CN104860881A - Methods for synthesizing 8-(nitro methyl) quinoline compounds and 8-methylamino tetrahydroquinoline compounds - Google Patents

Abstract

The invention provides a method for synthesizing 8-(nitro methyl) quinoline compounds. The method comprises steps as follows: 8-methylquinoline compounds are taken as raw materials and added to an organic solvent with a catalyst and a nitration reagent, the mixture is subjected to closed heating to the temperature of 80-130 DEG C for a reaction, TLC (thin layer chromatography) trace is performed until the reaction is finished, and the 8-(nitro methyl) quinoline compounds represented by the formula II are prepared through post-processing of a reaction liquid; the catalyst is bivalent palladium salt; the nitration reagent is tert-butyl nitrite. The 8-(nitro methyl) quinoline compounds can be further reduced for preparing 8-methylamino tetrahydroquinoline. The nitration method has the advantage of nitration position specificity, nitration is only performed on methyl, generation of nitration products on a benzene ring is avoided, the reaction process is safe and environment-friendly, the substrate adaptability is good, and methyl nitration of various substituent groups can be realized; 8-methylquinoline is directly taken as the raw material, the reaction steps are simple, and a new path for synthesizing various substituent group containing 8-(nitro methyl) quinoline compounds and further synthesizing 8-methylamino tetrahydroquinoline later is provided.

Description

The synthetic method of 8-(nitromethyl) quinoline compound and 8-methylaminotetrahydroquinoline compound

technical field

The invention relates to a method for synthesizing organic compounds, in particular to a method for synthesizing 8-(nitromethyl)quinoline compounds and then preparing 8-methylaminotetrahydroquinoline.

Background technique

8-methylquinoline compounds and 8-methylaminotetrahydroquinoline compounds are important chemical raw materials, mainly used as intermediates in medicine and organic synthesis, and are widely used in the pharmaceutical and chemical industries. The introduction of a nitro group on the 8-methylquinoline methyl segment can make this type of compound have potential physiological activity, and thus can obtain 8-aminomethylquinoline derivatives that are also physiologically active as drug intermediates . The 8-methylquinolines containing different substituents have expanded the types of such compounds through the above-mentioned process of introducing nitro groups, and can also make such compounds more widely used. Hydroquinoline compounds are mainly used as intermediates in medicine and organic synthesis, and are widely used in medicine and chemical industries. There is no report on the method of synthesizing these two compounds so far. At present, the direct nitration of the alkyl group usually requires a high temperature of more than 200°C. For 8-methylquinoline containing a heterocycle, under the condition of a high temperature of more than 200°C, its own structure is prone to fracture and ring opening. Moreover, the industry mainly uses nitric acid and sulfuric acid mixed acid nitration to introduce nitro groups. For 8-methylquinoline containing aromatic rings, nitro groups are more likely to be introduced into the aromatic rings, resulting in low purity of the target product or even failure to obtain the target product. . At the same time, strong acids are easy to form salts with quinoline compounds during the reaction process, which affects the progress of the reaction and causes waste of raw materials. In addition, a large amount of heat is released during the process, which is likely to cause production hazards. question.

At present, there is no known method for 8-(nitromethyl)quinoline and 8-methylaminotetrahydroquinoline compounds to be synthesized, and it is difficult to obtain the target product by utilizing the existing nitration method, and brings a series of Environmental issues and safety issues.

In view of the above problems, it is necessary to design a general and simple synthetic route of 8-(nitromethyl)quinoline compounds and 8-methylaminotetrahydroquinoline.

Contents of the invention

In order to solve many problems existing in the synthesis process of 8-(nitromethyl)quinoline compounds in the prior art, the present invention proposes a method for synthesizing 8-(nitromethyl)quinoline compounds and 8-methylaminotetrafluoroethylene A new method of hydroquinoline, which is simple and efficient.

The technical scheme adopted in the present invention is:

The method for the 8-(nitromethyl) quinoline compound shown in synthetic formula II, described method is: take the 8-methyl quinoline compound shown in formula I as raw material, add organic compound with catalyzer and nitrating reagent In a solvent, under an oxygen atmosphere, airtightly heat to 80-130 ° C to react, TLC tracking until the end of the reaction, post-treatment of the reaction solution to obtain the 8-(nitromethyl) quinoline compound shown in formula II;

In formula I or formula II, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are each independently hydrogen, C1-C3 alkyl, halogen, nitro, or C6-C12 aryl; Halogen is fluorine, chlorine, bromine or iodine;

Preferably, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are each independently hydrogen, methyl, fluorine, chlorine, bromine, nitro or phenyl.

Further, preferably R is hydrogen _; R is _hydrogen or phenyl _{; R} is hydrogen, R is hydrogen, methyl, fluorine, chlorine, bromine, nitro or phenyl _; R is hydrogen, methyl, Nitro or chlorine; R ₆ is hydrogen, fluorine or chlorine.

The catalyst is a divalent palladium salt, preferably palladium dichloride, palladium diacetate, diacetonitrile palladium dichloride or palladium trifluoroacetate, more preferably palladium diacetate;

The nitrating reagent is tert-butyl nitrite, and the ratio of the amount of the nitrating reagent to the 8-methylquinoline compound represented by formula I is 1-4:1, preferably 3:1.

The ratio of the amount of the catalyst to the 8-methylquinoline compound represented by formula I is 1:5-10, preferably 1:10.

The organic solvent is a low polar organic solvent, preferably acetonitrile, tetrahydrofuran or 1,2-dichloroethane, more preferably 1,2-dichloroethane.

Under the oxygen atmosphere, preferably the pressure of oxygen is one atmosphere.

The volumetric usage of the organic solvent is generally 5-20 mL/mmol, preferably 10 mL/mmol, based on the amount of the 8-methylquinoline compound represented by formula I.

The reaction temperature is 80-130°C, preferably 90°C.

The reaction of the present invention judges that the reaction is completely completed by TLC tracking and monitoring the reaction situation of the raw materials, and the general reaction time is 20-48 hours, preferably 48 hours.

The post-treatment method of the reaction liquid is that after the reaction is finished, the reaction liquid is diluted with dichloromethane and then filtered, the filtrate is separated by column chromatography, and the eluent is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 10:1. The eluate containing the product is collected, and the eluate is evaporated to remove the solvent to obtain the 8-(nitromethyl)quinoline compound shown in formula II.

The present invention also provides the method for preparing 8-methylaminotetrahydroquinoline compound, described method comprises the following steps:

(1) Take the 8-methylquinoline compound shown in formula I as raw material, add catalyst and nitrating reagent to organic solvent, under oxygen atmosphere, heat up to 80-130°C in airtight reaction, TLC tracking until the end of the reaction , the post-treatment of the reaction solution makes 8-(nitromethyl)quinoline compounds shown in formula II;

(2) Under an ice bath, add 8-(nitromethyl)quinoline compounds shown in formula II and nickel dichloride hexahydrate into methanol solvent, then slowly add sodium borohydride, and stir for 30 to 60 minutes , the reaction product is processed to obtain 8-methylaminotetrahydroquinoline compounds shown in formula III.

In formula I, formula II or formula III, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are each independently hydrogen, C1-C3 alkyl, halogen, nitro or C6-C12 aryl ; The halogen is fluorine, chlorine, bromine or iodine;

Preferably R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ are all hydrogen.

In the step (2), the ratio of the amount of the 8-(nitromethyl) quinoline compound shown in the formula II to the amount of nickel dichloride hexahydrate is 10:1, and the formula II shown in Shown 8-(nitromethyl) quinoline compound, the ratio of the amount of substance of sodium borohydride is 1:20.

In the step (2), the volumetric amount of the methanol is generally calculated as the amount of the 8-(nitromethyl)quinoline compound represented by formula II as 5-20 mL/mmol, preferably 10 mL/mmol.

In the step (2), the post-treatment method of the reaction product is: after the reaction, the reaction product is filtered, the filtrate is separated by column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 6:1. Solvent, collecting the eluent containing the product, and distilling the eluent to remove the solvent to obtain the 8-methylaminotetrahydroquinoline compound shown in formula III.

The present invention directly uses 8-methylquinoline (can contain various substituting groups) as raw material, under the situation that palladium is a catalyst, nitrating agent and oxygen atmosphere exist, mononitration reaction occurs on the methyl position of 8-methylquinoline , to obtain a series of 8-(nitromethyl)quinoline compounds and then to synthesize 8-methylaminotetrahydroquinoline.

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

(1) Safety and environmental protection, no waste gas and waste water;

(2) The substrate has good adaptability, and various substituents can realize nitration;

(3) Nitrification reaction regioselectivity is good;

(4) The reaction steps are simple, and it is a new route for synthesizing various 8-(nitromethyl) quinoline compounds containing substituents;

Detailed ways

The present invention will be described in further detail below through examples, but the protection scope of the present invention is not limited thereto.

Example 1:

(1) 0.5mmol (71.5mg) of 8-methylquinoline, 0.05mmol (11.2mg) of palladium diacetate, 1.5mmol (154.5mg) of tert-butyl nitrite and 1,2- Add 5ml of dichloroethane sequentially into a sealed pressure vessel with a volume of 25ml. The mixture was heated in an oil bath at 90°C for 48 hours. After the TLC detection reaction finished, the reaction solution was diluted with dichloromethane, filtered to obtain the clear liquid, separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and collected the product containing Eluate, eluate was evaporated to obtain 8-(nitromethyl)quinoline (93% yield).

White solid; mp64-65℃; IR(KBr): ν=1518(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ8.98(dd, J ₁ ＝4.5, J ₂ ＝2.0Hz ,1H),8.20(dd,J ₁ =8.5,J ₂ =2.0Hz,1H),7.89(dd,J ₁ =8.5Hz,J ₂ =1.0Hz,1H),7.81(d,J=7.0Hz, 1H), 7.57(t, J=8.5Hz, 1H), 7.48(dd, J ₁ ＝8.0Hz, J ₂ ＝4.5Hz, 1H), 6.22(s, 2H); ¹³ C NMR (CDCl ₃ , 125MHz) :δ150.3, 146.2, 136.3, 130.6, 129.9, 129.5, 128.3, 126.1, 121.7, 71.1;

Then under ice bath, 1mmol 8-(nitromethyl) quinoline, 0.1mmol hexahydrate nickel dichloride are added in 10mL methanol in molar ratio 10:1 ratio, then slowly add 20mmol sodium borohydride and stir for 30 minutes, After the reaction was completed, filter to obtain the clear liquid, which was separated by column chromatography (eluent ratio: petroleum ether to ethyl acetate volume ratio 6:1), and the eluent containing the product was collected, and the eluent was evaporated to remove the solvent 8-Methylaminotetrahydroquinoline was obtained (92% yield).

Yellow liquid; IR(neat): ν＝3396(NH)cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ6.96(d, J＝7.5Hz, 1H), 6.91(d, J＝7.5Hz ,1H),6.58(t,J=7.5Hz,1H),4.83(s,2H),3.38(t,J=5.5Hz,2H),3.15(br s,3H),2.81(t,J=6.0 Hz, 2H), 1.98–1.93 (m, 2H); ¹³ C NMR (CDCl ₃ , 125MHz): δ143.9, 129.7, 126.9, 123.7, 122.0, 116.0, 64.5, 42.0, 27.3, 21.8;

Example 2:

Add 0.5mmol of 8-methyl-3-phenylquinoline, 0.06mmol of palladium diacetate, 1.0mmol of tert-butyl nitrite and 5ml of 1,2-dichloroethane into a 25ml sealed pressure vessel in an oxygen atmosphere . The mixture was heated and reacted in an oil bath at 90° C. for 30 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluent, eluent was distilled off to obtain 8-(nitromethyl)3-phenylquinoline (64% yield).

Yellow liquid; IR(neat): ν=1518(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ ,500MHz): δ9.24(d, J=2.5Hz, 1H), 8.34(d, J=2.5 Hz, 1H), 7.95(dd, J ₁ = 7.5Hz, J ₂ = 1.5Hz, 1H), 7.80–7.48(m, 8H), 6.25(s, 2H); ¹³ C NMR (CDCl ₃ , 125 MHz) : δ149.8, 145.1, 138.5, 137.5, 134.5, 133.4, 130.5, 129.8, 129.6, 129.3, 128.3, 127.4, 126.6, 71.1;

Example 3:

Add 0.5mmol of 5,8-dimethyl-3-phenylquinoline, 0.05mmol of palladium diacetate, 1.5mmol of tert-butyl nitrite and 3ml of 1,2-dichloroethane into a 25ml sealed in a pressure vessel. The mixture was heated and reacted in an oil bath at 100° C. for 48 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluate, eluate was distilled off to obtain 5-methyl-8-(nitromethyl)3-phenylquinoline (81% yield).

Yellow liquid IR(neat):ν=1517(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ ,500MHz):δ9.26(d,J=2.0Hz,1H),8.52(s,1H),7.74 –7.72(m,3H),7.59–7.45(m,5H),6.22(s,2H),2.79(s,3H); ¹³ C NMR(CDCl ₃ ,125MHz):δ149.1,137.0,134.2,129.3,128.4 ,127.9,127.6,127.5,127.2,71.4,18.9;

Example 4:

Add 0.5mmol of 6-chloro-8-methyl 3-phenylquinoline, 0.06mmol of palladium trifluoroacetate, 1.5mmol of tert-butyl nitrite and 3ml of 1,2-dichloroethane to 25ml of In a sealed pressure vessel. The mixture was heated and reacted in an 80°C oil bath for 48 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluent, eluent was evaporated to obtain 6-chloro-8-(nitromethyl)3-phenylquinoline (50% yield).

Yellow liquid, IR(neat): ν=1518(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ ,500MHz): δ9.21(d, J=2.0Hz, 1H), 8.23(d, J=2.5 Hz,1H),7.90(d,J=2.0Hz,1H),7.74–7.47(m,6H),6.20(s,2H); ¹³ C NMR(CDCl ₃ ,125MHz):δ150.0,143.4,137.1,135.4 ,132.3,129.9,129.3,128.6,127.8,127.4,70.1;

Example 5:

Under an oxygen atmosphere, 0.5 mmol of 5,8-dimethylquinoline, 0.05 mmol of palladium dichloride, 1.5 mmol of tert-butyl nitrite and 5 ml of 1,2-dichloroethane were sequentially added into a 25 ml sealed pressure vessel. The mixture was heated and reacted in an oil bath at 1100° C. for 48 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluate, eluate was evaporated to give 5-methyl-8-(nitromethyl)quinoline (43% yield).

White solid, mp82-84℃; IR(neat): ν＝1515(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ8.98(dd, J ₁ ＝4.5Hz, J ₂ ＝1.5 Hz, 1H), 8.38 (dd, J1 ₌ 8.5Hz, J2 = 2.0Hz, 1H ₎ , 7.70 (d, J = 9.0Hz, 1H), 7.50 (dd, J1 ₌ 8.5Hz, _J2 = 4.0 Hz,1H),7.40(d,J=7.0Hz,1H),6.17(s,2H),2.72(s,3H); ¹³ CNMR(CDCl ₃ ,125MHz):δ149.8,146.3,136.8,132.9,130.2, 128.4, 127.7, 126.6, 121.2, 71.5, 18.7;

Embodiment 6:

Under an oxygen atmosphere, add 0.5mmol of 5-fluoro-8-methylquinoline, 0.05mmol of diacetonitrile palladium dichloride, 1.5mmol of tert-butyl nitrite and 5ml of 1,2-dichloroethane to a 25ml sealing pressure in the container. The mixture was heated and reacted in an oil bath at 120° C. for 48 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluent, eluent was evaporated to obtain 5fluoro-8-(nitromethyl)quinoline (63% yield).

White solid; mp51-53℃; IR(KBr): ν=1519(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ9.02(dd, J ₁ ＝4.5Hz, J ₂ ＝1.5 Hz, 1H), 8.47 (dd, J1 ₌ 8.5Hz, J2 = 2.0Hz, 1H ₎ , 7.77 (dd, J1 ₌ 7.5Hz, J2 = 2.0Hz, 1H ₎ , 7.54 (dd, J1 ₌ 8.5Hz, J ₂ ＝4.0Hz, 1H), 7.24(dd, J ₁ ＝8.0Hz, J ₂ ＝1.5Hz, 1H), 6.15(s, 2H); ¹³ C NMR (CDCl ₃ , 125MHz): δ158. 6(d, J=257.5Hz), 151.2, 146.9(d, J=2.5Hz), 130.2(d, J=10Hz), 129.5(d, J=5Hz), 126.7(d, J=3.8Hz), 121.7(d, J=2.5Hz), 119.2(d, J=16.3Hz), 109.7(d, J=20Hz), 70.7;

Embodiment 7:

Under an oxygen atmosphere, 0.5 mmol of 6,8-dimethylquinoline, 0.05 mmol of palladium trifluoroacetate, 2 mmol of tert-butyl nitrite and 5 ml of 1,2-dichloroethane were sequentially added into a 25 ml sealed pressure vessel. The mixture was heated and reacted in an 80° C. oil bath for 30 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluate, eluate was evaporated to obtain 6-methyl 8-(nitromethyl)quinoline (61% yield).

White solid; mp62-64℃; IR(KBr): ν=1517(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ8.90(d, J=2.5Hz, 1H), 8.11( dd, J ₁ =8.0Hz, J ₂ =1.5Hz, 1H), 7.64(s, 2H), 7.44(dd, J ₁ =8.0Hz, J ₂ =4.0Hz, 1H), 6.18(s, 2H), 2.56(s,3H); ¹³ C NMR (CDCl ₃ , 125MHz): δ149.5, 144.8, 136.1, 135.6, 132.2, 130.2, 128.4, 128.2, 71.2, 21.6;

Embodiment 8:

Under an oxygen atmosphere, 0.5 mmol of 5-chloro-8-methylquinoline, 0.05 mmol of palladium diacetate, 2 mmol of tert-butyl nitrite and 4 ml of 1,2-dichloroethane were sequentially added to a 25 ml sealed pressure vessel. The mixture was heated in an oil bath at 90°C for 48 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluent, eluent was evaporated to give 5-chloro-8-(nitromethyl)quinoline (83% yield).

White solid, mp49-51℃; IR(KBr): ν=1519(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ9.00(dd, J ₁ ＝4.0Hz, J ₂ ＝1.5 Hz, 1H), 8.60 (dd, J ₁ =8.5Hz, J ₂ =2.0Hz, 1H), 7.72 (d, J = 7.5Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.58 ( t, J=4.0Hz, 1H), 6.16(s, 2H); ¹³ C NMR (CDCl ₃ , 125MHz): δ150.9, 146.6, 133.1, 132.9, 130.1, 129.5, 126.4, 126.2, 122.4, 70.7

Example 9

Under an oxygen atmosphere, 0.5 mmol of 7-chloro-8-methylquinoline, 0.05 mmol of palladium diacetate, 1.5 mmol of tert-butyl nitrite and 5 ml of acetonitrile were sequentially added into a 25 ml sealed pressure vessel. The mixture was heated and reacted in an oil bath at 110° C. for 36 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluate, eluate was evaporated to give 7-chloro-8-(nitromethyl)quinoline (70% yield).

White solid, mp106-108℃; IR(KBr): ν=1520(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ8.99(dd, J ₁ ＝4.0Hz, J ₂ ＝1.5 Hz,1H),8.18(d,J=8.0Hz,1H),7.85(d,J=8.5Hz,1H),7.60(d,J=8.0Hz,1H),7.48(dd,J ₌ 8.5Hz , J ₂ =4.5Hz, 1H), 6.39(s, 2H); ¹³ C NMR (CDCl ₃ , 125MHz): δ151.4, 147.4, 138.0, 136.2, 128.1, 127.2, 126.8, 121.7, 67.6;

Example 10

Add 0.5mmol of 5-bromo-8-methylquinoline, 0.05mmol of palladium trifluoroacetate, 2.5mmol of tert-butyl nitrite and 5ml of 1,2-dichloroethane into a 25ml sealed pressure vessel in an oxygen atmosphere . The mixture was heated and reacted in an oil bath at 100° C. for 24 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluent, eluent was evaporated to give 5-bromo-8-(nitromethyl)quinoline (56% yield).

White solid, mp47-48℃; IR(KBr): ν=1520(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ8.99(dd, J ₁ =4.5Hz, J ₂ =1.5 Hz, 1H), 8.59 (dd, J ₁ =8.5Hz, J ₂ =1.5Hz, 1H), 7.87 (d, J = 8.0Hz, 1H), 7.67 (d, J = 8.0Hz, 1H), 7.59 ( t, J＝4.5Hz, 1H), 6.17(s, 1H); ¹³ C NMR (CDCl ₃ , 125MHz): δ151.0, 146.7, 135.9, 130.9, 130.0, 129.9, 127.8, 123.6, 122.8, 70.7;

Example 11:

Under an oxygen atmosphere, 0.5 mmol of 6-nitro 8-methylquinoline, 0.06 mmol of palladium diacetate, 2 mmol of tert-butyl nitrite and 3 ml of 1,2-dichloroethane were sequentially added into a 25 ml sealed pressure vessel. The mixture was heated and reacted in an oil bath at 100° C. for 48 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluent, eluent was distilled off to obtain 6-nitro-8-(nitromethyl)quinoline (66% yield).

White solid; mp105-107℃; IR(KBr): ν=1523(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ9.14(dd, J ₁ ＝4.5Hz, J ₂ ＝2.0 Hz, 1H), 8.84 (d, J = 2.5Hz, 1H), 8.56 (d, J = 2.5Hz, 1H), 8.42 (dd, J ₁ = 8.5Hz, J ₂ = 1.5Hz, 1H), 7.67 ( dd, J ₁ =8.5Hz, J ₂ =4.5Hz, 1H), 6.24(s, 2H); ¹³ C NMR (CDCl ₃ , 125MHz): δ153.6, 147.8, 145.0, 138.2, 133.7, 127.2, 125.5, 123.5, 122.4, 69.8;

Example 12

Add 0.5mmol of 5-nitro-8-methylquinoline, 0.05mmol of palladium diacetate, 3mmol of tert-butyl nitrite and 5ml of 1,2-dichloroethane into a 25ml sealed pressure vessel in an oxygen atmosphere . The mixture was heated and reacted in an 80°C oil bath for 48 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluate, eluate was evaporated to obtain 5-nitro 8-(nitromethyl)quinoline (59% yield).

White solid, mp68-70℃; IR(KBr): ν=1519(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ9.08–9.04(m,2H), 8.40(d,J =8.0Hz, 1H), 7.88(d, J=8.0Hz, 1H), 7.73(dd, J ₁ =9.0Hz, J ₂ =4.5Hz, 1H), 6.28(s, 1H); ¹³ C NMR (CDCl _3,125MHz ):δ151.2,145.9,145.6,138.7,132.4,126.2,124.4,124.1,121.3,70.2;

Example 13

Add 0.5mmol of 5-phenyl-8-methylquinoline, 0.05mmol of palladium dichloride, 1.5mmol of tert-butyl nitrite and 5ml of 1,2-dichloroethane into a 25ml sealed pressure vessel in an oxygen atmosphere middle. The mixture was heated in an oil bath at 90°C for 48 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluate, eluate was evaporated to give 8-(nitromethyl)-5-phenylquinoline (53% yield).

White solid, mp88-90℃; IR(KBr): ν＝1518(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ8.97(dd, J ₁ ＝4.0Hz, J ₂ ＝1.5 Hz, 1H), 8.24 (d, J = 1.5Hz, 1H), 8.06 (dd, J ₁ = 9.5Hz, J ₂ = 2.0Hz, 1H), 7.72 (dd, J ₁ = 8.0Hz, J ₂ = 1.0 Hz,1H),7.54–7.45(m,4H),6.27(s,2H); ¹³ C NMR(CDCl ₃ ,125MHz):δ150.2,145.5,139.8,139.1,136.5,131.2,129.7,129.1,128.6,128.1 ,127.5,126.9,122.0,71.1;

Example 14:

Under an oxygen atmosphere, 0.5 mmol of 7-fluoro-8-methylquinoline, 0.05 mmol of palladium chloride, 2 mmol of tert-butyl nitrite and 5 ml of 1,2-dichloroethane were successively added into a 25 ml sealed pressure vessel. The mixture was heated in an oil bath at 90°C for 48 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluate, eluate was evaporated to give 7-fluoro-8-(nitromethyl)quinoline (55% yield).

White solid, mp86-88℃; IR(KBr): ν=1524(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ9.00(dd, J ₁ ＝4.0Hz, J ₂ ＝1.5 Hz,1H),8.20(dd,J ₁ =8.5Hz,J ₂ =2.0Hz,1H),7.93(dd,J ₁ =9.0Hz,J ₂ =6.0Hz,1H),7.48–7.39(m,2H ), 6.24 (d, J=1.5Hz, 2H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ162.3 (d, J=253.8Hz), 151.5, 147.4 (d, J=7.5Hz), 136.3 ,131.9(d,J=10Hz),125.3,121.0,116.8(d,J=25Hz),114.5(d,J=13.8Hz),64.2;

Example 15:

Under an oxygen atmosphere, 0.5 mmol of 6-chloro-8-methylquinoline, 0.05 mmol of palladium chloride, 1.5 mmol of tert-butyl nitrite and 5 ml of acetonitrile were sequentially added into a 25 ml sealed pressure vessel. The mixture was heated and reacted in an oil bath at 120° C. for 48 hours. After the TLC detection reaction was finished, the reaction solution was diluted with dichloromethane and filtered to obtain a clear liquid, which was separated by column chromatography (eluent ratio: sherwood oil to ethyl acetate volume ratio 10:1), and the product containing Eluent, eluent was evaporated to give 6-chloro-8-(nitromethyl)quinoline (62% yield).

White solid; mp52-54℃; IR(KBr): ν=1520(NO ₂ )cm ^-1 ; ¹ H NMR(CDCl ₃ , 500MHz): δ8.95(dd, J ₁ =4.0Hz, J ₂ =1.5 Hz, 1H), 8.13 (dd, J ₁ =8.5Hz, J ₂ =1.5Hz, 1H), 7.86 (d, J = 2.5Hz, 1H), 7.75 (d, J = 2.5Hz, 1H), 7.51 ( dd, J ₁ =8.0Hz, J ₂ =4.0Hz, 1H), 6.18(s, 2H); ¹³ C NMR (CDCl ₃ , 125MHz): δ150.4, 144.5, 135.4, 133.1, 132.0, 130.1, 129.0, 127.7, 122.5, 70.1.

Claims (10)

1. the method for the 8-(nitromethyl) quinoline compound shown in synthetic formula II, it is characterized in that described method is: The 8-methylquinoline compound shown in formula I is used as the raw material, and the catalyst and the nitrating reagent are added to the organic solvent, under an oxygen atmosphere, sealed and heated to 80-130°C for reaction, TLC tracking until the end of the reaction, the reaction solution Aftertreatment makes the 8-(nitromethyl) quinoline compound shown in formula II; In formula I or formula II, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are each independently hydrogen, C1-C3 alkyl, halogen, nitro, or C6-C12 aryl; Halogen is fluorine, chlorine, bromine or iodine; The catalyst is divalent palladium salt; the nitrating reagent is tert-butyl nitrite. 2. The method according to claim 1, characterized in that each of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ is independently hydrogen, methyl, fluorine, chlorine, bromine, nitro or phenyl. 3. The method according to claim 1, characterized in that the catalyst is palladium dichloride, palladium diacetate, diacetonitrile palladium dichloride or palladium trifluoroacetate. 4. The method according to claim 1, characterized in that the ratio of the amount of the catalyst to the 8-methylquinoline compound represented by formula I is 1:5-10. 5. The method according to claim 1, characterized in that the ratio of the amount of said nitrating reagent to the amount of 8-methylquinoline compounds shown in formula I is 1 to 4:1. 6. The method according to claim 1, characterized in that the organic solvent is acetonitrile, tetrahydrofuran or 1,2-dichloroethane. 7. The method according to claim 1, characterized in that the volumetric amount of the organic solvent is 5 to 20 mL/mmol based on the amount of 8-methylquinoline compounds shown in formula I. 8. the method for claim 1, it is characterized in that described reaction solution aftertreatment method is, after reaction finishes, reaction solution is filtered with dichloromethane dilution, and filtrate is separated by column chromatography, and eluent is petroleum A mixed solvent of ether and ethyl acetate with a volume ratio of 10:1 was used to collect the eluate containing the product, and the eluate was evaporated to remove the solvent to obtain the 8-(nitromethyl)quinoline compound represented by formula II. 9. the method for the 8-methylaminotetrahydroquinoline compound shown in synthetic formula III, it is characterized in that described method comprises the following steps: (1) Take the 8-methylquinoline compound shown in formula I as raw material, add catalyst and nitrating reagent to organic solvent, under oxygen atmosphere, heat up to 80-130°C in airtight reaction, TLC tracking until the end of the reaction , the post-treatment of the reaction solution makes 8-(nitromethyl)quinoline compounds shown in formula II; (2) Under an ice bath, add 8-(nitromethyl)quinoline compounds shown in formula II and nickel dichloride hexahydrate into methanol solvent, then slowly add sodium borohydride, and stir for 30 to 60 minutes , the reaction product is processed to obtain 8-methylaminotetrahydroquinoline compounds shown in formula III; In formula I, formula II or formula III, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are each independently hydrogen, C1-C3 alkyl, halogen, nitro or C6-C12 aryl ; The halogen is fluorine, chlorine, bromine or iodine; In the step (1), the catalyst is divalent palladium salt; the nitrating reagent is tert-butyl nitrite. 10. the method for claim 9 is characterized in that in described step (2), the substance of 8-(nitromethyl) quinoline compounds shown in described formula II and nickel dichloride hexahydrate The ratio of the amount of the 8-(nitromethyl) quinoline compound shown in the formula II to the amount of sodium borohydride is 1:20.