阅读说明：本技术 一种8-（2-羟基苯甲酰胺基）辛酸钠的制备方法 (Preparation method of sodium 8- (2-hydroxybenzamido) caprylate ) 是由 王良友 赵勇 黄莉 李席全 于 2020-12-29 设计创作，主要内容包括：本发明涉及一种8-(2-羟基苯甲酰胺基)辛酸钠的制备方法。本发明以水杨酰胺为原料与草酰氯反应生成中间体2H-苯并[e][1,3]噁嗪-2,4(3H)-二酮,该中间体和8-溴辛酸乙酯反应得到8-(2,4-二羰基-2H-苯并[e][1,3]噁嗪-3(4H)-基)辛酸乙酯,经氢氧化钠水解后酸化得到8-(2-羟基苯甲酰胺基)辛酸,之后和氢氧化钠反应得到最终产物,即8-(2-羟基苯甲酰胺基)辛酸钠。本发明避免了羰基二咪唑的使用从而避免了含咪唑的废水产生,废水处理成本降低,生产成本降低,反应能耗低,副产物较少,收率高,工艺简洁,易于工业化生产。(The invention relates to a preparation method of 8- (2-hydroxybenzamido) sodium caprylate. The invention takes salicylamide as raw material to react with oxalyl chloride to generate an intermediate 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone, the intermediate reacts with 8-bromoethyl caprylate to obtain 8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazine-3 (4H) -yl) ethyl caprylate, 8- (2-hydroxybenzamide) caprylic acid is obtained by acidification after hydrolysis of sodium hydroxide, and then the final product, namely 8- (2-hydroxybenzamide) sodium caprylate, is obtained by reaction with sodium hydroxide. The method avoids the use of carbonyl diimidazole, thereby avoiding the generation of imidazole-containing wastewater, reducing the wastewater treatment cost, the production cost, the reaction energy consumption, fewer byproducts, high yield, simple process and easy industrial production.)

1. A preparation method of sodium 8- (2-hydroxybenzamido) caprylate is characterized by comprising the following steps:

(1) reacting salicylamide with oxalyl chloride to generate 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone;

(2) reacting 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone and 8-bromoethyl octanoate to obtain 8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazine-3 (4H) -yl) ethyl octanoate;

(3) hydrolyzing 8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazine-3 (4H) -yl) ethyl caprylate by sodium hydroxide, and adjusting the pH value by using acid to obtain 8- (2-hydroxybenzamide) caprylic acid;

(4)8- (2-hydroxybenzamido) caprylic acid reacts with sodium hydroxide to obtain the product 8- (2-hydroxybenzamido) sodium caprylate.

2. The method according to claim 1, wherein in the step (1) or the step (2), the reaction solvent is one or more of N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane and chloroform.

3. The method according to claim 1, wherein in the step (1), the reaction temperature is 30-80 ℃ and the reaction time is 6-10 h.

4. The method according to claim 1, wherein the step (1) further comprises a step of extracting the product, specifically, the reaction liquid obtained after the reaction of salicylamide and oxalyl chloride is subjected to rotary evaporation, water washing and filtration to obtain 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -dione.

5. The process according to claim 1, wherein in step (2), 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -dione and ethyl 8-bromooctanoate are reacted in the presence of anhydrous potassium carbonate.

6. The method of claim 1, wherein in the step (2), the reaction temperature is 60-80 ℃ and the reaction time is 2-4 h.

7. The method according to claim 1, wherein the step (2) further comprises a step of extracting the product, specifically, adding the reacted reaction solution into water, stirring for crystallization, filtering, and washing to obtain (8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazine-3 (4H) -yl) ethyl octanoate).

8. The method of claim 1, wherein in the step (3), the reaction temperature is 100-120 ℃ and the reaction time is 4-6 h.

9. The method according to claim 1, wherein in the step (3), the acid for adjusting the pH is hydrochloric acid or sulfuric acid, and the pH is adjusted to 1-3.

10. The method according to claim 1, wherein in the step (4), the solvent for reacting 8- (2-hydroxybenzamido) octanoic acid with sodium hydroxide is isopropanol.

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of sodium 8- (2-hydroxybenzamido) caprylate.

Background

Sodium 8- (2-hydroxybenzamido) caprylate, abbreviated as SNAC. The SNAC is a micromolecular fatty acid derivative, can promote the absorption of the drug in the epithelial cells of the gastrointestinal tract, effectively deals with the absorption obstacle of the oral polypeptide drug, and has better application prospect.

Chinese patent CN 108689876A reports a preparation method of 8- (2-hydroxybenzamido) sodium caprylate, which uses salicylamide and carbonyldiimidazole as starting materials to prepare an intermediate 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone, and then obtains the 8- (2-hydroxybenzamido) sodium caprylate through multi-step reaction. On the basis of world patent W000/46182 and Chinese patent CN 104974060A, ethyl chloroformate, which is a reactant with great harm to human bodies, is replaced by carbonyl diimidazole with relatively low toxicity, but the carbonyl diimidazole used in the patent can generate imidazole after reaction, and causes harm to the environment, especially water bodies, so that the waste liquid treatment difficulty is high, the cost is high, meanwhile, the atom economy of the carbonyl diimidazole is low, and the carbonyl diimidazole does not accord with the concept of green chemistry, therefore, a new preparation method is needed, and the cost is reduced on the premise of being more environment-friendly so as to adapt to industrial production.

Disclosure of Invention

In order to solve the technical problems, the invention provides a preparation method of sodium 8- (2-hydroxybenzamido) caprylate, which avoids the use of highly toxic substances, reduces the generation of wastewater, has small harm to human and environment and is suitable for industrial large-scale production.

The first purpose of the invention is to provide a preparation method of 8- (2-hydroxybenzamido) sodium caprylate, which comprises the following steps:

(1) reacting salicylamide with oxalyl chloride to generate 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone;

(2) reacting 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone and 8-bromoethyl octanoate to obtain 8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazine-3 (4H) -yl) ethyl octanoate;

(3) hydrolyzing 8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazine-3 (4H) -yl) ethyl caprylate by sodium hydroxide, and adjusting the pH value by using acid to obtain 8- (2-hydroxybenzamide) caprylic acid;

(4)8- (2-hydroxybenzamido) caprylic acid reacts with sodium hydroxide to obtain the product 8- (2-hydroxybenzamido) sodium caprylate.

Further, in the step (1) or the step (2), the reaction solvent is one or more of N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane and chloroform.

Further, in the step (1), the reaction temperature is 30-80 ℃, and the reaction lasts for 6-10 hours.

Further, the step (1) also comprises a step of extracting a product, specifically, a reaction solution obtained after reaction of salicylamide and oxalyl chloride is subjected to rotary evaporation, washing with water and filtering to obtain 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone.

Further, in the step (2), 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -dione and ethyl 8-bromooctanoate are reacted in the presence of anhydrous potassium carbonate.

Further, in the step (2), the reaction temperature is 60-80 ℃, and the reaction lasts for 2-4 hours.

Further, the step (2) further comprises a step of extracting a product, specifically, adding the reacted reaction solution into water, stirring and crystallizing, filtering, and washing to obtain (8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazine-3 (4H) -yl) ethyl caprylate).

Further, in the step (3), the reaction temperature is 100-120 ℃, and the reaction lasts for 4-6 hours.

Further, in the step (3), the acid for adjusting the pH is hydrochloric acid or sulfuric acid, and the pH is adjusted to 1-3.

Further, in the step (4), the solvent for the reaction of 8- (2-hydroxybenzamido) caprylic acid and sodium hydroxide is isopropanol.

The synthetic route of the invention is as follows:

by the scheme, the invention at least has the following advantages:

the invention avoids the generation of waste water containing imidazole and greatly reduces the harm to the environment. The oxalyl chloride is originally used as a raw material for substituting carbonyl, is cheap and has low toxicity, is easy to react with water to generate carbon monoxide, carbon dioxide and hydrochloric acid, and has simple subsequent treatment. Compared with carbonyl diimidazole, oxalyl chloride has higher atom economy and lower production cost.

The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following description is made with reference to the preferred embodiments of the present invention and the accompanying detailed drawings.

Drawings

FIG. 1 shows the hydrogen nuclear magnetic resonance spectrum of the compound (2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -dione) obtained in example 1.

FIG. 2 shows the NMR spectrum of the product of example 4 (sodium 8- (2-hydroxybenzamido) octanoate).

FIG. 3 is an HPLC chart of the product of example 4 (sodium 8- (2-hydroxybenzamido) octanoate).

FIG. 4 is a MS diagram of the product of example 4, sodium 8- (2-hydroxybenzamido) octanoate

Detailed Description

The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

Example 1: compound 1: preparation of (2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -dione)

13.7g (0.10mol) of salicylamide and 800mL of pre-refrigerated acetonitrile are added into a 1L four-mouth bottle with mechanical stirring, stirred and dissolved at the temperature of about 5 ℃, 25.4g (0.20mol) of pre-refrigerated oxalyl chloride is added into the system dropwise, and 100mL of acetonitrile is added after the dropwise addition is finished and stirring is continued. After being stirred evenly, the mixture is heated to 60 ℃ and reacts for 8 hours. And then, after most of the solvent and unreacted oxalyl chloride are removed by rotary evaporation, adding 250mL of purified water into the residual liquid, pulping and filtering, pulping and washing the filter cake twice by using the purified water, draining, and drying by blowing at 40-50 ℃ for 16h to obtain 15.2g of white-like solid with the yield of 93.2%.

Compound 1 (2H-benzo [ e ]][1,3]Oxazine-2, 4(3H) -diones)¹H NMR(500MHz,DMSO)δ12.09(s,1H),7.90～8.00(m,1H),7.42(dd,J＝13.1,7.9Hz,2H)。

Example 2: compound 2: preparation of (8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -yl) octanoic acid ethyl ester)

DMF100mL, compound 114.36 g (0.088mol) and anhydrous potassium carbonate 22.11g (0.160mol) were added to a 250mL reaction flask with magnetons, stirred, and 20.09g (0.080mol) of ethyl 8-bromooctanoate was slowly added dropwise, after the dropwise addition, the oil bath was heated to 70 ℃ to start the heating reaction for 3 hours. After the temperature is reduced to room temperature, the reaction solution is poured into 800mL of water, fully stirred, crystallized, filtered and fully washed, and a filter cake is placed in a vacuum drying oven at the temperature of 35-40 ℃ for drying for 16h to obtain 25.3g of off-white solid with the yield of 94.9%.

Example 3: compound 3: preparation of (8- (2-hydroxybenzamido) octanoic acid)

A250 mL reaction flask equipped with magnetons was charged with 223.34 g (0.070mol) of compound, 11.2g (0.280mol) of NaOH, and 180mL of purified water, and the mixture was stirred. The reaction was started for 5h with the oil bath set at 110 ℃. Cooling to room temperature, adjusting the pH value to 1-3 by using concentrated hydrochloric acid, and fully stirring for 30 min. The system was filtered, the filter cake was washed thoroughly with water, drained and air dried at 50-60 ℃ to give 18.5g of a pale pink solid with a yield of 94.6%.

Example 4: compound 4: preparation of sodium (8- (2-hydroxybenzamido) caprylate)

A250 mL reaction flask equipped with magnetons was charged with 200mL of compound 318.0 g (0.064mol) isopropanol, heated to 40-50 ℃ and dissolved with stirring. After the solution was dissolved, 2.6g (0.064mol) of NaOH was dissolved in 10mL of pure water and added dropwise to the system. Stirring for 30min at constant temperature after the dropwise addition. Turning off the heating, cooling to room temperature, stirring and crystallizing. Filtering after the crystal in the system is not increased any more, washing with a small amount of isopropanol, and vacuum drying at 30-40 ℃ to obtain 17.8g of off-white solid with the yield of 92.3%.

Compound 4(8- (2-hydroxybenzamido)) Sodium caprylate)¹H NMR(500MHz,MeOD)δ7.83(s,1H),7.37(s,1H),6.91(d,J＝31.5Hz,2H),3.39(d,J＝27.1Hz,2H),2.21(s,2H),1.65(s,4H),1.41(s,6H)。

The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.