Crystalline sugar compositions and method of making

A technology of crystal and furanose, applied in the field of crystallization of crystal pivaloyl furanose and pivaloyl furanose, can solve problems such as the inability to easily expand the scale

Inactive Publication Date: 2008-07-23
AMICUS THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this method also cannot be easily scaled up to multi-kilogram quantities

Method used

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  • Crystalline sugar compositions and method of making
  • Crystalline sugar compositions and method of making
  • Crystalline sugar compositions and method of making

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Example 1: Synthesis and identification of crystal 1,2,3,6-tetrapivaloyl-α-D-galactofuranose (II) 1-(trimethylacetyl)imidazole (pivaloyl imidazole) ( 42.2kg, 5-fold excess) was dissolved in DMF (90kg) and heptane (3.4kg), and the solution was warmed to 60°C. D-galactose (10 kg) was added to the solution, and the mixture was heated to 75°C. The reaction is exothermic to a temperature of 90-100°C. After the exotherm subsides, the reaction is maintained at 80-100°C until the reaction is complete. The progress of the reaction was monitored by TLC (hexane:ethyl acetate=4:1). To visualize progress, TLC was subsequently stained with dilute sulfuric acid and heated; f= 0.5) the reaction was considered complete when the product spot on it became the major component. Immediately after the reaction was complete, the reaction product was transferred to a mixture containing water (200 kg) and ice (82 kg). The crude product is isolated from this mixture by crystallization; this c...

Embodiment 2

[0090] Example 2: Preparation and identification of crystalline 1,2,3,6-tetrapivaloyl-α-L-altrofuranose (III)

[0091] A solution of pyridine (3.82 kg) in dichloromethane (15 L) was cooled to 0°C under a nitrogen atmosphere. Add trifluoromethanesulfonic anhydride (3.28kg) dropwise at 0°C, followed by dropwise addition of dichloromethane (10L) with 1,2,3,6-tetrapivaloyl-α-D-lactofuranoside (5kg) solution. The reaction mixture was stirred at 0°C for 2 hours, and the completion of the reaction was monitored by TLC (hexane:ethyl acetate=4:1). If the reaction was not complete by this point, an additional portion of trifluoromethanesulfonic anhydride (0.1 kg) was added. At this stage in the reaction, the triflated compound 5-trifluoromethanesulfonyloxy-5-deoxy-1,2,3,6-tetrapivaloyl is formed from galactofuranosides -α-D-Galactofuranoside. The reaction mixture was then washed with cold 6% hydrochloric acid (3 times, 30 L), brine (30 L) and 7.5% sodium bicarbonate solution (30 L)....

Embodiment 3

[0093] Example 3: Preparation and identification of crystalline 5-azido-5-deoxy-1,2,3,6-tetrapivaloyl-α-D-galactofuranose (IV)

[0094] According to the method described in Example 2, the trifluoromethanesulfonated compound, namely 5-trifluoromethanesulfonyloxy-5-deoxy- 1,2,3,6-tetrapivaloyl-α-L-altrofuranose. This compound was reacted with sodium azide (1.6 kg) in DMF (9.5 L). The reaction was carried out using the optimum conditions observed during the transformation reaction. The crude product was crystallized twice from methanol (1.3-1.7 mL / g). On a 5 kg scale, the yield of 5-azido-5-deoxy-1,2,3,6-tetrapivaloyl-α-D-galactofuranose (IV) from III is typically 65-70% (~3.3kg). The product is a white crystalline solid. M.P.103-104℃.IR(KBr, cm -1 ): 2090 (azido, s), 1740 (ester group of pivalate, vs), 1480 (weak), 1280 (C-O, s), 1160 (C-O, vs), 1042 (C-O, weak); 1 HNMR (CDCl 3 , 400 MHz, TMS): δ=1.19(s, 3H), 1.20(s, 3H), 1.22(s, 3H), 1.25(s, 3H), 3.83-3.79(m, 1H), 4.05(...

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Abstract

The present invention relates to novel crystalline pivaloyl furanoses and a method of crystallizing the pivaloyl furanoses. These compounds are useful as intermediates in the synthesis of compounds such as deoxynojirimycins and nojirimycins, especially in several kg scale production. Specific crystalline compounds include 1,2,3,6-tetrapivaloyl-α-D-galactofuranose, 1,2,3,6-tetrapivaloyl-α-L-altrofuranose and 5- Azido-5-deoxy-1,2,3,6-tetrapivaloyl-α-D-galactofuranose.

Description

[0001] This application claims priority to US Provisional Patent Application No. 60 / 689,119, filed June 8, 2005, the entire contents of which are hereby incorporated by reference. technical field [0002] The present invention relates to crystalline pivaloyl furanose and a method for crystallizing pivaloyl furanose. These compounds are useful as intermediates in the synthesis of sugars such as D-1-deoxygalactonojirimycin (DGJ). Background technique [0003] DGJ is also known as (2R, 3S, 4R, 5S)-2-hydroxymethyl-3,4,5-trihydroxypiperidine, 1-deoxy-galactostatin (galactostatin) and D-1-deoxy Galactonojirimycin. It is an iminosugar (5-amino-5-deoxy-D-glucopyranose) analogue of D-galactose and is a potent inhibitor of α- and β-D-galactosidases. Galactosidase catalyzes the hydrolysis of glycosidic bonds, and it is important in the metabolism of complex sugars. Galactosidase inhibitors such as DGJ can be used to treat many diseases and conditions, including diabetes (such as U.S...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H13/00C07H15/00C07H13/02
CPCC07H15/00C07H13/02C07H13/00C07H5/04
Inventor M·梅杰R·彼得森D·林瑟S·科辛斯基
Owner AMICUS THERAPEUTICS INC
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