Process for preparing 2,3'-O-cyclocytidine

Details Process for preparing 2,3'-O-cyclocytidine Process for preparing 2,3'-O-cyclocytidine

1992-10-05

1995-03-21

Rollins, John W.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

536 285, C07H 1906, C07H 19067

Patent

active

053996828

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel cytosine compounds, and a process for the production thereof. More specifically, the present invention relates to the production of 2,3'-O-cyclocytidine, 2,3'-O-cyclocytidine analogues and pharmaceutically acceptable salts thereof using novel 3'-O-tosylcytidine precursor compounds and pharmaceutically acceptable salts thereof. The invention also relates to the production of 1-(.beta.-D-xylo-pentofuranosyl)cytosine, 1-(.beta.-D-xylopento-furanosyl)cytosine analogues and pharmaceutically acceptable salts thereof.


BACKGROUND ART

Mizuno et al (Tet. Lett., 4579-4584 (1965)) teach the production of 2,3'-O-cyclocytidine via a six step process which includes the production of 3'-O-mesylcytidine via a four step process from acetylcytidine. This corresponds to a five step process, overall, if cytidine is used as the starting material. Thus, it is not surprising that the overall yield of 3'-O-mesylcytidine produced in this manner is less than 10% (even this low yield assumes theoretical yields for two of the five steps where yield was unreported).
Fromageot et al (Tet. Lett., 3499-3505, (1966)) speculated production of N.sup.4, O.sup.3', O.sup.5' -triacetyl-3-O'-tosylcytidine by reacting an equilibrium mixture of N.sup.4, O.sup.2', O.sup.5' -isomer with a slight excess of p-toluenesulfonyl chloride in an anhydrous pyridine solution. The 3'-O-tosylcytidine derivative was assumed to be a product present in a dichloromethane phase after an arabinofuranosylcytosine derivative had been extracted from the reaction mixture with water. However, the 3'-O-tosylcytidine derivative was not isolated nor is there any disclosure or suggestion of how to prepare this derivative.
Heretofore, the Applicants are not aware of prior an which teaches the production of 3'-O-tosylcytidine compounds.
Further, as taught in Mizuno et al (Tet. Lett., 4579-4584 (1965)), 2,3'-O-cyclocytidine is produced from 3'-O-mesylcytidine as a crystalline free-base. Specifically, the last step in the process comprises reacting 3'-O-mesylcytidine with an excess of sodium t-butoxide to produce 2,3'-O-cyclocytidine. Unfortunately, the first step in the process involved conversion of N.sup.4 -acetylcytidine (NOTE: this was obtained from cytidine in only a 65% yield) to 2',5'-di-O-trityl-N.sup.4 -acetylcytidine in only a 20% yield. Accordingly, the process of Mizuno et al is deficient in that it requires an onerous number of steps to produce 2,3'-O-cyclocytidine and, when produced, 2,3'-O-cyclocytidine is obtained in a relatively low yield of less than 8.5% (even this low yield assumes theoretical yields for two of the six steps where yield was unreported). Further, Doerr et al (J. Org. Chem., 32, 1462-1471 (1967)) found it surprising that Mizuno et al reported isolating 2,3'-O-cyclocytidine in neutral form.
Fox et al (J. Am. Chem. Soc., 29, 5060-5064 (1957)) teaches the production of 1-(.beta.-D-xylofuranosyl)cytosine via coupling of a 100% excess of protected xylosyl halide and protected mercuricytosine, followed by deprotection of the coupled compound to form 1-(.beta.-D-xylo-pentofuranosyl)cytosine. Unfortunately, the coupling step provided a product in only 23% yield which corresponds to an overall yield of 1-(.beta.-D-xylo-pentofuranosyl)cytosine of 18%. It will be appreciated that these yields would be even lower if they were based on xylose and cylosine as starting materials.
Gosselin et al (J. Med. Chem., 1986, 29, 203-213) teach the production of 1-.beta.-D-xylofuranosyl compounds by glycosylation of purine and pyrimidine aglycons with peracylated 1-O-acetyl-.alpha.-D-xylofuranoses, followed by removal of the blocking groups.
It would be desirable to have a relatively simply process for the production of 1-(.beta.-D-xylo-pentofuranosyl)cytosine compounds which did not comprise the use of blocking groups followed by removal of such blocking groups. It would also be desirable to have a more convenient process which provided higher or comparable yields of such 1-(.beta.-D-xylo-pentofuranosyl)cytosin

REFERENCES:
patent: 3792040 (1974-02-01), Moffatt et al.
patent: 3812098 (1974-05-01), Moffatt et al.
patent: 3856777 (1974-12-01), Ishido et al.
patent: 4118484 (1978-10-01), Wechter et al.
Mizuno et al., Tetrahedron Letters, 50:4579-4584, 1965.
Watanabe et al., J. Med. Chem., 23:1088-1094, 1980.
Wagner et al., J. Org. Chem., 39:24-30, 1974.
Fromageot et al., Tetrahedron Letters, 29:3499-3505, 1966.
Chemical Abstracts, vol. 86, p. 583, Abstr. No. 121712t, Ozaki et al., Japan. Kokai, 76,113,881, Oct. 7, 1976.

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