WO2019037161A1 - Procédé de synthèse de n-(4-chlorphényl)-1,2-phénylènediamine intermédiaire clé de la clofazimine - Google Patents

Procédé de synthèse de n-(4-chlorphényl)-1,2-phénylènediamine intermédiaire clé de la clofazimine Download PDF

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Publication number
WO2019037161A1
WO2019037161A1 PCT/CN2017/100965 CN2017100965W WO2019037161A1 WO 2019037161 A1 WO2019037161 A1 WO 2019037161A1 CN 2017100965 W CN2017100965 W CN 2017100965W WO 2019037161 A1 WO2019037161 A1 WO 2019037161A1
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Prior art keywords
chlorophenyl
phenylenediamine
clofazimine
reaction
nickel
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PCT/CN2017/100965
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English (en)
Chinese (zh)
Inventor
杨冰
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重庆沃肯精细化工有限公司
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Publication of WO2019037161A1 publication Critical patent/WO2019037161A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/60—Preparation of compounds containing amino groups bound to a carbon skeleton by condensation or addition reactions, e.g. Mannich reaction, addition of ammonia or amines to alkenes or to alkynes or addition of compounds containing an active hydrogen atom to Schiff's bases, quinone imines, or aziranes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
    • C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
    • C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst

Definitions

  • 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.
  • 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.
  • 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.
  • tuberculosis especially multidrug-resistant tuberculosis
  • tuberculosis has been on a high incidence, which is a serious threat to human health.
  • 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.
  • 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.
  • a combination of multiple anti-tuberculosis drugs is currently widely used clinically.
  • clofazimine can play a good therapeutic role.
  • clofazimine was classified as the fifth category and was allowed to be used in combination administration for anti-tuberculosis.
  • 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.
  • 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).
  • 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.
  • a metal/Lewis acid system Commonly used such as iron powder, zinc powder, titanium dichloride, etc., some of the methods can be seen in the above literature.
  • 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.
  • 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 Method of 2-phenylenediamine.
  • the synthesis method includes the following 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.
  • 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-diaza
  • 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.
  • 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.
  • 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.
  • organic solvents such as toluene, methanol, ethanol, DMF, etc.
  • the hydrogen pressure used in the reduction is generally maintained within 5 kg; the reaction temperature is generally between 50 and 80 degrees.
  • 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.
  • 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.
  • 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.
  • an organic solvent such as toluene, methanol, ethanol, etc.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • reaction was continued for 8 hours between 120 and 130 degrees, and the progress of the reaction was monitored by HPLC.
  • the reaction is complete, at which point about 18% of the p-chloroaniline remains. Then cool down to 60 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 is a diagrammatic representation of Embodiment 1:
  • 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.
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de synthèse de N-(4-chlorphényl)-1,2-phénylènediamine intermédiaire clé de la clofazimine. Le procédé comprend les étapes consistant à : 1) utiliser du o-fluoronitrobenzène et du p-chloroaniline en tant que matières premières et une base organique en tant que catalyseur pour une réaction de condensation, faire réagir dans un solvant organique, et effectuer un traitement classique après la fin de la réaction pour obtenir du N-(4-chlorphényl)-2-nitryl-1-aniline qui est un intermédiaire de condensation ; 2) procéder à une réduction d'hydrogénation catalytique sur l'intermédiaire de condensation obtenu dans le solvant organique en utilisant du nickel métallique en tant que catalyseur, et réaliser un traitement classique après réduction pour obtenir un produit brut de N-(4-chlorphényle)-1,2-phénylènediamine ; et 3) recristalliser le produit brut obtenu à l'aide du solvant organique, ce qui permet d'obtenir un produit final.
PCT/CN2017/100965 2017-08-24 2017-09-08 Procédé de synthèse de n-(4-chlorphényl)-1,2-phénylènediamine intermédiaire clé de la clofazimine WO2019037161A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710738472.0A CN107445845A (zh) 2017-08-24 2017-08-24 一种合成氯法齐明关键中间体n‑(4‑氯苯基)‑1，2‑苯二胺的方法
CN201710738472.0 2017-08-24

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CN109293587B (zh) * 2018-11-07 2023-06-16 浙江华海立诚药业有限公司 氯法齐明及其中间体的制备方法
KR102219563B1 (ko) * 2019-02-15 2021-02-24 에스티팜 주식회사 페나진 유도체 제조를 위한 중간체 및 그의 제조방법
CN112521339A (zh) * 2020-11-20 2021-03-19 山西立业制药有限公司 一种氯苯吩嗪的制备方法

Citations (2)

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CN101141958A (zh) * 2005-04-13 2008-03-12 神经研究公司 苯并咪唑衍生物及其用于调节gabaa受体复合物的用途
CN101384559A (zh) * 2006-03-24 2009-03-11 神经研究公司 苯并咪唑衍生物及其在调节gabaa受体复合物中的应用

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CL2007003590A1 (es) * 2006-12-12 2008-02-29 Wyeth Corp Compuestos derivados de aril sulfamida; procedimiento de preparacion; composicion farmaceutica que comprende a dichos compuestos; y su uso en prevencion y tratamiento de sintomas vasomotrices, disfuncion sexual, transtornos gastrointestinales, transt
CN106916069A (zh) * 2015-12-25 2017-07-04 上海科胜药物研发有限公司 一种制备氯法齐明中间体的方法

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CN101141958A (zh) * 2005-04-13 2008-03-12 神经研究公司 苯并咪唑衍生物及其用于调节gabaa受体复合物的用途
CN101384559A (zh) * 2006-03-24 2009-03-11 神经研究公司 苯并咪唑衍生物及其在调节gabaa受体复合物中的应用

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WANG X. J. ET AL.: "Synthesis, biological evaluation and SAR studies of benzimidazole derivatives as H1-antihistamine agents", CHINESE CHEMICAL LETTERS, vol. 23, 11 May 2012 (2012-05-11), pages 707 - 710, XP055545405 *

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