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Novel process for the recovery of beta acetylfuranoside

Inactive Publication Date: 2010-07-29
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]a) Evaporation to less than 1% residual solvent of the mother liquor remaining from an initial synthesis of ACF, to increase the content of residual α / β-ACF from about 8 to 15 weight-% to about 25 to 45 weight-%, followed by distillation to about 60 to 80 weight-% and subsequent crystallization of β-ACF out of the distillate by adding a suitable solvent;

Problems solved by technology

Consequently, and in particular when used on an industrial scale, considerable amounts of valuable β-ACF are wasted, huge amounts of waste residue have to be worked-up and the costs for the entire manufacturing process up to the final product rise significantly.

Method used

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  • Novel process for the recovery of beta acetylfuranoside
  • Novel process for the recovery of beta acetylfuranoside
  • Novel process for the recovery of beta acetylfuranoside

Examples

Experimental program
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example 1

Distillative Recovery of β-Acetylfuranoside

Distillation

[0039]3000 kg Acetylfuranoside mother liquor (ratio α / β 35:65) was evaporated to an oil (residual solvent <1%) at 30 to 80° C. and 5 to 100 mbar (about 1000 kg residual oil). The residual oil was distilled under vacuum at 1 to 3 mbar and 200 to 210° C. steam heating temperature in a continuous thin-film evaporator resulting in 609 kg distillate (containing α / β-Acetylfuranoside) and about 400 kg residue.

Crystallization

[0040]1247 kg distillate (ratio α / β 35:65) was dissolved in 541 L propan-2-ol at 20 to 25° C. and cooled to −12 to −8° C. The resulting suspension was agitated for 6 hours to complete crystallization. The crystallizate was isolated and washed with cold propan-2-ol. 425 kg of white crude product was obtained (2-3% residual moisture). 755 kg of crude product was recrystallized from propan-2-ol (ratio 1:1) under the same conditions. Yield: 748 kg β-Acetylfuranoside.

example 2

Chemical Conversion of α / β-Acetylfuranoside

[0041]811 kg Acetylfuranoside mother liquor (about 250 kg α / β-Acetylfuranoside) was concentrated by distillation to obtain an oily residue (ratio α / β 60:40). Then 1060 L of methanol was added and cooled to −8° C. 127 L of sodium methoxide was then added and stirred for 3 hours. The reaction mixture was neutralized with 126 L of semi concentrated hydrochloric acid to bring the pH to 5.1.

[0042]1235 L of solvents were distilled off 212 L of toluene; 322 L of triethylamine and 42 L of toluene were added. 265 L of acetic anhydride were added slowly, keeping the batch temperature between 15-17° C. The mixture was stirred at 16-17° C. for 1.5 hours. 6.06 kg of 4-dimethylaminopyridine and additionally 367 L of acetic anhydride were added. The batch was stirred for 1.5 hours. The reaction mixture was quenched with 212 L of water and 265 L of toluene were added. After the aqueous layer was separated, it was extracted 3 times with 265 L of toluene. Th...

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Abstract

There is provided an improved method for the recovery of residual, unseparated β-ACF from reaction mixtures remaining from an initial synthesis of ACF, which is in particular usable on a large industrial scale, more particularly in the production of capecitabine.

Description

PRIORITY TO RELATED APPLICATION(S)[0001]This application claims the benefit of European Patent Application No. 09151384.6, filed Jan. 27, 2009, which is hereby incorporated by reference in its entirety.[0002]The present invention is directed to a novel process for the recovery of further β-Acetylfuranoside (β-ACF, β-5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose) from mother liquors and process waste streams remaining from an initial synthesis of ACF.BACKGROUND OF THE INVENTION[0003]ACF can be prepared according to well known methods, as for example described in Helvetica Chimica Acta, Vol. 65(Nr. 149), Fasc. 5, 1982, 1531. The synthesis of ACF leads to a racemic mixture of α- and β-ACF which can be separated by selective crystallization and thus precipitation from the reaction mixture. Usually the β-ACF is the desired product, as it is a valuable starting material used in the manufacture of inter alia cytidine derivatives, such as capecitabine. Capecitabine is the active ingredient of t...

Claims

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Application Information

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IPC IPC(8): C07H1/06
CPCC07H1/00C07H13/04C07H1/06
Inventor BEHRINGER, MARTINJUNGHANS, BERNDKNIPP, BERNHARDPFEIL, BERNHARDZIERES, GERALD
Owner F HOFFMANN LA ROCHE & CO AG