CN114634482A - Diazo difluoromethylation reagent and synthesis method and application thereof - Google Patents
Diazo difluoromethylation reagent and synthesis method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of organic chemical industry and drug synthesis, and particularly relates to a novel diazodifluoromethyl reagent and a synthesis method and application thereof. Diazo high-valence iodine reagent and trimethylsilyl trifluoromethanesulfonic ketone, (2-diazo-1, 1-difluoroethyl) -sulfonyl benzene Ps-DFA react at room temperature to obtain a series of diazo difluoromethyl reagent derivatives, which can be widely applied to various nucleophilic reactions as diazo difluoromethyl radicals to introduce difluoromethyl structural units into organic molecules. The reaction is carried out for 3-5 hours at room temperature, a series of diazo difluoromethylation reagent derivatives can be obtained, the yield is 60% -80%, and a simple, convenient and efficient new method is provided for the diazo difluoromethylation reagent as a fluorine-containing block.
Description
Technical Field
The invention belongs to the field of organic chemical industry and drug synthesis, and particularly relates to a novel diazodifluoromethyl reagent and a synthesis method and application thereof.
Background
Organofluorine compounds play a very important role in medicine, pesticides, new materials and life sciences. Introduction of fluorine atoms into organic compounds can change the physicochemical and biological properties of the compounds, and in recent years, methods and means for efficiently introducing fluorine into molecules have received a great deal of attention from synthetic chemists. (a: Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V.chem.Soc.Rev.2008,37,320-330.b: Meanwell, N.A.J.Med.chem.2018,61, 5822-. Difluoromethyl methylene is more special in all fluorine-containing groups, hydrogen atoms in difluoromethyl have weak acidity, and can form hydrogen bonds with electron-rich systems in biomacromolecules to facilitate the combination of a medicament and a receptor, so that the activity of the medicament or a lead compound is improved (a: Lu, Y.; Liu, C.; Chen, Q. -Y.Curr.Org.Chem.2015,19,1638.b: Rewcastle, G.W.; Gamage, S.A.; Flanagan, J.U.;
Frederick,R.；Denny,W.A.；Baguley,B.C.；Kestell,P.；Singh,R.；Kendall,J.D.；Marshall,E.S.；Lill,C.L.；Lee,W.-J.；Kolekar,S.；Buchanan,C.M.；Jamieson,S.M.F.；Shepherd,P.R.J.Med.Chem.2011,54,7105.)。
compared with the mature method for introducing trifluoromethyl into molecules, difluoromethyl has high activity and poor stability, and difluoromethane is difficult to introduce into molecules. The traditional method for introducing difluoromethyl group into molecule is prepared by deoxofluorination of aldehyde and sulfur tetrafluoride or diethylaminosulfur trifluoride, but the compatibility of the functional group is poor and the reaction condition is harsh. The Dolbier topic group utilizes HCF2SO2Cl as a difluoromethyl radical precursor, developed a series of difluoromethylation reactions. Wasp et al reported the use of Beard reagent [ difluoromethyl-2-pyridylsulfone reagent 2-PySO ] in the department of Chinese medicine2CF2H]In situ iron catalystThe difluoromethylation of aromatic hydrocarbons by selective cleavage of the C-S bond and subsequent cross-coupling with aryl zinc, all of which have limitations requiring the use of HCF2Cl2Gas, or reaction at-40 deg.C. Therefore, the development of a novel diazodifluoromethylation reagent has important significance.
Disclosure of Invention
The invention aims to provide a novel fluorine building block diazo difluoromethylation reagent. A method for synthesizing diazodifluoromethylation reagent with simple operation and high efficiency is provided by taking a high-valence iodine reagent sold in the market, trimethylsilyl trifluoromethanesulfonate TMSOTf and a synthesized substrate (2-diazo-1, 1-difluoroethyl) -sulfonyl benzene Ps-DFA as raw materials.
The invention provides a synthesis method of a diazo difluoromethylation reagent, which takes a high-valence iodine reagent sold in the market, trimethylsilyl trifluoromethanesulfonate TMSOTf and a synthesized substrate (2-diazo-1, 1-difluoroethyl) -sulfonyl benzene Ps-DFA as raw materials, adds a proper amount of solvent, and then stirs and reacts at room temperature to generate the diazo difluoromethylation reagent.
The reaction conditions are as follows: the reaction time is 3-5 hours under the air condition.
The molar ratio of the high-valence iodine reagent, TMSOTf and Ps-DFA is 1:1:2-1:1: 2.5.
The high-valence iodine reagent can be iodobenzene acetate and 1-methoxy-1, 2-benzo iodo-3 (H) ketone.
The solvent is dichloromethane, acetonitrile or methanol.
The structural formula of the diazo difluoromethylation reagent is as follows:
the synthetic route of the raw material (2-diazo-1, 1-difluoroethyl) -sulfonyl benzene Ps-DFA is as follows:
the method comprises the following specific steps:
(1) p-methylthiophenol (5g, 1.0 equivi) was dissolved in 50mL of dimethyl sulfoxide, and sodium hydride (1.06g, 1.1equiv) was slowly added under ice-water bath conditions, followed by stirring at 40 ℃ for 1 hour. Ethyl difluorobromoacetate (1.1equiv) was added to the reaction solution and stirred for reaction for 15 hours, and TLC showed that the starting material was completely reacted. Quenching with aqueous ammonium chloride solution and extracting with diethyl ether, anhydrous MgSO4Drying, concentrating under reduced pressure to obtain crude product, and separating by column chromatography to obtain product A.
(2) Sodium borohydride (2.28g,60mmol) and anhydrous tetrahydrofuran (60mL) were added to a dry three-necked flask under nitrogen protection at 0 deg.C, anhydrous tetrahydrofuran (40mL) in which compound A (9.28g,40mmol) was dissolved was slowly added dropwise, and the mixture was stirred at room temperature for 3 hours to obtain compound B.
(3) Adding compound B (8.5 g, 44mmol), water-acetic acid mixed solution (1:1,70mL) and hydrogen peroxide (30%, 10ML) into a 250mL round-bottom flask, heating to 120 ℃, stirring for 5 hours, cooling to room temperature after the reaction is finished, extracting the reaction solution with ethyl acetate, and extracting with anhydrous Na2SO4Drying for 3 hours, filtering, and spin-drying the filtrate to obtain the compound C.
(4) Compound C (7.8g, 1equiv), pyridine (3.5mL,1equiv) and trifluoromethanesulfonic anhydride (8.8g,1.03equiv) were added to 50mL of acetonitrile at 0 ℃ and the reaction was stirred at this temperature for 30 minutes, then warmed to room temperature and stirred for 2 hours. Then, ammonia water (20mL) was added thereto, the reaction mixture was reacted at room temperature for 24 hours, and after completion of the reaction, the reaction mixture was poured into water, extracted with methylene chloride, and dried over anhydrous Na2SO4Drying for 3 hours, filtering, spin-drying the filtrate to obtain a crude product D, and recrystallizing with diethyl ether to obtain the compound D.
(5) Compound D (7.5g, 1equiv) and sodium nitrite (2.4g, 1.2equiv) were added to a mixed solution of 55mL of toluene and water (10:1), and after stirring at room temperature for 1 hour, the reaction solution was poured into water, extracted with ethyl acetate, and then anhydrous Na2SO4Drying for 3 hours, filtering, spin-drying the filtrate, and separating by column chromatography to obtain the compound Ps-DFA.
The diazodifluoromethylation reagent derivative can be produced smoothly under the above reaction conditions.
The post-treatment of the reaction is simple and convenient, and the pure diazodifluoromethylation reagent can be obtained by only using a simple column chromatography separation method and using a mixed solvent of petroleum ether and ethyl acetate as an eluent.
The invention has the advantages that: the organic fluoride has wide application in biology, pharmaceutical activity and new materials, such as a blood fat reducing drug rosuvastatin calcium tablet and PI3K target drugs. The hydrogen atom in the difluoromethyl has weak acidity, and can form a hydrogen bond with an electron-rich system in the biomacromolecule, so that the combination of the medicament and the receptor is facilitated, and the activity of the medicament or the lead compound is improved. Since difluoromethyl group has high activity and poor stability, it is difficult to introduce difluoromethane into the molecule. The invention uses high-valence iodine reagent, trimethylsilyl trifluoromethanesulfonic ketone and (2-diazo-1, 1-difluoroethyl) -sulfonyl benzene Ps-DFA as raw materials, and the diazo difluoromethylation reagent is constructed by a one-step method, and the yield reaches 60-80%. Provides a more convenient and efficient synthesis means for synthesizing more compounds containing difluoromethyl.
The invention can use diazo difluoromethyl reagent to react with benzaldehyde sold in the market, and 1,3, 4-oxadiazole derivative containing difluoromethyl can be obtained by one-step method, and the synthetic route is as follows:
R1＝H,F,Cl,Br,Me,OMe,tBu
the solvent is dichloromethane, chloroform or methanol.
Detailed Description
The present invention will be described in detail with reference to specific examples.
The synthesis method of the raw material (2-diazo-1, 1-difluoroethyl) -sulfonyl benzene Ps-DFA comprises the following steps:
(1) p-methylthiophenol (5g, 1.0 equivi) was dissolved in 50mL of dimethyl sulfoxide, and sodium hydride (1.06g, 1.1equiv) was slowly added under ice-water bath conditions, followed by stirring at 40 ℃ for 1 hour. Ethyl difluorobromoacetate (1.1equiv) was added to the reaction solution and stirred for reaction for 15 hours, and TLC showed that the starting material was completely reacted. Quenching with aqueous ammonium chloride solution and extracting with diethyl ether, anhydrous MgSO4Drying, concentrating under reduced pressure to obtain crude product, and separating by column chromatography to obtain product A.
(2) Sodium borohydride (2.28g,60mmol) and anhydrous tetrahydrofuran (60mL) were added to a dry three-necked flask under nitrogen protection at 0 deg.C, and anhydrous tetrahydrofuran (40mL) in which compound A (9.28g,40mmol) was dissolved was slowly added dropwise, followed by stirring at room temperature for 3 hours to obtain compound B.
(3) Adding compound B (8.5 g, 44mmol), water-acetic acid mixed solution (1:1,70mL) and hydrogen peroxide (30%, 10ML) into a 250mL round-bottom flask, heating to 120 ℃, stirring for 5 hours, cooling to room temperature after the reaction is finished, extracting the reaction solution with ethyl acetate, and extracting with anhydrous Na2SO4Drying for 3 hours, filtering, and spin-drying the filtrate to obtain the compound C.
(4) Compound C (7.8g, 1equiv), pyridine (3.5mL,1equiv) and trifluoromethanesulfonic anhydride (8.8g,1.03equiv) were added to 50mL of acetonitrile at 0 ℃ and the reaction was stirred at this temperature for 30 minutes, then warmed to room temperature and stirred for 2 hours. Then, ammonia water (20mL) was added thereto, the reaction mixture was reacted at room temperature for 24 hours, and after completion of the reaction, the reaction mixture was poured into water, extracted with methylene chloride, and dried over anhydrous Na2SO4Drying for 3 hours, filtering, spin-drying the filtrate to obtain a crude product D, and recrystallizing with diethyl ether to obtain the compound D.
(5) Compound D (7.5g, 1equiv) and sodium nitrite (2.4g, 1.2equiv) were added to a mixed solution of 55mL of toluene and water (10:1), and after stirring at room temperature for 1 hour, the reaction solution was poured into water, extracted with ethyl acetate, and then anhydrous Na2SO4Drying for 3 hours, filtering, spin-drying the filtrate, and separating by column chromatography to obtain the compound Ps-DFA.
Example 1
1-methoxy-1, 2-benzoiodo-3 (H) one 1a (CAS: 1829-25-0, 5mmol), TMSOTf (5mmol), Ps-DMA (11mmol) and 3mL DCM were added to a 15mL test tube, reacted at room temperature for 3 hours, and separated by silica gel column chromatography to give diazodifluoromethyl reagent 4a in 70% yield.1H NMR(300MHz,CDCl3)δ.8.12(d,J＝7.4Hz,1H),7.96(dd,J＝13.4,8.3Hz,3H),7.88(t,J＝7.5Hz,1H),7.80(t,J＝7.2Hz,1H),7.63(d,J＝8.0Hz,2H),2.50(s,3H).19F NMR(282MHz,CD3CN)δ-79.31,-93.77.HRMS(ESI)calcd for C16H12F2IN2O4S([M+H]+):492.9525found 492.9523.
Example 2
Iodobenzene acetate 1b (5mmol), trimethylsilyl trifluoromethanesulfonate TMSOTf (5mmol), Ps-DMA (11mmol) and 3mL of DCM were added to a 15mL test tube, reacted at room temperature for 3 hours, and separated by silica gel column chromatography to obtain diazodifluoromethyl reagent 4b in 80% yield.1H NMR(400MHz,CDCl3)δ.8.06(s,2H),7.82–7.71(m,3H),7.55(t,J＝7.9Hz,2H),7.46(d,J＝8.1Hz,2H),2.47(s,3H).19F NMR(282MHz,DMSO-d6)δ-77.8,-107.4.
Example 3
1-methoxy-1, 2-benzoiodo-3 (H) one 1a (CAS: 1829-25-0, 5mmol), TMSOTf (5mmol), Ps-DMA (13mmol) and 3mL DCM were added to a 15mL test tube, reacted at room temperature for 3 hours, and separated by silica gel column chromatography to give diazodifluoromethyl reagent 4a in 71% yield.
Example 4
1-methoxy-1, 2-benzoiodo-3 (H) one 1a (CAS: 1829-25-0, 5mmol), TMSOTf (5mmol), Ps-DMA (13mmol) and 3mL acetonitrile were added to a 15mL test tube, reacted at room temperature for 3 hours, and separated by silica gel column chromatography to give diazodifluoromethyl reagent 4a in 60% yield.
Comparative example 1
1-methoxy-1, 2-benzoiodo-3 (H) one 1a (CAS: 1829-25-0, 5mmol), TMSOTf (5mmol), Ps-DMA (13mmol) and 3mL DCM were added to a 15mL test tube, reacted at 40 ℃ for 3 hours, and separated by silica gel column chromatography to give diazodifluoromethyl reagent 4a in 45% yield.
Application example 1
Diazodifluoromethylating agent 4a (0.5mmol), benzaldehyde (0.75mmol), and 3mL methylene chloride were added to a 15mL test tube under white light irradiation, and after reacting at room temperature for 5 hours, 1mol/L hydrochloric acid (2ML) was added, and the organic layer was extracted with ethyl acetate (15mL X2), MgSO4Drying and silica gel column chromatography separation, the yield of the target compound 6 is 62%.
Claims (9)
1. A synthetic method of diazo difluoromethylation reagent is characterized in that the synthetic method takes a high-valence iodine reagent, trimethylsilyl trifluoromethanesulfonic ketone TMSOTf and (2-diazo-1, 1-difluoroethyl) -sulfonyl benzene Ps-DFA as raw materials, and after a solvent is added, the raw materials are stirred at room temperature to react to generate the diazo difluoromethylation reagent.
2. The method for synthesizing a diazodifluoromethylation reagent as claimed in claim 1, wherein the reaction condition is air condition, and the reaction is carried out for 3-5 hours.
3. The method for synthesizing a diazodifluoromethylation reagent as claimed in claim 1, wherein the molar ratio of the high-valent iodine reagent, TMSOTf and Ps-DFA is 1:1:2-1:1: 2.5.
4. The method for synthesizing diazodifluoromethylation reagent as claimed in claim 1, wherein the high-valent iodine reagent is 1-methoxy-1, 2-benzoiodo-3 (H) one or iodobenzene acetate.
5. The method for synthesizing a diazodifluoromethylation reagent as claimed in claim 1, wherein the solvent is dichloromethane, acetonitrile or methanol.
6. The method for synthesizing a diazodifluoromethylation reagent as claimed in claim 1, wherein the structural formula of (2-diazo-1, 1-difluoroethyl) -sulfonyl benzene Ps-DFA is as follows:
7. the method for synthesizing diazodifluoromethylation reagent as claimed in claim 1, wherein the method for synthesizing (2-diazo-1, 1-difluoroethyl) -sulfonyl benzene Ps-DFA comprises the following steps:
(1) dissolving p-methylthiophenol in dimethyl sulfoxide, slowly adding sodium hydride under ice water bath condition, stirring at 40 deg.C for 1 hr, adding ethyl difluorobromoacetate into the reaction solution, stirring for 15 hr, TLC for reaction, quenching with ammonium chloride aqueous solution, extracting with diethyl ether, and extracting with anhydrous MgSO4Drying, concentrating under reduced pressure to obtain crude product, and separating by column chromatography to obtain product A;
(2) adding sodium borohydride and anhydrous tetrahydrofuran into a dry three-neck flask at 0 ℃ under the protection of nitrogen, slowly dropwise adding the anhydrous tetrahydrofuran dissolved with the compound A, and stirring for 3 hours at room temperature to obtain a compound B;
(3) adding compound B, mixed solution of water and acetic acid and hydrogen peroxide into a round-bottom flask, heating to 120 ℃, stirring for 5 hours, cooling to room temperature after reaction, extracting reaction liquid with ethyl acetate, and extracting with anhydrous Na2SO4Drying for 3 hours, filtering, and spin-drying the filtrate to obtain a compound C;
(4) adding the compound C, pyridine and trifluoromethanesulfonic anhydride into 50ml of acetonitrile at 0 ℃, stirring at the temperature for reaction for 30 minutes, then raising the temperature to room temperature and stirring for 2 hours, then adding ammonia water, reacting at the room temperature for 24 hours, pouring the reaction liquid into water after the reaction is finished, extracting the reaction liquid with dichloromethane, and extracting with anhydrous Na2SO4Drying for 3 hours, filtering, spin-drying the filtrate to obtain a crude product D, and recrystallizing with diethyl ether to obtain a compound D;
(5) on the firstAdding compound D and sodium nitrite into the mixed solution of benzene and water, stirring at room temperature for 1 hour, pouring the reaction solution into water, extracting the reaction solution with ethyl acetate, and adding anhydrous Na2SO4Drying for 3 hours, filtering, spin-drying the filtrate, and separating by column chromatography to obtain the compound Ps-DFA.
8. A diazodifluoromethylating reagent synthesized according to the method of claim 1, wherein the diazodifluoromethylating reagent has the following structural formula:
9. use of a diazodifluoromethylation reagent synthesized according to the method of claim 1, characterized in that the diazodifluoromethylation reagent is used for the synthesis of 1,3, 4-oxadiazole derivatives containing difluoromethyl group.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115231988A (en) * | 2022-08-30 | 2022-10-25 | 山东华安新材料有限公司 | Method for synthesizing 3,3,3-trifluoropropionic acid |
| CN117003692A (en) * | 2023-10-07 | 2023-11-07 | 山东东岳高分子材料有限公司 | Process for producing difluoromethyl (2-pyridyl) sulfone |
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| CN108383761A (en) * | 2018-01-18 | 2018-08-10 | 天津大学 | 2- aryl sulfuryl -2,2- difluoro aziethane compounds and the preparation method and application thereof |
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| CN108383761A (en) * | 2018-01-18 | 2018-08-10 | 天津大学 | 2- aryl sulfuryl -2,2- difluoro aziethane compounds and the preparation method and application thereof |
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| JUN-LIANG ZENG等: "Chemodivergent and Stereoselective Construction of gem-Difluoroallylic Amines from Masked Difluorodiazo Reagents" * |
| NIEVES P. RAMIREZ等: "Cu(I)-Catalyzed gem-Aminoalkynylation of Diazo Compounds: Synthesis of Fluorinated Propargylic Amines" * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115231988A (en) * | 2022-08-30 | 2022-10-25 | 山东华安新材料有限公司 | Method for synthesizing 3,3,3-trifluoropropionic acid |
| CN115231988B (en) * | 2022-08-30 | 2024-03-22 | 山东华安新材料有限公司 | Method for synthesizing 3, 3-trifluoro propionic acid |
| CN117003692A (en) * | 2023-10-07 | 2023-11-07 | 山东东岳高分子材料有限公司 | Process for producing difluoromethyl (2-pyridyl) sulfone |
| CN117003692B (en) * | 2023-10-07 | 2023-12-29 | 山东东岳高分子材料有限公司 | Process for producing difluoromethyl (2-pyridyl) sulfone |
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