A process for the synthesis of dichloroamino aryl ethers

Abstract

The application provides a process for synthesizing dichloroamino aryl ether, and 2,4-dichloro-5-methoxyaniline or 2,4-dichloro-5-isopropoxyaniline is obtained by oxidizing 3-methoxyaniline or 3-isopropoxyaniline under the action of a catalyst and hydrogen peroxide. The method can catalyze the preparation of a key intermediate of bosutinib and dimethomorph by one-step high-selectivity oxidation and chlorination, and has a good industrial application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to a one-step high-selectivity catalytic synthesis process of a key intermediate of bosutinib and oxadiazon, in particular to a process for synthesizing dichloro amino aryl ether. BACKGROUND

[0002] Bosutinib, chemically named 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazine)propoxy]-3-quinoline carbonitrile, is a potent protein kinase inhibitor. Oxadiazon, chemically named 5-tert-butyl-3-(2,4-dichloro-5-isopropoxyphenyl)-3,4-diazoline-2-ketone, is a nitrogen-containing heterocyclic herbicide developed by Rhone-Poulenc Company in France. It can exert herbicidal activity under the action of light, and is absorbed by plant seedlings, roots and stems and leaves, causing them to stop growing and then rot and die.

[0003] The method disclosed in Chinese patent document CN201911310757.X is shown in formula 1. Interamino phenol is reacted with formic acid to generate 3-formamido phenol, which is then subjected to benzene ring chlorination reaction to generate 2,4-dichloro-5-formamido phenol, and the 2,4-dichloro-5-formamido phenol is subjected to phenolic hydroxyl methylation reaction to generate 2,4-dichloro-5-formamido anisole, and then the formyl group is removed by light to generate 2,4-dichloro-5-methoxy aniline.

[0004]

[0005] This method has mild reaction conditions, good selectivity and high yield, but has too many steps, too long cycle and low production efficiency.

[0006] The method disclosed in Chinese patent document CN202011633593.7 is shown in formula 2. A measured amount of dichlorophenol is put into a sulfonation and nitration kettle, then concentrated sulfuric acid is added dropwise, after the reaction is complete, the temperature is lowered, the solvent is dissolved, and then mixed acid is added dropwise for nitration, and then hydrolysis to obtain the oxadiazon intermediate 2,4-dichloro-5-nitrophenol.

[0007]

[0008] Compared with the traditional nitrophenol synthesis method, the operation process is simple and the process route is simplified. However, a large amount of concentrated nitric acid and concentrated sulfuric acid needs to be added in the reaction process, which has great safety hazards and environmental pollution.

[0009] In the synthesis process of using pre-acetylation and re-chlorination and reusing concentrated hydrochloric acid to deacetylate, the yield of 2,4-dichloro-5-methoxy aniline is only about 55%, which needs multi-step synthesis, and the reaction time needs more than 10h, and the product needs to be purified several times, and the reaction efficiency is low. And the reaction needs a high temperature of about 100℃ and adds a large amount of mixed acid. Therefore, in order to solve these problems, it is necessary to develop a new method with mild reaction conditions, green and environmental protection, simple and efficient, and low cost. SUMMARY

[0010] The purpose of the present application is to improve the deficiencies of the prior art and provide a process for synthesizing dichloro amino aryl ether. By controlling the reaction conditions, high conversion rate and selectivity are achieved, which has good industrial prospect.

[0011] The technical scheme of the present application is: a process for synthesizing dichloro amino aryl ether, the specific steps are: adding substrate amino aryl ether, hydrochloric acid, catalyst and oxidizing agent in a reaction container, reacting at a certain reaction temperature for a period of time, and then separating, distilling and purifying to obtain the product dichloro amino aryl ether; wherein the catalyst is a phosphotungstic acid catalyst supported by nitrogen-containing carbon material, the loading mass of tungsten is 37.38-50.04%, the loading mass of phosphorus is 0.62-0.81%, and the total loading amount of phosphotungsten is 38-50.86%.

[0012] Preferably, the substrate amino aryl ether is 3-methoxy aniline or 3-isopropoxy aniline; the product dichloro amino aryl ether is 2,4-dichloro-5-methoxy aniline or 2,4-dichloro-5-isopropoxy aniline.

[0013] Preferably, the above-mentioned catalyst is a phosphotungstic acid catalyst supported by nitrogen-containing carbon material synthesized by the present research group (see Chinese patent document CN202210595766.3); preferably, the addition mass of the catalyst is 1.5%-8.5% of the mass of the substrate amino aryl ether.

[0014] Preferably, the oxidizing agent is hydrogen peroxide; the molar ratio of the substrate amino aryl ether to hydrogen peroxide is 1:(2-3).

[0015] Preferably, the molar ratio of the substrate amino aryl ether to hydrochloric acid is 1:(2.2-2.5).

[0016] Preferably, the reaction temperature is 25-60℃; the reaction time is 2-5h.

[0017] The principle of the present application is shown in formula 3.

[0018]

[0019] Beneficial effects:

[0020] The present application is a process for synthesizing dichloro amino aryl ether. The method selects an appropriate amount of hydrochloric acid as a chlorine source, which is oxidized to chlorine gas under the dual action of a catalyst and hydrogen peroxide, and then selectively adds chlorine atoms to the benzene ring. As the reaction proceeds, the acidity of the system gradually decreases, which can improve the selectivity of the dichloro product while avoiding excessive chlorination. By controlling the reaction conditions, high conversion and selectivity are achieved. In this process, the reaction can selectively obtain 2,4-dichloro-5-methoxy aniline product, and its main by-products B1 and B2 are intermediates for generating the product, which can be further oxidized and chlorinated to obtain 2,4-dichloro-5-methoxy aniline product (such as formula 4). The excessive reaction product B3 can be controlled to be very low. The process is simple and efficient, has mild conditions, high selectivity, low risk, low equipment requirements, low cost, and is suitable for industrial production.

[0021] DETAILED DESCRIPTION

[0022] Example 1:

[0023] In a glass reaction vessel, 123 g (1 mol) of substrate 3-methoxy aniline, 220 g (2.2 mol) of hydrochloric acid (36.5%), 10 g of catalyst A, and the catalyst used is the nitrogen-containing carbon material supported phosphotungstic acid catalyst described in the implementation case 3 of Chinese patent document CN202210595766.3 (45.76% W, 0.74% P). Under stirring, 283 g (2.5 mol) of hydrogen peroxide (30%) is slowly added dropwise, the reaction vessel is sealed, and it is placed in a 60°C oil bath for 5h. After the reaction is completed, the catalyst is separated by centrifugation. The liquid phase is neutralized with sodium carbonate to remove excess hydrochloric acid, and extracted with ethyl acetate three times, and the combined organic phase ethyl acetate solution is obtained. Sampling for gas chromatography detection, the reaction products are shown in Table 1, and the detection results of each product are shown in Table 1. The solution is evaporated under reduced pressure to obtain 2,4-dichloro-5-methoxy aniline 130 g, with a yield of 67%.

[0024] Example 2:

[0025] The reaction temperature is changed to 25°C, and the rest of the operation is according to the description of embodiment 1. Sampling for gas chromatography detection, the detection results of each product are shown in Table 1. The solution is evaporated under reduced pressure to obtain 2,4-dichloro-5-methoxy aniline 102 g, with a yield of 53%.

[0026] Example 3:

[0027] The reaction temperature is changed to 50°C, and the rest of the operation is according to the description of embodiment 1. Sampling for gas chromatography detection, the detection results of each product are shown in Table 1. The solution is evaporated under reduced pressure to obtain 2,4-dichloro-5-methoxy aniline 120 g, with a yield of 62%.

[0028] Example 4:

[0029] The amount of hydrogen peroxide (30%) was changed to 227g (2mol), and the rest of the operation was performed according to the description in Example 1. Sampling was detected by gas chromatography, and the detection results of each product are shown in Table 1. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5-methoxyaniline 115g, with a yield of 59%.

[0030] Example 5:

[0031] The amount of hydrogen peroxide (30%) was changed to 340g (3mol), and the rest of the operation was performed according to the description in Example 1. Sampling was detected by gas chromatography, and the detection results of each product are shown in Table 1. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5-methoxyaniline 130g, with a yield of 67%.

[0032] Example 6:

[0033] The reaction time was changed to 2h, and the rest of the operation was performed according to the description in Example 1. Sampling was detected by gas chromatography, and the detection results of each product are shown in Table 1. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5-methoxyaniline 108g, with a yield of 56%.

[0034] Example 7:

[0035] The amount of catalyst was changed to 2g, and the rest of the operation was performed according to the description in Example 1. Sampling was detected by gas chromatography, and the detection results of each product are shown in Table 1. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5-methoxyaniline 106g, with a yield of 55%.

[0036] Example 8:

[0037] The amount of hydrogen chloride (36.5%) was changed to 250g (2.5mol), and the rest of the operation was performed according to the description in Example 1. Sampling was detected by gas chromatography, and the detection results of each product are shown in Table 1. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5-methoxyaniline 121g, with a yield of 63%.

[0038] Example 9:

[0039] The catalyst used was changed to the nitrogen-containing carbon material supported phosphotungstic acid catalyst described in Example 9 of the Chinese patent document CN202210595766.3 (containing 50.04% W, 0.81% P), and the rest of the operation was performed according to the description in Example 1. Sampling was detected by gas chromatography, and the detection results of each product are shown in Table 1. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5-methoxyaniline 127g, with a yield of 66%.

[0040] Example 10:

[0041] The used catalyst was changed to the nitrogen-containing carbon material supported phosphotungstic acid catalyst (37.38% W, 0.62% P) described in Example 10 of the Chinese patent document CN202210595766.3, and the remaining operations were performed according to the description in Example 1. Sampling was performed for gas chromatography detection, and the detection results of each product are shown in Table 1. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5-methoxyaniline 123 g, with a yield of 64%.

[0042] Example 11:

[0043] The catalyst after reaction in Example 1 was centrifuged and removed for reuse. The process flow was consistent with Example 1, sampling was performed for gas chromatography detection, and the detection results of each product are shown in Table 2.

[0044] Table 1. Yield of each product in Examples 1-8.

[0045]

[0046]

[0047] Table 2. Catalyst recycling use in Example 11

[0048] Number of recoveries P yield B1 yield B2 yield B3 yield 1 62％ 16％ 17％ - 2 64％ 14％ 16％ - 3 60％ 16％ 18％ - 4 58％ 16％ 20％ -

[0049] Example 12:

[0050] In a glass reaction vessel, 151 g (1 mol) of the substrate 3-isopropoxyaniline, 220 g (2.2 mol) of hydrochloric acid (36.5%), and 10 g of catalyst A were added. The used catalyst was the nitrogen-containing carbon material supported phosphotungstic acid catalyst (45.76% W, 0.74% P) described in Example 3 of the Chinese patent document CN202210595766.3. Under stirring, 283 g (2.5 mol) of hydrogen peroxide (30%) was slowly added dropwise, the reaction vessel was sealed, and it was placed in a 60°C oil bath for 5h. After the reaction was completed, the catalyst was centrifuged. The liquid phase was neutralized with sodium carbonate, and the excess hydrochloric acid was extracted with ethyl acetate three times, and the combined organic phase ethyl acetate solution was obtained. Sampling was performed for gas chromatography detection, and the reaction products were as shown in Formula 5, and the detection results of each product are shown in Table 3. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5-isopropoxyaniline 155 g, with a yield of 70%.

[0051]

[0052] Example 13:

[0053] The reaction temperature was changed to 25°C and the rest of the operations were performed as described in Example 12. The sample was analyzed by gas chromatography and the results of each product are shown in Table 3. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5- isopropoxyaniline 120 g, with a yield of 54%.

[0054] Example 14:

[0055] The reaction temperature was changed to 50°C and the rest of the operations were performed as described in Example 12. The sample was analyzed by gas chromatography and the results of each product are shown in Table 3. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5- isopropoxyaniline 142 g, with a yield of 64%.

[0056] Example 15:

[0057] The amount of hydrogen peroxide (30%) was changed to 227 g (2 mol) and the rest of the operations were performed as described in Example 12. The sample was analyzed by gas chromatography and the results of each product are shown in Table 3. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5- isopropoxyaniline 122 g, with a yield of 55%.

[0058] Example 16:

[0059] The amount of hydrogen peroxide (30%) was changed to 340 g (3 mol) and the rest of the operations were performed as described in Example 12. The sample was analyzed by gas chromatography and the results of each product are shown in Table 3. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5- isopropoxyaniline 147 g, with a yield of 66%.

[0060] Example 17:

[0061] The reaction time was changed to 2 h and the rest of the operations were performed as described in Example 12. The sample was analyzed by gas chromatography and the results of each product are shown in Table 3. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5- isopropoxyaniline 124 g, with a yield of 56%.

[0062] Example 18:

[0063] The amount of catalyst was changed to 2 g and the rest of the operations were performed as described in Example 12. The sample was analyzed by gas chromatography and the results of each product are shown in Table 3. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5- isopropoxyaniline 122 g, with a yield of 55%.

[0064] Example 19:

[0065] The amount of hydrochloric acid (36.5%) was changed to 250 g (2.5 mol) and the rest of the operations were performed as described in Example 12. The sample was analyzed by gas chromatography and the results of each product are shown in Table 3. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5- isopropoxyaniline 135 g, with a yield of 61%.

[0066] Example 20:

[0067] The catalyst used was changed to the nitrogen-containing carbon material supported phosphotungstic acid catalyst (50.04% W, 0.81% P) described in the implementation case 9 of the Chinese patent document CN202210595766.3, and the remaining operations were performed according to the description in the implementation 12. Sampling was performed for gas chromatography detection, and the detection results of each product are shown in Table 1. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5-isopropoxyaniline 151 g, with a yield of 68%.

[0068] Example 21:

[0069] The catalyst used was changed to the nitrogen-containing carbon material supported phosphotungstic acid catalyst (37.38% W, 0.62% P) described in the implementation case 10 of the Chinese patent document CN202210595766.3, and the remaining operations were performed according to the description in the implementation 12. Sampling was performed for gas chromatography detection, and the detection results of each product are shown in Table 1. The solution was evaporated under reduced pressure to obtain 2,4-dichloro-5-isopropoxyaniline 144 g, with a yield of 65%.

[0070] Example 22:

[0071] The catalyst after reaction in the implementation 10 was centrifuged and removed for repeated use. The process flow was consistent with the implementation 10, and sampling was performed for gas chromatography detection, and the detection results of each product are shown in Table 4.

[0072] Table 3. Yield of each product in the implementations 12-21

[0073] Embodiment P1 B11 B21 B31 12 70％ 18％ 9％ - 13 54％ 18％ 23％ - 14 64％ 18％ 13％ - 15 55％ 17％ 14％ - 16 66％ 19％ 9％ - 17 56％ 21％ 18％ - 18 55％ 17％ 18％ - 19 61％ 20％ 15％ - 20 68％ 17％ 15％ 21 65％ 18％ 12％

[0074] Table 4. Catalyst recycling use in the implementation 22

[0075] Number of recoveries P1 yield B11 yield B21 yield B31 yield 1 66％ 11％ 17％ - 2 65％ 12％ 17％ - 3 62％ 13％ 19％ - 4 63％ 15％ 16％ -

Claims

1. A process for synthesizing dichloroamino aryl ether, comprising the following steps: adding a substrate amino aryl ether, hydrochloric acid, a catalyst and an oxidant into a reaction container, reacting at a reaction temperature for a reaction time, and separating, distilling and purifying to obtain a product dichloroamino aryl ether; wherein the catalyst is a phosphotungstic acid catalyst supported by a nitrogen-containing carbon material, the supported mass of tungsten is 37.38-50.04%, and the supported mass of phosphorus is 0.62-0.81%; the substrate amino aryl ether is 3-methoxyaniline or 3-isopropoxyaniline; the oxidant is hydrogen peroxide; the reaction temperature is 25-60℃; and the reaction time is 2-5h.

2. The process according to claim 1, characterized in that The product dichloroamino aryl ether is 2,4-dichloro-5-methoxyaniline or 2,4-dichloro-5-isopropoxyaniline.

3. The process of claim 1, wherein The added mass of the catalyst is 1.5%-8.5% of the mass of the substrate amino aryl ether.

4. The process of claim 1, wherein The molar ratio of the substrate amino aryl ether to hydrogen peroxide is 1:(2-3).

5. The method of claim 1, wherein The molar ratio of the substrate amino aryl ether to hydrochloric acid is 1:(2.2-2.5).

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