阅读说明：本技术 一种2-氨基-5-氯二苯甲酮的制备方法 (Preparation method of 2-amino-5-chlorobenzophenone ) 是由 赵顺阳 周倩 赵树炎 周永锋 于 2021-10-27 设计创作，主要内容包括：本发明提出了一种2-氨基-5-氯二苯甲酮的制备方法,其包括：步骤S1、将5-氯-3-苯基-2,1-苯并异噁唑与催化剂混合后,加入乙酸乙酯,搅拌至溶解,保持反应体系在氢气氛围下,控制反应压力为1-5atm,20-30℃下反应；步骤S2、将步骤S1所得反应液过滤后蒸馏除去溶剂,得到稠状物,向稠状物中加入结晶溶剂,加热溶解后,冷却析晶过滤后得到2-氨基-5-氯二苯甲酮。本发明的制备反方相比现有技术,产物的收率更高,同时杂质更少,反应条件相对温和,适用于大规模工业化应用。(The invention provides a preparation method of 2-amino-5-chlorobenzophenone, which comprises the following steps: step S1, mixing 5-chloro-3-phenyl-2, 1-benzisoxazole with a catalyst, adding ethyl acetate, stirring until the ethyl acetate is dissolved, keeping the reaction system in a hydrogen atmosphere, controlling the reaction pressure to be 1-5atm, and reacting at 20-30 ℃; and S2, filtering the reaction liquid obtained in the step S1, distilling to remove the solvent to obtain a thick substance, adding a crystallization solvent into the thick substance, heating to dissolve, cooling to crystallize, and filtering to obtain the 2-amino-5-chlorobenzophenone. Compared with the prior art, the preparation method has the advantages of higher product yield, fewer impurities, relatively mild reaction conditions and suitability for large-scale industrial application.)

1. A preparation method of 2-amino-5-chlorobenzophenone is characterized by comprising the following steps:

step S1, mixing 5-chloro-3-phenyl-2, 1-benzisoxazole with a catalyst, adding ethyl acetate, stirring until the ethyl acetate is dissolved, keeping the reaction system in a hydrogen atmosphere, controlling the reaction pressure to be 1-5atm, and reacting at 20-30 ℃;

and S2, filtering the reaction liquid obtained in the step S1, distilling to remove the solvent to obtain a thick substance, adding a crystallization solvent into the thick substance, heating to dissolve, cooling to crystallize, and filtering to obtain the 2-amino-5-chlorobenzophenone.

2. The process for preparing 2-amino-5-chlorobenzophenone of claim 1 wherein the catalyst is a Pt/C catalyst.

3. The method of preparing 2-amino-5-chlorobenzophenone of claim 2 wherein the Pt/C catalyst has a water content of from 60 to 70 wt%.

4. The method of preparing 2-amino-5-chlorobenzophenone of claim 2 wherein the Pt/C catalyst has a dry platinum content of from 1 to 5 wt%.

5. The process for preparing 2-amino-5-chlorobenzophenone according to claim 1 wherein the mass ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to catalyst is 10: (1-2).

6. The process for the preparation of 2-amino-5-chlorobenzophenone according to claim 1 wherein the mass to volume ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to ethyl acetate is from 1: (6.5-8.7).

7. The process for preparing 2-amino-5-chlorobenzophenone of claim 1 wherein in step S1, the reaction time is 2 to 4 hours.

8. The process for preparing 2-amino-5-chlorobenzophenone of claim 1 wherein the crystallization solvent is ethanol.

9. The process for preparing 2-amino-5-chlorobenzophenone according to claim 1 wherein the mass to volume ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to crystallization solvent is from 1: (7.8-8).

Technical Field

The invention relates to the technical field of preparation of medical intermediates, in particular to a preparation method of 2-amino-5-chlorobenzophenone.

Background

The 2-amino-5-chlorobenzophenone is an important medical intermediate, the derivative thereof has wide application, and meanwhile, the derivative can be used as an intermediate for synthesizing benzodiazepine hypnotic and sedative drugs and is also an important raw material of quinoline.

In the synthesis method of 2-amino-5-chlorobenzophenone reported in the patent literature at present, 5-chloro-3-phenyl-2, 1-benzisoxazole is mainly used as a raw material for large-scale production, and the 2-amino-5-chlorobenzophenone is prepared by a catalytic hydrogenation mode.

For example, in the process disclosed in patent CN107827763A, the yield disclosed therein can reach 95%, but the applicant finds that the single-step reaction yield can only reach about 70% in the process of preparing 2-amino-5-chlorobenzophenone by using this scheme, and a large amount of impurities exist in the obtained reaction product, whereas the process disclosed in patent CN107935872A relies on a microchannel reactor, which is expensive, has high reaction efficiency, relatively small yield, and high equipment maintenance cost, and is not favorable for large-scale production by enterprises.

Therefore, an industrial preparation method of 2-amino-5-chlorobenzophenone with higher yield, less impurities and lower production cost is needed.

Disclosure of Invention

In view of the above, the present invention provides a preparation method of 2-amino-5-chlorobenzophenone.

The technical scheme of the invention is realized as follows: the invention provides a preparation method of 2-amino-5-chlorobenzophenone, which comprises the following steps:

step S1, mixing 5-chloro-3-phenyl-2, 1-benzisoxazole with a catalyst, adding ethyl acetate, stirring until the ethyl acetate is dissolved, keeping the reaction system in a hydrogen atmosphere, controlling the reaction pressure to be 1-5atm, and reacting at 20-30 ℃;

and S2, filtering the reaction liquid obtained in the step S1, distilling to remove the solvent to obtain a thick substance, adding a crystallization solvent into the thick substance, heating to dissolve, cooling to crystallize, and filtering to obtain the 2-amino-5-chlorobenzophenone.

1atm is a standard atmospheric pressure, and in the above technical scheme, it is preferable that the reaction pressure is 2atm

On the basis of the technical scheme, the catalyst is preferably a Pt/C catalyst.

Based on the above technical solution, it is preferable that the water content of the Pt/C catalyst is 60 to 70 (wt)%.

Based on the above technical solution, it is preferable that the Pt/C catalyst has a dry platinum content of 1 to 5 (wt)%.

Still further preferably, the mass ratio of the 5-chloro-3-phenyl-2, 1-benzisoxazole to the catalyst is 10: (1-2).

On the basis of the technical scheme, preferably, the mass volume ratio of the 5-chloro-3-phenyl-2, 1-benzisoxazole to the ethyl acetate is 1: (6.5-8.7).

Based on the above technical scheme, preferably, in step S1, the reaction time is 2-4 h.

On the basis of the above technical solution, preferably, the crystallization solvent is ethanol.

On the basis of the technical scheme, preferably, the mass volume ratio of the 5-chloro-3-phenyl-2, 1-benzisoxazole to the crystallization solvent is 1: (7.8-8).

Compared with the prior art, the 2-amino-5-chlorobenzophenone has the following beneficial effects:

(1) in the prior art, the prepared 2-amino-5-chlorobenzophenone is low in purity by adopting an industrial preparation process, and due to the fact that the catalytic activity of the adopted palladium carbon is high, a reaction product is easy to dechlorinate, so that impurities are generated;

(2) as a further preferred, the present application further prefers the platinum-carbon catalyst, the palladium-carbon catalyst in the conventional process is a direct purchase activity, wherein the water content is not limited, the applicant controls the water content in the platinum-carbon and the platinum content in the process of using the platinum-carbon as the catalyst, and finally finds that the reaction rate, the reaction progress, the yield and the content of the product are also affected, and the present application limits the water content and the platinum content of the platinum-carbon, so as to obtain a better parameter and make the preparation efficiency of the product higher.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 is a mass spectrum of impurities generated in comparative example 1 of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.

Example 1

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.46g of platinum carbon catalyst, wherein the water content of the platinum carbon catalyst is 65 percent and the platinum content is 3 percent, adding 30ml of ethyl acetate, adding into a three-neck flask, vacuumizing, introducing hydrogen until the pressure is 2 atmospheres, stirring at 20 ℃ for reaction for 3 hours, monitoring the disappearance of reaction raw materials by TLC, carrying out suction filtration to recover a platinum-carbon catalyst, carrying out spin-drying on filtrate to obtain about 5g of brown oily matter, adding 35ml of absolute ethyl alcohol, heating until the brown oily matter is completely dissolved, cooling to 0 ℃, stirring for crystallization, filtering, drying to obtain 1.9g of yellow needle-shaped crystals, distilling the obtained mother liquor to obtain about 5ml of ethanol, cooling to 0 ℃, precipitating a large amount of crystals, filtering, drying to obtain 2.6g of dark yellow needle-shaped solid, wherein the calculated yield is 96.98%, and the TLC monitoring shows that the impurity points are basically absent.

Comparative example 1

Mixing tetrahydrofuran and triethylamine, adding 5-chloro-3-phenyl-2, 1-benzisoxazole and a palladium carbon catalyst, mixing, wherein the palladium carbon catalyst is a dry palladium carbon catalyst, introducing nitrogen, replacing air for 10 times, introducing hydrogen to the pressure of 0.1MPa, magnetically stirring for 2h, filtering, and vacuum-drying the obtained filter residue at 50 ℃ for 4h, wherein the mass ratio of tetrahydrofuran, triethylamine, 5-chloro-3-phenyl-2-benzisoxazole and the palladium carbon catalyst is 30:5:2:0.08 to obtain 2-amino-5-chlorobenzophenone, the yield of the obtained 2-amino-5-chlorobenzophenone is 70%, the impurity content is 5% through detection, performing mass spectrum analysis on impurities, and the detection result is shown in figure 1, the impurity is a dechlorination product of 2-amino-5-chlorobenzophenone.

Compared with the scheme of adopting the dry palladium carbon catalyst and the triethylamine inhibitor in the prior art, the preparation scheme of each application has the advantages of less raw material feeding, higher product yield and higher purity.

Example 2

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.92g of platinum carbon catalyst, wherein the water content of the platinum carbon catalyst is 65 percent, the platinum content is 3 percent, adding 30ml of ethyl acetate, adding into a three-neck flask, vacuumizing, introducing hydrogen until the pressure is 2 atmospheres, stirring at 20 ℃ for reaction for 3 hours, monitoring the disappearance of reaction raw materials by TLC, carrying out suction filtration to recover a platinum-carbon catalyst, carrying out spin-drying on filtrate to obtain about 5g of brown oily matter, adding 35ml of absolute ethyl alcohol, heating until the brown oily matter is completely dissolved, cooling to 0 ℃, stirring for crystallization, filtering, drying to obtain 1.8g of yellow needle-shaped crystals, distilling the obtained mother liquor to obtain about 5ml of ethanol, cooling to 0 ℃, precipitating a large amount of crystals, filtering, drying to obtain 2.6g of dark yellow needle-shaped solid, wherein the calculated yield is 94.83%, and TLC monitoring shows that the impurity points are basically absent.

Example 3

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.23g of platinum carbon catalyst, wherein the water content of the platinum carbon catalyst is 65 percent and the platinum content is 3 percent, adding 30ml of ethyl acetate, adding into a three-neck flask, vacuumizing, introducing hydrogen until the pressure is 2 atmospheres, stirring at 20 ℃ for reaction for 3 hours, monitoring the disappearance of reaction raw materials by TLC, carrying out suction filtration to recover a platinum-carbon catalyst, carrying out spin-drying on filtrate to obtain about 5g of brown oily matter, adding 25ml of absolute ethanol, heating until the brown oily matter is completely dissolved, cooling to 0 ℃, stirring for crystallization, filtering, drying to obtain 1g of yellow needle-shaped crystals, distilling the obtained mother liquor to the residual about 5ml of ethanol, cooling to 0 ℃, precipitating a large amount of crystals, filtering, drying to obtain 1.2g of dark yellow needle-shaped solid, wherein the calculated yield is 47.41%, and the TLC monitoring shows that the impurity points are basically absent.

Example 4

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.46g of platinum carbon catalyst, wherein the water content of the platinum carbon catalyst is 60 percent, the platinum content is 3 percent, adding 30ml of ethyl acetate, adding into a three-neck flask, vacuumizing, introducing hydrogen until the pressure is 2 atmospheres, stirring at 20 ℃ for reaction for 3 hours, monitoring the disappearance of reaction raw materials by TLC, carrying out suction filtration to recover a platinum-carbon catalyst, carrying out spin-drying on filtrate to obtain about 5g of brown oily matter, adding 35ml of absolute ethyl alcohol, heating until the brown oily matter is completely dissolved, cooling to 0 ℃, stirring for crystallization, filtering, drying to obtain 1.9g of yellow needle-shaped crystals, distilling the obtained mother liquor to obtain about 5ml of ethanol, cooling to 0 ℃, precipitating a large amount of crystals, filtering, drying to obtain 2.5g of dark yellow needle-shaped solid, wherein the calculated yield is 94.83%, and TLC monitoring shows that the impurity points are basically absent.

Example 5

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.46g of platinum carbon catalyst, wherein the water content of the platinum carbon catalyst is 70 percent and the platinum content is 3 percent, adding 30ml of ethyl acetate, adding into a three-neck flask, vacuumizing, introducing hydrogen until the pressure is 2 atmospheres, stirring at 20 ℃ for reaction for 3 hours, monitoring the disappearance of reaction raw materials by TLC, carrying out suction filtration to recover a platinum-carbon catalyst, carrying out spin-drying on filtrate to obtain about 5g of brown oily matter, adding 36ml of absolute ethyl alcohol, heating until the brown oily matter is completely dissolved, cooling to 0 ℃, stirring for crystallization, filtering, drying to obtain 1.9g of yellow needle-shaped crystals, distilling the obtained mother liquor to obtain about 5ml of ethanol, cooling to 0 ℃, precipitating a large amount of crystals, filtering, drying to obtain 2.5g of dark yellow needle-shaped solid, wherein the calculated yield is 94.83%, and TLC monitoring shows that the impurity points are basically absent.

Example 6

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.46g of platinum carbon catalyst, wherein the water content of the platinum carbon catalyst is 65% and the platinum content is 1%, adding 30ml of ethyl acetate, adding the mixture into a three-neck flask, vacuumizing, introducing hydrogen until the pressure is 2 atmospheric pressures, stirring and reacting for 3 hours at 20 ℃, monitoring by TLC (thin layer chromatography) that reaction raw materials disappear, carrying out suction filtration and recovering the platinum carbon catalyst, spin-drying the filtrate to obtain 5g of brown oily matter, adding 37ml of anhydrous ethanol, heating until the brown oily matter is completely dissolved, cooling to 0 ℃, stirring and crystallizing, filtering and drying to obtain 1.1g of yellow needle-shaped crystals, distilling the obtained mother liquor until about 5ml of ethanol is remained, cooling to 0 ℃ to separate out a large amount of crystals, filtering and drying to obtain 1.8g of dark yellow needle-shaped solid, calculating the yield to be 62.5%, and monitoring by TLC to show that an impurity point exists.

Example 7

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.46g of platinum carbon catalyst, wherein the water content of the platinum carbon catalyst is 65 percent and the platinum content is 5 percent, adding 30ml of ethyl acetate, adding into a three-neck flask, vacuumizing, introducing hydrogen until the pressure is 2 atmospheres, stirring at 20 ℃ for reaction for 3 hours, monitoring the disappearance of reaction raw materials by TLC, carrying out suction filtration to recover a platinum-carbon catalyst, carrying out spin-drying on filtrate to obtain about 5g of brown oily matter, adding 38ml of absolute ethyl alcohol, heating until the brown oily matter is completely dissolved, cooling to 0 ℃, stirring for crystallization, filtering, drying to obtain 1.8g of yellow needle-shaped crystals, distilling the obtained mother liquor to obtain about 5ml of ethanol, cooling to 0 ℃, precipitating a large amount of crystals, filtering, drying to obtain 2.6g of dark yellow needle-shaped solid, wherein the calculated yield is 94.83%, and TLC monitoring shows that almost no impurity points exist.

Comparative example 2

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.46g of platinum-carbon catalyst, wherein the platinum-carbon catalyst is a dry catalyst, the water content is 0, the platinum content is 3%, adding 30ml of ethyl acetate, adding into a three-neck flask, vacuumizing, introducing hydrogen to the pressure of 2 atmospheric pressures, stirring and reacting at 20 ℃ for 3 hours, performing suction filtration to recover a platinum-carbon catalyst, spin-drying filtrate to obtain about 5g of brown oily matter, adding 25ml of absolute ethanol, heating to completely dissolve, cooling to 0 ℃, stirring and crystallizing, filtering, drying to obtain 1.2g of yellow needle-shaped crystals, distilling the obtained mother liquor to obtain about 5ml of ethanol, cooling to 0 ℃ to separate out a large amount of crystals, filtering and drying to obtain 2g of dark yellow needle-shaped solid, wherein the calculated yield is 68.97%, and TLC monitoring shows that a small amount of impurity points and a small amount of unreacted raw materials.

The comparison shows that when the dry platinum carbon catalyst is used for catalytic reaction, the reaction effect is not good as that of the wet platinum carbon catalyst, and the reaction process, the side reaction and the like are deteriorated in different degrees.

Example 8

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.46g of platinum carbon catalyst, wherein the water content of the platinum carbon catalyst is 65% and the platinum content is 3%, adding 40ml of ethyl acetate, adding into a three-neck flask, vacuumizing, introducing hydrogen, stirring and reacting at 20 ℃ for 2h, monitoring by TLC (thin layer chromatography) that reaction raw materials disappear, performing suction filtration and recovery of the platinum carbon catalyst, spin-drying the filtrate to obtain about 5g of brown oily matter, adding 25ml of absolute ethanol, heating to completely dissolve, cooling to 0 ℃, stirring and crystallizing, filtering, drying to obtain 1.9g of yellow needle-shaped crystals, distilling the obtained mother liquor to the residual about 5ml of ethanol, cooling to 0 ℃ to separate out a large amount of crystals, filtering and drying to obtain 2.6g of deep yellow needle-shaped solid, calculating the yield to 96.98%, and monitoring by TLC to show that basically no impurity point exists.

Example 9

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.46g of platinum carbon catalyst, wherein the water content of the platinum carbon catalyst is 65% and the platinum content is 3%, adding 30ml of ethyl acetate, adding the mixture into a three-neck flask, vacuumizing, introducing hydrogen, stirring and reacting for 4 hours at 30 ℃ under normal pressure, monitoring by TLC (thin layer chromatography) to ensure that reaction raw materials disappear, performing suction filtration to recover the platinum carbon catalyst, spin-drying the filtrate to obtain about 5g of brown oily matter, adding 25ml of absolute ethanol, heating to completely dissolve, cooling to 0 ℃, stirring and crystallizing, filtering, drying to obtain 1.8g of yellow needle-shaped crystals, distilling the obtained mother liquor to obtain about 5ml of ethanol, cooling to 0 ℃ to separate out a large amount of crystals, filtering and drying to obtain 2.6g of dark yellow needle-shaped solid, calculating the yield to 94.83%, and monitoring by TLC to show that basically no impurity point exists.

Comparative example 3

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.46g of platinum carbon catalyst, wherein the water content of the platinum carbon catalyst is 65 percent, the platinum content is 3 percent, adding 30ml of tetrahydrofuran, adding into a three-neck flask, vacuumizing, introducing hydrogen until the pressure is 2 atmospheric pressures, stirring and reacting for 3 hours at 20 ℃, monitoring residual raw materials by TLC, carrying out suction filtration and recovering the platinum carbon catalyst, carrying out spin drying on filtrate to obtain 5g of brown oily matter, adding 25ml of anhydrous ethanol, heating until the brown oily matter is completely dissolved, cooling to 0 ℃, stirring and crystallizing, filtering, drying to obtain 1.6g of yellow needle-shaped crystals, distilling the obtained mother liquor until about 5ml of ethanol is remained, cooling to 0 ℃, precipitating a large amount of crystals, filtering and drying to obtain 2.2g of dark yellow needle-shaped solid, calculating the yield to 81.9 percent, and monitoring by TLC to show that a small amount of impurity points exist.

The reaction is easy to adopt ethyl acetate better, the reaction completeness is higher, and impurities are generated a little at the same time, and tetrahydrofuran is adopted, and although the reaction completeness is also higher, a small amount of impurities are generated.

Comparative example 4

Weighing 4.6g of 5-chloro-3-phenyl-2, 1-benzisoxazole and 0.46g of platinum carbon catalyst, wherein the water content of the platinum carbon catalyst is 65 percent, the platinum content is 3 percent, adding 30ml of ethyl acetate and 1ml of triethylamine, adding into a three-neck flask, vacuumizing, introducing hydrogen until the pressure is 2 atmospheres, stirring at 20 ℃ for reaction for 3 hours, monitoring the disappearance of reaction raw materials by TLC, carrying out suction filtration to recover a platinum-carbon catalyst, drying a filtrate in a spinning mode to obtain about 5g of brown oily matter, adding 25ml of absolute ethyl alcohol, heating until the brown oily matter is completely dissolved, cooling to 0 ℃, stirring for crystallization, filtering, drying to obtain 1.8g of yellow needle-shaped crystals, distilling the obtained mother liquor to obtain about 5ml of ethanol, cooling to 0 ℃, precipitating a large amount of crystals, filtering and drying to obtain 2.4g of dark yellow needle-shaped solid, wherein the calculated yield is 90.52%, and the TLC monitoring shows that micro impurity points exist.

When the platinum carbon catalyst is used, the triethylamine inhibitor is added to slightly influence the difference rate of a final product, and partial impurities are generated.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.