Seven-element-ring polyhydroxy nitrone and preparation method and application thereof

A technology of cyclic polyhydroxynitrone and reaction, which is applied in the field of seven-membered cyclic polyhydroxynitrone and its preparation and application, and can solve the problems of no report and inapplicability

Active Publication Date: 2013-03-27
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis of five-membered ring and six-membered ring polyhydroxy nitrones mostly adopts the method of N-alkylation of intramolecular oxime, but this method is not suitable for the synthesis of seven-membered ring polyhydroxy nitrones, so we developed A method of intramolecular condensation of hydroxylamine and aldehydes to prepare
Although seven-membered nitrones have been reported in the literature [(a) Dondas, H.A.; Frederickson, M.; Grigg, R.; Markandu, J.; Thornton Pett, M. Tetrahedron 1997, 53, 14339. (b) Smith, B.T. ;Wendt, J.A.;Aubé,J.Org.Lett.2002,4,2577.(c)Gracias,V;Zeng,Y.B.;Desai,P.;Aubé,J.Org.Lett.2003,5,4999.] , but polyhydroxyl seven-membered ring nitrones with multiple chiral centers synthesized from sugars have not been reported yet

Method used

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  • Seven-element-ring polyhydroxy nitrone and preparation method and application thereof
  • Seven-element-ring polyhydroxy nitrone and preparation method and application thereof
  • Seven-element-ring polyhydroxy nitrone and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Embodiment 1, seven-membered ring polyhydroxynitrone I-1 (R in formula I 1 , R 2 , R 3 and R 4 are all benzyl compounds) and the synthesis of its intermediate formula XIII-1 (reaction scheme as figure 1 shown)

[0089]

[0090] According to literature [ O.; Redlich, H.; Frank, H. Synthesis 1995, 1383] Method for the preparation of thioacetal II-1 from D-glucose. D-glucose (10.0 g, 55.6 mmol) was dissolved in concentrated hydrochloric acid (10 mL), 1,3-propanedithiol (5.6 mL, 55.6 mmol) was added, and the reaction mixture was stirred overnight at room temperature. Ethanol (200 mL) was added to the reaction solution, and a large amount of white solid was precipitated. Filter and rinse the filter cake with ethanol. After drying, 13.4 g of a white solid was obtained, namely thioacetal II-1, with a yield of 89%.

[0091] A solution of thioacetal II-1 (11.3g, 42.0mmol), triphenylchloromethane (12.3g, 44.0mmol) and 4-dimethylaminopyridine (51mg, 0.42mmol) in pyridi...

Embodiment 2

[0103] Embodiment 2, seven-membered ring polyhydroxynitrone I-2 (R in formula I 1 , R 2 , R 3 and R 4 are all benzyl compounds) and the synthesis of intermediates shown in formula XIII-2 (the reaction process is as follows figure 2 shown)

[0104]

[0105] The raw material primary alcohol V-1 was prepared according to the steps in Example 1.

[0106] Dimethylsulfoxide (2.13mL, 30.0mmol) was added dropwise to a solution of oxalyl chloride (1.69mL, 20.0mmol) in dry dichloromethane (50mL) at -70°C. Gas evolved and the mixture was stirred at this temperature for 30 minutes after the addition was complete. A solution of primary alcohol V-1 (6.31 g, 10.0 mmol) in dry dichloromethane (20 mL) was added dropwise to the above reaction system at -70°C, and stirred at this temperature for 30 minutes after the addition was complete. Triethylamine (6.95 mL, 50.0 mmol) was added dropwise at -70°C. After the addition was complete, the mixture was reacted at this temperature for 20 m...

Embodiment 3

[0114] Embodiment 3, seven-membered ring polyhydroxynitrone I-3 (R in formula I 1 , R 2 , R 3 and R 4 are all benzyl compounds) and the synthesis of intermediates shown in formula XIII-3 (the reaction process is as follows image 3 shown)

[0115]

[0116] According to the literature[ O.; Redlich, H.; Frank, H. Synthesis 1995, 1383] A similar method was used to prepare thioacetal II-3 from D-mannose. D-mannose (9.0 g, 50.0 mmol) was dissolved in 6N hydrochloric acid (20 mL), 1,3-propanedithiol (5.55 mL, 55.0 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated, recrystallized with ethanol, filtered, and the filter cake was washed with ethanol. After drying, 8.6 g of white solid was obtained, namely thioacetal II-3, with a yield of 65%.

[0117] A solution of thioacetal II-3 (8.1g, 30.0mmol), triphenylchloromethane (8.79g, 31.5mmol) and 4-dimethylaminopyridine (37mg, 0.30mmol) in pyridine (150mL) ...

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Abstract

The invention discloses seven-element-ring polyhydroxy nitrone and a preparation method and an application thereof. The seven-element-ring polyhydroxy nitrone is shown as the formula I, wherein R1, R2, R3 and R4 are respectively selected from the following groups: C1-C12 linear or branched saturated alkyl groups, allyl, propylidene, acetyl, benzoyl, benzyl, or benzyl of which partial or all the positions of the benzene ring are replaced by alkoxy or halogen; and the spatial configurations of the Cs at the positions 1, 2, 3 and 4 are in R or S. According to the seven-element-ring polyhydroxy nitrone, various kinds of aldohexose are taken as raw materials, and the condensation reaction of intramolecular hydroxylamine and aldehyde is taken as a key step, so as to finish the preparation of seven-element-ring polyhydroxy nitrone, so that a method for simply and effectively synthesizing seven-element-ring polyhydroxy nitrone is provided; and seven-element-ring polyhydroxy nitrone prepared by using the method can be used for preparing imino sugar with glycosidase inhibitory activity.

Description

technical field [0001] The invention relates to the preparation of a seven-membered ring polyhydroxy nitrone and its application in the synthesis of seven-membered ring imino sugars. Background technique [0002] Glycosidases are involved in many important biological reactions related to glycoconjugates, such as intestinal digestion, glycoprotein synthesis and decomposition, lysosomal glycoconjugate metabolism, etc. It plays an important role and is closely related to many diseases. Imino sugars, also known as polyhydroxy alkaloids, aza sugars, imino sugars, etc., are effective inhibitors of glycosidases and have important pharmacological activities in antiviral, antitumor, and diabetes treatment [(a)Winchester, B; Fleet, G.W.J. Glycobiology 1992, 2, 199. (b) Stütz, A.E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-VCH: Weinheim, 1999. (c) Asano, N.; Nash, R.J.; Molyneux, R.J.; Fleet , G.W.J. Tetrahedron: Asymmetry 2000, 11, 1645. (d) Watson, A.A.; ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/08C07D487/04C07H15/18C07H1/00A61K31/55A61P35/00A61P31/12A61P3/10
Inventor 俞初一赵文博贾月梅胡祥国
Owner INST OF CHEM CHINESE ACAD OF SCI
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