CN109232592B - Synthetic method of benzofuran [2,3-b ] pyrazine derivative - Google Patents

Synthetic method of benzofuran [2,3-b ] pyrazine derivative Download PDF

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CN109232592B
CN109232592B CN201811128003.8A CN201811128003A CN109232592B CN 109232592 B CN109232592 B CN 109232592B CN 201811128003 A CN201811128003 A CN 201811128003A CN 109232592 B CN109232592 B CN 109232592B
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潘英明
唐海涛
王毛锐
邓黎
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Guangxi Normal University
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses benzofuran [2,3-b ]]Taking o-halogen phenol and benzylisonitrile as raw materials, adding 0.2 mmol of o-halogen phenol and 0.3 mmol of benzylisonitrile into a sealed tube, then adding 2 mol% of palladium catalyst, 2-3 times of potassium salt and 1 ml of solvent, reacting for 6-12 h at 100 ℃ and 150 ℃, and monitoring the reaction by TLC; cooling to room temperature after the reaction is completed, filtering, and finally adding anhydrous Na2SO4Drying, removing solvent under reduced pressure, purifying the residue with rapid silica gel column chromatography to obtain benzofuran [2,3-b ]]Pyrazine compound products. In this reaction, the palladium catalyst shows high catalytic activity and recyclability. The method has the advantages of simple operation, easily obtained raw materials, few reaction steps, high yield and wide application prospect, and is suitable for industrial production.

Description

Synthetic method of benzofuran [2,3-b ] pyrazine derivative
Technical Field
The invention relates to a synthesis method of a pyrazine derivative, in particular to a synthesis method of a benzofuran [2,3-b ] pyrazine derivative.
Background
Benzofuran [2,3-b ]]Pyrazines are a class of compounds with significant pharmacological activity. Benzofuran [3,2-d ]]Derivatives were found to be potent histamine H4 modulators (2006050965, 2006.). Benzofuran [3,2-d ]]Pyrimidine derivatives are novel inhibitors of multi-target tyrosine kinases and are currently in phase I clinical trials (eur. j. med. chem. 2006, 41, 367-. However, with respect to benzofuran [2,3-b ]]Synthetic methods and pharmacological activities of pyrazine derivatives have been rarely studied. In the past decades, reference has been made to benzofuran [2,3-b ]]Pyrazine derivatives are synthesized by a few methods, mainly including the following two methods: (1) salicylaldehydeoDeprotonation of the methyloxime with sodium to anhydrous tetrahydrofuran by addition of the hydride, followed by treatment with 3-methylsulfonyl-1, 2, 4-triazine to give an intermediate product, which is finally refluxed in nitrobenzene and slowly consumed over the course of 3 days to give 8% of benzofuran [2,3-b ] as]Pyrazine derivatives (Tetrahedron, 1987, 43, 5159-. (2) 2, 3-twoChloro-5, 6-dicyanopyrazine was dissolved in 50 mL of toluene and heated, then a toluene solution of 3-dimethylaminophenol was added dropwise, and the mixture was refluxed for 24 hours to obtain the product (Organic Reaction, 1998, 53). And the existing synthesis of benzofuran [2,3-b ]]The pyrazine derivative approach requires multiple steps or pre-functionalization of the starting materials. Currently benzofuran [2,3-b ]]Synthetic methods and pharmacological activities of pyrazine derivatives have been rarely studied. Thus, synthetic benzofurans [2,3-b ] are obtained from readily available starting materials]A simple and efficient method for pyrazine derivatives is a very meaningful work, and research on the pharmacological activity thereof is highly desired.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing benzofuran [2,3-b ] pyrazine derivatives, which synthesizes the benzofuran [2,3-b ] pyrazine derivatives by taking o-halogen phenol and benzylisonitrile as raw materials under the action of a palladium catalyst.
The technical scheme for realizing the purpose of the invention is as follows:
a synthetic method of benzofuran [2,3-b ] pyrazine derivatives is disclosed, which has the following general formula:
Figure 176765DEST_PATH_IMAGE001
R1 = H, aryl, aliphatic;
R2 = aliphatic, aromatic;
wherein, the Pd catalyst is: pd NPs/POL-xanthphos as palladium nano polymer;
the sylvite is as follows: potassium carbonate, potassium phosphate, potassium acetate, etc.;
the solvent is as follows: n, N-dimethylformamide, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile, toluene, and the like.
The general synthetic method of the benzofuran [2,3-b ] pyrazine derivative comprises the following steps:
(1) adding 0.2 mmol of o-halogen phenol and 0.3 mmol of benzylisonitrile into a sealed tube, adding 2 mol% of Pd catalyst, 2-3 times of potassium salt (potassium carbonate, potassium phosphate, potassium acetate and the like) and 1 ml of solvent (N, N-dimethylformamide, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile, toluene and the like), reacting for 6-12 h at 100 ℃ and 150 ℃, and monitoring the reaction by TLC;
(2) cooling to room temperature after the reaction is completed, filtering, and finally adding anhydrous Na2SO4Drying, removing solvent under reduced pressure, purifying the residue with rapid silica gel column chromatography to obtain benzofuran [2,3-b ]]Pyrazine derivatives.
The silica gel column is used for chromatography and purification, and the eluent is ethyl acetate, petroleum ether = 1: 100-200.
The structural formula of the benzofuran [2,3-b ] pyrazine derivative synthesized by the invention is as follows:
Figure 999227DEST_PATH_IMAGE002
Figure 203944DEST_PATH_IMAGE003
Figure 402844DEST_PATH_IMAGE004
。
nitrogen-containing heterocyclic compounds play an important role in modern organic chemistry, and they are widely found in many applications of natural products, drugs and material science with biological significance (chem. rev. 2012, 112, 3611-. Among the numerous nitrogen-containing polycyclic compounds, benzofuran [2,3-b ] pyrazine derivatives are common building blocks in drug candidates and biologically active compounds.
The present invention provides a novel method for synthesizing benzofuran [2,3-b ] pyrazine derivatives in which a palladium catalyst exhibits high catalytic activity and recyclability. The method has the advantages of simple operation, easily obtained raw materials, few reaction steps, high yield and wide application prospect, and is suitable for industrial production.
Drawings
FIG. 1 shows the general formula of the synthesis method of the present invention.
Detailed Description
The present invention will be further described with reference to the following figures and examples for the synthesis and product characterization of five benzofuran [2,3-b ] pyrazine derivatives, but is not limited thereto.
Example 1
Synthesis of 2, 3-diphenylbenzofuran [2,3-b ] pyrazine derivatives:
Figure 6476DEST_PATH_IMAGE005
referring to FIG. 1, 0.2 mmol (0.034 mg) of o-bromophenol and 0.3 mmol (37. mu.L) of benzylisonitrile were added to a lock tube, and 2 mol% Pd NPs/POL-xanthphos catalyst (15 mg), 2 times the amount of potassium carbonate (0.0637 mg) and 1 mL of N, N-dimethylformamide were added thereto, and the reaction was refluxed at 130 ℃ for 8 hours and monitored by TLC; cooling to room temperature after reaction is completed, filtering, and finally adding anhydrous Na2SO4Drying, removing solvent under reduced pressure, and purifying the residue with flash silica gel column chromatography (ethyl acetate: petroleum ether = 1: 120) to obtain yellow solid 1a 82.2 mg with yield of 85% (mp 208-210)oC）；
1H NMR (400 MHz, CDCl3) δ8.29 (d, 1H), 7.70 - 7.61 (m, 2H ), 7.53 - 7.46 (m, 5H), 7.37 - 7.30 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 156.90, 155.95, 149.63, 148.67, 139.17, 138.46, 135.53, 130.38, 130.14, 130.03, 128.55, 128.29, 128.25, 128.12, 124.21, 122.10, 121.73, 112.61, 77.32, 77.00, 76.68; HRES (m/z) (ESI): calcd for C22H15N2O [M+H]+ 323.1184, found 323.1184。
Example 2
Synthesis of 9-methyl-2, 3-diphenyl benzofuran [2,3-b ] pyrazine derivative:
Figure 999840DEST_PATH_IMAGE006
referring to FIG. 1, 0.2 mmol (0.037 mg) of 2 bromo-3 methylphenol and 0.3 mmol (37. mu.L) of benzylisonitrile were added to the tube,2 mol% Pd NPs/POL-xanthphos (15 mg), 2.1 times amount of potassium phosphate (0.0669 mg) and 1 ml of 1, 2-dichloroethane, refluxing at 100 ℃ for 8 h, and monitoring the reaction by TLC; cooling to room temperature after reaction is completed, filtering, and finally adding anhydrous Na2SO4Drying, removing solvent under reduced pressure, and purifying the residue with flash silica gel column chromatography (ethyl acetate: petroleum ether = 1: 150) to obtain yellow solid 2a 79.7 mg with 79% yield (mp 181-183)oC）；
1H NMR (400 MHz, CDCl3) δ 7.52 - 7.46 (m, 6H), 7.31 - 7.27 (m, 6H), 7.22 (S, 1H), 2.95 (S, 3H); 13C NMR (101 MHz, CDCl3) δ 157.01, 155.73, 149.17, 149.10, 147.63, 139.43, 138.82, 136.92, 136.29, 130.24, 130.17, 130.03, 128.48, 128.19, 128.15, 125.25, 120.39, 109.67, 77.32, 77.00, 76.68, 18.77; HRES (m/z) (ESI): calcd forC23H17N2O [M+H]+ 337.1341, found 337.1330。
Example 3
Synthesis of 2, 3-diphenyl-8- (trifluoromethyl) benzofuro [2,3-b ] pyrazine derivatives:
Figure 691852DEST_PATH_IMAGE007
referring to FIG. 1, 0.2 mmol (0.048 mg) of 2-bromo-4- (trifluoromethyl) phenol and 0.3 mmol (37. mu.L) of benzylisonitrile, 2 mol% Pd NPs/POL-xanthphos (15 mg), 2.3 times the amount of potassium phosphate (0.0732 mg) and 1 ml of 1, 4-dioxane were added to a sealed tube, refluxed at 140 ℃ for 8 hours, and the reaction was monitored by TLC; cooling to room temperature after reaction is completed, filtering, and finally adding anhydrous Na2SO4Drying, removing solvent from the product under reduced pressure, and purifying the residue by flash silica gel column chromatography (ethyl acetate: petroleum ether = 1: 130) to obtain yellow solid 3a 83.1 mg with yield of 71% (mp 144-145)oC）；
1H NMR (500 MHz, CDCl3) δ 8.61 (s, 1H), 7.91 (d, 1H), 7.81 (d, 1H), 7.52 – 7.49 (m, 4H), 7.37 – 7.33 (m, 6H); 13C NMR (126 MHz, CDCl3) δ 158.08, 156.55, 150.67, 150.03, 138.78, 138.12, 134.48, 130.16, 129.98, 128.95, 128.57, 128.42, 128.27, 127.21, 126.92, 125.11, 122.95, 122.57, 122.20, 119.91, 113.29, 77.25, 77.00, 76.75; HRES (m/z) (ESI): calcd for C23H14F3N2O [M+H]+ 391.1098, found 391.1051。
Example 4
Synthesis of 2, 3-diphenylbenzo [4,5] thieno [2,3-b ] pyrazine derivatives:
Figure 428864DEST_PATH_IMAGE008
referring to FIG. 1, 0.2 mmol (0.038 mg) of 2-bromophenylthiol and 0.3 mmol (37. mu.L) of benzylisonitrile, 2 mol% Pd NPs/POL-xanthphos (15 mg), 2.2 times the amount of potassium phosphate (0.070 mg) and 1 ml of acetonitrile were added to a sealed tube, and the reaction was refluxed at 150 ℃ for 8 hours and monitored by TLC; cooling to room temperature after reaction is completed, filtering, and finally adding anhydrous Na2SO4Drying, removing solvent under reduced pressure, and purifying the residue with flash silica gel column chromatography (ethyl acetate: petroleum ether = 1: 140) to obtain yellow solid 4a 22.3 mg with yield of 22% (mp 290-291)oC）；
1H NMR (400 MHz, CDCl3) δ 8.54 (d, 1H), 7.90 (d, 1H), 7.63 - 7.51 (m, 6H), 7.35 (t, 6H); 13C NMR (101 MHz, CDCl3) δ 154.47, 150.70, 149.69, 144.64, 139.40, 139.03, 138.86, 131.93, 130.09, 129.96, 129.33, 128.60, 128.47, 128.25, 125.44, 123.73, 123.33, 77.32, 77.00, 76.68; HRES (m/z) (ESI): calcd forC22H15N2S [M+H]+ 339.0956, found 339.0950。
Example 5
Synthesis of 2, 3-dipropylbenzofuran [2,3-b ] pyrazine derivative:
Figure 889933DEST_PATH_IMAGE009
referring to FIG. 1, 0.2 mmol (0.026 mg) of o-chlorophenol and 0.3 mmol (32. mu.L) of n-butylisonitrile, 2 mol% Pd NPs/POL-xanthphos (15 mg), 2.5 times the amount of potassium phosphate (0.079 mg) and 1 mL of toluene were added to a lock tube, refluxed at 120 ℃ for 8 hours, and the reaction was monitored by TLC; cooling to room temperature after reaction is completed, filtering, and finally adding anhydrous Na2SO4Drying, removing solvent under reduced pressure, and purifying the residue with flash silica gel column chromatography (ethyl acetate: petroleum ether = 1: 180) to obtain yellow oil 5a 27.4mg, yield 36%;
1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.61 - 7.52 (m, 2H), 7.41 (t, 1H), 2.98 - 2.90 (m, 4H), 1.88 - 1.08 (m, 4H), 1.08 - 1.0 3 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 155.90, 155.64, 151.58, 151.55, 134.00, 129.41, 123.76, 122.02, 121.38, 112.40, 77.32, 77.00, 76.68, 36.60, 36.55, 23.01, 22.36, 14.10, 14.03; HRES (m/z) (ESI): calcd for C16H19N2O [M+H]+ 255.1497, found 255.1494。

Claims (3)

1. a synthesis method of pyrazine derivatives is characterized in that the general formula of the synthesis method is as follows:
Figure 894187DEST_PATH_IMAGE001
R1 = H, aryl, aliphatic;
R2 = aliphatic, aromatic;
wherein, the Pd catalyst is: pd NPs/POL-xanthphos;
the sylvite is as follows: potassium carbonate, potassium phosphate, potassium acetate;
the solvent is as follows: n, N-dimethylformamide, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile and toluene;
the synthesis method of the pyrazine derivative comprises the following steps:
(1) adding 0.2 mmol of o-halogen phenol or o-halogen thiophenol and 0.3 mmol of isonitrile into a sealed tube, adding 2 mol% of palladium catalyst, 2-3 times of potassium salt and 1 ml of solvent, reacting for 6-12 h at the temperature of 100 ℃ and 150 ℃, and monitoring the reaction by TLC;
(2) cooling to room temperature after the reaction is completed, filtering, and finally adding anhydrous Na2SO4Drying, removing the solvent from the product under reduced pressure, and purifying the residue by a rapid silica gel column chromatography to obtain the pyrazine derivative product.
2. A method for synthesizing pyrazine derivatives according to claim 1, which comprises the following steps: and (3) performing purification by using the flash silica gel column chromatography in the step (2), wherein an eluent is ethyl acetate and petroleum ether = 1: 100-.
3. A method for synthesizing pyrazine derivatives according to claim 1, which comprises the following steps: the structural formula of the pyrazine derivative obtained in the step (2) is as follows:
Figure 481026DEST_PATH_IMAGE002
Figure 704197DEST_PATH_IMAGE003
Figure 785416DEST_PATH_IMAGE004
。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105884786A (en) * 2016-05-13 2016-08-24 苏州大学 Benzofuran [2,3-b ] pyrazine derivative and application thereof in organic electroluminescent device
WO2018122664A1 (en) * 2016-12-28 2018-07-05 Semiconductor Energy Laboratory Co., Ltd. Light-emitting element, organic compound, light-emitting device, electronic device, and lighting device

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JPH07247288A (en) * 1994-03-10 1995-09-26 Takasago Internatl Corp 2,3-dicyanobenzofuro(2,3-b)pyrazine derivative and method for production the same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105884786A (en) * 2016-05-13 2016-08-24 苏州大学 Benzofuran [2,3-b ] pyrazine derivative and application thereof in organic electroluminescent device
WO2018122664A1 (en) * 2016-12-28 2018-07-05 Semiconductor Energy Laboratory Co., Ltd. Light-emitting element, organic compound, light-emitting device, electronic device, and lighting device

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Heterodienophilic intramolecular Diels-Alder reactions of 1,2,4-triazines. Synthesis of novel polycyclic condensed pyrazines and lumazines;EDWARD C. TAYLOR，等;《Tetrahedron》;19871231;第43卷(第21期);第5159-5168页 *

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