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Amino acid modified glucosamine as well as preparation method and application thereof

A glucosamine and amino acid technology, applied in the field of amino acid modified glucosamine, can solve the problems of harsh reaction conditions, long reaction steps, expensive reagents and the like, and achieve the effects of short reaction steps, low cost and convenient post-processing

Inactive Publication Date: 2012-02-29
SOUTHWEST UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its preparation method mainly contains three kinds: the first kind is to simultaneously protect the hydroxyl group and amino group in D-glucosamine molecule with acetyl group, and then selectively remove the acetyl group on the amino group, such as onium salt method, etc., but this kind Method reagents are expensive, reaction conditions are harsh, and yield is low; However, the reaction steps of this type of method are too long and the yield is low; the third type is to directly and selectively protect the hydroxyl group with acetyl groups under acidic conditions, such as acetic anhydride-sulfuric acid method, etc.

Method used

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  • Amino acid modified glucosamine as well as preparation method and application thereof
  • Amino acid modified glucosamine as well as preparation method and application thereof
  • Amino acid modified glucosamine as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] The preparation of embodiment 1,2-amino-1,3,4,6-tetra-O-acetyl-β-D-glucose sulfate (intermediate II)

[0029] Add acetic anhydride to the round bottom flask, cool in ice-salt bath for 15 minutes, slowly add D-glucosamine hydrochloride, stir rapidly, then slowly add concentrated sulfuric acid dropwise, after the dropwise addition, stir the reaction at room temperature for 24 hours Then stop the reaction, slowly add absolute ethanol dropwise in the ice-salt bath, and a large amount of white solids are precipitated. After the dropwise addition, stir in the ice-salt bath for 30 minutes, filter with suction, wash the filter cake with ethyl acetate until it has no sour smell, and dry it in vacuum at 25°C , to obtain white solid; m.p.168~172℃; 1 H NMR (300MHz, DMSO-d 6 )δ: 6.01(d, 1H, J=3.32Hz, H-1), 5.17(t, 1H, J=9.51Hz, H-3), 4.97(t, 1H, J=9.51Hz, H-4) , 4.37~4.13(m, 3H, H-5, H-6), 3.92(m, 1H, H-2), 2.19, 2.09, 2.02, 1.99(s, 12H, 4×CH 3 ); IR (KBr, cm -1 ): 2986, 2908 (v...

Embodiment 2

[0033] Example 2, N-[N-(9-fluorenylmethoxycarbonyl)alanyl]-1,3,4,6-tetra-O-acetyl-β-D-glucosamine (compound I-1) preparation

[0034]

[0035] Dissolve Fmoc-Ala-OH in THF, add DIC, HOBt and DIPEA sequentially under ice bath and stirring, stir for 30 minutes, and set aside; dissolve intermediate II in THF, add triethylamine (Et 3 N), stir evenly, for subsequent use; Above-mentioned two kinds of solutions are mixed, stirring reaction under room temperature, monitor reaction progress with thin-layer chromatography (TLC); Extract with ethyl acetate, collect the aqueous layer and the organic layer respectively, extract the aqueous layer with ethyl acetate again, combine all the organic layers, and successively use a citric acid aqueous solution with a concentration of 0.5mol / L, and sodium bicarbonate with a concentration of 0.5mol / L Wash with aqueous solution and saturated aqueous sodium chloride solution, then dry with anhydrous sodium sulfate, concentrate, and purify by colum...

Embodiment 3

[0045] Example 3, N-[N-(9-fluorenylmethoxycarbonyl) valyl]-1,3,4,6-tetra-O-acetyl-β-D-glucosamine (compound I-2) preparation

[0046]

[0047] Dissolve Fmoc-Val-OH in THF, add DIC, HOBt and DIPEA sequentially under ice bath and stirring, stir for 30 minutes, set aside; dissolve intermediate II in THF, add Et 3 N, stir evenly, set aside; Mix the above two solutions, stir and react at room temperature, monitor the reaction process with TLC method; after the reaction is completed, remove THF by distillation under reduced pressure, add water to the residual liquid, extract with ethyl acetate, and Collect the aqueous layer and the organic layer, and then extract the aqueous layer with ethyl acetate, combine all the organic layers, and successively wash with citric acid aqueous solution with a concentration of 0.5mol / L, sodium bicarbonate aqueous solution with a concentration of 0.5mol / L, and saturated sodium chloride Wash with aqueous solution, dry with anhydrous sodium sulfate...

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Abstract

The invention discloses an amino acid modified glucosamine shown as the general formula I. By detection, the amino acid modified glucosamine has more favorable PPAR agonist activity and potential and wide application prospect in the field of treatment of diabetes, is a favorable diabetes resistant leading compound and can be further developed to prepare a diabetes resistant medicament. The invention also provides a preparation method of the amino acid modified glucosamine. An intermediate 2-amino-1,3,4,6-four-O-acetyl-beta-D-glucosamine sulfate is synthesized in one step by adopting D-amino glucosamine hydrochloride as an initial raw material through an improved acetic anhydride-sulfuric acid method, and the intermediate is coupled with protected amino acid under the action of a condensing agent to obtain the amino acid modified glucosamine. The invention has short reaction step, mild reaction condition, convenient post processing, high yield and low cost.

Description

technical field [0001] The invention relates to a glucosamine derivative, in particular to amino acid-modified glucosamine, and also relates to its preparation method and application in medicine. Background technique [0002] Diabetes mellitus is a chronic disease characterized by glucose metabolism disorder and hyperglycemia caused by insufficient insulin secretion. It is the third major disease that endangers human health after cardiovascular disease and cancer. According to the latest data from the International Diabetes Federation, there were about 246 million diabetics in the world in 2007, and it is expected to reach 380 million in 2025, or 7.1% of the adult population, of which type II diabetics account for about 90%. There are many types of antidiabetic drugs currently on the market, but they all have severe or mild side effects, such as: insulin drugs may cause hypoglycemia, allergic reactions, insulin resistance, etc.; There are disadvantages such as sudden failur...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H13/06C07H1/00A61K31/7024A61P3/10
CPCY02P20/55
Inventor 杨大成晏菊芳汪林发叶飞范莉牟霞李同金刘华玲陈伟东许荩宋小礼
Owner SOUTHWEST UNIV
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