CN115572210B - (1,2,2,2-tetrafluoroethyl) arene derivative and preparation method and application thereof - Google Patents

(1,2,2,2-tetrafluoroethyl) arene derivative and preparation method and application thereof Download PDF

Info

Publication number
CN115572210B
CN115572210B CN202211568730.2A CN202211568730A CN115572210B CN 115572210 B CN115572210 B CN 115572210B CN 202211568730 A CN202211568730 A CN 202211568730A CN 115572210 B CN115572210 B CN 115572210B
Authority
CN
China
Prior art keywords
tetrafluoroethyl
reaction
formula
added
difluorovinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202211568730.2A
Other languages
Chinese (zh)
Other versions
CN115572210A (en
Inventor
冯鹏举
孙承博
刘春燕
文林子
廖小建
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jinan University
Original Assignee
Jinan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jinan University filed Critical Jinan University
Priority to CN202211568730.2A priority Critical patent/CN115572210B/en
Publication of CN115572210A publication Critical patent/CN115572210A/en
Application granted granted Critical
Publication of CN115572210B publication Critical patent/CN115572210B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C22/00—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom
    • C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
    • C07C22/04—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings
    • C07C22/08—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings containing fluorine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/18—Polycyclic aromatic halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/257—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings
    • C07C43/29—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/01—Products
    • C25B3/05—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/01—Products
    • C25B3/07—Oxygen containing compounds
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/01—Products
    • C25B3/11—Halogen containing compounds
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/20—Processes
    • C25B3/27—Halogenation
    • C25B3/28—Fluorination

Abstract

The invention relates to the technical field of drug synthesis, and particularly discloses a (1,2,2,2-tetrafluoroethyl) arene derivative and a preparation method and application thereof. The (1,2,2,2-tetrafluoroethyl) arene derivative is characterized by having a structure shown in a formula I, a formula II or a formula III. Research shows that the (1,2,2,2-tetrafluoroethyl) arene derivative with the structure shown in the formula I, the formula II or the formula III has the effect of resisting lung cancer and bronchial cancer. Therefore, the derivative has important application prospect when being used as an active ingredient for developing medicaments with the effects of resisting lung cancer and bronchial cancer.

Description

(1,2,2,2-tetrafluoroethyl) arene derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a (1,2,2,2-tetrafluoroethyl) arene derivative and a preparation method and application thereof.
Background
According to statistics, 30-40% of pesticides and about 20% of medicine molecules sold in the market contain at least one fluorine atom, but naturally-existing fluorine-containing molecules have simple structures and limited quantity; therefore, the development of reactions for constructing fluorine-containing and polyfluoro molecules is receiving attention from chemists. However, how to develop a high-atom economy and quick and universal C-F bond construction method by using a cheap and easily available fluorine source in a green and sustainable manner is still one of the challenging scientific problems in the field of synthetic chemistry.
Under the continuous efforts of domestic and foreign chemists, many novel methods for generating C-F bonds have been developed along with the development of various fluorination reagents. Common fluorinating agents include: fluorine gas (F) 2 ) Diethylaminosulfur trifluoride (DAST), various hydrogen fluorides, selectfluor TM Various electron-deficient N-F reagents (NSFI, SFNA, etc.), and the like. However, these fluorinating agents still have certain limitations, such as being expensive, corrosive, toxic, air or moisture sensitive, and the like. The reaction mostly needs to use noble metal catalyst, equivalent oxidant, harsh conditions and the like. Therefore, how to synthesize fluorine-containing and polyfluoro molecules under mild conditions has very important significance, and the development of a diversified fluorine-containing molecule synthesis method based on the good performance of the fluorine-containing molecules in the field of medicines is helpful for the discovery of new medicines.
Disclosure of Invention
In order to overcome at least one of the technical problems in the prior art, the invention provides a (1,2,2,2-tetrafluoroethyl) arene derivative. Research shows that the (1,2,2,2-tetrafluoroethyl) arene derivative has an anticancer effect.
The technical problem to be solved by the invention is realized by the following technical scheme:
a (1,2,2,2-tetrafluoroethyl) arene derivative having a structure according to formula I, formula II or formula III:
Figure DEST_PATH_IMAGE001
formula I;
Figure 480740DEST_PATH_IMAGE002
a formula II;
Figure DEST_PATH_IMAGE003
a formula III;
in the formula I, R is selected from any one of the following groups: phenyl, substituted phenyl, phenoxy, benzoate and heterocyclic radical.
The inventor of the invention finds that the (1,2,2,2-tetrafluoroethyl) arene derivative with the structure shown in the formula I, the formula II or the formula III has the effect of resisting lung cancer and bronchial cancer. Therefore, the compound has important application prospect when being used as an active ingredient for developing medicaments with the effects of resisting lung cancer and bronchial cancer.
The inventors found in their studies that the difference in the above-mentioned (1,2,2,2-tetrafluoroethyl) arene derivatives of different structures in their anti-lung cancer and anti-bronchial cancer effects is great. The (1,2,2,2-tetrafluoroethyl) arene derivative with the structure shown in the formula III has a significantly higher effect on lung cancer and bronchial cancer than the (1,2,2,2-tetrafluoroethyl) arene derivative with the structure shown in the formula II, and most of the (1,2,2,2-tetrafluoroethyl) arene derivatives with the structure shown in the formula I.
Further preferably, in formula I, R is located at any position in the meta-pair of the phenyl group.
Further preferably, the substituted phenyl is phenyl substituted by halogen element.
Most preferably, the halogen is fluorine.
Further preferably, the halogen element-containing substituted phenyl group is selected from any one of the following groups: (2,2-difluorovinyl) phenyl, 1,3-difluorophenyl, (trifluoromethyl) phenyl, (trifluoromethoxy) phenyl, 1,2,2,2-tetrafluoroethylphenyl.
Further preferably, said heterocyclyl is thienyl.
Further preferably, the (1,2,2,2-tetrafluoroethyl) arene derivative is selected from any one of the following structures:
Figure 929039DEST_PATH_IMAGE004
、
Figure DEST_PATH_IMAGE005
、
Figure 833410DEST_PATH_IMAGE006
、
Figure DEST_PATH_IMAGE007
、
Figure 684078DEST_PATH_IMAGE008
、
Figure DEST_PATH_IMAGE009
、
Figure 29609DEST_PATH_IMAGE010
、
Figure DEST_PATH_IMAGE011
、
Figure 773443DEST_PATH_IMAGE012
、
Figure DEST_PATH_IMAGE013
、
Figure 961848DEST_PATH_IMAGE014
、
Figure DEST_PATH_IMAGE015
。
the inventor finds in research that in the (1,2,2,2-tetrafluoroethyl) arene derivative with the structure shown in the formula I, R groups are selected from different groups to obtain (1,2,2,2-tetrafluoroethyl) arene derivatives, and the effects of resisting lung cancer and bronchial cancer are different. Among them, most of the (1,2,2,2-tetrafluoroethyl) arene derivatives having the structure shown in formula I have significantly lower effect on lung cancer and bronchial cancer than the (1,2,2,2-tetrafluoroethyl) arene derivatives having the structure shown in formula III.
The inventor finds that in the (1,2,2,2-tetrafluoroethyl) arene derivative with the structure shown in I, when the R group is selected from 1,2,2,2-tetrafluoroethylphenyl, the formed (1,2,2,2-tetrafluoroethyl) arene derivative (4,4 '-bis (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl, see example 12) has far higher effect on resisting lung cancer and bronchial cancer than the effect of the R group selected from (1,2,2,2-tetrafluoroethyl) arene derivative obtained by other groups; (1,2,2,2-tetrafluoroethyl) arene derivatives which are also much higher than the structure shown in formula III; has excellent effect of resisting lung cancer and bronchial cancer.
The invention also provides a preparation method of the (1,2,2,2-tetrafluoroethyl) arene derivative, which comprises the following steps:
step (1): dissolving aryl metadifluoroolefin compounds in a solvent, and then adding triethylamine hydrogen fluoride and hexafluoroisopropanol to obtain a reaction mixture;
step (2): and (3) carrying out electrolytic reaction on the reaction mixture under the condition of stirring, and separating and washing a product after the electrolytic reaction is finished to obtain the (1,2,2,2-tetrafluoroethyl) arene derivative.
Preferably, the solvent in the step (1) is trifluorotoluene.
Preferably, the anode used in the electrolysis reaction in step (2) is a carbon plate (2.0 cm × 1.0 cm × 2.0 mm), and the cathode is a platinum plate electrode (1.5 cm × 1.5 cm × 0.1 mm).
Preferably, the constant voltage reaction voltage in the electrolysis reaction in the step (2) is 3.50V.
Preferably, the time of the reaction in the step (2) electrolysis reaction is 4h.
The invention also provides application of the (1,2,2,2-tetrafluoroethyl) arene derivative in preparation of a medicine with an anticancer effect.
Preferably, the cancer is lung cancer and/or bronchial cancer.
Preferably, the lung cancer is non-small cell lung cancer.
Preferably, the bronchial carcinoma is a bronchial epithelial cell carcinoma.
Has the advantages that: the inventor finds that the (1,2,2,2-tetrafluoroethyl) arene derivative with the structure shown in the formula I, the formula II or the formula III has the effect of resisting lung cancer and bronchial cancer. Therefore, the compound has important application prospect when being used as an active ingredient for developing medicaments with the effects of resisting lung cancer and bronchial cancer.
Among them, the (1,2,2,2-tetrafluoroethyl) arene derivative having the structure shown in the formula III has a significantly higher effect on lung cancer and bronchial cancer than the (1,2,2,2-tetrafluoroethyl) arene derivative having the structure shown in the formula II, and the (1,2,2,2-tetrafluoroethyl) arene derivative having the structure shown in most of the (1,2,2,2-tetrafluoroethyl) arene derivative having the structure shown in the formula I. Further, the inventors found that, in the (1,2,2,2-tetrafluoroethyl) arene derivative of the structure shown in I, when the R group is selected from 1,2,2,2-tetrafluoroethylphenyl, the formed (1,2,2,2-tetrafluoroethyl) arene derivative (i.e., 4,4 '-bis (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl prepared in example 12) has a far higher effect on lung cancer and bronchial cancer than the R group selected from (1,2,2,2-tetrafluoroethyl) arene derivatives obtained from other groups; also much higher than (1,2,2,2-tetrafluoroethyl) arene derivative with the structure shown in the formula III; has excellent effect of resisting lung cancer and bronchial cancer.
In addition, the invention adopts an electrochemical method with mild conditions, does not need to use expensive metal catalysts, does not need to use special fluorination reagents, does not need inert gas environment, realizes the oxidation of the substrate by current only in the reaction, takes hydrofluoride as a fluorine source, can realize the preparation of a plurality of fluorine-containing new compounds under the air condition, has simple whole process, uses cheap reagents in the whole and has great industrial potential. In the method, the difluoro derivative can be subjected to a difluorination reaction under mild reaction conditions; the reaction has higher functional group tolerance; the reaction can be started and stopped by controlling the switch of the external power supply, the operation is flexible, and the control is convenient. Particularly, the method can be used for directly preparing polyfluoro molecules, the fluorine-containing compounds with brand-new structures are not reported at present, and the method has wide exploration space based on the performance of the fluorine-containing molecules in the fields of medicines and materials.
Detailed Description
The present invention is further explained below with reference to specific examples, which are not intended to limit the present invention in any way.
Example 1 Synthesis of 4- (1,2,2,2-tetrafluoroethyl) -1,1' -Biphenyl preparation method
In the first step, 4- (2,2-difluorovinyl) -1,1 '-biphenyl (0.5 mmol, 108 mg, 1.0 equiv) was added to a dry 40 mL reaction tube, 4.0 mL dried trifluorotoluene was added and stirred until 4- (2,2-difluoroethyl) -1,1' -biphenyl was fully dissolved, and then triethylamine hydrogen fluoride (0.5 mmol, 80 mg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL were added to the reaction tube. The entire mixture was stirred in air at room temperature with carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as the anode and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as the cathode, and the reaction mixture was stirred and electrolyzed at room temperature at a cell potential of 3.5V. The progress of the reaction was checked by TLC, and the reaction was stopped when it was detected that all of 4- (2,2-difluorovinyl) -1,1' -biphenyl had reacted. The experimental treatment is to pump the solution in the reaction; the solute in the reaction tube was dissolved in petroleum ether and transferred to a 100 mL round bottom flask, 2 mL (200-300 mesh) silica gel was added to the round bottom flask and dried by spinning, and the silica gel column was passed through with petroleum ether. The product, 4- (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl, was obtained as a white solid. White solid (0.071 g, 0.30 mmol, 60% yield); r f = 0.66 (petroleum ether); see structural formula 1b:
Figure 683117DEST_PATH_IMAGE004
structural formula 1b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl3, 25 ºC, ): 8.21 (d, J =7.23 Hz, 2H), 7.66 (t, J = 7.59 Hz, 1H), 7.52 (t, J = 8.01 Hz, 3H), 7.37 (s,3H), 5.74-5.54 (m, 1H). 13C NMR (75 MHz, CDCl3, 25 ºC, ): 165.0, 151.3,134.0, 132.0(d, J =21.09 Hz, 1C), 130.2(d, J =24.37 Hz, 1C), 129.1(d, J=38.29 Hz, 1C),124.7(d, J=6.86 Hz, 1C), 124.1(d, J =1.10 Hz, 1C),120.8(d, J =7.20 Hz, 1C), 89.8 (dd, J =36.78, 71.68 Hz, 0.5C), 87.3(dd, J =37.19, 72.10 Hz, 0.5C). 19F NMR (282MHz, CDCl3, 25 ºC, ): -78.7(d, J=7.22 Hz, 3F), -195.3 mass spectrometry LRMS (ESI-TOF) (M/z) calcd for C14H11F4+ ([ M + H)]+), 255.1, found, 255.1.
The compound synthesized by the structural identification is determined to be the target compound 4- (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl.
Example 2 method for the preparation of Synthesis of 4- (2,2-difluorovinyl) -4'- (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl
First step 4,4 '-bis (2,2-difluorovinyl) -1,1' -biphenyl (0.5 mmol, 139 mg, 1.0 equiv) was added to a dry 40 mL reaction tube, 4.0 mL dried trifluorotoluene was added and stirred until 4,4 '-bis (2,2-difluorovinyl) -1,1' -biphenyl was completely dissolved, and then triethylamine hydrogen fluoride (0.5 mmol, 80 mg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL were added to the reaction tube. The entire mixture was stirred in air at room temperature with carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as the anode and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as the cathode, and the reaction mixture was stirred and electrolyzed at room temperature at a cell potential of 3.5V. The progress of the reaction was checked by TLC, and the reaction was stopped when 4,4 '-bis (2,2-difluorovinyl) -1,1' -biphenyl was completely reacted. The experimental treatment is to pump the solution in the reaction; the solute in the reaction tube was dissolved in petroleum ether and transferred to a 100 mL round bottom flask, 2 mL (200-300 mesh) silica gel was added to the round bottom flask and dried by spinning, and the silica gel column was passed through with petroleum ether. The product was obtained as a white solid, 4- (2,2-difluorovinyl) -4'- (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl. White solid (0.074 g, 0.33 mmol, 65% yield); r f = 0.64 (petroleum ether); see structural formula 2b:
Figure 211051DEST_PATH_IMAGE005
structural formula 2b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl3, 25 ºC, ):7.67 (d, J =8.1 Hz, 2H), 7.60 (s, 1H), 7.56 (d, J = 6.0 Hz, 2H), 7.52 (s, 1H), 7.43 (d, J = 8.31 Hz, 2H), 5.74-5.68 (m, 0.5H),5.60-5.54 (m, 0.5H), 5.37(d, J = 3.69 Hz, 0.5H),5.29(d, J = 3.66 Hz, 0.5H). 13 C NMR (75 MHz, CDCl 3 , 25 ºC, ): 142.8, 138.7, 130.2(d, J =6.85 Hz, 1C), 129.5, 129.2, 128.3 - 128.2 (m, 1C), 127.9 (d, J = 6.41 Hz,1C), 127.6, 127.4, 89.7 (dd, J =34.26, 68.25 Hz, 0.5C), 87.7 (dd, J =28.04, 62.66 Hz, 0.5C), 82.0(dd, J = 13.56, 29.15 Hz, 1C). 19 F NMR (282MHz, CDCl 3 25 ℃ C.) -57.7 mass spectrometry LRMS (ESI-TOF) (m/z) calcd for C 16 H 11 F 6 + ([M + H] + ),317.1, found, 317.1.
The compound synthesized by the structural identification is determined to be a target compound 4- (2,2-difluorovinyl) -4'- (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl.
Example 3 Synthesis of 3,5-difluoro-4 '- (1,2,2,2-tetrafluoroethyl) -1,1' -Biphenyl preparation method
In a first step, 4'- (2,2-difluorovinyl) -3,5-difluoro-1,1' -biphenyl (0.5 mmol, 139 mg, 1.0 equiv) was added to a dry 40 mL reaction tube, 4.0 mL dried trifluorotoluene was added and stirred until 4'- (2,2-difluorovinyl) -3,5-difluoro-1,1' -biphenyl was completely dissolved, and then triethylamine hydrogen fluoride (0.5 mmol, 80 mg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL were added to the reaction tube. The entire mixture was stirred in air at room temperature with carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as the anode and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as the cathode, and the reaction mixture was stirred and electrolyzed at room temperature at a cell potential of 3.5V. The progress of the reaction was checked by TLC, and the reaction was stopped when all 4'- (2,2-difluorovinyl) -3,5-difluoro-1,1' -biphenyl was detected to be reacted completely. The experimental treatment is to pump the solution in the reaction; the solute in the reaction tube was dissolved in petroleum ether and transferred to a 100 mL round bottom flaskThe flask was charged with 2 mL (200-300 mesh) silica gel, spin dried, and passed through a silica gel column with petroleum ether. The product was obtained as a colorless oil 3,5-difluoro-4 '- (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl. A colorless oil (0.058 g, 0.25 mmol, 50% yield); r f = 0.68 (petroleum ether); see structural formula 3b:
Figure 1152DEST_PATH_IMAGE006
structural formula 3b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl3, 25 ºC, ):7.61-7.53 (m, 4H),7.46-7.38 (m,1H), 7.02-6.90 (m,2H), 5.75-5.69 (m, 0.5H), 5.60-5.54 (m, 0.5H). 13 C NMR (75 MHz, CDCl 3 , 25 ºC, ): 163.1(dd, J = 11.85，214.71 Hz, 1C), 159.7(dd, J = 11.67，215.64 Hz, 1C), 137.4, 131.7-131.5 (m, 1C), 129.8 (d, J = 19.74 Hz, 1C), 129.4 (d, J = 2.89 Hz, 1C), 127.6(d, J = 6.48 Hz, 1C), 124.5 - 124.3 (m, 1C), 120.5 (dd, J = 250.91, 279.93 Hz, 1C), 112.0 (dd, J = 21.06, 3.83 Hz, 1C),104.7(t, J = 26.26 Hz, 1C),90.1(dd, J = 34.52, 69.39 Hz, 0.5C),87.7 (dd, J = 34.90, 69.54 Hz, 0.5C) 19 F NMR (282MHz, CDCl 3 , 25 ºC, ): -78.6(d, J = 12.69 Hz,3F), -110.3 (d, J = 7.95 Hz,1F), -113.4 (d, J= 7.47 Hz, 1F), -194.6-194.8 (m, 1F.) Mass Spectrometry GCMS (ESI-TOF) (m/z): calcd for C 14 H 8 F 6 ,290.0, found, 290.0.
The compound synthesized by the structural identification is the target compound 3,5-difluoro-4 '- (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl.
Example 4 preparation of a Synthesis of 3- (4- (1,2,2,2-tetrafluoroethyl) phenyl) thiophene
In the first step, 3- (4- (2,2-difluorovinyl) phenyl) thiophene (0.5 mmol, 139 mg, 1.0 equiv) was added to a dry 40 mL reaction tube, 4.0 mL dried trifluorotoluene was added and stirred until 3- (4- (2,2-difluorovinyl) phenyl) thiophene was completely dissolved, and triethylamine hydrogen fluoride (0.5 mmol, 80) was added to the reaction tubemg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL. The entire mixture was stirred in air at room temperature with carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as the anode and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as the cathode, and the reaction mixture was stirred and electrolyzed at room temperature at a cell potential of 3.5V. The progress of the reaction was checked by TLC, and the reaction was stopped when all the 3- (4- (2,2-difluorovinyl) phenyl) thiophene had reacted. The experimental treatment is to pump the solution in the reaction; the solute in the reaction tube was dissolved in petroleum ether and transferred to a 100 mL round bottom flask, 2 mL (200-300 mesh) silica gel was added to the round bottom flask and dried by spinning, and the silica gel column was passed through petroleum ether. The product was obtained as a colorless oil, 3- (4- (1,2,2,2-tetrafluoroethyl) phenyl) thiophene. A colorless oil (0.041 g, 0.18 mmol, 35% yield); r f = 0.65 (petroleum ether); see structural formula 4b:
Figure 83378DEST_PATH_IMAGE007
structural formula 4b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl3, 25 ºC, ): 7.67 (d, J = 8.16Hz, 2H), 7.49 (d, J = 8.73Hz, 3H), 7.43 - 7.37 (m, 2H), 5.71 - 5.51 (m, 1H). 13 C NMR (75 MHz, CDCl 3 , 25 ºC, ): 141.4, 138.1, 127.9(d, J = 6.50 Hz, 1C), 126.8 (d, J = 2.85 Hz, 1C), 126.3, 121.5, 114.8(t, J = 277.41 Hz, 1C), 90.2 (dd, J = 30.82, 70.34 Hz, 0.5C), 87.7 (dd, J = 29.96, 65.30 Hz, 0.5C). 19 F NMR (282MHz, CDCl 3 , 25 ºC, ): -78.7 (d, J = 12.89Hz,1F) ,- 194.1 (dd, Jmass spectrometry HRMS (ESI-TOF) (m/z) calcd for C = 12.49, 26.03 Hz, 1F) 17 H 12 N 3 O 2 - ([M - H] - ), 290.0935, found, 290.0942.
The compound synthesized by the structural identification is determined to be the target compound 3- (4- (1,2,2,2-tetrafluoroethyl) phenyl) thiophene.
Example 5 Synthesis of 4-phenyl-2- (1,2,2,2-tetrafluoroethyl) thiophene preparation method
In the first step, 2- (2,2-difluorovinyl) -4-phenylthiophene (0.5 mmol, 139 mg, 1.0 equiv) was added to a dry 40 mL reaction tube, 4.0 mL dried trifluorotoluene was added and stirred until 2- (2,2-difluorovinyl) -4-phenylthiophene was completely dissolved, and triethylamine hydrogen fluoride (0.5 mmol, 80 mg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL were added to the reaction tube. The entire mixture was stirred in air at room temperature with carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as the anode and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as the cathode, and the reaction mixture was stirred and electrolyzed at room temperature at a cell potential of 3.5V. The progress of the reaction was checked by TLC, and the reaction was stopped when all 2- (2,2-difluorovinyl) -4-phenylthiophene had reacted. The experimental treatment is to pump the solution in the reaction; the solute in the reaction tube was dissolved in petroleum ether and transferred to a 100 mL round bottom flask, 2 mL (200-300 mesh) silica gel was added to the round bottom flask and dried by spinning, and the silica gel column was passed through petroleum ether. The product was obtained as a colorless oil, 4-phenyl-2- (1,2,2,2-tetrafluoroethyl) thiophene. A colorless oil (0.036 g, 0.15 mmol, 30% yield); r is f = 0.66 (petroleum ether); see structural formula 5b:
Figure 85969DEST_PATH_IMAGE016
structural formula 5b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl3, 25 ºC, ): 7.58 (d, J = 7.1 Hz, 4H), 7.43 (t, J = 7.1 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 5.95-5.89 (m, 0.5H), 5.80-5.75 (m, 0.5H). 13 C NMR (75 MHz, CDCl 3 , 25 ºC, ): 142.7, 135.0, 131.8 (d, J = 21.71 Hz, 1C), 129.3 (d, J = 5.27 Hz, 1C), 129.1, 127.9, 126.5, 123.6 (d, J = 2.87 Hz, 1C), 120.1 (dd, J = 280.46,3 10.44 Hz, 1C), 86.6 (dd, J = 72.80,36.38 Hz, 0.5C), 84.09 (dd, J = 72.89,36.44 Hz, 0.5C). 19 FNMR (282MHz, CDCl 3 , 25 ºC, ): -78.4 (d, J= 14.24 Hz, 3F), -178.3-178.4 (m, 1F.) Mass Spectrometry GCMS (ESI-TOF) (m/z) calcd for C 12 H 8 F 4 S, 260.0, found, 260.0.
The compound synthesized by the structural identification is determined to be the target compound 4-phenyl-2- (1,2,2,2-tetrafluoroethyl) thiophene.
Example 6 Process for preparation of Synthesis of 4- (1,2,2,2-tetrafluoroethyl) -4'- (trifluoromethyl) -1,1' -Biphenyl
First step 4- (2,2-difluorovinyl) -4'- (trifluoromethyl) -1,1' -biphenyl (0.5 mmol, 139 mg, 1.0 equiv) was added to a dry 40 mL reaction tube, 4.0 mL dried trifluorotoluene was added and stirred until 4- (2,2-difluorovinyl) -4'- (trifluoromethyl) -1,1' -biphenyl was fully dissolved, then triethylamine hydrogen fluoride (0.5 mmol, 80 mg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL were added to the reaction tube. The entire mixture was stirred in air at room temperature with carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as the anode and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as the cathode, and the reaction mixture was stirred and electrolyzed at room temperature at a cell potential of 3.5V. The progress of the reaction was checked by TLC, and the reaction was stopped when it was detected that all of 4- (2,2-difluorovinyl) -4'- (trifluoromethyl) -1,1' -biphenyl had reacted. The experimental treatment is to pump the solution in the reaction; the solute in the reaction tube was dissolved in petroleum ether and transferred to a 100 mL round bottom flask, 2 mL (200-300 mesh) silica gel was added to the round bottom flask and dried by spinning, and the silica gel column was passed through with petroleum ether. The product was obtained as a colorless oil, 4- (1,2,2,2-tetrafluoroethyl) -4'- (trifluoromethyl) -1,1' -biphenyl. A colorless oil (0.058 g, 0.29 mmol, 58% yield); r is f = 0.68 (petroleum ether); see structural formula 6b:
Figure 671671DEST_PATH_IMAGE009
structural formula 6b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl3, 25 ºC, ): 7.75-7.70 (m, 5H), 7.67(m, 1H),7.58 (d, J = 8.19 Hz, 2H), 5.77 - 5.56 (m, 1H). 13 C NMR (75 MHz, CDCl 3 , 25 ºC, ): 143.8, 142.1, 130.4, 130.1(d, J = 12.94 Hz, 1C), 128.0 (d, J = 6.42 Hz, 2C), 127.8 (d, J = 6.02 Hz, 2C), 126.1 - 126.0 (m, 1C), 122.5 (t, J = 143.01 Hz, 1C), 90.1 (dd, J = 38.21,73.03 Hz, 0.5C), 85.6 (dd, J = 35.64, 70.51 Hz, 0.5 C). 19 F NMR (282MHz, CDCl 3 , 25 ºC, ): -62.5(s, 3F), -78.7(d, J= 13.20Hz, 3F), -194.7-194.8 (m, 1F) mass spectrometry LRMS (ESI-TOF) (m/z) calcd for C 15 H 10 F 7 + ([M + H] + ), 323.0, found, 323.0.
The compound synthesized by the structural identification is determined to be the target compound 4- (1,2,2,2-tetrafluoroethyl) -4'- (trifluoromethyl) -1,1' -biphenyl.
Example 7 preparation of a Synthesis of 4- (2,2-difluorovinyl) -4'- (trifluoromethoxy) -1,1' -biphenyl
First step 4- (2,2-difluorovinyl) -4'- (trifluoromethoxy) -1,1' -biphenyl (0.5 mmol, 139 mg, 1.0 equiv) was added to a dry 40 mL reaction tube, 4.0 mL dried trifluorotoluene was added and stirred until 4- (2,2-difluorovinyl) -4'- (trifluoromethoxy) -1,1' -biphenyl was fully dissolved, then triethylamine hydrogen fluoride (0.5 mmol, 80 mg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL were added to the reaction tube. The entire mixture was stirred in air at room temperature with carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as the anode and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as the cathode, and the reaction mixture was stirred and electrolyzed at room temperature at a cell potential of 3.5V. The progress of the reaction was checked by TLC, and the reaction was stopped when it was detected that all of 4- (2,2-difluorovinyl) -4'- (trifluoromethoxy) -1,1' -biphenyl had reacted. The experimental treatment is to pump the solution in the reaction; the solute in the reaction tube was dissolved in petroleum ether and transferred to a 100 mL round bottom flask, 2 mL (200-300 mesh) silica gel was added to the round bottom flask and dried by spinning, and the silica gel column was passed through petroleum ether. The product was obtained as a colorless oil 4- (2,2-difluorovinyl) -4'- (trifluoromethoxy) -1,1' -biphenyl. A colorless oil (0.056 g, 0.25 mmol, 50% yield); r f = 0.67 (petroleum ether); see structural formula 7b:
Figure 960570DEST_PATH_IMAGE010
structural formula 7b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl3, 25 ºC, ): 7.61 (t, J = 7.92 Hz, 4H), 7.54 (d, J = 8.22 Hz, 2H), 7.31 (d, J = 8.25 Hz, 2H), 5.78-5.54 (m, 1H). 13 C NMR (75 MHz, CDCl 3 , 25 ºC, ):149.3,142.2, 138.9, 129.7 (d, J = 19.38 Hz, 1C),128.8,128.3 (d, J = 6.68 Hz, 1C), 127.9 (d, J = 6.56 Hz, 1C), 127.5 (d, J = 14.46 Hz, 1C), 121.5, 122.4 (t, J = 257.09 Hz, 1C), 90.1 (dd, J = 34.97, 69.74 Hz, 0.5C),87.7 (dd, J = 34.88,69.62 Hz, 0.5C). 19 F NMR (282MHz, CDCl 3 , 25 ºC, ): -78.6 (d, J= 12.94Hz, 3F), -195.2-195.3 (m, 1F.) Mass Spectrometry LRMS (ESI-TOF) (m/z): calcd for C 15 H 10 F 7 O + ([M + H] + ),339.0, found, 339.0.
The compound synthesized by the structural identification is determined to be the target compound 4- (2,2-difluorovinyl) -4'- (trifluoromethoxy) -1,1' -biphenyl.
Example 8 Synthesis of 1-phenoxy-4- (1,2,2,2-tetrafluoroethyl) benzene preparation method
In the first step, 1- (2,2-difluorovinyl) -4-phenoxybenzene (0.5 mmol, 139 mg, 1.0 equiv) is added to a dry 40 mL reaction tube, 4.0 mL dried trifluorotoluene is added and stirred until 1- (2,2-difluorovinyl) -4-phenoxybenzene is completely dissolved, and then triethylamine hydrogen fluoride (0.5 mmol, 80 mg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL are added to the reaction tube. The reaction mixture was stirred and electrolyzed at room temperature at cell potential of 3.5V using carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as anodes and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as cathodes with all mixtures stirred in air at room temperature. The progress of the reaction was checked by TLC, and the reaction was stopped when all the 1- (2,2-difluorovinyl) -4-phenoxybenzene had reacted. The experimental treatment is to pump the solution in the reaction; dissolving the solute in the reaction tube with petroleum ether, transferring into 100 mL round-bottom flask, adding 2 mL (200-300 mesh) silica gel into round-bottom flask, spin drying, and adding petroleum etherPassing through a silica gel column. The product was obtained as a colorless oil, 1-phenoxy-4- (1,2,2,2-tetrafluoroethyl) benzene. A colorless oil (0.083 g, 0.36 mmol, 71% yield); r f = 0.67 (petroleum ether); see structural formula 8b:
Figure 998933DEST_PATH_IMAGE011
structural formula 8b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl3, 25 ºC, ): 7.45-7.37 (m, 4H), 7.19 (t, J = 7.35 Hz, 1H), 7.09-7.05 (m, 4H), 5.67-5.47 (m, 1H). 13 C NMR (75 MHz, CDCl 3 , 25 ºC, ):159.7 (d, J = 1.81 Hz, 2C),156.2,130.1,129.1 (d, J = 6.19 Hz, 1C) ,124.3,119.9,118.4, 117.8 (d, J = 287.92 Hz, 1C),90.00 (dd, J = 34.81,69.63 Hz, 0.5C),87.5 (dd, J = 34.94,69.77 Hz, 0.5C). 19 F NMR (282MHz, CDCl 3 , 25 ºC, ): -78.8 (d, J= 13.28 Hz, 3F), -191.8-192.0 (m, 1F.) Mass Spectrometry GCMS (ESI-TOF) (m/z): calcd for C 14 H 10 F 4 O,270.07, found, 270.11.
The compound synthesized by the structure identification is determined to be the target compound 1-phenoxy-4- (1,2,2,2-tetrafluoroethyl) benzene.
Example 9 Synthesis of 3- (1,2,2,2-tetrafluoroethyl) benzo [ b ] thiophene preparation method
In the first step, 3- (2,2-difluorovinyl) benzo [ b ] is added to a dry 40 mL reaction tube]Thiophene (0.5 mmol, 139 mg, 1.0 equiv), dried trifluorotoluene added 4.0 mL and stirred to 3- (2,2-difluorovinyl) benzo [ b]Thiophene was completely dissolved, and triethylamine hydrogen fluoride (0.5 mmol, 80 mg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL were then added to the reaction tube. The entire mixture was stirred in air at room temperature with carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as the anode and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as the cathode, and the reaction mixture was stirred and electrolyzed at room temperature at a cell potential of 3.5V. The progress of the reaction was checked by TLC and if 3- (2,2-difluorovinyl) benzo [ b ] was detected]Stopping the reaction after the thiophene is completely reacted. The experimental treatment is to pump the solution in the reaction; the solute in the reaction tube was dissolved in petroleum ether and transferred to a 100 mL round bottom flask, 2 mL (200-300 mesh) silica gel was added to the round bottom flask and dried by spinning, and the silica gel column was passed through petroleum ether. The product was obtained as a colorless oil, 3- (1,2,2,2-tetrafluoroethyl) benzo [ b]Thiophene. A colorless oil (0.054 g, 0.23 mmol, 45% yield); r f = 0.67 (petroleum ether); see structural formula 9b:
Figure DEST_PATH_IMAGE017
structural formula 9b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl3, 25 ºC, ): 7.92-7.84(m, 2H),7.74 (d, J = 1.68 Hz, 1H), 7.48-7.39 (m, 2H), 6.07 (dd, J = 6.03,12.09 Hz, 0.5H),5.92 (dd, J = 6.09,12.15 Hz, 0.5H). 13 C NMR (75 MHz, CDCl 3 , 25 ºC, ):140.4,136.8,128.8 (d, J = 8.10 Hz, 1C),125.4 (d, J = 13.20 Hz, 1C),125.1 (d, J = 9.74 Hz, 1C),123.1,122.2, 120.3 (t, J = 268.42 Hz, 1C), 111.2 (t, J = 202.87 Hz, 1C),86.5 (dd, J = 71.88,35.78 Hz, 0.5C),84.0(dd, J = 35.70,71.86 Hz, 0.5C). 19 F NMR (282MHz, CDCl 3 25 ℃ of-77.6 and-192.3 mass spectrometry LRMS (ESI-TOF) (m/z) of calcd for C 10 H 6 F 4 KS + ([M + K] + ),273.0, found, 273.0.
The compound synthesized by the structural identification is determined to be the target compound 3- (1,2,2,2-tetrafluoroethyl) benzo [ b ] thiophene.
Example 10 Synthesis of phenyl 4- (1,2,2,2-tetrafluoroethyl) benzoate preparation method
In the first step, 4- (2,2-difluorovinyl) benzoate (0.5 mmol, 139 mg, 1.0 equiv) was added to a dry 40 mL reaction tube, 4.0 mL dried trifluorotoluene was added and stirred until 4- (2,2-difluorovinyl) benzoate was fully dissolved, and then triethylamine hydrogen fluoride (0.5 mmol, 80 mg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL were added to the reaction tube. The whole mixture was at room temperatureThe reaction mixture was stirred and electrolyzed at room temperature at a cell potential of 3.5V using carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as the anode and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as the cathode with stirring in air. The progress of the reaction was checked by TLC, and the reaction was stopped when it was detected that all the phenyl 4- (2,2-difluorovinyl) benzoate had reacted. The experimental treatment is to pump the solution in the reaction; the solute in the reaction tube was dissolved in petroleum ether and transferred to a 100 mL round bottom flask, 2 mL (200-300 mesh) silica gel was added to the round bottom flask and dried by spinning, and the silica gel column was passed through with petroleum ether. The product was obtained as a colorless oil, phenyl 4- (1,2,2,2-tetrafluoroethyl) benzoate. A colorless oil (0.086 g, 0.38 mmol, 75% yield); r is f = 0.64 (petroleum ether); see structural formula 10b:
Figure 73724DEST_PATH_IMAGE013
structural formula 10b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl3, 25 ºC, ): 8.00 (d, J = 7.14 Hz, 2H),7.38 (t, J = 7.14 Hz, 1H),7.53 (t, J = 8.01 Hz, 4H),7.33 (d, J = 8.46 Hz, 2H),5.74 - 5.53 (m, 1H). 13 C NMR (75 MHz, CDCl 3 , 25 ºC, ):165.0, 152.7, 134.0, 130.4, 129.3, 128.8 (d, J = 4.45 Hz, 1C), 128.7, 127.9 (d, J = 20.41 Hz, 1C), 122.4, 120.6 (t, J = 279.90 Hz, 1C), 89.8(dd, J= 36.83, 71.63 Hz, 0.5C), 87.4 (dd, J = 34.83, 69.68 Hz, 0.5C). 19 F NMR (282MHz, CDCl 3 , 25 ºC, ): -78.6 (d, J= 13.00 Hz, 3F), -193.7-193.9 (m, 1F) mass spectrometry HRMS (ESI-TOF) (m/z) calcd for C 8 H 7 F 4 + ([M + H] + ), 299.0690, found, 299.0693.
The compound synthesized by the structure identification is confirmed to be the target compound 4- (1,2,2,2-tetrafluoroethyl) phenyl benzoate.
Example 11 Synthesis of phenyl 3- (1,2,2,2-tetrafluoroethyl) benzoate preparation method
First step of addingTo a dried 40 mL reaction tube was added 3- (2,2-difluorovinyl) benzoate (0.5 mmol, 139 mg, 1.0 equiv), 4.0 mL dried trifluorotoluene stirred until 3- (2,2-difluorovinyl) benzoate was fully dissolved, and then to the reaction tube was added triethylamine hydrogen fluoride (0.5 mmol, 80 mg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL. The reaction mixture was stirred and electrolyzed at room temperature at cell potential of 3.5V using carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as anodes and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as cathodes with all mixtures stirred in air at room temperature. The progress of the reaction was checked by TLC, and the reaction was stopped when it was detected that all the phenyl 3- (2,2-difluorovinyl) benzoate had reacted. The experimental treatment is to pump the solution in the reaction; the solute in the reaction tube was dissolved in petroleum ether and transferred to a 100 mL round bottom flask, 2 mL (200-300 mesh) silica gel was added to the round bottom flask and dried by spinning, and the silica gel column was passed through petroleum ether. The product, 3- (1,2,2,2-tetrafluoroethyl) phenyl benzoate, was obtained as a white solid. White solid (0.069 g, 0.38 mmol, 75% yield); r f = 0.30 (petroleum ether); see structural formula 11b:
Figure 107408DEST_PATH_IMAGE014
structural formula 11b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl3, 25 ºC, ): 8.22 (d, J = 7.23 Hz, 2H),7.66 (t, J = 7.44 Hz, 1H), 7.53 (t, J = 7.80 Hz, 3H), 7.38 (s, 3H), 5.75 -5.54 (m, 1H). 13 C NMR (75 MHz, CDCl 3 , 25 ºC, ):165.0, 151.3, 134.0, 132.0 (d, J = 19.95 Hz, 1C),130.2 (d, J = 24.17 Hz, 1C),129.1 (d, J = 36.56 Hz, 1C),124.7(d, J = 6.62 Hz, 1C), 124.1, 120.7 (d, J = 7.27 Hz, 1C), 119.3 (t, J = 252.13 Hz, 1C), 89.8 (dd, J = 34.81,69.72 Hz, 0.5C),87.2 (dd, J = 34.93,69.74 Hz, 0.5C). 19 F NMR (282MHz, CDCl 3 , 25 ºC, ): -78.6(d, J= 12.21 Hz, 3F), -195.2-195.3 (m, 1F) mass spectrometry HRMS (ESI-TOF) (m/z) calcd forC 15 H 9 F 7 Na + ([M + H] + ), 321.1, found, 321.1.
The synthesized compound is identified as the target compound 3- (1,2,2,2-tetrafluoroethyl) phenyl benzoate by structure identification.
Example 12 Process for Synthesis of 4,4 '-bis (1,2,2,2-tetrafluoroethyl) -1,1' -Biphenyl
First step 4,4 '-bis (2,2-difluorovinyl) -1,1' -biphenyl (0.5 mmol, 139 mg, 1.0 equiv) was added to a dry 40 mL reaction tube, 4.0 mL dried trifluorotoluene was added and stirred until 4,4 '-bis (2,2-difluorovinyl) -1,1' -biphenyl was completely dissolved, and then triethylamine hydrogen fluoride (0.5 mmol, 80 mg, 1.0 equiv) and hexafluoroisopropanol 1.0 mL were added to the reaction tube. The entire mixture was stirred in air at room temperature with carbon plates (2.0 cm × 1.0 cm × 2.0 mm) as the anode and platinum plate electrodes (1.5 cm × 1.5 cm × 0.1 mm) as the cathode, and the reaction mixture was stirred and electrolyzed at room temperature at a cell potential of 3.5V. The progress of the reaction was checked by TLC, and the reaction was stopped when 4,4 '-bis (2,2-difluorovinyl) -1,1' -biphenyl was detected to be completely reacted. The experimental treatment is to pump the solution in the reaction; the solute in the reaction tube was dissolved in petroleum ether and transferred to a 100 mL round bottom flask, 2 mL (200-300 mesh) silica gel was added to the round bottom flask and dried by spinning, and the silica gel column was passed through petroleum ether. The product was obtained as a white solid 4,4 '-bis (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl. White solid (0.087 g, 0.34 mmol, 68% yield); r is f = 0.68 (petroleum ether); see structural formula 12b:
Figure 504891DEST_PATH_IMAGE015
structural formula 12b;
the structure confirmation structure is as follows: nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl 3 , 25 ºC, ): 7.67 (d, J =8.10 Hz, 4H), 7.56 (d, J =8.19 Hz, 4H), 5.76-5.70 (m, 1H), 5.61-5.55 (m, 1H). 13 C NMR (75 MHz, CDCl 3 , 25 ºC, ): 142.4, 130.0 (d, J = 19.60 Hz, 2C), 128.0 (d, J = 6.54 Hz, 2C), 127.7, 124.2 (d, J = 29.05 Hz, 2C), 120.5 (d, J = 29.07 Hz, 2C), 90.1 (dd, J = 34.83, 40.25 Hz, 0.5C), 87.6 (dd, J = 34.67, 34.79 Hz, 0.5C). 19 F NMR (282MHz, CDCl 3 , 25 ºC, ): -78.7 (d, J= 12.86 Hz, 6F), -194.5-194.7 (m, 2F). Mass Spectrometry HRMS (ESI-TOF) (m/z): calcd for C 16 H 11 F 8 + ([M + H] + ), 355.0728, found, 355.0703.
The compound synthesized by the structural identification is the target compound 4,4 '-bis (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl.
Example 13, inhibition of tumor cell proliferation by Compounds of examples 1-12
Cells in logarithmic growth phase (including human non-small cell lung carcinoma cells PC9, EKVX, and human bronchial epithelial cell Beas-2B) (three cell lines were purchased from American Type Culture Collection, ATCC) were trypsinized, centrifuged, resuspended, and counted at 1X 10 6 Inoculating each/mL of the extract into a 96-well culture plate with each well being 100 μ L, diluting the drug to be tested into a certain concentration gradient after the cells adhere to the wall, setting 4 parallel multiple wells for each concentration, setting a blank control group, and placing the mixture in a constant temperature incubator (37 ℃,5% CO) 2 And culturing for 72h. The medium was aspirated off, 30. Mu.L of MTT solution (5 mg/mL) was added to each well, incubation was continued for 4h, the supernatant was removed, 100. Mu.L of DMSO was added to each well, the mixture was sufficiently shaken until the particles were dissolved, and the OD value of absorbance of each well was measured at a wavelength of 570nm using a microplate reader. The cell growth inhibition rate was calculated according to the following formula, and the experiment was repeated at least 3 times more. The cell growth inhibition rate calculation formula is as follows: inhibition (%) = (1-addition drug OD value)/control OD value x 100%. The concentration of the sample was plotted on the horizontal axis and the cell growth inhibition ratio on the vertical axis. Calculating half effective inhibition concentration IC according to cell growth inhibition curve 50 A value; the results of the tests are given in the following table.
The drugs tested were (1,2,2,2-tetrafluoroethyl) arene derivatives (abbreviated as compounds in the tables) prepared in examples 1 to 12.
TABLE 1 IC50 values (μ M) of compounds on individual cancer cells
PC 9 EKVX Beas-2b
Example 1 Compounds 30.5± 1.3 29.2± 1.6 32.5± 1.3
Example 2 Compounds 28.3± 2.1 38.8± 1.6 35.2± 1.8
Example 3 Compounds 25.6 ± 0.8 27.5 ± 1.1 29.2± 1.2
Example 4 Compounds 18.6± 1.1 16.3± 1.7 22.5 ± 1.4
Example 5 Compounds 17.1 ± 0.8 17.9 ± 1.1 18.3 ±0.8
Example 6 Compounds 33.3± 1.6 29.6 ± 1.3 31.5 ± 1.1
Example 7 Compounds 29.8± 1.1 32.5± 1.5 33.1± 1.1
Example 8 Compounds 27.4 ± 1.3 28.9± 1.5 33.1 ± 0.9
Example 9 Compounds 11.2 ± 0.5 9.7± 2.1 15.4± 1.2
Example 10 Compounds 27.1 ± 1.3 29.8± 2.2 29.8 ± 0.8
Example 11 Compounds 25.6 ± 1.6 24.3 ± 0.8 31.5 ± 1.2
Practice ofEXAMPLE 12 Compounds 1.42 ± 0.2 0.67± 0.2 1.25± 0.2
As can be seen from the experimental data in the above table, the difference between the effects of the (1,2,2,2-tetrafluoroethyl) arene derivatives with different structures on lung cancer and bronchial cancer is great. Among them, the (1,2,2,2-tetrafluoroethyl) arene derivative having the structure shown in the formula III, which is prepared in example 9, has significant effect on lung cancer and bronchial cancer
(1,2,2,2-tetrafluoroethyl) arene derivatives of structure II, prepared in example 5, and (1,2,2,2-tetrafluoroethyl) arene derivatives, mostly of structure I (e.g., example 1~4, example 6~8, and (1,2,2,2-tetrafluoroethyl) arene derivatives prepared in examples 10 and 11), are superior to those prepared in example 5.
From the above experimental data, it can be seen that the (1,2,2,2-tetrafluoroethyl) arene derivative with the structure shown in formula i, in which R groups are selected from different groups, can obtain a (1,2,2,2-tetrafluoroethyl) arene derivative, and has different effects on resisting lung cancer and bronchial cancer. Of these, most of the (1,2,2,2-tetrafluoroethyl) arene derivatives of the structure shown in formula i had significantly lower effects on lung cancer and bronchial cancer than the (1,2,2,2-tetrafluoroethyl) arene derivative of the structure shown in formula iii prepared in example 9. However, of the (1,2,2,2-tetrafluoroethyl) arene derivatives of the structure shown in formula I, the (1,2,2,2-tetrafluoroethyl) arene derivative obtained when the R group is selected from 1,2,2,2-tetrafluoroethylphenyl (i.e., 4,4 '-bis (1,2,2,2-tetrafluoroethyl) -1,1' -biphenyl prepared in example 12) has a far higher effect against lung cancer and bronchial cancer than the (1,2,2,2-tetrafluoroethyl) arene derivative obtained when the R group is selected from other groups; is also much higher than the (1,2,2,2-tetrafluoroethyl) arene derivative with the structure shown in the formula III prepared in the example 9; has excellent effect of resisting lung cancer and bronchial cancer.

Claims (1)

1. The application of the (1,2,2,2-tetrafluoroethyl) arene derivative in preparing a medicament with an anticancer effect; characterized in that the cancer is lung cancer and/or bronchial cancer;
the (1,2,2,2-tetrafluoroethyl) arene derivative is selected from any one of the following structures:
Figure QLYQS_1
CN202211568730.2A 2022-12-08 2022-12-08 (1,2,2,2-tetrafluoroethyl) arene derivative and preparation method and application thereof Active CN115572210B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211568730.2A CN115572210B (en) 2022-12-08 2022-12-08 (1,2,2,2-tetrafluoroethyl) arene derivative and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211568730.2A CN115572210B (en) 2022-12-08 2022-12-08 (1,2,2,2-tetrafluoroethyl) arene derivative and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN115572210A CN115572210A (en) 2023-01-06
CN115572210B true CN115572210B (en) 2023-03-21

Family

ID=84590035

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211568730.2A Active CN115572210B (en) 2022-12-08 2022-12-08 (1,2,2,2-tetrafluoroethyl) arene derivative and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN115572210B (en)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2582320B1 (en) * 1985-05-21 1987-06-26 Atochem ELECTROCHEMICAL PROCESS FOR THE PREPARATION OF ORGANIC DERIVATIVES TRIFLUORO (OR CHLORODIFLUORO OR DICHLOROFLUORO) METHYLES
GB8712989D0 (en) * 1987-06-03 1987-07-08 Ici Plc Electrochemical process
JPH08504001A (en) * 1992-12-04 1996-04-30 インペリアル・ケミカル・インダストリーズ・ピーエルシー Electrochemical fluorination method
US5573654A (en) * 1994-03-04 1996-11-12 Minnesota Mining And Manufacturing Company Process for making hexafluoropropane and perfluoropropane
DE10351088A1 (en) * 2003-10-31 2005-06-02 Bayer Cropscience Gmbh Process for preparing fluoromethyl-substituted heterocycles
CN102690167B (en) * 2012-06-14 2014-10-22 江苏和成显示科技股份有限公司 Liquid crystal compound containing saturated indene rings and composition thereof
WO2021141120A1 (en) * 2020-01-08 2021-07-15 ダイキン工業株式会社 Method for producing fluorine-containing organic compound

Also Published As

Publication number Publication date
CN115572210A (en) 2023-01-06

Similar Documents

Publication Publication Date Title
JPS62289544A (en) Fluorine-containing compound
CN111690947B (en) Electrochemical synthesis method of trifluoromethylated aryl amide derivative
CN109438365A (en) N- (3- ((4- trifluoromethyl) -2- pyrimidine radicals) aminophenyl) -2,6- difluorobenzenesulfonamide derivative
CN111303028B (en) 4-cyano-2-difluoromethyl substituted quinoline compound and synthetic method thereof
CN106188044B (en) A kind of synthetic method of 3- arylthios imidazo [1,5-a] N- heterocyclic compounds of catalysis of iodine
CN115572210B (en) (1,2,2,2-tetrafluoroethyl) arene derivative and preparation method and application thereof
CN110669001A (en) Synthetic method of 3-fluoro-4-halogeno-5-methoxypyridine
Yuan et al. Visible-light-induced tandem difluoroalkylated spirocyclization of N-arylpropiolamides: access to C3-difluoroacetylated spiro [4, 5] trienones
Tsukada et al. Fine electronic state tuning of cobaltadithiolene complexes by substituent groups on the benzene ring
Zia et al. Regio-isomeric isoxazole sulfonates: Synthesis, characterization, electrochemical studies and DNA binding activity
Guieu et al. Gold-Catalyzed Synthesis of Substituted 3-Trifluoromethylpyrroles from Mesylated Amino Trifluoromethylpropargylic Alcohols
CN117105845A (en) Electrophilic trifluoro methyl selenizing reagent and preparation method and application thereof
WO2023109254A1 (en) Method for one-step direct preparation of 3-acyl imidazo[1,5-a]pyridine by means of [4+1] dual amination reactions of ketomethyl
Wang et al. Conformational Study of N, N′-Diacyl Bispidines and Dioxo Bis-bispidines: Planar Chirality and Molecular Switching
CN111170924B (en) Method for electrochemically synthesizing hexafluoroisopropoxyindole compound
Marc et al. Rational Synthesis of Some New para-Aminobenzoic Acid Hybrids with Thiazolidin-2, 4-diones with Antimicrobial Properties
Thulasi et al. Calix [4] bis (spirodienone) as a versatile synthon for upper rim alkoxylation of calixarenes and synthesis of novel triazole-based biscalixarene by ‘CuAAC’chemistry
Al-Masoudi et al. Synthesis and conformational analysis of new arylated-diphenylurea derivatives related to sorafenib drug via Suzuki-Miyaura cross-coupling reaction
EP3782977A1 (en) Cyclopropanation method and reagent
CN106243053B (en) A kind of triazolylamide ketone fungicide, synthetic method and its application
CN111253415A (en) Norcantharidin carboxylic acid trifluorobenzyl ester and synthetic method and application thereof
CN110862339A (en) Indole micromolecule compound and preparation method thereof
CN106146417B (en) A method of 4- aryl-NH-1,2,3- triazole is prepared using aldehyde sodium bisulfite adduct
Maschke et al. Influence of chlorine substituents on the aggregation behavior of chlorobenzoyl-substituted ferrocene derivates
CN114890957B (en) Triazole derivative and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant