A synthesis method and application of 1-acetyl-1H-indol-3-yl acetate derivative

Abstract

The present invention provides a synthesis method and application of 1-acetyl-1H-indol-3-yl acetate derivatives, belonging to the technical field of chemical drug synthesis. The present invention uses halogenated benzoic acid as raw material, reacts with glycine under alkaline conditions by metal catalysis, then acylates with acetic anhydride under alkaline conditions, and finally cyclizes with acetic anhydride by organic base catalysis to obtain a crude product, and the crude product is recrystallized in an alcohol solvent to obtain a 1-acetyl-1H-indol-3-yl acetate derivative; the derivative is used as an aldose reductase inhibitor for preparing a candidate drug molecule for treating diabetic nephropathy. The synthesis method of the present invention is simple to operate, raw materials are easily available, high yield, high purity, low cost, and is beneficial to mass production.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical drug synthesis, and in particular to a synthesis method and application of a 1-acetyl-1H-indol-3-yl acetate derivative. Background Art

[0002] Diabetic nephropathy (DN) is one of the chronic complications of microvascular disease and an important complication of diabetic patients, which is extremely harmful to health. Aldose reductase inhibitors (ARI) have been the first choice for the treatment of diabetic nephropathy.

[0003] In recent years, a variety of new ARIs have been reported for the treatment of diabetic nephropathy, but few have passed clinical evaluation, and the inhibitory activity of existing aldose reductase inhibitors is not high. Therefore, it is very necessary to continuously discover some new compound molecules as new aldose reductase inhibitors for the preparation of candidate drug molecules for the treatment of diabetic nephropathy. Summary of the invention

[0004] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a synthesis method and application of 1-acetyl-1H-indol-3-yl acetate derivatives.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a method for synthesizing a 1-acetyl-1H-indol-3-yl acetate derivative, and the synthetic route is as follows:

[0007]

[0008] Wherein, R is H, F, Cl or Br;

[0009] The following steps are involved:

[0010] 1) reacting a halogenated benzoic acid and glycine in the presence of a carbonate and a metal powder to obtain a compound b;

[0011] 2) subjecting compound b to an acylation reaction with acetic anhydride under alkaline conditions to obtain compound c;

[0012] 3) Compound c is reacted with acetic anhydride in the presence of an organic base to undergo a cyclization reaction to obtain a 1-acetyl-1H-indol-3-yl acetate derivative;

[0013] The general structural formula of the 1-acetyl-1H-indol-3-yl acetate derivative is as follows:

[0014]

[0015] Wherein, R is H, F, Cl or Br.

[0016] Furthermore, the halogenated benzoic acid comprises one or more of o-fluorobenzoic acid, o-chlorobenzoic acid, o-bromobenzoic acid, 2,6-difluorobenzoic acid, 2,6-dichlorobenzoic acid and 2,6-dibromobenzoic acid.

[0017] Furthermore, the reaction in step 1) is carried out in a solvent, and the solvent comprises dimethylformamide and / or diisopropylethylamine.

[0018] Furthermore, the carbonate comprises one or more of lithium carbonate, sodium carbonate and potassium carbonate; the metal powder comprises copper powder and / or iron powder; and the molar ratio of the halogenated benzoic acid, glycine, carbonate and metal powder is 0.1:0.1-0.2:0.1-0.2:0.01-0.3.

[0019] Further, the molar volume ratio of glycine to solvent is 0.1-0.2 mol:100 mL;

[0020] In the step 1), the reaction temperature is 50-75° C. and the reaction time is 3-4 hours.

[0021] Furthermore, in the step 2), the alkaline condition is an alkaline solution, the alkaline solution comprises one or more of a potassium carbonate solution, a sodium carbonate solution and a lithium carbonate solution, and the concentration of the alkaline solution is 0.65 to 0.8 mol / L; the molar volume ratio of the compound b and acetic anhydride is 0.08 to 0.1 mol:15 mL.

[0022] Furthermore, in the step 2), the temperature of the acylation reaction is 0 to 60° C., and the time of the acylation reaction is 1 to 12 hours.

[0023] Furthermore, in the step 3), the molar volume ratio of the compound c, acetic anhydride and the organic base is 0.07-0.09 mol:80-90 mL:18-22 mL; and the organic base comprises one or more of triethylamine, ethylenediamine and pyridine.

[0024] Furthermore, in the step 3), the temperature of the ring-closing reaction is 60 to 90° C., and the time of the ring-closing reaction is 1 to 6 hours.

[0025] The present invention provides an application of a 1-acetyl-1H-indol-3-yl acetate derivative as an aldose reductase inhibitor in the preparation of a drug for treating diabetic nephropathy.

[0026] Beneficial effects of the present invention:

[0027] The existing synthesis methods of the 1-acetyl-1H-indol-3-yl acetate derivatives of the present invention mainly include two routes:

[0028] Route 1: Two-step reaction, specifically, o-chlorobenzoic acid is used as the starting material, reacted with glycine to obtain an intermediate compound, and the intermediate compound reacts with acetic anhydride under the catalysis of sodium acetate to undergo an acylation ring reaction to directly obtain the target product;

[0029] Route 2: A three-step reaction, which uses anthranilic acid as the starting material, obtains an intermediate compound through alkylation and acetylation, and then obtains the target product through acylation and cyclization.

[0030] The experimental results of the present invention compared with route 1 and route 2 show that:

[0031] Route 1: Although it is a two-step reaction, the actual yield is low (total yield <50%) and the purity is low (70%);

[0032] Route 2: Three-step reaction, and the starting materials are not easy to obtain, the yield is low (total yield <55%), the purity is low (90%), and the cost is high;

[0033] Compared with route 1 and route 2, the synthetic route of the present invention not only has readily available raw materials, high yield (total yield ≥ 65%), high purity (≥ 99%), and low cost, but also has a simple synthetic method and is more conducive to mass production.

[0034] The high-purity 1-acetyl-1H-indol-3-yl acetate derivative obtained by the present invention has higher aldose reductase inhibitory activity and has a lower IC50 half inhibition concentration than epalrestat. DETAILED DESCRIPTION

[0035] The present invention provides a method for synthesizing a 1-acetyl-1H-indol-3-yl acetate derivative, and the synthetic route is as follows:

[0036]

[0037] Wherein, R is H, F, Cl or Br;

[0038] The following steps are involved:

[0039] 1) reacting a halogenated benzoic acid and glycine in the presence of a carbonate and a metal powder to obtain a compound b;

[0040] 2) subjecting compound b to an acylation reaction with acetic anhydride under alkaline conditions to obtain compound c;

[0041] 3) Compound c is reacted with acetic anhydride in the presence of an organic base to undergo a cyclization reaction to obtain a 1-acetyl-1H-indol-3-yl acetate derivative;

[0042] The general structural formula of the 1-acetyl-1H-indol-3-yl acetate derivative is as follows:

[0043]

[0044] Wherein, R is H, F, Cl or Br.

[0045] In the present invention, the halogenated benzoic acid comprises one or more of o-fluorobenzoic acid, o-chlorobenzoic acid, o-bromobenzoic acid, 2,6-difluorobenzoic acid, 2,6-dichlorobenzoic acid and 2,6-dibromobenzoic acid, preferably o-fluorobenzoic acid and / or o-chlorobenzoic acid.

[0046] In the present invention, the reaction in step 1) is carried out in a solvent, and the solvent comprises dimethylformamide and / or diisopropylethylamine, preferably dimethylformamide.

[0047] In the present invention, the carbonate comprises one or more of lithium carbonate, sodium carbonate and potassium carbonate, preferably lithium carbonate.

[0048] In the present invention, the metal powder comprises copper powder and / or iron powder, preferably copper powder.

[0049] In the present invention, the molar ratio of the halogenated benzoic acid, glycine, carbonate and metal powder is 0.1:0.1-0.2:0.1-0.2:0.01-0.3, preferably 0.1:0.12-0.18:0.12-0.18:0.05-0.2, and more preferably 0.1:0.15:0.15:0.1-0.15.

[0050] In the present invention, the molar volume ratio of glycine to the solvent is 0.1-0.2 mol:100 mL, preferably 0.15 mol:100 mL.

[0051] In the present invention, in the step 1), the reaction temperature is 50-75°C, and the reaction time is 3-4h; preferably, the reaction temperature is 55-70°C, and the reaction time is 3.5h; further preferably, the reaction temperature is 60-65°C, and the reaction time is 3.5h.

[0052] In the present invention, in the step 2), the alkaline condition is an alkaline solution, and the alkaline solution comprises one or more of a potassium carbonate solution, a sodium carbonate solution and a lithium carbonate solution, preferably a potassium carbonate solution.

[0053] In the present invention, in step 2), after the acylation reaction, the obtained reaction product is acidified with hydrochloric acid to pH = 2 to 3, preferably pH = 3; wherein the volume ratio of the reaction product to the hydrochloric acid is 1:1.

[0054] In the present invention, the concentration of the alkaline solution is 0.65 to 0.8 mol / L, preferably 0.68 to 0.75 mol / L, and more preferably 0.68 to 0.72 mol / L.

[0055] In the present invention, the molar volume ratio of the base, compound b and acetic anhydride in the alkaline solution is 0.130-0.140 mol: 0.08-0.1 mol: 15 mL, preferably 0.132-0.138 mol: 0.09-0.095: 15 mL, and more preferably 0.134-0.136 mol: 0.092-0.094: 15 mL.

[0056] In the present invention, the molar volume ratio of the compound b to acetic anhydride is 0.08-0.1 mol:15 mL, preferably 0.09-0.095:15 mL, and more preferably 0.092-0.094:15 mL.

[0057] In the present invention, in the step 2), the temperature of the acylation reaction is 0-60°C, and the time of the acylation reaction is 1-12h; preferably, the temperature of the acylation reaction is 0-40°C, and the time of the acylation reaction is 1-6h; further preferably, the temperature of the acylation reaction is 0-30°C, and the time of the acylation reaction is 1-3h.

[0058] In the present invention, in the step 3), the molar volume ratio of the compound c, acetic anhydride and the organic base is 0.07-0.09 mol:80-90 mL:18-22 mL, preferably 0.075-0.085 mol:82-88 mL:20-21 mL, and more preferably 0.080 mol:85 mL:21 mL.

[0059] In the present invention, the organic base comprises one or more of triethylamine, ethylenediamine and pyridine, preferably triethylamine.

[0060] In the present invention, in the step 3), the temperature of the ring-closing reaction is 60-90°C, and the time of the ring-closing reaction is 1-6h; preferably, the temperature of the ring-closing reaction is 75-85°C, and the time of the ring-closing reaction is 2-5; further preferably, the temperature of the ring-closing reaction is 80°C, and the time of the ring-closing reaction is 3-4h.

[0061] In the present invention, in step 3), the product after the ring-closing reaction is recrystallized to obtain a 1-acetyl-1H-indol-3-yl acetate derivative, and the recrystallization is carried out in an alcohol solvent, wherein the alcohol solvent comprises one or more of methanol, ethanol, propanol and isopropanol, preferably methanol and / or ethanol.

[0062] In the present invention, the 1-acetyl-1H-indol-3-yl acetate derivative is preferably one of the following compounds:

[0063] Table 1 1-Acetyl-1H-indol-3-yl acetate derivatives

[0064] Compound name Compound 1, AIA 1-Acetyl-1H-indol-3-yl acetate Compound 2 1-Acetyl-4-fluoroindole-3-acetate Compound 3 1-Acetyl-5-fluoroindole-3-acetate Compound 4 1-Acetyl-6-fluoroindole-3-acetate Compound 5 1-Acetyl-7-fluoroindole-3-acetate Compound 6 1-Acetyl-4-chloroindole-3-acetate Compound 7 1-Acetyl-5-chloroindole-3-acetate Compound 8 1-Acetyl-6-chloroindole-3-acetate Compound 9 1-Acetyl-7-chloroindole-3-acetate Compound 10 1-Acetyl-4-bromoindole-3-acetate Compound 11 1-Acetyl-5-bromoindole-3-acetate Compound 12 1-Acetyl-6-bromoindole-3-acetate Compound 13 1-Acetyl-7-bromoindole-3-acetate

[0065] The present invention provides an application of a 1-acetyl-1H-indol-3-yl acetate derivative as an aldose reductase inhibitor in the preparation of a drug for treating diabetic nephropathy.

[0066] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0067] Example 1

[0068] Preparation of 1-acetyl-1H-indol-3-yl acetate (Compound 1, AIA)

[0069] 1) Compound b: 15.6 g of 2-chlorobenzoic acid (0.1 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 11.3 g of glycine (0.15 mol) and 9.5 g of copper powder (0.15 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 75°C for 3 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, and the precipitate was collected and dried at 60°C for 3 hours to obtain 18.0 g of the product with a yield of 92.5%.

[0070] 2) Compound c: 18.0 g of the product from the previous step (0.092 mol) was added to the reactor, and 19.1 g of potassium carbonate (0.138 mol) / 180 mL of aqueous solution was added. After stirring evenly, 15 mL of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 50°C for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 3. The mixture was filtered, the filter cake was collected, and dried at 60°C for 3 hours to obtain 20.36 g of the product with a yield of 93.3%.

[0071] 3) Compound d: 20.36 g of the product from the previous step (0.086 mol) was added to the reactor, followed by 85 mL of acetic anhydride and 21 mL of triethylamine. The mixture was stirred and slowly heated to 80°C. The reaction was carried out under temperature control for 2 hours. After the reaction was completed, the mixture was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. The product was then recrystallized with ethanol, filtered, collected, and dried to obtain 18.3 g of the product, with a yield of 91.5% and a purity of 99.42%.

[0072] Example 2

[0073] 1-Acetyl-4-fluoroindole-3-acetate (Compound 2)

[0074] 1) Compound b: 15.8 g of 2,6-difluorobenzoic acid (0.1 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 9.5 g of copper powder (0.15 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 70°C for 4 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, the precipitate was collected, and dried at 60°C for 3 hours to obtain 19.2 g of the product, with a yield of 90.1%.

[0075] 2) Compound c: 19.2 g of the product from the previous step (0.090 mol) was added to a reactor, and 18.9 g of potassium carbonate (0.137 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 mL of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 20°C for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 2. The mixture was filtered, the filter cake was collected, and dried at 60°C for 3 hours to obtain 20.9 g of the product with a yield of 91.2%.

[0076] 3) Compound d: 20.9 g of the product from the previous step (0.082 mol) was added to the reactor, followed by 83 mL of acetic anhydride and 20 mL of triethylamine. The temperature was slowly raised to 80°C under stirring and the reaction was carried out for 2 hours under temperature control. After the reaction was completed, the product was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. Then the product was recrystallized with ethanol, filtered, collected, and dried to obtain 18.2 g of the product, with a yield of 88.3% and a purity of 99.12%.

[0077] Example 3

[0078] 1-Acetyl-5-fluoroindole-3-acetate (Compound 3)

[0079] 1) Compound b: 15.8 g of 2,5-difluorobenzoic acid (0.1 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 9.5 g of copper powder (0.15 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 70°C for 3 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, the precipitate was collected, and dried at 60°C for 3 hours to obtain 19.4 g of the product, with a yield of 91.1%.

[0080] 2) Compound c: 19.4 g of the product from the previous step (0.091 mol) was added to a reactor, and 18.9 g of potassium carbonate (0.137 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 mL of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 15°C for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 3. The mixture was filtered, the filter cake was collected, and dried at 60°C for 3 hours to obtain 21.2 g of the product with a yield of 91.2%.

[0081] 3) Compound d: 21.2 g of the product from the previous step (0.083 mol) was added to the reactor, followed by 83 mL of acetic anhydride and 20 mL of triethylamine. The mixture was stirred and slowly heated to 80°C. The reaction was carried out under temperature control for 2 hours. After the reaction was completed, the mixture was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. The product was then recrystallized with ethanol, filtered, collected, and dried to obtain 20.9 g of the product, with a yield of 91.5% and a purity of 99.16%.

[0082] Example 4

[0083] 1-Acetyl-6-fluoroindole-3-acetate (Compound 4)

[0084] 1) Compound b: 15.8 g of 2,4-difluorobenzoic acid (0.1 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 9.5 g of copper powder (0.15 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 70°C for 4 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, the precipitate was collected, and dried at 60°C for 3 hours to obtain 19.1 g of the product, with a yield of 89.5%.

[0085] 2) Compound c: 19.1 g of the product from the previous step (0.090 mol) was added to a reactor, and 18.9 g of potassium carbonate (0.137 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 mL of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 0°C for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 2. The mixture was filtered, the filter cake was collected, and dried at 60°C for 3 hours to obtain 20.8 g of the product with a yield of 90.5%.

[0086] 3) Compound d: 20.8 g of the product from the previous step (0.082 mol) was added to the reactor, followed by 83 mL of acetic anhydride and 20 mL of triethylamine. The temperature was slowly raised to 80°C under stirring and the reaction was carried out for 2 hours under temperature control. After the reaction was completed, the product was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. Then the product was recrystallized with ethanol, filtered, collected, and dried to obtain 18.9 g of the product, with a yield of 92.4% and a purity of 99.04%.

[0087] Example 5

[0088] 1-Acetyl-7-fluoroindole-3-acetate (Compound 5)

[0089] 1) Compound b: 15.8 g of 2,3-difluorobenzoic acid (0.1 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 9.5 g of copper powder (0.15 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 70°C for 3 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, the precipitate was collected, and dried at 60°C for 3 hours to obtain 19.9 g of the product, with a yield of 93.5%.

[0090] 2) Compound c: 19.9 g of the product from the previous step (0.094 mol) was added to a reactor, and 18.9 g of potassium carbonate (0.137 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 mL of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 30°C for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 2. The mixture was filtered, the filter cake was collected, and dried at 60°C for 3 hours to obtain 21.5 g of the product with a yield of 89.6%.

[0091] 3) Compound d: 21.5 g of the product from the previous step (0.084 mol) was added to the reactor, followed by 83 mL of acetic anhydride and 20 mL of triethylamine. The temperature was slowly raised to 80°C under stirring and the reaction was carried out for 2 hours under temperature control. After the reaction was completed, the product was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. Then the product was recrystallized with ethanol, filtered, collected, and dried to obtain 19.5 g of the product, with a yield of 92.6% and a purity of 99.13%.

[0092] Example 6

[0093] 1-Acetyl-4-chloroindole-3-acetate (Compound 6)

[0094] 1) Compound b: 19.1 g of 2,6-dichlorobenzoic acid (0.1 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 6.4 g of copper powder (0.10 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 60°C for 3 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, the precipitate was collected, and dried at 60°C for 3 hours to obtain 20.5 g of the product, with a yield of 89.3%.

[0095] 2) Compound c: 20.5 g of the product from the previous step (0.089 mol) was added to a reactor, and 18.9 g of potassium carbonate (0.137 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 mL of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 45°C for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 3. The mixture was filtered, the filter cake was collected, and dried at 60°C for 3 hours to obtain 22.0 g of the product with a yield of 91.2%.

[0096] 3) Compound d: 22.0 g of the product from the previous step (0.081 mol) was added to the reactor, followed by 83 mL of acetic anhydride and 20 mL of triethylamine. The mixture was stirred and slowly heated to 80°C. The reaction was controlled for 2 hours. After the reaction was completed, the mixture was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. The product was then recrystallized with ethanol, filtered, collected, and dried to obtain 19.6 g of the product, with a yield of 90.3% and a purity of 99.21%.

[0097] Example 7

[0098] 1-Acetyl-5-chloroindole-3-acetate (Compound 7)

[0099] 1) Compound b: 19.1 g of 2,5-dichlorobenzoic acid (0.1 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 6.4 g of copper powder (0.10 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 60°C for 4 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, the precipitate was collected, and dried at 60°C for 3 hours to obtain 20.4 g of the product, with a yield of 89.1%.

[0100] 2) Compound c: 20.4 g of the product from the previous step (0.089 mol) was added to a reactor, and 18.7 g of potassium carbonate (0.135 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 ml of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 60° C. for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH=3. The mixture was filtered, the filter cake was collected, and dried at 60° C. for 3 hours to obtain 21.8 g of the product with a yield of 90.3%.

[0101] 3) Compound d: 21.8 g of the product from the previous step (0.081 mol) was added to the reactor, followed by 83 mL of acetic anhydride and 20 mL of triethylamine. The mixture was stirred and slowly heated to 80°C. The reaction was carried out under temperature control for 2 hours. After the reaction was completed, the mixture was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. The product was then recrystallized with ethanol, filtered, collected, and dried to obtain 19.3 g of the product, with a yield of 89.1% and a purity of 99.24%.

[0102] Example 8

[0103] 1-Acetyl-6-chloroindole-3-acetate (Compound 8)

[0104] 1) Compound b: 19.1 g of 2,4-dichlorobenzoic acid (0.1 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 6.4 g of copper powder (0.10 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 60°C for 3 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, and the precipitate was collected and dried at 60°C for 3 hours to obtain 20.2 g of the product with a yield of 88.1%.

[0105] 2) Compound c: 20.2 g of the product from the previous step (0.088 mol) was added to the reactor, and 18.2 g of potassium carbonate (0.132 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 ml of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 35°C for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 3. The mixture was filtered, the filter cake was collected, and dried at 60°C for 3 hours to obtain 21.3 g of the product with a yield of 89.2%.

[0106] 3) Compound d: 21.3 g of the product from the previous step (0.078 mol) was added to the reactor, followed by 83 mL of acetic anhydride and 20 mL of triethylamine. The temperature was slowly raised to 80°C under stirring and the reaction was carried out for 2 hours under temperature control. After the reaction was completed, the product was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. Then the product was recrystallized with ethanol, filtered, collected, and dried to obtain 19.1 g of the product, with a yield of 91.5% and a purity of 99.35%.

[0107] Example 9

[0108] 1-Acetyl-7-chloroindole-3-acetate (Compound 9)

[0109] 1) Compound b: 19.1 g of 2,3-dichlorobenzoic acid (0.1 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 6.4 g of copper powder (0.10 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 60°C for 4 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, the precipitate was collected, and dried at 60°C for 3 hours to obtain 20.3 g of the product, with a yield of 88.3%.

[0110] 2) Compound c: 20.3 g of the product from the previous step (0.088 mol) was added to a reactor, and 18.9 g of potassium carbonate (0.137 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 ml of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 30°C for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 3. The mixture was filtered, the filter cake was collected, and dried at 60°C for 3 hours to obtain 22.0 g of the product with a yield of 92.1%.

[0111] 3) Compound d: 22.0 g of the product from the previous step (0.081 mol) was added to the reactor, followed by 83 mL of acetic anhydride and 20 mL of triethylamine. The mixture was stirred and slowly heated to 80°C. The reaction was carried out under temperature control for 2 hours. After the reaction was completed, the mixture was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. The product was then recrystallized with ethanol, filtered, collected, and dried to obtain 19.5 g of the product, with a yield of 89.9% and a purity of 99.15%.

[0112] Example 10

[0113] 1-Acetyl-4-bromoindole-3-acetate (Compound 10)

[0114] 1) Compound b: 28.0 g of 2,6-dibromobenzoic acid (0.10 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 3.2 g of copper powder (0.05 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 50°C for 3.5 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, the precipitate was collected, and dried at 60°C for 3 hours to obtain 24.0 g of the product, with a yield of 87.4%.

[0115] 2) Compound c: 24.0 g of the product from the previous step (0.088 mol) was added to a reactor, and 19.1 g of potassium carbonate (0.138 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 mL of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 40°C for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 2.5. The mixture was filtered, the filter cake was collected, and dried at 60°C for 3 hours to obtain 25.1 g of the product with a yield of 90.3%.

[0116] 3) Compound d: 25.1 g of the product from the previous step (0.079 mol) was added to the reactor, followed by 80 mL of acetic anhydride and 20 mL of triethylamine. The temperature was slowly raised to 80°C under stirring and the reaction was carried out for 2 hours under temperature control. After the reaction was completed, the product was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. Then the product was recrystallized with ethanol, filtered, collected, and dried to obtain 22.6 g of the product, with a yield of 91.5% and a purity of 99.07%.

[0117] Embodiment 11

[0118] 1-Acetyl-5-bromoindole-3-acetate (Compound 11)

[0119] 1) Compound b: 28.0 g of 2,5-dibromobenzoic acid (0.10 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 3.2 g of copper powder (0.05 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 50°C for 4 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, the precipitate was collected, and dried at 60°C for 3 hours to obtain 24.5 g of the product, with a yield of 89.4%.

[0120] 2) Compound c: 24.5 g of the product from the previous step (0.089 mol) was added to a reactor, and 19.1 g of potassium carbonate (0.138 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 mL of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 20°C for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 3. The mixture was filtered, the filter cake was collected, and dried at 60°C for 3 hours to obtain 25.4 g of the product with a yield of 90.4%.

[0121] 3) Compound d: 25.4 g of the product from the previous step (0.080 mol) was added to the reactor, followed by 80 mL of acetic anhydride and 20 mL of triethylamine. The mixture was stirred and slowly heated to 80°C. The reaction was controlled for 2 hours. After the reaction was completed, the mixture was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. The product was then recrystallized with ethanol, filtered, collected, and dried to obtain 23.1 g of the product, with a yield of 92.6% and a purity of 99.11%.

[0122] Example 12

[0123] 1-Acetyl-6-bromoindole-3-acetate (Compound 12)

[0124] 1) Compound b: 28.0 g of 2,4-dibromobenzoic acid (0.10 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 3.2 g of copper powder (0.05 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 50°C for 3 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, the precipitate was collected, and dried at 60°C for 3 hours to obtain 24.2 g of the product, with a yield of 88.4%.

[0125] 2) Compound c: 24.2 g of the product from the previous step (0.088 mol) was added to a reactor, and 19.1 g of potassium carbonate (0.138 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 mL of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 45°C for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 2. The mixture was filtered, the filter cake was collected, and dried at 60°C for 3 hours to obtain 25.2 g of the product with a yield of 90.5%.

[0126] 3) Compound d: 25.2 g of the product from the previous step (0.080 mol) was added to the reactor, followed by 80 mL of acetic anhydride and 20 mL of triethylamine. The temperature was slowly raised to 80°C under stirring and the reaction was carried out for 2 hours under temperature control. After the reaction was completed, the product was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. Then the product was recrystallized with ethanol, filtered, collected, and dried to obtain 23.2 g of the product, with a yield of 93.1% and a purity of 99.22%.

[0127] Example 13

[0128] 1-Acetyl-7-bromoindole-3-acetate (Compound 13)

[0129] 1) Compound b: 28.0 g of 2,3-dibromobenzoic acid (0.10 mol) and 100 mL of dimethylformamide were added to the reactor, stirred evenly, and then 7.5 g of glycine (0.10 mol) and 3.2 g of copper powder (0.05 mol) were added in sequence, and then 20.7 potassium carbonate (0.15 mol) was added to the suspension, heated at 50°C for 4 hours, and the reaction was stopped after the reaction was complete. The mixture was poured into 100 ml of 1:1 dilute hydrochloric acid, stirred for 30 minutes, the precipitate was collected, and dried at 60°C for 3 hours to obtain 24.0 g of the product, with a yield of 87.5%.

[0130] 2) Compound c: 24.0 g of the product from the previous step (0.088 mol) was added to a reactor, and 19.1 g of potassium carbonate (0.138 mol) / 190 mL of aqueous solution was added. After stirring evenly, 15 mL of acetic anhydride was added dropwise using a constant pressure funnel. After the addition was complete, stirring was continued at 55° C. for 1 hour, and 1:1 hydrochloric acid was added to acidify to pH = 2. The mixture was filtered, the filter cake was collected, and dried at 60° C. for 3 hours to obtain 24.8 g of the product with a yield of 89.7%.

[0131] 3) Compound d: 24.8 g of the product from the previous step (0.078 mol) was added to the reactor, followed by 80 mL of acetic anhydride and 20 mL of triethylamine. The mixture was stirred and slowly heated to 80°C. The reaction was carried out under temperature control for 2 hours. After the reaction was completed, the mixture was distilled under reduced pressure until there was no distillate. The concentrate was poured into 400 ml of water, left overnight, filtered, the solid was collected, and dried at 60°C for 3 hours. The product was then recrystallized with ethanol, filtered, collected, and dried to obtain 22.6 g of the product, with a yield of 92.8% and a purity of 99.07%.

[0132] Experimental Example 1

[0133] IC50 Determination of Aldose Reductase Inhibitors of 1-Acetyl-1H-Indol-3-yl Acetate Derivatives

[0134] 1) ARIs activity assay system: The enzymatic reaction system was composed as follows: the total volume was 1 mL, including 100 μL of 5 mM DL-glyceraldehyde, 100 μL of 0.15 mM NADPH, 100 μL of AR, 100 μL of 0.6 mM lithium sulfate, and the rest was supplemented with 0.1 M phosphate buffer (pH 6.2). The reaction time was 1 min and the reaction temperature was 37 °C, as shown in Table 2.

[0135] Table 2 Aldose reductase inhibitor screening model

[0136]

[0137]

[0138] Determination of ARIs activity: The target compounds 1-13 were dissolved in PB buffer and diluted to various concentration gradients. An appropriate amount of DMSO was added to assist dissolution, and the DMSO content in the test system did not exceed 5%. Epalrestat was used as a positive control to measure the AR inhibition rate at various concentrations of compounds 1-13, and the inhibition percentage was plotted against the inhibitor concentration. Based on the inhibition curves, the IC50 of Epalrestat and compounds 1-13 was obtained, as shown in Table 3 below.

[0139] Table 3 IC50 of aldose reductase inhibitors of 1-acetyl-1H-indol-3-yl acetate derivatives

[0140] Compound Name <![CDATA[IC50 / (×10 -2 μM)]]> 1-Acetyl-1H-indol-3-yl acetate (Compound 1, AIA) 2.4 1-Acetyl-4-fluoroindole-3-acetate (Compound 2) 5.5 1-Acetyl-5-fluoroindole-3-acetate (Compound 3) 4.6 1-Acetyl-6-fluoroindole-3-acetate (Compound 4) 4.2 1-Acetyl-7-fluoroindole-3-acetate (Compound 5) 5.1 1-Acetyl-4-chloroindole-3-acetate (Compound 6) 3.5 1-Acetyl-5-chloroindole-3-acetate (Compound 7) 2.7 1-Acetyl-6-chloroindole-3-acetate (Compound 8) 2.2 1-Acetyl-7-chloroindole-3-acetate (Compound 9) 3.6 1-Acetyl-4-bromoindole-3-acetate (Compound 10) 7.8 1-Acetyl-5-bromoindole-3-acetate (Compound 11) 7.1 1-Acetyl-6-bromoindole-3-acetate (Compound 12) 7.3 1-Acetyl-7-bromoindole-3-acetate (Compound 13) 8.1 Epalrestat 10.6

[0141] Experimental Example 2

[0142] Effect of AIA on apoptosis of glomerular mesangial cells (HBZY-1)

[0143] 1) Establishment of high glucose-induced apoptosis model: Methods: HBZY-1 cells were cultured at 10 4 The cells were inoculated at a density of 100 / well in a 96-well plate. After culturing for 12 hours, the cells were completely attached to the wall, the culture medium was discarded, and DMEM culture medium containing different glucose concentrations (22mM, 33mM, 44mM) was added and cultured for 24h, 36h, 72h, and 96h. The cell apoptosis was detected by MTT method to determine the best conditions for high glucose-induced cell apoptosis. Results: The experiment determined that compared with the control group, the inhibitory effect on HBZY-1 cells was most significant when the sugar concentration was 33mM and cultured for 72h, and there was no more obvious change in cell damage when the culture time was extended.

[0144] Effect of AIA on the proliferation of glomerular mesangial cells (HBZY-1) 4 The cells were seeded at a density of 100 / well in a 96-well plate and incubated at 37°C with 5% CO 2After 12 hours of culture, when the cells are completely attached, the culture medium is discarded, and the cells are treated with different concentrations of AIA drugs for 1 hour. 3-5 duplicate wells are set, and zero wells (culture medium, MTT, dimethyl sulfoxide) and control wells (cells, drug dissolution medium of the same concentration, culture medium, MTT, dimethyl sulfoxide) are set at the same time; 33mmol / L glucose is added, and 15μl MTT (5mg / mL, i.e. 0.5% MTT) is added to each well 4 hours before the end of cell culture. After the end of culture, the culture medium is aspirated, and 150μl DMSO is added to each well. The wells are placed on a 37°C shaker and shaken at a low speed for 10 minutes to fully dissolve the crystals, and the absorbance of each well is measured at OD490nm on an enzyme-linked immunosorbent assay. Experimental groups: ① blank control group (NS, DMEM low-glucose medium); ② high-glucose induced group (HG, DMEM low-glucose medium + 33mM glucose); ③ AIA administration group (low-dose AL-0.3μM, medium-dose AM-0.6μM, high-dose AH-0.9μM); ④ EPS-10μM positive control group; the above groups were induced for more than 24h, digested with 0.05% trypsin to a single cell suspension, and the cell concentration was adjusted to 10 6 Each group was cultured at a sugar concentration of 33 mmol / L for 72 hours and the results were measured.

[0145] Experimental results: Compared with the NS group, the OD values ​​of each experimental group decreased, HG, AL, AM, EPS groups P < 0.001, AH group P < 0.05. Compared with the HG group, the OD values ​​of the AM and EPS groups increased significantly P < 0.05, and the OD value of the AH group increased most significantly P < 0.01.

[0146] Application Example 1

[0147] Preparation of AIA oral capsules

[0148] Raw material ratio of oral capsules:

[0149]

[0150] Made into 1000 tablets

[0151] Preparation filling: Take 300 grams of AIA passed through a 100-mesh sieve and mix it evenly with 30 grams of starch, add an appropriate amount of 50% ethanol, stir, pass through an 18-mesh sieve, make granules with appropriate tightness, dry at 60-70°C, pass the dry granules through a 16-mesh sieve, add 3.0 grams of magnesium stearate and mix well, make 1000 granules, determine the content, and fill.

[0152] Application Example 2

[0153] Preparation of AIA tablets

[0154] Raw material ratio of oral tablets:

[0155]

[0156] 1000 pieces

[0157] Preparation filling: Take 200 grams of AIA passed through a 100-mesh sieve and mix it evenly with 30 grams of starch, add an appropriate amount of 50% ethanol, stir, pass through an 18-mesh sieve, and make granules with appropriate tightness, dry at 60-70°C, pass the dry granules through a 16-mesh sieve, add 3.0 grams of magnesium stearate and mix well, and make 1000 granules, determine the moisture and content, press into tablets, and package after inspection.

[0158] As can be seen from the above embodiments, the present invention provides a synthesis method and application of 1-acetyl-1H-indol-3-yl acetate derivatives. The present invention uses halogenated benzoic acid as a raw material, reacts with glycine under alkaline conditions by metal catalysis, then acylates with acetic anhydride under alkaline conditions, and finally cyclizes with acetic anhydride by organic base catalysis to obtain a crude product, and the crude product is recrystallized in an alcohol solvent to obtain a 1-acetyl-1H-indol-3-yl acetate derivative; the derivative is used as an aldose reductase inhibitor for preparing a candidate drug molecule for treating diabetic nephropathy. The synthesis method of the present invention is simple to operate, the raw materials are easily available, the yield is high, the purity is high, the cost is low, and it is beneficial to mass production.

[0159] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Use of a 1-acetyl-1H-indol-3-yl acetate derivative as an aldose reductase inhibitor in the preparation of a drug for treating diabetic nephropathy, characterized in that: The general structural formula of the 1-acetyl-1H-indol-3-yl acetate derivative is shown below: Wherein, R is H, F, Cl or Br.

2. The use according to claim 1, characterized in that: The synthetic route of the 1-acetyl-1H-indol-3-yl acetate derivative is as follows: ； The synthesis method of the 1-acetyl-1H-indol-3-yl acetate derivative comprises the following steps: 1) reacting halogenated benzoic acid and glycine in the presence of carbonate and metal powder to obtain compound b; 2) Compound b is subjected to an acylation reaction with acetic anhydride under alkaline conditions to obtain compound c; 3) Compound c is reacted with acetic anhydride in the presence of an organic base to undergo a cyclization reaction to obtain a 1-acetyl-1H-indol-3-yl acetate derivative; Wherein, R is H, F, Cl or Br; In the step 1), the reaction temperature is 50-75°C, and the reaction time is 3-4 hours; the molar ratio of the halogenated benzoic acid, glycine, carbonate and metal powder is 0.1:0.1-0.2:0.1-0.2:0.01-0.3; In the step 2), the alkaline condition is an alkaline solution, the concentration of the alkaline solution is 0.65-0.8 mol / L; the molar volume ratio of the compound b and acetic anhydride is 0.08-0.1 mol:15 mL; In the step 3), the molar volume ratio of the compound c, acetic anhydride and organic base is 0.07-0.09 mol: 80-90 mL: 18-22 mL.

3. The use according to claim 2, characterized in that: The halogenated benzoic acid comprises one or more of o-fluorobenzoic acid, o-chlorobenzoic acid, o-bromobenzoic acid, 2,6-difluorobenzoic acid, 2,6-dichlorobenzoic acid and 2,6-dibromobenzoic acid.

4. The use according to claim 2, characterized in that: The reaction in step 1) is carried out in a solvent, and the solvent comprises dimethylformamide and / or diisopropylethylamine.

5. The use according to claim 4, characterized in that: The carbonate comprises one or more of lithium carbonate, sodium carbonate and potassium carbonate; the metal powder comprises copper powder and / or iron powder.

6. The use according to claim 4 or 5, characterized in that: The molar volume ratio of the glycine to the solvent is 0.1-0.2 mol:100 mL.

7. The use according to claim 6, characterized in that: In the step 2), the alkaline condition is an alkaline solution, and the alkaline solution includes one or more of a potassium carbonate solution, a sodium carbonate solution and a lithium carbonate solution.

8. The use according to claim 2 or 3 or 5 or 7, characterized in that: In the step 2), the temperature of the acylation reaction is 0-60° C., and the time of the acylation reaction is 1-12 hours.

9. The use according to claim 8, characterized in that: In the step 3), the organic base comprises one or more of triethylamine, ethylenediamine and pyridine.

10. The use according to claim 9, characterized in that: In the step 3), the temperature of the ring-closing reaction is 60-90° C., and the time of the ring-closing reaction is 1-6 hours.

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