CN107056680A - Spiral shell [indoline of cyclopropane 1,3 '] 2 ' ketone compounds and medicinal usage containing difluoromethyl - Google Patents
Spiral shell [indoline of cyclopropane 1,3 '] 2 ' ketone compounds and medicinal usage containing difluoromethyl Download PDFInfo
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Abstract
The invention discloses a kind of spiral shell [cyclopropane 1 containing difluoromethyl, 3' indolines] 2' ketone compounds, preparation method and its medicinal usage, the present invention is with generated in-situ difluoromethyl diazomethane and 3 alkenyl Oxoindoles derived from isatin under without catalysts conditions, [3+2] reaction and Norfloxacin Reaction are carried out in organic solvent, a series of spiral shell [cyclopropane 1,3' indolines] 2' ketone compounds containing difluoromethyl are synthesized.Such compound contains the difluoromethyl group and 3,3' Oxoindole loop coil cyclopropane skeleton of potential source biomolecule activity, chemical combination material resource can be provided for bioactivity screening, the screening and pharmaceutical industry to medicine have important application value.Meanwhile, the present invention has carried out tumor growth inhibiting activity screening for such compound to two kinds of tumor cell lines such as human prostate (PC 3) and human lung carcinoma cell (A549).Result of study finds that such compound has certain suppression tumor cell growth activity, it is contemplated that be used as antineoplastic use.
Description
Technical field
The present invention relates to technical field of chemistry, especially a kind of spiral shell [cyclopropane -1,3'- indoline] containing difluoromethyl -
2'- ketone compounds and medicinal usage.
Background technology
Loop coil Oxoindole construction unit is widely present in many natural molecules and clinical medicine molecule, what is had found
In the oxidized indole compounds for containing 3,3'- spirane structures, much all there is higher bioactivity, it is such as antitumor, anti-
Virus, AntiHIV1 RT activity, inoxidizability etc..Wherein, the molecule containing Oxoindole loop coil cyclopropane moiety unit is more noticeable,
Because such compound can be used as progesterone receptor antagonist, RSV inhibitor, kinase inhibitor, antineoplastic etc..
On the other hand, difluoromethyl (- CF2H), as an important fluoro-containing group, a low acidified C-H is contained
Key, is the isostere of hydroxyl, sulfydryl and methylol, can adjust bioactivity, metabolic stability and the lipophilic of molecule
Property etc., play a part of in fields such as medicine, agricultural chemicals and other fluoroalkyl no less importants.Therefore, difluoro first is introduced in the molecule
Base can assign its many premium properties, while introducing or maintaining the crucial recognition element of biological targets.These determine its
The great potential and scientific research value in the fields such as biological medicine, bio-imaging.
In view of Oxoindole loop coil cyclopropane compound has potential bioactivity and difluoromethyl in pharmaceutical chemistry
In important function, therefore, using difluoromethyl diazomethane as building block, pass through [3+2] reaction and Norfloxacin Reaction strategy and 3- alkene
Base Oxoindole reacts, and 3,3'- Oxoindole loop coil cyclopropane of the synthesis containing difluoromethyl group may produce a series of
Structure and the upper significant noval chemical compound of activity, their synthesis can be spiral shell [cyclopropane -1,3'- indoles containing difluoromethyl
Quinoline] the application of -2'- ketone compounds in drug discovery and druggability evaluation set up material base.
The content of the invention
It is an object of the invention to provide a kind of spiral shell [cyclopropane -1,3'- indolines] -2'- ketones containing difluoromethyl
Compound and its application for preparing preventing and treating tumor disease medicine, such compound is the important pharmaceutical activity molecule of a class, to medicine
Screening and pharmaceutical industry have an important application value, and the quasi-molecule synthesis have reaction condition it is gentle, simple to operate,
The good advantage of substrate universality.
What the present invention was realized in：Generated in-situ difluoromethyl diazomethane aoxidizes Yin with 3- alkenyls derived from isatin
Diindyl carries out [3+2] reaction and Norfloxacin Reaction under without catalysts conditions, in organic solvent, obtains the spiral shell [ring containing difluoromethyl
Propane -1,3'- indolines] -2'- ketone compounds.Such compound has the structure as shown in formula (I)：
In formula, R1For alkyl, alkoxy or halogen, R2For alkyl, R3For alkyl, aryl or acyl group.
Described organic solvent is dichloromethane, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, benzene, toluene, diformazan
Benzene, mesitylene, 1,4- dioxane, glycol dimethyl ether, ethylene glycol diethyl ether or methyl tertiary butyl ether(MTBE).
The reaction temperature of generated in-situ difluoromethyl diazomethane and 3- alkenyls Oxoindole derived from isatin is 25-
130 DEG C, the reaction time is 1-50 hours.
Described spiral shell [cyclopropane -1,3'- indolines] -2'- ketone compounds containing difluoromethyl are preparing anti-curing oncoma
The application of disease medicament.
The reaction principle of the present invention is as follows：
Wherein, R1, R2, R3It is as described above with organic solvent.
By using above-mentioned technical proposal, difluoroethylamine (1) is positioned in reaction bulb, sequentially adds organic solvent, nitrous
Tert-butyl acrylate and acetic acid, and reacted 10 minutes under the conditions of 70 DEG C, stop heating, you can original position obtains difluoromethyl diazomethane
(2).Then 3- alkenyls Oxoindole (3) derived from isatin is added in reaction bulb, by [3+2] reaction and Norfloxacin Reaction, closed
Into a series of spiral shell [cyclopropane -1,3'- indolines] -2'- ketone compounds (4) containing difluoromethyl.Such compound contains
The difluoromethyl group and 3,3'- Oxoindole loop coil cyclopropane skeleton of potential source biomolecule activity, can be drug discovery and patent medicine
Material base is set up in property evaluation, with important application value.Raw material of the present invention is easily obtained, can be in various organic solvents
Carry out, have the advantages that reaction condition is gentle, simple to operate, substrate universality is good.
Brief description of the drawings
Accompanying drawing 1 is embodiments of the invention compound 4a monocrystalline-X-ray diffraction structure.
Accompanying drawing 2 is embodiments of the invention compound 4g monocrystalline-X-ray diffraction structure.
Accompanying drawing 3 is embodiments of the invention compound 4r monocrystalline-X-ray diffraction structure.
Accompanying drawing 4-6 is embodiments of the invention compound 4a nmr spectrum.
Embodiment
The present invention is further described with reference to embodiment and accompanying drawing, but the present invention is not limited only to following embodiments, can be with
Those skilled in the art are predicted in the case where combining prior art, there may be many variations for performance.
Embodiments of the invention 1：The preparation of spiral shell [cyclopropane -1,3'- indolines] -2'- ketone (4) containing difluoromethyl；Change
Compound 4a：In round-bottomed flask, dichloromethane (15mL), difluoroethylamine (1,97.3mg, 1.2mmol), nitrous acid are sequentially added
The tert-butyl ester (148.5mg, 1.44mmol), acetic acid (14.5mg, 0.24mmol) reacts 10 minutes under the conditions of 70 DEG C, stops adding
Heat, you can original position prepares difluoromethyl diazomethane (2).Add 3- alkenyls Oxoindole derived from isatin (3a,
92.5mg, 0.4mmol), and be sufficiently stirred at room temperature 48 hours, concentrate, add under the conditions of toluene (15mL), 120 DEG C instead
Answer 2 hours, thin-layer chromatography is detected after completion of the reaction, silica gel column chromatography (300-400 mesh) separation (petroleum ether：Ethyl acetate=5：
1) light yellow solid 103.9mg, yield 88%, fusing point, are obtained：88.9-90.0 DEG C, nuclear magnetic resonance and high resolution mass spectrum test divide
Analyse result as follows：94:6trans/cis(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ
(major) 7.36-7.31 (m, 2H), 7.06 (t, J=7.8Hz, 1H), 6.91 (d, J=7.8Hz, 1H), 6.40 (td, J=
6.0,56.0Hz, 1H), 4.19-4.11 (m, 2H), 3.28 (s, 3H), 2.99-2.95 (m, 2H), 1.22 (t, J=7.2Hz,
3H)；13C NMR(100MHz,CDCl3)δ(major+minor)173.1,172.3,167.4,166.8,144.8,144.2,
(t, J=236.3Hz), 132.5,128.7,128.6,124.3,124.0,122.9,122.8,113.4 108.9,108.5,
(d, J=8.6Hz), 108.2,62.0,61.9,35.8 34.9 (d, J=9.7Hz), 34.6 (t, J=33.7Hz), 33.3 (t, J
=33.9Hz), 32.8 (d, J=7.9Hz), 27.0,27.9,25.9,14.2,14.1；19F NMR(376MHz,CDCl3)δ
(major+minor) -111.04 (ABd, J=54.2,293.9Hz, major), -112.94 (ABd, J=55.4,297.4Hz,
), minor -114.43 (ABd, J=54.1,297.6Hz, minor), -115.88 (ABd, J=54.1,293.4Hz, major)；
HRMS(ESI-TOF)Calcd.for C15H16F2NO3[M+H]+:296.1093；found:296.1101.
Monocrystalline-X-ray diffraction structure chart and nmr spectrum are by prior art Software Create, art technology in accompanying drawing
The characteristics of personnel can be by figure is that can be appreciated that each compound attribute, may not be very because submitting reason for the numeral in figure
Clearly, the full disclosure of the present invention but is not influenceed.
Compound 4b~the 4s prepared by embodiment preparation method is with compound 4a, rate of charge and compound 4a phases
Together, compound 4b~4s is can obtain, reaction yield is shown in Table 1, but it is emphasized that the compound of the present invention is not limited to represented by table 1
Content.
Table 1 is the chemical constitution of spiral shell [cyclopropane -1,3'- indolines] -2'- ketone compounds containing difluoromethyl
Table 1：
The present embodiment prepare compound 4b：Red oil, yield 91%；Nuclear magnetic resonance and high resolution mass spectrum test analysis
As a result it is as follows：93:7trans/cis(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ
(major+minor) 7.18 (s, 0.07H), 7.16 (s, 0.93H), 7.12 (d, J=7.9Hz, 0.93H), 6.83 (d, J=
7.9Hz, 0.07H), 6.79 (d, J=7.9Hz, 0.93H), 6.68 (d, J=7.9Hz, 0.07H), 6.40 (td, J=7.2,
55.8, Hz, 1H), 4.36-4.30 (m, 0.14H), 4.24-4.07 (m, 1.86H), 3.25 (d, J=1.6Hz, 2.79H), 3.20
(d, J=1.6Hz, 0.21H), 2.99-2.90 (m, 1.86H), 2.86-2.83 (m, 0.14H), 2.34 (s, 0.21H), 2.32
(s,2.79H),1.39-1.35(m,0.21H),1.24-1.20(m,2.79H)；13C NMR(100MHz,CDCl3)δ(major+
Minor) 172.2,167.6,166.8 (d, J=2.0Hz), 165.9,141.8,132.9,132.4,129.4,128.9,
(125.0,124.0,123.6,122.2,113.4 t, J=236.3Hz), 108.2,61.9,61.2,35.9 (d, J=8.6Hz),
34.8 (d, J=9.7Hz), 34.5 (t, J=33.7Hz), 26.9,26.3,21.4,21.3,21.2,14.3,14.2；19F NMR
(376MHz,CDCl3) δ (major+minor) -111.03 (ABdd, J=5.9,54.7,294.3Hz, major), -112.87
(ABdd, J=8.6,55.9,297.2Hz, minor) -114.51 (ABdd, J=7.1,53.6,297.3Hz, minor), -
115.84 (ABdd, J=7.0,56.1,294.6Hz, major)；HRMS(ESI-TOF)Calcd.for C16H18F2NO3[M+H
]+:310.1249；found:310.1253.
The present embodiment prepare compound 4c：Orange, yield 81%；Nuclear magnetic resonance and high resolution mass spectrum test analysis
As a result it is as follows：>99:1trans/cis(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ
7.16 (dd, J=2.6,8.6Hz, 1H), 7.02 (td, J=2.6,8.6Hz, 1H), 6.79 (dd, J=8.0,8.6Hz, 1H),
6.38 (td, J=7.4,55.2Hz, 1H), 4.25-4.09 (m, 2H), 3.26 (s, 3H), 3.02-3.01 (m, 1H), 2.96-
2.89 (m, 1H), 1.23 (t, J=7.2Hz, 3H)；13C NMR(100MHz,CDCl3) δ 172.0,166.7 (d, J=2.0Hz,
1C), 159.2 (d, J=239.2Hz, 1C), 140.2 (d, J=1.8Hz, 1C), 125.6 (d, J=9.5Hz, 1C), 114.9 (d,
J=23.6Hz, 1C), 113.2 (t, J=236.5Hz, 1C), 111.4 (d, J=26.8Hz, 1C), 108.9 (d, J=8.3Hz,
1C), 62.2,35.9 (dd, J=2.0,8.6Hz, 1C), 34.9 (d, J=4.5Hz, 1C), 34.9 (t, J=28.9Hz, 1C),
27.0,14.1；19F NMR(376MHz,CDCl3) δ -111.07 (ABddd, J=1.6,5.9,54.7,295.3Hz, 1F), -
116.01 (ABdd, J=7.2,55.6,295.2Hz, 1F), -119.47 (td, J=4.1,8.8Hz, 1F)；HRMS(ESI-TOF)
Calcd.for C15H15F3NO3[M+H]+:314.0999；found:314.1010.
The present embodiment prepare compound 4d：Orange, yield 71%；Nuclear magnetic resonance and high resolution mass spectrum test analysis
As a result it is as follows：>99:1trans/cis(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ
(major) 7.37 (d, J=2.0Hz, 1H), 7.02 (dd, J=2.0,8.4Hz, 1H), 6.82 (d, J=8.4Hz, 1H), 6.37
(td, J=7.2,55.2Hz, 1H), 4.26-4.10 (m, 2H), 3.26 (s, 3H), 3.02-2.91 (m, 2H), 1.24 (t, J=
7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ(major+minor)172.3,166.7,145.3,134.7,125.3,
(t, J=236.6Hz), 124.0,112.7,122.3,113.2 109.7,109.3,62.2,35.6 (d, J=8.6Hz), 34.9
(d, J=8.6Hz), 34.7 (t, J=34.0Hz), 27.2,27.0,14.2；19F NMR(376MHz,CDCl3)δ(major)-
111.06 (ABdd, J=5.6,54.5,295.4Hz, major, 1F), -116.01 (ABdd, J=7.0,55.8,295.6Hz,
major,1F)；HRMS(ESI-TOF)Calcd.for C15H15ClF2NO3[M+H]+:330.0703；found:330.0708.
The present embodiment prepare compound 4e：Yellow oil, yield 85%；Nuclear magnetic resonance and high resolution mass spectrum test analysis
As a result it is as follows：97:3trans/cis(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ
(major) 7.49 (s, 1H), 7.44 (dd, J=1.9,8.4Hz, 1H), 6.77 (d, J=8.4Hz, 1H), 6.36 (td, J=
7.2,55.3Hz, 1H), 4.26-4.10 (m, 2H), 3.25 (s, 3H), 3.01-2.93 (m, 2H), 1.24 (t, J=7.2Hz,
3H)；13C NMR(100MHz,CDCl3)δ(major)171.7,166.5,143.2,131.5,126.2,125.9,115.5,
113.1 (t, J=236.7Hz, 1C), 109.9,62.2,35.5 (d, J=8.6Hz, 1C), 35.1 (d, J=9.5Hz, 1C),
35.0 (t, J=34.0Hz, 1C), 27.0,14.2；19F NMR(376MHz,CDCl3)δ(major+minor)-111.02
(ABdd, J=3.7,54.6,295.3Hz, major), -112.80 (ABdd, J=8.2,55.9,298.9Hz, minor), -
114.42 (ABdd, J=7.2,53.4,298.9Hz, minor), -115.98 (ABdd, J=6.7,55.8,295.7Hz,
major)；HRMS(ESI-TOF)Calcd.for C15H15BrF2NO3[M+H]+:374.0198；found:374.0204.
The present embodiment prepare compound 4f：Yellow oil, yield 80%；Nuclear magnetic resonance and high resolution mass spectrum test analysis
As a result it is as follows：97:3trans/cis(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ
(major) 7.29 (s, 1H), 7.20 (d, J=8.2Hz, 1H), 6.89 (d, J=8.4Hz, 1H), 6.38 (td, J=7.0,
55.2Hz,1H),4.20-4.11(m,2H),3.28(s,3H),3.03-2.94(m,2H),1.23-1.19(m,3H)；13C NMR
(100MHz,CDCl3) δ (major) 172.1,166.5,144.8,142.9,125.5,121.9,120.6 (q, J=255.2Hz,
1C), 117.3,113.1 (t, J=236.2Hz), 108.9,62.3,35.7 (d, J=8.6Hz), 35.1 (d, J=9.5Hz),
34.9 (t, J=34.1Hz), 27.0,14.0；19F NMR(376MHz,CDCl3)δ(major+minor)-58.54(s,3F),-
111.14 (ABdd, J=5.6,54.6,295.2Hz, major), -113.01 (ABdd, J=8.3,55.9,299.7Hz,
), minor -114.46 (ABdd, J=7.4,53.4,299.3Hz, minor), -116.14 (ABdd, J=7.1,55.6,
295.6Hz,major)；HRMS(ESI-TOF)Calcd.for C16H15F5NO4[M+H]+:380.0916；found:
380.0922.
The present embodiment prepare compound 4g：Yellow solid, yield 92%；Fusing point:102.0–103.8℃；Nuclear magnetic resonance and
High resolution mass spectrum Measurement results are as follows：89:11trans/cis(determined by19F NMR analysis)；1H
NMR(400MHz,CDCl3) δ (major+minor) 7.39 (d, J=8.2Hz, 0.11H), 7.28 (d, J=8.2Hz, 0.89H),
7.05 (d, J=1.9Hz, 0.11H), 7.02 (dd, J=1.8,8.2Hz, 0.89H), 6.94 (d, J=1.8Hz, 0.11H),
6.90 (d, J=1.8Hz, 0.89H), 6.37 (td, J=7.1,55.2Hz, 1H), 4.34-4.29 (m, 0.22H), 4.23-4.07
(m,1.78H),3.26(s,2.67H),3.22(s,0.33H)3.00-2.93(m,1.78H),2.65-2.57(m,0.22H),
1.36 (t, J=7.2Hz, 0.33H), 1.22 (t, J=7.2Hz, 2.67H)；13C NMR(100MHz,CDCl3)δ(major+
Minor) 172.3,166.7,145.3,134.7,125.3,124.0,122.7,122.6,122.3,11 3.2 (t, J=
236.6Hz), 109.7,109.3,62.2,62.1,35.6 (d, J=8.6Hz), 35.0 (d, J=8.6Hz), 34.7 (t, J=
34.0Hz), 32.9 (d, J=7.6Hz), 27.2,27.0,14.2,14.1；19F NMR(376MHz,CDCl3)δ(major+
Minor) -111.03 (ABdd, J=5.6,54.6,295.2Hz, major), -113.05 (ABdd, J=8.2,55.8,
298.8Hz, minor), -114.40 (ABdd, J=7.4,53.6,298.7Hz, minor), -115.96 (ABdd, J=7.0,
55.6,295.3Hz,major)；HRMS(ESI-TOF)Calcd.for C15H15ClF2NO3[M+H]+:330.0703；found:
330.0713.
The present embodiment prepare compound 4h：Yellow solid, yield 83%；Fusing point:103.7–105.2℃；Nuclear magnetic resonance and
High resolution mass spectrum Measurement results are as follows：92:8trans/cis(determined by19F NMR analysis)；1H
NMR(400MHz,CDCl3) δ (major+minor) 7.32 (d, J=8.2Hz, 0.08H), 7.22 (d, J=8.2Hz, 0.92H),
7.18-7.16 (m, 1H), 7.09 (d, J=1.6Hz, 0.08H), 7.04 (d, J=1.6Hz, 0.92H), 6.37 (td, J=7.2,
55.1Hz,1H),4.32-4.28(m,0.16H),4.23-4.06(m,1.84H),3.26(s,2.76H),3.21(s,0.24H),
3.00-2.91 (m, 1.84H), 2.65-2.57 (m, 0.16H), 1.22 (t, J=7.2Hz, 2.76H), 0.95 (t, J=7.3Hz,
0.24H)；13C NMR(100MHz,CDCl3)δ(major+minor)172.2,166.7,145.4,125.6,125.5,124.3,
(t, J=236.6, Hz), 122.9,122.4,113.1 112.4,112.1,62.1,35.6 (d, J=8.7Hz), 35.0 (d, J=
9.6Hz), 34.7 (t, J=33.9Hz), 27.1,27.0,14.2；19F NMR(376MHz,CDCl3)δ(major+minor)-
111.03 (ABdd, J=3.9,54.6,295.1Hz, major), -113.05 (ABdd, J=6.6,55.8,298.6Hz,
), minor -114.40 (ABdd, J=7.1,55.5,298.8Hz, minor), -115.96 (ABdd, J=6.5,55.6,
295.3Hz,major)；HRMS(ESI-TOF)Calcd.for C15H15BrF2NO3[M+H]+:374.0198；found:
374.0210.
The present embodiment prepare compound 4i：Yellow solid, yield 96%；Fusing point:83.3–85.0℃；Nuclear magnetic resonance and height
Resolution Mass Spectrometry Measurement results are as follows：92:8trans/cis(determined by19F NMR analysis)；1H NMR
(400MHz,CDCl3)δ(major+minor)7.05-7.03(m,0.16H),6.98-6.92(m,1.84H),6.90-6.87
(m, 0.92H), 6.84-6.81 (m, 0.08H), 6.40 (td, J=7.2Hz, 1H), 4.34-4.28 (m, 0.16H), 4.22-
4.04(m,1.84H),3.86(s,3H),3.55(s,2.76H),3.50(s,0.24H),2.99-2.83(m,1.84H),2.61-
2.53 (m, 0.16H), 1.36 (t, J=7.1Hz, 0.24H), 1.21 (t, J=7.2Hz, 2.76H)；13C NMR(100MHz,
CDCl3)δ(major+minor)172.5,166.7,146.0,145.6,132.1,125.6,123.3,122.9,121.4,
(116.7,115.3,113.4 t, J=236.3Hz), 112.7,112.5,62.0,61.9,61.3,56.1,36.0 (d, J=
8.6Hz), 35.3 (d, J=8.6Hz), 34.8 (t, J=33.8Hz), 33.1 (d, J=8.7Hz), 30.6,30.4,14.3,
14.2；19F NMR(376MHz,CDCl3) δ (major+minor) -111.12 (ABdd, J=5.8,54.8,294.4Hz,
), major -112.85 (ABdd, J=8.3,56.0,297.4Hz, minor), -114.53 (ABdd, J=7.2,53.5,
297.3Hz, minor), -116.05 (ABdd, J=7.0,55.8,294.3Hz, major)；HRMS(ESI-TOF)Calcd.for
C16H18F2NO4[M+H]+:326.1198；found:326.1202.
The present embodiment prepare compound 4j：Yellow solid, yield 75%；Fusing point:96.0–97.5℃；Nuclear magnetic resonance and height
Resolution Mass Spectrometry Measurement results are as follows：90:10trans/cis(determined by19F NMR analysis)；1H NMR
(400MHz,CDCl3) δ (major+minor) 7.24 (d, J=7.8Hz, 0.10H), 7.13 (d, J=7.4Hz, 0.90H),
7.07-7.02 (m, 1H), 6.99-6.95 (m, 0.90H), 6.81-6.79 (m, 0.10H), 6.38 (td, J=6.9,55.2Hz,
1H), 4.23-4.07 (m, 2H), 3.50 (s, 3H), 3.01 (d, J=7.4Hz, 0.90H), 2.97-2.92 (m, 0.90H), 2.87
(d, J=9.3Hz, 0.10H), 2.65-2.57 (m, 0.10H), 1.22 (t, J=7.0Hz, 3H)；13C NMR(100MHz,
CDCl3) δ (major+minor) 172.0,170.9,167.2,166.5,147.9 (d, J=242.3Hz), 130.7 (d, J=
23.9Hz), 126.8 (d, J=3.7Hz), 123.3 (d, J=6.6Hz), 120.1 (d, J=3.4Hz), 118.7 (d, J=
3.3Hz), 116.9,116.7 (d, J=18.9Hz), 113.2 (t, J=236.6Hz), 62.1,62.0,36.0 (d, J=
12.0Hz), 35.5 (d, J=9.6Hz), 35.0 (t, J=33.9Hz), 33.3 (d, J=7.9Hz), 29.7 (d, J=6.1Hz),
29.5 (d, J=6.0Hz), 14.2,14.1；19F NMR(376MHz,CDCl3)δ(major+minor)-111.09(ABddd,J
=1.3,5.7,54.7,295.3Hz, major), -112.99 (ABddd, J=1.7,8.3,55.9,298.6Hz, minor), -
114.60 (ABdd, J=7.3,53.5,298.5Hz, minor), -116.13 (ABdd, J=6.8,55.3,295.3Hz,
major),(-135.65)–(-135.69)(m,minor),(-136.40)–(-136.45)(m,major)；HRMS(ESI-
TOF)Calcd.for C15H15F3NO3[M+H]+:314.0999；found:314.1004.
The present embodiment prepare compound 4k：White solid, yield 90%；Fusing point:117.0–118.7℃；Nuclear magnetic resonance and
High resolution mass spectrum Measurement results are as follows：93:7trans/cis(determined by19F NMR analysis)；1H
NMR(400MHz,CDCl3) δ (major+minor) 7.34 (d, J=7.8Hz, 0.07H), 7.29 (d, J=1.2Hz, 0.07H),
7.26-7.22 (m, 1.86H), 6.95 (t, J=8.0Hz, 1H), 6.38 (td, J=7.3Hz, 1H), 4.21-4.08 (m, 2H),
3.67 (s, 0.21H), 3.66 (s, 2.79H), 3.01 (d, J=7.8Hz, 0.93H), 2.98-2.92 (m, 0.93H), 2.88 (d,
J=9.3Hz, 0.07H), 2.64-2.60 (m, 0.07H), 1.22 (t, J=7.2Hz, 3H)；13C NMR(100MHz,CDCl3)δ
(major+minor)172.7,166.4,140.0,131.2,131.0,126.7,123.5,123.4,122.6,121.3,
116.1,113.2 (t, J=236.7Hz), 62.2,62.1,35.8 (d, J=9.6Hz), 35.6 (d, J=8.6Hz), 35.1 (t,
), J=33.9Hz 33.5 (d, J=7.6Hz), 30.8,30.5,14.2；19F NMR(376MHz,CDCl3)δ(major+
Minor) -111.07 (ABddd, J=2.3,5.4,54.6,295.5Hz, major), -112.87 (ABdd, J=8.2,56.1,
299.2Hz, minor) -114.52 (ABddd, J=3.0,7.6,53.4,299.1Hz, minor), -116.08 (ABddd, J=
2.3,7.1,55.7,295.4Hz,major)；HRMS(ESI-TOF)Calcd.for C15H14F2NNaO3[M+Na]+:
352.0523；found:352.0532.
The present embodiment prepare compound 4l：Light tan solid, yield 97%；Fusing point:104.3–105.7℃；Nuclear magnetic resonance
It is as follows with high resolution mass spectrum Measurement results：89:11trans/cis(determined by19F NMR analysis)；1H
NMR(400MHz,CDCl3) δ (major+minor) 7.45 (dd, J=1.0,8.2Hz, 0.11H), 7.42 (dd, J=1.0,
8.2Hz, 0.89H), 7.39 (d, J=8.8Hz, 0.11H), 7.27 (d, J=7.6Hz, 0.89H), 6.90 (t, J=7.9Hz,
1H), 6.38 (td, J=7.2,55.2Hz, 1H), 4.23-4.06 (m, 2H), 3.68 (s, 0.33H), 3.66 (s, 2.67H),
3.02 (d, J=7.6Hz, 0.89H), 2.98-2.91 (m, 0.89H), 2.88 (d, J=9.4Hz, 0.11H), 2.66-2.58 (m,
0.11H), 1.21 (t, J=7.2Hz, 3H)；13C NMR(100MHz,CDCl3)δ(major+minor)173.8,172.8,
167.1,166.4,141.4,134.5,134.3,127.0,125.2,123.8,123.7,12 3.1,121.8,113.2 (t, J=
236.6Hz), 103.2,102.8,62.2,62.1,35.9 (d, J=9.6Hz), 35.5 (d, J=8.7Hz), 35.0 (t, J=
34.0Hz), 33.6 (d, J=8.1Hz), 31.1,30.7,14.2；19F NMR(376MHz,CDCl3)δ(major+minor)-
111.06 (ABdd, J=4.3,54.6,295.3Hz, major), -112.28 (ABdd, J=6.8,56.4,299.2Hz,
), minor -114.49 (ABdd, J=7.2,53.5,299.2Hz, minor), -116.05 (ABdd, J=6.6,54.6,
295.3Hz,major)；HRMS(ESI-TOF)Calcd.for C15H15BrF2NO3[M+H]+:374.0198；found:
374.0202.
The present embodiment prepare compound 4m：Yellow solid, yield 60%；Fusing point:118.2–119.3℃；Nuclear magnetic resonance and
High resolution mass spectrum Measurement results are as follows：>99:1trans/cis(determined by19F NMR analysis)；1H
NMR(400MHz,CDCl3) δ 7.35-7.31 (m, 2H), 7.08-7.04 (m, 1H), 6.91 (d, J=7.5Hz, 1H), 6.40
(td, J=7.2,55.6Hz, 1H), 3.70 (s, 3H), 3.28 (s, 3H), 3.02-2.94 (m, 2H)；13C NMR(100MHz,
CDCl3) δ 172.3,167.3,144.2,128.7,124.0,123.0 (d, J=2.7Hz), 122.0 113.3 (t, J=
236.4Hz), 108.6,52.8,35.9 (d, J=8.5Hz), 34.7 (d, J=9.5Hz), 34.6 (t, J=33.7Hz), 26.9
；19F NMR(376MHz,CDCl3) δ -111.09 (ABdd, J=5.3,54.9,295.1Hz, 1F), -115.91 (ABdd, J=
5.9,55.5,294.2Hz,1F)；HRMS(ESI-TOF)Calcd.for C14H14F2NO3[M+H]+:282.0936；found:
282.0945.
The present embodiment prepare compound 4n：Light yellow solid, yield 87%；Fusing point:63.2–64.0℃；Nuclear magnetic resonance and
High resolution mass spectrum Measurement results are as follows：>99:1trans/cis(determined by19F NMR analysis)；1H
NMR(400MHz,CDCl3) δ 7.36-7.31 (m, 2H), 7.06 (t, J=7.7Hz, 1H), 6.91 (d, J=7.8Hz, 1H),
6.41 (td, J=7.1,55.3Hz, 1H), 4.12-3.98 (m, 2H), 3.29 (s, 3H), 3.02-2.95 (m, 2H) 1.62-1.59
(m, 2H) 0.86 (t, J=7.4Hz, 3H)；13C NMR(100MHz,CDCl3)δ172.4,166.9,144.2,128.7,124.1,
(t, J=236.4Hz, 1C), 122.9,122.8,113.4 108.6,67.6,35.9 (d, J=8.6Hz, 1C), 34.9 (d, J=
9.6Hz, 1C), 34.7 (t, J=33.7Hz, 1C), 26.9,21.9,10.3；19F NMR(376MHz,CDCl3)δ-111.04
(ABdd, J=5.6,55.0,294.6Hz, 1F), -115.89 (ABdd, J=7.0,55.6,294.4Hz, 1F)；HRMS(ESI-
TOF)Calcd.for C16H18F2NO3[M+H]+:310.1249；found:310.1255.
The present embodiment prepare compound 4o：Light yellow solid, yield 99%；Fusing point:80.3–82.0℃；Nuclear magnetic resonance and
High resolution mass spectrum Measurement results are as follows：87:13trans/cis(determined by19F NMR analysis)；1H
NMR(400MHz,CDCl3) δ (major+minor) 7.38-7.29 (m, 2H), 7.08-7.02 (m, 1H), 6.90 (d, J=
8.2Hz, 0.87H), 6.79 (d, J=7.8Hz, 0.13H), 6.38 (td, J=7.2,55.7Hz, 1H), 3.29 (s, 2.61H),
3.23(s,0.39H),2.95-2.87(m,1.74H),2.81-2.78(m,0.13H),2.60-2.49(m,0.13H),1.41
(s,1.17H),1.38(s,7.83H)；13C NMR(100MHz,CDCl3)δ(major+minor)172.6,165.7,144.1,
(132.2,128.7,128.6,128.5,125.0,124.2,124.1,122.9,122.7 d, J=5.9Hz), 113.5 (t, J=
236.2Hz), 108.9,108.5,108.2,82.9,35.9 (d, J=9.0Hz), 35.6 (d, J=9.0Hz), 34.3 (t, J=
33.6Hz), 33.8 (d, J=8.0Hz), 28.2,28.1,26.9；19F NMR(376MHz,CDCl3)δ(major+minor)-
110.97 (ABdd, J=5.2,54.5,293.8Hz, major), -112.66 (ABdd, J=8.8,56.1,296.4Hz,
), minor -115.20 (ABdd, J=6.9,53.5,296.3Hz, minor), -115.90 (ABdd, J=6.7,55.6,
293.7Hz,major)；HRMS(ESI-TOF)Calcd.for C17H20F2NO3[M+H]+:324.1406；found:
324.1415.
The present embodiment prepare compound 4p：Yellow solid, yield 93%；Fusing point:70.3–72.3℃；Nuclear magnetic resonance and height
Resolution Mass Spectrometry Measurement results are as follows：85:15trans/cis(determined by19F NMR analysis)；1H NMR
(400MHz,CDCl3) δ (major+minor) 7.47 (d, J=7.8Hz, 0.15H), 7.37 (d, J=7.8Hz, 0.85H),
7.32 (t, J=7.8Hz, 1H), 7.04 (t, J=6.0Hz, 0.85H), 6.97 (d, J=8.0Hz, 0.15H), 6.93 (d, J=
7.8Hz, 0.85H), 6.83 (t, J=8.2Hz, 0.15H), 6.40 (td, J=8.0,56.0Hz, 1H), 4.35-4.30 (m,
0.3H), 4.25-4.07 (m, 1.7H), 3.86-3.80 (q, J=7.2Hz, 2H), 2.95 (d, J=7.5Hz, 0.85H), 2.97-
2.92 (m, 0.85H), 2.85 (d, J=9.4Hz, 0.15H), 2.65-2.56 (m, 0.15H), 1.39-1.35 (m, 0.9H),
1.32-1.21(m,5.1H)；13C NMR(100MHz,CDCl3)δ(major+minor)172.8,171.9,167.5,166.9,
143.3,132.5,129.1,128.7,128.6,124.6,124.3,123.2,122.8,122.7,122.6,122.5,113.4
(t, J=236.5Hz), 109.0,108.7,108.4,62.0,61.3,35.9 (d, J=9.0Hz), 35.7,35.5,34.7 (d,
), J=9.6Hz 34.6 (t, J=33.8Hz), 32.8 (d, J=7.8Hz), 14.3,14.2,12.9,12.8；19F NMR
(376MHz,CDCl3) δ (major+minor) -111.06 (ABddd, J=1.8,5.7,54.7,294.5Hz, major), -
113.01 (ABddd, J=1.7,8.3,55.9,297.6Hz, minor), -114.45 (ABdd, J=7.3,53.7,297.6Hz,
), minor -113.01 (ABdd, J=7.3,55.1,294.3Hz, major)；HRMS(ESI-TOF)Calcd.for
C16H18F2NO3[M+H]+:310.1249；found:310.1252.
The present embodiment prepare compound 4q：Orange, yield 99%；Nuclear magnetic resonance and high resolution mass spectrum test analysis
As a result it is as follows：85:15trans/cis(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ
(major+minor) 7.50 (d, J=7.6Hz, 0.15H), 7.39 (d, J=7.6Hz, 0.85H), 7.36-7.20 (m, 6H),
7.07-7.01 (m, 1H), 6.87 (d, J=7.8Hz, 0.15H), 6.81 (d, J=7.8Hz, 0.85H), 6.47 (td, J=7.4,
55.2Hz,1H),5.08-4.90(m,2H),4.38-4.33(m,0.30H),4.27-4.09(m,1.70H),3.13-3.11(m,
0.85H), 3.07-3.00 (m, 0.85H), 2.98-2.95 (m, 0.15H), 2.74-2.66 (m, 0.15H), 1.39 (t, J=
7.2Hz, 0.45H), 1.25 (t, J=7.2Hz, 2.55H)；13C NMR(100MHz,CDCl3)δ(major+minor)173.4,
172.5,167.4,166.8,144.0,143.3,135.4,132.5,129.0,128.9,128.7,128.6,127.9,
127.8,127.4,127.3,124.5,124.1,123.0,122.9,122.8,1227,113 .5 (t, J=236.5Hz),
(d, J=9.0Hz), 109.9,109.5,62.1,62.0,44.6,44.4,35.90 35.0 (d, J=9.7Hz), 34.9 (t, J=
33.8Hz), 33.5 (t, J=34.1Hz), 32.9 (d, J=7.7Hz), 14.1,14.2；19F NMR(376MHz,CDCl3)δ
(major+minor) -110.88 (ABdd, J=5.5,54.7,294.6Hz, major), -112.87 (ABdd, J=8.3,
55.9,297.8Hz, minor) -114.44 (ABdd, J=7.3,53.7,297.6Hz, minor), -112.87 (ABdd, J=
7.6,55.7,294.5Hz,major)；HRMS(ESI-TOF)Calcd.for C21H20F2NO3[M+H]+:372.1406；
found:372.1418.
The present embodiment prepare compound 4r：Yellow oil, yield 94%；Nuclear magnetic resonance and high resolution mass spectrum test analysis
As a result it is as follows：92:8trans/cis(determined by19F NMR analysis)；1H NMR(400MHz,CDCl3)δ
(major+minor) 7.57-7.54 (m, 2H), 7.46-6.43 (m, 4H), 7.26 (t, J=7.8Hz, 1H), 7.10 (t, J=
7.8Hz, 1H), 6.89 (d, J=7.8Hz, 1H), 6.44 (td, J=7.0,55.2Hz, 1H), 4.30-4.12 (m, 2H), 3.13-
3.03 (m, 1.84H), 2.97 (d, J=9.4Hz, 0.08H), 2.76-2.68 (m, 0.08H), 1.40 (t, J=7.2Hz,
0.24H), 1.27 (t, J=7.2Hz, 2.76H)；13C NMR(100MHz,CDCl3)δ(major+minor)172.7,171.9,
167.4,166.8,144.2,134.1,134.0,129.8,128.7,128.6,128.5,126.8,126.7,124.6,
(123.9,123.3,123.2,113.3 t, J=236.5Hz), 110.2,109.9,62.1,62.0,36.1 (d, J=8.5Hz),
35.4 (d, J=9.6Hz), 35.2 (t, J=33.9Hz), 33.3 (d, J=7.9Hz), 14.2,14.1；19F NMR(376MHz,
CDCl3) δ (major+minor) -110.83 (ABdd, J=3.6,54.7,295.2Hz, major), -115.18 (ABdd, J=
8.0,55.9,298.4Hz, minor), -114.42 (ABdd, J=7.0,53.6,298.2Hz, minor), -115.94 (ABdd,
J=6.8,55.4,294.9Hz, major)；HRMS(ESI-TOF)Calcd.for C20H18F2NO3[M+H]+:358.1249；
found:328.1253.
The present embodiment prepare compound 4s：Light yellow solid, yield 70%；Fusing point:98.7–100.2℃；Nuclear magnetic resonance and
High resolution mass spectrum Measurement results are as follows：87:13trans/cis(determined by19F NMR analysis)；1H
NMR(400MHz,CDCl3) δ (major+minor) 7.99 (d, J=8.2Hz, 0.13H), 7.89 (d, J=8.2Hz, 0.87H),
7.44 (d, J=7.8Hz, 0.13H), 7.38-7.32 (m, 1.87H), 7.19-7.13 (m, 1H), 6.36 (td, J=7.0,
55.3Hz, 1H), 4.23-4.08 (m, 2H), 3.04-3.00 (m, 1.74H), 2.90 (d, J=9.4Hz, 0.13H), 2.66-
2.61(m,0.13H),1.65(s,7.83H),1.59(s,1.17H),1.27-1.19(m,3H)；13C NMR(100MHz,
CDCl3)δ(major+minor)171.3,166.2,148.8,140.3,129.0,125.0,124.7,122.9,122.5,
115.2,113.0 (t, J=236.8Hz), 85.3,62.2,36.8 (d, J=9.6Hz), 36.3 (d, J=9.6Hz), 35.6 (t,
), J=34.1Hz 28.2,14.2；19F NMR(376MHz,CDCl3) δ (major+minor) -115.69 (ABd, J=54.6,
296.2Hz, major), -112.80 (ABd, J=52.2,303.1Hz, minor), -114.78 (ABd, J=53.3,
297.6Hz, minor), -115.99 (ABd, J=55.7,296.2Hz, major)；HRMS(ESI-TOF)Calcd.for
C19H22F2NO5[M+H]+:382.1461；found:382.1466.
Formula (1) compound of the present invention has important bioactivity, thin to human prostate (PC-3) and human lung cancer in vitro
The cell toxicity test of born of the same parents (A549) totally two plants of tumour cells shows：Spiral shell [the ring third containing difluoromethyl shown in such formula (1)
Alkane -1,3'- indoline] -2'- ketone compounds are inhibited to growth of tumour cell, it is possible to develop into new anti-
Curing oncoma medicine.
Formula (1) compound or pharmaceutically acceptable salt thereof and its solvate of the present invention can be with pharmaceutically conventional auxiliary material or load
Body is combined, and is prepared with growth of tumour cell inhibitory activity so as to the pharmaceutical composition for anti-curing oncoma.It is above-mentioned
Various kinds of drug composition can be solid form, such as tablet, capsule, granule, pulvis；It can also be liquid form, such as note
Penetrate agent, suspending agent and emulsion etc..In addition to this it is possible to using controlled release agent or sustained release agent or nanometer well known to modern pharmaceutical circle
Agent.
Formula (1) compound or pharmaceutically acceptable salt thereof and its solvate of the present invention can be with the antineoplastic that has listed
Such as platinum medicine cis-platinum (DDP), deoxidation born of the same parents' former times class medicine gemcitabine (Gemcitabine, Gemzar, gemzar), taxol
(Paclitaxel), vinca alkaloids medicine carbon loss vinblastine (Vinorebine, NVB NVB), camptothecine she
It is vertical to be used in combination for health (Irinatecan, CPT-11), etoposide (Etoposide) etc., prepare with tumour growth
The cytotoxic composition of inhibitory activity, available for treatment tumor disease.Such pharmaceutical composition can be solid form, such as piece
Agent, capsule, granule, pulvis；Can also be liquid form, such as injection, suspending agent and emulsion.In addition, may be used also
With using the controlled release agent well known to modern pharmaceutical circle or sustained release agent or nanometer agent.
Pharmacological Examples 1：The cytotoxicity of compound 4f, 4l, 4o or 4p to PC-3 cells
Containing 10% hyclone in PC-3 (human prostata cancer) cell RPMI-1640 medium cultures, culture medium,
The streptomysin of 100U/mL penicillin and 100U/mL.Cell is added in 96 holes with the concentration of every 5000 cells in hole, at 37 DEG C
Containing 5%CO2Cultivated 24 hours in the incubator of humid air.
The measure of cell survival rate improvement mtt assay.Cell is after the incubation of 24 hours, respectively by the compound newly matched somebody with somebody
4f, 4l, 4o or 4p dimethyl sulphoxide solution are added in each hole with concentration gradient, make the compound ultimate density in hole be respectively
6.25 μm of ol/L, 12.5 μm of ol/L, 25 μm of ol/L, 50 μm of ol/L and 100 μm of ol/L.After 48 hours, 10 μ L MTT are added per hole
The phosphate buffer of (5mg/mL), is further continued for after 37 DEG C are cultivated 4 hours, and centrifugation removes unconverted MTT in 5 minutes, per hole
150 μ L dimethyl sulfoxide (DMSO)s of middle addition.With the MTT crystal formazan (formazan) of dissolving and reducing, surveyed with ELIASA in 490nm wavelength
Determine OD values.Wherein compound 4f, 4l, 4o or 4p is to PC-3 cell 503nhibiting concentrations IC50Analyzed by spss softwares (19 version)
Arrive.ICs of the compound 4f to PC-3 tumour cells50For 72.1 μm of ol/L；ICs of the compound 4l to PC-3 tumour cells50For 80.8
μmol/L；ICs of the compound 4o to PC-3 tumour cells50For 25.7 μm of ol/L；ICs of the compound 4p to PC-3 tumour cells50For
81.8μmol/L；And positive control cis-platinum is to the IC of PC-3 tumour cells50For 23.7 μm of ol/L.
Experiment conclusion：PC-3 cells are that test compound refers to the effective tool of the cytotoxicity of tumour cell and evaluation
Mark.This experiment shows spiral shell [cyclopropane -1,3'- indolines] -2'- ketone compounds containing difluoromethyl shown in such formula (1)
There is certain cytotoxicity to PC-3 cells, it is possible to develop into the new medicine with antitumor action.
Pharmacological Examples 2：The cytotoxicity of compound 4n, 4o, 4q or 4r to A549 cells
A549 (human lung carcinoma cell) is used in DMEM medium cultures, culture medium containing 10% hyclone, 100U/mL green grass or young crops
Mycin and 100U/mL streptomysins.Cell is added in 96 holes with the concentration of every 4000 cells in hole, contains 5%CO at 37 DEG C2It is moist
Cultivated 24 hours in the incubator of air.
The measure of cell survival rate improvement mtt assay.Specific method such as Pharmacological Examples 1.Compound 4n is to A549 tumours
The IC of cell50For 89.9 μm of ol/L；ICs of the compound 4o to A549 tumour cells50For 36.8 μm of ol/L；Compound 4q is to A549
The IC of tumour cell50For 87.9 μm of ol/L；ICs of the compound 4r to A549 tumour cells50For 62.4 μm of ol/L；And positive control
IC of the cis-platinum to A540 tumour cells50For 23.0 μm of ol/L.
Experiment conclusion：A549 cells are that test compound refers to the effective tool of the cytotoxicity of tumour cell and evaluation
Mark.This experiment shows spiral shell [cyclopropane -1,3'- indolines] -2'- ketone compounds containing difluoromethyl shown in such formula (1)
There is certain cytotoxicity to A549 cells, it is possible to develop into the new medicine with antitumor action.
We can see that such compound is all shown necessarily to this two plants of tumour cells from above Pharmacological Examples
Cytotoxicity.It can be seen that these compounds have the potentiality for being developed into antineoplastic, it is worth continuing deeper into research.
Claims (3)
1. a kind of spiral shell [cyclopropane -1,3'- indoline] -2'- ketone compounds containing difluoromethyl, it is characterised in that：The chemical combination
Thing has the structure as shown in formula (I)：
In formula, R1For alkyl, alkoxy or halogen, R2For alkyl, R3For alkyl, aryl or acyl group.
2. a kind of antineoplastic pharmaceutical compositions, the spiral shell [ring third as claimed in claim 1 containing difluoromethyl containing effective dose
Alkane -1,3'- indolines] -2'- ketone compounds and pharmaceutically acceptable carrier.
3. it is prepared by spiral shell [cyclopropane -1,3'- the indolines] -2'- ketone compounds as claimed in claim 1 containing difluoromethyl
Prevent and treat the application in tumor disease medicine.
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| CN107827774A (en) * | 2017-11-13 | 2018-03-23 | 遵义医学院 | Nitrosamine compound containing two fluoro ethyls and preparation method thereof |
| CN108299440A (en) * | 2018-02-07 | 2018-07-20 | 遵义医学院 | Containing " difluoromethyl " pyrazoles [1,5-c] quinazoline derivant and preparation method thereof |
| CN116514897A (en) * | 2023-05-09 | 2023-08-01 | 暨南大学 | Cyclopropane or cyclopropene compound and application thereof |
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| CN107827774A (en) * | 2017-11-13 | 2018-03-23 | 遵义医学院 | Nitrosamine compound containing two fluoro ethyls and preparation method thereof |
| CN108299440A (en) * | 2018-02-07 | 2018-07-20 | 遵义医学院 | Containing " difluoromethyl " pyrazoles [1,5-c] quinazoline derivant and preparation method thereof |
| CN116514897A (en) * | 2023-05-09 | 2023-08-01 | 暨南大学 | Cyclopropane or cyclopropene compound and application thereof |
| CN116514897B (en) * | 2023-05-09 | 2024-03-29 | 暨南大学 | Cyclopropane or cyclopropene compound and application thereof |
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