Sodium 8-(2-hydroxylbenzamido)caprylate and preparation method therefor

A technology of hydroxybenzamide and sodium octanoate, which is applied in the preparation of carboxylic acid amides, chemical instruments and methods, and the preparation of organic compounds, and can solve the problems of difficult removal of impurities, low yield, and unsuitability for industrial production. To achieve the effect of increasing the yield

Inactive Publication Date: 2020-11-24
无锡紫杉药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The first type of route involves special raw materials, the yield is generally low, and is not suitable for industrial production; the second type of route is relatively easier to carry out industrial production, but it will be found that the impurities in this route are difficult to remove through practice.
Because when the first step forms Carsalam, a small amount of salicylamide cannot react completely, and the liquid phase retention time of the first step intermediate Carsalam is completely consistent with salicylamide, which makes it difficult to monitor the water in the first step intermediate Salicylamide content

Method used

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  • Sodium 8-(2-hydroxylbenzamido)caprylate and preparation method therefor
  • Sodium 8-(2-hydroxylbenzamido)caprylate and preparation method therefor
  • Sodium 8-(2-hydroxylbenzamido)caprylate and preparation method therefor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] A kind of preparation method of 8-(2-hydroxybenzamido) octanoic acid sodium, comprises the following steps:

[0038] S1: Weigh 20.0628g of salicylic acid into a 500mL reaction flask, add 100ml of tetrahydrofuran, slowly add 23.4132g of N,N-carbonyldiimidazole under stirring, a large amount of gas is generated. After the addition, continue to stir at room temperature for 1.5h. Then 32.4143g of ethyl 8-aminocaprylate hydrochloride was added, and then 24ml of triethylamine was added dropwise, and the reaction was continued for 28h at 20°C with stirring. The reaction solution was concentrated to dryness, that is, when no solvent was evaporated, 200 mL of dichloromethane was added to dissolve, and then washed with 1 mol / L dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, and the organic phase was concentrated to obtain 45.8 g of intermediate I. Yield 102.9% (wet weight yield).

[0039] S2: Add 460 mL of 2 mol / L sodium hydroxide solution ...

Embodiment 2

[0047] S1: Weigh 5g of salicylic acid into a 100mL reaction flask, add 20ml of tetrahydrofuran, slowly add 5.85g of N,N-carbonyldiimidazole under stirring, a large amount of gas is generated. After the addition, continue to stir at room temperature for 2h. Then 8.1g of ethyl 8-aminocaprylate hydrochloride was added, and then 7.5ml of triethylamine was added dropwise, and the reaction was continued to stir at 23°C for 22h. The reaction solution was concentrated to dryness, that is, when no solvent was evaporated, 50 mL of dichloromethane was added to dissolve, and then washed with 1 mol / L dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, and the organic phase was concentrated to obtain 11.3 g of intermediate I. Yield 101.6% (wet weight yield).

[0048] S2: Add 200 mL of 2 mol / L sodium hydroxide solution to the concentrated bottle containing intermediate I in S1, and stir the reaction until all solids are dissolved at room temperature of 25°C...

Embodiment 3

[0051] S1: Weigh 200g of salicylic acid into a 4L reaction flask, add 1L of tetrahydrofuran, slowly add 234N,N-carbonyldiimidazole under stirring, a large amount of gas is generated. After the addition, continue to stir at room temperature for 2h. Then, 324g of ethyl 8-aminocaprylate hydrochloride was added, and then 300ml of triethylamine was added dropwise, and the stirring reaction was continued at 30°C for 30h. The reaction solution was concentrated to dryness, that is, when no solvent was evaporated, 2L of dichloromethane was added to dissolve, and then washed with 1mol / L dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine respectively, and the organic phase was concentrated to obtain 447g of intermediate I. Yield 100.5% (wet weight yield).

[0052] S2: Add 5L of 2mol / L sodium hydroxide solution to the concentrated bottle containing intermediate I in S1, and stir the reaction until all solids are dissolved at room temperature of 30°C. Th...

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Abstract

The invention discloses sodium 8-(2-hydroxylbenzamido)caprylate and a preparation method therefor and belongs to the field of preparation of compounds. A key of the technical scheme of the invention is as follows: the preparation method comprises the steps: mixing salicylic acid with tetrahydrofuran, adding N,N-carbonyl diimidazole, adding 8-amino ethyl caprylate hydrochloride, and dropwise addingtriethylamine; carrying out a concentrating reaction solution until no solvent is distilled off, adding dichloromethane for dissolving, and carrying out washing once separately with diluted hydrochloric acid, a saturated sodium carbonate solution and a saturated saline solution, so as to obtain an intermediate I; mixing a sodium hydroxide solution with the intermediate I, and carrying out stirring until solids are dissolved; cooling the temperature of a reaction solution to 10 DEG C or below, dropwise adding diluted hydrochloric acid, adjusting a pH value of a reaction solution to 4.5 to 5, and carrying out solid precipitation, so as to obtain free acids; and dissolving the free acids with isopropanol, dropwise adding a sodium hydroxide solution, carrying out a reaction for 1 to 1.5 hours, supplementing isopropanol, and continuing to carry out stirring for 1.5 to 2 hours. The method has the advantages that steps are few, the yield of each step is high, the product purity is good, impurities are more easily controlled, and raw materials are more readily available.

Description

technical field [0001] The invention relates to the field of compound preparation, in particular to sodium 8-(2-hydroxybenzamido) octanoate and a preparation method thereof. Background technique [0002] 8-(2-hydroxybenzamido) octanoate sodium, namely Salcaprozate sodium, referred to as SNAC, the SNAC in the present invention is 8-(2-hydroxybenzamido) octanoate sodium. SNAC is an absorption enhancer for dicarbonate phosphate compounds, which is used for treating gastrointestinal diseases, especially for gastrointestinal diseases caused by malabsorption of dicarbonate phosphate compounds. It has been used as an excipient in semaglutide, and its combination with SNAC enables semaglutide to be absorbed in the stomach, and the partial dissolution of SNAC can form a relatively high pH environment locally in the stomach, thereby improving the semaglutide Peptide solubility, reducing degradation by gastric endopeptidases. [0003] The synthesis route of SNAC can be roughly divide...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C231/12C07C231/24C07C235/52
CPCC07C231/02C07C231/12C07C231/24C07C235/52
Inventor 王莉佳黄春王旭阳
Owner 无锡紫杉药业股份有限公司
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