Process for the production of arabinonucleotides

Details Process for the production of arabinonucleotides Process for the production of arabinonucleotides

1996-09-04

1997-12-23

Lilling, Herbert J.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing compound containing saccharide radical

536 263, 5362671, 536 274, 536 2761, 536 2763, 435822, 435824, 435829, 435850, 435874, C12P 1940, C12N 120

Patent

active

057006660

DESCRIPTION:

BRIEF SUMMARY
The invention relates to a process for the production of arabinonucleotides of general formula I ##STR4## in which X represents a hydrogen atom or a fluorine atom, which is characterized in that an arabinonucleoside of general formula II ##STR5## in which X has the above-mentioned meaning, is fermented in the presence of an aryl phosphate of general formula III ##STR6## in which Y symbolizes a hydrogen atom or a nitro group and
As is generally known, the arabinonucleotides of general formula I, 9(5-0-phosphono-.beta.-D-arabinofuranosyl)-9-H-purine-6-amine (=vidarabine phosphate) and 2-fluoro-9-(5-0)-phosphono-.beta.-D-arabinofuranosyl)-9H-purine-6-amine (=fludarabine phosphate), are pharmacologically effective substances that are distinguished by an antiviral and cyclostatic action (EP-A 317,728 and WO 9209604).
According to the known processes, these compounds are produced by phosphorylation of the corresponding nucleosides (Bull. of th. Chem. Soc. Japan 42, 1969, 3505-3508, New Journal of Chem. 11, 1987, 779-785 and WO 9209604). In this process, heavily contaminated crude products, whose purification is very expensive and loss-prone, are obtained.
The process according to the invention makes it possible to synthesize these substances in a relatively simple way in a considerably more pure form than that which is possible by means of the previously known processes.
This is surprising to one skilled in the art. Although from the studies by Koji Mitsugi et al. (Agr. Biol. Chem. 28, 1964, 586-600), it has already been known for a long time that the nucleoside inosine can be microbiologically phosphorylated, it had to be expected that basically less advantageous results would be achieved when the nucleosides of general formula II were phosphorylated. This is the case especially for two reasons: From the works of Koji Mitsugi et al., it is known that mixtures of isomeric nucleotides are often obtained in the phosphorylation of inosine. It was to be expected, consequently, that when the nucleosides of general formula II were phosphorylated, isomeric mixtures would be obtained to the same extent--if not to an even greater extent.
It is known that during metabolism adenosine is degraded, with deamination and oxidation (Rompps Chemie-Lexikon, 8th ed, Frankch Publishing House, Stuttgart (DE) 65), and it was accordingly to be feared that during the microbiological reaction of the adenine derivatives of general formula II, degradation of the compounds would also occur, at least partially.
As separate tests, which with the microorganism Pseudomonas trifolii that is also mentioned by Koji Mitsugi et al. (according to a study of the DSM-identification service, IAM 1309 is now classified as Pantoeaagglomerans), the above-mentioned feared drawbacks in the case of the phosphorylation of the nucleosides of general formula II do not occur; rather, the reaction seems to proceed even more advantageously than that of inosine.
It is highly probable that the process according to the invention can be carried out not only with the tested microorganism Pseudomonas trifolii (IAM 1309), but also with other microorganisms, which are described by Koji Mitsugi et al. as suitable for phosphorylation of nucleosides. These are, for example, the microorganisms:


______________________________________ Pseudomonas trifolii IAM 1543 and IAM 1555 Pseudomonas perlurdia IAM 1589, IAM 1600, IAM 1610 and IAM 1627, Pseudomonas melanogenum F-11, Alcaligenes visco lactis ATCC 9039 and IFM AN-14, Achromobacter superficialis IAM 1433 Flavobacterium lactis IFM F101 Flavobacterium fuscum IAM 1181 Flavobacterium flavescens IFO 3085 Flavobacterium breve IFM S-15 Serracina marcescens IAM 1022, IAM 1065, IAM 1067, IAM 1104, IAM 1135, IAM 1161, IAM 1205, IAM 1223, IAM 1703 ______________________________________
To achieve adequate phosphorylation of the arabinonucleosides of general formula II that can be produced only at very great expense, the process according to the invention must be carried out in the presenc

REFERENCES:
patent: 5180824 (1993-01-01), Bauman et al.
patent: 5602246 (1997-02-01), Bauman et al.
Patent Abstract Japan Band 5, No. 152 C-75 JP 56-82098 Jul. 4, 1981 (Ajinomoto KK).
Patent Abstract Japan Band 7 No. 219 C-188 JP58-116698 Jul. 11, 1983 (Ajinomoto KK).

Affiliated with

Also associated with

Rating

Process for the production of arabinonucleotides does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the production of arabinonucleotides, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the production of arabinonucleotides will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1801917