CN112552285A - Synthesis method of 4- (2,2, 2-trichloroethyl) -beta-lactam derivative - Google Patents
Synthesis method of 4- (2,2, 2-trichloroethyl) -beta-lactam derivative Download PDFInfo
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- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 title description 27
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 106
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 59
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 230000009471 action Effects 0.000 claims abstract description 3
- -1 halopropyl Chemical group 0.000 claims description 34
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical group CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 26
- 239000010949 copper Substances 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 150000001879 copper Chemical class 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000007800 oxidant agent Substances 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 5
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical group Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 12
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 229960001701 chloroform Drugs 0.000 description 27
- 230000015572 biosynthetic process Effects 0.000 description 22
- 239000012043 crude product Substances 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- 239000003208 petroleum Substances 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 22
- 238000010898 silica gel chromatography Methods 0.000 description 21
- 229940125782 compound 2 Drugs 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 238000005303 weighing Methods 0.000 description 12
- 150000003952 β-lactams Chemical class 0.000 description 9
- RBBJXENQWXGNST-UHFFFAOYSA-N N-quinolin-8-ylbut-3-enamide Chemical compound N1=CC=CC2=CC=CC(=C12)NC(CC=C)=O RBBJXENQWXGNST-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical group Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- QBHCDUCXRVOUCN-UHFFFAOYSA-N 2-benzyl-N-quinolin-8-ylbut-3-enamide Chemical compound N1=CC=CC2=CC=CC(=C12)NC(C(C=C)CC1=CC=CC=C1)=O QBHCDUCXRVOUCN-UHFFFAOYSA-N 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- RZTNANZSMJVWAR-UHFFFAOYSA-N C=CC(CCC(C=C1)=CC=C1F)C(NC1=C2N=CC=CC2=CC=C1)=O Chemical compound C=CC(CCC(C=C1)=CC=C1F)C(NC1=C2N=CC=CC2=CC=C1)=O RZTNANZSMJVWAR-UHFFFAOYSA-N 0.000 description 1
- QCIOLZTWFGDRKZ-UHFFFAOYSA-N CC(C=CCC(NC1=C2N=CC=CC2=CC=C1)=O)C1=CC=CC=C1 Chemical compound CC(C=CCC(NC1=C2N=CC=CC2=CC=C1)=O)C1=CC=CC=C1 QCIOLZTWFGDRKZ-UHFFFAOYSA-N 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- MDIILATYPIDCQV-UHFFFAOYSA-N N-quinolin-8-ylpent-3-enamide Chemical compound N1=CC=CC2=CC=CC(=C12)NC(CC=CC)=O MDIILATYPIDCQV-UHFFFAOYSA-N 0.000 description 1
- ADLCINRDGVAUKU-UHFFFAOYSA-N N1=CC=CC2=CC=CC(=C12)NC(C(C=C)C(C)C)=O Chemical compound N1=CC=CC2=CC=CC(=C12)NC(C(C=C)C(C)C)=O ADLCINRDGVAUKU-UHFFFAOYSA-N 0.000 description 1
- AQHUQAGJIBUBHG-UHFFFAOYSA-N N1=CC=CC2=CC=CC(=C12)NC(C(C=C)C)=O Chemical compound N1=CC=CC2=CC=CC(=C12)NC(C(C=C)C)=O AQHUQAGJIBUBHG-UHFFFAOYSA-N 0.000 description 1
- OHYGZNZPKLAJSE-UHFFFAOYSA-N N1=CC=CC2=CC=CC(=C12)NC(C(C=C)CC)=O Chemical compound N1=CC=CC2=CC=CC(=C12)NC(C(C=C)CC)=O OHYGZNZPKLAJSE-UHFFFAOYSA-N 0.000 description 1
- SSCVUFQUIVCJOH-UHFFFAOYSA-N N1=CC=CC2=CC=CC(=C12)NC(C(C=C)CCC1=CC=CC=C1)=O Chemical compound N1=CC=CC2=CC=CC(=C12)NC(C(C=C)CCC1=CC=CC=C1)=O SSCVUFQUIVCJOH-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 229940076286 cupric acetate Drugs 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007342 radical addition reaction Methods 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及一种4‑(2,2,2‑三氯乙基)‑β‑内酰胺衍生物的制备方法，将取代N‑喹啉‑3‑丁烯酰胺衍生物在氧化剂和铜盐催化剂的作用下，在三氯甲烷中于100～120℃下反应，反应完全后得到4‑(2,2,2‑三氯乙基)‑β‑内酰胺衍生物。按照本发明的方法可以高收率的得到多种4‑(2,2,2‑三氯乙基)‑β‑内酰胺衍生物。本发明反应条件较温和、反应操作和后处理过程简单，适合于规模化生产。The present invention relates to a preparation method of 4-(2,2,2-trichloroethyl)-β-lactam derivatives. Under the action of , the reaction is carried out in chloroform at 100-120° C., and the 4-(2,2,2-trichloroethyl)-β-lactam derivative is obtained after the reaction is completed. According to the method of the present invention, various 4-(2,2,2-trichloroethyl)-β-lactam derivatives can be obtained in high yield. The invention has mild reaction conditions, simple reaction operation and post-treatment process, and is suitable for large-scale production.
Description
Technical Field
The invention relates to the technical field of preparation of organic compounds, in particular to a synthesis method of a 4- (2,2, 2-trichloroethyl) -beta-lactam derivative.
Background
Beta-lactams are an important component of the N-heterocycle and are the core backbone of many natural products and drug molecules, especially specific drugs for some antibiotics. Therefore, the synthesis of the beta-lactam derivative has important value.
To date, the synthesis of β -lactam derivatives has been mainly as follows:
the synthesis of beta-lactam derivatives is described inJ. Am. Chem. Soc， 1982, 1043233 the method is described by oxidation of the ring.J. Org. Chem. 1995, 601276 discloses a method of preparing beta-lactam derivatives by ring closure reaction by reduction.
A method for synthesizing beta-lactam by utilizing C-H bond activation and metal catalysis respectively inAngewandte Chemie，2013, 52, 13588、Angewandte Chemie 2014, 533496 andChem. Eur. J, 2014, 209530.
In 2019, the group of the inventor isChem. Common.2019,55, 10523 reported a free radical-promoted addition cyclization reaction that synthesized beta-lactams. This reaction has certain technical advantages, however, it is limited to benzyl radical promoted reactions, and it is not suitable for the synthesis of 4- (2,2, 2-trichloroethyl) - β -lactam derivatives.
In summary, the existing method for synthesizing 4- (2,2, 2-trichloroethyl) -beta-lactam derivatives generally uses very expensive raw materials, and has harsh reaction conditions and is not environment-friendly.
Disclosure of Invention
In order to overcome the defects of low yield, use of expensive raw materials, harsh reaction conditions and environmental friendliness of the 4- (2,2, 2-trichloroethyl) -beta-lactam derivative prepared by the prior art, the invention aims to provide the preparation method of the 4- (2,2, 2-trichloroethyl) -beta-lactam derivative, which has the advantages of easily available raw materials, high yield, mild reaction conditions, good universality and environmental protection.
The inventors of the present invention have found through intensive studies that 4- (2,2, 2-trichloroethyl) - β -lactam derivatives can be efficiently synthesized by initiating the trichloromethyl radical ring formation reaction, and 4- (2,2, 2-trichloroethyl) - β -lactam derivatives can be obtained in high yield by reacting substituted N-quinoline-3-butenamide derivatives with chloroform at 100 ℃ and 120 ℃ under the catalysis of copper salt and the oxidation of an oxidizing agent.
Specifically, the technical scheme of the invention is as follows:
a method for preparing a 4- (2,2, 2-trichloroethyl) -beta-lactam derivative, comprising the following steps: reacting the substituted N-quinoline-3-butenamide derivative shown in the formula (1) in chloroform at 100-120 ℃ under the action of an oxidant and a copper salt catalyst, and obtaining a 4- (2,2, 2-trichloroethyl) -beta-lactam derivative shown in the formula (2) after the reaction is completed;
wherein R is1Hydrogen, C1-C6 alkyl, phenyl or substituted phenyl;
R2and R3Independently selected from hydrogen, C1-C6 alkyl, phenyl, substituted phenyl or C1-C6 unsaturated alkyl;
and the substituent on the substituted phenyl is one or more of C1-C6 alkyl, halogen and an ester group.
In the invention, trichloromethane is used as a solvent required by the reaction and also used as a reactant.
The reaction route of the method is as follows:
the method belongs to a double-bond free radical addition cyclization reaction promoted by trichloromethyl free radical, has mild conditions and meets the requirement of green chemistry.
Further, the C1-C6 alkyl comprises one of substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched-chain alkyl and substituted or unsubstituted cycloalkyl; wherein the substituents on the substituted linear alkyl, the substituted branched alkyl and the substituted cyclic alkyl are respectively and independently selected from alkyl and halogen.
Further, R1Is hydrogen, R3Is hydrogen or methyl, R2The alkyl group is hydrogen, unsubstituted C1-C6 linear alkyl, ester group substituted C1-C6 alkyl, allyl, benzyl, phenethyl, cyclopropylmethyl, cyclobutylmethyl, halopropyl, p-tolylethyl or halophenethyl.
Further, R2Is hydrogen, R3Is hydrogen, R1Is C1-C6 alkyl or benzyl.
Further, the oxidizing agent is di-tert-butyl peroxide (DTBP).
Further, the cupric salt catalyst is cuprous bromide (CuBr), cupric acetate (Cu (OAc)2) Cuprous chloride, copper tetraethyl-hexafluorophosphate (Cu (CH)3CN)4PF6) Copper triflate and copper bromide (CuBr)2) One or more of them. Preference is given toThe copper salt catalyst is tetraethyl nitrile copper hexafluorophosphate.
Further, the mol ratio of the substituted N-quinoline-3-butenamide derivative to the chloroform to the oxidant to the copper salt catalyst is 1: 8-12: 3-8: 0.05 to 0.2.
Preferably, the molar ratio of the substituted N-quinoline-3-butenamide derivative, the trichloromethane, the oxidizing agent and the copper salt catalyst is 1:10:6: 0.1.
Preferably, the reaction temperature is 110 ℃.
By the scheme, the invention at least has the following advantages:
1. the invention provides a brand new system, and realizes the synthesis of the 4- (2,2, 2-trichloroethyl) -beta-lactam derivative by utilizing the free radical reaction.
2. The invention uses the substituted N-quinoline-3-butene amide derivative as the starting material, and the raw materials are easy to obtain and have a plurality of varieties; the products obtained by the method of the invention are of various types, and can be directly used and can also be used for other further reactions.
3. The invention has novel reaction, simple reaction operation and post-treatment process and high yield, and is suitable for large-scale production.
The foregoing is a summary of the present invention, and in order to provide a clear understanding of the technical means of the present invention and to be implemented in accordance with the present specification, the following is a preferred embodiment of the present invention and is described in detail below.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
The first embodiment is as follows: synthesis of 4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
(1) Weighing N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 92%.
(2) Weighing N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 100 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 83%.
(3) Weighing N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 120 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 41%.
(4) Weighing N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol) and CuBr2(0.005g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 62%.
(5) N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol), Cu (OAc) were weighed2(0.004g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 45%.
(6) N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol) and CuBr (0.003g, 0.02 mmol) were dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 50%.
2a:1H NMR (400 MHz, CDCl3) δ8.84 (dd, J = 4.1, 1.8 Hz, 1H), 8.33 (dd, J = 7.5, 1.4 Hz, 1H), 8.15 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 (dd, J = 8.2, 1.3 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.42 (dd, J = 8.3, 4.1 Hz, 1H), 5.70 – 5.62 (m, 1H), 3.66 (dd, J = 14.3, 1.6 Hz, 1H), 3.57 (dd, J = 15.6, 5.2 Hz, 1H), 3.29 (dd, J = 15.6, 2.6 Hz, 1H), 2.91 (dd, J = 14.3, 10.2 Hz, 1H).; 13C NMR (101 MHz, CDCl3) δ165.82, 149.13, 140.06, 136.13, 132.86, 128.97, 126.82, 124.12, 121.58, 121.17, 96.68, 57.07, 54.23, 45.56; HRMS(ESI-TOF) Calcd for C14H12Cl3N2O [M+H]+:329.0015，found: 329.0013.
Example two: synthesis of 3-methyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
N- (8-quinolyl) -2-methyl-3-butenamide 1b (0.045 g, 0.2 mmol), Cu (CH) were weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 b. The isolated yield was 59%.
2b: 1H NMR (400 MHz, CDCl3) δ 8.83 (dd, J = 4.1, 1.8 Hz, 1H), 8.33 (dd, J = 7.5, 1.4 Hz, 1H), 7.59 (dd, J = 8.2, 1.4 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.42 (dd, J = 8.4, 4.1 Hz, 1H), 5.28 (dt, J = 10.2, 2.0 Hz, 1H), 3.64 (dd, J = 14.3, 1.8 Hz, 1H), 3.47 – 3.40 (m, 1H), 2.93 (dd, J = 14.3, 10.2 Hz, 1H), 1.57 (d, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ169.54, 149.11, 140.12, 136.12, 132.77, 129.00, 126.82, 124.03, 121.54, 121.43, 96.62, 62.25, 56.97, 53.02, 13.40；HRMS Calcd for C15H14Cl3N2O [M+H] +: 343.0172, Found: 343.0169.
Example three: synthesis of 3-ethyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
N- (8-quinolyl) -2-ethyl-3-butenamide 1c (0.048 g, 0.2 mmol), Cu (CH) were weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 c. The isolated yield was 61%.
2c: 1H NMR (400 MHz, CDCl3) δ8.84 (dd, J = 4.1, 1.8 Hz, 1H), 8.35 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.3, 1.7 Hz, 1H), 7.59 (dd, J = 8.2, 1.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.42 (dd, J = 8.3, 4.1 Hz, 1H), 5.39 (dt, J = 10.1, 2.0 Hz, 1H), 3.63 (dd, J = 14.3, 1.9 Hz, 1H), 3.46 – 3.41 (m, 1H), 2.94 (dd, J = 14.3, 10.1 Hz, 1H), 2.09 – 1.97 (m, 2H), 1.19 (t, J = 7.5 Hz, 3H)；13C NMR (101 MHz, CDCl3) δ169.09, 149.12, 140.16, 136.09, 132.76, 128.99, 126.82, 123.98, 121.52, 121.35, 96.67, 59.65, 59.01, 56.97, 21.89, 11.22; HRMS Calcd for C16H16Cl3N2O [M+H] +: 357.0328, Found: 357.0321.
Example four: synthesis of 3-isopropyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Weighing N- (8-quinolyl) -2-isopropyl-3-butenamide 1d (0.051 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 d. The isolated yield was 50%.
2d:1H NMR (400 MHz, CDCl3) δ8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.36 (dd, J = 7.5, 1.2 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.40 (dd, J = 8.3, 4.1 Hz, 1H), 5.45 (dt, J = 9.8, 2.0 Hz, 1H), 3.59 (dd, J = 14.4, 2.1 Hz, 1H), 3.38 (dd, J = 5.6, 2.0 Hz, 1H), 2.93 (dd, J = 14.4, 9.9 Hz, 1H), 2.35 – 2.26 (m, 1H), 1.21 (dd, J = 9.6, 6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 168.40, 149.14, 140.24, 136.06, 132.65, 128.96, 126.80, 123.99, 121.50, 121.37, 96.63, 63.75, 58.41, 57.03, 28.22, 21.52, 18.91; HRMS Calcd for C17H18Cl3N2O [M+H] +: 371.0485,Found: 371.0491.
Example five: synthesis of 3-allyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Weighing N- (8-quinolyl) -2-allyl-3-butylEnamide 1e (0.050 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 e. The isolated yield was 47%.
2e:1H NMR (400 MHz, CDCl3) δ8.84 (dd, J = 4.1, 1.8 Hz, 1H), 8.34 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.4, 1.8 Hz, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.42 (dd, J = 8.4, 4.1 Hz, 1H), 6.04 – 5.97 (m, 1H), 5.42 (dt, J = 10.1, 2.1 Hz, 1H), 5.28 – 5.23 (m, 1H), 5.16 – 5.12 (m, 1H), 3.65 (dd, J = 14.3, 1.9 Hz, 1H), 3.56 – 3.51 (m, 1H), 2.95 (dd, J = 14.3, 10.1 Hz, 1H), 2.79 – 2.67 (m, 2H). 13C NMR (101 MHz, CDCl3) δ168.28, 149.15, 140.11, 136.08, 133.89, 132.70, 128.98, 126.81, 124.05, 121.53, 121.35, 118.12, 96.59, 59.24, 57.23, 56.84, 32.68 (s), 120.83 (s), 55.58 (s), 42.68 (s), 33.30 (s), 28.99 (s); HRMS Calcd for C17H15Cl3N2ONa [M+H]+: 391.0148, Found: 391.0148.
Example six: synthesis of 3-benzyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
N- (8-quinolyl) -2-benzyl-3-butenamide 1f (0.061 g, 0.2 mmol), Cu (CH) were weighed out3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 f. The isolated yield was 70%.
2f:1H NMR (400 MHz, CDCl3) δ8.79 (dd, J = 4.1, 1.8 Hz, 1H), 8.27 (dd, J = 7.5, 1.3 Hz, 1H), 8.14 – 8.09 (m, 1H), 7.58 (dd, J = 8.2, 1.3 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.42 – 7.35 (m, 3H), 7.32 – 7.25 (m, 2H), 7.22 – 7.17 (m, 1H), 5.40 (dt, J = 10.0, 2.0 Hz, 1H), 3.74 – 3.67 (m, 1H), 3.60 (dd, J = 14.4, 1.9 Hz, 1H), 3.37 – 3.24 (m, 2H), 2.95 (dd, J = 14.4, 10.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ168.30, 149.11, 140.19, 137.93, 136.03, 132.59, 129.51, 128.94, 128.51, 126.76, 126.64, 124.19, 121.52, 121.49, 96.51, 59.44, 58.91, 56.85, 34.73; HRMS Calcd for C21H18Cl3N2O [M+H]+: 419.0485, Found: 419.0485.
Example seven: synthesis of 3-phenethyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
1g (0.063 g, 0.2 mmol) of N- (8-quinolyl) -2-phenethyl-3-butenamide and Cu (CH) were weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain 2g of the compound. The isolated yield was 61%.
2g:1H NMR (400 MHz, CDCl3) δ8.82 (dd, J = 4.1, 1.8 Hz, 1H), 8.35 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.56 – 7.50 (m, 1H), 7.41 (dd, J = 8.3, 4.1 Hz, 1H), 7.28 – 7.24 (m, 4H), 7.22 – 7.15 (m, 1H), 5.39 (dt, J = 10.1, 2.0 Hz, 1H), 3.61 (dd, J = 14.3, 1.9 Hz, 1H), 3.50 – 3.42 (m, 1H), 3.11 – 3.01 (m, 1H), 2.94 – 2.84 (m, 2H), 2.38 – 2.26 (m, 2H). 13C NMR (101 MHz, CDCl3) δ168.88, 149.14, 141.38, 140.16, 136.12, 132.72, 129.00, 128.56, 128.42, 126.83, 126.03, 124.08, 121.56, 121.37, 96.59, 60.20, 57.01, 56.90, 32.98, 30.74; HRMS Calcd for C22H20Cl3N2O[M+H]+: 433.0641, Found: 433.0646.
Example eight: synthesis of 3-methylcyclopropane-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
N- (8-quinolyl) -2-methylcyclopropane-3-butenamide was weighed for 1h (0.063 g, 0.2 mmol), and Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction is finished, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain a compound for 2 h. The isolated yield was 50%.
2h:1H NMR (400 MHz, CDCl3) δ 8.84 (dd, J = 4.1, 1.8 Hz, 1H), 8.36 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.4, 1.7 Hz, 1H), 7.59 (dd, J = 8.2, 1.4 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.42 (dd, J = 8.3, 4.1 Hz, 1H), 5.54 (dt, J = 10.1, 2.0 Hz, 1H), 3.64 (dd, J = 14.3, 1.9 Hz, 1H), 3.58 – 3.52 (m, 1H), 2.94 (dd, J = 14.3, 10.1 Hz, 1H), 1.95 – 1.83 (m, 2H), 1.08 – 0.98 (m, 1H), 0.57 – 0.47 (m, 2H), 0.23 – 0.12 (m, 2H).13C NMR (101 MHz, CDCl3) δ169.14, 149.11, 140.17, 136.08, 132.80, 128.99, 126.83, 123.98, 121.52, 121.34, 96.72, 59.62, 58.08, 57.04, 33.62, 8.42, 5.25, 4.65; HRMS Calcd for C18H18Cl3N2O [M+H+]: 383.0485, Found: 383.0481.
Example nine: synthesis of 3-methylcyclobutane-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Weighing N- (8-quinolyl) -2-methylcyclobutane-3-butenamide 1i (0.056 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 i. The isolated yield was 50%.
2i:1H NMR (400 MHz, CDCl3) δ 8.83 (dd, J = 4.1, 1.8 Hz, 1H), 8.34 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.4, 1.7 Hz, 1H), 7.59 (dd, J = 8.2, 1.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.3, 4.1 Hz, 1H), 5.37 (dt, J = 10.1, 2.0 Hz, 1H), 3.60 (dd, J = 14.3, 1.9 Hz, 1H), 3.40 – 3.34 (m, 1H), 2.90 (dd, J = 14.3, 10.1 Hz, 1H), 2.75 – 2.65 (m, 1H), 2.20 – 2.12 (m, 2H), 2.09 (t, J = 7.2 Hz, 2H), 1.86 – 1.67 (m, 4H)..13C NMR (101 MHz, CDCl3) δ 169.18, 149.07, 140.12, 136.07, 132.77, 128.96, 126.81, 123.93, 121.50, 121.29, 96.70, 59.97, 57.06, 56.33, 35.95, 33.52, 29.02, 28.35, 18.44; HRMS Calcd for C19H20Cl3N2O [M+H]+: 397.0641, Found: 397.0638.
Example ten: synthesis of ethyl 2- (2-oxo-1- (8-quinolyl) -4- (2,2, 2-trichloroethyl) azetidinyl) acetate
Ethyl 3- (8-quinolinecarbonyl) -4-pentenoate 1j (0.060 g, 0.2 mmol), Cu (CH) was weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of trichloromethylTo the alkane, DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction is finished, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain a compound 2 j. The isolated yield was 62%.
2j:1H NMR (400 MHz, CDCl3) δ 8.83 (dd, J = 4.1, 1.8 Hz, 1H), 8.30 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 (dd, J = 8.2, 1.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.3, 4.1 Hz, 1H), 5.51 (dt, J = 9.9, 2.2 Hz, 1H), 4.19 – 4.12 (m, 2H), 3.78 – 3.73 (m, 1H), 3.69 (dd, J = 14.4, 2.0 Hz, 1H), 3.04 – 2.93 (m, 3H), 1.20 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3)δ170.62, 167.09, 149.20, 140.21, 136.13, 132.53, 128.98, 126.79, 124.28, 121.63, 121.57, 96.40, 61.01, 59.83, 57.03, 53.51, 32.85, 14.08; HRMS Calcd for C18H17Cl3N2O3Na [M+Na]+: 437.0202, Found: 437.0201.
Example eleven: synthesis of 3- (1-chloropropyl) -4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Weighing N- (8-quinolyl) -2- (1-chloropropane) -3-butenamide 1k (0.058 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 k. The isolated yield was 48%.
2k:1H NMR (400 MHz, CDCl3) δ8.84 (dd, J = 4.1, 1.7 Hz, 1H), 8.32 (dd, J = 7.5, 1.2 Hz, 1H), 8.15 (dd, J = 8.4, 1.7 Hz, 1H), 7.61 (dd, J = 8.2, 1.2 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 5.38 (dt, J = 10.1, 2.0 Hz, 1H), 3.66 – 3.59 (m, 3H), 3.50 – 3.44 (m, 1H), 2.94 (dd, J = 14.4, 10.1 Hz, 1H), 2.27 – 2.16 (m, 2H), 2.12 – 2.00 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 168.50, 149.21, 140.16, 136.14, 132.54, 128.99, 126.79, 124.23, 121.60, 121.46, 96.52, 60.22, 56.89, 56.87, 44.75, 29.71, 26.36; HRMS Calcd for C17H17Cl4N2O [M+H]+: 321.1403, Found: 405.0087.
Example twelve: synthesis of 3, 3' -dimethyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
N- (8-quinolyl) -2, 2' -dimethyl-3-butenamide 1l (0.048 g, 0.2 mmol), Cu (CH) were weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain 2l of the compound. The isolated yield was 43%.
2l: 1H NMR (400 MHz, CDCl3) δ 8.84 (dd, J = 4.2, 1.8 Hz, 1H), 8.13 (dd, J = 8.3, 1.7 Hz, 1H), 8.11 (dd, J = 7.5, 1.3 Hz, 1H), 7.65 (dd, J = 8.2, 1.3 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 5.32 (dd, J= 9.4, 1.5 Hz, 1H), 3.28 (dd, J = 15.1, 1.5 Hz, 1H), 3.15 (dd, J = 15.1, 9.4 Hz, 1H), 1.59 (s, 3H), 1.52 (s, 3H).13C NMR (101 MHz, CDCl3) δ 172.94, 149.41, 141.43, 136.02, 132.17, 129.03, 126.61, 125.05, 123.52, 121.60, 96.82, 65.61, 54.19, 52.55, 22.11, 18.76; HRMS Calcd for C16H15Cl3N2ONa [M+Na]+: 379.0148, Found: 379.0149.
Example thirteen: synthesis of 3-p-toluylethyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) beta-lactam
Weighing N- (8-quinolyl) -2-p-toluenethyl-3-butenamide 1m (0.063 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 m. The isolated yield was 52%.
2m: 1H NMR (400 MHz, CDCl3) δ 8.80 (dd, J = 4.1, 1.8 Hz, 1H), 8.28 (dd, J = 7.5, 1.3 Hz, 1H), 8.11 (dd, J = 8.3, 1.7 Hz, 1H), 7.58 (dd, J = 8.2, 1.3 Hz, 1H), 7.52 – 7.48 (m, 1H), 7.39 (dd, J = 8.3, 4.1 Hz, 1H), 7.25 (d, J= 7.6 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 5.39 (dt, J = 10.0, 2.0 Hz, 1H), 3.71 – 3.65 (m, 1H), 3.61 (dd, J = 14.4, 1.9 Hz, 1H), 3.33 – 3.20 (m, 2H), 2.94 (dd, J = 14.4, 10.1 Hz, 1H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.41, 149.09, 140.18, 136.06, 136.02, 134.81, 132.65, 129.34, 129.18, 128.94, 126.76, 124.12, 121.50, 121.46, 96.54, 59.48, 59.04, 56.88, 34.29, 21.07; HRMS Calcd for C22H19Cl3N2ONa[M+Na]+: 455.0461, Found: 455.0461.
Example fourteen: synthesis of 3-p-fluorophenethyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) beta-lactam
Weighing N- (8-quinolyl) -2-p-fluorophenethyl-3-butenamide 1N ((B))0.064 g, 0.2 mmol），Cu(CH3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 n. The isolated yield was 61%.
2n: 1H NMR (400 MHz, CDCl3) δ 8.78 (dd, J = 4.1, 1.7 Hz, 1H), 8.26 (dd, J = 7.5, 1.2 Hz, 1H), 8.12 (dd, J = 8.3, 1.7 Hz, 1H), 7.59 (dd, J = 8.1, 1.1 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 8.3, 4.1 Hz, 1H), 7.34 – 7.30 (m, 2H), 7.00 – 6.93 (m, 2H), 5.38 (dt, J = 10.1, 2.0 Hz, 1H), 3.70 – 3.65 (m, 1H), 3.59 (dd, J = 14.4, 1.9 Hz, 1H), 3.32 (dd, J = 14.3, 5.0 Hz, 1H), 3.23 (dd, J = 14.3, 7.6 Hz, 1H), 2.95 (dd, J = 14.4, 10.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 168.08 , 161.77 (d, J = 244.3 Hz),149.14, 140.17, 136.05, 133.52, 133.49, 132.42, 131.05, 130.97, 128.95, 126.73, 124.28, 121.55, 121.50, 115.40, 115.19, 96.52, 59.16, 58.81, 56.74, 33.73. 19F NMR (377 MHz, CDCl3) δ -116.53 (s); HRMS Calcd for C21H17Cl3FN2O[M+H]+: 437.0390, Found: 437.0388.
Example fifteen: synthesis of 1- (8-quinolyl) -4- (2- (1,1, 1-trichloropropyl)) azetidin-2-one
N- (8-quinolyl) -3-pentenamide 1o (0.045 g, 0.2 mmol), Cu (CH) were weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction is finished, the crude product is chromatographically separated by a silica gel column (petroleum ether: B)Ethyl acid = 30: 1) to yield compound 2o after purification. The isolated yield was 41%.
2o: 1H NMR (400 MHz, CDCl3) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.15 (dd, J = 8.3, 1.7 Hz, 1H), 7.89 (dd, J = 7.4, 1.3 Hz, 1H), 7.68 (dd, J = 8.2, 1.2 Hz, 1H), 7.59 – 7.50 (m, 1H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 5.80 (ddd, J = 6.7, 5.6, 2.6 Hz, 1H), 3.64 (dd, J = 15.5, 5.5 Hz, 1H), 3.27 (dd, J = 15.5, 2.6 Hz, 1H), 3.08 (p, J = 6.8 Hz, 1H), 1.22 (d, J = 6.8 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 166.29 (s), 148.92 (s), 140.72 (s), 140.58 (s), 137.37 (s), 136.09 (s), 133.51 (s), 130.38 (s), 128.99 (s), 126.73 (s), 124.08 (s), 121.62 (s), 121.37 (s), 91.01 (s), 55.89 (s), 43.04 (s), 34.93 (s), 31.09 (s); HRMS Calcd for C15H14Cl3N2O [M+H]+: 343.0172, found: 343.0168.
Example sixteen: synthesis of 1- (8-quinolyl) -4- (2- (1,1, 1-trichlorobutyl)) azetidin-2-one
Weighing N- (8-quinolyl) -3-hexenylamide 1p (0.048 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 p. The isolated yield was 33%.
2p: 1H NMR (400 MHz, CDCl3) δ 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.16 (dd, J = 8.3, 1.7 Hz, 1H), 8.01 (dd, J = 7.5, 1.3 Hz, 1H), 7.66 (dd, J = 8.2, 1.2 Hz, 1H), 7.57 – 7.52 (m, 1H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 5.83 (dd, J= 8.6, 4.8 Hz, 1H), 3.55 – 3.50 (m, 2H), 2.94 – 2.88 (m, 1H), 1.68 – 1.53 (m, 2H), 1.13 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.62, 149.19, 141.95, 136.24, 133.22, 129.10, 126.65, 125.24, 123.97, 121.51, 102.53, 62.31, 57.22, 42.94, 24.11, 14.02; HRMS Calcd for C16H16Cl3N2O [M+H]+: 357.0328, found:357.0320.
Example seventeen: synthesis of 1- (8-quinolyl) -4- (1,1, 1-trichloro-3-phenyl-2-propyl) azetidin-2-one
Weighing N- (8-quinolyl) -5-phenyl-3-hexenamide 1q (0.048 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 q. The isolated yield was 21%.
2q: 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 4.2, 1.8 Hz, 1H), 8.08 (dd, J = 8.3, 1.7 Hz, 1H), 7.89 (dd, J = 7.5, 1.3 Hz, 1H), 7.58 (dd, J = 8.2, 1.3 Hz, 1H), 7.49 – 7.42 (m, 1H), 7.37 – 7.27 (m, 4H), 7.24 – 7.19 (m, 2H), 5.83 (dt, J = 6.4, 3.3 Hz, 1H), 3.61 – 3.53 (m, 2H), 3.49 – 3.38 (m, 2H), 2.84 (dd, J = 14.7, 9.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ166.04, 148.90, 141.45, 138.55, 135.98, 133.23, 128.98, 128.84, 128.71, 126.77, 126.59, 124.76, 123.33, 121.23, 102.07, 60.87, 56.80, 41.27, 36.48; HRMS Calcd for C21H18Cl3N2O [M+H]+: 393.1191, Found: 393.1198.
In summary, the present invention discloses a method for preparing 4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam derivatives, which is characterized in that: dissolving copper salts such as substituted N-quinoline-3-butenamide derivatives, di-tert-butyl peroxide, copper tetranitrile hexafluorophosphate and the like in trichloromethane, reacting at 110 ℃, and preparing a plurality of 4- (2,2, 2-trichloroethyl) -beta-lactam derivatives with high yield.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
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