Method for producing...

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2001-06-17

2002-08-13

Ford, John M. (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

06433170

ABSTRACT:

DESCRIPTION
The present invention relates to a novel process for preparing 4-[(2′,5′-diamino-6′-halopyrimidin-4′-yl)amino]cyclopent-2-enylmethanols of the general formula
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-4,6-dichloropyrimidine in butanol using diisopropylethylamine as base is known. Here, the [(2′-amino-6′-chloro-pyrimidin-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 hydrolyzed to give the end product (J. Chem. Soc. Perkin 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.
This object is achieved with the process according to claim
1
.
Surprisingly, it has been found that, if instead of 2-amino-4,6-dichloropyrimidine, a 2,5-diamino-4,6-dihalopyrimidine of the general formula
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
or one of its salts, the desired end product of the general formula
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-dihalopyrimidines, 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)-, (1R, 4R)-, or (1S, 4S)-4-amino-cyclopent-2-enylmethanols. Suitable salts thereof are the acid addition salts, in particular, the hydrohalide 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 the 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 tertiary 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 tertiary amine, such as, diisopropylethylamine.
The base is advantageously employed in excess, based on the 2,5-diamino4,6-dihalopyrimidine; preferably, 1 to 4 mol of base are employed per mol of 2,5-diamino-4,6-dihalopyrimidine.
Suitable polar protic solvents are, in particular, C
1-4
-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-amino-cyclopent-2-enylmethanol and the 2,5-diamino-4,6-dihalopyrimidine are employed in equimolar amounts.
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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