CN117447421A - Synthesis method of 3, 7-bis- (dimethylamino) -phenothiazine - Google Patents

Abstract

The invention discloses a method for synthesizing 3, 7-bis- (dimethylamino) -phenothiazine, which comprises the following steps: s1, in the presence of a nano copper-aluminum catalyst, taking 3, 7-binitro-10H-phenothiazine as a starting material to perform one-step reaction in a solvent containing paraformaldehyde and alkali; s2, removing the solvent after the reaction, crystallizing, filtering and drying to obtain the 3, 7-bis- (dimethylamino) -phenothiazine. According to the synthesis method provided by the invention, the nano copper-aluminum catalyst is adopted, 3, 7-binitro-10H-phenothiazine is taken as a starting material, and a key intermediate 3, 7-bis- (dimethylamino) -phenothiazine for preparing methylene blue is synthesized through one-step aminomethylation, so that the synthesis process of the methylene blue is greatly simplified, the generation of heavy metal waste liquid is avoided, and the problems of complex synthesis process, serious heavy metal pollution and the like of the original methylene blue can be avoided; meanwhile, the method for synthesizing the intermediate has the advantages of mild reaction conditions, short reaction time, simple operation and high yield, and is suitable for industrial production.

Description

A kind of synthesis method of 3,7-bis-(dimethylamino)-phenothiazine

Technical field

The invention relates to the technical field of fine chemical synthesis, and specifically relates to a synthesis method of 3,7-bis-(dimethylamino)-phenothiazine.

Background technique

3,7-Bis-(dimethylamino)-phenothiazine can be used to synthesize the compound methylene blue. Methylene blue, chemically named 3,7-bis(dimethylamino)phenothiazin-5-onium chloride, is widely used in chemical indicators, dyes, biological stains and drugs. Chinese patent CN200610201306.9 reports on the synthesis of methylene blue, which mainly uses N,N-dimethyl-p-phenylenediamine as raw material, and then oxidizes it with manganese dioxide and replaces it with sodium thiosulfate to obtain 2-amino-5 -Dimethylaminophenyl thiosulfonic acid, and then condensed with N,N-dimethylaniline, oxidized and cyclized by manganese dioxide and copper sulfate to obtain methylene blue zinc chloride salt, and finally neutralized with sodium carbonate Methylene blue is obtained. Chinese patent CN1970548A reports on the synthesis of methylene blue, which uses N,N-dimethyl-p-phenylenediamine hydrochloride as raw material, oxidizes it with sodium dichromate, and replaces it with sodium thiosulfate to obtain 2-amino-5- Dimethylaminophenyl thiosulfonic acid is then condensed with N,N-dimethyl-p-phenylenediamine, and oxidized and cyclized by manganese dioxide to obtain methylene blue zinc chloride salt in the presence of zinc chloride. , and finally neutralized with sodium carbonate to obtain methylene blue. It can be seen that the existing methylene blue synthesis method has long synthesis steps, cumbersome operations, and will form a large amount of waste liquid containing chromium and manganese, which is not conducive to industrial production.

Using 3,7-bis-(dimethylamino)-phenothiazine as the raw material to synthesize methylene blue, the synthesis process is relatively simple. Methylene blue can be obtained by oxidizing ferric chloride in the presence of hydrochloric acid. Its synthesis The process is as follows:

Although this methylene blue synthesis method has short steps, simple operation, and avoids the generation of heavy metal waste liquid, the synthesis of the intermediate 3,7-bis-(dimethylamino)-phenothiazine is the key to this process route. However, there are few literature reports on the simple preparation method of 3,7-bis-(dimethylamino)-phenothiazine.

Contents of the invention

The object of the present invention is to provide a simple synthesis method of 3,7-bis-(dimethylamino)-phenothiazine, and to synthesize the obtained 3,7-bis-(dimethylamino)-phenothiazine. Thiazide is used as a key intermediate to synthesize methylene blue, which solves the shortcomings of the existing technology such as complicated methylene blue synthesis process, low yield, heavy metal pollution, and unfavorable industrial production.

The present invention is achieved through the following technical solutions:

A method for synthesizing 3,7-bis-(dimethylamino)-phenothiazine, which is characterized in that the method includes the following steps:

S1. In the presence of nano-copper and aluminum catalysts, use 3,7-dinitro-10H-phenothiazine as the starting material to perform a one-step reaction in a solvent containing paraformaldehyde and alkali;

S2. After the reaction, the solvent is removed, crystallized, filtered, and dried to prepare 3,7-bis-(dimethylamino)-phenothiazine.

The method of the present invention uses 3,7-dinitro-10H-phenothiazine as a starting material, and uses 3,7-dinitro-10H-phenothiazine and paraformaldehyde in one step in the presence of a nanometer copper-aluminum catalyst. 3,7-Bis-(dimethylamino)-phenothiazine was synthesized by N-methylation reaction.

Specifically, the process of synthesizing 3,7-bis-(dimethylamino)-phenothiazine in the present invention is as follows:

Further, a method for synthesizing 3,7-bis-(dimethylamino)-phenothiazine: the degree of polymerization of paraformaldehyde described in step S1 is 10 to 20. A degree of polymerization of 12 is preferred.

Further, a synthesis method of 3,7-bis-(dimethylamino)-phenothiazine: the base described in step S1 is selected from sodium carbonate or potassium carbonate.

Further, a synthesis method of 3,7-bis-(dimethylamino)-phenothiazine: the combination of 3,7-dinitro-10H-phenothiazine, paraformaldehyde and alkali described in step S1 The molar ratio between them is 1: (5～20): (0.3～3.0).

Further, a synthesis method of 3,7-bis-(dimethylamino)-phenothiazine: the solvent described in step S1 is a mixture of N,N-dimethylformamide and water, wherein water and The volume ratio of N,N-dimethylformamide is 1: (10~20).

Further, a synthesis method of 3,7-bis-(dimethylamino)-phenothiazine: the reaction temperature described in step S1 is 70-150°C, and the reaction time is 4-12 hours.

Further, a synthesis method of 3,7-bis-(dimethylamino)-phenothiazine: step S2, after the reaction, the solvent is distilled under reduced pressure, then dichloromethane or methanol is added to stir and crystallize, and then filtered, Dry to prepare 3,7-bis-(dimethylamino)-phenothiazine.

Further, a synthesis method of 3,7-bis-(dimethylamino)-phenothiazine: the preparation method of the nanometer copper-aluminum catalyst described in step S1 includes the following steps:

(1) Dissolve copper nitrate and aluminum nitrate in deionized water, then add precipitant, stir evenly, and perform hydrothermal reaction;

(2) After the reaction, cool, filter, wash, dry, and reduce at high temperature under H ₂ /N ₂ atmosphere to prepare nano-copper and aluminum catalysts.

Furthermore, a synthesis method of 3,7-bis-(dimethylamino)-phenothiazine: the preparation method of the nano-copper-aluminum catalyst: step (1) molar ratio (2-3): 1 , dissolve copper nitrate and aluminum nitrate in deionized water, then add urea as a precipitant, stir evenly, and perform a hydrothermal reaction at 100 to 110°C for 6 to 12 hours.

Furthermore, a synthesis method of 3,7-bis-(dimethylamino)-phenothiazine: the preparation method of the nano-copper aluminum catalyst: after the reaction in step (2), cool to room temperature, suction filtration, Wash until neutral, then dry at 60-80°C, and then reduce at 300-400°C for 3-6 hours in an H ₂ /N ₂ atmosphere to prepare a nano-copper-aluminum catalyst.

Beneficial effects of the present invention:

(1) The synthesis method provided by the invention uses nano-copper aluminum catalyst, uses 3,7-dinitro-10H-phenothiazine as the starting material, and synthesizes the key intermediate for preparing methylene blue through one-step aminomethylation. 3,7-Bis-(dimethylamino)-phenothiazine, this intermediate greatly simplifies the synthesis process of methylene blue, avoids the generation of heavy metal waste liquid, and can avoid the original methylene blue synthesis process complexity and serious heavy metal pollution and other problems; at the same time, the reaction conditions for synthesizing the intermediate in the present invention are mild, the reaction time is short, the operation is simple, the yield is high, and it is suitable for industrial production.

(2) The synthesis method of the present invention uses nano-copper and aluminum catalysts to replace the precious metal catalysts commonly used in traditional aromatic nitro compound reduction and methylation reactions, resulting in lower production costs; the method of the present invention uses paraformaldehyde as the methylation reagent, It replaces commonly used toxic methylation reagents such as methyl halides and dimethyl sulfate, and paraformaldehyde can be decomposed to produce hydrogen under the nano-copper and aluminum catalyst to complete the reduction process, avoiding the use of hydrogen, making the operation simpler and safer.

(3) The active components of the nano-copper-aluminum catalyst prepared by the present invention using urea as a precipitant and a hydrothermal reaction method are highly dispersed, have strong interaction between components, and have good thermal stability, and exhibit excellent performance in N-methylation reactions. Good catalytic activity and stability enable the yield of 3,7-bis-(dimethylamino)-phenothiazine to reach more than 90%.

Detailed ways

The technical solution of the present invention will be described clearly and completely below with reference to specific embodiments. Obviously, the described embodiments are only some of the embodiments of the present invention, not all of them. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application or uses. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts fall within the scope of protection of the present invention.

Example 1

A synthesis method of 3,7-bis-(dimethylamino)-phenothiazine, including the following steps:

S1. Add 4.0g of nano-copper aluminum catalyst, 0.2mol of 3,7-dinitro-10H-phenothiazine (about 58.0g), 1.0mol of paraformaldehyde, and 0.1mol of carbonic acid into the high-pressure reaction kettle. Sodium, 300.0 ml of N,N-dimethylformamide (DMF) and 30.0 ml of water were heated to 90°C with stirring for 6 hours;

S2. After the reaction, remove the solvent by distillation under reduced pressure, then add dichloromethane to stir and crystallize, then filter and dry to obtain about 52.9g of 3,7-bis-(dimethylamino)-phenothiazine, purity 99 %; based on 3,7-dinitro-10H-phenothiazine, the yield of 3,7-bis-(dimethylamino)-phenothiazine is 91.21%.

The process of synthesizing 3,7-bis-(dimethylamino)-phenothiazine in the above Example 1 is as follows:

The preparation method of the nanometer copper-aluminum catalyst in the above embodiment 1 includes the following steps:

(1) The molar ratio is 3:1. Dissolve copper nitrate and aluminum nitrate in deionized water to prepare a mixed nitrate solution with a total concentration of 0.4mol/L. Then add urea (precipitant) until the solution contains 0.2% urea. mol/L, stir evenly and then move it into a hydrothermal reactor and react at 110°C for 12 hours;

(2) After the reaction, cool to room temperature, suction filter, wash until neutral, then dry at 80°C, and then reduce in a tube furnace at 350°C for 6 hours under H ₂ /N ₂ atmosphere to prepare nano-copper Aluminum catalyst.

Example 2

A synthesis method of 3,7-bis-(dimethylamino)-phenothiazine, including the following steps:

S1. Add 6.0g of nano-copper aluminum catalyst, 0.2mol of 3,7-dinitro-10H-phenothiazine (about 58.0g), 2.0mol of paraformaldehyde, and 0.3mol of carbonic acid into the high-pressure reaction kettle. Sodium, 300.0 ml of N,N-dimethylformamide (DMF) and 20.0 ml of water were heated to 130°C with stirring for 4 hours;

S2. After the reaction, remove the solvent by distillation under reduced pressure, then add dichloromethane to stir and crystallize, then filter and dry to obtain about 53.7g of 3,7-bis-(dimethylamino)-phenothiazine, purity 99 %; based on 3,7-dinitro-10H-phenothiazine, the yield of 3,7-bis-(dimethylamino)-phenothiazine is 92.59%.

The preparation method of the nanometer copper-aluminum catalyst in the above embodiment 2 includes the following steps:

(1) The molar ratio is 2:1. Dissolve copper nitrate and aluminum nitrate in deionized water to prepare a mixed nitrate solution with a total concentration of 0.4 mol/L. Then add urea (precipitant) until the solution contains 0.2 urea. mol/L, stir evenly and then move it into a hydrothermal reactor and react at 100°C for 6 hours;

(2) After the reaction, cool to room temperature, suction filter, wash until neutral, then dry at 60°C, and then reduce in a tube furnace at 400°C for 3 hours in an H ₂ /N ₂ atmosphere to prepare nano-copper Aluminum catalyst.

Example 3

A synthesis method of 3,7-bis-(dimethylamino)-phenothiazine, including the following steps:

S1. Add 6.0g of nano-copper aluminum catalyst, 0.2mol of 3,7-dinitro-10H-phenothiazine (about 58.0g), 4.0mol of paraformaldehyde, and 0.6mol of carbonic acid into the high-pressure reaction kettle. Sodium, 300.0 ml of N,N-dimethylformamide (DMF) and 15.0 ml of water were heated to 70°C with stirring for 8 hours;

S2. After the reaction, remove the solvent by distillation under reduced pressure, then add dichloromethane to stir and crystallize, then filter and dry to obtain about 53.5g of 3,7-bis-(dimethylamino)-phenothiazine, purity 99 %; based on 3,7-dinitro-10H-phenothiazine, the yield of 3,7-bis-(dimethylamino)-phenothiazine is 92.24%.

The 3,7-bis-(dimethylamino)-phenothiazine synthesized in the present invention can be used as an intermediate for synthesizing methylene blue, which simplifies the synthesis process of methylene blue. The specific process of using the 3,7-bis-(dimethylamino)-phenothiazine intermediate to synthesize methylene blue is as follows: oxidizing the intermediate with ferric chloride in the presence of hydrochloric acid to obtain methylene blue, Its synthesis process is as follows:

The above-mentioned preferred embodiments of the present invention are only used to explain the present invention and are not intended to limit the present invention. Any obvious changes or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims (10)

1. A synthetic method of 3,7-bis-(dimethylamino)-phenothiazine, characterized in that the method includes the following steps: S1. In the presence of nano-copper and aluminum catalysts, use 3,7-dinitro-10H-phenothiazine as the starting material to perform a one-step reaction in a solvent containing paraformaldehyde and alkali; S2. After the reaction, the solvent is removed, crystallized, filtered, and dried to prepare 3,7-bis-(dimethylamino)-phenothiazine. 2. A kind of synthesis method of 3,7-bis-(dimethylamino)-phenothiazine according to claim 1, characterized in that the degree of polymerization of paraformaldehyde in step S1 is 10 to 20 . 3. A method for synthesizing 3,7-bis-(dimethylamino)-phenothiazine according to claim 1, characterized in that the base described in step S1 is selected from sodium carbonate or potassium carbonate. 4. A kind of synthetic method of 3,7-bis-(dimethylamino)-phenothiazine according to claim 1, characterized in that, the 3,7-dinitro-10H- described in step S1 The molar ratio between phenothiazine, paraformaldehyde and alkali is 1: (5～20): (0.3～3.0). 5. A kind of synthetic method of 3,7-bis-(dimethylamino)-phenothiazine according to claim 1, characterized in that the solvent described in step S1 is N,N-dimethyl A mixture of formamide and water, in which the volume ratio of water to N,N-dimethylformamide is 1: (10~20). 6. A kind of synthesis method of 3,7-bis-(dimethylamino)-phenothiazine according to claim 1, characterized in that the reaction temperature described in step S1 is 70-150°C, and the reaction The time is 4 to 12 hours. 7. A kind of synthesis method of 3,7-bis-(dimethylamino)-phenothiazine according to claim 1, characterized in that, step S2, after the reaction, the solvent is distilled under reduced pressure, and then dichloride is added. Methane or methanol is stirred and crystallized, followed by filtration and drying to prepare 3,7-bis-(dimethylamino)-phenothiazine. 8. A kind of synthesis method of 3,7-bis-(dimethylamino)-phenothiazine according to claim 1, characterized in that the preparation method of the nanometer copper-aluminum catalyst in step S1 includes the following step: (1) Dissolve copper nitrate and aluminum nitrate in deionized water, then add precipitant, stir evenly, and perform hydrothermal reaction; (2) After the reaction, cool, filter, wash, dry, and reduce at high temperature under H ₂ /N ₂ atmosphere to prepare nano-copper and aluminum catalysts. 9. A kind of synthesis method of 3,7-bis-(dimethylamino)-phenothiazine according to claim 8, characterized in that the preparation method of the nano-copper aluminum catalyst: Step (1) molar ratio (2-3): 1. Dissolve copper nitrate and aluminum nitrate in deionized water, then add urea as a precipitant, stir evenly, and perform a hydrothermal reaction at 100-110°C for 6-12 hours. 10. A kind of synthesis method of 3,7-bis-(dimethylamino)-phenothiazine according to claim 8, characterized in that the preparation method of the nano-copper aluminum catalyst: After the reaction in step (2), cool to room temperature, suction filter, wash until neutral, then dry at 60-80°C, and then reduce at 300-400°C for 3-6 hours in H ₂ /N ₂ atmosphere to obtain Nano-copper aluminum catalyst.