CN116410136A - Quinoline derivative and preparation method thereof - Google Patents

Abstract

The invention discloses a quinoline derivative and a preparation method thereof, which belong to the technical field of organic synthesis; the preparation method of a quinoline derivative provided by the invention is to use the compound shown in formula I as a raw material, in an inert gas and an organic acid Under the action of the dehydrogenation ring-closing reaction in an organic solvent, the quinoline derivative shown in formula II is obtained; in the preparation method provided by the invention, the carbon-carbon double bond at the 1,2 position of the raw material is not needed, and the Under the action of the provided organic acid, it can dehydrogenate and then close the ring, so that the scope of applicable substrates is wider and the actual utilization value is higher. In addition, the preparation method provided by the present invention is simple in operation, low in equipment requirements, and high in yield, which is beneficial to practical application. Specifically, the yield of the obtained product can reach 90%;

Description

A kind of quinoline derivative and preparation method thereof

technical field

The invention belongs to the technical field of organic synthesis, and in particular relates to a quinoline derivative and a preparation method thereof.

Background technique

The structure of quinoline (formula A) is a class of molecules composed of benzopyrrole rings, most of its derivatives (formula B and formula C) have biological activity. Quinoline compounds are widely used in medicine, dyes, photosensitive materials, rubber, solvents and chemical reagents. Quinoline is mainly used in the manufacture of three major categories of drugs, niacin, 8-hydroxyquinoline and quinine. Niacin-based drugs include nicotinamide, cardiotonic agents, stimulants and taeniasis drugs; 8-hydroxyquinolines can be used to manufacture medicines for treating amoebiasis and wound disinfectants, as well as antifungal agents and textile auxiliaries, etc.; Primine, chloroquine, and hydroxyquine are synthetic antimalarial drugs. Methylquinoline can be used to make color film sensitizers and dyes, and can also be used as solvents, impregnating agents, corrosion inhibitors, quinine-based drugs and insecticides, etc.

Reaction、Pfitinger Reaction、Niementowski quinoline Synthesis；(3)在苯胺N的γ位，构建一个亲电中心，通过SEAr反应关环，如Combes Reaction、SkraupReaction、Gould-Jacobs Reaction、Doebner-Miller Reaction、Doebner Reaction、KnorrReaction、Conrad-Limpach Reaction；(4)利用N的亲和性，通过SNAr反应构建喹啉类化合物，如构建沙星类药物母核(喹诺酮)。According to existing literature reports, the widely used approach for the synthesis of quinoline and quinoline derivatives is that aniline or aniline derivatives are used as starting materials to form a pyridine ring through the following four methods to obtain quinoline or quinoline derivatives : (1) Pericyclic reaction (Aza DA Reaction); (2) Aldol Reaction ring-closing reaction, such as Camps quinoline Synthesis,

Reaction, Pfitinger Reaction, Niementowski quinoline Synthesis; (3) At the γ-position of aniline N, construct an electrophilic center, and close the ring through SEAr reaction, such as Combes Reaction, SkraupReaction, Gould-Jacobs Reaction, Doebner-Miller Reaction, Doebner Reaction, KnorrReaction, Conrad-Limpach Reaction; (4) Utilize the affinity of N to construct quinoline compounds through SNAr reaction, such as constructing the mother core (quinolone) of floxacin drugs.

Among these strategies, the methods used for the synthesis of quinoline and quinoline derivatives either use expensive reagents or use relatively large amounts of catalysts. Some reactions require the use of expensive ligands and metal oxidants, which do not conform to the development of green chemistry. In the past, the synthesis of quinoline and quinoline derivatives mostly used aniline or aniline derivatives to complete the construction of the quinoline skeleton through intermolecular reactions. There were few intramolecular reactions, and the quinoline skeleton was constructed through intramolecular reactions. . In addition, the currently synthesized quinoline derivatives are all derivatized at the 1, 2, 3, and 4 positions of quinoline, and there is no one-step reaction to construct quinoline while derivatizing on the benzene ring. Because the substituent has the positioning effect caused by electron-withdrawing and electron-donating, therefore, the group on the benzene ring of quinoline is often not conducive to the subsequent reaction, so the current derivatization on the benzene ring is especially at the 6-position carbon. No direct derivatization has been found and reported, and the past methods were all directly carried on the raw material;

Contents of the invention

The purpose of the present invention is to overcome the shortcomings of the above-mentioned prior art and provide a quinoline derivative that can efficiently construct a quinoline skeleton in one step in the molecule, and simultaneously derivatize the benzene ring carbon of quinoline and its preparation method .

In order to achieve the above object, the technical solution adopted by the present invention is: a preparation method of quinoline derivatives, the preparation method comprising the following steps: using the compound shown in formula I as a raw material, under the action of an inert gas and an organic acid, A dehydrogenation ring-closing reaction occurs in an organic solvent to obtain a quinoline derivative shown in formula II,

Wherein, R _is selected from any one of hydrogen, alkyl, acyl, alkoxy, ester, and carbonyl;

_R is selected from any one of hydrogen, alkyl, acyl, alkoxy, ester, and carbonyl;

_R is selected from any one of alkyl, alkoxy and ester groups;

R' is selected from any one of -OMs, -OTf, -NTf ₂ .

In the preparation method of a quinoline derivative provided by the present invention, by using the compound shown in formula I (phenyl azide ketone derivative) as a substrate, the intramolecular dehydrogenation ring-closing reaction is carried out under the action of an organic acid, Form quinoline ring structure compound; Simultaneously in the intramolecular dehydrogenation ring-closing reaction process provided by the present invention, do not need the 1,2 carbon-carbon double bond of raw material, can dehydrogenate directly under the action of the organic acid provided by the present invention and then Close the ring, so that the scope of applicable substrates is wider, and the actual utilization value is higher.

As a preferred embodiment of the preparation method of the present invention, R _is selected from any one of hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester, and C1-C6 carbonyl _R2 is selected from any one of hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester, C1-C6 carbonyl; _R3 is selected from C1-C6 alkane Any one of C1-C6 alkoxy group, C1-C6 ester group.

Preferably, R _is selected from hydrogen, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propionyl, methoxy, ethoxy, propoxy, ethyl formate, methyl acetate Any one of ester group, ethyl acetate group, ketone group, cyclopentanone group; _R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propionyl, Any one of methoxy, ethoxy, propoxy, ethyl formate, methyl acetate, ethyl acetate, ketone, cyclopentanone; _R3 is selected from methyl, ethyl , propyl, isopropyl, methoxy, ethoxy, propoxy, ethyl formate, methyl acetate, 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, and bistrifluoromethanesulfonimide.

Preferably, the organic acid is any one of trifluoromethanesulfonic acid and methanesulfonic acid; more preferably, the organic acid is trifluoromethanesulfonic acid.

The inventors have found that trifluoromethanesulfonic acid, methanesulfonic acid, and bistrifluoromethanesulfonimide are strong protonic acids, and by adding strong protonic acids, dehydrogenation reactions can occur efficiently, thereby facilitating subsequent ring closure Form a quinoline ring; further preferably trifluoromethanesulfonic acid, methanesulfonic acid, because considering that the synthetic quinoline derivatives are intermediates, subsequent reactions need to be further reacted to synthesize corresponding active substances, while trifluoromethanesulfonic acid Ester and methanesulfonate are a kind of very active reactive groups, which are easy to leave, and then undergo chemical reactions such as substitution and hydrolysis to form quinoline active substances.

As a preferred embodiment of the preparation method of the present invention, the molar ratio of the organic acid to the compound represented by formula I is organic acid:compound represented by formula I=(1-8):1.

Preferably, when the selected organic acid is trifluoromethanesulfonic acid, the molar ratio of the organic acid to the compound shown in formula I is organic acid:compound shown in formula I=3:1; when the selected organic acid is formic acid When sulfonic acid is used, the molar ratio of the organic acid to the compound shown in formula I is organic acid:compound shown in formula I=(5-8):1.

The inventors have found that when the molar ratio of the organic acid to the compound shown in Formula I is further controlled at the above-mentioned point value or a small range of values according to the selection of the organic acid, the yield of the product obtained is better, more than 60%, and can even be up to 90%.

As a preferred embodiment of the preparation method of the present invention, the organic solvent is at least one of toluene, acetonitrile, chloroform, dichloromethane, and dichloroethane.

As a preferred embodiment of the preparation method of the present invention, the mass volume ratio of the compound represented by formula I to the organic solvent is (0.01-0.1) g: 1 mL.

As a preferred embodiment of the preparation method of the present invention, the temperature of the dehydrogenation and ring-closing reaction is (-40) to 25°C.

Preferably, the temperature of the dehydrogenation ring-closing reaction is (-20)-25°C.

The inventors have found that when the temperature is further preferably (-20) to 25°C, the yield of the product obtained is higher, the reaction conditions are relatively simple, and the requirements for equipment are low.

As a preferred embodiment of the preparation method of the present invention, the time for the dehydrogenation and ring-closing reaction is 6-18 hours; in actual experiments, the end point of the reaction is determined by TLC spotting.

As a preferred embodiment of the preparation method of the present invention, the inert gas is any one of nitrogen or rare gas.

As a preferred embodiment of the preparation method of the present invention, after the reaction is completed, a post-processing step is also included, and the post-processing step includes adding a saturated aqueous sodium bicarbonate solution to quench, extracting with ethyl acetate, and collecting the organic phase after washing, then Concentrate the organic phase and perform column chromatography.

Preferably, the washing is sequentially washing with water and saturated brine.

Preferably, the silica gel mesh used in the column chromatography is 200-300 mesh, the eluent is petroleum ether and ethyl acetate, and 2 mL of triethylamine is added to every 100 mL of the eluent.

In addition, the present invention also provides a quinoline derivative prepared by the preparation method described in the present invention.

A quinoline derivative provided by the invention can be used to synthesize various quinoline active compounds or natural products containing the quinoline derivative of the present invention, such as topotecan (Topotecan, formula C), RORgt modulator (formula B) wait;

Compared with prior art, the beneficial effect of the present invention is:

In the preparation method of a quinoline derivative provided by the present invention, by using the compound shown in formula I (phenyl azide ketone derivative) as a substrate, the intramolecular dehydrogenation ring-closing reaction is carried out under the action of an organic acid, Form quinoline ring structure compound; Simultaneously in the intramolecular dehydrogenation ring-closing reaction process provided by the present invention, do not need the 1,2 carbon-carbon double bond of raw material, can dehydrogenate directly under the action of the organic acid provided by the present invention and then Close the ring, so that the scope of applicable substrates is wider, and the actual utilization value is higher. In addition, the preparation method provided by the invention is simple in operation, low in equipment requirements, and high in yield, which is beneficial to practical application. Specifically, the yield of the obtained product can reach 90%, and the purity is also above 95%.

Detailed ways

In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific examples.

The reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art unless otherwise specified.

Example 1

The embodiment of the present invention provides a quinoline derivative T-1, the structure of which is shown in formula T-1,

The preparation method of described quinoline derivative T-1 comprises the steps:

The synthetic route is as follows:

specifically,

(1) Synthesis of S-2

Add S-1 (3.278g, 21.98mmol) into a dry 100mL round-bottom flask, add 65mL dichloromethane under nitrogen atmosphere and stir to dissolve, slowly add thionyl chloride (2.4mL, 32.97mmol) dropwise under ice bath and stir After 6 hours of reaction, TLC detected that the reaction of the raw materials was complete. Excess thionyl chloride and solvent were distilled off under reduced pressure to obtain a yellow oily liquid. After dissolving with 60 mL of acetone, sodium iodide (6.600 g, 44.00 mmol) was added, and the reaction was stirred for 10 h. After adding 60 mL of water and stirring, a large amount of solids precipitated, and the solids were filtered to obtain the product S-2 (3.80 g, 14.67 mmol). The total yield of the two-step reaction was 67%;

Characterization of S-2: 1H NMR (500MHz, Chloroform-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 (126 MHz, Chloroform-d) δ 138.2, 130.7, 130.3, 129.5, 125.1, 118.7, 0.3.

(2) Synthesis of S-6

S-5 (1.261g, 10.00mmol), S-2 (2.590g, 10.00mmol), potassium carbonate (2.764g, 20.00mmol) and 50mL tetrahydrofuran were successively added into a 100mL dry round bottom flask and stirred for 8 hours. TLC detected that the reaction was complete, and 50 mL of water quenched the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrated by distillation under reduced pressure, purified by column chromatography (200-300 mesh silica gel, petroleum ether and ethyl acetate as eluent) to obtain compound S-6, yellow oily liquid, 2.187 g, yield 85%.

Characterization of S-5: 1H NMR (500MHz, Chloroform-d) δ7.33-7.25 (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

Add compound S-6 (0.257g, 1.00mmol) into a 15mL dry reaction tube, add 5mL DCM (dichloromethane) under N ₂ atmosphere, cool the reaction system to 0°C, slowly add methanesulfonic acid (0.577 g, 6.00 mmol), stirring was continued at 0°C for 30 minutes. After reacting for 6 hours, TLC monitored the completion of the reaction of the raw materials, and quenched the reaction by adding 5 mL of saturated aqueous sodium bicarbonate solution at 0°C and stirring for 10 minutes. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added to every 100 mL of eluent) and purified to obtain compound T-1 with a yield of 68%, and the color of the compound in air was purple-black.

Characterization of T-1: 1H NMR (500MHz, Chloroform-d) δ7.35 (d, J = 8.4Hz, 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=16.1Hz,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, 19.3 1.

Example 2

The embodiment of the present invention provides a quinoline derivative T-2,

The only difference between it and Example 1 is that in the synthesis of step (3), the synthesis step (3) of T-2 in this example is: add compound S-6 (0.257g, 1.00mmol) to a 15mL dry reaction tube , added 5 mL of DCM (dichloromethane) under N ₂ atmosphere, cooled the reaction system to 0°C, slowly added trifluoromethanesulfonic acid (0.300g, 2.00mmol) dropwise, and continued to stir at 0°C for 30 minutes. After reacting for 8 hours, TLC monitored the complete reaction of the raw materials, and then quenched the reaction by adding 5 mL of saturated aqueous sodium bicarbonate solution at 0°C and stirring for 10 minutes. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added to every 100 mL of eluent) and purified to obtain compound T-1 with a yield of 70%.

Example 3

In the embodiment of the present invention, on the basis of Example 1-2, the molar ratio of raw materials in the reaction process, the reaction temperature, and the selection of organic solvents have an impact on the synthesis of quinoline derivatives using S-6 as a raw material;

1. Explore on the basis of Example 1, except for the difference in the conditions given in Table 1, all the other are completely consistent with step (3) in Example 1;

Table 1

2, explore on the basis of embodiment 2, except the difference of the condition that provides in table 2, all the other are completely consistent with step (3) in embodiment 2;

Table 2

From No. 5 and No. 18 in Table 1-2, No. 8 and No. 21, No. 9 and No. 22, it can be seen that even if the reaction temperature, organic solvent and reactant molar ratio in the reaction process are the same, the organic acid The difference will also have a significant impact on the yield of the product; in addition, as can be seen from Table 1 and Table 2, when the organic acid is fixed, the reaction temperature, organic solvent and reactant molar ratio in the reaction process will also Bring obvious influence to yield; When using methanesulfonic acid as organic acid, along with the mol ratio of methanesulfonic acid and S-6 increases gradually, yield increases first and then almost remains unchanged, when the molar ratio of the two When being (2-8): 1, the yield that obtains is between 44-69%; When using trifluoromethanesulfonic acid as organic acid, along with the mol ratio of trifluoromethanesulfonic acid and S-6 increases gradually , the yield first increases and then significantly decreases. When the preferred molar ratio of the two is (2-3): 1, the yield obtained is between 70-86%. In addition, as the reaction temperature increases gradually, the yield also increases. It shows a trend of increasing and then decreasing, and it is more preferable that the yield is between 75-90% when the reaction temperature is (-20)-25°C.

Example 4

The embodiment of the present invention provides a quinoline derivative T-3, the structure of which is shown in formula T-3,

The preparation method of described quinoline derivative T-3 comprises the steps:

The synthetic route is as follows:

specifically,

(1) The synthesis of S-2 is consistent with that in Example 1

(2) Synthesis of S-4

S-2 (3.80g, 14.67mmol), S3 (2.06g, 14.67mmol), potassium carbonate (4.055g, 29.34mmol) and 50mL tetrahydrofuran were successively added into a 100mL dry round bottom flask and stirred for 8 hours. TLC detected that the reaction was complete, and 50 mL of water quenched the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. It was concentrated by distillation under reduced pressure, and purified by column chromatography (200-300 mesh silica gel, petroleum ether and ethyl acetate as eluent) to obtain 2.963 g of compound S-4.

Characterization of S-4: 1H NMR (500MHz, Chloroform-d) δ7.40–7.25 (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=6.5Hz,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) δ 211.9, 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

Add compound S-4 (0.085g, 1.00mmol) into a 15mL dry reaction tube, add 2mL DCM (dichloromethane) under N ₂ atmosphere, cool the reaction system to 0°C, slowly add methanesulfonic acid (0.577 g, 6.00 mmol), stirring was continued at 0°C for 15 minutes. After reacting for 6 hours, TLC monitored the completion of the reaction of the raw materials, and quenched the reaction by adding 5 mL of saturated aqueous sodium bicarbonate solution at 0°C and stirring for 10 minutes. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added to every 100 mL of eluent) and purified to obtain compound T-3 with a yield of 55%, and the color of the compound in air was purple-black.

Characterization of T-3: 1H NMR (500MHz, Chloroform-d) δ7.38(d, J=8.4Hz, 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 present invention provides a quinoline derivative T-4, the structure of which is shown in formula T-4,

The preparation method of described quinoline derivative T-4 comprises the steps:

The synthetic route is as follows:

specifically,

(1) The synthesis of S-2 is consistent with that in Example 1

(2) Synthesis of S-8

S-7 (1.141g, 10mmol), S-2 (2.590g, 10mmol), potassium carbonate (2.764g, 15mmol) and 50mL tetrahydrofuran were successively added into a 100mL dry round bottom flask and stirred for 8 hours. TLC detected that the reaction was complete, and 50 mL of water quenched the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 1.594 g of compound S-8 with a yield of 65%.

Characterization of S-8: 1H NMR (500MHz, Chloroform-d) δ7.28 (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

Add compound S-8 (0.245g, 1.00mmol) into a 15mL dry reaction tube, add 5mL DCM (dichloromethane) under N ₂ atmosphere, cool the reaction system to 0°C, slowly add methanesulfonic acid (0.577 g, 6.00 mmol), stirring was continued at 0°C for 15 minutes. After reacting for 8 hours, TLC monitored the complete reaction of the raw materials, and then quenched the reaction by adding 5 mL of saturated aqueous sodium bicarbonate solution at 0°C and stirring for 10 minutes. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added to every 100 mL of eluent) and purified to obtain compound T-4 with a yield of 23%, and the color of the compound in air was purple-black.

Characterization of T-4: 1H NMR (500MHz, Chloroform-d) δ6.83(d, J=8.0Hz, 1H), 6.15(dd, J=8.1, 2.4Hz, 1H), 6.01(d, J=2.5 Hz, 1H), 3.11(d, J=7.5Hz, 2H), 2.19(s, 2H), 1.17(s, 3H), 1.09(s, 3H), 1.05(s, 3H).

Example 6

The embodiment of the present invention provides a quinoline derivative T-5, the structure of which is shown in the formula T-5,

The preparation method of described quinoline derivative T-5 comprises the steps:

The synthetic route is as follows:

specifically,

(1) The synthesis of S-2 is consistent with that in Example 1

(2) Synthesis of S-10

S-2 (3.80g, 14.67mmol), S9 (2.06g, 14.67mmol), potassium carbonate (4.055g, 29.34mmol) and 50mL tetrahydrofuran were successively added into a 100mL dry round bottom flask and stirred for 8 hours. TLC detected that the reaction was complete, and 50 mL of water quenched the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 2.625 g of compound S-1010, with a yield of 69%.

Characterization of S-10: 1H NMR (500MHz, Chloroform-d) δ7.32-7.23 (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=7.3Hz, 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 (126 MHz, Chloroform-d) δ 206.2, 138.0, 131.5, 129.5, 128.3, 118.1, 65.9, 36.2, 30.2, 7.5.

(3) Synthesis of T-5

Add S-10 (0.259g, 1.00mmol) into a 15mL dry reaction tube, add 5mL DCM under _N2 atmosphere, cool down to 0°C, slowly drop TfOH (0.450g, 3.00mmol), and continue stirring at 0°C 15min. After 10 h of reaction, TLC monitored the completion of the reaction, and 5 mL of saturated sodium bicarbonate was added to quench the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added per 100 mL of eluent) to obtain 0.184 g of compound T-5 with a yield of 51%.

Characterization of T-5: 1H NMR (500MHz, Chloroform-d) δ8.36(s, 1H), 8.18(d, J=9.2Hz, 1H), 7.80(d, J=2.7Hz, 1H), 7.67( dd, J=9.2, 2.8Hz, 1H), 3.19(q, J=7.5Hz, 2H), 3.06(q, J=7.2Hz, 2H), 1.37(t, J=7.5Hz, 3H), 1.30( t,J=7.2Hz,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 (471 MHz, Chloroform-d) δ-72.61.

Example 7

The embodiment of the present invention provides a quinoline derivative T-6, the structure of which is shown in formula T-6,

The only difference between the preparation method of the quinoline derivative T-6 and Example 6 is the difference in step (3), the step (3) of the embodiment of the present invention is the synthesis of T-6:

Add compound S-10 (0.259g, 1.00mmol) into a 15mL dry reaction tube, add 5mL DCM under _N2 atmosphere, cool down to 0°C, slowly drop MsOH (0.577g, 6.00mmol), and continue stirring at 0°C 15min. After 10 h of reaction, TLC monitored the completion of the reaction, and 5 mL of saturated sodium bicarbonate was added to quench the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added to every 100 mL of eluent) to obtain 0.080 g of compound T-6 with a yield of 26%.

Characterization of T-6: 1H NMR (500MHz, Chloroform-d) δ8.35(s, 1H), 8.15(d, J=9.1Hz, 1H), 7.82(d, J=2.7Hz, 1H), 7.68( dd, J=9.1, 2.6Hz, 1H), 3.25(s, 3H), 3.19(q, J=7.5Hz, 3H), 3.06(q, J=7.2Hz, 3H), 1.37(t, J=7.5 Hz, 3H), 1.29 (t, J = 7.3Hz, 3H).

Example 8

The embodiment of the present invention provides a quinoline derivative T-7, the structure of which is shown in the formula T-7,

The preparation method of described quinoline derivative T-7 comprises the steps:

The synthetic route is as follows:

specifically,

(1) The synthesis of S-2 is consistent with that in Example 1

(2) Synthesis of S-12

S-2 (3.80g, 14.67mmol), S-11 (2.06g, 14.67mmol), potassium carbonate (4.055g, 29.34mmol) and 50mL tetrahydrofuran were successively added into a 100mL dry round bottom flask and stirred for 8 hours. TLC detected that the reaction was complete, and 50 mL of water quenched the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 2.951 g of compound S-12 with a yield of 77%.

(3) Synthesis of T-7

Compound S-12 (0.261g, 1.00mmol) was added to a 15mL dry reaction tube, 5.0mL DCM was added under _N2 atmosphere, the temperature was lowered to 0°C, TfOH (0.450g, 3.00mmol) was slowly added dropwise, and at 0°C Stirring was continued for 15 min. After 12 h of reaction, TLC monitored the completion of the reaction, and 5 mL of saturated sodium bicarbonate was added to quench the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added per 100 mL of eluent) to obtain 0.185 g of compound T-7 with a yield of 51%.

Characterization of T-7: 1H NMR (500MHz, Chloroform-d) δ8.80(s, 1H), 8.29-8.11(m, 1H), 7.84(d, J=2.7Hz, 1H), 7.69(dd, J =9.3,2.7Hz,1H),4.49(d,J=7.1Hz,2H),3.05(s,3H),1.49(s,1H);

19F NMR (471 MHz, Chloroform-d) δ-72.80.

Example 9

The embodiment of the present invention provides a quinoline derivative T-8, the structure of which is shown in formula T-8,

The only difference between the preparation method of the quinoline derivative T-8 and Example 8 is the difference in step (3), the step (3) of the embodiment of the present invention is the synthesis of T-8:

Add compound S-12 (0.261g, 1.00mmol) into a 15mL dry reaction tube, add 5mL DCM under _N2 atmosphere, cool down to 0°C, slowly drop MsOH (0.577g, 6.00mmol), and continue stirring at 0°C 15min. After 14 h of reaction, TLC monitored the completion of the reaction, and 1 mL of saturated sodium bicarbonate was added to quench the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added per 100 mL of eluent) to obtain 0.109 g of compound T-8 with a yield of 35%.

Characterization of T-8: 1H NMR (500MHz, Chloroform-d) δ8.78(s, 1H), 8.16(d, J=9.2Hz, 1H), 7.85(d, J=2.7Hz, 1H), 7.70( dd, J=9.1, 2.7Hz, 1H), 4.47(q, J=7.1Hz, 2H), 3.26(s, 3H), 3.03(s, 3H), 1.48(t, J=7.2Hz, 3H).

Example 10

The embodiment of the present invention provides a kind of application transformation of quinoline derivative T-2, the conversion route from T-2 to compound 2 is:

specifically,

Weigh quinoline derivative T-2 (0.181g, 0.5mmol, 1.0eq.) into a dry 25mL round bottom flask, and add 3mL of ultra-dry tetrahydrofuran to dissolve the system. Tetrabutylammonium fluoride solution (1.5mL, 1.5mmol, 3.0eq., 1M in THF) was slowly added dropwise under ice-cooling, the temperature was raised to 40°C, and the reaction was stirred at 40°C for 3 hours. The complete reaction of raw materials was monitored by TLC (petroleum ether:ethyl acetate=1:1, Rf=0.35), and 5 mL of saturated ammonium chloride solution was added to quench the reaction. The reaction system was extracted with ethyl acetate, the organic phase was washed with water and saturated brine, the organic phase was combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 0.084 g of a yellow oily liquid with a yield of 73%.

Characterization of Compound 2: 1H NMR (500MHz, Chloroform-d) δ7.15(d, J=9.1Hz, 1H), 6.71-6.59(m, 2H), 2.95(d, J=15.8Hz, 1H), 2.53 (d,J=15.9Hz,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 present invention can not only efficiently construct a quinoline skeleton in one step in the molecule, but also obtain products that can be easily converted into other reactive substrates, thereby forming quinoline-like active compounds. things.

Finally, it should be noted that the above examples are to illustrate the technical solutions of the present invention rather than limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the present invention can be Modifications or equivalent replacements shall be made to the technical solutions without departing from the spirit and scope of the technical solutions of the present 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,

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.