A process for the preparation of 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid

Abstract

The application discloses a preparation method of 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid, which comprises the following steps: S1, mixing an intermediate 2, an organic solvent, a base and 4-hydroxyphenyl propionyl chloride for reaction, and performing solid-liquid separation to obtain an intermediate 3; S2, mixing the intermediate 3 and an acid catalyst for reaction to obtain 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid; the preparation method disclosed by the application takes the intermediate 2 as a raw material, and 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid can be prepared through two steps of amidation and deprotection, the method has high yield and less environmental pollution.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid. Background Technology

[0002] 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid is an effective active ingredient derived from oats, possessing rapid anti-inflammatory and antipruritic activity. Studies have shown that oat alkaloids have multifunctional anti-inflammatory activities, including inhibiting the degradation of keratinocyte nuclear factors directly related to inflammation, preventing phosphorylation of protein subunits on nuclear factors, thereby blocking the process of cellular inflammation; reducing the occurrence of inflammatory immune responses and the reaction of neurodermatitis. Oat alkaloids can inhibit tumor necrosis factor, induce the activity of degrading enzymes, and reduce the release of inflammatory factors and factors leading to atopic dermatitis. At a low concentration of 30 ppm, oat alkaloids can significantly reduce the frequency of itching in contact dermatitis and neurodermatitis. The above evidence indicates that oat alkaloids have potent anti-inflammatory and antipruritic properties, and are a potent non-steroidal anti-inflammatory and antipruritic natural ingredient with bioactivity comparable to hydrocortisone, but without any side effects of steroid hormones.

[0003] However, the existing synthetic routes for 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid involve thionyl chloride waste liquid and a large amount of dilute alkali and acid waste liquid from ester hydrolysis, which are extremely harmful to the environment. At the same time, the amide bond is easily broken during hydrolysis, resulting in a large number of by-products in the waste liquid and the product, thus making product purification difficult.

[0004] Therefore, it is necessary to provide a new method for preparing 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid. Summary of the Invention

[0005] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the first aspect of the present invention proposes a method for preparing 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid, which has a high yield and generates little waste liquid.

[0006] A method for preparing 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid according to a first aspect embodiment of the present invention includes the following steps:

[0007] S1. Intermediate 2, organic solvent, base and 4-hydroxyphenylpropionyl chloride are mixed and reacted, and the solid-liquid separation is performed to obtain intermediate 3;

[0008] S2. Intermediate 3 and acid catalyst are mixed and reacted to obtain 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid;

[0009] The structural formulas of intermediates 2 and 3 and 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid are as follows:

[0010]

[0011] The preparation method according to embodiments of the present invention has at least the following beneficial effects:

[0012] The preparation method of the present invention uses intermediate 2 as raw material and can prepare 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid through two steps of amidation and deprotection. The method has high yield and low environmental pollution.

[0013] According to some embodiments of the present invention, the base is selected from at least one of triethylamine, pyridine, diisopropylethylamine, potassium carbonate, sodium carbonate, or cesium carbonate.

[0014] According to some embodiments of the present invention, the organic solvent is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, DMF or DMSO.

[0015] According to some embodiments of the present invention, in step S1, the temperature of the reaction is 0 to 25°C.

[0016] According to some embodiments of the present invention, in step S1, the molar ratio of intermediate 2 and 4-hydroxyphenylpropionyl chloride is 1:(0.8-1.5).

[0017] According to some embodiments of the present invention, the acid catalyst comprises trifluoroacetic acid.

[0018] According to some embodiments of the present invention, the intermediate 2 is prepared by the following method:

[0019] Intermediate 1, Raney nickel, and solvent are mixed and reacted to obtain intermediate 2;

[0020] The structural formula of intermediate 1 is as follows:

[0021]

[0022] According to some embodiments of the present invention, the solvent includes at least one selected from methanol, ethanol, isopropanol, and tert-butanol.

[0023] According to some embodiments of the present invention, the intermediate 1 is prepared by the following method:

[0024] The mixture of o-nitrobenzoic acid, dichloromethane, DMAP, base, and N,N'-dicyclohexylcarboimide was reacted to obtain intermediate 1.

[0025] According to some embodiments of the present invention, the alkali includes organic alkali and / or inorganic alkali.

[0026] According to some embodiments of the present invention, the organic base is selected from at least one of triethylamine, N,N-diisopropylethylamine, and trimethylamine.

[0027] According to some embodiments of the present invention, the inorganic base is selected from at least one of potassium carbonate, sodium carbonate, and cesium carbonate.

[0028] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Attached Figure Description

[0029] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0030] Figure 1 This is the hydrogen spectrum of 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid prepared in Example 1 of this invention. Detailed Implementation

[0031] The following are specific embodiments of the present invention, and the technical solutions of the present invention will be further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0032] Unless otherwise specified, the reagents, methods and equipment used in this invention are all conventional reagents, methods and equipment in this technical field.

[0033] Example 1

[0034] Example 1 provides a method for preparing 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid, comprising the following steps:

[0035] Synthesis of intermediate 1:

[0036] Under mechanical stirring at 0°C, o-nitrobenzoic acid (8.35 kg), dichloromethane (25 L), DMAP (300 mg), and tert-butanol (5 kg) were added sequentially to a 50 L reactor. Then, N,N'-dicyclohexylcarboimide (11.33 kg) was added in batches. After the addition was complete, the reaction system was allowed to rise naturally to room temperature and then stirred until the reaction was complete (TLC detection). The mixture was filtered, and the dichloromethane layer was washed twice with 1 M hydrochloric acid (1 kg each time) and once with saturated sodium chloride aqueous solution (1 kg). The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was recovered. The mixture was then evaporated to dryness to obtain intermediate 1 (yield 95.56%).

[0037] Synthesis of intermediate 2:

[0038] Under mechanical stirring at room temperature, the obtained intermediate 1 (10.0 kg), Raney nickel (500 g) and methanol (30 L) were sequentially added into a 50 L reactor. After replacing the hydrogen gas, the mixture was heated under reflux at one atmosphere until the reaction was complete. After rapid filtration, the solvent was recovered and the mixture was dried by rotary evaporation to obtain intermediate 2 (yield 99.50%).

[0039] S1. Under mechanical stirring at 0°C, intermediate 2 (7.72 kg), dichloromethane (15 L), and triethylamine (4.04 kg) were added sequentially to a 30 L reactor. After the addition was complete, p-hydroxyphenylpropionyl chloride (6.13 kg) was slowly added dropwise. After the addition was complete, the system temperature was slowly raised to room temperature, and the reaction continued until complete. After the reaction was complete, the solvent was recovered, and 4 kg of water was added to the solid part. After stirring for 30 minutes, the mixture was filtered. The solid part was washed with a small amount of water and dried to obtain intermediate 3 (yield 96.80%).

[0040] S2. Under ice-water magnetic stirring, 6.82 kg of intermediate 3 was dissolved in 10 L of dichloromethane, and then 3 kg of trifluoroacetic acid was slowly added dropwise. After the addition was complete, the system was slowly raised to room temperature and stirred until the reaction was complete. After concentrating and recovering the solvent, 2 kg of the remaining solid was added and stirred for 30 minutes. The mixture was then filtered, and the solid part was washed with a small amount of water and dried to obtain 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid with a yield of 99.71% (the overall yield of the four steps was 91.77%).

[0041] The prepared 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid was subjected to 1H NMR spectroscopy, and its 1H NMR spectrum is shown below. Figure 1 The data is as follows:

[0042] 1 HNMR: δ=11.12(s,1H),8.45-8.46(d,1H),7.92-7.94(d,1H),7.51-7.54(m,1H),7.07-7 .10(m,1H),7.00-7.01(d,2H),6.62-6.63(d,2H),2.78-2.81(m,2H),2.59-2.61(m,2H).

[0043] The present invention has been described in detail above with reference to the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A method for preparing 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid, characterized in that, The process includes the following steps: S1, reacting intermediate 2, an organic solvent, a base, and 4-hydroxyphenylpropionyl chloride, followed by solid-liquid separation to obtain intermediate 3; S2, reacting intermediate 3 with an acid catalyst to obtain 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid; wherein the structural formulas of intermediate 2, intermediate 3, and 2-(3-(4-hydroxyphenyl)propionylamino)benzoic acid are as follows: ； The intermediate 2 is prepared by the following method: intermediate 1, Raney nickel and solvent are mixed and reacted to obtain intermediate 2; The structural formula of the intermediate 1 is as follows: ； The intermediate 1 is prepared by the following method: The mixture of o-nitrobenzoic acid, dichloromethane, DMAP, base, and N,N-dicyclohexylcarboimide was reacted to obtain intermediate 1.

2. The preparation method according to claim 1, characterized in that, The base used to prepare intermediate 3 is selected from at least one of triethylamine, pyridine, diisopropylethylamine, potassium carbonate, sodium carbonate, or cesium carbonate.

3. The preparation method according to claim 1, characterized in that, The organic solvent is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, DMF, or DMSO.

4. The preparation method according to claim 1, characterized in that, In step S1, the reaction temperature is 0~25°C.

5. The preparation method according to claim 1, characterized in that, In step S1, the molar ratio of intermediate 2 and 4-hydroxyphenylpropionyl chloride is 1:(0.8~1.5).

6. The preparation method according to claim 1, characterized in that, The acid catalyst includes trifluoroacetic acid.

7. The preparation method according to claim 1, characterized in that, The solvent includes at least one of methanol, ethanol or tert-butanol.

8. The preparation method according to claim 1, characterized in that, The base used to prepare intermediate 1 includes organic bases and / or inorganic bases.

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