CN112812068B - Alpha-amino alkylation method for C3 site of quinoxalinone - Google Patents

Alpha-amino alkylation method for C3 site of quinoxalinone Download PDF

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CN112812068B
CN112812068B CN202110134862.3A CN202110134862A CN112812068B CN 112812068 B CN112812068 B CN 112812068B CN 202110134862 A CN202110134862 A CN 202110134862A CN 112812068 B CN112812068 B CN 112812068B
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quinoxalinone
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姜昕鹏
方丽云
杜晓帆
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Zhejiang University of Technology ZJUT
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    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
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Abstract

The invention discloses a method for alkylating alpha-amino at C3 position of quinoxalinone. The method comprises the following steps: adding quinoxalinone and organic amine into a reaction vessel, then adding a high iodine reagent, an azide compound and an organic solvent, reacting for 1-24 h, then adding saturated sodium bicarbonate to quench the reaction, diluting the reaction mixture with dichloromethane and water, and extracting with dichloromethane. The organic layer was washed with brine and separated to give the corresponding α -aminoalkylated product of quinoxalinone at C3. The invention adopts high iodine reagent and azide as catalyst, and has the advantages of high reaction efficiency, low reaction cost and simple process.

Description

Alpha-amino alkylation method for C3 site of quinoxalinone
Technical Field
The present invention relates to a non-transition metal catalyzed alpha-aminoalkylation of quinoxalinone at position C3.
Background
Quinoxalinones are a class of compounds containing aromatic heterocyclic structures, and are generally applied to the research of various small molecule drugs based on the structural specificity. The 3-position functionalization of quinoxalinone has wide application in natural products and synthetic drugs, and is related to broad-spectrum biological activity, such as antithrombotic, antioxidant and anticancer effects. Can synthesize aldose reductase inhibitor Prolyl Oligopeptidase (POP). Meanwhile, the alpha-carbamate modified heterocyclic compounds have important significance in the fields of synthesis and medicinal chemistry, and are key components for constructing a plurality of medicinal molecules. For example: TRPM8 inhibitors, plasma kallikrein inhibitors, and melanin concentrating hormone receptor antagonists.
Quincbo et al in 2018 realized a quinoxalinone C3-alkylation reaction with ether as an alkyl source and TBHP as an oxidant (Org. Chem. Front.，2018， 5, 2820-2828). In 2018, Weiwei et al reported that rose bengal was used as a photosensitizer and that the same product was synthesized using an oxidizing agent and an equivalent amount of base. The method can be carried out under the condition of room temperature, and the reaction condition is milder (a)ACS Sustainable Chem. Eng.2018， 6，17252-17257). 2019 Liwanmei et al reported that NHP ester of a photocatalytic amino acid derivative reacts with quinoxalinone to produce an amino-alkylated product (Org. Biomol. Chem., 2019, 17,10201-10208). However, this document only reports one structure, and no research has been made on other structures.
Orexin (Orexin) is found in the mammalian brain, and this may have many effects on pathologies such as depression; the present invention includes α -aminoalkylated derivatives of quinoxalinone C3, which derivatives can be used to synthesize orexin receptor antagonists. These compounds have potential use in the treatment of disorders of homeostasis and eating disorders or irritable bowel syndrome, sleep disorders or stress-related disorders or any other disorder associated with orexin dysfunction. Therefore, it is of great significance to develop a green, environmentally friendly, and efficient synthesis to study such aminoalkylation structures.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a non-transition metal catalyzed alpha-amino alkylation method of quinoxalinone at C3 with high efficiency, simple operation, mild reaction conditions and strong substrate universality.
The invention relates to a method for alkylating alpha-amino at C3 position of quinoxalinone, which is characterized in that the method comprises the following steps: adding a quinoxalinone compound shown in formula (I) and organic amine shown in formula (II) into a reaction vessel, then adding a high-valence iodine reagent, an azide reagent and a solvent, reacting at a certain temperature, adding saturated sodium bicarbonate after the reaction is finished to quench the reaction, diluting with dichloromethane and water, and extracting with dichloromethane. The organic layer was washed with brine and purified to give a product represented by the formula (III) according to the following reaction equation:
Figure 100002_DEST_PATH_IMAGE001
in the formula, R1Is an electron donating group or an electron withdrawing group, preferably methyl, methoxy, fluorine, chlorine, bromine or nitro; r2Is one of alkyl, alkene, alkyne or substituted aryl with 1-15 carbons and substituted benzenesulfonyl; r3Is alkyl, cyclic substituted alkane or aryl with 1-10 carbons; r4Is H or is alkyl of 1-10 carbons; r5Is H, alkyl with 1-10 carbon atoms, aryl, benzyl, formate group or fluorenylmethyloxycarbonyl.
Further, the high-valence iodine reagent of the invention is one or more of iodobenzene acetate, o-iodobenzoic acid, iodobenzene bis (trifluoroacetic acid) and diphenyliodocarbonyl chloride, and the high-valence iodine reagent is used in an amount of 0.5 to 4 molar equivalents, preferably 2 to 3 molar equivalents, of the quinoxalinone compound.
Further, the solvent for the reaction of the present invention is one or more of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 1, 2-dichloromethane and nitromethane, preferably 1, 2-dichloromethane.
Further, the azide reagent adopted by the invention is one or more of trimethylsilyl azide and sodium azide, preferably trimethylsilyl azide, and the use amount of the azide reagent is 0.5-4 molar equivalents, preferably 2-3 molar equivalents of the quinoxalinone compound.
Furthermore, the reaction temperature of the method is-20-30 ℃, and preferably-10-20 ℃; the reaction time is 1-24 h, preferably 8-15 h.
Further, the molar ratio of the quinoxalinone compound of formula (I) and the organic amine of formula (II) is 1:1 to 1:5, preferably 1:2 to 1: 3.
By adopting the synthesis route, the invention defines the method for the alpha-amino alkylation reaction of the C3 site of the quinoxalinone, the invention synthesizes the alpha-aminoalkyl substituted quinoxalinone compound of the C3 site by adopting high-valence iodine and azide reagents as catalysts without transition metals participating in the reaction, the reaction has the advantages of environmental protection, simple and convenient operation, mild condition, good substrate universality, higher reaction yield and the like, and the obtained product can be used as an intermediate to synthesize the orexin receptor antagonist and is used for treating internal balance disorder, eating disorder, insomnia, anxiety and the like.
Detailed Description
The synthesis scheme of the present invention is illustrated below with reference to specific examples, but the scope of the present invention is not limited thereto.
EXAMPLE 1 Synthesis of tert-butyl (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate
Figure 317192DEST_PATH_IMAGE002
To a 25mL reaction flask was added 1-methylquinoxaline-2 (1)H) -ketone (0.3 mmol, 0.048 g) and tert-butyl N-butylcarbamate (0.3 mmol, 0.052 g), diiodophenyliodocarbonyl chloride (1.2 mmol, 0.380 g), trimethylsilyl azide (0.15 mmol, 0.017 g), N, N-dimethylformamide (0.3 mL), the reaction was stirred at 10 ℃ under nitrogen for 8 h and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate =12:1 volume ratio was eluted to give 71mg of tert-butyl 1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate as a pale yellow solid in a yield of 71%.1H NMR (400 MHz， CDCl3) δ 7.86 (dd， J = 8.0， 1.5 Hz， 1H)， 7.55 (m， 1H)， 7.39 – 7.28 (m， 2H)， 5.82 (d， J = 9.1 Hz， 1H)， 5.21 (d， J = 7.4 Hz， 1H)， 3.70 (s， 3H)， 1.92 (q， J = 10.8， 8.1 Hz， 1H)， 1.74 – 1.59 (m， 1H)， 1.44 (s， 11H)， 0.93 (t， J = 7.3 Hz， 3H).; 13C NMR (101 MHz， CDCl3)δ 159.10， 155.49， 153.86， 133.20， 132.25， 130.24， 130.04， 123.72， 113.65， 52.92， 36.32， 29.01， 28.44， 19.12， 13.91; ESI-MS [M + H] m/z 332.1970。
EXAMPLE 2 Synthesis of tert-butyl (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate
To a 25mL reaction flask were added 1-methylquinoxalin-2 (1H) -one (0.3 mmol, 0.048 g) and tert-butyl n-butylcarbamate (0.9 mmol, 0.156 g), iodobenzene acetate (0.75 mmol, 0.244 g), trimethylsilyl azide (0.75 mmol, 0.086 g), dichloromethane (0.3 mL). The reaction was stirred at-10 ℃ under nitrogen for 10 h and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate =12:1 volume ratio was eluted to give tert-butyl 1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate as a pale yellow solid in 80 mg with a yield of 80%.
EXAMPLE 3 Synthesis of tert-butyl (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate
To a 25mL reaction flask were added 1-methylquinoxalin-2 (1H) -one (0.3 mmol, 0.048 g) and tert-butyl n-butylcarbamate (0.9 mmol, 0.156 g), iodobenzene acetate (0.15 mmol, 0.049 g), trimethylsilyl azide (0.75 mmol, 0.086 g), nitromethane (0.3 mL). The reaction was stirred at 30 ℃ under air for 1h and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate =12:1 volume ratio elution gave 45 mg of t-butyl 1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate as a pale yellow solid in a yield of 45%.
EXAMPLE 4 Synthesis of tert-butyl (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate
To a 25mL reaction flask were added 1-methylquinoxalin-2 (1H) -one (0.3 mmol, 0.048 g) and tert-butyl n-butylcarbamate (0.9 mmol, 0.156 g), 2-iodoxybenzoic acid (0.75 mmol, 0.210 g), azidotrimethylsilane (0.75 mmol, 0.086 g), dichloromethane (0.3 mL). The reaction was stirred at-10 ℃ under nitrogen for 24 h and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate =12:1 volume ratio was eluted to give 63 mg of t-butyl (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate as a pale yellow solid in a yield of 63%.
EXAMPLE 5 Synthesis of tert-butyl (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate
To a 25mL reaction flask were added 1-methylquinoxalin-2 (1H) -one (0.3 mmol, 0.048 g) and tert-butyl n-butylcarbamate (0.9 mmol, 0.156 g), bis (trifluoroacetic acid) iodobenzene (0.75 mmol, 0.322 g), sodium azide (1.2 mmol, 0.078 g), acetonitrile (0.3 mL). The reaction was stirred at 0 ℃ under oxygen for 24 h and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate =12:1 volume ratio was eluted to give 70 mg of t-butyl (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate as a pale yellow solid in a yield of 70%.
EXAMPLE 6 Synthesis of tert-butyl (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) cyclopentyl) carbamate
Figure DEST_PATH_IMAGE003
To a 25mL reaction flask were added 1-methylquinoxalin-2 (1H) -one (0.3 mmol, 0.048 g) and tert-butyl cyclopentylcarbamate (0.9 mmol, 0.167 g), iodobenzene acetate (0.75 mmol, 0.244 g), trimethylsilyl azide (0.75 mmol, 0.086 g), 1, 2-dichloroethane (0.3 mL). The reaction was stirred at 0 ℃ under nitrogen for 15 h and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: elution with ethyl acetate =12:1 volume ratio gave 67 mg of α - (3- (2-hydroxyquinoxaline)) cyclopentylcarbamate as a pale yellow solid, in 65% yield, melting point: 143.8-144.3oC; 1H NMR (400 MHz， Chloroform-d) δ 7.85 (dd， J = 8.0， 1.5 Hz， 1H)， 7.52 (m， 1H)， 7.41 – 7.26 (m， 2H)， 5.37 (s， 1H)， 3.66 (s， 3H)， 2.69 – 2.30 (m， 2H)， 2.25 – 1.91 (m， 2H)， 1.91 – 1.62 (m， 4H)， 1.34 (s， 9H).; 13C NMR (101 MHz， CDCl3)δ 159.43， 155.20， 153.28， 133.02， 131.58， 130.15， 129.52， 123.05， 113.00， 78.68， 67.07， 36.81， 28.45， 27.96， 23.95; ESI-MS [M + H] m/z 349.1966。
EXAMPLE 71 Synthesis of methyl-3- (1-methyl-5-oxopyrrolidin-2-yl) quinoxalin-2 (1H) -one
Figure 424825DEST_PATH_IMAGE004
To a 25mL reaction flask were added 1-methylquinoxalin-2 (1H) -one (0.3 mmol, 0.048 g) and N-methylpyrrolidone (0.9 mmol, 0.089 g), iodobenzene acetate (0.75 mmol, 0.244 g), trimethylsilyl azide (0.75 mmol, 0.086 g), dichloromethane (0.3 mL). The reaction was stirred at-10 ℃ for 8 h under air and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate =12:1 volume ratio to elute to give 47 mg of 1-methyl-3- (1-methyl-5-oxopyrrolidin-2-yl) quinoxalin-2 (1H) -one as a yellow oily liquid. The yield was 61%.1H NMR (400 MHz， Chloroform-d) δ 7.86 (d， J = 8.0 Hz， 1H)， 7.59 (m， 1H)， 7.36 (m， 2H)， 5.38 – 5.03 (m， 1H)， 3.72 (d， J = 1.7 Hz， 3H)， 2.86 (s， 3H)， 2.50 (m， 4H)， 2.07 – 1.70 (m， 3H). 13C NMR (151 MHz， Chloroform-d) δ 176.03， 157.16， 154.11， 133.18， 132.39， 130.70， 130.57， 124.01， 113.66， 60.92， 29.50， 28.97， 28.92， 24.03; ESI-MS [M + H] m/z 258.1647。
EXAMPLE 8 Synthesis of (3- (1, 3-dimethyl-2-oxopiperidin-4-yl) -1-methyl-quinoxalin-2-one
Figure DEST_PATH_IMAGE005
To a 25mL reaction flask were added 1-methylquinoxalin-2 (1H) -one (0.3 mmol, 0.048 g) and 1, 3-dimethyltetrahydropyrimidin-2 (1H) -one (0.9 mmol, 0.115 g), iodobenzene acetate (0.75 mmol, 0.244 g), azidotrimethylsilane (0.75 mmol, 0.086 g), 1, 2-dichloroethane (0.3 mL). The reaction was stirred at 0 ℃ under nitrogen for 10 h and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate =12:1 by volume to give a brown solid (3- (1, 3-dimethyl-2-oxopiperidin-4-yl) -1-methyl-quinoxalin-2-one 58 mg. melting point: 134.6-136.6oC, yield 67%.1H NMR (400 MHz， Chloroform-d) δ 7.95 (dd， J = 8.1， 1.5 Hz， 1H)， 7.61 (m， 1H)， 7.45 – 7.32 (m， 2H)， 5.11 (dd， J = 6.1， 2.4 Hz， 1H)， 3.74 (s， 3H)， 3.29 – 3.03 (m， 2H)， 2.99 (s， 3H)， 2.93 (s， 3H)， 2.53 (m， 1H)， 2.31 – 2.17 (m， 1H). 13C NMR (101 MHz， Chloroform-d) δ 157.72， 156.98， 153.98， 133.09， 132.49， 130.80， 130.66， 124.00， 113.66， 58.12， 44.45， 35.84， 35.33， 29.02， 24.82; ESI-MS [M + H] m/z 287.1501 。
Example 9 (1- (4-benzyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamic acid tert-butyl ester
Figure 449063DEST_PATH_IMAGE006
To a 25mL reaction flask was added 1-benzylquinoxalin-2 (1H) -one (0.3 mmol, 0.071 g) and tert-butyl n-butylcarbamate (0.9 mmol, 0.156 g), iodobenzene acetate (0.75 mmol, 0.244 g), superimpositionsAzotrimethylsilane (0.75 mmol, 0.086 g), dichloromethane (0.3 mL). The reaction was stirred at-20 ℃ under nitrogen for 36 h and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate =12:1 volume ratio was eluted to give 94 mg of t-butyl 1- (4-benzyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate as a pale yellow solid. Melting point: 143-145oC, the yield is 77%.1H NMR (400 MHz， Chloroform-d) δ 7.86 (d， J = 7.9 Hz， 1H)， 7.42 (m， 1H)，7.30 (m， 2H)， 7.22 (d， J = 8.1 Hz， 3H)， 5.86 (s， 1H)， 5.49 (s， 2H)， 5.28 (s， 1H)， 1.95 (s， 1H)， 1.75 (d， J = 47.5 Hz， 2H)， 1.47 (s， 11H)， 0.95 (t， J = 7.4 Hz， 3H). 13C NMR (101 MHz， Chloroform-d) δ 159.19， 155.46， 153.83， 135.04， 132.46， 132.41， 130.15， 130.05， 128.92， 127.69， 126.77， 123.70， 114.40， 79.18， 52.78， 45.74， 36.44， 28.39， 19.11， 13.88; ESI-MS [M+H]+ m/z 408.2273。
Example 101 Synthesis of- (3-oxo-4- (propyl-2-yn-1-yl) -3, 4-dihydroquinoxalin-2-yl) butyl) carbamate
Figure DEST_PATH_IMAGE007
To a 25mL reaction vial was added 1- (prop-2-en-1-yl) quinoxalin-2 (1H) -one (0.3 mmol, 0.055 g) and tert-butyl n-butylcarbamate (0.9 mmol, 0.156 g), iodobenzene acetate (0.75 mmol, 0.244 g), trimethylsilyl azide (0.75 mmol, 0.086 g), acetonitrile (0.3 mL). The reaction was stirred at-10 ℃ under nitrogen for 10 h and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. Washed with brine of saturated saltThe organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate =12:1 volume ratio to give 80 mg of 1- (3-oxo-4- (propyl-2-yn-1-yl) -3, 4-dihydroquinoxalin-2-yl) butyl) carbamate as a pale yellow liquid. The yield was 75%. 1H NMR (400 MHz, Chloroform-d) δ 7.86 (dd， J = 8.0， 1.5 Hz， 1H)， 7.58 (m， 1H)， 7.47 (dd， J = 8.4， 1.2 Hz， 1H)， 7.42 – 7.33 (m， 1H)， 5.75 (d， J = 9.2 Hz， 1H)， 5.21 (m， 1H)， 5.12 – 5.00 (m， 2H)， 2.30 (t， J = 2.5 Hz， 1H)， 1.94 – 1.85 (m， 1H)， 1.73 – 1.60 (m， 1H)， 1.44 (s， 11H)， 0.93 (t， J = 7.3 Hz， 3H). 13C NMR (101 MHz， Chloroform-d) δ 159.03， 155.43， 152.78， 132.37， 131.64， 130.29， 130.11， 124.05， 114.12， 79.25， 73.35， 52.77， 36.29， 31.36， 28.37， 28.18， 19.08， 13.83; ESI-MS [M+Na]+ m/z 378.1807。
EXAMPLE 11 Synthesis of (9H-fluoren-9-yl) methyl (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate
To a 25mL reaction vial were added 1-methylquinoxalin-2 (1H) -one (0.3 mmol, 0.048 g) and tert-butyl (9H-fluoren-9-yl) methyl (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate (0.9 mmol, 0.266 g), iodobenzene acetate (0.75 mmol, 0.244 g), sodium azide (0.75 mmol, 0.049 g), dichloromethane (0.3 mL). The reaction was stirred at 30 ℃ under nitrogen for 7 h and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate =12:1 elution gave 82 mg of (9H-fluoren-9-yl) methyl (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) carbamate as a pale yellow liquid. The yield was 60%.
EXAMPLE 124 Synthesis of methyl-N- (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) benzenesulfonamide
To a 25mL reaction flask were added 1-methylquinoxalin-2 (1H) -one (0.3 mmol, 0.048 g) and N-butyl-4-methylbenzenesulfonamide (0.9 mmol, 0.205 g), diiodophenyliodocarbonyl chloride (1.2 mmol, 0.380 g), trimethylsilyl azide (0.75 mmol, 0.086 g), dichloromethane (0.3 mL). The reaction was stirred at 20 ℃ under nitrogen for 10 h and quenched with saturated sodium bicarbonate. The reaction mixture was then diluted with dichloromethane and water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel chromatography, with petroleum ether: ethyl acetate =12:1 volume ratio was eluted to give 71mg of 4-methyl-N- (1- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) butyl) benzenesulfonamide as a pale yellow liquid. The yield was 65%.

Claims (12)

1. A process for the alkylation of the α -amino group at position C3 of a quinoxalinone characterized in that said process is as follows: adding a quinoxalinone compound shown in a formula (I) and an organic amine shown in a formula (II) into a reaction vessel, then adding a high-valence iodine reagent, an azide reagent and a solvent, reacting at a certain temperature, adding saturated sodium bicarbonate after the reaction is finished to quench the reaction, diluting dichloromethane and water, extracting with dichloromethane, washing an organic layer with saturated saline solution, and purifying to obtain a product shown in a formula (III), wherein the reaction equation is as follows:
Figure DEST_PATH_IMAGE001
in the formula, R1Is methyl, methoxy, fluorine, chlorine, bromine or nitro; r2Is one of alkyl, alkene, alkyne or substituted aryl with 1-15 carbons and substituted benzenesulfonyl; r3Is alkyl, cyclic substituted alkane or aryl with 1-10 carbons; r4Is H or is alkyl of 1-10 carbons; r5Is H, alkyl with 1-10 carbons, aryl, benzyl, formate group or fluorenylmethoxycarbonyl; the high-valence iodineThe reagent is one or more of iodobenzene acetate, o-iodoxybenzoic acid, bis (trifluoroacetic acid) iodobenzene and diphenyl iodoxychloride; the azide reagent is one or more of trimethylsilyl azide and sodium azide, and the reaction temperature is-20-30 ℃.
2. The process for the alkylation of α -amino group at position C3 of quinoxalinone according to claim 1 characterized in that the higher iodine reagent is one or more of iodobenzene acetate, o-iodobenzoic acid, iodobenzene bis (trifluoroacetic acid) and diphenyliodocarbonyl chloride and is used in an amount of 0.5 to 4 molar equivalents of quinoxalinone compound.
3. The process for the alkylation of α -amino group at position C3 of quinoxalinone according to claim 1 characterized in that the higher iodine reagent is one or more of iodobenzene acetate, o-iodobenzoic acid, iodobenzene bis (trifluoroacetic acid) and diphenyliodocarbonyl chloride and is used in an amount of 2 to 3 molar equivalents of quinoxalinone compound.
4. The process for the alkylation of the α -amino group at C3 of quinoxalinone according to claim 1 characterized in that the solvent of the reaction is one or more of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 1, 2-dichloromethane, nitromethane.
5. The process for the alkylation of the α -amino group at position C3 of a quinoxalinone according to claim 1 characterized in that the solvent of the reaction is 1, 2-dichloromethane.
6. The process for the alpha-aminoalkylation of the quinoxalinone C3 according to claim 1 wherein the azide reagent is azidotrimethylsilane and the amount of azide reagent is 0.5 to 4 molar equivalents of the quinoxalinone compound.
7. The method for the alkylation of α -amino group at C3 of quinoxalinone according to claim 1 characterized in that the azide reagent is used in an amount of 2 to 3 molar equivalents of quinoxalinone compound.
8. The process for the alkylation of the α -amino group at position C3 of quinoxalinone according to claim 1 characterized in that the reaction temperature is-10 to 10 ℃.
9. The process for the alkylation of the α -amino group at position C3 of a quinoxalinone according to claim 1 characterized in that the reaction time is 1-24 h.
10. A process for the alkylation of the α -amino group at C3 of a quinoxalinone according to claim 1 characterized in that the reaction time is 8-15 h.
11. The method for the alkylation of the α -amino group at the C3 position of quinoxalinone according to claim 1, the molar ratio of the quinoxalinone compound of formula (I) to the organic amine of formula (II) is from 1:1 to 1: 5.
12. The method for the alkylation of the α -amino group at the C3 position of quinoxalinone according to claim 1, the molar ratio of the quinoxalinone compound of formula (I) to the organic amine of formula (II) is from 1:2 to 1: 3.
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