydrogen, 5-methoxy, 5-fluoro, 5-chloro, 5-bromo; R ² is methyl, n-butyl; R ³ is hydrogen, 5-methyl, 5-methyl Oxygen, 5-fluoro, 5-chloro, 5-bromo, 7-chloro.

Further preferably, R ¹ is hydrogen, 5-methoxy, 5-fluoro; R ² is methyl, n-butyl; R ³ is hydrogen, 5-methyl, 5-methoxy, 7-chloro.

Further preferably, the benzothiophene spirooxindole derivative includes the following structure:

In a specific embodiment, the synthesis steps of the benzothiophene spirooxindole derivatives are as follows: 2-thiophenyl substituted ketone, rhodium acetate, chiral BINOL phosphoric acid, Molecular sieves are dissolved in organic solvents to prepare a mixed solution; 3-diazoindole compound is dissolved in an organic solvent to prepare a diazo compound solution; the diazo compound solution is added to the aforementioned mixed solution for reaction and purification to obtain high enantioselectivity Benzothiophene spirooxindole derivatives with high diastereoselectivity and high diastereoselectivity.

Wherein, the temperature of the reaction is -20°C-40°C; preferably, it is 0°C.

Wherein, the reaction time is 0.5h-24h; preferably, 1h.

Wherein, the organic solvent includes one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, tetrahydrofuran, etc.; preferably, it is dichloromethane.

Wherein, the structure of the chiral BINOL phosphoric acid is shown in the following formula (a),

Wherein, R is selected from 4-CF ₃ C ₆ H ₄ , anthracenyl, 2,4,6-(i-Pr) ₃ C ₆ H ₂ , SiPh ₃ , 3,5-(CF ₃ )C ₆ H ₃ ; Preferably, R is SiPh ₃ .

That is, the chiral BINOL phosphoric acid is R-4a, R-4b, R-4c, R-4d, R-4e, etc.; preferably, it is R-4d phosphoric acid.

Among them, with Molecular sieve is water absorbing agent; The molecular sieve charging amount is 50-100mg/mmol; Preferably, it is 100mg/mmol (based on the amount of 2-thiophenyl substituted ketone shown in formula (1));

Wherein, the molar ratio of 2-thiophenyl substituted ketone shown in formula (1), 3-diazoindole shown in formula (2), rhodium acetate, BINOL phosphoric acid is 1.0: (1.1-1.5): 0.01 :0.05; preferably, 1.0:1.1:0.01:0.05.

Wherein, the dosage ratio of the organic solvent to the 2-thiophenyl substituted ketone is 0.5mL-1mL: 1mmol; preferably, 0.5mL: 1mmol.

The inventive method preferably, 2-thiophenyl ketone, rhodium acetate, chiral BINOL phosphoric acid, Molecular sieves are dissolved in organic solvents to prepare a mixed solution; 3-diazoxindole compounds are dissolved in organic solvents to prepare 3-diazoxindole compound solutions; at 0°C, 3-diazoxindole compounds The solution was added to the aforementioned mixed solution while vigorously stirring to carry out the reaction.

The reaction mechanism of the inventive method is shown in the following formula (a), at first rhodium acetate reacts with diazo to generate a metal carbene intermediate, and the metal carbene is subjected to the electrophilic attack of sulfur to form a mercapto ylide; The benzothiophene spirooxindole product can be obtained.

In a specific embodiment, the synthetic method of benzothiophene spirooxindole derivative of the present invention comprises the following steps: by 2-thiophenyl substituted ketone: 3-diazoindole: rhodium acetate: chiral BINOL Phosphoric acid=1.0:1.1:0.01:0.05 (molar ratio), weigh raw materials. 2-thiophenyl ketone, rhodium acetate, chiral BINOL phosphoric acid, Molecular sieves are dissolved in organic solvents to prepare a mixed solution; diazo compounds are dissolved in organic solvents to prepare a diazo compound solution; at 0°C, add the diazo compound solution to the aforementioned mixed solution with a syringe pump; at the same time, stir vigorously; After the compound solution was added dropwise, the stirring was continued at room temperature for 30 minutes until the diazo compound was completely consumed; the crude product was subjected to column chromatography (using ethyl acetate:petroleum ether=1:20～1:10 as the eluent), The pure product formula (I) benzothiophene spirooxindole derivative is obtained.

The present invention also proposes the benzothiophene spirooxindole derivatives of formula (I) prepared according to the synthesis method of the present invention.

The present invention also proposes the application of the benzothiophene spirooxindole derivative of formula (I) in the preparation of anti-tumor drugs, and the tumors include colon cancer.

The benzothiophene spirooxindole derivative with two quaternary carbon centers represented by the formula (I) prepared by the present invention is an important chemical and pharmaceutical intermediate, widely used in the field of pharmaceutical and chemical industry, and has great application prospects. The preparation method of the benzothiophene spirooxindole derivative of the present invention uses cheap and easy-to-obtain compounds as raw materials, and has the advantages of mild reaction conditions, few reaction steps, fast reaction, low cost, less waste generated, simple and safe operation, and atom economy High, high selectivity (≥90:10), high yield (88%-96%) and other beneficial effects.

Description of drawings

FIG. 1 is a schematic diagram of ¹ H NMR of the product obtained in Example 1.

FIG. 2 is a schematic diagram of ¹³ C NMR of the product obtained in Example 1.

Figure 3 is a liquid phase diagram of the racemic product obtained in Example 1.

Figure 4 is a liquid phase diagram of the chiral product obtained in Example 1.

FIG. 5 is a schematic diagram of ¹ H NMR of the product obtained in Example 2.

FIG. 6 is a schematic diagram of ¹³ C NMR of the product obtained in Example 2.

Figure 7 is a liquid phase diagram of the racemic product obtained in Example 2.

Figure 8 is a liquid phase diagram of the chiral product obtained in Example 2.

FIG. 9 is a schematic diagram of ¹ H NMR of the product obtained in Example 3.

FIG. 10 is a schematic diagram of ¹³ C NMR of the product obtained in Example 3.

Figure 11 is the liquid phase diagram of the racemic product obtained in Example 3.

Figure 12 is a liquid phase diagram of the chiral product obtained in Example 3.

FIG. 13 is a schematic diagram of ¹ H NMR of the product obtained in Example 4.

FIG. 14 is a schematic diagram of ¹³ C NMR of the product obtained in Example 4.

FIG. 15 is a schematic diagram of ¹⁹ F NMR of the product obtained in Example 4.

Figure 16 is a liquid phase diagram of the racemic product obtained in Example 4.

Figure 17 is a liquid phase diagram of the chiral product obtained in Example 4.

FIG. 18 is a schematic diagram of ¹ H NMR of the product obtained in Example 5.

FIG. 19 is a schematic diagram of ¹³ C NMR of the product obtained in Example 5.

Figure 20 is a liquid phase diagram of the racemic product obtained in Example 5.

Figure 21 is a liquid phase diagram of the chiral product obtained in Example 5.

Fig. 22 is a schematic diagram of ¹ H NMR of the product obtained in Example 6.

Fig. 23 is a schematic diagram of ¹³ C NMR of the product obtained in Example 6.

Figure 24 is the liquid phase diagram of the racemic product obtained in Example 6.

Figure 25 is a liquid phase diagram of the chiral product obtained in Example 6.

Fig. 26 is a schematic diagram of ¹ H NMR of the product obtained in Example 7.

27 is a schematic diagram of ¹³ C NMR of the product obtained in Example 7.

Figure 28 is a liquid phase diagram of the racemic product obtained in Example 7.

Figure 29 is a liquid phase diagram of the chiral product obtained in Example 7.

30 is a schematic diagram of ¹ H NMR of the product obtained in Example 8.

Fig. 31 is a schematic diagram of ¹³ C NMR of the product obtained in Example 8.

Figure 32 is a liquid phase diagram of the racemic product obtained in Example 8.

Figure 33 is a liquid phase diagram of the chiral product obtained in Example 8.

Fig. 34 is a schematic diagram of ¹ H NMR of the product obtained in Example 9.

Fig. 35 is a schematic diagram of ¹³ C NMR of the product obtained in Example 9.

Fig. 36 is a schematic diagram of ¹⁹ F NMR of the product obtained in Example 9.

Figure 37 is a liquid phase diagram of the racemic product obtained in Example 9.

Figure 38 is a liquid phase diagram of the chiral product obtained in Example 9.

Fig. 39 is a schematic diagram of ¹ H NMR of the product obtained in Example 10.

40 is a schematic diagram of ¹³ C NMR of the product obtained in Example 10.

Figure 41 is a liquid phase diagram of the racemic product obtained in Example 10.

Figure 42 is a liquid phase diagram of the chiral product obtained in Example 10.

Fig. 43 is a schematic diagram of ¹ H NMR of the product obtained in Example 11.

Fig. 44 is a schematic diagram of ¹³ C NMR of the product obtained in Example 11.

Figure 45 is a liquid phase diagram of the racemic product obtained in Example 11.

Figure 46 is a liquid phase diagram of the chiral product obtained in Example 11.

47 is a schematic diagram of ¹ H NMR of the product obtained in Example 12.

48 is a schematic diagram of ¹³ C NMR of the product obtained in Example 12.

Figure 49 is a liquid phase diagram of the racemic product obtained in Example 12.

Figure 50 is a liquid phase diagram of the chiral product obtained in Example 12.

Figure 51 is the activity diagram of the chiral product obtained in Example 1.

Detailed ways

In conjunction with the following specific examples and accompanying drawings, the present invention is described in further detail, and the process, conditions, reagents, experimental methods, etc. of implementing the present invention, except for the content specifically mentioned below, are general knowledge and known in the art Common sense, the present invention is not particularly limited.

Example 1

With 2-mercaptoacetophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazoindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product with the structure shown as syn-3a. Yield 95%, dr value equal to 92:8, ee value equal to 96%. The ¹ H NMR schematic diagram of the product is shown in Figure 1, the ¹³ C NMR schematic diagram is shown in Figure 2, the racemic product liquid phase diagram is shown in Figure 3, and the chiral product liquid phase diagram is shown in Figure 4.

¹ H NMR (400MHz, CDCl ₃ ) δ7.36–7.18(m, 11H), 7.02(td, J=7.7, 1.1Hz, 1H), 6.73(d, J=7.9Hz, 1H), 5.03(d, J＝15.8Hz, 1H), 4.80(d, J＝15.7Hz, 1H), 3.66(s, 1H), 1.66(s, 3H); ¹³ C NMR(100MHz, CDCl3) δ176.29, 143.82, 143.18, 136.95, 135.22, 129.64, 129.30, 128.89, _127.75 , _127.16 , 126.16, 126.05, 126.00, _123.96 , 122.98, 122.94, 109.77, 86.69, 66.63, 43.97, 25.23; +Na] ⁺ :396.1034, found: 396.1051.HPLC (chiral IC column, wavelength equal to 254 nm, n-hexane/isopropanol=10:1, flow rate=1.0ml/min), t _major =27.94 minutes, t _minor = 20.85 minutes.

Example 2

With 2-mercaptoacetophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazo-5-methylindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product, whose structure is shown in formula syn-3b. Yield 90%, dr value equal to 92:8, ee value equal to 94%. The schematic diagram of ¹ H NMR of the product is shown in Figure 5, the schematic diagram of ¹³ C NMR is shown in Figure 6, the liquid phase diagram of the racemic product is shown in Figure 7, and the liquid phase diagram of the chiral product is shown in Figure 8.

¹ H NMR (400MHz, CDCl ₃ ) δ7.35–7.19(m, 9H), 7.13(d, J=1.6Hz, 1H), 7.01(dd, J=8.1, 1.6Hz, 1H), 6.62(d, J＝8.0Hz, 1H), 5.01(d, J＝15.7Hz, 1H), 4.79(d, J＝15.7Hz, 1H), 3.70(s, 1H), 2.28(s, 3H), 1.67(s, 3H)； ¹³ C NMR(100MHz,CDCl ₃ )δ176.25,143.89,140.73,136.98,135.30,132.62,130.00,129.26,128.85,127.69,127.13,126.78,126.01,125.97,123.93,122.90,109.53,86.58,66.67, 43.96, 25.23, 21.18; HRMS-ESI: calcd.for C ₂₄ H ₂₁ NO ₂ NaS[M+Na] ⁺ :410.1191, found: 410.1210.HPLC (chiral IC column, wavelength equal to 254 nm, n-hexane/isopropanol =10:1, flow rate=1.0 ml/min), t _major =33.06 minutes, t _minor =25.17 minutes.

Example 3

With 2-mercaptoacetophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazo-5-methoxyindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product, whose structure is shown in the formula syn-3c. Yield 92%, dr value equal to 90:10, ee value equal to 96%. The schematic diagram of ¹ H NMR of the product is shown in Figure 9, the schematic diagram of ¹³ C NMR is shown in Figure 10, the liquid phase diagram of the racemic product is shown in Figure 11, and the liquid phase diagram of the chiral product is shown in Figure 12.

¹ H NMR (400MHz, CDCl ₃ ) δ7.35–7.17 (m, 9H), 6.91 (s, 1H), 6.73 (d, J＝8.6Hz, 1H), 6.62 (d, J＝8.5Hz, 1H) , 5.00(d, J=15.7Hz, 1H), 4.77(d, J=15.7Hz, 1H), 3.84(s, 1H), 3.71(s, 3H), 1.65(s, 3H); ¹³ C NMR ( 100MHz,CDCl ₃ )δ175.91,156.06,143.71,137.01,136.47,135.27,129.32,128.89,127.74,127.57,127.17,126.06,123.98,122.95,113.80,113.54,110.12,86.60,66.91,55.80,44.05,25.03；HRMS -ESI: calcd.for C ₂₄ H ₂₁ NO ₃ NaS[M+Na] ⁺ :426.1140, found: 426.1149.HPLC (chiral IC column, wavelength equal to 254 nm, n-hexane/isopropanol=10:1, flow rate ＝1.0ml/min), t _major ＝47.04 minutes, t _minor ＝36.36 minutes.

Example 4

With 2-mercaptoacetophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazo-5-fluoroindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product, whose structure is shown in the formula syn-3d. Yield 91%, dr value equal to 92:8, ee value equal to 90%. The ¹ H NMR schematic diagram of this product is shown in Figure 13, its ¹³ C NMR schematic diagram is shown in Figure 14, its ¹⁹ F NMR schematic diagram is shown in Figure 15, and the liquid phase diagram of the racemic product is shown in Figure 16. The liquid phase diagram of the product is shown in Figure 17.

¹ H NMR (400MHz, CDCl ₃ ) δ7.37–7.20 (m, 9H), 7.06 (dd, J=8.1, 2.6Hz, 1H), 6.92 (t, J=8.8Hz, 1H), 6.64 (dd, ¹³ C NMR(100MHz,CDCl3)δ176.05,160.33,157.93,143.42,139.05,136.58,134.87,129.47,128.97,127.89,127.80,127.72,127.12,126.23,124.02,123.02,116.24,116.01,114.17,113.92,110.42,110.34, 86.77, 66.77, 44.10, 25.07; ¹⁹ FNMR (376MHz, CDCl ₃ ) δ-119.30; HRMS-ESI: calcd.for C ₂₃ H ₁₈ NO ₂ NaSF[M+Na] ⁺ :414.0940, found: 414.0960.HPLC (hand IC column, wavelength equal to 254 nm, n-hexane/isopropanol = 10:1, flow rate = 1.0 ml/min), t _major = 23.05 minutes, t _minor = 17.36 minutes.

Example 5

With 2-mercaptoacetophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazo-5-chloroindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product, whose structure is shown in the formula syn-3e. Yield 90%, dr value equal to 92:8, ee value equal to 90%. The schematic diagram of ¹ H NMR of the product is shown in Figure 18, the schematic diagram of ¹³ C NMR is shown in Figure 19, the liquid phase diagram of the racemic product is shown in Figure 20, and the liquid phase diagram of the chiral product is shown in Figure 21.

¹ H NMR (400MHz, CDCl ₃ ) δ7.36–7.16(m, 11H), 6.64(d, J=8.4Hz, 1H), 5.01(d, J=15.8Hz, 1H), 4.78(d, J= 15.8Hz,1H),3.60(s,1H),1.67(s,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ175.94,143.43,141.75,136.41,134.75,129.65,129.50,128.99,128.40,127.68,127. ,127.10,126.49,126.27,124.00,123.01,110.72,86.88,66.57,44.06,25.29; HRMS-ESI:calcd.for C ₂₃ H ₁₈ NO ₂ NaSCl[M+Na] ⁺ :430.0644,found:430.0641.HPLC( Chiral IC column, wavelength equal to 254 nm, n-hexane/isopropanol = 10:1, flow rate = 1.0 ml/min), t _major = 19.49 minutes, t _minor = 15.23 minutes.

Example 6

With 2-mercaptoacetophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazo-5-bromoindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product with the structure shown as syn-3f. The yield was 90%, the dr value was equal to 92:8, the ee value was equal to 88%. The schematic diagram of ¹ H NMR of the product is shown in Figure 22, the schematic diagram of ¹³ C NMR is shown in Figure 23, the liquid phase diagram of the racemic product is shown in Figure 24, and the liquid phase diagram of the chiral product is shown in Figure 25.

¹ H NMR (400MHz, CDCl ₃ ) δ7.45(d, J=1.9Hz, 1H), 7.38–7.16(m, 10H), 6.59(d, J=8.4Hz, 1H), 5.00(d, J= 15.8Hz, 1H), 4.77(d, J＝15.8Hz, 1H), 3.57(s, 1H), 1.67(s, 3H); ¹³ CNMR(100MHz, CDCl ₃ ) δ175.87, 143.44, 142.28, 136.35, 134.72, 132.55, 129.50, 129.27, 128.99, 127.96, _127.92 , _127.09 , _126.28 , 124.00, 123.00, 115.63, 111.21, 86.93, 66.52, 44.03, 25.39; ] ⁺ : 474.0139, found: 474.0122. HPLC (chiral IC column, wavelength equal to 254 nm, n-hexane/isopropanol = 10:1, flow rate = 1.0 ml/min), t _major = 33.80 minutes, t _minor = 25.79 minute.

Example 7

With 2-mercaptoacetophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazo-7-chloroindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product, whose structure is shown in the formula syn-3g. Yield 88%, dr value equal to 90:10, ee value equal to 92%. The ¹ H NMR schematic diagram of the product is shown in Figure 26, the ¹³ C NMR schematic diagram is shown in Figure 27, the racemic product liquid phase diagram is shown in Figure 28, and the chiral product liquid phase diagram is shown in Figure 29.

¹ H NMR (400MHz, CDCl ₃ ) δ7.34–7.15(m, 11H), 6.97(t, J=7.9Hz, 1H), 5.36(s, 2H), 3.65(s, 1H), 1.64(s, 3H)； ¹³ C NMR(100MHz,CDCl ₃ )δ176.95,143.44,139.35,136.99,136.64,132.23,129.44,129.03,128.66,127.27,126.40,126.21,124.80,124.04,123.79,122.99,116.01,87.04,66.07, 45.24, 25.29; HRMS-ESI: calcd.for C ₂₃ H ₁₈ NO ₂ NaSCl[M+Na] ⁺ :430.0644, found: 430.0641.HPLC (chiral IC column, wavelength equal to 254 nm, n-hexane/isopropanol = 10:1, flow rate = 1.0 ml/min), t _major = 24.96 minutes, t _minor = 17.34 minutes.

Example 8

With 2-mercapto-5-methoxyacetophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazo-5-methoxyindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product with the structure shown as syn-3h. The yield was 90%, the dr value was equal to 90:10, the ee value was equal to 92%. The schematic diagram of ¹ H NMR of the product is shown in Figure 30, the schematic diagram of ¹³ C NMR is shown in Figure 31, the liquid phase diagram of the racemic product is shown in Figure 32, and the liquid phase diagram of the chiral product is shown in Figure 33.

¹ H NMR (400MHz, CDCl ₃ ) δ7.36, 7.34, 7.33, 7.31, 7.29, 7.28, 7.27, 7.26, 7.25, 7.24, 7.23, 7.22, 7.22, 7.20, 7.20, 7.18, 7.18, 7.13, 7.11, 7.04 , ^{7.02,7.00,6.90,6.90,6.84,6.84,6.82,6.82,6.73,6.71,5.03,4.99,4.82,4.78,3.80,1.67} ; _{, 129.62,128.89,127.73,127.17,127.11,126.28,125.84,123.56,122.95,115.11,110.23,109.75,86.56,67.06,55.60,43.93,25.06 ;} M+Na] ⁺ : 426.1140, found: 426.1149.HPLC (chiral IA column, wavelength is equal to 254 nanometers, n-hexane/isopropanol=10:1, flow rate=1.0 ml/min), t _major =34.68 minutes, t _minor = 31.65 minutes.

Example 9

With 2-mercapto-5-fluoroacetophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazo-5-methoxyindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product, whose structure is shown in the formula syn-3i. Yield 91%, dr value equal to 92:8, ee value equal to 93%. The ¹ H NMR schematic diagram of this product is shown in Figure 34, its ¹³ C NMR schematic diagram is shown in Figure 35, its ¹⁹ F NMR schematic diagram is shown in Figure 36, and the liquid phase diagram of the racemic product is shown in Figure 37. The liquid phase diagram of the product is shown in Figure 38.

¹ H NMR (400MHz, CDCl ₃ )δ7.39–7.12(m,8H),7.08–6.94(m,3H),6.74(d,J=7.8Hz,1H),5.01(d,J=15.7Hz, 1H), 4.81(d, J=15.7Hz, 1H), 3.60(s, 1H), 1.67(s, 3H); ¹³ C NMR(100MHz, CDCl3) δ176.22, 163.28, 160.84, 146.28, 146.21, 143.21, 135.11 ,131.40,131.37,129.82,128.90,127.78,127.14,126.29,125.32,123.82,123.74,123.02,116.30,116.07,111.89,111.65,109.84,86.38,86.36,67.15,43.98,25.09； ¹⁹ F NMR(376MHz,CDCl ₃ ) δ-116.77; HRMS-ESI: calcd.for C ₂₃ H ₁₈ NO ₂ NaSF[M+Na] ⁺ :414.0940, found: 414.0927.HPLC (chiral OD column, wavelength equal to 254 nm, n-hexane/isopropyl Alcohol = 10:1, flow rate = 1.0 ml/min), t _major = 12.18 min, t _minor = 9.40 min.

Example 10

With 2-mercapto-5-chloroacetophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazo-5-methoxyindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product, whose structure is shown in the formula syn-3j. Yield 92%, dr value equal to 92:8, ee value equal to 90%. The schematic diagram of ¹ H NMR of the product is shown in Figure 39, the schematic diagram of ¹³ C NMR is shown in Figure 40, the liquid phase diagram of the racemic product is shown in Figure 41, and the liquid phase diagram of the chiral product is shown in Figure 42.

¹ H NMR (400MHz, CDCl ₃ ) δ7.38–7.12 (m, 10H), 7.04 (s, 1H), 6.74 (d, J=7.9Hz, 1H), 5.01 (d, J=15.7Hz, 1H) ,4.80(d,J=15.7Hz,1H),3.59(s,1H),1.66(s,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ176.05,145.90,143.21,135.33,135.09,131.93,129.87, 129.28,128.91,127.80,127.15,126.26,125.24,124.42,123.83,123.05,109.87,86.40,66.99,44.01,25.16; HRMS-ESI:calcd.for C ₂₃ H _{18 6} NO ₂ NaSCl[M ⁺ Na] , found: 430.0641.HPLC (chiral IC column, wavelength equal to 254 nm, n-hexane/isopropanol = 10:1, flow rate = 1.0 ml/min), t _major = 28.65 minutes, t _minor = 12.87 minutes.

Example 11

2-mercapto-5-bromoacetophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazo-5-methoxyindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product, whose structure is shown in the formula syn-3k. Yield 92%, dr value equal to 93:7, ee value equal to 95%. The schematic diagram of ¹ H NMR of the product is shown in Figure 43, the schematic diagram of ¹³ C NMR is shown in Figure 44, the liquid phase diagram of the racemic product is shown in Figure 45, and the liquid phase diagram of the chiral product is shown in Figure 46.

¹ H NMR (400MHz, CDCl ₃ ) δ7.43–7.18(m, 9H), 7.10(d, J=8.1Hz, 1H), 7.04(t, J=7.6Hz, 1H), 6.74(d, J= 7.9Hz, 1H), 5.00(d, J＝15.7Hz, 1H), 4.79(d, J＝15.7Hz, 1H), 3.59(s, 1H), 1.66(s, 3H); ¹³ C NMR (100MHz, CDCl ₃ )δ176.01,146.18,143.23,136.07,135.10,132.15,129.88,128.91,127.80,127.29,127.16,126.27,125.19,124.24,123.05,119.46,109.87,86.40,66.94,44.01,25.22；HRMS-ESI:calcd .for C23H18NO2NaSBr[M+Na] ⁺ : 474.0139, found: 474.0122.HPLC (chiral IC column, wavelength is equal to 254 nanometers, n-hexane/isopropanol=3:1, flow rate=1.0 ml/min), t _major = 12.87 minutes, t _minor = 7.30 minutes.

Example 12

With 2-mercaptophenone (0.20mmol), rhodium acetate (0.002mmol), A mixture of molecular sieves (300 mg) and (R)-SiPh ₃ -BINOL (0.01 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 0°C for 10 minutes. Then 1-benzyl-3-diazo-5-methoxyindol-2-one (0.22 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 0°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain the pure product with the structure shown as syn-3l. The yield was 90%, the dr value was equal to 90:10, the ee value was equal to 96%. The schematic diagram of ¹ H NMR of the product is shown in Figure 47, the schematic diagram of ¹³ C NMR is shown in Figure 48, the liquid phase diagram of the racemic product is shown in Figure 49, and the liquid phase diagram of the chiral product is shown in Figure 50.

¹ H NMR (400MHz, CDCl ₃ ) δ7.55–7.14(m, 11H), 7.02(t, J=7.6Hz, 1H), 6.76(d, J=7.8Hz, 1H), 5.02(d, J= 15.7Hz, 1H), 4.79(d, J=15.7Hz, 1H), 3.81(s, 1H), 2.42–2.26(m, 1H), 1.84(td, J=12.9, 12.3, 3.4Hz, 1H), 1.45–1.25(m,2H),1.22–1.11(m,2H),0.77(t,J=6.9Hz,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ176.50,142.96,142.25,137.34,135.12,129.58 _{, 129.11,128.87,127.76,127.35,126.12,125.38,125.14,123.11,122.91,109.76,88.26,66.69,44.04,35.82,24.90,22.97,13.96 ;} M+Na] ⁺ : 438.1504, found: 438.1511.HPLC (chiral IC column, wavelength equal to 254 nm, n-hexane/isopropanol=10:1, flow rate=1.0 ml/min), t _major =21.67 minutes, t _minor = 13.08 minutes.

Embodiment 13 antitumor activity test

Human colon cancer HCT116 cells were inoculated in a medium containing 10% serum and 1% penicillin-streptomycin solution, placed in a 5% CO ₂ incubator at 37°C, passaged once every 2-3 days, and the logarithm was taken for the test growing cells. The IC ₅₀ value was determined by CCK8 method.

Take the cells in the logarithmic growth phase, adjust the cell suspension to ³ ×104 cells/mL with the prepared fresh medium, and transfer them to a 96-well culture plate. Each well has a volume of 100 μL, 5% CO ₂ , and incubated at 37°C for 24 hours, then added the chiral products obtained in Examples 1 and 3 at concentrations of 25, 12.5, 6.25, 3.125, 1.56, 0.78, 0.39, and 0.195 μM, and incubated for 72 hours. , Discard the culture medium and add 100 μL and 10 μL CCK8 mixed solution to each well for further incubation for 2 hours, then detect the absorbance at 450 nm and 620 nm in a multifunctional microplate reader (Molecular Devices M5).

The chiral products obtained in Examples 1, 2, 6, and 8 were respectively dissolved in DMSO and further diluted in culture medium. The final concentration of DMSO does not exceed 0.25% (v/v). The control group contained HCT116 cells and DMSO, but no compound, and the blank group contained only DMSO and no cells. Results for each experimental condition are the average of 3 replicate wells within one experiment. All A450 values minus A620 values can be subtracted from errors caused by cell number differences, etc., and then the control value and sample value are subtracted from the blank value. Cell viability (%)=[A (dosing)-A (blank)]/[A (0 dosing)-A (blank)]×100, inhibition rate=1-cell viability (%).

For each sample, the mean cell growth was expressed as a percentage of the mean control cell growth and the _IC50 (concentration of drug required to reduce cell growth to 50% of the control) was calculated using Graphpad prism.

The following are the corresponding test results:

The IC ₅₀ of the chiral product prepared in Example 1 of the present invention to inhibit the proliferation of HCT116 cells was 28.36 μM.

The IC ₅₀ of the racemic product prepared in Example 1 of the present invention to inhibit the proliferation of HCT116 cells was 28.34 μM. The IC ₅₀ of the chiral product prepared in Example 3 for inhibiting the proliferation of HCT116 cells was 33.24 μM. Experimental results show that the benzothiophene spirooxindole derivatives of the formula (I) prepared by the present invention have good activity in inhibiting colon cancer, and can provide a broad development space for the development of drugs for treating colon cancer.

The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present invention, and the appended claims are the protection scope.

Claims (13)

1. A benzothiophene spirooxindole derivative, characterized in that its structure is as shown in formula (I), Wherein, R ¹ is hydrogen, C1-C10 alkoxy or halogen; R ² is C1-C10 alkyl; R ³ is hydrogen, C1-C10 alkyl, C1-C10 alkoxy or halogen. 2. benzothiophene spirooxindole derivatives as claimed in claim 1, is characterized in that, R ¹ is hydrogen, methoxy, fluorine, chlorine or bromine; R ² is methyl or n-butyl; R ³ is hydrogen, methyl, methoxy, fluorine, chlorine or bromine. 3. a synthetic method of benzothiophene spirooxindole derivative, characterized in that, with 3-diazoindole shown in formula (2) and 2-thiophenyl group shown in formula (1) Substituted ketones as raw materials, with Molecular sieve is water absorbing agent, with rhodium acetate and chiral BINOL phosphoric acid as catalyzer, in organic solvent, obtain the benzothiophene spirooxindole derivative shown in formula (I) through one-step reaction; Described synthetic reaction is as formula (II ) as shown: Wherein, R ¹ is hydrogen, C1-C10 alkoxy or halogen; R ² is C1-C10 alkyl; R ³ is hydrogen, C1-C10 alkyl, C1-C10 alkoxy or halogen. 4. The synthetic method according to claim 3, characterized in that, the temperature of the reaction is -20°C-40°C. 5. synthetic method as claimed in claim 3, is characterized in that, the temperature of described reaction is 0 ℃. 6. synthetic method as claimed in claim 3, is characterized in that, the structure of described chiral BINOL phosphoric acid is as shown in formula (a), R is selected from 4-CF ₃ C ₆ H ₄ , anthracenyl, 2,4,6-(i-Pr) ₃ C ₆ H ₂ , SiPh ₃ , 3,5-(CF ₃ )C ₆ H ₃ . 7. synthetic method as claimed in claim 3, is characterized in that, 2-thiophenyl substituted ketone shown in described formula (1), 3-diazoindole shown in formula (2), acetic acid The molar ratio of rhodium and chiral BINOL phosphoric acid is 1.0:(1.1-1.5):0.01:0.05. 8. synthetic method as claimed in claim 3, is characterized in that, described The dosage of molecular sieve is 50-100mg/mmol based on the dosage of 2-thiophenyl substituted ketone. 9. The synthetic method according to claim 3, characterized in that, the ratio of the amount of the organic solvent to the 2-thiophenyl substituted ketone is (0.5-1) mL: 1 mmol. 10. The synthesis method according to claim 3, wherein the organic solvent is selected from one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, and tetrahydrofuran. 11. synthetic method as claimed in claim 3 is characterized in that, at first 2-thiophenyl substituted ketone, rhodium acetate, chiral BINOL phosphoric acid, Molecular sieves are dissolved in an organic solvent to prepare a mixed solution A; 3-diazoindole compound is dissolved in an organic solvent to prepare a diazo compound solution B; the diazo compound solution B is added to the mixed solution A for reaction to obtain the benzene Thiophene spirooxindole derivatives. 12. The use of the benzothiophene spirooxindole derivative as claimed in claim 1 or 2 in the preparation of antitumor drugs. 13. The use according to claim 12, wherein the tumor is colon cancer.