CN104774171B - The methylol Oxoindole of 3 amino 3, the methylol oxoindole derivative of 3 hydroxyl 3 and its preparation method and application - Google Patents

Abstract

The invention discloses a preparation method of 3-amino-3-hydroxymethyl oxindole and 3-hydroxy-3-hydroxymethyl oxindole derivatives. 3‑diazoindole, water and formaldehyde are raw materials, with rhodium acetate as a catalyst, with an organic solvent as a solvent, through a one-step reaction, the product 3‑amino‑3‑hydroxymethyl indole, 3‑hydroxy‑3 ‑Hydroxymethyloxindole derivatives. The preparation method of the invention has the advantages of efficient atom economy, high selectivity, etc., and is simple, safe and reliable in operation. The 3-amino-3-hydroxymethyl oxindole and 3-hydroxyl-3-hydroxymethyl oxindole derivatives of the present invention have anticancer activity, contain important natural products and intermediate skeletons of active drug molecules, and are used in medicine The field of chemical industry has broad application prospects.

Description

3-Amino-3-hydroxymethyloxindole, 3-hydroxy-3-hydroxymethyloxindole derivative substances and their preparation methods and applications

technical field

The invention belongs to the technical field of drug synthesis and chemical engineering, and in particular relates to a preparation method of 3-amino-3-hydroxymethyl oxindole and 3-hydroxy-3-hydroxymethyl oxindole derivatives.

Background technique

Many natural products and active compounds contain 3-aminoindole and 3-hydroxyindole structures, so the preparation of 3-aminoindole and 3-hydroxyindole derivatives is of great significance. For example: J.Org.Chem.2012, 77, 3589-3594 pointed out that 3-aminoindole derivative AG-041R can stimulate chondrocyte proliferation and synthesis of cartilage-specific extracellular matrix in vitro without changing differentiated features. World Chinese Journal of Digestion 2006, 14(13): 1262-1266 reported that AG-041R has the activity of inhibiting the proliferation of MKN-45 cells. J.Org.Chem.2012, 77, 3589-3594 also reported that 3-aminoindole derivative SSR-149415 can be used to treat anxiety and depression. Curr.Bioact.Compd.2009, 5, 20 reported 3-hydroxy oxindole derivatives Convolutamydines, arundaphine, donaxaridine, maremycins, paratunamide, celogentin K, TMC-95AD, neuroprotectin B, fluxraminol A and B, 3-hydroxy welwitindolinones and pyrrolidinoindoline -type alkaloid, CPC-1 is a natural compound with anti-oxidation, anti-cancer, anti-AIDS and other biological activities.

Therefore, efficient synthesis of such compounds has very important theoretical and economic value. However, the 3-amino-3-hydroxymethyloxindole derivative provided by this patent has a special structure, it is difficult to synthesize this type of compound by traditional methods, and there is no report of this type of compound at present; the 3 provided by this patent -Hydroxy-3-hydroxymethyl oxindole derivatives are brand new compounds, although some 3-hydroxy-3-hydroxymethyl oxindole derivatives can be derived from the literature Nat.Med.2009, 15, 750-756 , but the reaction conditions of this method are harsh and the operation is complicated. Therefore, it is very important and urgent to explore and develop a synthetic method with low cost, high yield, mild reaction conditions, good selectivity, wide substrate applicability, simple post-treatment, and safe operation.

Contents of the invention

The invention proposes 3-amino-3-hydroxymethyl oxindole, 3-hydroxyl-3-hydroxymethyl oxindole derivatives and a preparation method thereof. The preparation method of the invention has beneficial effects such as efficient atom economy, high selectivity, high yield, simple and safe operation, and the like. The preparation of 3-amino-3-hydroxymethyl oxindole and 3-hydroxyl-3-hydroxymethyl oxindole derivatives in the present invention can be used as intermediates for drug discovery or other purposes.

The present invention proposes a compound 3-amino-3-hydroxymethyloxindole with an innovative structure, the structure of which is shown in formula (A),

in,

R ¹ includes alkyl, H, halogen, formate;

R ² includes alkyl, halogen, benzyl, formate, acyl;

R ³ includes alkyl, halogen, formate, acyl.

The present invention proposes a preparation method of 3-amino-3-hydroxymethyl oxindole, which uses 3-diazo indole, aniline and formaldehyde or 3-diazo indole, water and formaldehyde as raw materials, and Rhodium acetate is used as a catalyst, an organic solvent is used as a solvent, the aniline, formaldehyde aqueous solution, and rhodium acetate are dissolved in the organic solvent, and the 3-diazoindole is added under stirring, and after one-step reaction, the described 3-amino-3-hydroxymethyloxindole, 3-hydroxy-3-hydroxymethyloxindole derivatives; wherein, the aniline includes aniline and substituted aniline;

Described preparation method is shown in reaction formula (I):

in,

R ¹ includes alkyl, H, halogen, formate, etc.;

R ² includes alkyl, halogen, benzyl, formate, acyl, etc.;

^R3 includes alkyl, halogen, formate, acyl, and the like.

Wherein, the molar ratio of raw materials and catalysts in the method is 3-diazoindole:aniline:formaldehyde:rhodium acetate=0.1:1.0:1.0:0.01-2:1.0:10.0:0.10.

The present invention also proposes a compound 3-hydroxyl-3-hydroxymethyloxindole derivative with an innovative structure, the structure of which is shown in formula (B),

in,

R ⁴ includes alkyl, H, halogen, formate;

R ⁵ includes alkyl, halogen, benzyl, formate, acyl.

The present invention also proposes a preparation method of 3-hydroxyl-3-hydroxymethyloxindole derivatives, using 3-diazoindole, water and formaldehyde as raw materials, using rhodium acetate as a catalyst, and using an organic solvent as Solvent, dissolve the aqueous formaldehyde solution and rhodium acetate in the organic solvent, add the 3-diazoindole under stirring, and undergo a one-step reaction to obtain the 3-hydroxyl-3-hydroxymethylindole Indole derivatives;

Described preparation method is shown in reaction formula (II):

in,

R ⁴ includes alkyl, H, halogen, formate, etc.;

R ⁵ includes alkyl, halogen, benzyl, formate, acyl and the like.

Wherein, the molar ratio of the raw material and the catalyst is 3-diazoindole:water:formaldehyde:rhodium acetate=0.1:3.0:1.0:0.01-2:1.0:10.0:0.10.

In the preparation method of the present invention, the method comprises: respectively dissolving the aniline, formaldehyde aqueous solution or formaldehyde aqueous solution, and rhodium acetate in the organic solvent, and adding the diazo compound dissolved in the organic solvent under stirring. The solution is reacted to obtain the product 3-amino-3-hydroxymethyloxindole or 3-hydroxyl-3-hydroxymethyloxindole derivatives respectively.

In the preparation method of the present invention, the product 3-amino-3-hydroxymethyloxindole or 3-hydroxy-3-hydroxymethyloxindole derivative is separated and purified by column chromatography or other methods.

In the preparation method of the present invention, the organic solvent includes tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, toluene, ethyl acetate, dichloromethane and other solvents.

In the preparation method of the present invention, the 3-diazo-2-oxindole includes 3-diazo-2-oxindole, various benzene substituted 3-diazo-2-oxindole, various N Substituted 3-diazo-2-oxindole.

In the preparation method of the present invention, the aniline includes aniline and substituted aniline. The water and aldehydes are limited to water and formaldehyde.

The product obtained by the preparation method of the present invention is 3-amino-3-hydroxymethyloxindole shown in formula (A), 3-hydroxyl-3-hydroxymethyloxindole derivative shown in formula (B) Compounds are chemical compounds with innovative structures.

In the 3-amino-3-hydroxymethyloxindole and the 3-hydroxy-3-hydroxymethyloxindole derivatives of the present invention, the 3-position is a quaternary carbon center and a methylol base.

The synthesis process of the preparation method of the present invention is as follows: 3-diazoindole, aniline and formaldehyde or 3-diazoindole, water, formaldehyde are used as raw materials, rhodium acetate is used as a catalyst, and an organic solvent is used as a solvent. Reaction, removal of the solvent to obtain a crude product, separation and purification of the product by column chromatography. The specific steps are: dissolving the aldehyde and aniline in the organic solvent, under stirring, within 1 hour, the solution composed of dissolving the diazo compound in the organic solvent is added dropwise into the reaction system, and reacting for 1 hour after the dropwise addition is completed. After the reaction, the organic solvent was removed under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the product.

The present invention also proposes the application of the 3-amino-3-hydroxymethyloxindole in the preparation of colon cancer cell growth inhibitors.

The present invention also proposes the application of the 3-hydroxy-3-hydroxymethyloxindole derivative in the preparation of colon cancer cell growth inhibitors.

The beneficial effects of the present invention include that the present invention designs and synthesizes a class of 3-amino-3-hydroxymethyloxindole, 3-hydroxy-3-hydroxymethyloxindole derivatives, diazo, aniline, formaldehyde or 3-heavy Indole nitrogen oxide, water, and formaldehyde are used as raw materials, rhodium acetate is used as a catalyst, and an organic solvent is used as a solvent to obtain a product through one-step reaction. The present invention proposes to construct a class of 3-amino-3-hydroxymethyloxindole and 3-hydroxy-3-hydroxymethyloxindole derivatives by one-step reaction for the first time, and adopts one-step three-component reaction to obtain products. Due to the characteristics of multicomponent reactions such as high flexibility, high selectivity, efficient atom economy, high exploration energy, high yield, and simple and safe operation, in recent years, with the increasing development of the concept of atom economy, multicomponent reactions have become more and more increasingly become a research hotspot. The application of multicomponent reactions in the field of drug synthesis has broad prospects. The 3-amino-3-hydroxymethyl oxindole and 3-hydroxyl-3-hydroxymethyl oxindole derivatives of the present invention are important natural product skeletons or active drug intermediates, and these compounds themselves also have anticancer properties. activity, and has wide application prospects in the field of medicine and chemical industry.

detailed description

In conjunction with the following specific examples, the present invention will be further described in detail, and the protection content of the present invention is not limited to the following examples. 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.

The reaction process of preparation method of the present invention is as follows:

Wherein, R ¹ includes alkyl, H, halogen, formate, etc.; R ² includes alkyl, halogen, benzyl, formate, acyl, etc.; R ³ includes alkyl, halogen, formate, acyl, etc.; R ⁴ includes alkyl, H, halogen, formate; R ⁵ includes alkyl, halogen, benzyl, formate, acyl.

Example 1:

Dissolve 2,6-dichloroaniline (0.1mmol), formaldehyde (0.6mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl A solution of 3-diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was Compound 1 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 94%

¹ H NMR (400MHz, CDCl ₃ ) δ7.40-7.27(m, 5H), 7.15(td, 1H), 7.09(d, 2H), 6.78(dt, 3H), 6.69-6.59(m, 1H), 5.27(s, 1H), 5.04(d, 1H), 4.82(d, 1H), 3.97(t, 1H), 3.87(dd, 1H), 3.15(dd, 1H);

¹³ C NMR (100MHz, CDCl ₃ ) δ178.10, 142.99, 139.96, 135.51, 129.69, 129.39, 128.82, 128.13, 127.86, 127.82, 125.84, 124.12, 123.71, 122.35, 114.54.66.69

Example 2:

Dissolve aniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an autosampler pump to inject 1-benzyl-3-diazo - A solution of 2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the compound 2 whose structure was shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 42%

¹ H NMR (400MHz, CDCl ₃ ) δ7.40-7.16(m, 8H), 7.06(t, 1H), 6.95(t, 2H), 6.84(d, 1H), 6.70(t, 1H), 6.27( d, 2H), 5.18(s, 1H), 5.11(d, 1H), 4.76(d, 1H), 3.92(t, 1H), 3.75-3.64(m, 1H), 3.12(d, 1H);

¹³ C NMR (100MHz, CDCl ₃ ) δ178.04, 145.56, 141.88, 129.57, 129.13, 128.84, 127.88, 127.62, 124.03, 123.55, 119.59, 115.53, 110.07, 68.08, 64.95, 44.09.

Example 3:

Dissolve 4-chloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl-3 - A solution of diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 3 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 89%

¹ H NMR (400MHz, CDCl ₃ ) δ7.60(dd, 4H), 7.26-7.22(m, 1H), 7.22-7.16(m, 2H), 7.06(t, 1H), 6.88(t, 2H), 6.84(d, 1H), 6.24-6.12(m, 2H), 5.24(s, 1H), 5.09(d, 1H), 4.73(d, 1H), 3.97-3.82(m, 1H), 3.75-3.66( m, 1H), 3.46(d, 1H);

¹³ C NMR (100MHz, CDCl ₃ ) δ177.73, 144.18, 141.87, 135.24, 129.75, 128.98, 128.88, 128.01, 127.61, 127.60, 124.40, 124.05, 123.65, 116.95, 110.145, 4.65.67

Example 4:

Dissolve 4-bromoaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl-3 - A solution of diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 4 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 86%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.23(d, 4H), 7.18(d, 1H), 7.14(d, 2H), 6.99(t, 1H), 6.94(d, 2H), 6.78(d, 1H), 6.05(d, 2H), 5.18(s, 1H), 5.02(d, 1H), 4.67(d, 1H), 3.83(s, 1H), 3.63(d, 1H), 3.25(s, 1H );

¹³ C NMR (100MHz, CDCl ₃ ) δ177.69, 144.63, 141.81, 135.21, 131.89, 129.79, 128.90, 128.04, 127.64, 127.16, 124.02, 123.68, 117.25, 111.60, 110.938, 4.65.67

Example 5:

Dissolve 4-iodoaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl-3 - A solution of diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 5 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 88%

¹ H NMR (400MHz, CDCl ₃ ) δ7.21(d, 4H), 7.17(dd, 3H), 7.11(d, 2H), 6.98(t, 1H), 6.78(d, 1H), 5.94(d, 2H), 5.18(s, 1H), 5.02(d, 1H), 4.68(d, 1H), 3.82(s, 1H), 3.63(d, 1H), 3.25(d, 1H);

¹³ C NMR (100MHz, CDCl ₃ ) δ177.69, 145.28, 141.75, 137.77, 135.22, 129.78, 128.92, 128.05, 127.67, 127.13, 124.00, 123.69, 117.57, 110.19, 81.03, 64.8, 64.9

Embodiment 6:

Dissolve 4-nitroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl- A solution of 3-diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 6 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 94%

¹ H NMR (400MHz, CDCl ₃ ) δ7.80(d, J=9.0Hz, 2H), 7.40-7.28(m, 6H), 7.26(s, 1H), 7.07(t, J=7.5Hz, 1H) , 6.97(d, J=7.9Hz, 1H), 6.14(d, J=9.0Hz, 2H), 6.03(s, 1H), 5.11(d, J=15.3Hz, 1H), 4.85(d, J= 15.3Hz, 1H), 3.92(d, J=11.5Hz, 1H), 3.78(d, J=11.6Hz, 1H), 3.51(s, 1H);

¹³ C NMR(100MHz，CDCl ₃ )δ176.51，151.05，141.62，139.55，135.09，160.25，129.03，128.92，128.35，127.84，127.12，125.95，125.89，123.96，123.84，113.22，110.48，67.90，64.20，44.41 .

Embodiment 7:

Dissolve 3-nitroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl- A solution of 3-diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 7 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 95%

¹ H NMR (400MHz, CDCl ₃ ) δ7.40(d, 1H), 7.28-7.13(m, 8H), 6.98(dt, 3H), 6.86(d, 1H), 6.43(d, 1H), 5.64( s, 1H), 4.96(d, 1H), 4.86(d, 1H), 3.87(t, 1H), 3.69(d, 1H), 3.41(s, 1H);

¹³ C NMR(100MHz，CDCl ₃ )δ177.29，149.01，146.54，141.82，135.14，160.18，129.72，128.97，128.06，127.48，126.33，123.90，120.56，113.69，110.52，108.83，67.93，64.71，44.32。

Embodiment 8:

2-Chloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) were dissolved in 1mL of ethyl acetate to form a reaction system, keeping the temperature at 60°C, and 1-benzyl-3 - A solution of diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 8 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 84%

¹ H NMR (400 MHz, CDCl ₃ ) δ7.28-7.12 (m, 8H), 6.98 (t, 1H), 6.82 (d, 1H), 6.55 (dt, 2H), 5.81 (s, 1H), 5.62 ( d, 1H), 5.06(d, 1H), 4.72(d, 1H), 3.91(t, 1H), 3.66(d, 1H), 3.01(d, 1H);

¹³ C NMR(100MHz，CDCl ₃ )δ177.39，141.72，135.37，129.76，129.44，128.89，128.03，127.83，127.50，127.09，123.95，123.70，120.89，119.18，113.15，110.13，68.18，64.49，44.24。

Embodiment 9:

Dissolve 3-chloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl-3 - A solution of diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the compound 9 having the structure shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 82%

¹ H NMR (400 MHz, CDCl ₃ ) δ7.31-7.11 (m, 8H), 6.99 (t, 1H), 6.75 (t, 2H), 6.57 (d, 1H), 6.21 (s, 1H), 6.01 ( d, 1H), 5.26(s, 1H), 5.06(d, 1H), 4.70(d, 1H), 3.86-3.75(m, 1H), 3.62(d, 1H), 3.24(s, 1H);

¹³ C NMR(100MHz，CDCl ₃ )δ177.59，146.83，141.74，135.18，134.75，160.14，129.84，129.02，127.93，127.45，127.03，123.93，123.73，119.60，115.02，113.14，110.28，68.07，64.74，44.23 .

Example 10:

Dissolve 2,4-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl A solution of 3-diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 10 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 98%

¹ H NMR (400MHz, CDCl ₃ ) δ7.19(dd, 8H), 6.98(t, 1H), 6.83(d, 1H), 6.51(d, 1H), 5.77(s, 1H), 5.50(d, 1H), 5.04(d, 1H), 4.70(d, 1H), 3.88(t, 1H), 3.66(d, 1H), 3.11(s, 1H);

¹³ C NMR(100MHz，CDCl ₃ )δ177.07，141.69，140.53，135.28，129.95，129.07，128.94，128.16，127.86，127.46，126.70，123.96，123.80，123.25，121.42，113.81，110.23，68.04，64.58，44.27 .

Example 11:

Dissolve 2,6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an auto-sampling pump to inject 1-benzyl A solution of 3-diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the compound 11 having the structure shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 94%

¹ H NMR (400 MHz, CDCl ₃ ) δ7.32-7.14 (m, 7H), 7.07 (d, 1H), 7.00 (t, 1H), 6.78 (d, 1H), 6.50 (d, 1H), 5.88 ( s, 1H), 5.67(s, 1H), 5.09(d, 1H), 4.73(d, 1H), 3.88(t, 1H), 3.66(d, 1H), 3.11(d, 1H);

¹³ C NMR(100MHz，CDCl ₃ )δ176.85，142.59，141.74，135.05，160.15，160.09，129.21，127.94，127.25，126.22，123.90，123.87，119.12，118.95，112.91，110.44，68.20，64.38，44.41。

Example 12:

Dissolve 2,6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an auto-sampling pump to inject 1-benzyl A solution of 3-diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 12 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 64%

¹ H NMR (400MHz, CDCl ₃ ) δ8.89(s, 1H), 7.80(d, 1H), 7.27(dd, 6H), 7.19(d, 1H), 7.01(t, 1H), 6.93(d, 1H), 6.61(dd, 1H), 5.63(dd, 1H), 5.09(d, 1H), 4.77(d, 1H), 3.92(t, 1H), 3.76(d, 1H), 2.91(d, 1H );

¹³ C NMR(100MHz，CDCl ₃ )δ175.93，153.32，141.48，139.89，135.26，133.02，160.20，129.00，128.31，128.05，126.31，124.17，124.14-123.80，116.24112.80，112.54，110.41，68.15，64.58 , 44.42.

Example 13.

Dissolve 2-iodoaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl-3 - A solution of diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 13 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 76%

¹ H NMR (400MHz, CDCl ₃ ) δ7.66(dd, J=7.8, 1.3Hz, 1H), 7.34-7.27(m, 7H), 7.07(t, J=7.4Hz, 1H), 6.90(d, J=7.8Hz, 1H), 6.72(dd, J=11.3, 4.2Hz, 1H), 6.45-6.34(m, 1H), 5.72(s, 1H), 5.64(dd, J=8.1, 1.1Hz, 1H ), 5.13(d, J=15.3Hz, 1H), 4.81(d, J=15.3Hz, 1H), 4.00(t, J=11.4Hz, 1H), 3.72(dd, J=11.5, 2.5Hz, 1H ), 2.95 (dd, J=11.3, 2.5Hz, 1H);

¹³ C NMR(100MHz，CDCl ₃ )δ177.26，145.04，141.79，139.39，135.39，129.74，129.14，128.89，128.03，127.84，126.92，123.94，123.69，120.44，112.51，110.10，87.14，68.26，65.01，44.24 .

Example 14:

2-Chloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) were dissolved in 1mL of ethyl acetate to form a reaction system, keeping the temperature at 60°C, and 1-benzyl-3 - A solution of diazo-5-methyl-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 14 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 73%

¹ H NMR (400 MHz, CDCl ₃ ) δ7.36-7.27 (m, 5H), 7.24 (dd, 1H), 7.12 (s, 1H), 7.07 (d, 1H), 6.78 (d, 1H), 6.66 ( td, 1H), 6.60(td, 1H), 5.87(s, 1H), 5.71(dd, 1H), 5.12(d, 1H), 4.78(d, 1H), 3.97(d, 1H), 3.72(d , 1H), 3.05(s, 1H), 2.27(s, 3H);

¹³ C NMR (100MHz, CDCl ₃ ) δ177.32, 141.78, 139.27, 135.48, 133.46, 160.06, 129.41, 128.85, 127.90 (d, J=14.2Hz), 127.51, 127.04, 124.63, 120.84, 1110.09 , 68.23, 64.44, 44.24, 21.05.

Example 15:

Dissolve 4-iodoaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl-3 - A solution of diazo-5-methyl-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 15 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 29%

¹ H NMR (400MHz, CDCl ₃ ) δ7.35-7.28(m, 3H), 7.25-7.18(m, 4H), 7.11(s, 1H), 7.06(d, 1H), 6.75(d, 1H), 6.09-5.95(m, 2H), 5.20(s, 1H), 5.09(d, 1H), 4.74(d, 1H), 3.89(d, 1H), 3.67(d, 1H), 3.02(s, 1H) , 2.28(s, 3H);

¹³ C NMR (100MHz, CDCl ₃ ) δ177.56, 145.36, 139.32, 137.78, 135.33, 133.45, 160.10, 128.86, 127.99, 127.69, 127.02, 124.65, 117.47, 109.97, 68.00, 44.

Example 16:

Dissolve 2,6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an auto-sampling pump to inject 1-benzyl A solution of 3-diazo-5-methyl-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the compound 16 having the structure shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 84%

¹ H NMR (400MHz, CDCl ₃ ) δ7.38-7.23(m, 5H), 6.94(dd, 1H), 6.77(t, 1H), 6.66(d, 1H), 6.44(d, 1H), 5.25( s, 1H), 5.00(d, 1H), 4.80(d, 1H), 3.95(t, 1H), 3.85(d, 1H), 3.19(d, 1H), 2.08(s, 3H).

¹³ C NMR (100MHz, CDCl ₃ ) δ177.95, 140.54, 140.00, 135.61, 131.95, 129.65, 129.62, 128.78(s), 128.09, 127.80, 126.02, 124.90, 123.62, 109.26, 69.501, 26.62

Example 17:

Dissolve 2,4,6-dibromoaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an auto-sampling pump to inject 1 - A solution of benzyl-3-diazo-5-methyl-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the compound 17 having the structure shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 80%

NMR (400MHz, CDCl ₃ ) δ7.48(s, 2H), 7.40-7.35(m, 2H), 7.29(dt, 3H), 6.98(d, 1H), 6.71(d, 1H), 6.34(s, 1H), 5.27(s, 1H), 5.00(d, 1H), 4.79(d, 1H), 3.99(t, 1H), 3.80(d, 1H), 3.26(s, 1H), 2.11(s, 3H );

¹³ C NMR (100MHz, CDCl ₃ ) δ177.88, 141.94, 140.69, 135.39, 134.21, 132.11, 129.86, 128.80, 128.03, 127.93, 125.18, 121.04, 115.81, 109.37, 70.01, 446.3

Example 18:

Dissolve 2,6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an auto-sampling pump to inject 1-benzyl A solution of 3-diazo-5-bromo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 18 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 89%

¹ H NMR (400MHz, CDCl ₃ ) δ7.47-7.24(m, 12H), 7.15(d, J=8.0Hz, 2H), 6.91-6.75(m, 2H), 6.64(d, J=8.3Hz, 1H), 5.18(s, 1H), 5.01(d, J=15.5Hz, 1H), 4.80(d, J=15.4Hz, 1H), 4.02-3.78(m, 2H), 2.93(dd, J=10.2 , 3.5Hz, 1H);

¹³ C NMR (100MHz, CDCl ₃ ) δ177.29, 141.99, 139.43, 135.01, 132.22, 129.66, 128.90, 128.31, 128.02, 127.72, 127.36, 124.15, 115.08, 110.95, 69.424, 64.6.

Example 19:

Dissolve 2,6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and inject 1-benzyl A solution of 3-diazo-7-chloro-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the compound 19 having the structure shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 93%

¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.15(m, 12H), 7.15-7.08(m, 5H), 6.77(dt, J=15.7, 8.0Hz, 4H), 6.59(d, J=7.3 Hz, 2H), 5.43(d, J=15.9Hz, 2H), 5.29(d, J=15.9Hz, 2H), 5.22(s, 2H), 4.01-3.77(m, 4H), 3.14(s, 2H );

¹³ C NMR (100MHz, CDCl ₃ ) δ178.55, 139.57, 139.05, 137.17, 132.04, 129.50, 129.12, 128.56, 128.26, 127.41, 127.19, 123.85, 123.26, 122.73, 115.75, 45.69

Example 20:

Dissolve 2,6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an auto-sampling pump to inject 1-benzyl A solution of 3-diazo-4-chloro-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 20 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 74%

¹ H NMR (400MHz, CDCl3) δ7.36-7.27(m, 5H), 7.13(t, J=8.1Hz, 1H), 7.09(d, J=8.0Hz, 2H), 6.83(d, J=8.2 Hz, 1H), 6.74(t, J=8.0Hz, 1H), 6.70(d, J=7.8Hz, 1H), 5.50(s, 1H), 4.99(d, J=15.5Hz, 1H), 4.81( d, J=15.5Hz, 1H), 4.43(t, J=11.0Hz, 1H), 3.98-3.85(m, 1H), 3.18-2.99(m, 1H);

¹³ C NMR (100MHz, CDCl3) δ176.98, 145.00, 140.07, 135.01, 131.50, 130.74, 128.88, 128.36, 127.99, 127.73, 127.24, 124.05, 123.67, 122.46, 108.12, 667.29

Example 21:

Dissolve 2,6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-methanol A solution of 3-diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 21 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 78%

¹ H NMR (400MHz, CDCl ₃ ) δ7.26(d, J=6.5Hz, 1H), 7.11(d, J=8.0Hz, 2H), 6.86-6.73(m, 3H), 6.68(d, J= 7.3Hz, 1H), 5.22(s, 1H), 3.92(t, J=10.8Hz, 1H), 3.83(dd, J=11.3, 3.2Hz, 1H), 3.24(s, 3H), 3.15(d, J=9.0Hz, 1H);

¹³ C NMR (100MHz, CDCl ₃ ) δ178.16, 143.79, 140.04, 129.61, 129.50, 128.18, 125.89, 124.08, 123.68, 122.35, 108.62, 69.49, 66.45, 26.27.

Example 22:

Dissolve 2,6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-acetyl A solution of 3-diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 22 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 89%

¹ H NMR (400MHz, CDCl ₃ ) δ8.23(d, 1H), 7.60(t, 1H), 7.13(d, 2H), 6.98(t, 1H), 6.81(t, 1H), 6.74(d, 1H), 5.12(s, 1H), 3.92(s, 2H), 2.73(s, 3H), 2.62(d, 1H);

¹³ C NMR (100MHz, CDCl ₃ ) δ178.52, 170.75, 140.25, 139.02, 129.93, 129.70, 128.34, 125.24, 124.86, 124.13, 123.71, 116.91, 69.57, 66.59, 26.68.

Example 23:

Dissolve 37% formaldehyde aqueous solution (98mg, containing 3.4mmol water and 1.2mmol formaldehyde) and rhodium acetate (0.004mmol) in 2mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl - A solution of 3-diazo 5-methyl-2-oxindole (0.20 mmol) dissolved in 4 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 23 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-3:1) to obtain a pure product. Yield: 73%

¹ H NMR (400MHz, CDCl ₃ ) δ7.34-7.16(m, 6H), 7.00(d, J=7.9Hz, 1H), 6.58(d, J=7.9Hz, 1H), 4.91(d, J= 15.7Hz, 1H), 4.76(d, J=15.7Hz, 1H), 4.48(s, 1H), 3.88(q, J=11.8Hz, 2H), 3.36(s, 1H), 2.28(s, 3H) .

¹³ C NMR (100MHz, CDCl ₃ ) δ177.80, 140.22), 135.28, 133.14, 130.25, 128.85, 127.76 (d, J=10.8Hz), 127.13, 125.21, 109.49, 75.80, 66.99, 43.73, 21.00

Example 24:

Dissolve 37% formaldehyde aqueous solution (98mg, containing 3.4mmol water and 1.2mmol formaldehyde) and rhodium acetate (0.004mmol) in 2mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl - A solution of 3-diazo 5-bromo-2-oxindole (0.20 mmol) dissolved in 4 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 24 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-3:1) to obtain a pure product. Yield: 54%

¹ H NMR (400MHz, CDCl ₃ ) δ7.47(s, 1H), 7.21(ddd, J=21.5, 15.1, 7.8Hz, 6H), 6.49(d, J=8.3Hz, 1H), 4.85(d, J=15.8Hz, 1H), 4.69(d, J=15.8Hz, 1H), 4.42(s, 1H), 3.81(s, 2H), 3.22(s, 1H).

¹³ C NMR (100MHz, CDCl ₃ ) δ177.25, 141.63, 134.65, 132.84, 129.91, 128.99, 127.96, 127.85, 127.08, 116.24, 111.21, 75.80, 66.79, 43.85.

Example 25:

Dissolve 37% formaldehyde aqueous solution (98mg, containing 3.4mmol water and 1.2mmol formaldehyde) and rhodium acetate (0.004mmol) in 2mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl - A solution of 3-diazo-4-chloro-2-oxindole (0.20 mmol) dissolved in 2 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 25 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-3:1) to obtain a pure product. Yield: 74%

¹ H NMR (400MHz, MeOD) δ8.78(d, J=7.2Hz, 2H), 8.68(dt, J=23.3, 6.9Hz, 3H), 8.59(t, J=8.0Hz, 1H), 8.43( d, J=8.2Hz, 1H), 8.10(d, J=7.8Hz, 1H), 6.44(d, J=16.0Hz, 1H), 6.25(s, 1H), 5.82(d, J=10.1Hz, 1H), 5.41(d, J=10.1Hz, 1H).

¹³ C NMR (100MHz, MeOD) δ179.19, 146.88, 136.77, 132.76, 131.97, 129.74, 128.60, 128.19, 127.23, 125.12, 109.33, 79.03, 64.02, 44.53.

Example 26:

Dissolve 37% formaldehyde aqueous solution (98mg, containing 3.4mmol water and 1.2mmol formaldehyde) and rhodium acetate (0.004mmol) in 2mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl - A solution of 3-diazo 5-chloro-2-oxindole (0.20 mmol) dissolved in 4 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the compound 26 having the structure shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-3:1) to obtain a pure product. Yield: 55%

¹ H NMR (400MHz, MeOD) δ8.86(s, 1H), 8.81-8.69(m, 4H), 8.65(dd, J=15.5, 7.8Hz, 2H), 8.15(d, J=8.3Hz, 1H ), 6.41(d, J=15.9Hz, 1H), 6.32-6.19(m, 5H), 5.31(s, 2H).

¹³ C NMR (100MHz, MeOD) δ179.12, 143.27, 136.81, 133.34, 130.31, 129.77, 129.44, 128.65, 128.25, 125.82, 111.79, 77.89, 66.85, 44.44.

Example 27:

Dissolve 37% formaldehyde aqueous solution (98mg, containing 3.4mmol water and 1.2mmol formaldehyde) and rhodium acetate (0.004mmol) in 2mL ethyl acetate to form a reaction system. - A solution of 3-diazo-2-oxindole (0.20 mmol) dissolved in 2 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 27 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-3:1) to obtain a pure product. Yield: 46%

¹ H NMR (400MHz, MeOD) δ7.43-7.19(m, 6H), 7.07(dd, J=7.9, 1.2Hz, 1H), 6.76(s, 1H), 4.99(d, J=16.0Hz, 1H ), 4.86(d, J=9.4Hz, 1H), 3.89(s, 2H).

¹³ C NMR (100MHz, MeOD) δ179.50, 146.04, 136.73, 136.19, 129.97, 129.83, 128.72, 128.23, 126.53, 123.82, 111.07, 77.51, 66.83, 44.41.

Example 28:

Dissolve 37% formaldehyde aqueous solution (98mg, containing 3.4mmol water and 1.2mmol formaldehyde) and rhodium acetate (0.004mmol) in 2mL ethyl acetate to form a reaction system. - A solution of 3-diazo-2-oxindole (0.20 mmol) dissolved in 2 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 28 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-3:1) to obtain a pure product. Yield: 73%

¹ H NMR (400MHz, MeOD) δ7.40(d, J=7.3Hz, 1H), 7.26(t, J=6.2Hz, 4H), 7.21(dd, J=8.3, 3.7Hz, 2H), 7.07( t, J=7.7Hz, 1H), 5.32(q, J=16.5Hz, 2H), 3.91(q, J=10.4Hz, 2H).

¹³ C NMR (100MHz, MeOD) δ180.19, 140.65, 138.78, 134.66, 132.98, 129.54, 128.04, 127.27, 125.34, 124.19, 116.55, 77.21, 67.12, 45.79.

Embodiment 29: Antitumor activity experiment

Take human colon cancer HCT116 cells in the logarithmic growth phase, digest with trypsin, resuspend the cells, count them with a cell counting plate, inoculate them into 96-well culture plates with a cell density of ² ×10, and place them in a 37°C, 5% _CO2 incubator Incubate overnight. Add drugs with different concentration gradients and incubate for 72 hours, add 20ul MTS solution to each well, incubate for 2 hours, use SpectraMAX340 to measure the light absorption value at 490nm (L1), and use the SpectraMAX340 to measure the light absorption value at 490nm (L2), and use the (L1-L2) value for different concentrations of inhibitors. Figure, IC50 obtained by formula fitting

The representative compounds 1, 3-6, 23-27 obtained in the above-mentioned Examples 1, 3-6, 23-27 were dissolved in DMSO and further diluted in the culture medium. The final concentration of DMSO does not exceed 0.1% (v/v). Nutlin-3 was used as the control, the control sample contained HCT116 cells and DMSO, but no compound, and the blank sample contained DMSO but no cells. Results for each experimental condition are the average of 3 replicate wells within one set of experiments. Subtract the blank value from all control and sample values. For each sample, the mean value of cell growth was expressed as a percentage of the mean value of control cell growth, and the _IC50 (drug concentration required to reduce cell growth to 50% of the control sample) was calculated using SigmaPlot 10.0. Most of the compounds tested showed a higher effect on cell growth of p53WTHCT116 compared to p53knockoutHCT116. The corresponding test results are shown in Table 1. Compared with the reference substance, the compound of the present invention shows a higher effect on the cell growth of p53WTHCT116, and at the same time, it has no obvious activity on p53knockoutWTHCT116, showing good selectivity, and has potential anticancer activity prospects and further structural modification and activity testing space.

Table 1 Compound 1, 3-6, 23-27 inhibit data on HCT116 colon cancer cells

Claims (7)

1. A3-amino-3-hydroxymethyl oxoindole is characterized in that the structure is shown in formula (A),

wherein,

R¹is methyl, H, halogen;

R²is methyl, benzyl, acetyl;

R³is H, halogen or nitro.

2. A preparation method of 3-amino-3-hydroxymethyl oxoindole is characterized in that 3-diazooxoindole, aniline and formaldehyde are used as raw materials, rhodium acetate is used as a catalyst, an organic solvent is used as a solvent, the aniline, formaldehyde aqueous solution and rhodium acetate are dissolved in the organic solvent, the 3-diazooxoindole is added under stirring, and the 3-amino-3-hydroxymethyl oxoindole is obtained through one-step reaction; wherein the aniline is aniline and substituted aniline;

the preparation method is shown as a reaction formula (I):

wherein,

R¹is methyl, H, halogen;

R²is methyl, benzyl, acetyl;

R³is H, halogen, nitro;

wherein, the molar ratio of the raw material to the catalyst in the method is 3-diazo oxoindole: aniline: formaldehyde: rhodium acetate 0.1:1.0:1.0:0.01-2:1.0:10.0: 0.10;

the organic solvent is tetrahydrofuran, 1, 4-dioxane, glycol dimethyl ether, toluene, ethyl acetate and dichloromethane.

3. A3-hydroxy-3-hydroxymethyl oxoindole derivative is characterized in that the structure is shown as a formula (B),

wherein,

R⁴is methyl, H, halogen;

R⁵is benzyl.

4. A preparation method of a 3-hydroxy-3-hydroxymethyl oxoindole derivative is characterized in that 3-diazooxoindole, water and formaldehyde are used as raw materials, rhodium acetate is used as a catalyst, an organic solvent is used as a solvent, the formaldehyde aqueous solution and the rhodium acetate are dissolved in the organic solvent, the 3-diazooxoindole is added under stirring, and the 3-hydroxy-3-hydroxymethyl oxoindole derivative is obtained through one-step reaction;

the preparation method is shown as a reaction formula (II):

wherein,

R⁴is methyl, H, halogen;

R⁵is benzyl;

the 3-diazoxyindole: water: formaldehyde: rhodium acetate 0.1:3.0:1.0:0.01-2:1.0:10.0: 0.10.

The organic solvent is tetrahydrofuran, 1, 4-dioxane, glycol dimethyl ether, toluene, ethyl acetate and dichloromethane.

5. The method according to claim 2 or 4, wherein the product obtained by the method is separated and purified by column chromatography.

6. Use of 3-amino-3-hydroxymethyloxindole according to claim 1 for the preparation of an inhibitor of colon cancer cell growth.

7. Use of the 3-hydroxy-3-hydroxymethyloxindole derivative according to claim 3 for the preparation of a colon cancer cell growth inhibitor.