阅读说明：本技术 用于制备吩嗪衍生物的中间体及其制备方法 (Intermediate for preparing phenazine derivative and preparation method thereof ) 是由 禹锡勋 朴硬台 张淳基 林根兆 于 2020-02-13 设计创作，主要内容包括：本发明揭示使用具有高于4-CA与F-NO2反应温度的沸点(boiling point)的极性非质子溶剂(polar aprotic solvent)让4-CA与F-NO-2进行反应制备的CPNA、将其和氧化数为-2的硫化合物进行反应制备的CPDA、利用在此制备的CPNA或CPDA制备的氯法齐明以及它们的制备方法。本发明在制备CPNA时简化工艺并提高工艺稳定性而能够大幅提升生产效率。而且,本发明把硫化合物作为还原剂使用而能制备高收率与高纯度的CPDA。而且,相比于现有技术通常采取的通过后处理过程清除副产物的工艺,本发明只通过精制水洗涤就能简单清除副产物而有利于商业化,大幅减少溶剂而能实现环境亲和性工艺。(The present invention discloses the use of polar aprotic solvents (polar aprotic solvents) having boiling points (boiling points) higher than the reaction temperature of 4-CA and F-NO2 for reacting 4-CA and F-NO 2 CPNA produced by the reaction, CPDA produced by reacting it with a sulfur compound having an oxidation number of-2, clofazimine produced using CPNA or CPDA produced herein, and processes for producing the same. The invention simplifies the process and improves the process stability during the preparation of CPNAGreatly improving the production efficiency. In addition, the present invention can produce CPDA in high yield and high purity by using a sulfur compound as a reducing agent. Moreover, compared with the process for removing the byproducts through the post-treatment process commonly adopted in the prior art, the method can simply remove the byproducts through the washing of the refined water, is favorable for commercialization, greatly reduces the solvent and can realize the environment affinity process.)

1. A method for preparing CPNA is characterized in that,

using a mixture of more than 4-CA and F-NO₂Polar aprotic solvent (polar aprotic solvent) with boiling point (bonding point) at reaction temperature 4-CA and F-NO2 were allowed to react.

2. A CPNA preparation method according to claim 1,

the polar aprotic solvent is selected from one of the group consisting of DMAC, DMF, NMP.

3. A CPNA preparation method according to claim 1,

F-NO₂and 4-CA using organic base.

4. A CPNA preparation method according to claim 3,

the organic base is one selected from the group consisting of DIPA and N-methylpiperidine.

5. A CPNA preparation method according to claim 4,

to compare with F-NO₂The organic base is added in a ratio of 80 to 120 of 100.

6. A CPNA preparation method according to claim 1,

crystallization was carried out after further addition of EtOH as an anti-solvent (anti solvent).

7. A CPNA preparation method according to claim 1,

the F-NO₂And 4-CA in a ratio of 1:2 to 2.5.

8. A CPNA preparation method according to claim 1,

the polar aprotic solvent is added at a ratio of 70 to 110 parts by weight to 100 parts by weight of the 4-CA.

9. A CPNA, characterized in that,

prepared by the preparation method of any one of claims 1 to 8.

10. A method for preparing CPDA is characterized in that,

reacting CPNA with a sulfur compound having an oxidation number of-2.

11. A CPDA preparation process according to claim 10,

the sulfur compound having an oxidation number of-2 is sodium sulfide (Na)₂S)。

12. A CPDA preparation process according to claim 11,

the sulfur compound having an oxidation number of-2 is Na₂S_xH₂O (but x is 5 to 9).

13. A CPDA preparation process according to claim 10,

reacting the CPNA and a sulfur compound having an oxidation number of-2 using a polar aprotic solvent.

14. A CPDA preparation process according to claim 13,

the polar aprotic solvent (polar aprotic solvent) is selected from one of the group consisting of DMAC, DMF.

15. A CPDA preparation process according to claim 10,

further, purified water as an anti-solvent (anti) was added thereto, followed by crystallization.

16. A CPDA preparation process according to claim 10,

the CPNA and the sulfur compound having an oxidation number of-2 are mixed in a ratio of 1:3.3 to 4.5.

17. A CPDA preparation process according to claim 13,

the polar aprotic solvent is added in a ratio of 600 to 1200 parts by weight to 100 parts by weight of the CPNA.

18. A CPDA, characterized in that,

prepared by the preparation method of any one of claims 10 to 17.

19. A clofazimine is characterized in that,

prepared using the CPNA of claim 9.

20. A clofazimine is characterized in that,

prepared using the CPDA of claim 18.

Technical Field

The invention discloses a clofazimine intermediate, and more particularly discloses N- (4-chlorphenyl) -2-nitroaniline (CPNA) and N' - (4-chlorphenyl) benzene-1, 2-diamine (CPDA) which are intermediates generated in the preparation of clofazimine and a preparation method thereof.

Disclosed is a method for preparing CPNA using a polar aprotic solvent to simplify the process and improve the process stability, and using an optimized reducing agent to prepare CPDA having high yield and high purity.

Background

The group leader led by the Vencent Barry doctor, university of Santa Clary, dublin in 1953, first synthesized clofazimine and started its use for the treatment of Hansen disease.

Clofazimine and Dapsone (Dapsone), rifampin (rifampicin) are the major agents for treating hansen's disease, which are distributed under the trade name clofazimine (Lamprene).

Clofazimine has a bactericidal effect of inhibiting bacterial DNA replication, and has an anti-inflammatory effect in addition to the bactericidal effect. One of its side effects is that the skin often shows a purple pigmentation when taken, but it disappears after a certain period of time.

As described above, clofazimine inhibits DNA replication of bacteria and alleviates inflammatory reactions, but its mechanism has not been clearly confirmed, so that it has been continuously studied. Clofazimine, which has been actively studied so far, will be fully applied to bacterial infections, infectious diseases, and the like in the future.

The process for the preparation of clofazimine, which may be, for example, F-NO, is briefly described below₂→ CPNA → CPDA → PBCI → CloFazimine proceed sequentially in stages, and intermediates produced exist in each stage. The intermediate for producing clofazimine is an intermediate that must be produced for producing clofazimine, and a high-purity clofazimine intermediate with a high yield is required for producing good quality clofazimine.

In the chloro-azimine intermediate, CPNA is usually prepared by using a metal catalyst, but the yield of CPNA only reaches 60-80% and mass production is difficult, and CPDA has the problems of yield reduction and quality reduction caused by side reactions. In order to solve the problems described above, the following prior arts are being studied.

In the method disclosed in the chinese patent document 2015-10996236, CPNA is prepared without solvent to reduce environmental pollution and prepare high-yield and high-purity CPNA, but the process stability is weakened due to the stiffness of the process during the process crystallization process, so that the CPNA is difficult to be practically applied to industrial manufacturers, and the chinese patent document 2017-10738472 uses Raney Ni during the process of preparing CPDA to remove metal impurities, and the purity is also reduced, so that there is an urgent need to develop a method for preparing a high-purity chloro-process ziming intermediate, which can ensure the process stability while producing at high yield.

[ Prior art documents ]

[ patent document ]

Chinese patent publication No. 2015-

Chinese patent publication No. 2017-10738472

Disclosure of Invention

Technical problem

The present invention is directed to solving the problems of the prior art, and an object of the present invention is to simplify the process and improve the process stability while preparing CPNA, thereby greatly improving the production efficiency.

Furthermore, it is an object of the present invention to prepare CPDA in high yield and purity using a sulfur compound as a reducing agent.

Moreover, the present invention has an object to simply remove byproducts by washing with refined water to facilitate commercialization, and to greatly reduce solvents to enable an environment-friendly process, compared to a process of removing byproducts by a solvent extraction process, which is generally adopted in the prior art.

Means for solving the problems

The present invention has been made to solve the problems, and the present invention discloses a method for preparing CPNA using a mixture of more than 4-chloroaniline (hereinafter referred to as "4-CA") and 1-fluoro-2-nitrobenzene (hereinafter referred to as "F-NO")₂") the reaction is allowed to proceed in a polar aprotic solvent (polar aprotic solvent) having a boiling point at the reaction temperature.

Polar aprotic solvent (polar aprotic solvent) having a boiling point (boiling point) higher than the reaction temperature can be selected from the group consisting of N, N-dimethylacetamide (hereinafter referred to as "DMAC"), N-dimethylformamide (hereinafter referred to as "DMF"), and N-methyl-2-pyrrolidone (hereinafter referred to as "NMP").

The 4-CA and F-NO₂The reaction of (3) can be carried out using an organic base.

Diisopropylamine (hereinafter referred to as "DIPA") and N-methylpiperidine may be used as the organic base.

Preferably, in comparison with F-NO₂The organic base is added at a ratio (equivalent ratio) of 80 to 120 of 100.

It can be crystallized by further adding EtOH as an anti-solvent (anti solvent).

Preferably, said F-NO₂And 4-CA in a ratio of 1:2 to 2.5.

Preferably, to compare to said F-NO₂The polar aprotic solvent is added in a ratio of 70 to 110 parts by weight based on 100 parts by weight.

Also, disclosed is a CPNA prepared by the preparation method.

Also, disclosed is a method for producing CPDA by reacting CPNA with a sulfur compound having an oxidation number of-2.

As the sulfur compound having an oxidation number of-2, sodium sulfide may be used, and more preferably, Na may be used₂S_xH₂O (but x is 5 to 9).

The CPNA and the sulfur compound having an oxidation number of-2 can be reacted using a polar aprotic solvent.

The polar aprotic solvent (polar aprotic solvent) may be selected from the group consisting of DMAC and DMF and then used.

Further, purified water as an anti-solvent (anti solvent) may be added thereto for crystallization.

Preferably, the CPNA and the sulfur compound having an oxidation number of-2 are mixed in a molar ratio of 1:3.3 to 4.5.

Preferably, the polar aprotic solvent is added in a ratio of 600 to 1200 parts by weight compared to 100 parts by weight of the CPNA.

Also, disclosed is a CPDA prepared by the preparation method.

Also, the present invention discloses a clofazimine prepared using the CPNA or CPDA of the present invention.

Efficacy of the invention

The invention simplifies the process and improves the process stability when preparing the CPNA, thereby greatly improving the production efficiency.

Furthermore, the present invention can produce CPDA in high yield and high purity by using a sulfur compound as a reducing agent.

Moreover, compared with the process for removing the by-product through the solvent extraction process generally adopted in the prior art, the method can simply remove the by-product through washing with refined water, is favorable for commercialization, greatly reduces the solvent and can realize the environment affinity process.

Drawings

Fig. 1 shows the preparation reaction formulae of CPNA and CPDA according to an embodiment of the present invention.

Detailed Description

The advantages, features and methods of accomplishing the same will become apparent from the following detailed description of the embodiments when taken in conjunction with the accompanying drawings.

However, the present invention is not limited to the embodiments disclosed below, and the present invention can be realized in various forms different from each other.

These embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art, and the scope of the invention will be defined by the appended claims.

Therefore, in order to avoid the present invention from being explained in a fuzzy manner, detailed descriptions of well-known elements, well-known operations, and well-known technologies may be omitted in the following embodiments.

Unless specifically mentioned in a sentence, the singular expressions also include the plural, and the elements and acts that "comprise (or, are provided with)" by volume do not exclude the presence or addition of one or more other elements and acts.

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The present invention is described in detail below.

The present invention discloses a method for using a composition with a molecular weight higher than 4-CA and F-NO₂CPNA prepared by allowing a polar aprotic solvent (polar aprotic solvent) having a boiling point (bonding point) at a reaction temperature to react, and a method for preparing the same.

Also disclosed are CPDA prepared by reacting a sulfur compound having an oxidation number of-2, and a method for preparing the same.

Also, the present invention discloses a clofazimine prepared using the CPNA or CPDA of the present invention.

First, a method for producing CPNA is explained.

Can be used in the field of medicine with the content of more than 4-CA and F-NO₂Polar aprotic solvent (pol) boiling point (bonding point) of reaction temperaturear aprotic solvent) was allowed to proceed.

Specifically, 4-CA and F-NO₂The reaction of (a) can be carried out using an organic base under the polar aprotic solvent (polar aprotic solvent) mentioned above, and here, preferably, DIPA, N-methylpiperidine can be used as the organic base. Here, the organic base exerts a function of removing proton of 4-CA.

Preferably, in comparison with F-NO₂And 4-CA 100 in a ratio of 80 to 120 (equivalent ratio).

Here, if the organic base is added beyond the upper limit of the above range, the reaction rate may be lowered, and if the organic base is added below the lower limit of the above range, the stirring in the process may not be performed satisfactorily.

Mixing the 4-CA and F-NO₂And organic alkali, raising the temperature to 100-120 ℃, and stirring for 23-30 hours for reaction.

Preferably, the 4-CA and F-NO are₂Mixing at a ratio of 1:2 to 2.5. Mixing below the lower limit of the range may result in a problem of a slow reaction rate, and mixing above the upper limit of the range may result in an economically inefficient process.

The reaction temperature is maintained at 100-120 ℃, and after the polar aprotic solvent is added dropwise, the internal temperature is cooled to 55-65 ℃ for reaction.

The polar aprotic solvent (polar aprotic solvent) may be selected from the group consisting of DMAC, DMF and NMP. The polar aprotic solvent having a boiling point (boiling point) higher than the reaction temperature is selected so as to prevent the risk of vaporization of the solvent during the reaction, and DMAC may be selected as the most preferable polar aprotic solvent to be used.

Preferably, the polar aprotic solvent is added in an amount that enables minimal stirring, in particular, in comparison to F-NO₂The polar aprotic solvent is preferably added in an amount of 70 to 110 parts by weight based on 100 parts by weight, and when the amount exceeds the upper limit of the above range, the product may be lost as a part of the remaining liquid.

The yield is only 60 to 80% when a metal catalyst such as Pd is used in the preparation of CPNA as in the prior art, but high quality CPNA having a yield of 90% or more and a purity of 99.5% or more can be mass-produced by using an optimized organic base as in the present invention.

Subsequently, EtOH as an anti-solvent (anti solvent) was added to control the viscosity of CPNA and to control the formulation for crystallization.

Adding the anti-solvent, raising the temperature to 75-85 ℃, stirring for more than 1 hour, and then reducing the temperature to 0-10 ℃. The internal temperature is maintained at 0-10 ℃ and the mixture is stirred for more than 2 hours, and then the crystals are filtered and washed with ethanol cooled to 5 ℃.

The filtered crystals are dried under vacuum at 40 to 60 ℃ to obtain CNPA.

Next, a method for producing CPDA will be described.

Reacting the CPNA of the present invention with a sulfur compound having an oxidation number of-2. As the sulfur compound having an oxidation number of-2, Na may be used₂S, more preferably, Na may be used₂S_xH₂O (but x is 5 to 9).

Preferably, CPNA and the sulfur compound having an oxidation number of-2 are mixed in a ratio of 1:3.3 to 4.5.

Mixing below the lower limit of the range may cause problems in that the reaction is not completely completed, and mixing above the upper limit of the range may cause problems in terms of the economy of the reaction.

The Na is₂S_xH₂O (but x is 5-9) is a reducing agent, and sulfide is oxidized into thiosulfate to reduce the aromatic nitro group into an amino group. The reaction is a chichening reaction, and the reaction formula of the chichening reaction is as follows.

[4C₆H₅NO₂+6S^2-+7H₂O->4C₆H₅NH₂+3S₂O3^2-+6OH--^-]

The prior method for reducing the cloxacillin intermediate mainly uses FeCl₃、SnCl₂Raney-Ni, Pd/c hydrogen, but the reduction process results in reduced yield or reduced quality due to side reactions.

A solvent may be used for the reaction of CPNA and a sulfur compound having an oxidation number of-2, and a polar aprotic solvent (polar aprotic solvent) may be used as the solvent, and may be selected from the group consisting of DMF and DMAC.

Preferably, the polar aprotic solvent is added in a ratio of 600 to 1200 parts by weight compared to 100 parts by weight of the CPNA.

Preferably, the amount of the polar aprotic solvent added is an amount that enables minimum stirring, and when the amount exceeds the upper limit of the range, the amount of the liquid increases, which may decrease the economy of the reaction.

And (3) when the CPNA, the sulfur compound with the oxidation number of-2 and the polar aprotic solvent are reacted, the temperature is increased to 60-80 ℃, and then the mixture is stirred for 3-6 hours. The reacted reaction solution is cooled to 35 to 45 ℃.

Subsequently, purified water as an anti-solvent (anti solvent) was added to control the viscosity and formulation of CPDA, and crystallization was performed.

The mixed solution with the added anti-solvent is stirred at 20-30 ℃ for more than 2 hours to generate crystals. The crystals formed are filtered and washed with purified water, and then dried under vacuum at 50 to 70 ℃ to obtain CPDA.

Finally, the washing and filtration steps performed in the preparation of CPNA and CPDA can be performed in the methods generally used in the art.

The present invention will be described in further detail below with reference to examples. These examples are only for illustrating the present invention more specifically, and it will be understood by those skilled in the art that the scope of the present invention is not limited to these examples according to the gist of the present invention.

First example preparation of CPNA (DIPA)

After 4-CA (113.0g), DIPA (35.8g) and FNB (50.0g) were charged, the temperature was raised to 105 ℃ and the mixture was stirred for 24 hours. DMAC (47.0g) was added dropwise at 95 ℃ or higher, and the internal temperature was cooled to 60 ℃. EtOH (295.9g) was charged and the temperature was raised to 80 ℃ and stirred for 1 hour or more, and then the temperature was lowered to 5 ℃. After keeping the internal temperature at 5 degrees and stirring for 2 hours, the formed crystals were filtered and washed with EtOH (295.9g) cooled to 5 degrees. The filtered crystals were vacuum-dried at 50 degrees to obtain 79.3g of the title compound (yield: 90%).

Second example preparation of CPNA (N-methylpiperidine)

After 4-CA (113.0g), N-methylpiperidine (35.2g) and FNB (50.0g) were charged, the temperature was raised to 105 ℃ and the mixture was stirred for 24 hours. DMAC (47.0g) was added dropwise at 95 ℃ or higher, and the internal temperature was cooled to 60 ℃. EtOH (295.9g) was charged and the temperature was raised to 80 ℃ and stirred for 1 hour or more, and then the temperature was lowered to 5 ℃. After keeping the internal temperature at 5 degrees and stirring for 2 hours, the formed crystals were filtered and washed with EtOH (295.9g) cooled to 5 degrees. The filtered crystals were vacuum-dried at 50 ℃ to obtain 81.1g (yield: 92%) of the title compound.

Third example preparation of CPNA (DMF)

After 4-CA (113.0g), DIPA (35.8g) and FNB (50.0g) were charged, the temperature was raised to 105 ℃ and the mixture was stirred for 24 hours. DMF (47.2g) was added dropwise at 95 ℃ or higher, and then the internal temperature was cooled to 60 ℃. EtOH (295.9g) was charged and the temperature was raised to 80 ℃ and stirred for 1 hour or more, and then the temperature was lowered to 5 ℃. After keeping the internal temperature at 5 degrees and stirring for 2 hours, the formed crystals were filtered and washed with EtOH (295.9g) cooled to 5 degrees. The filtered crystals were vacuum-dried at 50 degrees to obtain 79.3g of the title compound (yield: 90%).

Fourth example preparation of CPNA (NMP)

After 4-CA (113.0g), DIPA (35.8g) and FNB (50.0g) were charged, the temperature was raised to 105 ℃ and the mixture was stirred for 24 hours. NMP (51.5g) was added dropwise at 95 ℃ or higher, and then the internal temperature was cooled to 60 ℃. EtOH (295.9g) was charged and the temperature was raised to 80 ℃ and stirred for 1 hour or more, and then the temperature was lowered to 5 ℃. After keeping the internal temperature at 5 degrees and stirring for 2 hours, the formed crystals were filtered and washed with EtOH (295.9g) cooled to 5 degrees. The filtered crystals were vacuum-dried at 50 degrees to obtain 79.3g of the title compound (yield: 90%).

Fifth example preparation of CPDA

Adding CPNA (20.0g) and Na₂S*5H₂O (47.3g) was added followed by DMF (151.0g) solvent, and the mixture was stirred for 4 hours after raising the temperature to about 60 ℃. After the stirred reaction solution was cooled to about 40 degrees, purified water (240.0g) was added thereto. The mixture was stirred at about 25 ℃ for 2 hours, and the resulting crystals were filtered, washed with purified water (100.0g), and dried under vacuum at about 60 ℃ to give 16.7g of the title compound (yield: 95%).

As described above, the present specification and the accompanying drawings disclose preferred embodiments of the present invention, and although specific terms are used, they are used in a general sense only for the purpose of simplicity and clarity of explanation of the technical contents of the present invention and to assist understanding of the present invention, and they are not intended to limit the scope of the present invention.

It will be apparent to those skilled in the art that other modifications based on the technical spirit of the present invention can be implemented in addition to the embodiments disclosed herein.