CN113024548B

CN113024548B - Process for preparing 2-amino-9H-pyridine [2,3-b ] indole

Info

Publication number: CN113024548B
Application number: CN202110123133.8A
Authority: CN
Inventors: 龙韬; 陈丕证; 邹增龙
Original assignee: SUZHOU BAILING WEICHAO FINE MATERIALS CO Ltd
Current assignee: SUZHOU BAILING WEICHAO FINE MATERIALS CO Ltd
Priority date: 2021-01-29
Filing date: 2021-01-29
Publication date: 2022-04-22
Anticipated expiration: 2041-01-29
Also published as: CN113024548A

Abstract

The invention discloses a process method for preparing 2-amino-9H-pyridine [2,3-b ] indole, which comprises the following steps: s1: preparing N, N-dibenzyl-6-halogenated pyridine-2-amine; s2: preparing 6- (1H-benzo [ d ] [1,2,3] triazole-1-yl) -N, N-dibenzylpyridine-2-amine; s3: preparing N, N-dibenzyl-9H-pyridine [2,3-b ] indole-2-amine; s4: preparing 2-amino-9H-pyridine [2,3-b ] indole. The method has the advantages of low raw material price, safe operation, high reaction yield and high product purity.

Description

Process for preparing 2-amino-9H-pyridine [2,3-b ] indole

Technical Field

The invention relates to the field of preparation of mutagenesis reagents, in particular to a process method for preparing 2-amino-9H-pyridine [2,3-b ] indole.

Background

2-Amino-9H-pyridine [2,3-b ] indole (2-Amino-9H-pyrido [2,3-b ] indole, CAS:26148-68-5), abbreviated as AaC (A-alpha-C), is an important mutagenesis research reagent. Since the first isolation and structure determination in the seventies of the last century, their mutagenic activity has been studied more and more extensively.

The only practical synthetic routes reported for 2-amino-9H-pyridine [2,3-b ] indole are 1, the following in 1979, in agriculture and biochemistry (Agricultural and Biological Chemistry, 1979,43(3), 675-677):

the route adopts a 4-step synthesis method, 6-bromo-2-picolinic acid is used as a starting material, is coupled with o-phenylenediamine, is subjected to triazole ring closing with nitrous acid, is subjected to Coptis rearrangement with DPPA (diphenylphosphoryl azide), and is subjected to ring closing after thermal decomposition of triazole to obtain 2-amino-9H-pyridine [2,3-b ] indole.

There are four more serious problems with this approach: firstly, the price of the main material 6-bromo-2-picolinic acid is high, and the price of each kilogram of the main material is more than 6000 yuan, so that the produced 2-amino-9H-pyridine [2,3-b ] indole is high in price and does not accord with the economic principle, and the large-scale application of the product is hindered; the nitrous acid and the azide with poor stability are used in the second step and the third step respectively, so that the reaction risk is high, the process safety is poor, and the method is not friendly to operators; thirdly, the ring closing efficiency of triazole in the second step is very low, the reaction yield of the step for preparing 1.42g of the intermediate in the step is only 19 percent in original documents, and the yield is lower and is not up to 10 percent when the actual production is enlarged to hectogram production. Fourthly, because the amino group with higher reaction activity exists in the fourth step, the generation amount of the side product is more, the yield of 2-amino-9H-pyridine [2,3-b ] indole obtained by ring closing through triazole thermal decomposition is lower, and the yield of 0.15g of product produced by the original document is only 24%.

These four problems severely limit the further application of the process and also make the hectogram and kilogram scale up of the product very difficult.

In order to solve the problems of expensive raw materials, low yield, poor process safety, unfriendliness to operators and the like of the key process route of the 2-amino-9H-pyridine [2,3-b ] indole, the method for synthesizing the 2-amino-9H-pyridine [2,3-b ] indole, which has reasonable route design, low raw material price and friendliness to operators, is very important.

Disclosure of Invention

In order to overcome the defects in the prior art, the embodiment of the invention provides a process method for preparing 2-amino-9H-pyridine [2,3-b ] indole, which has the advantages of low raw material price, safe operation, high reaction yield and high product purity.

In order to achieve the above objects, the embodiments of the present application disclose a process for preparing 2-amino-9H-pyrido [2,3-b ] indole, comprising the steps of:

s1: 2, 6-dihalogenated pyridine is used as a raw material to react with dibenzylamine to obtain N, N-dibenzyl-6-halogenated pyridine-2-amine;

s2: taking N, N-dibenzyl-6-halogenated pyridine-2-amine as a raw material, and reacting the raw material with benzotriazole under the action of a catalyst to obtain 6- (1H-benzo [ d ] [1,2,3] triazole-1-yl) -N, N-dibenzyl pyridine-2-amine;

s3: taking 6- (1H-benzo [ d ] [1,2,3] triazole-1-yl) -N, N-dibenzyl pyridine-2-amine as a raw material, reacting under the action of a catalyst, and performing thermal decomposition and ring closure to obtain N, N-dibenzyl-9H-pyridine [2,3-b ] indole-2-amine;

s4: n, N-dibenzyl-9H-pyridine [2,3-b ] indole-2-amine is used as a raw material, and reacts under the action of a hydrogenation reduction catalyst and a synergistic catalyst to remove benzyl to obtain 2-amino-9H-pyridine [2,3-b ] indole;

preferably, the 2, 6-dihalopyridine is one or more of 2, 6-difluoropyridine, 2, 6-dichloropyridine, 2, 6-dibromopyridine, 2, 6-diiodopyridine, 2-bromo-6-chloropyridine, 2-bromo-6-fluoropyridine, 2-bromo-6-iodopyridine, 2-chloro-6-fluoropyridine, 2-chloro-6-iodopyridine and 2-fluoro-6-iodopyridine.

Preferably, the reaction of the 2, 6-dihalopyridine with dibenzylamine is carried out in a solvent which is one or more of toluene, xylene, o-xylene, m-xylene, p-xylene, nitrobenzene, N-methylpyrrolidone, DMF, DMSO, diphenyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and ethylene glycol monoethyl ether.

Preferably, the dosage of the dibenzylamine is 0.01-10 equivalents; the reaction temperature of the S1 is-20-250 ℃.

Preferably, the catalyst used in S2 is one or more of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, tributylamine, DBU, N-diisopropylethylamine, pyridine, and DMAP.

Preferably, the reaction of the N, N-dibenzyl-6-halopyridine-2-amine and benzotriazole is carried out in a solvent under the action of a catalyst, wherein the solvent is one or more of tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, xylene, o-xylene, m-xylene, p-xylene, nitrobenzene, N-methylpyrrolidone, DMF, DMSO, diphenyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether and ethylene glycol monoethyl ether.

Preferably, the dosage of the benzotriazole in the S2 is 0.5-10 equivalent; the dosage of the catalyst is 0.001 to 20 equivalent; the reaction temperature of the S2 is-20-250 ℃.

Preferably, the catalyst in S3 is lithium tetrafluoroborate;

the reaction of the 6- (1H-benzo [ d ] [1,2,3] triazole-1-yl) -N, N-dibenzylpyridine-2-amine under the action of the catalyst is carried out in a solvent, wherein the solvent is one or more of polyphosphoric acid, pyrophosphoric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, diphenyl ether, chlorobenzene, o-dichlorobenzene, nitrobenzene, N-methylpyrrolidone, DMF and DMSO.

Preferably, the amount of the catalyst in S3 is: 0.001 to 20 equivalents; the reaction temperature of the S3 is-20-250 ℃.

Preferably, the hydrogenation reduction catalyst used in S4 is one or more of the following: palladium carbon, palladium hydroxide carbon, platinum dioxide; the enhanced catalyst used in said S4 is 1,1, 2-tribromoethane;

the reaction of the N, N-dibenzyl-9H-pyridine [2,3-b ] indole-2-amine under the action of a hydrogenation reduction catalyst and a synergistic catalyst is carried out in a solvent, wherein the solvent is one or more of tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, xylene, o-xylene, m-xylene, p-xylene, nitrobenzene, N-methylpyrrolidone, DMF, DMSO, diphenyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol monoethyl ether, methanol, ethanol, isopropanol, tert-butanol, ethyl acetate and dichloromethane;

the reaction of the N, N-dibenzyl-9H-pyridine [2,3-b ] indole-2-amine under the action of the hydrogenation reduction catalyst and the synergistic catalyst needs to add a hydrogen source, wherein the hydrogen source is one or more of hydrogen, formic acid, ammonium formate, hydrazine formate, sodium formate and potassium formate; the dosage of the hydrogenation reduction catalyst is 0.001-20 equivalent; the dosage of the used synergistic catalyst is 0.001 to 20 equivalent; the reaction temperature of the S4 is-20-250 ℃.

The invention has the following beneficial effects: key raw materials in the adopted synthetic route are cheap and easy to obtain; the reaction condition is mild, the operation is convenient and fast, and the process safety is high; the reaction yield is high, the product purity is high, the production cost is greatly reduced, and the requirement of large-scale industrial production of the product can be fully met.

In order to make the aforementioned and other objects, features and advantages of the invention more comprehensible, preferred embodiments accompanied with figures are described in detail below.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

In order to achieve the above object, the present invention provides a process for preparing 2-amino-9H-pyrido [2,3-b ] indole, comprising the steps of:

further, the 2, 6-dihalopyridine is one or more of 2, 6-difluoropyridine, 2, 6-dichloropyridine, 2, 6-dibromopyridine, 2, 6-diiodopyridine, 2-bromo-6-chloropyridine, 2-bromo-6-fluoropyridine, 2-bromo-6-iodopyridine, 2-chloro-6-fluoropyridine, 2-chloro-6-iodopyridine and 2-fluoro-6-iodopyridine.

Further, the reaction of the 2, 6-dihalopyridine and dibenzylamine is carried out in a solvent, wherein the solvent is one or more of toluene, xylene, o-xylene, m-xylene, p-xylene, nitrobenzene, N-methylpyrrolidone, DMF, DMSO, diphenyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether and ethylene glycol monoethyl ether.

Further, the dosage of the dibenzylamine is 0.2-0.5 equivalent; the reaction temperature of the S1 is 80-130 ℃.

Further, the catalyst used in S2 is one or more of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, tributylamine, DBU, N-diisopropylethylamine, pyridine, and DMAP.

Further, the reaction of the N, N-dibenzyl-6-halopyridine-2-amine and benzotriazole is carried out in a solvent under the action of a catalyst, wherein the solvent is one or more of tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, xylene, o-xylene, m-xylene, p-xylene, nitrobenzene, N-methylpyrrolidone, DMF, DMSO, diphenyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether and ethylene glycol monoethyl ether.

Further, the dosage of the benzotriazole in the S2 is 0.8-1.5 equivalent; the dosage of the catalyst is 0.5-8 equivalent; the reaction temperature of the S2 is 60-130 ℃.

Further, the catalyst in S3 is lithium tetrafluoroborate;

Preferably, the amount of the catalyst in S3 is: 0.001 to 0.1 equivalent; the reaction temperature of the S3 is 140-250 ℃.

the reaction of the N, N-dibenzyl-9H-pyridine [2,3-b ] indole-2-amine under the action of the hydrogenation reduction catalyst and the synergistic catalyst needs to add a hydrogen source, wherein the hydrogen source is one or more of hydrogen, formic acid, ammonium formate, hydrazine formate, sodium formate and potassium formate; the dosage of the hydrogenation reduction catalyst is 0.001-1 equivalent; the dosage of the used synergistic catalyst is 0.001 to 0.1 equivalent; the reaction temperature of the S4 is 20-80 ℃.

Example 1

S1: preparation of N, N-dibenzyl-6-chloropyridine-2-amine

To a 20L reactor, 8L of toluene, 2.5Kg of 2, 6-dichloropyridine and 2Kg of dibenzylamine were added in order while stirring at room temperature. After the addition, the reaction solution was heated under reflux and stirred for 6 hours, and the reaction was completed by monitoring and confirming the completion of the dibenzylamine reaction.

The reaction kettle is connected with a distillation device, and about 8L of toluene is recovered by atmospheric distillation. After almost no toluene is distilled out, the reaction solution is cooled to about 90 ℃, a water pump is replaced for reduced pressure distillation, and 980g of 2, 6-dichloropyridine is recovered.

The residue was directly subjected to the next reaction without further purification.

S2: preparation of 6- (1H-benzo [ d ] [1,2,3] triazole-1-yl) -N, N-dibenzylpyridine-2-amine

The 20L reactor containing the residue from the previous step was charged with 8L of toluene and stirred. 1.3kg of benzotriazole is added and stirred evenly. Then 2kg of potassium carbonate was added. The reaction was completed by vigorous stirring and then by warming to 110 for 5 hours.

The reaction solution was cooled to about 70 ℃ and filtered while hot to remove insoluble matter. The filtrate was naturally cooled and crystallized to obtain 3.9kg of crude product. The crude product was recrystallized once more with ethanol and then dried in a vacuum oven to give 3.5kg of pure solid product with a total yield of 87% over the two steps (calculated on the actual consumption of 2, 6-dichloropyridine).

S3: preparation of N, N-dibenzyl-9H-pyridine [2,3-b ] indole-2-amine

To a 50L reactor, 20kg of polyphosphoric acid, 3.5kg of the above-step intermediate, and 100g of lithium tetrafluoroborate were added. Slowly stirring, and then heating to 150 ℃. And (4) keeping the temperature of 150 ℃ under vigorous stirring for reacting for 4 hours until a large amount of bubbles are not generated any more, and finishing the reaction.

The reaction solution was cooled to room temperature, then slowly poured into 100kg of ice water, and then adjusted to pH 9-10 with sodium hydroxide. Standing overnight, precipitating a large amount of solid from the aqueous solution, filtering under reduced pressure, and collecting the solid. The solid was recrystallized from ethanol to give 2.9kg of solid product in 89% yield.

S4: preparation of 2-amino-9H-pyrido [2,3-b ] indoles

Under stirring at room temperature, 30L of methanol and 2.9kg of the intermediate in the previous step are sequentially added into a 50L reaction kettle and stirred uniformly. To this was added 50g of 10% palladium on carbon, 50g of 1,1, 2-tribromoethane and 3kg of ammonium formate. After the addition was complete, the mixture was stirred at room temperature for 1 hour.

The reaction was then heated to reflux for 8 hours and was complete. The reaction solution is cooled to room temperature, filtered and the palladium-carbon is recovered. The filtrate was distilled at atmospheric pressure to recover about 20L of methanol.

The residual liquid was slowly added to 30L of ice water with stirring, and the pH was adjusted to 9-10 with sodium hydroxide to precipitate a large amount of off-white solid.

Filtering and collecting filter cakes. The filter cake was recrystallized from ethanol to yield 1.3kg of a white solid powdered product with a yield of 90%.

The total yield of the four-step reaction is as follows: 70 percent.

HPLC purity of the product: 99.79 percent.

Nuclear magnetic data: 1H NMR (400MHz, d 6-DMSO): δ 6.12(s, 2H), 6.43(d, 1H), 7.05-7.44 (m, 3H), 7.85(d, 1H), 8.06(d, 1H), 11.29(s, 1H).

Example 2

S1: preparation of N, N-dibenzyl-6-bromopyridine-2-amine

To a 1L reaction flask, 500mL of xylene, 150g of 2, 6-dibromopyridine and 60g of dibenzylamine were added in this order while stirring at room temperature. After the addition, the reaction solution was heated to 130 ℃ and stirred for 2 hours, and the reaction was completed by monitoring and confirming the completion of the dibenzylamine reaction.

The reaction kettle is connected with a distillation device, and the xylene is recovered by reduced pressure distillation. Then 76g of 2, 6-dibromopyridine is recovered by reduced pressure distillation.

To a 1L reaction flask containing the residue of the previous step was added about 500mL of the recovered xylene and stirred. 47g of benzotriazole was added thereto, and stirred uniformly. Then 40g of sodium carbonate were added. The reaction was completed by vigorous stirring and then heating to 120 deg.C for 3 hours.

The reaction solution is cooled to about 60 ℃, filtered while hot, and insoluble substances are filtered off. The filtrate was distilled under reduced pressure to recover xylene, and the residue was recrystallized once from methanol and then dried under vacuum to give 104g of a pure solid product in a total yield of 85% in two steps (based on the actually consumed 2, 6-dibromopyridine).

S3: preparation of N, N-dibenzyl-9H-pyridine [2,3-b ] indole-2-amine

To a 2L reaction flask, 500g of pyrophosphoric acid, 104g of the intermediate of the previous step and 1g of lithium tetrafluoroborate were added. Slowly stirring, and then heating to 140 ℃. And (4) keeping the temperature of 140 ℃ under vigorous stirring, reacting for 5 hours until a large amount of bubbles are not generated any more, and finishing the reaction.

The reaction solution was cooled to room temperature, then slowly poured into 5kg of ice water, and then adjusted to pH 8.5 with potassium hydroxide. Standing for 2 hr to precipitate large amount of solid, filtering under reduced pressure, and collecting solid. The solid was recrystallized from methanol to give 89g of solid product in 92% yield.

S4: preparation of 2-amino-9H-pyrido [2,3-b ] indoles

Under stirring at room temperature, 500mL of ethanol and 89g of the intermediate in the previous step are sequentially added into a 1L reaction bottle and stirred uniformly. 2g of 10% palladium hydroxide on carbon and 2g of 1,1, 2-tribromoethane were further added thereto. After the addition, a hydrogen balloon is added on the reaction flask, and the reaction system is in a hydrogen atmosphere.

The reaction was stirred at room temperature for 8 hours and was complete. The reaction solution is cooled to room temperature, filtered and the palladium hydroxide carbon is recovered. The filtrate was distilled at atmospheric pressure to recover about 400mL of ethanol.

The residue was slowly added to 1L of ice water with stirring, and the pH was adjusted to 9 with sodium hydrogencarbonate to precipitate a large amount of off-white solid.

Filtering and collecting filter cakes. The filter cake was recrystallized from ethanol to yield 41g of white solid powdery product in 91% yield.

The total yield of the four-step reaction is as follows: 71 percent.

HPLC purity of the product: 99.26 percent.

Example 3

S1: preparation of N, N-dibenzyl-6-fluoropyridin-2-amine

To a 500mL reaction flask, 250mL of N-methylpyrrolidone, 50g of 2, 6-difluoropyridine and 40g of dibenzylamine were added in this order while stirring at room temperature. After the addition, the reaction solution was heated to 100 ℃ and stirred for 3 hours, and the reaction was completed by monitoring and confirming the completion of the dibenzylamine reaction.

The reaction kettle is connected with a distillation device, and 28g of 2, 6-difluoropyridine is recovered by reduced pressure distillation.

30g of benzotriazole and 20g of cesium carbonate were added to the residual liquid in the previous step. The reaction was completed by vigorously stirring and then heating to 100 deg.f for 3 hours.

The reaction solution was cooled to about 70 ℃ and filtered while hot to remove insoluble matter. The filtrate was distilled under reduced pressure to recover N-methylpyrrolidone, and the residue was recrystallized once from isopropanol and then dried under vacuum to give 68g of pure solid product in a total yield of 91% in two steps (calculated on the basis of the actually consumed 2, 6-difluoropyridine).

S3: preparation of N, N-dibenzyl-9H-pyridine [2,3-b ] indole-2-amine

To a 1L reaction flask, 500g of diphenyl ether, 68g of the above-mentioned intermediate and 0.5g of lithium tetrafluoroborate were added. Slowly stirring, and then heating to 200 ℃. And (4) keeping the temperature of 200 ℃ for 2 hours under vigorous stirring, so that a large amount of bubbles are not generated any more, and the reaction is finished.

The reaction solution was directly subjected to the next reaction without further treatment.

S4: preparation of 2-amino-9H-pyrido [2,3-b ] indoles

The reaction liquid in the previous step was cooled to about 35 ℃, and 1.5g of recovered 10% palladium on carbon, 1.5g of 1,1, 2-tribromoethane and 50g of hydrazine formate were added thereto. Then heated to 80 ℃ for 4 hours, and the reaction is completed.

The reaction solution was filtered while hot, and palladium on carbon was recovered. The filtrate was cooled to 50 degrees, then added with 500mL recovery toluene, stirred, again natural cooling to room temperature, and then with 3L 10% sodium hydroxide aqueous solution washing. The organic phase was collected and extracted with 2L of 10% hydrochloric acid solution. The aqueous phase was collected and adjusted to pH 11 with sodium hydroxide to precipitate a large amount of white solid.

Filtering and collecting filter cakes. The filter cake was recrystallized from isopropanol to give 30g of white solid powdery product in 94% yield.

The total yield of the four-step reaction is as follows: 85 percent.

HPLC purity of the product: 99.34 percent.

Comparative example 1

The comparative example 1 differs from example 1 only in that the catalyst of S3 is sodium tetrafluoroborate.

Comparative example 2

The comparative example 2 differs from example 1 only in that the catalyst of S3 is tetrafluoroboric acid.

Comparative example 3

The comparative example 3 differs from example 1 only in that S3 does not have the catalyst lithium tetrafluoroborate added.

Comparative example 4

The comparative example 4 differs from example 1 only in that the enhanced catalyst of S4 is 1,1, 2-trichloroethane.

Comparative example 5

The comparative example 5 differs from example 1 only in that S4 has no added efficiency enhancing catalyst 1,1, 2-tribromoethane.

Comparative example 6

Said comparative example 6 is different from example 1 only in that the starting dibenzylamine of S1 is replaced with benzylamine.

Comparative example 7

The comparative example 7 is different from example 1 only in that the starting dibenzylamine of S1 was replaced with a methanol solution of ammonia.

Comparative example 8

The comparative example 8 differs from example 2 only in that the catalyst of S3 is sodium tetrafluoroborate.

Comparative example 9

The comparative example 9 differs from example 2 only in that the catalyst of S3 is tetrafluoroboric acid.

Comparative example 10

The comparative example 10 differs from example 2 only in that S3 does not have the catalyst lithium tetrafluoroborate added.

Comparative example 11

The comparative example 11 differs from example 2 only in that the enhanced catalyst of S4 is 1,1, 2-trichloroethane.

Comparative example 12

The comparative example 12 differs from example 2 only in that S4 has no added efficiency enhancing catalyst 1,1, 2-tribromoethane.

Comparative example 13

Said comparative example 13 is different from example 2 only in that the starting dibenzylamine of S1 is replaced with benzylamine.

Comparative example 14

The comparative example 14 is different from example 2 only in that the starting dibenzylamine of S1 is replaced with a methanol solution of ammonia.

Comparative example 15

The comparative example 15 differs from example 3 only in that the catalyst of S3 is sodium tetrafluoroborate.

Comparative example 16

The comparative example 16 differs from example 3 only in that the catalyst of S3 is tetrafluoroboric acid.

Comparative example 17

Comparative example 17 differs from example 3 only in that S3 does not have the catalyst lithium tetrafluoroborate added.

Comparative example 18

The comparative example 18 differs from example 3 only in that the enhanced catalyst of S4 is 1,1, 2-trichloroethane.

Comparative example 19

The comparative example 19 differs from example 3 only in that S4 has no added efficiency enhancing catalyst 1,1, 2-tribromoethane.

Comparative example 20

The comparative example 20 is different from example 3 only in that the starting dibenzylamine of S1 is replaced with benzylamine.

Comparative example 21

The comparative example 21 is different from example 3 only in that the starting dibenzylamine of S1 was changed to a methanol solution of ammonia.

Table 1 shows the results of the measurements in each example and each comparative example

1. Comparison of Total yield

As shown in table 1, the overall yield of example 1 is better than the comparative examples.

Comparative examples 1-2 show that the total yield decreases significantly when the S3 catalyst species is replaced with sodium tetrafluoroborate or tetrafluoroboric acid.

Comparative example 3 shows that the overall yield drops very significantly without addition of catalyst to S3.

Comparative examples 4-5 show that the overall yield decreases significantly when S4 was used without the addition of the enhanced catalyst or the enhanced catalyst was changed to 1,1, 2-trichloroethane.

Comparative examples 6 to 7 show that when the starting dibenzylamine of S1 was changed to benzylamine or ammonia in methanol, the total yield decreased to 0 and no product could be obtained.

Comparative examples 8-9 show that the total yield decreases significantly when the S3 catalyst species is replaced with sodium tetrafluoroborate or tetrafluoroboric acid.

Comparative example 10 shows that the overall yield drops very significantly without addition of catalyst to S3.

Comparative examples 11-12 show that the overall yield decreases significantly when S4 was used without the addition of the enhanced catalyst or the enhanced catalyst was changed to 1,1, 2-trichloroethane.

Comparative examples 13 to 14 show that when the starting dibenzylamine of S1 was changed to benzylamine or ammonia in methanol, the total yield decreased to 0 and no product could be obtained.

Comparative examples 15-16 show that the overall yield decreases significantly when the S3 catalyst species is replaced with sodium tetrafluoroborate or tetrafluoroboric acid.

Comparative example 17 shows that the overall yield drops very significantly without addition of catalyst to S3.

Comparative examples 18-19 show that the overall yield decreases significantly when S4 was used without the addition of the enhanced catalyst or the enhanced catalyst was changed to 1,1, 2-trichloroethane.

Comparative examples 20 to 21 show that when the starting dibenzylamine of S1 was changed to benzylamine or ammonia in methanol, the total yield decreased to 0 and no product could be obtained.

As can be seen from table 1, the kind of the raw material in S1, the use or absence of the catalyst and the kind of the catalyst in S3, and the use or absence of the efficiency-enhancing catalyst and the kind of the efficiency-enhancing catalyst in S4 all affect the total yield.

2. Purity of the product

Example 1 and comparative examples 1 to 7 were checked by HPLC, and as shown in table 1, example 1 had better purity than comparative examples 1 to 7 than each comparative example.

Example 2 and comparative examples 8 to 14 were checked by HPLC, and as shown in table 1, example 1 had better purity than comparative examples 1-7 than each comparative example.

Example 3 and comparative examples 15 to 21 were checked by HPLC, and as shown in table 1, example 1 had better purity than comparative examples 1-7 than each comparative example.

The principle and the implementation mode of the invention are explained by applying specific embodiments in the invention, and the description of the embodiments is only used for helping to understand the method and the core idea of the invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.

Claims

1. A process for preparing 2-amino-9H-pyrido [2,3-b ] indole, comprising:

2. the process of claim 1, wherein the 2, 6-dihalopyridine is one or more of 2, 6-difluoropyridine, 2, 6-dichloropyridine, 2, 6-dibromopyridine, 2, 6-diiodopyridine, 2-bromo-6-chloropyridine, 2-bromo-6-fluoropyridine, 2-bromo-6-iodopyridine, 2-chloro-6-fluoropyridine, 2-chloro-6-iodopyridine, and 2-fluoro-6-iodopyridine.

3. The process of claim 1, wherein the reaction of the 2, 6-dihalopyridine with dibenzylamine is carried out in a solvent selected from one or more of toluene, xylene, o-xylene, m-xylene, p-xylene, nitrobenzene, N-methylpyrrolidone, DMF, DMSO, diphenyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and ethylene glycol monoethyl ether.

4. The process for preparing 2-amino-9H-pyrido [2,3-b ] indole according to claim 1, wherein dibenzylamine is used in an amount of 0.01 to 10 equivalents; the reaction temperature of the S1 is-20-250 ℃.

5. The process for preparing 2-amino-9H-pyrido [2,3-b ] indole according to claim 1, wherein the catalyst used in S2 is one or more of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, tributylamine, DBU, N-diisopropylethylamine, pyridine, DMAP.

6. The process for preparing 2-amino-9H-pyrido [2,3-b ] indole as claimed in claim 1, wherein the reaction of N, N-dibenzyl-6-halopyridine-2-amine with benzotriazole in the presence of a catalyst is carried out in a solvent selected from one or more of tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, xylene, o-xylene, m-xylene, p-xylene, nitrobenzene, N-methylpyrrolidone, DMF, DMSO, diphenyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and ethylene glycol monoethyl ether.

7. The process method for preparing 2-amino-9H-pyridine [2,3-b ] indole according to claim 1, wherein the amount of benzotriazole in S2 is 0.5-10 equivalents; the dosage of the catalyst is 0.001-20 equivalent; the reaction temperature of the S2 is-20-250 ℃.

8. The process for preparing 2-amino-9H-pyrido [2,3-b ] indole according to claim 1, wherein the catalyst in S3 is lithium tetrafluoroborate;

9. The process for preparing 2-amino-9H-pyrido [2,3-b ] indole according to claim 1, wherein the amount of catalyst used in S3 is: 0.001 to 20 equivalents; the reaction temperature of the S3 is-20-250 ℃.

10. The process for preparing 2-amino-9H-pyrido [2,3-b ] indole according to claim 1, wherein the hydrogenation reduction catalyst used in S4 is one or more of: palladium carbon, palladium hydroxide carbon, platinum dioxide; the enhanced catalyst used in said S4 is 1,1, 2-tribromoethane;

the reaction of the N, N-dibenzyl-9H-pyridine [2,3-b ] indole-2-amine under the action of the hydrogenation reduction catalyst and the synergistic catalyst needs to add a hydrogen source, wherein the hydrogen source is one or more of hydrogen, formic acid, ammonium formate, hydrazine formate, sodium formate and potassium formate; the dosage of the hydrogenation reduction catalyst is 0.001-20 equivalent; the dosage of the synergistic catalyst is 0.001-20 equivalent; the reaction temperature of the S4 is-20-250 ℃.