Preparation method of 2, 2, 4-trimethyl-1, 2-dihydroquinoline

Abstract

The invention discloses a preparation method of 2, 2, 4-trimethyl-1, 2-dihydroquinoline, and relates to a preparation method of 2, 2, 4-trimethyl-1, 2-dihydroquinoline. The method comprises the following steps: by taking o-aminoacetophenone and isobutenyl magnesium bromide as raw materials, reacting in the presence of a polymerization inhibitor and a solvent, then adding water to decompose, extracting, distilling to remove the solvent and lightly separating to obtain high-purity and high-yield 2, 2, 4-trimethyl-1, 2-dihydroquinoline. By adopting the method, carcinogenic primary amine impurities are not generated.

Description

Technical Field

[0001] The invention belongs to the field of rubber additives, and specifically relates to a preparation method of 2,2,4-trimethyl-1,2-dihydroquinoline, and in particular to a preparation method using isobutylenyl magnesium bromide and o-aminoacetophenone as raw materials. Background Art

[0002] 2,2,4-Trimethyl-1,2-dihydroquinoline is a key monomer for the preparation of antioxidant TMQ and pharmaceutical intermediates. The main component of antioxidant TMQ is the di-, tri- and tetra-polymers of 2,2,4-trimethyl-1,2-dihydroquinoline. It is one of the rubber antioxidants with the largest demand in the domestic and foreign markets. At present, the preparation of 2,2,4-trimethyl-1,2-dihydroquinoline is usually made of aniline and acetone as raw materials, and is prepared by a series of steps such as salt formation, condensation, neutralization and distillation under the catalytic action of an acid catalyst. Under the catalytic action of acid, aniline and acetone undergo condensation reaction, and polymerization reaction and primary amine side reaction of harmful impurities occur at the same time. Therefore, the obtained monomer product has low purity. After purification and post-treatment, it can only reach about 97%. There are defects such as low raw material single-pass conversion rate (70-80%) and carcinogenic primary amine impurities, which cannot meet the needs of pharmaceutical-grade products. Summary of the invention

[0003] The purpose of the present invention is to provide a method for preparing 2,2,4-trimethyl-1,2-dihydroquinoline in order to overcome the above technical deficiencies. The method uses o-aminoacetophenone and isobutylene magnesium bromide as raw materials and is prepared by liquid phase reaction in a solvent. At the same time, a high-purity product can be obtained and the generation of primary amine impurities can be avoided.

[0004] To achieve the above object, the preparation method provided by the present invention is implemented in the following manner.

[0005] A method for preparing 2,2,4-trimethyl-1,2-dihydroquinoline, comprising taking o-aminoacetophenone and isobutylene magnesium bromide as raw materials, reacting in the presence of a polymerization inhibitor and a solvent, then hydrolyzing, extracting and distilling to remove the solvent and light components, and obtaining 2,2,4-trimethyl-1,2-dihydroquinoline Generally, in the method, the reaction temperature is -10°C to 10°C, preferably 0-5°C.

[0006] In the method, the reaction time is 1 to 5 hours, preferably 2 to 3 hours.

[0007] In the method, the ratio of o-aminoacetophenone to isobutylenylmagnesium bromide is 1:1-5, preferably 1:3.

[0008] In the method, the polymerization inhibitor used is a phenolic compound, selected from 2,6-di-tert-butyl-p-cresol, hydroquinone, p-methoxyphenol, 2,5-di-tert-butyl-hydroquinone, 2-tert-butyl-hydroquinone, or a mixture of any proportions of the above-mentioned compounds.

[0009] In the method, the weight ratio of the inhibitor to o-aminoacetophenone is 0.0001-0.01:1, preferably 0.001-0.005:1.

[0010] In the method, the reaction solvent refers to a non-protonic polar solvent, which is selected from one of tetrahydrofuran, DMF, dimethyl sulfoxide, acetone, and N-methylpyrrolidone, or a mixture of several of them in any proportion.

[0011] In the method, the weight ratio of the added solvent volume to the o-aminoacetophenone is 2-10:1, preferably 3-5:1.

[0012] In the method, the extraction solvent refers to an aliphatic carboxylic acid ester solvent, such as ethyl acetate, propyl acetate, butyl acetate, or a mixture of any proportion of the above.

[0013] Beneficial effects of the present invention: The present invention can obtain high-purity products and avoid the generation of primary amine impurities.

[0014] Implementation In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention. Example 1

[0015] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 ml of tetrahydrofuran, and 0.027 g of 2,6-di-tert-butyl-p-cresol to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, start the stirrer, cool the mixture to 0°C, stir and maintain at this temperature for 5-10 minutes, then drop 300 ml (containing 0.6 mol of isobutylene magnesium bromide, 2 mol / L) of tetrahydrofuran-isobutylene magnesium bromide solution, control the reaction temperature not to exceed 5°C, drop for 30 minutes, continue to maintain at this temperature for 2 hours after addition, take samples for analysis until o-aminoacetophenone completely disappears, then raise the temperature to 20°C, drop 100 ml of water to the reaction mixture, drop for 30 minutes, continue to maintain for 1 hour after addition, extract with 500 ml of ethyl acetate, and distill the organic phase under reduced pressure to obtain 34.5 g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 99.7%. Example 2

[0016] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 ml of tetrahydrofuran, and 0.027 g of 2,6-di-tert-butyl-p-cresol to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, start the stirrer, cool the mixture to 0°C, stir and maintain at this temperature for 5-10 minutes, then drop 200 ml (containing 0.4 mol of isobutylene magnesium bromide, 2 mol / L) of tetrahydrofuran-isobutylene magnesium bromide solution, control the reaction temperature not to exceed 5°C, drop for 30 minutes, continue to maintain at this temperature for 2 hours after addition, take samples for analysis until o-aminoacetophenone completely disappears, then raise the temperature to 20°C, drop 100 ml of water to the reaction mixture, drop for 30 minutes, continue to maintain for 1 hour after addition, extract with 500 ml of ethyl acetate, and distill the organic phase under reduced pressure to obtain 32 g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 99%. Example 3

[0017] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 g of tetrahydrofuran, and 0.027 g of 2,6-di-tert-butyl-p-cresol to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, start the stirrer, cool the mixture to 0°C, stir and maintain at this temperature for 5-10 minutes, then drop 400 ml (containing 0.8 mol of isobutylene magnesium bromide, 2 mol / L) of tetrahydrofuran-isobutylene magnesium bromide solution, control the reaction temperature not to exceed 5°C, drop for 30 minutes, continue to maintain at this temperature for 2 hours after addition, take samples for analysis until o-aminoacetophenone completely disappears, then raise the temperature to 20°C, drop 100 ml of water to the reaction mixture, drop for 30 minutes, continue to maintain for 1 hour after addition, extract with 500 ml of ethyl acetate, and distill the organic phase under reduced pressure to obtain 34 g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 99.5%. Example 4

[0018] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 ml of tetrahydrofuran, and 0.135 g of 2,6-di-tert-butyl-p-cresol to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, start the stirrer, cool the mixture to 0°C, stir and maintain at this temperature for 5-10 minutes, then drop 300 ml of tetrahydrofuran-isobutylenylmagnesium bromide solution (containing 0.6 mol of isobutylenylmagnesium bromide, 2 mol / L), control the reaction temperature not to exceed 5°C, drop for 30 minutes, continue to maintain at this temperature for 2 hours after addition, take samples for analysis until o-aminoacetophenone completely disappears, then raise the temperature to 20°C, drop 100 ml of water to the reaction mixture, drop for 30 minutes, continue to maintain for 1 hour after addition, extract with 500 ml of ethyl acetate, and distill the organic phase under reduced pressure to obtain 34.2 g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 99.4%. Example 5

[0019] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 ml of DMSO, and 0.027 g of 2,6-di-tert-butyl-p-cresol to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, start the stirrer, cool the mixture to 0°C, stir and maintain at this temperature for 5-10 minutes, then drop 300 ml of tetrahydrofuran-isobutylenylmagnesium bromide solution (containing 0.6 mol of isobutylenylmagnesium bromide, 2 mol / L), control the reaction temperature not to exceed 5°C, drop for 30 minutes, continue to maintain at this temperature for 2 hours after addition, take samples for analysis until o-aminoacetophenone completely disappears, then raise the temperature to 20°C, drop 100 ml of water to the reaction mixture, drop for 30 minutes, continue to maintain for 1 hour after addition, extract with 500 ml of ethyl acetate, and distill the organic phase under reduced pressure to obtain 33 g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 98.7%. Example 6

[0020] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 ml of DMSO, and 0.027 g of 2,6-di-tert-butyl-p-cresol to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, start the stirrer, cool the mixture to 10°C, stir and maintain at this temperature for 5-10 minutes, then drop 300 ml of tetrahydrofuran-isobutylenylmagnesium bromide solution (containing 0.6 mol of isobutylenylmagnesium bromide, 2 mol / L), control the reaction temperature not to exceed 10°C, drop for 30 minutes, continue to maintain at this temperature for 2 hours after addition, take samples for analysis until o-aminoacetophenone completely disappears, then raise the temperature to 20°C, drop 100 ml of water to the reaction mixture, drop for 30 minutes, continue to maintain for 1 hour after addition, extract with 500 ml of ethyl acetate, and distill the organic phase under reduced pressure to obtain 30 g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 98.5%. Example 7

[0021] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 ml of tetrahydrofuran, and 0.027 g of 2,6-di-tert-butyl-p-cresol to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, start the stirrer, cool the mixture to -10°C, stir and maintain at this temperature for 5-10 minutes, then drop 300 ml (containing 0.6 mol of isobutylene magnesium bromide, 2 mol / L) of tetrahydrofuran-isobutylene magnesium bromide solution, control the reaction temperature not to exceed 0°C, drop for 30 minutes, continue to maintain at this temperature for 2 hours after addition, take samples for analysis until the o-aminoacetophenone completely disappears, then raise the temperature to 20°C , add 100 ml of water to the reaction mixture for 30 minutes. Continue to maintain the mixture for 1 hour. Extract with 500 ml of ethyl acetate. Distill the organic phase under reduced pressure to obtain 34.4 g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 99.2%. Example 8

[0022] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 ml of DMF, and 0.027 g of 2,6-di-tert-butyl-p-cresol to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, start the stirrer, cool the mixture to 10°C, stir and maintain at this temperature for 5-10 minutes, then drop 300 ml of tetrahydrofuran-isobutylenylmagnesium bromide solution (containing 0.6 mol of isobutylenylmagnesium bromide, 2 mol / L), control the reaction temperature not to exceed 10°C, drop for 30 minutes, continue to maintain at this temperature for 2 hours after addition, take samples for analysis until o-aminoacetophenone completely disappears, then raise the temperature to 20°C, drop 100 ml of water to the reaction mixture, drop for 30 minutes, continue to maintain for 1 hour after addition, extract with 500 ml of ethyl acetate, and distill the organic phase under reduced pressure to obtain 32 g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 98.8%. Example 9

[0023] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 ml of DMSO, and 0.027 g of 2,6-di-tert-butyl-p-cresol to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device. Turn on the stirrer and cool the mixture to 0°C in an ice bath. Stir at this temperature for 5-10 minutes, then dropwise add 300 ml of tetrahydrofuran-isobutylenylmagnesium bromide solution (containing 0.6 mol of isobutylenylmagnesium bromide, 2 mol / L). Control the reaction temperature not to exceed 5°C. The reaction mixture was added dropwise for 30 minutes, and the temperature was maintained for 2 hours after the addition. Sampling was performed until the o-aminoacetophenone completely disappeared. The temperature was then raised to 20°C, and 100 ml of water was added dropwise to the reaction mixture. The addition time was 30 minutes, and the temperature was maintained for 1 hour after the addition. The mixture was extracted with 500 ml of ethyl acetate, and the organic phase was distilled under reduced pressure to obtain 31.5 g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 98.5%. Example 10

[0024] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 ml of a 1:1 volume mixture of tetrahydrofuran and DMF, and 0.027 g of 2,6-di-tert-butyl-p-cresol to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, start the stirrer, cool the mixture to 0°C, stir and maintain at this temperature for 5-10 minutes, then drop 300 ml (containing 0.6 mol of isobutylene magnesium bromide, 2 mol / L) of tetrahydrofuran-isobutylene magnesium bromide solution, control the reaction temperature not to exceed 5°C, drop for 30 minutes, continue to maintain at this temperature for 2 hours after addition, take samples for analysis until the o-aminoacetophenone completely disappears, then raise the temperature to 20°C , add 100 ml of water to the reaction mixture for 30 minutes. Continue to maintain the mixture for 1 hour. Extract with 500 ml of ethyl acetate. Distill the organic phase under reduced pressure to obtain 33.5 grams of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 99.1%. Embodiment 11

[0025] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 ml of a 1:1 volume mixture of tetrahydrofuran and DMF, and 0.027 g of 2,5-di-tert-butyl-p-cresol to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, start the stirrer, cool the mixture to 0°C, stir and maintain at this temperature for 5-10 minutes, then drop 300 ml (containing 0.6 mol of isobutylene magnesium bromide, 2 mol / L) of tetrahydrofuran-isobutylene magnesium bromide solution, control the reaction temperature not to exceed 5°C, drop for 30 minutes, continue to maintain at this temperature for 2 hours after addition, take samples for analysis until the o-aminoacetophenone completely disappears, then raise the temperature to 20°C , add 100 ml of water to the reaction mixture for 30 minutes. Continue to maintain the mixture for 1 hour. Extract with 500 ml of ethyl acetate. Distill the organic phase under reduced pressure to obtain 33.8 g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 99.0%. Example 12

[0026] To a 1000ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, 27g (0.2mol) of o-aminoacetophenone, 100ml of a 1:1 volume mixture of tetrahydrofuran and DMF, and 0.027g of hydroquinone were added. The stirrer was turned on, and the mixture was cooled to 0°C. Stirring was maintained at this temperature for 5-10 minutes, and then 300ml (containing 0.6mol of isobutylene magnesium bromide, 2mol / L) of tetrahydrofuran-isobutylene magnesium bromide solution was added dropwise. The reaction temperature was controlled not to exceed 5°C. The addition time was 30 minutes. After the addition, the temperature was maintained for 2 hours. Samples were taken for analysis until the o-aminoacetophenone completely disappeared. Then the temperature was raised to 20°C, 100ml of water was added dropwise to the reaction mixture for 30 minutes. After the addition, the temperature was maintained for 1 hour. Extraction was performed with 500ml of ethyl acetate, and the organic phase was distilled under reduced pressure to obtain 33.4g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 99.2%. Embodiment 13

[0027] Add 27 g (0.2 mol) of o-aminoacetophenone, 100 ml of a 1:1 volume mixture of tetrahydrofuran and DMF, and 0.027 g of a 1:1 weight ratio mixture of 2,6-di-tert-butyl-p-cresol and hydroquinone to a 1000 ml four-necked glass bottle equipped with a stirrer, a thermometer, and a cooling device, start the stirrer, cool the mixture to 0°C, stir and maintain at this temperature for 5-10 minutes, then drop 300 ml (containing 0.6 mol of isobutylene magnesium bromide, 2 mol / L) of tetrahydrofuran-isobutylene magnesium bromide solution, control the reaction temperature not to exceed 5°C, drop for 30 minutes, continue to maintain at this temperature for 2 hours after addition, take samples for analysis until the o-aminoacetophenone completely disappears, then raise the temperature to 20°C , add 100 ml of water to the reaction mixture for 30 minutes. Continue to maintain the mixture for 1 hour. Extract with 500 ml of ethyl acetate. Distill the organic phase under reduced pressure to obtain 33.0 g of 2,2,4-trimethyl-1,2-dihydroquinoline with a purity of 99.0%.

[0028] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations, such as changing the conversion conditions of the biological system and the proportion of the reaction materials such as aniline, etc. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing 2,2,4-trimethyl-1,2-dihydroquinoline, characterized in that: Taking o-aminoacetophenone and isobutylene magnesium bromide as raw materials, reacting in the presence of an inhibitor and a solvent, then hydrolyzing, extracting and distilling to remove the solvent and light components, 2,2,4-trimethyl-1,2-dihydroquinoline is obtained.

2. The preparation method according to claim 1, characterized in that: The reaction temperature is -10°C to 10°C.

3. The preparation method according to claim 1 or 2, characterized in that: The reaction temperature is 0-5°C.

4. The preparation method according to claim 1, characterized in that: The reaction time is 1-5 hours.

5. The preparation method according to claim 1 or 4, characterized in that: The reaction time is 2-3 hours.

6. The preparation method according to claim 1, characterized in that: The molar ratio of o-aminoacetophenone to isobutylenylmagnesium bromide is 1:1-5.

7. The preparation method according to claim 1 or 6, characterized in that: The molar ratio of o-aminoacetophenone to isobutylenylmagnesium bromide is 1:

3.

8. The preparation method according to claim 1, characterized in that: The polymerization inhibitor used is a phenolic compound, selected from 2,6-di-tert-butyl-p-cresol, hydroquinone, p-methoxyphenol, 2,5-di-tert-butyl-hydroquinone, 2-tert-butyl-hydroquinone, or a mixture of any proportions thereof.

9. The preparation method according to claim 1, characterized in that The weight ratio of the inhibitor to o-aminoacetophenone is 0.0001~0.01:

1.

10. The preparation method according to claim 1 or 9, characterized in that The weight ratio of the polymerization inhibitor to the o-aminoacetophenone is 0.001-0.005:

1.

11. The preparation method according to claim 1, characterized in that: The reaction solvent is a non-protonic polar solvent, selected from tetrahydrofuran, DMF, dimethyl sulfoxide, acetone, N-methylpyrrolidone or a mixture of several of them in any proportion.

12. The preparation method according to claim 1, characterized in that: The weight ratio of the added solvent volume to the o-aminoacetophenone is 2-10:

1.

13. The preparation method according to claim 1 or 12, characterized in that: The weight ratio of the added solvent volume to the o-aminoacetophenone is 3-5:

1.

14. The preparation method according to claim 1, characterized in that: The extraction solvent is an aliphatic carboxylic acid ester solvent, selected from ethyl acetate, propyl acetate, butyl acetate or a mixture of several of them in any proportion.