METHOD FOR PRODUCING 4- [(2',5'- DIAMINO-6'- HALOPYRIMIDINE- 4'-YL)AMINO]- CYCLOPENT- 2-ENYLMETHANOLS

PROCEDE DE PRODUCTION DE 4- [(2',5'- DIAMINO-6'- HALOPYRIMIDIN- 4'-YL)AMINO]- CYCLOPENT-2- ENYLMETHANOLS

English Abstract

A novel process for preparing
4-[(2',5'-diamino-6'--halopyrimidin-4'-yl)amino]cyclopent-2-enylmethanols of
the general
formula

(see formula I)
in which X is a halogen atom, is described. According to this
process, a 2,5-diamino-4,6-dihalopyrimidine of the general formula
(see formula II)
in which X is as defined above, is reacted with a
4-aminocyclopent-2-enylmethanol of the formula

(see formula III)
or one of its salts, in the presence of a base in a polar protic
solvent.

French Abstract

L'invention concerne un nouveau procédé de 4-[(2',5'-diamino-6'-halopyrimidin-4'-yl)amino]cyclopent-2-énylméthanols de formule générale (I) dans laquelle X représente un atome d'halogène. Selon ce procédé, une 2,5-diamino-4,6-dihalopyrimidine de formule générale (II), dans laquelle X a la signification mentionnée, réagit avec un 4-aminocyclopent-2-énylméthanol de formule (III) ou avec un sel de ce dernier en présence d'une base dans un solvant polaire protique.

Claims

7


THE EMBODIMENTS OF THE PRESENT INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:


1. Process for preparing 4-[(2',5'-diamino-6'-
halopyrimidin-4'-yl)amino]cyclopent-2-enylmethanols of the
general formula

Image
in which X is a halogen atom, wherein a 2,5-diamino-4,6-
dihalopyrimidine of the general formula

Image
in which X is defined as above, is reacted with a 4-
aminocyclopent-2-enylmethanol of the formula

Image
or one of its salts, in the presence of a base selected from the
group consisting of an alkali metal bicarbonate, an alkali earth
metal bicarbonate, an alkali metal carbonate and an alkali earth
metal carbonate, in a polar protic solvent to give the end
product of the general formula I.



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2. Process according to claim 1, wherein the polar protic
solvent used is a C1-4-alcohol.

3. Process according to Claim 1 or 2, wherein the reaction
is carried out at a temperature of from 20°C to the reflux
temperature of the solvent in question.

Description

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1

Method for producing 4-[(2',5'-Diamino-61-halopyrimidin-4'-
yl)amino] cyclopent-2-enylmethanols

Description

The present invention relates to a novel process for
preparing 4-[(2',5'-diamino-61-halopyrimidin-4'-
yl)amino]cyclopent-2-enylmethanols of the general formula

X
H,N N
HO ~ . I
HI~ NIi2


4-[(2',5'-diamino-6'-halopyrimidin-4'-yl)-
amino]cyclopent-2-enylmethanols are important intermediates for
preparing antiviral nucleotide derivatives (WO 91/01310).

The 3-step synthesis of 4-[(2',5'-diamino-6'-
chloropyrimidin-4'-yl)amino]cyclopent-2-enylmethanol starting from
4-acetamidocyclopent-2-enylmethanol by reaction with 2-amino-
4,6dichloropyrimidine in butanol using diisopropylethylamine as
base is known. Here, the [(21-amino-6'-chloropyrimidin-4'-
yl)amino]cyclopent-2-enylmethanol is initially formed, which is

then converted in a subsequent step by diazotization into the
corresponding amine which is then hydrolysed to give the end
product (J. Chem. Soc. Perkins Trans, 1, 1992).

This process has the disadvantage that it is too
costly and that the desired end product is obtained in only
moderate yield.

It is the object of the present invention to provide
a 1-step and thus more cost-efficient process for preparing 4-
[(2',5'-diamino-6'-halopyrimidin-4'-yl)amino]cyclopent-2-
enylmethanols in which the desired products are obtained in good
yield.


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2
According to the invention, there is provided a process for
preparing 4-[(2',5'-diamino-6'-halopyrimidin-4'-
yl)amino]cyclopent-2-enylmethanols of the general formula

x
H2 O'l
HO H~,=~N/~NH2

in which X is a halogen atom, wherein a 2,5-diamino-4,6-
dihalopyrimidine of the general formula
x
H2N / N lI
X N NH2


in which X is defined as above, is reacted with a 4-
aminocyclopent-2-enylmethanol of the formula


~-I U NHl I I I
or one of its salts, in the presence of a base selected from the
group consisting of an alkali metal bicarbonate, an alkali earth
metal bicarbonate, an alkali metal carbonate and an alkali earth
metal carbonate, in a polar protic solvent to give the end
product of the general formula I.


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Surprisingly, it has been found that, if instead of
2-amino-4,6-dichloropyri.midine, a 2,5-diamino-4,6-dihalopyrimidine
of the general formula

x
NzN ~
~ N II
X N NHI

is used as starting material, and this is allowed to react in the
presence of a base in a polar protic solvent with a 4-
aminocyclopent-2-enylmethanol of the formula

HO NH2 z1t

or one of its salts, the desired eiid product of the general
formula
x
H2N

F{0 ~u i
~t N Nl~

is obtained much more cost-efficiently and in good yield.

The substituent X is a halogen atom, such as F, Cl,
Br or I.

The 2,5-diamino-4,6-dihalopyrimdines, such as the 2,5-
diamino-4,6-dichloropyrimidine, can be prepared in accordance with
EP-A 0 684 326.

The 4-aminocyclopent-2-enylmethanols used can be both
the racemic and the optically active compounds, such as (1R,4S)-,
(1S,4R)-, (lR,4R)-, or (iS,4S)-4-aminocyclopent-2-enylmethanols.


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Suitable salts thereof are the acid addition salts,
in particular the hydrobalide salts, for example the
hydrochlorides or hydrobromides. These 4-aminocyclopent-2-
enylmethanols, in particular the (1R,4S)- or the (1S,4R)-
enantiomers, can be prepared in accordance with WO 97/45529.

The reaction is advantageously carried out in the
presence of an alkali metal carbonate or alkaline earth metal
carbonate, alkali metal bicarbonate or alkaline earth metal
bicarbonate or in the presence of nitrogen bases, such as, for

example, tert. amines, as base. The alkali metal carbonate or
alkali metal bicarbonate used can be sodium carbonate, potassium
carbonate or sodium bicarbonate or potassium bicarbonate. The
alkaline earth metal carbonate or alkaline earth metal bicarbonate
used can be calcium carbonate or magnesium carbonate or calcium
bicarbonate.

Suitable tert. amines are, for example, triethylamine
and diisopropylethylamine. The reaction is preferably carried out
in the presence of an alkali metal bicarbonate such as sodium
bicarbonate or in the presence of a tert. amine such as
diisopropylethylamine.

The base is advantageously employed in excess, based
on the 2,5-diamino-4,6-dihalopyrimidine; preferably, 1 to 4 mol
of base are employed per mole of 2,5-diamino-4,6-dihalopyrimidine.

Suitable polar protic solvents are, in particular,
C1_4-alcohols, such as methanol, ethanol, propanol and its isomers,
and butanol and its isomers.

The reaction is advantageously carried out at a
temperature of from 20 C to the reflux temperature of the solvent
in question, preferably from 50 C to the reflux temperature.

Advantageously, the 4-aminocyclopent-2-enylmethanol and the 2,5-
diamino-4,6-dihalopyrimidine are employed in equimolar amounts.


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After a customary reaction time of from 2 to 20 h, the
end products of formula I, preferably the (1S,4R)-4-[(2',-5'-
diamino-6'-halopyrimidin-4'-yl)-amino]cyclopent-2-enylmethanol,
can then be obtained by customary work-up methods.

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Examples
Example 1

Preparation of 4-[(21,51 -diamino-61 -chloropyrimidin-
4'-yl)amino]cyclopent-2--enylmethanol in the presence of sodium
bicarbonate.

(1S,4R) -4-aminocyclopent-2-enylmethanol hydrochloride
(0.14 mol, 23.25 g) , ethanol (3 mol, 138.12 g, 176 m:l), 2,5-
diamino-4,6-dichloropyri.midine (0.14 mol, 25 g) and. sodium

bicarbonate (0.34 mol, 28.68 g) were added to a dry reactor. This
mixture was heated at reflux temperature (about 80 C) for 16 h.
The rate of conversion was tested by TLC using 13/i methylene
chloride:methanol as mobile phase. The reaction mixture was
cooled to room temperature and stirred for 45 min. The salts were

removed by filtration and the filter cake was washed twice with
ethanol (0.86 mol, 39.5 g, 50 ml).

2/3 of the organic phase were removed by distillation
under reduced pressure, and hexane (150 ml) was then added
dropwise. The suspension was cooled to below 10 C. After

filtration, the product was dried under reduced pressure at 50 C.
This gave 21.5 g (0.08 mol) of end product, corresponding to a
yield of 601.

Example 2

Preparation of 4-[(2',5'-diamino-6'-chloropyrimidin-
4'-yl)amino]cyclopent-2-enylmethanol in the presence of
diisopropylethylamine.


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(1S,4R)-4-aminocyclopent-2-enylmethanol hydrochloride
(0.14 mol, 23.18 g), butanol (1.26 mol, 93.39 g, 115.3 ml), 2,5-
diamino-4,6-dichloropyrimidine (0.14 mol, 25.67 g) and
diisopropylethylamine (0.29 mol, 37.09 g, 49.99 ml) were added to
a dry reactor. This mixture was heated at reflux temperature
(about 115 C) overnight. The rate of conversion was tested by
TLC using 13/1 methylene chloride:methanol as mobile phase. The
reaction mixture was cooled to room temperature. Water was then
added, and the mixture was subsequently extracted twice with
ethyl acetate.
The organic phase was washed twice with water, and then
filtered through celiteTM. 2/3 of the organic phase were removed
by distillation under reduced pressure, and hexane was then added
dropwise. The suspension was cooled to below 10 C. After
filtration, the product was dried under reduced pressure at 50 C.
This gave 21.47 g (0.08 mol) of end product,
corresponding to a yield of 60%.

Representative Drawing