CN105001169B - A kind of synthetic method of 3 aminoquinoxaline 2 (1H) ketone compounds - Google Patents
A kind of synthetic method of 3 aminoquinoxaline 2 (1H) ketone compounds Download PDFInfo
- Publication number
- CN105001169B CN105001169B CN201510399965.7A CN201510399965A CN105001169B CN 105001169 B CN105001169 B CN 105001169B CN 201510399965 A CN201510399965 A CN 201510399965A CN 105001169 B CN105001169 B CN 105001169B
- Authority
- CN
- China
- Prior art keywords
- quinoxalin
- quinoxaline
- benzyl
- reaction
- synthetic method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 ketone compounds Chemical class 0.000 title claims description 27
- 238000010189 synthetic method Methods 0.000 title claims description 12
- YOWAEZWWQFSEJD-UHFFFAOYSA-N quinoxalin-2-amine Chemical compound C1=CC=CC2=NC(N)=CN=C21 YOWAEZWWQFSEJD-UHFFFAOYSA-N 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 86
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 82
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims abstract description 37
- 150000001412 amines Chemical class 0.000 claims abstract description 17
- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical class C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 claims abstract description 14
- QBBADXPVZMYLKN-UHFFFAOYSA-N 3-amino-1h-quinoxalin-2-one Chemical class C1=CC=C2NC(=O)C(N)=NC2=C1 QBBADXPVZMYLKN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 87
- 238000004440 column chromatography Methods 0.000 claims description 26
- 239000012074 organic phase Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 24
- XSIQIJZHBWPBDQ-UHFFFAOYSA-N 1-benzylquinoxalin-2-one Chemical compound O=C1C=NC2=CC=CC=C2N1CC1=CC=CC=C1 XSIQIJZHBWPBDQ-UHFFFAOYSA-N 0.000 claims description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 6
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 6
- MXCHQPNFSLYUJV-UHFFFAOYSA-N 1-ethylquinoxalin-2-one Chemical compound C1=CC=C2N=CC(=O)N(CC)C2=C1 MXCHQPNFSLYUJV-UHFFFAOYSA-N 0.000 claims description 4
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- CJAAPVQEZPAQNI-UHFFFAOYSA-N (2-methylphenyl)methanamine Chemical compound CC1=CC=CC=C1CN CJAAPVQEZPAQNI-UHFFFAOYSA-N 0.000 claims description 3
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 claims description 3
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 claims description 3
- QMIXTCHIBACQHV-UHFFFAOYSA-N 1-benzyl-6,7-dimethylquinoxalin-2-one Chemical compound CC=1C=C2N=CC(N(C2=CC=1C)CC1=CC=CC=C1)=O QMIXTCHIBACQHV-UHFFFAOYSA-N 0.000 claims description 3
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims description 3
- LRSIAADTOWRQHP-UHFFFAOYSA-N 1h-benzo[h]quinoxalin-2-one Chemical compound C1=CC=CC2=C(NC(=O)C=N3)C3=CC=C21 LRSIAADTOWRQHP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 3
- BDVJLKWSNDCCPL-UHFFFAOYSA-N 6,7-dichloro-1h-quinoxalin-2-one Chemical compound N1=CC(=O)NC2=C1C=C(Cl)C(Cl)=C2 BDVJLKWSNDCCPL-UHFFFAOYSA-N 0.000 claims description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical group OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 3
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- NWJUMMHVDMNYMJ-UHFFFAOYSA-N n-benzyl-1,1,1-trifluoromethanamine Chemical compound FC(F)(F)NCC1=CC=CC=C1 NWJUMMHVDMNYMJ-UHFFFAOYSA-N 0.000 claims description 3
- XKJNNAHTBHNMRH-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]quinoxalin-2-one Chemical compound C1=CC(OC)=CC=C1CN1C(=O)C=NC2=CC=CC=C21 XKJNNAHTBHNMRH-UHFFFAOYSA-N 0.000 claims description 2
- BDMMFGNGMKADPW-UHFFFAOYSA-N 1-benzyl-6,7-dichloroquinoxalin-2-one Chemical compound ClC=1C=C2N=CC(N(C2=CC=1Cl)CC1=CC=CC=C1)=O BDMMFGNGMKADPW-UHFFFAOYSA-N 0.000 claims description 2
- YXHOLYSXLHTIOT-UHFFFAOYSA-N 6,7-dimethyl-1h-quinoxalin-2-one Chemical compound N1=CC(=O)NC2=C1C=C(C)C(C)=C2 YXHOLYSXLHTIOT-UHFFFAOYSA-N 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims 4
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims 2
- 239000000243 solution Substances 0.000 claims 2
- 101100074846 Caenorhabditis elegans lin-2 gene Proteins 0.000 claims 1
- 101100497386 Mus musculus Cask gene Proteins 0.000 claims 1
- 238000010790 dilution Methods 0.000 claims 1
- 239000012895 dilution Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 abstract description 8
- 125000000217 alkyl group Chemical group 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 150000002367 halogens Chemical group 0.000 abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- 150000002148 esters Chemical group 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 239000000654 additive Substances 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 150000003457 sulfones Chemical class 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 239000011734 sodium Substances 0.000 description 24
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- XGIHSLWERDNSQU-UHFFFAOYSA-N 3-morpholin-4-yl-1h-quinoxalin-2-one Chemical compound O=C1NC2=CC=CC=C2N=C1N1CCOCC1 XGIHSLWERDNSQU-UHFFFAOYSA-N 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明公开了一种3‑氨基喹喔啉‑2(1H)‑酮类化合物的合成方法，将喹喔啉‑2(1H)‑酮衍生物、有机胺和醋酸铜溶于二甲基亚砜中，在空气条件下，于95～110℃反应10～25小时后，经分离纯化，即得所述3‑氨基喹喔啉‑2(1H)‑酮类化合物，其中喹喔啉‑2(1H)‑酮衍生物、有机胺和醋酸铜的摩尔比为0.9～1.2:2.8～3.3:0.03～0.06，每毫摩尔喹喔啉‑2(1H)‑酮衍生物需2～3mL二甲基亚砜溶液，上述喹喔啉‑2(1H)‑酮衍生物的结构通式如下：其中R1为氢、烷基、芳基、卤素或烷氧基，R2为氢、苄基、烷基或酯基。本发明的方法所用原料易得，反应条件温和，无需额外加入添加剂，催化剂投量低，收率高；底物范围广，反应专一性强，后处理简便且绿色。The invention discloses a method for synthesizing 3-aminoquinoxaline-2(1H)-one compounds, which comprises dissolving quinoxaline-2(1H)-one derivatives, organic amine and copper acetate in dimethyl In the sulfone, under air conditions, react at 95-110°C for 10-25 hours, and then separate and purify to obtain the 3-aminoquinoxaline-2(1H)-ketone compounds, wherein quinoxaline-2 The molar ratio of (1H)-ketone derivatives, organic amines and copper acetate is 0.9-1.2:2.8-3.3:0.03-0.06, and each millimole of quinoxaline-2(1H)-one derivatives requires 2-3 mL of dimethyl sulfoxide solution, the general structural formula of the above-mentioned quinoxaline-2 (1H)-ketone derivative is as follows: wherein R1 is hydrogen, alkyl, aryl, halogen or alkoxy, and R2 is hydrogen , benzyl, alkyl or ester. The raw materials used in the method of the invention are easy to obtain, the reaction conditions are mild, no additional additives are needed, the catalyst dosage is low, and the yield is high; the substrate range is wide, the reaction specificity is strong, and the aftertreatment is simple and green.
Description
技术领域technical field
本发明属于有机合成技术领域，具体涉及一种3-氨基喹喔啉-2(1H)-酮类化合物的合成方法。The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method of 3-aminoquinoxaline-2(1H)-one compounds.
背景技术Background technique
3-氨基喹喔啉-2(1H)-酮类化合物是是药物设计领域的常用药效团，含有该结构母核的衍生物具有多种药理活性，被广泛用作抗肿瘤剂、抗癌剂、醛糖还原酶抑制剂、抗菌剂等，是一类潜在的多用途先导化合物，已经在不同的临床试验中使用，具有广阔的开发应用前景。近年来化学家们一直在尝试。一些体系已经成功地应用于这一反应，取得了一定的研究结果。但存在诸多问题，比如：反应步骤复杂、反应条件苛刻、反应时间长、副产物多，收率低、底物范围较窄，需要强氧化剂等不绿化环保试剂等等。3-Aminoquinoxaline-2(1H)-one compounds are commonly used pharmacophore in the field of drug design. Derivatives containing the core of this structure have a variety of pharmacological activities and are widely used as anti-tumor agents, anti-cancer Drugs, aldose reductase inhibitors, antibacterial agents, etc., are a class of potential multi-purpose lead compounds, which have been used in different clinical trials and have broad development and application prospects. Chemists have been trying in recent years. Some systems have been successfully applied to this reaction, and some research results have been obtained. However, there are many problems, such as: complex reaction steps, harsh reaction conditions, long reaction time, many by-products, low yield, narrow substrate range, and the need for strong oxidants and other non-green and environmentally friendly reagents.
发明内容Contents of the invention
本发明的目的在于克服现有技术缺陷，提供一种3-氨基喹喔啉-2(1H)-酮类化合物的合成方法。The purpose of the present invention is to overcome the defects of the prior art and provide a synthetic method of 3-aminoquinoxalin-2(1H)-one compounds.
本发明的具体技术方案如下：Concrete technical scheme of the present invention is as follows:
一种3-氨基喹喔啉-2(1H)-酮类化合物的合成方法，将喹喔啉-2(1H)-酮衍生物、有机胺和醋酸铜溶于二甲基亚砜中，在空气条件下，于95～110℃反应10～25小时后，经分离纯化，即得所述3-氨基喹喔啉-2(1H)-酮类化合物，其中喹喔啉-2(1H)-酮衍生物、有机胺和醋酸铜的摩尔比为0.9～1.2:2.8～3.3:0.03～0.06，每毫摩尔喹喔啉-2(1H)-酮衍生物需2～3mL二甲基亚砜溶液，上述喹喔啉-2(1H)-酮衍生物的结构通式如下：A kind of synthetic method of 3-aminoquinoxaline-2 (1H)-one compound, quinoxaline-2 (1H)-ketone derivative, organic amine and copper acetate are dissolved in dimethyl sulfoxide, in Under air conditions, react at 95-110°C for 10-25 hours, and then separate and purify to obtain the 3-aminoquinoxaline-2(1H)-one compounds, wherein quinoxaline-2(1H)- The molar ratio of ketone derivatives, organic amines and copper acetate is 0.9~1.2:2.8~3.3:0.03~0.06, and 2~3mL dimethyl sulfoxide solution is required for every millimole of quinoxalin-2(1H)-one derivatives , the general structural formula of the above-mentioned quinoxaline-2 (1H)-ketone derivatives is as follows:
其中R1为氢、烷基、芳基、卤素或烷氧基，R2为氢、苄基、烷基或酯基。wherein R1 is hydrogen, alkyl, aryl, halogen or alkoxy, and R2 is hydrogen , benzyl, alkyl or ester.
在本发明的一个优选实施方案中，所述R1为甲基或Cl，R2为氢、苄基、乙基、乙酸乙酯基或4-甲氧基苄基。In a preferred embodiment of the present invention, said R 1 is methyl or Cl, and R 2 is hydrogen, benzyl, ethyl, ethyl acetate or 4-methoxybenzyl.
在本发明的一个优选实施方案中，所述喹喔啉-2(1H)-酮衍生物为喹喔啉-2(1H)-酮、6,7-二甲基-喹喔啉-2(1H)-酮、6,7-二氯-喹喔啉-2(1H)-酮、苯并喹喔啉-2(1H)-酮、1-苄基-喹喔啉-2(1H)-酮、1-乙基-喹喔啉-2(1H)-酮、1-乙酸乙酯基-喹喔啉-2(1H)-酮、4-甲氧基苄基-喹喔啉-2(1H)-酮、6,7-二甲基-1-苄基-喹喔啉-2(1H)-酮或6,7-二氯-1-苄基-喹喔啉-2(1H)-酮。In a preferred embodiment of the present invention, the quinoxalin-2(1H)-one derivatives are quinoxalin-2(1H)-one, 6,7-dimethyl-quinoxaline-2( 1H)-one, 6,7-dichloro-quinoxaline-2(1H)-one, benzoquinoxaline-2(1H)-one, 1-benzyl-quinoxaline-2(1H)- Ketone, 1-ethyl-quinoxaline-2(1H)-one, 1-acetate ethyl-quinoxaline-2(1H)-one, 4-methoxybenzyl-quinoxaline-2( 1H)-one, 6,7-dimethyl-1-benzyl-quinoxaline-2(1H)-one or 6,7-dichloro-1-benzyl-quinoxaline-2(1H)- ketone.
在本发明的一个优选实施方案中，所述有机胺为脂肪胺。进一步优选的，所述有机胺为吗啉、哌啶、四氢吡咯、正丙胺、异丙胺、异丙胺、环己胺、苄胺、4-甲基苄胺、2-甲基苄胺、4-甲氧基苄胺、三氟甲基苄胺、α-甲基苄胺、二苯甲胺或乙醇胺。In a preferred embodiment of the present invention, the organic amine is an aliphatic amine. Further preferably, the organic amine is morpholine, piperidine, tetrahydropyrrole, n-propylamine, isopropylamine, isopropylamine, cyclohexylamine, benzylamine, 4-methylbenzylamine, 2-methylbenzylamine, 4 - methoxybenzylamine, trifluoromethylbenzylamine, α-methylbenzylamine, benzhydrylamine or ethanolamine.
在本发明的一个优选实施方案中，将喹喔啉-2(1H)-酮衍生物、有机胺和醋酸铜溶于二甲基亚砜中，在空气条件下，于100℃反应12～24小时。In a preferred embodiment of the present invention, quinoxalin-2(1H)-one derivatives, organic amines and copper acetate are dissolved in dimethyl sulfoxide, and reacted at 100°C for 12 to 24 hours under air conditions. Hour.
在本发明的一个优选实施方案中，喹喔啉-2(1H)-酮衍生物、有机胺和醋酸铜的摩尔比为1:3:0.05。In a preferred embodiment of the present invention, the molar ratio of quinoxalin-2(1H)-one derivative, organic amine and copper acetate is 1:3:0.05.
在本发明的一个优选实施方案中，每毫摩尔喹喔啉-2(1H)-酮衍生物需2mL二甲基亚砜溶液。In a preferred embodiment of the present invention, 2 mL of dimethylsulfoxide solution is required per mmol of quinoxalin-2(1H)-one derivative.
在本发明的一个优选实施方案中，所述分离纯化包括：反应完毕后降到室温，加入乙酸乙酯稀释，用水萃取，有机相用无水硫酸钠干燥再过滤后，经柱色谱分离纯化即得所述3-氨基喹喔啉-2(1H)-酮类化合物。In a preferred embodiment of the present invention, the separation and purification include: cooling down to room temperature after the reaction is completed, diluting with ethyl acetate, extracting with water, drying the organic phase with anhydrous sodium sulfate and filtering, and separating and purifying by column chromatography. The 3-aminoquinoxalin-2(1H)-one compounds are obtained.
本发明的有益效果是：The beneficial effects of the present invention are:
1、本发明的合成方法将喹喔啉-2(1H)-酮衍生物、有机胺和醋酸铜溶于有机溶剂中，在空气条件下，于95～110℃反应10～25小时后，经分离纯化，即得所述3-氨基喹喔啉-2(1H)-酮类化合物，原料易得，反应条件温和，无需额外加入添加剂，催化剂投量低，收率高(最高达98％)；底物范围广，反应专一性强，后处理简便且绿色。1. In the synthetic method of the present invention, quinoxalin-2(1H)-ketone derivatives, organic amines and copper acetate are dissolved in an organic solvent, and under air conditions, after reacting for 10 to 25 hours at 95 to 110° C., through Separation and purification to obtain the 3-aminoquinoxalin-2(1H)-one compounds, the raw materials are easy to obtain, the reaction conditions are mild, no additional additives are needed, the catalyst dosage is low, and the yield is high (up to 98%) ; Wide range of substrates, strong reaction specificity, easy post-processing and green.
2、本发明的合成方法的体系适用范围较广，兼容卤素，甲基，甲氧基，三氟甲基等多种基团。2. The system of the synthesis method of the present invention has a wide range of applications, and is compatible with various groups such as halogen, methyl, methoxy, and trifluoromethyl.
具体实施方式detailed description
以下通过具体实施方式对本发明的技术方案进行进一步的说明和描述。The technical solutions of the present invention will be further illustrated and described below through specific embodiments.
实施例1Example 1
3-吗啉基喹喔啉-2(1H)-酮的制备Preparation of 3-Morpholinylquinoxalin-2(1H)-one
将喹喔啉-2(1H)-酮0.2mmol，吗啉0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到44.8mg目标产物，收率为97％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ10.83(s,1H),7.57–7.51(m,1H),7.26–7.18(m,2H),7.15–7.09(m,1H),4.07–4.00(m,4H),3.90–3.85(m,4H)ppm；13C NMR(100MHz,CDCl3):δ153.4,150.8,133.1,128.5,126.0,125.3,124.3,114.3,66.9,47.3ppm；HRMS(ESI,m/z):calculated for C12H13N3O2[M+H]+:232.1086,found:232.1082.Add 0.2mmol of quinoxalin-2(1H)-one, 0.6mmol of morpholine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place it in an oil bath at 100°C under air conditions. Reaction 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 44.8 mg of the target product with a yield of 97%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ10.83(s, 1H), 7.57–7.51(m, 1H), 7.26–7.18(m, 2H), 7.15–7.09(m, 1H ),4.07–4.00(m,4H),3.90–3.85(m,4H)ppm; 13 C NMR(100MHz,CDCl 3 ):δ153.4,150.8,133.1,128.5,126.0,125.3,124.3,114.3,66.9,47.3 ppm; HRMS(ESI,m/z):calculated for C 12 H 13 N 3 O 2 [M+H] + :232.1086,found:232.1082.
实施例2Example 2
6,7-二甲基-3-吗啉基喹喔啉-2(1H)-酮的制备Preparation of 6,7-Dimethyl-3-morpholinylquinoxalin-2(1H)-one
将6,7-二甲基-喹喔啉-2(1H)-酮0.2mmol，吗啉0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到50.3mg目标产物，收率为97％。该化合物的表征如下：1H NMR(400MHz,DMSO):δ12.02(s,1H),7.21(s,1H),6.94(s,1H),3.90–3.75(m,4H),3.75–3.62(m,4H),2.23(d,J＝2.5Hz,6H)ppm；13C NMR(101MHz,DMSO):δ152.9,151.8,134.6,132.3,131.2,128.2,126.6,115.6,67.0,47.7,20.3,19.9ppm；HRMS(ESI,m/z):calculated for C14H17N3O2[M+H]+:260.1399,found:260.1397.Add 0.2mmol of 6,7-dimethyl-quinoxalin-2(1H)-one, 0.6mmol of morpholine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place at 100°C In an oil bath, react under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 50.3 mg of the target product with a yield of 97%. The compound was characterized as follows: 1 H NMR (400MHz, DMSO): δ12.02(s,1H),7.21(s,1H),6.94(s,1H),3.90–3.75(m,4H),3.75–3.62 (m,4H),2.23(d,J=2.5Hz,6H)ppm; 13 C NMR(101MHz,DMSO):δ152.9,151.8,134.6,132.3,131.2,128.2,126.6,115.6,67.0,47.7,20.3, 19.9ppm; HRMS(ESI,m/z):calculated for C 14 H 17 N 3 O 2 [M+H] + :260.1399,found:260.1397.
实施例3Example 3
6,7-二氯-3-吗啉基喹喔啉-2(1H)-酮的制备Preparation of 6,7-dichloro-3-morpholinylquinoxalin-2(1H)-one
将6,7-二氯-喹喔啉-2(1H)-酮0.2mmol，吗啉0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到55.2mg目标产物，收率为92％。该化合物的表征如下：1H NMR(400MHz,DMSO):δ12.23(s,1H),7.55(s,1H),7.29(s,1H),3.95(s,4H),3.70(s,4H)ppm；13C NMR(100MHz,DMSO):δ152.7,152.1,133.3,130.0,126.6,126.5,125.7,116.1,67.0,47.6ppm；HRMS(ESI,m/z):calculated for C12H11Cl2N3O2[M+H]+:300.0307,found:300.0303.Add 0.2mmol of 6,7-dichloro-quinoxalin-2(1H)-one, 0.6mmol of morpholine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in a 100°C In an oil bath, react under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 55.2 mg of the target product with a yield of 92%. The compound was characterized as follows: 1 H NMR (400MHz, DMSO): δ12.23(s,1H),7.55(s,1H),7.29(s,1H),3.95(s,4H),3.70(s,4H )ppm; 13 C NMR (100MHz, DMSO): δ152.7, 152.1, 133.3, 130.0, 126.6, 126.5, 125.7, 116.1, 67.0, 47.6ppm; HRMS (ESI, m/z): calculated for C 12 H 11 Cl 2 N 3 O 2 [M+H] + :300.0307,found:300.0303.
实施例4Example 4
3-吗啉基-苯并喹喔啉-2(1H)-酮的制备Preparation of 3-Morpholinyl-Benzoquinoxalin-2(1H)-one
将苯并喹喔啉-2(1H)-酮0.2mmol，吗啉0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到43.3mg目标产物，收率为77％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ9.42(s,1H),7.98(s,1H),7.86(d,J＝7.4Hz,1H),7.79(d,J＝7.6Hz,1H),7.50–7.35(m,3H),4.13–4.01(m,4H),3.96–3.80(m,4H)ppm；13C NMR(100MHz,CDCl3):δ153.1,150.3,132.6,131.0,131.0,128.3,127.8,126.6,125.9,124.9,123.3,109.7,67.0,47.4ppm；HRMS(ESI,m/z):calculated for C16H15N3O2[M+H]+:282.1243,found:282.1239.Add 0.2mmol of benzoquinoxalin-2(1H)-one, 0.6mmol of morpholine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, place in an oil bath at 100°C, and air Under the condition of reaction for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 43.3 mg of the target product with a yield of 77%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ9.42(s, 1H), 7.98(s, 1H), 7.86(d, J=7.4Hz, 1H), 7.79(d, J= 7.6Hz,1H),7.50–7.35(m,3H),4.13–4.01(m,4H),3.96–3.80(m,4H)ppm; 13 C NMR(100MHz,CDCl 3 ):δ153.1,150.3,132.6, 131.0,131.0,128.3,127.8,126.6,125.9,124.9,123.3,109.7,67.0,47.4ppm; HRMS(ESI,m/z):calculated for C 16 H 15 N 3 O 2 [M+H] + :282.1243 ,found: 282.1239.
实施例5Example 5
1-苄基-3-吗啉基喹喔啉-2(1H)-酮的制备Preparation of 1-Benzyl-3-Morpholinylquinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，吗啉0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到62.9mg目标产物，收率为98％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.61–7.51(m,1H),7.30(ddd,J1＝7.5Hz,J2＝6.2Hz,J3＝1.3Hz,2H),7.26–7.04(m,6H),5.47(s,2H),4.05–3.95(m,4H),3.86(dd,J1＝6.0Hz,J2＝3.5Hz,4H)ppm；13C NMR(100MHz,CDCl3):δ152.3,150.8,135.5,133.2,130.2,128.9,127.5,127.0,126.7,125.4,123.9,114.1,67.0,47.6,46.1ppm；HRMS(ESI,m/z):calculated for C19H19N3O2[M+H]+:322.1556,found:322.1554.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of morpholine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in an oil bath at 100°C , under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 62.9 mg of the target product with a yield of 98%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.61–7.51 (m, 1H), 7.30 (ddd, J 1 =7.5Hz, J 2 =6.2Hz, J 3 =1.3Hz, 2H ), 7.26–7.04(m,6H), 5.47(s,2H), 4.05–3.95(m,4H), 3.86(dd, J 1 =6.0Hz, J 2 =3.5Hz,4H) ppm; 13 C NMR (100MHz, CDCl 3 ): δ152.3, 150.8, 135.5, 133.2, 130.2, 128.9, 127.5, 127.0, 126.7, 125.4, 123.9, 114.1, 67.0, 47.6, 46.1ppm; HRMS (ESI, m/z): calculated for C 19 H 19 N 3 O 2 [M+H] + :322.1556,found:322.1554.
实施例6Example 6
1-乙基-3-吗啉基喹喔啉-2(1H)-酮的制备Preparation of 1-ethyl-3-morpholinoquinoxalin-2(1H)-one
将1-乙基-喹喔啉-2(1H)-酮0.2mmol，吗啉0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到49.2mg目标产物，收率为95％。该化合物的表征如下：1H NMR(400MHz,DMSO):δ7.50–7.42(m,2H),7.31(dd,J1＝8.3Hz,J2＝1.3Hz,1H),7.27–7.21(m,1H),4.24(q,J＝7.1Hz,2H),3.91–3.80(m,4H),3.76–3.65(m,4H),1.23(t,J＝7.1Hz,3H)ppm；13C NMR(100MHz,DMSO)δ151.7,151.3,133.5,130.3,127.3,126.3,124.3,114.8,67.0,48.0,37.9,13.2ppm；HRMS(ESI,m/z):calculated for C14H17N3O2[M+H]+:260.1399,found:260.1396.Add 0.2mmol of 1-ethyl-quinoxalin-2(1H)-one, 0.6mmol of morpholine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in an oil bath at 100°C , under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 49.2 mg of the target product with a yield of 95%. The compound was characterized as follows: 1 H NMR (400MHz, DMSO): δ7.50-7.42(m, 2H), 7.31(dd, J 1 =8.3Hz, J 2 =1.3Hz, 1H), 7.27-7.21(m ,1H),4.24(q,J=7.1Hz,2H),3.91–3.80(m,4H),3.76–3.65(m,4H),1.23(t,J=7.1Hz,3H)ppm; 13 C NMR [ _ _ _ M+H] + :260.1399,found:260.1396.
实施例7Example 7
1-乙酸乙酯基-3-吗啉基喹喔啉-2(1H)-酮制备Preparation of 1-acetate ethyl-3-morpholinoquinoxalin-2(1H)-one
将1-乙酸乙酯基-喹喔啉-2(1H)-酮0.2mmol，吗啉0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到62.1mg目标产物，收率为98％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.59–7.52(m,1H),7.26–7.22(m,2H),7.01–6.93(m,1H),4.99(s,2H),4.25(q,J＝7.2Hz,2H),4.01–3.93(m,4H),3.88–3.80(m,4H),1.31–1.24(m,3H)ppm；13C NMR(100MHz,CDCl3)δ167.3,152.0,150.2,133.1,123.0,127.1,125.5,124.1,112.7,67.0,62.0,47.5,43.9,14.1ppm；HRMS(ESI,m/z):calculated for C16H19N3O4[M+H]+:318.1454,found:318.1451.Add 0.2mmol of 1-ethyl acetate-quinoxalin-2(1H)-one, 0.6mmol of morpholine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in a 100°C In an oil bath, react under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 62.1 mg of the target product with a yield of 98%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.59–7.52(m,1H),7.26–7.22(m,2H),7.01–6.93(m,1H),4.99(s,2H ), 4.25(q, J=7.2Hz, 2H), 4.01–3.93(m,4H), 3.88–3.80(m,4H), 1.31–1.24(m,3H)ppm; 13 C NMR (100MHz, CDCl 3 )δ167.3, 152.0, 150.2, 133.1, 123.0, 127.1, 125.5, 124.1, 112.7, 67.0, 62.0, 47.5, 43.9, 14.1ppm; HRMS (ESI, m/z): calculated for C 16 H 19 N 3 O 4 [ M+H] + :318.1454,found:318.1451.
实施例8Example 8
4-甲氧基苄基-3-吗啉基喹喔啉-2(1H)-酮的制备Preparation of 4-methoxybenzyl-3-morpholinoquinoxalin-2(1H)-one
将4-甲氧基苄基-喹喔啉-2(1H)-酮0.2mmol，吗啉0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到65.4mg目标产物，收率为93％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.58–7.53(m,1H),7.23–7.16(m,5H),6.86–6.79(m,2H),5.41(s,2H),4.01–3.95(m,4H),3.89–3.84(m,4H),3.76(s,3H)ppm；13C NMR(100MHz,CDCl3):δ159.0,152.3,150.9,133.2,130.2,128.2,127.5,127.0,125.4,123.8,114.2,114.1,67.0,55.3,47.6,45.6ppm；HRMS(ESI,m/z):calculated for C20H21N3O3[M+H]+:352.1661,found:352.1657.Add 0.2mmol of 4-methoxybenzyl-quinoxalin-2(1H)-one, 0.6mmol of morpholine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place at 100°C In an oil bath, react under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 65.4 mg of the target product with a yield of 93%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.58–7.53(m,1H),7.23–7.16(m,5H),6.86–6.79(m,2H),5.41(s,2H ),4.01–3.95(m,4H),3.89–3.84(m,4H),3.76(s,3H)ppm; 13 C NMR(100MHz,CDCl 3 ):δ159.0,152.3,150.9,133.2,130.2,128.2, 127.5,127.0,125.4,123.8,114.2,114.1,67.0,55.3,47.6,45.6ppm; HRMS(ESI,m/z):calculated for C 20 H 21 N 3 O 3 [M+H] + :352.1661,found :352.1657.
实施例9Example 9
6,7-二甲基-1-苄基-3-吗啉基喹喔啉-2(1H)-酮的制备Preparation of 6,7-Dimethyl-1-benzyl-3-morpholinylquinoxalin-2(1H)-one
将6,7-二甲基-1-苄基-喹喔啉-2(1H)-酮0.2mmol，吗啉0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到54.5mg目标产物，收率为78％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.38–7.27(m,3H),7.24(dt,J1＝12.0Hz,J2＝4.1Hz,3H),6.92(s,1H),5.44(s,2H),3.96–3.83(m,8H),2.26(d,J＝9.4Hz,6H)ppm；13C NMR(100MHz,CDCl3):δ152.2,150.7,135.7,134.7,132.6,131.3,128.8,128.2,127.5,127.4,126.7,114.7,66.9,47.7,46.0,20.2,19.1ppm；HRMS(ESI,m/z):calculated for C21H23N3O2[M+H]+:350.1869,found:350.1865.Add 0.2mmol of 6,7-dimethyl-1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of morpholine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube , placed in an oil bath at 100°C, and reacted under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 54.5 mg of the target product with a yield of 78%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.38–7.27(m, 3H), 7.24(dt, J 1 =12.0Hz, J 2 =4.1Hz, 3H), 6.92(s, 1H), 5.44(s, 2H), 3.96–3.83(m, 8H), 2.26(d, J=9.4Hz, 6H) ppm; 13 C NMR (100MHz, CDCl 3 ): δ152.2, 150.7, 135.7, 134.7, 132.6, 131.3, 128.8, 128.2, 127.5, 127.4, 126.7, 114.7, 66.9, 47.7, 46.0, 20.2, 19.1ppm; HRMS (ESI, m/z): calculated for C 21 H 23 N 3 O 2 [M+H ] + :350.1869,found:350.1865.
实施例10Example 10
6,7-二氯-1-苄基-3-吗啉基喹喔啉-2(1H)-酮的制备Preparation of 6,7-dichloro-1-benzyl-3-morpholinylquinoxalin-2(1H)-one
将6,7-二氯-1-苄基-喹喔啉-2(1H)-酮0.2mmol，吗啉0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到60.1mg目标产物，收率为77％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.60(s,1H),7.39–7.27(m,3H),7.23–7.16(m,3H),5.38(s,2H),4.07–4.00(m,4H),3.87–3.81(m,4H)ppm；13C NMR(101MHz,CDCl3):δ151.8,150.6,134.6,132.9,129.4,129.1,128.3,127.9,127.5,127.4,126.7,115.3,66.947.5,46.4ppm；HRMS(ESI,m/z):calculated for C19H17Cl2N3O2[M+H]+:390.0776,found:390.0773.Add 0.2mmol of 6,7-dichloro-1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of morpholine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, Placed in an oil bath at 100°C, reacted under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 60.1 mg of the target product with a yield of 77%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.60(s,1H),7.39–7.27(m,3H),7.23–7.16(m,3H),5.38(s,2H), 4.07–4.00(m,4H),3.87–3.81(m,4H)ppm; 13 C NMR(101MHz,CDCl 3 ):δ151.8,150.6,134.6,132.9,129.4,129.1,128.3,127.9,127.5,127.4,126.7 ,115.3,66.947.5,46.4ppm; HRMS(ESI,m/z):calculated for C 19 H 17 C l2 N 3 O 2 [M+H] + :390.0776,found:390.0773.
实施例11Example 11
3-哌啶基-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-piperidinyl-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，哌啶0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到60.0mg目标产物，收率为94％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.53(s,1H),7.29(d,J＝7.3Hz,2H),7.23(t,J＝8.1Hz,3H),7.12(dd,J1＝17.3Hz,J2＝14.4Hz,3H),5.47(s,2H),3.89(d,J＝5.3Hz,4H),1.72(s,6H)ppm；13CNMR(101MHz,CDCl3):δ152.5,151.4,135.7,133.7,130.0,128.8,127.4,126.7,126.6,124.6,123.7,114.0,48.4,46.1,26.1,24.9ppm；HRMS(ESI,m/z):calculated for C20H21N3O[M+H]+:320.1763,found:320.1761.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of piperidine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in an oil bath at 100°C , under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 60.0 mg of the target product with a yield of 94%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.53(s, 1H), 7.29(d, J=7.3Hz, 2H), 7.23(t, J=8.1Hz, 3H), 7.12 (dd, J 1 ＝17.3Hz, J 2 ＝14.4Hz, 3H), 5.47(s, 2H), 3.89(d, J＝5.3Hz, 4H), 1.72(s, 6H)ppm; 13 CNMR(101MHz, CDCl 3 ): δ152.5, 151.4, 135.7, 133.7, 130.0, 128.8, 127.4, 126.7, 126.6, 124.6, 123.7, 114.0, 48.4, 46.1, 26.1, 24.9ppm; HRMS (ESI, m/z): calculated for C 20 H 21 N 3 O[M+H] + :320.1763,found:320.1761.
实施例12Example 12
3-四氢吡咯基-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-tetrahydropyrrolyl-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，四氢吡咯0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到44.6mg目标产物，收率为73％。该化合物的表征如下：1HNMR(400MHz,CDCl3):δ7.51–7.44(m,1H),7.34–7.27(m,2H),7.24(dt,J1＝13.3Hz,J2＝4.3Hz,3H),7.17–7.10(m,1H),7.03(dd,J1＝6.1Hz,J2＝1.4Hz,2H),5.44(s,2H),3.99(s,4H),1.99–1.92(m,4H)ppm；13C NMR(100MHz,CDCl3):δ152.8,149.0,135.8,134.9,129.3,128.8,127.4,126.6,125.8,123.8,123.3,113.9,49.7,45.8ppm；HRMS(ESI,m/z):calculated for C19H19N3O[M+H]+:306.1606,found:306.1604.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of tetrahydropyrrole, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in an oil In the bath, react under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 44.6 mg of the target product with a yield of 73%. The compound is characterized as follows: 1 HNMR (400MHz, CDCl 3 ): δ7.51–7.44 (m, 1H), 7.34–7.27 (m, 2H), 7.24 (dt, J 1 =13.3Hz, J 2 =4.3Hz ,3H),7.17–7.10(m,1H),7.03(dd,J 1 =6.1Hz,J 2 =1.4Hz,2H),5.44(s,2H),3.99(s,4H),1.99–1.92( m, 4H) ppm; 13 C NMR (100MHz, CDCl 3 ): δ152.8, 149.0, 135.8, 134.9, 129.3, 128.8, 127.4, 126.6, 125.8, 123.8, 123.3, 113.9, 49.7, 45.8ppm; HRMS (ESI, m /z):calculated for C 19 H 19 N 3 O[M+H] + :306.1606,found:306.1604.
实施例13Example 13
3-正丙胺基-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-n-propylamino-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，正丙胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应24h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到53.4mg目标产物，收率为91％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.55(dd,J1＝8.0Hz,J2＝1.3Hz,1H),7.35–7.26(m,3H),7.25–7.04(m,5H),6.44(s,1H),5.50(s,2H),3.59–3.49(m,2H),1.74(dd,J1＝14.5Hz,J2＝7.3Hz,2H),1.04(t,J＝7.4Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ152.7,149.0,135.3,134.5,128.9,128.6,127.6,126.7,126.2,124.1,123.8,114.4,46.2,42.7,22.4,11.6ppm；HRMS(ESI,m/z):calculated for C18H19N3O[M+H]+:294.1606,found:294.1604.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of n-propylamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in an oil bath at 100°C In the air, the reaction was 24h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 53.4 mg of the target product with a yield of 91%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.55 (dd, J 1 =8.0Hz, J 2 =1.3Hz, 1H), 7.35-7.26 (m, 3H), 7.25-7.04( m,5H),6.44(s,1H),5.50(s,2H),3.59–3.49(m,2H),1.74(dd,J 1 =14.5Hz,J 2 =7.3Hz,2H),1.04(t , J=7.4Hz, 3H)ppm; 13 C NMR (100MHz, CDCl 3 ): δ152.7, 149.0, 135.3, 134.5, 128.9, 128.6, 127.6, 126.7, 126.2, 124.1, 123.8, 114.4, 46.2, 42.7, 22.4, 11.6ppm; HRMS(ESI,m/z):calculated for C 18 H 19 N 3 O[M+H] + :294.1606,found:294.1604.
实施例14Example 14
3-异丙胺基-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-isopropylamino-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，异丙胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应24h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到56.9mg目标产物，收率为97％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.55(d,J＝7.8Hz,1H),7.32(dd,J1＝11.4,J2＝4.2Hz,2H),7.26–7.04(m,6H),6.29(d,J＝7.6Hz,1H),5.50(s,2H),4.35(dd,J1＝14.1,J2＝6.7Hz,1H),1.33(d,J＝6.5Hz,6H)ppm；13CNMR(101MHz,CDCl3):δ152.2,148.1,135.4,134.6,128.9,128.5,127.6,126.8,126.2,124.1,123.7,114.4,46.2,42.4,22.5ppm；HRMS(ESI,m/z):calculated for C18H19N3O[M+H]+:294.1606,found:294.1604.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of isopropylamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in an oil bath at 100°C In the air, the reaction was 24h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 56.9 mg of the target product with a yield of 97%. The compound is characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.55 (d, J=7.8Hz, 1H), 7.32 (dd, J 1 =11.4, J 2 =4.2Hz, 2H), 7.26– 7.04(m, 6H), 6.29(d, J=7.6Hz, 1H), 5.50(s, 2H), 4.35(dd, J 1 =14.1, J 2 =6.7Hz, 1H), 1.33(d, J= 6.5Hz, 6H) ppm; 13 CNMR (101MHz, CDCl 3 ): δ152.2, 148.1, 135.4, 134.6, 128.9, 128.5, 127.6, 126.8, 126.2, 124.1, 123.7, 114.4, 46.2, 42.4, 22.5ppm; HRMS (ESI ,m/z):calculated for C 18 H 19 N 3 O[M+H] + :294.1606,found:294.1604.
实施例15Example 15
3-正丁胺基-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-n-butylamino-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，正丁胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应24h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到60.2mg目标产物，收率为98％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.55(dd,J1＝7.9Hz,J2＝1.2Hz,1H),7.38–7.26(m,3H),7.25–7.16(m,3H),7.15–7.02(m,2H),6.41(s,1H),5.50(s,2H),3.57(td,J1＝7.1Hz,J2＝5.9Hz,2H),1.77–1.64(m,2H),1.48(dq,J1＝14.5Hz,J2＝7.3Hz,2H),0.99(t,J＝7.4Hz,3H)ppm；13C NMR(100MHz,CDCl3)δ152.2,149.0,135.3,134.5,128.9,128.6,127.6,126.7,126.2,124.1,123.8,114.4,46.2,40.6,31.3,20.2,13.8ppm；HRMS(ESI,m/z):calculated for C19H21N3O[M+H]+:3081763,found:308.1761.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of n-butylamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in an oil In the bath, react under air conditions for 24h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 60.2 mg of the target product with a yield of 98%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.55 (dd, J 1 =7.9Hz, J 2 =1.2Hz, 1H), 7.38-7.26 (m, 3H), 7.25-7.16( m,3H),7.15–7.02(m,2H),6.41(s,1H),5.50(s,2H),3.57(td,J 1 =7.1Hz,J 2 =5.9Hz,2H),1.77–1.64 (m, 2H), 1.48 (dq, J 1 =14.5Hz, J 2 =7.3Hz, 2H), 0.99 (t, J = 7.4Hz, 3H) ppm; 13 C NMR (100MHz, CDCl 3 ) δ152.2, 149.0 ,135.3,134.5,128.9,128.6,127.6,126.7,126.2,124.1,123.8,114.4,46.2,40.6,31.3,20.2,13.8ppm; HRMS(ESI,m/z):calculated for C 19 H 21 N 3 O [M+H] + :3081763,found:308.1761.
实施例16Example 16
3-环己胺基-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-cyclohexylamino-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，环己胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应24h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到32.0mg目标产物，收率为48％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.54(dd,J＝8.0,1.3Hz,1H),7.37–7.27(m,2H),7.26–7.00(m,6H),6.36(d,J＝8.1Hz,1H),5.49(s,2H),4.14–4.00(m,1H),2.17–2.06(m,2H),1.86–1.74(m,2H),1.61–0.98(m,6H)ppm；13CNMR(100MHz,CDCl3):δ152.2,148.0,135.4,134.6,128.9,128.5,127.6,126.8,126.2,124.1,123.6,114.3,53.4,49.1,46.2,32.8,25.7,24.8ppm；HRMS(ESI,m/z):calculatedfor C21H23N3O[M+H]+:334.1919,found:334.1917.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of cyclohexylamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in an oil In the bath, react under air conditions for 24h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 32.0 mg of the target product with a yield of 48%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.54 (dd, J=8.0, 1.3Hz, 1H), 7.37–7.27 (m, 2H), 7.26–7.00 (m, 6H), 6.36(d,J＝8.1Hz,1H),5.49(s,2H),4.14–4.00(m,1H),2.17–2.06(m,2H),1.86–1.74(m,2H),1.61–0.98( m, 6H) ppm; 13 CNMR (100MHz, CDCl 3 ): δ152.2, 148.0, 135.4, 134.6, 128.9, 128.5, 127.6, 126.8, 126.2, 124.1, 123.6, 114.3, 53.4, 49.1, 46.2, 32.8, 25.7, 2 ppm; HRMS(ESI,m/z): calculated for C 21 H 23 N 3 O[M+H] + :334.1919,found:334.1917.
实施例17Example 17
3-苄胺基-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-benzylamino-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，苄胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到58.7mg目标产物，收率为86％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.59(d,J＝7.9Hz,1H),7.47–7.26(m,7H),7.26–7.18(m,4H),7.18–7.05(m,2H),6.70(s,1H),5.51(s,2H),4.77(d,J＝5.8Hz,2H)ppm；13C NMR(100MHz,CDCl3):δ152.1,148.7,138.2,135.3,134.3,128.9,128.8,128.7,128.1,127.6,127.5,126.8,126.4,124.2,124.1,114.4,46.2,45.0ppm；HRMS(ESI,m/z):calculated for C22H19N3O[M+H]+:342.1606,found:342.1602.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of benzylamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in an oil bath at 100°C , under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 58.7 mg of the target product with a yield of 86%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.59 (d, J=7.9Hz, 1H), 7.47–7.26 (m, 7H), 7.26–7.18 (m, 4H), 7.18– 7.05(m,2H),6.70(s,1H),5.51(s,2H),4.77(d,J=5.8Hz,2H)ppm; 13 C NMR(100MHz,CDCl 3 ):δ152.1,148.7,138.2, 135.3,134.3,128.9,128.8,128.7,128.1,127.6,127.5,126.8,126.4,124.2,124.1,114.4,46.2,45.0ppm ; _ M+H] + :342.1606,found:342.1602.
实施例18Example 18
3-(4-甲基苄胺基)-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-(4-methylbenzylamino)-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，4-甲基苄胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到65.4mg目标产物，收率为92％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.58(d,J＝7.8Hz,1H),7.31(t,J＝7.4Hz,4H),7.26–7.05(m,8H),6.67(s,1H),5.50(s,2H),4.72(d,J＝5.7Hz,2H),2.35(s,3H)ppm；13C NMR(100MHz,CDCl3):δ152.1,148.7,137.2,135.3,135.1,134.3,129.3,128.9,128.8,128.1,127.6,126.7,126.4,124.2,124.0,114.4,46.2,44.8,21.1ppm；HRMS(ESI,m/z):calculated for C23H21N3O[M+H]+:356.1763,found:356.1759.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of 4-methylbenzylamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, place in 100 In an oil bath at ℃, react under air condition for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 65.4 mg of the target product with a yield of 92%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.58 (d, J=7.8Hz, 1H), 7.31 (t, J=7.4Hz, 4H), 7.26–7.05 (m, 8H) ,6.67(s,1H),5.50(s,2H),4.72(d,J＝5.7Hz,2H),2.35(s,3H)ppm; 13 C NMR(100MHz,CDCl 3 ):δ152.1,148.7,137.2 ,135.3,135.1,134.3,129.3,128.9,128.8,128.1,127.6,126.7,126.4,124.2,124.0,114.4,46.2,44.8,21.1ppm; HRMS(ESI,m/z):calculated for C 23 H 21 N 3 O[M+H] + :356.1763,found:356.1759.
实施例19Example 19
3-(2-甲基苄胺基)-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-(2-methylbenzylamino)-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，2-甲基苄胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到57.5mg目标产物，收率为81％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.59(d,J＝7.9Hz,1H),7.41–7.28(m,3H),7.26–7.06(m,9H),6.55(s,1H),5.50(s,2H),4.74(d,J＝5.5Hz,2H),2.42(s,3H)ppm；13C NMR(100MHz,CDCl3):δ152.0,148.6,136.7,135.9,135.3,134.3,130.5,128.9,128.9,128.8,127.8,127.6,126.8,126.4,126.2,124.2,124.1,114.4,46.2,43.2,19.2ppm；HRMS(ESI,m/z):calculated for C23H21N3O[M+H]+:356.1763,found:356.1759.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of 2-methylbenzylamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, place in 100 In an oil bath at ℃, react under air condition for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 57.5 mg of the target product with a yield of 81%. The compound was characterized as follows: 1 H NMR (400MHz, CDC 13 ): δ7.59 (d, J=7.9Hz, 1H), 7.41-7.28 (m, 3H), 7.26-7.06 (m, 9H), 6.55( s, 1H), 5.50 (s, 2H), 4.74 (d, J=5.5Hz, 2H), 2.42 (s, 3H) ppm; 13 C NMR (100MHz, CDCl 3 ): δ152.0, 148.6, 136.7, 135.9, 135.3, 134.3, 130.5, 128.9, 128.9, 128.8, 127.8, 127.6, 126.8, 126.4, 126.2, 124.2, 124.1, 114.4, 46.2, 43.2, 19.2ppm; HRMS (ESI, m/z): calculated for C 23 H 21 N 3 O[M+H] + :356.1763,found:356.1759.
实施例20Example 20
3-(4-甲氧基苄胺基)-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-(4-methoxybenzylamino)-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，4-甲氧基苄胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到70.5mg目标产物，收率为95％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.58(d,J＝7.9Hz,1H),7.39–7.27(m,4H),7.26–7.06(m,6H),6.94–6.79(m,2H),6.64(s,1H),5.49(s,2H),4.69(d,J＝5.7Hz,2H),3.80(s,3H)ppm；13C NMR(101MHz,CDCl3):δ159.1,152.1,148.7,135.3,134.3,130.2,129.5,128.9,128.8,127.6,126.7,126.4,124.2,124.0,114.4,114.1,55.3,46.2,44.5ppm；HRMS(ESI,m/z):calculated for C23H21N3O2[M+H]+:372.1712,found:372.1708.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of 4-methoxybenzylamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place In an oil bath at 100°C, react under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 70.5 mg of the target product with a yield of 95%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.58 (d, J=7.9Hz, 1H), 7.39–7.27 (m, 4H), 7.26–7.06 (m, 6H), 6.94– 6.79(m,2H),6.64(s,1H),5.49(s,2H),4.69(d,J=5.7Hz,2H),3.80(s,3H)ppm; 13 C NMR(101MHz,CDCl 3 ) :δ159.1,152.1,148.7,135.3,134.3,130.2,129.5,128.9,128.8,127.6,126.7,126.4,124.2,124.0,114.4,114.1,55.3,46.2,44.5ppcalm; HRMS(:ESI,m/z) for C 23 H 21 N 3 O 2 [M+H] + :372.1712,found:372.1708.
实施例21Example 21
3-(4-三氟甲基苄胺基)-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-(4-trifluoromethylbenzylamino)-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，三氟甲基苄胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到43.4mg目标产物，收率为53％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.75–7.44(m,5H),7.39–7.26(m,3H),7.25–7.04(m,5H),6.79(s,1H),5.51(s,2H),4.84(d,J＝6.1Hz,2H)ppm；13C NMR(100MHz,CDCl3):δ152.01(s),148.67(s),142.57(s),135.19(s),134.06(s),129.69(q,J＝32.4Hz),128.94(s),128.91(s),128.16(s),127.71(s),126.76(s),126.52(s),125.57(q,J＝3.7Hz),124.47(s),124.30(s),122.45(q,J＝270.5Hz),114.51(s),46.25(s),44.36(s)ppm；19F NMR(376MHz,CDCl3)δ-62.42(s,3F)ppm；HRMS(ESI,m/z):calculated for C23H18F3N3O[M+H]+:410.1480,found:410.1475.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of trifluoromethylbenzylamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, place in 100 In an oil bath at ℃, react under air condition for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 43.4 mg of the target product with a yield of 53%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.75–7.44(m,5H),7.39–7.26(m,3H),7.25–7.04(m,5H),6.79(s,1H ), 5.51(s, 2H), 4.84(d, J=6.1Hz, 2H) ppm; 13 C NMR (100MHz, CDCl 3 ): δ152.01(s), 148.67(s), 142.57(s), 135.19 (s), 134.06(s), 129.69(q, J=32.4Hz), 128.94(s), 128.91(s), 128.16(s), 127.71(s), 126.76(s), 126.52(s), 125.57 (q, J=3.7Hz), 124.47(s), 124.30(s), 122.45(q, J=270.5Hz), 114.51(s), 46.25(s), 44.36(s)ppm; 19 F NMR (376MHz ,CDCl 3 )δ-62.42(s,3F)ppm; HRMS(ESI,m/z):calculated for C 23 H 18 F 3 N 3 O[M+H] + :410.1480,found:410.1475.
实施例22Example 22
3-(α-甲基苄胺基)-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-(α-methylbenzylamino)-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，α-甲基苄胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到54.7mg目标产物，收率为77％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.52(d,J＝8.0Hz,1H),7.46(d,J＝7.5Hz,2H),7.38–7.26(m,5H),7.25–7.04(m,6H),6.69(d,J＝7.8Hz,1H),5.50(t,J＝13.3Hz,2H),5.41(dd,J1＝13.5Hz,J2＝6.2Hz,1H),1.65(d,J＝6.9Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ152.0,147.9,143.6,135.3,134.4,128.9,128.7,128.6,127.6,127.2,126.8,126.5,126.4,124.1,124.0,114.3,50.0,46.2,22.2ppm；HRMS(ESI,m/z):calculated for C23H21N3O[M+H]+:356.1763,found:356.1761.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of α-methylbenzylamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, place in 100 In an oil bath at ℃, react under air condition for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 54.7 mg of the target product with a yield of 77%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.52 (d, J=8.0Hz, 1H), 7.46 (d, J=7.5Hz, 2H), 7.38–7.26 (m, 5H) ,7.25–7.04(m,6H),6.69(d,J=7.8Hz,1H),5.50(t,J=13.3Hz,2H),5.41(dd,J 1 ＝13.5Hz,J 2 ＝6.2Hz, 1H), 1.65 (d, J=6.9Hz, 3H) ppm; 13 C NMR (100MHz, CDCl 3 ): δ152.0, 147.9, 143.6, 135.3, 134.4, 128.9, 128.7, 128.6, 127.6, 127.2, 126.8, 126.5, 126.4,124.1,124.0,114.3,50.0,46.2,22.2ppm; HRMS(ESI,m/z):calculated for C 23 H 21 N 3 O[M+H] + :356.1763,found:356.1761.
实施例23Example 23
3-(二苯甲胺基)-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-(benzhydrylamino)-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，二苯甲胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到39.2mg目标产物，收率为47％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.50(d,J＝7.8Hz,1H),7.32(ddd,J1＝20.0Hz,J2＝11.5Hz,J3＝7.1Hz,12H),7.25–6.95(m,6H),6.55(d,J＝8.2Hz,1H),5.50(s,2H),1.56(s,1H)ppm；13C NMR(100MHz,CDCl3):δ152.0,147.8,141.9,135.3,134.2,128.9,128.6,127.6,127.4,126.8,126.7,124.3,124.1,114.3,58.1,46.3ppm；HRMS(ESI,m/z):calculated for C28H23N3O[M+H]+:418.1919,found:418.1911.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of benzhydrylamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in a 100°C In an oil bath, react under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 39.2 mg of the target product with a yield of 47%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.50 (d, J=7.8Hz, 1H), 7.32 (ddd, J 1 =20.0Hz, J 2 =11.5Hz, J 3 =7.1 Hz, 12H), 7.25–6.95(m, 6H), 6.55(d, J=8.2Hz, 1H), 5.50(s, 2H), 1.56(s, 1H) ppm; 13 C NMR (100MHz, CDCl 3 ) :δ152.0,147.8,141.9,135.3,134.2,128.9,128.6,127.6,127.4,126.8,126.7,124.3,124.1,114.3,58.1,46.3ppm; HRMS(ESI,m/z):calculated for C 28 H 23 N 3 O[M+H] + :418.1919,found:418.1911.
实施例24Example 24
3-乙醇胺基-1-苄基-喹喔啉-2(1H)-酮的制备Preparation of 3-ethanolamino-1-benzyl-quinoxalin-2(1H)-one
将1-苄基-喹喔啉-2(1H)-酮0.2mmol，乙醇胺0.6mmol，醋酸铜0.01mmol，二甲基亚砜2.0mL加入10mL的反应管中，置于100℃的油浴中，空气条件下反应12h。停止反应，冷却至室温。反应液用乙酸乙酯稀释，用水萃取三次，有机相用无水Na2SO4干燥，过滤，经柱色谱分离得到39.0mg目标产物，收率为66％。该化合物的表征如下：1H NMR(400MHz,CDCl3):δ7.55–7.48(m,1H),7.30(dd,J1＝15.4Hz,J2＝7.9Hz,3H),7.25–7.08(m,5H),6.87(s,1H),5.50(s,2H),4.50(s,1H),3.96–3.88(m,2H),3.75(dd,J1＝9.4Hz,J2＝5.6Hz,2H)ppm；13C NMR(100MHz,CDCl3):δ152.1,149.9,135.1,133.3,128.9,128.8,127.7,126.7,125.9,124.5,124.4,114.5,63.5,46.3,45.0ppm；HRMS(ESI,m/z):calculated for C17H17N3O2[M+H]+:296.1399,found:296.1397.Add 0.2mmol of 1-benzyl-quinoxalin-2(1H)-one, 0.6mmol of ethanolamine, 0.01mmol of copper acetate, and 2.0mL of dimethyl sulfoxide into a 10mL reaction tube, and place in an oil bath at 100°C , Reaction under air conditions for 12h. Stop the reaction and cool to room temperature. The reaction solution was diluted with ethyl acetate, extracted three times with water, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and separated by column chromatography to obtain 39.0 mg of the target product with a yield of 66%. The compound was characterized as follows: 1 H NMR (400MHz, CDCl 3 ): δ7.55–7.48 (m, 1H), 7.30 (dd, J 1 =15.4Hz, J 2 =7.9Hz, 3H), 7.25–7.08( m,5H),6.87(s,1H),5.50(s,2H),4.50(s,1H),3.96–3.88(m,2H),3.75(dd,J 1 =9.4Hz,J 2 =5.6Hz ,2H)ppm; 13 C NMR (100MHz, CDCl 3 ): δ152.1, 149.9, 135.1, 133.3, 128.9, 128.8, 127.7, 126.7, 125.9, 124.5, 124.4, 114.5, 63.5, 46.3, 45.0ppm; HRMS (ESI, m/z): calculated for C 17 H 17 N 3 O 2 [M+H] + :296.1399,found:296.1397.
本领域技术人员可知，本发明的技术参数在下属范围内变化时，仍能够得到与上述实施例相同或相近的技术效果，皆属于本发明的保护范围：Those skilled in the art will know that when the technical parameters of the present invention vary within the subordinate scope, the same or similar technical effects as those of the above-mentioned embodiments can still be obtained, and all belong to the protection scope of the present invention:
一种3-氨基喹喔啉-2(1H)-酮类化合物的合成方法，将喹喔啉-2(1H)-酮衍生物、有机胺(优选脂肪胺)和醋酸铜溶于二甲基亚砜中，在空气条件下，于95～110℃反应10～25小时(优选于100℃反应12～24小时)后，经分离纯化，即得所述3-氨基喹喔啉-2(1H)-酮类化合物，其中喹喔啉-2(1H)-酮衍生物、有机胺和醋酸铜的摩尔比为0.9～1.2:2.8～3.3:0.03～0.06，每毫摩尔喹喔啉-2(1H)-酮衍生物需2～3mL二甲基亚砜溶液，上述喹喔啉-2(1H)-酮衍生物的结构通式如下：A kind of synthetic method of 3-aminoquinoxaline-2 (1H)-one compound, quinoxaline-2 (1H)-ketone derivative, organic amine (preferably aliphatic amine) and copper acetate are dissolved in dimethyl In sulfoxide, under air conditions, react at 95-110°C for 10-25 hours (preferably react at 100°C for 12-24 hours), and then separate and purify to obtain the 3-aminoquinoxaline-2(1H )-ketone compounds, wherein the mol ratio of quinoxaline-2(1H)-ketone derivatives, organic amines and copper acetate is 0.9～1.2:2.8～3.3:0.03～0.06, every mmol quinoxaline-2( 1H)-one derivatives need 2-3mL dimethyl sulfoxide solution, and the general structural formula of the above-mentioned quinoxalin-2(1H)-one derivatives is as follows:
其中R1为氢、烷基、芳基、卤素或烷氧基，R2为氢、苄基、烷基或酯基。wherein R1 is hydrogen, alkyl, aryl, halogen or alkoxy, and R2 is hydrogen , benzyl, alkyl or ester.
优选R1为甲基或Cl，R2为氢、苄基、乙基、乙酸乙酯基或4-甲氧基苄基。Preferably R1 is methyl or Cl and R2 is hydrogen , benzyl, ethyl, ethyl acetate or 4 -methoxybenzyl.
以上所述，仅为本发明的较佳实施例而已，故不能依此限定本发明实施的范围，即依本发明专利范围及说明书内容所作的等效变化与修饰，皆应仍属本发明涵盖的范围内。The above is only a preferred embodiment of the present invention, so the scope of the present invention cannot be limited accordingly, that is, the equivalent changes and modifications made according to the patent scope of the present invention and the content of the specification should still be covered by the present invention In the range.
Claims (7)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510399965.7A CN105001169B (en) | 2015-07-09 | 2015-07-09 | A kind of synthetic method of 3 aminoquinoxaline 2 (1H) ketone compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510399965.7A CN105001169B (en) | 2015-07-09 | 2015-07-09 | A kind of synthetic method of 3 aminoquinoxaline 2 (1H) ketone compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105001169A CN105001169A (en) | 2015-10-28 |
| CN105001169B true CN105001169B (en) | 2017-07-21 |
Family
ID=54374079
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510399965.7A Active CN105001169B (en) | 2015-07-09 | 2015-07-09 | A kind of synthetic method of 3 aminoquinoxaline 2 (1H) ketone compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105001169B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109160903B (en) * | 2018-09-28 | 2021-07-16 | 曲阜师范大学 | A kind of photocatalytic preparation method of 3-aminoquinoxalin-2(1H)-one compound |
| CN111689951A (en) * | 2020-06-11 | 2020-09-22 | 西北师范大学 | Synthesis method of 1-benzyl-3-alkyl quinoxaline-2 (1H) -ketone |
| CN111807942B (en) * | 2020-08-05 | 2022-11-18 | 厦门华厦学院 | Preparation method of polysubstituted indanone derivative |
| CN112679423B (en) * | 2021-01-08 | 2022-04-26 | 中南大学 | Amination reagent and synthesis method and application thereof |
| CN115385863A (en) * | 2022-08-17 | 2022-11-25 | 河南师范大学 | Synthetic method of 3- (diethoxymethyl) -1-alkyl-2 (1H) -quinoxalinone derivative |
| CN116813593A (en) * | 2023-06-28 | 2023-09-29 | 郑州泰基鸿诺医药股份有限公司 | A kind of 3-aminoquinoxalinone compound and its synthesis method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4636562A (en) * | 1982-05-07 | 1987-01-13 | E. I. Du Pont De Nemours And Company | Process for preparing 6-halo-2-chloroquinoxaline |
| CN1886389A (en) * | 2003-09-30 | 2006-12-27 | 詹森药业有限公司 | Quinoxaline compounds |
| CN102250022A (en) * | 2011-05-26 | 2011-11-23 | 浙江大学 | Substituted quinoxalinamine compounds, and preparation method and application thereof |
-
2015
- 2015-07-09 CN CN201510399965.7A patent/CN105001169B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4636562A (en) * | 1982-05-07 | 1987-01-13 | E. I. Du Pont De Nemours And Company | Process for preparing 6-halo-2-chloroquinoxaline |
| CN1886389A (en) * | 2003-09-30 | 2006-12-27 | 詹森药业有限公司 | Quinoxaline compounds |
| CN102250022A (en) * | 2011-05-26 | 2011-11-23 | 浙江大学 | Substituted quinoxalinamine compounds, and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Fragment Based Design of New H4 Receptor-Ligands with Anti-inflammatory Properties in Vivo;Rogier A. Smits，等;《J. Med. Chem.》;20080322;第51卷(第8期);第2457-2467页 * |
| Oxidative alkylamination of azinones as a direct route to aminoazinones: study of some condensed diazinones;Anna V. Gulevskaya，等;《Tetrahedron》;20071112;第696-707页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105001169A (en) | 2015-10-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105001169B (en) | A kind of synthetic method of 3 aminoquinoxaline 2 (1H) ketone compounds | |
| CN104520275B (en) | For preparation method and the intermediate product of integrase inhibitor | |
| CN107382803A (en) | A kind of preparation method of β hydroxy phenyls selenide compound | |
| CN110498770B (en) | Method for preparing intermediate of oxaagolide | |
| CN106831737B (en) | Preparation of vipatavir and derivatives thereof | |
| CN104803919A (en) | Preparation method of enzalutamide intermediate F | |
| CN104447686B (en) | Polysubstituted 2-pyrroles's pyridine derivate and preparation method thereof | |
| CN114524773A (en) | Method for synthesizing aryl quinoxaline compound promoted by mechanical force | |
| KR20170084075A (en) | Preparation method for revaprazan hydrochloride | |
| CN108530365A (en) | 1,4- naphthoquinones/anthraquinone imdazole derivatives and its preparation and use | |
| CN111777564A (en) | A kind of method for synthesizing quinazolinone compound by photocatalytic alcohol oxidation in water phase | |
| CN103880776B (en) | A kind of method preparing 2-amino-5-alkyl-1,3,4-thiadiazoles | |
| CN104230743B (en) | Method for preparing 4-benzyl-1-phenethyl piperazine-2,6-diketone | |
| CN102887856A (en) | Method for synthesizing Blonanserin | |
| CN103554023B (en) | The synthetic method of acridine derivatives and the polycyclic acridine derivative of synthesis | |
| CN104230885B (en) | The preparation method of imatinib | |
| CN102336763B (en) | Synthesis method for pyranocoumarin derivatives | |
| CN106588786A (en) | Preparation method of high purity favipiravir impurity | |
| CN104860881A (en) | Methods for synthesizing 8-(nitro methyl) quinoline compounds and 8-methylamino tetrahydroquinoline compounds | |
| CN103739541B (en) | The preparation method of 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-piperidino) phenyl]-2 (1H)-pyridones | |
| CN101691354B (en) | Chemical synthesis method of 2-heteroaryl substituted quinoline compound | |
| CN105820168A (en) | Preparation method of Ibrutinib intermediate | |
| CN103755667B (en) | A kind of chirality 3-(2-nitro-ethyl) tetrahydrofuran-compound and preparation method thereof | |
| CN103275086B (en) | 6-substituted quinazoline and quinazolinone compound, its synthesis method and application | |
| CN107721917A (en) | A kind of green synthesis method of polysubstituted nicotinate compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant |