RU2785191C1 - Method for producing derivatives of tetrazolo[5',1':3,4]pyrazino[1,2-a]indole - Google Patents
Method for producing derivatives of tetrazolo[5',1':3,4]pyrazino[1,2-a]indole Download PDFInfo
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- RU2785191C1 RU2785191C1 RU2022111081A RU2022111081A RU2785191C1 RU 2785191 C1 RU2785191 C1 RU 2785191C1 RU 2022111081 A RU2022111081 A RU 2022111081A RU 2022111081 A RU2022111081 A RU 2022111081A RU 2785191 C1 RU2785191 C1 RU 2785191C1
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- indole
- pyrazino
- tetrazolo
- proline
- sodium azide
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- -1 derivatives of tetrazolo[5',1':3,4]pyrazino[1,2-a]indole Chemical class 0.000 title claims description 19
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims abstract description 11
- 229960002429 Proline Drugs 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 239000000460 chlorine Chemical group 0.000 claims abstract 4
- 229910052801 chlorine Chemical group 0.000 claims abstract 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract 4
- 238000005406 washing Methods 0.000 claims abstract 2
- 238000001035 drying Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 2
- GCZDLZHMAMLSJF-UHFFFAOYSA-N pyrazino[1,2-a]indole Chemical compound C1=CN=CC2=CC3=CC=CC=C3N21 GCZDLZHMAMLSJF-UHFFFAOYSA-N 0.000 abstract 3
- 238000007605 air drying Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 239000000843 powder Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000002194 synthesizing Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic Effects 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 210000004940 Nucleus Anatomy 0.000 description 1
- VNDYJBBGRKZCSX-UHFFFAOYSA-L Zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 1
- 238000010958 [3+2] cycloaddition reaction Methods 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Abstract
Description
Изобретение относится к способу получения производных тетразоло[5',1':3,4]пиразино[1,2-а]индола с общей формулой 1-3:The invention relates to a method for obtaining tetrazolo[5',1':3,4]pyrazino[1,2-a]indole derivatives with the general formula 1-3:
Образование тетразола с последующей циклизацией по алкиновому фрагменту в присутствии избытка азида натрия и бромида цинка было описано в работе (Tsai C.-W., Yang S.-C, Liu, Y.-M., Wu M.-J. Microwave-assisted cycloadditions of 2-alkynylbenzonitriles with sodium azide: selective synthesis of tetrazolo[5,1-a]pyridines and 4,5-disubstituted-2H-1,2,3-triazoles. Tetrahedron Letters, 2009, Vol. 65, p. 8367-8372):The formation of tetrazole followed by cyclization at the alkyne fragment in the presence of excess sodium azide and zinc bromide was described in (Tsai C.-W., Yang S.-C, Liu, Y.-M., Wu M.-J. Microwave- assisted cycloadditions of 2-alkynylbenzonitriles with sodium azide: selective synthesis of tetrazolo[5,1-a]pyridines and 4,5-disubstituted-2H-1,2,3-triazoles Tetrahedron Letters, 2009, Vol 65, p. 8367-8372):
Образование тетразолов из нитрилов в присутствии каталитического количества L-пролина описано в работе (Bhagat S.B., Telvekar V.N. L-Proline: An Efficient Organocatalyst for the Synthesis of 5-Substituted 1H-Tetrazoles via [3+2] Cycloaddition of Nitriles and Sodium Azide. Synlett, 2018, Vol. 29, p. 874-879):The formation of tetrazoles from nitriles in the presence of a catalytic amount of L-proline is described in (Bhagat S.B., Telvekar V.N. L-Proline: An Efficient Organocatalyst for the Synthesis of 5-Substituted 1H-Tetrazoles via [3+2] Cycloaddition of Nitriles and Sodium Azide. Synlett, 2018, Vol.29, pp. 874-879):
В 
DBU-Catalyzed Alkyne-Imidate Cyclization toward l-Alkoxypyrazino[1,2-a]indole Synthesis, Festa A.A. et al, J. Org. Chem. 2018, 83, 9305-9311, описана схема образования цикла на примере воздействия на замещенный индол спирта в каталитической системе.DBU-Catalyzed Alkyne-Imidate Cyclization towards l-Alkoxypyrazino[1,2-a]indole Synthesis, Festa A.A. et al, J. Org. Chem. 2018, 83, 9305-9311, a cycle formation scheme is described using the example of exposing a substituted indole to an alcohol in a catalytic system.
Известные способы синтеза не раскрывают способов получения соединений, описанных в настоящем изобретении.Known methods of synthesis do not disclose methods for obtaining the compounds described in the present invention.
Авторами был предложен уникальный способ, не известный ранее из уровня техники, который не был использован для синтеза соединений, согласно настоящему изобретению, включающих четыре конденсированных кольца. Полученные соединения могут быть интересны при поиске препаратов для лечения онкологических заболеваний.The authors proposed a unique method, not previously known from the prior art, which was not used for the synthesis of compounds according to the present invention, including four fused rings. The resulting compounds may be of interest in the search for drugs for the treatment of cancer.
Таким образом, технический результат настоящего изобретения состоит в разработке удобного способа получения производных тетразоло[5',1':3,4]пиразино[1,2-а]индола в результате катализируемой L-пролином реакции N-(пропаргил)индол-2-карбонитрилов с азидом натрия. Технический результат достигается тем, что способ получения производных тетразоло[5',1':3,4]пиразино[1,2-а]индола, с общей структурной формулой:Thus, the technical result of the present invention is to develop a convenient method for obtaining tetrazolo[5',1':3,4]pyrazino[1,2-a]indole derivatives as a result of the L-proline catalyzed reaction of N-(propargyl)indole-2 -carbonitriles with sodium azide. The technical result is achieved by the fact that the method for obtaining tetrazolo[5',1':3,4]pyrazino[1,2-a]indole derivatives, with the general structural formula:
заключается в том, что на различно замещенные N-(пропаргил)индол-2-карбонитрилы действуют азидом натрия в ДМФА в присутствии пролина (30 мол. %), нагревают 15 часов при температуре 130°С и получают тетразоло[5',1':3,4]пиразино[1,2-а]индолы (1-3). Вещества выделяют фильтрованием, промывают спиртом и сушат на воздухе.is that variously substituted N-(propargyl)indole-2-carbonitriles are treated with sodium azide in DMF in the presence of proline (30 mol.%), heated for 15 hours at a temperature of 130°C and tetrazolo[5',1' :3,4]pyrazino[1,2-a]indoles (1-3). Substances are isolated by filtration, washed with alcohol and dried in air.
Таким образом, предложенный способ позволяет получить тетразоло[5',1':3,4]пиразино[1,2-a]индолы 1-3.Thus, the proposed method makes it possible to obtain tetrazolo[5',1':3,4]pyrazino[1,2-a]indoles 1-3.
Способ осуществляется следующим образом.The method is carried out as follows.
К раствору 0.5 ммоль N-(пропаргил)индол-2-карбонитрила (4-6) в 4 мл ДМФА добавляют 0.75 ммоль азида натрия и 0.15 ммоль L-пролина. Смесь нагревают до 130°С при перемешивании 15 часов. После завершения реакции, растворитель упаривают на ротационном испарителе при пониженном давлении. Остаток затирают в воде, отфильтровывают и промывают водой, а затем метанолом (1 мл × 3 р.). Сушат на воздухе.To a solution of 0.5 mmol of N-(propargyl)indole-2-carbonitrile (4-6) in 4 ml of DMF, 0.75 mmol of sodium azide and 0.15 mmol of L-proline are added. The mixture is heated to 130°C with stirring for 15 hours. After completion of the reaction, the solvent is evaporated on a rotary evaporator under reduced pressure. The residue is triturated in water, filtered and washed with water and then with methanol (1 ml x 3 times). Air dry.
Выходы тетразоло[5',1':3,4]пиразино[1,2-a]индолов 1-3 колеблются от 32% до 45%.The yields of tetrazolo[5',1':3,4]pyrazino[1,2-a]indoles 1-3 range from 32% to 45%.
Строение полученных соединений подтверждено методами масс-спектрометрии, ИК спектроскопии и спектроскопии ЯМР на ядрах 1Н и 13С.The structure of the compounds obtained was confirmed by mass spectrometry, IR spectroscopy, and NMR spectroscopy on 1 H and 13 C nuclei.
Пример №1Example #1
К раствору 90 мг (0.5 ммоль) N-(пропаргил)индол-2-карбонитрила (4) в 4 мл ДМФА добавляют 49 мг (0.75 ммоль) азида натрия и 17 мг (0.15 ммоль) L-пролина. Смесь нагревают до 130°С при перемешивании 15 часов. После завершения реакции, растворитель упаривают на ротационном испарителе при пониженном давлении. Остаток затирают в воде, отфильтровывают и промывают водой, а затем метанолом (1 мл × 3 р.). Сушат на воздухе. Получают 36 мг вещества 1 в виде бежевого порошка.To a solution of 90 mg (0.5 mmol) of N-(propargyl)indole-2-carbonitrile (4) in 4 ml of DMF was added 49 mg (0.75 mmol) of sodium azide and 17 mg (0.15 mmol) of L-proline. The mixture is heated to 130°C with stirring for 15 hours. After completion of the reaction, the solvent is evaporated on a rotary evaporator under reduced pressure. The residue is triturated in water, filtered and washed with water and then with methanol (1 ml x 3 times). Air dry. 36 mg of compound 1 are obtained in the form of a beige powder.
5-Метилтетразоло[5',1':3,4]пиразино[1,2-а]индол (1): выход 32%, бежевый порошок с т.пл. >250°С, ИК спектр (в ICBr): 3084, 3032, 2960, 2923, 1669, 1601, 1500, 1484, 1447, 1325, 1252, 1217, 1089, 1036, 985, 866, 847, 793 см-1. 1H ЯМР (ДМСО-d6, 600 МГц): δ=2.69 (с, 3Н), 7.42 (т, J=7.9, Ш), 7.51 (т, J=7.7, 1Н), 7.60 (с, 1Н), 7.93 (д, J=8.0, 1Н), 8.19 (д, J=8.0, 1H), 8.64 (с, 1Н). 13С NMR (ДМСО-d6, 100 МГц): δС ppm=14.2, 99.8, 111.9, 113.4, 116.5, 120.7, 122.4, 123.7, 124.4, 128.1, 132.2, 144.1. Масс-спектр, m/z: 224 [М+Н]+. C12H9N5: Вычислено, %: С 64.56, Н 4.06, N 31.37; найдено, %: С 64.60, Н 4.08, N 31.40.5-Methyltetrazolo[5',1':3,4]pyrazino[1,2-a]indole (1): 32% yield, beige powder, m.p. >250°С, IR spectrum (in ICBr): 3084, 3032, 2960, 2923, 1669, 1601, 1500, 1484, 1447, 1325, 1252, 1217, 1089, 1036, 985, 866, 847, 793 cm -1 . 1 H NMR (DMSO-d 6 , 600 MHz): δ=2.69 (s, 3H), 7.42 (t, J=7.9, W), 7.51 (t, J=7.7, 1H), 7.60 (s, 1H) , 7.93 (d, J=8.0, 1H), 8.19 (d, J=8.0, 1H), 8.64 (s, 1H). 13 C NMR (DMSO-d 6 , 100 MHz): δ C ppm=14.2, 99.8, 111.9, 113.4, 116.5, 120.7, 122.4, 123.7, 124.4, 128.1, 132.2, 144.1. Mass spectrum, m/z: 224 [M+H] + . C 12 H 9 N 5 : Calculated, %: C 64.56, H 4.06, N 31.37; found, %: С 64.60, Н 4.08, N 31.40.
Пример №2.Example #2.
К раствору 97 мг (0.5 ммоль) 5-метил-N-(пропаргил)индол-2-карбонитрила (5) в 4 мл ДМФА добавляют 49 мг (0.75 ммоль) азида натрия и 17 мг (0.15 ммоль) L-пролина. Смесь нагревают до 130°С при перемешивании 15 часов. После завершения реакции, растворитель упаривают на ротационном испарителе при пониженном давлении. Остаток затирают в воде, отфильтровывают и промывают метанолом (1 мл × 3 р.). Сушат на воздухе. Получают 53 мг вещества 2 в виде бежевого порошка.To a solution of 97 mg (0.5 mmol) of 5-methyl-N-(propargyl)indole-2-carbonitrile (5) in 4 ml of DMF was added 49 mg (0.75 mmol) of sodium azide and 17 mg (0.15 mmol) of L-proline. The mixture is heated to 130°C with stirring for 15 hours. After completion of the reaction, the solvent is evaporated on a rotary evaporator under reduced pressure. The residue is triturated in water, filtered off and washed with methanol (1 ml x 3 times). Air dry. 53 mg of compound 2 are obtained in the form of a beige powder.
5,10-Диметилтетразоло[5',1':3,4]пиразино[1,2-а]индол (2): выход 45%, бежевый порошок с т.пл. >250°С, ИК спектр (в KBr): 3083, 3030, 2960, 2923, 1670, 1601, 1501, 1484, 1446, 1252, 1218, 1090, 1036, 985, 866, 846, 794 см-1. 1Н ЯМР (ДМСО-d6, 600 МГц): δ=2.48 (с, 3Н), 2.69 (с, 1Н), 7.35 (д, J=8.6, 1Н), 7.52 (с, 1Н), 7.70 (с, 1Н), 8.09 (д, J=8.6, 1Н), 8.61 (с, 1Н). 13С NMR (ДМСО-d6, 100 МГц): δС ppm=14.6, 16.9, 99.6, 111.8, 115.11, 116.5, 120.7, 122.4, 123.7, 124.6, 128.1, 137.2, 142.4. Масс-спектр, m/z: 238 [М+Н]+. C13H11N5: Вычислено, %: С 65.81, Н 4.67, N 29.52; найдено, %: С 65.76, Н 4.69, N 29.48.5,10-Dimethyltetrazolo[5',1':3,4]pyrazino[1,2-a]indole (2): 45% yield, beige powder, m.p. >250°С, IR spectrum (in KBr): 3083, 3030, 2960, 2923, 1670, 1601, 1501, 1484, 1446, 1252, 1218, 1090, 1036, 985, 866, 846, 794 cm -1 . 1 H NMR (DMSO-d 6 , 600 MHz): δ=2.48 (s, 3H), 2.69 (s, 1H), 7.35 (d, J=8.6, 1H), 7.52 (s, 1H), 7.70 (s , 1H), 8.09 (d, J=8.6, 1H), 8.61 (s, 1H). 13 C NMR (DMSO-d 6 , 100 MHz): δ C ppm=14.6, 16.9, 99.6, 111.8, 115.11, 116.5, 120.7, 122.4, 123.7, 124.6, 128.1, 137.2, 142.4. Mass spectrum, m/z: 238 [M+H] + . C 13 H 11 N 5 : Calculated, %: C 65.81, H 4.67, N 29.52; found, %: С 65.76, Н 4.69, N 29.48.
Пример №3Example #3
К раствору 107 мг (0.5 ммоль) 5-хлор-N-(пропаргил)индол-2-карбонитрила (6) в 4 мл ДМФА добавляют 49 мг (0.75 ммоль) азида натрия и 17 мг (0.15 ммоль) L-пролина. Смесь нагревают до 130°С при перемешивании 15 часов.To a solution of 107 mg (0.5 mmol) of 5-chloro-N-(propargyl)indole-2-carbonitrile (6) in 4 ml of DMF was added 49 mg (0.75 mmol) of sodium azide and 17 mg (0.15 mmol) of L-proline. The mixture is heated to 130°C with stirring for 15 hours.
После завершения реакции, растворитель упаривают на ротационном испарителе при пониженном давлении. Остаток затирают в воде, отфильтровывают и промывают метанолом (1 мл × 3 р.). Сушат на воздухе. Получают 48 мг вещества 3 в виде бежевого порошка.After completion of the reaction, the solvent is evaporated on a rotary evaporator under reduced pressure. The residue is triturated in water, filtered off and washed with methanol (1 ml x 3 times). Air dry. 48 mg of compound 3 are obtained in the form of a beige powder.
5-метил-10-хлортетразоло[5',1':3,4]пиразино[1,2-а]индол (3): выход 37%, бежевый порошок с т.пл. >250°С, ИК спектр (в KBr): 3084, 3032, 2961, 2924, 1670,1603,1500,1447,1325,1252,1217,1089,1036, 985, 866, 847, 793, 722 см-1. 1Н ЯМР (ДМСО-d6, 600 МГц): δ=2.73 (с, 3Н), 7.27 (д, J=8.1, 1Н), 7.55 (с, 1Н), 7.97 (с, 1Н), 8.09 (д, J=8.1, 1Н), 8.62 (с, 1Н). 13С NMR (ДМСО-d6, 100 МГц): δС ppm=19.5, 90.1,117.4,117.6, 120.5,121.9, 122.0, 123.6, 123.6,126.3, 137.5, 142.4. Масс-спектр, m/z: 258 [М+Н]+. C12H8ClN5: Вычислено, %: С 55.93, Н 3.13, N 27.18; найдено, %: С 55.99, Н 3.09, N 27.14.5-methyl-10-chlorotetrazolo[5',1':3,4]pyrazino[1,2-a]indole (3): 37% yield, beige powder, m.p. >250°С, IR spectrum (in KBr): 3084, 3032, 2961, 2924, 1670,1603,1500,1447,1325,1252,1217,1089,1036, 985, 866, 847, 793, 722 cm -1 . 1 H NMR (DMSO-d 6 , 600 MHz): δ=2.73 (s, 3H), 7.27 (d, J=8.1, 1H), 7.55 (s, 1H), 7.97 (s, 1H), 8.09 (d , J=8.1, 1H), 8.62 (s, 1H). 13 C NMR (DMSO-d 6 , 100 MHz): δ C ppm=19.5, 90.1,117.4,117.6, 120.5,121.9, 122.0, 123.6, 123.6,126.3, 137.5, 142.4. Mass spectrum, m/z: 258 [M+H] + . C 12 H 8 ClN 5 : Calculated, %: C 55.93, H 3.13, N 27.18; found, %: С 55.99, Н 3.09, N 27.14.
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| RU2575174C1 (en) * | 2015-03-12 | 2016-02-20 | федеральное государственное автономное образовательное учреждение высшего образования "Российский университет дружбы народов" (РУДН) | METHOD OF OBTAINING DERIVATIVES OF 5,6-DIHYDROPYRROLO[2,1-a]ISOQUINOLINES, WHICH CONTAIN FUNCTIONAL GROUP IN POSITION 2 |
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| RU2575174C1 (en) * | 2015-03-12 | 2016-02-20 | федеральное государственное автономное образовательное учреждение высшего образования "Российский университет дружбы народов" (РУДН) | METHOD OF OBTAINING DERIVATIVES OF 5,6-DIHYDROPYRROLO[2,1-a]ISOQUINOLINES, WHICH CONTAIN FUNCTIONAL GROUP IN POSITION 2 |
Non-Patent Citations (1)
| Title |
|---|
| Tsai C.-W., Yang S.-C, Liu, Y.-M., Wu M.-J. Microwave-assisted cycloadditions of 2-alkynylbenzonitriles with sodium azide: selective synthesis of tetrazolo[5,1-a]pyridines and 4,5-disubstituted-2H-1,2,3-triazoles. Tetrahedron Letters, Vol. 65, p. 8367-8372, 2009. Festa A.A. et al., DBU-Catalyzed Alkyne-Imidate Cyclization toward l-Alkoxypyrazino[1,2-a]indole Synthesis, J. Org. Chem., 83, 9305-9311, 2018. * |
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