Preparation method for 3,7-dichloro-8-methylquinoline and use thereof

Abstract

Disclosed in the present invention is a preparation method for 3,7-dichloro-8-methylquinoline, comprising the following step: using 3-chloro-2-methylaniline as a starting material, carrying out a one-step cyclization or two-step cyclization reaction with chloro-substituted propanal or chloro-substituted acrolein to prepare 3,7-dichloro-8-methylquinoline. The 3,7-dichloro-8-methylquinoline prepared by the method has a high yield. Also disclosed in the present invention is use of the 3,7-dichloro-8-methylquinoline prepared by the preparation method in the preparation of 3,7-dichloro-8-quinolinecarboxylic acid. Since the quinoline ring of the starting material 3,7-dichloro-8-methylquinoline already bears chloro substituents, only a free radical reaction on the side chain of the quinoline ring occurs during chlorination, resulting in good selectivity and high purity.

Description

A method for preparing 3,7-dichloro-8-methylquinoline and its application Technical Field

[0001] This invention relates to the field of herbicide technology, specifically to a method for preparing 3,7-dichloro-8-methylquinoline and its application. Background Technology

[0002] Quinoline carboxylic acid herbicides (3,7-dichloro-8-quinoline carboxylic acid, CAS: 84087-01-4) are a new type of herbicide developed by BASF. Trade names include Quick Kill Barnyardgrass and Kebab. It can effectively control barnyardgrass, duckweed, foxtail grass, water celery and other weeds in rice fields. It is especially effective against barnyardgrass. It is safe for crops and the application time is not limited by the growth of weeds.

[0003] Chinese patent document CN101851197A discloses a method for synthesizing and purifying quinoline carboxylic acid herbicides. The method uses 3-chloro-2-methylaniline and glycerol as raw materials to prepare 7-chloro-8-methylquinoline. Then, 7-chloro-8-methylquinoline is chlorinated with chlorine to generate 3,7-dichloro-8-chloromethylquinoline. Finally, 3,7-dichloro-8-chloromethylquinoline is oxidized in concentrated sulfuric acid with concentrated nitric acid to obtain dichloroquinoline acid. A chlorination co-catalyst is added during the chlorination reaction, and an oxidation co-catalyst is added during the oxidation reaction. The use of catalysts increases the reaction yield to over 65%.

[0004] Chinese patent CN111377862A discloses a method for synthesizing quinoline carboxylic acid herbicides. The method involves preparing 7-chloro-8-methylquinoline using 3-chloro-2-methylaniline and glycerol as raw materials, chlorinating the side chain of 7-chloro-8-methylquinoline to obtain 7-chloro-8-quinoline carboxylic acid, and finally chlorinating at the 3-position to obtain the quinoline carboxylic acid herbicide.

[0005] Existing synthetic methods all require simultaneous chlorination reactions on the benzene ring and the methyl group. This process necessitates controlling the degree of chlorination to obtain a mixture of 3,7-dichloro-8-chloromethylquinoline and 3,7-dichloro-8,8-dichloromethylquinoline as the main components. However, the conditions for the chlorination reaction are difficult to control, making it challenging to focus on the target chlorinated product. The formation of other chlorinated impurities is unavoidable, and separating the target chlorinated product from these impurities is challenging. Laboratory methods typically employ post-treatment techniques such as column chromatography before proceeding with subsequent reactions, which is insufficient to meet the capacity and efficiency requirements of industrial production.

[0006] Industrial refining processes generate large volumes of wastewater, resulting in low yields and poor product quality. The traditional process of preparing quinoline rings using concentrated sulfuric acid, glycerol, and potassium iodide catalytic dehydration condensation involves complex intermolecular and intramolecular side reactions, leading to numerous and complex side reactions. The two-step byproducts are difficult to separate, resulting in low yields. Wastewater production varies from factory to factory, generating approximately 40-60 tons per ton, resulting in severe and difficult-to-treat waste.

[0007] Currently, the highest yield of quinoline carboxylic acid herbicides produced by existing technologies is only 80%–83%. Due to numerous and complex side reactions, the product purity is only 83%–86%. Even after complex purification processes, the content is only 88%–92%, resulting in significant purification losses, yet high-content products are still not obtainable. The highest purity on the market is only around 96%. During the production process, chlorinated impurities are carried into the final product, affecting its content. In some commercially available products, chlorine impurities at 3–4% of the ring can even be detected, leading to phytotoxicity and inhibiting demand and wider promotion.

[0008] Therefore, designing new routes and processes to reduce the generation of chlorinated impurities in side reactions is a problem that existing methods urgently need to overcome. Summary of the Invention

[0009] To address the aforementioned technical problems, this invention provides a method for preparing 3,7-dichloro-8-methylquinoline. This method uses 3-chloro-2-methylaniline as a raw material and synthesizes 3,7-dichloro-8-methylquinoline through a one-step or two-step cyclization process. The method yields 3,7-dichloro-8-methylquinoline in high yield.

[0010] A method for preparing 3,7-dichloro-8-methylquinoline includes the following steps: using 3-chloro-2-methylaniline as a starting material, 3,7-dichloro-8-methylquinoline is prepared by a one-step or two-step cyclization reaction with chlorinated propionaldehyde or chlorinated acrolein. The specific synthetic route is as follows:

[0011] X and Y are each independently selected from one of the following groups: halogen, sulfonyl, ester, diazo, hydroxyl, and cyano.

[0012] In this invention, the halogen can be fluorine, chlorine, bromine, or iodine; the sulfonyl group can be trifluoromethanesulfonyl or p-toluenesulfonyl; and the ester group can be nitrate ester, acetate ester, propionate ester, isopropionate ester, tert-butyrate ester, butyrate ester, valerate ester, or isovalerate ester.

[0013] In this invention, 3,7-dichloro-8-methylquinoline can be synthesized using one-step and two-step cyclization. The principle of cyclization is that aniline first undergoes a condensation reaction with an aldehyde starting material (Ⅱ-1~Ⅱ-3) to obtain an imine intermediate (Ⅲ-1~Ⅲ-3), and then the imine intermediate (Ⅲ-1~Ⅲ-3) undergoes a cyclization reaction to obtain 3,7-dichloro-8-methylquinoline. When using the one-step cyclization method, the temperature required for the condensation reaction between aniline and the aldehyde starting material (Ⅱ-1~Ⅱ-3) is relatively high, which may reduce the selectivity of the condensation reaction and lead to more byproducts. When using the two-step cyclization method, the condensation reaction between aniline and the aldehyde starting material (Ⅱ-1~Ⅱ-3) can occur at a lower temperature. The condensation reaction at a lower temperature has better selectivity and almost no byproducts; therefore, the yield of the two-step cyclization method is higher than that of the one-step cyclization method.

[0014] The one-step cyclization reaction step is as follows: 3-chloro-2-methylaniline is reacted with chlorinated propionaldehyde (II-2) or chlorinated acrolein (II-1, II-3) in a solvent under the action of a catalyst.

[0015] Preferably, in the one-step cyclization reaction, the molar ratio of 3-chloro-2-methylaniline to the catalyst is 10 to 500:1.

[0016] Preferably, the temperature of the one-step cyclization reaction is 50–150°C, and the reaction time is 4–15 h.

[0017] More preferably, the molar ratio of 3-chloro-2-methylaniline to catalyst is 15-30:1, the temperature of the one-step cyclization reaction is 80-100°C, and the reaction time is 7-12 h.

[0018] The two-step cyclization reaction is as follows:

[0019] (1) 3-Chloro-2-methylaniline is condensed with chlorinated propionaldehyde or chlorinated acrolein in a solvent to generate an imine intermediate (Ⅲ-1~Ⅲ-3).

[0020] (2) The imine intermediate obtained in step (1) is placed in a solvent and subjected to intramolecular cyclization under the action of a catalyst to obtain 3,7-dichloro-8-methylquinoline.

[0021] In this invention, the two-step cyclization reaction is carried out by condensation reaction at a lower temperature and intramolecular cyclization reaction at a higher temperature. The dichloro compound with quinoline ring structure is prepared from aniline and aldehyde raw materials (Ⅱ-1~Ⅱ-3). The condensation reaction at the lower temperature has good selectivity, fewer by-products, and higher yield.

[0022] Preferably, the condensation reaction temperature is 30–60°C and the reaction time is 0.1–6 h.

[0023] More preferably, the condensation reaction temperature is 40–50°C and the reaction time is 0.5–3 h.

[0024] Preferably, the molar ratio of the imine intermediate to the catalyst is 10 to 500:1.

[0025] More preferably, the molar ratio of the imine intermediate to the catalyst is 15 to 30:1.

[0026] Preferably, the intramolecular cyclization reaction temperature is 80–180°C, and the reaction time is 2–10 h.

[0027] More preferably, the intramolecular cyclization reaction temperature is 90–150°C, and the reaction time is 5–8 h.

[0028] In this invention, when the reaction temperature and time are within the above range, the yield of the intramolecular cyclization reaction can be as high as 97%.

[0029] More preferably, the molar ratio of 3-chloro-2-methylaniline to chlorinated propionaldehyde or chlorinated acrolein is 1 to 2:1.

[0030] More preferably, the catalysts for the one-step cyclization reaction and the intramolecular cyclization reaction are all selected from metal halides, organic ammonium salts, cyclic ethers, organic acids, and inorganic acids.

[0031] In this invention, the metal halide can be potassium iodide, sodium iodide, lithium iodide, sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, lithium bromide, potassium fluoride, sodium fluoride, or lithium fluoride; the organic ammonium salt can be benzyltriethylammonium chloride, tetrabutylammonium hydroxide, or tetrabutylammonium bromide; the cyclic ether can be 18-crown-6 or 15-crown-5; the inorganic acid can be hydrochloric acid, sulfuric acid, or phosphoric acid; and the organic acid can be acetic acid, oxalic acid, propionic acid, butyric acid, isopropionic acid, or tert-butyric acid.

[0032] Preferably, the solvents for both one-step and two-step cyclization are alkyl acids, such as acetic acid, propionic acid, butyric acid, tert-butyric acid, valeric acid, isovaleric acid, hexanoic acid, heptanoic acid, octanoic acid, etc.

[0033] The present invention also provides 3,7-dichloro-8-methylquinoline prepared by the above preparation method.

[0034] The present invention also provides the use of 3,7-dichloro-8-methylquinoline in the preparation of 3,7-dichloro-8-quinoline carboxylic acid.

[0035] This invention provides a method for preparing 3,7-dichloro-8-quinoline carboxylic acid from 3,7-dichloro-8-methylquinoline. Since the quinoline ring of the raw material 3,7-dichloro-8-methylquinoline is already chlorinated, only the free radical reaction of the quinoline ring side chain occurs during chlorination, resulting in good selectivity and high purity.

[0036] A method for preparing 3,7-dichloro-8-quinoline carboxylic acid includes the following steps:

[0037] The 3,7-dichloro-8-methylquinoline obtained by the above method was placed in solvent I and subjected to a chlorination reaction of the side chain with chlorine gas under the action of an initiator to obtain the chlorinated methylquinoline product. The chlorinated methylquinoline product was then reacted with an oxidant in solvent II to obtain 3,7-dichloro-8-quinoline carboxylic acid.

[0038] The specific synthetic route is as follows:

[0039] In this invention, only the free radical reaction of the quinoline ring side chain occurs during chlorination, resulting in good selectivity and high purity. This avoids the generation of chlorination byproducts in the chlorination step on the quinoline ring in traditional methods, making the operation simpler and the conditions milder. At the same time, it improves selectivity and yield, with the highest yield reaching over 97%.

[0040] In this invention, the crude product of quinoline carboxylic acid herbicides obtained by the new process of side-chain chlorination followed by oxidation can reach a content of over 98%. After simple processing, the content can exceed 99%, resulting in a high-purity product. The oxidation process is simpler and more efficient, with a high yield, significantly reduced waste, and easy treatment and recycling. The operation is simpler, and the reaction conditions are milder. Each step of the reaction makes good use of the matching between molecular structure and activity, which can fundamentally solve the above-mentioned problems. Compared with the traditional process, it has greatly improved, reduced production costs, avoided or reduced the phytotoxicity caused by it, improved product efficacy, enhanced the applicability of the product, and may open up new space for the application market of the product.

[0041] Preferably, the initiator is an azo initiator, a peroxide initiator, or a persulfate initiator.

[0042] In this invention, the azo initiator can be azobisisobutyronitrile or azobisisoheptanenitrile; the peroxide initiator can be benzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, tert-butyl hydroperoxide, dicumyl peroxide, tert-butyl peroxide, tert-butyl peroxybenzoate, tert-butyl peroxyvalerate, methyl ethyl ketone peroxide or cyclohexanone peroxide; and the persulfate initiator can be potassium persulfate, sodium persulfate or ammonium persulfate.

[0043] Preferably, the molar ratio of 3,7-dichloro-8-methylquinoline to the initiator is 50 to 200:1.

[0044] Preferably, the chlorination reaction temperature of the side chain is 20–100°C, and the reaction time is 1–10 h.

[0045] More preferably, the initiator is an azo initiator, the molar ratio of 3,7-dichloro-8-methylquinoline to the initiator is 80-120:1, the chlorination reaction temperature of the side chain is 60-140°C, and the reaction time is 2-6 hours.

[0046] Preferably, the solvent I for the chlorination reaction of the side chain is one of o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, chlorobenzene, chloroform, carbon tetrachloride, 4-chlorotrifluoromethylbenzene, 3,4,5-trichlorotrifluoromethylbenzene, 1,3,5-trichloromethylbenzene, and 1,3,5-trifluoromethylbenzene.

[0047] More preferably, the chlorinated methylquinoline product is 3,7-dichloro-8-monochloromethylquinoline (Ⅳ-1) and 3,7-dichloro-8-dichloromethylquinoline (Ⅳ-2).

[0048] In this invention, the chlorination reaction occurs only at the 8-methyl group and not on the quinoline ring; therefore, the required chlorination temperature is relatively low (20–100 °C). The chlorination of the 8-methyl group yields a monochloro product, and the activation energy for the further formation of a dichloro product from the monochloro product is low. At the aforementioned temperature, both monochloro and dichloro products can be obtained. However, the activation energy for the further chlorination of the dichloro product to form a trichloro product is high, and this energy barrier cannot be reached at the chlorination temperature of this invention; therefore, no trichloro product is formed.

[0049] Preferably, the molar ratio of 3,7-dichloro-8-methylquinoline to the oxidant is 1:5 to 200.

[0050] Preferably, the oxidation reaction is carried out at a temperature of 40–180°C for 1–28 hours.

[0051] More preferably, the molar ratio of 3,7-dichloro-8-methylquinoline to the oxidant is 1:5 to 20, the oxidation reaction temperature is 70 to 130°C, and the reaction time is 2 to 5 hours. A method for preparing 3,7-dichloro-8-quinoline carboxylic acid includes the following steps:

[0052] The 3,7-dichloro-8-methylquinoline obtained by the above method was reacted directly with an oxidant in solvent II to obtain 3,7-dichloro-8-quinoline carboxylic acid.

[0053] The specific synthesis route is as follows:

[0054] Preferably, the oxidation reaction is carried out at a temperature of 50–200°C for 2–10 hours.

[0055] Preferably, the oxidant is at least one of hydrogen peroxide, oxygen, ozone, potassium permanganate, manganese dioxide, nitric acid, sulfuric acid, fuming nitric acid, sodium hypochlorite, cobalt triacetylacetonate, cobalt tetrapyridine dichromate, cobalt acetate, and manganese acetate, or a combination of hydrogen peroxide and an organic base.

[0056] In this invention, the aforementioned organic base may be pyridine, triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, trimethylamine, tri-n-butylamine, dimethylamine, methylamine, diethylamine, ethylamine, di-n-butylamine, n-butylamine, etc.

[0057] Preferably, the molar ratio of 3,7-dichloro-8-methylquinoline to the oxidant is 1:5 to 200.

[0058] More preferably, the molar ratio of 3,7-dichloro-8-methylquinoline to the oxidant is 1:5 to 20, the oxidation reaction temperature is 110 to 180°C, and the reaction time is 4 to 6 hours.

[0059] Preferably, the solvent II is an alkyl acid, such as acetic acid, propionic acid, butyric acid, tert-butyric acid, valeric acid, isovaleric acid, hexanoic acid, heptanoic acid, octanoic acid, etc.

[0060] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0061] (1) The present invention uses a newly self-synthesized halogenated propionaldehyde (or acrolein) intermediate as raw material, compared with the traditional method, and a two-step synthesis method with 3-chloro-2-methylaniline is simple and efficient, with high quinoline cyclization yield and no waste.

[0062] (2) The method for preparing 3,7-dichloro-8-quinoline carboxylic acid from 3,7-dichloro-8-methylquinoline is simpler and milder because the quinoline ring of the raw material 3,7-dichloro-8-methylquinoline has chlorine substitution. Therefore, only the free radical reaction of the quinoline ring side chain occurs during chlorination, avoiding the generation of chlorination byproducts in the chlorination step of the quinoline ring in the traditional method. The operation is simpler and the conditions are milder. At the same time, the selectivity and yield are improved. The yield can reach more than 97%. The crude product of the new process of obtaining quinoline carboxylic acid herbicides by direct oxidation with oxidant or chlorination of the side chain followed by oxidation can reach more than 98%. After simple treatment, the content can exceed 99%, and a high-purity product can be obtained.

[0063] (3) The oxidation process is simpler and more efficient, with a high yield. The amount of waste is greatly reduced and is easy to treat, recycle and reuse. The operation is simpler and the reaction conditions are milder. Each step of the reaction makes good use of the matching between molecular structure and activity, which can fundamentally solve the above problems. Compared with the traditional process, it has greatly improved, reduced production costs, and avoided or reduced the resulting phytotoxicity. It has improved product efficacy, enhanced the appropriateness of product promotion, and may open up new space for the application market of the product. Attached Figure Description

[0064] Figure 1 shows the 1H NMR spectrum of compound III-2 in Example 1.

[0065] Figure 2 shows the 1H NMR spectrum of 3,7-dichloro-8-methylquinoline (IV) in Example 1.

[0066] Figure 3 shows the purity test results of 3,7-dichloro-8-methylquinoline (IV) in Example 1.

[0067] Figure 4 is a comparison diagram of 3,7-dichloro-8-quinoline carboxylic acid (V) and dichloroquinoline acid standard in Example 12.

[0068] Figure 5 shows the purity test results of 3,7-dichloro-8-quinoline carboxylic acid (V) in Example 12. Detailed Implementation

[0069] The present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited to the following embodiments.

[0070] All raw materials used in this invention are commercially available. The synthesis methods of propionaldehyde and acrolein substituted with other leaving groups such as hydroxyl, trifluoromethanesulfonyl, and p-toluenesulfonyl are similar to those of propionaldehyde and acrolein substituted with chlorine.

[0071] Example 1: Synthesis of 3,7-dichloro-8-methylquinoline (IV)

[0072] (1) In a 250 mL three-necked flask, 3-chloro-2-methylaniline (Ⅰ) (14.1 g, 0.1 mol) and 50 mL acetic acid were added. The mixture was heated to 50 °C with stirring, and then 2,2,3-trichloropropanal (Ⅱ-2) (16.1 g, 0.1 mol) was added. After the addition was complete, the mixture was heated for another 1 h. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give 28.2 g of compound (Ⅲ-2), with a yield of 99.2%. The proton NMR spectrum of the obtained compound (Ⅲ-2) is shown in Figure 1. 1H NMR (500MHz, CDCl3) δ7.82(s,1H),7.26(dd,J=8.1,1.2Hz,1H),7.11(t,J=7.9Hz,1H),6.76(dd,J=7.9,1.2Hz,1H),4.39(s,2H),2.32(s,3H).

[0073] (2) Compound (III-2) (28.4 g, 0.1 mol) obtained in step (1) and potassium iodide (0.83 g, 0.005 mol) were added to a 250 mL three-necked flask. Then, 50 mL of acetic acid was added to dissolve the compound. The mixture was heated to 110 °C with stirring and kept at this temperature for 6 h. The mixture was then diluted with water, filtered, and alkalized with NaOH. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give 21.1 g of 3,7-dichloro-8-methylquinoline (Ⅳ), with a yield of 99.5%. The 1H NMR spectrum of 3,7-dichloro-8-methylquinoline (Ⅳ) is shown in Figure 2. 1 ¹H NMR (500MHz, CDCl₃) δ 8.85 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.64–7.47 (m, 2H), 2.87 (s, 3H); purity test results are shown in Figure 3, purity is above 99%.

[0074] Example 2: Synthesis of 3,7-dichloro-8-methylquinoline (IV)

[0075] (1) In a 250 mL three-necked flask, 3-chloro-2-methylaniline (Ⅰ) (14.1 g, 0.1 mol) and 50 mL acetic acid were added. The mixture was heated to 30 °C with stirring, and then 2,3-dichloropropenal (Ⅱ-1) (12.4 g, 0.1 mol) was added. After the addition was complete, the mixture was heated for another 0.5 h. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give 28.2 g of compound (Ⅲ-2), with a yield of 99.2%. 1 H NMR (500MHz, CDCl3) δ7.82(s,1H),7.26(dd,J=8.1,1.2Hz,1H),7.11(t,J=7.9Hz,1H),6.76(dd,J=7.9,1.2Hz,1H),4.39(s,2H),2.32(s,3H).

[0076] (2) Compound (III-2) (28.4 g, 0.1 mol) obtained in step (1) and tetrabutylammonium bromide (3.22 g, 0.01 mol) were added to a 250 mL three-necked flask. Then 50 mL of acetic acid was added to dissolve the compound. The mixture was heated to 80 °C with stirring and kept at that temperature for 2 h. The mixture was then diluted with water, filtered, and alkalized with NaOH. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried with anhydrous sodium sulfate. The mixture was concentrated to give 20.6 g of 3,7-dichloro-8-methylquinoline (Ⅳ), with a yield of 97.1% and a purity of over 99%. 1 H NMR (500MHz, CDCl3) δ8.85 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.64–7.47 (m, 2H), 2.87 (s, 3H).

[0077] Example 3: Synthesis of 3,7-dichloro-8-methylquinoline (IV)

[0078] (1) 3-chloro-2-methylaniline (Ⅰ) (14.1 g, 0.1 mol) and 50 mL of acetic acid were added to a 250 mL three-necked flask. The mixture was heated to 60 °C with stirring, and then 2-chloropropenal (Ⅱ-3) (9.01 g, 0.1 mol) was added. After the addition was complete, the mixture was heated for another 6 h. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give 28.2 g of compound (Ⅲ-2), with a yield of 99.2%. 1 H NMR (500MHz, CDCl3) δ7.82(s,1H),7.26(dd,J=8.1,1.2Hz,1H),7.11(t,J=7.9Hz,1H),6.76(dd,J=7.9,1.2Hz,1H),4.39(s,2H),2.32(s,3H).

[0079] (2) Compound (III-2) (28.4 g, 0.1 mol) and 18-crown-6 (0.5 g, 0.002 mol) obtained in step (1) were added to a 250 mL three-necked flask and then dissolved in 50 mL of acetic acid. The mixture was heated to 180 °C with stirring and kept at that temperature for 10 h. The mixture was then diluted with water, filtered, and alkalized with NaOH. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried with anhydrous sodium sulfate. The mixture was concentrated to give 20.4 g of 3,7-dichloro-8-methylquinoline (Ⅳ), with a yield of 96.2% and a purity of over 99%. 1H NMR (500MHz, CDCl3) δ8.85 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.64–7.47 (m, 2H), 2.87 (s, 3H).

[0080] Example 4: Synthesis of 3,7-dichloro-8-methylquinoline (IV)

[0081] (1) In a 250 mL three-necked flask, 3-chloro-2-methylaniline (Ⅰ) (14.1 g, 0.1 mol) and 50 mL acetic acid were added. The mixture was heated to 50 °C with stirring, and then 2,2,3-trichloropropanal (Ⅱ-2) (16.1 g, 0.1 mol) was added. After the addition was complete, the mixture was heated for another 1 h. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give 28.2 g of compound (Ⅲ-2), with a yield of 99.2%. 1 H NMR (500MHz, CDCl3) δ7.82(s,1H),7.26(dd,J=8.1,1.2Hz,1H),7.11(t,J=7.9Hz,1H),6.76(dd,J=7.9,1.2Hz,1H),4.39(s,2H),2.32(s,3H).

[0082] (2) Compound (III-2) (28.4 g, 0.1 mol) obtained in step (1) and potassium iodide (0.03 g, 0.0002 mol) were added to a 250 mL three-necked flask. Then 50 mL of acetic acid was added to dissolve the compound. The mixture was heated to 110 °C with stirring and kept at that temperature for 6 h. The mixture was then diluted with water, filtered, and alkalized with NaOH. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried with anhydrous sodium sulfate. The mixture was concentrated to give 18.2 g of 3,7-dichloro-8-methylquinoline (Ⅳ), with a yield of 85.4% and a purity of over 99%. 1 H NMR (500MHz, CDCl3) δ8.85 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.64–7.47 (m, 2H), 2.87 (s, 3H).

[0083] Example 5: Synthesis of 3,7-dichloro-8-methylquinoline (IV)

[0084] (1) 3-chloro-2-methylaniline (Ⅰ) (14.1 g, 0.1 mol) and 50 mL of acetic acid were added to a 250 mL three-necked flask. The mixture was heated to 60 °C with stirring, and then 2-chloropropenal (Ⅱ-3) (9.01 g, 0.1 mol) was added. After the addition was complete, the mixture was heated for another 6 h. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give 28.2 g of compound (Ⅲ-2), with a yield of 99.2%. 1 H NMR (500MHz, CDCl3) δ7.82(s,1H),7.26(dd,J=8.1,1.2Hz,1H),7.11(t,J=7.9Hz,1H),6.76(dd,J=7.9,1.2Hz,1H),4.39(s,2H),2.32(s,3H).

[0085] (2) The compound (III-2) (28.4 g, 0.1 mol) obtained in step (1) was added to a 250 mL three-necked flask and then dissolved in 50 mL of acetic acid. The mixture was heated to 180 °C with stirring and kept at that temperature for 10 h. The mixture was then diluted with water, filtered, and alkalized with NaOH. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried with anhydrous sodium sulfate. The mixture was concentrated to give 17.9 g of 3,7-dichloro-8-methylquinoline (Ⅳ), with a yield of 84.4% and a purity of over 99%. 1 H NMR (500MHz, CDCl3) δ8.85 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.64–7.47 (m, 2H), 2.87 (s, 3H).

[0086] Example 6: Synthesis of 3,7-dichloro-8-methylquinoline (IV)

[0087] In a 250 mL three-necked flask, 14.1 g (0.1 mol) of 3-chloro-2-methylaniline (Ⅰ), 0.83 g (0.005 mol) of potassium iodide, and 50 mL of acetic acid were added. The mixture was heated to 110 °C with stirring, and then 12.4 g (0.1 mol) of 2,3-dichloropropenal (Ⅱ-1) was added dropwise. After the addition was complete, the mixture was heated for another 9 h. After the reaction was complete, the mixture was diluted with water, filtered, and alkalized with NaOH. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give 19.8 g of 3,7-dichloro-8-methylquinoline (Ⅳ), with a yield of 93.4% and a purity of over 99%. 1H NMR (500MHz, CDCl3) δ8.85 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.64–7.47 (m, 2H), 2.87 (s, 3H).

[0088] Example 7: Synthesis of 3,7-dichloro-8-methylquinoline (IV)

[0089] In a 250 mL three-necked flask, 14.1 g (0.1 mol) of 3-chloro-2-methylaniline (Ⅰ), 3.22 g (0.01 mol) of tetrabutylammonium bromide, and 50 mL of acetic acid were added. The mixture was heated to 70 °C with stirring, and then 16.1 g (0.1 mol) of 2-chloropropenal (Ⅱ-3) was added dropwise. After the addition was complete, the mixture was heated for another 4 h. After the reaction was complete, the mixture was diluted with water, filtered, and alkalized with NaOH. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give 17.2 g of 3,7-dichloro-8-methylquinoline (Ⅳ), with a yield of 81.6% and a purity of over 99%. 1 H NMR (500MHz, CDCl3) δ8.85 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.64–7.47 (m, 2H), 2.87 (s, 3H).

[0090] Example 8: Synthesis of 3,7-dichloro-8-methylquinoline (IV)

[0091] In a 250 mL three-necked flask, 3-chloro-2-methylaniline (I) (14.1 g, 0.1 mol), 18-crown-6 (0.5 g, 0.002 mol), and 50 mL of acetic acid were added. The mixture was heated to 130 °C with stirring, and then 2,2,3-trichloropropanal (II-2) (16.1 g, 0.1 mol) was added dropwise. After the addition was complete, the mixture was heated for another 15 h. After the reaction was complete, the mixture was diluted with water, filtered, and alkalized with NaOH. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give 19.7 g of 3,7-dichloro-8-methylquinoline (IV), with a yield of 93.3% and a purity of over 99%. 1 H NMR (500MHz, CDCl3) δ8.85 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.64–7.47 (m, 2H), 2.87 (s, 3H).

[0092] Example 9: Synthesis of 3,7-dichloro-8-methylquinoline (IV)

[0093] At 0 °C and under a nitrogen atmosphere, 2,2,3-trichloropropanal (II-2) (16.1 g, 0.1 mol) was slowly added to a suspension of 3-chloro-2-methylaniline (14.1 g, 0.1 mol) in 200 mL of glacial acetic acid. The reaction mixture was heated to 110 °C and reacted for 4 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The remaining solid was washed with diethyl ether, then suspended in water. The pH was adjusted to 9 with a saturated sodium bicarbonate aqueous solution. The solid was then transferred to a separatory funnel and extracted with ethyl acetate. After drying with magnesium sulfate to remove the solvent, the solid was purified by silica gel chromatography using ethyl acetate and heptane as eluents to obtain 18.5 g of 3,7-dichloro-8-methylquinoline (IV), with a yield of 81.2% and a purity of over 99%. 1 H NMR (500MHz, CDCl3) δ8.85 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.64–7.47 (m, 2H), 2.87 (s, 3H).

[0094] Example 10: Synthesis of 3,7-dichloro-8-methylquinoline (IV)

[0095] In a 250 mL three-necked flask, 14.1 g (0.1 mol) of 3-chloro-2-methylaniline (Ⅰ), 0.03 g (0.0002 mol) of potassium iodide, and 50 mL of acetic acid were added. The mixture was heated to 50 °C with stirring, and then 12.4 g (0.1 mol) of 2,3-dichloropropenal (Ⅱ-1) was added dropwise. After the addition was complete, the mixture was heated for another 9 h. After the reaction was complete, the mixture was diluted with water, filtered, and alkalized with NaOH. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give 18.0 g of 3,7-dichloro-8-methylquinoline (Ⅳ), with a yield of 84.5% and a purity of over 99%. 1 H NMR (500MHz, CDCl3) δ8.85 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.64–7.47 (m, 2H), 2.87 (s, 3H).

[0096] Example 11: Synthesis of 3,7-dichloro-8-methylquinoline (IV)

[0097] In a 250 mL three-necked flask, 14.1 g (0.1 mol) of 3-chloro-2-methylaniline (Ⅰ), 0.83 g (0.005 mol) of potassium iodide, and 50 mL of acetic acid were added. The mixture was heated to 150 °C with stirring, and then 12.4 g (0.1 mol) of 2,3-dichloropropenal (Ⅱ-1) was added dropwise. After the addition was complete, the mixture was heated for another 9 h. After the reaction was complete, the mixture was diluted with water, filtered, and alkalized with NaOH. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated to give 20.9 g of 3,7-dichloro-8-methylquinoline (Ⅳ), with a yield of 98.1% and a purity of over 99%. 1 H NMR (500MHz, CDCl3) δ8.85 (d, J = 2.4Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.64–7.47 (m, 2H), 2.87 (s, 3H).

[0098] Example 12: Synthesis of 3,7-dichloro-8-quinoline carboxylic acid (V)

[0099] (1) Add 3,7-dichloro-8-methylquinoline (Ⅳ) (21.2g, 0.1mol), benzoyl peroxide (0.5g, 0.002mol) and 20mL of 4-chlorotrifluoromethylbenzene to a 250mL reaction flask. Start purging with chlorine gas at a temperature above 40℃ and take samples for analysis. Stop purging with chlorine gas when the content of 3,7-dichloro-8-methylquinoline (Ⅳ) is below 0.4%. Purge excess chlorine gas and generated hydrogen chloride gas into the reaction flask. Absorb the tail gas with sodium hydroxide solution. Concentrate the reaction solution and proceed directly to the next oxidation reaction without further treatment.

[0100] (2) Add the reaction solution obtained in step (1) to the reaction flask, and dilute with 40 mL of acetic acid. Heat to 80 °C, add pyridine (15.8 g, 0.2 mol), and slowly add 50 mL of 30% hydrogen peroxide dropwise over half an hour. After the addition is complete, continue the reaction at this temperature for 2 h. After the reaction is complete, cool the reaction system to room temperature, add 200 mL of water, filter and collect the residue. After washing with water, 23.9 g of solid is obtained, with a yield of 98.7%. HPLC comparison with the standard confirms that it is 3,7-dichloro-8-quinoline carboxylic acid (V). The comparison diagram is shown in Figure 4. The purity test of the obtained 3,7-dichloro-8-quinoline carboxylic acid (V) is shown in Figure 5. The purity can reach more than 99%.

[0101] Example 13: Synthesis of 3,7-dichloro-8-quinoline carboxylic acid (V)

[0102] (1) Add 3,7-dichloro-8-methylquinoline (Ⅳ) (21.2g, 0.1mol), azobisisobutyronitrile (0.16g, 0.001mol) and 20mL of o-dichlorobenzene to a 250mL reaction flask. Start purging with chlorine gas at a temperature above 20℃ and take samples for analysis. Stop purging with chlorine gas when the content of 3,7-dichloro-8-methylquinoline (Ⅳ) is below 0.4%. Purge excess chlorine gas and generated hydrogen chloride gas into the reaction flask. Absorb the tail gas with sodium hydroxide solution. Concentrate the reaction solution and proceed directly to the next oxidation reaction without any treatment.

[0103] (2) Add the reaction solution obtained in step (1) to the reaction flask and dilute with 40 mL of water. Then add 100 mL of concentrated sulfuric acid dropwise. After the addition is complete, raise the temperature to 180 °C and slowly add 200 mL of 67% nitric acid dropwise over half an hour. After the addition is complete, continue the reaction at this temperature for 1 hour. After the reaction is complete, cool the reaction system to room temperature, add 200 mL of water, filter and collect the residue. After washing with water, 22.9 g of solid is obtained. HPLC comparison with the standard confirms that it is 3,7-dichloro-8-quinoline carboxylic acid (V), with a purity of over 99% and a yield of 94.6%.

[0104] Example 14: Synthesis of 3,7-dichloro-8-quinoline carboxylic acid (V)

[0105] (1) Add 3,7-dichloro-8-methylquinoline (Ⅳ) (21.2g, 0.1mol), potassium persulfate (0.13g, 0.0005mol), and 20mL of carbon tetrachloride to a 250mL reaction flask. Start purging with chlorine gas at a temperature above 100℃ and take samples for analysis. Stop purging with chlorine gas when the content of 3,7-dichloro-8-methylquinoline (Ⅳ) is below 0.4%. Purge excess chlorine gas and generated hydrogen chloride gas into the reaction flask. Absorb the tail gas with sodium hydroxide solution. Concentrate the reaction solution and proceed directly to the next oxidation reaction without any treatment.

[0106] (2) Add the reaction solution obtained in step (1) to the reaction flask, and add 40 mL of acetic acid. After purging with oxygen three times, introduce oxygen (pressure 1.8 MPa) and react at 40 °C in an oil bath for 8 hours. After the reaction, dilute with methanol to neutralize the pH of the reaction mixture to 2-3. Remove most of the solvent under reduced pressure, and separate by column chromatography to obtain 21.5 g of solid. HPLC comparison with the standard confirmed that it was 3,7-dichloro-8-quinoline carboxylic acid (V), with a purity of over 99% and a yield of 88.8%.

[0107] Example 15: Synthesis of 3,7-dichloro-8-quinoline carboxylic acid (V)

[0108] (1) Add 3,7-dichloro-8-methylquinoline (Ⅳ) (21.2g, 0.1mol), potassium persulfate (0.13g, 0.0005mol), and 20mL of carbon tetrachloride to a 250mL reaction flask. Start purging with chlorine gas at a temperature above 100℃ and take samples for analysis. Stop purging with chlorine gas when the content of 3,7-dichloro-8-methylquinoline (Ⅳ) is below 0.4%. Purge excess chlorine gas and generated hydrogen chloride gas into the reaction flask. Absorb the tail gas with sodium hydroxide solution. Concentrate the reaction solution and proceed directly to the next oxidation reaction without any treatment.

[0109] (2) Add the reaction solution obtained in step (1) to the reaction flask, and add 40 mL of acetic acid. After purging with oxygen three times, introduce oxygen (pressure 1.8 MPa) and react at 40 °C in an oil bath for 28 h. After the reaction, dilute with methanol to neutralize the pH of the reaction mixture to 2-3. Remove most of the solvent under reduced pressure, and separate by column chromatography to obtain 22.3 g of solid. HPLC comparison with the standard confirmed that it was 3,7-dichloro-8-quinoline carboxylic acid (V), with a purity of over 99% and a yield of 92.1%.

[0110] Example 16: Synthesis of 3,7-dichloro-8-quinoline carboxylic acid (V)

[0111] 100 mL of concentrated sulfuric acid and 21.2 g (0.1 mol) of 3,7-dichloro-8-methylquinoline (IV) were added to a round-bottom flask, followed by 40 mL of acetic acid. The mixture was heated to 80 °C, and 15.8 g (0.2 mol) of pyridine was added. 50 mL of 30% hydrogen peroxide was slowly added dropwise over half an hour. After the addition was complete, the reaction was continued at this temperature for 2 hours. After the reaction was complete, the reaction system was cooled to room temperature, 200 mL of water was added, and the mixture was filtered. The residue was collected, washed with water, and 23.9 g of solid was obtained. HPLC comparison with standards confirmed that it was 3,7-dichloro-8-quinoline carboxylic acid (V) with a purity of over 99% and a yield of 98.7%.

[0112] Example 17: Synthesis of 3,7-dichloro-8-quinoline carboxylic acid (V)

[0113] 21.2 g (0.1 mol) of 3,7-dichloro-8-methylquinoline (Ⅳ) and 2.4 g (0.6 mol) of sodium hydroxide were added to a reaction vessel, along with 50 mL of acetic acid. After purging with oxygen three times, oxygen was introduced (pressure 1.8 MPa), and the reaction was carried out at 50 °C in an oil bath for 10 h. After the reaction, methanol was added to dilute the mixture and neutralize the pH to 2-3. Most of the solvent was removed under reduced pressure, and the mixture was separated by column chromatography to obtain 21.5 g of solid. HPLC comparison with the standard confirmed that it was 3,7-dichloro-8-quinoline carboxylic acid (Ⅴ) with a purity of over 99% and a yield of 88.8%.

[0114] Example 18: Synthesis of 3,7-dichloro-8-quinoline carboxylic acid (V)

[0115] 100 mL of concentrated sulfuric acid and 21.2 g (0.1 mol) of 3,7-dichloro-8-methylquinoline (IV) were added to a round-bottom flask. 14 g (0.15 mol) of 67% nitric acid aqueous solution was carefully added, and the mixture was heated to 180 °C for 5 h. After the reaction was complete, the reaction solution was cooled and carefully and slowly poured into a suitable amount of ice-water mixture while continuously and vigorously stirring. A solid precipitated out. The mixture was filtered to obtain a white solid, which was slurried with methanol, filtered, and dried to obtain 22.6 g of solid. HPLC comparison with standards confirmed that it was 3,7-dichloro-8-quinoline carboxylic acid (V) with a purity of over 99% and a yield of 93.4%.

[0116] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing 3,7-dichloro-8-methylquinoline, characterized in that, Includes the following steps: Using 3-chloro-2-methylaniline as a starting material, 3,7-dichloro-8-methylquinoline was prepared by a one-step or two-step cyclization reaction with chlorinated propionaldehyde or chlorinated acrolein. The specific synthetic route is as follows: X and Y are each independently selected from one of the following groups: halogen, sulfonyl, ester, diazo, hydroxyl, and cyano.

2. The method for preparing 3,7-dichloro-8-methylquinoline according to claim 1, characterized in that, The one-step cyclization reaction step is as follows: 3-chloro-2-methylaniline is reacted with chlorinated propionaldehyde or chlorinated acrolein in a solvent under the action of a catalyst in a one-step cyclization reaction.

3. The method for preparing 3,7-dichloro-8-methylquinoline according to claim 2, characterized in that, In the one-step cyclization reaction, the molar ratio of 3-chloro-2-methylaniline to the catalyst is 10 to 500:

1.

4. The method for preparing 3,7-dichloro-8-methylquinoline according to claim 2, characterized in that, The one-step cyclization reaction is carried out at a temperature of 50–150°C for 4–15 hours.

5. The method for preparing 3,7-dichloro-8-methylquinoline according to claim 1, characterized in that, The two-step cyclization reaction is as follows: (1) 3-Chloro-2-methylaniline is condensed with chlorinated propionaldehyde or chlorinated acrolein in a solvent to generate an imine intermediate. (2) The imine intermediate obtained in step (1) is placed in a solvent and subjected to intramolecular cyclization under the action of a catalyst to obtain 3,7-dichloro-8-methylquinoline.

6. The method for preparing 3,7-dichloro-8-methylquinoline according to claim 5, characterized in that, In step (1), the condensation reaction temperature is 30-60℃; in step (2), the intramolecular cyclization reaction temperature is 80-180℃.

7. The method for preparing 3,7-dichloro-8-methylquinoline according to claim 5, characterized in that, The molar ratio of the imine intermediate to the catalyst is 10 to 500:

1.

8. The method for preparing 3,7-dichloro-8-methylquinoline according to claim 2 or 5, characterized in that, The molar ratio of 3-chloro-2-methylaniline to chlorinated propionaldehyde or chlorinated acrolein is 1 to 2:

1.

9. The method for preparing 3,7-dichloro-8-methylquinoline according to claim 2 or 5, characterized in that, The catalysts mentioned are all one of the following: metal halides, organic ammonium salts, cyclic ethers, organic acids, and inorganic acids.

10. The method for preparing 3,7-dichloro-8-methylquinoline according to claim 2 or 5, characterized in that, The solvents used in both the one-step and two-step cyclization reactions are alkyl acids.

11. 3,7-Dichloro-8-methylquinoline prepared by any one of the preparation methods according to claims 1 to 10.

12. The use of 3,7-dichloro-8-methylquinoline according to claim 11 in the preparation of 3,7-dichloro-8-quinoline carboxylic acid.

13. A method for preparing 3,7-dichloro-8-quinoline carboxylic acid, characterized in that, The process includes the following steps: 3,7-dichloro-8-methylquinoline, prepared by any one of the methods described in claims 1 to 10, is placed in solvent I and subjected to a side-chain chlorination reaction with chlorine gas under the action of an initiator to obtain a chlorinated methylquinoline product. The chlorinated methylquinoline product is then reacted with an oxidant in solvent II to obtain 3,7-dichloro-8-quinoline carboxylic acid. The specific synthetic route is as follows:

14. The method for preparing 3,7-dichloro-8-quinoline carboxylic acid according to claim 13, characterized in that, The initiator is an azo initiator, a peroxide initiator, or a persulfate initiator; the molar ratio of 3,7-dichloro-8-methylquinoline to the initiator is 50 to 200:

1.

15. The method for preparing 3,7-dichloro-8-quinoline carboxylic acid according to claim 13, characterized in that, The chlorination reaction temperature of the side chain is 20–100°C, and the reaction time is 1–10 h. The oxidation reaction temperature is 40–180°C, and the reaction time is 1–28 h.

16. The method for preparing 3,7-dichloro-8-quinoline carboxylic acid according to claim 13, characterized in that, Solvent I for the chlorination reaction of the side chain is one of o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, chlorobenzene, chloroform, carbon tetrachloride, 4-chlorotrifluoromethylbenzene, 3,4,5-trichlorotrifluoromethylbenzene, 1,3,5-trichloromethylbenzene, and 1,3,5-trifluoromethylbenzene.

17. The method for preparing 3,7-dichloro-8-quinoline carboxylic acid according to claim 13, characterized in that, The chlorinated methylquinoline products are 3,7-dichloro-8-monochloromethylquinoline and 3,7-dichloro-8-dichloromethylquinoline.

18. A method for preparing 3,7-dichloro-8-quinoline carboxylic acid, characterized in that, The process includes the following steps: reacting 3,7-dichloro-8-methylquinoline obtained by any of the preparation methods described in claims 1 to 10 with an oxidant in solvent II to obtain 3,7-dichloro-8-quinoline carboxylic acid; The specific synthesis route is as follows:

19. The method for preparing 3,7-dichloro-8-quinoline carboxylic acid according to claim 18, characterized in that, The oxidation reaction is carried out at a temperature of 50–200°C for 2–10 hours.

20. The method for preparing 3,7-dichloro-8-quinoline carboxylic acid according to claim 13 or 18, characterized in that, The oxidant is at least one of hydrogen peroxide, oxygen, ozone, potassium permanganate, manganese dioxide, nitric acid, sulfuric acid, fuming nitric acid, sodium hypochlorite, cobalt triacetylacetonate, cobalt tetrapyridine dichromate, cobalt acetate, and manganese acetate, or a combination of hydrogen peroxide and an organic base; the molar ratio of 3,7-dichloro-8-methylquinoline to the oxidant is 1:5 to 200.

21. The method for preparing 3,7-dichloro-8-quinoline carboxylic acid according to claim 13 or 18, characterized in that, All solvents II are alkyl acids.

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