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Iminosugar in crystalline form

a technology of iminosugar and crystalline form, which is applied in the direction of aminosugars, biocide, plant growth regulators, etc., can solve the problem of insufficient pureness

Inactive Publication Date: 2014-07-24
DIPHARMA FRANCIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about a new substance, called N-butyl 1,5-dideoxy-1,5-imino-d-glucitol, that can be crystallized and used as a drug. The text describes a process for making this substance and a pharmaceutical composition that contains it. The technical effect of this patent is the creation of a useful new substance for the treatment of certain diseases.

Problems solved by technology

There are three main problems associated with development on an industrial scale of the Baxter and Reitz process, which relate to: 1) the preparation of 5-keto glucose, which involves a number of synthesis steps, the use of compounds based on tin, and low yields; 2) the stereochemistry of the reductive amination, which is selective to give the isomer with gluco stereochemistry only with some types of substituents on the hydroxyls of the starting dicarbonyl; and last but not least 3) the critical steps concerning the handling and purification of the end product, which is purified by flash chromatography.
When the process was repeated, and the resulting solid of formula (III) was analysed, it proved insufficiently pure on HPLC analysis, and the solid was amorphous, with a melting point around 64° C.

Method used

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  • Iminosugar in crystalline form
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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of N-butyl 2,3,4,6-tetra-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (III)

[0069]A solution of oxalyl chloride (99.8 g, 0.79 mol) in dichloromethane (300 mL) is cooled to −75° C., treated under inert atmosphere in sequence with a solution of DMSO (77.1 g, 0.99 mol) in dichloromethane (100 ml) added by slow dripping, and then, after about 1 h, with a solution obtained by dissolving 2,3,4,6-tetra-O-benzyl-D-glucitol, prepared as in Synthesis 1999, 571-573 (HPLC assay 94.5%, 105.9 g, 0.18 mol) in dichloromethane (100 mL), added by slow dripping. The reaction mixture is maintained under stirring at a temperature not exceeding 65° C., and treated after about 2 hours with triethylamine (187 g, 1.85 mol), added by slow dripping, maintaining the reaction mixture under stirring at a temperature not exceeding 50° C. for at least 4 hours. The end-of-reaction mixture is then added to a mixture maintained under stirring in an inert atmosphere at the temperature of 0° C., obtained by mixin...

example 2

Crystallisation of N-butyl 2,3,4,6-tetra-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (III)

[0070]The crude compound of formula (III), obtained as in Example 1, is dissolved in isopropanol (120 mL), and the resulting solution is cooled in an ice bath and treated with water (18 mL). The suspension obtained is maintained under stirring at about 20° C. for 15 hours, and then filtered through a Büchner funnel and the panel washed with isopropanol. The wet solid is stove-dried at the temperature of 50° C., under vacuum, to a constant weight, supplying 50 g of compound of formula (III) with high chemical purity, in crystalline form A, wherein the main peaks (expressed in 2θ°) are found at 4.83, 5.76, 6.96, 7.80, 13.08, 16.50, 17.97, 18.75, 19.14, 19.62. Said crystalline product presents a DSC thermogram as illustrated in FIG. 2, and a water content below 0.1%.

[0071]The compound of formula (III) can be recrystallised from isopropanol alone to obtain a compound of formula (III) with a purity, c...

example 3

Synthesis of Miglustat of Formula (I)

[0072]A solution obtained by mixing N-butyl 2,3,4,6-tetra-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol of formula (III), obtained as in Example 2 (105.1 g, 0.17 mol) in methanol (500 mL) in the presence of 32% HCl (43.5 g), is treated with 16% Pd / C (10.2 g). The mixture is maintained under vigorous stirring under hydrogen atmosphere at 4 bars for about 4 hours, and then filtered through a perlite panel, and the solution obtained is concentrated at low pressure. The solid residue thus obtained is dissolved in water (100 mL), and the acid solution obtained is passed through a column on an ion-exchange resin activated in basic form (Amberlite IRA 900Cl). The fractions that tested positive to the ninhydrin assay were combined and concentrated at low pressure, obtaining 50 g of miglustat as an oily residue, having a chemical purity exceeding 98%, calculated by HPLC.

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Abstract

Iminosugar, which possesses known activity as a glycosyltransferase inhibitor, and is used, for example, in the treatment of Gaucher's disease, in crystalline form, a process for its preparation and a pharmaceutical composition thereof.

Description

[0001]The present invention relates to a glycosyltransferase-inhibiting iminosugar in crystalline form, useful in the treatment of Gaucher's disease, a process for its preparation and a pharmaceutical composition thereof.PRIOR ART[0002]N-butyl 1,5-dideoxy-1,5-imino-D-glucitol of formula (I), also known as N-butyl 1-deoxynojirimycin or miglustat, is a potent glycosyltransferase inhibitor, and is primarily used in the treatment of Gaucher's disease.[0003]Miglustat belongs to the class of azasugars or iminosugars, namely compounds with multiple biological activities characterised by the presence of a nitrogen atom on the furanose or pyranose ring of the sugar instead of an oxygen atom. The synthesis of azasugars as carbohydrate mimics began over 50 years ago. The first azasugar was synthesised more than forty years ago, and was 1-deoxynojirimycin of formula (II), which was only isolated from natural sources years later, and demonstrated its enormous biological activity.[0004]In the 198...

Claims

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Application Information

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IPC IPC(8): C07H5/06
CPCC07H5/06C07D211/46Y10T428/2982
Inventor ATTOLINO, EMANUELEMALVESTITI, ANDREA
Owner DIPHARMA FRANCIS
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