4-CNAB and preparation method thereof

A 4-CNAB and solution technology, applied in the field of 4-CNAB and its preparation, can solve the problems of large loss, difficult to remove, and low overall yield in the purification process, and achieve the effect of improving the yield

Active Publication Date: 2020-11-13
无锡紫杉药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] (1) overall yield is very low, and the yield of free acid obtained by the preceding two-step reaction has only 37%;
[0007] (2) the product purity is not high, mainly due to the difficult removal of mono-hetero-4-chlorosalicylic acid in the free acid, and the 4-chlorosalicylic acid content can reach about 5% in the free acid of the unpurified stage, so the purification process loss is relatively large Large, resulting in lower yields in problem (1);
[0008] (3) In the last step of salt formation, a jelly-like product will be obtained, which cannot be filtered at all

Method used

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  • 4-CNAB and preparation method thereof
  • 4-CNAB and preparation method thereof
  • 4-CNAB and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Such as figure 1 Shown, a kind of preparation method of 4-CNAB comprises the following steps:

[0040] S1: Weigh 5.0062g of 4-chlorosalicylic acid into a 100mL reaction flask, add 20ml of dichloromethane, add 2.5072g of sodium bentonite, slowly add 5.1772g 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. Add 5.3507g of ethyl 4-aminobutyrate hydrochloride, then dropwise add 6ml of triethylamine, stir and react at 25°C for 22h to obtain a reaction solution;

[0041] Transfer the reaction solution into a separatory funnel, add an equal volume of 2mol / L dilute hydrochloric acid to the reaction solution, adjust the pH value of the reaction solution to 4.5-5, and shake it sufficiently to have a large amount of solids precipitate out, then filter with suction (diatomaceous earth filter aid) The filter cake was obtained, and the filtrate was collected; then extracted with dilute a...

Embodiment 2

[0051] S1: Weigh 50g of 4-chlorosalicylic acid into a 1L reaction bottle, add 250ml of dichloromethane, add 50g of sodium bentonite, slowly add 50g of N,N-carbonyldiimidazole under stirring, a large amount of gas is generated. After the addition, continue to stir at room temperature for 2h. Add 50 g of ethyl 4-aminobutyrate hydrochloride, then dropwise add 50 ml of triethylamine, stir and react at 20° C. for 30 h to obtain a reaction solution.

[0052] The reaction solution was moved into a separatory funnel, and an equal volume of 2mol / L dilute hydrochloric acid was added to the reaction solution to adjust the pH value of the reaction solution to 5. After fully shaking, a large amount of solids were precipitated, and suction filtration (diatomaceous earth filter aid) was obtained. cake, and the filtrate was collected; then extracted with dilute ammonia water, pure water, and saturated sodium chloride solution, and the organic phase was concentrated to obtain 74.2 g of interme...

Embodiment 3

[0056] S1: Weigh 200g of 4-chlorosalicylic acid into a 2L reaction bottle, add 800ml of dichloromethane, add 150g of sodium bentonite, slowly add 220g of N,N-carbonyldiimidazole under stirring, a large amount of gas is generated. After the addition, the reaction bottle was moved into a 25°C oil bath, and the stirring was continued at room temperature for 2h. Add 220 g of ethyl 4-aminobutyrate hydrochloride, then dropwise add 220 ml of triethylamine, raise the temperature to 30° C. and stir for 26 h to prepare a reaction solution.

[0057] The reaction solution was moved into a separatory funnel, and an equal volume of 2mol / L dilute hydrochloric acid was added to the reaction solution to adjust the pH value of the reaction solution to 5. After fully shaking, a large amount of solids were precipitated, and suction filtration (diatomaceous earth filter aid) was obtained. Cake, and the filtrate was collected; then extracted with dilute ammonia water, pure water, and saturated sodi...

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Abstract

The invention discloses 4-CNAB and a preparation method thereof, and belongs to the field of drug preparation. According to the technical scheme, the preparation method comprises the following steps:S1, adding dichloromethane into 4-chlorosalicylic acid, adding sodium bentonite and N, N-carbonyl diimidazole, then adding ethyl 4-aminobutyrate hydrochloride, dropwise adding triethylamine, adding adiluted hydrochloric acid solution, adjusting the pH value to 4.5-5, performing suction filtration, collecting filtrate, sequentially extracting with dilute ammonia water, pure water and a saturated sodium chloride solution, and concentrating an organic phase to obtain an intermediate I; S2, dissolving the intermediate I with a sodium hydroxide solution, dropwise adding a dilute hydrochloric acidsolution, adjusting the pH value to 4.5-5, separating out a product, and carrying out suction filtration and drying to obtain free acid; S3, dissolving free acid with isopropanol, adding a sodium hydroxide solution, after a reaction is carried out for 1 h, supplementing isopropanol and reacting for 1-2 h, performing suction filtration and drying to obtain 4-CNAB. The yield of each step is high, the product purity is good, and the salified product is easy for suction filtration.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a 4-CNAB and a preparation method thereof. Background technique [0002] 4-(2-hydroxy-4-chlorobenzamido) sodium butyrate (4-CNAB) is a new type of pharmaceutical excipient, and 4-CNAB in this case is 4-(2-hydroxy-4- Chlorobenzamido) Sodium Butyrate. 4-CNAB is an analogue of sodium 8-(2-hydroxybenzamido) octanoate (SNAC), an absorption enhancer of dicarbophosphate compounds used in the treatment of gastrointestinal disorders, especially bicarbonate Gastrointestinal disorders caused by malabsorption of phosphate compounds. [0003] Recently, the world's first oral GLP-1 hypoglycemic drug semaglutide was approved by the FDA. Since semaglutide is a polypeptide drug, in order to achieve oral and intestinal absorption, it must face the challenge of degradation by various peptidases in the intestine. The researchers combined semaglutide with the small molecule absorptio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C231/12C07C235/60
CPCC07C231/02C07C231/12C07C235/60Y02A50/30
Inventor 黄春陆叶梦王旭阳
Owner 无锡紫杉药业股份有限公司
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