Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1995-12-12
1998-07-21
Kight, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 2714, 536 2853, C07H 19073
Patent
active
057836884
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the purification of 2',3'-dideoxy-3'-fluorouridine (3'-FDDU) of formula: ##STR1##
2',3'-dideoxy-3'-fluorouridine A is a well known intermediate in the preparation of therapeutically useful ribonucleosides, disclosed in, for example EP-A-305117 and 356166 (Wellcome Foundation).
In order to qualify for use in the pharmaceutical field, it is necessary that the 3'-FDDU meet the required purity specification. Unfortunately however, 3'-FDDU, by whatever method it is produced, often contains impurities which are exceedingly difficult to remove. In addition, coloured impurities are often formed during processing of white, pure 3'-FDDU.
Currently 3'-FDDU is produced by the deprotection of an intermediate of formula: ##STR2## where P is a protecting group, preferably a 4-methoxybenzoyl radical. 3'-FDDU is recovered by a simple transesterification process using NaOH/MeOH reaction as described in EP-A-0356166.
The aforesaid starting material may be prepared as described in EP-A-0470355, by reaction of a corresponding anhydro-nucleoside with hydrogen fluoride in the presence of an aluminium-containing catalyst.
All known processes for producing 3'-FDDU yield a product containing significant amounts of impurities. The exact nature and identity of the 2 major impurities are known. They are anisic acid of formula: ##STR3## and a dimer of formula: ##STR4##
In order to meet the high purity standards required for pharmaceutical uses, various methods of purification can be used. These methods, however, often involve extensive and complicated neocrystallizations, solvent extractions, etc., requiring elaborate and costly apparatus and the expenditure of extended periods of time.
The present invention provides a method for the purification of crude 3'-FDDU which is more efficient than those heretofore commonly employed, at a significant saving in time and expense.
The present invention provides a method of purifying crude 3'-FDDU (2'3'-dideoxy-3'-fluorouridine) containing anisic acid and a dimer which comprises contacting an aqueous or aqueous methanolic solution of crude 3'-FDDU with adsorbent carbon. This carbon treatment of crude 3'-FDDU results in a product having a higher degree of purity and whiteness than other, known methods.
Carbon treatment of crude 3'-FDDU solution in accordance with the invention removes a large percentage of the impurities present therein, including the two major impurities: anisic acid and the dimer. The method of the present invention is particularly adapted for the removal of impurities from 3'-FDDU produced by the hydrofluorination, deprotection process
The aforesaid hydrofluorination, deprotection process can be operated to produce directly an aqueous methanolic solution of 3'-FDDU to which the process of the invention can be directly applied. In preferred embodiments of the invention however, the 3'-FDDU is first isolated in crude solid form and this solid is washed with acetone to remove a significant proportion of anisic acid impurity before the 3'-FDDU is dissolved in water or aqueous methanol and contacted with adsorbent carbon. Alternatively, or in addition, the aqueous or aqueous methanolic solution of 3'-FDDU is washed with toluene before it is contacted with the adsorbent carbon: this removes any traces of methyl anisic ester that may be present.
Any substantially pure carbon absorbent material may be employed in the method of the invention. It is a well known type of material and an article of commerce. Such carbon has a large surface area available for the adsorption of impurities. Examples of the carbons which may be utilised are charcoal and bone black. Particularly preferred are the so-called activated carbons (or activated charcoal). Activated carbons are usually produced by heating ordinary carbon to high temperatures, e.g. 80.degree.-900.degree. C., in the presence of steam or carbon dioxide and a hygroscopic substance such as zinc chloride, phosphoric acid or sodium sulfate. Activated carbons are particularly effective for the removal of impuri
REFERENCES:
patent: 5157114 (1992-10-01), Rahim et al.
patent: 5223263 (1993-06-01), Hostetler et al.
patent: 5376644 (1994-12-01), Selway et al.
patent: 5449664 (1995-09-01), Verheyden et al.
Hilgetag et al. (ed.), Preparative Organic Chemistry, John Wiley & Sons, New York, NY, 1972, Appendix III(b) and (c), only pp. 1114-1120 supplied.
Crane L. Eric
Kight John
Rhone-Poulenc Chemicals Limited
LandOfFree
Purification of 3'-FDDU and resultant compositions does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Purification of 3'-FDDU and resultant compositions, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Purification of 3'-FDDU and resultant compositions will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1647967