RU2784429C1 - Method for producing pyridine-2(1h)-one - Google Patents
Method for producing pyridine-2(1h)-one Download PDFInfo
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- RU2784429C1 RU2784429C1 RU2022124039A RU2022124039A RU2784429C1 RU 2784429 C1 RU2784429 C1 RU 2784429C1 RU 2022124039 A RU2022124039 A RU 2022124039A RU 2022124039 A RU2022124039 A RU 2022124039A RU 2784429 C1 RU2784429 C1 RU 2784429C1
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- pyridine
- pyridone
- iron
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- phthalocyanine
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- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000004519 manufacturing process Methods 0.000 title abstract 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 29
- ROOXNKNUYICQNP-UHFFFAOYSA-N Ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 10
- 230000003647 oxidation Effects 0.000 claims abstract description 9
- UPUWBGZZDIUZQD-UHFFFAOYSA-M [O-]S(=O)(=O)Oc1ccccn1 Chemical compound [O-]S(=O)(=O)Oc1ccccn1 UPUWBGZZDIUZQD-UHFFFAOYSA-M 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 229910052742 iron Inorganic materials 0.000 claims abstract description 6
- 239000011572 manganese Substances 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N Phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 claims abstract description 3
- PWHULOQIROXLJO-UHFFFAOYSA-N manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052748 manganese Inorganic materials 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 239000011701 zinc Substances 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- MPMSMUBQXQALQI-UHFFFAOYSA-N Cobalt phthalocyanine Chemical compound [Co+2].C12=CC=CC=C2C(N=C2[N-]C(C3=CC=CC=C32)=N2)=NC1=NC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 MPMSMUBQXQALQI-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000002194 synthesizing Effects 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 7
- 239000011541 reaction mixture Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000004160 Ammonium persulphate Substances 0.000 abstract 1
- LVIYYTJTOKJJOC-UHFFFAOYSA-N Nickel phthalocyanine Chemical compound [Ni+2].C12=CC=CC=C2C(N=C2[N-]C(C3=CC=CC=C32)=N2)=NC1=NC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 LVIYYTJTOKJJOC-UHFFFAOYSA-N 0.000 abstract 1
- 230000002378 acidificating Effects 0.000 abstract 1
- 235000019395 ammonium persulphate Nutrition 0.000 abstract 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 abstract 1
- 229910052803 cobalt Inorganic materials 0.000 abstract 1
- 239000010941 cobalt Substances 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- PODBBOVVOGJETB-UHFFFAOYSA-N zinc phthalocyanine Chemical compound N1=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N33)=[N]2[Zn]23N3C1=C1C=CC=CC1=C3N=C1[N]2=C4C2=CC=CC=C21 PODBBOVVOGJETB-UHFFFAOYSA-N 0.000 abstract 1
- 238000005805 hydroxylation reaction Methods 0.000 description 7
- 230000000640 hydroxylating Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HUCVOHYBFXVBRW-UHFFFAOYSA-M Caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 4
- 150000001502 aryl halides Chemical class 0.000 description 4
- 230000003197 catalytic Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- UMLDUMMLRZFROX-UHFFFAOYSA-N pyridin-2-ylboronic acid Chemical class OB(O)C1=CC=CC=N1 UMLDUMMLRZFROX-UHFFFAOYSA-N 0.000 description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-Aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 150000002989 phenols Chemical class 0.000 description 3
- UJIBOGAQJRDRES-UHFFFAOYSA-N 1H-pyridin-2-one Chemical compound OC1=CC=CC=N1.O=C1C=CC=CN1 UJIBOGAQJRDRES-UHFFFAOYSA-N 0.000 description 2
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-Chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 2
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 2
- MSHFRERJPWKJFX-UHFFFAOYSA-N Anisyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 2
- KVKFRMCSXWQSNT-UHFFFAOYSA-N N,N'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Natural products O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CCZWSTFVHJPCEM-UHFFFAOYSA-N 2-iodopyridine Chemical compound IC1=CC=CC=N1 CCZWSTFVHJPCEM-UHFFFAOYSA-N 0.000 description 1
- -1 4-methoxybenzyl ester Chemical class 0.000 description 1
- WZNJWVWKTVETCG-YFKPBYRVSA-N L-mimosine zwitterion Chemical compound OC(=O)[C@@H](N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-YFKPBYRVSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L Zinc sulfate Chemical class [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 229930013930 alkaloids Natural products 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 230000000845 anti-microbial Effects 0.000 description 1
- 230000000840 anti-viral Effects 0.000 description 1
- 230000003078 antioxidant Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002034 butanolic fraction Substances 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000374 eutectic mixture Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010493 gram-scale synthesis Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229950002289 mimosine Drugs 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001590 oxidative Effects 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000010151 yanghe Substances 0.000 description 1
- 235000009529 zinc sulphate Nutrition 0.000 description 1
Abstract
Description
Изобретение относится к органической химии, конкретно к синтезу пиридин-2(1Н)-она (другие названия соединения - 2-гидроксипиридин, 2-пиридон, далее в тексте - 2-пиридон), который является важным сырьем для химической и фармацевтической промышленности.The invention relates to organic chemistry, specifically to the synthesis of pyridin-2(1H)-one (other names for the compound - 2-hydroxypyridine, 2-pyridone, hereinafter - 2-pyridone), which is an important raw material for the chemical and pharmaceutical industries.
2-Пиридон (или 2-гидроксипиридин) представляет интерес как катализатор различных протон-зависимых реакций, например, аминолиз эфиров [Hamama W.S., Waly M., El-Hawary I., Zoorob H.H. Developments in the Chemistry of 2-Pyridone // Synthetic Communications, 2014, 44, 12, pp. 1730-1759], а также как лиганд в координационной химии [Rawson J.M., Winpenny R.E.P. The coordination chemistry of 2-pyridone and its derivatives // Coordination Chemistry Reviews, 1995, 139, pp. 313-374]. Кроме того, 2-пиридон имеет большой синтетический потенциал и является ценным субстратом для синтеза различных лекарственных препаратов, алкалоидов и других биологически активных соединений [Torres M., Gil S., Parra M. New Synthetic Methods to 2-Pyridone Rings // Current Organic Chemistry, 2005, 9, pp. 1757-1779; Yong Shang, Chenggui Wu, Qianwen Gao, Chang Liu, Lisha Li, Xinping Zhang, Hong-Gang Cheng, Shanshan Liu, Qianghui Zhou. Diversity-oriented functionalization of 2-pyridones and uracils // Nature communications, 2021, 12, p. 2988]. Производные 2-пиридона проявляют противораковые, противомикробные, противовоспалительные, анальгетические, антиоксидантные и противовирусные свойства [Amer M.M.K., Aziz M.A., Shehab W.S., Abdellattif M.H., Mouneir S.M. Recent advances in chemistry and pharmacological aspects of 2-pyridone scaffolds // Journal of Saudi Chemical Society, 2021, 25, p. 101259].2-Pyridone (or 2-hydroxypyridine) is of interest as a catalyst for various proton-dependent reactions, for example, aminolysis of esters [Hamama WS, Waly M., El-Hawary I., Zoorob HH Developments in the Chemistry of 2-Pyridone // Synthetic Communications, 2014, 44 , 12, pp. 1730-1759] and also as a ligand in coordination chemistry [Rawson JM, Winpenny REP The coordination chemistry of 2-pyridone and its derivatives // Coordination Chemistry Reviews, 1995, 139 , pp. 313-374]. In addition, 2-pyridone has great synthetic potential and is a valuable substrate for the synthesis of various drugs, alkaloids and other biologically active compounds [Torres M., Gil S., Parra M. New Synthetic Methods to 2-Pyridone Rings // Current Organic Chemistry, 2005, 9 , pp. 1757-1779; Yong Shang, Chenggui Wu, Qianwen Gao, Chang Liu, Lisha Li, Xinping Zhang, Hong-Gang Cheng, Shanshan Liu, Qianghui Zhou. Diversity-oriented functionalization of 2-pyridones and uracils // Nature communications, 2021, 12 , p. 2988]. 2-pyridone derivatives exhibit anti-cancer, antimicrobial, anti-inflammatory, analgesic, antioxidant and antiviral properties [Amer MMK, Aziz MA, Shehab WS, Abdellattif MH, Mouneir SM Recent advances in chemistry and pharmacological aspects of 2-pyridone scaffolds // Journal of Saudi Chemical Society, 2021, 25, p. 101259].
2-Пиридон можно получить несколькими способами: диазотированием 2-аминопиридина (А), кислотным гидролизом 2-галогенпиридина (Б), каталитическим окислением пиридинборониевых кислот (В), прямым гидроксилированием пиридина (Г) (схема 1).2-Pyridone can be obtained in several ways: diazotization of 2-aminopyridine (A), acid hydrolysis of 2-halopyridine (B), catalytic oxidation of pyridineboronic acids (C), direct hydroxylation of pyridine (D) (Scheme 1).
Схема 1Scheme 1
Способами А-В 2-пиридон можно получить с высокими выходами. Однако у этих способов есть один существенный недостаток - необходимость предварительного синтеза исходных соединений - 2-амино- и 2-галогенпиридинов, а также пиридин-2-борониевых кислот.Methods A-B 2-pyridone can be obtained in high yields. However, these methods have one significant drawback - the need for preliminary synthesis of the starting compounds - 2-amino- and 2-halopyridines, as well as pyridine-2-boronic acids.
Гидролиз 2-галопиридинов (схема 1, способ А) является распространенным способом для синтеза 2-пиридонов, которые в зависимости от условий гидролиза можно получить с выходами 51-85%.Hydrolysis of 2-halopyridines (Scheme 1, method A) is a common method for the synthesis of 2-pyridones, which, depending on the hydrolysis conditions, can be obtained in 51-85% yields.
Так, при микроволновом нагревании (MW) водного раствора 2-бромпиридина в каталитической системе, состоящей из CuI, N,N'-диметилэтилендиамина (DMEDA) и К3РО4 в качестве основания, при 180°С в течение 30 мин 2-пиридон получен с выходом 85% [Mehmood A., Leadbeater N.E. Copper-catalyzed direct preparation of phenols from aryl halides // Catalysis Communications, 2010, 12 (1), рр. 64-66]. Недостаток способа - высокая температура процесса, использование сложного и дорогостоящего оборудования для микроволнового излучения.Thus, during microwave heating (MW) of an aqueous solution of 2-bromopyridine in a catalytic system consisting of CuI, N,N'-dimethylethylenediamine (DMEDA) and K 3 PO 4 as a base, at 180 ° C for 30 min, 2-pyridone obtained with a yield of 85% [Mehmood A., Leadbeater NE Copper-catalyzed direct preparation of phenols from aryl halides // Catalysis Communications, 2010, 12 (1), pp. 64-66]. The disadvantage of this method is the high temperature of the process, the use of complex and expensive equipment for microwave radiation.
2-Пиридон может быть получен при обработке 2-бромпиридина 4-метоксибензиловым спиртом (PMBOH) и Cs2CO3 в присутствии 5 мол.% CuI, 10 мол.% 1,10-фенантролина в толуоле при 110°С, с последующим гидролизом трифторуксусной кислотой промежуточно образовавшегося 4-метоксибензилового эфира, с общим выходом 84%. 2-Хлорпиридин в этих условиях дает меньший выход (51%) [Tao Chuan Zhou, Liu Wei Wei, Sun Ji You. Copper-catalyzed synthesis of phenols from aryl halides and 4-methoxybenzyl alcohol // Chinese Chemical Letters, 2009, 20(10), рр. 1170-1174]. Недостаток способа - высокая температура процесса, использование высококипящего растворителя, дорогостоящих реактивов.2-Pyridone can be obtained by treating 2-bromopyridine with 4-methoxybenzyl alcohol (PMBOH) and Cs 2 CO 3 in the presence of 5 mol.% CuI, 10 mol.% 1,10-phenanthroline in toluene at 110°C, followed by hydrolysis trifluoroacetic acid of the intermediately formed 4-methoxybenzyl ester, with a total yield of 84%. 2-Chloropyridine under these conditions gives a lower yield (51%) [Tao Chuan Zhou, Liu Wei Wei, Sun Ji You. Copper-catalyzed synthesis of phenols from aryl halides and 4-methoxybenzyl alcohol // Chinese Chemical Letters, 2009, 20(10), pp. 1170-1174]. The disadvantage of this method is the high temperature of the process, the use of a high-boiling solvent, expensive reagents.
Электрохимически индуцированное гидроксилирование на платиновых электродах 2-иодпиридина в присутствии Et3N и Bu4NPF6 в воде приводит к 2-пиридону с выходом 72%. [Li Yang, Qinglong Zhuang, Mei Wu, Hua Long, Chen Lin, Mei Lin, Fang Ke. Electrochemical-induced hydroxylation of aryl halides in the presence of Et3N in water // Organic and Biomolecular Chemistry, 2021, 19(29), pp. 6417-6421]. Недостаток способа - использование сложного и дорогостоящего оборудования.Electrochemically induced hydroxylation of 2-iodopyridine on platinum electrodes in the presence of Et 3 N and Bu 4 NPF 6 in water leads to 2-pyridone in 72% yield. [Li Yang, Qinglong Zhuang, Mei Wu, Hua Long, Chen Lin, Mei Lin, Fang Ke. Electrochemical-induced hydroxylation of aryl halides in the presence of Et 3 N in water // Organic and Biomolecular Chemistry, 2021, 19(29), pp. 6417-6421]. The disadvantage of this method is the use of complex and expensive equipment.
Каталитическое гидроксилирование 2-хлорпиридина гидроксидом цезия CsOH в 1,4-диоксане при 100°С в присутствии каталитической системы трис(дибензилиденацетон)дипалладий(0) (Pd2dba3) и 5-(ди-трет-бутилфосфино)-1,3,5-трифенил-1H-[1,4]бипиразола (Bippyphos (L4) приводит к 2-пиридону с выходом 72%. [Lavery Ch.B., Rotta-Loria N.L., McDonald R., Stradiotto M. Pd2dba3/Bippyphos: A Robust Catalyst System for the Hydroxylation of Aryl Halides with Broad Substrate Scope // Advanced Synthesis and Catalysis, 2013, 355(5), pp. 981-987]. Недостаток способа - высокая температура процесса, использование дорогостоящих реактивов.Catalytic hydroxylation of 2-chloropyridine with cesium hydroxide CsOH in 1,4-dioxane at 100°C in the presence of the catalytic system tris(dibenzylideneacetone)dipalladium(0) (Pd 2 dba 3 ) and 5-(di-tert-butylphosphino)-1,3 ,5-triphenyl-1H-[1,4]bipyrazole (Bippyphos (L4) leads to 2-pyridone in 72% yield. [Lavery Ch.B., Rotta-Loria NL, McDonald R., Stradiotto M. Pd2dba3/Bippyphos : A Robust Catalyst System for the Hydroxylation of Aryl Halides with Broad Substrate Scope // Advanced Synthesis and Catalysis, 2013, 355(5), pp. 981-987].
Диазотированием 2-аминопиридина (схема 1, способ Б) можно получить 2-гидроксипиридин с выходами 78-95% [Xie Lin et al. Study on synthesis of 2-hydroxypyridine // Shandong Huagong, 2014, 43(9), рр. 13-15; Adam R., Jones V.V. Structure of leucenol. II // Journal of the American Chemical Society, 1947, 69, рр. 1803-1805; Caldwell Wm. T. et al. Substituted 2-sulfonamido-5-aminopyridines. II // Journal of the American Chemical Society, 1944, 66, рр. 1479-1484]. Недостаток - трудность выделения чистого 2-пиридона из реакционной массы, а также необходимость получения исходного 2-аминопиридина.By diazotization of 2-aminopyridine (Scheme 1, method B), 2-hydroxypyridine can be obtained in 78-95% yields [Xie Lin et al. Study on synthesis of 2-hydroxypyridine // Shandong Huagong, 2014, 43(9), pp. 13-15; Adam R., Jones VV Structure of leucenol. II // Journal of the American Chemical Society, 1947, 69, pp. 1803-1805; Caldwell Wm. T. et al. Substituted 2-sulfonamido-5-aminopyridines. II // Journal of the American Chemical Society, 1944, 66, pp. 1479-1484]. The disadvantage is the difficulty of isolating pure 2-pyridone from the reaction mass, as well as the need to obtain the original 2-aminopyridine.
H+ = HCl, H2SO4, HBrH + \u003d HCl, H 2 SO 4 , HBr
Окислительным гидроксилированием пиридинборониевых кислот (схема 1, способ В) 2-пиридон можно получить с выходом 81% [Liang Wang, Dong-Yan Dai, Qun Chen, and Ming-Yang He. Rapid, Sustainable, and Gram-Scale Synthesis of Phenols Catalyzed by a Biodegradable Deep Eutectic Mixture in Water // Asian Journal of Organic Chemistry, 2013, 2(12), pp. 1040-1043]. Данный способ имеет ряд недостатков - использование дорогостоящих катализаторов, ионных жидкостей, необходимость синтеза исходных пиридинборониевых кислот.By oxidative hydroxylation of pyridineboronic acids (Scheme 1, method B), 2-pyridone can be obtained in 81% yield [Liang Wang, Dong-Yan Dai, Qun Chen, and Ming-Yang He. Rapid, Sustainable, and Gram-Scale Synthesis of Phenols Catalyzed by a Biodegradable Deep Eutectic Mixture in Water // Asian Journal of Organic Chemistry, 2013, 2(12), pp. 1040-1043]. This method has a number of disadvantages - the use of expensive catalysts, ionic liquids, the need to synthesize the original pyridineboronic acids.
2-Пиридон можно также получить реакциями прямого гидроксилирования или окисления (схема 1, способ Г).2-Pyridone can also be obtained by direct hydroxylation or oxidation reactions (Scheme 1, method D).
При окислении пиридина гидратами CuSO4 в автоклаве при 300°С в течение 6-8 ч получен 2-пиридон с выходом 95%, [Tomasik P., Woszczyk A. A novel nucleophilic substitution of the pyridine ring // Tetrahedron Letters, 1977, (25), рр. 2193-2194]. Недостаток способа - высокая температура процесса, высокое давление, использование сложного оборудования для проведения процесса - автоклава.Oxidation of pyridine with CuSO 4 hydrates in an autoclave at 300°C for 6-8 hours yielded 2-pyridone with a yield of 95%, [Tomasik P., Woszczyk A. A novel nucleophilic substitution of the pyridine ring // Tetrahedron Letters, 1977, (25), pp. 2193-2194]. The disadvantage of this method is the high temperature of the process, high pressure, the use of sophisticated equipment for the process - an autoclave.
Однако при выдерживании пиридина в запаянной стеклянной ампуле при 300°С в течение 8 ч с [Zn(C5H5N)(OH2)3]SO4, ZnSO4⋅7 H2O или CdSО4⋅8H2О в среде воздуха или кислорода 2-пиридон получен с выходами менее 15% [Gillard R.D., Hall D.P.J. Simple Oxidations of Pyridines: Zinc Sulphates or Natural Sand as Remarkably Specific Catalysts // J. Chem. Soc., Chem. Commun., 1988, рр. 1163-1164]. Недостаток - низкий выход, высокая температура процесса, повышенное давление, сложное оборудование.However, when keeping pyridine in a sealed glass ampoule at 300°C for 8 h with [Zn(C 5 H 5 N)(OH 2 ) 3 ]SO 4 , ZnSO 4 ⋅7 H 2 O or CdSO 4 ⋅8H 2 O in in air or oxygen, 2-pyridone was obtained in yields less than 15% [Gillard RD, Hall DPJ Simple Oxidations of Pyridines: Zinc Sulphates or Natural Sand as Remarkably Specific Catalysts // J. Chem. Soc., Chem. Commun., 1988, pp. 1163-1164]. Disadvantage - low yield, high process temperature, high pressure, complex equipment.
Задача, на решение которой направлено настоящее изобретение - получение 2-пиридона (2-гидроксипиридина), заключается в упрощении способа получения, в том числе за счет использования недорогих реагентов, а также простого в аппаратурном оформлении, увеличении выхода целевого соединения.The problem to be solved by the present invention - the preparation of 2-pyridone (2-hydroxypyridine) - is to simplify the method of preparation, including through the use of inexpensive reagents, as well as simple instrumentation, increasing the yield of the target compound.
Поставленная задача решается предлагаемым способом получения 2-пиридона, на первой стадии которого пиридин окисляют персульфатом аммония (ПСА) при 40-60°С в щелочной среде (24% NaOH) при мольном соотношении пиридин:NaOH:ПСА равном 1:4:1,5 в присутствии 0,01-0,3 мас.% фталоцианинового катализатора окисления (фталоцианина кобальта, или железа (II), или железа (III), или марганца, или никеля, или цинка - ФцМе) при перемешивании в течение 10 ч до промежуточного 2-пиридинилсульфата (ПС). Затем реакционную смесь охлаждают до комнатной температуры, путем экстракции бутанолом выделяют 2-пиридинилсульфат (выход 50-81%), который затем гидролизуют соляной кислотой при 85-95°С и получают 2-пиридон с выходом 45-74%, суммарно в пересчете на исходный пиридин (схема 2, табл.).The problem is solved by the proposed method for obtaining 2-pyridone, at the first stage of which pyridine is oxidized with ammonium persulfate (APS) at 40-60°C in an alkaline medium (24% NaOH) at a molar ratio of pyridine:NaOH:PSA equal to 1:4:1, 5 in the presence of 0.01-0.3 wt.% phthalocyanine oxidation catalyst (cobalt phthalocyanine, or iron (II), or iron (III), or manganese, or nickel, or zinc - FcMe) with stirring for 10 h until intermediate 2-pyridinyl sulfate (PS). Then the reaction mixture is cooled to room temperature, 2-pyridinyl sulfate is isolated by extraction with butanol (yield 50-81%), which is then hydrolyzed with hydrochloric acid at 85-95°C and 2-pyridone is obtained with a yield of 45-74%, in total in terms of initial pyridine (scheme 2, table).
Схема 2Scheme 2
Сущность заявленного технического решения подтверждается примерами конкретного выполнения.The essence of the claimed technical solution is confirmed by examples of a specific implementation.
Пример 1. Получение 2-пиридона при катализе фталоцианином кобальта (табл., п. 2)Example 1. Obtaining 2-pyridone by catalysis of cobalt phthalocyanine (table, p. 2)
а) в трехгорлой колбе, снабженной обратным холодильником и механической мешалкой, к 20 мл 24%-ного раствора NaOH медленно приливают раствор 4,9 г (0,06 моль) пиридина в 20 мл азеотропного раствора воды и ацетона (1:1), температуру реакции поднимают до 45оС и прикапывают раствор 20,52 г (0,09 моль) персульфата аммония в 30 мл воды. После полного прибавления персульфата аммония вносят 0,01 мас.% катализатора - фталоцианина кобальта. Реакционную смесь перемешивают при температуре 45° в течение 10 ч, охлаждают до комнатной температуры, упаривают при пониженном давлении на 1/3 объема, экстрагируют этилацетатом (2×20 мл) для удаления непрореагировавшего пиридина, бутанолом (3×50 мл). Бутаноловые фракции объединяют, упаривают досуха, остаток промывают горячим этанолом, выдерживают 12 ч при 0°С, выпавший осадок декантируют, фильтрат упаривают, получают 6,33 г (55%) 2-пиридинилсульфата в виде густой массы темно-коричневого цвета;a) in a three-necked flask equipped with a reflux condenser and a mechanical stirrer, a solution of 4.9 g (0.06 mol) of pyridine in 20 ml of an azeotropic solution of water and acetone (1: 1) is slowly added to 20 ml of a 24% NaOH solution, the reaction temperature was raised to 45° C. and a solution of 20.52 g (0.09 mol) of ammonium persulfate in 30 ml of water was added dropwise. After complete addition of ammonium persulfate contribute 0.01 wt.% catalyst - cobalt phthalocyanine. The reaction mixture was stirred at 45° for 10 h, cooled to room temperature, evaporated under reduced pressure by 1/3 volume, extracted with ethyl acetate (2×20 ml) to remove unreacted pyridine, butanol (3×50 ml). The butanol fractions are combined, evaporated to dryness, the residue is washed with hot ethanol, kept for 12 h at 0°C, the precipitate is decanted, the filtrate is evaporated, 6.33 g (55%) of 2-pyridinyl sulfate is obtained in the form of a thick dark brown mass;
б) 2,8 г (0,0146 моль) 2-пиридинилсульфата растворяют в 30 мл дистиллированной воды при 90°С при перемешивании, после полного растворения прикапывают 1,43 г 0,82 мл (0,0146 моль) соляной кислоты. Реакционную смесь нагревают 3 ч, контролируя по ТСХ (элюент этанол:аммиак 4:1), охлаждают до комнатной температуры, подщелачивают раствором NaHCO3 до рН 7-8, экстрагируют хлороформом (3×10 мл), органический слой сушат MgSO4, после удаления растворителя получают 1,17 г (95%) 2-пиридона в виде густой массы светло-коричневого цвета. После перекристаллизации из этанола получили 1,11 г (90%) порошка светло-желтого цвета. В пересчете на исходный пиридин выход 2-пиридона составляет 50%.b) 2.8 g (0.0146 mol) of 2-pyridinyl sulfate are dissolved in 30 ml of distilled water at 90°C with stirring, after complete dissolution, 1.43 g of 0.82 ml (0.0146 mol) of hydrochloric acid are added dropwise. The reaction mixture was heated for 3 h, monitored by TLC (eluent ethanol:ammonia 4:1), cooled to room temperature, basified with NaHCO 3 solution to pH 7-8, extracted with chloroform (3×10 ml), the organic layer was dried with MgSO 4 , after removal of the solvent gives 1.17 g (95%) of 2-pyridone in the form of a dense mass of light brown color. Recrystallization from ethanol gave 1.11 g (90%) of a light yellow powder. In terms of the starting pyridine, the yield of 2-pyridone is 50%.
2-Пиридон (3). Порошок светло-желтого цвета. Тпл=107-110°С. ЯМР 1H (CDCl3, δ, м.д.): 6.16 (1H, dd, С5 H), 6.38 (1H, d, С3 H), 7.38 (1H, d, С6 H), 7.40 (1H, dd, С4 H), 11.5 (1H, c, C1-OH). ЯМР 13С (CDCl3, δ, м.д.): 104.8 (С4), 119.77 (С3), 135.19 (С6), 140.81 (С4), 162.32 (С5).2-Pyridone (3). Light yellow powder. Tpl=107-110°C. NMRoneH(CDCl3, δ, ppm): 6.16 (1H, dd, C5 H), 6.38 (1H, d, C3 H), 7.38 (1H, d, С6 H), 7.40 (1H, dd, Cfour H), 11.5 (1H, s, Cone-OH). NMR13C(CDCl3, δ, ppm): 104.8 (Cfour), 119.77 (C3), 135.19 (C6), 140.81 (Cfour), 162.32 (C5).
Результаты экспериментов с варьированием количества и вида катализатора приведены в табл., пп 1,3-26. Оптимальные продолжительность окисления, мольное соотношение реагентов и температура установлены в предварительных экспериментах.The results of experiments with varying the amount and type of catalyst are given in table., PP 1.3-26. The optimal duration of oxidation, the molar ratio of the reactants, and the temperature were established in preliminary experiments.
Таким образом, предложен простой в аппаратурном оформлении способ получения 2-пиридона (2-гидроксипиридина), позволяющий получить целевое соединение с выходом до 74%, суммарно в пересчете на исходный пиридин.Thus, we have proposed a method for the preparation of 2-pyridone (2-hydroxypyridine), which is simple in hardware design, and which makes it possible to obtain the target compound with a yield of up to 74%, in total, in terms of the starting pyridine.
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| DE406208C (en) * | 1922-08-16 | 1924-11-15 | A E Tschitschibabin Dr | Process for preparing oxy derivatives of pyridine, quinoline, their homologues and other bases containing pyridine nuclei |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE406208C (en) * | 1922-08-16 | 1924-11-15 | A E Tschitschibabin Dr | Process for preparing oxy derivatives of pyridine, quinoline, their homologues and other bases containing pyridine nuclei |
Non-Patent Citations (2)
| Title |
|---|
| Gillard R.D., Hall D.P.J. Simple Oxidations of Pyridines: Zinc Sulphates or Natural Sand as Remarkably Specific Catalysts // J. Chem. Soc., Chem. Commun., 1988, рр. 1163-1164. Tomasik P., Woszczyk A. A novel nucleophilic substitution of the pyridine ring // Tetrahedron Letters, 1977, (25), рр. 2193-2194. * |
| Selvarajan, N.; и др. Reaction of hydroxyl with pyridine. Pulse-radiolytic and product-analysis studies. The Journal of Physical Chemistry, 84(20), 2548-2551. * |
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