The present invention relates to methods for producing 2',3'-dideoxyinosine useful as an antiviral agent, represented by the following formula (7), (which is called didanosine (DDI) and herein after referred to as "DDI"), intermediate compounds that are essential in producing the DDI, and methods for producing the intermediate compounds.
0

(7)
DDI is usefiil as an antiviral agent and has already been approved as an anti-AIDS drug in many countries including the U.S.A., Japan and European countries.
To obtain a dideoxy (DD) derivative from nucleoside, there is conventionally known, for example, a method where hydroxyl groups at the 2'-and 3'-positions of nucleoside and subjected to thiocarbonylation, followed by radical reduction to form a didehydrodideoxy (D4) derivative, and the D4 derivative is subjected to hydrogenation or the like, thereby obtaining a dideoxy (DD) derivative. Some sunthesis methods for various antiviral agents based on the above mentioned technique are reported, which include a method

described in-' Chu, C. K. et. al. J. Org. Chem. 1989, 54, 2217-2225. However, the
method described in the aforementioned literature needs a step of protecting a
hydroxyl group at the 5'-position of nucleoside in advance. For example, when
adenosine is used as a raw material for the production of the DD derivative,
tert-butyldimethylsilyl group (e.g., refer to Chu, C. K. et. al. J. Org. Chem. 1989,
54, 2217-2225) and trityl group (e.g., refer to Yurkevich, A. M. et al. Tetrahedron,
1969, 25, 477-484) are adopted as the protective groups. However, when the DDI
is produced using inosine as a raw material, the aforementioned protective
groups cause the problems shown below. Namely, as for the
tert-butyldimethylsilyl group, it is expensive and a fluorine-based reagent
becomes necessary in the process of deprotection. The use of trityl group
prevents the progress of the reaction with satisfactory yields (e.g., refer to
Japanese Patent Unexamined Publication (JP Kokai ) Hei 07-109290). In light
of the above, there is an increasing demand for development of methods for
producing DDI (7) and 2',3'-didehydro-2',3'- dideoxyinosine (4) (which is called D4
inosine and hereinafter referred to as "D4I") inexpensively so as to obtain
satisfactory yields. 0

(4)
There is known a compound where amino group and hydroxyl group respectively at the 1-position and the 5'-position of inosine are protected by benzyl (e.g., Luzzio, F. A. et al. J. Org. Chem., 1994, 59, 7267-7272). However, nothing has been known about a production method for the DDI from the

above-mentioned compound as a raw material by subjecting two hydroxyl groups at the 2'- and S'-positions to deoxylation.
Disclosure of Invention
Objects of the present invention are to provide methods for producing DDI (7), D4I (4) and derivatives thereof in good yields.
After intensive researches and studies, the inventors of the present invention newly found that an inosine derivative represented by the following general formula (l) can be derived from S'-O-benzyl-N^-benzylinosine derivative that has been ssmthesized in accordance with a method, for example, as described in Luzzio, F. A. et al. J. Org. Chem., 1994, 59, 7267-7272, by subjecting the raw material to thiocarbonylation of hydroxyl groups at the 2'- and S'-positions and subsequently carrying out radical reduction. The present invention has been accompHshed based on the above-mentioned finding. Namely, the present invention provides a method for producing an inosine derivative represented by the following general formula (l), 0
-N.

U
(1)
comprising the steps of subjecting an inosine derivative of the following general formula (3) to dithiocarbonylation to obtain a compound, and subjecting the obtained compound to radical reduction:
^

wherein Rl may be the same or different and are each benzyl group, benzhydryl group or trityl group, each of which may have a substituent in general formula (l) and (3).
Also, the present invention provides a method for producing an inosine derivative represented by the following general formvda (2), comprising the step of hydrogenating the inosine derivative represented by the above-mentioned general formula (l):

■J


\r

(2)
wherein Rl may be the same or different and are each benzyl group, benzhydryl group or trityl group, each of which may have a substituent.__ ^
The present invention also provides a method for producing 2',3'-dideoxyinosine (DDI), characterized by hydrogenating the inosine derivative represented by the above-mentioned general formula (l) or the inosine derivative

^'1
represented by the above-mentioned general formula (2).

In addition, the present invention provides a method for producing 2',3'-didehydro-2',3'-dideox5dnosine (D4I) represented by the above-mentioned general formula (4), comprising the step of eliminating substituents Rl from the inosine derivative represented by the above-mentioned general formula (l).
Further, the present invention provides a method for producing 2',3'-dideoxyinosine (DDI), comprising the steps of
subjecting the inosine derivative represented by the above-mentioned general formula (3) to dithiocarbonylation to obtain a compound of the following general formula (5):

A


'.I
s s
(5)
wherein Rl may be the same or different and are each benzyl group,
N"
benzhydryl group or trityl group, each of which may have a substituentl andj \ R2 are each an alkylthio group having 1 to 12 carbon atoms, an alkoxyl group ,\ p' having 1 to 12 carbon atoms or an alkylamino group having 1 to 12 carbon \ ^ atoms;
'L
subjecting the compound of the general formula (5) to radical reduction to "^

obtain the inosine derivative represented by the above-mentioned general formtila (l)l
hydrogenating the inosine derivative represented by the general formula (l) to obtain the compound represented by the above-mentioned general formula (2); and
eliminating the substituents Rl from the compound represented by the general formxila (2).
Also, the present invention provides a method for producing 2',3'-didehydro-2',3'-dideoxyinosine (D4I) represented by the above-mentioned general formula (4), comprising the steps of-
subjecting the inosine derivative represented by the above-mentioned general formula (3) to dithiocarbonylation to obtain the compound of the above-mentioned general formtila (5);
eliminating the substituents Rl from, the compound represented by the general formula (5) to obtain a compound of the following general formula (6)"-

R2--^0 0--^R2
(6)
wherein R2 are each an alkylthio group having 1 to 12 carbon atoms, an alkoxyl group having 1 to 12 carbon atoms or an alkylamino group having 1 to 12 carbon atoms; and

subjecting the compound of the general formula (6) to radical reduction.
Also, the present invention provides a method for producing 2',3'-didehydro-2',3'-dideox3dnosine (D4I) represented by the above-mentioned general formula (4), comprising the steps of subjecting the inosine derivative represented by the above-mentioned general formula (3) to dithiocarbonylation to obtaia the compound of the above-mentioned general formula (5), subjecting the compound of the general formula (5) to radical reduction to obtain the inosine derivative represented by the above-mentioned general formula (l), and eliminating the substituents Rl from the inosine derivative represented by the general formula (1).
The present invention provides a method for producing DDI comprising the step of hydrogenating 2',3'-didehydro-2',3'-dideoxyinosine (D4I) obtained by the above-mentioned methods, and 2',3'-dideoxyinosine (DDI) obtainable by the above-mentioned production method.
Furthermore, the present invention provides inosine derivatives represented by the following general formula (l)'-0
(1)
wherein Rl may be the same or different and are each benzyl group, benzhydryl group or trityl group, each of which may have a substituent.

s
■
^

The present invention also provides inosine derivatives represented by the following general formula (2). 0

(2)
The present invention also provides inosine derivatives represented by the
following general formula (5). 0

^N
RK../V^N
\^

s s
(5)
The present invention also provides inosine derivatives represented by the following general formula (6).