RU2645917C1 - METHOD OF SYNTHESIS OF PYRIDO [1,2-a]IMIDAZO[4,5-f]BENZIMIDAZOLE AND ITS DERIVATIVES - Google Patents
METHOD OF SYNTHESIS OF PYRIDO [1,2-a]IMIDAZO[4,5-f]BENZIMIDAZOLE AND ITS DERIVATIVES Download PDFInfo
- Publication number
- RU2645917C1 RU2645917C1 RU2017112644A RU2017112644A RU2645917C1 RU 2645917 C1 RU2645917 C1 RU 2645917C1 RU 2017112644 A RU2017112644 A RU 2017112644A RU 2017112644 A RU2017112644 A RU 2017112644A RU 2645917 C1 RU2645917 C1 RU 2645917C1
- Authority
- RU
- Russia
- Prior art keywords
- benzimidazole
- pyrido
- temperature
- molar ratio
- derivatives
- Prior art date
Links
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 13
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims abstract description 12
- LZSGQWSNXVWHRA-UHFFFAOYSA-N imidazo[4,5-f]benzimidazole Chemical compound C=1C2=NC=NC2=CC2=NC=NC2=1 LZSGQWSNXVWHRA-UHFFFAOYSA-N 0.000 title claims abstract description 7
- UZKUAAKXKWTZJN-UHFFFAOYSA-N 7-nitropyrido[1,2-a]benzimidazole Chemical compound C1=CC=CN2C3=CC=C([N+](=O)[O-])C=C3N=C21 UZKUAAKXKWTZJN-UHFFFAOYSA-N 0.000 claims abstract description 8
- KHCOCYBWNDUZRP-UHFFFAOYSA-N pyrido[1,2-a]benzimidazole-7,8-diamine Chemical compound C1=CC=CC2=NC3=C(N21)C=C(C(=C3)N)N KHCOCYBWNDUZRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 6
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims abstract description 3
- 230000003197 catalytic effect Effects 0.000 claims abstract description 3
- 238000009833 condensation Methods 0.000 claims abstract description 3
- 230000005494 condensation Effects 0.000 claims abstract description 3
- 238000006396 nitration reaction Methods 0.000 claims abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 3
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims abstract 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 7
- 235000010333 potassium nitrate Nutrition 0.000 claims 1
- 239000004323 potassium nitrate Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- JYZIHLWOWKMNNX-UHFFFAOYSA-N benzimidazole Chemical compound C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 abstract 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract 3
- MZYXAQPZXYTSBH-UHFFFAOYSA-N 7,8-dinitropyrido[1,2-a]benzimidazole Chemical compound [N+](=O)([O-])C1=CC2=C(N3C(=N2)C=CC=C3)C=C1[N+](=O)[O-] MZYXAQPZXYTSBH-UHFFFAOYSA-N 0.000 abstract 2
- 229910010062 TiCl3 Inorganic materials 0.000 abstract 2
- 238000011084 recovery Methods 0.000 abstract 2
- 230000000694 effects Effects 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 abstract 1
- FODVQKYUAIWTKY-UHFFFAOYSA-N pyrido[1,2-a]benzimidazole Chemical compound C1=CC=CN2C3=CC=CC=C3N=C21 FODVQKYUAIWTKY-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- -1 1 ', 3'-dihydrospiro [cyclohexane-1,2'-imidazo [4,5- b ] pyridine] manganese oxide Chemical compound 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- QVTXGGYWFVUIMX-UHFFFAOYSA-N 1,3,5,10-tetrazatetracyclo[7.7.0.02,6.011,16]hexadeca-2(6),3,7,9,11,13,15-heptaene Chemical compound c1nc2c(ccc3nc4ccccc4n23)[nH]1 QVTXGGYWFVUIMX-UHFFFAOYSA-N 0.000 description 1
- VYZAHLCBVHPDDF-UHFFFAOYSA-N Dinitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 VYZAHLCBVHPDDF-UHFFFAOYSA-N 0.000 description 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 238000011138 biotechnological process Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- NEBKTUSLOFKGKH-UHFFFAOYSA-N pyrido[1,2-a]benzimidazole-1,2-diamine Chemical compound C1=CC=C2N(C(=C(N)C=C3)N)C3=NC2=C1 NEBKTUSLOFKGKH-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- IRFLWUABEAVYHH-UHFFFAOYSA-N spiro[cyclohexane-1,2'-imidazo[4,5-b]pyridine] Chemical compound C1CCCCC21N=C1N=CC=CC1=N2 IRFLWUABEAVYHH-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000001149 thermolysis Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Изобретение относится к способу синтеза конденсированных полиазагетероциклов общей формулыThe invention relates to a method for the synthesis of condensed polyazheterocycles of the general formula
где R = а) H, б) CH3, в) CF3,where R = a) H, b) CH 3 , c) CF 3 ,
которые применяются в качестве флуоресцентных меток. Последние используются для контроля за состоянием продуцентов в современных биотехнологических процессах (Hyka, P. Combined Use of Fluorescent Dyes and Flow Cytometry To Quantify the Physiological State of Pichia pastoris during the Production of Heterologous Proteins in High-Cell-Density Fed-Batch Cultures / P. Hyka, T. Züllig, C. Ruth et al. // Applied and Environmental Microbiology. – 2010. – V.76, is. 13. – pp. 4486-4496). Это позволяет отслеживать возможный стресс клеток и их культур и вовремя реагировать на возникшие изменения для поддержания максимальной продуктивности. Флуоресцентные метки также широко применяются в ПЦР в реальном времени, что позволяет одновременно проводить детекцию и количественно измерять содержание специфических последовательностей ДНК в образце исследуемого биообъекта (Navarro, E. Real-time PCR detection chemistry / E. Navarro, G. Serrano-Heras, M.J. Castaño et al. // Clinica Chimica Acta. – 2015. – V. 439. – pp. 231-250).which are used as fluorescent labels. The latter are used to monitor the state of producers in modern biotechnological processes (Hyka, P. Combined Use of Fluorescent Dyes and Flow Cytometry To Quantify the Physiological State of Pichia pastoris during the Production of Heterologous Proteins in High-Cell-Density Fed-Batch Cultures / P Hyka, T. Züllig, C. Ruth et al. // Applied and Environmental Microbiology. - 2010 .-- V.76, is. 13. - pp. 4486-4496). This allows you to track the possible stress of cells and their cultures and respond to changes in time to maintain maximum productivity. Fluorescence labels are also widely used in real-time PCR, which allows simultaneous detection and quantitative measurement of the content of specific DNA sequences in a sample of the studied biological object (Navarro, E. Real-time PCR detection chemistry / E. Navarro, G. Serrano-Heras, MJ Castaño et al. // Clinica Chimica Acta. - 2015 .-- V. 439. - pp. 231-250).
Известен многостадийный способ синтеза аналогичной структуры - 1H-имидазо[4',5':5,6]пиридо[1,2-a]бензимидазола, включающий синтез 1',3'-дигидроспиро[циклогексан-1,2'-имидазо[4,5-b]пиридина] при кипячении пиридин-2,3-диамина с циклогексаноном 71 ч в изопропаноле, окисление 1',3'-дигидроспиро[циклогексан-1,2'-имидазо[4,5-b]пиридина] оксидом марганца в течение 12 ч, взаимодействие полученного спиро[циклогексан-1,2'-имидазо[4,5-b]пиридина] с бензтриазолом в течение 14 ч, кипячение в толуоле 5-(бензотриазолил)спиро[2H-имидазо[4,5-b]пиридин-2,1′-циклогесана] в присутствии N-этилдиизопропиламина, приводящее к спиро[(2Н-имидазо[4,5:2,4]пиридо[1,2-а]бензимидазол)-2,1′-циклогексану], который восстанавливается дитионитом натрия в водном тетрагидрофуране с получением пиридо[1,2-а]бензимидазола-1,2-диамина, который при кипячении в течение 4 ч в муравьиной кислоте дает целевой 1H-имидазо[4',5':5,6]пиридо[1,2-a]бензимидазол. Суммарный выход целевого соединения менее 10 % (Huu Phuoc Le, Anna Kelbig, Andreas Lindauer, Richard Neidlein and Hans Suschitzky Synthesis of indolo-quinonediimine derivatives by the thermolysis of 5-(1-benzotriazolyl)-substituted spiro[2H-benzimidazole-2,1'-cyclohexane] // Journal of Chemical Research.-2004/-July, 453–456).Known multistep process for the synthesis of similar structure - 1H- imidazo [4 ', 5': 5,6] pyrido [1,2-a] benzimidazole 1 comprising the synthesis', 3'-dihydrospiro [cyclohexane-1,2'-imidazo [ 4,5- b ] pyridine] by boiling pyridin-2,3-diamine with cyclohexanone 71 hours in isopropanol, oxidation of 1 ', 3'-dihydrospiro [cyclohexane-1,2'-imidazo [4,5- b ] pyridine] manganese oxide for 12 hours, the interaction of the obtained spiro [cyclohexane-1,2'-imidazo [4,5- b ] pyridine] with benztriazole for 14 hours, boiling in toluene of 5- (benzotriazolyl) spiro [2H-imidazo [4 , 5-b] pyridin-2,1′-cyclohexane] in the presence of N-e tildiisopropylamine, resulting in spiro [(2H-imidazo [4,5: 2,4] pyrido [1,2- a ] benzimidazole) -2,1′-cyclohexane], which is reduced with sodium dithionite in aqueous tetrahydrofuran to give pyrido [1 , 2- a] benzimidazole-1,2-diamine, which is under reflux for 4 hours in formic acid yields the desired 1H- imidazo [4 ', 5': 5,6] pyrido [1,2-a] benzimidazole. The total yield of the target compound is less than 10% (Huu Phuoc Le , Anna Kelbig, Andreas Lindauer, Richard Neidlein and Hans Suschitzky Synthesis of indolo-quinonediimine derivatives by the thermolysis of 5- (1-benzotriazolyl) -substituted spiro [2 H- benzimidazole-2 , 1'-cyclohexane] // Journal of Chemical Research.-2004 / -July, 453–456).
Недостатками известного способа синтеза конденсированных производных пиридо[1,2-a]бензимидазола являются: использование дорогостоящих реагентов, многостадийность процесса и низкий выход продукта.The disadvantages of the known method for the synthesis of condensed pyrido [1,2-a] benzimidazole derivatives are: the use of expensive reagents, a multi-stage process and a low product yield.
Цель изобретения – снижение стоимости синтеза, сокращение времени и температуры проведения процесса, повышение выхода конденсированных производных пиридо[1,2-a]бензимидазола.The purpose of the invention is to reduce the cost of synthesis, reduce the time and temperature of the process, increase the yield of condensed derivatives of pyrido [1,2-a] benzimidazole.
Поставленная цель достигается тем, что в качестве субстрата вместо пиридин-2,3-диамина используется 7-нитропиридо[1,2-a]бензимидазол, легко получаемый в 2 стадии из продуктов многотоннажного производства – пиридина и 2,4-динитрохлорбензола (Патент РФ № 2556001. Бегунов Р.С., Соколов А.А., Калина С.А. Бездиафрагменный электросинтез замещенных пиридо[1,2-а]бензимидазолов. Опубликован 10.07.2015. Бюл. № 19). В результате количество стадий синтеза конденсированных производных пиридо[1,2-a]бензимидазола уменьшается с 6 до 3 и отпадает необходимость в применении дорогостоящего пиридин-2,3-диамина. Все стадии протекают в мягких условиях и с хорошим выходом. Причем нитрование 7-нитропиридо[1,2-a]бензимидазола KNO3 проводят в концентрированной серной кислоте при температуре 25 ºС и мольном соотношении 7-нитропиридо[1,2-a]бензимидазол : KNO3 = 1 : 1.1 в течение 1 часа, восстановление спиртового раствора 7,8-динитропиридо[1,2-a]бензимидазола осуществляют 15% раствором хлорида титана (III) в 10%-ной соляной кислоте и мольном соотношении 7,8-динитропиридо[1,2-a]бензимидазол : TiCl3 = 1:15 при температуре 40 °С в течение 0.5 ч, конденсацию пиридо[1,2-a]бензимидазол-7,8-диамина с алифатическими кислотами проводят при температуре 100 °С и мольном соотношении пиридо[1,2-a]бензимидазол-7,8-диамин : алифатическая кислота = 1 : 10 в течение 1 часа в присутствии каталитических количеств HCl. Реализация предложенного метода синтеза пиридо[1,2-a]имидазо[4,5-f]бензимидазола и его производных позволяет уменьшить температуру и сократить общее операционное время процесса со 105 ч до 2.5 ч. Суммарный выход целевых продуктов больше 70 %.This goal is achieved by the fact that instead of pyridin-2,3-diamine, 7-nitropyrido [1,2-a] benzimidazole is used, which is easily obtained in 2 stages from the products of large-tonnage production - pyridine and 2,4-dinitrochlorobenzene (RF Patent No. 2556001. Begunov RS, Sokolov AA, Kalina SA Non-diaphragm electrosynthesis of substituted pyrido [1,2-a] benzimidazoles. Published July 10, 2015. Bull. No. 19). As a result, the number of stages of the synthesis of condensed pyrido [1,2-a] benzimidazole derivatives decreases from 6 to 3 and there is no need to use expensive pyridin-2,3-diamine. All stages proceed under mild conditions and with a good yield. Moreover, the nitration of 7-nitropyrido [1,2-a] benzimidazole KNO 3 is carried out in concentrated sulfuric acid at a temperature of 25 ° C and a molar ratio of 7-nitropyrido [1,2-a] benzimidazole: KNO 3 = 1: 1.1 for 1 hour, The alcohol solution of 7.8-dinitropyrido [1,2-a] benzimidazole is reduced with a 15% solution of titanium (III) chloride in 10% hydrochloric acid and a molar ratio of 7.8-dinitropyrido [1,2-a] benzimidazole: TiCl 3 = 1:15 at 40 ° C for 0.5 hours, the condensation pyrido [1,2- a] benzimidazole-7,8-diamine with aliphatic acids is carried out at a temperature of 100 ° C molar ratio pyrido [1,2- a] benzimidazole-7,8-diamine: aliphatic acid = 1: 10 for 1 hour in the presence of catalytic amounts of HCl. Implementation of the proposed method for the synthesis of pyrido [1,2-a] imidazo [4,5-f] benzimidazole and its derivatives can reduce the temperature and reduce the total operating time of the process from 105 hours to 2.5 hours. The total yield of the target products is more than 70%.
Строение и чистоту синтезированных соединений анализировали методом ЯМР-спектроскопии и масс-спектрометрии высокого разрешения, определением температуры плавления.The structure and purity of the synthesized compounds were analyzed by high resolution NMR spectroscopy and mass spectrometry, by determining the melting point.
Изобретение иллюстрируется следующими примерами.The invention is illustrated by the following examples.
Пример 1. 7,8-Динитропиридо[1,2-а]бензимидазол.Example 1. 7.8-Dinitropyrido [1,2- a ] benzimidazole.
К раствору 21.30 г (0.100 моль) 7-нитропиридо[1,2-a]бензимидазола в 30 мл H2SO4 при 25 ºС медленно прикапывают 11.11 г (0.110 ммоль) KNO3 в 30 мл H2SO4 и перемешивают в течение 1 часа. Реакционную массу выливают в воду, нейтрализуют NH4OH. Выпавший осадок отфильтровывают, несколько раз промывают водой на фильтре и сушат. Выход 7,8-динитропиридо[1,2-а]бензимидазола 23.48 г (91%). Т. пл. 276-278 °C.To a solution of 21.30 g (0.100 mol) of 7-nitropyrido [1,2- a ] benzimidazole in 30 ml of H 2 SO 4 at 25 ° C, 11.11 g (0.110 mmol) of KNO 3 in 30 ml of H 2 SO 4 are slowly added and stirred for 1 hour The reaction mass is poured into water, neutralized with NH 4 OH. The precipitate formed is filtered off, washed several times with water on a filter and dried. The yield of 7.8-dinitropyrido [1,2- a ] benzimidazole was 23.48 g (91%). T. pl. 276-278 ° C.
Спектр 1H ЯМР (ДМСО-d6, δ, м.д., J/Гц): 7.30 (тд, 1H, H2, J 6.5, 1.5 Гц); 7.85 (ддд, 1H, H3, J 9.0, 6.5, 0.9 Гц); 7.87 (д, 1H, H4, J 9.0 Гц); 8.54 (с, 1H, H6); 9.39 (д, 1H, H1, J 6.9 Гц); 9.48 с (1H, H9). 1 H NMR spectrum (DMSO-d 6 , δ, ppm, J / Hz): 7.30 (td, 1H, H 2 , J 6.5, 1.5 Hz); 7.85 (ddd, 1H, H 3 , J 9.0, 6.5, 0.9 Hz); 7.87 (d, 1H, H 4 , J 9.0 Hz); 8.54 (s, 1H, H 6 ); 9.39 (d, 1H, H 1 , J 6.9 Hz); 9.48 s (1H, H 9 ).
Спектр 13C ЯМР (ДМСО-d6, δ, м.д.): 112.5 (C9), 113.3 (C2), 115.6 (C6), 117.5 (C4), 128.6 (C1), 128.8 (C9a), 133.8 (C7), 134.1 (C3), 141.9 (C8), 145.6 (C5a), 152.9 (C4a). 13 C NMR Spectrum (DMSO-d 6 , δ , ppm): 112.5 (C 9 ), 113.3 (C 2 ), 115.6 (C 6 ), 117.5 (C 4 ), 128.6 (C 1 ), 128.8 ( C 9a ), 133.8 (C 7 ), 134.1 (C 3 ), 141.9 (C 8 ), 145.6 (C 5a ), 152.9 (C 4a ).
HRMS: m/z вычислено C11H7N4O4 + 259.0469 [M+H]+, найдено: 259.0463.HRMS: m / z calculated C 11 H 7 N 4 O 4 + 259.0469 [M + H] + , found: 259.0463.
Пример 2. Пиридо[1,2-a]бензимидазол-7,8-диамин.Example 2. Pyrido [1,2- a ] benzimidazole-7,8-diamine.
В трёхгорлую колбу помещают 0.078 ммоль 7,8-динитропиридо[1,2-а]бензимидазола, приливают 1200 мл (1.163 моль) 15% раствора хлорида титана (III) в 10% HCl. Синтез ведут 30 минут при температуре 40 °С. После окончания синтеза реакционную смесь охлаждают, обрабатывают NH4OH до pH=7 и экстрагируют горячим хлороформом (∑=150 мл). После отгонки хлороформа получают 12.05 г (78%) пиридо[1,2-a]бензимидазол-7,8-диамина. Т. пл. 241-243 ºС.0.078 mmol of 7.8-dinitropyrido is placed in a three-necked flask [1,2-but] benzimidazole, 1200 ml (1.163 mol) of a 15% solution of titanium (III) chloride in 10% HCl are added. Synthesis is carried out for 30 minutes at a temperature of 40 ° C. After the synthesis, the reaction mixture is cooled, treated with NHfourOH to pH = 7 and extracted with hot chloroform (∑ = 150 ml). After distillation of chloroform, 12.05 g (78%) of pyrido are obtained [1,2-a] benzimidazole-7,8-diamine. T. pl. 241-243 ºС.
Спектр 1H ЯМР (ДМСО-d6, δ, м.д., J/Гц): 4.67 (c, 4H, NH2); 6.73 (тд, 1H, H2, J 6.6, 1.0 Гц); 6.94 (с, 1H, H6); 7.21 (ддд, 1H, H3, J = 9.2 Гц, 6.6 Гц, 1.3 Гц); 7.22 (с, 1H, H9); 7.42 (дт, 1H, H4, J 9.2 Гц, 1.0 Гц); 8.54 (дт, 1H, H1, J 6.8 Гц, 1.0 Гц). 1 H NMR Spectrum (DMSO-d 6 , δ, ppm, J / Hz): 4.67 (s, 4H, NH 2 ); 6.73 (td, 1H, H 2 , J 6.6, 1.0 Hz); 6.94 (s, 1H, H 6 ); 7.21 (ddd, 1H, H 3 , J = 9.2 Hz, 6.6 Hz, 1.3 Hz); 7.22 (s, 1H, H 9 ); 7.42 (dt, 1H, H 4 , J 9.2 Hz, 1.0 Hz); 8.54 (dt, 1H, H 1 , J 6.8 Hz, 1.0 Hz).
Спектр 13C ЯМР (ДМСО-d6, δ, м.д.): 94.2 (C9), 101.3 (C6), 108.8 (C2), 115.8 (C4), 121.4 (C9a), 125.0 (C1), 125.6 (C3), 133.0 (C8), 136.7 (C7), 138.0 (C5a), 145.3 (C4a). 13 C NMR Spectrum (DMSO-d 6 , δ , ppm): 94.2 (C 9 ), 101.3 (C 6 ), 108.8 (C 2 ), 115.8 (C 4 ), 121.4 (C 9a ), 125.0 ( C 1 ), 125.6 (C 3 ), 133.0 (C 8 ), 136.7 (C 7 ), 138.0 (C 5a ), 145.3 (C 4a ).
HRMS: m/z вычислено C11H11N4 199.0984 [M+H]+, найдено: 199.0981.HRMS: m / z calculated C 11 H 11 N 4 199.0984 [M + H] + , found: 199.0981.
Пример 3. Пиридо[1,2-а]имидазо[4,5-f]бензимидазол (а).Example 3. Pyrido [1,2- a ] imidazo [4,5-f] benzimidazole (a).
В круглодонную колбу помещают 4 г (0.020 моль) пиридо[1,2-а]бензимидазол-7,8-диамина и приливают 7.55 мл (0.2 моль) муравьиной кислоты и 0.05 мл 36 % соляной кислоты. Реакционную массу нагревают при 100 °С в течение 1 часа, после охлаждают и выливают в воду. Раствор нейтрализуют NH4ОН до pH=8 и отфильтровывают выпавший осадок. Выход 4.08 г (98 %). Т.пл. 296-298 ºС.4 g (0.020 mol) of pyrido [1,2- a ] benzimidazole-7,8-diamine are placed in a round bottom flask and 7.55 ml (0.2 mol) of formic acid and 0.05 ml of 36% hydrochloric acid are added. The reaction mass is heated at 100 ° C for 1 hour, then cooled and poured into water. The solution was neutralized with NH 4 OH to pH = 8 and the precipitate formed was filtered off. Yield 4.08 g (98%). Mp 296-298 ºС.
Спектр 1H ЯМР (ДМСО-d6, δ, м.д., J/Гц): 6.91 (т, 1Н, Н2, J 6.2 Гц); 7.43-7.54 (м, 1H, H3); 7.59 (д, 1H, H4, J 9.3 Гц); 7.86 (с, 1H, H6); 8.34 (с, 1H, H8); 8.52 (с, 1H, H10); 9.12 (д, 1H, Н1, J 6.9 Гц); 12.46 (с, 1H, Н12). 1 H NMR spectrum (DMSO-d 6 , δ, ppm, J / Hz): 6.91 (t, 1H, H 2 , J 6.2 Hz); 7.43-7.54 (m, 1H, H 3 ); 7.59 (d, 1H, H 4 , J 9.3 Hz); 7.86 (s, 1H, H 6 ); 8.34 (s, 1H, H 8 ); 8.52 (s, 1H, H 10 ); 9.12 (d, 1H, H 1 , J 6.9 Hz); 12.46 (s, 1H, H 12 ).
Спектр 13C ЯМР (ДМСО-d6, δ, м.д.): 109.54, 116.95, 126.75, 127.59, 130.18, 141.78, 144.17, 148.71. 13 C NMR Spectrum (DMSO-d 6 , δ , ppm): 109.54, 116.95, 126.75, 127.59, 130.18, 141.78, 144.17, 148.71.
HRMS: m/z вычислено C12H8N4 209.0828 [M+H]+ , найдено: 209.0822.HRMS: m / z calculated C 12 H 8 N 4 209.0828 [M + H] + , found: 209.0822.
Примеры 4-5. Другие конденсированные производные пиридо[1,2-а]бензимидазола получают аналогично примеру 3.Examples 4-5. Other condensed pyrido [1,2-a] benzimidazole derivatives are prepared analogously to example 3.
8-метилпиридо[1,2-а]имидазо[4,5-f]бензимидазол (б). Выход 4.22 г (95 %). Т.пл. > 320 ºС.8-methylpyrido [1,2- a ] imidazo [4,5-f] benzimidazole (b). Yield 4.22 g (95%). Mp > 320 ºС.
Спектр 1H ЯМР (ДМСО-d6, δ, м.д., J/Гц): 2.54 (с, 3H, CH3); 6.89 (т, 1Н, Н2, J 6.5 Гц); 7.41-7.51 (м, 1H, H3); 7.57 (д, 1H, H4, J 9.2 Гц); 7.68 (с, 1H, H6); 8.39 (с, 1H, H10); 9.09 (д, 1H, Н1, J 6.8 Гц); 12.19 (с, 1H, NН). 1 H NMR Spectrum (DMSO-d 6 , δ, ppm, J / Hz): 2.54 (s, 3H, CH 3 ); 6.89 (t, 1H, H 2 , J 6.5 Hz); 7.41-7.51 (m, 1H, H 3 ); 7.57 (d, 1H, H 4 , J 9.2 Hz); 7.68 (s, 1H, H 6 ); 8.39 (s, 1H, H 10 ); 9.09 (d, 1H, H 1 , J 6.8 Hz); 12.19 (s, 1H, NH).
Спектр 13C ЯМР (ДМСО-d6, δ, м.д.): 14.92, 108.95, 116.54, 125.81, 126.79, 128.99, 141.04, 147.99, 153.26. 13 C NMR Spectrum (DMSO-d 6 , δ , ppm): 14.92, 108.95, 116.54, 125.81, 126.79, 128.99, 141.04, 147.99, 153.26.
HRMS: m/z вычислено C13H11N4 223.0984 [M+H]+, найдено: 223.0980.HRMS: m / z calculated C 13 H 11 N 4 223.0984 [M + H] + , found: 223.0980.
8-(трифторметил)пиридо[1,2-а]имидазо[4,5-f]бензимидазол (в). Выход 5.13 г (93 %). Т.пл. > 320 ºС.8- (trifluoromethyl) pyrido [1,2- a ] imidazo [4,5- f ] benzimidazole (c). Yield 5.13 g (93%). Mp > 320 ºС.
Спектр 1H ЯМР (ДМСО-d6, δ, м.д., J/Гц): 6.98 (т, 1Н, Н2, J 6.5 Гц); 7.55-7.65 (м, 2H, H3,4); 7.95 (c, 1H, H6); 8.71 (с, 1H, H10); 9.20 (д, 1H, H1, J 6.9 Гц); 13.93 (с, 1H, NН).SpectrumoneH NMR (DMSO-d6, δ, ppm,J/ Hz): 6.98 (t, 1H, N2,J 6.5 Hz); 7.55-7.65 (m, 2H, H3.4); 7.95 (s, 1H, H6); 8.71 (s, 1H, H10); 9.20 (d, 1H, Hone, J 6.9 Hz); 13.93 (s, 1H, NH).
HRMS: m/z вычислено C13H7F3N4 277.0702 [M+H]+, найдено: 277.0700.HRMS: m / z calculated C 13 H 7 F 3 N 4 277.0702 [M + H] + , found: 277.0700.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2017112644A RU2645917C1 (en) | 2017-04-12 | 2017-04-12 | METHOD OF SYNTHESIS OF PYRIDO [1,2-a]IMIDAZO[4,5-f]BENZIMIDAZOLE AND ITS DERIVATIVES |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2017112644A RU2645917C1 (en) | 2017-04-12 | 2017-04-12 | METHOD OF SYNTHESIS OF PYRIDO [1,2-a]IMIDAZO[4,5-f]BENZIMIDAZOLE AND ITS DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| RU2645917C1 true RU2645917C1 (en) | 2018-03-01 |
Family
ID=61568588
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2017112644A RU2645917C1 (en) | 2017-04-12 | 2017-04-12 | METHOD OF SYNTHESIS OF PYRIDO [1,2-a]IMIDAZO[4,5-f]BENZIMIDAZOLE AND ITS DERIVATIVES |
Country Status (1)
| Country | Link |
|---|---|
| RU (1) | RU2645917C1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4585775A (en) * | 1983-09-15 | 1986-04-29 | Hoechst Aktiengesellschaft | Substituted pyrido (1,2-c)imidazo(1,2-a)benzimidazoles, processes for their preparation, their use and pharmaceutical preparations based on these compounds |
| RU2241710C1 (en) * | 2003-04-24 | 2004-12-10 | Ярославский государственный технический университет | Method for preparing substituted pyrido[1,2-a][1,3]-benzimidazoles |
| RU2522549C1 (en) * | 2012-12-25 | 2014-07-20 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Ярославский государственный университет им. П.Г. Демидова" | METHOD OF OBTAINING 7-R-PYRIDO[1,2-a]BENZIMIDAZOLES |
-
2017
- 2017-04-12 RU RU2017112644A patent/RU2645917C1/en active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4585775A (en) * | 1983-09-15 | 1986-04-29 | Hoechst Aktiengesellschaft | Substituted pyrido (1,2-c)imidazo(1,2-a)benzimidazoles, processes for their preparation, their use and pharmaceutical preparations based on these compounds |
| RU2241710C1 (en) * | 2003-04-24 | 2004-12-10 | Ярославский государственный технический университет | Method for preparing substituted pyrido[1,2-a][1,3]-benzimidazoles |
| RU2522549C1 (en) * | 2012-12-25 | 2014-07-20 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Ярославский государственный университет им. П.Г. Демидова" | METHOD OF OBTAINING 7-R-PYRIDO[1,2-a]BENZIMIDAZOLES |
Non-Patent Citations (1)
| Title |
|---|
| HUU PHUOC LE ET AL, Journal of Chemical Research, 2004, vol.7, pp.453-456. * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104447421B (en) | The preparation and application of a kind of novel cysteine and homocysteine fluorescent probe | |
| CN105802606B (en) | The preparation and application of a kind of fluorescence probe containing mercaptoamino acid | |
| CN105542752A (en) | Formaldehyde fluorescence probe and preparation method and application thereof | |
| CN103804369A (en) | Synthesis and application of fluorescence molecular probe containing cyanogens ions by naked eyes and fluorescence ratio detection | |
| CN107857750A (en) | A kind of fluorescent probe compounds and its preparation and application | |
| CN102391150B (en) | Iron-ion fluorescent probe compound and preparation method thereof | |
| RU2645917C1 (en) | METHOD OF SYNTHESIS OF PYRIDO [1,2-a]IMIDAZO[4,5-f]BENZIMIDAZOLE AND ITS DERIVATIVES | |
| Elinson et al. | Multicomponent assembling of salicylaldehydes, malononitrile and cyanoacetamides: A simple and efficient approach to medicinally relevant 2-amino-4H-chromene scaffold | |
| CN111116564B (en) | Ratio type fluorescent molecular probe for detecting hypochlorite ions and preparation method and application thereof | |
| RU2522549C1 (en) | METHOD OF OBTAINING 7-R-PYRIDO[1,2-a]BENZIMIDAZOLES | |
| CN114773305B (en) | Preparation method and application of 2-cycloarone pH fluorescence ratio probe | |
| CN105985770A (en) | Preparation method and application of hydrogen sulfide fluorescent probe | |
| CN102030707A (en) | Method for preparing Blonanserin intermediate | |
| RU2638928C1 (en) | Derivatives of 1h-pyrazolo [3,4-d] pyrimidine and method of their production | |
| Jiang et al. | Synthesis of Bis‐benzimidazolium Cyclic Receptors and Their Anion Binding Properties | |
| CN108949159B (en) | Fluorescent probe for detecting palladium ions and synthetic method and application thereof | |
| RU2241710C1 (en) | Method for preparing substituted pyrido[1,2-a][1,3]-benzimidazoles | |
| CN112724069A (en) | Carbazolyl ethanone fluorescent probe compound for identifying and detecting iron and mercury | |
| RU2236409C1 (en) | Method for preparing 7-aminopyrido[1,2-a][1,3]-benzimidazole | |
| CN112480016B (en) | (E) -1-acyl-1- (3-quinoxalinone) methyl ketoxime and synthesis method thereof | |
| CN100522936C (en) | Synthesis process of 2,4-dichloro-5-sulfonyl benzoic acid | |
| RU2642456C2 (en) | METHOD FOR OBTAINING OF N-ARYL-SUBSTITUTED 3H-IMIDAZO[4,5-b] PYRIDINES | |
| CN110498803B (en) | Compound based on rhodamine hydrazide structure and preparation method and application thereof | |
| CN105541840B (en) | Key intermediate and its synthetic method and the application in terms of Tadalafei is prepared | |
| Hirai et al. | Revisiting dimerization of acetoacetamide leading to 4, 6-dimethyl-2-pyridone-5-carboxamide |