Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-10-26
2003-06-17
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S027800, C536S027810, C536S028500, C536S028530, C536S028540, C536S027400, C536S027110, C536S027120, C536S027140, C536S028100, C536S028400, C536S028510, C536S028520
Reexamination Certificate
active
06579976
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel process for producing nucleic acid derivatives and in particular to an industrially useful process for reducing sugar-moiety hydroxyl groups and halogen atoms in nucleic acids and their derivatives (their related compounds etc.).
According to the present invention, an intermediate for producing various pharmaceutical preparations, for example an intermediate for producing 9-(2,3-dideoxy-2-fluoro-&bgr;-D-threo-pentofuranosyl) adenine (also may be called “FddA” as the abbreviation in the specification) and 2′,3′-dideoxyadenosine (also may be called “ddA” as the abbreviation in the specification) useful as antiviral agents can be produced industrially advantageously.
2. Description of the Related Art
For dehydroxylation (deoxylation) of sugar-moiety hydroxyl groups in nucleic acids or in their related compounds, the method of radically reducing thiocarbonyl derivatives of such hydroxyl groups has been generally used. Further, for dehalogenation of sugar-moiety halogen atoms in nucleic acids or in their related compounds, the method of radically reducing them has been generally used (for example, see A. G. Sutherland, “Comprehensive Organic Functional Group Transformations”, Vol. 1, A. R. Katritzky, et al., Ed., Pergamon, London, pp. 1-25).
In the radical reduction described above, tin compounds such as tributyl tin hydride are used most generally as radical reducing agents. However, tin compounds when used in industrial production are problematic in their toxicity during operation, and when used in production of pharmaceutical preparations etc., their presence even in a trace amount is not allowable and their use is virtually not possible. Silyl hydride-type compounds such as tris (trimethylsilyl) silane are used as radical reducing agents in some cases, but these silyl hydride-type compounds are generally not produced in industrial scale, and even if produced, they are very expensive and very difficult to use in industry.
In recent years, Barton et al. conducted radical reduction of thiocarbonyl derivatives and halogen atoms with hypophosphorous acid or salts thereof or with esters of phosphorous acid (for example, see D. H. R. Barton, et al., Tetrahedron Lett., 33(39), 5709 (1992) and D. H. R. Barton, et al., J. Org. Chem., 58, 6838 (1993)). However, these literatures illustrate the radical reduction of only simple hydrocarbons or sugar derivatives having a few functional groups, and whether this radical reduction can be applied to complex heterocyclic nucleic acid derivatives was not known.
Accordingly, there is a need for an industrially advantageous and safe process applicable widely to nucleic acid derivatives in order to produce the reduced compound.
PROBLEMS TO BE SOLVED BY THE INVENTION
The object of the present invention is to establish an industrially useful and highly safe process for producing the reduced compounds at low costs, wherein sugar-moiety hydroxyl groups and halogen atoms in nucleic acids or in their derivatives (including their related compounds etc.) can be selectively reduced to advantageously produce a wide variety of useful nucleic acid derivatives such as intermediates for producing the active ingredients (FddA, ddA etc.) in pharmaceutical preparations.
SUMMARY OF THE INVENTION
As a result of their eager study to solve the problem described above, the present inventors found that compounds wherein sugar-moiety hydroxyl groups or halogen atoms in nucleic acids and derivatives thereof (referred to collectively as “nucleic acid derivatives”) have been reduced can be easily obtained by allowing O-thiocarbonyl derivatives of sugar-moiety hydroxyl groups, or halogenated derivatives in the sugar-moiety thereof, to react with any one of hypophosphorous acids (including salts thereof) and esters of phosphorous acid which are inexpensive, non-toxic and safely usable as radical reducing agents in industrial scale, in the presence of a radical reaction initiator, and as a result, the present inventors found that it is thereby possible to derive a wide variety of useful nucleic acid derivatives industrially efficiently, to arrive at the completion of the present invention.
That is, the present invention encompasses the following inventions.
(i) A process for producing a nucleic acid derivative represented by the general formula (II):
wherein B represents a nucleic acid base, R represents a hydrogen atom or a hydroxy group-protecting group, and one of Y′ and X′ represents a hydrogen atom and the other represents a hydrogen atom, a fluorine atom, a hydroxyl group or a protected hydroxyl group, respectively, which comprises allowing a nucleic acid derivative having an eliminating group represented by the general formula (I):
wherein B and R have the same meanings as defined above, and one of Y and X represents an eliminating group and the other represents a hydrogen atom, a fluorine atom, a hydroxyl group or a protected hydroxyl group, respectively, to react with at least one compound selected from hypophosphorous acid (including salts thereof) and esters of phosphorous acid in the presence of a radical reaction initiator. In this reaction, the above eliminating group is reduced and converted into a hydrogen atom.
In the present invention, the nucleic acid base represented by the above group B also includes nucleic acid base derivatives. The nucleic acid base derivatives include e.g. N-acetylguanine, N-acetyladenine, N-benzoylguanine, N-benzoyladenine, 2-amino-6-chloropurine and 6-chloropurine.
(ii) The process according to item (i) above, wherein B is a purine base or a pyrimidine base or a derivative thereof.
(iii) The process according to any one of the above items, wherein B is any one of hypoxanthine, adenine, guanine, uracil, thymine and cytosine, or a derivative thereof.
(iv) The process according to item (i) above, wherein R is any one of a hydrogen atom, an acyl group, an alkyl group, an aralkyl group and a silyl group.
(v) The process according to any one of the above items, wherein R is any one of a hydrogen atom, an acetyl group, a benzoyl group and a trityl group.
(vi) The process according to any one of the above items, wherein the eliminating group is either a halogen atom excluding a fluorine atom or an O-thiocarbonyl derivative (residue).
The halogen atom includes the respective atoms of chlorine, bromine and iodine, and the O-thiocarbonyl derivative (residue) includes O-phenoxythiocarbonyl group: PhO(C═S)O—, O-parafluorophenoxythiocarbonyl group: p-F—PhO(C═S)O—, O-methylthiothiocarbonyl group: MeS(C═S)O—, O-phenylthiothiocarbonyl group: PhS(C═S)O—, and O-imidazolylthiocarbonyl group:
(vii) The process according to any one of the above items, wherein one of Y and X is an eliminating group and the other is any one of a hydroxyl group, an acyloxy group, an alkyloxy group, an aralkyloxy group and a silyloxy group.
(viii) The process according to any one of the above items, wherein one of Y and X is an eliminating group and the other is any one of a hydroxyl group, an acetyloxy group and a benzoyloxy group.
(ix) The process according to any one of the above items, wherein hypophosphorous acid is in the form of sodium hypophosphite.
(x) The process according to item (i) above, wherein the radical reaction initiator is an azo compound.
The azo compound is preferably an azonitrile compound, an azoamidine compound, a cyclic azoamidine compound, an azoamide compound, an alkyl azo compound etc. Specific individual compounds contained in these respective compounds include compounds known to be contained in these compounds, but may be compounds to be found in the future.
(xi) The process according to any one of the above items, wherein the compound produced in the above process wherein B is a purine base or a derivative thereof, Y′ is a hydrogen atom, X′ is a hydroxyl group or a protected hydroxyl group, is subjected to at least one step selected from the step deprotecting the hydroxyl group, the step of halo
Hirose Naoko
Izawa Kunisuke
Katayama Satoshi
Takamatsu Satoshi
Ajinomoto Co. Inc.
Lewis Patrick
Wilson James O.
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