CN110028447A - A kind of preparation method of mono- methyl fluoride quinoline of 2- - Google Patents
A kind of preparation method of mono- methyl fluoride quinoline of 2- Download PDFInfo
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- CN110028447A CN110028447A CN201910412061.1A CN201910412061A CN110028447A CN 110028447 A CN110028447 A CN 110028447A CN 201910412061 A CN201910412061 A CN 201910412061A CN 110028447 A CN110028447 A CN 110028447A
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- methylquinoline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
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Abstract
The invention belongs to chemosynthesis technical fields, and in particular to a kind of preparation method of mono- methyl fluoride quinoline of 2-.This method is through the following steps that realize: in DMF solution, 2- methylquinoline and its derivative and Selectfluor reaction obtain a fluoro 2- methylquinoline derivatives after chromatographing by column.Method provided by the invention carries out in DMF solution, and substrate dissolubility is good, applicability is wide；Reaction yield is high, and controllability is strong.Method provided by the invention is environmentally protective, and side reaction product is few, green, efficient.
Description
Technical field
The invention belongs to chemosynthesis technical fields, and in particular to a kind of preparation side of mono- methyl fluoride quinoline of 2-
Method.
Background technique
Organic molecule containing halogenated functional group is that one kind is widely used in pharmaceutical chemistry, agriculture chemistry and functional material section
Organic framework material.In addition, presoma of the organohalogen compound used also as organic synthesis.In view of these advantages, closely
The formation of carbon-halogen bond has received widespread attention over year, and achieves huge progress.Especially fluorine-containing organic molecule is due to it
The features such as unique bulk effect, strong bond energy, lipophilic variation, hydrogen bond receptor, biochemical activity and high electronegativity,
Become star's product in many fields.
Therefore, in the past few decades, people have been devoted to the research of fluorination reaction, and small molecule constructs carbon-fluorine bond
There are three types of general strategies: nucleophilic, electrophilic, free radical fluorination.Recently, various efficient transition metal are attributed to the fact that in the success in this field
The exploitation of catalyst, as palladium, copper, silver, Jin C-F are bonded in technique and are widely used.In recent years, with people couple
The research of free radical fluorination reaction, C (sp2)-F key formation comparative maturity, and C (sp3)-F key is more rare, especially
It is C (sp in building 2- alkyl quinoline3)-F key strategy it is even more limited.Therefore, in the C (sp of 2- alkyl quinoline class compound3)-F
The development of the fast construction method of key is ideal and useful.Pang et al. is using C-H key elder generation iodine in 2- alkyl quinoline
Then in generation, uses AgF again2Substituted method obtain mono- methyl fluoride quinoline of 2- (RSC Adv., 2016,6,
111713–111717).Due to having used expensive AgF in reaction process2, seriously limit industrial application.Therefore, it sends out
Mild condition is opened up, the research and development of economical and practical mono- methyl fluoride quinoline synthetic method of 2- become the task of top priority.
Summary of the invention
In view of the problems of the existing technology, the present invention provides a kind of preparation sides of mono- methyl fluoride quinoline of 2-
Method, this method is easy to operate, wide application range of substrates, and yield is high, and application is strong.
Present invention technical solution used in order to achieve the above object are as follows:
The present invention provides a kind of preparation methods of mono- methyl fluoride quinoline of 2-, comprising the following steps:
(1) 2- methylquinoline or derivatives thereof, Selectfluor are added in reaction dissolvent, are reacted, after reaction
It is neutralized using saturated sodium bicarbonate solution, ethyl acetate extraction merges organic layer, saturated common salt water washing, and anhydrous sodium sulfate is done
It is dry, it filters, concentration；
(2) product after concentration is chromatographed into obtain product list fluoro 2- methylquinoline derivatives using column；
The structural formula of the list fluoro 2- methylquinoline derivatives is as follows:
In formula, the R is alkyl, halogen, alkoxy or hydrogen.
Further, in step (1), described 2- methylquinoline or derivatives thereof and the molar ratio of Selectfluor are 1:
3-5；It optimizes, the molar ratio of described 2- methylquinoline or derivatives thereof and Selectfluor are 1:4.
Further, in step (1), the reaction dissolvent is DMF.
Reaction provided by the invention is to react 18-28 hours at 30 DEG C.
Further, in step (2), eluant, eluent is ethyl acetate and n-hexane according to volume ratio 1:15 in the column chromatography
Composition.
The invention has the benefit that
(1) method provided by the invention carries out in DMF solution, and substrate dissolubility is good, applicability is wide；Reaction yield is high, controllably
Property is strong.
(2) method provided by the invention is environmentally protective, and side reaction product is few, green, efficient.
Specific embodiment
Following embodiment further illustrates technical solution of the present invention, but not as limiting the scope of the invention.
Embodiment 1
2- methylquinoline (1mmol, 143mg), Selectfluor(4mmol, 1.4g) it is added to DMF solution (5ml) and at 30 DEG C
For 24 hours, saturated sodium bicarbonate solution neutralizes for reaction, and ethyl acetate extracts (3*10mL), merges organic layer, saturated common salt water washing
(20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product 2- mono-
Methyl fluoride quinoline 139mg, yield 86%.
1H NMR (600 MHz, CDCl3) δ 8.26 (d, J = 8.0 Hz, 1 H), 8.08 (d, J = 8.0
Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.78-7.72 (m, 1 H), 7.64-7.57 (m, 2 H),
5.69(d, J = 48.0 Hz, 2 H).; 13C NMR (151 MHz, CDCl3) δ 156.8 (d, J = 20.0 Hz),
147.5, 137.1, 129.9, 129.1, 127.7, 127.6, 126.7, 118.2 (d, J = 5.0 Hz), 85.0
(d, J = 170.0 Hz)。
Embodiment 2
2- methyl -8- chloroquinoline (1mmol, 177mg), Selectfluor(4mmol, 1.4g) it is added to DMF solution (5ml) simultaneously
It is reacted at 30 DEG C for 24 hours, saturated sodium bicarbonate solution neutralizes, and ethyl acetate extracts (3*10mL), merges organic layer, saturated salt solution
It washs (20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product
Mono- methyl fluoride -8- chloroquinoline 131mg of 2-, yield 67%.
1H NMR (600 MHz, CDCl3) δ 8.23 (d, J = 8.5 Hz, 1H), 7.83 (dd, J = 7.5,
1.2 Hz, 1H), 7.74 (dd, J = 8.2, 1.0 Hz, 1H), 7.67 (dd, J = 8.5, 1.1 Hz, 1H),
7.45 (t, J = 7.8 Hz, 1H), 5.73 (d, J = 46.9 Hz, 2H).; 13C NMR (151 MHz, CDCl3)
δ 157.9 (d, J = 22.7 Hz), 143.6 (d, J = 2.2 Hz), 137.5, 133.2, 130.0 , 128.9,
126.9, 126.5, 118.9 (d, J = 5.6 Hz), 84.9 (d, J = 170.5 Hz)。
Embodiment 3
2- methyl -8- nitroquinoline (1mmol, 188mg), Selectfluor(4mmol, 1.4g) it is added to DMF solution (5ml)
And reacted at 30 DEG C for 24 hours, saturated sodium bicarbonate solution neutralizes, and ethyl acetate extracts (3*10mL), merges organic layer, saturated common salt
Water washing (20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatography (eluant, eluent: ethyl acetate/n-hexane=1:15) must produce
Object 2- methyl fluoride -8- nitroquinoline 142mg, yield 69%.
1H NMR (600 MHz, CDCl3) δ 8.34 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.2
Hz, 1H), 8.02 (d, J = 7.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.62 (t, J = 7.9
Hz, 1H), 5.67 (d, J = 46.9 Hz, 2H).13C NMR (151 MHz, CDCl3) δ 159.9 (d, J =
23.3 Hz), 148.1, 138.6 (d, J = 2.7 Hz), 137.1, 131.7, 128.4, 125.3, 123.8,
119.7 (d, J = 5.9 Hz), 84.6 (d, J = 171.2 Hz)。
Embodiment 4
2-methyl-7- chloroquinolines (1mmol, 177mg), Selectfluor(4mmol, 1.4g) it is added to DMF solution (5ml) simultaneously
It is reacted at 30 DEG C for 24 hours, saturated sodium bicarbonate solution neutralizes, and ethyl acetate extracts (3*10mL), merges organic layer, saturated salt solution
It washs (20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product
Mono- methyl fluoride -7- chloroquinoline 127mg of 2-, yield 65%.
1H NMR (600 MHz, CDCl3) δ 8.20 (d, J = 8.5 Hz, 1H), 8.04 (s, 1H), 7.76
(d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.7, 1.8 Hz,
1H), 5.64 (d, J = 46.9 Hz, 2H)。
Embodiment 5
2- methyl -5,7- difluoro-quinoline (1mmol, 179mg), Selectfluor(4mmol, 1.4g) it is added to DMF solution
It (5ml) and is reacted for 24 hours at 30 DEG C, saturated sodium bicarbonate solution neutralizes, and ethyl acetate extracts (3*10mL), merges organic layer, satisfies
With brine It (20mL), anhydrous sodium sulfate is dried, filtered, concentration.Column chromatography (eluant, eluent: ethyl acetate/n-hexane=1:
15) mono- methyl fluoride -5,7- difluoro-quinoline 127mg of product 2-, yield 64% are obtained.
1H NMR (600 MHz, CDCl3) δ 8.46 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 8.6
Hz, 1H), 7.52 (d, J = 9.7 Hz, 1H), 7.07 (td, J = 9.3, 2.3 Hz, 1H), 5.65 (d, J
= 46.8 Hz, 2H)。
Embodiment 6
- 6 nitroquinoline of 2- methyl (1mmol, 188mg), Selectfluor(4mmol, 1.4g) it is added to DMF solution (5ml) simultaneously
It is reacted at 30 DEG C for 24 hours, saturated sodium bicarbonate solution neutralizes, and ethyl acetate extracts (3*10mL), merges organic layer, saturated salt solution
It washs (20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product
Mono- methyl fluoride -8- methylquinoline 166mg of 2-, yield 80%.
1H NMR (600 MHz, CDCl3) δ 8.82 (d, J = 2.3 Hz, 1H), 8.50 (dd, J = 9.2,
2.4 Hz, 1H), 8.44 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.79 (d, J =
8.5 Hz, 1H), 5.71 (d, J = 46.8 Hz, 2H)。
Comparative example 1
2- methylquinoline (1mmol, 143mg), Selectfluor(2mmol, 0.35g) it is added to DMF solution (5ml) and 30
DEG C reaction for 24 hours, saturated sodium bicarbonate solution neutralize, ethyl acetate extract (3*10mL), merge organic layer, saturated common salt water washing
(20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product 2- fluorine
Methylquinoline 61mg, yield 38%.
Comparative example 2
2- methylquinoline (1mmol, 143mg), Selectfluor(6mmol, 2.1g) it is added to DMF solution (5ml) and at 30 DEG C
For 24 hours, saturated sodium bicarbonate solution neutralizes for reaction, and ethyl acetate extracts (3*10mL), merges organic layer, saturated common salt water washing
(20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product 2- fluorine
Methylquinoline 97mg, yield 60%.
Comparative example 3
2- methylquinoline (1mmol, 143mg), Selectfluor(4mmol, 1.4g are added to DMF solution (5ml) and at 10 DEG C
For 24 hours, saturated sodium bicarbonate solution neutralizes for reaction, and ethyl acetate extracts (3*10mL), merges organic layer, saturated common salt water washing
(20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product 2- fluorine
Methylquinoline 76mg, yield 47%.
Comparative example 4
2- methylquinoline (1mmol, 143mg), Selectfluor(4mmol, 1.4g) it is added to DMF solution (5ml) and at 50 DEG C
For 24 hours, saturated sodium bicarbonate solution neutralizes for reaction, and ethyl acetate extracts (3*10mL), merges organic layer, saturated common salt water washing
(20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product 2- fluorine
Methylquinoline 90mg, yield 56%.
Comparative example 5
2- methylquinoline (1mmol, 143mg), Selectfluor(4mmol, 1.4g) it is added to DMF solution (5ml) and at 30 DEG C
15h is reacted, saturated sodium bicarbonate solution neutralizes, and ethyl acetate extracts (3*10mL), merges organic layer, saturated common salt water washing
(20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product 2- fluorine
Methylquinoline 84mg, yield 52%.
Comparative example 6
2- methylquinoline (1mmol, 143mg), Selectfluor(4mmol, 1.4g) it is added to DMF solution (5ml) and at 30 DEG C
36h is reacted, saturated sodium bicarbonate solution neutralizes, and ethyl acetate extracts (3*10mL), merges organic layer, saturated common salt water washing
(20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product 2- fluorine
Methylquinoline 116mg, yield 72%.
Comparative example 7
2- methylquinoline (1mmol, 143mg), Selectfluor(4mmol, 1.4g) it is added to acetonitrile solution (5ml) and 30
DEG C reaction for 24 hours, saturated sodium bicarbonate solution neutralize, ethyl acetate extract (3*10mL), merge organic layer, saturated common salt water washing
(20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product 2- fluorine
Methylquinoline 40mg, yield 25%.
Comparative example 8
2- methylquinoline (1mmol, 143mg), Selectfluor(4mmol, 1.4g) it is added to acetone soln (5ml) and 30
DEG C reaction for 24 hours, saturated sodium bicarbonate solution neutralize, ethyl acetate extract (3*10mL), merge organic layer, saturated common salt water washing
(20mL), anhydrous sodium sulfate dries, filters, concentration.Column chromatographs (eluant, eluent: ethyl acetate/n-hexane=1:15) and obtains product 2- fluorine
Methylquinoline 98mg, yield 61%.
Claims (6)
1. a kind of preparation method of mono- methyl fluoride quinoline of 2-, which comprises the following steps:
(1) 2- methylquinoline or derivatives thereof, Selectfluor are added in reaction dissolvent, are reacted, after reaction
It is neutralized using saturated sodium bicarbonate solution, ethyl acetate extraction merges organic layer, saturated common salt water washing, and anhydrous sodium sulfate is done
It is dry, it filters, concentration；
(2) product after concentration is chromatographed into obtain product list fluoro 2- methylquinoline derivatives using column；
The structural formula of the list fluoro 2- methylquinoline derivatives is as follows:
；
In formula, the R is alkyl, halogen, alkoxy or hydrogen.
2. preparation method according to claim 1, which is characterized in that described 2- methylquinoline or derivatives thereof with
The molar ratio of Selectfluor is 1:3-5.
3. preparation method according to claim 2, which is characterized in that described 2- methylquinoline or derivatives thereof with
The molar ratio of Selectfluor is 1:4.
4. preparation method according to claim 1, which is characterized in that the reaction dissolvent is DMF.
5. preparation method according to claim 1-4, which is characterized in that the reaction is to react at 30 DEG C
18-28 hours.
6. preparation method according to claim 1, which is characterized in that eluant, eluent is ethyl acetate and just in column chromatography
Hexane is formed according to volume ratio 1:15.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115108980A (en) * | 2022-06-22 | 2022-09-27 | 济南大学 | Preparation method of 4-bit acylated derivative of 2-methylquinoline compound |
| CN115286569A (en) * | 2022-08-29 | 2022-11-04 | 南昌大学 | Method for synthesizing fluoro-aza-arene compound through C-H bond functionalization |
| CN116283759A (en) * | 2023-03-17 | 2023-06-23 | 济南大学 | Preparation method of 2-monofluoromethylquinoline and derivatives thereof |
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| CN1585775A (en) * | 2001-12-05 | 2005-02-23 | 奥索-麦克尼尔药品公司 | 6-O-acyl ketolide derivatives of erythromycine useful as antibacterials |
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2019
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1585775A (en) * | 2001-12-05 | 2005-02-23 | 奥索-麦克尼尔药品公司 | 6-O-acyl ketolide derivatives of erythromycine useful as antibacterials |
Non-Patent Citations (2)
| Title |
|---|
| KELLEY E. DANAHY ET AL.: "Benzylic Fluorination of Aza-Heterocycles Induced by Single-Electron Transfer to Selectfluor", 《ANGEW. CHEM. INT. ED.》 * |
| XIAOBO PANG ET AL.: "Halogenations of substituted 2-alkylquinoline with iodine and halide exchange with AgF2", 《RSC ADV.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115108980A (en) * | 2022-06-22 | 2022-09-27 | 济南大学 | Preparation method of 4-bit acylated derivative of 2-methylquinoline compound |
| CN115286569A (en) * | 2022-08-29 | 2022-11-04 | 南昌大学 | Method for synthesizing fluoro-aza-arene compound through C-H bond functionalization |
| CN116283759A (en) * | 2023-03-17 | 2023-06-23 | 济南大学 | Preparation method of 2-monofluoromethylquinoline and derivatives thereof |
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