U.S. patent application number 10/210083 was filed with the patent office on 2003-01-02 for methods for producing nucleoside derivatives and intermediates therefor.
This patent application is currently assigned to AJINOMOTO CO. INC. Invention is credited to Hirose, Naoko, Izawa, Kunisuke, Katayama, Satoshi, Maruyama, Tokumi, Takamatsu, Satoshi.
Application Number | 20030004330 10/210083 |
Document ID | / |
Family ID | 13935271 |
Filed Date | 2003-01-02 |
United States Patent
Application |
20030004330 |
Kind Code |
A1 |
Takamatsu, Satoshi ; et
al. |
January 2, 2003 |
Methods for producing nucleoside derivatives and intermediates
therefor
Abstract
Novel intermediates of nucleoside derivatives, of which the
6-position of the nucleic acid base moiety is substituted with a
halogen atom, are produced. Using those novel intermediates, even
substrates, of which the 3'-position of the saccharide moiety is
deoxylated, can be substituted at the 2'-position at an extremely
high yield. Specifically, by subjecting a 3'-deoxy derivative of
inosine to 6-halogenation to give a 6-halide of the derivative, and
then subjecting it to 2'-deoxylation/substitution with a fluorine
atom or the like, followed by further subjecting it to substitution
with an amino group, a hydroxyl group or any other intended
substituent at the 6-positioned halogen atom, nucleoside
derivatives are produced at a high yield. Methods for producing
nucleoside derivatives including
9-(2,3-dideoxy-2-fluoro-.beta.-D-threo-pentofuranosyl)adenine
(FddA) and their related compounds, in a simplified manner, at a
high yield and at low costs, and especially Economical methods for
substituting substrates, of which the 3'-position of the saccharide
moiety is deoxylated, at the 2'-position to produce those
nucleoside derivatives on an industrial scale are also
provided.
Inventors: |
Takamatsu, Satoshi;
(Kawasaki-shi, JP) ; Katayama, Satoshi;
(Kawasaki-shi, JP) ; Hirose, Naoko; (Kawasaki-shi,
JP) ; Izawa, Kunisuke; (Kawasaki-shi, JP) ;
Maruyama, Tokumi; (Tokushima-shi, JP) |
Correspondence
Address: |
OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC
FOURTH FLOOR
1755 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Assignee: |
AJINOMOTO CO. INC
Tokyo
JP
|
Family ID: |
13935271 |
Appl. No.: |
10/210083 |
Filed: |
August 2, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10210083 |
Aug 2, 2002 |
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09567980 |
May 10, 2000 |
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09567980 |
May 10, 2000 |
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09267789 |
Mar 15, 1999 |
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6090937 |
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Current U.S.
Class: |
536/27.14 ;
536/27.21; 544/277 |
Current CPC
Class: |
C07H 19/16 20130101;
C07D 473/00 20130101 |
Class at
Publication: |
536/27.14 ;
536/27.21; 544/277 |
International
Class: |
C07H 019/16; C07H
019/22; C07D 473/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 17, 1998 |
JP |
10-088163 |
Claims
What is claimed is:
1. A method for producing a nucleoside derivative represented by
the following general formula (8) or (9), which comprises
subjecting a 3'-deoxy derivative of inosine to 6-halogenation step
to give a 6-halide of the derivative, and then subjecting it to
2'-deoxylation/Y-substitutio- n reaction step followed by further
subjecting it to Z-substitution reaction at its 6-halogen atom:
6wherein Y represents a substituent of any one of a fluorine atom,
an azido group and a cyano group; Z represents any one of a
hydrogen atom, an amino group, a hydroxyl group, an azido group, a
substituent of a formula OR.sup.4, a substituent of a formula
SR.sup.4 and a substituent of a formula NHR.sup.4; R.sup.1
represents a protective group for the hydroxyl group; and
R.sup.4represents a lower alkyl group which may or may not be
optionally substituted with one or more phenyl groups.
2. A method for producing a nucleoside derivative represented by
the following general formula (8) or (8'), which comprises
subjecting a compound represented by the following general formula
(1) to 2'-deoxylation/Y-substitution reaction step to give a
compound represented by the following general formula (3); and then
subjecting the resulting compound to substitution with a group Z at
its 6-halogen atom to give the compound (8), or subjecting the
resulting compound (3) to the deprotecting reaction to remove the
protective group R.sup.1 therefrom to give the compound (8'):
7wherein X represents a halogen atom; Y represents a substituent of
any one of a fluorine atom, an azido group and a cyano group; Z
represents any one of a hydrogen atom, an amino group, a hydroxyl
group, an azido group, a substituent of a formula OR.sup.4, a
substituent of a formula SR.sup.4 and a substituent of a formula
NHR.sup.4; R.sup.1 represents a protective group for the hydroxyl
group; and R.sup.4 represents a lower alkyl group which may or may
not be optionally substituted with one or more phenyl groups.
3. The method as claimed in the claim 2, wherein said reaction step
includes a compound represented by the following formula (2) as the
intermediate: 8wherein X represents a halogen atom; R.sup.1
represents a protective group for the hydroxyl group; and
SO.sub.2R.sup.2represents a sulfonic acid-type leaving group.
4. The method as claimed in the claim 1 or 2, wherein said
Y-substitution reaction step is a substitution reaction step with a
fluorine atom.
5. The method as claimed in the claim 1 or 2, wherein the group Z
is an amino group.
6. The method as claimed in the claim 1 or 2, which additionally
comprises deprotecting the product (8) to remove the protective
group R.sup.1 therefrom; or subjecting the compound (8') to
substitution with a group Z at its 6-halogen atom, to give a
compound represented by the following general formula (9): 9wherein
Y represents a substituent of any one of a fluorine atom, an azido
group and a cyano group; Z represents any one of a hydrogen atom,
an amino group, a hydroxyl group, an azido group, a substituent of
a formula OR.sup.4, a substituent of a formula SR.sup.4 and a
substituent of a formula NHR.sup.4; and R.sup.4 represents a lower
alkyl group which may or may not be optionally substituted with one
or more phenyl groups.
7. A method for producing a compound represented by the following
general formula (3), which comprise; (a) subjecting a compound
represented by the following general formula (1) to
2'-deoxylation/Y-substitution reaction step, or (b) subjecting a
compound represented by the following general formula (2) to
removal of leaving group/Y-substitution reaction step: 10wherein X
represents a halogen atom; Y represents any one of a fluorine atom,
an azido group and a cyano group; R.sup.1 represents a protective
group for the hydroxyl group; and SO.sub.2R.sup.2represents a
sulfonic acid-type leaving group.
8. The method as claimed in the claim 7, wherein said compound
represented by the formula (2) is prepared by subjecting said
compound represented by formula (1) to a reaction step for
inserting a sulfonic acid-type leaving group thereinto.
9. The method as claimed in the claim 1 or 2, which comprises at
least one of the following steps (A) to (E): (A): the method of the
claim 7, (B): a step of dehalogenating a compound represented by
the following general formula (7) to give a compound represented by
the following general formula (4), (C): a step of reacting a
compound represented by the following general formula (6) with a
reagent for selectively protecting the 5'-position of said compound
to give a compound represented by the following general formula
(1), (D): a step of subjecting a compound represented by the
following general formula (1) to reaction of inserting a sulfonic
acid-type leaving group thereinto to give a compound represented by
the following general formula (2), and (E): a step of selectively
halogenating a compound represented by the following general
formula (4) at its 6-position with a halogenating agent to give a
compound represented by the following general formula (5):
11wherein W represents a halogen atom; X represents a halogen atom;
R.sup.1 represents a protective group for the hydroxyl group;
SO.sub.2R.sup.2represents a sulfonic acid-type leaving group;
R.sup.3 represents a protective group for the hydroxyl group; Y
represents a substituent of any one of a fluorine atom, an azido
group and a cyano group; Z represents any one of a hydrogen atom,
an amino group, a hydroxyl group, an azido group, a substituent of
a formula OR.sup.4, a substituent of a formula SR.sup.4 and a
substitutent of a formula NHR.sup.4; R.sup.1 represents a
protective group for the hydroxyl group; and R.sup.4represents a
lower alkyl group which may or may not be optionally substituted
with one or more phenyl groups.
10. An intermediate represented by any one in the following general
formulae (4), (1) and (2): 12wherein X represents a halogen atom; Y
represents a substituent of any one of a fluorine atom, an azido
group and a cyano group; R.sup.1 represents a protective group for
the hydroxyl group; SO.sub.2R.sup.2 represents a sulfonic acid-type
leaving group; and R.sup.3 represents a protective group for the
hydroxyl group.
11. A method for producing nucleoside derivative represented by the
following general formula (8) (8') or (9), in which is used any one
of the intermediates in the claim 10 in their production: 13wherein
Y represents a substituent of any one of a fluorine atom, an azido
group and a cyano group; Z represents any one of a hydrogen atom,
an amino group, a hydroxyl group, an azido group, a substitutent of
a formula OR.sup.4, a substituent of a formula SR.sup.4 and a
substitutent of a formula NHR.sup.4; R.sup.1 represents a
protective group for the hydroxyl group; and R.sup.4 represents a
lower alkyl group which may or may not be optionally substituted
with one or more phenyl groups.
12. The method as claimed in the claim 9, wherein said reaction of
inserting a sulfonic acid-type leaving group into the compound
comprises reacting the compound with a sulfonyl halide or a
sulfonic acid anhydride, or reacting the compound with sulfuryl
chloride and then with an amine or a halogen.
13. The method as claimed in the claim 7, wherein the reagent for
said 2'deoxylation/Y-substitution reaction is an alkylaminosulfur
trifluoride reagent or a fluoroalkylamine reagent, and the reagent
for said removal of leaving group/Y-substitution reaction is any
one of azides, cyanides and fluorides.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a novel method for
producing nucleoside derivatives, more precisely to a novel method
for producing nucleoside derivatives including
9-(2,3-dideoxy-2-fluoro-.beta.-D-threo-p- entofuranosyl)adenine
(hereinafter referred to as "FddA") and its related compounds which
are useful as anti-viral agents, to novel intermediates in the
method, and to a novel method for producing the intermediates.
[0003] 2. Description of the Related Art
[0004] It is reported that
9-(2,3-dideoxy-2-fluoro-.beta.-D-threo-pentofur- anosyl)adenine
(FddA) has a strong anti-viral activity against human
immunodeficiency virus (HIV) and is greatly effective for treatment
of acquired immune deficiency syndrome (AIDS) (see V. E. Marquetz,
et al., Biochem. Pharmacol., (36) page 2719, 1987; P. Herdewijn, et
al., J. Med. Chem., (30), page 2131, 1987), and many clinical tests
using it for the treatment of AIDS and AIDS-related complications
(ARC) are being made at present. Recently, in addition, reported
are FddA derivatives as modified at the nucleic acid base site to
improve their potency (see C. K. Chu, et al., J. Med. Chem., (37),
page 821,1994; J. S. Driscoll, et al., J. Med. Chem., (39), page
1619, 1996; C. K. Chu, et al., J. Med. Chem., (39), page 4676,
1996).
[0005] The most direct method for producing FddA and its related
compounds comprises substituting a substrate, of which the
3'-position in the saccharide moiety is deoxylated, at its
2'-position (see P. Herdewijn, et al., J. Med. Chem., (30), page
2131, 1987; V. E. Marquez, et al., J. Med. Chem., (33), page 978,
1990; H. Shiragami, et al., Nucleosides & Nucleotides, (11),
page 391, 1992). However, the yield in the conventional methods is
extremely low or is not higher than 10% and the reagent,
diethylaminosulfer trifuluoride (DAST), is not available in
industrial amount, and therefore the methods could not be used for
industrial production of FddA and its related compounds.
[0006] 1. Problems to be Solved by the Invention
[0007] In the course of the completion to the present invention,
the above and following problems in the related art have been also
found by the present inventors.
[0008] Given the situation as above, it is desired to develop an
inexpensive method for producing nucleoside derivatives including
9-(2,3-dideoxy-2-fluoro-.beta.-D-threo-pentofuranosyl)adenine
(FddA) and its related compounds, in a simplified manner and at a
high yield, in particular, an economical and industrial method for
producing those nucleoside derivatives that comprises substituting
a substrate, of which the 3'-position of the saccharide moiety is
deoxylated, at its 2'-position at a high yield. Accordingly, the
subject matter in the art is to provide such an excellent
production method.
[0009] The object of the present invention is to develop an
advantageous method for producing the nucleoside derivatives noted
above, especially those having anti-viral activity, and to provide
intermediates in the method and also a simple method for producing
the intermediates.
SUMMARY OF THE INVENTION
[0010] We, the present inventors have assiduously studied in order
to solve the problems noted above, and, as a result, have found, in
a process for producing nucleoside derivatives including
9-(2,3-dideoxy-2-fluoro-.beta.-D-threo-pentofuranosyl)adenine
(FddA) and its related compounds, by subjecting a 3'-deoxy
derivative of adenine to 2'-deoxylation/substitution with a flurine
atom or the like (see P. herdewijn, et al., J. Med. Chem.,(30),
page 2131, 1987; V. E. Marquez, et al., J. Med. Chem., (33), page
978, 1990; H. Shiragami, et al., Nucleosides & Nucleotides,
(11), page 391, 1992), the yield thereof is extremely low mainly
due to a rearrangement of adenine base.
[0011] It is reported that, by subjecting a derivative of adenine,
of which the 3'-position is not deoxylated, to
2'-deoxylation/substitution with a fluorine atom or the like, the
same kind of rearrangement has occurred as side reaction and
lowered the yield (see K. A. Watanabe, et al., J. Org. Chem., (57),
page 553, 1992). Furthermore, it is reported that, by chlorination
at the 6-position of the nucleic acid, this kind of rearrangement
can be suppressed (see T. Maruyama, et al., Chem. Pharm. Bull.,
(44), page 2331, 1996). However, it is not known the case of
3'-deoxy derivatives.
[0012] Therefore, we, the present inventors have produced novel
intermediates of a general formula (1) mentioned below, which are
derivatives as deoxylated at the 3'-position and substituted by a
halogen atom at the 6-position of the nucleic acid. Using those
novel intermediates, we have found that even substrates, of which
the 3'-position of the nucleic acid is deoxylated, can suppress the
troblesome rearrangement completely and can be substituted at the
2'-position at an extremely high yield. On the basis of these
findings, we have completed the present invention.
[0013] Specifically, by subjecting a 3'-deoxy derivative of inosine
to 6-halogenation step for halogenating it at the 6-position
thereof to give a 6-halide of the derivative, and then subjecting
it to 2'-deoxylation/substitution with a fluorine atom or the like,
followed by further subjecting it to substitution with an amino
group, a hydroxyl group or any other intended substituent at the
6-positioned halogen atom, we have made it possible to produce the
intended nucleoside derivatives.
[0014] On the basis of our findings noted above, hereinunder
illustrated is one embodiment of the production route to give
nucleoside derivatives, which covers all the steps in series as
concretely demonstrated in Examples to be mentioned hereinafter.
All those steps and the compounds as produced therein are usable in
the process of producing nucleoside derivatives of the present
invention. Naturally, the invention encompasses not only all the
steps constituting this production route but also any and every
method comprising any one of those steps, novel intermediates as
produced in those steps and even the use of those novel
intermediates, especially the use thereof for producing various
nucleoside derivatives.
[0015] Production Route: 1
[0016] In those formulae, W represents a halogen atom, X represents
a halogen atom, Y represents a substituent of any of a fluorine
atom, an azido group or a cyano group, Z represents any one of a
hydrogen atom, an amino group, a hydroxyl group, an azido group, a
substituent of a formula OR.sup.4, a substituent of a formula
SR.sup.4 and a substituent of a formula NHR.sup.4, R.sup.1
represents a protective group for the hydroxyl group,
SO.sub.2R.sup.2represents a sulfonic acid-type leaving group,
R.sup.3represents a protective group for the hydroxyl group, and
R.sup.4 represents an optionally phenyl-substituted, lower (e.g.,
C1-5) alkyl group.
[0017] Preferably, R.sup.2 represents a halogen atom, an
optionally-substituted aryl, alkyl or aralkyl group, or an
optionally-substituted alkylamino group.
[0018] Regarding the definitions and the meanings of the compounds
of general formula (1) to (9) as referred to herein, it shall be
understood that the compounds designated by the same formula number
are the same ones even though they are not individually described
herein.
[0019] The invention encompasses a novel method for producing the
nucleoside derivatives mentioned herein from the novel
intermediates (1) and also from various raw compounds, novel
intermediates including the intermediates (1) which are for
producing the nucleotide derivatives, a novel method for producing
those intermediates, and the use of the intermediates. More
precisely, the present invention encompasses the following
matters.
[0020] (i) A method for producing a nucleoside derivative
represented by the following general formula (8) or (9), comprising
subjecting a 3'-deoxy derivative of inosine, of which a part or all
of the two hydroxyl groups may or may not be optionally protected,
to 6-halogenation step for halogenating the compound at the
6-position thereof to give a 6-halide of the derivative, and then
subjecting it, optionally after protecting its 5'-position, to
2'-deoxylation/Y-substitution reaction step followed by further
subjecting it to Z-substitution reaction at its 6-halogen atom:
2
[0021] In the case of optionally protected 5'-position with a
protective group in the derivative, the protective group may be
de-protected in the suitable step, for example, before or after the
Z-substitution reaction at its 6-halogen atom.
[0022] In such formula, as so mentioned hereinabove, Y represents a
substituent of any one of a fluorine atom, an azido group and a
cyano group, Z represents any one of a hydrogen atom, an amino
group, a hydroxyl group, an azido group, a substituent of a formula
OR.sup.4, a substituent of a formula SR.sup.4 and a substituent of
a formula NHR.sup.4, R.sup.1 represents a protective group for the
hydroxyl group, and R.sup.4 represents an optionally
phenyl-substituted, lower (e.g., C1-5) alkyl group.
[0023] The compound (8) obtained herein may be optionally subjected
to deprotection at the 5'-position to convert them into
5'-deprotected derivative (9), as will be mentioned after.
[0024] On the other hand, the obtained compound (8') mentioned
after may be optionally subjected to substitution with a group Z at
its 6-halogen atom to give such derivative (9), as will be also
mentioned after.
[0025] The nucleoside derivatives, compounds (9) in the present
invention have anti-viral activity, in which Z is preferably a
hydrogen atom, an amino group, a hydroxyl group, an azido group, a
methylamino group, a methyloxy group or the like.
[0026] (ii) A method for producing a nucleoside derivative
represented by the general formula (8) or (8') noted above, which
comprises subjecting a compound represented by the following
general formula (1) to 2'-deoxylation/Y-substitution reaction to
give a compound represented by the following general formula
(3);
[0027] and then subjecting the resulting compound (3) to
substitution with a group Z at its 6-halogen atom to give the
compound (8),
[0028] or subjecting the compound (3) to deprotection at the
5'-position to convert the same into 5'-deprotected derivative
(8').
[0029] One embodiment of the method comprises a step of processing
the compound of formula (3), especially preferably that in which X
is a chlorine atom and Y is a fluorine atom, to thereby substitute
the substituent X with an amino group, preferably processing it in
a solution of ammonia in an alcohol (e.g., methanol, ethanol,
propanol, etc.), or a step of processing the compound to thereby
substitute the substituent X with a hydroxyl group, preferably
processing it in an aqueous solution of an alkali hydroxide (e.g.,
sodium hydroxide, potassium hydroxide, etc.), or a step of
processing the compound to thereby substitute the substituent X
with a hydrogen atom, preferably processing it with hydrogen in the
presence of a reduction catalyst (e.g., palladium-carbon, Raney
nickel, etc.), or a step of processing the compound to thereby
substitute the substituent X with an azido group, preferably
processing it with an alkalimetal azide (e.g., sodium azide,
lithium azide, etc.), to thereby produceng the nucleoside
derivative of formula (8), and optionally comprises a step of
deprotecting the resulting derivative at the protective group
R.sup.1 to obtain a nucleoside derivative represented by the
following general formula (9).
[0030] Alternatively, the compound firstly (3) may be subjected to
such above deprotecting step at the protective group R.sup.1 to
give the derivative (8'), and then the obtained this derivative
(8') may be subjected to substitution with a group Z at its
6-halogen atom to give the compound (9) in the same manner as
above. 3
[0031] In those above formulae, as so mentioned hereinabove, X
represents a halogen atom, Y represents a substituent of any one of
a fluorine atom, an azido group and a cyano group, Z represents any
one of a hydrogen atom, an amino group, a hydroxyl group, an azido
group, a substituent of a formula OR.sup.4, a substituent of a
formula SR.sup.4 and a substituent of a formula NHR.sup.4, R.sup.1
represents a protective group for the hydroxyl group, and R.sup.4
represents an optionally phenyl-substituted, lower (e.g., C1-5)
alkyl group.
[0032] (iii) One embodiment of the method of (ii), wherein the
reaction step includes a compound of the following formula (2) as
the intermediate: 4
[0033] In this formula, as so mentioned hereinabove, X represents a
halogen atom, R.sup.1 represents a protective group for the
hydroxyl group, and SO.sub.2R.sup.2 represents a sulfonic acid-type
leaving group.
[0034] (iv) A method for producing compounds of formula (3) noted
above, which comprise;
[0035] (a) subjecting a compound of formula (1) noted above to
2'-deoxylation/Y-substitution reaction step, preferably for
removing the hydroxyl group from the compound followed by
introducing a substituent Y, a fluorine atom, an azido group or a
cyano group, thereinto, more preferably by reacting the compound
with an alkylaminosulfur trifluoride reagent or a fluoroalkylamine
reagent, or
[0036] (b) subjecting a compound of formula (2) noted above to
removal of 2'-leaving group/Y-substitution reaction step, or that
is, processing the compound to thereby remove its O-sulfonic
acid-type leaving group therefrom and introduce a substitutent Y, a
fluorine atom, an azido group or a cyano group, thereinto,
preferably by reacting the compound with a reagent for attaining
the substitution with a fluorine atom, an azido group or a cyano
group, for example, reacting it with any one of azides, cyanides
and fluorides, to thereby produce the intended compound (3).
[0037] In the meantime, the removal of 2'-leaving group in the
present invention, the sulfonic acid-type leaving group is removed
in the form of the O-sulfonic acid-type leaving group.
[0038] In these formulae, as so mentioned hereinabove, X represents
a halogen atom, Y represents any one of a fluorine atom, an azido
group and a cyano group, R.sup.1 represents a protective group for
the hydroxyl group, and SO.sub.2R.sup.2 represents a sulfonic
acid-type leaving group. Preferably, R.sup.2 represents a
substituent of any one of a halogen atom, an aryl, alkyl and
aralkyl group and also an alkylamino group, which may be optionally
substituted (for example, with a halogen atom, etc.).
[0039] (v) Novel compounds of formulae (1) and (2) noted above,
which are intermediates in the above-mentioned methods.
[0040] In those, X, Y, R.sup.1 and SO.sub.2R.sup.2 have the same
meanings as defined above.
[0041] (vi) One embodiment of the method (iv), in which the
compound of formula (2) is prepared by reacting a compound of
formula (1) noted above with a reagent for inserting a sulfonic
acid-type leaving group thereinto, preferably by reacting it with a
sulfonyl halide or a sulfonic acid anhydride, or reacting it with
sulfuryl chloride and then with an amine or a halogens such as a
fluorine or the like.
[0042] (vii) One embodiment of the method (i) or (ii), which
comprises at least one of the following steps (A) to (E):
[0043] (A): a step of forming a compound of formula (3) according
to the step (a) or (b) in the method (iv) noted above,
[0044] (B): a step of dehalogenating a compound represented by the
following general formula (7) to give a compound represented by the
following general formula (4),
[0045] (C): a step of reacting a compound represented by the
following general formula (6) with a reagent for selectively
protecting the 5'-position of the compound to give a compound of
formula (1) noted above,
[0046] (D): a step of subjecting a compound of formula (1) noted
above to reaction of inserting a sulfonic acid-type leaving group
thereinto, preferably by reacting the compound with a sulfonyl
halide or a sulfonic acid anhydride, or reacting it with sulfuryl
chloride and then with an amine or a halogen such as a fluorine or
the like, to give a compound of the following general formula (2),
and
[0047] (E): a step of selectively halogenating a compound of the
following general formula (4) at its 6-position with a halogenating
agent to give a compound represented by the following general
formula (5). 5
[0048] In those above formulae, as so mentioned hereinabove, X
represents a halogen atom, Y represents a substituent of any one of
a fluorine atom, an azido group and a cyano group, R.sup.1
represents a protective group for the hydroxyl group,
SO.sub.2R.sup.2 represents a sulfonic acid-type leaving group, in
which R.sup.2 is preferably a substituent of any of a halogen atom,
and an aryl, alkyl or aralkyl group which may be optionally
substituted (for example, with a halogen atom, etc.), and an
alkylamino group which may be optionally substituted (for example,
with a halogen atom, etc.), and R.sup.3 represents a protective
group for the hydroxyl group.
[0049] (viii) Novel compounds of formula (4) noted above, which are
intermediates in the above-mentioned methods.
[0050] As so mentioned hereinabove, R.sup.3 represents a protective
group for the hydroxyl group.
[0051] (ix) A method for producing intermediates, which comprises
at least any one of the steps (B) to (E).
[0052] This method for producing intermediates is usable in the
method (vii) noted above. Apart from this, the method is also
applicable to the production of other various useful compounds, as
being simple and easy. Anyhow, this method is an excellent method
for producing various intermediates.
[0053] In those formulae, as so mentioned hereinabove, X represents
a halogen atom, Y represents a substituent of any one of a fluorine
atom, an azido group and a cyano group, R.sup.1 represents a
protective group for the hydroxyl group, SO.sub.2R.sup.2 represents
a sulfonic acid-type leaving group, in which R.sup.2 is preferably
a substituent of any one of a halogen atom, and an aryl, alkyl or
aralkyl group which may be optionally substituted (for example,
with a halogen atom, etc.), and also an alkylamino group which may
be optionally substituted (for example, with a halogen atom, etc.),
and R.sup.3 represents a protective group for the hydroxyl
group.
[0054] (x) Another embodiment of the method (i) or (ii) for
producing nucleoside derivatives of the above-mentioned compounds
(8), (8') or (9), in which is used any one in the intermediates
covered in the (viii) noted above.
[0055] In this, as so mentioned hereinabove, X represents a halogen
atom, Y represents a substituent of any one of a fluorine atom, an
azido group and a cyano group, R.sup.1 represents a protective
group for the hydroxyl group, SO.sub.2R.sup.2 represents a sulfonic
acid-type leaving group such as that mentioned above, in which
R.sup.2 is preferably a substituent of any one of a halogen atom,
and an aryl, alkyl or aralkyl group which may be optionally
substituted (for example, with a halogen atom, etc.), and also an
alkylamino group which may be optionally substituted (for example,
with a halogen atom, etc.), and R.sup.3 represents a protective
group for the hydroxyl group.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0056] Modes of carrying out the invention are described below.
[0057] Compounds of formula (7) noted above, such as typically
9-(2,5-di-O-acetyl-3-bromo-3-deoxy-.beta.-D-xylofuranosyl)adenine,
which are used in the invention, can be produced with ease in
accordance with known methods (for example, see J. G. Moffatt, et
al., J. Am. Chem. Soc., (95), page 4025, 1973). The substituent W
is a halogen atom such as bromine.
[0058] The hydroxyl-protecting group, R.sup.3 includes, for
example, an acyl group (having from 1 to 10 carbon atoms), such as
acetyl or benzoyl; an aralkyl group such as benzyl; and an alkyl
group (having from 1 to 5 carbon atoms), such as allyl.
[0059] Compounds of formula (4) noted above for use in the
invention can be obtained by de-halogenating the compounds of
formula (7). To de-halogenate them, employable is any per-se known
de-halogenating method, but preferred is a method of reducing the
compound (7) with a radical reaction reagent, such as tri-n-butyl
tin hydride, tris(trimethylsilyl)silane, diphenylsilane or
diphenylmethylsilane in the presence of a radical reaction
initiator such as azobisisobutyronitrile; or a method of reducing
it with hydrogen in the presence of a reduction catalyst such as
palladium-carbon or Raney nickel.
[0060] The compounds of formula (4) for use in the invention can
also be obtained in any per-se known method (for example, a method
for producing them from compounds of formula (7), such as that
described by H. Shiragami et al., in Nucleosides & Nucleotides,
(15), page 31, 1996). For example, 3'-deoxyinosine is prepared and
any hydroxyl groups of the compound are protected to give the
intended compound (4).
[0061] Compounds of formula (5) noted above for use in the
invention have a halogen atom (e.g., chlorine) at the 6-position,
and these are preferably obtained by halogenating a compound of
formula (4) selectively at its 6-position with a halogenating
agent. The halogenating agent includes, for example, a chlorinating
agent of a combination of phosphorus oxychloride and
N,N-dimethylaniline or a combination of sulfuryl chloride and
dimethylformamide, and a chlorinating agent of
dimethylchloromethyleneammonium chloride.
[0062] Compounds of formula (6) noted above for use in the
invention can be obtained by de-protecting the compounds of formula
(5). For the de-protection, preferably used is a mild method that
may have no influence on the 6-halogen atom of the compounds (5).
For example, compounds of formula (5) wherein X is a chlorine atom
and R.sup.3 is an acyl group, can be easily de-protected with
ammonia or sodium methoxide as dissolved in an alcohol, such as
methanol, without being influenced at the chlorine atom.
[0063] Compounds of formulae (5) and (6) noted above for use in the
invention may be produced in per-se known methods (for example, see
C. K. Chu et al., WO-9709052 (1997); Frederick William Hurry et
al., Japanese Patent Kokoku Publication JP-B-42-17903), or that is,
by coupling the nucleic acid base moiety and the saccharide moiety.
In general, however, the known methods produce mixtures with
unnecessary .alpha.-anomers, and therefore indispensably require
the separation of the intended products from the mixtures. In
addition, the yield of the intended products to be produced in the
known methods is low. Therefore, the method of the invention that
uses compounds (4) is preferred, as being easy and economical in
industrial production of the compounds (5) and (6). The invention
encompasses those compounds (4).
[0064] Compounds of formula (1) noted above, which the invention
encompasses, can be produced by reacting the compound of formula
(6) with a reagent capable of selectively protecting the
5'-position of the nucleosides.
[0065] In formula (1), R.sup.1 is a protective group for the
hydroxyl group, which may or may not be substituted (for example,
with a halogen atom, an alkyl group having from 1 to 5 carbon
atoms, an alkyloxy group having from 1 to 5 carbon atoms, etc.),
and the protective group includes, for example, an acyl group such
as acetyl or benzoyl; an alkyl group such as methoxymethyl or
allyl; an aralkyl group such as benzyl or triphenylmethyl; a silyl
group such as trimethylsilyl. As the reagent that gives such a
protective group, for example, preferably used is any of an
acylating agent, an alkylating agent, an aralkylating agent and an
organic silylating agent. The acylating agent includes, for
example, acid anhydrides such as acetic anhydride and benzoic
anhydride, and acid halides such as acyl chloride and benzoyl
chloride.
[0066] The alkylating agent includes, for example, alkyl halides
such as chloromethyl methyl ether and allyl bromide. The
aralkylating agent includes, for example, aralkyl halides such as
benzyl bromide and triphenylmethyl chloride. The organic silylating
agent includes, for example, organic silyl halides such as
trimethylsilyl chloride. The reaction of the compound (6) with the
protecting reagent is preferably effected in the presence of a
base. The base usable in the reaction includes, for example,
hydroxylamine, ammonia and their salts; primary to quaternary
amines and their salts; metal hydroxides such as barium hydroxide;
metal alkoxides such as sodium methoxide and potassium methoxide;
lithium-ammonia solution; ion exchange resins; carbonates such as
potassium carbonate, sodium carbonate and sodium hydrogencarbonate;
phosphates such as disodium phosphate; acetates such as sodium
acetate; and alkaline solutions of sodium hydroxide, lithium
hydroxide or the like.
[0067] Regarding the reaction condition, the two may be reacted in
a suitable solvent. As the solvent, preferably used is an organic
solvent such as ethyl acetate, toluene, methylene chloride or
methanol. The reaction solvent may be or may not be dewatered.
Anyhow, after the reaction, the base, if used, in the reaction
mixture is optionally neutralized, and the product formed can be
isolated from the mixture through ordinary extraction using an
organic solvent such as ethyl acetate, toluene or methylene
chloride. Apart from this, the reaction mixture may be directly
subjected to the next step without isolating the product
therefrom.
[0068] Compounds of formula (1) wherein R.sup.3 and R.sup.1 are the
same, for example, R.sup.3.dbd.R.sup.1=acetyl or benzoyl, may be
obtained by de-protecting the compound of formula (5) selectively
at the 2'-protective group.
[0069] Of compounds of formula (2) noted above, the hydrogen atom
in the 2'-hydroxyl group is substituted with a sulfonic acid-type
leaving group (SO.sub.2R.sup.2). In those, R.sup.2 is preferably a
substituent of any one of a halogen atom, and an aryl (having from
6 to 10 carbon atoms, such as phenyl), alkyl (having from 1 to 5
carbon atoms) or aralkyl (having from 7 to 19 carbon atoms, such as
benzyl) group, which may or may not be substituted (for example,
with a halogen atom, an alkyl group having from 1 to 5 carbon
atoms, a nitro group, an alkyloxy group of which the alkyl moiety
has from 1 to 5 carbon atoms, and the like), and also an alkylamino
group (having from 1 to 6 carbon atoms), which may or may not be
substituted (for example, with a halogen atom, an alkyl group
having from 1 to 5 carbon atoms, a nitro group, an alkyloxy group
of which the alkyl moiety has from 1 to 5 carbon atoms, and the
like). More preferably, the protective group is any one of a
chlorosulfonyl group, a fluorosulfonyl group, an imidazolesulfonyl
group, a trifluoromethanesulfonyl group, a methanesulfonyl group, a
an arylsulfonyl group such as a paratoluenesulfonyl,
paranitrobenzenesulfony- l and benzenesulfonyl group, and the
like.
[0070] Those compounds of formula (2) can be obtained by reacting
the compound of formula (1) with a sulfonyl halide or a sulfonic
acid anhydride, or by reacting it with sulfuryl chloride and then
with an amine or a halogen. The sulfonyl halide includes, for
example, arylsulfonyl halides such as paratoluenesulfonyl chloride
and paranitrobenzenesulfonyl chloride; alkylsulfonyl halides such
as methanesulfonyl chloride; aralkylsulfonyl halides such as
benzylsulfonyl chloride; and halogenoalkylsulfonyl halides such as
trifluoromethanesulfonyl chloride. The sulfonic acid anhydride
includes, for example, arylsulfonic acid anhydrides such as
paratoluenesulfonic acid anhydride and paranitrobenzenesulfonic
acid anhydride; alkylsulfonic acid anhydrides such as
methanesulfonic acid anhydride; aralkylsulfonic acid anhydrides
such as benzylsulfonic acid anhydride; and halogenoalkylsulfonic
acid anhydrides such as trifluoromethanesulfonic acid anhydride.
The amine includes, for example, imidazole. The halogen includes,
for example, fluorine.
[0071] The reaction to give compounds (2) may be effected in a
suitable solvent. For this, preferably used is an organic solvent
such as ethyl acetate, toluene or methylene chloride. The reaction
may be effected in the presence of a basic catalyst such as
pyridine, dimethylaminopyridine, triethylamine or the like. After
the reaction, the basic catalyst, if used, in the reaction mixture
is optionally neutralized, and the product formed can be isolated
from the mixture through ordinary extraction using an organic
solvent such as ethyl acetate, toluene and methylene chloride, And
the like. Apart from this, the reaction mixture may be directly
subjected to the next step without isolating the product
therefrom.
[0072] In compounds of formula (3) noted above for use in the
invention, Y is any one of a fluorine atom, an azido group and a
cyano group. Those compounds (3) can be obtained by reacting the
compound of formula (2) preferably with an azide, a cyanide or a
fluoride. The azide includes, for example, alkali metal azides such
as sodium azide and lithium azide; as well as ammonium azide and
trimethylsilyl azide. The cyanide includes, for example, alkali
metal cyanides such as sodium cyanide and lithium cyanide. The
fluoride includes, for example, hydrogen fluoride; alkali metal
fluorides such as lithium fluoride, potassium fluoride and cesium
fluoride; alkylammonium fluorides such as tetrabutylammonium
fluoride, pyridinium polyhydrogenfluoride and triethylamine
trihydrofluoride; alkylaminosulfur trifluorides such as
diethylaminosulfur trifluoride and morpholinosulfur trifluoride;
and fluoroalkylamines such as Yarovenko reagent and Ishikawa
reagent.
[0073] The reaction to give compounds (3) may be effected in a
suitable solvent. For this, preferably used is an organic solvent
such as ethyl acetate, toluene or methylene chloride. The reaction
may be effected in the presence of a basic catalyst such as
pyridine, dimethylaminopyridine or triethylamine. After the
reaction, the basic catalyst, if used, in the reaction mixture is
optionally neutralized, and the product formed can be isolated from
the mixture through ordinary extraction using an organic solvent
such as ethyl acetate, toluene or methylene chloride.
[0074] Compounds of formula (3) noted above for use in the
invention, wherein Y is a fluorine atom, can be obtained by
reacting the compound of formula (1) with a fluoride. The fluoride
for this includes, for example, alkylaminosulfur trifluorides such
as diethylaminosulfur trifluoride and morpholinosulfur trifluoride.
This reaction may be effected in a suitable solvent. For this,
preferably used is an organic solvent such as ethyl acetate,
toluene and methylene chloride. The reaction may be effected in the
presence of a basic catalyst such as pyridine,
dimethylaminopyridine and triethylamine.
[0075] Compounds of formula (3) noted above for use in the
invention, wherein X is a chlorine atom and Y is a fluorine atom,
may be processed with ammonia as dissolved in methanol under
pressure to thereby substitute X with an amino group, and
thereafter the protective group R.sup.1 in the resulting compounds
may be de-protected in any suitable manner to give FddA. However,
the usefulness of the compounds illustrated herein is not limited
to this case.
[0076] To produce nucleoside derivatives of formula (8) noted
above, for example, the compounds of formula (3) may be subjected
to any of the following reaction steps.
[0077] To obtain the derivatives (8) wherein Z is an amino group,
the compound (3) is processed with ammonia as dissolved in an
alcohol such as methanol under pressure.
[0078] To obtain the derivatives (8) wherein Z is a hydroxyl group,
the compound (3) is processed with an aqueous solution of an alkali
hydroxide such as sodium hydroxide and potassium hydroxide.
[0079] To obtain the derivatives (8) wherein Z is a hydrogen atom,
the compound (3) is processed with hydrogen in the presence of a
reduction catalyst such as palladium-carbon.
[0080] To obtain the derivatives (8) wherein Z is an azido group,
the compound (3) is processed with an alkali metal azide, such as
sodium azide or lithium azide, in a solvent capable of dissolving
the metal azide, such as dimethylformamide.
[0081] To obtain the derivatives (8) wherein Z is OR.sup.4 or
SR.sup.4 the compound (3) is processed with a corresponding alkyl
alcohol or alkyl thiol having been activated with an alkali metal
halide such as a sodium halide.
[0082] To obtain the derivatives (8) wherein Z is NHR.sup.4, the
compound (3) is processed with an alkylamine (corresponding to the
intended substituent, such as methylamine), preferably in an inert
solvent such as dimethylformamide.
[0083] In formula (8), R.sup.4 indicates an optionally
phenyl-substituted lower (C1-5) alkyl group, such as a methyl,
ethyl, propyl, butyl and benzyl group.
[0084] Nucleoside derivatives of formula (9) may be produced with
ease by de-protecting the compounds of formula (8). For example,
compounds (8) wherein R.sup.1 is an acyl group such as an acetyl
and benzoyl group may be processed with an alkali (e.g., sodium
hydroxide, potassium hydroxide); those wherein R.sup.1 is an alkyl
group such as a methoxymethyl and allyl group may be processed with
an acid such as hydrochloric acid and acetic acid; those wherein
R.sup.1 is an aralkyl group such as a benzyl or triphenylmethyl
group may be processed with hydrogen in the presence of a reduction
catalyst such as palladium-carbon and Raney nickel, or may be
processed with an acid such as acetic acid; and those wherein
R.sup.1 is a silyl group such as a trimethylsilyl group may be
processed with tetraammonium fluoride or the like, to thereby give
the derivatives of formula (9).
[0085] Alternatively, the above mentioned de-protecting reaction
step at the 5'-potion thereof may be conducted and then
substitution reaction with Z group may be conducted. In this case,
the compound (3) firstly may be subjected to such above
deprotecting step at the protective group R.sup.1 in the same
manner as above to give the derivative (8'), and then thus obtained
derivative (8') may be subjected to substitution with a group Z at
its 6-halogen atom to give the compound (9) also in the same manner
as above.
EXAMPLES
[0086] Now, the invention is described in detail with reference to
the following Examples.
Example 1
[0087] Production of
9-(2,5-di-O-acetyl-3-bromo-3-deoxy-.beta.-D-xylofuran-
osyl)-1,9-dihydro-6H-purine-6-one:
[0088] 400 g (1.49 mols) of inosine was suspended in 800 ml of
acetic acid in a 2-liter glass reactor, to which was added 240 ml
(1.92 mols) of trimethyl ortho-acetate, and reacted at 35.degree.
C. for 5 hours. The reaction mixture was concentrated under reduced
pressure while acetic acid was added thereto, to thereby remove
almost all methanol therefrom. The resulting concentrate was
dissolved in 900 ml of acetonitrile added thereto, and cooled at
0.degree. C., to which was dropwise and slowly added 280 ml (3.79
mols) of acetyl bromide over a period of about 5 hours. The
resulting white slurry was dropwise added to 1.6 liters of a 1/1
mixture of water and acetonitrile that had been prepared
separately, while being neutralized with an aqueous solution of 25%
sodium hydroxide, whereby the reaction was stopped. The
neutralizing rate was so adjusted that the pH value of the system
might fall between 6.0 and 7.0 or so. For this neutralization, used
was about 1.3 liters of the aqueous solution of 25% sodium
hydroxide. To the resulting reaction mixture, added was 800 ml of
acetonitrile to separate the organic layer and the aqueous layer.
The aqueous layer was back-extracted with acetonitrile and ethyl
acetate. The organic layers were combined and concentrated to have
a desired volume, and then washed with a saturated saline solution
and an aqueous saturated solution of sodium hydrogencarbonate,
dried with anhydrous magnesium sulfate, and filtered. The solvent
was evaporated out from the resulting filtrate, and a syrupy
product was obtained. This was analyzed through liquid
chromatography. The yield of the entitled compound was 53.8%.
[0089] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 8.34 (1H, s, H2),
8.24 (1H, s, H8), 6.20 (1H, bs, H1'), 5.74 (1H, bs, H2'), 4.4 to
4.6 (4H, m, H3', H4', H5'ab), 2.20 (3H, s, 5'OAc), 2.14 (3H, s,
2'OAc).
[0090] IR (KBr, cm.sup.-1): 1750, 1698, 1376, 1226, 1043.
[0091] UV (MeOH) .lambda.max: 206 (log .epsilon. 2.22), 245 (log
.epsilon. 1.53) nm.
[0092] MS (ESI) m/z: 415, 417 (M+H).sup.+, 829, 831, 833
(2M+H).sup.+.
Example 2
[0093] Production of 2', 5'-di-O-acetyl-3'-deoxyinosine:
[0094] 3.67 g (8.85 mmols) of
9-(2,5-di-O-acetyl-3-bromo-3-deoxy-.beta.-D--
xylofuranosyl)-1,9-dihydro-6H-purine-6-one was dissolved in 66 ml
of toluene in a 200-ml reactor, to which were added 7.35 ml (26.5
mmols) of tributyl tin hydride and 125 mg (0.761 mmols) of
2,2'-azobisisobutyronitr- ile. The reaction mixture was heated up
to 95.degree. C. and reacted for 1 hour, and then cooled to
0.degree. C., and then dropwise added to 35 ml of petroleum ether
that had been prepared separately, to stop the reaction. The white
precipitate thus formed was taken out through filtration, and
recrystallized from 46 ml of ethanol and 35 ml of acetonitrile
hydrate. The crystals were taken out through filtration and dried
at 40.degree. C. under reduced pressure to obtain 1.88 g (5.58
mmols, yield: 63.1%) of white crystals.
[0095] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 8.08 (1H, s, H2),
8.07 (1H, s, H2), 6.04 (1H, d, J=1.1 Hz, H1'), 5.59 (1H, bd, J=5.9
Hz, H2'), 4.60 (1H, m, H4'), 4.39 (1H, dd, J=12.3, 2.9 Hz, H5'a),
4.22 (1H, dd, J=12.3, 5.2 Hz, H5'b), 2.50 (1H, ddd, J=14.0, 10.5,
5.9 Hz, H3'a), 2.16 (1H, ddd, J=14.0, 5.8, 1.1 Hz, H3'b), 2.09 (3H,
s, 5'OAc), 2.04 (3H, s, 2'OAc).
[0096] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 8.26 (1H, s,
H2), 8.10 (1H, s H8), 6.11 (1H, d, J=1.4 Hz, H1'), 5.61 (1H, bd,
J=6.3 Hz, H2'), 4.52 (1H, m, H4'), 4.29 (1H, dd, J=12.0, 2.9 Hz,
H5'a), 4.16 (1H, dd, J=12.0, 5.8 Hz, H5'b), 2.60 (1H, ddd, J=14.1,
10.3, 6.3 Hz, H3'a), 2.22 (1H, ddd, J=14.1, 5.9, 1.1 Hz, H3'b),
2.10 (3H, s, 5'OAc), 1.99 (3H, s, 2'OAc).
[0097] IR (KBr, cm.sup.-1): 1746, 1724, 1707, 1419, 1344, 1230,
1205, 1122, 1100.
[0098] UV (MeOH) .lambda.max: 203 (log .epsilon. 1.42), 245 (log
.epsilon. 0.83) nm.
[0099] MS (ESI) m/z: 359 (M+Na).sup.+, 695 (2M+Na).sup.+.
Example 3
[0100] Production of
6-chloro-9-(2,5-di-O-acetyl-3-deoxy-.beta.-D-erythro--
pentofuranosyl)-9H-purine:
[0101] 32.7 g (97.2 mmols) of 2', 5'-di-O-acetyl-3'-deoxyinosine
was suspended in 449 ml of methylene chloride in a 1-liter reactor,
to which were added 30.1 ml (389 mmols) of dimethylformamide and
28.0 ml (389 mmols) of thionyl chloride, and reacted for about 7
hours while heating under reflux. The reaction mixture was cooled
to 0.degree. C., and then dropwise added to 500 ml of water that
had been cooled at 0.degree. C. to stop the reaction. The reaction
mixture was separated into layers, and the organic layer was taken
out, and washed with water, an aqueous saturated solution of sodium
hydrogencarbonate and a saturated saline solution in that order.
The solvent was evaporated, and 31.0 g of an oily product was
obtained. This crude product was directly subjected to the next
reaction.
Example 4
[0102] Production of
6-chloro-9-(3-deoxy-.beta.-D-erythro-pentofuranosyl)--
9H-purine:
[0103] 31.0 g (83.4 mmols) of
6-chloro-9-(2,5-di-O-acetyl-3-deoxy-.beta.-D-
-erythro-pentofuranosyl)-9H-purine was dissolved in 103 ml of
methanol in a 500-ml reactor, and cooled to 0.degree. C., to which
was added 1.60 g (8.31 mmols) of 28% sodium methoxide. These were
reacted at room temperature for 3 hours, and then cooled to
0.degree. C. The crystals thus formed were taken out through
filtration. These were washed with 18 ml of cold methanol, and then
dried at 50.degree. C. under reduced pressure to obtain 14.7 g of
white crystals (purity 99.2%; 53.9 mmols; overall yield 55.4%[2
stages]).
[0104] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 8.68 (1H, s, H2),
8.33 (1H, s, H8), 5.83 (1H, d, J=4.6 Hz, H1'), 4.92 (1H, ddd,
J=7.2, 6.5, 4.6 Hz, H2'), 4.56 (1H, m, H4'), 3.98 (1H, dd, J=12.5,
2.1 Hz, H5'a), 3.60 (1H, dd, d=12.5, 2.6 Hz, H5'b), 2.53 (1H, ddd,
J=12.9, 7.2, 5.7 Hz, H3'a), 2.18 (1H, ddd, J=12.9, 8.0, 6.5 Hz,
H3'b).
[0105] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 8.97 (1H, s,
H2), 8.82 (1H, s, H8), 6.06 (1H, d, J=1.4 Hz, H1'), 5.80 (1H, s,
J=3.9 Hz, H2'-OH), 5.12 (1H, dd, J=5.3, 5.2 Hz, H5'-OH), 4.65 (1H,
m, H2'), 4.46 (1H, m, H4'), 3.78 (1H, ddd, J=12.1, 5.3, 3.2 Hz,
H5'a), 3.59 (1H, ddd, J=12.1, 5.2, 3.8 Hz, H5'b), 2.28 (1H, ddd,
J=13.3, 9.6, 5.3 Hz, H3'a), 1.93 (1H, ddd, J=12.3, 6.0, 2.2 Hz,
H3'b).
[0106] IR (KBr, cm.sup.-1): 3331, 3105, 3074, 2938, 2920, 1596,
1562, 1492, 1442, 1426, 1405, 1391, 1337, 1207, 1129, 1079, 1068,
1002, 979, 834, 806, 635.
[0107] UV (MeOH) .lambda.max: 204 (log .epsilon. 1.17), 265 (log
.epsilon. 0.45) nm.
[0108] MS (ESI) m/z: 271 (M+H).sup.+.
Example 5
[0109] Production of
6-chloro-9-[3-deoxy-5-O-(triphenylmethyl)-.beta.-D-er-
ythro-pentofuranosyl]-9H-purine:
[0110] 1.38 g (5.10 mmols) of
6-chloro-9-(3-deoxy-.beta.-D-erythro-pentofu- ranosyl)-9H-purine
was dissolved in 41 ml of dry dimethylformamide, to which were
added 2.3 ml (16.5 mmols) of triethylamine and 0.424 g (3.47 mmols)
of 4-dimethylaminopyridine. Then, 4.79 g (16.8 mmols) of trityl
chloride was added thereto, and these were reacted for about 16.5
hours at 50.degree. C. After having been cooled, 8 ml of water was
added to the reaction mixture, and the solvent was evaporated
therefrom. The removal of the solvent was repeated four times. The
residue was dissolved in 100 ml of methylene chloride and 50 ml of
water. After having been thus separated, the organic layer was
washed four times with 50 ml of water each, dried with anhydrous
sodium sulfate, and then filtered. The resulting filtrate was
applied to a silica gel column (silica: 100 g), and eluted with
methylene chloride and then with 1 to 10% methanol/methylene
chloride solutions. The solvent was evaporated to obtain 2.71 g of
an oily product (purity 85.3%; yield 88.5%).
[0111] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 8.64 (1H, s, H2),
8.40 (1H, s H8), 7.41 to 7.21 (15H, m, 5'OTr), 6.04 (1H, d, J=2.2
Hz, H1'), 4.87 (1H, m, H2'), 4.73 (1H, m, H4'), 3.44 (1H, dd,
J=10.6, 3.1 Hz, H5'a), 3.33 (1H, dd, J=10.6, 4.6 Hz, H5'b), 2.30
(1H, ddd, J=13.3. 7.7, 5.6 Hz, H3'a), 2.17 (1H, ddd, J=13.3, 6.5,
3.9 Hz, H3'b).
[0112] IR (KBr, cm.sup.-1): 3354, 3059, 1592, 1562, 1491, 1449,
1400, 1338, 1206, 1130, 1078, 1018, 952, 766, 748, 704, 634.
[0113] UV (MeOH) .lambda.max: 207 (log .epsilon. 2.27), 265 (log
.epsilon. 0.31) nm.
[0114] MS (ESI) m/z: 513 (M+H).sup.+.
Example 6
[0115] Production of
6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(triphenylmethyl-
)-.beta.-D-threo-pentofuranosyl]-9H-purine, Part 1:
[0116] 104 mg (0.202 mmols) of
6-chloro-9-(3-deoxy-5-O-(triphenylmethyl)-.-
beta.-D-erythro-pentofuranosyl)-9H-purine was dissolved in 10 ml of
methylene chloride in a 30-ml reactor, to which was added 0.12 ml
(1.48 mmols) of pyridine. This mixture was cooled to 0.degree. C.,
to which was dropwise added 0.07 ml (0.530 mmols) of
diethylaminosulfur trifluoride with stirring. Next, this was
restored to be at room temperature, and then heated under reflux
for about 4 hours. After having been again restored to be at room
temperature, this was dropped into a mixture of 20 ml of an aqueous
saturated solution of sodium hydrogencarbonate and 10 ml of
methylene chloride with vigorously stirring, and then further
stirred for about 20 minutes. The reaction mixture was separated
into layers, and the organic layer was concentrated azeotropically
with toluene. The residue was taken out and purified through a
silica gel plate (using 50% hexane/ethyl acetate). The fraction of
the intended product was extracted with ethyl acetate, and the
solvent was evaporated to obtain 44.3 mg (yield 42.6%) of the
objective compound, which was white solid.
[0117] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 8.73 (1H, s, H2),
8.34 (1H, d, J=2.8 Hz, H8), 7.52to 7.22 (15H, m, 5'OTr), 6.41 (1H,
dd, J=19.1, 3.1 Hz, H1'), 5.25 (1H, dddd, J=53.7, 5.2, 3.1, 2.0 Hz,
H2'), 4.46 (1H, m, H4'), 3.48 (1H, dd, J=9.9, 6.6 Hz, H5'a), 3.30
(1H, dd, J=9.9, 3.8 Hz, H5'b), 2.57 (1H, dddd, H=35.0, 14.8, 9.0,
5.6 Hz, H3'a), 2.36 (1H, dddd, J=27.5, 15.1, 5.1, 1.7 Hz,
H3'b).
[0118] IR (KBr, cm.sup.-1): 1593, 1567, 1492, 1220, 1206, 1079,
708.
[0119] UV (MeOH) .lambda.max: 204 (log .epsilon. 1.17), 265 (log
.epsilon. 0.45) nm.
[0120] MS (ESI) m/z: 515 (M+H).sup.+.
Example 7
[0121] Production of
6-chloro-9-[2-O-(sulfurylimidazolyl)-3-deoxy-5-O-(tri-
phenylmethyl)-.beta.-D-erythro-pentofuranosyl]-9H-purine:
[0122] 604 mg (1.18 mmols) of
6-chloro-9-[3-deoxy-5-O-(triphenylmethyl)-.b-
eta.-D-erythro-pentofuranosyl]-9H-purine was dissolved in 11.8 ml
of methylene chloride, to which was added 486 mg (7.07 mmols) of
imidazole. This reaction mixture was cooled to -35.degree. C., to
which was added 0.15 ml (1.77 mmols) of sulfuryl chloride, and
stirred for 30 minutes. Then, after having been restored to be at
room temperature, this was stirred overnight. To the reaction
mixture, water was added to stop the reaction. Then, the mixture
was separated into layers, and the aqueous layer was washed with
dichloromethane. The organic layers were combined together, dried
with anhydrous sodium sulfate, and filtered. The solvent was
evaporated from the resulting filtrate. The residue was purified
through silica gel column (silica 40 g), using 33 to 50%
hexane/ethyl acetate, to obtain 570 mg (yield 75.0%) of the
intended product, which was colorless oil.
[0123] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 8.67 (1H, s, H2),
8.25 (1H, s, H8), 8.03 (1H, s, imidazole), 7.37 to 7.24 (16H, m,
5'OTr+imidazole), 7.16 (1H, s, imidazole), 6.11 (1H, s, H1'), 5.93
(1H, d, J=5.3 Hz, H2'), 4.65 (1H, m, H4'), 3.46 (1H, dd, J=10.8,
3.2 Hz, H5'a), 3.35 (1H, dd, J=10.8, 4.5 Hz, H5'b), 2.61 (1H, ddd,
J=14.6, 9.7, 5.3 Hz, H3'a), 2.27 (1H, ddd, J=14.6, 5.7, 1.6 Hz,
H3'b).
Example 8
[0124] Production of
6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(triphenylmethyl-
)-p-D-threo-pentofuranosyl]-9H-purine, Part 2:
[0125] 113 mg (0.176 mmols) of
6-chloro-9-[2-O-(sulfurylimidazolyl)-3-deox-
y-5-O-(triphenylmethyl)-.beta.-D-erythro-pentofuranosyl]-9H-purine
was dissolved in 1.80 ml of toluene, to which was added 0.18 ml
(1.06 mmols) of triethylamine trihydrofluoride, and stirred
overnight at 50.degree. C. After having been cooled, 10.0 ml of
ethyl acetate and 8.0 ml of an aqueous saturated solution of sodium
hydrogencarbonate were added to this, to separate it into layers.
The organic layer was dried with anhydrous sodium sulfate, and
filtered. Then, the solvent was evaporated from the filtrate. The
residue was dissolved in acetonitrile and analyzed through liquid
chromatography. The intended product was obtained at an yield of
41.9%.
Example 9
[0126] Production of
6-chloro-9-[2-O-(trifluoromethanesulfonyl)-3-deoxy-5--
O-(triphenylmethyl)-.beta.-D-erythro-pentofuranosyl]-9H-purine:
[0127] 164 mg (0.320 mmols) of
6-chloro-9-[3-deoxy-5-O-(triphenylmethyl)-.-
beta.-D-erythro-pentofuranosyl]-9H-purine was dissolved in 9 ml of
methylene chloride, to which was added 253 mg (3.20 mmols) of
pyridine. To this mixture, dropwise added was a mixture of 361 ml
of trifluoromethanesulfonic acid anhydride and 2 ml of methylene
chloride at room temperature, and the resulting mixture was then
stirred at room temperature for about 15 minutes. To the reaction
mixture was added a mixture of 20 ml of an aqueous saturated
solution of ammonium chloride and 10 ml of methylene chloride, by
which the reaction was stopped. The organic layer separated was
taken out, and then washed with an aqueous saturated solution of
ammonium chloride, an aqueous saturated solution of sodium
hydrogencarbonate and a saturated saline in that order. Then, the
thus-washed organic layer was dried with anhydrous magnesium
sulfate, and filtered. The solvent was evaporated out from the
filtrate to obtain a white foamy solid. Analyzing this through
high-performance liquid chromatography (HPLC) verified that the
solid obtained was nearly a single substance. This solid was
directly subjected to the next reaction step.
Example 10
[0128] Production of
6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(triphenylmethyl-
)-.beta.-D-threo-pentofuranosyl]-9H-purine, Part 3:
[0129] 22.9 mg (0.0356 mmols) of
6-chloro-9-[2-O-(trifluoromethanesulfonyl-
)-3-deoxy-5-O-(triphenylmethyl)-.beta.-D-erythro-pentofuranosyl]-9H-purine
was dissolved in 2.0 ml of toluene, to which were added 10.8 mg
(0.107 mmols) of triethylamine and 34.5 mg (0.214 mmols) of
triethylamine trihydrofluoride, and stirred at room temperature for
about 5 days. After having been cooled, all the mixture was
dissolved in methanol, and analyzed through liquid chromatography.
The intended product was obtained at an yield of 57.8%.
Example 11
[0130] Production of
9-[2,3-dideoxy-2-fluoro-5-O-(triphenylmethyl)-.beta.--
D-threo-pentofuranosyl]-9H-purine-6-amine:
[0131] 110 mg (0.214 mmols) of
6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(triph-
enylmethyl)-p-D-threo-pentofuranosyl]-9H-purine was dissolved in
17.2 ml of a solution of 20% ammonia/methanol, and kept overnight
in a closed vessel at 60.degree. C. After having been cooled, the
reaction mixture was concentrated, and then distilled
azeotropically with toluene. The crystals formed were taken out
through filtration. These were dried at room temperature under
reduced pressure to obtain 82.3 mg of a white solid (purity 74.4%;
yield 57.7%).
[0132] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 8.33 (1H, s, H2),
8.06 (1H, d, J=3.0 Hz, H8), 7.52 to 7.20 (15H, m, 5'OTr), 6.33 (1H,
dd, J=19.9, 2.9 Hz, H1'), 6.18 (2H, bs, 6-NH2), 5.20 (1H, md,
J=53.8 Hz, H2'), 4.40 (1H, m, H4'), 3.46 (1H, dd, J=10.0, 6.5 Hz,
H5'a), 3.27 (1H, dd, J=10.0, 4.1 Hz, H5'b), 2.50 (1H, dddd, J=35.5,
14.9, 9.0, 5.4 Hz, H3'a), 2.31 (1H, dddd, J=27.5, 14.9, 4.8, 1.4
Hz, H3'b).
[0133] IR (KBr, cm.sup.-1): 3151, 1649, 1599, 1578, 1403, 1063,
703
[0134] UV (MeOH) .lambda.max: 208 (log .epsilon. 2.19), 259 (log
.epsilon. 0.58) nm.
[0135] MS (ESI) m/z: 496 (M+H).sup.+.
Example 12
[0136] Production of
9-(2,3-dideoxy-2-fluoro-.beta.-D-threo-pentofuranosyl-
)-9H-purine-6-amine:
[0137] 35.3 mg (0.0710 mmols) of
9-[2,3-dideoxy-2-fluoro-5-O-(triphenylmet-
hyl)-.beta.-D-threo-pentofuranosyl]-9H-purine-6-amine was dissolved
in 1.0 ml of acetic acid, and stirred at room temperature for about
4 hours and then at 80C for about 3 hours. To this was added 1.0 ml
of acetic acid, and cooled to room temperature. This was
concentrated, and the residue formed was taken out and purified
through a silica gel plate (using 91% methylene chloride/ethanol).
The fraction of the intended product was extracted with methanol,
and the solvent was evaporated out to obtain 11.1 mg (yield 61.5%)
of the product which was white solid. The physical data of the
product obtained herein were the same as those disclosed in the
literature.
Example 13
[0138] Production of 6-chloro-9-[2-azido-2,3-dideoxy-
5-O-(triphenylmethyl)-.beta.-D-threo-pentofuranosyl]-9H-purine:
[0139] 1.0 g (1.95 mmols) of
6-chloro-9-[3-deoxy-5-O-(triphenylmethyl)-.be-
ta.-D-erythro-pentofuranosyl]-9H-purine was dissolved in 20 ml of
methylene chloride. This mixture was cooled to 0.degree. C., to
which was added 0.47 ml (5.85 mmols) of pyridine. To this mixture,
dropwise was added 0.66 ml (3.90 mmols) of trifluoromethanesulfonic
acid anhydride, and the resulting mixture was then stirred at room
temperature for about 1 hour. To the reaction mixture was added a
mixture of 20 ml of an aqueous saturated solution of sodium
hydrogencarbonate and 20 ml of methylene chloride, by which the
reaction was stopped. The organic layer thus separated was taken
out, and then washed with water. Then, the thus-washed organic
layer was dried with anhydrous sodium sulfate, and filtered. The
solvent was evaporated out from the filtrate to obtain an oily
material. This oily material was dissolved in 10 ml of toluene and
the solvent was evaporated out from the mixture to obtain a white
foamy solid. This solid was directly subjected to the next
step.
[0140] 1.473 g of this solid was dissolved in 20 ml of dry
dimethylformamide. This mixture was cooled to 0.degree. C., to
which was added 126.8 mg (1.95 mmols) of sodium azide, and stirred
at room temperature for 1.5 hours. To the reaction mixture was
added a mixture of 100 ml of methylene chloride and 70 ml of water
having two phases, by which the reaction was stopped. The organic
layer and the aqueous layer were separated. The aqueous layer was
back extracted with a mixture of 100 ml of ethyl acetate and 100 ml
of a saturated saline. The organic layers were combined together,
dried with anhydrous sodium sulfate and filtered. The solvent was
evaporated from the resulting filtrate. The residue was purified
through silica gel column (silica gel 80 g), using 30 to 80% ethyl
acetate/hexane, to obtain 0.84 g (yield 80%) of the intended
product.
[0141] .sup.1H-NMR(300 MHz, CDCl.sub.3).delta.: 8.72 (s, 1H, H8),
8.37 (s, 1, H2), 7.20-7.54 (m, 15H, Tr), 6.43 (d, J=5.4 Hz, 1H,
H1'), 4.54 (m, 1H, H2'), 4.40 (m, 1H, H4'), 3.50 (dd, J=10.4, 5.5
Hz, 1H, H5'a), 3.41 (dd, J=10.4, 4.0 Hz, 1H, H5'b), 2.20-2.59 (m,
2H, H3').
[0142] MS (ESI) m/z: 538 (M+H).sup.+.
Example 14
[0143] Production of
9-(2,3-dideoxy-2-fluoro-.beta.-D-threo-pentofuranosyl- )
-9H-purine-6-amine (FddA), Part 2:
[0144] 3.65 g (7.09 mmols) of
6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(tripen-
ylmethyl-.beta.-D-threo-pentofuranosyl]-9H-purine was dissolved in
18 ml of methanol and 18 ml of toluene which is containing 0.5
equivalent of hydrogen chloride. This mixture was stirred at room
temperature for about 4 hours. This was treated with 2 equivalents
of poly (4-vinylpyridine), and filtered. The solvent was evaporated
out from the filtrate under the reduced pressure. The residue was
dissolved in 200 ml of methanol and 200 ml of toluene. The mixture
was kept under 3.5 bar of ammonia pressure in a closed vessel at 40
to 60.degree. C. for 5 days. After having been cooled, the reaction
mixture was concentrated, and added 80% acetone water solution. The
crystals thus formed were taken out through filtration. These were
dried and analyzed through liquid chromatography. The intended
product, FddA, was obtained at an yield of 73% in two steps.
[0145] Effects of the Invention
[0146] According to the present invention, substrates of which the
3'-position of the saccharide moiety is deoxylated can be
substituted at the 2'-position at a high yield to give nucleoside
derivatives. Therefore, using the method of the invention,
nucleoside derivatives including
9-(2,3-dideoxy-2-fluoro-.beta.-D-threo-pentofuranosyl)adenine
(FddA) and their related compounds can be produced in a simplified
manner at a high yield. Accordingly, the method of the invention
gives those nucleoside derivatives at low costs.
* * * * *