A method of synthesizing 2-methyl-8-nitroquinoline

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 2-methyl-8-nitroquinoline. The method comprises the following steps: in an inert gas atmosphere, under the action of an oxidant, o-nitroaniline is first reacted with a protonic acid, and then an aldehyde compound is added to perform a condensation reaction, and 2-methyl-8-nitroquinoline is obtained. In the condensation process, the inert gas protection is adopted to avoid the generation of tar-like by-products in the reaction system, and the yield and purity of 2-methyl-8-nitroquinoline are improved. A new type of oxidant, such as 1,2-dinitrobenzene, dinitrobenzene, 3,5-dinitroaniline and 2,4-dinitroaniline, is adopted to avoid the participation of the substrate o-nitroaniline in the reaction as an oxygen source, and the yield and purity of the product are improved. Meanwhile, the oxidant itself is completely or partially generated into o-nitroaniline, which can be used as a substrate to react, and the yield of the product is further improved. The reaction condition is mild, raw materials are cheap, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 2-methyl-8-nitroquinoline. Background Art

[0002] Nitro-substituted quinolines (nitro-substituted quinalidines) are an important class of compounds and essential intermediates for a variety of fine chemicals. They can be used in certain functional materials such as dyes and pigments. Due to the wide range of applications of nitro-substituted quinalidine compounds, several synthetic methods have been developed in recent years. 2-Methyl-8-nitroquinoline is an intermediate used in the preparation of 2-methyl-8-aminoquinoline, an organic pigment intermediate. The structural formula of 2-methyl-8-nitroquinoline is shown in Formula I.

[0003] Its molecular weight is 188 g / mol.

[0004] Ganesabaskaran Sivaprasad et al. used phosphotungstic acid as a catalyst, 2-nitroaniline or 4-nitroaniline and crotonaldehyde under heating or microwave treatment with a yield of 75-83% to synthesize 6-nitroquinaidine and 8-nitroquinaidine (Tetrahedron Letters 2006, 47, 1783-1785).

[0005] Chinese invention patent CN108727261A provides a method for preparing a nitro-substituted quinaldine. The method is specifically achieved by the following steps: nitroaniline and crotonaldehyde compounds react under the conditions of hydrochloric acid and zinc chloride catalysis to obtain the target nitro-substituted quinaldine. The disadvantage of this method is that since the reaction is carried out in an air atmosphere, both o-nitroaniline and crotonaldehyde are extremely easy to deteriorate during the reaction, producing a large amount of tar-like byproducts. Therefore, crotonaldehyde needs to be fed in excess. The final yield is 83-93%, but the product contains a large number of byproducts and has low purity, which seriously affects the subsequent nitro reduction reaction.

[0006] Another Chinese invention patent, CN101429157A, provides a method for preparing 2-methyl-8-nitroquinoline. The method comprises reacting o-nitroaniline in a hydrochloric acid and benzene solution to generate o-nitroaniline hydrochloride, then subjecting the o-nitroaniline hydrochloride to a cyclization reaction with an aldehyde at 10-100°C, followed by an oxidation reaction with an oxidant at 10-100°C, and finally obtaining 2-methyl-8-nitroquinoline through separation, neutralization, water washing, and drying. The yield is 80% and the purity is 95%.

[0007] In summary, the existing methods for synthesizing 2-methyl-8-nitroquinoline generally have disadvantages such as low yield, low purity, and harsh reaction conditions, which are not conducive to industrial production. In view of this, the development of a new method for synthesizing 2-methyl-8-nitroquinoline is particularly important. Summary of the Invention

[0008] In view of the problems existing in the prior art, the present invention provides a method for synthesizing 2-methyl-8-nitroquinoline, which has the advantages of simple and mild reaction conditions, high product yield and high purity.

[0009] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0010] A method for synthesizing 2-methyl-8-nitroquinoline comprises the following steps: firstly reacting o-nitroaniline with a protonic acid in an inert atmosphere under the action of an oxidant, and then adding an aldehyde compound for condensation reaction to obtain the product.

[0011] Preferably, the inert atmosphere is nitrogen or argon.

[0012] Preferably, the oxidant is selected from one or more of 1,2-dinitrobenzene, dinitrobenzene, 3,5-dinitroaniline and 2,4-dinitroaniline.

[0013] More preferably, the oxidant is 1,2-dinitrobenzene or 2,4-dinitrobenzene.

[0014] Preferably, the molar ratio of o-nitroaniline to the oxidant is 3-10:1.

[0015] More preferably, the molar ratio of o-nitroaniline to the oxidant is 3-5:1.

[0016] Preferably, the protonic acid is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, formic acid and acetic acid.

[0017] Preferably, the molar amount of hydrogen ions in the protonic acid is 3-5 times the molar amount of o-nitroaniline.

[0018] Preferably, the temperature for the reaction of o-nitroaniline with protonic acid is 20-60° C., and the reaction time is 1-2 h.

[0019] More preferably, the temperature for the reaction of o-nitroaniline with protonic acid is 50-60° C., and the reaction time is 1-1.5 h.

[0020] Preferably, the reaction of o-nitroaniline with protonic acid requires adding a solvent and stirring.

[0021] Preferably, the solvent is selected from one or more of toluene, xylene, chlorobenzene and cyclohexane.

[0022] Preferably, the volume-mass ratio of the solvent to o-nitroaniline is 6-10 mL:1 g.

[0023] More preferably, the volume-mass ratio of the solvent to o-nitroaniline is 6-8 mL:1 g.

[0024] Preferably, the aldehyde compound is selected from one or more of acetaldehyde, paraldehyde and crotonaldehyde.

[0025] Preferably, the aldehyde compound is diluted with a solvent, and the molar volume ratio of the aldehyde compound to the solvent is 1 mol:100-200 mL.

[0026] Preferably, the molar ratio of the o-nitroaniline to the aldehyde compound is 1:1-1.3.

[0027] Preferably, the addition of the aldehyde compound is controlled in terms of temperature and time, the temperature being 20-70℃ and the time being 1.5-2.5 h.

[0028] More preferably, the temperature is 50-70℃ and the time is 2-2.5 h.

[0029] Preferably, the temperature of the condensation reaction is 20-70℃ and the time of the condensation reaction is 2-8 h.

[0030] More preferably, the temperature of the condensation reaction is 50-70℃ and the time of the condensation reaction is 5-7 h.

[0031] Preferably, after the condensation reaction, the inert environment is removed, the reaction is continued in an air atmosphere, water-phase extraction is performed, a lye is added to a pH of 5.5-7, and filtration, washing and drying are performed.

[0032] Preferably, the reaction in the air atmosphere is continued with stirring, and the stirring time is 0.5-1 h.

[0033] Preferably, the extraction solvent is toluene, xylene, chlorobenzene or cyclohexane, and the extraction is performed 2-4 times.

[0034] Preferably, the lye is selected from any one of a 30% sodium hydroxide solution, a sodium bicarbonate solution or a sodium carbonate solution.

[0035] The application also provides the use of 2-methyl-8-nitroquinoline synthesized by the above method in the preparation of pigments and pharmaceutical intermediates.

[0036] Compared with the prior art, the application has the following beneficial effects:

[0037] 1. The present invention adopts inert gas protection during the condensation process to avoid the phenomenon that the substrate o-nitroaniline and aldehyde compound undergo qualitative change to generate tar-like by-products in the reaction system, thereby greatly improving the yield and purity of 2-methyl-8-nitroquinoline.

[0038] 2. The present invention uses a new oxidant in the condensation process, such as 1,2-dinitrobenzene, dinitrobenzene, 3,5-dinitroaniline and 2,4-dinitroaniline, which has a better oxidizing ability than o-nitroaniline, thereby avoiding the substrate o-nitroaniline from acting as an oxygen source to participate in the oxidative dehydrogenation reaction; at the same time, after the oxidant is reduced, all or part of the product itself generates o-nitroaniline, which can be used as a substrate for the condensation reaction, thereby further improving the yield of 2-methyl-8-nitroquinoline.

[0039] 3. The reaction conditions of the present invention are mild, the raw materials are cheap, and compared with the existing technology, the yield and purity of 2-methyl-8-nitroquinoline are greatly improved, so the present invention is suitable for industrial production and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 This is the mass spectrum of the product 2-methyl-8-nitroquinoline prepared in Example 2. DETAILED DESCRIPTION

[0041] The present invention will be further described below with reference to specific examples. The advantages and features of the present invention will become more apparent as the description proceeds. However, these examples are merely exemplary and do not limit the scope of the present invention in any way. The methods, ingredients, and amounts used in the following examples are all conventional methods known to those skilled in the art, unless otherwise specified.

[0042] It is worth noting that the raw materials used in the present invention are all common commercially available products, among which hydrochloric acid, with a specification of 30%, was purchased from Hangzhou Yongbang Chemical Co., Ltd.; sulfuric acid, with a specification of 98%, was purchased from Hangzhou Liuyuan Chemical Co., Ltd.; nitric acid, with a specification of 50%, was purchased from Hangzhou Tenglong Chemical Co., Ltd.; acetic acid, with a specification of 68%, was purchased from Shanghai Huayi Energy Chemical Co., Ltd.; dinitrobenzene was purchased from Lanzhou Huishunyuan Fine Chemical Co., Ltd.; and 1,2-dinitrobenzene was purchased from Adamas Beta Chemical Reagent Co., Ltd.

[0043] Example 1

[0044] Under nitrogen, 250 mL of cyclohexane and 27.6 g (0.2 mol) of o-nitroaniline were added to a four-necked flask and stirred thoroughly. 108 g of nitric acid and 8.9 g (0.053 mol) of dinitrobenzene were then added dropwise at 50°C for 1 hour. Then, 26.4 g (0.2 mol, previously diluted with 35 mL of cyclohexane) of paraldehyde were added dropwise at 65°C for 2 hours. After the addition was complete, the reaction was continued at this temperature for 3 hours. The nitrogen atmosphere was removed and stirring continued for 0.5 hours. After the reaction was complete, the aqueous phase was removed and extracted twice with 100 mL of cyclohexane each. Finally, the aqueous phase was neutralized to pH 7 with 82 mL of 30% sodium hydroxide solution, filtered, washed, and dried to obtain the desired product, 2-methyl-8-nitroquinoline, as a light brown solid in a yield of 78.7% and a purity of 98.8%.

[0045] Example 2

[0046] Under argon, 200 mL of xylene and 27.6 g (0.2 mol) of o-nitroaniline were added to a four-necked flask and stirred thoroughly. Then, 97.3 g of hydrochloric acid and 8.4 g (0.05 mol) of 1,2-dinitrobenzene were added and allowed to react at 55°C for 1 hour. Then, 16.8 g (0.24 mol, diluted with 30 mL of xylene) of crotonaldehyde was added dropwise at 70°C for 2 hours. After the addition was complete, the reaction was continued at this temperature for 3 hours. The argon atmosphere was removed and stirring continued for 0.5 hours. After the reaction, the aqueous phase was removed and extracted twice with 100 mL of xylene. Finally, the aqueous phase was neutralized to pH 6 with 80 mL of 30% sodium hydroxide solution. The mixture was filtered, washed, and dried to obtain the desired product, 2-methyl-8-nitroquinoline, as a light brown solid in an 80.8% yield and 99.2% purity.

[0047] The mass spectrum of the product 2-methyl-8-nitroquinoline prepared in this example is as follows Figure 1 shown.

[0048] Example 3

[0049] Under nitrogen, 200 mL of toluene and 28.3 g (0.205 mol) of o-nitroaniline were added to a four-necked flask and stirred thoroughly. 70 g of hydrochloric acid, 14 g of sulfuric acid, and 8.4 g (0.05 mol) of 1,2-dinitrobenzene were then added dropwise at 50°C for 1.2 hours. Then, 16.8 g (0.24 mol, diluted with 30 mL of toluene) of crotonaldehyde was added dropwise at 65°C for 2 hours. After the addition was complete, the reaction was continued at this temperature for 3 hours. The nitrogen atmosphere was removed and stirring continued for 0.5 hours. After the reaction, the aqueous phase was removed and extracted twice with 100 mL of toluene each time. Finally, the aqueous phase was neutralized to pH 5.5 with 150 mL of 30% sodium carbonate solution. The mixture was filtered, washed, and dried to obtain the desired product, 2-methyl-8-nitroquinoline, as a light brown solid in an 80.6% yield and 99.3% purity.

[0050] Example 4

[0051] Under nitrogen, add 200 mL of chlorobenzene and 27.9 g (0.202 mol) of o-nitroaniline to a four-necked flask and stir thoroughly. Then add 88 g of acetic acid and 8.4 g (0.05 mol) of 2,4-dinitroaniline. React at 55°C for 1.5 hours. Then, add a mixture of 19.8 g (0.15 mol) of paraldehyde and 3.1 g (0.07 mol) of acetaldehyde (previously diluted with 32 mL of chlorobenzene) dropwise at 55°C for 2.5 hours. After completion, continue the reaction at this temperature for 4 hours. Remove the nitrogen atmosphere and continue stirring for 0.5 hours. After the reaction, the lower aqueous phase was removed and extracted three times with 100 mL of chlorobenzene. Finally, the aqueous phase was neutralized to pH 6 with 143 mL of 30% sodium carbonate solution, filtered, washed, and dried to obtain the target product 2-methyl-8-nitroquinoline as a light brown solid with a yield of 80.3% and a purity of 98.9%.

[0052] Comparative Example 1

[0053] The same as Example 2, the only difference is that the reaction atmosphere is air.

[0054] Under air, 200 mL of xylene and 27.6 g (0.2 mol) of o-nitroaniline were added to a four-necked flask and stirred thoroughly. Then, 97.3 g of hydrochloric acid and 8.4 g (0.05 mol) of 1,2-dinitrobenzene were added and allowed to react at 55°C for 1 hour. Then, 16.8 g (0.24 mol, diluted in 30 mL of xylene) of crotonaldehyde was added dropwise at 70°C for 2 hours. After the addition was complete, the reaction was continued at this temperature for 3 hours and stirring was continued for 0.5 hour. After the reaction, the aqueous phase was removed and extracted twice with 100 mL of xylene. Finally, the aqueous phase was neutralized to pH 6 with 80 mL of 30% sodium hydroxide solution. The mixture was filtered, washed, and dried to obtain the desired product, 2-methyl-8-nitroquinoline, as a light brown solid with a yield of 75.3% and a purity of 96.6%.

[0055] Comparative Example 2

[0056] The same as Example 2, except that the oxidant is zinc chloride.

[0057] Under argon, 200 mL of xylene and 27.6 g (0.2 mol) of o-nitroaniline were added to a four-necked flask and stirred thoroughly. 97.3 g of hydrochloric acid and 6.8 g (0.05 mol) of zinc chloride were then added dropwise at 55°C for 1 hour. Then, 16.8 g (0.24 mol, diluted with 30 mL of xylene) of crotonaldehyde was added dropwise at 70°C for 2 hours. After the addition was complete, the reaction was continued at this temperature for 3 hours. The argon atmosphere was removed and stirring continued for 0.5 hours. After the reaction was complete, the aqueous phase was removed and extracted twice with 100 mL of xylene. Finally, the aqueous phase was neutralized to pH 6 with 80 mL of 30% sodium hydroxide solution. The mixture was filtered, washed, and dried to obtain the desired product, 2-methyl-8-nitroquinoline, as a light brown solid in a yield of 77.9% and a purity of 98.2%.

[0058] Comparative Example 3

[0059] The same as Example 2, except that the oxidant is nitrobenzene.

[0060] Under argon, 200 mL of xylene and 27.6 g (0.2 mol) of o-nitroaniline were added to a four-necked flask and stirred thoroughly. 97.3 g of hydrochloric acid and 6.2 g (0.05 mol) of nitrobenzene were then added dropwise at 55°C for 1 hour. Then, 16.8 g (0.24 mol, previously diluted with 30 mL of xylene) of crotonaldehyde was added dropwise at 70°C for 2 hours. After the addition was complete, the reaction was continued at this temperature for 3 hours. The argon atmosphere was removed and stirring continued for 0.5 hours. After the reaction was complete, the aqueous phase was removed and extracted twice with 100 mL of xylene. Finally, the aqueous phase was neutralized to pH 6 with 80 mL of 30% sodium hydroxide solution, filtered, washed, and dried to obtain the desired product, 2-methyl-8-nitroquinoline, as a light brown solid in a yield of 78.7% and a purity of 98.6%.

[0061] Comparative Example 4

[0062] The same as Example 2, except that no extraction was performed after the reaction was completed.

[0063] Under argon, 200 mL of xylene and 27.6 g (0.2 mol) of o-nitroaniline were added to a four-necked flask and stirred thoroughly. Then, 97.3 g of hydrochloric acid and 8.4 g (0.05 mol) of 1,2-dinitrobenzene were added and allowed to react at 55°C for 1 hour. Then, 16.8 g (0.24 mol, previously diluted with 30 mL of xylene) of crotonaldehyde was added dropwise at 70°C for 2 hours. After the addition was complete, the reaction was continued at this temperature for 3 hours. The argon atmosphere was removed and stirring continued for 0.5 hours. After the reaction, the aqueous phase was neutralized to pH 6 with 80 mL of 30% sodium hydroxide solution, filtered, washed, and dried to obtain the desired product, 2-methyl-8-nitroquinoline, as a dark brown solid in an 89.8% yield and 94.4% purity.

[0064] Comparative Example 5

[0065] The same as Example 2, the only difference is that it is a one-step reaction.

[0066] Under argon, 200 mL of xylene and 27.6 g (0.2 mol) of o-nitroaniline were added to a four-necked flask and stirred thoroughly. 97.3 g of hydrochloric acid and 8.4 g (0.05 mol) of 1,2-dinitrobenzene were then added dropwise. 16.8 g (0.24 mol, previously diluted with 30 mL of xylene) of crotonaldehyde was added dropwise at 70°C for 2 hours. After the addition was complete, the reaction was continued at this temperature for 3 hours. The argon atmosphere was removed and stirring continued for 0.5 hours. After the reaction, the aqueous phase was removed and extracted twice with 100 mL of xylene. Finally, the aqueous phase was neutralized to pH 6 with 80 mL of 30% sodium hydroxide solution. The mixture was filtered, washed, and dried to obtain the desired product, 2-methyl-8-nitroquinoline, as a dark brown solid in a yield of 73.8% and a purity of 98.3%.

[0067] Comparative Example 6

[0068] The same as Example 2, except that the molar ratio of o-nitroaniline to the oxidant is different.

[0069] Under argon, 200 mL of xylene and 27.6 g (0.2 mol) of o-nitroaniline were added to a four-necked flask and stirred thoroughly. 82.7 g of hydrochloric acid and 2.5 g (0.015 mol) of 1,2-dinitrobenzene were then added dropwise at 55°C for 1 hour. Then, 15.4 g (0.22 mol, diluted in 25 mL of xylene) of crotonaldehyde was added dropwise at 70°C for 2 hours. After the addition was complete, the reaction was continued at this temperature for 3 hours. The nitrogen atmosphere was removed and stirring continued for 0.5 hours. After the reaction, the aqueous phase was removed and extracted twice with 100 mL of xylene. Finally, the aqueous phase was neutralized to pH 6 with 68 mL of 30% sodium hydroxide solution. The mixture was filtered, washed, and dried to obtain the desired product, 2-methyl-8-nitroquinoline, as a brownish-yellow solid in a yield of 75.9% and a purity of 98.6%.

[0070] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing 2-methyl-8-nitroquinoline, characterized in that: The method comprises the following steps: firstly reacting o-nitroaniline with protonic acid in an inert atmosphere under the action of an oxidant, and then adding an aldehyde compound to carry out a condensation reaction to obtain: The inert atmosphere is nitrogen or argon, the oxidant is 1,2-dinitrobenzene, and the molar ratio of o-nitroaniline to the oxidant is 4:1 or 4.1:

1. After the condensation reaction is completed, the inert environment is removed, the reaction is continued in an air atmosphere, and then aqueous phase extraction is performed, alkali solution is added to the pH value of 5.5 or 6, and the reaction is filtered, washed and dried.

2. The method according to claim 1, characterized in that The protonic acid is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, formic acid and acetic acid. The molar amount of hydrogen ions in the protonic acid is 3-5 times the molar amount of o-nitroaniline. The temperature of the reaction of o-nitroaniline and the protonic acid is 20-60° C., and the reaction time is 1-2 h.

3. The method according to claim 2, characterized in that The temperature for the reaction of o-nitroaniline and protonic acid is 50-60° C., and the reaction time is 1-1.5 h.

4. The method according to claim 1, wherein The reaction between o-nitroaniline and protonic acid requires adding a solvent and stirring. The solvent is selected from one or more of toluene, xylene, chlorobenzene, and cyclohexane. The volume mass ratio of the solvent to o-nitroaniline is 6-10 mL:1 g.

5. The method according to claim 4, characterized in that The aldehyde compound is selected from one or more of acetaldehyde, paraldehyde and crotonaldehyde. The aldehyde compound is diluted with a solvent, and the molar volume ratio of the aldehyde compound to the solvent is 1 mol:100-200 mL.

6. The method according to claim 1, characterized in that The molar ratio of o-nitroaniline to the aldehyde compound is 1:1-1.

3. The temperature and time of adding the aldehyde compound need to be controlled, and the temperature is 20-70° C. and the time is 1.5-2.5 h.

7. The method according to any one of claims 1 to 6, characterized in that The condensation reaction temperature is 20-70° C., and the condensation reaction time is 2-8 h.

8. The method according to claim 7, characterized in that The reaction is continued under air atmosphere and stirring is required, the stirring time is 0.5-1 h, the extraction solvent is toluene, xylene, chlorobenzene or cyclohexane, the number of extractions is 2-4 times, and the alkali solution is selected from any one of sodium hydroxide solution, sodium bicarbonate solution and sodium carbonate solution with a mass fraction of 30%.

Images