WO2022126388A1 - Procédé de synthèse du 5-bromo-1h-3-amino-1,2,4-triazole - Google Patents

Procédé de synthèse du 5-bromo-1h-3-amino-1,2,4-triazole Download PDF

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Publication number
WO2022126388A1
WO2022126388A1 PCT/CN2020/136575 CN2020136575W WO2022126388A1 WO 2022126388 A1 WO2022126388 A1 WO 2022126388A1 CN 2020136575 W CN2020136575 W CN 2020136575W WO 2022126388 A1 WO2022126388 A1 WO 2022126388A1
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WIPO (PCT)
Prior art keywords
reaction
sodium
triazole
amino
equivalent
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PCT/CN2020/136575
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English (en)
Chinese (zh)
Inventor
叶伟平
费安杰
周章涛
谢阳银
习林刚
向卫
Original Assignee
深圳市华先医药科技有限公司
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Priority to PCT/CN2020/136575 priority Critical patent/WO2022126388A1/fr
Publication of WO2022126388A1 publication Critical patent/WO2022126388A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the invention belongs to the field of organic chemical synthesis, in particular to a new method for synthesizing 5-bromo-1H-3-amino-1,2,4-triazole.
  • 5-Bromo-1H-3-amino-1,2,4-triazole (structure shown below) is widely used as electroluminescent material, KDM5 inhibitor, PDE2 inhibitor, PIK3/AKt inhibitor and anti-tumor key intermediates of medicines.
  • the present invention has developed a process route suitable for industrial production, wherein the raw material 3-amino-1,2,4-triazole is cheaper, and the reaction does not require an organic solvent , the yield is greatly improved, and the production cost is significantly reduced.
  • the inventor of the present invention needs to prepare 5-bromo-1H-3-amino-1,2,4-triazole in the research and development process.
  • the inventor tried to repeat the synthetic route disclosed in the patent document WO2017188596, but encountered many difficulties.
  • this route includes the step of diazotization reaction, which makes this route have potential safety risks, especially when the scale of the reaction is expanded, the safety risks are even more uncontrollable.
  • this synthetic route has many side reactions, and when the scale of the reaction is enlarged, the reproducibility of the reaction becomes poor.
  • the above reaction was carried out in trifluoroacetic acid and acetonitrile (ACN), but the yield of this route is still low.
  • ACN acetonitrile
  • the inventors of the present invention realized that the conversion rate of the above-mentioned synthetic route is low, and the reason may be that the concentration of the bromination reagent is uneven, and the local concentration is too high, which leads to an increase in side reactions and a decrease in the conversion rate of the bromination reaction. Therefore, the inventor tried to add bromine reagents in batches and slowly during the reaction process (bromine was added dropwise in liquid, and the drop was completed in about 10-15 hours; NBS was solid, and was added in batches many times), and the conversion rate was improved to a certain extent. , but still unsatisfactory.
  • the inventors tried to use sodium bromate and sodium bromide as bromination reagents, and sodium bromate and sodium bromide reacted under acidic conditions to produce bromine, so the release rate of bromine was slow enough, and the When it comes out, it is uniformly dispersed into the reaction system at the molecular level, and the reaction yield has indeed been greatly improved.
  • Both examples in the detailed description section achieved overall yields above 50%, and the conversions were also sufficiently high. This yield is more than twice the yield of the previous route disclosed in the patent document WO2017188596, and there is no safety risk brought by the diazotization reaction, and the raw materials are cheap and the synthesis cost is low.
  • the inventors of the present invention have found that in the above-mentioned route proposed by the present invention, as long as the brominating reagent can release bromine sufficiently uniformly and slowly enough in the reaction system, the yield of the reaction can be significantly improved. Therefore, the slow-release bromine reagent is not limited to the few examples presented in the Examples section, and it can be expected that any system that can slowly release bromine through a chemical reaction can achieve similar effects. For example, the mixture of potassium bromate and potassium bromide, these systems can slowly release bromine under acidic conditions, so they can be used as the bromination reagent of the present invention.
  • An embodiment of the present invention provides a method for synthesizing 5-bromo-1H-3-amino-1,2,4-triazole, and the method route is as follows:
  • the brominating agent is bromine, or N-bromosuccinimide (NBS), or a slow-release brominating agent;
  • the reaction scheme is as follows:
  • the reaction scheme is as follows:
  • the slow-release brominating agent comprises a mixture of sodium bromate and sodium bromide
  • the slow-release brominating agent comprises a mixture of potassium bromate and potassium bromide
  • the reaction temperature is controlled at 40°C-70°C, preferably 55°C-60°C.
  • the purpose of controlling the temperature is, on the one hand, to control the generation speed of bromine;
  • the solvent includes water or acetonitrile
  • the solvent includes water.
  • the reasons for choosing water as the solvent are: on the one hand, the cost of water is low; on the other hand, the specific heat capacity of water is high, which is beneficial to control the temperature of the system.
  • the slow-release bromination reagent includes a mixture of sodium bromate and sodium bromide, and the reaction scheme is as follows:
  • the molar ratio of the sodium bromate and the sodium bromide is 1:3-8, preferably 1:4-6, more preferably 1:5;
  • the raw material 3-amino-1,2,4-triazole is 1 equivalent, the amount of sodium bromate is 0.5-0.8 equivalent, and the amount of sodium bromide is 2.5-4.0 equivalent;
  • the sodium bromate consumption is 0.6 equivalent, and the consumption of sodium bromide is 3.0 equivalent;
  • the raw material 3-amino-1,2,4-triazole is 1 equivalent, and the amount of concentrated sulfuric acid is 2.5-3.5 equivalents, preferably 3.0 equivalents.
  • the method includes:
  • Dissolve sodium bromate in water add dropwise to the reactor under temperature control at 55°C-60°C, keep the reaction for a period of time after the dropwise addition, cool down to 20°C-30°C after the reaction, and quench the reaction;
  • the holding time for the reaction is: holding the reaction for 10-40 hours, preferably 15-25 hours;
  • the quenching of the reaction is: quenching the reaction with saturated sodium sulfite;
  • adjusting the pH of the system to a weak acid is as follows: adjusting the pH to 5.5-6.5 with 20% sodium hydroxide solution;
  • the extraction and purification include: adding an extractant to the filtrate for extraction, and concentrating at 55°C-60°C until there is no fraction; adding ethyl acetate to dissolve, filtering, concentrating the ethyl acetate until there is no fraction, adding 1,4- Dioxane was heated to 80°C for beating, cooled to 20°C-30°C for filtration, and the filter cake was vacuum-dried at 50°C-60°C for 12 hours to obtain a white solid.
  • the extractant includes n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, and more preferably 2-methyltetrahydrofuran.
  • the excellent technical effects brought by the present invention include: using the synthesis method of the present invention to synthesize 5-bromo-1H-3-amino-1,2,4-triazole, the process route is novel, and the total molar yield is greater than 50%.
  • the reaction has high safety, easy industrialization, high yield, low cost and relatively mild reaction conditions.
  • Acetonitrile (30L), sulfuric acid (18kg), 3-amino-1,2,4-triazole (5kg) and sodium bromide (21kg) were added to the reaction kettle, and the system was heated to 55°C-60°C.
  • Dissolve sodium bromate (6.2kg) in water (15L) add dropwise to the reaction kettle with temperature control at 55°C-60°C, complete the dropwise addition, keep the reaction for 20h, the reaction is over, cool down to 20°C-30°C, add saturated sodium sulfite Quenched, concentrated acetonitrile to no fractions at 50°C-55°C, adjusted pH to 5.5-6.5 with 20% sodium hydroxide solution, and filtered.
  • Example 3 Compared with the route disclosed in the patent document WO2017188596 (see Comparative Example 1), although the method of Example 3 has a decrease in purity and yield, the cost of raw materials is lower, and the potential safety hazard is eliminated due to avoiding the diazotization reaction, It also has certain practical value.
  • 5-Bromo-1H-3-amino-1,2,4-triazole was synthesized according to the route disclosed in the patent document WO2017188596.
  • a 48% HBr aqueous solution (9.0 L) was added to the reaction flask, stirring was started, and 3,5-diamino-1,2,4-triazole (600 g) was added and stirred for half an hour.
  • the temperature was lowered to 20°C-30°C, an aqueous solution of sodium nitrite (501.3 g) was added dropwise, and the temperature was controlled at 20°C-30°C. After the dropwise addition, the temperature was kept for 1 hour, the temperature was raised to 40° C. and stirred for 1 hour, and the temperature was raised to 60° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de synthèse du 5-bromo-1H-3-amino-1,2,4-triazole. Le procédé comprend un mécanisme tel que (aa), dans lequel un mélange de bromate de sodium et de bromure de sodium est utilisé pour servir de réactif de bromation ; et un mécanisme réactionnel en tant que (bb). La synthèse du 5-bromo-1H-3-amino-1,2,4-triazole par le procédé possède un nouveau mécanisme réactionnel et un rendement molaire total supérieur à 50 %. La réaction présente une grande sécurité et est facile à industrialiser et présente un rendement élevé, un coût économique et des conditions de réaction relativement ménagées.
PCT/CN2020/136575 2020-12-15 2020-12-15 Procédé de synthèse du 5-bromo-1h-3-amino-1,2,4-triazole WO2022126388A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/136575 WO2022126388A1 (fr) 2020-12-15 2020-12-15 Procédé de synthèse du 5-bromo-1h-3-amino-1,2,4-triazole

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/136575 WO2022126388A1 (fr) 2020-12-15 2020-12-15 Procédé de synthèse du 5-bromo-1h-3-amino-1,2,4-triazole

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WO2022126388A1 true WO2022126388A1 (fr) 2022-06-23

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011010840A1 (fr) * 2009-07-21 2011-01-27 Rohm And Haas Electronic Materials Korea Ltd. Nouveaux composés organiques électroluminescents et dispositif organique électroluminescent utilisant ces derniers
CN103044466A (zh) * 2012-06-28 2013-04-17 广东鑫钰新材料股份有限公司 联吡啶三唑类稀土配合物及其制备方法
CN105153027A (zh) * 2015-07-21 2015-12-16 东华大学 一种3-氰基-4-羟基-2-吡啶酮类化合物及其制备和应用
CN109071555A (zh) * 2016-04-29 2018-12-21 株式会社斗山 有机发光化合物及利用其的有机电致发光元件

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011010840A1 (fr) * 2009-07-21 2011-01-27 Rohm And Haas Electronic Materials Korea Ltd. Nouveaux composés organiques électroluminescents et dispositif organique électroluminescent utilisant ces derniers
CN103044466A (zh) * 2012-06-28 2013-04-17 广东鑫钰新材料股份有限公司 联吡啶三唑类稀土配合物及其制备方法
CN105153027A (zh) * 2015-07-21 2015-12-16 东华大学 一种3-氰基-4-羟基-2-吡啶酮类化合物及其制备和应用
CN109071555A (zh) * 2016-04-29 2018-12-21 株式会社斗山 有机发光化合物及利用其的有机电致发光元件

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GAO XUEZHI, ET AL.: "Synthesis Improvement of the Key Intermediate of Lansoprazole 2,3-Dimethyl-4-(2,2,2-Trifluoroethoxy)pyridine-N-Oxide", CHINESE JOURNAL OF PHARMACEUTICALS, SHANGHAI YIYAO GONGYE YANJIUYUAN,SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY, CN, vol. 49, no. 9, 31 December 2018 (2018-12-31), CN , pages 1252 - 1254, XP055942985, ISSN: 1001-8255, DOI: 10.16522/j.cnki.cjph.2018.09.007 *

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