Preparation method of sodium 8-[(2-hydroxybenzoyl) amino] octanoate

A technology of hydroxybenzamide and sodium octanoate, which is applied in the field of medicine and chemical industry, can solve the problems of high toxicity of ethyl chloroformate, great harm to humans and the environment, and genotoxicity, so as to avoid recrystallization or column chromatography, reduce Harmful to the environment and humans, less toxic effects

Active Publication Date: 2018-10-23
江苏东南纳米材料有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ethyl chloroformate is highly toxic and has genotoxicity, which is very harmful to humans and the environment, and the reaction in this step needs to be carried out at high temperature, so the energy consumption is relatively large, and there are relatively many side reactions, and the production cost is relatively high

Method used

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  • Preparation method of sodium 8-[(2-hydroxybenzoyl) amino] octanoate
  • Preparation method of sodium 8-[(2-hydroxybenzoyl) amino] octanoate
  • Preparation method of sodium 8-[(2-hydroxybenzoyl) amino] octanoate

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Example 1 Preparation of compound 1 (2H-benzo[e][1,3]oxazine-2,4(3H)-dione)

[0025] Add 20.0g (0.146mol) of salicylamide and 80ml of DMF into a 250ml reaction bottle with a magnet and a thermometer, stir and cool down to 0-5°C, add 28.4g (0.175mol) of N'N-carbonyldiimidazole in batches, Temperature control 0 ~ 5 ℃. Then react at room temperature for 2 to 3 hours, add 240ml of purified water, adjust the pH to 1 to 3 with 6M hydrochloric acid aqueous solution, continue to stir for 30 minutes, filter, rinse the filter cake with purified water, put the filter cake in a blast drying oven at 45 to After drying at 50°C for 16 hours, 23.3 g of an off-white solid was obtained, with a yield of 97.9%.

[0026] Compound 1 (2H-Benzo[e][1,3]oxazine-2,4(3H)-dione) 1 H NMR(500MHz,DMSO)δ12.09(s,1H),7.90~8.00(m,1H),7.42(dd,J=13.1,7.9Hz,2H)

Embodiment 2

[0027] Example 2 Preparation of compound 2 (8-(2,4-dicarbonyl-2H-benzo[e][1,3]oxazin-3(4H)-yl) octanoic acid ethyl ester)

[0028] Add 45ml DMF, 14.50g (0.058mol) of ethyl 8-bromooctanoate, 10.36g (0.064mol) of compound 1, 13.03g (0.123mol) of anhydrous sodium carbonate in a 250ml reaction flask with a magnet and a thermometer, and stir , heat up to 70±5°C and react for 2-2.5 hours. Cool down to room temperature, filter, pour the filtrate into 420ml of water under stirring, continue stirring for 1-1.5h, filter, rinse the filter cake with purified water, put it in a blast drying oven at 35-40°C and dry for 24h to obtain 18.3g of pale pink solid , yield 95.1%.

Embodiment 3

[0029] Preparation of Example Three Compound 3 (8-(2-hydroxybenzamido) octanoic acid)

[0030] Add 90ml of purified water and 8.64g (0.216mol) of sodium hydroxide to a 250ml reaction bottle with a magnet and a thermometer, stir to dissolve, add 18.00g (0.054mol) of compound 2, heat and reflux for 1.5-2 hours, and drop to At room temperature, use 6M hydrochloric acid aqueous solution to adjust the pH to 1-2, continue to stir for 30 minutes, filter, rinse the filter cake with purified water, and dry in a blast drying oven at 45-55°C for 14-18 hours to obtain 14.5 g of a pale pink solid, with a yield of 96.1% .

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Abstract

The invention discloses a preparation method of a pharmaceutical intermediate, i.e., sodium 8-[(2-hydroxybenzoyl) amino] octanoate. The preparation method comprises the steps of enabling salicylamide,used as a raw material, to react with N' N-carbonyl diimidazole so as to generate an intermediate, i.e., 2H-benzo[e][1,3]oxazine-2, 4 (3H)-dione; enabling the intermediate to react with 8-ethyl bromooctanoate to obtain 8-(2, 4-dicarbonyl-2H-benzo[e][1, 3]oxazine-3(4H)-yl) ethyl caprylate; hydrolyzing by using sodium hydroxide, and then acidizing to obtain 8-[(2-hydroxybenzoyl) amino] caprylic acid; then, enabling the 8-[(2-hydroxybenzoyl) amino] caprylic acid to react with sodium hydroxide to obtain the final product, i.e., the sodium 8-[(2-hydroxybenzoyl) amino] octanoate. The preparation method avoids the use of a genotoxic raw material-ethyl chloroformate, is low in reaction energy consumption, less in by-products and high in yield, greatly lowers the production cost, and is simple inprocess and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of 8-(2-hydroxybenzamido) octanoic acid sodium. technical background [0002] 8-(2-Hydroxybenzamido)sodium octanoate, referred to as SNAC, is an amino acid derivative absorption enhancer, which can promote the oral absorption of various protein drug solutions such as heparin and human growth hormone, and can be used to treat gastric Intestinal diseases have good application prospects. [0003] World patent WO 00 / 46182 and Chinese patent CN 104974060 A all report the preparation method of 8-(2-hydroxybenzamido) octanoic acid sodium, but these two patents all start with salicylamide and ethyl chloroformate The intermediate 2H-benzo[e][1,3]oxazine-2,4(3H)-dione was prepared from the starting materials, and then 8-(2-hydroxybenzamido)octanoic acid sodium was obtained through multi-step reactions. Ethyl chloroformate is highly toxic and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/52C07C231/12C07C231/24C07D265/26
CPCC07C231/12C07C231/24C07D265/26C07C235/52
Inventor 王冬冬吉民刘海东李锐宗熙蔡进万广朋于文源胡海燕张影
Owner 江苏东南纳米材料有限公司
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