Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1993-02-12
1995-05-16
Rollins, John W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 285, 536 2851, 536 2852, 536 2853, 536 2854, 536 2855, C07H 19073, C07H 100
Patent
active
054162041
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a method of manufacturing 2',3'-dideoxy-.beta.-nucleoside. 2',3'-dideoxy-.beta.-nucleoside itself is a compound having an antiviral activity. For example, the compound exhibits anti-AIDS virus activity. Further, the compound can be used as a raw material for manufacturing the other compounds which are associated with the compound of the present invention, and are useful as medicines.
BACKGROUND ART
The conventional methods of manufacturing 2',3'-dideoxy-.beta.-nucleoside include, for example, selectively removed from (i) ribonucleoside derivatives or (ii) 2'-deoxynucleoside derivatives, and 2,3-dideoxyribose derivative and a base which is a composition of a nucleoside.
An example of conventional method (i) is described in, for example, "J. Org. Chem., 1988, vol. 53, page 5170". It is described that 2',3'-cyclic ortho ester of uridine is thermally decomposed to obtain 2',3',-dideoxy-.beta.-uridine. Then, the base of the nuclooside thus obtained is replaced by another base by using a special strain of Escherichia coli.
An example of conventional method (ii) is described in, for example, "Synth. Commun., 1985, vol. 15, page 401". It is described that the hydroxyl group in the 3'-position of 2'-deoxynucleoside is converted into a thiocarbonate ester, followed by subjecting the resultant compound to a deoxidation reaction.
Further, conventional method (iii) is exemplified in, for example, Japanese Patent Application No. 2-6970 filed by the present inventors, "Heterocycles, 1990, vol. 31, page 2041", "Tetrahedron Lett., 1988, vol. 29, page 1239, Falina et al" and "J. Org. Chem., 1988, vol. 53, page 4780, Okabe et al".
In conventional method (i), however, it is necessary to use a bacterium which is difficult to obtain in general. Also, in each of conventional methods (i) and (ii), ribonucleoside derivatives available in the nature are used as raw materials. Thus, in the case of manufacturing various derivatives, it is necessary to prepare a synthetic riboculeoside, followed by converting the synthetic riboculeoside into the desired 2',3'-dideoxy-.beta.-nucleoside derivative.
On the other hand, the conventional method (iii) is poor in its stereoselectivity. Specifically, the product obtained by the conventional method (iii) is a mixture of a desired .beta.-isomer and a .alpha.-isomer as byproduct. The mixing ratio of .beta.:.alpha. is 7:3 even in the highest case. In general, the .beta.- and .alpha.-isomers are mixed in the equivalent amount.
A measure for solving the above-noted problems inherent in the conventional methods is proposed in, for example, Japanese Patent Application No. 2-133913 and "Chem. Lett., 1990, page 1549". It is proposed that a condensation reaction is carried out between a 2,3-dideoxy-2-.alpha.-(organothio)pentofuranose derivative and a 5-substituted pyrimidine derivative in the presence of Lewis acid so as to obtain a 1-(2,3-dideoxy-2-organothio-.beta.-D-pentofuranosyl) pyrimidine derivative. The derivative thus obtained is oxidized in the presence of a peroxide to obtain 2',3'-dideoxy-2',3'-didehydro-.beta.-ribonucleoside via a 1-(2,3-dideoxy-2-organosulfynyl-.beta.-D-pentofuranosyl) pyrimidine derivative.
It should be noted that an organothio group is .alpha.-coordinated with the carbon atom in 2-position of the 2,3-dideoxy-2-.alpha.-(organothio)pentofuranose derivative used as one of the starting materials in the method described above. Thus, in the condensation reaction between the pentofuranose derivative and the 5-substituted pyrimidine derivative, the approach of the 5-substituted pyrimidine derivative toward the organothio group in an .alpha. direction is inhibited by the steric effect of the organothio group and involvement of the adjacent group. As a result, a high selectivity of the .beta.-isomer of the resultant pyrimidine derivative can be achieved. It follows that the method described above permits obtaining 2',3'-dideoxy-2',3'-didehydro-.beta.-ribonucleoside in a high stereoselectivity.
As described above, the conventional
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Kawakami et al., Chemical Abstracts, vol. 117, 1992, p. 728, col. 2, abstract No. 251686g.
Ebata Takashi
Itoh Kazuo
Kawakami Hiroshi
Koseki Koshi
Matsumoto Katsuya
Japan Tobacco Incorporated
Kunz Gary L.
Rollins John W.
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