阅读说明：本技术 一种n-（8-[2-羟基苯甲酰基]-氨基）辛酸钠的合成方法 (Synthesis method of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate ) 是由 李运铎 张宝国 王新房 朱赞梅 李沁沁 常欢 张银霞 季萍 于 2021-10-28 设计创作，主要内容包括：本发明公开了一种N-(8-[2-羟基苯甲酰基]-氨基)辛酸钠的合成方法。首先将邻羟基苯甲酸甲酯加入反应容器中,然后加入溶剂和8-氨基辛酸进行反应；反应后所得反应物减压蒸馏,除去溶剂,所得剩余物冷却至室温,得到N-(8-[2-羟基苯甲酰基]-氨基)辛酸；所得N-(8-[2-羟基苯甲酰基]-氨基)辛酸加入反应容器中,然后加入水和碱进行反应,反应后加入异丙醇析晶,过滤取固体,所得产物进行重结晶,得到N-(8-[2-羟基苯甲酰基]-氨基)辛酸钠纯品。本发明制备方法原料易得,反应条件温和,制备所得成品纯度高,适合于工业化生产。(The invention discloses a method for synthesizing N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate. Firstly, adding methyl o-hydroxybenzoate into a reaction vessel, and then adding a solvent and 8-aminocaprylic acid for reaction; distilling the obtained reactant under reduced pressure after the reaction, removing the solvent, and cooling the obtained residue to room temperature to obtain N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid; adding the obtained N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid into a reaction container, then adding water and alkali for reaction, adding isopropanol for crystallization after reaction, filtering to obtain a solid, and recrystallizing the obtained product to obtain the pure product of the N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid sodium. The preparation method has the advantages of easily available raw materials, mild reaction conditions and high purity of the prepared finished product, and is suitable for industrial production.)

1. A method for synthesizing sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, which is characterized by comprising the following steps:

a. firstly, adding a raw material methyl o-hydroxybenzoate into a reaction vessel, then adding a solvent and 8-aminocaprylic acid for reaction, wherein the reaction temperature is 20-40 ℃, and the reaction time is 8-12 hours;

b. c, carrying out reduced pressure distillation on the reactant obtained after the reaction in the step a, removing the solvent, and cooling the obtained residue to room temperature to obtain N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid;

c. and c, adding the N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid obtained in the step b into a reaction vessel, then adding water for dissolving, adding alkali for reacting after full dissolution, adding isopropanol for crystallization after the reaction is finished, filtering to obtain a solid, and recrystallizing the obtained product to obtain the pure product of the N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid sodium.

2. The method of claim 1 for the synthesis of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, characterized in that: the molar ratio of the methyl o-hydroxybenzoate and the 8-aminocaprylic acid added in the step a is 1: 1.2 to 2.0; the mass ratio of the methyl o-hydroxybenzoate to the solvent is 1: 5 to 10.

3. The method of claim 1 for the synthesis of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, characterized in that: the solvent in step a is any one of dichloromethane, chloroform, acetonitrile and dimethylformamide.

4. The method of claim 1 for the synthesis of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, characterized in that: and c, adding water in the step c, wherein the mass of the added water is 5-10 times of that of the o-hydroxybenzoic acid methyl ester.

5. The method of claim 1 for the synthesis of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, characterized in that: in step c, the base is sodium bicarbonate.

6. The method of claim 1 for the synthesis of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, characterized in that: the molar ratio of the N- (8- [ 2-hydroxybenzoyl ] -amino) octanoic acid to the base added in step c is 1: 1.2 to 2.0.

7. The method of claim 1 for the synthesis of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, characterized in that: and c, in the process of adding alkali for reaction in the step c, the reaction temperature is room temperature, and the reaction time is 1-3 h.

8. The method of claim 1 for the synthesis of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, characterized in that: in the step c, the adding mass of the isopropanol is 2-3 times of the mass of the water.

9. The method of claim 1 for the synthesis of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, characterized in that: and c, adopting absolute ethyl alcohol as a solvent in the recrystallization process.

The technical field is as follows:

the invention relates to the technical field of organic matter synthesis, in particular to a preparation method of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate.

Secondly, background art:

sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate (SNAC for short) is an accelerant capable of promoting drug absorption, and the structural formula is as follows:

SNAC is used as an enhancer, and can be combined with high molecular weight oral drugs to increase the permeability of the drugs in the gastrointestinal tract, thereby achieving the purpose of absorption by the human body.

At present, there are various methods for synthesizing sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, and in U.S. Pat. No. 5650386, O-acetylsalicyloyl chloride is reacted with 8-aminocaprylic acid to prepare sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate. The method has the advantages of short route, difficult storage, high reaction activity, more side reactions and high impurity content of the finished product, and the raw material is O-acetylsalicyloyl chloride. In patent WO0046182, salicylamide is used as a starting material, and reacts with ethyl chloroformate to generate 2H-1, 3-benzoxazine-2, 4(3H) -diketone, and then reacts with 8-bromoethyl caprylate, and the product is hydrolyzed by acid and alkali to generate N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate. The method has a long route, and the ethyl chloroformate serving as a reaction raw material is a highly toxic substance and is not friendly to the environment and workers. In the technical scheme disclosed in patent CN 03114941.3A, salicylic acid is used as a starting material, and reacts with omega-sodium aminocaprylate after an acylchlorination reaction to prepare SNAC. The method has a short route, and the acyl chlorination reaction of the salicylic acid usually uses thionyl chloride and other acyl chlorination reagents, so that the reaction conditions are severe and the pollution is large.

Thirdly, the invention content:

the technical problem to be solved by the invention is as follows: provides a new preparation method of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate. The technical scheme of the invention adopts methyl o-hydroxybenzoate as a raw material, and the sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate is generated by reacting with 8-aminocaprylic acid, the raw materials of the preparation method are easy to obtain, the reaction conditions are mild, and the prepared finished product has high purity and is suitable for industrial production.

In order to solve the problems, the invention adopts the technical scheme that:

the invention provides a synthesis method of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate, which comprises the following steps:

a. firstly, adding a raw material methyl o-hydroxybenzoate into a reaction vessel, then adding a solvent and 8-aminocaprylic acid for reaction, wherein the reaction temperature is 20-40 ℃, and the reaction time is 8-12 hours;

b. c, carrying out reduced pressure distillation on the reactant obtained after the reaction in the step a, removing the solvent, and cooling the obtained residue to room temperature to obtain N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid;

c. and c, adding the N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid obtained in the step b into a reaction vessel, then adding water for dissolving, adding alkali for reacting after full dissolution, adding isopropanol for crystallization after the reaction is finished, filtering to obtain a solid, and recrystallizing the obtained product to obtain the pure product of the N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid sodium.

According to the above method for synthesizing sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, the molar ratio of methyl o-hydroxybenzoate and 8-aminocaprylic acid added in step a is 1: 1.2 to 2.0; the mass ratio of the methyl o-hydroxybenzoate to the solvent is 1: 5 to 10.

According to the above method for synthesizing sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, the solvent in step a is any one of dichloromethane, chloroform, acetonitrile and dimethylformamide.

According to the synthesis method of the sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, the mass of the added water in the step c is 5-10 times of that of the o-hydroxybenzoic acid methyl ester.

According to the above synthesis of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, the base in step c is sodium bicarbonate.

According to the above method for synthesizing sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, the molar ratio of the N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid and the alkali added in the step c is 1: 1.2 to 2.0.

According to the synthesis method of the sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, in the step c, the alkali is added for reaction, the reaction temperature is room temperature, and the reaction time is 1-3 hours.

According to the method for synthesizing the sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, the adding mass of the isopropanol in the step c is 2-3 times of the mass of the water.

According to the above method for synthesizing sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, the solvent used in the recrystallization process in step c is absolute ethyl alcohol.

The invention has the following positive beneficial effects:

1. in the technical scheme of the invention, the adopted reaction raw materials are easy to obtain, and the product has stable properties and is beneficial to storage.

2. In the technical scheme of the invention, the adopted reaction raw materials are nontoxic, environment-friendly and worker-friendly, and beneficial to environmental protection.

3. In the technical scheme of the invention, the reaction condition is mild, the reaction can be carried out at room temperature, heating or cooling operation is not needed, the energy consumption is reduced, and the preparation method is more green and environment-friendly.

4. The invention has shorter synthesis process steps and simple post-treatment, and is more beneficial to industrialized mass production.

5. The finished product of the N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate prepared by the technical scheme has high purity which is up to more than 99 percent.

In conclusion, the invention has obvious economic benefit and social benefit.

Fourthly, explanation of the attached drawings:

FIG. 1 is a chemical reaction scheme of the method for synthesizing sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate.

FIG. 2 is a liquid chromatogram of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) octanoate prepared in example 1 of the present invention.

The fifth embodiment is as follows:

the invention is further illustrated by the following examples, which do not limit the scope of the invention.

Example 1:

the invention relates to a method for synthesizing N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate, which comprises the following steps:

a. firstly, introducing nitrogen into a 500mL three-port reaction bottle, and then adding 20.0g (0.13mol) of raw material methyl o-hydroxybenzoate, 150.0g of solvent dimethylformamide and 31.8g (0.20mol) of 8-aminocaprylic acid for reaction at the reaction temperature of 35 ℃ for 10 hours;

b. c, carrying out reduced pressure distillation on the reactant obtained after the reaction in the step a (in the process of reduced pressure distillation, controlling the vacuum degree to be 0.09MPa and the temperature to be 50 ℃), removing the solvent, and cooling the obtained residue to room temperature to obtain N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid;

c. adding the N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid obtained in the step b, 100g of water and 16.8g (0.20mol) of sodium bicarbonate into a 500mL three-mouth reaction bottle, and reacting for 1h at room temperature under the condition of continuous stirring; after the reaction is finished, 200g of isopropanol is added, the temperature is reduced to 4 ℃, the temperature is kept for 2h, and solid is separated out; filtering to obtain solid, and obtaining crude product of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate; the crude product is recrystallized by absolute ethyl alcohol to obtain 28.6g of pure N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate (the liquid chromatogram of the pure product is shown in figure 1 in detail, the purity of the pure product reaches 100 percent), and the yield is 73.1 percent.

Example 2:

the invention relates to a method for synthesizing N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate, which comprises the following steps:

a. firstly, introducing nitrogen into a 500mL three-mouth reaction bottle, and then adding 20.0g (0.13mol) of raw material methyl o-hydroxybenzoate, 200.0g of solvent chloroform and 24.8g (0.156mol) of 8-aminocaprylic acid for reaction at the reaction temperature of 40 ℃ for 8 hours; after the reaction, adding water into the obtained reaction liquid for extraction for 3 times, and extracting with 50mL of water each time to obtain an organic phase;

b. c, carrying out reduced pressure distillation on the organic phase obtained in the step a (in the process of reduced pressure distillation, controlling the vacuum degree to be 0.09MPa and the temperature to be 50 ℃), removing the solvent, and cooling the obtained residue to room temperature to obtain N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid;

c. adding the N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid obtained in the step b, 140g of water and 13.1g (0.156mol) of sodium bicarbonate into a 500mL three-mouth reaction bottle, and reacting for 1h at room temperature under the condition of continuous stirring; after the reaction is finished, 350g of isopropanol is added, the temperature is reduced to 5 ℃, the temperature is kept for 3h, and solid is separated out; filtering to obtain solid, and obtaining crude product of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate; the crude product was recrystallized from absolute ethanol to obtain 27.6g of pure sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate with a yield of 70.5%.

Example 3:

the invention relates to a method for synthesizing N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate, which comprises the following steps:

a. firstly, introducing nitrogen into a 500mL three-mouth reaction bottle, and then adding 20.0g (0.13mol) of raw material methyl o-hydroxybenzoate, 160.0g of solvent dichloromethane and 41.4g (0.26mol) of 8-aminocaprylic acid for reaction at the reaction temperature of 35 ℃ for 12 hours; after the reaction, adding water into the obtained reaction liquid for extraction for 3 times, and extracting with 50mL of water each time to obtain an organic phase;

b. c, carrying out reduced pressure distillation on the organic phase obtained in the step a (in the process of reduced pressure distillation, controlling the vacuum degree to be 0.09MPa and the temperature to be 40 ℃), removing the solvent, and cooling the obtained residue to room temperature to obtain N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid;

c. adding the N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid obtained in the step b, 200g of water and 21.8g (0.26mol) of sodium bicarbonate into a 500mL three-mouth reaction bottle, and reacting for 1h at room temperature under the condition of continuous stirring; after the reaction is finished, 600g of isopropanol is added, the temperature is reduced to 0 ℃, the temperature is kept for 2h, and solid is separated out; filtering to obtain solid, and obtaining crude product of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate; the crude product was recrystallized from absolute ethanol to obtain 27.9g of pure sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate with a yield of 71.3%.