A two-step heating method for preparing high-purity 3,3'-diaminobenzidine

Abstract

The invention discloses a method for preparing high-purity 3,3'-diaminobenzidine by a two-step temperature increase method, which relates to the technical field of preparation of benzidine compounds. The preparation steps are: two-step temperature increase reaction: 3,3'-dichlorobenzidine hydrochloride, copper salt, water and liquid ammonia are added sequentially in a stainless steel autoclave, and a two-step temperature increase reaction is performed; filtration crystallization: filtering to obtain a dark brown ammoniate, hot melting, hot filtering, cooling crystallization to obtain a crude product; purification: the crude product is added with water, activated carbon and ammonium thiohydrochloride, fully dissolved and filtered, the filtrate is slowly cooled and crystallized to obtain a relatively pure product, and the purification step is repeated multiple times to obtain high-purity 3,3'-diaminobenzidine. The advantages of the present invention are: a two-stage temperature increase preparation method is adopted to reduce impurity generation and obtain a high-purity product; purification uses ammonium thiohydrochloride as an antioxidant to reduce the generation of oxidative impurities, improve purity, and purified wastewater can be applied, with good economy and environmental protection, and with a high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of benzidine compounds, and in particular to a method for preparing high-purity 3,3'-diaminobenzidine by a two-step temperature increase method. Background Art

[0002] 3,3'-Diaminobenzidine, a benzidine compound, can be used for spectrophotometric determination of selenium and is a peroxidase substrate. It is also a key intermediate in the Phase 3 clinical trial-approved new drug, Ridinilazole. Ridinilazole is an oral small molecule antibiotic candidate that selectively kills Clostridium difficile, thereby protecting beneficial intestinal flora. 3,3'-Diaminobenzidine has been previously studied.

[0003] Melvin L. Druin, Kenneth Oringer, Edward C. et al. used 3,3'-dichlorobenzidine as the raw material and cuprous chloride as the catalyst to produce the product through an amination reaction at 225°C. The crude product was purified through sulfuric acid salt formation, neutralization, and hot water recrystallization to obtain relatively pure 3,3'-diaminobenzidine. However, the purity of the 3,3'-diaminobenzidine prepared by this method was still relatively low, and large amounts of acid and base were used, resulting in a large amount of wastewater. Due to the high reaction temperature, a large amount of tar was present in the product. (Melvin L. Druin, Kenneth Oringer. Synthesis of pure 3,3'-diaminobenzidine (P). US 3943175A, 1973 & Synthesis of 3,3'-diaminobenzidine from 3,3'-dichlorobenzidine (P). US 3943175A, 1969)

[0004] Donald E. Orgen, Arthur E. Prince, and others reported using activated carbon columns to remove insoluble colloidal impurities from 3,3'-diaminobenzidine. Sodium chloride was added as a flocculant, and 3,3'-diaminobenzidine was dissolved in water at 120-125°C. The solution passed through the activated carbon column, where it crystallized to obtain the 3,3'-diaminobenzidine product. This method had low production efficiency and high costs. (Donald E. Orgen, Arthur E. Prince. Method of purifying crude bis(orthodiaminophenyl) compounds (P). US Pat. No. 3481984, 1967)

[0005] Dr. Edgar Vorwerk used 3,3'-dichlorobenzidine as the raw material, copper powder and cuprous chloride as catalysts, and performed an amination reaction at 200-210°C. Purification methods included washing and recrystallization to obtain 3,3'-diaminobenzidine. This method required the use of large amounts of ammonia to wash away the copper residue. (Edgar Dr. Vorwerk. Process for the preparation of pure 3,3',4,4'-tetraaminobiphenyl (P). EP0522577B1, 1993)

[0006] Based on the above methods, it can be seen that the synthesis of 3,3'-diaminobenzidine is essentially a one-step temperature-elevated reaction using 3,3'-dichlorobenzidine as the raw material. These methods differ only in the reaction conditions, catalysts, and purification options. They also suffer from numerous impurities, low purity, low yield, high heavy metal residues, large wastewater volumes, and high costs. The present invention provides a two-step temperature-elevated method for preparing high-purity 3,3'-diaminobenzidine. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a two-step temperature-raising method for preparing high-purity 3,3'-diaminobenzidine, which can solve the problems of the prior art such as high product impurities, low purity, low yield, high heavy metal residues, large amount of wastewater and high cost.

[0008] In order to solve the above technical problems, the technical solution of the present invention is as follows:

[0009] S1. Two-step temperature-elevation reaction: 3,3'-dichlorobenzidine hydrochloride, copper salt, water and liquid ammonia are sequentially added to a stainless steel autoclave. After two temperature-elevation steps, the temperature is controlled at 130-140°C, the pressure is 4.0-5.5 MPa, and the reaction time is 15-20 h in the first step. The temperature is controlled at 210-220°C, the pressure is 6.0-8.0 MPa, and the reaction time is 3-5 h in the second step to generate 3,3'-diaminobenzidine. The specific reaction formula is as follows:

[0010]

[0011] The present invention adopts more stable 3,3'-dichlorobenzidine hydrochloride as a raw material, thereby preventing the raw material from deteriorating before reaction and introducing impurities, and is suitable for industrial large-scale stable production. At the same time, a two-stage heating process is adopted, wherein the first stage produces most of the monoaminated product 3'-chloro-3-aminobenzidine at a lower temperature, and the second stage further aminates the monoaminated product to produce the diaminated product 3,3'-diaminobenzidine at a higher temperature. The staged heating prevents the prematurely generated 3,3'-diaminobenzidine from deteriorating under high temperature conditions for a long time, thereby reducing the generation of impurities.

[0012] The temperature of the first stage is relatively low, and the energy required to generate the monoaminated product is relatively low, but the time is relatively long; the temperature of the second stage is relatively high, ensuring that the monoaminated product is further aminated to obtain 3,3'-diaminobenzidine. This period is short, avoiding the damage of the product caused by long-term high temperature.

[0013] S2. Filtration and crystallization: Filtration obtains a dark brown amide, which is melted in hot water, hot filtered, and cooled to crystallize to obtain a light yellow crude 3,3'-diaminobenzidine;

[0014] S3. Purification: Add water, activated carbon and ammonium sulfate hydrochloride to the crude 3,3'-diaminobenzidine obtained by the amination reaction, control the temperature at 97-103°C, and after complete dissolution, filter while hot, and slowly cool the filtrate to crystallize to obtain relatively pure 3,3'-diaminobenzidine;

[0015] S4. Purity improvement: Repeat the above purification operation several times to obtain high-purity 3,3'-diaminobenzidine.

[0016] Furthermore, in step S1, the copper salt is cuprous bromide.

[0017] Furthermore, in step S1, the molar equivalent ratio of 3,3'-dichlorobenzidine hydrochloride to liquid ammonia is 1:40-100; the mass ratio of 3,3'-dichlorobenzidine hydrochloride, copper salt and water is 100:19-21:195-390.

[0018] The preferred molar ratio of 3,3'-dichlorobenzidine hydrochloride to liquid ammonia can further suppress the generation of impurities and improve the purity of 3,3'-diaminobenzidine.

[0019] Furthermore, steps S1, S2, S3 and S4 are all performed under nitrogen protection.

[0020] Furthermore, in step S2, the temperature of the hot melt in hot water is 95-100°C.

[0021] Furthermore, in step S3, the mass ratio of the crude 3,3'-diaminobenzidine to water is 1:40-50, and the mass ratio of the activated carbon to ammonium sulfate hydrochloride is 1:1.

[0022] The above preferred water amount reduces the water consumption while ensuring that 3,3'-diaminobenzidine can be fully dissolved and the material will not precipitate during the material transfer process.

[0023] The above-mentioned ammonium sulfate hydrochloride is an antioxidant. Adding ammonium sulfate hydrochloride during the refining process of 3,3'-diaminobenzidine can protect 3,3'-diaminobenzidine from oxidation and reduce the generation of oxidative impurities.

[0024] The advantages of the present invention are that: the present invention uses 3,3'-dichlorobenzidine hydrochloride as an initial raw material, liquid ammonia as an aminating agent, copper salt as a catalyst, and water as a solvent, adopts a specific ratio, and adopts two-stage heating to prepare 3,3'-diaminobenzidine, thereby changing the existing synthesis method of single heating, reducing the generation of impurities, and the prepared 3,3'-diaminobenzidine has less tar, a light appearance color, and high purity; the purification method is simple and easy to operate; ammonium sulfate hydrochloride is used as an antioxidant for purification, which reduces the generation of oxidative impurities and improves the purity; the prepared 3,3'-diaminobenzidine has high purity, can be used as a pharmaceutical intermediate in the synthesis research of new drugs, reduces heavy metal residues, can be applied to purified wastewater, has good economic and environmental performance, and has a high yield. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is further described in detail below in conjunction with specific embodiments. The following examples can enable those skilled in the art to understand the present invention more comprehensively, but the present invention is not limited to the scope of the embodiments.

[0026] This specific implementation adopts the following technical solution: including the following steps:

[0027] S1. Two-step temperature-elevating reaction: 3,3'-dichlorobenzidine hydrochloride, copper salt, water and liquid ammonia are sequentially added to a stainless steel autoclave. After two steps of temperature elevation, the temperature is controlled at 130-140°C, the pressure is 4.0-5.5 MPa, and the reaction time is 15-20 h in the first step. The temperature is controlled at 210-220°C, the pressure is 6.0-8.0 MPa, and the reaction time is 3-5 h in the second step to generate 3,3'-diaminobenzidine, and the copper salt is cuprous bromide.

[0028] The specific reaction formula is as follows:

[0029]

[0030] The molar equivalent ratio of 3,3'-dichlorobenzidine hydrochloride to liquid ammonia is 1:40-100; the mass ratio of 3,3'-dichlorobenzidine hydrochloride, copper salt and water is 100:19-21:195-390.

[0031] The more stable 3,3'-dichlorobenzidine hydrochloride is used as the raw material to avoid the deterioration of the raw material before the reaction and the introduction of impurities, which is suitable for industrial large-scale stable production. At the same time, a two-stage heating process is adopted. The majority of the monoaminated product 3'-chloro-3-aminobenzidine is produced at a lower temperature in the first stage. The lower temperature in the first stage requires less energy to generate the monoaminated product, but the time is longer.

[0032] Under higher temperature conditions in the second section, the monoamide is further aminated to produce the diamide 3,3'-diaminobenzidine. The higher temperature in the second section ensures that the monoamide is further aminated to obtain 3,3'-diaminobenzidine. This period is short, which avoids damage to the product by long-term high temperature. The staged temperature increase prevents prematurely generated 3,3'-diaminobenzidine from deteriorating under high temperature conditions for a long time, thereby reducing the generation of impurities.

[0033] The molar ratio of 3,3'-dichlorobenzidine hydrochloride to liquid ammonia can further inhibit the generation of impurities and improve the purity of 3,3'-diaminobenzidine.

[0034] S2. Filtration and crystallization: Filtration obtains dark brown amide, which is melted in hot water at a temperature of 95-100°C, hot-filtered, and cooled to crystallize to obtain a light yellow crude 3,3'-diaminobenzidine.

[0035] S3. Purification: Add water, activated carbon and ammonium sulfate hydrochloride to the crude 3,3'-diaminobenzidine obtained by the amination reaction, control the temperature at 97-103°C, filter while hot after complete dissolution, and slowly cool the filtrate to crystallize to obtain relatively pure 3,3'-diaminobenzidine.

[0036] The mass ratio of crude 3,3'-diaminobenzidine to water is 1:40-50, and the mass ratio of activated carbon to ammonium sulfate hydrochloride is 1:1.

[0037] While reducing the water consumption, it is ensured that 3,3'-diaminobenzidine can be completely dissolved and the material will not precipitate during the material transfer process.

[0038] S4. Purity improvement: Repeat the above purification operation several times to obtain high-purity 3,3'-diaminobenzidine.

[0039] Ammonium sulfate hydrochloride is an antioxidant. Adding ammonium sulfate hydrochloride during the refining process of 3,3'-diaminobenzidine can protect 3,3'-diaminobenzidine from oxidation and reduce the generation of oxidative impurities.

[0040] The preparation of 3,3'-diaminobenzidine needs to be carried out under nitrogen protection throughout the process.

[0041] Example 1:

[0042] To a 1L stainless steel autoclave, add 100g of 3,3'-dichlorobenzidine hydrochloride, 21g of cuprous bromide, and 390g of water respectively. Close the autoclave, replace the atmosphere with nitrogen three times, and then charge with 420g of liquid ammonia. First, heat to 130°C and pressure to 4.2 MPa, and keep the reaction for 20h. Then heat to 210°C and pressure to 7.3 MPa, and keep the reaction for 4h.

[0043] The mixture was cooled naturally to 30° C., and the material was pressed out of the autoclave, filtered, and washed with 5% ammonia water. The mass ratio of the ammonia water used for washing and the input material 3,3'-dichlorobenzidine hydrochloride was 1:1. The mixture was then washed with purified water until it became weakly alkaline to obtain a light brown crude 3,3'-diaminobenzidine product. The purity of the crude 3,3'-diaminobenzidine product was ≥95% by liquid area percentage.

[0044] The obtained solid was added to a four-necked flask, and 2500 ml of purified water, 2.5 g of ammonium sulfate hydrochloride, and 2.5 g of activated carbon were added. After nitrogen replacement, the temperature was raised to 100°C and kept warm for 30 minutes. The filtrate was filtered while hot, and the filtrate was slowly cooled to 35°C. Solids precipitated, which were filtered and dried to obtain 47.2 g of relatively pure light yellow 3,3'-diaminobenzidine with a yield of 72%.

[0045] The obtained primary crystallized 3,3'-diaminobenzidine was added to a four-necked flask, and 2210 ml of purified water, 2.21 g of ammonium sulfate hydrochloride, and 2.21 g of activated carbon were added. After nitrogen substitution, the temperature was raised to 100°C, kept warm for 30 minutes, and filtered while hot. The filtrate was heated to 100°C again to ensure complete dissolution, and then slowly cooled to 35°C, kept warm for 1 hour, and filtered to obtain light yellow secondary crystallized 3,3'-diaminobenzidine.

[0046] The obtained secondary crystallized 3,3'-diaminobenzidine was added to a four-necked flask, and 1989 ml of purified water, 2 g of ammonium sulfate hydrochloride, and 2 g of activated carbon were added. After nitrogen replacement, the temperature was raised to 100°C, kept warm for 30 minutes, and filtered while hot. The filtrate was heated to 100°C again to ensure complete dissolution, and then slowly cooled to 35°C, kept warm for 1 hour, and filtered to obtain light yellow tertiary crystallized 3,3'-diaminobenzidine, which was dried under reduced pressure at 60°C to obtain 38.23 g, with a yield of 81% and a purity of 99.3%.

[0047] Example 2:

[0048] To a 1L stainless steel autoclave, add 160g of 3,3'-dichlorobenzidine hydrochloride, 30.82g of cuprous bromide, and 312g of water respectively. Close the autoclave, replace the atmosphere with nitrogen three times, and then charge with 334g of liquid ammonia. First, heat to 130°C and pressure to 4.2 MPa, and keep warm for 18 hours. Then heat to 220°C and pressure to 7.8 MPa, and keep warm for 3 hours.

[0049] The temperature was naturally lowered to 30° C., the material was pressed out of the autoclave, filtered, washed with 5% ammonia water, and then washed with purified water until weak alkalinity to obtain a light yellow crude 3,3'-diaminobenzidine. The purity of the crude 3,3'-diaminobenzidine was ≥95% by liquid area.

[0050] The obtained solid was added to a four-necked flask, and 4235 ml of purified water, 4.22 g of ammonium sulfate hydrochloride, and 4.22 g of activated carbon were added. After nitrogen replacement, the temperature was raised to 100°C and kept warm for 30 minutes. The filtrate was filtered while hot, and the filtrate was slowly cooled to 35°C. Solids precipitated, which were filtered and dried to obtain 76.23 g of light yellow crude 3,3'-diaminobenzidine with a yield of 72.6%.

[0051] The obtained primary crystallized 3,3'-diaminobenzidine was added to a four-necked flask, and 3810 ml of purified water, 3.8 g of ammonium sulfate hydrochloride, and 3.8 g of activated carbon were added. After nitrogen substitution, the temperature was raised to 100°C, kept warm for 30 minutes, and filtered while hot. The filtrate was heated to 100°C again to ensure complete dissolution, and then slowly cooled to 35°C, kept warm for 1 hour, and filtered to obtain light yellow secondary crystallized 3,3'-diaminobenzidine.

[0052] The obtained secondary crystallized 3,3'-diaminobenzidine was added to a four-necked flask, and 3400 ml of purified water, 3.4 g of ammonium sulfate hydrochloride, and 3.4 g of activated carbon were added. After nitrogen replacement, the temperature was raised to 100°C, kept warm for 30 minutes, and filtered while hot. The filtrate was heated to 100°C again to ensure complete dissolution, and then slowly cooled to 35°C, kept warm for 1 hour, and filtered to obtain light yellow tertiary crystallized 3,3'-diaminobenzidine.

[0053] The obtained tertiary crystallized 3,3'-diaminobenzidine was added to a four-necked flask, and 3000 ml of purified water, 3.1 g of ammonium sulfate hydrochloride, and 3.1 g of activated carbon were added. After nitrogen replacement, the temperature was raised to 100°C, kept warm for 30 minutes, and filtered while hot. The filtrate was heated to 100°C again to ensure complete dissolution, and then slowly cooled to 35°C, kept warm for 1 hour, and filtered to obtain light yellow tertiary crystallized 3,3'-diaminobenzidine. 57.17 g was obtained by drying under reduced pressure at 60°C, with a yield of 75% and a purity of 99.6%.

[0054] Comparative Example 1:

[0055] The method uses 3,3'-dichlorobenzidine as raw material and cuprous chloride as catalyst to carry out an amination reaction at a high temperature of 225°C to prepare the product. The raw materials are 100g of 3,3'-dichlorobenzidine, 13.9g of cuprous chloride, and 200g of liquid ammonia. The molar ratio of liquid ammonia to 3,3'-dichlorobenzidine is 40:1. The crude product is purified by sulfuric acid salt formation, neutralization and freeing, and hot water recrystallization to obtain relatively pure 3,3'-diaminobenzidine. The prepared 3,3'-diaminobenzidine has a purity of 82.3% and a yield of 35.3%. Due to the high reaction temperature, a large amount of tar is contained in the product, and a large amount of acid and alkali is used, resulting in a large amount of wastewater.

[0056] Comparative Example 2:

[0057] The invention uses 3,3'-dichlorobenzidine as a raw material, copper powder and cuprous chloride as catalysts, and carries out an amination reaction at a high temperature of 200-210°C to prepare the product. The raw materials are 100g of 3,3'-dichlorobenzidine, 13.9g of cuprous chloride, and 200g of liquid ammonia. The molar ratio of liquid ammonia to 3,3'-dichlorobenzidine is 40:1. 3,3'-diaminobenzidine is prepared through purification methods such as washing and recrystallization. The prepared 3,3'-diaminobenzidine has a purity of 84.6% and a yield of 35.6%. In comparative example 2, a large amount of ammonia water is required to wash the copper residue, and the heavy metal residue is still relatively high, resulting in a large amount of wastewater.

[0058] Comparative Example 3:

[0059] Comparative Example 3 is the same as Example 1, except that the molar equivalent ratio of 3,3'-dichlorobenzidine hydrochloride to liquid ammonia is 1:30, that is, the amount of liquid ammonia added is 157 g. The purity of the prepared 3,3'-diaminobenzidine is 83.7%, and the yield is 32.5%.

[0060] Comparative Example 4:

[0061] Comparative Example 4 is the same as Example 1, except that during purification, the crude product was added to a four-necked flask, purified water was added, and ammonium sulfate hydrochloride and activated carbon were not added. The purity of the prepared 3,3'-diaminobenzidine was 85.4%, and the yield was 31.2%.

[0062] Comparing Example 1-2 with Comparative Example 1-2, it can be seen that the 3,3'-diaminobenzidine prepared by the synthesis route of Example 1-2 has fewer impurities, higher purity, and higher yield. In addition, Example 1-2 has a lower risk of heavy metal residues and can be applied to purified wastewater, which has better economy and environmental protection.

[0063] By comparing Example 1 with Comparative Example 3, it can be seen that when preparing 3,3'-diaminobenzidine, the molar ratio of 3,3'-dichlorobenzidine hydrochloride to liquid ammonia is not within a specific range, and the obtained 3,3'-diaminobenzidine has more impurities, lower purity, and significantly lower yield; by comparing Example 1 with Comparative Example 4, it can be seen that when preparing 3,3'-diaminobenzidine, ammonium sulfate hydrochloride and activated carbon are not added during the purification of crude 3,3'-diaminobenzidine, and the obtained 3,3'-diaminobenzidine has more impurities, lower purity, and significantly lower yield.

[0064] The basic principles, main features, and advantages of the present invention are shown and described above. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and modifications are intended to fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing high-purity 3,3'-diaminobenzidine by a two-step temperature increase method, characterized in that: The following steps are involved: S1. Two-step temperature reaction: 3,3'-dichlorobenzidine hydrochloride, copper salt, water and liquid ammonia are added sequentially into a stainless steel autoclave, and the temperature is increased in two steps. In the first step, the temperature is controlled at 130-140°C, the pressure is 4.0-5.5 MPa, and the reaction time is 15-20 h. In the second step, the temperature is controlled at 210-220°C, the pressure is 6.0-8.0 MPa, and the reaction time is 3-5 h to generate 3,3'-diaminobenzidine. S2. Filtration and crystallization: Filtration obtains a dark brown amide, which is melted in hot water, hot filtered, and cooled to crystallize to obtain a light yellow crude 3,3'-diaminobenzidine; S3. Purification: Add water, activated carbon and ammonium sulfate hydrochloride to the crude 3,3'-diaminobenzidine obtained by the amination reaction, control the temperature at 97-103°C, and after complete dissolution, filter while hot, and slowly cool the filtrate to crystallize to obtain relatively pure 3,3'-diaminobenzidine; S4. Purity improvement: Repeat the above purification operation several times to obtain high-purity 3,3'-diaminobenzidine.

2. The method for preparing high-purity 3,3'-diaminobenzidine by a two-step temperature increase method according to claim 1, characterized in that: In the step S1, the copper salt is cuprous bromide.

3. The method for preparing high-purity 3,3'-diaminobenzidine by a two-step temperature-raising method according to claim 1, characterized in that: In step S1, the molar equivalent ratio of 3,3'-dichlorobenzidine hydrochloride to liquid ammonia is 1:40-100; the mass ratio of 3,3'-dichlorobenzidine hydrochloride, copper salt and water is 100:19-21:195-390.

4. The method for preparing high-purity 3,3'-diaminobenzidine by a two-step temperature-raising method according to claim 1, characterized in that: Steps S1, S2, S3 and S4 are all carried out under nitrogen protection.

5. The method for preparing high-purity 3,3'-diaminobenzidine by a two-step temperature-raising method according to claim 1, characterized in that: In step S2, the temperature of the hot melt in hot water is 95-100°C.

6. The method for preparing high-purity 3,3'-diaminobenzidine by a two-step temperature-raising method according to claim 1, characterized in that: In step S3, the mass ratio of the crude 3,3'-diaminobenzidine to water is 1:40-50, and the mass ratio of the activated carbon to ammonium sulfate hydrochloride is 1:1.

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