CN113943257A - Synthesis method and application of photocatalytic C-3-position alkyl substituted quinoxaline-2 (1H) -ketone compound - Google Patents
Synthesis method and application of photocatalytic C-3-position alkyl substituted quinoxaline-2 (1H) -ketone compound Download PDFInfo
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- CN113943257A CN113943257A CN202111040645.4A CN202111040645A CN113943257A CN 113943257 A CN113943257 A CN 113943257A CN 202111040645 A CN202111040645 A CN 202111040645A CN 113943257 A CN113943257 A CN 113943257A
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- 125000000217 alkyl group Chemical group 0.000 title claims abstract description 38
- 230000001699 photocatalysis Effects 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 137
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000003513 alkali Substances 0.000 claims abstract description 15
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 13
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 12
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 10
- 239000011261 inert gas Substances 0.000 claims abstract description 10
- 238000007146 photocatalysis Methods 0.000 claims abstract description 10
- 239000011941 photocatalyst Substances 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 171
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 110
- 229910052757 nitrogen Inorganic materials 0.000 claims description 55
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 54
- 239000000047 product Substances 0.000 claims description 54
- 239000000741 silica gel Substances 0.000 claims description 54
- 229910002027 silica gel Inorganic materials 0.000 claims description 54
- 239000002904 solvent Substances 0.000 claims description 34
- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical compound C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 claims description 33
- 239000012043 crude product Substances 0.000 claims description 31
- 239000008367 deionised water Substances 0.000 claims description 31
- 229910021641 deionized water Inorganic materials 0.000 claims description 31
- 238000000605 extraction Methods 0.000 claims description 31
- 239000007791 liquid phase Substances 0.000 claims description 31
- 238000005191 phase separation Methods 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000000543 intermediate Substances 0.000 claims description 28
- 239000000284 extract Substances 0.000 claims description 27
- PRWATGACIORDEL-UHFFFAOYSA-N 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile Chemical compound C12=CC=CC=C2C2=CC=CC=C2N1C1=C(C#N)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C(N2C3=CC=CC=C3C3=CC=CC=C32)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C1C#N PRWATGACIORDEL-UHFFFAOYSA-N 0.000 claims description 21
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 230000002194 synthesizing effect Effects 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- -1 quinoxaline-2 (1H) -one compound Chemical class 0.000 claims description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 229960002477 riboflavin Drugs 0.000 claims description 9
- 235000019192 riboflavin Nutrition 0.000 claims description 9
- 239000002151 riboflavin Substances 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 230000027756 respiratory electron transport chain Effects 0.000 claims description 6
- 208000007101 Muscle Cramp Diseases 0.000 claims description 5
- 208000009205 Tinnitus Diseases 0.000 claims description 5
- 239000005557 antagonist Substances 0.000 claims description 5
- 230000002490 cerebral effect Effects 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000001678 irradiating effect Effects 0.000 claims description 5
- 210000002460 smooth muscle Anatomy 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 231100000886 tinnitus Toxicity 0.000 claims description 5
- 108010061711 Gliadin Proteins 0.000 claims description 4
- 230000001093 anti-cancer Effects 0.000 claims description 4
- 230000000840 anti-viral effect Effects 0.000 claims description 4
- 150000002611 lead compounds Chemical class 0.000 claims description 4
- 229930014626 natural product Natural products 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000012216 screening Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 238000007259 addition reaction Methods 0.000 claims description 3
- 150000001336 alkenes Chemical class 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 230000005283 ground state Effects 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 238000003760 magnetic stirring Methods 0.000 claims description 3
- 230000007246 mechanism Effects 0.000 claims description 3
- 238000013508 migration Methods 0.000 claims description 3
- 230000005012 migration Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 3
- 238000006053 organic reaction Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 abstract description 4
- 238000005804 alkylation reaction Methods 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 238000010189 synthetic method Methods 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 239000003480 eluent Substances 0.000 description 26
- 238000001819 mass spectrum Methods 0.000 description 26
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- 239000000203 mixture Substances 0.000 description 25
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 3
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- 229910001868 water Inorganic materials 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Abstract
The invention relates to the technical field of a synthesis method of quinoxaline-2 (1H) -ketone compounds, in particular to a synthesis method and application of a photocatalysis C-3 site alkyl substituted quinoxaline-2 (1H) -ketone compound. Quinoxaline-2 (1H) -ketone and derivatives thereof and substituted sulfonium salt are taken as raw materials, an organic photosensitizer is taken as a photocatalyst, at least one carbonate or nitrogen-containing organic alkali is taken as alkali under the conditions of inert gas environment and normal temperature, and near blue light is adopted to irradiate reaction liquid to synthesize the quinoxaline-2 (1H) -ketone compound substituted by C-3 alkyl. The synthetic method has simple preparation process and device, takes near blue light as energy, has mild reaction conditions, and is green and environment-friendly; as the synthesis method is the direct alkylation of the C-3 position, complex pretreatment is not needed, and the environment-friendly concept of green chemistry and atom economy is met.
Description
Technical Field
The invention relates to the technical field of a synthesis method of quinoxaline-2 (1H) -ketone compounds, in particular to a synthesis method and application of a photocatalysis C-3 site alkyl substituted quinoxaline-2 (1H) -ketone compound.
Background
Quinoxaline-2 (1H) -ketone is an important nitrogen-containing heterocyclic unit, and is widely applied to the fields of medicines, natural products and material industries due to excellent chemical characteristics and strong biological activity, so that the quinoxaline-2 (1H) -ketone has a great application value. Wherein, the C-3 substituted quinoxaline-2 (1H) -ketone has unique pharmaceutical activity, and is often applied to the research and development of strong-effect medicaments, such as antitumor drugs, anti-inflammatory drugs, antidiabetics, cardiovascular drugs, weight-losing drugs and the like. As shown in FIG. 2, six commercially available drug molecules A-F are listed. At present, the application development of C-3 substituted quinoxaline-2 (1H) -ketone compounds and the research on the synthesis method thereof have attracted people's attention and become one of the research hotspots in recent years.
Recently, a number of methods for synthesizing C-3 substituted quinoxalin-2 (1H) -ones have been reported, including arylation, acylation, alkoxylation, trifluoromethylation, silylation, sulfinylation, phosphorylation, etherification, etc. of C-3 substituted quinoxalin-2 (1H) -ones. However, the C-H alkylation of quinoxalin-2 (1H) -ones is still rare. Due to the importance of the compounds in the field of medicinal chemistry, the development of a novel and efficient green synthesis method of C-3 alkyl substituted quinoxaline-2 (1H) -ketone is very necessary in the field of medicine research and development. The existing synthesis method of C-3 alkyl substituted quinoxaline-2 (1H) -ketone compounds usually has some disadvantages, such as the need of multi-step reaction, high reaction temperature, the need of metal catalyst, the need of pre-functionalization of substrate, narrow substrate range, relatively harsh or complex reaction conditions and the like. Therefore, the synthesis and application of the compounds are restricted to a certain extent, so that the screening requirement of active lead compounds in the development of new drugs is difficult to meet.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a synthesis method and application of a photocatalysis C-3 position alkyl substituted quinoxaline-2 (1H) -ketone compound, does not need harsh synthesis conditions, can synthesize various quinoxaline-2 (1H) -ketone C-3 position alkylated compounds and derivatives thereof in one step, and has higher universality on various functional groups.
The technical scheme adopted by the invention for realizing the purpose is as follows: a method for synthesizing a C-3 alkyl substituted quinoxaline-2 (1H) -ketone compound by photocatalysis uses quinoxaline-2 (1H) -ketone and derivatives thereof and substituted sulfonium salt as raw materials, an organic photosensitizer as a photocatalyst, and at least one carbonate or nitrogen-containing organic base as a base under the conditions of inert gas environment and normal temperature, and near blue light is adopted to irradiate a reaction solution to synthesize the C-3 alkyl substituted quinoxaline-2 (1H) -ketone compound.
Further, the general formula of the C-3-position alkyl substituted quinoxaline-2 (1H) -ketone compound is shown as a formula I; the general formula of the quinoxaline-2 (1H) -ketone and the derivative thereof is shown as a formula II; the general formula of the substituted sulfonium salt is shown as a formula III;
in the formula:
R1one selected from halogen, methyl and methoxy substituents;
R2one of hydrogen, trifluoromethoxy, alkyl, aryl, alcohol, olefin, ester group and natural product and drug molecule derivative substituent;
R3one selected from methyl or hydrogen;
R4one selected from halogen, methyl, methoxy, aryl, ester group or cyano substituent;
ar is selected from one of benzene ring or thiophene ring;
x is selected from PF6Or BF4One kind of (1).
Further, the synthesis method comprises the following steps:
(1) at room temperature, adding substituted quinoxaline-2 (1H) -ketone, substituted sulfonium salt and photosensitizer in turn into a reaction tube filled with inert gas and provided with a magnetic stirring bar, adding carbonate or nitrogenous organic base as alkali, adding an organic reaction solvent by using an injector, and irradiating reaction liquid by adopting near blue light at normal temperature to promote reaction;
(2) after the reaction is finished, adding a proper amount of deionized water into the reaction liquid, shaking to ensure uniform mixing, performing liquid phase separation and extraction by taking 3mL of ethyl acetate as an extracting agent every time, extracting a crude product from the reaction liquid, combining extracting solutions, removing a solvent through a rotary evaporator, and removing the solvent through the rotary evaporator; purifying the residue by silica gel column chromatography to obtain C-3 alkyl substituted quinoxaline-2 (1H) -ketone compounds.
Further, the inert gas is nitrogen or argon;
the wavelength range of the near blue light is 420nm-470 nm;
the light source of near blue light is preferably a blue LED lamp.
Further, the amount of the sulfonium salt is 1.0-2.5 times of that of quinoxaline-2 (1H) -ketone and derivatives thereof;
the quantity of the photosensitizer is 0.01-0.05 times of quinoxaline-2 (1H) -ketone and derivatives thereof.
Further, the synthesis reaction is carried out under atmospheric pressure, and the reaction time is 12-24 h;
the photosensitizer is an organic catalyst;
the organic catalyst is one of riboflavin, gliadin and 4CzIPN (2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile).
Further, the carbonate is one of potassium carbonate, sodium carbonate or sodium bicarbonate;
the nitrogen-containing organic base is one of triethylamine or DIPEA (N, N-diisopropylethylamine);
the dosage of the alkali is 2.0 to 4.0 times of the dosage of the quinoxaline-2 (1H) -ketone and the derivative thereof;
the polarity parameter of the organic solvent is greater than 2.4,
the organic solvent is preferably one of DMSO, DMF, and NMP.
Further, the reaction formula is:
at room temperature, 0.2mmol of quinoxaline-2 (1H) -one, 0.3mmol of a sulfonium salt, 0.4mmol of Na in the above reaction scheme2CO30.005mmol of riboflavin was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer; adding 2.0mL of NMP in a nitrogen environment by using an injector, placing the reaction tube at a position 3cm away from a 10-watt blue LED lamp, irradiating by blue light and stirring for 24 hours;
after the reaction is finished, adding 2mL of deionized water into the reaction solution, uniformly stirring, extracting a crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extracting agent each time, combining the extract solutions, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column to obtain 43mg of the objective product in 86% yield.
Further, the reaction mechanism of the synthesis is as follows:
the substituted sulfonium salt (1a) and the photocatalyst (P) absorb energy to excited states (1a') and (P) respectively through blue light irradiation of a blue LED lamp, and the two obtain first intermediates (2) and (P) through a single electron transfer process+·) The first intermediate (2) and quinoxaline-2 (1H) -ketone (3) are subjected to addition reaction to obtain a second intermediate (4), the second intermediate (4) undergoes intramolecular 1, 2-hydrogen migration to obtain a third intermediate (5), and the third intermediate (5) and (P)+·) Single electron transfer is carried out to obtain a fourth intermediate (6) and a photocatalyst (P) in a ground state, and the fourth intermediate (6) is deprotonated under the action of alkali to obtain a final product of quinoxaline-2 (1H) -ketone and a derivative thereof, namely a C-3 alkylated compound (7).
The application of the synthesis method of the photocatalysis C-3 position alkyl substituted quinoxaline-2 (1H) -ketone compound can be used for synthesizing a medicament MDR antagonist and a Carovirine intermediate for treating smooth muscle cramp, cerebral circulation disorder and tinnitus, and can be used for screening anticancer or antiviral biomedical lead compounds.
The synthesis method and application of the photocatalysis C-3 position alkyl substituted quinoxaline-2 (1H) -ketone compound have the beneficial effects that: the method does not need harsh synthesis conditions, can complete the reaction in one step, is suitable for synthesizing various C-3-position alkyl substituted quinoxaline-2 (1H) -ketone compounds, has higher universality on various functional groups on an aromatic ring, and has no special limitation on the number and the type of the substituent groups of the quinoxaline-2 (1H) -ketone compounds. Further, the number and type of the substituents of the sulfonium salt are not particularly limited. The synthetic method has simple preparation process and device, takes near blue light as energy, has mild reaction conditions, and is green and environment-friendly; as the synthesis method is the direct alkylation of the C-3 position, complex pretreatment is not needed, and the environment-friendly concept of green chemistry and atom economy is met.
Drawings
FIG. 1 is a reaction scheme of a synthesis method according to an embodiment of the present invention;
FIG. 2 is a diagram of a pharmaceutically active molecule containing a quinoxalin-2 (1H) -one backbone according to an embodiment of the present invention.
Detailed Description
The invention is described in further detail below with reference to the following detailed description and accompanying drawings:
example 1:
the synthesis of MDR antagonist for treating multidrug resistance antagonist:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), Na in the above reaction formula2CO3(0.4mmol), riboflavin (0.005mmol) was added to a 25mL SchlenkIn a tube, the tube was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 43mg of the expected product are obtained in 86% yield. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.87(d,J＝8.0Hz,1H),7.52(t,J＝7.8Hz,1H),7.48(d,J＝7.6Hz,2H),7.37–7.27(m,4H),7.22(t,J＝7.3Hz,1H),4.28(s,2H),3.67(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ159.3,154.7,137.0,133.3,132.7,130.0,129.9,129.5,128.4,126.6,123.5,113.5,40.7,29.1.
the high resolution mass spectra data are: HRMS calcd for C16H15N2O+[M+H]+:251.1179；found 251.1183.
Example 2:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), K in the above reaction scheme2CO3(0.4mmol), 4CzIPN (0.005mmol) was added to a 25mL Schlenk tube, which was filled with argon and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10W 450nm wavelength blue LED lamp, irradiated with blue light and stirred for 18 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction with 3mL ethyl acetate each time as extractant, combining the extractive solutions, and passing through cycloneRemoving the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (4:1 v/v)). 51mg of the expected product are obtained in a yield of 78%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.84(d,J＝7.9Hz,1H),7.54(t,J＝7.7Hz,1H),7.40(d,J＝8.3Hz,2H),7.34(t,J＝7.9Hz,3H),7.28(d,J＝8.4Hz,1H),4.21(s,2H),3.67(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ158.7,154.6,136.0,133.3,132.7,131.5,131.3,130.1,130.0,123.7,120.6,113.6,40.2,29.1.
the high resolution mass spectra data are: HRMS calcd for C16H14BrN2O+[M+H]+:329.0284；found 329.0286.
Example 3:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), K in the above reaction scheme2CO3(0.4mmol), gliadin (0.002mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of DMF was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 420nm wavelength blue LED lamp, irradiated with blue light and stirred for 22 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (3:1 v/v)). 49mg of the target product are obtained with a yield of 91%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.85(dd,J＝8.1,0.9Hz,1H),7.55-7.51(m,1H),7.44-7.41(m,2H),7.34(t,J＝7.5Hz,1H),7.28(d,J＝8.4Hz,1H),6.97(t,J＝8.7Hz,2H),4.23(s,2H),3.67(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ162.7,160.8,159.0,154.7,133.3,132.7,132.6,131.0,130.9,130.0,129.9,123.6,115.2,115.1,113.6,39.9,29.1.
the high resolution mass spectra data are: HRMS calcd for C16H14FN2O+[M+H]+:269.1085；found 269.1089.
Example 4:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), Na in the above reaction formula2CO3(0.5mmol), 4CzIPN (0.004mmol) was added to a 25mL Schlenk tube, which was filled with argon and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 420nm wavelength blue LED lamp, irradiated with blue light and stirred for 12 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 22mg of the expected product are obtained in a yield of 40%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.85(d,J＝8.0Hz,1H),7.74(s,1H),7.70(d,J＝7.8Hz,1H),7.58–7.54(m,1H),7.51(d,J＝7.8Hz,1H),7.41–7.35(m,2H),7.30(d,J＝8.3Hz,1H),4.28(s,2H),3.68(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ157.9,154.6,138.6,134.2,133.3,133.0,132.6,130.4,130.3,130.1,129.1,123.8,118.9,113.7,112.4,40.1,29.2.
the high resolution mass spectra data are: HRMS calcd for C17H14N3O+[M+H]+:276.1131；found 276.1137.
Example 5:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.5mmol), K in the above reaction scheme2CO3(0.4mmol), riboflavin (0.005mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 35mg of the expected product are obtained in 58% yield.
The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ8.40(d,J＝8.5Hz,1H),7.83(d,J＝8.1Hz,1H),7.79-7.74(m,2H),7.63(d,J＝7.0Hz,1H),7.52–7.42(m,4H),7.28(t,J＝7.6Hz,1H),7.24(d,J＝8.4Hz,1H),4.75(s,2H),3.67(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ158.9,154.8,133.9,133.3,133.2,132.7,132.5,130.0,129.9,128.5,128.3,127.4,125.9,125.5,125.4,124.8,123.5,113.5,37.7,29.1.
the high resolution mass spectra data are: HRMS calcd for C20H17N2O+[M+H]+:301.1335；found 301.1344.
Example 6:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), Na in the above reaction formula2CO3(0.4mmol), 4CzIPN (0.005mmol) was added to a 25mL Schlenk tube, which was filled with argon and equipped with a magnetic stirrer. 2.0mL of DMF was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 420nm wavelength blue LED lamp, irradiated with blue light and stirred for 17 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (6:1 v/v)). The desired product was obtained in 46mg with a yield of 86%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.82–7.79(m,1H),7.48–7.44(m,1H),7.32–7.28(m,3H),7.20(d,J＝8.8Hz,1H),7.05(d,J＝7.8Hz,2H),4.18(s,2H),3.60(s,3H),2.25(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ159.5,154.7,136.1,133.9,133.3,132.7,129.9,129.8,129.4,129.1,123.5,113.5,40.4,29.1,21.0.
the high resolution mass spectra data are: HRMS calcd for C17H17N2O+[M+H]+:265.1335；found 265.1340.
Example 7:
at room temperature, the quinoxalin-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), NaHCO in the above reaction scheme3(0.6mmol), 4CzIPN (0.002mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 470nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours.After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 44mg of the desired product are obtained in 67% yield. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.84(d,J＝7.8Hz,1H),7.59(s,1H),7.52(t,J＝7.7Hz,1H),7.39(d,J＝7.5Hz,1H),7.33(t,J＝6.7Hz,2H),7.26(d,J＝8.6Hz,1H),7.15(t,J＝7.8Hz,1H),4.21(s,2H),3.66(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ158.5,154.6,139.3,133.3,132.7,132.3,130.1,130.0,129.9,129.7,128.3,123.6,122.4,113.6,40.2,29.1.
the high resolution mass spectra data are: HRMS calcd for C16H14BrN2O+[M+H]+:329.0284；found 329.0287.
Example 8:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), Na in the above reaction formula2CO3(0.4mmol), EY (0.005mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 420nm wavelength blue LED lamp, irradiated with blue light and stirred for 20 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 37mg of the target product are obtained with a yield of 52％。
The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.87–7.81(m,1H),7.70(d,J＝7.8Hz,1H),7.59–7.55(m,3H),7.51–7.43(m,4H),7.37(t,J＝7.6Hz,1H),7.31(t,J＝7.6Hz,1H),7.26–7.23(m,1H),4.29(s,2H),3.65(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ158.8,154.7,145.3,137.8,136.4,133.7,133.3,132.7,130.1,130.0,129.9,128.7,127.3,123.6,118.8,113.6,111.1,40.4,29.1.
the high resolution mass spectra data are: HRMS calcd for C23H18N3O+[M+H]+:352.1444；found 352.1446.
Example 9:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), K in the above reaction scheme2CO3(0.4mmol), 4CzIPN (0.005mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). The desired product was obtained in 40mg with a yield of 60%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.82(d,J＝8.1Hz,1H),7.51(t,J＝7.5Hz,1H),7.46(d,J＝8.5Hz,2H),7.32(t,J＝7.5Hz,1H),7.24(d,J＝6.0Hz,1H),7.10(d,J＝8.1Hz,2H),4.23(s,2H),3.64(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ158.7,154.7,148.0,135.7,133.3,132.7,130.8,130.1,130.0,123.7,120.9,113.6,40.0,29.1.
the high resolution mass spectra data are: HRMS calcd for C17H14F3N2O2 +[M+H]+:335.1002；found 335.1005.
Example 10:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), Na in the above reaction formula2CO3(0.4mmol), 4CzIPN (0.005mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 43mg of the expected product are obtained in 69%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.96(d,J＝8.1Hz,2H),7.84(d,J＝8.0Hz,1H),7.55-7.51(m,3H),7.34(t,J＝7.6Hz,1H),7.28(d,J＝8.3Hz,1H),4.31(s,2H),3.88(s,3H),3.67(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ167.0,158.5,154.6,142.4,133.3,132.7,130.1,130.0,129.7,129.5,128.5,123.7,113.6,52.0,40.7,29.1.
the high resolution mass spectra data are: HRMS calcd for C18H17N2O3 +[M+H]+:309.1234；found 309.1233.
Example 11:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), K in the above reaction scheme2CO3(0.4mmol), EY (0.004mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 470nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (6:1 v/v)). 62mg of the expected product are obtained in 87% yield.
The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.85(d,J＝8.1Hz,1H),7.54–7.48(m,1H),7.42–7.29(m,8H),7.25(d,J＝7.5Hz,1H),6.91(d,J＝8.6Hz,2H),5.02(s,2H),4.21(s,2H),3.65(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ159.5,157.6,154.7,137.1,133.3,132.7,130.5,129.9,129.8,129.3,128.5,127.8,127.4,123.5,114.8,113.5,70.0,39.9,29.1.
the high resolution mass spectra data are: HRMS calcd for C23H21N2O2 +[M+H]+:357.1598；found 357.1593.
Example 12:
quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0) in the above reaction scheme is reacted at room temperature.3mmol)，Na2CO3(0.4mmol), 4CzIPN (0.002mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (3:1 v/v)). The desired product was obtained in 32mg, yield 63%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.86(d,J＝8.0Hz,1H),7.53(t,J＝7.8Hz,1H),7.34(t,J＝7.6Hz,1H),7.28(d,J＝8.4Hz,1H),7.16(d,J＝5.0Hz,1H),7.06(d,J＝2.6Hz,1H),6.96–6.89(m,1H),4.47(s,2H),3.70(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ158.0,154.6,138.6,133.4,132.7,130.1,130.0,126.8,126.6,124.6,123.7,113.6,34.8,29.2.
the high resolution mass spectra data are: HRMS calcd for C14H13N2OS+[M+H]+:257.0743；found 257.0745.
Example 13:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.4mmol), Na in the above reaction formula2CO3(0.6mmol), 4CzIPN (0.005mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of DMF was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 420nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, followed by stirringAnd (4) uniformity. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (6:1 v/v)). The desired product was obtained in 46mg with a yield of 86%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.92(d,J＝8.0Hz,1H),7.49(t,J＝7.7Hz,1H),7.45(d,J＝7.5Hz,2H),7.33(t,J＝7.6Hz,1H),7.29-7.22(m,3H),7.17(t,J＝7.3Hz,1H),4.83(q,J＝7.1Hz,1H),3.61(s,3H),1.69(d,J＝7.1Hz,3H).
13C NMR(CDCl3,500MHz,ppm)δ161.8,154.4,143.1,133.0,132.7,130.1,129.6,128.3,128.1,126.4,123.4,113.4,41.8,29.0,19.6.
the high resolution mass spectra data are: HRMS calcd for C17H17N2O+[M+H]+:265.1355；found 265.1340.
Example 14:
at room temperature, the quinoxalin-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), triethylamine (0.3mmol), 4CzIPN (0.002mmol) in the above reaction scheme was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of DMF was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 470nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). The desired product was obtained in a yield of 93 mg. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.58(s,1H),7.44(d,J＝7.5Hz,2H),7.26(t,J＝7.5Hz,2H),7.18(t,J＝7.2Hz,1H),6.99(s,1H),4.22(s,2H),3.60(s,3H),2.37(s,3H),2.32(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ157.9,154.7,139.5,137.3,132.3,131.3,131.1,129.9,129.4,128.3,126.4,114.1,40.6,28.9,20.4,19.1.
the high resolution mass spectra data are: HRMS calcd for C18H19N2O+[M+H]+:279.1492；found 279.1496.
Example 15:
at room temperature, the quinoxalin-2 (1H) -one (0.2mmol), sulfonium salt (0.4mmol), NaHCO in the above reaction scheme3(0.5mmol), EY (0.003mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of DMF was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 53mg of the expected product are obtained in a yield of 80%.
The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.99(d,J＝1.2Hz,1H),7.64-7.54(m,1H),7.43(d,J＝7.1Hz,2H),7.31-7.19(m,3H),7.12(d,J＝8.8Hz,1H),4.24(s,2H),3.62(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ160.7,154.4,136.6,133.6,132.6,132.5,132.4,129.6,128.4,126.7,116.1,115.0,40.7,29.2.
the high resolution mass spectra data are: HRMS calcd for C16H14BrN2O+[M+H]+:329.0284；found 329.0286.
Example 16:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), K in the above reaction scheme2CO3(0.5mmol), riboflavin (0.005mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of DMSO was added using a syringe under nitrogen, and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light, and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 51mg of the expected product are obtained in a yield of 90%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.47(d,J＝7.5Hz,2H),7.34–7.27(m,3H),7.21(t,J＝7.3Hz,1H),7.17(d,J＝9.1Hz,1H),7.14-7.11(m,1H),4.26(s,2H),3.87(s,3H),3.64(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ159.8,155.9,154.3,137.1,133.4,129.5,128.4,127.5,126.5,119.0,114.4,111.4,55.7,40.8,29.2.
the high resolution mass spectra data are: HRMS calcd for C17H17N2O2 +[M+H]+:281.1285；found 281.1286.
Example 17:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), Na in the above reaction formula2CO3(0.4mmol), EY (0.002mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 420nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). The desired product was obtained in 48mg, 75% yield.
The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.87(d,J＝8.0Hz,1H),7.50-7.44(m,3H),7.35-7.28(m,3H),7.21(t,J＝7.3Hz,1H),7.03(d,J＝8.3Hz,1H),4.98(s,2H),4.28(s,2H),4.22(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H).
13C NMR(CDCl3,125MHz,ppm)δ167.0,159.1,154.3,136.8,132.8,132.4,130.3,130.0,129.5,128.4,126.6,123.8,113.0,62.0,43.6,40.6,14.0.
the high resolution mass spectra data are: HRMS calcd for C19H19N2O3 +[M+H]+:323.1390；found 323.1399.
Example 18:
at room temperature, the quinoxalin-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), DIPEA (0.3mmol), 4CzIPN (0.002mmol) in the above reaction scheme was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 62mg of the expected product are obtained in 83% yield. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.78(d,J＝8.0Hz,1H),7.46–7.41(m,1H),7.38(d,J＝7.5Hz,2H),7.27–7.19(m,4H),7.13(t,J＝7.4Hz,1H),4.20–4.15(m,4H),3.37(t,J＝6.2Hz,2H),1.94–1.81(m,4H).
13C NMR(CDCl3,125MHz,ppm)δ159.2,154.4,137.0,133.0,132.3,130.3,129.9,129.5,128.4,126.5,123.5,113.4,41.2,40.6,32.8,29.7,25.8.
the high resolution mass spectra data are: HRMS calcd for C19H20BrN2O+[M+H]+:371.0754；found 371.0752.
Example 19:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.4mmol), Na in the above reaction formula2CO3(0.4mmol), riboflavin (0.005mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; silica gel column for residuePurification (silica gel size 200-300 mesh, eluent petroleum ether/ethyl acetate (5:1 v/v)). The desired product was obtained in 48mg, 85% yield. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.82(d,J＝7.9Hz,1H),7.47(t,J＝7.7Hz,1H),7.40(d,J＝7.5Hz,2H),7.36(d,J＝8.4Hz,1H),7.29(t,J＝7.6Hz,1H),7.25(t,J＝7.3Hz,2H),7.16(t,J＝7.3Hz,1H),4.39(t,J＝5.4Hz,2H),4.20(s,2H),3.95(t,J＝5.3Hz,2H),2.75(s,1H).
13C NMR(CDCl3,125MHz,ppm)δ159.0,155.5,136.9,133.0,132.7,130.2,129.9,129.5,128.4,126.6,123.8,113.8,60.3,44.9,40.5.
the high resolution mass spectra data are: HRMS calcd for C17H17N2O2 +[M+H]+:281.1285；found 281.1289.
Example 20:
at room temperature, the quinoxalin-2 (1H) -one (0.2mmol), sulfonium salt (0.5mmol), NaHCO in the above reaction scheme3(0.6mmol), 4CzIPN (0.002mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of DMF was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 420nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (3:1 v/v)). 38mg of the expected product are obtained in a yield of 68%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.84(d,J＝8.3Hz,1H),7.47-7.44(m,3H),7.31-7.26(m,3H),7.23-7.18(m,2H),5.92-5.85(m,1H),5.22(d,J＝10.4Hz,1H),5.12(d,J＝17.3Hz,1H),4.84(d,J＝5.0Hz,2H),4.26(s,2H).
13C NMR(CDCl3,125MHz,ppm)δ159.3,154.3,137.0,132.9,132.5,130.6,130.0,129.7,129.5,128.4,126.5,123.5,118.1,114.1,44.5,40.6.
the high resolution mass spectra data are: HRMS calcd for C18H17N2O+[M+H]+:277.1335；found 277.1340.
Example 21:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.4mmol), K in the above reaction scheme2CO3(0.4mmol), EY (0.005mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 18 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (6:1 v/v)). The desired product was obtained in 48mg, yield 82%.
The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.85(d,J＝7.6Hz,1H),7.51(d,J＝7.6Hz,1H),7.33(t,J＝7.6Hz,1H),7.27(d,J＝7.5Hz,1H),6.96(d,J＝0.9Hz,1H),6.92(d,J＝7.8Hz,1H),6.73(d,J＝8.0Hz,1H),5.89(s,2H),4.17(s,2H),3.66(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ159.2,154.7,147.5,146.3,133.3,132.7,130.6,129.9,129.9,123.6,122.5,113.5,110.0,108.2,100.8,40.3,29.1.
the high resolution mass spectra data are: HRMS calcd for C17H15N2O3 +[M+H]+:295.1077；found 298.1082.
Example 22:
the synthesis of a Carovirine intermediate for synthesizing a medicament for treating smooth muscle cramp, cerebral circulation disturbance and tinnitus:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), Na in the above reaction formula2CO3(0.4mmol), 4CzIPN (0.005mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (4:1 v/v)). The desired product was obtained in 32mg, yield 61%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(500MHz,CDCl3)δ12.17(s,1H),7.84(d,J＝7.9Hz,1H),7.50–7.46(m,1H),7.40(d,J＝8.6Hz,2H),7.32(t,J＝7.6Hz,1H),7.25(d,J＝9.6Hz,1H),6.83(d,J＝8.6Hz,2H),4.23(s,2H),3.75(s,3H).
13C NMR(126MHz,CDCl3)δ160.0,158.4,156.3,132.9,131.1,130.5,129.8,129.1,129.0,124.1,115.6,113.9,55.2,39.1.
the high resolution mass spectra data are: HRMS calcd for C16H15N2O+[M+H]+:267.1128；found 267.1131.
Example 23:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), K in the above reaction scheme2CO3(0.4mmol), 4CzIPN (0.005mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 18 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 82mg of the expected product are obtained in a yield of 75%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.87(dd,J＝8.1,0.8Hz,1H),7.51–7.41(m,4H),7.33-7.28(m,3H),7.23-7.20(m,2H),6.71(dd,J＝8.5,2.4Hz,1H),6.65(d,J＝2.2Hz,1H),4.45–4.39(m,2H),4.27(s,2H),4.04(t,J＝5.7Hz,2H),2.92-2.88(m,2H),2.54-2.48(m,1H),2.40(d,J＝10.4Hz,1H),2.28-2.22(m,2H),2.14(d,J＝9.8Hz,1H),2.09–1.95(m,3H),1.69–1.39(m,7H),0.92(s,3H).
13C NMR(CDCl3,125MHz,ppm)δ220.8,159.2,156.6,154.5,137.8,137.1,133.0,132.5,132.4,130.1,129.9,129.5,128.4,126.5,126.4,123.5,114.6,113.6,112.2,65.2,50.4,48.0,44.0,40.6,39.8,38.3,35.8,31.6,29.7,29.6,27.2,26.5,25.9,21.6,13.8.
the high resolution mass spectra data are: HRMS calcd for C36H39N2O3 +[M+H]+:547.2955；found 547.2960.
Example 24:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), Na in the above reaction formula2CO3(0.4mmol), 4CzIPN (0.002mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of DMF was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 18 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 80mg of the expected product are obtained in a yield of 78%. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.84(d,J＝8.1Hz,1H),7.46-7.43(m,1H),7.32(t,J＝7.9Hz,2H),7.05(q,J＝8.1Hz,4H),6.96(s,1H),6.93–6.88(m,1H),6.73(d,J＝8.0Hz,1H),5.88(s,2H),4.52–4.32(m,4H),4.16(d,J＝8.2Hz,2H),3.53(q,J＝7.1Hz,1H),2.43(d,J＝7.2Hz,2H),1.88–1.79(m,1H),1.39(d,J＝7.2Hz,3H),0.89(d,J＝6.5Hz,6H).
13C NMR(CDCl3,125MHz,ppm)δ174.7,159.0,154.5,147.5,146.3,140.6,137.2,132.9,132.8,130.5,130.1,129.9,129.3,127.0,123.6,122.5,113.7,110.0,108.2,100.8,60.9,45.0,44.9,40.8,40.2,30.1,22.4,18.3.
the high resolution mass spectra data are: HRMS calcd for C31H33N2O5 +[M+H]+:513.2384；found 513.2388.
Example 25:
at room temperature, quinoxaline-2 (1) in the above reaction formulaH) Ketones (0.2mmol), sulfonium salts (0.3mmol), K2CO3(0.4mmol), EY (0.003mmol) was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 24 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (3:1 v/v)). 84mg of the target product are obtained with a yield of 85%.
The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ7.82(d,J＝7.9Hz,1H),7.47(d,J＝7.4Hz,2H),7.35–7.20(m,7H),7.15(t,J＝8.7Hz,3H),5.42(s,2H),4.58(d,J＝11.5Hz,1H),4.32(d,J＝8.0Hz,3H),3.14-3.09(m,1H),2.24-2.21(m,1H),2.13(d,J＝11.9Hz,1H),1.64-1.57(m,2H),1.27-1.22(m,2H),0.97-0.79(m,9H),0.65(d,J＝6.8Hz,3H).
13C NMR(CDCl3,125MHz,ppm)δ159.4,154.8,138.6,137.1,134.3,133.0,132.6,130.0,129.8,129.5,128.4,128.3,126.8,126.5,123.5,114.4,78.8,69.9,48.2,45.7,40.7,40.2,34.5,31.5,25.5,23.2,22.3,21.0,16.00.
the high resolution mass spectra data are: HRMS calcd for C33H39N2O2 +[M+H]+:495.3006；found 495.3008.
Example 26:
at room temperature, quinoxaline-2 (1H) -one (0.2mmol), sulfonium salt (0.3mmol), K in the above reaction scheme2CO3(0.4mmol), 4CzIPN (0.002mmol) was added to a 25mL Schlenk tube, which was filled with nitrogenAnd equipped with a magnetic stirrer. 2.0mL of NMP was added using a syringe under nitrogen and the reaction tube was placed 3cm from a 10 watt 455nm wavelength blue LED lamp, irradiated with blue light and stirred for 20 hours. After the reaction, 2mL of deionized water was added to the reaction mixture, and the mixture was stirred well. Extracting the crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extractant, combining the extracts, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column (silica gel size: 200 to 300 mesh; eluent: petroleum ether/ethyl acetate (5:1 v/v)). 75mg of the expected product are obtained in 88% yield. The nuclear magnetic spectrum data of the obtained product are as follows:
1H NMR(CDCl3,500MHz,ppm)δ9.84(s,1H),8.00(d,J＝8.0Hz,1H),7.76(d,J＝8.1Hz,1H),7.60(t,J＝7.4Hz,1H),7.54(t,J＝7.4Hz,1H),7.40(d,J＝7.2Hz,2H),7.29(d,J＝7.4Hz,2H),7.21(t,J＝7.4Hz,2H),7.15(t,J＝7.1Hz,1H),6.80(d,J＝8.4Hz,1H),4.65(t,J＝5.9Hz,2H),4.31(s,2H),4.05(t,J＝6.4Hz,2H),3.90(s,3H),2.39-2.34(m,2H).
13C NMR(CDCl3,125MHz,ppm)δ190.8,155.8,153.8,149.8,149.1,140.0,138.6,137.6,130.1,129.2,128.9,128.5,128.4,126.7,126.5,126.5,111.6,109.3,65.7,63.0,55.9,40.3,28.5.
the high resolution mass spectra data are: HRMS calcd for C26H25N2O4 +[M+H]+:429.1809；found 429.1809.
Example 27:
a method for synthesizing a C-3 alkyl substituted quinoxaline-2 (1H) -ketone compound by photocatalysis is characterized by comprising the following steps: quinoxaline-2 (1H) -ketone and derivatives thereof and substituted sulfonium salt are taken as raw materials, an organic photosensitizer is taken as a photocatalyst, at least one carbonate or nitrogen-containing organic alkali is taken as alkali under the conditions of inert gas environment and normal temperature, and near blue light is adopted to irradiate reaction liquid to synthesize the quinoxaline-2 (1H) -ketone compound substituted by C-3 alkyl.
The general formula of the C-3-position alkyl substituted quinoxaline-2 (1H) -ketone compound is shown as a formula I; the general formula of the quinoxaline-2 (1H) -ketone and the derivative thereof is shown as a formula II; the general formula of the substituted sulfonium salt is shown as a formula III;
in the formula:
R1one selected from halogen, methyl and methoxy substituents;
R2one of hydrogen, trifluoromethoxy, alkyl, aryl, alcohol, olefin, ester group and natural product and drug molecule derivative substituent;
R3one selected from methyl or hydrogen;
R4one selected from halogen, methyl, methoxy, aryl, ester group or cyano substituent;
ar is selected from one of benzene ring or thiophene ring;
x is selected from PF6Or BF4One kind of (1).
The synthesis method comprises the following steps:
(1) at room temperature, adding substituted quinoxaline-2 (1H) -ketone, substituted sulfonium salt and photosensitizer in turn into a reaction tube filled with inert gas and provided with a magnetic stirring bar, adding carbonate or nitrogenous organic base as alkali, adding an organic reaction solvent by using an injector, and irradiating reaction liquid by adopting near blue light at normal temperature to promote reaction;
(2) after the reaction is finished, adding a proper amount of deionized water into the reaction liquid, shaking to ensure uniform mixing, performing liquid phase separation and extraction by taking 3mL of ethyl acetate as an extracting agent every time, extracting a crude product from the reaction liquid, combining extracting solutions, removing a solvent through a rotary evaporator, and removing the solvent through the rotary evaporator; purifying the residue by silica gel column chromatography to obtain C-3 alkyl substituted quinoxaline-2 (1H) -ketone compounds.
The inert gas is nitrogen or argon;
the wavelength range of the near blue light is 420nm-470 nm;
the light source of near blue light is preferably a blue LED lamp.
The amount of the sulfonium salt is 1.0-2.5 times of that of quinoxaline-2 (1H) -ketone and derivatives thereof;
the quantity of the photosensitizer is 0.01-0.05 times of quinoxaline-2 (1H) -ketone and derivatives thereof.
The synthesis reaction is carried out under atmospheric pressure, and the reaction time is 12-24 h;
the photosensitizer is an organic catalyst;
the organic catalyst is one of riboflavin, gliadin and 4CzIPN (2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile).
The carbonate is one of potassium carbonate, sodium carbonate or sodium bicarbonate;
the nitrogen-containing organic base is one of triethylamine or DIPEA (N, N-diisopropylethylamine);
the dosage of the alkali is 2.0 to 4.0 times of the dosage of the quinoxaline-2 (1H) -ketone and the derivative thereof;
the polarity parameter of the organic solvent is greater than 2.4,
the organic solvent is preferably one of DMSO, DMF, and NMP.
As shown in figure 1, the metallo-free organic photocatalysis sulfonium salt C-S bond is broken, and the direct alkylation is carried out to construct the C-3 position alkyl substituted quinoxaline-2 (1H) -ketone heterocyclic compound, and the reaction mechanism of the synthesis is as follows:
the substituted sulfonium salt (1a) and the photocatalyst (P) absorb energy to excited states (1a') and (P) respectively through blue light irradiation of a blue LED lamp, and the two obtain first intermediates (2) and (P) through a single electron transfer process+·) The first intermediate (2) and quinoxaline-2 (1H) -ketone (3) are subjected to addition reaction to obtain a second intermediate (4), the second intermediate (4) undergoes intramolecular 1, 2-hydrogen migration to obtain a third intermediate (5), and the third intermediate (5) and (P)+·) Single electron transfer is carried out to obtain a fourth intermediate (6) and a photocatalyst (P) in a ground state, and the fourth intermediate (6) is deprotonated under the action of alkali to obtain a final product of quinoxaline-2 (1H) -ketone and a derivative thereof, namely a C-3 alkylated compound (7).
The application of the synthesis method of the photocatalysis C-3 position alkyl substituted quinoxaline-2 (1H) -ketone compound can be used for synthesizing a medicament MDR antagonist and a Carovirine intermediate for treating smooth muscle cramp, cerebral circulation disorder and tinnitus, and can be used for screening anticancer or antiviral biomedical lead compounds.
The C-3 alkyl substituted quinoxaline-2 (1H) -ketone compound has potential anticancer and antiviral activities, and the compound is also a commercially available medicine for treating smooth muscle cramp, treating cerebral circulation disturbance, treating tinnitus and the like, however, the synthesis method of the compounds is very limited at present. Therefore, the development of a new synthetic method of the compound has important application value in the field of pharmaceutical chemistry.
In the preparation method of the present invention, the order of addition of various materials and the specific reaction steps can be adjusted by those skilled in the art, and the method is not only suitable for small-scale preparation in a laboratory, but also suitable for industrial large-scale production in a chemical plant. In industrial mass production, specific reaction parameters can be determined experimentally by a person skilled in the art.
Unless otherwise specified, the experimental procedures used in the following examples are all conventional.
Unless otherwise specified, reagents, materials and the like used in the following examples are commercially available or synthesized from commercially available raw materials.
The above embodiments are only for illustrating the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention accordingly, and not to limit the protection scope of the present invention accordingly. All equivalent changes or modifications made in accordance with the spirit of the present disclosure are intended to be covered by the scope of the present disclosure.
Claims (10)
1. A method for synthesizing a C-3 alkyl substituted quinoxaline-2 (1H) -ketone compound by photocatalysis is characterized by comprising the following steps: quinoxaline-2 (1H) -ketone and derivatives thereof and substituted sulfonium salt are taken as raw materials, an organic photosensitizer is taken as a photocatalyst, at least one carbonate or nitrogen-containing organic alkali is taken as alkali under the conditions of inert gas environment and normal temperature, and near blue light is adopted to irradiate reaction liquid to synthesize the quinoxaline-2 (1H) -ketone compound substituted by C-3 alkyl.
2. The method for synthesizing the photocatalytic C-3 alkyl substituted quinoxaline-2 (1H) -one compound according to claim 1, wherein:
the general formula of the C-3-position alkyl substituted quinoxaline-2 (1H) -ketone compound is shown as a formula I; the general formula of the quinoxaline-2 (1H) -ketone and the derivative thereof is shown as a formula II; the general formula of the substituted sulfonium salt is shown as a formula III;
in the formula:
R1one selected from halogen, methyl and methoxy substituents;
R2one of hydrogen, trifluoromethoxy, alkyl, aryl, alcohol, olefin, ester group and natural product and drug molecule derivative substituent;
R3one selected from methyl or hydrogen;
R4one selected from halogen, methyl, methoxy, aryl, ester group or cyano substituent;
ar is selected from one of benzene ring or thiophene ring;
x is selected from PF6Or BF4One kind of (1).
3. The method for synthesizing the photocatalytic C-3 alkyl substituted quinoxaline-2 (1H) -one compound according to claim 1, wherein: the synthesis method comprises the following steps:
(1) at room temperature, adding substituted quinoxaline-2 (1H) -ketone, substituted sulfonium salt and photosensitizer in turn into a reaction tube filled with inert gas and provided with a magnetic stirring bar, adding carbonate or nitrogenous organic base as alkali, adding an organic reaction solvent by using an injector, and irradiating reaction liquid by adopting near blue light at normal temperature to promote reaction;
(2) after the reaction is finished, adding a proper amount of deionized water into the reaction liquid, shaking to ensure uniform mixing, performing liquid phase separation and extraction by taking 3mL of ethyl acetate as an extracting agent every time, extracting a crude product from the reaction liquid, combining extracting solutions, removing a solvent through a rotary evaporator, and removing the solvent through the rotary evaporator; purifying the residue by silica gel column chromatography to obtain C-3 alkyl substituted quinoxaline-2 (1H) -ketone compounds.
4. The method for synthesizing a photocatalytic C-3 alkyl substituted quinoxalin-2 (1H) -one compound according to any one of claims 1 or 3, characterized in that:
the inert gas is nitrogen or argon;
the wavelength range of the near blue light is 420nm-470 nm;
the light source of near blue light is preferably a blue LED lamp.
5. The method for synthesizing a photocatalytic C-3 alkyl substituted quinoxalin-2 (1H) -one compound according to any one of claims 1 or 3, characterized in that:
the amount of the sulfonium salt is 1.0-2.5 times of that of quinoxaline-2 (1H) -ketone and derivatives thereof;
the quantity of the photosensitizer is 0.01-0.05 times of quinoxaline-2 (1H) -ketone and derivatives thereof.
6. The method for synthesizing a photocatalytic C-3 alkyl substituted quinoxalin-2 (1H) -one compound according to any one of claims 1 or 3, characterized in that:
the synthesis reaction is carried out under atmospheric pressure, and the reaction time is 12-24 h;
the photosensitizer is an organic catalyst;
the organic catalyst is one of riboflavin, gliadin and 4CzIPN (2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile).
7. The method for synthesizing a photocatalytic C-3 alkyl substituted quinoxalin-2 (1H) -one compound according to any one of claims 1 or 3, characterized in that:
the carbonate is one of potassium carbonate, sodium carbonate or sodium bicarbonate;
the nitrogen-containing organic base is one of triethylamine or DIPEA (N, N-diisopropylethylamine);
the dosage of the alkali is 2.0 to 4.0 times of the dosage of the quinoxaline-2 (1H) -ketone and the derivative thereof;
the polarity parameter of the organic solvent is more than 2.4;
the organic solvent is preferably one of DMSO, DMF, and NMP.
8. The method for synthesizing the photocatalytic C-3 alkyl substituted quinoxaline-2 (1H) -one compound according to claim 3, wherein the reaction formula is as follows:
at room temperature, 0.2mmol of quinoxaline-2 (1H) -one, 0.3mmol of a sulfonium salt, 0.4mmol of Na in the above reaction scheme2CO30.005mmol of riboflavin was added to a 25mL Schlenk tube, which was filled with nitrogen and equipped with a magnetic stirrer; adding 2.0mL of NMP in a nitrogen environment by using an injector, placing the reaction tube at a position 3cm away from a 10-watt blue LED lamp, irradiating by blue light and stirring for 24 hours;
after the reaction is finished, adding 2mL of deionized water into the reaction solution, uniformly stirring, extracting a crude product from the reaction solution by liquid phase separation and extraction operation with 3mL of ethyl acetate as an extracting agent each time, combining the extract solutions, and removing the solvent by a rotary evaporator; the residue was purified by a silica gel column to obtain 43mg of the objective product in 86% yield.
9. The method for synthesizing photocatalytic C-3 alkyl substituted quinoxaline-2 (1H) -one compounds according to any one of claims 1, 3 or 8, wherein the reaction mechanism of the synthesis is as follows:
the substituted sulfonium salt (1a) and the photocatalyst (P) respectively reach laser by absorbing energy through blue light irradiation of a blue LED lampGenerating states (1a') and (P), and obtaining first intermediates (2) and (P) through single electron transfer process+·) The first intermediate (2) and quinoxaline-2 (1H) -ketone (3) are subjected to addition reaction to obtain a second intermediate (4), the second intermediate (4) undergoes intramolecular 1, 2-hydrogen migration to obtain a third intermediate (5), and the third intermediate (5) and (P)+·) Single electron transfer is carried out to obtain a fourth intermediate (6) and a photocatalyst (P) in a ground state, and the fourth intermediate (6) is deprotonated under the action of alkali to obtain a final product of quinoxaline-2 (1H) -ketone and a derivative thereof, namely a C-3 alkylated compound (7).
10. Use of a method according to any one of claims 1 to 9 for the photocatalytic synthesis of quinoxaline-2 (1H) -one compounds substituted by an alkyl group at the C-3 position, characterized in that: the synthesis method can be used for synthesizing the medicine MDR antagonist and synthesizing the medicine Carovirine intermediate for treating smooth muscle cramp, cerebral circulation disorder and tinnitus, and can be used for screening anticancer or antiviral biological medicine lead compounds.
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