Method of preparing polyhydroxy annular nitrone

A polyhydroxyl and cyclic technology, applied in organic chemistry and other directions, can solve the problems of limited research and the process of new drug development, low yield of polyhydroxyl cyclic nitrones, and inability to prepare in large quantities, and achieve efficient preparation and preparation methods. Simple, high-yield effects

Active Publication Date: 2009-07-15
INST OF CHEM CHINESE ACAD OF SCI
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Problems solved by technology

[0003] Polyhydroxycyclic nitrones are one of the effective intermediates for the preparation of iminosugars [Ref: (a) Cicchi, S.; Marradi, M.; Vogel, P.; Goti, A.J.Org.Chem.2006, 71, 1614 -1619. (b) Carmona, A.T.; Wightman, R.H.; Robina, I.; Vogel, P. Helv. Chim. Acta 2003, 86, 3066-3073. (c) Desvergnes, S.; Py, S.; , Y.J.Org.Chem.2005, 70, 1459-1462. (d) Holzapfel, C.W.; Crous, R. Heterocycles 1998, 48, 1337-1346. (b) Duff, F.J.; Vivien, V.; Wightman, R.H.Chem .Commun.2000, 2127-2128. (c) Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003, 35-38. (d) Chevrier, C.; LeNouen, D. ; Neuburger, M.; Defoin, A.; Tarnus, C.Tetrahedron Lett.2004,45,5363-5366.], but the yield of the reported polyhydroxycyclic nitrones is not high, the efficiency is low, and cannot A large number of preparations, which severely limit the research in this field and the progress of new drug development

Method used

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  • Method of preparing polyhydroxy annular nitrone
  • Method of preparing polyhydroxy annular nitrone
  • Method of preparing polyhydroxy annular nitrone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1, Preparation of polyhydroxy cyclic nitrone (2S, 3S, 4S)-2-benzyloxymethyl-3,4-dibenzyloxy-3,4-dihydro-1-oxypyrrole I

[0030]

[0031] According to literature methods [(a) Barker, R.; Fletcher, H.G.J.Org.Chem. 1961, 26, 4605-4609. (b) Tejima, S.; Fletcher, H.G.J.Org.Chem. ] Preparation of hemiacetal 2,3,5-O-tribenzyl-D-xylofuranose II from D-xylose. Pyridine (30mL, 0.37mol) was added to the dichloromethane (100mL) solution of the hemiacetal crude product (calculated according to 0.2mol), and O-methylhydroxylamine hydrochloride (20.88g, 0.25mol) was added thereto, at room temperature After stirring for 12 hours, the solvent was evaporated to dryness, then ethyl acetate and hydrochloric acid (1N, 30mL) were added to the concentrated solution, and after extraction and separation, the organic phases were combined, dried, and concentrated to obtain a yellow oil (2S, 3S, 4R )-2,3,5-tribenzyloxy-4-hydroxyl-1-pentanal methyl oxime ether III, directly put into the ...

Embodiment 2

[0042] Example 2, Preparation of polyhydroxy cyclic nitrone (2R, 3R, 4S)-2-benzyloxymethyl-3,4-dibenzyloxy-3,4-dihydro-1-oxypyrrole I

[0043]

[0044] According to literature methods [(a) Barker, R.; Fletcher, H.G.J.Org.Chem. 1961, 26, 4605-4609. (b) Tejima, S.; Fletcher, H.G.J.Org.Chem. ], Preparation of hemiacetal 2,3,5-O-tribenzyl-D-arabinofuranose II from D-arabinose. Pyridine (2.7 mL, 34.2 mmol) was added to a solution of the hemiacetal (8.40 g, 11.4 mmol) in dichloromethane (20 mL), and O-methylhydroxylamine hydrochloride (1.91 g, 22.8 mmol) was added thereto, After stirring at room temperature for 24 hours, the solvent was evaporated to dryness, then ethyl acetate and hydrochloric acid (1N, 30mL) were added to the concentrated solution, after extraction and separation, the organic phases were combined, dried and concentrated, and the obtained crude product was purified by column chromatography to obtain Pale yellow oil (2R,3R,4R)-2,3,5-tribenzyloxy-4-hydroxy-1-pent...

Embodiment 3

[0051] Example 3: Addition reaction of nitrone and phenylmagnesium bromide to obtain (2S, 3S, 4S, 5S)-2-(benzyloxymethyl)-3,4-dibenzyloxy-5-phenyl- N-Hydroxypyrrolidine VI

[0052]

[0053] Under nitrogen protection conditions, bromobenzene (0.26mL, 2.5mmol) was added to the suspension of magnesium strips (60mg, 2.5mmol) and freshly distilled tetrahydrofuran (5mL), and heated to reflux for 3 hours to prepare a tetrahydrofuran solution of phenylmagnesium bromide . In an ice bath, add nitrone (2R, 3R, 4R)-2-benzyloxymethyl-3,4-dibenzyloxy-3,4-dihydro-1-oxopyrrole containing vigorously stirring (200mg, 0.5mmol) tetrahydrofuran solution was added dropwise to the Grignard reagent prepared by the above method, and stirring was continued for half an hour after the addition was completed. Then add saturated aqueous ammonium chloride solution to quench the reaction, add ethyl acetate for extraction, and combine the organic phases. The solvent was spin-dried under vacuum, and the ...

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Abstract

The invention discloses a method for preparing polyhydroxy cyclic nitrones. The method for preparing the polyhydroxy cyclic nitrones of the structure of formula I provided by the present invention comprises the following steps: 1) reacting the hemiacetal of the structure of formula II with O-methylhydroxylamine hydrochloride under alkaline conditions to obtain The methyl oxime ether of the structure of formula III; 2) the methyl oxime ether of the structure of formula III is reacted with methanesulfonyl chloride to obtain the mesylate of the structure of formula IV; 3) The mesylate of the structure of formula IV is subjected to acidic conditions 4) The aldehyde of formula V structure reacts with hydroxylamine hydrochloride under alkaline conditions to obtain the polyhydroxy cyclic nitrone; wherein, R1, R2 and R3 is an alkyl, alkenyl, aryl or substituted aryl group. The present invention can prepare polyhydroxy cyclic nitrones with high reactivity through several steps of reactions by using sugars widely existing in nature as raw materials, thereby realizing the concise, efficient and large-scale preparation of such compounds.

Description

technical field [0001] The invention relates to a simple and practical preparation method of polyhydroxyl cyclic nitrones. Background technique [0002] Glycosidases play an important role in the living body, and they participate in a series of important biological reactions related to glycoconjugates, such as digestion in the intestine, synthesis and decomposition of glycoproteins, sugar in lysosomal Metabolism of conjugates, etc., therefore, they are closely related to many diseases. Imino sugars have been shown to be potent inhibitors of glycosidases and potential drugs for the treatment of many diseases [see (a) Stütz, A.E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-VCH: Weinheim, 1999. (b) Asano, N .; Nash, R.J.; Molyneux, R.J.; Fleet, G.W.J. Tetrahedron: Asymmetry 2000, 11, 1645-1680. (c) Watson, A.A.; , 265-295.]. Many imino sugars (such as: NBDNJ, Miglitol) have been developed into drugs and marketed. [0003] Polyhydroxycyclic nitrones ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/46
Inventor 俞初一黄木华胡素琴胡祥国侯研博黄志镗
Owner INST OF CHEM CHINESE ACAD OF SCI
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