RU2782194C1 - Method for preparation of 2,3,5,6-tetraalkylpyrazines - Google Patents
Method for preparation of 2,3,5,6-tetraalkylpyrazines Download PDFInfo
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- RU2782194C1 RU2782194C1 RU2021127043A RU2021127043A RU2782194C1 RU 2782194 C1 RU2782194 C1 RU 2782194C1 RU 2021127043 A RU2021127043 A RU 2021127043A RU 2021127043 A RU2021127043 A RU 2021127043A RU 2782194 C1 RU2782194 C1 RU 2782194C1
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- tetraalkylpyrazines
- ticl
- etalcl
- nitriles
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- 239000011777 magnesium Substances 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 7
- 239000000843 powder Substances 0.000 claims abstract description 5
- 230000003993 interaction Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000012300 argon atmosphere Substances 0.000 claims description 4
- 230000003197 catalytic Effects 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract 2
- 229910010068 TiCl2 Inorganic materials 0.000 abstract 1
- 230000002058 anti-hyperglycaemic Effects 0.000 abstract 1
- 230000000702 anti-platelet Effects 0.000 abstract 1
- 239000003146 anticoagulant agent Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 229940079593 drugs Drugs 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 102000015694 estrogen receptors Human genes 0.000 abstract 1
- 108010038795 estrogen receptors Proteins 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 150000003216 pyrazines Chemical class 0.000 description 4
- 230000003595 spectral Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- OSISQXHQGOYLNG-UHFFFAOYSA-N 2,3,5,6-tetrachloropyrazine Chemical compound ClC1=NC(Cl)=C(Cl)N=C1Cl OSISQXHQGOYLNG-UHFFFAOYSA-N 0.000 description 2
- FINHMKGKINIASC-UHFFFAOYSA-N TMPZ Chemical compound CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical class [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000006476 reductive cyclization reaction Methods 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- DWKJRIKJDAOXBV-UHFFFAOYSA-N 2,3,5,6-tetrabutylpyrazine Chemical compound CCCCC1=NC(CCCC)=C(CCCC)N=C1CCCC DWKJRIKJDAOXBV-UHFFFAOYSA-N 0.000 description 1
- OEDVLMOQTFMJCV-UHFFFAOYSA-N 2,3,5,6-tetraethylpyrazine Chemical compound CCC1=NC(CC)=C(CC)N=C1CC OEDVLMOQTFMJCV-UHFFFAOYSA-N 0.000 description 1
- ZPKCJXWKXAHCSX-UHFFFAOYSA-N 2,3,5,6-tetraphenylpyrazine Chemical compound C1=CC=CC=C1C1=NC(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)N=C1C1=CC=CC=C1 ZPKCJXWKXAHCSX-UHFFFAOYSA-N 0.000 description 1
- -1 2,3,5,6-tetrapropylpyrazine Chemical compound 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- ISAOCJYIOMOJEB-UHFFFAOYSA-N Benzoin Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 1
- 229960002130 Benzoin Drugs 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N Butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 229910052692 Dysprosium Inorganic materials 0.000 description 1
- 238000007006 Miyaura reaction Methods 0.000 description 1
- RFFFKMOABOFIDF-UHFFFAOYSA-N Pentanenitrile Chemical compound CCCCC#N RFFFKMOABOFIDF-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N Propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 240000008975 Styrax benzoin Species 0.000 description 1
- 235000000126 Styrax benzoin Nutrition 0.000 description 1
- 235000008411 Sumatra benzointree Nutrition 0.000 description 1
- 229910052775 Thulium Inorganic materials 0.000 description 1
- CTHFQDYUBRIODB-UHFFFAOYSA-L [I-].[I-].[Nd+2] Chemical class [I-].[I-].[Nd+2] CTHFQDYUBRIODB-UHFFFAOYSA-L 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000008359 benzonitriles Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-M chloride;hydrate Chemical class O.[Cl-] DKAGJZJALZXOOV-UHFFFAOYSA-M 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- KVXNKFYSHAUJIA-UHFFFAOYSA-M ethoxyethane;acetate Chemical compound CC([O-])=O.CCOCC KVXNKFYSHAUJIA-UHFFFAOYSA-M 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000019382 gum benzoic Nutrition 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910001510 metal chloride Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000005445 natural product Substances 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Abstract
Description
Предлагаемое изобретение относится к области органической химии, в частности, к новому способу получения 2,3,5,6-тетраалкилпиразинов формулы (1):The present invention relates to the field of organic chemistry, in particular, to a new method for obtaining 2,3,5,6-tetraalkylpyrazines of formula (1):
Пиразины входят в состав большого количества природных соединений ((а) О. Ceder In Methods of Organic Chemistry (Houben-Weyl); E. Schaumann, Ed.; Georg Thieme Stuttgart: New York, 1998; 9b/l, 250-259; (b) R. Muller, S. Rappert. Appl. Microbiol. Biotechnol. 2010, 85, 1315-1320; (с) M. Dolezal. Chem. Listy 2006, 100, 959-966) и представляют значительный интерес для фармакологии. Ряд пиразинов показал активность в качестве антитромбоцитарных ((a) A. Ohta, Н. Takahashi, N. Miyata, Н. Hirono, Т. Nishio, Е. Uchino, К. Yamada, Y. Aoyagi, Y. Suwabe, M. Fujitake, T. Suzuki, K. Okamoto. Biol. Pharm. Bull. 1997, 20, 1076-1081; (b) A. Nakamura, T. Yamada, T. Asaki. Bioorg. Med. Chem. 2007, 15, 7720-7725), антигипергликемических агентов (A. Goel, N. Agarwal, F.V. Singh, A. Sharon, P. Tiwari, M. Dixit, R. Pratap, A.K. Srivastava, P.R. Maulik, V.J. Ram. Bioorg. Med. Chem. Lett. 2004, 14, 1089-1092), а также регуляторов эстрогенновых рецепторов (U. Ghosh, D. Ganessunker, V.J. Sattigeri, K.E. Carlson, D.J. Mortensen, B.S. Katzenellenbogen, J.A. Katzenellenbogen. Bioorg. Med. Chem. 2003, 11, 629-657).Pyrazines are found in a large number of natural compounds ((a) O. Ceder In Methods of Organic Chemistry (Houben-Weyl); E. Schaumann, Ed.; Georg Thieme Stuttgart: New York, 1998; 9b/l, 250-259; (b) R. Muller, S. Rappert Appl Microbiol Biotechnol 2010, 85, 1315-1320 (c) M. Dolezal Chem Listy 2006, 100, 959-966) and are of considerable pharmacological interest. A number of pyrazines have shown antiplatelet activity ((a) A. Ohta, H. Takahashi, N. Miyata, H. Hirono, T. Nishio, E. Uchino, K. Yamada, Y. Aoyagi, Y. Suwabe, M. Fujitake (b) A. Nakamura, T. Yamada, T. Asaki Bioorg Med Chem 2007 15 7720- 7725), antihyperglycemic agents (A. Goel, N. Agarwal, F.V. Singh, A. Sharon, P. Tiwari, M. Dixit, R. Pratap, A.K. Srivastava, P.R. Maulik, V.J. Ram. Bioorg. Med. Chem. Lett. 2004, 14, 1089-1092), as well as regulators of estrogen receptors (U. Ghosh, D. Ganessunker, V. J. Sattigeri, K. E. Carlson, D. J. Mortensen, B. S. Katzenellenbogen, J. A. Katzenellenbogen. Bioorg. Med. Chem. 2003, 11, 629- 657).
Известен способ (A. Petrosyan, P. Ehlers, S. Reimann, T.V. Ghochikyan, A.S. Saghyan, A. Spannenberg, S. Lochbrunnere, P. Langer. Synthesis of tetraaryl-and tetraalkenylpyrazines by Suzukie-Miyaura reactions of tetrachloropyrazine. Tetrahedron 2015, 71, 6803-6812) 2,3,5,6-тетраарилпиразинов, путем взаимодействия тетрахлорпиразина с арилборной кислотой в присутствии фосфатов калия, катализируемый Pd(OAc)2/P(Cy)3 с выходом 50-99% по схеме:A known method (A. Petrosyan, P. Ehlers, S. Reimann, TV Ghochikyan, AS Saghyan, A. Spannenberg, S. Lochbrunnere, P. Langer. Synthesis of tetraaryl-and tetraalkenylpyrazines by Suzukie-Miyaura reactions of tetrachloropyrazine. Tetrahedron 2015, 71, 6803-6812) 2,3,5,6-tetraarylpyrazines, by reacting tetrachloropyrazine with arylboronic acid in the presence of potassium phosphates, catalyzed by Pd(OAc) 2 /P(Cy) 3 with a yield of 50-99% according to the scheme:
Известным способом не могут быть получены 2,3,5,6-тетраалкилпиразины формулы (1).The 2,3,5,6-tetraalkylpyrazines of formula (1) cannot be obtained by a known method.
Известен способ (M.V. Marques, М.М. Ruthner, L.A.M. Fontoura, D. Russowsky. Metal chloride hydrates as Lewis acid catalysts in multicomponent synthesis of 2,4,5-triarylimidazoles or 2,4,5-triaryloxazoles. J.Braz.Chem. Soc. 2012, 23, 171-179) получения тетрафенилпиразина, путем нагревания бензоина в этаноле в присутствии ацетата аммония и CeCl3⋅7H2O с выходом 87% по схеме:A known method (MV Marques, M.M. Ruthner, LAM Fontoura, D. Russowsky. Metal chloride hydrates as Lewis acid catalysts in multicomponent synthesis of 2,4,5-triarylimidazoles or 2,4,5-triaryloxazoles. J.Braz. Chem. Soc. 2012, 23, 171-179) obtaining tetraphenylpyrazine by heating benzoin in ethanol in the presence of ammonium acetate and CeCl 3 ⋅ 7H 2 O with a yield of 87% according to the scheme:
Известным способом не могут быть получены 2,3,5,6-тетраалкилпиразины формулы (1).The 2,3,5,6-tetraalkylpyrazines of formula (1) cannot be obtained by a known method.
Известен способ (Т.В. Балашова, Г.В. Хорошенков, Д.М. Кусаев, И.Л. Еременко, Г.Г. Александров, Г.К. Фукин, М.Н. Бочкарева. Реакции бензонитрилов с дийодидами неодима, диспрозия и тулия. Изв. АН, Сер. хим., 2004, 4, 789-793), получения арилзамещенных пиразинов взаимодействием солей лантанидов с бензонитрилом.A known method (T.V. Balashova, G.V. Khoroshenkov, D.M. Kusaev, I.L. Eremenko, G.G. Aleksandrov, G.K. Fukin, M.N. Bochkareva. Reactions of benzonitriles with neodymium diiodides , dysprosium, and thulium, Izv.
Известным способом не могут быть получены 2,3,5,6-тетраалкилпиразины формулы (1).The 2,3,5,6-tetraalkylpyrazines of formula (1) cannot be obtained by a known method.
Известен способ (Shaibakova, M.G., Khafizova, L.O., Dzhemilev U.M.. A New One-Pot Synthesis of Tetrasubstituted Pyrazines by the Ti-Catalyzed Reaction of Aromatic and Benzyl-Substituted Nitriles with EtAlC12. Chemistry Select 2018, 3, 11451-1145,). получения тетразамещенных пиразинов взаимодействием нитрилов с EtAlCl2 в присутствии магния (Mg, порошок), катализатора Cp2TiCl2 и BF3⋅Et2O, при температуре 20-22°C и атмосферном давлении. Время реакции 4-8 ч.A known method (Shaibakova, MG, Khafizova, LO, Dzhemilev UM. A New One-Pot Synthesis of Tetrasubstituted Pyrazines by the Ti-Catalyzed Reaction of Aromatic and Benzyl-Substituted Nitriles with EtAlC12. Chemistry Select 2018, 3, 11451-1145,) . obtaining tetrasubstituted pyrazines by the interaction of nitriles with EtAlCl 2 in the presence of magnesium (Mg, powder), catalyst Cp 2 TiCl 2 and BF 3 ⋅Et 2 O, at a temperature of 20-22°C and atmospheric pressure. Reaction time 4-8 hours.
Алкилнитрилы в указанную реакцию не вступают.Alkylnitriles do not enter into this reaction.
Известен способ (Wei-xing Chen, Jun-hu Zhang, Ming-yang Hu, Xiao-chun Wang. Low-valent titanium induced reductive cyclization of nitriles to symmetrically substituted tetraalkylpyrazines. Synthesis 1990, 8, 701-702) получения тетразамещенных пиразинов (1), восстановительной циклизацией нитрилов под действием низковалентного титана, генерируемого из TiCl4 и Zn в ТГФ, при температуре 65°C в течение 4-6 дней.There is a method (Wei-xing Chen, Jun-hu Zhang, Ming-yang Hu, Xiao-chun Wang. Low-valent titanium induced reductive cyclization of nitriles to symmetrically substituted tetraalkylpyrazines. Synthesis 1990, 8, 701-702) for obtaining tetrasubstituted pyrazines ( 1), reductive cyclization of nitriles under the action of low-valent titanium generated from TiCl 4 and Zn in THF at a temperature of 65°C for 4-6 days.
Известным способом могут быть получены 2,3,5,6-тетраалкилпиразины формулы (1).In a known manner, 2,3,5,6-tetraalkylpyrazines of formula (1) can be obtained.
Недостатки способа: длительное кипячение в течение 4-6 дней, требует использования стехиометрических количеств TiCl4 более низкие выхода целевых продуктов.The disadvantages of the method: prolonged boiling for 4-6 days, requires the use of stoichiometric amounts of TiCl 4 lower output of the target products.
Задачей изобретения является разработка нового эффективного способа получения 2,3,5,6-тетраалкилпиразинов.The objective of the invention is to develop a new efficient method for obtaining 2,3,5,6-tetraalkylpyrazines.
Сущность способа заключается во взаимодействии нитрилов общей формулы R-C≡N, (где R=СН3, С2Н5, С3Н7, С4Н9) с EtAlCl2 в присутствии магния (Mg, порошок) и катализатора Cp2TiCl2 и взятых в мольном соотношении R-C≡N : EtAlCl2 : Mg : Cp2TiCl2 = 10:(8-12):(8-12):(0.8-1.2), предпочтительно 10:10:10: 1 ммоль. Реакцию проводят в тетрагидрофуране, в атмосфере аргона при температуре 60-65°C и атмосферном давлении. Время реакции 12-18 ч. Целевые продукты 2,3,5,6-тетраалкилпиразины образуются с выходом 60-91%. Реакция протекает по схеме:The essence of the method lies in the interaction of nitriles of the general formula RC≡N, (where R=CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 ) with EtAlCl 2 in the presence of magnesium (Mg, powder) and catalyst Cp 2 TiCl 2 and taken in the molar ratio RC≡N : EtAlCl 2 : Mg : Cp 2 TiCl 2 = 10:(8-12):(8-12):(0.8-1.2), preferably 10:10:10: 1 mmol. The reaction is carried out in tetrahydrofuran, in an argon atmosphere at a temperature of 60-65°C and atmospheric pressure. Reaction time 12-18 hours Target products 2,3,5,6-tetraalkylpyrazines are formed with a yield of 60-91%. The reaction proceeds according to the scheme:
Целевые продукты (1) образуются только лишь с участием нитрилов, EtAlCl2, катализатора Cp2TiCl2 и магния. В присутствии, других металлов (например, Al, Cu, Fe) целевые продукты (1) не образуются.Target products (1) are formed only with the participation of nitriles, EtAlCl 2 , catalyst Cp 2 TiCl 2 and magnesium. In the presence of other metals (for example, Al, Cu, Fe), the target products (1) are not formed.
Изменение соотношения исходного нитрила в сторону увеличения его содержания по отношению к EtAlCl2 не приводит к существенному повышению выхода целевого продукта (1). Снижение количества EtAlCl2 или Mg по отношению к нитрилу уменьшает выход 2,3,5,6-тетраалкилпиразинов (1).Changing the ratio of the original nitrile in the direction of increasing its content with respect to EtAlCl 2 does not lead to a significant increase in the yield of the target product (1). Reducing the amount of EtAlCl 2 or Mg relative to the nitrile reduces the yield of 2,3,5,6-tetraalkylpyrazines (1).
Проведение указанной реакции в присутствии катализатора Cp2TiCl2 больше 2.2 ммолей приводит к образованию продуктов полимеризации и олигомеризации нитрилов и существенному уменьшению выхода целевых продуктов (1). Использование катализатора Cp2TiCl2 менее 1.8 ммолей снижает выход 2,3,5,6-тетраалкилпиразинов (1), что связано, возможно, со снижением каталитически активных центров в реакционной массе. Реакции проводили при температуре 60-65°C. При более высокой температуре (например, 80°C) увеличиваются энергозатраты на проведение процесса, при меньшей температуре (например, 20°C) реакция не идет.Conducting this reaction in the presence of a catalyst Cp 2 TiCl 2 more than 2.2 mmol leads to the formation of products of polymerization and oligomerization of nitriles and a significant decrease in the yield of target products (1). The use of a Cp 2 TiCl 2 catalyst of less than 1.8 mmol reduces the yield of 2,3,5,6-tetraalkylpyrazines (1), which is possibly associated with a decrease in catalytically active sites in the reaction mass. The reactions were carried out at a temperature of 60-65°C. At a higher temperature (for example, 80°C) the energy consumption for the process increases, at a lower temperature (for example, 20°C) the reaction does not proceed.
Существенные отличия предлагаемого способа:Significant differences of the proposed method:
В известном способе в качестве исходных реагентов используются нитрилы, TiCl4, Zn. Реакции проводят в ТГФ при перемешивании и нагревании от 4 до 6 дней. Выход тетраалкилпиразинов 44-63%.In a known method, nitriles, TiCl 4 , Zn are used as initial reagents. The reactions are carried out in THF with stirring and heating for 4 to 6 days. The yield of tetraalkylpyrazines is 44-63%.
Предлагаемый способ базируется на использовании в качестве исходных реагентов нитрилов (ацетонитрил, пропионитрил, бутиронитрил, валеронитрил), EtAlCl2, магния (Mg, порошок), катализатора Cp2TiCl2.The proposed method is based on the use of nitriles (acetonitrile, propionitrile, butyronitrile, valeronitrile), EtAlCl 2 , magnesium (Mg, powder), Cp 2 TiCl 2 catalyst as initial reagents.
Предлагаемый способ обладает следующими преимуществами:The proposed method has the following advantages:
В отличие от известного способа предлагаемый способ позволяет получать 2,3,5,6-тетралкилпиразины формулы (1) с высокими выходами за более короткое время (12-18)ч.In contrast to the known method, the proposed method makes it possible to obtain 2,3,5,6-tetralkylpyrazines of formula (1) with high yields in a shorter time (12-18) hours.
Способ поясняется следующими примерами:The method is illustrated by the following examples:
ПРИМЕР 1. В стеклянный реактор, установленный на магнитной мешалке, при охлаждении до 0°C, в атмосфере аргона помещают 15 мл тетрагидрофурана, 1.41 мл (10 ммолей) EtAlCl2, 0.24 г (10 ммоль) магния, 0.025 г (10 ммолей) катализатора Cp2TiCl2. Перемешивают при 0°C в течение 10-20 минут до появления зеленой окраски, после чего добавляют 0.41 г (10 ммоль) ацетонитрила. После нагревания при 60°C в течение 12-18 часов реакционную массу охлаждают в атмосфере аргона, добавляют 40 мл хлористого метилена и медленно в течение 6 ч добавляют 2-3 мл 10% раствора NaOH. Продукты реакции экстрагируют хлористым метиленом, сушат над прокаленным MgSO4 и упаривают растворитель. Целевой продукт выделяют колоночной хроматографией, элюент (петролейный эфир → петролейный эфир / этилацетат 20:1 → 10:1). Получают 2,3,5,6-тетрметилпиразин с выходом 91%.EXAMPLE 1. 15 ml of tetrahydrofuran, 1.41 ml (10 mmol) EtAlCl 2 , 0.24 g (10 mmol) magnesium, 0.025 g (10 mmol) are placed in a glass reactor mounted on a magnetic stirrer, while cooling to 0°C, in an argon atmosphere. catalyst Cp 2 TiCl 2 . The mixture is stirred at 0°C for 10-20 minutes until a green color appears, after which 0.41 g (10 mmol) of acetonitrile is added. After heating at 60°C for 12-18 hours, the reaction mass is cooled in an argon atmosphere, 40 ml of methylene chloride are added and 2-3 ml of 10% NaOH solution are added slowly over 6 hours. The reaction products are extracted with methylene chloride, dried over calcined MgSO 4 and the solvent is evaporated. The target product is isolated by column chromatography, eluent (petroleum ether → petroleum ether / ethyl acetate 20:1 → 10:1). Get 2,3,5,6-tetrmethylpyrazine with a yield of 91%.
Спектральные характеристики 2,3,5,6-тетраметилпиразина.Spectral characteristics of 2,3,5,6-tetramethylpyrazine.
Спектр ЯМР [Н, CDCl3, δ, м.д.: 2,71 (s, 12Н, СН3).NMR spectrum [H, CDCl 3 , δ, ppm: 2.71 (s, 12H, CH 3 ).
Спектр ЯМР 13С, δ, м.д.: 21.28, 148.17.13C NMR spectrum, δ, ppm: 21.28 , 148.17.
Примеры 2-12 выполнены аналогично примеру 1 и их результаты приведены в таблице.Examples 2-12 performed similarly to example 1 and their results are shown in the table.
Реакции проводили при температуре 60-65°C в тетрагидрофуране.The reactions were carried out at a temperature of 60-65°C in tetrahydrofuran.
Спектральные характеристики 2,3,5,6-тетраэтилпиразина.Spectral characteristics of 2,3,5,6-tetraethylpyrazine.
Спектр ЯМР 1Н, CDCl3, δ, м.д.: 1.26 (т, 12Н, СН3, J=8 Гц), 2,78 (кв, 8Н, СН2, J=8 Гц.1H NMR spectrum , CDCl 3 , δ, ppm: 1.26 (t, 12H, CH 3 , J=8 Hz), 2.78 (q, 8H, CH 2 , J=8 Hz.
Спектр ЯМР 13С, δ, м.д.: 13.57, 27.18, 152.24. 13С NMR spectrum, δ, ppm: 13.57, 27.18, 152.24.
Спектральные характеристики 2,3,5,6-тетрапропилпиразина.Spectral characteristics of 2,3,5,6-tetrapropylpyrazine.
Спектр ЯМР 1Н, CDCl3, δ, м.д.: 0.92 (т, 12Н, СН3, J=8 Гц), 1,67-2,11 (м, 8Н, СН2, 2,77 (т, 8Н, J=8,4 Гц.1Н NMR spectrum, CDCl 3 , δ, ppm: 0.92 (t, 12Н, CH 3 , J=8 Hz), 1.67-2.11 (m, 8Н, CH2, 2.77 (t, 8Н , J=8.4 Hz.
Спектр ЯМР 13С, δ, м.д.: 14.15, 22.70, 37.1, 152.44.13С NMR spectrum, δ, ppm: 14.15, 22.70, 37.1, 152.44.
Спектральные характеристики 2,3,5,6-тетрабутилпиразина.Spectral characteristics of 2,3,5,6-tetrabutylpyrazine.
Спектр ЯМР 1H, CDCl3, δ, м.д.: 0.99 (м, 12Н, СН3), 1,33-2,01 (м, 16Н, СН2, 2,70 (т, 8Н, J=8,6 Гц.1H NMR spectrum, CDCl 3 , δ, ppm: 0.99 (m, 12H, CH 3 ), 1.33-2.01 (m, 16H, CH 2 , 2.70 (t, 8H, J=8 .6 Hz.
Спектр ЯМР 13С, δ, м.д.: 14.10, 22.68, 32.1, 33.8, 151.92.13С NMR spectrum, δ, ppm: 14.10, 22.68, 32.1, 33.8, 151.92.
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| RU2672470C1 (en) * | 2017-07-10 | 2018-11-15 | Федеральное государственное бюджетное учреждение науки Институт нефтехимии и катализа Российской академии наук | Production process of 2,3,5,6-tetrafenyl(benzyl)pyrasine |
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| RU2672470C1 (en) * | 2017-07-10 | 2018-11-15 | Федеральное государственное бюджетное учреждение науки Институт нефтехимии и катализа Российской академии наук | Production process of 2,3,5,6-tetrafenyl(benzyl)pyrasine |
Non-Patent Citations (1)
| Title |
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| Wei-xing Chen, Jun-hu Zhang, Ming-yang Hu, Xiao-chun Wang. Low-valent titanium induced reductive cyclization of nitriles to symmetrically substituted tetraalkylpyrazines, Synthesis, 8, 701-702, 1990. Shaibakova, M.G., Khafizova, L.O., Dzhemilev U.M. A New One-Pot Synthesis of Tetrasubstituted Pyrazines by the Ti-Catalyzed Reaction of Aromatic and Benzyl-Substituted Nitriles with EtAlC12. Chemistry SelectGeorg Frey et al, Titanium-Catalyzed Reductive Umpolung Reactions with a Metal-Free Terminal Reducing Agent, Chem. Eur. J., 21, 1 - 5, 2015, 3, 11451-1145, 2018. Georg Frey et al. Titanium-Catalyzed Reductive Umpolung Reactions with a Metal-Free Terminal Reducing Agent, Chem. Eur. J., 21, 1-5, 2015. * |
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