CN116410136A - Quinoline derivative and preparation method thereof - Google Patents

Quinoline derivative and preparation method thereof Download PDF

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CN116410136A
CN116410136A CN202310195220.3A CN202310195220A CN116410136A CN 116410136 A CN116410136 A CN 116410136A CN 202310195220 A CN202310195220 A CN 202310195220A CN 116410136 A CN116410136 A CN 116410136A
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reaction
preparation
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quinoline derivative
quinoline
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马爱军
郑景云
罗颖
冯娜
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Wuyi University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • 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
    • C07D215/20—Oxygen atoms
    • 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3

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Abstract

The invention discloses a quinoline derivative and a preparation method thereof, belonging to the technical field of organic synthesis; the preparation method of the quinoline derivative provided by the invention comprises the steps of taking a compound shown in a formula I as a raw material, and carrying out dehydrogenation ring-closure reaction in an organic solvent under the action of inert gas and organic acid to obtain the quinoline derivative shown in a formula II; in the preparation method provided by the invention, the dehydrogenation can be carried out under the action of the organic acid provided by the invention directly without carbon-carbon double bonds at 1 and 2 positions of raw materials, so that the applicable substrate range is wider, and the practical utilization value is higher. In addition, the preparation method provided by the invention is simple to operate, low in equipment requirement and high in yield, is beneficial to practical application, and specifically, the yield of the obtained product can reach 90%;

Description

Quinoline derivative and preparation method thereof
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a quinoline derivative and a preparation method thereof.
Background
The structure of quinoline (formula A) is a class of molecules consisting of a benzopyrrole ring, the derivatives of which (formulas B and C) are mostly biologically active. Quinoline compounds are widely used in medicine, dyes, photosensitive materials, rubber, solvents, chemical reagents and the like. The quinoline is mainly used for preparing three major medicines of nicotinic acid, 8-hydroxyquinoline and quinine. Nicotinic acid series medicines include niacinamide, cardiotonic, stimulant and taeniasis treating medicines; the 8-hydroxyquinoline can be used for preparing medicines for treating amoebae diseases, wound disinfectants, mildewcides, textile assistants and the like; the primary quinine, quinine chloride and quinine hydroxylamine are synthetic malaria-treating specific drugs. The methylquinoline can be used for manufacturing color film sensitizers and dyes, and can also be used as solvents, impregnants, corrosion inhibitors, quinine medicaments, pesticides and the like.
According to the report of the prior literature, the synthesis of quinoline and quinoline derivatives is widely applied to the preparation of quinoline or quinoline derivatives by using aniline or aniline derivatives as starting materials and forming pyridine rings by the following 4 methods: (1) pericyclic Reaction (Aza D-A Reaction); (2) Aldol Reaction ring closure, e.g. Camps quinoline Synthesis,
Figure BDA0004106912180000011
Reactions, pfitinger Reaction, niementowski quinoline Synthesis; (3) Constructing an electrophilic center at gamma position of aniline N, and closing a ring through SEAr Reaction, such as Combes Reaction, skraup Reaction, gould-Jacobs Reaction, doebner-Miller Reaction, doebner Reaction, knorr Reaction, conrad-Limpach Reaction; (4) By utilizing the affinity of N, quinoline compounds, such as a parent nucleus (quinolone) of the sarcin medicaments, are constructed through an SNAr reaction.
In these strategies, the methods used to synthesize quinolines and quinoline derivatives either use expensive reagents or use relatively large amounts of catalysts, etc. Some reactions require the use of expensive ligands and metal oxidants, etc., which are not in line with the development of green chemistry. In the past, most of the synthesis of quinoline and quinoline derivatives has been to complete the construction of a quinoline skeleton by intermolecular reaction with aniline or an aniline derivative, and few intramolecular reactions have been carried out to construct a quinoline skeleton by intramolecular reaction. In addition, the quinoline derivatives synthesized at present are all quinoline derivatives which are derived at the 1,2, 3 and 4 positions of quinoline, and the quinoline derivatives which are derived on benzene rings at the same time are not formed by one-step reaction. Since the substituent has a positioning effect caused by electron withdrawing and electron donating, the benzene ring of quinoline is provided with a group which is unfavorable for subsequent reaction in many times, so that no report is found on the direct derivatization of the benzene ring, particularly on the 6-carbon, and the traditional method is carried out on the raw material directly;
Figure BDA0004106912180000021
disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a quinoline derivative which can efficiently construct a quinoline skeleton in one step in a molecule and simultaneously derivatize the quinoline skeleton on benzene ring carbon of quinoline, and a preparation method thereof.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: a process for the preparation of a quinoline derivative, comprising the steps of: using a compound shown as a formula I as a raw material, under the action of inert gas and organic acid, carrying out dehydrogenation ring-closure reaction in an organic solvent to obtain a quinoline derivative shown as a formula II,
Figure BDA0004106912180000022
wherein R is 1 Any one selected from hydrogen, alkyl, acyl, alkoxy, ester and carbonyl;
R 2 any one selected from hydrogen, alkyl, acyl, alkoxy, ester and carbonyl;
R 3 any one selected from alkyl, alkoxy and ester groups;
r' is selected from-OMs, -OTf, -NTf 2 Any one of the following.
In the preparation method of the quinoline derivative, a compound (phenyl azide ketone derivative) shown in a formula I is used as a substrate, and a dehydrogenation ring-closure reaction in a molecule is carried out under the action of organic acid to form a quinoline ring structure compound; meanwhile, in the intramolecular dehydrogenation ring-closing reaction process, the dehydrogenation can be carried out under the action of the organic acid provided by the invention directly without carbon-carbon double bonds at 1 and 2 positions of raw materials, so that the applicable substrate range is wider, and the practical utilization value is higher.
As a preferred embodiment of the preparation process according to the invention, R 1 Any one selected from hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester group and C1-C6 carbonyl; r is R 2 Any one selected from hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester group and C1-C6 carbonyl; r is R 3 Is selected from any one of C1-C6 alkyl, C1-C6 alkoxy and C1-C6 ester.
Preferably, R 1 Any one selected from hydrogen, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propionyl, methoxy, ethoxy, propoxy, ethyl formate, methyl acetate, ethyl acetate, methyl ketone and cyclopentanone; r is R 2 Any one selected from hydrogen, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propionyl, methoxy, ethoxy, propoxy, ethyl formate, methyl acetate, ethyl acetate, methyl ketone and cyclopentanone; r is R 3 Any one of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, ethyl formate, methyl acetate and ethyl acetate.
As a preferred embodiment of the preparation method of the present invention, the organic acid is any one of trifluoromethanesulfonic acid, methanesulfonic acid, bistrifluoromethanesulfonimide.
Preferably, the organic acid is any one of trifluoromethanesulfonic acid and methanesulfonic acid; further preferably, the organic acid is trifluoromethanesulfonic acid.
The inventor researches find that the trifluoro methanesulfonic acid, the methanesulfonic acid and the bistrifluoromethane sulfimide are strong protonic acid, and the dehydrogenation reaction can be efficiently carried out by adding the strong protonic acid, thereby being beneficial to the subsequent ring closure to form a quinoline ring; the preferred compounds are trifluoromethanesulfonic acid and methanesulfonic acid, because the synthesized quinoline derivatives are taken as intermediates, and further reaction is needed to synthesize corresponding active substances, while the trifluoromethanesulfonic acid ester and methanesulfonic acid ester are very active reactive groups and are easy to leave, and further chemical reactions such as substitution, hydrolysis and the like are carried out to form quinoline active substances.
As a preferred embodiment of the preparation method of the invention, the molar ratio of the organic acid to the compound of formula I is: compound of formula i= (1-8): 1.
preferably, when the organic acid is selected to be trifluoromethanesulfonic acid, the molar ratio of the organic acid to the compound of formula I is such that: a compound of formula i = 3:1, a step of; when the organic acid is selected to be methylsulfonic acid, the molar ratio of the organic acid to the compound of formula I is: compound of formula i= (5-8): 1.
the inventors have found that when the molar ratio of the organic acid to the compound of formula I is further controlled according to the choice of the organic acid, the yield of the product obtained is better, more than 60% and even up to 90% at the above point values or at values in a small range.
As a preferred embodiment of the preparation method of the present invention, the organic solvent is at least one of toluene, acetonitrile, chloroform, methylene chloride and dichloroethane.
As a preferred embodiment of the preparation method of the invention, the mass-to-volume ratio of the compound shown in the formula I to the organic solvent is (0.01-0.1) g:1mL.
As a preferred embodiment of the preparation method of the present invention, the temperature of the dehydrogenation-ring-closure reaction is (-40) to 25 ℃.
Preferably, the temperature of the dehydrogenation ring-closure reaction is (-20) to 25 ℃.
The inventors have found that when the temperature is further preferably (-20) to 25 ℃, the yield of the obtained product is higher and the reaction conditions are relatively simple, with low requirements on equipment.
As a preferred embodiment of the preparation method of the invention, the dehydrogenation and cyclization reaction time is 6-18 hours; in practical experiments, the endpoint of the reaction was determined by TLC plates.
As a preferred embodiment of the production method of the present invention, the inert gas is any one of nitrogen and a rare gas.
As a preferred embodiment of the preparation method of the present invention, a post-treatment step is further included after the completion of the reaction, the post-treatment step comprising extraction with ethyl acetate after quenching with saturated aqueous sodium bicarbonate solution, washing, and collecting the organic phase, followed by concentration of the organic phase followed by column chromatography.
Preferably, the washing is sequentially performed by water and saturated saline.
Preferably, the silica gel mesh number used in the column chromatography is 200-300 mesh, the eluent is petroleum ether and ethyl acetate, and 2mL of triethylamine is added to every 100mL of eluent.
In addition, the invention also provides a quinoline derivative which is prepared by adopting the preparation method.
The quinoline derivative provided by the invention can be used for synthesizing various quinoline active compounds or natural products containing the quinoline derivative, such as Topotecan (formula C), RORgt modulator (formula B) and the like;
Figure BDA0004106912180000041
compared with the prior art, the invention has the beneficial effects that:
in the preparation method of the quinoline derivative, a compound (phenyl azide ketone derivative) shown in a formula I is used as a substrate, and a dehydrogenation ring-closure reaction in a molecule is carried out under the action of organic acid to form a quinoline ring structure compound; meanwhile, in the intramolecular dehydrogenation ring-closing reaction process, the dehydrogenation can be carried out under the action of the organic acid provided by the invention directly without carbon-carbon double bonds at 1 and 2 positions of raw materials, so that the applicable substrate range is wider, and the practical utilization value is higher. In addition, the preparation method provided by the invention is simple to operate, low in equipment requirement and high in yield, is beneficial to practical application, and specifically, the yield of the obtained product can reach 90% and the purity is above 95%.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the following specific examples.
The reagents, methods and apparatus employed in the present invention are those conventional in the art unless otherwise indicated.
Example 1
The embodiment of the invention provides a quinoline derivative T-1, the structure of which is shown as a formula T-1,
Figure BDA0004106912180000051
the preparation method of the quinoline derivative T-1 comprises the following steps:
the synthetic route is as follows:
Figure BDA0004106912180000052
in particular, the method comprises the steps of,
(1) Synthesis of S-2
S-1 (3.274 g,21.98 mmol) was added to a 100mL dry round bottom flask, and 65mL of methylene chloride was added under nitrogen atmosphere and stirred to dissolve, thionyl chloride (2.4 mL,32.97 mmol) was slowly added dropwise under ice-bath and stirred for 6h, and TLC indicated complete reaction of the starting materials. Excess thionyl chloride and solvent were removed by distillation under reduced pressure to give a yellow oily liquid. After 60mL of acetone was dissolved, sodium iodide (6.600 g,44.00 mmol) was added thereto, and the reaction was stirred for 10 hours. 60mL of water is added and stirred, a large amount of solid is separated out, and the solid is filtered out to obtain the product S-2 (3.80 g,14.67 mmol), and the total yield of the two steps of reaction is 67%;
characterization of S-2: 1H NMR (500 MHz, chloro-d) δ7.55 (dd, J=8.0, 1.3Hz, 1H), 7.46 (dd, J=7.6, 1.7Hz, 1H), 7.28 (td, J=7.5, 1.2Hz, 1H), 7.14 (td, J=7.7, 1.7Hz, 1H), 4.57 (s, 2H);
13C NMR(126MHz,Chloroform-d)δ138.2,130.7,130.3,129.5,125.1,118.7,0.3。
(2) Synthesis of S-6
Into a 100mL dry round bottom flask was added S-5 (1.261 g,10.00 mmol), S-2 (2.630 g,10.00 mmol), potassium carbonate (2.764 g,20.00 mmol) and 50mL tetrahydrofuran in sequence and the reaction was stirred for 8 hours. The reaction was complete by TLC and quenched with 50mL water. The mixture was extracted with ethyl acetate, the organic phase was washed with water 2 times, the organic phase was washed with saturated brine 1 time, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrating by distillation under reduced pressure, and purifying by column chromatography (200-300 mesh silica gel, petroleum ether and ethyl acetate as eluent) to obtain compound S-6 as yellow oily liquid (2.187 g) with yield of 85%.
Characterization of S-5: 1H NMR (500 MHz, chloroform-d) delta 7.33-7.25 (m, 1H), 7.14 (ddd, J=8.0, 2.5,1.2Hz, 1H), 7.10-7.00 (m, 2H), 3.26 (dd, J=14.1, 2.1Hz, 1H), 3.12 (dd, J=14.1, 2.5Hz, 1H), 2.53 (ddt, J=11.7, 5.7,1.8Hz, 1H), 2.37-2.26 (m, 4H), 2.15-2.04 (m, 1H), 1.83-1.64 (m, 3H);
13C NMR(126MHz,Chloroform-d)δ216.11,204.12,138.90,131.37,128.47,128.23,124.88,118.15,77.05,69.47,38.57,33.91,30.12,26.39,19.42。
(3) Synthesis of T-1
Into a 15mL dry reaction tube was charged compound S-6 (0.257 g,1.00 mmol) in N 2 5mL of DCM (dichloromethane) was added under an atmosphere, the reaction was cooled to 0deg.C, and methanesulfonic acid (0.577 g,6.00 mmol) was slowly added dropwise, and stirring was continued at 0deg.C for 30 minutes. After 6h of reaction, TLC monitored complete reaction of starting material, quenched by addition of 5mL of saturated aqueous sodium bicarbonate at 0deg.C for 10 min with stirring. The mixture was extracted with ethyl acetate, and the organic phase was washed with water 2 times and saturated brine 1 time. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by distillation under reduced pressure, column chromatography (stationary phase is 200-300 mesh silica gel pretreated with triethylamine, eluent is petroleum ether and ethyl acetate. 2mL of triethylamine was added to every 100mL of eluent), to give compound T-1 in 68% yield, and the color of the compound in air was purple black.
Characterization of T-1: 1H NMR (500 MHz, chloroform-d) delta 7.35 (d, J=8.4 Hz, 1H), 7.16 (ddd, J=8.5, 2.7,1.0Hz, 1H), 7.09 (dd, J=2.9, 1.2Hz, 1H), 3.16 (s, 3H), 2.98 (dd, J=16.1, 1.2Hz, 1H), 2.59 (d, J=16.1 Hz, 1H), 2.53-2.41 (m, 2H), 2.12 (s, 3H), 2.08-2.05 (m, 1H), 2.01-1.89 (m, 2H), 1.90-1.77 (m, 1H);
13C NMR(126MHz,Chloroform-d)δ171.20,170.20,147.23,141.96,127.43,126.75,121.71,121.07,53.22,39.19,37.45,32.51,30.99,23.65,19.18,19.31。
example 2
The embodiment of the invention provides a quinoline derivative T-2,
Figure BDA0004106912180000071
the only difference from example 1 is that in the synthesis of step (3), the synthesis of this example T-2, step (3), is: into a 15mL dry reaction tube was charged compound S-6 (0.257 g,1.00 mmol) in N 2 5mL of DCM (dichloromethane) was added under an atmosphere, the reaction system was cooled to 0deg.C, and trifluoromethanesulfonic acid (0.300 g,2.00 mmol) was slowly added dropwise, and stirring was continued at 0deg.C for 30 minutes. After 8h of reaction, TLC monitored complete reaction of starting material, quenched by addition of 5mL of saturated aqueous sodium bicarbonate at 0deg.C for 10 min with stirring. The mixture was extracted with ethyl acetate, and the organic phase was washed with water 2 times and saturated brine 1 time. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by distillation under reduced pressure, column chromatography (stationary phase is triethylamine-pretreated 200-300 mesh silica gel, eluent is petroleum ether and ethyl acetate. 2mL of triethylamine was added per 100mL of eluent), to give compound T-1 in 70% yield.
Example 3
The embodiment of the invention explores the influence of the mole ratio of raw materials, the reaction temperature and the selection of an organic solvent in the reaction process on the synthesis of quinoline derivatives by taking S-6 as a raw material on the basis of the embodiment 1-2;
1. the study was conducted on the basis of example 1, and the procedure was completely identical to that of step (3) in example 1, except for the differences in the conditions given in Table 1;
TABLE 1
Figure BDA0004106912180000072
Figure BDA0004106912180000081
2. The study was conducted on the basis of example 2, and the procedure was completely identical to that of step (3) in example 2, except for the differences in the conditions given in Table 2;
TABLE 2
Figure BDA0004106912180000082
As can be seen from the sequence numbers 5 and 18, the sequence numbers 8 and 21, and the sequence numbers 9 and 22 in tables 1-2, even when the reaction temperature, the molar ratio of the organic solvent and the reactant in the reaction process are the same, the difference of the organic acid can have obvious influence on the yield of the product; in addition, as can be seen from tables 1 and 2, when the organic acid is fixed, the reaction temperature, the molar ratio of the organic solvent and the reactant in the reaction process also have a significant influence on the yield; when methanesulfonic acid is used as the organic acid, as the molar ratio of methanesulfonic acid to S-6 is gradually increased, the yield is increased first and then is almost unchanged, and when the molar ratio of the methanesulfonic acid to S-6 is (2-8): 1, the yield is 44-69%; when trifluoromethanesulfonic acid is used as the organic acid, as the molar ratio of trifluoromethanesulfonic acid to S-6 gradually increases, the yield increases first and then decreases significantly, and when the molar ratio of trifluoromethanesulfonic acid to S-6 is preferably (2-3): 1, the yield is from 70 to 86%, and the yield tends to decrease after the increase with the gradual increase of the reaction temperature, and more preferably from 75 to 90% at (-20) to 25 ℃.
Example 4
The embodiment of the invention provides a quinoline derivative T-3, the structure of which is shown as a formula T-3,
Figure BDA0004106912180000091
the preparation method of the quinoline derivative T-3 comprises the following steps:
the synthetic route is as follows:
Figure BDA0004106912180000092
in particular, the method comprises the steps of,
(1) The synthesis of S-2 was identical to that in example 1
(2) Synthesis of S-4
S-2 (3.80 g,14.67 mmol), S3 (2.06 g,14.67 mmol), potassium carbonate (4.055 g,29.34 mmol) and 50mL tetrahydrofuran were added sequentially to a 100mL dry round bottom flask and reacted for 8 hours with stirring. The reaction was complete by TLC and quenched with 50mL water. The mixture was extracted with ethyl acetate, the organic phase was washed with water 2 times, the organic phase was washed with saturated brine 1 time, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrating by distillation under reduced pressure, and purifying by column chromatography (200-300 mesh silica gel, petroleum ether and ethyl acetate as eluent) to obtain compound S-4.963 g.
Characterization of S-4: 1H NMR (500 MHz, chloroform-d) delta 7.40-7.25 (m, 1H), 7.16 (dd, J=8.1, 1.2Hz, 1H), 7.13 (dd, J=7.6, 1.6Hz, 1H), 7.04 (td, J=7.5, 1.2Hz, 1H), 3.08 (s, 2H), 2.88 (p, J=6.5 Hz, 1H), 2.37 (ddd, J=18.8, 8.7,6.3Hz, 2H), 2.16 (ddd, J=18.8, 9.3,7.0Hz, 2H), 2.05 (ddt, J=13.5, 9.3,6.7Hz, 2H), 1.85-1.57 (m, 2H);
13C NMR(126MHz,Chloroform-d)δ211.9,138.7,131.9,128.6,128.2,125.1,118.0,70.8,42.6,37.3,33.2,24.6。
(3) Synthesis of T-3
Into a 15mL dry reaction tube was charged compound S-4 (0.085 g,1.00 mmol) in N 2 2mL of DCM (dichloromethane) was added under an atmosphere, the reaction was cooled to 0deg.C, and methanesulfonic acid (0.577 g,6.00 mmol) was slowly added dropwise and stirring was continued at 0deg.C for 15min. After 6h of reaction, TLC monitored complete reaction of starting material, quenched by addition of 5mL of saturated aqueous sodium bicarbonate at 0deg.C for 10 min with stirring. The mixture was extracted with ethyl acetate, and the organic phase was washed with water 2 times and saturated brine 1 time. The organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and subjected to column chromatography (solidThe phase is 200-300 mesh silica gel pretreated by triethylamine, and the eluent is petroleum ether and ethyl acetate. And 2mL of triethylamine is added into every 100mL of eluent) to obtain the compound T-3, the yield is 55%, and the color of the compound in the air is purple black.
Characterization of T-3: 1H NMR (500 MHz, chloroform-d) delta 7.38 (d, J=8.4 Hz, 1H), 7.15 (dd, J=2.7, 0.9Hz, 0H), 7.04 (d, 1H), 3.14 (s, 3H), 2.94 (t, 2H), 2.78-2.60 (m, 3H), 2.60-2.51 (m, 1H), 2.49-2.37 (m, 1H), 2.04-1.95 (m, 1H), 1.71-1.53 (m, 1H).
Example 5
The embodiment of the invention provides a quinoline derivative T-4, the structure of which is shown as a formula T-4,
Figure BDA0004106912180000101
the preparation method of the quinoline derivative T-4 comprises the following steps:
the synthetic route is as follows:
Figure BDA0004106912180000102
in particular, the method comprises the steps of,
(1) The synthesis of S-2 was identical to that in example 1
(2) Synthesis of S-8
S-7 (1.141 g,10 mmol), S-2 (2.630 g,10 mmol), potassium carbonate (2.764 g,15 mmol) and 50mL tetrahydrofuran were added sequentially to a 100mL dry round bottom flask and reacted for 8 hours with stirring. The reaction was complete by TLC and quenched with 50mL water. The mixture was extracted with ethyl acetate, the organic phase was washed with water 2 times, the organic phase was washed with saturated brine 1 time, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrating under reduced pressure, and purifying by column chromatography to obtain compound S-8.594 g with 65% yield.
Characterization of S-8: 1H NMR (500 MHz, chloro form-d) delta 7.28 (ddd, J=9.4, 4.9,2.1Hz, 1H), 7.13 (dt, J=8.0, 1.7Hz, 1H), 7.06 (dtt, J=16.6, 7.4,1.9Hz, 2H), 3.34-3.12 (m, 2H), 2.18 (p, J=3.9, 3.0Hz, 6H), 1.34-1.18 (m, 3H);
13C NMR(126MHz,Chloroform-d)δ207.02,207.00,138.91,132.12,128.37,128.27,124.68,118.17,67.19,67.17,33.70,27.11,17.70。
(3) Synthesis of T-4
Into a 15mL dry reaction tube was added compound S-8 (0.245 g,1.00 mmol) in N 2 5mL of DCM (dichloromethane) was added under an atmosphere, the reaction was cooled to 0deg.C, and methanesulfonic acid (0.577 g,6.00 mmol) was slowly added dropwise and stirring was continued at 0deg.C for 15min. After 8h of reaction, TLC monitored complete reaction of starting material, quenched by addition of 5mL of saturated aqueous sodium bicarbonate at 0deg.C for 10 min with stirring. The mixture was extracted with ethyl acetate, and the organic phase was washed with water 2 times and saturated brine 1 time. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by distillation under reduced pressure, column chromatography (stationary phase is 200-300 mesh silica gel pretreated with triethylamine, eluent is petroleum ether and ethyl acetate. 2mL of triethylamine was added to every 100mL of eluent), to give compound T-4 in 23% yield, and the color of the compound in air was purple black.
Characterization of T-4: 1H NMR (500 MHz, chloroform-d) delta 6.83 (d, J=8.0 Hz, 1H), 6.15 (dd, J=8.1, 2.4Hz, 1H), 6.01 (d, J=2.5 Hz, 1H), 3.11 (d, J=7.5 Hz, 2H), 2.19 (s, 2H), 1.17 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H).
Example 6
The embodiment of the invention provides a quinoline derivative T-5, the structure of which is shown as a formula T-5,
Figure BDA0004106912180000121
the preparation method of the quinoline derivative T-5 comprises the following steps:
the synthetic route is as follows:
Figure BDA0004106912180000122
in particular, the method comprises the steps of,
(1) The synthesis of S-2 was identical to that in example 1
(2) Synthesis of S-10
S-2 (3.80 g,14.67 mmol), S9 (2.06 g,14.67 mmol), potassium carbonate (4.055 g,29.34 mmol) and 50mL tetrahydrofuran were added sequentially to a 100mL dry round bottom flask and reacted for 8 hours with stirring. The reaction was complete by TLC and quenched with 50mL water. The mixture was extracted with ethyl acetate, the organic phase was washed with water 2 times, the organic phase was washed with saturated brine 1 time, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrating by distillation under reduced pressure, and purifying by column chromatography to obtain compound S-10.625 g with a yield of 69%.
Characterization of S-10: 1H NMR (500 MHz, chloroform-d) delta 7.32-7.23 (m, 1H), 7.12 (ddd, J=8.3, 7.3,1.5Hz, 2H), 7.03 (tt, J=7.5, 1.2Hz, 1H), 4.09 (t, J=7.3 Hz, 1H), 3.08 (dd, J=7.4, 1.3Hz, 2H), 2.64-2.42 (m, 2H), 2.43-2.27 (m, 2H), 0.98 (td, J=7.2, 1.2Hz, 5H);
13C NMR(126MHz,Chloroform-d)δ206.2,138.0,131.5,129.5,128.3,118.1,65.9,36.2,30.2,7.5。
(3) Synthesis of T-5
Into a 15mL dry reaction tube was added S-10 (0.259 g,1.00 mmol) in N 2 5mL of DCM was added under an atmosphere, cooled to 0deg.C, and TfOH (0.450 g,3.00 mmol) was slowly added dropwise and stirring was continued at 0deg.C for 15min. After 10h of reaction, TLC monitored completion of the reaction and quenched by the addition of 5mL of saturated sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic phase was washed with water 2 times and saturated brine 1 time. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by distillation under reduced pressure, column chromatography (stationary phase is triethylamine-pretreated 200-300 mesh silica gel, eluent is petroleum ether and ethyl acetate. 2mL of triethylamine was added per 100mL of eluent), to give compound T-5.184 g, yield 51%.
Characterization of T-5: 1H NMR (500 mhz, chloro-d) delta 8.36 (s, 1H), 8.18 (d, j=9.2 hz, 1H), 7.80 (d, j=2.7 hz, 1H), 7.67 (dd, j=9.2, 2.8hz, 1H), 3.19 (q, j=7.5 hz, 2H), 3.06 (q, j=7.2 hz, 2H), 1.37 (t, j=7.5 hz, 3H), 1.30 (t, j=7.2 hz, 3H);
13C NMR(126MHz,Chloroform-d)δ203.7,163.3,147.0,146.8,135.9,133.5,131.7,125.6,124.6,120.0,119.5,117.5,35.5,30.5,21.6,13.7,8.3；
19F NMR(471MHz,Chloroform-d)δ-72.61。
example 7
The embodiment of the invention provides a quinoline derivative T-6, the structure of which is shown as a formula T-6,
Figure BDA0004106912180000131
the only difference between the preparation method of the quinoline derivative T-6 and the example 6 is that the step (3) is different, and the step (3) is the synthesis of T-6:
into a 15mL dry reaction tube was charged compound S-10 (0.259 g,1.00 mmol) in N 2 5mL of DCM was added under an atmosphere, cooled to 0deg.C, and MsOH (0.577 g,6.00 mmol) was slowly added dropwise and stirring was continued at 0deg.C for 15min. After 10h of reaction, TLC monitored completion of the reaction and quenched by the addition of 5mL of saturated sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic phase was washed with water 2 times and saturated brine 1 time. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by distillation under reduced pressure, column chromatography (stationary phase is triethylamine-pretreated 200-300 mesh silica gel, eluent is petroleum ether and ethyl acetate. 2mL of triethylamine was added per 100mL of eluent), to give compound T-6.080 g in 26% yield.
Characterization of T-6: 1H NMR (500 MHz, chloroform-d) δ8.35 (s, 1H), 8.15 (d, J=9.1 Hz, 1H), 7.82 (d, J=2.7 Hz, 1H), 7.68 (dd, J=9.1, 2.6Hz, 1H), 3.25 (s, 3H), 3.19 (q, J=7.5 Hz, 3H), 3.06 (q, J=7.2 Hz, 3H), 1.37 (t, J=7.5 Hz, 3H), 1.29 (t, J=7.3 Hz, 3H).
Example 8
The embodiment of the invention provides a quinoline derivative T-7, the structure of which is shown as a formula T-7,
Figure BDA0004106912180000141
the preparation method of the quinoline derivative T-7 comprises the following steps:
the synthetic route is as follows:
Figure BDA0004106912180000142
in particular, the method comprises the steps of,
(1) The synthesis of S-2 was identical to that in example 1
(2) Synthesis of S-12
Into a 100mL dry round bottom flask was added S-2 (3.80 g,14.67 mmol), S-11 (2.06 g,14.67 mmol), potassium carbonate (4.055 g,29.34 mmol) and 50mL tetrahydrofuran in sequence and the reaction stirred for 8 hours. The reaction was complete by TLC and quenched with 50mL water. The mixture was extracted with ethyl acetate, the organic phase was washed with water 2 times, the organic phase was washed with saturated brine 1 time, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrating under reduced pressure, and purifying by column chromatography to obtain compound S-12.951 g with 77% yield.
(3) Synthesis of T-7
Into a 15mL dry reaction tube was charged compound S-12 (0.261 g,1.00 mmol) in N 2 5.0mL of DCM was added under an atmosphere, cooled to 0deg.C, and TfOH (0.450 g,3.00 mmol) was slowly added dropwise and stirring was continued at 0deg.C for 15min. After 12h of reaction, TLC monitored completion of the reaction and quenched by the addition of 5mL of saturated sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic phase was washed with water 2 times and saturated brine 1 time. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by distillation under reduced pressure, column chromatography (stationary phase is triethylamine-pretreated 200-300 mesh silica gel, eluent is petroleum ether and ethyl acetate. 2mL of triethylamine was added per 100mL of eluent), to give compound T-7.185 g in 51% yield.
Characterization of T-7: 1H NMR (500 MHz, chloroform-d) δ8.80 (s, 1H), 8.29-8.11 (m, 1H), 7.84 (d, J=2.7 Hz, 1H), 7.69 (dd, J=9.3, 2.7Hz, 1H), 4.49 (d, J=7.1 Hz, 2H), 3.05 (s, 3H), 1.49 (s, 1H);
19F NMR(471MHz,Chloroform-d)δ-72.80。
example 9
The embodiment of the invention provides a quinoline derivative T-8, the structure of which is shown as a formula T-8,
Figure BDA0004106912180000151
the only difference between the preparation method of the quinoline derivative T-8 and the example 8 is the difference of the step (3), wherein the step (3) is the synthesis of the T-8:
into a 15mL dry reaction tube was charged compound S-12 (0.261 g,1.00 mmol) in N 2 5mL of DCM was added under an atmosphere, cooled to 0deg.C, and MsOH (0.577 g,6.00 mmol) was slowly added dropwise and stirring was continued at 0deg.C for 15min. After 14h of reaction, TLC monitored completion of the reaction and quenched by the addition of 1mL of saturated sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic phase was washed with water 2 times and saturated brine 1 time. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by distillation under reduced pressure, column chromatography (stationary phase is triethylamine-pretreated 200-300 mesh silica gel, eluent is petroleum ether and ethyl acetate. 2mL of triethylamine was added per 100mL of eluent), to give compound T-8.109 g, yield was 35%.
Characterization of T-8: 1H NMR (500 MHz, chloroform-d) δ8.78 (s, 1H), 8.16 (d, J=9.2 Hz, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.70 (dd, J=9.1, 2.7Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.26 (s, 3H), 3.03 (s, 3H), 1.48 (t, J=7.2 Hz, 3H).
Example 10
The embodiment of the invention provides application conversion of a quinoline derivative T-2, wherein the conversion route from the T-2 to a compound 2 is as follows:
Figure BDA0004106912180000152
in particular, the method comprises the steps of,
quinoline derivative T-2 (0.181 g,0.5mmol,1.0 eq.) was weighed into a dry round bottom 25mL flask and 3mL of an ultra dry tetrahydrofuran dissolution system was added. Tetrabutylammonium fluoride solution (1.5 mL,1.5mmol,3.0eq.,1M in THF) was slowly added dropwise under ice bath, the temperature was raised to 40℃and the reaction stirred at 40℃for 3 hours. TLC monitored complete reaction of starting material, petroleum ether: ethyl acetate = 1:1, rf=0.35), 5mL of saturated ammonium chloride solution was added to quench the reaction. The reaction system was extracted with ethyl acetate, the organic phases were washed with water and saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to give 0.084g of a yellow oily liquid in 73% yield.
Characterization of compound 2: 1H NMR (500 MHz, chloro form-d) delta 7.15 (d, J=9.1 Hz, 1H), 6.71-6.59 (m, 2H), 2.95 (d, J=15.8 Hz, 1H), 2.53 (d, J=15.9 Hz, 1H), 2.49-2.36 (m, 2H), 2.12 (s, 3H), 2.09-2.01 (m, 3H), 2.00-1.89 (m, 1H), 1.90-1.77 (m, 1H);
13C NMR(126MHz,Chloroform-d)δ167.0,156.5,134.7,126.6,126.3,115.7,114.4,54.0,39.2,32.6,30.8,22.5,19.1。
as can be seen from example 10, the preparation method of the invention can not only efficiently construct a quinoline skeleton in one step in a molecule, but also can simply and conveniently convert the obtained product into other reactive substrates, thereby forming quinoline active substances.
Finally, it should be noted that the above-mentioned embodiments illustrate rather than limit the scope of the invention, and that those skilled in the art will understand that changes can be made to the technical solutions of the invention or equivalents thereof without departing from the spirit and scope of the technical solutions of the invention.

Claims (10)

1. A process for the preparation of a quinoline derivative, comprising the steps of: using a compound shown as a formula I as a raw material, under the action of inert gas and organic acid, carrying out dehydrogenation ring-closure reaction in an organic solvent to obtain a quinoline derivative shown as a formula II,
Figure FDA0004106912170000011
wherein R is 1 Any one selected from hydrogen, alkyl, acyl, alkoxy, ester and carbonyl;
R 2 any one selected from hydrogen, alkyl, acyl, alkoxy, ester and carbonyl;
R 3 any one selected from alkyl, alkoxy and ester groups;
r' is selected from-OMs, -OTf, -NTf 2 Any one of the following.
2. The process of claim 1, wherein R is 1 Any one selected from hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester group and C1-C6 carbonyl; r is R 2 Any one selected from hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester group and C1-C6 carbonyl; r is R 3 Is selected from any one of C1-C6 alkyl, C1-C6 alkoxy and C1-C6 ester.
3. The method according to claim 1, wherein the organic acid is any one of trifluoromethanesulfonic acid, methanesulfonic acid, bistrifluoromethanesulfonimide.
4. The process according to claim 1, wherein the molar ratio of the organic acid to the compound of formula i is: compound of formula i= (1-8): 1.
5. the method according to claim 1, wherein the organic solvent is at least one of toluene, acetonitrile, chloroform, dichloromethane, and dichloroethane.
6. The preparation method according to claim 1, wherein the mass-to-volume ratio of the compound represented by the formula i to the organic solvent is (0.01 to 0.1) g:1mL.
7. The method according to claim 1, wherein the dehydrogenation-cyclization reaction temperature is (-40) to 25 ℃.
8. The method according to claim 1, wherein the dehydrogenation-cyclization reaction is performed for a period of 6 to 18 hours.
9. The production method according to claim 1, wherein the inert gas is any one of nitrogen gas and a rare gas.
10. A quinoline derivative prepared by the method according to any one of claims 1-9.
CN202310195220.3A 2023-03-03 2023-03-03 Quinoline derivative and preparation method thereof Pending CN116410136A (en)

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