CN110698380B - Lactam derivative and preparation method and application thereof - Google Patents

Lactam derivative and preparation method and application thereof Download PDF

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CN110698380B
CN110698380B CN201911018651.2A CN201911018651A CN110698380B CN 110698380 B CN110698380 B CN 110698380B CN 201911018651 A CN201911018651 A CN 201911018651A CN 110698380 B CN110698380 B CN 110698380B
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CN110698380A (en
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王佳毅
宋恭华
张娟
夏琦
赵心蕾
张阳
张萍
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East China University of Science and Technology
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Abstract

The invention relates to a lactam derivative and a preparation method and application thereof. Compared with the prior art, the invention provides a lactam compound with a novel structure, and the compound and the composition thereof have obvious cancer cell proliferation inhibition activity (including but not limited to liver cancer cell line HepG2 and lung cancer cell line A549), and the activity of a plurality of compounds and the activity of a commercial drug adriamycin is in the same order of magnitude or better than the activity of the adriamycin; the compound can be prepared by reacting an N-substituted pyrrole compound, and the preparation method is convenient, rapid and efficient.

Description

Lactam derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to a lactam derivative with a cytotoxic effect, and a preparation method and application thereof.
Background
Malignant tumors are one of the most dangerous diseases affecting human health. Surgical treatment radical resection is the most basic and common cancer treatment method at present, but surgical resection has large trauma and is easy to cause tissue damage, and is not suitable for the elderly or patients with poor physical quality. In recent years, the field of cancer pharmaceuticals has been rapidly developed with the increase of cancer patients and the deepening of understanding of science on cancer. Although various drugs for treating cancer are already available on the market, more or less defects exist, such as low bioavailability, great toxic and side effects and the like. Therefore, a novel compound lead structure with anticancer activity is discovered, a new action target is explored, and then a high-activity compound is rapidly discovered through structural modification and optimization, so that the method has important significance for discovering new anticancer drugs.
The structure of gamma-butyrolactam is widely existed in natural products, and the research finds that the compound containing the structure of gamma-butyrolactam has a series of biological activities, including: antibacterial, antioxidant, anticonvulsant, and antidepressant effects. Therefore, the method for screening the compound with the obvious cancer cell proliferation inhibition activity from various gamma-butyrolactams has good practical significance and value.
Disclosure of Invention
The present invention aims at providing one kind of lactam derivative and its preparation process and application. The invention is designed based on the structure, obtains the lactam compound with novel structure and anticancer activity, has simple and effective synthetic route and better application prospect in anticancer drugs.
The purpose of the invention can be realized by the following technical scheme:
a lactam derivative, which is a compound of formula I, an optical isomer of a compound of formula I, a cis-trans isomer of a compound of formula I, or a pharmaceutically acceptable salt of a compound of formula I:
Figure BDA0002246490020000021
wherein:
ra is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted arylformyl, substituted or unsubstituted 9, 10-dihydrophenanthryl, substituted or unsubstituted C1～C15One of alkyl groups;
rb and Rc are respectively and independently selected from cyano, ester group or acyl, the general formula of the ester group is COOR, the general formula of the acyl group is COR ', and R' are respectively and independently selected from cyano, ester group or acylIs selected from substituted or unsubstituted C1～C15One of an alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic aryl group.
Further, in the Ra, the substituted aryl is aryl substituted by one or more substituents, the substituted heterocyclic aryl is heterocyclic aryl substituted by one or more substituents, the substituted arylformyl is arylformyl substituted by one or more substituents, the substituted 9, 10-dihydrophenanthryl is 9, 10-dihydrophenanthryl substituted by one or more substituents, and the substituted C is1～C15C with alkyl radicals substituted by one or more substituents1～C15An alkyl group; in said R and R', substituted C1～C15C with alkyl radicals substituted by one or more substituents1～C15The substituted aryl is aryl substituted by one or more substituents, and the substituted heterocyclic aryl is heterocyclic aryl substituted by one or more substituents; the substituent is selected from hydroxyl, halogen, cyano, nitro, trifluoromethyl, aryl, substituted aryl, heterocyclic aryl, substituted heterocyclic aryl and C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Haloalkyl, C1～C6Haloalkoxy, -C1～C6alkylene-O-C1～C6alkylene-or-C1～C6alkylene-S-C1～C6Alkylene-.
Further, the substituted aryl is aryl substituted by one or more substituents, and the substituents in the substituted aryl are selected from halogen, cyano, nitro, trifluoromethyl and C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Haloalkyl, C1～C6Haloalkoxy, -C1～C6alkylene-O-C1～C6alkylene-or-C1～C6alkylene-S-C1～C6Alkylene-; the substituted heterocyclic aryl is heterocyclic aryl substituted by one or more substituents, and the substituent in the substituted heterocyclic aryl is selected fromHalogen, cyano, nitro, trifluoromethyl, C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Haloalkyl, C1～C6Haloalkoxy, -C1～C6alkylene-O-C1～C6alkylene-or-C1～C6alkylene-S-C1～C6Alkylene-.
Further, the aryl group is selected from one of phenyl, naphthyl or phenanthryl, and the heterocyclic aryl group is selected from one of furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl. The heterocyclic aryl group may also be selected from other nitrogen-containing heterocyclic aryl groups.
A method for preparing a lactam derivative comprises the following steps: in an inert acid solvent, to
Figure BDA0002246490020000031
Using manganese acetate dihydrate (Mn (OAc)3 .2H2O) is used as a catalyst, the reaction is carried out for 4 to 72 hours at the temperature of between 30 and 110 ℃, and the lactam derivative is obtained after the reaction is finished and separation.
The reaction formula is as follows:
Figure BDA0002246490020000032
further, the
Figure BDA0002246490020000033
And the molar ratio of manganese acetate dihydrate is 1 (1.0-6.0) to 3.0-6.0.
The application of a lactam derivative in preparing an anti-tumor medicament.
A composition comprising said lactam derivative.
Further, the composition comprises one or more lactam derivatives, and a pharmaceutically acceptable carrier medium and/or excipient. The composition can only comprise one lactam derivative, and can also combine a plurality of lactam derivatives containing different Ra, Rb and Rc into a mixture. The composition also contains pharmaceutically acceptable carrier medium and/or excipient.
The mass percentage of the lactam derivative in the composition is 0.001-99.99%.
The application of a composition for preparing an antitumor drug.
The tumor is selected from: nasopharyngeal carcinoma, esophageal carcinoma, gastric carcinoma, liver carcinoma, breast carcinoma, colon carcinoma, prostate carcinoma, lung carcinoma, cervical carcinoma, leukemia, oral carcinoma, salivary gland tumor, malignant tumor of nasal cavity and paranasal sinuses, laryngeal carcinoma, ear tumor, eye tumor, thyroid tumor, mediastinal tumor, chest wall, pleural tumor, small intestine tumor, biliary tract tumor, pancreatic and peri-ampullar tumor, mesenteric and retroperitoneal tumor, kidney tumor, adrenal tumor, bladder tumor, prostate carcinoma, testicular tumor, penile carcinoma, endometrial carcinoma, ovarian malignant tumor, malignant trophoblastic tumor, vulval carcinoma and vaginal carcinoma, malignant lymphoma, multiple myeloma, soft tissue tumor, bone tumor, skin and accessory tumor, malignant melanoma, or nervous system tumor.
The method for treating tumors by using the lactam derivative or the composition comprises the following steps: administering to a patient in need thereof a compound of formula I, an optical isomer of a compound of formula I, a cis-trans isomer of a compound of formula I, a pharmaceutically acceptable salt of a compound of formula I, or a combination thereof.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Compared with the prior art, the invention has the following characteristics:
1) the invention provides a lactam compound with a novel structure, and the compound and a composition thereof have obvious cancer cell proliferation inhibition activity (including but not limited to: liver cancer cell line HepG2 and lung cancer cell line A549), the activity of a plurality of compounds and commercial drug adriamycin is in the same order of magnitude or better than the activity of the adriamycin;
2) the compound can be prepared by reacting an N-substituted pyrrole compound, and the preparation method is convenient, rapid and efficient.
Detailed Description
A series of lactam compounds which are synthesized in the invention, have novel structures and obvious anticancer activity, and show obvious proliferation activity for inhibiting liver cancer cell lines HepG2 and lung cancer cell lines A549 after MTT (methyl thiazolyl tetrazolium) method test.
Group definition:
the term "alkyl" refers to a group derived from an alkane molecule by the removal of one hydrogen atom; the term "alkylene" refers to a group of an alkane molecule lacking two hydrogen atoms.
The term "halogen" refers to fluorine, chlorine, bromine, or iodine. The term "halogenated" refers to a group substituted with one or more of the above halogen atoms, which may be the same or different, such as trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, or the like.
The term "inert acid solvent" refers to a variety of acidic solvents that do not react with the starting materials, including a variety of straight, branched, or cyclic alkyl or aryl carboxylic acids, such as formic, acetic, propionic, isopropanoic, butyric, benzoic, phenylacetic, and the like.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of formula I of the present invention with pharmaceutically acceptable inorganic and organic acids, wherein preferred inorganic acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; preferred organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, succinic acid, 1, 5-naphthalenedisulfonic acid, sulfinic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids.
The term "optical isomers" means that the chiral carbon atoms involved in the compounds of the present invention may be in the R configuration, or may be in the S configuration, or a combination thereof. The compounds of the invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the invention. The present invention includes all isomeric forms of the compounds.
Pharmaceutical compositions and methods of administration:
as used herein, "composition" refers to any mixture. It can be a solution, a mixture, a liquid, a powder, an ointment, an aqueous, a non-aqueous, or any combination thereof.
The compounds of the present invention and their pharmaceutically acceptable salts or compositions containing them may be administered in unit dosage forms, and the administration bursts may be divided into enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including O/W, W/O type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound and the pharmaceutically acceptable salt thereof can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compound of the present invention and pharmaceutically acceptable salts thereof, a wide variety of excipients well known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, and residence agents. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.: the binder can be starch, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. In order to encapsulate the administration unit, the active ingredient of the compound of the present invention and a pharmaceutically acceptable salt thereof may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or preparing the effective component of the compound and the pharmaceutically acceptable salt thereof into granules or pellets with a diluent, an adhesive and a disintegrating agent, and placing the granules or pellets into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compounds of the present invention and their pharmaceutically acceptable salts in tablets may also be used to prepare capsules of the compounds of the present invention and their pharmaceutically acceptable salts.
In order to prepare the compound and the pharmaceutically acceptable salt thereof into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a solubilizer, a cosolvent, a pH regulator and an osmotic pressure regulator which are commonly used in the field are added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin and the like, and the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide and the like; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The invention will be further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are exemplary only.
Example 1:
synthesis of 1- (3-methoxyphenyl) -1H-pyrrole
Figure BDA0002246490020000061
A25 mL round-bottom flask was charged with 3mmol of sodium methoxide, 3mL of DMSO solution, then 10 mol% of CuI (0.2mmol, 38mg) and 10 mol% of N-hydroxyphthalimide (L1, 0.2mmol, 33mg) were added and stirred at room temperature for 30 minutes. Iodobenzene (2mmol, 408mg) and pyrrole (2mmol, 134mg) dissolved in DMSO (2mL) were then added dropwise to the reaction over 3 minutes. The temperature is raised to 90 ℃ by oil bath, and the reaction is stirred for 12 hours. After the reaction, 10mL of saturated brine was added, extraction was performed with ethyl acetate (3X 10mL), the extracts were combined, and the crude product from which the solvent was removed by rotary evaporation was purified by column chromatography to obtain 0.243g of a white solid with a yield of 85%.
m.p.61.5-62.0℃。1H NMR(400MHz,CDCl3)δ7.44–7.37(m,4H),7.27–7.22(m,1H),7.09(t,J＝2.2Hz,2H),6.35(t,J＝2.2Hz,2H)；13C NMR(101MHz,CDCl3)δ129.6(2C),125.7(2C),120.6(2C),119.4(2C),110.4(2C)；MS(GC-MS):m/z 143.1(M+).
Example 2:
synthesis of 1- (phenanthren-9-yl) -1H-pyrrole
Figure BDA0002246490020000071
In a 100mL round bottom flask were charged o-bromobenzaldehyde (1.84g, 10mmol), 2-formylphenylboronic acid (0.164g, 1.1mmol), bis (dibenzylideneacetone) palladium (0.060g, 0.1mmol), tricyclohexylphosphine (0.003g, 0.12mmol), and potassium fluoride dihydrate (3.10g, 33mmol), 2mL of tetrahydrofuran as a solvent, and the reaction was carried out in an oil bath at reflux temperature for 8h to complete the reaction. After the temperature of the reaction solution is reduced to room temperature, the solvent is removed under reduced pressure, deionized water (100mL) is added for washing, dichloromethane is used for extraction (3X 50mL), organic phases are combined and washed by saturated sodium chloride solution, anhydrous magnesium sulfate is used for drying, and the filtrate is dried in a rotary manner after suction filtration to obtain a crude product. The yellow solid [1,1 '-biphenyl ] -2, 2' -diformaldehyde is obtained by column chromatography purification and separation, 1.9g, the yield is 90%.
Yellow oil；1H NMR(400MHz,CDCl3)δ9.84(s,1H),8.06(s,1H),7.68(td,J＝7.5,1.4Hz,1H),7.60(t,J＝7.5Hz,1H),7.40–7.32(m,1H).13C NMR(101MHz,CDCl3)δ191.07(2C),141.25(2C),134.59(2C),133.46(2C),131.73(2C),128.85(2C),128.59(2C).MS(GC-MS):m/z 210.0(M+).
To a 10mL round bottom flask was added [1, 1' -biphenyl ]]-2, 2' -dicarboxaldehyde (0.105g, 0.5mmol), trans-4-hydroxy-L-proline (0.098g,0.75mmol) in 1.5mL dimethyl sulfoxide as a solvent, and the reaction was carried out at 140 ℃ in an oil bath for 30 min. After the temperature of the reaction solution is reduced to room temperature, deionized water (10mL) is added for washing,extracted three times with ethyl acetate and the ethyl acetate extracts combined. Washing the extract with saturated sodium chloride solution, drying with anhydrous magnesium sulfate, suction filtering, and spin drying the filtrate to obtain crude product. Purifying and separating by column chromatography to obtain 10- (1H-pyrrole-1-yl) -9, 10-dihydrophenanthrene-9-alcohol solid. A white solid; trans/cis 87: 13; HRMS (EI) calcd for C18H15NO[M]+261.1154,found 2261.1153.
10- (1H-pyrrol-1-yl) -9, 10-dihydrophenanthren-9-ol (2mmol, 522mg), phosphorus pentoxide (6mmol, 852mg) and benzene (10mL) were added to a 25mL round bottom flask and stirred under reflux for 6H. After the reaction, 10mL of saturated saline was added, extraction was performed with ethyl acetate (3X 10mL), the extracts were combined, and the crude product after solvent removal by rotary evaporation was purified and separated by column chromatography to give 0.403g of 1- (phenanthren-9-yl) -1H-pyrrole as a white solid with a yield of 83%.
m.p.108.2-108.9℃。1H NMR(400MHz,CDCl3)δ8.70(dd,J＝17.4,8.3Hz,2H),7.90–7.83(m,1H),7.76–7.53(m,6H),7.03(t,J＝2.1Hz,2H),6.43(t,J＝2.1Hz,2H)；13C NMR(101MHz,CDCl3)δ136.8,131.2,131.2,129.9,129.5,128.8,127.3,127.29,127.28,127.2,124.1,123.9,123.3(2C),122.9,122.7,109.1(2C)；MS(GC-MS):m/z 243.1(M+).
Example 3:
synthesis of 1- (4-nitrobenzyl) -1H-pyrrole
Figure BDA0002246490020000081
A25 mL two-necked round bottom flask was charged with trans-4-hydroxy-L-proline (0.983g, 7.5mmol), 10 mol% acetic acid (0.03mL, 0.5mmol) and DMF (10mL), and then heated to reflux. 4-nitrobenzaldehyde (5.0mmol, 755mg) was dissolved in DMF (5mL) and added dropwise to the above reaction mixture over 30 minutes for 10 minutes. After the reaction, 10mL of saturated saline was added, extraction was performed with ethyl acetate (3X 10mL), the extracts were combined, and the crude product from which the solvent was removed by rotary evaporation was purified by column chromatography to obtain 0.909g of a pale yellow solid, with a yield of 90%.
m.p.61.0-61.4℃。1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.7Hz,2H),7.19(d,J＝8.6Hz,2H),6.69(t,J＝2.0Hz,2H),6.24(t,J＝2.0Hz,2H),5.18(s,2H)；13C NMR(101MHz,CDCl3)δ147.5,145.8,127.4(2C),124.0(2C),121.3(2C),109.4(2C),52.6；MS(GC-MS):m/z 202.1(M+).
Example 4:
synthesis of 1-benzyl-1H-pyrrole
Figure BDA0002246490020000082
Pyrrole (2mmol, 134mg), sodium hydroxide (6mmol, 240mg) and DMSO (10mL) were added to a 25mL round bottom flask, stirred at room temperature for 20-30 min, then benzyl chloride was added slowly. The mixture was stirred at room temperature for 3 hours. After the reaction, 10mL of saturated brine was added, extraction was performed with ethyl acetate (3X 10mL), the extracts were combined, and the crude product from which the solvent was removed by rotary evaporation was purified by column chromatography to obtain 0.266g of a colorless liquid, with a yield of 85%.
1H NMR(400MHz,CDCl3)δ7.37–7.22(m,3H),7.10(d,J＝7.2Hz,2H),6.68(t,J＝2.0Hz,2H),6.19(t,J＝2.0Hz,2H),5.05(s,2H)；13C NMR(101MHz,CDCl3)δ138.2,128.8(2C),127.7,127.0(2C),121.2(2C),108.5(2C),53.4；MS(GC-MS):m/z157.1(M+).
Example 5:
synthesis of 1-benzyl-1H-pyrrole
Figure BDA0002246490020000091
A10 mL microwave reaction flask was charged with 3-nitrobenzaldehyde (0.151g,1.00mmol), trans-4-hydroxy-L-proline (0.098g,0.75mmol), and 1.5mL dimethyl sulfoxide (DMSO) as a solvent, and the reaction was carried out under sealed conditions at an oil bath temperature of 110 ℃ for 24 hours after completion of the reaction. After the reaction solution is cooled to room temperature, 10mL of deionized water is added to generate a large amount of flocculent solids, and the filtration is carried out to keep a filter cake. The filtrate was extracted three times with Ethyl Acetate (EA), and the organic layers were combined. Washing the organic phase with saturated saline solution, drying with anhydrous magnesium sulfate, filtering, and spin-drying the filtrate to obtain a crude product. The crude product and the filter cake were combined and separated by flash liquid chromatography (mobile phase: petroleum ether: ethyl acetate (PE: EA) ═ 10:1) to give 0.168g of a pale yellow solid with an isolated yield of 95%.
M.p.137–145℃。dr＝66:34,major isomer:1H NMR(400MHz,CDCl3)δ8.14–8.06(m,4H),7.50–7.37(m,4H),6.66–6.58(m,2H),6.06(t,J＝2.1Hz,2H),5.60(d,J＝7.9Hz,1H),5.23(d,J＝7.7Hz,1H),2.99(s,1H)；13C NMR(100MHz,CDCl3)δ148.28,148.19,142.79,139.31,134.80,132.27,129.70,129.43,123.39,123.26,121.17,120.84,119.86(2C),109.46(2C),74.56,68.11；HRMS(EI)calcd for C18H15N3O5[M]+353.1012,found 353.1015.
The N-substituted pyrroles shown below were prepared as described in examples 1 to 5 above using different starting materials.
Figure BDA0002246490020000092
:1H NMR(400MHz,CDCl3)δ7.30(t,J＝8.1Hz,1H),7.12–7.04(m,2H),7.01–6.90(m,2H),6.82–6.72(m,1H),6.42–6.26(m,2H),3.82(s,3H)；13C NMR(101MHz,CDCl3)δ160.6,142.0,130.4,119.4(2C),112.9,110.9,110.4(2C),106.8,55.5；MS(GC-MS):m/z 173.1(M+).
Figure BDA0002246490020000101
:M.p.112.5-113.3℃。1H NMR(400MHz,CDCl3)δ7.35–7.25(m,2H),7.03–6.88(m,4H),6.31(t,J＝2.1Hz,2H),3.81(s,3H)；13C NMR(101MHz,CDCl3)δ157.7,134.5,122.2(2C),119.7(2C),114.7(2C),109.9(2C),55.6；MS(GC-MS):m/z 173.1(M+).
Figure BDA0002246490020000102
:1H NMR(400MHz,CDCl3)δ7.63(s,1H),7.53(dt,J＝23.0,7.6Hz,3H),7.10(s,2H),6.38(s,2H)；13C NMR(101MHz,CDCl3)δ141.1,132.1(q,JCF＝32.7Hz),130.2,123.7(q,JCF＝272.5Hz),123.4,122.1(q,JCF＝3.8Hz),119.2(2C),117.2(q,JCF＝3.8Hz),111.3(2C)；MS(GC-MS):m/z 211.1(M+).
Figure BDA0002246490020000103
:1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.4Hz,2H),7.47(d,J＝8.4Hz,2H),7.20–7.04(m,2H),6.49–6.31(m,2H)；13C NMR(101MHz,CDCl3)δ143.2,127.45(d,JCF＝33.0Hz),126.90(q,JCF＝3.7Hz,2C),124.03(d,JCF＝271.7Hz),120.0(2C),119.1(2C),111.5(2C)；MS(GC-MS):m/z 211.1(M+).
Figure BDA0002246490020000104
:1H NMR(400MHz,CDCl3)δ7.69–7.59(m,2H),7.57–7.48(m,2H),7.15–7.01(m,2H),6.49–6.27(m,2H)；13C NMR(101MHz,CDCl3)δ141.3,130.6,128.9,124.4,123.4,119.0(2C),118.1,113.8,111.8(2C)；MS(GC-MS):m/z 168.1(M+).
Figure BDA0002246490020000105
:1H NMR(400MHz,CDCl3)δ8.21(ddt,J＝9.3,8.2,2.0Hz,2H),7.77–7.46(m,2H),7.23–7.07(m,2H),6.53–6.32(m,2H)；13C NMR(101MHz,CDCl3)δ130.5,125.6,125.6,120.0,119.4,119.2,119.1,114.9,112.6,111.9；MS(GC-MS):m/z 188.1(M+).
Figure BDA0002246490020000106
:1H NMR(400MHz,CDCl3)δ7.28(t,J＝7.7Hz,1H),7.23–7.14(m,2H),7.13–6.98(m,3H),6.45–6.25(m,2H),2.39(s,3H)；13C NMR(101MHz,CDCl3)δ140.8,139.6,129.4,126.4,121.4,119.4(2C),117.7,110.3(2C),21.5；MS(GC-MS):m/z 157.1(M+).
Figure BDA0002246490020000107
:1H NMR(400MHz,CDCl3)δ7.75–7.67(m,2H),7.52–7.44(m,2H),7.19–7.10(m,2H),6.45–6.36(m,2H)；13C NMR(101MHz,CDCl3)δ143.7,133.9(2C),120.0(2C),118.9(2C),118.5,112.2(2C),108.6；MS(GC-MS):m/z 168.1(M+).
Figure BDA0002246490020000111
:1H NMR(400MHz,CDCl3)δ7.30–7.24(m,2H),7.20(d,J＝8.2Hz,2H),7.04(t,J＝2.2Hz,2H),6.32(t,J＝2.1Hz,2H),2.36(s,3H)；13C NMR(101MHz,CDCl3)δ138.5,135.4,130.1(2C),120.6(2C),119.4(2C),110.1(2C),20.9；MS(GC-MS):m/z 157.1(M+).
Figure BDA0002246490020000112
:1H NMR(400MHz,CDCl3)δ7.44–7.37(m,4H),7.27–7.22(m,1H),7.09(t,J＝2.2Hz,2H),6.35(t,J＝2.2Hz,2H)；13C NMR(101MHz,CDCl3)δ138.2,134.3,129.9,128.2,127.9,127.0,126.6,125.3,123.3,123.3,123.3(2C),109.1(2C)；MS(GC-MS):m/z 193.2(M+).
Figure BDA0002246490020000113
:1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.7Hz,2H),7.19(d,J＝8.6Hz,2H),6.69(t,J＝2.0Hz,2H),6.24(t,J＝2.0Hz,2H),5.18(s,2H)；13C NMR(101MHz,CDCl3)δ147.5,145.8,127.4(2C),124.0(2C),121.3(2C),109.4(2C),52.6；MS(GC-MS):m/z 202.1(M+).
Figure BDA0002246490020000114
:1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.1Hz,2H),7.17(d,J＝8.0Hz,2H),6.67(t,J＝2.1Hz,2H),6.21(t,J＝2.1Hz,2H),5.11(s,2H),13C NMR(101MHz,CDCl3)δ142.4(d,JCF＝1.2Hz,2C),130.0(q,JCF＝32.6Hz),127.1(2C),125.7(q,JCF＝3.8Hz,2C),124.1(q,JCF＝272.1Hz),121.2,109.1(2C),52.8；MS(GC-MS):m/z 225.1(M+).
Figure BDA0002246490020000115
:1H NMR(400MHz,CDCl3)δ8.12(dd,J＝8.2,1.6Hz,1H),7.97(s,1H),7.48(t,J＝7.9Hz,1H),7.36(d,J＝8.3Hz,1H),6.70(t,J＝2.1Hz,2H),6.23(t,J＝2.1Hz,2H),5.16(s,2H).13C NMR(101MHz,CDCl3)δ148.6,140.5,132.8,129.8,122.7,121.8,121.1(2C),109.4(2C),52.5；MS(GC-MS):m/z 202.1(M+).
Figure BDA0002246490020000116
:1H NMR(400MHz,CDCl3)δ7.55(d,J＝7.7Hz,1H),7.42(t,J＝7.7Hz,1H),7.34(s,1H),7.32–7.27(m,1H),6.67(t,J＝2.1Hz,2H),6.22(t,J＝2.1Hz,2H),5.10(s,2H)；13C NMR(101MHz,CDCl3)δ140.0,131.4,131.1,130.3,129.6,121.1(2C),118.5,112.9,109.3(2C),52.4；MS(GC-MS):m/z 182.1(M+).
Figure BDA0002246490020000117
:1H NMR(400MHz,CDCl3)δ8.53(dd,J＝4.8,1.3Hz,1H),8.46(d,J＝1.8Hz,1H),7.38–7.33(m,1H),7.23(dd,J＝7.9,4.8Hz,1H),6.68(t,J＝2.1Hz,2H),6.20(t,J＝2.1Hz,2H),5.07(s,2H).13C NMR(101MHz,CDCl3)δ149.2,148.5,134.7,133.7,123.7,121.0(2C),109.1(2C),50.8；MS(GC-MS):m/z 158.1(M+).
Figure BDA0002246490020000121
:1H NMR(400MHz,CDCl3)δ7.53(d,J＝7.8Hz,1H),7.42(t,J＝7.8Hz,1H),7.38(s,1H),7.26–7.20(m,1H),6.68(t,J＝2.1Hz,2H),6.21(t,J＝2.0Hz,2H),5.11(s,2H)；13C NMR(101MHz,CDCl3)δ139.4,131.1(q,JCF＝32.4Hz),130.2(d,JCF＝0.7Hz),129.3,121.2(2C),124.6(q,JCF＝3.8Hz),124.0(q,JCF＝272.3Hz),123.7(q,JCF＝3.8Hz).109.1(2C),52.8；MS(GC-MS):m/z 225.1(M+).
Figure BDA0002246490020000122
:1H NMR(400MHz,CDCl3)δ7.07(ddd,J＝8.1,5.3,2.4Hz,2H),7.03–6.95(m,2H),6.66(t,J＝2.0Hz,2H),6.18(t,J＝1.8Hz,2H),5.01(s,2H)；13C NMR(101MHz,CDCl3)δ162.3(d,JCF＝246.0Hz),134.0(d,JCF＝3.2Hz),128.7(d,JCF＝8.2Hz,2C),121.0(2C),115.6(d,JCF＝21.6Hz,2C),108.7(2C),52.6；MS(GC-MS):m/z 175.1(M+).
Figure BDA0002246490020000123
:1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.3Hz,2H),7.14(d,J＝8.5Hz,2H),6.67(t,J＝2.1Hz,2H),6.22(t,J＝2.1Hz,2H),5.13(s,2H).13C NMR(101MHz,CDCl3)δ143.8,132.6(2C),127.3(2C),121.3(2C),118.6,111.6,109.3(2C),52.8；MS(GC-MS):m/z 182.1(M+).
Figure BDA0002246490020000124
:1H NMR(400MHz,CDCl3)δ7.25–7.19(m,1H),6.99–6.89(m,2H),6.71(t,J＝1.9Hz,2H),6.17(d,J＝1.7Hz,2H),5.19(s,2H).13C NMR(101MHz,CDCl3)δ140.64,126.94,126.01,125.59,120.72,108.74,48.07.
Figure BDA0002246490020000125
:1H NMR(400MHz,CDCl3)δ7.35(d,J＝1.1Hz,1H),6.69(t,J＝1.8Hz,2H),6.31(dd,J＝3.1,1.9Hz,1H),6.23(d,J＝3.0Hz,1H),6.16(s,2H),5.00(s,2H).13C NMR(101MHz,CDCl3)δ150.83,142.72,120.74,110.43,108.58,108.15,46.10.
Figure BDA0002246490020000126
:1H NMR(400MHz,CDCl3)δ7.30–7.24(m,2H),7.22(ddd,J＝7.3,3.5,1.3Hz,1H),7.14–7.05(m,2H),6.58(s,2H),6.12(s,2H),4.15–4.04(m,2H),3.09–2.96(m,2H).13C NMR(101MHz,CDCl3)δ138.51,128.72,128.60,126.65,120.52,108.07,51.20,38.43.
Figure BDA0002246490020000127
:1H NMR(400MHz,CDCl3)δ7.73(dd,J＝5.2,3.3Hz,2H),7.63–7.56(m,1H),7.49(dd,J＝10.4,4.7Hz,2H),7.34–7.26(m,2H),6.40–6.29(m,2H).13C NMR(101MHz,CDCl3)δ167.71,133.28,132.27,129.50,128.48,121.30,113.15.
Figure BDA0002246490020000131
White solid; trans/cis 96: 4; HRMS (EI) calcd for C18H13F2NO[M]+297.0965,found 297.0963.
Figure BDA0002246490020000132
White solid; trans/cis 60: 40;1H NMR(400MHz,CDCl3)δ8.06(s,0.6H),8.00(dd,J＝15.8,8.2Hz,0.8H),7.91(dd,J＝13.2,8.2Hz,1.2H),7.80(d,J＝3.8Hz,0.4H),7.74(d,J＝10.0Hz,1.2H),7.71–7.66(m,0.8H),7.48(s,0.4H),6.90(s,0.6H),6.80(t,J＝2.1Hz,1.2H),6.52(t,J＝2.1Hz,0.8H),6.34(t,J＝2.0Hz,1.2H),6.11(t,J＝2.1Hz,0.8H),5.36(d,J＝4.8Hz,0.4H),5.20(q,J＝11.6Hz,1.2H),5.11(d,J＝4.7Hz,0.4H),2.59(s,0.4H),2.04(s,0.6H).HRMS(EI)calcd for C20H13F6NO[M]+297.0901,found 297.0900.
Figure BDA0002246490020000133
white solid, m.p. 141-149 ℃; trans isomer:1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.91(dd,J＝13.2,8.2Hz,2H),7.70(dd,J＝16.1,8.2Hz,2H),6.90(s,1H),6.81(t,J＝2.1Hz,2H),6.36(t,J＝2.1Hz,2H),5.23(d,J＝11.7Hz,1H),5.18(d,J＝11.6Hz,1H),2.60(s,1H)；13C NMR(100MHz,DMSO)δ148.05,147.99,141.46,139.30,136.59,136.26,126.66,126.52,123.62,123.35,121.32,121.16,120.54(2C),108.70(2C),68.58,62.83.HRMS(EI)calcd for C18H13N3O5[M]+351.0855,found 351.0871.
Figure BDA0002246490020000134
white solid; trans/cis 58: 42;1H NMR(400MHz,CDCl3)δ7.79–7.63(m,2.65H),7.44–7.32(m,2H),7.19(ddd,J＝8.6,5.1,1.1Hz,0.39H),7.11–6.98(m,1H),6.75(t,J＝2.1Hz,0.83H),6.73(t,J＝2.1Hz,1.16H),6.60(d,J＝7.6Hz,0.39H),6.34(ddd,J＝9.3,2.6,0.8Hz,0.57H),6.29–6.22(m,2H),5.12–5.03(m,2H),2.43(s,1H).HRMS(EI)calcd for C18H14FNO[M]+279.1059,found 279.1033.
Figure BDA0002246490020000135
white solid; trans/cis-69: 31;1H NMR(400MHz,CDCl3)δ7.80–7.66(m,3H),7.45–7.32(m,2.42H),7.23(ddd,J＝7.6,3.7,1.2Hz,0.77H),6.78(t,J＝2.1Hz,1.39H),6.76(t,J＝2.1Hz,0.61H),6.70–6.61(m,1H),6.33–6.26(m,2H),5.16–5.07(m,2H),2.31(s,1H).HRMS(EI)calcd for C18H14 35ClNO[M]+295.0764,found 295.0762,calcd for C18H14 37ClNO[M]+297.0734,found 297.0733.
Figure BDA0002246490020000141
white solid; trans, cis 33: 67;1H NMR(400MHz,CDCl3)δ8.01(s,0.41H),7.90–7.77(m,2H),7.75–7.70(m,0.6H),7.64(dd,J＝13.9,8.4Hz,1H),7.48–7.38(m,1.59H),7.28(t,J＝7.5Hz,0.41H),6.92(s,0.58H),6.80(s,0.82H),6.76(s,1.17H),6.65(d,J＝7.7Hz,0.42H),6.36–6.25(m,2H),5.21–5.12(m,2H),2.34(s,1H).HRMS(EI)calcd for C19H14F3NO[M]+329.1027,found 329.1021.
Figure BDA0002246490020000142
white solid; trans/cis 57: 43; HRMS (EI) calcd for C19H17NO2[M]+291.1259,found 291.1254.
Obtaining trans (trans) isomer m.p.131-134 ℃ by further separation;1H NMR(400MHz,CDCl3)δ7.75(t,J＝8.7Hz,2H),7.70–7.64(m,1H),7.38(dtd,J＝15.2,7.6,1.7Hz,3H),7.19(td,J＝7.6,1.0Hz,1H),6.75(t,J＝2.1Hz,2H),6.65(d,J＝7.7Hz,1H),6.24(t,J＝2.1Hz,2H),5.20–5.03(m,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ160.08,137.60,133.69,133.14,128.71,127.52,126.43,125.26,124.85,122.97,120.41(2C),114.49,110.43,109.31(2C),72.13,65.94,55.44.HRMS(EI)calcd for C19H17NO2[M]+291.1259,found 291.1260.
Figure BDA0002246490020000143
white solid, m.p. 142-146 ℃; trans isomer:1H NMR(400MHz,CDCl3)δ8.64(d,J＝1.4Hz,1H),8.29(dd,J＝8.5,2.2Hz,1H),7.91(d,J＝8.6Hz,1H),7.85(d,J＝7.7Hz,1H),7.46(t,J＝7.6Hz,1H),7.35(t,J＝7.6Hz,1H),6.85(t,J＝2.0Hz,2H),6.70(d,J＝7.7Hz,1H),6.37(t,J＝2.0Hz,2H),5.24(dd,J＝26.0,11.7Hz,2H),2.45(s,1H)；13C NMR(100MHz,CDCl3)δ135.91,134.51,133.12,132.12,128.78,128.57,128.54,128.50,126.59,125.58,123.77,123.66,120.45(2C),109.26(2C),72.02,65.80；HRMS(EI)calcd for C18H14N2O3[M]+306.1004,found 306.1023.
Figure BDA0002246490020000144
white solid, m.p. 141-149 ℃; trans isomer:1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.91(dd,J＝13.2,8.2Hz,2H),7.70(dd,J＝16.1,8.2Hz,2H),6.90(s,1H),6.81(t,J＝2.1Hz,2H),6.36(t,J＝2.1Hz,2H),5.23(d,J＝11.7Hz,1H),5.18(d,J＝11.6Hz,1H),2.60(s,1H)；13C NMR(100MHz,DMSO)δ148.05,147.99,141.46,139.30,136.59,136.26,126.66,126.52,123.62,123.35,121.32,121.16,120.54(2C),108.70(2C),68.58,62.83.HRMS(EI)calcd for C18H13N3O5[M]+351.0855,found 351.0871.
Figure BDA0002246490020000151
white solid; trans/cis 60: 40;1H NMR(400MHz,CDCl3)δ8.06(s,0.6H),8.00(dd,J＝15.8,8.2Hz,0.8H),7.91(dd,J＝13.2,8.2Hz,1.2H),7.80(d,J＝3.8Hz,0.4H),7.74(d,J＝10.0Hz,1.2H),7.71–7.66(m,0.8H),7.48(s,0.4H),6.90(s,0.6H),6.80(t,J＝2.1Hz,1.2H),6.52(t,J＝2.1Hz,0.8H),6.34(t,J＝2.0Hz,1.2H),6.11(t,J＝2.1Hz,0.8H),5.36(d,J＝4.8Hz,0.4H),5.20(q,J＝11.6Hz,1.2H),5.11(d,J＝4.7Hz,0.4H),2.59(s,0.4H),2.04(s,0.6H).HRMS(EI)calcd for C20H13F6NO[M]+297.0901,found 297.0900.
Figure BDA0002246490020000152
white solid; trans/cis 96: 4; HRMS (EI) calcd for C18H13F2NO[M]+297.0965,found 297.0963.
Obtaining trans (trans) isomer m.p.143-148 deg.C by further separation;1H NMR(400MHz,CDCl3)δ7.71–7.64(m,2H),7.46(ddd,J＝9.4,2.7,0.8Hz,1H),7.14–7.03(m,2H),6.82(t,J＝2.1Hz,2H),6.42–6.28(m,3H),5.14(q,J＝11.7Hz,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ162.95(d,JCF＝248.4Hz),162.86(d,JCF＝248.3Hz),138.10(d,JCF＝7.3Hz),136.86(d,JCF＝6.8Hz),128.63(d,JCF＝3.3Hz),127.56(d,JCF＝3.3Hz),125.45(d,JCF＝8.1Hz),125.37(d,JCF＝7.9Hz),120.24,115.79(d,JCF＝21.8Hz),115.41(d,JCF＝21.9Hz),113.45(d,JCF＝23.6Hz),112.66(d,JCF＝23.7Hz),109.98,71.51,65.70.
Figure BDA0002246490020000153
:1H NMR(400MHz,CDCl3)δ8.84(dd,J＝20.3,8.7Hz,2H),8.20(s,1H),8.12(s,1H),8.00–7.85(m,3H),7.04(t,J＝2.1Hz,2H),6.49(t,J＝2.1Hz,2H)；13C NMR(101MHz,CDCl3)δ137.9,132.5,131.4,130.9,130.2(qd,JCF＝33.0,3.5Hz,2C),129.6,126.1(q,JCF＝4.1Hz),124.7,124.4,124.1,124.0(qd,JCF＝272.6,3.9Hz,2C),123.8(dd,JCF＝6.4,3.1Hz),123.5(q,JCF＝3.2Hz),123.1(2C),121.9(q,JCF＝4.2Hz),110.3(2C)；HRMS(EI)calcd for C20H11F6N[M]+379.0796,found 379.0797.
Figure BDA0002246490020000154
:1H NMR(400MHz,CDCl3)δ8.66–8.52(m,2H),7.68(s,1H),7.49(dd,J＝9.1,2.7Hz,1H),7.45–7.35(m,3H),6.99(t,J＝2.1Hz,2H),6.44(t,J＝2.1Hz,2H)；13C NMR(101MHz,CDCl3)δ161.8(dd,JCF＝247.1,0.8Hz),161.5(dd,JCF＝248.8,1.7Hz),137.4(d,JCF＝3.8Hz),132.1(dd,JCF＝9.0,1.0Hz),130.5(dd,JCF＝8.6,1.2Hz),127.6(d,JCF＝1.7Hz),126.1(d,JCF＝1.3Hz),125.2(d,JCF＝8.6Hz),124.9(d,JCF＝8.9Hz),124.3(d,JCF＝3.8Hz),123.0,116.8(d,JCF＝20.5Hz),116.6(d,JCF＝20.3Hz),112.9(d,JCF＝20.9Hz),109.7,109.1(d,JCF＝23.1Hz)；HRMS(EI)calcd for C18H11F2N[M]+279.0860,found 279.0863.
Figure BDA0002246490020000161
:1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3)δ8.87(d,J＝8.8Hz,1H),8.82(d,J＝8.7Hz,1H),8.20(s,1H),8.12(s,1H),7.94(td,J＝8.7,1.7Hz,2H),7.87(s,1H),7.04(t,J＝2.1Hz,2H),6.49(t,J＝2.1Hz,2H),3.91(s,3H),3.78(s,3H)；13C NMR(101MHz,CDCl3)δ158.2,158.0,136.9,131.4,129.7,125.7,124.4,124.1,124.0,123.8,123.0(2C),117.9,117.9,109.1(2C),108.5,104.4,55.5,55.3；HRMS(EI)calcd for C20H17NO2[M]+303.1259,found 303.1262.
Figure BDA0002246490020000162
:1H NMR(400MHz,CDCl3)δ8.85(d,J＝9.2Hz,1H),8.78–8.62(m,2H),8.45(dd,J＝9.1,2.4Hz,1H),8.01–7.72(m,4H),7.04(t,J＝2.1Hz,2H),6.49(t,J＝2.1Hz,2H)；13C NMR(101MHz,CDCl3)δ146.6,136.7,134.9,132.5,129.3,129.2,129.1,128.7,128.1,125.9,124.6,123.6,123.3(2C),121.0,120.4,110.2(2C)；HRMS(EI)calcd for C18H12N2O2[M]+288.0899,found 288.0897.
example 6:
synthesis of dimethyl 2- (5-oxo-1-phenyl-1, 5-dihydro-2H-pyrrol-2-ylidene) malonate
Figure BDA0002246490020000163
A25 mL round bottom flask was charged with 1-phenyl-1H-pyrrole (2mmol, 286mg), dimethyl malonate (4mmol, 528mg), manganese acetate dihydrate (6mmol, 1608mg) and 15mL of acetic acid. Stirred in an oil bath at 70 ℃ for 12 h. After the reaction, 10mL of saturated brine was added, extraction was performed with ethyl acetate (3X 10mL), the extracts were combined, and the crude product after solvent removal by rotary evaporation was purified by column chromatography to obtain 0.287g of a pale yellow solid, 50% yield, m.p.133.7-134.7 ℃.1H NMR(400MHz,CDCl3)δ8.34(d,J＝6.1Hz,1H),7.50–7.37(m,3H),7.20(d,J＝7.4Hz,2H),6.46(d,J＝6.1Hz,1H),3.79(s,3H),3.07(s,3H)；13C NMR(101MHz,CDCl3)δ170.4,163.9,149.1,138.5(2C),133.4,129.1(2C),128.9(2C),126.2(2C),108.0,52.8,52.2；HRMS(EI)calcd for C15H13NO5[M]+287.0794,found 287.0792.
The lactam compounds shown below were prepared according to the procedure described above for example 6, using different starting materials.
Figure BDA0002246490020000171
:1H NMR(400MHz,CDCl3)δ8.33(d,J＝6.1Hz,1H),7.33(t,J＝7.7Hz,1H),7.20(d,J＝7.5Hz,1H),7.00(dd,J＝8.1,0.5Hz,2H),6.45(d,J＝6.1Hz,1H),3.79(s,3H),3.08(s,3H),2.38(s,3H)；13C NMR(101MHz,CDCl3)δ170.4,163.9(2C),149.2,139.0,138.4,133.3,129.6,129.4,128.8,126.2,125.9,107.9,52.7,52.0,21.2；HRMS(EI)calcd for C16H15NO5[M]+301.0950,found 301.0949.
Figure BDA0002246490020000172
:1H NMR(400MHz,CDCl3)δ8.37(d,J＝6.1Hz,1H),8.30–8.26(m,1H),8.09(t,J＝2.1Hz,1H),7.65(t,J＝8.1Hz,1H),7.57(ddd,J＝7.9,1.9,1.1Hz,1H),6.50(dd,J＝6.1,2.4Hz,1H),3.81(s,3H),3.13(s,3H)；13C NMR(101MHz,CDCl3)δ169.7,163.6,163.5,148.3,139.0,134.8(3C),129.9,126.0,123.9,123.5,108.6,52.9,52.2；HRMS(EI)calcd for C16H12N2O5[M]+332.0645,found 332.0647.
Figure BDA0002246490020000173
:1H NMR(400MHz,CDCl3)δ8.34(d,J＝6.1Hz,1H),7.72(d,J＝8.3Hz,2H),7.34(d,J＝8.2Hz,2H),6.48(d,J＝6.1Hz,1H),3.80(s,3H),3.08(s,3H)；13C NMR(101MHz,CDCl3)δ169.8,163.70,163.66,148.6,138.9(2C),136.9,130.8(q,JCF＝33.1Hz),129.1(2C),126.1(dd,JCF＝6.5,2.6Hz,2C),123.6(q,JCF＝272.4Hz),108.5,52.9,52.1；HRMS(EI)calcd for C16H12F3NO5[M]+355.0668,found355.0670.
Figure BDA0002246490020000174
:1H NMR(400MHz,CDCl3)δ8.34(d,J＝6.1Hz,1H),7.15–7.08(m,2H),6.97–6.92(m,2H),6.45(d,J＝6.1Hz,1H),3.83(s,3H),3.78(s,3H),3.16(s,3H)；13C NMR(101MHz,CDCl3)δ170.7,164.0,163.9,159.8,149.2,138.3,130.4(2C),126.2,125.6,114.3(2C),107.8,55.5,52.7,52.3；HRMS(EI)calcd for C16H15NO6[M]+317.0899,found 317.0900.
Figure BDA0002246490020000175
:1H NMR(400MHz,CDCl3)δ8.35(d,J＝6.1Hz,1H),7.70(dt,J＝7.8,1.3Hz,1H),7.58(dd,J＝10.4,5.4Hz,1H),7.52(t,J＝1.6Hz,1H),7.46(ddd,J＝8.0,2.0,1.1Hz,1H),6.49(d,J＝6.1Hz,1H),3.81(s,3H),3.18(s,3H)；13C NMR(101MHz,CDCl3)δ169.7,163.6,163.5,148.3,139.0,134.6,133.3,132.2,132.2,130.1,126.1,117.4,113.3,108.5,53.0,52.3；HRMS(EI)calcd for C16H12N2O5[M]+312.0746,found 312.0745.
Figure BDA0002246490020000181
:1H NMR(400MHz,CDCl3)δ8.36(d,J＝6.1Hz,1H),7.68(d,J＝7.9Hz,1H),7.60(t,J＝7.8Hz,1H),7.52–7.38(m,2H),6.48(d,J＝6.1Hz,1H),3.80(s,3H),3.10(s,3H)；13C NMR(101MHz,CDCl3)δ169.9,163.7,163.6,148.6,138.8,134.2,132.6,131.5(q,JCF＝33.1Hz),129.8,126.1,125.63,125.61,123.4(d,JCF＝272.6Hz),108.4,52.9,52.2；HRMS(EI)calcd for C16H12F3NO5[M]+355.0668,found 355.0670.
Figure BDA0002246490020000182
:1H NMR(400MHz,CDCl3)δ8.33(d,J＝6.1Hz,1H),7.75(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),6.49(d,J＝6.1Hz,1H),3.82(s,3H),3.14(s,3H)；13C NMR(101MHz,CDCl3)δ169.5,163.6,163.6,148.4,139.1,137.9,132.8(2C),129.2(2C),126.0,117.8,112.4,108.6,53.0,52.3；HRMS(EI)calcd forC16H12N2O5[M]+312.0746,found 312.0748.
Figure BDA0002246490020000183
:1H NMR(400MHz,CDCl3)δ8.33(d,J＝6.1Hz,1H),7.24(d,J＝8.1Hz,2H),7.07(d,J＝8.2Hz,2H),6.45(d,J＝6.1Hz,1H),3.78(s,3H),3.09(s,3H),2.38(s,3H)；13C NMR(101MHz,CDCl3)δ170.6,164.0,163.9,149.2,139.0,138.4,130.6,129.7(2C),128.8(2C),126.2,107.8,52.7,52.1,21.2；HRMS(EI)calcd for C16H15NO5[M]+301.0950,found 301.0951.
Figure BDA0002246490020000184
:1H NMR(400MHz,CDCl3)δ8.33(d,J＝6.1Hz,1H),7.34(t,J＝8.1Hz,1H),6.94(dd,J＝8.4,2.4Hz,1H),6.83–6.76(m,1H),6.71(t,J＝2.1Hz,1H),6.45(d,J＝6.1Hz,1H),3.80(d,J＝6.7Hz,6H),3.14(s,3H)；13C NMR(101MHz,CDCl3)δ170.2,163.9(2C),159.9,149.0,138.5,134.4,129.6,126.1,121.0,115.2,114.0,108.1,55.4,5.7,52.1；HRMS(EI)calcd for C16H15NO6[M]+317.0899,found 317.0897.
Figure BDA0002246490020000191
:1H NMR(400MHz,CDCl3)δ8.51(d,J＝6.1Hz,1H),7.98–7.86(m,2H),7.60–7.47(m,4H),7.36(d,J＝7.1Hz,1H),6.57(d,J＝6.1Hz,1H),3.74(s,3H),2.53(s,3H)；13C NMR(101MHz,CDCl3)δ170.6,163.7,163.6,149.3,138.6,134.1,131.3,130.1,129.9,128.3,128.3,127.4,126.7,126.4,125.2,122.7,108.4,52.7,51.5；HRMS(EI)calcd for C19H15NO5[M]+337.0950,found 337.0952.
Figure BDA0002246490020000192
:1H NMR(400MHz,CDCl3)δ8.71(dd,J＝13.9,8.3Hz,2H),8.55(d,J＝6.1Hz,1H),7.88(d,J＝7.3Hz,1H),7.75–7.57(m,6H),6.59(d,J＝6.1Hz,1H),3.74(s,3H),2.37(s,3H)；13C NMR(101MHz,CDCl3)δ170.6,163.7,163.7,149.3,138.7,131.0,130.7,130.7,129.5(2C),129.1,128.6,128.1,127.5(2C),127.3,126.5,123.5,123.0,122.7,108.5,52.7,51.6；HRMS(EI)calcd for C23H17NO5[M]+387.1107,found 387.1106.
Figure BDA0002246490020000193
:1H NMR(400MHz,CDCl3)δ8.83(d,J＝9.1Hz,1H),8.70(d,J＝8.2Hz,1H),8.58(d,J＝6.1Hz,1H),8.51(d,J＝2.3Hz,1H),8.45(dd,J＝9.1,2.3Hz,1H),7.93(dd,J＝7.7,0.9Hz,1H),7.84–7.72(m,3H),6.65(d,J＝6.1Hz,1H),3.77(s,3H),2.43(s,3H)；13C NMR(101MHz,CDCl3)δ170.5,163.6,163.4,149.0,146.5,139.2,134.8,131.9,131.2,129.7,129.5,129.3,129.3,129.2,129.1,126.5,124.7,123.8,121.2,119.8,108.9,52.9,51.7；HRMS(EI)calcd for C23H16N2O7[M]+432.0958,found 432.0957.
Figure BDA0002246490020000194
:1H NMR(400MHz,CDCl3)δ8.83(t,J＝9.4Hz,2H),8.58(d,J＝6.1Hz,1H),8.19(s,1H),8.00–7.92(m,3H),7.77(s,1H),6.64(d,J＝6.1Hz,1H),3.78(s,3H),2.38(s,3H)；13C NMR(101MHz,CDCl3)δ170.4,163.6,163.4,149.0,139.3,132.3,131.7,130.8,130.6,130.5,130.4,130.2,130.1,130.0,126.5,126.4,126.4,124.6(t,JCF＝4.7Hz),124.5,124.3,124.1(dd,JCF＝6.4,3.2Hz),121.5(d,JCF＝4.3Hz).108.9,52.9,51.6；HRMS(EI)calcd for C25H15F6NO5[M]+523.0854,found 523.0852.
Figure BDA0002246490020000195
:1H NMR(400MHz,CDCl3)δ8.58(ddd,J＝19.3,9.6,5.7Hz,3H),7.63(s,1H),7.47(dtd,J＝17.5,9.1,2.6Hz,3H),7.24(dd,J＝9.6,2.5Hz,1H),6.60(d,J＝6.1Hz,1H),3.76(s,3H),2.46(s,3H)；13C NMR(101MHz,CDCl3)δ170.3,163.6,163.5,161.8(d,JCF＝247.3Hz),161.3(d,JCF＝248.1Hz),148.8,139.0,131.5(d,JCF＝8.2Hz),130.9(d,JCF＝9.7Hz),129.8(d,JCF＝3.8Hz),129.6(d,JCF＝3.9Hz),127.4,127.0,126.4,125.4(d,JCF＝8.6Hz),125.0(d,JCF＝8.9Hz),117.6(d,JCF＝23.8Hz),117.0(d,JCF＝23.9Hz),113.2(d,JCF＝21.0Hz),108.7,108.7(d,JCF＝22.6Hz),52.8,51.6；HRMS(EI)calcd for C23H15F2NO5[M]+423.0918,found 423.0922.
Figure BDA0002246490020000201
:1H NMR(400MHz,CDCl3)δ8.61–8.41(m,3H),7.56(s,1H),7.30(ddd,J＝8.9,5.3,2.6Hz,2H),7.20(d,J＝2.6Hz,1H),6.89(d,J＝2.6Hz,1H),6.59(d,J＝6.1Hz,1H),3.89(d,J＝26.6Hz,6H),3.75(s,3H),2.42(s,3H)；13C NMR(101MHz,CDCl3)δ170.5,163.7,163.6,158.2,157.9,149.2,138.7,131.0,129.9,129.5,128.6,126.5,125.6,125.2,124.2,123.8,119.0,117.7,108.7,108.6,104.2,55.4,55.4,52.7,51.6；HRMS(EI)calcd for C25H21NO7[M]+447.1318,found 447.1321.
Figure BDA0002246490020000202
:1H NMR(400MHz,CDCl3)δ8.25(d,J＝6.1Hz,1H),7.25(dt,J＝26.9,7.2Hz,3H),7.00(d,J＝7.3Hz,2H),6.45(d,J＝6.1Hz,1H),4.97(s,2H),3.76(s,3H),3.35(s,3H)；13C NMR(101MHz,CDCl3)δ171.0,165.0,164.0,147.8,138.8,135.9,128.6(2C),127.3,125.9,125.6(2C),108.1,52.8,52.6,43.7；HRMS(EI)calcdfor C16H15NO5[M]+301.0950,found 301.0949.
Figure BDA0002246490020000203
:1H NMR(400MHz,CDCl3)δ8.23(dd,J＝44.7,7.4Hz,3H),7.20(d,J＝8.6Hz,2H),6.49(d,J＝6.1Hz,1H),5.03(s,2H),3.78(s,3H),3.42(s,3H)；13C NMR(101MHz,CDCl3)δ170.7,164.8,163.6,147.3,147.3,143.7,139.2,126.7(2C),125.9,123.8(2C),108.3,52.9,52.8,43.5；HRMS(EI)calcd for C16H14N2O7[M]+346.0801,found 346.0799.
Figure BDA0002246490020000204
:1H NMR(400MHz,CDCl3)δ8.27(d,J＝6.1Hz,1H),7.55(d,J＝7.7Hz,1H),7.43(t,J＝7.8Hz,1H),7.32(s,1H),7.28(d,J＝7.7Hz,1H),6.48(d,J＝6.1Hz,1H),4.97(s,2H),3.78(s,3H),3.43(s,3H)；13C NMR(101MHz,CDCl3)δ170.8,164.8,163.6,147.3,139.1,137.9,131.1,130.4,129.5,129.5,125.9,118.4,112.8,108.3,52.9,52.7,43.2；HRMS(EI)calcd for C17H14N2O5[M]+326.0903,found 326.0906.
Figure BDA0002246490020000211
:1H NMR(400MHz,CDCl3)δ8.28(d,J＝6.1Hz,1H),7.61(d,J＝8.2Hz,2H),7.14(d,J＝8.2Hz,2H),6.48(d,J＝6.1Hz,1H),4.99(s,2H),3.78(s,3H),3.39(s,3H).13C NMR(101MHz,CDCl3)δ170.7,164.8,163.6,147.3,141.7,139.1,132.4(2C),126.5(2C),125.9,118.5,111.4,108.3,52.9,52.7,43.6；HRMS(EI)calcd for C17H14N2O5[M]+326.0903,found 326.0905.
Figure BDA0002246490020000212
:E/Z＝81:19；major isomer:1H NMR(400MHz,CDCl3)δ8.55(d,J＝6.2Hz,1H),7.64(d,J＝8.4Hz,2H),7.31(d,J＝8.5Hz,2H),6.56(d,J＝6.2Hz,1H),5.37(s,2H),4.31(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H).HRMS(EI)calcd for C16H11N3O3[M]+293.0800,found 293.0802.
Figure BDA0002246490020000213
:1H NMR(400MHz,CDCl3)δ7.67–7.59(m,3H),7.40(dt,J＝16.3,8.2Hz,6H),7.31–7.26(m,2H),7.19(dd,J＝8.0,4.4Hz,2H),6.97(s,1H),6.84(d,J＝8.1Hz,1H),6.75(s,1H),4.72(s,1H),4.59(s,1H).HRMS(EI)calcd for C27H18N2O3[M]+418.1317,found 418.1318.
Figure BDA0002246490020000214
:E/Z＝63:37；major isomer:1H NMR(400MHz,CDCl3)δ8.19(d,J＝6.1Hz,1H),7.59(d,J＝8.1Hz,2H),7.09(d,J＝8.1Hz,2H),6.47(d,J＝6.1Hz,1H),4.95(s,2H),3.81(s,3H),1.69(ddd,J＝12.2,7.9,4.5Hz,1H),0.98–0.93(m,2H),0.76(dq,J＝7.4,3.7Hz,2H).HRMS(EI)calcd for C19H16N2O4[M]+336.1110,found 336.1110.
Figure BDA0002246490020000215
:E/Z＝66:34；major isomer:1H NMR(400MHz,CDCl3)δ8.14(d,J＝6.1Hz,1H),7.61(d,J＝8.0Hz,2H),7.10(d,J＝8.1Hz,2H),6.47(d,J＝6.2Hz,1H),4.95(s,2H),4.39–4.32(m,2H),3.64–3.55(m,2H),3.34(s,3H),1.72(s,3H).HRMS(EI)calcd for C19H18N2O5[M]+322.1216,found 322.1219.
Figure BDA0002246490020000221
:1H NMR(400MHz,CDCl3)δ8.26(d,J＝6.1Hz,1H),7.51(d,J＝7.8Hz,1H),7.43(t,J＝7.8Hz,1H),7.32(s,1H),7.17(d,J＝7.7Hz,1H),6.47(d,J＝6.1Hz,1H),5.01(s,2H),3.77(s,3H),3.37(s,3H)；13C NMR(101MHz,CDCl3)δ170.9,164.9,163.8,147.5,139.1,137.3,131.0(q,JCF＝32.4Hz),129.2,129.1,125.8,124.3(q,JCF＝3.8Hz),123.9(d,JCF＝272.3Hz),122.8(q,JCF＝3.8Hz),108.3,52.8,52.6,43.5；HRMS(EI)calcd for C17H14F3NO5[M]+369.0842,found 369.0838.
Figure BDA0002246490020000222
:1H NMR(400MHz,CDCl3)δ8.28(d,J＝6.1Hz,1H),7.56(d,J＝8.2Hz,2H),7.14(d,J＝8.1Hz,2H),6.47(d,J＝6.1Hz,1H),5.01(s,2H),3.77(s,3H),3.35(s,3H)；13C NMR(101MHz,CDCl3)δ170.8,164.9,163.7,147.4,140.3,139.0(2C),129.7(d,JCF＝32.6Hz),126.1,125.9,125.5(q,JCF＝3.8Hz,2C),124.0(q,JCF＝272.0Hz),108.3,52.8,52.6,43.5；HRMS(EI)calcd for C17H14F3NO5[M]+369.0824,found 369.0827.
Figure BDA0002246490020000223
:1H NMR(400MHz,CDCl3)δ8.27(d,J＝6.1Hz,1H),8.12(dd,J＝8.1,1.3Hz,1H),7.92(s,1H),7.50(t,J＝7.9Hz,1H),7.37(dd,J＝7.7,0.4Hz,1H),6.49(d,J＝6.1Hz,1H),5.03(s,2H),3.78(s,3H),3.46(s,3H).13C NMR(101MHz,CDCl3)δ170.83,164.84,163.65,148.40,147.34,139.21,138.50,132.06,129.69,125.89,122.55,121.10,108.30,52.89,52.78,43.28；HRMS(EI)calcd for C16H14N2O7[M]+346.0801,found 346.0799.
Figure BDA0002246490020000224
:1H NMR(400MHz,CDCl3)δ8.24(d,J＝6.1Hz,1H),6.99(d,J＝6.9Hz,4H),6.44(d,J＝6.1Hz,1H),4.92(s,2H),3.77(s,3H),3.44(s,3H)；13C NMR(101MHz,CDCl3)δ171.0,164.9,163.9,162.0(d,JCF＝245.7Hz),147.6,138.9,131.7(d,JCF＝3.1Hz),127.5(d,JCF＝8.1Hz,2C),125.9,115.5(d,JCF＝21.6Hz,2C),108.1,52.8,52.7,43.1；HRMS(EI)calcd for C16H14FNO5[M]+319.0856,found 319.0858.
Figure BDA0002246490020000225
:1H NMR(400MHz,CDCl3)δ8.57–8.46(m,1H),8.39(s,1H),8.24(d,J＝6.1Hz,1H),7.32(d,J＝7.8Hz,1H),7.24(dd,J＝7.6,4.3Hz,1H),6.46(d,J＝6.1Hz,1H),4.98(s,2H),3.77(s,3H),3.46(s,3H)；13C NMR(101MHz,CDCl3)δ170.9,164.9,163.7,148.7,147.8,147.3,139.1,133.7,131.8,125.8,123.5,108.3,52.8,52.7,41.6；HRMS(EI)calcd for C15H14N2O5[M]+302.0903,found 302.0906.
Figure BDA0002246490020000231
:1H NMR(400MHz,CDCl3)δ8.11(d,J＝6.1Hz,1H),7.29(d,J＝1.1Hz,1H),6.39(d,J＝6.1Hz,1H),6.28(dd,J＝3.2,1.9Hz,1H),6.04(dd,J＝3.3,0.8Hz,1H),4.94(s,2H),3.79(s,3H),3.74(s,3H).13C NMR(101MHz,CDCl3)δ170.76,164.94,164.12,149.23,147.63,142.12,139.06,125.77,110.51,108.01,107.27,52.92,52.79,37.51.HRMS(EI)calcd for C14H13NO6[M]+291.0743,found 291.0742.
Figure BDA0002246490020000232
:1H NMR(400MHz,CDCl3)δ8.14(d,J＝6.1Hz,1H),7.18(dd,J＝5.1,1.2Hz,1H),6.90(dd,J＝5.1,3.5Hz,1H),6.81–6.76(m,1H),6.40(d,J＝6.1Hz,1H),5.10(d,J＝0.7Hz,2H),3.78(s,3H),3.67(s,3H).13C NMR(101MHz,CDCl3)δ170.75,165.00,164.02,147.46,139.13,138.83,126.77,125.82,125.21,125.01,108.11,52.98,52.81,39.48.HRMS(EI)calcd for C14H13NO5S[M]+307.0514,found 307.0508.
Figure BDA0002246490020000233
:1H NMR(400MHz,CDCl3)δ8.21(d,J＝6.1Hz,1H),7.32–7.27(m,2H),7.26–7.18(m,3H),6.32(d,J＝6.1Hz,1H),3.84(s,3H),3.83(s,3H),3.77–3.69(m,2H),2.80(dd,J＝9.3,7.2Hz,2H).13C NMR(101MHz,CDCl3)δ170.82,165.77,163.88,148.18,138.33,137.82,128.81,128.57,126.68,126.19,106.75,53.08,52.77,42.17,34.69.HRMS(EI)calcd for C17H17NO5[M]+315.1107,found 315.1109.
Figure BDA0002246490020000234
:1H NMR(400MHz,CDCl3)δ8.31(d,J＝6.1Hz,1H),7.78–7.63(m,3H),7.41–7.31(m,3H),7.25(t,J＝7.4Hz,1H),7.02(d,J＝7.6Hz,1H),6.38(d,J＝6.1Hz,1H),5.79(d,J＝11.3Hz,1H),4.84(d,J＝8.6Hz,1H),3.78(s,3H),3.27(s,3H),2.76(s,1H).13C NMR(101MHz,CDCl3)δ171.30,165.72,163.96,151.01,139.01,138.45,133.14,132.24,132.05,128.40,128.38,128.16,127.96,126.79,124.88,124.31,123.97,123.75,107.39,68.68,61.84,52.89,52.68.HRMS(EI)calcd for C23H19NO6[M]+405.1212,found 405.1197.
Figure BDA0002246490020000241
:1H NMR(400MHz,DMSO-d6)δ8.26(d,J＝7.8Hz,1H，CH-C＝C),8.22–8.15(m,1H,PhH),8.12(s,1H,PhH),7.96(t,J＝12.2Hz,1H,PhH),7.90(s,1H,PhH),7.60(d,J＝24.5Hz,1H,PhH),7.56–7.36(m,2H,PhH),6.77(d,J＝5.3Hz,1H,-OH),6.35(s,1H,CO-CH),5.51(d,J＝6.0Hz,1H,OH-CH),4.66(s,1H,-N-CH),3.74(d,J＝29.3Hz,3H,-COOMe),3.17(s,3H,-COOMe)；13C NMR(101MHz,DMSO)δ171.17(1C,CO),164.45(1C,COOMe),163.81(1C,COOMe),146.58(1C,PhC),145.60(1C,-N-C＝C),140.02(1C,PhC),139.44(1C,PhC),139.13(1C,-CH-C＝C),134.65(1C,PhC),130.20(1C,PhC),129.54(1C,PhC),128.35(1C,PhC),127.34(1C,PhC),125.49(1C,CO-CH),125.15(1C,PhC),125.08(1C,PhC),123.45(1C,PhC),120.34(1C,PhC),107.22(1C,-N-C＝C),66.00(1C,OH-CH),61.42(1C,-N-CH),52.98(1C,COOMe),52.34.(1C,COOMe).HRMS(EI)calcd for C23H16N2O7[M-H2O]+432.0958,found 432.0956.
Figure BDA0002246490020000242
:1H NMR(400MHz,CDCl3)δ8.32(d,J＝6.1Hz,1H,CH-C＝C),7.69(d,J＝8.6Hz,1H,PhH),7.66–7.58(m,2H,PhH),7.39–7.27(m,2H,PhH),6.89(dd,J＝8.6,2.6Hz,1H,PhH),6.61–6.48(m,1H,PhH),6.40(d,J＝6.1Hz,1H,CO-CH),5.77(d,J＝11.6Hz,1H,OH-CH),4.82(s,1H,-N-CH),3.79(s,3H,-COOMe),3.78(s,3H,-COOMe),3.32(s,3H,OMe),2.82–2.32(m,1H,-OH)；13C NMR(101MHz,CDCl3)δ165.74(1C,CO),163.92(1C,COOMe),159.55(1C,COOMe),151.10(1C,-N-C＝C),139.09,137.53(1C,-CH-C＝C),133.98(1C,PhC),132.05(1C,PhC),128.15(2C,PhC),127.46(1C,PhC),126.761C,CO-CH),125.94(1C,PhC),125.41(1C,PhC),124.19(1C,PhC),123.12(1C,PhC),113.01(1C,PhC),111.25(1C,PhC),107.41(1C,-N-C＝C),68.88(1C,OH-CH),61.80(1C,-N-CH),55.34(1C,-OMe),52.89(1C,COOMe),52.76(1C,COOMe).HRMS(EI)calcd for C24H19NO6[M-H2O]+417.1212,found 417.1215.
Figure BDA0002246490020000243
:1H NMR(400MHz,CDCl3)δ8.31(d,J＝6.2Hz,1H,CH-C＝C),7.86(d,J＝8.2Hz,1H,PhH),7.75–7.70(m,1H,PhH),7.69–7.59(m,2H,PhH),7.45–7.36(m,2H,PhH),7.30(s,1H,PhH),6.39(d,J＝6.1Hz,1H,PhH),5.76(d,J＝11.2Hz,1H,OH-CH),4.85(s,1H,-N-CH),3.79(s,3H,-COOMe),3.25(s,3H,-COOMe),3.01(dd,J＝17.2,12.0Hz,1H,-OH)；13C NMR(101MHz,CDCl3)δ171.36,165.59,163.91,150.90,139.26,139.19,135.55,132.71,131.77,130.06(q,J＝32.5Hz),129.14,128.66,126.72,125.11,125.04(q,J＝3.8Hz),124.17(q,J＝272.2Hz),124.51,124.09,121.85(d,J＝2.9Hz),107.71,68.24,61.41,52.99,52.74.HRMS(EI)calcd for C24H16F3NO5[M-H2O]+455.0982,found 455.0979.
Figure BDA0002246490020000251
:1H NMR(400MHz,CDCl3)δ8.31(d,J＝6.2Hz,1H),7.75–7.61(m,3H),7.37(dd,J＝5.7,3.3Hz,2H),7.33(dd,J＝8.4,1.5Hz,1H),7.01(s,1H),6.40(d,J＝6.1Hz,1H),5.75(d,J＝11.6Hz,1H),4.80(s,1H),3.80(s,3H),3.30(s,3H),2.53(d,J＝123.3Hz,1H)；13CNMR(101MHz,CDCl3)δ171.20,165.52,163.84,150.89,139.23,138.18,134.19,133.85,131.73,131.09,128.73,128.58,128.32,126.78,125.39,125.18,124.45,123.73,107.62,68.45,61.42,52.98,52.75.HRMS(EI)calcdfor C23H16 35ClNO5[M-H2O]+421.0717,found 421.0713；calcd for C23H16 37ClNO5[M-H2O]+423.0688,found 423.0703.
Figure BDA0002246490020000252
:1H NMR(400MHz,CDCl3)δ8.32(d,J＝6.2Hz,1H),7.99(s,1H),7.74(dd,J＝5.9,3.1Hz,1H),7.70–7.63(m,1H),7.50(d,J＝8.0Hz,1H),7.45–7.38(m,2H),7.17(d,J＝8.1Hz,1H),6.40(d,J＝6.1Hz,1H),5.77(dd,J＝10.5,7.3Hz,1H),4.85(s,1H),3.80(s,3H),3.31(s,3H),2.81(s,1H)；13C NMR(101MHz,CDCl3)δ171.28,165.58,163.85,162.58(d,J＝247.7Hz),150.88,139.19,137.89,134.97(d,J＝7.4Hz),131.29,129.31(d,J＝3.2Hz),128.28(2C),126.76,125.89(d,J＝8.2Hz),124.40,123.58,115.35(d,J＝21.7Hz),112.33(d,J＝23.7Hz),107.63,68.43,61.62,52.97,52.73.HRMS(EI)calcd for C23H16FNO5[M-H2O]+405.1013,found405.1014.
Figure BDA0002246490020000253
:1H NMR(400MHz,DMSO-d6)δ8.23(d,J＝8.2Hz,1H),8.18(d,J＝8.2Hz,1H),8.11(d,J＝5.9Hz,1H),7.88(s,1H),7.83(t,J＝6.8Hz,2H),7.45(s,1H),6.76(d,J＝6.1Hz,1H),6.54(d,J＝6.5Hz,1H),5.58(dd,J＝10.7,6.5Hz,1H),4.70(d,J＝11.1Hz,1H),3.78(s,3H),3.16(s,3H)；13C NMR(101MHz,DMSO-d6)δ171.14,164.40,163.82,151.53,140.93,139.40,135.03,134.53,134.11,129.30(q,J＝32.1Hz),129.08(q,J＝31.9Hz),127.39,125.78,125.71,125.26,125.00(q,J＝3.3Hz),124.07(q,J＝272.3Hz),123.92(q,J＝274.3Hz),122.34(q,J＝4.0Hz),121.64(q,J＝4.6Hz),107.10,65.88,61.22,52.95,52.25.HRMS(EI)calcd forC25H15F6NO5[M-H2O]+523.0854,found 523.0853.
Figure BDA0002246490020000254
:1H NMR(400MHz,CDCl3)δ8.32(d,J＝6.2Hz,1H),7.99(s,1H),7.74(dd,J＝5.9,3.1Hz,1H),7.70–7.63(m,1H),7.50(d,J＝8.0Hz,1H),7.45–7.38(m,2H),7.17(d,J＝8.1Hz,1H),6.40(d,J＝6.1Hz,1H),5.77(dd,J＝10.5,7.3Hz,1H),4.85(s,1H),3.80(s,3H),3.31(s,3H),2.81(s,1H)；13C NMR(101MHz,CDCl3)δ171.21,165.61,163.86(t,J＝20.1Hz),163.78,δ,161.44(d,J＝40.1Hz),150.64,140.62(d,J＝7.3Hz),139.29,134.48(d,J＝7.4Hz),128.57(d,J＝3.2Hz),127.47(d,J＝3.3Hz),126.71,125.72(d,J＝8.0Hz),125.55(d,J＝8.1Hz),115.42(d,J＝33.1Hz),115.20(d,J＝33.4Hz),112.34(d,J＝23.8Hz),111.92(d,J＝23.6Hz),107.78,68.24,61.25,53.02,52.82.HRMS(EI)calcd for C23H15F2NO5[M-H2O]+423.0918,found 423.0917.
Figure BDA0002246490020000261
:1H NMR(400MHz,CDCl3)δ8.32(d,J＝6.2Hz,1H),7.99(s,1H),7.74(m,3.1Hz,1H),7.70–7.63(m,1H),7.50(d,J＝8.0Hz,1H),7.45–7.38(m,2H),7.17(d,J＝8.1Hz,1H),6.40(d,J＝6.1Hz,1H),5.77(dd,J＝10.5,7.3Hz,1H),4.85(s,1H),3.80(s,3H),3.31(s,3H),2.81(s,1H)；13C NMR(101MHz,CDCl3)δ171.27,165.61,163.83,150.81,139.29,138.43,136.08(d,J＝0.9Hz),134.00,130.78(q,J＝32.4Hz),130.69,129.33,128.50,126.75,125.65,124.52(d,J＝3.2Hz),124.45(d,J＝3.6Hz),124.05(q,J＝272.4Hz),124.03,120.95(d,J＝3.1Hz),107.70,68.31,61.56,53.04,52.85.HRMS(EI)calcd for C23H15F3NO5[M-H2O]+455.0981,found 455.0979.
Figure BDA0002246490020000262
:1H NMR(400MHz,DMSO-d6)δ8.36(d,J＝10.2Hz,1H),8.31–8.25(m,4H),8.09(t,J＝14.4Hz,1H),7.96(s,1H),6.79(d,J＝6.1Hz,1H),6.73(d,J＝6.5Hz,1H),5.61(dd,J＝11.3,6.6Hz,1H),4.78(d,J＝10.6Hz,1H),3.78(d,J＝12.3Hz,3H),3.23(s,3H)；13C NMR(101MHz,DMSO-d6)δ171.20,164.33,163.84,151.19,148.03,147.76,141.89,139.64,136.76,135.82,135.62,127.37,126.98,126.90,123.59,123.33,120.61,120.17,107.47,65.78,60.86,53.03,52.52.HRMS(EI)calcd for C23H15N3O9[M-H2O]+477.0808,found 477.0799.
Figure BDA0002246490020000263
:1H NMR(400MHz,CDCl3)δ8.32(d,J＝6.2Hz,1H),7.99(s,1H),7.74(dd,J＝5.9,3.1Hz,1H),7.70–7.63(m,1H),7.50(d,J＝8.0Hz,1H),7.45–7.38(m,2H),7.17(d,J＝8.1Hz,1H),6.40(d,J＝6.1Hz,1H),5.77(dd,J＝10.5,7.3Hz,1H),4.85(s,1H),3.80(s,3H),3.31(s,3H),2.81(s,1H)；13C NMR(101MHz,CDCl3)δ172.73,165.12,163.25,148.20,147.96,147.72,142.39,139.47,137.89,134.41,132.99,129.50,129.32,126.12,123.57,123.48,123.22,121.87,109.09,72.65,63.62,53.52,53.20.HRMS(EI)calcd for C23H17N3O9[M-H2O]+479.0808,found.479.2361.
Figure BDA0002246490020000271
:E/Z＝50:50；1H NMR(400MHz,CDCl3)δ8.25(d,J＝6.1Hz,0.5H),7.94(d,J＝6.1Hz,0.5H),7.69–7.60(m,2H),7.42–7.32(m,2H),7.12–7.01(m,1H),6.77(ddd,J＝9.3,2.6,1.1Hz,0.5H),6.71(ddd,J＝9.3,2.6,1.1Hz,0.5H),6.41(d,J＝6.1Hz,1H)5.79(d,J＝11.7Hz,1H),4.84(dd,J＝19.9,11.5Hz,1H),4.43–4.19(m,1H),3.98(dq,J＝14.2,7.0Hz,0.5H),3.75(dq,J＝10.8,7.1Hz,0.5H),2.31(s,3H),1.32(t,J＝7.1Hz,1.5H),0.91(t,J＝7.1Hz,1.5H).HRMS(EI)calcd forC24H18FNO4[M-H2O]+403.1220,found.403.1221.
Figure BDA0002246490020000272
:E/Z＝50:50；1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3)δ8.22(d,J＝6.1Hz,0.5H),7.89(d,J＝6.1Hz,0.5H),7.70(d,J＝7.8Hz,1H),7.67–7.64(m,1H),7.62(d,J＝8.4Hz,1H),7.34(ddd,J＝10.4,8.3,4.4Hz,2H),7.30–7.21(m,1H),7.01(d,J＝7.7Hz,0.5H),6.96(d,J＝7.7Hz,0.5H),6.35(dd,J＝6.1,1.5Hz,1H),5.75(dd,J＝11.7,4.9Hz,1H),4.89(d,J＝11.3Hz,0.5H),4.81(d,J＝10.6Hz,0.5H),4.43–4.20(m,1H),3.96(d,J＝6.8Hz,0.5H),3.72(dq,J＝10.8,7.1Hz,0.5H),2.30(s,3H),1.30(t,J＝7.1Hz,1.5H),0.89(t,J＝7.1Hz,1.5H).HRMS(EI)calcd for C24H18 35ClNO4[M-H2O]+419.0924,found 419.0925；calcd for C24H18 37ClNO4[M-H2O]+421.0895,found 421.0905.
Example 7:
antitumor Activity test of Compounds of the present invention
1. Principle of experiment
Succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple crystalline Formazan (Formazan) and deposit in cells, while dead cells do not have the function. Dimethyl sulfoxide (DMSO), which was used to lyse formazan in cells and the number of viable cells was measured by measuring the light absorption with a microplate reader.
2. Experiment on antitumor Activity
Sample preparation: EXAMPLES Compounds
Cell line: hepatoma cell line HepG2 and lung cancer cell line A549
Reagent: 0.5% MTT solution, RPMI 1640 culture solution, newborn bovine serum; pancreatin; 96-well culture plates; dimethyl sulfoxide;
the instrument comprises the following steps: super clean bench, incubator, Perkin Elmer full-automatic multifunctional enzyme-labeling instrument
The experimental steps are as follows:
1) HepG2 and A549 cells (2X 10) in exponential growth phase5one/mL) were inoculated onto 96-well plates and cultured overnight, and then the cells were treated with the drug at the set concentration.
2) After 24 hours of drug treatment, 20. mu.L of MTT reagent (5mg/mL) was added to each well. 5% CO2After incubation at 37 ℃ for 4 hours, the supernatant of the medium was aspirated, and 150. mu.L of DMSO was added to each well to dissolve formazan crystals.
3) The absorbance at 492 and 630nm was measured by a microplate reader using a dual wavelength method.
3. Evaluation of antitumor Activity
1) Calculation of cell viability inhibition Rate
Cell viability inhibition rate [ 1-drug administration (OD)492-OD630) Control (OD)492-OD630)]×100(％)
2)IC50Value calculation
The sample concentration and the cell inhibition rate are linearly regressed, and the half inhibition concentration IC of the sample on the cells is calculated by using software50The value is obtained.
TABLE 1 cell viability inhibition IC50Value of
Figure BDA0002246490020000281
Figure BDA0002246490020000291
As can be seen from Table 1, forHepG2 cell, IC with 33 Compounds50Values below 10. mu.M; for A549 cells, there are 26 compounds IC50Values below 10. mu.M. Moreover, for HepG2 cells, 11 compounds showed superior activity to the positive control doxorubicin; for a549 cells, 34 compounds showed superior activity to the positive control doxorubicin. Therefore, the lactam compound with a novel structure has excellent anticancer activity.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims (7)

1. A lactam derivative, wherein said derivative is a compound of formula I or a pharmaceutically acceptable salt of a compound of formula I:
Figure FDA0002723764090000011
wherein:
ra is substituted or unsubstituted aryl, substituted or unsubstituted benzoyl, substituted or unsubstituted 9, 10-dihydrophenanthryl, substituted or unsubstituted C1～C15One of alkyl groups;
rb and Rc are respectively and independently selected from ester group or acyl group, the general formula of the ester group is COOR, the general formula of the acyl group is COR ', and R' are respectively and independently selected from substituted or unsubstituted C1～C15An alkyl group;
in Ra, the substituted aryl is aryl substituted by one or more substituents, and the substituted benzoyl is benzoyl substituted by one or more substituentsSubstituted 9, 10-dihydrophenanthryl is one or more substituent substituted 9, 10-dihydrophenanthryl, substituted C1～C15C with alkyl radicals substituted by one or more substituents1～C15An alkyl group; in said R and R', substituted C1～C15C with alkyl radicals substituted by one or more substituents1～C15An alkyl group; the substituent is selected from hydroxyl, halogen, cyano, nitro, trifluoromethyl, aryl, substituted aryl, heterocyclic aryl, substituted heterocyclic aryl and C1～C6Alkyl or C1～C6An alkoxy group;
the substituted aryl is aryl substituted by one or more substituents, and the substituents in the substituted aryl are selected from halogen, cyano, nitro, trifluoromethyl and C1～C6Alkyl or C1～C6An alkoxy group; the substituted heterocyclic aryl is heterocyclic aryl substituted by one or more substituents, and the substituent in the substituted heterocyclic aryl is selected from C1～C6An alkyl group;
the aryl is selected from one of phenyl, naphthyl or phenanthryl; the heterocyclic aryl is selected from one of furyl, thienyl or pyridyl.
2. A process for the preparation of the lactam derivative of claim 1, wherein said process comprises: in an inert acid solvent, to
Figure FDA0002723764090000012
Taking manganese acetate dihydrate as a catalyst, reacting for 4-72 hours at 30-110 ℃, and separating after the reaction is finished to obtain the lactam derivative.
3. The process for preparing a lactam derivative according to claim 2, wherein said lactam derivative is selected from the group consisting of
Figure FDA0002723764090000021
And the molar ratio of manganese acetate dihydrate is 1 (1.0-6.0) to 3.0-6.0.
4. Use of a lactam derivative according to claim 1, wherein said lactam derivative is useful in the preparation of an anti-tumor agent.
5. A composition comprising the lactam derivative of claim 1.
6. A composition according to claim 5, characterized in that it comprises one or more of said lactam derivatives, and a pharmaceutically acceptable carrier medium and/or excipient.
7. Use of a composition according to claim 5 for the preparation of an anti-tumor medicament.
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