A process for the preparation of 5-cyanoindoles

Abstract

The application discloses a preparation method of 5-cyanoindole, S1) o-chloroaniline and dimethyl malonate are dissolved and subjected to catalytic reaction to prepare dimethyl 2-(2-aminophenyl)malonate; S2) dimethyl 2-(2-aminophenyl)malonate is dissolved, hydrolysis reaction is carried out by adding alkali, and then high-temperature decarboxylation reaction is carried out by adding acid to prepare o-aminophenylacetic acid; S3) o-aminophenylacetic acid is dissolved and subjected to amino para-bromination to prepare 2-(2-amino-5-bromophenyl)acetic acid; S4) 2-(2-amino-5-bromophenyl)acetic acid is dissolved, and intramolecular condensation is carried out by adding a condensing agent to prepare 5-bromo-oxindole; S5) 5-bromo-oxindole is subjected to reduction reaction to prepare 5-bromoindoline; S6) 5-bromoindoline is subjected to oxidation reaction to prepare 5-bromoindole; and S7) substitution reaction is carried out on the bromine of 5-bromoindole by using cyano to prepare 5-cyanoindole. The application has the advantages of simple process, environmental protection, no pollution, low cost, safe operation, easy scale production, mild reaction condition, high conversion rate and good product quality.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing 5-cyanoindole. Background Technology

[0002] 5-Cyanoynindole is an important chemical and pharmaceutical intermediate, attracting widespread attention due to its extensive use in synthesizing drug molecules for various diseases, such as depression, malignant tumors, leukemia, and cardiovascular diseases. The synthesis of 5-cyanoynindole typically involves diazotization and reduction of p-cyanoaniline to prepare cyanophenylhydrazine, followed by cyclization with an aldehyde. The process is shown below:

[0003]

[0004] Although this method is low-cost and quick, it is extremely dangerous, not conducive to large-scale production, and cannot meet the growing market demand. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing 5-cyanoindole to solve the problems mentioned in the background art.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is: a method for preparing 5-cyanoindole, comprising the following steps:

[0007] S1) Dissolve o-chloroaniline and dimethyl malonate, and carry out a catalytic reaction to obtain dimethyl 2-(2-aminophenyl)malonate;

[0008] S2) Dissolve dimethyl 2-(2-aminophenyl)malonate, add alkali to carry out hydrolysis, and then add acid to carry out high-temperature decarboxylation to obtain o-aminophenylacetic acid;

[0009] S3) Dissolve o-aminophenylacetic acid and perform para-bromination of the amino group to obtain 2-(2-amino-5-bromophenyl)acetic acid;

[0010] S4) Dissolve 2-(2-amino-5-bromophenyl)acetic acid, add a condensing agent to perform intramolecular condensation, and obtain 5-bromoindole oxyoxygenate;

[0011] S5) 5-Bromo-indoline was prepared by reducing 5-bromo-oxy-indoline.

[0012] S6) Oxidation of 5-bromoindoline yields 5-bromoindoline;

[0013] S7) 5-Cyanoidole was prepared by substituting the bromine of 5-bromoindole with a cyano group.

[0014] As a further optimization, in S1, the molar ratio of o-chloroaniline to dimethyl malonate is (0.5-1):1; the solvent is one or more of methanol, ethanol, isopropanol, tert-butanol, DMF and ethyl acetate, and its weight ratio with o-chloroaniline is (1-10):1; the catalyst is a basic reagent, and its molar ratio with o-chloroaniline is (1-5):1.

[0015] As a further optimization, the reaction temperature in S1 is 20-100℃, and the reaction time is 1-24 hours, preferably 80-100℃ for 24 hours.

[0016] As a further optimization, in S2, the solvent is water, methanol, or ethanol, and its weight ratio with dimethyl 2-(2-aminophenyl)malonate is (1-10):1; the base is one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide, and its molar ratio with dimethyl 2-(2-aminophenyl)malonate is (2-5):1; the acid is one or more of hydrochloric acid, sulfuric acid, and acetic acid, and its molar ratio with dimethyl 2-(2-aminophenyl)malonate is (5-20):1.

[0017] As a further optimization, the decarboxylation reaction temperature in S2 is 80-100℃.

[0018] As a further optimization, in S3, the solvent is DMF, acetone, dichloromethane or THF, and its weight ratio with o-aminophenylacetic acid is (3-10):1; the brominating agent is NBS, DBH or bromine, and its molar ratio with o-aminophenylacetic acid is (0.5-3):1.

[0019] As a further optimization, in S4, the solvent is one or more of dichloromethane, THF, DMF and toluene, with a weight ratio of (1-10):1 to 2-(2-amino-5-bromophenyl)acetic acid; the condensing agent is one or more of CDI, EDCI, DCC and HBTU, with a molar ratio of (1-2):1 to 2-(2-amino-5-bromophenyl)acetic acid.

[0020] As a further optimization, in S5, the reducing agent is lithium aluminum hydride, dimethyl sulfide borane, boron trifluoride ether, or sodium borohydride, with a molar ratio of (1-3):1 to 5-bromoindole; the solvent used in the reduction reaction is DMF, THF, or DMSO, with a weight ratio of (1-10):1 to 5-bromoindole.

[0021] As a further optimization, in S6, when the oxidant is manganese dioxide or DDQ, its molar ratio with 5-bromoindoline is (1-5):1; when the oxygen / catalyst system is used, it is O2 / LiOH or O2 / 10%Pt / C, and the weight ratio of catalyst to 5-bromoindoline is (0.1-0.5):1.

[0022] As a further optimization, in S6, the solvent used for the oxidation reaction is dichloromethane, THF, toluene, or water, with a weight ratio of (1-10):1 to 5-bromoindoline.

[0023] As a further optimization, in S7, a cyaniding agent is used, which is sodium cyanide, potassium cyanide or cuprous cyanide, and its molar ratio with 5-bromoindole is (1-3):1; the solvent used in the reaction is DMF, DMSO or toluene, and its weight ratio with 5-bromoindole is (1-10):1.

[0024] The specific preparation process of this invention is as follows:

[0025]

[0026] Compared with existing technologies, the beneficial effects of this invention are reflected in:

[0027] 1. The method of the present invention is simple, easy to operate, environmentally friendly and pollution-free, low in cost, safe to operate, and easy to scale up for industrial production;

[0028] 2. The reaction conditions of this invention are mild, the conversion rate is high, and the product quality is good. Detailed Implementation

[0029] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention, but the present invention is not limited to these embodiments.

[0030] Example 1

[0031] A method for preparing 5-cyanoindole includes: S1) adding 650g of ethanol, 102g of o-chloroaniline and 132g of dimethyl malonate to a three-necked flask, adding 183g of 30% sodium ethoxide ethanol solution dropwise, refluxing for 24 hours, detecting the end of the reaction, filtering the reaction solution, drying the filtrate, adding water, extracting twice with EA, washing twice with 10% sodium hydroxide aqueous solution, washing once with water, drying to obtain 178g of dimethyl 2-(2-aminophenyl)malonate (100%);

[0032] S2) Add 178g of dimethyl 2-(2-aminophenyl)malonate, 1.8L of water, and 159g of sodium hydroxide to a bottle. React at 50°C for 3 hours. After the reaction is complete, cool down to 10°C and add 809g of concentrated hydrochloric acid to adjust the pH to strong acidity. Heat up to 100°C and react for 10 hours. After the reaction is complete, cool down to 20°C and extract twice with ethyl acetate. Combine the organic phases, wash twice with water, wash once with saturated brine, and concentrate to dryness to obtain 102g of o-aminophenylacetic acid (84.8%).

[0033] S3) Add 800g DMF and 102g o-aminophenylacetic acid to the bottle, and slowly add 120g NBS in portions at room temperature. After the addition is complete, react at room temperature for 1 hour. When the reaction is finished, pour the reaction solution into water, extract three times with EA, combine the organic phases, wash three times with water, dry, and evaporate to dryness to obtain 147g 2-(2-amino-5-bromophenyl)acetic acid (94.7%).

[0034] S4) Add 1400g of dichloromethane and 147g of 2-(2-amino-5-bromophenyl)acetic acid to a bottle, place in a water bath at 20°C, and slowly add 103.5g of CDI in batches. After the addition is complete, react at 20°C for 2 hours. When the reaction is complete, add water, separate the layers, wash the organic layer twice with water, dry, and evaporate to dryness to obtain 130g of 5-bromoindole oxychloride (96%).

[0035] S5) Add 1300g THF and 130g 5-bromoindoline to a bottle, place in an ice bath at 0℃, slowly add 75mL 10M borane dimethyl sulfide, and react at 20℃ for 6 hours after the addition is complete. After the reaction is complete, slowly add 30g concentrated hydrochloric acid, stir for 2 hours, add water, extract three times with EA, wash the organic layer twice with water, dry, and evaporate to dryness to obtain 111.7g 5-bromoindoline (92%).

[0036] S6) Add 1200g dichloromethane, 111.7g 5-bromoindoline, and 49g active manganese dioxide to a bottle. After the addition is complete, react at 30℃ for 24 hours. When the reaction is finished, filter the reaction solution and evaporate the filtrate to dryness to obtain 110g 5-bromoindoline (100%).

[0037] S7) Add 1100g DMF, 110g 5-bromoindole, and 75.4g cuprous cyanide to a flask. After the addition is complete, react at 140℃ for 6 hours. When the reaction is complete, add 3kg of water to the reaction solution, filter, and extract the filtrate three times with EA. Combine the organic phases, wash the organic phase three times with water, dry the organic phase, evaporate to dryness, and recrystallize to obtain 66g of 5-cyanoindole (83%).

[0038] Example 2

[0039] A method for preparing 5-cyanoindole includes: S1) adding 650g of ethanol, 102g of o-chloroaniline and 132g of dimethyl malonate to a three-necked flask, adding 145g of 30% sodium methoxide methanol solution dropwise, refluxing for 24 hours, detecting the end of the reaction, filtering the reaction solution, drying the filtrate, adding water, extracting twice with EA, washing twice with 10% sodium hydroxide aqueous solution, washing once with water, drying to obtain 178g of dimethyl 2-(2-aminophenyl)malonate (100%);

[0040] S2) Add 178g of dimethyl 2-(2-aminophenyl)malonate, 1.8L of water, 300g of ethanol, and 220g of sodium hydroxide to a bottle. React at 50°C for 3 hours. After the reaction is complete, cool down to 10°C, add 800g of concentrated hydrochloric acid to adjust the pH to strong acidity, raise the temperature to 90°C, and react for 10 hours. After the reaction is complete, cool down to 20°C, extract twice with ethyl acetate, combine the organic phases, wash twice with water, wash once with saturated brine, and concentrate to dryness to obtain 98g of o-aminophenylacetic acid (81.5%).

[0041] S3) Add 800g acetone and 98g o-aminophenylacetic acid to the bottle, and slowly add 115g NBS in portions at room temperature. After the addition is complete, react at room temperature for 1 hour. When the reaction is finished, pour the reaction solution into water, extract three times with EA, combine the organic phases, wash three times with water, dry, and evaporate to dryness to obtain 139.8g 2-(2-amino-5-bromophenyl)acetic acid (93.7%).

[0042] S4) Add 1400g of dichloromethane and 139.8g of 2-(2-amino-5-bromophenyl)acetic acid to a bottle, place in a water bath at 20°C, and slowly add 116.2g of EDCI in batches. After the addition is complete, react at 20°C for 2 hours. When the reaction is complete, add water, separate the layers, wash the organic layer twice with water, dry, and evaporate to dryness to obtain 125g of 5-bromoindole oxychloride (97%).

[0043] S5) Add 1250g THF and 125g 5-bromoindoline to a bottle, place in an ice bath at 0℃, slowly add 70mL of 10M borane dimethyl sulfide, and react at 20℃ for 6 hours after the addition is complete. After the reaction is complete, slowly add 30g concentrated hydrochloric acid, stir for 2 hours, add water, extract three times with EA, wash the organic layer twice with water, dry, and evaporate to dryness to obtain 106g 5-bromoindoline (91%).

[0044] S6) Add 1000g of dichloromethane, 106g of 5-bromoindoline, and 47g of active manganese dioxide to a bottle. After the addition is complete, react at 30°C for 24 hours. When the reaction is complete, filter the reaction solution and evaporate the filtrate to dryness to obtain 104g of 5-bromoindoline (100%).

[0045] S7) Add 1000g DMF, 104g 5-bromoindole, and 71.3g cuprous cyanide to a flask. After the addition is complete, react at 140℃ for 6 hours. When the reaction is complete, add 3Kg water to the reaction solution, filter, and extract the filtrate three times with EA. Combine the organic phases, wash the organic phase three times with water, dry the organic phase, evaporate to dryness, and recrystallize to obtain 62.6g 5-cyanoindole (83%).

[0046] Example 3

[0047] A method for preparing 5-cyanoindole includes: S1) adding 650g DMF, 102g o-chloroaniline, 132g dimethyl malonate, and 330g potassium carbonate to a three-necked flask, heating to 100℃ and reacting for 24 hours, detecting the end of the reaction, filtering the reaction solution, evaporating most of the DMF from the filtrate under reduced pressure, adding water, extracting twice with EA, washing twice with 10% sodium hydroxide aqueous solution, washing once with water, and drying to obtain 178g of dimethyl 2-(2-aminophenyl)malonate (100%);

[0048] S2) Add 178g of dimethyl 2-(2-aminophenyl)malonate, 1.8L of water, and 96g of lithium hydroxide to a bottle. React at 50°C for 3 hours. After the reaction is complete, cool down to 10°C, add 390g of concentrated sulfuric acid to adjust the pH to strong acidity, raise the temperature to 90°C, and react for 10 hours. After the reaction is complete, cool down to 20°C, extract twice with ethyl acetate, combine the organic phases, wash twice with water, wash once with saturated brine, and concentrate to dryness to obtain 95.2g of o-aminophenylacetic acid (79%).

[0049] S3) Add 800g of dichloromethane and 95.2g of o-aminophenylacetic acid to the bottle. Add 112g of NBS in portions at room temperature. After the addition is complete, react at room temperature for 1 hour. When the reaction is finished, pour the reaction solution into water, extract three times with EA, combine the organic phases, wash three times with water, dry, and evaporate to dryness to obtain 131.8g of 2-(2-amino-5-bromophenyl)acetic acid (91%).

[0050] S4) Add 1400g of dichloromethane and 131.8g of 2-(2-amino-5-bromophenyl)acetic acid to a bottle, heat in a water bath at 20°C, slowly add 118.2g of DCC in batches, and react at 20°C for 2 hours after the addition is complete. After the reaction is complete, add water, separate the layers, wash the organic layer with water twice, dry it, and evaporate it to dryness to obtain 117.8g of 5-bromoindole oxychloride (97%).

[0051] S5) Add 1200g THF and 117.8g 5-bromoindoline to a bottle, place in an ice bath at 0℃, slowly add 66mL 10M borane dimethyl sulfide, and react at 20℃ for 6 hours after the addition is complete. After the reaction is complete, slowly add 30g concentrated hydrochloric acid, stir for 2 hours, add water, extract three times with EA, wash the organic layer twice with water, dry, and evaporate to dryness to obtain 99.03g 5-bromoindoline (90%).

[0052] S6) Add 1000g dichloromethane, 99.03g 5-bromoindoline, and 10g 10% Pt / C to a 2L autoclave. Replace with nitrogen three times, purge with oxygen at 1.0MPa, and react at 60℃ for 24 hours. After the reaction is complete, filter the reaction solution and evaporate the filtrate to dryness to obtain 98.02g 5-bromoindoline (100%).

[0053] S7) Add 980g DMF, 98.02g 5-bromoindole, and 66.5g cuprous cyanide to a flask. After adding all the ingredients, react at 140℃ for 6 hours. Once the reaction is complete, add 3kg of water to the reaction solution, filter, and extract the filtrate three times with EA. Combine the organic phases, wash the organic phase three times with water, dry the organic phase, evaporate to dryness, and recrystallize to obtain 54g of 5-cyanoindole (76%).

[0054] Example 4

[0055] A method for preparing 5-cyanoindole includes: S1) adding 650g DMF, 102g o-chloroaniline, 132g dimethyl malonate, and 330g potassium carbonate to a three-necked flask, heating to 100℃ and reacting for 24 hours, detecting the end of the reaction, filtering the reaction solution, evaporating most of the DMF from the filtrate under reduced pressure, adding water, extracting twice with EA, washing twice with 10% sodium hydroxide aqueous solution, washing once with water, and drying to obtain 174.4g of dimethyl 2-(2-aminophenyl)malonate (98%);

[0056] S2) Add 174.4 g of dimethyl 2-(2-aminophenyl)malonate, 1.8 L of water, and 157 g of lithium hydroxide to a bottle. React at 50 °C for 3 hours. After the reaction is complete, cool down to 10 °C, add 390 g of concentrated sulfuric acid to adjust the pH to strong acidity, raise the temperature to 90 °C, and react for 10 hours. After the reaction is complete, cool down to 20 °C, extract twice with ethyl acetate, combine the organic phases, wash twice with water, wash once with saturated brine, and concentrate to dryness to obtain 97.36 g of o-aminophenylacetic acid (82.5%).

[0057] S3) Add 800g of dichloromethane and 97.36g of o-aminophenylacetic acid to the bottle, and slowly add 114.63g of NBS in portions at room temperature. After the addition is complete, react at room temperature for 1 hour. When the reaction is finished, pour the reaction solution into water, extract three times with EA, combine the organic phases, wash three times with water, dry, and evaporate to dryness to obtain 133.5g of 2-(2-amino-5-bromophenyl)acetic acid (90.2%).

[0058] S4) Add 1400g dichloromethane / 133.5g 2-(2-amino-5-bromophenyl)acetic acid to a bottle, heat in a water bath at 20°C, slowly add 92.74g CDI in batches, and react at 20°C for 2 hours after the addition is complete. After the reaction is complete, add water, separate the layers, wash the organic layer twice with water, dry, and evaporate to dryness to obtain 114.4g 5-bromoindole oxychloride (93%).

[0059] S5) Add 1200g THF and 114.4g 5-bromoindoline to a bottle, place in an ice bath at 0℃, slowly add 63mL 10M borane dimethyl sulfide, and react at 20℃ for 6 hours after the addition is complete. After the reaction is complete, slowly add 30g concentrated hydrochloric acid, stir for 2 hours, add water, extract three times with EA, wash the organic layer twice with water, dry, and evaporate to dryness to obtain 94.03g 5-bromoindoline (88%).

[0060] S6) Add 1000g dichloromethane, 94.03g 5-bromoindoline, and 9g 10% Pt / C to a 2L autoclave. Replace with nitrogen three times, purge with oxygen at 1.0MPa, and react at 60℃ for 24 hours. After the reaction is complete, filter the reaction solution and evaporate the filtrate to dryness to obtain 93.07g 5-bromoindoline (100%).

[0061] S7) Add 980g DMF, 93.07g 5-bromoindole, and 63.1g cuprous cyanide to a flask. After the addition is complete, react at 140℃ for 6 hours. When the reaction is complete, add 3kg of water to the reaction solution, filter, and extract the filtrate three times with EA. Combine the organic phases, wash the organic phase three times with water, dry the organic phase, evaporate to dryness, and recrystallize to obtain 55g 5-cyanoindole (81.5%).

[0062] This invention features simple process, easy operation, environmental protection and no pollution, low cost, safe operation, and easy industrial-scale production. It also has mild reaction conditions, high conversion rate, and good product quality.

[0063] The specific embodiments described herein are merely illustrative of the spirit of the invention. Those skilled in the art to which this invention pertains may make various modifications or additions to the described specific embodiments or use similar methods to substitute them, without departing from the spirit of the invention or exceeding the scope defined by the appended claims.

Claims

1. A process for the preparation of 5-cyanoindole, characterized in that, The method comprises the following steps: S1) dissolving o-chloroaniline and dimethyl malonate, and performing catalytic reaction to obtain dimethyl 2-(2-aminophenyl) propanedioate; S2) dissolving dimethyl 2-(2-aminophenyl) propanedioate, adding a base to perform hydrolysis reaction, and then adding an acid to perform high-temperature decarboxylation reaction to obtain o-aminophenylacetic acid; S3) dissolving o-aminophenylacetic acid, and performing amino para-bromination to obtain 2-(2-amino-5-bromophenyl) acetic acid, wherein the solvent is DMF, acetone, dichloromethane or THF, and the weight ratio of the solvent to o-aminophenylacetic acid is (3-10):1; the bromination reagent is NBS, DBH or bromine, and the molar ratio of the bromination reagent to o-aminophenylacetic acid is (0.5-3):1; S4) dissolving 2-(2-amino-5-bromophenyl) acetic acid, and adding a condensing agent to perform intramolecular condensation to obtain 5-bromo-oxindole; S5) performing reduction reaction on 5-bromo-oxindole to obtain 5-bromoindoline; S6) performing oxidation reaction on 5-bromoindoline to obtain 5-bromoindole; S7) performing substitution reaction on the bromine of 5-bromoindole by using a cyanation reagent to obtain 5-cyanoindole, wherein the cyanation reagent is sodium cyanide, potassium cyanide or cuprous cyanide, and the molar ratio of the cyanation reagent to 5-bromoindole is (1-3):1; the solvent used in the reaction is DMF, DMSO or toluene, and the weight ratio of the solvent to 5-bromoindole is (1-10):

1.

2. The process for the preparation of 5-cyanoindole according to claim 1, characterized in that, In S1, the molar ratio of o-chloroaniline to dimethyl malonate is (0.5-1):1; the solvent is one or more of methanol, ethanol, isopropanol, tert-butanol, DMF and ethyl acetate, and the weight ratio of the solvent to o-chloroaniline is (1-10):1; and the catalyst is a basic reagent, and the molar ratio of the catalyst to o-chloroaniline is (1-5):

1.

3. The process for the preparation of 5-cyanoindole according to claim 1, characterized in that, In S2, the solvent is water, methanol or ethanol, and the weight ratio of the solvent to dimethyl 2-(2-aminophenyl) propanedioate is (1-10):1; the base is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide, and the molar ratio of the base to dimethyl 2-(2-aminophenyl) propanedioate is (2-5):1; and the acid is one or more of hydrochloric acid, sulfuric acid and acetic acid, and the molar ratio of the acid to dimethyl 2-(2-aminophenyl) propanedioate is (5-20):

1.

4. The process for the preparation of 5-cyanoindole according to claim 1, characterized in that, In S4, the solvent is one or more of dichloromethane, THF, DMF and toluene, and the weight ratio of the solvent to 2-(2-amino-5-bromophenyl) acetic acid is (1-10):1; the condensing agent is one or more of CDI, EDCI, DCC and HBTU, and the molar ratio of the condensing agent to 2-(2-amino-5-bromophenyl) acetic acid is (1-2):

1.

5. The process for the preparation of 5-cyanoindoles according to claim 1, characterized in that, In S5, the reducing agent is lithium aluminum hydride, borane dimethyl sulfide, boron trifluoride etherate or sodium borohydride, and the molar ratio of the reducing agent to 5-bromo-oxindole is (1-3):1; the solvent used in the reduction reaction is DMF, THF or DMSO, and the weight ratio of the solvent to 5-bromo-oxindole is (1-10):

1.

6. The process for the preparation of 5-cyanoindoles according to claim 1, characterized in that, In S6, when an oxidizing agent is used, it is manganese dioxide or DDQ, and the molar ratio of the oxidizing agent to 5-bromoindoline is (1-5): 1; when an oxygen / catalyst system is used, it is O2 / LiOH or O2 / 10% Pt / C, and the weight ratio of the catalyst to 5-bromoindoline is (0.1-0.5):

1.

7. The process for the preparation of 5-cyanoindoles according to claim 1 or 6, characterized in that, In S6, the solvent used in the oxidation reaction is dichloromethane, THF, toluene or water, and the weight ratio of the solvent to 5-bromoindoline is (1-10): 1.

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