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 essentia! in producing the DDI, and methods for producing the intermediate compounds.
0

(7)
DDI is useful 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 hydroxy! 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, tliereby obtaining a dideoxy (DD) derivative. Some sunthesis methods for various antiviral agents based on the above mentioned technique are reported, which include a method
2

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
hydi'oxyl gi'oup 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,
tertbutyldimethylsilyl 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. Tetrahedi'on,
1969, 25, 477-484) are adopted as the protective gi'oups. However, when the DDI
is produced using inosine as a raw material, the aforementioned protective
gi'oups cause the problems shown below. Namely, as for the
tert-butyldimethylsilyl gi'oup, it is expensive and a fluorine-based reagent becomes necessary in the process of deprotection. The use of trityl group prevents the progi-ess of the reaction with satisfactory yields (e.g., refer to Japanese Patent Unexamined Publication (JP Kokai ) Hei 07-109290), In hght 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 gi-oup and hydi'oxyl group respectively at the l-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 hydi'oxyl groups at the 2'- and 3'-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 synthesized 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 3'-positions and subsequently carrs^ng out radical reduction. The present invention has been accomplished 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

(1)
corapiising 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 gi-oup 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 formula (2), comprising the step of hydi'ogenating the inosine derivative represented by the above-mentioned general formula (l)-

(2)
wherein Rl may be the same or different and are each benzyl group, benzhydryl gi'oup 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

represented by the above-mentioned general formula (2).
In addition, the present invention provides a method for producing 2',3'-didehydro-2',3'-dideoxyinosine (D4l) 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 (S)-

wherein Rl may be the same or different and are each benzyl group, benzhydryl group or trityl gi'oup, each of which may have a substituent; and R2 are each an alkylthio group having 1 to 12 carbon atoms, an alkoxyl group having 1 to 12 carbon atoms or an aUcylamino group having 1 to 12 carbon atoms!
subjecting the compound of the general formula (5) to radical reduction to

obtain the inosine derivative represented by the above-mentioned general formula (l);
hydi"Ogenating 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 formula (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 formula (5);
ehminating the substituents Rl from the compound represented by the general formula (5) to obtain a compound of the following general formula (6):

S S
(6)
wherein R2 are each an alkylthio group having 1 to 12 carbon atoms, an alkoxyl gi-oup having 1 to 12 carbon atoms or an alkylamino gi'oup having 1 to 12 carbon atoms; and

subjecting- the compound of the general formula (G) to radical reduction.
Also, the present invention provides a method for producing 2',3'-didehydi'o-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 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 hydi'ogenating 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 iiivention provides inosine derivatives represented by the following general formula (l): 0
Cc:>
CD
wherein Rl may be the same or different and are each benzyl group, benzhydi'yl group or trityl gi'oup, each of which may have a substituent.

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

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

'N


^0
R]

~H'

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


In general formulas (2), (5) and (6), Rl and R2 are the same as those previously defined.
Best Mode for Carrying out the Invention
In the aforementioned general formulas (l) through (3) and (5), Rl may be the same or different and are each benzyl group, benzhydiyl group or trityl group, each of which may have a substituent. In particular, benzyl group which may have a substituent is preferable from the viewpoints of yield and economical efficiency. In the case where Rl has a substituent, the position and the number of substituents are not particularly limited. Examples of the substituents for Rl include an alkyl group having 1 to 12 carbon atoms such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, tert-butyl group or the hke; a cycloalkyl groups having 3 to 12 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyi group or the Hke; an alkoxyl group having 1 to 12 carbon atoms such as methoxy group, ethoxy group, n-propoxy gi-oup, i-propoxy group, n-butoxy group, tert"butoxy group or the Hlce; an acyloxy group having 2 to 12 carbon atoms such as acetoxy group, benzoyloxy gi'oup or the Hke; hydroxyl group; a halogen atom such as fluorine, chlorine, bromine, iodine or the hke; vinyl group; allyl group; an aryl gi-oup such as phenyl gi'oup, naphthyl group, fiiryl group, indolyl gi'oup,

pyridyl group or the like; a caxbonyl group such as formyl group, acetyl group,
trifluoroacetyl group, benzoyl group, methoxycarbunyl group, ethoxycarbonyl
group, tert-butoxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group,
benzyloxycarbonyl group, methylaminocarbonyl group or the like; a sulfonyl
group such as alkylsulfonyl group, arylsulfonyl group, sulfonamide or the hke;
amino group; a primary amino group such as N-methylamino group,
N-ethylamino group, N-n-propylamino group, N-isopropylaijaino group,
N-n-butylamino group, N-isobutylamino group, N-tert-butylamino group,
N'benzylamino group, N-methoxycarbonylamino group,
N-tert-butoxycarbonylamino group, H'phenylamino group, N-mesylamino group,
N-tosylamino group, N-formylamino group or the hke; a secondary amino group
such as N,N-dimethylaniino group, N,N-diethylamino group, N.N-dibenzylamino
group, N-ethyl-N-methylamino group, N,N-di-n-propylamino group,
N.N-diisopropylatnino group, N,N-diphenylamino group,
N-methyl-N-phenylamino group, N-methyl-N-benzylamin.o group,
N-mesyl-N-methylamino group, piperidyl group, pyrrolidyl group or the hke; nitro group; nitroso group; cyano group; and a haloalkyl group such as monofluoromethyl group, difluoromethyl group, trifluoromethyl group, monochloromethyl group, dichloromethyl group, trichloromethyl group, pen tafluoro ethyl group or the Hke. The alkoxyl group having 1 to 12 carbon atoms is preferable as the substituent for Rl. As the group represented by Rl, particularly preferable are unsubsti-tuted benzyl group and benzyl group having as a substituent an alkoxyl group with 1 to 12 carbon atoms, preferably methoxy group, more preferably methoxy group at the para-position.
The inosine derivative represented by the above-mentioned general formula (l) can be produced, for example, by (i) subjecting the inosine derivative represented by the above-mentioned general formula (3) to dithiocarbonylation to obtain the thiocarbonylated inosine derivative of the above-mentioned general formula (5), and (iO carrjdng out the radical reduction of the obtained compound

of general formula (5).
The inosine derivative represented by the above-mentioned general formula (3) can be prepared, for example, by a conventional method described in the literature: Luzzio, F. A. et al. J. Org. Chem., 1994, 59, 7267-7272. More specifically, hydx'oxyl groups at the 2'- and 3'-positions of inosine are protected by ketal, and thereafter benzyl group or the like is introduced into the obtained compound to achieve deprotection of the ketal, so that the inosine derivative of general formula (3) can be produced. The amounts of raw materials, proper reaction conditions, the kind and the amount of solvent, the catalyst and the like are known to those skilled in the art.
In the above-mentioned formulas (5) and (6), R2 may be the same or different, and are each an allcylthio gi'oup 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. Each of those groups may have a substituent. In consideration of the yield and economical efB.ciency, an alkylthio gi'onp having 1 to 12 carbon atoms which may have a substituent is preferable. In the case where R2 has a substituent, the position and the number of substituents are not particularly limited. Examples of the substituents for R2 include an alkoxyl group having 1 to 12 carbon atoms such as methoxy group, ethoxy group, n"propoxy group, i-propoxy group, n-butoxy group, tert-butoxy group or the lilce; hydi-oxyl group; a halogen atom such as fluorine, chlorine, bromine, iodine or the like; a heteroaryl group such as furyl gi'oup, indolyl gi'oup, pyridyi gz'oup or the like; a sulfonyl group such as alkylsulfonyl group, arylsulfonyl group, sulfonamide or the Hke; amino group; a primary amino group such as N-methylamino group, N-ethylamino group, N-n-propylamino group, N-isopropylamino group, N-n-butylamino group, N-is obutyl amino group, N-tert-butylamino gi'oup, N-benzylamino group, N-phenylamino group, N-mesylamino group, N-tosylamino group or the Uke; a secondary amino gi'oup such as N,N-dimethylamino gi"Oup, N,N-diethylamino gi"oup, N,N-dibenzylamino group, N-ethyl-N-methylamino

gi'oup, N,N-di-n-propylamino gi'oup, N,N-diisopropylamino ^oup,
N,N-diphenylamino group, N-methyl-N-phenylamino gi'oup,
N-methyl-N-benzylamino gi-oup, N-mesyl-N-methyl amino gi'oup, piperidyl group, pyrrolidyl gi'oup or the hkel nitro gi-oup; nitroso ^'oup; cyano gi'oup, and so on. Particularly, cyano gi'oup is preferable as the substituent for R2. As the group represented by R2, raethylthio gi"Oup, and ethylthio group and 2xyanoethylthio gi'oup are preferable, and methylthio group is more preferable.
G) In the present invention, the inosine derivative of general formula (3) is first subjected to dithiocarbonylation to obtain the thiocarbonylated inosine derivative represented by general formula (5). To achieve the step of dithiocarbonylation, the processes for thiocarbonylation, such as alkylthio-thiocarbonylation, alkoxythiocarbonylation, alkylamino-thiocarbonylation and the hke can be employed.
The process of aikylthio-thiocarbonylation can be carried out by allowing the inosine derivative of general formula (3) to react with carbon disulfide and an alkyl hahde in the presence of a base in an appropriate solvent. Examples of the solvent include dimethyl sulfoxide (DMSO), dimethylform amide (DMF), N-methylpyrrolidone, tetrahydi'ofuran and the hke. In particular, DMSO is preferable. The amount of solvent may be preferably in the range of 0.5 to 5 L, more preferably 1 to 2 L, with respect to 1 mol of the inosine derivative of general formula (3). It is preferable that the amount of carbon disulfide be 2 to 4 equivalent weights, more preferably 2 to 2.5 equivalent weights, with respect to the inosine derivative of general formula (3). The base includes sodium hydi'oxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride and the Like, and sodium hydi'oxide and potassium hydroxide are preferably used. The amount of base may be preferably 2 to 4 equivalent weights, more preferably 2 to 2.5 equivalent weights, with respect to the inosine derivative of general formula (3). Examples of the alkyl halide to be used include methyl iodide, ethyl iodide, 2-cyanoethyl bromide and the like. In

particular, methyl iodide and 2-cyanoethyl bromide are preferable. The amount of alkyl hahde is preferably 2 to 5 equivalent weights, more preferably 2 to 3 equivalent weights, with respect to the inosine derivative of general formula (3). The reaction temperature, which varies depending upon the kind of solvent, is generally in the range of -20 to SO^C. preferably 0 to 30°C. It is preferable to carry out the reaction within the above-mentioned temperature range from the viewpoint of yield. The reaction time is generally in the range of 0.1 to 10 hours, preferably 1 to 3 hours. To cause the reaction within, the above-mentioned time range produces good results in terms of yield.
The process of alkoxy-thiocarbonylation can be carried out, for example, as described in WOO 173095, by allowing the inosine deiivative of general formula (3) to react with an aUcoxy-thiocarbonyl halide in the presence of a base in an appropriate solvent. Examples of the solvent include organic solvents such as acetonitrile, dimethylformamide (DMF), pyridine, ethyl acetate, toluene and the like. Acetonitrile is preferable. The amount of solvent may be preferably in the range of 0.5 to 5 L. more preferably 1 to 2 L, with respect to 1 mol of the inosine derivative of general formula (3). The base includes organic tertiary amines such as pyridine, triethylamine, N-ethyipiperidine, N-ethylmorpholine and the Hke, and triethylamine and pyridine are preferably used. The amount of base is preferably 2 to 4 equivalent weights, more preferably 2 to 2.5 equivalent weights, with respect to the inosine derivative of general formula (3). The reaction temperature, which varies depending upon the land of solvent, is generally in the range of -50 to 50°C, preferably -20 to 20''C. It is preferable to carry out the reaction within the above-mentioned temperature range from the viewpoint of yield. The reaction time is generally in the range of 0.1 to 5 hours, preferably 0.5 to 2 hours, lb cause the reaction within the above-mentioned time range produces good results in terms of yield.
The process of alkylamino-thiocarbonylation can be carried out by a method as described in, for example, Nishiyama, K. et al. Tetrahedron Lett., 2003, 44,

4027-4029, Izawa, K. et al. Tetrahedron Lett., 2001, 42, 7605-7608, or the Uke. More specifically, the inosine derivative of general formula (3) may be allowed to react with phenyl isothiocyanate or l,r-thiocarbonyl diimidazole in an appropriate solvent, in the presence of a base when necessary. Examples of the solvent include organic solvents such as dimethylform amide (DMF), tetrahydrofuran, acetonitiile and the hke. In particular, dimethylform amide and tetrahydr-ofuran are preferable. The amount of solvent may be preferably in the range of 0.5 to 5 L, more preferably 1 to 2 L, with respect to 1 mol of the inosine derivative of general formula (3). The base includes sodium hydride, sodium hydroxide, potassium hydi'oxide and the hlce, and sodium hydride is preferably used. The amount of base is preferably 2 to 4 equivalent weights, more preferably 2 to 2.5 equivalent weights, with respect to the inosine derivative of general formula (3). The reaction may proceed in the absence of a base, and therefore the base is not always necessary. The reaction temperature, which varies depending upon the kind of solvent, is generally in the range of -20 to lOO^C, preferably 0 to 80°C. It is preferable to carry out the reaction within the above-mentioned temperature range from the viewpoint of yield. The reaction time is generally in the range of 0.1 to 5 hours, preferably 0.5 to 2 hours. To cause the reaction within the above-mentioned time range produces good results in terms of jaeld.
(ii) According to the present invention, the compound of general formula (l) can be obtained by subjecting the compound represented by general formula (5) to radical reduction.
Examples of the solvent that can be used in this step include djmethoxyethane (DME), acetonitrile, acetic ester, 1,4-dioxane, tetrahydrofuran (THF), and alcohols such as methanol, ethanol, 2-propanol and the hke. In particular, acetonitrile, 1,4-dLoxane and tetrahydrofuran (THF) are preferable. The amount of solvent may be preferably in the range of 0.5 to 5 L, more preferably 1 to 2 L, with respect to 1 mol of the compound represented by general

formula (5).
A radical reducing agent that can be used in this step includes hypophosphorous acid and salts thereof, for example, N-ethylpipeiidine hypophosphite, tributyl tin hydride, silane compounds such as diphenyl silane, and the hke. In particular, hypophosphorous acid and salts thereof are preferable, and N-ethylpiperidine hypophosphite is particularly preferable. The amount of radical reducing agent is generally 1 to 20 equivalent weights, preferably 1 to 5 equivalent weights, with respect to 1 mol of the compound obtained in the step G).
A radical initiator that can be used in this step includes azobisisobutyronitrile (AIBN), triethylborane, and the Kke. In particular, AIBN is preferable. The amount of radical initiator is generally 0.01 to 2 equivalent weights, preferably 0.1 to one equivalent weight, with respect to 1 mol of the compound represented by general formula (5).
The reaction temperature for this step, which varies depending upon the kind of solvent, is preferably in the range of 0 to 120°C, more preferably 20 to 9Q°C. It is preferable to carry out the reaction within the above-mentioned temperature range from the viewpoint of yield.
In this step, the reaction time is typically in the range of 0.1 to 10 hours, preferably 1 to 5 hours. To cause the reaction within the above-mentioned time range produces good results in terms of yield.
After the completion of the above-mentioned reaction in the present invention, the obtained product may be further purified by chromatography or the hke.
(iii) According to the present invention, the compound represented by the aforementioned general formula (2) can be produced by, for example, hydrogenating the compound represented by the aforementioned general formula
(1).
A catalyst that can be used in the present invention includes palladium ■

carbon, palladium hydi-oxide - carbon, platinum - carbon and the Hke. In particular, palladium ■ carbon and palladium hydi-oxide - carbon are preferable.
The atmospheric pressure of hydi'ogen is preferably in the range of 0.5 to 10 atmospheres, more preferably 0.8 to 2 atmospheres.
Any organic solvents can freely be used for the solvent for use in the present invention. DMF, methanol, ethanol, acetonitiile and tetrahydi'ofuran are preferable, and methanol is particularly preferable.
The reaction temperature in the present invention, which varies depending upon the kind of solvent, is preferably in the range of 10 to 60°C, more preferably 20 to 50°C.
In this step, the reaction time is typically in the range of 0.1 to 10 hours, preferably 1 to 5 hours.
After the completion of the above-mentioned reaction in the present invention, the obtained product may be further purified by chromatography or the Uke.
(iv) In the present invention, the intended DDI (7) can be derived from the inosine derivative represented by the above-mentioned general formula (l) or (2) through hydrogenation. To be more specihc, a double bond in a sugar moiety of the inosine derivative represented by the above-mentioned general foi-mula (l) is subjected to hydrogenation, so as to derive the inosine derivative represented by the above-mentioned general formula (2). Further, the protective gi'oups Rl are ehminated by hydro gen olysis, thereby leading to the intended DDI. In this case, according to a preferred embodiment, a double bond in a sugar moiety of the inosine derivative represented by the above-mentioned general formula (l) is subjected to hydrogenation in the presence of a metal catalyst in an atmosphere of hydrogen so as to derive the inosine derivative represented by the above-mentioned general formula (2). Subsequently, a first benzyl gi-oup is ehminated in the presence of an aUcah at room temperature, and thereafter a second benzyl group is ehminated by the reaction where the pressure of hydi-ogen

is increased and/or the temperature is raised, thereby converting the inosine derivative of general formula (2) into the desired DDL According to a particularly preferable embodiment in this case, sodium hydi'oxide or potassium hydi-oxide is used as an alliah, and the reaction time for elimination of the first benzyl gxoup is in the range of 0.5 to 5 hours. The second benzyl group is eliminated under the conditions that the pressure of hydrogen is preferably set to 0.5 to 10 atmospheres, more preferably 0.8 to 2 atmospheres, the temperature is set to 40 to I50°C, preferably 60 to 120°C, and the reaction time is set to 2 to 24 hours.
(v) From the compound of aforementioned general formula (l), D4I (4) can also be obtained by subsequent elimination of the substituents represented by Rl. This process is particularly useful in the case where the inosine derivative of general formula (3) is used as a starting material where Rl is benzyl group having an alkoxyl gi-oup with 1 to 12 carbon atoms, preferably methoxy group, more preferably methoxy group at the para-position.
As an agent for eliminating the substituents Rl (i.e., deprotecting agent)
that can be used in this step, diammonium cerium (IV) nitrate,
2,3-dichloro-5,6-dicyano- 1,4-benzoquinone and the like can be employed. In
particular, diammonium cerium (IV) nitrate and
2,3-dichioro-5,6-dicyano-l,4-benzoquinone are preferable. The amount of this agent is preferably in the range of 1 to 5 mol, more preferably 2 to 3 mol, with respect to 1 mol of the compound of general formula (l).
Examples of the solvent that can be used in this step include a mixed solvent of acetonitrile and water, a mixed solvent of dichloromethane and water, tetrahydi'ofuran, and so on. In particular, a mixed solvent of acetonitrile and water is preferable. The amount of solvent is preferably in the range of 1 to 100 mL, more preferably 10 to 50 mL, with respect to 1 mol of the compound having general formula (l).
The reaction temperature for this step, which varies depending upon the

kind of solvent, is preferably in the rang'e of 0 to 100°C, more preferably room temperature. It is preferable to carry out the reaction within the above-mentioned temperature range from the viewpoint of yield. The reaction time for this step is typically in the range of 0.1 to 10 hours, preferably 2 to 5 hours. To cause the reaction within the above-mentioned time range produces good results in terms of yield. This step can preferably give the D4I (4) in high yields.
After the completion of the reaction in this step, the obtained product may be further pui-ified by chromatography or the like.
(vi) In the present invention, a thiocarbonyl inosine represented by general formula (6) is obtained by eliminating the substituents Rl from the compound of general formula (5). This process is particularly useful in the case where the inosine derivative of general formula (3) is used as a starting material where Rl is benzyl group having an allcoxyl gi'oup with 1 to 12 carbon atoms, preferably, methoxy group, more preferably, methoxy group at the para-position.
The same agent for eliminating the substituents Rl as used in the step (v) can be used in this step. In particular, diammonium cerium Cl\0 nitrate and 2,3-dichloro-5,6-dicyano-l,4-ben2oquinone are preferable. The amount of this agent is preferably in the range of I to 5 raol, more preferably 2 to 3 mol, with respect to 1 mol of the compound having general formula (5).
The solvent that can be used in this step and the amount thereof, the reaction temperature, and the reaction time are the same as those described in the conditions of the step (iv), and the preferable conditions and the reasons therefor described in the step (iv) are also appHed to this case.
After the completion of the reaction in this step, the obtained product may be further purified by chromatogi-aphy or the like.
(vii) In the present invention, D41 (4) can be obtained by subjecting the compound represented by general formula (6) to radical reduction.
The same radical reducing agents that can be used in the step (ii) are

applicable to this step. In particular, hypophosphorous acid and salts thereof are preferable, and N-ethylpiperidine hypophosphite is more preferable. The amount of radical reducing agent is preferably 1 to 20 equivalent weights, more preferably 1 to 5 equivalent weights, with respect to 1 mol of the compound of general formula (6).
Examples of the solvent that can be used in this step include a mixed solvent of tetrahydi'ofuran and triethylborane hexane solution, acetonitrile, 1,4-dioxane, tetrahydrofuran (THF) and the Uke. In particular, a mixed solvent of tetrahydi-ofuran and triethylborane hexane solution is preferable. The amount of solvent is preferably in the range of 0.5 to 5 L, more preferably I to 2 L, with respect to 1 mol of the compound of general formula (6).
The reaction temperature for this step, which varies depending upon the kind of solvent, is preferably in the range of 0 to 120°C, more preferably, room temperature. It is preferable to cai'ry out the reaction within the above-mentioned temperature range from the viewpoint of yield. In this step, the reaction time is typically in the range of 0.1 to 10 hours, preferably 1 to 50 hours. To cause the reaction within the above-mentioned time range produces good results in terms of yield. This step can preferably give the D4I in high yields.
After the completion of the reaction in this step, the obtained product may be further purified by chromatography or the like.
(viii) In the present invention, DDI (7) can also be obtained by subjecting the D4I (4) prepared through the step (vii) to hydro gen ation, using the technique known in the art {refer to, for example, Chu, C. K. et al. J. Org. Chem. 1989, 54, 2217-2225).
The catalyst that can be used in this step and the amount thereof, the solvent that can be used in this step and the amount thereof, the reaction temperature, and the reaction time are the same as those described in the conditions of the step Gii), and the preferable conditions and the reasons therefor

described in the step (iii) are also applied to this case.
The D4I (4) or the inosine derivative represented by general formula (2) can be produced by following the sequence of the steps combined as shown below^ (i) -Gi) ■ (iii), (i) - (ii) - (v), or (i) - (vi) - (vh). In particular, the D4I can preferably be obtained in remarkably high yields by following the steps of G), (vi) and (vii) in this order, using as the raw material an inosine derivative of general formula (3) where Rl is p-methoxybenzyl gi'oup.
After the D4I or the inosine derivative represented by general formula (2) is obtained by any of the aforementioned combinations of the steps, the additional step (iv) or (viii) can provide the DDI (7). Namely, the DDI can be produced by following the sequence of the steps combined as shown below- (0 - (iO - (hi) - (iv), (i) - (ii) - (v) ■ (viii), or (i) - (vi) - (vii) - (viii). In particular, the DDI can preferably be obtained in remarkably high yields by following the steps of (i), (vi), (viO and (viii) in this order, using as the raw material an inosine derivative of general formula (3) where Rl is p-methoxybenzyl gi'oup.
After the completion of the reactions in the present invention, the obtained product may further be purified by conventional processes, such as chromatography, crystallization and the like to obtain a targeted DDI.
The present invention wiU now be explained in detail with reference to the following Examples.
Examples
Example 1
Synthesis of Ni,5'-0-dibenzyl-2',3'-bis-0-[(methylthio)thiocarbonyl]inosine
To a dimethyl sulfoxide solution (l mL) of Ni,5'-0-dibenzyl inosine (224 mg, 0.5 mmol) synthesized in accordance with a method described in Luzzio, F. A, et al. J. Org. Chem., 1994, 59, 7267-7272, an aqueous solution of sodium hydroxide (0.28 mL, 1.1 mmol) at a concentration of 4.0 mol/L and carbon disulfide (0.09 mL, 1.5 mmol) were added, and the obtained mixture was stirred at room temperature

for 2 hours. To the obtained solution, methyl iodide (0.07 mL, 1.1 mmol) was
added dropwise, the mixture was then stirred at room temperature for one hour.
Then, with the addition of ethyl acetate (lO mL) and water (2 niL), the reaction
was terminated. After the layers were separated, the resultant water layer was
again extracted by the addition of ethyl acetate (lO mL). The two organic layers
thus obtained were combined and dried over anhydi'ous magnesium sulfate, and
then concentrated under reduced pressure. After purification by
chromatography (using 15 g of sihca gel and a mixed solvent of hexane and ethyl acetate (L2) as an elating solution), 276 mg of the intended product was obtained in a yield of 88% as a colorless oily material.
' H-NMR (CDCI3) - 6 2.53 (s, 3H), 6 2.60 (s, 3H), 6 3.75-3.90 (m, 2H), 5 4.58 (m, IH),
5 4.63 (s, 2H), 5 5.25 (s, IH), 8 6.44 (m, 2H), 5 6.62 (m, IH), 5 7.25-7.39 (m, lOH),
5 7.96 (s, IH), 5 8.01 (s, IH). '' C-NMR (CDCl,) : 5 19.79, 19.88, 49.58, 69.68,
74.30, 79.55, 80.87, 83.56, 85,60, 125.11, 128.05, 128.35, 128.55, 128.71, 129.03,
129.41, 136.35, 137.40, 138.76, 147.81, 148.02, 156.84, 214.71, 215.05. ESIMS
m/z:629(M-^H).
Example 2
Synthesis of Ni,5'-0-dibenzyl-2',3'-didehydi-o-2',3'-dideoxyinosine
An acetonitrile solution (l mL) of Ni,5'-0-dibenzyl-2',3'-bis-0-[(methylthio) thiocarbonyljinosine (314 mg, 0.5 mmol) was heated to SO^C. To this solution, an acetonitrile solution (l mL) of N-ethylpiperidine hypophosphite (358 mg, 2 mmol) and 2,2'-azobisisobutyronitrile (l6.4 mg, 0.1 mmol) were added, and the mixture was then stirred at 90°C for one hour. After the reaction mixture was cooled, the reaction was terminated with the addition of water (3 mL). The reaction mixture was extracted by the addition of ethyl acetate (15 mL), and the resultant organic layer was diied over anhydi'ous magnesium sulfate and concentrated under reduced pressure. After purification by chromatography (using 12 g of

silica gel and a mixed solvent of hexane and ethyl acetate (1:2) as an eluting solution), 150 mg of the intended product was obtained in a yield of 71% as a colorless ody material.
'H-NMR (CDCI3) : 53.61 (d, 2H, J-3.8 Hz), 64.45 (d, IH, J=12.2 Hz), 5 4.54 (d,
IH, J^12.2 Hz), 5 5.06 (m, IH), 5 5.25 (d, IH, J=14.7 Hz), 5 5.31 (d, IH, J=14.7
Hz), S 6.01 (d, IH, J^G.O Hz), 5 6.40 (d, IH, J=6.0 Hz), 5 6.98 (s, IH), 5 7.21-7.37
(m, lOH), 5 8.00 (s, IH), S 8.03 (s, IH). '' C-NMR (CDCI3) : 5 49.47, 71.13, 73.82,
86.89, 88.54, 124.80, 125.38, 128.27, 128.48, 128.62, 128.71, 128.87, 129.36,
135.02, 136.56, 137.82, 139.24, 147.65, 147.69, 157.04. ESIMS m/z: 417 (M+H).
Example 3
Synthesis of N',5'-0-dibenzyl-2',3'-dideoxyinosine
To a methanol solution (l mL) of N',5'-0-dibenzyl-2',3'-didehydi-o-2',3'-dideoxyinosine (207 mg, 0.5 mmol), 5% palladium - carbon (20 mg) was added, and the mixture was stirred at room temperature for 2 hours in an atmosphere of hydrogen (l atm). The palladium catalyst was removed from the obtained reaction mixture by filtration, and the resultant filtrate was concentrated under reduced pressure. After pui-ification by chromatography (using 15 g of silica gel and ethyl acetate as an eluting solution), 187 mg of the intended product was obtained in a yield of 90% as a white sohd.
' H-NMR (CDCI3): 5 2.08-2.17 (m, 2H), 6 2.40-2.49 (m, 2H), 5 3.59 (d-d, IH, J=10.5,
4.4 Hz). 5 3.73 (d-d, IH, J^IO.5, 3.3 Hz), 5 4.30-4.40 (m, IH), 5 4.55 (d, IH, J=12.2
Hz), 5 4.60 (d, IH, J=12.2 Hz), 5 5.24 (d, IH, J=14.7 Hz), 5 5.28 (d, IH, J=14.7 Hz),
6 6.24 (d-d, IH, J-6.5, 3,3 Hz), 5 7.27-7.37 (m, lOH), 6 7.97 (s, IH), 5 8.14 (s, IH).
''C-NMR (CDCI3) : 5 26.43, 33.58, 49.43, 71.48, 73.90, 81.20, 85.78, 125.29,
128.20, 128.26, 128.41, 128.52, 128.91, 129.38, 136.55, 138.05, 138.83, 147.08,

147.16, 157.04. ESIMS m/z: 415 (M+H).
Example 4
Synthesis of 2',3'-dideoxyinosine (DDI)
To a N,N-dimethylformamide solution (l mL) of Ni,5'-0-dibenzyl-2',3'-dideoxyinosine (52 mg, 0.125 mmol), an aqueous solution of sodium hydroxide (0.3 mL) at a concentration of Imol/L was added, and the mixture was stirred at room temperature for 2 hours. To the obtained solution, 20% palladium hydroxide ~ carbon (10 mg) was added, and the mixture was stirred at room temperature for 2 hours in an atmosphere of hydi'ogen (l atm) and thereafter stirred at SOT) for 16 hours and at lOO^C for 6 hours. The palladium catalyst was removed from the obtained reaction mixture by filtration, and the resultant filtrate was concentrated under reduced pressure. After purification by chromatography (using 10 g of silica gel and a mixed solvent of dichloromethane and methanol (4-1) as an eluting solution), 21 mg of the intended product was obtained in a yield of 70% as a white soUd.
^H-NMR (DMSO-dg) : 5 2.00-2.07 (m, 2H), 5 2.31-2.53 (m, 2H), 6 3.52 (m, IH),
5 3.62 (m, IH), 5 4.11 (m, IH), 5 4.96 (m, IH), 5 6.21 (d-d, IH, J=6.8, 3.3 Hz), 5 8.05
(s, IH), 58.33 (s, IH). '^C-NMK (DMSO-ds) :525.77, 32.49, 62.96, 82.40, 84.80,
124.64, 138.54, 145.97, 147.94, 156.98. ESIMS m/z: 237 (M-^H).
Example 5
Synthesis of Ni,5'-0-di-p-methoxybenzyl-2',3'-bis-0-[(m6thylthio)thiocarbonyl] inosine
To a N,N-dimethylformamide solution (5 mL) of Ni,5'-0-di-p-methoxybenzyl
inosine (400 mg, 0.78 mmol) synthesized in accordance with a method described
in Luzzio, F. A. et al. J. Org. Chem., 1994, 59, 7267-7272, a 60% mineral oil

dispersion of sodium hydride (94 mg", 2.34 mmol) was added and the obtained mixture was stirred at room temperature for 2 hours, and thereafter carbon disulfide (0.48 mL, 7.88 mmol) was added thereto and the obtained mixture was stirred at room temperature for 12 hours. With the addition of methyl iodide (0.5 mL, 7.88 mmol), the obtained solution was stirred at room temperature for 3 hours. Then, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The resultant organic layer was washed with water, and thereafter dried over anhydi'ous magnesium sulfate and concentrated under reduced pressure. After purification by chromatography (using as eluting solutions a mixed solvent of hexane and ethyl acetate (l-l), a mixed solvent of hexane and ethyl acetate (3:7), and ethyl acetate successively in this order), 484 mg of the intended product was obtained in a yield of 82%. ^H NMR (CDCI3) ■ 5 2.50 (s, 6H), 5 2.89 (s, 2H), 5 2.96 (s, 2H), 8 3.80 (s, 6H), 6 4.69—4.87 (m, 3H), 6 5.71—5.81 (m, IH), 5 6.13 (m, IH), 5 6.29 (m, IH), 5 6.84-6.92 (m, 4H), 5 7.15-7.36 (m, 4H), 5 7.88 (s, IH), 5 8.04 (s, IH).
Example 6
Synthesis of NS5'-0-di-p-methoxybenzyl-2',3'-didehydro-2',3'-dideoxyiiiosine
To a 1,4-dioxane solution of N-ethyipiperidine hypophosphite (2.04 mL, 3.6 ramol) at a Concentration of 1.764 mol/L, a mixed solution of a tetrahydrofuran solution (3 mL) containing N^5'-0-di-p-methoxybenzyl-2',3'-bis-0-[(methylthio) thiocarbonyljinosine (250 mg, 0.36 mraol) and a trie thy lb or ane hexane solution (0.36 mL, 0.36 mmol) at a concentration of 1.0 mol/L was added, and the obtained mixture was stirred at room temperature for one hour. The obtained reaction

mixture was diluted with ethyl acetate. The resultant organic layer was washed with brine solution, and thereafter dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After purification by chromatogi'aphy (using as eluting solutions a mixed solvent of hexane and ethyl acetate (3:7), ethyl acetate, and a mixed solvent of dichloromethane and methanol (lO'-l) successively in this order), 169 mg of the intended product was obtained in a yield of 98%. ^H NMR (CDCI3) : 5 2.89 (s, 2H), 5 2.97 (s, 2H), 5 3.79 (s, 6H), 5 3.9 (m. 2H), 6 4.5X (m, IH), 5 4.87 (m, IH), 5 5.95 (m, IH), 5 6.81 (m, IH) 5 6.78—6.90 (m, 4H), 5 7.10— 7.39 (m, 4H), 5 7.99 (s, IH), 5 8.0l(s, IH).
Example 7
Synthesis of 2',3'-didehydro-2',3'-dideoxyinosine (D4I)
To an acetonitrile ■ water mixed (3^1) solution (5 mL) containing Ni,5'-0-di-p-methoxybenzyl-2',3'-didehydro-2',3'-dideoxyinosine (150 mg, 0.32 mmol), diammonium cerium (IV) nitrate (526 mg, 0.96 mmol) was added, and the obtained mixture was stirred at room temperature for 3 hours. The obtained reaction mixture was diluted with ethyl acetate. The resultant organic layer was washed with brine solution, and thereafter dried over anhydi-ous magnesium sulfate and concentrated under reduced pressure, whereby 75 mg of the intended product was obtained in a yield of 99%. ^H NMR (J)USO-ik) ■ 5 3.57 (m, 2H), 5 4.89 (m, lH),5 6.14(m, lH),5 6.48(m, lH),6 6.9l(m, IH), 5 8.08(3, IH), 5 8.1l(s, IH).
Example 8
Synthesis of 2',3'-bis-0-[(methylthio)thiocarbonyI]inosine

To an acetonitrile - water mixed (3-1) solution (4 mL) containing Ni,5*-0-di-p-raethoxyben2yl-2',3'-bis-0-[(methyltliio)thiocarboayl]inosine (151 mg, 0.22 mmoD, diammonium cerium (IV) nitrate (362 mg, 0.66 mmol) was added, and the obtained mixture was stirred at room temperature for 3 hours. The obtained reaction mixture was diluted with ethyl acetate. The resultant organic layer was washed with brine solution, and thereafter dried over anhydi'ous magnesium sulfate and concentrated under reduced pressure, whereby 99 mg of the intended product was obtained in a yield of 99%. 'H NMR (DMSO-de) ■ 8 2.50 (s, GH), 5 3.59 (m, 2H), 5 4.95 (m, IH), 5 5.18 (m, IH) 8 6.11 (m, iH), 5 6.25 (m, IH), 5 7.89 (s, IH), 5 8.04 (s, IH).
Example 9
Synthesis of 2',3'-bis-0-[(methylthio)thiocarbonyl]inosine
To a dichloromethane - water mixed (l8:i) solution (7.2 mL) containing Ni,5'-0-di-p-methoxybenzyl-2',3'-bis-0'[(methylthio)thiocarbonyl]inosiiie (l51 mg, 0.22 mmol), 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (150 mg, 0.66 mmol) was added, and the obtained mixture was stirred at room temperature for 3 hours. The obtained reaction mixture was diluted with ethyl acetate. The resultant organic layer was washed with brine solution, and thereafter dried over ) anhydrous magnesium sulfate and concentrated under reduced pressure. After purification by chromatogi-aphy (using as eiuting solutions mixed solvents of hexane and ethyl acetate at concentrations of 1-1, 37, and 2:8 successively in this order), 87 mg of the intended product was obtained in a yield of 88%.
5 Example 10
Synthesis of 2',3'-bis-0-[(methylthio)thiocarbonyl]inosine
To a tetrahydrofuran solution (lO mL) containing N^5'-0-di-p-methoxybenzyl-2',3'-bis-0-[(methylthio)thiocarbonyl]inosLQe (151 mg, 0.22 mmol), 10% palladium • carbon (23 mg) was added, and the obtained mixture was stirred

at room temperature for 2 days in an atmosphere of hydi'Og'en (l atm). The palladium catalyst was removed from the obtained reaction mixture by filtration, and the resultant filtrate was concentrated under reduced pressure. After purification by chromatogTaphy (Using as eluting solutions mixed solvents of hexane and ethyl acetate at concentrations of lU, 3-7, and 2:8 successively in this order), 42 mg of the intended product was obtained in a yield of 43%.
Example 11
Synthesis of 2',3'-didehydro-2'.3'-dideoxyinosine (D4I)
To a 1,4-dioxane solution containing N-ethylpiperidine hypophosphite (l.25 mL, 2.2 mmol) at a concentration of 1.764 mol/L, a mixed solution of a tetrahydrofuran solution (2 mL) of 2',3'-bis-0-[(methylthio)thiocarbonyl]inosine (99 mg, 0.22 mmol) and a triethylborane hexane solution (0.22 mL, 0.22 mmol) at a concentration of 1.0 mol/L was added, and the obtained mixture was stirred at room temperature for one hour. The obtained reaction mixture was diluted with ethyl acetate. The resultant organic layer was washed with brine solution, and thereafter dried over anhydi'ous magnesium sulfate and concentrated under reduced pressure. After purification by chromatogi-aphy (using as eluting solutions a mixed solvent of hexane and ethyl acetate (3^7), ethyl acetate, and a ) mixed solvent of dichloromethane and methanol (lO:i) successively in this order), 47 mg of the intended product was obtained in a yield of 92%.
According to the production methods of the present invention, DDI can
inexpensively be synthesized in satisfactory yields through the curtailed steps.
5 As a result, the value of the present invention can be enhanced because the
production of compounds useful as the anti-AIDS drugs can be achieved on
industrial scale.

kVE CLAIM :
1. A method for producing 2',3'-didehydro-2',3'-dideoxyinosine represented by general formula (4),

comprising the step of eliminating substituents RJ, by using as an agent for eliminating the substituents selected from the group consisting of diammonium cerium (IV) nitrate and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone in a solvent selected from the group consisting of a mixed solvent of acetonitrile and water, a mixed solvent of dichloromethane and water and tetrahydrofuran at a temperature of 0 to 100 °C for 0.1 to 10 hours, from an inosine derivative represented by general formula (1);

wherein Rl may be the same or different and are each benzyl group, benzhydryl group or trity! group, each of which may have a substituent in the general formula (I).
29

2. A method for producing 2',3'-didehydro-2',3'-dideoxyinosine represented by general formula (4),
0

HN

\^


HO
Ov

comprising the steps of:
subjecting an inosine derivative represented by general formula (3):
0

to dithiocarbonylation to obtain a compound of general formula (5);

0
Rl

X^/\^N
\^

N O'

R2--.^,^0 0-~-„.-'R2
S S
30 '^'

eliminating substituents Rl. by using as an agent for eliminating the substituents selected from the group consisting of diammonium cerium (IV) nitrate and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone in a solvent selected from the group consisting of a mixed solvent of acetonitrile and water, a mixed solvent of dichloromethane and water and tetrahydrofuran at a temperature of 0 to 100 "^C for 0.1 to 10 hours, from the compound represented by general formula (5) to obtain a compound of general formula (6):

S S
{6) 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
the general formula (3) and (5), and R2 are each an alkylthio group having
1 to 12 carbon atoms, an alkoxyl group having I to 12 carbon atoms or an
alkylamino group having 1 to 12 carbon atoms in the general formula (5)
and (6); and
subjecting the compound of general formula (6) to radical reduction.
3. The production method for 2',3'-didehydro-2',3'-dideoxyinosine according to Claim 2, wherein Rl are each benzyl group having as a substituent an
3!

alkoxyl group with 1 to 12 carbon atoms or unsubstituted benzyl group in the general formulas (3) and (5), and R2 are each an alkylthio group having 1 to 12 carbon atoms in the general formulas (5) and (6).
4. The production method for 2',3'-didehydro-2',3'-dideoxyinosine according
to Claim 2, wherein Rl are each benzyl group having as a substituent an
alkoxyl group with 1 to 12 carbon atoms in the general formulas (3) and
(5).
5. The production method for 2',3'-didehydro-2',3'-dideoxyinosine according to Claim 2, wherein Rl are each methoxybenzyl group in the general formulas (3) and (5).
6. The production method for 2'.3'-didehydro-2',3'-dideoxyinosine according to Claim 2, wherein Rl are each p-methoxybenzyl group in the general formulas (3) and (5), and R2 are each methylthio group in the general formulas (5) and (6).
7. A method for producing 2',3'-didehydro-2',3'-dideoxy!nosine represented
by general formula (4),

32
comprising the steps of:

subjecting an inosine derivative represented by general formula (3):


R1\^-^X^N.

to dithiocarbonylation to obtain a compound of general formula (5);

0
N

N
Rl-
N O'

N

R2--^,.,^0 0-^^,---R2
s s
(5)

(1)
33
subjecting the compound of general formula (5) to radical reduction to obtain an inosine derivative represented by general formula (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 in the general formula (1). (3) and (5), and R2 are each an aikyithio 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 in the general formula (5); and
eliminating substituents Rl, by using as an agent for eliminating the substituents selected from the group consisting of diammonium cerium (IV) nitrate and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone in a solvent selected from the group consisting of a mixed solvent of acetonitrile and water, a mixed solvent of dichloromethane and water and tetrahydrofiaran at a temperature of 0 to 100 ^'C for OT to 10 hours, from the inosine derivative of general formula (1).
8. The production method for 2',3'-d(dehydro-2',3'-dideoxyinosfne according to Claim 7, wherein Rl are each benzyl group having as a substituent an alkoxyl group with 1 to 12 carbon atoms or unsubstituted benzyl group in the general formulas (1), (3) and (5), and R2 are each an aikyithio group having 1 to 12 carbon atoms in the general formula (5).
9. The production method for 2',3'-didehydro-2',3'-dideoxyinosine according to Claim 7, wherein Rl are each benzyl group having as a substituent an alkoxyl group with 1 to 12 carbon atoms in the general formulas (1), (3) and (5).
10. The production method for 2',3'-didehydro-2',3'-dideoxyinosine according to Claim 7, wherein Rl are each methoxybenzyl group in the general formulas (1), (3) and (5).
34

11. The production method for 2',3'-didehydro-2',3'-dideoxyinosine according to Claim 7, wherein Rl are each p-methoxybenzyl group in the general formulas (I), (3) and (5), and R2 are each methylthio group in the general formula (5).