SK285271B6 - Method for producing 4-[(2',5'-diamino-6'-halopyrimidine-4'- yl)amino]-cyclopent-2-enylmethanols - Google Patents

Abstract

Described is a method for producing 4-[(2',5'-diamino-6'- halopyrimidine-4'-yl)amino]-cyclopent-2-enylmethanols of general formula (I), wherein X represents a halogen atom. According to the method, a 2,5-diamino-4,6-halopyrimidine of general formula (II), wherein X has the aforementioned meaning, is reacted with a 4-aminocyclopent-2-enylmethanol of formula (III) or with a salt thereof in the presence of a base in a polar protic solvent.

Description

Technical field

The present invention relates to a novel process for the preparation of 4 - [(2 ', 5'-diamino-6'-halopyrimidin-4'-yl) amino] cyclopent-2-enylmethanols. 4 - [(2 ', 5'-Diamino-6'-halopyrimidin-4'-yl) amino] cyclopent-2-enylmethanols are important intermediates for the production of antiviral nucleotide derivatives (WO 91/01310).

BACKGROUND OF THE INVENTION

The 3-step synthesis of 4- [2 ', 5'-diamino-6'-halopyrimidin-4'-yl) amino] cyclopent-2-enylmethanol from 4-acetamidocyclopent-2-enylmethanol by reaction with 2-amino-4 is known. 6-dichloropyrimidine in butanol using diisopropylethylamine as the base. In this case, [(2'-amino-6'-chloropyrimidin-4'-yl) amino] cyclopent-2-enylmethanol is formed first, which is then diazotized to the corresponding atine in the next step, which is then hydrolyzed to the final product (J). Chem. Soc. Perkin Trans., 1, 1992). The disadvantage of this method is the excessive cost and lower yields of the desired end product.

It is an object of the present invention to provide a one-step and thus cheaper process for the preparation of 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 solved by the method of claim 1.

SUMMARY OF THE INVENTION

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

where X represents a halogen atom such as F, Cl, Br or 1, the following was surprising. When 2,5-diamino-4,6-dihalopyrimidine of formula (II) is used as the starting material in place of 2-amino-4,6-dichloropyrimidine

X

and this is reacted with 4-aminocyclopent-2-enylmethanol of formula (111) in the presence of a base in a polar protic solvent.

or a salt thereof, yielding the desired end product of formula (I) several times cheaper and in good yield.

2,5-Diamino-4,6-dihalopyrimidines such as 2,5-diamino-4,6-dichloropyrimidine can be prepared according to EP-A-0 684 326.

Both racemic and optically active compounds such as (1R, 4S) -, (1S, 4R) -, (1R, 4R) -, or (1S, 4S) -4 can be used as 4-aminocyclopent-2-enylmethanols. amino-cyclopent-2-enylmethanols. Suitable salts are acid addition salts, especially hydrohalide salts, for example hydrochlorides or hydrobromides. 4-Aminocyclopent-2-enylmethanols, especially the (1R, 4S) - or (1S, 4R) -enantiomers can be prepared according to WO 97/45529.

Conveniently, the reaction is carried out in the presence of an alkali metal or alkaline earth metal carbonate, an alkali metal bicarbonate or an alkaline earth metal bicarbonate, or in the presence of nitrogenous bases such as tertiary amines such as bases. As the alkali metal carbonate or alkali metal bicarbonate, sodium carbonate, potassium carbonate or sodium bicarbonate, or potassium bicarbonate may be used. As the alkaline earth metal carbonate or alkaline earth metal bicarbonate, calcium carbonate or magnesium carbonate or calcium bicarbonate can be used. Suitable tertiary amines are, for example, triethylamine and diisopropylethylamine. Preferably, the reaction is 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 conveniently used in excess based on 2,5-diamino-4,6-dihalopyrimidine, preferably 1 to 4 moles of base per mole of 2,5-diamino-4,6-dihalopyrimidine are used.

Particularly suitable as the polar protic solvent are C 1-4 alcohols such as methanol, ethanol, propanol and its isomers and butanol and its isomers.

The reaction is conveniently carried out at a temperature of from 20 ° C to the reflux temperature of the corresponding solvent, preferably from 50 ° C to reflux temperature. Suitably, 4-aminocyclopent-2-enylmethanol and 2,5-diamino-4,6-dihalopyrimidine are used in equimolar amounts.

After the usual reaction time of 2 to 20 hours, the end products of formula (I), preferably (1S, 4R) -4 - [(2 ', 5'-diamino-6'-halopyrimidin-4'-yl) amino] cyclopent- 2-enylmethanol, obtained by the usual processing methods.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 4 - [(2 ', 5'-diamino-6'-chloropyrimidin-4'-yl) amino] cyclopent-2-enylmethanol in the presence of sodium bicarbonate (1S, 4R) -4-Aminocyclopent-2-enylmethanol hydrochloride (0.14 mole, 23.25 g), ethanol (3 moles, 138.12 g, 176 mL),

2,5-diamino-4,6-dichloropyrimide (0.14 mol, 25 g) and sodium bicarbonate (0.34 mol, 28.68 g) were charged to a dry reactor. This mixture was heated to reflux (ca. 80 ° C) for 16 hours. Reaction ratios (rates) were tested by TLC with 13/1 methylene chloride: methanol as a developing agent. The reaction mixture was cooled to room temperature and stirred for 45 minutes. The salts were removed by filtration and the filter cake was washed 2 times with ethanol (0.86 mol, 39.5 g, 50 mL).

After 2/3 of the organic phase was removed by vacuum distillation, hexane (150 mL) was added dropwise. The suspension was cooled below 10 ° C. After filtration, it was dried under vacuum at 50 ° C.

21.5 g (0.08 mol) of the final product was obtained, corresponding to a 60% yield.

Example 2

Preparation of 4 - [(2 ', 5'-diamino-6'-chloropyrimidin-4'-yl) amino] cyclopent-2-enylmethanol in the presence of diisopropylethylamine (1S, 4R) -4-Aminocyclopent-2-enylmethanol hydrochloride 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 charged to a dry reactor. The mixture was heated overnight to reflux (ca. 115 ° C). Reaction rates (rate) were tested by TLC with 13/1 methylene chloride: methanol as a developing agent. The reaction mixture was cooled to room temperature. Water was then added followed by extraction twice with ethyl acetate.

The organic phase was washed twice with water and then the organic phase was filtered through Celite. After 2/3 of the organic phase was removed by vacuum distillation, hexane was added dropwise. The suspension was cooled below 10 ° C. After filtration, it was vacuum dried at 50 ° C.

21.47 g (0.08 mol) of the final product was obtained, corresponding to a 60% yield.

Claims (3)

PATENT CLAIMS A process for the preparation of 4 - [(2 ', 5'-diamino-6'-halopyrimidin-4'-yl] amino] cyclopent-2-enylmethanols of formula (I), HN HO wherein X is a halogen atom, characterized in that 2,5-diamino-4,6-dihalopyrimidine of formula (II) (Π) is reacted with 4-aminocyclopent-2-enylmethanol of formula (III) HO (III) or one of its salts, in the presence of an alkali metal or alkaline earth carbonate, or in the presence of an alkali metal or alkaline earth bicarbonate in a polar protic solvent to give the final product of formula (I). Process according to claim 1, characterized in that a C 1-6 alcohol is used as the polar protic solvent. Process according to claim 1 or 2, characterized in that the reaction is carried out at a temperature of from 20 ° C to the reflux temperature of the corresponding solvent.