WO2019037161A1

WO2019037161A1 - Method for synthesizing key clofazimine intermediate n-(4-chlorphenyl)-1,2-phenylenediamine

Info

Publication number: WO2019037161A1
Application number: PCT/CN2017/100965
Authority: WO
Inventors: 杨冰
Original assignee: 重庆沃肯精细化工有限公司
Priority date: 2017-08-24
Filing date: 2017-09-08
Publication date: 2019-02-28
Also published as: CN107445845A

Abstract

A method for synthesizing a key clofazimine intermediate N-(4-chlorphenyl)-1,2-phenylenediamine. The method comprises: 1) using o-fluoronitrobenzene and p-chloroaniline as raw materials and an organic base as a catalyst for condensation reaction, reacting in an organic solvent, and performing conventional treatment after ending the reaction to acquire a condensation intermediate N-(4-chlorphenyl)-2-nitryl-1-aniline; 2) performing catalytic hydrogenation reduction on the acquired condensation intermediate in the organic solvent by using metallic nickel as the catalyst, and performing conventional treatment after reducing to acquire a rough product of N-(4-chlorphenyl)-1,2-phenylenediamine; and 3) re-crystallizing the acquired rough product using the organic solvent, thereby acquiring an end product.

Description

Method for synthesizing key intermediate of chlorofazamine N-(4-chlorophenyl)-1,2-phenylenediamine

Technical field

The invention belongs to the field of organic synthesis, and more specifically to a method for synthesizing a key intermediate of chlorhexidine, N-(4-chlorophenyl)-1,2-phenylenediamine.

Background technique

Chlorpheniramine (structured as shown below), also known as chlorpheniramine, was developed in the 1960s. The compound was originally intended to be used as an anti-tuberculosis drug, but early studies have shown little effect on anti-tuberculosis. Thereafter, the compound was used for the treatment of leprosy and achieved good results. Nowadays, this compound is widely used as a few effective drugs against leprosy and is widely used in combination chemotherapy and type II leprosy of MB type leprosy.

At present, tuberculosis, especially multidrug-resistant tuberculosis, has been on a high incidence, which is a serious threat to human health. However, in the discovery of anti-tuberculosis drugs, no significant progress has been made. Some anti-tuberculosis drugs used as first-line or second-line have been used for more than half a century. There are many problems in clinical application, such as long treatment period, ineffective treatment of multidrug-resistant tuberculosis, and no effect on latent M. tuberculosis. Strong and so on. In order to effectively avoid treatment failure caused by drug resistance during treatment, a combination of multiple anti-tuberculosis drugs is currently widely used clinically. In this therapy, studies have shown that clofazimine can play a good therapeutic role. In the 2014 WHO guidelines for tuberculosis drugs, clofazimine was classified as the fifth category and was allowed to be used in combination administration for anti-tuberculosis.

With the expansion of the use of clofibrate, it becomes necessary to synthesize the compound quickly and efficiently. The simplest synthetic route to clofazimine is the condensation of two molecules of N-(4-chlorophenyl)-1,2-phenylenediamine. That is to say, N-(4-chlorophenyl)-1,2-phenylenediamine is a key intermediate for the synthesis of clofaryn, and its cost and quality will have a direct impact on the synthesis of clofazimine.

At present, the synthesis of N-(4-chlorophenyl)-1,2-phenylenediamine is generally carried out by using o-chloronitrobenzene or o-fluoronitrobenzene and p-chloroaniline in the presence of an inorganic base, and then using the metal. / Acid system for reduction (as shown below).

In the first condensation reaction, an inorganic base such as sodium acetate (Chem. Ber., 1902, 35, 957), potassium carbonate (Bioorg. And Med. Chem. Lett., 2005, 15, 1923; Bioorg is generally used. .And Med. Chem. Lett., 2017, 27, 90), potassium fluoride (WO 20123190; Molecules, 1012, 17, 4545; J. Med. Chem., 2012, 55, 8409; Chinese J. Chem., 2013, 31, 1473), a mixed system of potassium fluoride and potassium carbonate (WO 2012151512; ACS Med. Chem. Lett., 2016, 7, 145; Chinese J. Chem., 2012, 23, 707) and sodium hydrogen ( Bioorg. And Med. Chem. Lett., 2017, 16, 4475). The above-mentioned bases have high reaction temperatures (greater than 160 degrees), longer reaction times (greater than 20 hours), low reaction yields (less than 50%), poor safety, etc. in practical applications. Disadvantages.

The reduction reaction of the second step is generally carried out by using a metal/Lewis acid system or a low-valent metal chloride. Commonly used such as iron powder, zinc powder, titanium dichloride, etc., some of the methods can be seen in the above literature. In addition, reduction with palladium on carbon/hydrogen is used (Chinese J. Chem., 2013, 31, 1473). The metal/Lewis acid system is used for the reduction, and the metal needs a large excess. After the reaction is completed, a large amount of metal residue is generated, and the pollution is huge. Catalytic hydrogenation reduction using palladium on carbon as a catalyst, although relatively clean, is very expensive and results in higher raw material costs.

Summary of the invention

In view of the above deficiencies in the prior art, the present invention provides a safe and efficient synthesis of N-(4-chlorophenyl)-1 on the basis of the original synthetic route by selecting a new condensation reagent and a reduction catalyst. Method of 2-phenylenediamine.

Specifically, the synthesis method includes the following steps:

1) using o-fluoronitrobenzene and p-chloroaniline as raw materials, and using an organic base as a catalyst for the condensation reaction to carry out a condensation reaction in an organic solvent; after the reaction is completed, a condensation intermediate N-(4-chlorobenzene) is obtained by a conventional treatment. 2-nitro-1-aniline;

2) The condensed intermediate obtained above is subjected to catalytic hydrogenation reduction in an organic solvent using metallic nickel as a catalyst; after reduction, conventionally, N-(4-chlorophenyl)-1,2- Phenylenediamine crude product.

3) The crude product is recrystallized from an organic solvent to obtain a final acceptable product.

In the above steps:

The organic base used is usually an organic amine compound such as triethylamine, diisopropylethylamine, dimethylisopropylamine, 4-methylmorpholine, 1,4-diazabicyclo[2 , 2,2]octane (DABCO), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), 1,5-diazabicyclo[4,3,0 11--7-ene (DBN), 1-methylpyrrolidine, and the like. They may be used one by one or a mixture of two or more kinds in order to achieve a better catalytic effect.

When the organic base to be used is used as a catalyst, the molar ratio of the amount usually added to the raw material p-chloroaniline is between 0.8 and 2, preferably between 1 and 1.3.

The solvent used in the condensation reaction is preferably a polar aprotic solvent such as DMF, DMAC, DMSO, dioxane or the like. It can be a certain kind in the course of use, or it can be a mixed system of them.

The condensation reaction is generally carried out at a temperature of from 80 to 150 degrees, preferably from 100 to 120 degrees. The progress of the reaction was monitored by HPLC.

Under normal circumstances, due to the poor reactivity of p-chloroaniline, there will be more surplus. Therefore, the excess of o-fluoronitrobenzene is selected, and p-chloroaniline is slowly added to the reaction system containing o-fluoronitrobenzene and an organic base to This improves the conversion of p-chloroaniline. Even so, p-chloroaniline still has nearly 10% remaining near the end of the reaction, but it does not affect subsequent product purification.

After the reaction is completed, the reaction system is cooled to 50 to 60 degrees, and a certain amount of water or a protic polar solvent such as methanol or ethanol is added, and then the crystal is stirred and cooled to within 20 degrees. Thereafter, the condensation intermediate N-(4-chlorophenyl)-2-nitro-1-aniline was isolated.

In the reduction step, the catalyst used is metallic nickel, which may be supported nickel, framework nickel (Raney nickel), nickel nanoclusters or amorphous nickel alloys. Among them, the safety performance is high, Low-cost supported nickel is used as a catalyst.

The amount of catalyst used in this type is generally from 5% to 20%, preferably from 5 to 8% by weight of the condensed intermediate to be reduced.

The reduction reaction can be carried out in a variety of organic solvents, such as toluene, methanol, ethanol, DMF, etc., and the selected solvent mainly needs to consider the condensate intermediate and the solubility of the final product and the ease of post-treatment.

For safety reasons, the hydrogen pressure used in the reduction is generally maintained within 5 kg; the reaction temperature is generally between 50 and 80 degrees.

The reaction was monitored by HPLC and the reaction ended with the disappearance of the condensate intermediate.

After the completion of the reaction, the metal nickel catalyst was separated by hot filtration, and the catalyst was repeatedly used three times or more after washing with methanol, and the catalytic activity was not significantly decreased.

After the hot filtered mother liquor is concentrated to a certain amount of the reaction solvent, it is cooled to within 20 degrees to crystallize. After that, the N-(4-chlorophenyl)-1,2-phenylenediamine product is separated by centrifugation, and the purity of the product is generally above 98%, and the color is taupe.

If the product is re-crystallized by using an organic solvent such as toluene, methanol, ethanol, etc., a purity of 99.5% or more, a single impurity of less than 0.1%, and a silver-white color of N-(4-chlorophenyl group) can be obtained. )-1,2-Phenylenediamine end product.

From this, by using the above technical scheme, a compound of N-(4-chlorophenyl)-1,2-phenylenediamine is synthesized by using an organic base as a catalyst for a condensation reaction and by using a metal nickel as a catalyst for a reduction reaction. It is safer, more convenient, and less polluting; at the same time, the cost of the technical solution will be lower and the quality will be more easily controlled. Taken together, this technical solution is suitable for large production applications.

Detailed ways

The invention will be further described in detail below with reference to specific embodiments.

Condensation reaction:

Embodiment 1:

In a dry, clean pressure reaction flask, 104 g of o-fluoronitrobenzene and 200 g of DMF were charged, and 88 g of triethylamine was added with stirring, and then the temperature was raised to 120 degrees under nitrogen protection, and the pressure was raised to less than 1 kg. 86 g of p-chloroaniline was dissolved in 100 g of DMF to prepare a solution, and then the solution was slowly added dropwise to the above reaction system. The temperature will rise during the addition process, and the reaction temperature should be controlled within 125 degrees by cooling.

The reaction was continued for 8 hours between 120 and 130 degrees, and the progress of the reaction was monitored by HPLC. When the p-chloroaniline content does not decrease, the reaction is complete, at which point about 18% of the p-chloroaniline remains. Then cool down to 60 degrees.

To the reaction liquid, 300 g of deionized water of 50 to 60 degrees was added under stirring, and the mixture was stirred for 30 minutes. Then slowly cool down to crystallize within 20 degrees.

The crystalline solid was isolated by filtration. The solid was washed with an appropriate amount of deionized water and then washed with a small amount of cold methanol. After suction filtration and drying, 103 g of the condensate intermediate N-(4-chlorophenyl)-2-nitro-1-aniline was obtained in a yield of 62%, and the HPLC purity was more than 98%.

Embodiment 2:

In a reaction flask, 87 g of o-fluoronitrobenzene and 200 g of DMAC were charged, and 94 g of diisopropylethylamine was placed under stirring, and then the temperature was raised to 120 °C under nitrogen atmosphere. 71 g of p-chloroaniline was dissolved in 100 g of DMAC to prepare a solution, and then the solution was slowly added dropwise to the above reaction system. The temperature will rise during the addition process, and the reaction temperature should be controlled within 125 degrees by cooling.

The reaction was continued for 8 hours between 120 and 125 degrees, and the progress of the reaction was monitored by HPLC. When the p-chloroaniline content did not decrease, the reaction was completed, at which time about 11% of p-chloroaniline remained. Cool down to 60 degrees.

Thereafter, in the same manner as in the first embodiment, 100 g of the condensate intermediate N-(4-chlorophenyl)-2-nitro-1-aniline was obtained in a yield of 72%, and the HPLC purity was more than 98%.

Embodiment 3:

In a reaction flask, 92 g of o-fluoronitrobenzene and 200 g of DMSO were charged, and 117 g of DBU was charged with stirring, and then heated to 120 °C under nitrogen atmosphere. 75 g of p-chloroaniline was dissolved in 100 g of DMSO to prepare a solution, and then the solution was slowly added dropwise to the above reaction system. The temperature will rise during the addition process, and the reaction temperature should be controlled within 125 degrees by cooling.

The reaction was continued for 5 hours between 120 and 125 degrees and the progress of the reaction was monitored by HPLC. When the p-chloroaniline content does not decrease, the reaction is complete, at which point p-chloroaniline remains about 12%. Cool down to 80 degrees.

Then, in the same manner as in the first embodiment, 100 g of the condensate intermediate N-(4-chlorophenyl)-2-nitro-1-aniline was obtained in a yield of 68%, and the HPLC purity was more than 98%.

Reduction reaction:

Embodiment 4:

Into a hydrogenation reactor, 100 g of N-(4-chlorophenyl)-2-nitro-1-aniline and 800 g of toluene were charged, and after replacing with nitrogen, 10 g of a nickel metal catalyst was charged. Turn on the stirring, warm up to 60 degrees, and pass hydrogen to 3 Kilogram pressure. Maintain the above and continue to pass hydrogen between 60 and 70 degrees until hydrogen is no longer absorbed, and the progress of the reaction is controlled by HPLC. When the condensate intermediate disappears, the reaction reaches the end point.

The reaction system was replaced with nitrogen, and the nickel catalyst was removed by hot filtration. The obtained filtrate was evaporated under reduced pressure to give about 600 g of toluene, and then slowly cooled to crystals within 20 degrees. The solid was separated by filtration, and the solid was washed with an appropriate amount of cold toluene and dried. Finally, 72 g of crude N-(4-chlorophenyl)-1,2-phenylenediamine was obtained in a yield of 82%, purity was greater than 98%, and the color was succulent.

Embodiment 5:

In a hydrogenation reactor, 100 g of N-(4-chlorophenyl)-2-nitro-1-aniline and 200 g of DMF were charged, and after replacing with nitrogen, 10 g of a nickel metal catalyst was charged. The stirring was turned on, the temperature was raised to 60 degrees, and hydrogen gas was introduced to a pressure of 3 kg. Hydrogen was continuously introduced between 60 and 70 degrees until hydrogen was no longer absorbed, and the progress of the reaction was controlled by HPLC. When the condensate intermediate disappears, the reaction reaches the end point.

The reaction system was replaced with nitrogen, and the nickel catalyst was removed by hot filtration. The obtained filtrate was evaporated under reduced pressure to give a mixture of about 100 g of DMF, and then 200 g of deionized water was added thereto, followed by slowly cooling to crystallize within 20 degrees. The solid was separated by filtration, and the solid was washed with an appropriate amount of deionized water, then washed with cold toluene and dried. Finally, 81 g of crude N-(4-chlorophenyl)-1,2-phenylenediamine was obtained in a yield of 92%, purity was greater than 98%, and the color was succulent.

Example 6:

The nickel metal catalyst separated in the reduction step was washed with a small amount of methanol and filtered. Thereafter, according to the fourth or fifth embodiment, a crude N-(4-chlorophenyl)-1,2-phenylenediamine was obtained in almost the same yield and mass. The catalyst was applied three times and it was found that the catalytic activity did not decrease significantly.

Recrystallization process:

Example 7:

In a reaction flask, 100 g of N-(4-chlorophenyl)-1,2-phenylenediamine and 225 g of methanol were charged, and after nitrogen substitution, the temperature was raised to 60 °C to reflux, and then slowly cooled to crystallize within 20 degrees. The solid was separated by filtration, and the solid was washed with an appropriate amount of cold methanol and dried. Finally, 86 g of N-(4-chlorophenyl)-1,2-phenylenediamine final product was obtained, the yield was 86%, the purity was more than 99.5%, and the color was silver white.

Example 8:

In a reaction flask, 100 g of N-(4-chlorophenyl)-1,2-phenylenediamine and 200 g of toluene were charged, and after nitrogen substitution, the temperature was raised to 80 °C to reflux, and then slowly cooled to crystallize within 20 degrees. The solid was separated by filtration, and the solid was washed with an appropriate amount of cold toluene and dried. Finally, 88 g of N-(4-chlorophenyl)-1,2-phenylenediamine was obtained. The final product, the yield is 88%, the purity is more than 99.5%, and the color is silver white.

The technical solutions provided by the embodiments of the present invention are described in detail above. The principles and implementation manners of the embodiments of the present invention are described in the following. The description of the foregoing embodiments is only applicable to help understand the embodiments of the present invention. The present invention is not limited by the scope of the present invention, and the description of the present invention is not limited to the details of the present invention.

Claims

A method for synthesizing a key intermediate of chlorofazamine, N-(4-chlorophenyl)-1,2-phenylenediamine, which comprises the following steps:

1), using o-fluoronitrobenzene and p-chloroaniline as raw materials, using an organic base as a catalyst for the condensation reaction in an organic solvent; after the reaction is completed, a condensation intermediate N-(4-chlorophenyl) is obtained by conventional treatment. -2-nitro-1-aniline;

2) The obtained condensation intermediate is subjected to catalytic hydrogenation reduction in an organic solvent using metallic nickel as a catalyst; after reduction, conventionally obtained N-(4-chlorophenyl)-1,2-phenylenediamine crude product ;

3), the obtained crude N-(4-chlorophenyl)-1,2-phenylenediamine is recrystallized from an organic solvent to obtain a final product;
The method for synthesizing the key intermediate of the clofazimine N-(4-chlorophenyl)-1,2-phenylenediamine according to claim 1, wherein in the step 1), the method is used The organic base is an organic amine compound, including triethylamine, diisopropylethylamine, dimethylisopropylamine, 4-methylmorpholine, 1,4-diazabicyclo[2,2, 2] Octane (DABCO), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), 1,5-diazabicyclo[4,3,0] eleven -7-ene (DBN) and 1-methylpyrrolidine may be used singly or in combination of two or more kinds.
The method for synthesizing the key intermediate of the clofazimine N-(4-chlorophenyl)-1,2-phenylenediamine according to claim 1, wherein in the step 1), the organic base The molar ratio of the amount added to the p-chloroaniline used is from 0.8 to 2:1.
The method for synthesizing the key intermediate of the clofazimine N-(4-chlorophenyl)-1,2-phenylenediamine according to claim 1, wherein in the step 1), the method is used The solvent is a polar aprotic solvent, including DMF, DMAC, DMSO, dioxane, which may be used in a certain process or a mixed system thereof.
The method for synthesizing the key intermediate of the clofazimine N-(4-chlorophenyl)-1,2-phenylenediamine according to claim 1, wherein in the step 2), the method is used The catalyst is metallic nickel, which may be supported nickel, framework nickel, nickel nanoclusters or amorphous nickel alloys.
A novel method for synthesizing the key intermediate of the clofazimine N-(4-chlorophenyl)-1,2-phenylenediamine according to claim 1, wherein in the step 2), the metal The nickel catalyst is used in an amount of from 5% to 20% by weight based on the weight of the condensation intermediate to be reduced.
A key intermediate of the synthesis of clofazimine, N-(4-chlorophenyl)-1, according to claim 1 A novel method of 2-phenylenediamine, characterized in that in the step 3), the recrystallization solvent is toluene, methanol, ethanol, acetone, ethyl acetate; one of them or a mixed system thereof may be selected.