A PROCESS FOR THE PREPARATION OF 9-(HYDROXYALKYL)-HYPOXANTHINES

Abstract: A process for the preparation of 9-(hydroxyalkyl)-hypoxanthines of general formula (I), wherein R is hydrogen or a straight or branched C1-C10 alkyl group; R' is hydrogen or a straight or branched C1-C4 alkyl group; n is an integer 0 to 5, in which process a 5-amino-6-chloro-4-(hydroxylalkylamino)-pyrimidine of general formula (IV), wherein R, R' and n have the above-mentioned meanings, is reacted with formic acid.

Description: A PROCESS FOR THE PREPARATION OF 9-(HYDROXY-ALKYL)-HYPO- XANTHINES. The present invention relates to an novel and im¬ proved process for the preparation of 9- (hydroxyal- kyl)-hypoxanthines of general formula I R In formula I above, R is hydrogen or a straight or branched C -C alkyl group; R 1 is hydrogen or a straight or branched C -C alkyl group; n is an integer 0 to 5. Compounds (I) are important intermediates for the synthesis of compounds having antiviral, antitumoral and immunomodulating activities as described, for example, in EP-A-79103233.7. A suitable process for obtaining the compounds of general formula (I) is already known both in scientific and patent literature. For example, in J. Chem. , 8, 502 (1965) and in J. Med. Chem., 1 , 689 (1967) synthesis of compounds (I) is described, according to the following scheme: Cl II) (IV) (V) According to said process, 4, 6-dichloro-5-amino-ρy- rim dine (II) is reacted with an aminoalcohol of formula (III) to give the corresponding 5-amino-6-chloro-4-(hydro- xyalkylamino)-pyrimidine (IV) which is cyclized to 6-chlo- ro-9-(hydroxyalkyl)-purine (V) with an excess of ethyl ortoformiate and compound (V) is finally hydrolyzed to corresponding compound (I) . The main drawback of said reaction resides in the use of a large excess of ethyl ortoformiate, which is known to be remarkably expensive and hardly available on industrial scale, as well as in the practical difficulties connected with the purification of the intermediate purine derivative (V) . This applies particularly when n is an integer above 2. Now, it ' has been surprisingly found that compounds of general formula (I), wherein R, R' and n have the above mentioned meanings, may be advantageously obtained by an economic process, when the above defined compound IV is cyclized with formic acid instead of ethyl ortoformiate. Thus, the present invention relates to a process for the preparation of 9-(hydroxyalkyl)-hypoxanthines of general formula (I), wherein R, R 1 and n have the above mentioned meanings, in which process a 5-amino-6-chlo- ro-4- (hydroxyalkylamino)-pyrimidine of general formula (IV) Cl R wherein R, R' and n have the above mentioned meanings, in form of the hydrochloride or of other salts, is refluxed with concentrated formic acid (HCOOH), to give the com¬ pound of general formula (I). The process of the invention is carried out by heating to the reflux temperature a solution or suspension of compound; (IV), as the hydrochloride or another salt, in formic acid of suitably high concentration, preferably 99%. The reaction is carried out for a time ranging from 10 to 20 hours, suitably 15 hours. The highly pure final compound is recovered according to usual techniques. The scheme hereinbelow summarizes the process of the invention: < IV > ( I ) The process of the invention has remarkable advan¬ tages. First, use of expensive ethyl ortoformiate, which is replaced by much more economic formic acid, is avoided. On the other hand, treatment of derivative (IV) according to the invention carries out in a single operative ste.p both cyclization, with formation of purine ring, and hy¬ drolysis of chlorine substituent, thus avoiding the need for isolation of intermediate (V) with evident savings in time, labour and materials. The following examples further illustrate the in¬ vention. EXAMPLE 1 9-(4-hydroxybutyl)-hypoxanthine (Formula I, R = H; R' = H; n = 2) 16.4 g (0.1 mole) of 4, 6-dichloro-5-aminopyrimidi- ne, 18.5 g (0.1 mole) of tributylamine and 8.91 g (0.1 mole) of 4-amino-l-butanol were placed into a 250 ml flask. The mixture was heated to reflux for 15 hours, cooled and treated with a gaseous HCl flow to persistent acidity, then cooled, left to stand at 0°C for 12 hours. 4-chloro-5-amino-6- ( 4-hydroxybutyl) -amino-pyrimidine hy¬ drochloride was filtered and dried at 60°C. The crude dried hydrochloride (22,2 g) was dissol- ved in 99% formic acid and refluxed for 15 hours. Solvent was evaporated off, the residue was dissolved in the mini- mun water amount, treated with NH at 10-20°C for some hours, and the white precipitate formed was filtered and recrystallized from ethanol, to yield 18.2 g. Melting point 200-202°C. EXAMPLES 2-9 Following an analogous process, using corresponding amounts of the appropriate aminoalcohol, the compounds listed in the following table were obtained: Examples 2-9: compounds of general formula I

Claims: CLAIMS 1. A process for the preparation of 9-(hydroxyalkyl)- hypoxanthines of general formula I OH wherein R is hydrogen or a straight or branched C -C alkyl grou ; R 1 is hydrogen or a straight or branched C -C alkyl group; n is an integer 0 to 5, in which process a 5-amino-6-chloro-4-(hydroxylalkylami- no)-pyrimidine of general formula (IV) Cl R wherein R, R' and n have the above mentioned meanings, is reacted with formic acid. 2. A process according to claim 1, wherein compound (IV) is in form of the hydrochloride or of another salt. 3. A process according to claims 1 and 2, wherein formic acid is 99% formic acid. 4. A process according to claims 1-3, wherein the reaction is carried out at the reflux temperature, for a time ranging from 10 to 20 hours.

Inventors: STRADI RICCARDO, STRADI, RICCARDO
Applicants: CO PHARMA CORP SRL, CO PHARMA CORPORATION S.R.L.
Application year: 1988
Main classification: C07D473
IPC codes: C07D473