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Synthesis of 6-azido-6-deoxy-2-N-acetyl-hexosamine-nucleoside diphosphate

A nucleoside diphosphate and azido-based technology, applied in the direction of sugar derivatives, sugar derivatives, esterified saccharides, etc., can solve the problems of no high yield, scalability, and incompatibility, and achieve easy access and high efficiency And yield, the effect of high yield

Pending Publication Date: 2022-04-29
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite the availability of various methods, there is no generally accepted, high-yield and scalable route to obtain UDP derivatives of monosaccharides, especially N-acetylated hexosamines
Furthermore, the presence of the 6-azido group in UDP 6-azido-N-acetyl-hexosamine further limits the choice of conditions due to its electron-withdrawing properties and incompatibility with a range of (reducing) conditions sex

Method used

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  • Synthesis of 6-azido-6-deoxy-2-N-acetyl-hexosamine-nucleoside diphosphate
  • Synthesis of 6-azido-6-deoxy-2-N-acetyl-hexosamine-nucleoside diphosphate
  • Synthesis of 6-azido-6-deoxy-2-N-acetyl-hexosamine-nucleoside diphosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0357] Example 1-1: Synthesis of 4,6-O-benzylidene-N-acetyl-D-galactosamine

[0358]

[0359] To a suspension of N-acetyl-D-galactosamine (1299 g, 5.9 mol) in MeCN (13 L) was added DL-camphorsulfonic acid (81 g, 352 mmol) and benzaldehyde dimethyl acetal (2190 g, 2160 mL ,14.4mol). The reaction was stirred at room temperature and filtered through a Buchner funnel. The white filter cake was rinsed with MeCN (10 x 1 L) and dried on the filter overnight. Drying in a circulating oven at 35°C for four days gave the product (1938 g, 107%). By heating from EtOH / H at 5-8°C 2 Crystallization in O (13:1-9:1) for 16-24 hours afforded the pure product as a white crystalline solid. 1 H NMR (400MHz, DMSO) δ (ppm) 7.49-7.46 (m, 2H), 7.38-7.34 (m, 3H), 5.56 (s, 1H), 5.04-5.03 (m, 1H), 4.14-4.13 (m ,1H), 4.08-3.94(m,3H), 3.85-3.78(m,2H), 1.82(s,3H).

Embodiment 1-2

[0360] Example 1-2: Synthesis of 1,3-di-O-acetyl-4,6-O-benzylidene-N-acetyl-D-galactosamine

[0361]

[0362] The starting material 4,6-O-benzylidene-N-acetyl-D-galactosamine (1938 g, 6.3 mmol) was dissolved in pyridine (7750 mL) and acetic anhydride (1919 g, 1.765 L ,18.8mol). The reaction mixture was stirred overnight at room temperature, then ice water (19.5 L) was added. After stirring for 15 minutes, another scoop of ice was added, and after a further 15 minutes, the mixture was filtered. The filter cake was washed with ice water (3 x 6 L) and dried on the filter overnight, then in a circulating oven at 45°C overnight. The crude product was dissolved in methanol (13.7 L) and the mixture was heated to reflux to obtain a clear solution. The solution was cooled to room temperature overnight, then cooled to 0 °C in an ice bath for 4 hours, then filtered. The filter cake was washed 3 times with the filtrate and dried on the filter for 1.5 hours. Drying in a circulating o...

Embodiment 1-3

[0363] Example 1-3: Synthesis of 1,3-di-O-acetyl-N-acetyl-D-galactosamine (2)

[0364]

[0365] The starting material 1,3-di-O-acetyl-4,6-O-benzylidene-N-acetyl-D-galactosamine (230 g, 585 mmol) was dissolved in MeOH / dioxane (1:1, 3 L), placed in a Parr vessel and added AcOH (1.9 g, 1.77 mL, 31 mmol). Subsequently, Pd-C (37.3 g, 175 mmol) was added and the vessel was mounted on a Parr apparatus. reactant in H 2 Stir overnight under atmosphere (5 bar). Then, the mixture was filtered through a pad of celite and washed with 1,4-dioxane (1200 mL). Acetic acid (12 mL) was added to the filtrate, then concentrated under reduced pressure to give product 3 (224 g, 126%). 1 H NMR (400MHz, DMSO) δ (ppm) 7.91 (d, J = 8.4Hz, 1H), 5.96 (d, J = 3.6Hz, 1H), 5.20 (d, J = 5.2Hz, 1H), 4.84 (dd ,J=8.8,2.8Hz,1H),4.49-4.43(m,1H),3.79(t,J=6.4Hz,1H),3.55-3.50(m,1H),3.44-3.40(m,1H), 2.11(s,3H), 2.01(s,3H), 1.78(s,3H).

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Abstract

The present invention relates to a process for the synthesis of 6-azido-6-deoxy-2-N-acetyl-monosaccharide-nucleoside diphosphate, in particular 6-azido-6-deoxy-2-N-acetyl-D-galactosamine-nucleoside diphosphate or 6-azido-6-deoxy-2-N-acetyl-D-glucosamine-nucleoside diphosphate, in particular to a process for the synthesis of 6-azido-6-deoxy-2-N-acetyl-D-galactosamine-nucleoside diphosphate or 6-azido-6-deoxy-2-N-acetyl-D-glucosamine-nucleoside diphosphate. The synthesis method according to the invention is characterized by high efficiency and high yield. The other part of the invention is a key intermediate of the method.

Description

technical field [0001] The present invention is in the field of functionalized nucleoside sugars and relates to the improved preparation of sugar nucleoside diphosphates. More specifically, the present invention relates to a method for the chemical conversion of GalNAc or GlcNAc to their respective 6-azido derivatives via a cyclic sulfate followed by an anomeric phosphorylation step and UMP coupling The coupling step is carried out into the respective UDP derivatives. The invention also relates to various specific intermediates and purification steps. Background technique [0002] Carbohydrates play key roles in cell biology through their functions in energy metabolism and storage and as key components of genetic material and other structural elements. Furthermore, carbohydrates (also known as glycans) attached to proteins or lipids are important in cellular communication during cell differentiation and development. Glycans are defined as the oligosaccharide moieties of g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/04C07H9/00C07H19/10C07H11/04C07H13/04C07H1/00C07H5/04C07H9/06
CPCC07H1/04C07H9/00C07H19/10C07H11/04C07H13/04C07H1/00C07H5/04C07H9/06C07H1/02C07H15/12
Inventor J·胡根布姆M·A·维基德文J·M·M·韦卡德F·L·范代尔夫特S·S·范博凯尔
Owner SYNAFFIX
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