Process for preparing...

Details Process for preparing... Process for preparing...

2002-04-18

2004-02-17

Shah, Mukund J. (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

06693193

ABSTRACT:

TECHNICAL FIELD
This invention relates to processes for the preparation of certain nucleoside analogues, to new intermediate compounds useful in such processes, and to the preparation of intermediate compounds useful in such processes.
BACKGROUND ART
Compounds which are potent inhibitors of purine nucleoside phosphorylase and are useful for suppressing T-cell function and/or treating and/or preventing infections caused by protozoan parasites are described in
Biochemistry
, 1998, 37, 8615-8621 and in our co-pending PCT International Patent Application No. PCT/US98/21717 (WO 99/19338).
There remains a need for alternate, simpler methods of preparing these compounds.
It is therefore an object of the present invention to provide an alternate process for preparing these compounds, which will at least provide the public with a useful choice.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides a process of preparing a compound of the formula
wherein B is chosen from OH, NH
2
, NHR, H or halogen; D is chosen from OH, NH
2
, NHR, H, halogen or SCH
3
; R is an optionally substituted alkyl, aralkyl or aryl group; and Z is selected from OH, hydrogen, halogen, hydroxy, SQ or OQ, Q is an optionally substituted alkyl, aralkyl or aryl group; or a tautomer thereof; or a pharmaceutically acceptable salt thereof; or an ester thereof; or a prodrug thereof, wherein the process comprises the following steps:
(a) reacting a compound of the formula (II)
 wherein Z′ is a hydrogen or halogen atom, a group of formula SQ or OQ, or a trialkylsilyloxy, alkyldiarylsilyloxy or optionally substituted triarylmethoxy group and Q is an optionally substituted alkyl, aralkyl or aryl group, sequentially with a halogenating agent and a sterically hindered base to form an imine;
(b) condensing the imine thus prepared with an anion produced by abstraction of the bromine or iodine atom from a compound of formula (XIX):
 wherein R
5
is a bromine or iodine atom, R
6
is an N-protecting group, B′ and D′ are independently selected from H, OR
7
and N(R
8
)
2
, and R
7
and R
8
are O- and N-protecting groups respectively, to produce a 1-C-(pyrrolo[3,2-d]pyrimidin-7-yl)-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol derivative of formula (SAC):
 wherein R
9
is a hydrogen atom, Z′ is as defined above for compounds of formula (II) and R
6
, B′ and D′ are as defined above for compounds of formula (XIX);
(c) optionally, converting the compound of formula (XX) to a compound of formula (XX) wherein Z′, R
6
, B′ and D′ are as defined above but R
9
is alkoxycarbonyl or aralkoxycarbonyl, or optionally, where Z′ in the compound of formula (XX) is trialkylsilyloxy, alkyldiarylsilyloxy or optionally substituted triarylmethoxy, converting the compound of formula (XX) to a compound of formula (XX) wherein R
6
, R
9
, B′ and D′ are as defined above but Z′ is OH; and
(d) N- and O-deprotecting the compound of formula (XX) prepared from step (b) or (c), by acid- or alkali-catalyzed hydrolysis or alcoholysis or catalytic hydrogenolysis as required for the O- and N-protecting groups in use, to produce a compound of the formula (I) as defined above.
Where a pharmaceutically acceptable salt, ester or prodrug of the compound of formula (I) is desired, the process will also include the further step of converting the compound of formula (I) thus prepared to the desired pharmaceutically acceptable salt, ester or prodrug, using methods known in the art.
In a preferred embodiment, the halogenating agent used in step (a) is N-chlorosuccinimide.
In a preferred embodiment, the hindered base used in step (a) is lithium tetramethyl piperidide.
Preferably, in step (b) the bromine or iodine atom is abstracted from the compound of formula (XIX) using butyllithium or magnesium.
Preferably, the N-protecting group R
6
in the compound of formula (XIX) is an alkoxymethyl group (such as benzyloxymethyl), a silyl group (such as tert-butyldimethylsilyl) or an arylmethyl group (such as benzyl).
Preferably, the O-protecting group R
7
is an alkyl or arylmethyl group (such as methyl, tert-butyl or benzyl).
Preferably, each N-protecting group R
8
is independently an arylmethyl group (such as benzyl or 4-methoxybenzyl), or the two R
8
groups together form the 2,4-hexadien-2,5-yl group.
In a further aspect, the present invention provides a compound of formula (XX):
wherein R
9
is a hydrogen atom, an alkoxycarbonyl or aralkyloxycarbonyl group, Z′ is a hydrogen or halogen atom, a hydroxy group, a group of formula SQ or OQ, or a trialkylsilyloxy, alkyldiarylsilyloxy or optionally substituted triarylmethoxy group and Q is an optionally substituted alkyl, aralkyl or aryl group, and R
6
is an N-protecting group, B′ and D′ are independently selected from H, OR
7
and N(R
8
)
2
, and R
7
and R
8
are O- and N-protecting groups respectively.
Preferred are compounds of formula (XX) wherein R
9
is a hydrogen atom or a tert-butoxycarbonyl group, Z′ is a hydroxy group, a tert-butyldimethylsilyloxy or methylthio group, and R
6
is a benzyloxymethyl, allyl, tert-butyldimethylsilyl, 2-(trimethylsilylethoxy)methyl or benzyl group, B′ is a methoxy, tert-butoxy or benzyloxy group and D′ is a hydrogen or fluorine atom, a dibenzylamino group or a bis(4-methoxybenzyl)amino group.
In a further aspect, the present invention provides a process of preparing a compound of formula (XX) as defined above, wherein the process comprises the steps (a) and (b) as defined above for preparing compounds of the formula (I); and optionally
(a) converting R
9
from a hydrogen atom to an alkoxycarbonyl or aralkyloxycarbonyl group by reaction with an alkoxycarbonylating or aralyloxycarbonylating reagent; or
(b) converting Z′ from a trialkylsilyloxy, alkyldiarylsilyloxy or optionally substituted triarylmethoxy group to a hydroxy group by reaction with a source of fluoride or acid.
In a further aspect, the present invention provides a process of preparing a compound of the formula (I) as defined above, or a pharmaceutically acceptable salt, ester or prodrug thereof, comprising the step of N- and O-deprotecting a compound of the formula (XX) as defined above by acid- or alkali-catalyzed hydrolysis or alcoholysis or catalytic hydrogenolysis, as required for the O- and N-protecting groups in use, to produce a compound of the formula (I) as defined above.
In further aspects, the present invention provides compounds of the formula (I) and (XX) when prepared by processes as defined above.
In a further aspect, the present invention provides a process of preparing the compound 2-amino-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one, comprising the step of reacting the compound 2-(N-dimethylaminomethylene)amino-6-(2-dimethylaminovinyl)-5-nitropyrimid-4-one with a reagent capable of reducing the nitro group, to produce the compound 2-amino-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one.
Preferably, the reducing agent used is aqueous sodium dithionite. Alternatively, the reduction may be carried out using catalytic hydrogenation. Where the reagent is aqueous sodium dithionite (a preferred reagent), the process is preferably carried out at elevated temperature, preferably at about 100° C.
Preferably, the process includes the initial step of preparing the compound 2-(N-dimethylaminomethylene)amino-6-(2-dimethylaminovinyl)-nitropyrimidin-4-one by reacting the compound 2-amino-6-methyl-5-nitro-pyrimidin-4-one with a reagent capable of effecting dialklaminomethylation.
Preferably, the reagent used to effect the dialkylaminomethylation is a combination of DMF dimethylacetal and DMF.
Preferably, this step is carried out with heating at about 100° C.
Alternatively, the reagent may be Bredereck's reagent (t-butoxy bis(dimethylamino)methane).
In a further aspect, the invention provides the compound 2-amino-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one when prepared by a process as defined above.
In a further aspect, the invention provides a compou

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