CN108689876B

CN108689876B - Preparation method of sodium 8- (2-hydroxybenzamido) caprylate

Info

Publication number: CN108689876B
Application number: CN201810706074.5A
Authority: CN
Inventors: 王冬冬; 宗熙; 于文渊; 吉民; 胡海燕; 张影
Original assignee: Southeast Pharmaceuticals Co ltd
Current assignee: Jiangsu Dongnan Nano Material Co ltd
Priority date: 2018-06-28
Filing date: 2018-06-28
Publication date: 2020-11-27
Anticipated expiration: 2038-06-28
Also published as: CN108689876A

Abstract

The invention discloses a preparation method of a drug intermediate 8- (2-hydroxybenzamido) sodium caprylate, which comprises the steps of reacting salicylamide serving as a raw material with N' N-carbonyl diimidazole to generate an intermediate 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone, reacting the intermediate with 8-bromoethyl caprylate to obtain 8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazine-3 (4H) -yl) ethyl caprylate, hydrolyzing with sodium hydroxide, acidifying to obtain 8- (2-hydroxybenzamido) caprylate, and reacting with sodium hydroxide to obtain a final product, namely 8- (2-hydroxybenzamido) sodium caprylate. The method avoids the use of genotoxic ethyl chloroformate, has low reaction energy consumption, fewer byproducts, high yield, greatly reduced production cost, simple process and easy industrial production.

Description

Preparation method of sodium 8- (2-hydroxybenzamido) caprylate

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of sodium 8- (2-hydroxybenzamido) caprylate.

Technical Field

Sodium 8- (2-hydroxybenzamide) caprylate, SNAC for short, is an amino acid derivative absorption enhancer, can promote oral absorption of various protein drug solutions such as heparin, human growth hormone and the like, can be used for treating gastrointestinal diseases, and has good application prospect.

World patent WO 00/46182 and Chinese patent CN 104974060A both report methods for preparing sodium 8- (2-hydroxybenzamido) caprylate, but both patents use salicylamide and ethyl chloroformate as starting materials to prepare intermediate 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone, and then obtain sodium 8- (2-hydroxybenzamido) caprylate through multi-step reaction. The ethyl chloroformate has high toxicity, genotoxicity and great harm to human and environment, and the reaction needs to be carried out at high temperature, so that the energy consumption is relatively high, side reactions are relatively more, and the production cost is relatively high. Therefore, a new preparation method is needed, and the method is suitable for industrial production on the premise of more environmental protection.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide the preparation method for preparing the sodium 8- (2-hydroxybenzamido) caprylate according to the synthesis concept of green chemistry, and the preparation method avoids using highly toxic substances, has simple process, mild conditions, less side reactions and less harm to human and environment, and is suitable for industrial scale-up production.

In order to achieve the purpose, the main technical scheme provided by the invention is as follows:

(1) reacting salicylamide with N' N-carbonyl diimidazole 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.

In the step (1), salicylamide and N' N-carbonyl diimidazole are used as raw materials.

The reaction solvent used in the step (1) is one or more selected from N, N-dimethylformamide, N-dimethylacetamide, acetonitrile and tetrahydrofuran.

The reaction temperature in the step (1) is preferably 0-30 ℃.

And (2) the step (1) also comprises the post-treatment of the product, specifically, after the reaction of salicylamide and N' N-carbonyldiimidazole, adding a proper amount of water into the reaction liquid, adjusting the pH (preferably the pH is 1-3) by using hydrochloric acid until a solid is separated out, and filtering and drying to further obtain the 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone.

And (2) post-treating the product, namely specifically, reacting 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone with 8-bromoethyl octanoate, adding a proper amount of water into the reaction solution, precipitating a solid, filtering and drying to obtain 8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazine-3 (4H) -yl) ethyl octanoate.

The acid forming solvent in the step (3) is preferably hydrochloric acid or sulfuric acid;

in the step (4), isopropanol is preferably used as the reaction solvent.

The synthetic route of the invention is as follows:

compared with the prior art, the invention has the following advantages and effects: 1) avoids the use of ethyl chloroformate which is a highly toxic raw material, and greatly reduces the harm to the environment and people. 2) The intermediate 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone is prepared by using N' N-Carbonyl Diimidazole (CDI) as a raw material, and the raw material is cheap and easy to obtain, has low toxicity and good selectivity, and greatly improves the reaction yield. 3) The preparation process of the intermediate 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone does not need high-temperature heating, and has the advantages of mild reaction conditions, less side reactions, high yield and greatly reduced production cost. 4) All intermediates in the whole reaction step do not need to be further separated and purified, so that the method avoids using a large amount of solvents for recrystallization or column chromatography, and has less pollution to the environment.

Drawings

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

FIG. 2 NMR spectrum of compound 4 (sodium 8- (2-hydroxybenzamido) octanoate), a product obtained in example four.

FIG. 3 HPLC of the product, Compound 4 (sodium 8- (2-hydroxybenzamido) octanoate), obtained in example four.

Detailed Description

The present invention is further illustrated by the following examples, which are illustrative of the present invention and are not to be construed as being limited thereto.

EXAMPLE preparation of 1 (2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -dione), Compound

Adding 20.0g (0.146mol) of salicylamide and 80ml of DMF (dimethyl formamide) into a 250ml reaction bottle with a magneton thermometer, stirring and cooling to 0-5 ℃, adding 28.4g (0.175mol) of N' -N-carbonyldiimidazole in batches, and controlling the temperature to 0-5 ℃. And then reacting at room temperature for 2-3 h, adding 240ml of purified water, adjusting the pH value to 1-3 with 6M hydrochloric acid aqueous solution, continuing stirring for 30min, filtering, leaching a filter cake with the purified water, and drying the filter cake in an air drying oven at 45-50 ℃ for 16h to obtain 23.3g of off-white solid with the yield of 97.9%.

Compound 1 (2H-benzo [ e ]][1,3]Oxazine-2, 4(3H) -diones)¹H NMR(500MHz,DMSO)12.09(s,1H),7.90～8.00(m,1H),7.42(dd,J＝13.1,7.9Hz,2H)

EXAMPLE preparation of Compound 2 (ethyl 8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazin-3 (4H) -yl) octanoate)

Adding 45ml of DMF, 14.50g (0.058mol) of ethyl 8-bromooctanoate, 110.36 g (0.064mol) of compound and 13.03g (0.123mol) of anhydrous sodium carbonate into a 250ml reaction bottle with a magneton and a thermometer, stirring, and heating to 70 +/-5 ℃ for reaction for 2-2.5 h. Cooling to room temperature, filtering, pouring the filtrate into 420ml of stirred water, continuously stirring for 1-1.5 h, filtering, leaching the filter cake with purified water, and drying in an air-blast drying oven at 35-40 ℃ for 24h to obtain 18.3g of light pink solid with the yield of 95.1%.

EXAMPLE preparation of the Compound 3(8- (2-hydroxybenzamido) octanoic acid)

Adding 90ml of purified water and 8.64g (0.216mol) of sodium hydroxide into a 250ml reaction bottle with a magneton and a thermometer, stirring to dissolve the mixture, adding 218.00 g (0.054mol) of a compound, heating and refluxing for reaction for 1.5-2 h, cooling to room temperature, adjusting the pH value to 1-2 with 6M hydrochloric acid aqueous solution, continuing stirring for 30min, filtering, leaching a filter cake with purified water, and drying for 14-18 h at 45-55 ℃ by using an air drying oven to obtain 14.5g of light pink solid with the yield of 96.1%.

EXAMPLE preparation of Tetracompound 4 (sodium 8- (2-hydroxybenzamido) octanoate)

Adding 314.5 g (0.052mol) of compound and 220ml of isopropanol into a 250ml reaction bottle with a magneton and a thermometer, stirring and heating to 45-55 ℃ for dissolving, adding 2.12g (0.053mol) of sodium hydroxide solution dissolved in 8.5ml of purified water, continuously stirring for 0.5-1 h at 45-55 ℃, cooling to 15-25 ℃, stirring and crystallizing for 4-6 h, filtering, leaching a filter cake with isopropanol, and drying for 24h at 40-50 ℃ in a blast drying oven to obtain 12.3g of light pink solid with the yield of 78.6%.

Compound 4(8- (2-hydroxybenzamido) sodium caprylate)¹H NMR(500MHz,MeOD)7.83(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)。

Diluting with water to obtain a solution containing about 0.04mg of the above product (compound 4) per 1ml, precisely measuring 10 μ l, and using octadecylsilane chemically bonded silica as filler; using 0.4% acetic acid solution-methanol (45: 55) as mobile phase; the detection wavelength was 270 nm. The gradient elution is performed according to the following table.

Time (min)	A (0.4% acetic acid)	B (methanol)
			0	45	55
15	20	80
			20	20	80
20.01	45	80
			25	45	80

An HPLC chromatogram is shown in figure 3, and the result shows that the purity of the 8- (2-hydroxybenzamido) sodium caprylate prepared by the method can reach more than 99.88 percent.

It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

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

(1) adding 20.0g of salicylamide and 80ml of DMF (dimethyl formamide) into a 250ml reaction bottle with a magneton and a thermometer, stirring and cooling to 0-5 ℃, adding 28.4g of N' -N-carbonyldiimidazole in batches, and controlling the temperature to 0-5 ℃; then reacting for 2-3 h at room temperature, adding 240ml of purified water, adjusting the pH to be 1-3 by using 6M hydrochloric acid aqueous solution, continuously stirring for 30min, filtering, leaching a filter cake by using the purified water, and drying the filter cake in an air drying oven at 45-50 ℃ for 16 h;

(2) adding 45ml of DMF (dimethyl formamide), 14.50g of ethyl 8-bromooctanoate, 10.36g of 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -dione and 13.03g of anhydrous sodium carbonate into a 250ml reaction bottle with a magneton and a thermometer, stirring, heating to 70 +/-5 ℃, reacting for 2-2.5H, cooling to room temperature, filtering, pouring the filtrate into 420ml of stirred water, continuously stirring for 1-1.5H, filtering, leaching the filter cake with purified water, and drying for 24H at 35-40 ℃ in a blast drying oven;

(3) adding 90ml of purified water and 8.64g of sodium hydroxide into a 250ml reaction bottle with a magneton and a thermometer, stirring to dissolve the purified water, adding 18.00g of (8- (2, 4-dicarbonyl-2H-benzo [ e ] [1,3] oxazine-3 (4H) -yl) ethyl caprylate), heating and refluxing for reaction for 1.5-2H, cooling to room temperature, adjusting the pH to = 1-2 with 6M hydrochloric acid aqueous solution, continuing stirring for 30min, filtering, leaching filter cakes with purified water, and drying for 14-18H at 45-55 ℃ by using a blast drying oven;

(4) adding 14.5g (0.052mol) of (8- (2-hydroxybenzamide) caprylic acid) and 220ml of isopropanol into a 250ml reaction bottle with a magneton and a thermometer, stirring and heating to 45-55 ℃ for clearing, adding 2.12g (0.053mol) of sodium hydroxide solution dissolved in 8.5ml of purified water, continuing stirring at 45-55 ℃ for 0.5-1 h, cooling to 15-25 ℃, stirring and crystallizing for 4-6 h, filtering, leaching a filter cake with isopropanol, and drying in a blast drying oven at 40-50 ℃ for 24 h.

2. A preparation method of 2H-benzo [ e ] [1,3] oxazine-2, 4(3H) -diketone is characterized in that 20.0g of salicylamide and 80ml of DMF are added into a 250ml reaction bottle with a magneton and a thermometer, the temperature is reduced to 0-5 ℃ by stirring, 28.4g of N' N-carbonyldiimidazole is added in batches, and the temperature is controlled to 0-5 ℃; and then reacting for 2-3 h at room temperature, adding 240ml of purified water, adjusting the pH to be 1-3 by using 6M hydrochloric acid aqueous solution, continuously stirring for 30min, filtering, leaching a filter cake by using the purified water, and drying the filter cake in an air drying oven at 45-50 ℃ for 16 h.