Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1999-03-08
2001-01-09
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06172224
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing nucleoside acid derivatives useful as antiviral agents. In particular, the invention relates to a process for preparing nucleoside derivatives by alkylating purine bases.
It is known that 2-amino-9-[(1′S,2′R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylpurine represented by the following formula (1) and 9-[(1′S,2′R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylguanine represented by the following formula (2) have a strong antiviral activity [Japanese Patent Unexamined Published Application (hereinafter referred to as “J. P. KOKAI”) Nos. Hei 5-78357 and Hei 6-227982].
It is also known that the compounds of the above formulae (1) and (2) are produced by alkylating protected purine bases to obtain corresponding purine bases alkylated at the N-7 position and N-9 position and purifying them by silica gel column chromatography and removing the protecting group (J. P. KOKAI Nos. Hei 6-80670 and Hei 7-316155.
It is generally known that in the preparation of the antiviral agents by the condensation reaction of a purine base and an alkylating agent, the alkylation reaction occurs at both N-7 position and N-9 position of the purine base as described above. Since the intended compound is usually the purine base substituted at the N-9 position, conventionally it was inevitable to isolate it by the column chromatography.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a process for preparing antiviral agents of the above general formulae (1) and (2) having a satisfactory medicinal quality on an industrial scale without necessitating complicated operations such as chromatographic purification.
This and other objects of the present invention will be apparent from the following description and Examples.
After intensive investigations made for the purpose of solving the above-described problems, the inventors have found that an intended compound (5) substituted at the N-9 position and having a high purity can be obtained in the preparation of 2-amino-9-[(1′S, 2′R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl] methylpurine (1) or 2-amino-9-[(1′S, 2R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl] methylguanine (2), by condensing 2-amino-6-chloropurine (as a purine base) with a compound, obtained by substituting hydroxyl group of (3-oxa-2-oxobicyclo [3.1.0]hexane-1-yl)methanol (as an alkylating agent) with a leaving group, to obtain 2-amino-6-chloro-9-[(1′S,2′R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylpurine represented by the following formula (3) and an isomer thereof at the N-7 position, i.e. 2-amino-6-chloro-7-[(1′S,2′R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylpurine represented by the following formula (4) which is a by-product, and without separating them from each other by the silica gel column chromatography, subjecting a mixture of 2-amino-6-chloro-9-[(1′S,2′R)-1′,2′-bis(hydroxymethyl) cyclopropane-1′-yl]methylpurine represented by the following formula (5) and 2-amino-6-chloro-7-[(1′S,2′R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylpurine represented by the following formula (6) obtained by reducing the lactone parts of the compounds represented by the following formulae (3) and (4) to the crystallization from water or isopropanol to precipitate only the intended isomer at the N-9 position in the form of crystals, and isolating it. The inventors have also found that the obtained compound can be subjected to the hydrogenolysis to obtain a compound of formula (1) or chlorine group at the 6-position of the nucleic acid base can be hydrolyzed to obtain a compound of formula (2). The present invention has been completed on the basis of these findings.
Namely, the present invention provides a process for purifying 2-amino-6-chloro-9-[(1′S,2′R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylpurine represented by the following formula (5), which comprises the step of selectively isolating 2-amino-6-chloro-9-[(1′S,2′R)-1′, 2′-bis(hydroxymethyl)cyclopropane-1′-yl] methylpurine from a mixture of 2-amino-6-chloro-9-[(1′S,2′R)-1′,2′-bis(hydroxymethyl) cyclopropane-1′-yl]methylpurine and 2-amino-6-chloro-7-[(1′S,2′R)-1′,2′-bis (hydroxymethyl)cyclopropane-1′-yl]methylpurine represented by the following formula (6) by the crystallization:
The purification can be efficiently conducted by using water or isopropyl alcohol as the solvent in the crystallization.
The present invention also provides 2-amino-6-chloro-9-[(1′S,2′R)-1′, 2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylpurine (5) represented by the following formula (5) which is an important intermediate for the preparation of 2-amino-9-[(1′S,2′R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylpurine (1) or 2-amino-9-[(1′S,2′R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylguanine (2).
The present invention is also effective for the purification of a mixture of optical isomers of compounds (5) and (6). Namely, the present invention provides a process for purifying 2-amino-6-chloro-9-[(1′R,2′S)-1′,2′-bis(hydroxymethyl) cyclopropane-1′-yl]methylpurine, which comprises the steps of selectively isolating 2- amino-6-chloro-9-[(1′R,2′S)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylpurine from a mixture of 2-amino-6-chloro-9-[(1′R,2′S)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylpurine and 2-amino-6-chloro-7-[(1′R,2′S)-1′,2′-bis(hydroxymethyl) cyclopropane-1′-yl]methylpurine by the crystallization. Also in this process, the purification can be efficiently conducted by using water or isopropyl alcohol as the solvent.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The mixture of 2-amino-6-chloro-9-[(1′S,2′R)-1′,2′-bis(hydroxymethyl) cyclopropane-1′-yl]methylpurine (5) and 2-amino-6-chloro-7-[(1′S,2′R)-1′,2′-bis (hydroxymethyl)cyclopropane-1′-yl]methylpurine (6) is obtained by reducing lactone parts of a mixture of 2-amino-6-chloro-9-(3′-oxa-2′-oxobicyclo[3.1.0]hexane-1′-yl)methylpurine (3) and 2-amino-6-chloro-7-(3′-oxa-2′-oxobicydo[3.1.0]hexane-1′-yl)methylpurine (4), obtained by reacting 2-amino-6-chloropurine with a compound obtained by introducing a leaving group into a hydroxyl group of (3-oxa-2-oxobicydo[3.1.0]hexane-1-yl)methanol.
In particular, the intended mixture of 2-amino-6-chloro-9-[(1′S,2′R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylpurine (5) and 2-amino-6-chloro-7-[(1′S,2′R)-1′,2′-bis(hydroxymethyl)cyclopropane-1′-yl]methylpurine (6) can be obtained by reacting 2-amino-6-chloropurine with a compound obtained by introducing a leaving group into a hydroxyl group of a (3-oxa-2-oxobicydo[3.1.0]hexane-1-yl)methanol such as (3-oxa-2-oxobicydo[3.1.0]hexane-1-yl)methylmethanesulfonate in the presence of a base such as potassium carbonate in a solvent such as N,N-dimethylformamide, removing insoluble matters such as potassium carbonate by the filtration, concentrating the filtrate, adding an excess amount of ethanol to the concentrate to precipitate crystals, thereby obtaining a mixture of the condensation product substituted at the N-9 position and that substituted at the N-7 position (J. P.
Kataoka Noriyasu
Matsuzawa Toshihiro
Yatagai Masanobu
Ajinomoto Co. Inc.
Berch Mark L.
McKenzie Thomas
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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