CN112300048A - Preparation method of indoline with low cost - Google Patents

Abstract

The invention relates to the technical field of indoline, and discloses a preparation method of low-cost indoline, which comprises the following steps of 1) putting indole extracted from tar and a hydrogenation catalyst into a high-pressure reaction kettle; 2) the reaction kettle is closed, and the temperature of the reaction kettle is increased to 100-150 ℃ after the air in the reaction kettle is replaced by nitrogen; 3) introducing hydrogen in a pulse mode, wherein the pressure is 3.0-4.0 Mpa, and carrying out hydrogenation reaction; 4) after the reaction is finished, reducing the temperature in the reaction kettle to 35 +/-5 ℃, then decompressing, taking out the supernatant, namely the indoline crude product, and carrying out vacuum rectification to obtain high-quality indoline; 5) the catalyst at the bottom of the autoclave is recycled, and a trace amount of catalyst is added during each hydrogenation. The method has the advantages of low requirement on hydrogenation equipment, high essential safety of the process, high purity of the prepared indoline, high yield, low cost and less solid waste, is very suitable for industrial production, reduces the cost of waste treatment, and saves a large amount of manpower and material resources.

Description

Preparation method of indoline with low cost

Technical Field

The invention relates to the technical field of preparation of indole downstream derivatives, in particular to a preparation method of indoline with low cost.

Background

Indoline is an important organic intermediate, the indoline has a unique chemical structure, and is endowed with unique physiological activity when being applied to pesticides, so the indoline has an important position in the field of pesticides, the indoline can be widely applied to pharmacy, the indoline can be used as a medical intermediate, a series of-3-benzylidene-2 and 3-indoline-2-ketone derivatives can be synthesized by taking triethylbenzylammonium chloride as a catalyst to react with aromatic aldehyde, the indoline can be used for synthesizing bromfenac sodium, is a non-steroidal anti-inflammatory drug and has a strong analgesic effect, and indoline dyes can also be used as a sensitizer of a quasi-solid dye sensitized solar cell and have good photoelectric conversion performance.

Indolines in the prior art generally take the following synthetic route: in nitrogen flow, in the presence of aluminum nitrate or aluminum oxide, the o-aminoethylbenzene is dehydrocyclized at about 550 ℃, and then is subjected to reduced pressure distillation to obtain indoline. The method has low yield and low product purity.

In patent CN103664733A, a synthesis method of indoline is proposed, in which indoline is hydrogenated and then subjected to vacuum rectification to obtain an indoline product, but on one hand, the hydrogenation temperature and pressure are both high, and the requirements and investment on equipment are high, resulting in high survival cost; on the other hand, the hydrogenation catalyst is not used mechanically, so that the hydrogenation cost is high, and the hydrogenation catalyst becomes solid waste, so that the pressure of environmental protection treatment is increased.

Disclosure of Invention

Technical problem to be solved

Aiming at the defects of the prior art, the invention provides a low-cost indoline preparation method, which reduces the temperature and pressure of hydrogenation reaction, reduces the generation amount of byproducts, and recycles the catalyst, so that the indoline preparation method has the advantages of lower cost, higher safety and higher purity of the prepared indoline.

(II) technical scheme

In order to realize the purpose of low cost of the preparation method of the indoline with low cost, the invention provides the following technical scheme: a preparation method of low-cost indoline comprises the following steps:

1) adding indole and hydrogenation catalyst extracted from tar into a high-pressure reaction kettle;

2) the reaction kettle is closed, and the temperature of the reaction kettle is increased to 100-150 ℃ after the air in the reaction kettle is replaced by nitrogen;

3) introducing hydrogen in a pulse mode, wherein the pressure is 3.0-4.0 Mpa, and stopping the reaction when hydrogen is not consumed;

4) after the temperature in the reaction kettle is reduced to 35 +/-5 ℃, the pressure is relieved, and the supernatant, namely the indoline crude product, is taken out and subjected to vacuum rectification to obtain high-quality indoline;

5) the catalyst at the bottom of the autoclave is recycled, and a trace amount of catalyst is added during hydrogenation after each feeding.

The indole in the step 1) is indole extracted from coal tar or wash oil.

The catalyst in the step 1) is binary and ternary nickel catalyst, the nickel content is more than or equal to 90 percent, and the preferred catalyst is ternary nickel.

The feeding proportion of the catalyst and the indole in the step 1) is that the initial feeding is 1: 10 to 20.

The catalytic hydrogenation temperature in the step 2) is 100-150 ℃, and the preferred catalytic hydrogenation temperature is 120-140 ℃.

And in the catalytic hydrogenation process in the step 3), hydrogen is introduced in a pulse mode, and the pressure in the hydrogenation kettle is controlled to be 3.0-4.0 MPa.

After the catalytic strengthening process of the steps 4) and 5) is finished, only the indoline crude product of the supernatant is taken out for decompression and rectification, and the hydrogenated nickel catalyst is left in the kettle to participate in the next hydrogenation catalytic process, so that the nickel catalyst is recycled and the cost is reduced.

The rectification of the crude indoline in the step 4) is vacuum rectification, and the pressure is-90 to-80 kpa.

And 5) adding a trace amount of catalyst during each feeding, wherein the adding amount is 1-3% of the feeding amount of indole during each circulation use.

(III) advantageous effects

Compared with the prior art, the invention provides a preparation method of indoline with low cost, which has the following beneficial effects:

1. compared with the traditional indoline synthesis method, the preparation method of the indoline with low cost greatly reduces the raw materials required by the indole reaction, and the use of the indoline preparation method can further reduce the processing budget, so that the expense budget of a factory is greatly reduced, the generated solid waste is greatly reduced, the treatment cost of the solid waste is reduced, and a large amount of manpower and material resources are saved.

2. Compared with the traditional indoline synthesis method, the preparation method of the indoline has the advantages that the crude indoline produced by the traditional indoline synthesis method has fewer impurities, the purity of the indoline product prepared after rectification is higher, good drug effect can be achieved by using the indoline as an organic intermediate in subsequent use, particularly in the drug production process, and the indoline can better perform chemical reaction due to fewer impurities and better purity.

Drawings

FIG. 1 is a schematic view of example 1 of the present invention;

FIG. 2 is a schematic view of example 2 of the present invention;

FIG. 3 is a schematic view of example 3 of the present invention;

FIG. 4 is a schematic view of example 4 of the present invention;

FIG. 5 is a schematic view of embodiment 5 of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the 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.

Example 1:

1) weighing 100g of indole and 5g of catalyst, adding into a high-pressure reaction kettle, and sealing;

2) after nitrogen replacement, heating the kettle to 135 ℃, and starting stirring;

3) hydrogen is introduced into the hydrogenation kettle in a pulse mode for hydrogenation, and the pressure in the hydrogenation kettle is 3.0-4.0 Mpa;

4) the hydrogenation reaction time is 3 hours;

5) and cooling to 35 ℃, stopping stirring, opening the hydrogenation kettle, and taking out the supernatant to obtain the crude indoline.

6) And (3) carrying out vacuum rectification on the crude product under the condition of-87 kpa to obtain an indoline product.

Three hydrogenation catalysts of binary nickel, ternary nickel and palladium-carbon are respectively selected for screening, under the same reaction condition, crude indoline prepared by different catalysts is subjected to GC analysis, and the experimental result is shown in figure 1. As can be seen from FIG. 1, under the same conditions, the ternary nickel has the best catalytic effect, and the purity of the crude product is the highest. Compared with other catalysts, the ternary nickel catalyst has larger specific surface area and is more favorable for the hydrogenation reaction, and trace metal elements contained in the catalyst have better hydrogenation selectivity in the catalytic process. The indoline content of the indoline crude product obtained by the ternary nickel catalyst is 99.6 percent and the yield is 90.3 percent through the vacuum rectification

Example 2:

1) weighing 100g of indole and several g of ternary nickel catalyst, adding into a high-pressure reaction kettle, and sealing;

2) after nitrogen replacement, heating the kettle to 135 ℃, and starting stirring;

3) hydrogen is introduced into the hydrogenation kettle in a pulse mode for hydrogenation, and the pressure in the hydrogenation kettle is 3.0-4.0 Mpa;

4) the hydrogenation reaction time is 3 hours;

5) and cooling to 35 ℃, stopping stirring, opening the hydrogenation kettle, and taking out the supernatant to obtain the crude indoline.

6) And (3) carrying out vacuum rectification on the crude product under the condition of-87 kpa to obtain an indoline product.

Under the premise of consistent other conditions, the feeding amount of the indole and ternary nickel catalysts is 100g:4g respectively; 100g to 5 g; 100g, 6 g; the results of a catalytic hydrogenation experiment at 100g:7g and GC analysis of the crude indoline prepared are shown in FIG. 2. As can be seen from fig. 2, the ratio of indole to three-way nickel catalyst charged for the first time is 100: and 6, the purity of the crude indoline is the highest, the content of the obtained indoline is 99.6 percent after vacuum rectification, and the yield is 90.8 percent.

Example 3:

1) weighing 100g of indole and 6g of ternary nickel catalyst, adding into a high-pressure reaction kettle, and sealing;

2) after nitrogen replacement, heating the kettle to 120-140 ℃, and starting stirring;

3) hydrogen is introduced into the hydrogenation kettle in a pulse mode for hydrogenation, and the pressure in the hydrogenation kettle is 3.0-4.0 Mpa;

4) the hydrogenation reaction time is 3 hours;

5) and cooling to 35 ℃, stopping stirring, opening the hydrogenation kettle, and taking out the supernatant to obtain the crude indoline.

6) And (3) carrying out vacuum rectification on the crude product under the condition of-87 kpa to obtain an indoline product.

Under the premise of other consistent conditions, catalytic hydrogenation experiments at the hydrogenation temperatures of 120 ℃, 130 ℃, 135 ℃ and 140 ℃ are respectively carried out, and the GC analysis is carried out on the prepared crude indoline, and the result is shown in figure 3. As can be seen from fig. 3, the purity of crude indoline is highest when the hydrogenation temperature is 130 ℃, and rapidly decreases as the temperature continues to increase. After the crude indoline product hydrogenated at the temperature of 130 ℃ is subjected to vacuum rectification, the content of the indoline is 99.7 percent, and the yield is 91.6 percent.

Example 4:

1) weighing 100g of indole and 6g of ternary nickel catalyst, adding into a high-pressure reaction kettle, and sealing;

2) after nitrogen replacement, heating the kettle to 130 ℃, and starting stirring;

3) hydrogen is introduced into the hydrogenation kettle in a pulse mode for hydrogenation, and the pressure in the hydrogenation kettle is 3.0-4.0 Mpa;

4) the hydrogenation reaction time is 1-4 hours;

5) and cooling to 35 ℃, stopping stirring, opening the hydrogenation kettle, and taking out the supernatant to obtain the crude indoline.

6) And (3) carrying out vacuum rectification on the crude product under the condition of-87 kpa to obtain an indoline product.

On the premise of other consistent conditions, catalytic hydrogenation experiments with hydrogenation time of 1.5 hours, 2.0 hours, 3.0 hours and 4.0 hours were respectively performed, and the results of GC analysis of the prepared crude indoline are shown in fig. 4. As can be seen from fig. 4, when the hydrogenation reaction time is 2.0, the purity of the crude indoline is the highest, and when the hydrogenation time is continuously prolonged, the number of by-products increases, resulting in a rapid decrease in the purity of the crude indoline. The indoline crude product with the hydrogenation time of 2.0 hours is rectified under reduced pressure to obtain indoline with the content of 99.7 percent and the yield of 91.9 percent.

Example 5:

1) weighing 100g of indole and 6g of ternary nickel catalyst, adding into a high-pressure reaction kettle, and sealing;

2) after nitrogen replacement, heating the kettle to 130 ℃, and starting stirring;

3) hydrogen is introduced into the hydrogenation kettle in a pulse mode for hydrogenation, and the pressure in the hydrogenation kettle is 3.0-4.0 Mpa;

4) the hydrogenation reaction time is 2 hours;

5) and cooling to 35 ℃, stopping stirring, opening the hydrogenation kettle, and taking out the supernatant to obtain the crude indoline.

6) Continuously adding indole into the kettle, and supplementing a ternary nickel catalyst with indole stripping amount of 1%, and carrying out a catalyst application experiment.

7) And (3) carrying out vacuum rectification on the crude product under the condition of-87 kpa to obtain an indoline product.

And after the hydrogenation is finished, taking out the supernatant, recycling the ternary nickel catalyst left in the kettle, carrying out 6 times of recycling experiments in total, and carrying out GC analysis on the indoline crude product after the hydrogenation is finished, wherein the result is shown in figure 5. As can be seen from fig. 5, under the condition that the catalyst is continuously used for 6 times, the content of the obtained indoline crude product is basically unchanged, which shows that the cyclic use effect of the ternary nickel catalyst is good, so that the use amount of the catalyst for hydrogenation reaction is effectively reduced, and the catalyst has a very good effect on cost reduction, solid waste reduction and environmental protection capability improvement. After the indoline crude products obtained by 6 times of hydrogenation are mixed and subjected to vacuum rectification, the indoline content is 99.7%, and the yield is 91.7%.

In summary, compared with the traditional indoline synthesis method, the preparation method of the low-cost indoline reduces the raw materials required by the indoline reaction, can further reduce the processing budget, reduces the expense budget of a factory, correspondingly reduces the generated waste, reduces the cost of waste treatment, saves manpower and material resources, reduces the temperature and pressure in the reaction process, reduces the risk coefficient of the production process, obtains a crude indoline with higher content, can achieve good drug effect by using the indoline as an organic intermediate in the subsequent purification process, especially in the drug production process, and can better perform chemical reaction due to less impurities and better purity.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (9)

1. A preparation method of indoline with low cost is characterized by comprising the following steps:

1) adding indole and hydrogenation catalyst extracted from tar into a high-pressure reaction kettle;

2) the reaction kettle is closed, and the temperature of the reaction kettle is increased to 100-150 ℃ after the air in the reaction kettle is replaced by nitrogen;

3) introducing hydrogen in a pulse mode, wherein the pressure is 3.0-4.0 Mpa, and stopping the reaction when hydrogen is not consumed;

4) after the temperature in the reaction kettle is reduced to 35 +/-5 ℃, the pressure is relieved, and the supernatant, namely the indoline crude product, is taken out and subjected to vacuum rectification to obtain high-quality indoline;

5) the catalyst at the bottom of the autoclave is recycled, and a trace amount of catalyst is added during hydrogenation after each feeding.

2. The method for preparing indoline according to claim 1, wherein the method comprises the following steps: the indole in the step 1) is indole extracted from coal tar or wash oil.

3. The method for preparing indoline according to claim 1, wherein the method comprises the following steps: the catalyst in the step 1) is binary and ternary nickel catalyst, and the nickel content is more than or equal to 90 percent.

4. The method for preparing indoline according to claim 1, wherein the method comprises the following steps: the feeding proportion of the catalyst and the indole in the step 1) is that the initial feeding is 1: 10 to 20.

5. The method for preparing indoline according to claim 1, wherein the method comprises the following steps: the catalytic hydrogenation temperature in the step 2) is 100-150 ℃, and the preferred catalytic hydrogenation temperature is 120-140 ℃.

6. The method for preparing indoline according to claim 1, wherein the method comprises the following steps: and in the catalytic hydrogenation process in the step 3), hydrogen is introduced in a pulse mode, and the pressure in the hydrogenation kettle is controlled to be 3.0-4.0 MPa.

7. The method for preparing indoline according to claim 1, wherein the method comprises the following steps: after the catalytic strengthening process of the steps 4) and 5) is finished, only the indoline crude product of the supernatant is taken out for decompression and rectification, and the hydrogenated nickel catalyst is left in the kettle to participate in the next hydrogenation catalytic process, so that the nickel catalyst is recycled and the cost is reduced.

8. The method for preparing indoline according to claim 1, wherein the method comprises the following steps: the rectification of the crude indoline in the step 4) is vacuum rectification, and the pressure is-90 to-80 kpa.

9. The method for preparing indoline according to claim 1, wherein the method comprises the following steps:

and 5) adding a trace amount of catalyst during each feeding, wherein the adding amount is 1-3% of the feeding amount of indole during each circulation use.

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