CN116693531A - Synthesis method of bridged polycyclic lactam compound - Google Patents
Synthesis method of bridged polycyclic lactam compound Download PDFInfo
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- CN116693531A CN116693531A CN202310681131.XA CN202310681131A CN116693531A CN 116693531 A CN116693531 A CN 116693531A CN 202310681131 A CN202310681131 A CN 202310681131A CN 116693531 A CN116693531 A CN 116693531A
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- -1 polycyclic lactam compound Chemical class 0.000 title claims abstract description 38
- 238000001308 synthesis method Methods 0.000 title abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 14
- 238000004440 column chromatography Methods 0.000 claims description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 11
- 238000001704 evaporation Methods 0.000 claims description 10
- 230000008020 evaporation Effects 0.000 claims description 9
- 238000010189 synthetic method Methods 0.000 claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- KJSKGJKEWQJVHV-UHFFFAOYSA-N ethyl 3-anilino-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NC1=CC=CC=C1 KJSKGJKEWQJVHV-UHFFFAOYSA-N 0.000 claims description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000000758 substrate Substances 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 150000003951 lactams Chemical class 0.000 description 5
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000463 material Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 241000219495 Betulaceae Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DEZBFFHVGYJJEU-UHFFFAOYSA-N ethyl 3-(3-chloroanilino)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NC1=CC=CC(Cl)=C1 DEZBFFHVGYJJEU-UHFFFAOYSA-N 0.000 description 1
- NEGQZYYDIHYHMQ-UHFFFAOYSA-N ethyl 3-(4-chloroanilino)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NC1=CC=C(Cl)C=C1 NEGQZYYDIHYHMQ-UHFFFAOYSA-N 0.000 description 1
- OQWGDDYVTJJPEG-UHFFFAOYSA-N ethyl 3-(4-methoxyanilino)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NC1=CC=C(OC)C=C1 OQWGDDYVTJJPEG-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing a bridged polycyclic lactam compound, which belongs to the technical field of organic synthesis. The synthesis method has the characteristics of green, simplicity, effectiveness and high selectivity, is carried out under the metal-free condition, and can obtain the bridged polycyclic lactam compound through one-step reaction, so that the substrate is low in cost, the steps are simple, and the operation is easy.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a bridged polycyclic lactam compound.
Background
Nitrogen-containing bridged ring systems are present in a variety of biologically important molecules, which have attracted considerable attention in the past decades by organic and bioorganic chemists as important components of a variety of natural products and pharmaceutical agents. Bridged bicyclic lactams, in particular comprising a lactam nitrogen at the bridgehead position, have been of interest for many years because they comprise distorted amides which fail to achieve standard planar geometries. The distorted amide moiety embedded in the bridge ring causes rapid hydrolysis of these amides. Thus, standard methods for amide synthesis of these compounds typically proceed in low yields or with difficulties in product isolation. Under such circumstances, various synthetic methods have been explored which avoid the direct use of amide bond formation as a key reaction step. However, most of these reactions require pre-functionalized starting materials, cumbersome procedures and demanding reaction conditions. Thus, it is highly desirable, but challenging, to be able to efficiently transfer readily available acyclic substrates to such bridged polycyclic lactams.
At present, there are reports of synthetic methods of bridged polycyclic lactam derivatives, and from the viewpoint of synthetic strategies, these methods can be classified into three categories:
the first is the rapid acquisition of lactams by intramolecular hydrocarbonylation of olefins, however, selective carbonylation with lactam nitrogen at the bridgehead position to form bridged polycyclic lactams has been less studied. A modular palladium catalyzed process is reported to perform an Alder cycloaddition reaction of a series of hydrocarbylated lactams/Diels-with 2-vinylarylaldehyde imines, olefins and CO, providing a convenient route to bridging polycyclic lactams in high selectivity and yield, such as literature: P.Xu, B.Qian, B.Hu, H, huang. Org Lett,2022,24,147-151.
The second category is palladium-catalyzed aza-packer cyclisation to form bridged lactams by formation of C-N bonds, such as literature: C.Xie, J.Luo, Y.Zhang, S-H.H, L.Zhu, R.Hong.Org Lett,2018,20,2386-2390.
The third category is the problem of the cationic-pi controlled intramolecular schmitt reaction to form bridged bicyclic lactams, the reaction promoted by the acid of the alkyl azide and ketone to synthesize bridged bicyclic lactams, where regiochemistry is controlled by the trans-steric interaction of the key reaction intermediate aryl and the cationic leaving group, such as in documents L.Yao, J.Aube.J.Am.Chem.Soc.2007,129,2766-2767.
Bridged polycyclic lactams are special motifs that are ubiquitous in natural products, pharmaceuticals and agrochemicals. The importance of bridged polycyclic lactam compounds can be found in chemical disciplines, and with the use of drugs/bioactivity studies, polymerization studies, etc., as well as a basis for larger, more complex organic molecules, the need for new ways to obtain these ideal molecules is expanding. Although the synthesis of bridged polycyclic lactam compounds has been reported in the literature, the problems are also apparent, and thus the development of a greener, simple and efficient method for synthesizing bridged bicyclic lactam compounds is still of great practical significance.
Disclosure of Invention
In order to solve the technical problems, the invention provides a synthesis method of a bridged polycyclic lactam compound, which has the characteristics of green, simplicity, effectiveness and high selectivity, is carried out under the condition of no metal, and can obtain the bridged polycyclic lactam compound through one-step reaction, and has the advantages of low substrate cost, simple steps and easy operation.
The invention provides a method for synthesizing bridged polycyclic lactam compound, which takes 3-oxo-3- (phenylamino) ethyl propionate compounds and methyl styryl ketone as raw materials and potassium tert-butoxide t BuOK) provides an alkaline environment and uses ethanol (EtOH) as a solvent to synthesize the bridged polycyclic lactam compound in one step.
The synthesis method disclosed by the invention has the advantages of simple reaction conditions, effective method, wide application range and green economy, not only can further enrich the synthesis method of the bridged polycyclic lactam compound, but also provides more candidate methods for industrial screening.
Preferably, the molar ratio of the 3-oxo-3- (phenylamino) propionic acid ethyl ester compound to the benzine is 1:2.2, for example, the molar number of the 3-oxo-3- (phenylamino) propionic acid ethyl ester compound may be 0.3mmol, and the molar number of the benzine is 0.66mmol.
Preferably, the structural formula of the 3-oxo-3- (phenylamino) propionic acid ethyl ester compound is as follows:
the substituent R is selected from-4-Me, -4-OMe, -3-Me, -2-Me, -H, -4-Cl, -3-Cl or-4-CO 2 Et。
Preferably, the reaction is carried out under air conditions.
Preferably, the reaction temperature is 60℃and the reaction is carried out with stirring.
Preferably, the method further comprises the step of removing the solvent by reduced pressure evaporation after the reaction is finished, and separating by column chromatography to obtain the bridged polycyclic lactam compound.
Preferably, the bridged polycyclic lactam compound of the present invention is synthesized as follows:
the substituent R is selected from-4-Me, -4-OMe, -3-Me, -2-Me, -H, -4-Cl, -3-Cl or-4-CO 2 Et。
In the synthetic method of the present invention, the reaction step requires only one step. The ethyl 3-oxo-3- (phenylamino) propionate compound and the methyl styrene ketone are all easy-to-obtain chemicals, and preferably when 2.2 equivalents of methyl styrene ketone, 4.0 equivalents of potassium tert-butoxide and 3mL of ethanol are used, the bridged polycyclic lactam compound is generated.
Compared with the prior art, the invention has the following advantages and technical effects:
the synthesis method has the advantages of few steps, low raw material cost, easy acquisition, low technical difficulty and easy operation. The synthesis method avoids the process of using multi-step reaction and the use of metal catalysts, and the target product can be obtained only by evaporating the solvent under reduced pressure after the reaction is finished and separating the solvent by column chromatography.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, 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. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the invention described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present invention. The specification and examples of the present invention are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
Example 1
Ethyl 3-oxo-3- (p-tolylamino) propionate (66 mg,0.3 mmol), methyl styrene ketone (154 mg,0.66 mmol), potassium tert-butoxide (135 mg,1.2 mmol) and 3mL of ethanol are added into a 15mL pressure-resistant tube, the mixture is stirred for 1 hour at 60 ℃ under the air condition, TCL is used for monitoring the reaction process, the solvent is removed by reduced pressure evaporation after the reaction is finished, and the white solid is obtained after column chromatography separation: 146mg, 71% yield.
White solid, yield 71%. 1 H NMR(400MHz,CDCl 3 )δ7.46(d,J＝8.0Hz,2H),7.34(d,J＝8.0Hz,2H),7.29(d,J＝6.8Hz,2H),7.25–7.14(m,12H),7.09(d,J＝7.2Hz,1H),6.97–6.95(m,3H),6.80–6.73(m,3H),6.29(s,1H),6.13(d,J＝16.4Hz,1H),3.94(d,J＝13.2Hz,1H),3.34(d,J＝5.2Hz,1H),3.26(d,J＝4.8Hz,1H),3.01(s,3H),2.96(d,J＝12.0Hz,2H),2.77(s,1H),2.47(s,1H),2.44(s,1H),2.18(d,J＝11.2Hz,1H). 13 C NMR(151MHz,CDCl 3 )δ169.6,165.5,141.3,141.1,140.5,137.3,135.7,133.2,132.9,130.7,129.4,129.1,128.9,128.6,128.6,128.3,128.2,128.0,128.0,127.4,127.3,126.7,126.6,126.5,87.5,60.7,55.5,55.3,51.4,51.3,48.5,35.5,30.2,21.3.
Example 2
Ethyl 3- ((4-methoxyphenyl) amino) -3-oxopropionate (71 mg,0.3 mmol), methyl styryl ketone (154 mg,0.66 mmol), potassium tert-butoxide (135 mg,1.2 mmol) and 3mL of ethanol are added into a 15mL pressure-resistant tube, the mixture is stirred for 1 hour at 60 ℃ under the air condition, the reaction process is monitored by using TCL, the solvent is removed under reduced pressure after the reaction is finished, and the white solid is obtained after column chromatography separation: 106mg, 50% yield.
White solid, yield 50%. 1 H NMR(600MHz,CDCl 3 )δ7.47(d,J＝9.0Hz,2H),7.30–7.27(m,3H),7.24(d,J＝7.8Hz,2H),7.22–7.20(m,2H),7.18–7.14(m,7H),7.09(d,J＝7.2Hz,1H),7.05(d,J＝9.0Hz,2H),6.93–6.91(m,3H),6.76–6.75(m,2H),6.72(d,J＝16.2Hz,1H),6.32(s,1H),6.11(d,J＝16.2Hz,1H),3.90(d,J＝12.6Hz,1H),3.87(s,3H),3.46(q,J＝7.2Hz,2H),3.31(d,J＝4.8Hz,1H),3.23(d,J＝5.4Hz,1H),2.97–2.92(m,2H),2.70(d,J＝5.4Hz,2H),2.17–2.14(m,1H),0.45(t,J＝13.2Hz,3H). 13 C NMR(151MHz,CDCl 3 )δ169.3,165.9,158.7,141.5,141.3,140.6,135.8,132.9,130.6,130.1,129.3,128.6,128.3,128.2,127.9,127.4,127.3,126.8,126.6,126.4,114.2,87.5,60.6,60.2,55.8,55.5,55.5,51.3,48.5,35.5,30.1 13.1.
Example 3
Ethyl 3-oxo-3- (m-tolylamino) propionate (66 mg,0.3 mmol), methyl styrene ketone (154 mg,0.66 mmol), potassium tert-butoxide (135 mg,1.2 mmol) and 3mL of ethanol are added into a 15mL pressure-resistant tube, the mixture is stirred for 1 hour at 60 ℃ under the air condition, the reaction process is monitored by using TCL, the solvent is removed by reduced pressure evaporation after the reaction is finished, and the white solid is obtained after column chromatography separation: 93mg, 45% yield.
White solid, yield: 45%. 1 H NMR(400MHz,CDCl 3 )δ7.40(t,J＝8.4Hz,1H),7.34(d,J＝6.8Hz,2H),7.30–7.27(m,2H),7.24–7.20(m,5H),7.18–7.12(m,7H),7.09(t,J＝7.2Hz,1H),6.94–6.90(m,3H),6.78–6.76(m,2H),6.70(d,J＝16.0Hz,1H),6.39(s,1H),6.09(d,J＝16.0Hz,1H),3.91–3.87(m,1H),3.45(q,J＝7.2Hz,2H),3.31(d,J＝4.8Hz,1H),3.23(d,J＝5.2Hz,1H),2.94–2.88(m,3H),2.72(d,J＝2.8Hz,1H),2.46(s,3H),2.13(dd,J＝14.4,5.4Hz,1H),0.45(t,J＝7.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ169.3,165.7,141.5,141.3,140.6,138.6,135.9,135.8,132.9,130.7,129.9,129.3,128.6,128.5,128.3,128.2,127.9,127.4,127.3,126.8,126.6,126.4,126.2,87.6,60.6,60.2,55.8,55.6,51.4,48.6,35.5,30.1,21.6,13.1.
Example 4
Ethyl 3-oxo-3- (o-tolylamino) propionate (66 mg,0.3 mmol), methyl styrene ketone (154 mg,0.66 mmol), potassium tert-butoxide (135 mg,1.2 mmol) and 3mL of ethanol are added into a 15mL pressure-resistant tube, the mixture is stirred for 1 hour at 60 ℃ under the air condition, the reaction process is monitored by using TCL, the solvent is removed by reduced pressure evaporation after the reaction is finished, and the white solid is obtained after column chromatography separation: 116mg, 56% yield.
White solid, yield: 56%. 1 H NMR(400MHz,DMSO)δ7.65(d,J＝56.8Hz,1H),7.42–7.39(m,3H),7.37–7.30(m,8H),7.28–7.19(m,3H),7.15(d,J＝7.2Hz,3H),7.03–6.79(m,4H),6.64(dd,J＝11.6,8.0Hz,2H),6.44–6.31(m,2H),3.86–3.77(m,1H),3.55–3.51(m,1H),3.48–3.38(m,3H),3.33(s,1H),3.13(t,J＝14.0Hz,1H),2.77(d,J＝14.0Hz,1H),2.50(s,3H),2.32(s,1H),1.95–1.89(m,1H),0.52–0.46(m,3H). 13 C NMR(101MHz,DMSO)δ168.3,168.1,166.7,166.0,142.6,142.3,142.2,142.0,141.9,138.5,138.4,137.2,137.1,137.0,135.3,135.2,131.3,131.2,129.8,129.6,128.9,128.9,128.8,128.7,128.5,128.4,128.3,128.2,128.0,127.8,127.3,127.0,126.9,126.8,88.2,76.2,75.9,60.0,59.1,58.9,55.9,55.7,51.6,50.7,48.9,47.5,35.9,20.8,13.6.
Example 5
Ethyl 3-oxo-3- (phenylamino) propionate (62 mg,0.3 mmol), benzine (154 mg,0.66 mmol), potassium tert-butoxide (135 mg,1.2 mmol) and 3mL of ethanol are added into a 15mL pressure-resistant tube, the reaction process is monitored by TCL under the condition of air and is stirred for 1 hour at 60 ℃, the solvent is removed by reduced pressure evaporation after the reaction is finished, and the white solid is obtained after column chromatography separation: 119mg, 59% yield.
White solid, yield 59%. 1 H NMR(400MHz,CDCl 3 )δ7.56–7.50(m,4H),7.40(dd,J＝6.8,1.6Hz,1H),7.32–7.28(m,3H),7.23–7.20(m,4H),7.17–7.13(m,6H),7.08(t,J＝6.8Hz,1H),6.94–6.90(m,3H),6.76(dd,J＝7.2,1.6Hz,1H),6.70(d,J＝16.0Hz,1H),6.43(s,1H),6.08(d,J＝16.4Hz,1H),3.91–3.88(m,1H),3.45(q,J＝7.2Hz,2H),3.31(d,J＝5.2Hz,1H),3.23(d,J＝4.8Hz,1H),2.95–2.92(m,2H),2.88(s,1H),2.73(d,J＝4.8Hz,1H),2.14(dd,J＝14.0,3.6Hz,1H),0.45(t,J＝6.8Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ169.3,165.7,141.4,141.2,140.5,136.0,135.7,132.9,130.7,129.3,129.2,128.7,128.6,128.3,128.2,127.9,127.5,127.4,127.3,126.8,126.6,126.4,87.6,60.6,60.2,55.8,55.6,51.3,48.5,35.5,30.1,13.1.
Example 6
Ethyl 3- ((4-chlorophenyl) amino) -3-oxopropionate (72 mg,0.3 mmol), methyl styryl ketone (154 mg,0.66 mmol), potassium tert-butoxide (135 mg,1.2 mmol) and 3mL of ethanol are added into a 15mL pressure-resistant tube, the mixture is stirred for 1 hour at 60 ℃ under the condition of air, the reaction process is monitored by using TCL, the solvent is removed by reduced pressure evaporation after the reaction, and the mixture is separated by column chromatography to obtain white solid: 125mg, 59% yield.
White solid, yield: 59%. 1 H NMR(400MHz,CDCl 3 )δ7.52–7.49(m,4H),7.30(d,J＝6.4Hz,3H),7.24(d,J＝7.2Hz,2H),7.18–7.16(m,9H),7.10(d,J＝6.8Hz,1H),6.94(d,J＝6.0Hz,3H),6.76–6.72(m,3H),6.49(s,1H),6.10(d,J＝16.4Hz,1H),3.92(d,J＝13.2Hz,1H),3.48(q,J＝7.2Hz,2H),3.32(d,J＝4.8Hz,1H),3.25(d,J＝5.2Hz,1H),2.99–2.92(m,2H),2.73(s,1H),2.51(s,1H),2.17(d,J＝14.0Hz,1H),0.47(t,J＝6.8Hz,3H). 13 C NMR(151MHz,CDCl 3 )δ169.0,165.8,141.2,141.0,140.4,135.7,134.4,133.1,132.7,130.8,130.5,129.2,128.8,128.6,128.4,128.3,128.1,128.0,127.4,127.3,126.7,126.6,126.5,87.7,60.7,60.1,55.7,55.4,51.2,48.5,35.5,30.0,13.2.
Example 7
Ethyl 3- ((3-chlorophenyl) amino) -3-oxopropionate (72 mg,0.3 mmol), methyl styryl ketone (154 mg,0.66 mmol), potassium tert-butoxide (135 mg,1.2 mmol) and 3mL of ethanol are added into a 15mL pressure-resistant tube, the mixture is stirred for 1 hour at 60 ℃ under the condition of air, the reaction process is monitored by using TCL, the solvent is removed by reduced pressure evaporation after the reaction, and the mixture is separated by column chromatography to obtain white solid: 123mg, 58% yield.
White solid, yield: 58%. 1 H NMR(400MHz,CDCl 3 )δ7.57(s,1H),7.49–7.48(m,1H),7.45(d,J＝8.0Hz,1H),7.39(d,J＝7.6Hz,1H),7.31–7.27(m,1H),7.25–7.24(m,1H),7.19–7.15(m,9H),7.10(t,J＝5.6Hz,1H),6.96–6.95(m,3H),6.78–6.74(m,3H),6.48(s,1H),6.12(d,J＝16.4Hz,1H),3.94(d,J＝13.2Hz,1H),3.50(q,J＝6.8Hz,2H),3.34(d,J＝5.2Hz,1H),3.26(d,J＝4.8Hz,1H),3.02–2.95(m,2H),2.75(s,1H),2.41(s,1H),2.18(d,J＝10.8Hz,1H),0.48(t,J＝7.2Hz,3H). 13 C NMR(151MHz,CDCl 3 )δ169.0,165.6,141.1,140.9,140.3,137.0,135.6,134.0,132.6,130.9,129.5,129.4,129.2,128.6,128.6,128.4,128.3,128.0 127.9,127.6,127.5,127.4,127.3,126.7,126.6,126.5,87.8,60.7,60.2,55.6,55.4,51.2,48.4,35.5,30.1,13.1.
Example 8
Ethyl 4- (3-ethoxy-3-oxopropanamido) benzoate (84 mg,0.3 mmol), methyl styryl ketone (154 mg,0.66 mmol), potassium tert-butoxide (135 mg,1.2 mmol) and 3mL of ethanol are added into a 15mL pressure-resistant pipe, the mixture is stirred for 1 hour at 60 ℃ under the air condition, TCL is used for monitoring the reaction process, the solvent is removed by reduced pressure evaporation after the reaction is finished, and the white solid is obtained after column chromatography separation: 110mg, 61% yield.
White solid, yield: 61%. 1 H NMR(600MHz,CDCl3)δ8.19(d,J＝8.4Hz,2H),7.63(d,J＝8.4Hz,2H),7.29(d,J＝7.2Hz,2H),7.24(d,J＝7.2Hz,2H),7.18–7.15(m,8H),7.10(d,J＝7.2Hz,2H),6.94(d,J＝7.8Hz,3H),6.75(d,J＝5.4Hz,3H),6.55(s,1H),6.11(d,J＝16.2Hz,1H),4.42(dd,J＝14.4,7.2Hz,2H),3.93(d,J＝12.6Hz,1H),3.48–3.47(m,2H),3.34(d,J＝5.4Hz,1H),3.27(d,J＝4.2Hz,1H),2.97–2.93(m,2H),2.77(s,1H),2.69(s,1H),2.18(d,J＝13.8Hz,1H),1.42(t,J＝6.6Hz,2H),0.47(t,J＝7.2Hz,2H). 13 C NMR(151MHz,CDCl3)δ191.9,170.0,167.2,135.8,132.8,130.8,129.9,129.2,129.2,129.1,128.6,128.3,128.1,128.0,127.5,127.4,126.8,126.7,126.6,88.0,61.2,60.8,60.3,55.7,55.4,51.2,48.6,35.8,30.1,14.4,13.2,10.8.
The present invention is not limited to the above-mentioned embodiments, and any changes or substitutions that can be easily understood by those skilled in the art within the technical scope of the present invention are intended to be included in the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims.
Claims (6)
1. A method for synthesizing a bridged polycyclic lactam compound is characterized in that 3-oxo-3- (phenylamino) ethyl propionate compounds and methyl styrene ketone are used as raw materials, potassium tert-butoxide is used for providing an alkaline environment, ethanol is used as a solvent, and the bridged polycyclic lactam compound is synthesized in one step.
2. The method according to claim 1, wherein the molar ratio of the ethyl 3-oxo-3- (phenylamino) propionate to the benzine is 1:2.2.
3. The synthetic method according to claim 2, wherein the ethyl 3-oxo-3- (phenylamino) propionate compound has the following structural formula:
the substituent R is selected from-4-Me, -4-OMe, -3-Me, -2-Me, -H, -4-Cl, -3-Cl or-4-CO 2 Et。
4. The synthetic method of claim 1 wherein the reaction is carried out under air conditions.
5. The synthesis according to claim 1, wherein the reaction temperature is 60 ℃, and the reaction is carried out under stirring.
6. The method according to claim 1, wherein the reaction further comprises removing the solvent by evaporation under reduced pressure after completion of the reaction, and separating by column chromatography.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5525723A (en) * | 1993-11-18 | 1996-06-11 | Bristol-Myers Squibb Co. | Compounds containing a fused multiple ring lactam |
| CN104364254A (en) * | 2012-04-02 | 2015-02-18 | 阿斯利康(瑞典)有限公司 | Heterobicyclic compounds as beta-lactamase inhibitors |
| US20170002003A1 (en) * | 2014-01-24 | 2017-01-05 | Max-Planck-Gesellschaft Zur Forderung Der Wissensc Haften E.V. | Diazabicyclo[4.3.1]decane derivatives for treatment of psychiatric disorders |
| CN109715630A (en) * | 2016-09-16 | 2019-05-03 | 恩塔西斯治疗有限公司 | Beta-lactamase inhibitor compound |
| CN114075196A (en) * | 2020-08-21 | 2022-02-22 | 上海凌达生物医药有限公司 | Aromatic ring-lactam compound, preparation method and application thereof |
| CN114195671A (en) * | 2021-12-27 | 2022-03-18 | 河南师范大学 | Asymmetric malonanilide compound and synthesis method thereof |
-
2023
- 2023-06-09 CN CN202310681131.XA patent/CN116693531A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5525723A (en) * | 1993-11-18 | 1996-06-11 | Bristol-Myers Squibb Co. | Compounds containing a fused multiple ring lactam |
| CN104364254A (en) * | 2012-04-02 | 2015-02-18 | 阿斯利康(瑞典)有限公司 | Heterobicyclic compounds as beta-lactamase inhibitors |
| US20170002003A1 (en) * | 2014-01-24 | 2017-01-05 | Max-Planck-Gesellschaft Zur Forderung Der Wissensc Haften E.V. | Diazabicyclo[4.3.1]decane derivatives for treatment of psychiatric disorders |
| CN109715630A (en) * | 2016-09-16 | 2019-05-03 | 恩塔西斯治疗有限公司 | Beta-lactamase inhibitor compound |
| CN114075196A (en) * | 2020-08-21 | 2022-02-22 | 上海凌达生物医药有限公司 | Aromatic ring-lactam compound, preparation method and application thereof |
| CN114195671A (en) * | 2021-12-27 | 2022-03-18 | 河南师范大学 | Asymmetric malonanilide compound and synthesis method thereof |
Non-Patent Citations (1)
| Title |
|---|
| BINGBING SHI ET AL.: "Anion Cascade Reactions II: Synthesis of 3‑Isoquinuclidone-Based Bridged Polycyclic Lactams", 《ORG. LETT.》, vol. 25, 8 September 2023 (2023-09-08), pages 6846 * |
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