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A kind of polyhydroxy demethyltropane compound and its preparation method and application

A compound, hydroxymethyl technology, applied in the field of polyhydroxy demethyltropane compounds and their preparation and application, can solve the problems of low yield and lengthy steps

Active Publication Date: 2011-12-07
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above methods have their own defects, such as tedious steps and low yield.

Method used

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  • A kind of polyhydroxy demethyltropane compound and its preparation method and application
  • A kind of polyhydroxy demethyltropane compound and its preparation method and application
  • A kind of polyhydroxy demethyltropane compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0124] The preparation method of nitrone is illustrated with the preparation of III-b:

[0125] 1. Preparation of III-b

[0126] Add 10 ml of acetyl chloride dropwise to 500 ml of dry methanol under stirring in ice bath, then add D-xylose (30 g, 0.2 mol), keep the reaction at zero temperature until the raw materials disappear, neutralize with sodium bicarbonate to neutral , filtered to remove inorganic salts, and the crude product D-xylofuranoside obtained by evaporating the solvent to dryness was directly cast into the next step reaction.

[0127] Dissolve the crude product D-xylofuranoside (calculated according to 0.2mol) in dry DMF (200mL) from the previous step, and add NaH (29g, 0.72mol, content 60%) in THF (200mL) dropwise and DMF (200mL), after the addition, TBAI (2.0g) was added, and after half an hour, BnBr (0.66mol, 78.3mL) was added dropwise, and reacted until the raw material disappeared, then slowly added dropwise saturated ammonium chloride aqueous solution to q...

Embodiment 1

[0139] Embodiment 1: (1S, 3R, 5S, 6R, 7S)-1-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-3,6 shown in synthetic formula (I-1) , 7-triol

[0140]

[0141] Under nitrogen protection conditions, allyl bromide (9.6mmol, 0.8mL) was slowly added dropwise to a solution of freshly ground magnesium chips (19.2mmol, 0.46g) in ether (9.6mL), and the solution was kept at In a slightly boiling state, a 1mol / L ether solution of allylmagnesium bromide was obtained. The above solution was slowly added to the THF solution of nitrone (Formula III-a) (1 g, 2.4 mmol) in an ice-water bath, and after half an hour of reaction, saturated ammonium chloride aqueous solution (5 mL) was added to quench the reaction, and at the same time, The organic phase was extracted with ethyl acetate (5 mL), the aqueous phase was extracted three times with ethyl acetate (10 mL each), and the combined organic phases were dried and concentrated. The resulting oil was subjected to silica gel chromatography (ethyl acet...

Embodiment 2

[0145] Embodiment 2: Compound (1S, 3R, 5S, 6S, 7S)-1-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-3 shown in synthetic formula (I-2), 6,7-triol and the compound (1S, 3R, 5S, 6S, 7S)-1-(hydroxymethyl)-3-methyl-8-azabicyclo[3.2.1] shown in formula (I-5) ]octane-3,6,7-triol

[0146]

[0147]

[0148] Add allylmagnesium bromide ether solution (10mL) slowly to nitrone III-b (1.0g, 2.4mmol) tetrahydrofuran solution (15mL) under ice-water bath conditions, add saturated chloride solution after half an hour of reaction Aqueous ammonium solution (5 mL) was used to quench the reaction, and ethyl acetate (5 mL) was added to extract the organic phase. The aqueous phase was extracted three times with ethyl acetate (10 mL each), and the combined organic phases were dried and concentrated. The resulting oil was separated by silica gel column chromatography (ethyl acetate:petroleum ether=1:12, v / v) to obtain (2S, 3S, 4S, 5S)-1-hydroxy-2-allyl-3,4- Bis(benzyloxy)-5-(benzyloxymethyl)pyrroli...

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Abstract

The invention discloses polyhydroxy desmethyl tropane alkaloids and use thereof. The structural formula of the components is shown by the formula (I), wherein n is equal to 0 to 1; R1, R2 and R3 may be hydrogen, benzyl, benzyl in which one or all hydrogen atoms in the benzene ring are substituted by hydroxyl, alkoxy, nitro and halo, acetyl, methoxymethyl, ethoxymethyl, isopropylidene or cyclohexanone; R4 may be hydrogen, cyano, nitro, methylamino, ester group, carboxyl, hydroxymethyl, methyl, trifluoromethyl, fluoro, phenyl or substituted phenyl; R5 may be hydrogen and C1 to C18 straight-chain or branched-chain saturated alkyl; R6 may be hydrogen, hydroxymethyl, benzyloxy methyl in which one or all hydrogen atoms in the benzene ring are substituted by hydroxyl, alkoxy, nitro and halo, acetyl, methoxymethyl, ethoxymethyl, isopropylidene or cyclohexanone; and X may be hydrogen, hydroxyl, fluoro, chloro or bromo. The result of a glycosidase inhibition effect test proves the compounds shown by the formula (I) has exclusive inhibition activity for alpha-glucuroide.

Description

technical field [0001] The invention relates to a polyhydroxy demethyltropane compound and a preparation method and application thereof. Background technique [0002] Imino sugar, structurally speaking, is a kind of analogue of monosaccharide, which is a product in which the oxygen atom in the sugar ring is replaced by a nitrogen atom. It can achieve therapeutic and glycoside by simulating the transition state of enzyme and substrate binding. The purpose of enzyme-related diseases, therefore, is an important class of glycosidase inhibitors, which have potential pharmacological activities in antiviral, antitumor, and treatment of diabetes [(a) Stütz, A.E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond ; Wiley-VCH: Weinheim, 1999. (b) Compain, P. et al., Iminosugars: From Synthesis to Therapeutic Applications; Wiley, 2007. (c) Asano, N.; Nash, R.J.; Molyneux, R.J.; : Asymmetry 2000, 11, 1645-1680. (d) Watson, A.A.; Fleet, G.W.J.; Asano, N.; Molyneux, R.J.; At ...

Claims

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Application Information

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IPC IPC(8): C07D451/06C07D487/08C07D451/02C07D451/04A61K31/46A61K31/407A61P3/10A61P3/06A61P35/00A61P31/12
CPCY02P20/55
Inventor 俞初一张朝兰贾月梅胡祥国加藤敦
Owner INST OF CHEM CHINESE ACAD OF SCI
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