MXPA96003091A

MXPA96003091A - Cloropirimid intermediaries

Info

Publication number: MXPA96003091A
Application number: MXPA/A/1996/003091A
Authority: MX
Inventors: Mary Daluge Susan; Tolar Martin Michael; Joanne Ferry Fugett Michelle
Original assignee: Wellcome Foundation The Limited
Priority date: 1994-02-04
Filing date: 1996-07-30
Publication date: 1998-01-01

Abstract

The present invention relates to a compound of formula (VI) characterized in that R3 can be hydrogen or any group that is not linked by a glycoside bond.

Description

CHLOROPIRIMIDINE INTERMEDIARIES, r The present invention relates to certain novel pyrimidine intermediates, to processes for their preparation, and to their conversion to substituted 9-position aranopurines in the 9-position, such as certain carbocyclic, heterocyclic and acyclic purine nucleoside analogs, and the salts , esters and pharmaceutically acceptable derivatives thereof. It has been shown that a number of 2-aminopurine nucleoside analogs are useful in the treatment or prophylaxis of viral infections, for example the compound of formula (A) it is described as having potent activity against the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV) (EP 0434450). Processes have been proposed for the preparation of substituted 2-amino-purines at position 9, which generally start from a pyrimidine compound, with coupling with a residue of a sugar analogue, and cyclization to form the imidazole ring and the introduction of any suitable substitution at position 6. The pyrimidine compounds that have been identified REF: 22768 'j. as useful in the preparation of substituted 2-aminopurines in the 9-position include 2,5-diamino-4,6-dichloropyrimidine, N '- (4,6-dichloro-2,5-pyrimidindiyl) bis formamide and also the derivatives of N-2-acylated pyrimidine, such as the derivatives of 2-acetamido and 2-isobutyramide (U.S. Patent No. 5087697). The processes for the synthesis of these intermediaries generally involve a number of steps, some of which are difficult to carry out and produce poor yields, preventing any practical scaling of these processes above a few grams, and thus, are difficult. and expensive. The processes for the synthesis of the intermediate 2,5-diamino-4,6-dichloropyrimidine include the direct chlorination of 5 2,5-diamino-4,6-dihydroxypyrimidine, readily available, using phosphorus oxychloride. The original examination of this reaction was carried out by Temple et al. (J. Org. Chem. 1975, 40: 3141-3142). These researchers concluded that the reaction was not successful, apparently because of the degradation of the pyrimidine ring system. Hanson (SmithKline Beecham, WO 91/01310, in U.S. Patent No. 5216161) subsequently described a process for the direct chlorination of 2,5-diamino-6-dihydroxypyrimidine, refluxing with phosphorus oxychloride in the presence of a large molar 25% of quaternary ammonium chlorides or amine hydrochlorides. We have examined this process and have repeatedly obtained much lower yields (< 10%) of 2, 5-diamino-4,6-dichloropyrimidine than those specified in the SmithKline Beecham patent specification. The extensive decomposition of 2, 5-diamino-4,6-dihydroxypi-rimidine to tar-like material, which coats the equipment, combined with the problem of the treatment of copious solids due to insoluble amine salts, are disadvantages significant, and make the escalation of such a process impractical. The modifications of Legraverend (Syn-theesis 1990: 587-589), that is, using acetonitrile as a solvent and adding phosphorus pentachloride to phosphorus oxychloride and quaternary ammonium chloride, result, in our experience, in the isolation of approximately 30% (after chromatographic purification) of 2,5-diamino-4,6-dichloropyrimidine, on a scale of 2-5 grams. Again, scaling beyond a few grams is not practical, due to the formation of tar-like precipitates. A recent Lonza AG patent specification (EP 0552 758) suggests that higher yields (35-65%) can be obtained with chlorination by phosphorus oxychloride when the amino group which is in the 5-position of 2,5-diamino-4 , 6-dihydroxypyrimidine is protected with an alkoxycarbonyl protecting group. It is claimed that this modification simplifies the passage of chlorination, because the amines and phosphorus pentachloride, used in the above processes discussed above, are not required. This creates a new problem, that is, the need to remove the alkoxycarbonyl protecting group, to be able to convert the pi-rimidine intermediates to purines. Indeed, the specification of Lonza AG does not show that such 2, 5-diamino-4,6-dichloropyrimidines protected in position 5 can be converted to purines in an advantageous manner. A process for the synthesis of N, N '- (4,6-dichloro-2, 5-pyrimidindiyl) bis formamide is the reaction of 2,5-diamino-4,6-dichloropyrimidine with formic acid and acetic anhydride (Har -den et al., J. Med. Chem. 1990, 33: 187-196 and U.S. Patent No. 5,159,976). The 5-step pathway to the N-2-acylated derivatives, and also to the 2,5-diamine-, 6-dichloropyrimidine required for the synthesis of N, N '- (4,6-dichloro-2, 5 -pyrimidindiyl) bis form-form (Temple et al., J. Org. Chem. 1975, 40: 3141-3142), initiates from 2-amino-6-chloropyrimidin-4-one, and contains steps, which they include the introduction of the 5-nitro group, and the subsequent handling and reduction of the highly reactive intermediates of 5-nitro-4,6-dichloropyrimidine, which makes scaling impractical. The yields in a number of the steps to these intermediaries are poor (Legraverend et al., Synthesis 1990: 587-589). Now, some new intermediates of pyrimidine have been discovered, which are useful in a new synthetic route for the preparation of the substituted 2-aminopurines in position 9, and in addition, they can be used in the synthesis of the known intermediates described. above. In one aspect of this invention, we provide the following novel intermediates, which can be used in the synthesis of 2-aminopurines, ie, compounds of formulas (I), (II) and (III); 1 2 wherein R and R, which may be the same or different, are selected from straight chain alkyl groups of 1 to 8 carbon atoms, branched alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms , and aryl (such as phenyl or naphthyl), which may be optionally substituted, for example, by alkyl of 1 to 4 carbon atoms or halogen (for example Cl). In a preferred embodiment of the invention, R 1 and R 2 are both methyl. These novel intermediates can be readily prepared in good yields, and are useful for the preparation of a wide variety of different types of 2-amino-purines, including the nucleoside analog of formula (A), famciclovir (EP 0182024), penciclovir ( EP 0141927), H2G (EP 0343133), (1S, 3'S, 4'S) -2-amino-1, 9? -hydro-9- [3, 4-dihydroxy-3-hydroxymethyl-1-cyclopentyl] -6H-purin- 6-one (EP 0420518), and other substituted 2-aminopurines in position 9, provided that the substituent which is in position 9 is not linked by a glycosidic linkage. In a further aspect of this invention, we provide processes for the synthesis of novel intermediates of formulas (I), (I) and (III), and the known intermediate 2,5-diamino-4,6-dichloropyrimidine (IV) . These processes are illustrated in the simplified diagram below, which is designed to illustrate only the possible ways to synthesize these intermediaries; 2,5-diamino-4,6-dihydroxypyrimidine The present invention also provides a process for the preparation of compounds of formula (I), which comprises the chlorination of 2,5-diamino-4,6-dihydroxypyrimidine with a halomethyleneiraine salt (Vilsmeier reagent) of formula (V) . wherein R 1 and R 2 are as defined above. The compounds of formula (V) can be prepared from a variety of secondary amine formamides, by reaction with a variety of acid halides, such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosgene, and sodium chloride. oxalyl, for example as detailed in a review by CM Marson, Tetrahedron 1992, 48: 3660-3720 and the references therein. The advantage of protecting diaminopyridine from extensive decomposition during chlorination is achieved by the in situ protection of the amino groups with two molar equivalents of Vilsmeier reagent (V) to give an intermediate of bis-formamidine (detected by thin layer), which is subsequently chlorinated to a compound of formula (I) when the reaction proceeds with additional equivalents of Vilsmeier reagent. The increased solubility of such bis-formamidine derivatives is an added advantage of this process, facilitating the subsequent chlorination to the compounds of formula (I) and their isolation and simple purification. The disadvantage of the use of 5-alkoxycarbonyl protecting groups, described in the Lonza specification (EP 0552758) is avoided, since the formamidine groups present in the compounds of formula (I) are easily hydrolyzed under mild conditions, from a gradually, to form intermediaries (II) and (III); or alternatively, the compounds of formula (I) can be hydrolyzed directly to compounds of formula (III). The compound 2,5-diamino-4,6-dichloropyrimidine (IV) can be prepared by: A) hydrolysis of a compound of formula (I); B) hydrolysis of a compound of formula (II); or C) hydrolysis of a compound of formula (III). The hydrolysis of (I), (II) or (III) to 2, 5-diamino-4,6-dichloropyrimidine is conveniently carried out at pH 3 ± 0.5, adding a cosolvent miscible with water, such as eta-nol. Hydrolysis is more efficient at pH 1-2, and shorter reaction times than at a higher pH are required. It is advisable at pH 1-2, however, to protect 2, 5-diamino-, 6-di-chloropyrimidine from hydrolysis to hydroxypyrimidines by extraction, when formed, in an organic layer that is not miscible with aqueous acid. When the pH of the aqueous layer is below 1, the extraction of the product in the aqueous layer is inefficient (it was found that the pKa of (IV) is about 0.5, and thus, the pyrimidine ring is significantly protonated below of a pH of 1). Preferably, the acid used for this hydrolysis must be one which is not appreciably soluble in the organic layer, for example phosphoric or sulfuric acid. The organic solvent must be one that is stable to aqueous acid, and in which it is soluble (IV). Solvents satisfactory for the organic layer include toluene and halocarbon solvents, such as methylene chloride, chloroform, and 1,2-dichloroethane. When the reaction is finished, the organic layer is simply washed, for example with saturated aqueous bicarbonate, dried and concentrates to provide (IV) without requiring purification. The compounds of formula (III) can be prepared by: A) selective hydrolysis of a compound of formula (I); or B) Selective hydrolysis of a compound of formula (II). Hydrolysis of the compounds of formula (I) or (II) a (III) is carried out more efficiently in dilute aqueous acid, preferably in dilute aqueous mineral acid, such as sulfuric acid, hydrochloric acid, or phosphoric acid. Prolonged exposure to a pH below 1 should be avoided, since the chloropyrimidine ring is protonated signifi- ¬ ¬ cactically below a pH of 1, and can therefore undergo an attack by water, generated by undesired hydroxy-rimidine byproducts. Preferably, the pH is maintained above 2, and optimally at 3 ± 0.5 for the efficient formation of (III). In this optimum pH range, the formate-midin groups of (I) and (II) are selectively hydrolyzed, to give (III) in about 70% yield. Upon hydrolysis of the formamidine groups of (I) and (II), the secondary amine (HNR R) from which the Vilsmeier reagent (V) is formed is liberated, and causes the pH of the the solution, thereby delaying hydrolysis. Furthermore, with certain reactive aliphatic amines HNR 1 R2, such as N, N-dimethylamine, it is necessary to maintain a pH sufficiently low to prevent the chlorine groups of the pyrimidine ring from being displaced by the secondary amine. We have found that maintaining the pH of the reaction mixtures below 4 prevents a significant displacement of the chlorine groups by the secondary amine, even with reactive amines such as N, N-dimethylamine. Thus, hydrolysis of (I) and (II) to (III) at pH 3 ± 0.5, or adding acid increments during the entire hydrolysis, was found to buffer the pH in this range. Optimally, the hydrolysis of the compounds of formula (I) or (II) to (III) is carried out in a minimum of water, with the pH controlled, as described above. Under these condi- - li ¬ (III) precipitates when formed, and is simply separated by filtration and washed with water. The hydrolysis is carried out at gentle reflux for 4 hours, or at lower temperatures for longer periods of time. The compounds of formula (II) can be prepared by the selective hydrolysis of the compounds of formula (I). Preferably, the selective hydrolysis is carried out with slightly more than two molar equivalents of mineral acid in water or ethanol, and heated for 15-30 minutes. The compounds of formula (I) can be prepared by reacting 2,5-diamino-4,6-dihydroxypyrimidine with a Vilsmeier reagent of formula (V). The 2,5-diamino-4,6-dihydroxypyrimidine compound is commercially available (Sigma, Maybridge BTB, Pfalz and Bauer, Polyorganix). The novel bis-formamidines of formula (I) are conveniently formed and isolated in high yield when 2,5-diamino-, 6-dihydroxypyrimidine (or a salt thereof, such as hydrochloride or hemisulfate) is treated with minus 4 molar equivalents of a Vilsmeier reagent (V). These chlorination reactions proceed under extremely mild conditions, without formation of copious precipitates of tar-like material which characterize direct chlorinations, as previously described with phosphorus oxychloride and phosphorus oxychloride / quaternary ammonium halides. The Vilsmeier chlorination of 2,5-diamino-4,6-dihydroxypyrimidine can be carried out in an inert solvent, such as toluene, chloroalkenes, or chloroalkanes (such as methylene chloride, chloroform or 1,2-dichloroethane) ). Preferably, the solvent is 1,2-dichloroethane, chloroform, or methylene chloride. The chlorination can be carried out from 0 to 110 ° C, preferably at 40-100 ° C, conveniently at reflux for the solvent used. Reaction times are typically 12 to 48 hours. The isolation of the compounds of formula (I) is simple, and can be easily scaled, simply involving the washing of the reaction solution with an aqueous solution containing sufficient base., such as sodium bicarbonate, to neutralize any hydrogen chloride formed, and then concentrate the dried organic layer to obtain the novel chlorinated pyrimidines of formula (I). The compounds of formula (I) are generally stable, and can be precipitated from a variety of solvents, such as ethyl acetate, and stored or used without further purification. Particularly preferred examples of the compounds of the formulas (I), (II) and (III) are: a) 4,6-Dichloro-2,5-bis- [(dimethylamino) methyleneamino] pyrimidine b) 2-Amino- 4,6-dichloro-5 - [(dimethylamino) methyleneamino] pyrimidine c) N- (2-Amino-, 6-dichloro-5-pyrimidinyl) formamide According to a further aspect of this invention, the novel intermediate of formula ( III) can be used in the synthesis of 2-amino-6-chloropurines. In addition, the compounds of formula (I) or (II) can also be used in the synthesis of 2-amino-6-chloropurine nucledides, with the proviso that the amine HNR 1R2 (wherein R1 and R2 are defined above) released during the conversion of the pyrimidine intermediate to the purine, is sufficiently inert towards the displacement of the chloro group of the 2-araino-6-chloropurines generated. The compounds of formula (III) share with the N-2-acylated derivatives previously described the property of greater reactivity than 2, 5-diamino-4,6-dichloropyrimidine towards the displacement of a chloro group by a primary amine or protected hydroxylamine. appropriate However, such condensations with (III) (described in more detail below) can be carried out under milder conditions, at lower temperatures, and with shorter reaction times than with the compound (IV), resulting in less decomposition of the amines. The condensation products (VI) are isolated in higher yield and purity than the corresponding products (VIII), formed in the condensations with 2,5-diamino-4,6-dichloropyrimidine (IV). Another advantage of the use of the intermediate (III) on the N-2-acylated derivatives previously described, in addition to a greater ease of synthesis, is that the purines generated from (III) do not require deprotection, it is - 1.4 - cir, the hydrolysis of the N-2-acyl group (these longer processes are described in U.S. Patent Nos. 5,087,697 and 5,159,076).

(IXa) Where R is defined later. The compound of formula (III) can be used to prepare the novel intermediates of formula (VI), which represent a further aspect of the invention. wherein R can be hydrogen or any group that is not linked by a glycosidic linkage. Preferably, R is a hydroxyl or a protected hydroxyl; or a carbocyclic group (e.g., carbocyclic of 3 to 7 carbon atoms, an acyclic group (e.g., hydrocarbyl of 2 to 8 carbon atoms), wherein the carbon atoms may be substituted by one or more heteroatoms, such as N, 0 or S, or a heterocyclic group (for example heterocyclic of 4 to 7 carbon atoms), in which, at least one carbon atom is replaced by an atom of N, 0, 0 S, or a substituted analog of any of them (for example, such substituents are independently selected from alkyl of 1 to 4 carbon atoms, alkoxy 1 to 4 carbon atoms, hydroxyl or protected hydroxyl, azide, phosphonyl, or halogen), with the proviso that such groups are not linked by a glycosidic bond. 3 Preferred groups for R are protected hydroxyl or hydroxyl. 3 The additional preferred groups for R are: d. (AcOCH2) 2CHCH2CH2-; 3 An additional preferred group for R is - 3 The groups suitable for R are selected from a; b; c; and f;, defined above. By "hydrocarbyl" is meant a group containing only hydrogen and carbon atoms, which may contain double and / or triple bonds, and which may be straight, branched, cyclic or aromatic. According to a further aspect of the invention, we provide a process for the preparation of compounds of formula (VI), which comprises reacting a compound of formula (III) with an amine of formula R NH, , where R 3 is defined above. Such condensations are preferably carried out under reflux in a solvent such as ethanol, butanol, water or acetonitrile, in the presence of at least one equivalent of a base, such as trialkylamine or potassium or sodium carbonate. Subsequent references to formula compounds (Via, b, c, d, e, f, g, oh) denote a compound of formula 3 (VI) in which R is a group of a, b, c, d, e, f, g, oh, defined above. A particularly preferred compound of formula (VI) is (1S, 4R) -4- [(2-amino-6-chloro-5-formamido-4-pyrimidinyl) -amino] -2-cyclopenten-1-methanol (Via ). The novel intermediates (VI) can be converted by ring enclosure to the corresponding compounds of formula (VII): where R is defined above. The closing of the ring from (VI) to (VII) is conveniently carried out in trialkylorthoformates (for example, tri-ethyl ortho-formate or trimethylorthoformate) with concentrated aqueous acid (for example 2-4 molar equivalents of hydrochloric, sulfuric or methane acid). sulfonic). For example, the salt of chlor-3-hydrate of (Vlla), ie, where R represents the group a, starts to precipitate from such solutions of ortho-form of (Via) in minutes, and yields above 90% can be achieved by filtering the precipitate, optimally after several hours at room temperature. The synthesis of substituted 2-amino-6-chloropurines in position 9, such as the compounds of formula (VII), thus represents a significant improvement over the previously published syntheses, which utilize tri-aminopyrimidine intermediates such as (VIII): (VIII) described in the U.S. Patent. No. 4,916,224. The routes previously described to intermediaries such as (VIII) are more extensive and, more importantly, the number of steps to the objective purines after the incorporation of the group 3 R is greater. Also, triaminopyrimidine intermediates such as (VIII) are sensitive to air and light, and extremely difficult to purify, due to their polarity and their chelating or metal sequestering capabilities (the isolation of the zinc reduction of the diazo intermediates is especially problematic). The novel 5-formamide intermediates of formula (VI) are easily and directly available from compounds of formula (III) in one step, and they are generally solids that are stable and easily purified by precipitation of a suitable solvent. (1S, 3'S, 4'S) -2-amino-1, 9-dihydro-9- [3, 4-dihydroxy-3-hydroxymethyl-1-cyclopentyl] -6H-purin-6-one (IXh) (EPO 420,518 ) can be prepared by condensation of the compound of formula (III) with 4-amino-3-cyclopenten-1-methanol (US Patent No. 5,049,671) to form the compound of formula (VIg) followed by the ring closure of the compound of formula (VIg) to prepare the compound of formula (Vllg), which can be hydroxylated, with osmium tetratride / N-methyl-morpholine N-oxide, to provide the compound of formula (Vllh). The compound of formula (Vllh) is hydrolyzed to form the compound of formula (IXh). The 2-amino-6-chloropurine (Vllb) can be prepared by ring closure of the novel 2, 4-diamino-6-chloro-5-formamidopyrimidine (VIb), conveniently synthesized by condensation of the compound of the formula (III) with ammonia. The compound of formula (Vllb) is a suitable intermediate for the synthesis of acyclic antiviral nucleases, such as famciclovir, wherein the 2-amino-6-chloro-purine intermediate (Vlld) is conveniently subjected to hydrogendlysis to give the nucleoside of 2-aminopurine. Carbocyclic nucleosides can also be synthesized from the compound of formula (Vllb), for example by Pd catalyzed coupling with an appropriate carbocyclic intermediate, as described in Mac Keith et al., J. Chem. Soc. Perkin Trans 1, 1993: 313-314 and the references that are in it. The compounds of formula (Vlla), (VIIc), (Vlle), (Vllf), (Vllg) and (Vllh) are conveniently hydrolyzed to the corresponding guanine compound by refluxing them with base or aqueous acid. As an additional aspect of this invention, we have found an alternative process for the synthesis of 2, 6-diaminopurines (wherein the 6-amino group is substituted by R and R, which may be the same or different, and are selected from H, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl (such as fe-nyl), in particular R 4 is H and R 5 is cyclopropyl) directly from (VI) which advantageously eliminates a step in the process. Such 2-aminopurine compounds can be synthesized directly from the intermediates (VI). refluxing the compound of formula (VI) with an excess of the amine (HNR R) in a refluxing solvent, such as ethanol, isopropanol, n-propanol, t-butanol or n-butanol. In particular cases, it may be more useful to use 2,5-diamino-4,6-dichloropyriraidine (IV) to prepare compounds of formula (VIII), useful in the synthesis of modified 2-aminopurine nucleoside analogues in position 8, such as the 8-aza-2-aminopurines (which have broad spectrum anti-herpes activities, described in Storer et al., Spec. Publ.Roy. Soc. Chem. (Rec. Adv. Chem. Anti-Infect. Agents) 1993, 119: 251-265); in such cases, intermediaries (I), (II) and (III) can be used to provide (IV). Pharmaceutically acceptable esters of certain compounds of the invention can be prepared by esterification, using conventional methods known in the art. Such methods include, for example, the use of an appropriate acid halide or anhydride. The compounds of the invention, which include the esters thereof, can be converted to pharmaceutically acceptable salts in a conventional manner, by treatment with an appropriate acid or base. An ester or salt of a compound of the invention can be converted to the parent compound, for example, by hydrolysis. The following examples are proposed for illustration only, and are not intended to limit the scope of the invention in any way. Example 1 4,6-Pieloro-2, 5-bis [[(dimethylamino) methylene lamino} pyrimidine 2,5-diamino-4,6-dihydroxypyrimidine hemisulfate (Sigma, 25.0 g, 0.131 mol) in chloroform (AR Ma-llinckrodt, 400 ml) was stirred in a 2-liter 3-neck round bottom flask , equipped with a reflux condenser (with a nitrogen source connected to the top of the condenser), and an outlet for the gaseous HCl, which connected another mouth of the flask to an NaOH trap. Chloromethyl (dimethyl ammonium) chloride (Vilsmeier reagent, Aldrich, 88.0 g, 0.651 mol as 95%) was added to the flask with additional chloroform (400 ml). The reaction mixture was carefully brought to reflux, flushing the discharged HCl with nitrogen to the trap. When the evolution of HCl decreased after about 1 hour of reflux, the sweep was stopped with nitrogen, and j. the reaction was maintained under a gentle positive nitrogen pressure from that point. Additional Vilsmeier reagent (50.0 g, 0.370 mol) was added after 24 hours, and reflux was continued for an additional 20 hours. The stirred reaction mixture (yellow solution with dark yellow solid) was cooled (with ice bath) and diluted with water (sufficient to dissolve the solid, approximately 300 ml). The aqueous layer was adjusted to pH 7 with sodium hydroxide or solid sodium carbonate. The chloroform layer was separated, washed with water (3 x 400 mL), dried (sodium sulfate), and concentrated in vacuo, to give a dark yellow solid (36 grams). This solid was dissolved in ethyl acetate (300 mL), stirred with charcoal (1 g), and filtered with a pad of silica gel (7.62 cm x 7.62 cm, 3 x 3 inches, 5 packed in ethyl acetate ). The pad was washed with additional ethyl acetate, and the eluents were concentrated in vacuo, to give the title compound as a pale tan solid (30.75 g, 81%); p.f. 116-119 ° C; H NMR: identical to that of recrystallized samples. 0 Analysis Calculated for CJQH. , N6C12.0. lOEtOAc: C, 41.92; H, 5.01; N, 28.20; Cl, 23.80. Found: C, 42.23; H, 4.95; N, 28.46; Cl, 24.11. Recrystallization of such an ethyl acetate sample gave the title compound as white granules; p.f. 123-5 125 ° C; mass spectrum (CI / CH4): 291, 289 (M + 1); 1 H NMR (DMSO-d,)? : 8.49 and 8.69 (both s, 1 H each, 2 CH.). 3. 16 (s, 3 H, CH3), 3.03 (s, 6 H, 2CH3), 2.97 (s, 3 H, CH "), UV (pH 7, phosphate buffer) 1 3 max 296 nM (F 33,300), 248 (5200). Analysis Calculated for C. ^ H. , N, C1": C, 41.54; H, 4.88; N, 29.06; Cl, 24.52. Found: C, 41.59; H, 4.91; N, 29.01; Cl, 24.47. Example 2 2-Amino-4,6-dichloro-5} [(dimethylamino) methylene] amino) pyrimidine 4,6-Dichloro-2,5-bis [[(dimethylamino) methylene] -aminoj pyrimidine (Example 1, 5.87 g, 20.3 mmol) was dissolved in 95% ethanol (200 ml. ) and 6 N aqueous hydrochloric acid (13.5 ml) was added. The solution was heated in an oil bath at 55 ° C under nitrogen for 30 minutes, and at this point the TLC (silica gel, 5% methanol-chloroform) showed that the raw material had been cleanly converted to a product with Lower Rf. The cooled solution (ice bath) was adjusted to pH 8 with concentrated ammonium hydroxide, and the resulting mixture (the white precipitate formed) was concentrated in a rotary evaporator to * v5 ml, to remove the ethanol. Additional water (20 ml) was added, and the cooled mixture was filtered. The white precipitate was washed with additional water (2 x 20 mL), and dried to give the title compound as a white powder (4.50 g, 95%), m.p. > 250 ° C (decomposition); mass spectrum (CI / CH4): 236, 234 (M + l); NMR of 1 ñ (DMS0-d &) S: 7.59 (s, 1 H, CH), 6.90 (s, 2 H, NH2), 3.00 and 2.94 (both s, 3 H each, 2CH "); UV (phosphate buffer for p * H 7),? max: 328 nM (i 4500), 255 (15,800). Analysis Calculated for C-, HgN-.Cl2: C, 35.92; H, 3.88; N, 29.92; Cl, 30.29. Found: C, 35.66; H, 3.86; N, 29.74; Cl, 30.54. In another experiment, 2,5-diamino-4,6-dihydroxypyrimidine hemisulfate (Sigma, 48.0 g, 0.250 mol) was reacted as in Example 1 with less Vilsmeier reagent (7.2 molar equivalents), and 4,6-dichloro The resulting 2, 5-bis [(dimethylamino) methylene] amino) pyrimidine (92%), without recrystallization, was hydrolysed in 95% ethanol (11) and 6N aqueous hydrochloric acid (110 ml) to provide the compound of the same purity title (elemental analysis and H NMR) as the characterized sample described above (44.2 g, 76% total from the hemisulfate of 2,5-diamino-4,6-dihydroxypyrimidine). Example 3 N- (2-Amino-4,6-dichloro-5-pyrimidinyl) formamide (III) A slurry of 2-amino-4,6-dichloro-5-J [(dimethylamino) methylene] amino} pyrimidine (Example 2, 1.50 g, 6.41 mmol) v 1.5 M aqueous potassium phosphate buffer solution (35 ml, prepared by adjusting the pH of a 1.5 M solution of KHjPO, to 3.2 by the addition of 85% phosphoric acid) was subjected to at gentle reflux (in an oil bath at 125 ° C). After 4 hours of reflux, the pH of the mixture was adjusted from 4 to 3 by the addition of 4 drops of 85% phosphoric acid. After a total of 6 hours of reflux, the TLC (silica gel plates developed in 5% methanol-chloroform) showed that the raw material had been largely converted to a product with a lower Rf. The solid was filtered, and washed with water (5 ml), methanol (5 ml), and dried to give the title compound as a white solid (0.900 g, 68%), m.p. 250 ° C (decomposition); mass spectrum (CI / CH4): 209, 207 (M + 1); 1 H NMR (DMS0-d &) S: 9.81 and 9.46 (syd, J = 11 Hz, total 1 H, NH), 8.25 and 8.00 (syd, J = 11 Hz, total 1 H, CHO), 7.69 and 7.63 (both s, total 2 H, NH2). Analysis Calculated for C-.H, N, 0C12: C, 29.01; H, 1.95; N, 27.07; Cl, 34.25. Found: C, 29.12; H, 1.96, N, 27.13; Cl, 34.34. In another experiment, a slurry of 2-amino-4,6-di-chloro-5-c [(dimethylamino) methylene] aminoj-pyrimidine (Example 2, 25.0 g, 0.107 moles) in aqueous potassium phosphate buffer 1.5 M (300 ml, prepared as above) was subjected to gentle reflux for 4 hours. The pH was maintained at 3.2 by the addition of 85% phosphoric acid, when required, during this period. The precipitate was filtered, washed with water (3 x 10 ml), methanol (2 x 10 ml), and dried (50 ° C, 3.4 x 10 -2 kg / cm2 [25 mmHg]) to give the of the title as a whitish powder (16.0 g, 72%) with purity identical to that of the characterized sample described above (elemental analysis and H NMR). Example 4 2,5-Diamino-4,6-dichloropyrimidine (IV) 6-Dichloro-2,5-bis- [[(dimethylamino) methylene] aminoj pyrimidine was refluxed for 24 hours (Example 1, 1.00 g, 3.36 mmole) in ethanol (25 ml) and aqueous potassium phosphate buffer solution pH 3.2 (1.5 M, 10 ml, prepared as described in Example 3). During reflux, the pH was maintained at about 3 by the addition of 85% phosphoric acid, when required. The methanol was evaporated in vacuo, and water (10 ml) was added. This solution was extracted with chloroform (3 x 25 ml). The combined chloroform layers were dried (sodium sulfate) and the chloroform was evaporated to leave a solid (0.40 g). Crystallization of this ethanol-water / 4: 1 solid gave the title compound (IV) as whitish needles (0.324 g, 52%); it darkens and contracts to a black solid above 185 ° C, does not become fluid below 300 ° C; [from Literature 198 ° C (Legraverend et al., Synthesis 1990: 587-589) and 188-191 ° C (Temple et al., J. Org. Chem. 1975, 40: 3141-3142)]; mass spectrum (CI / CH4): 181, 179 (M + 1); NMR of * H (DMS0-d6) • '6.50 (br s, 2 H, NH2), 4.73 (br s, 2 H, NH2).

Analysis Calculated for C4H4N4C12.0.12EtOH: C, 27.60; H, 2.58; N, 30.36; Cl, 38.42. Found: C, 27.99; H, 2.39; N, 30.42; Cl, 38.74. Example 5 2,5-Diamino-4,6-dichloropyrimidine (IV) A mixture of 2-amino-4,6-dichloro-5- [(dimethylamino) methylene-lamino) pyrimidine (Example 2, 500 mg, 2.14 mmol ), aqueous potassium phosphate buffer solution pH 3.2 (1.5 M, 6 ml, prepared as described in Example 3), water (1 ml), and ethanol (5 ml) was subjected to gentle reflux for 28 hours. During the reflux period, the pH was maintained at about 3 by the addition of 85% phosphoric acid. The volatiles were evaporated in vacuo, and the residual solids were partitioned between water (30 ml, adjusted to pH 8 with dilute ammonium hydroxide) and chloroform (75 ml). The chloroform layer (sodium sulfate) was dried, and the chloroform was evaporated to give a whitish solid (0.30 g). Crystallization of this ethanol: water / 4: 1 solid made the title compound (IV) as pale pink needles (332 mg, 61%); which darken and contract to a black solid above 185 ° C, do not become fluid below 300 ° C; H NMR (DMS0-d,) and mass spectrum identical to those described in Example 4.

Analysis Calculated for C4H4N4C12: C, 26.83; H, 2.25; N, 31.30; Cl, 39.61. Found: C, 26.93; H, 2.25; N, 31.24; Cl, 39.52. Example 6 2,5-Diamino-4,6-dichloropyrimidine (IV) N- (2-amino-4,6-dichloro-5-pyrimidinyl) formamide (Example 3, 500 mg, 2.42 mmol) was dissolved in acid hydrochloric 0.1 N (5 ral, 2.5 mequivalents) and ethanol (7 ml) at reflux. The solution was refluxed for 5 hours. The volatiles were removed in vacuo. The residue was partitioned between water (30 ml) adjusted to pH 8 with dilute ammonium hydroxide, and ethyl acetate (75 ml). The ethyl acetate layer was dried (sodium sulfate). Evaporation of the ethyl acetate left a pink solid (0.40 g). Recrystallization from the 95% ethanol solid gave the title compound (IV) as pale pink needles (280 mg, 65%); that darken and contract to a black solid above 185 ° C, does not become fluid below 300 ° C; H-NMR (DMS0-d &) and mass spectrum identical to those described in Example 4. Analysis Calculated for C 4.H4.N4.C12: C, 26.83; H, 2.25; N, 31.30; Cl, 39.61. Found: C, 26.95; H, 2.24; N, 31.19; Cl, 39.53.

Example 7 (1S, 4R) -4- [(2-Amino-6-chloro-5-formarpido-4-pyrimidinyl) amino] -2-cyclopenten-1-methanol (Via) N- (2-amino- , 6-dichloro-5-pyrimidinyl) formamide (Example 3, 2.07 g, 10.0 mmol) in absolute ethanol at reflux (40 ml) under nitrogen, to achieve partial dissolution. To this stirred mixture was added a solution of (1S, 4R) -4-amino-2-cyclopenten-1-methanol prepared recently (PCT Application 9204015.3, 1.57 g, 12.5 mmoles at 90%) in ethanol (15 ml) followed by triethylamine (3.5 ml, 25 mmol, freshly distilled from calcium hydride). After 14 hours of reflux, the resulting dark solution was cooled and 1N sodium hydroxide (10 ml) was added. The volatiles were evaporated in vacuo. The residual tan solid color foam was dissolved in 5% methanol-ethyl acetate, and the solution was washed through a pad of silica gel to give the title compound as a whitish solid (2.50 g, 88%) , after evaporation of the solvents The recrystallization of the ethyl acetate-methanol solid (20: 1) did the title compound (Vía) as fine white crystals (2.29 g, 81%), mp. 177-178 ° C; mass spectrum (CI / CH4): 286, 284 (M + 1), 190, 188 (B + H); 1 H NMR (DMS0-d6) g: 8.99 and 8.58 (syd, J-11.1 Hz, total 1 H, amide NH), 8.11 and 7.80 (syd, J = 11.1 Hz, total 1 H, amide CH), 6.77 and 6.61 (two d, J = 8.0 Hz) surpassing 6.60 and 6.48 (two sa, total 3 H, NH and NH2), 5.85 and 5.70 (two m, 1 H each, CH = CH), 5.15-5.00 (m, 1 H, NCH), 4.71 (t, J = 5.1 Hz, 1 H, OH), 3.45-3.30 (m which is superimposed on that of H2), 0CH2), 2.80-2.65 (m, 1 H, CH), 2.45- 5 2.25 and 1.45-1.30 (both m, 1 H each, CH2); Mron = + 21.2 °, [*] 52 = + 22.2 °, [< *] 206 = + 25.2 °, M ^ ° 6 - + 41.4 °, ^ 365 = + 48'3 ° (c ° -50 'methanol). Analysis Calculated for C .. H, 4N-.02C1: C, 46.57; H, 4.97; N, 24.69; Cl, 12.50. Found: 0 C, 46.63; H, 4.99; N, 24.58; Cl, 12.59. Example 8 (1S, 4R) -4- (2-amino-6-chloro-9H-purin-9-yl) -2-cyclopenten-1-methanol hydrochloride (Vlla) A mixture of (1S, R) -4- [(2-amino-6-chloro-5-formamido-5-pyrimidinyl) amino] -2-cyclopenten-l-methanol (Example 7, 1.00 g, 3.50 mmol) and triethylorthoformate (Aldrich, Sure Seal, 18 ml) was stirred while concentrated hydrochloric acid (37%, 1.25 ml) was added in one portion. The clear, colorless, clear solution was stirred under nitrogen. A white precipitate was started at-0 sea after 15 minutes. After 4 hours, the TLC of a drop of the reaction mixture dissolved in methanol and neutralized with sodium hydroxide (plates of silica gel developed in 10% methanol-chloroform, visualized with UV light) showed an almost complete conversion. of Via to a material with a higher Rf. The precipitate was filtered, washed with t-butyl methyl ether (15 ml), and dried at 2.72 x 10 ~ kg / cm (0.2 mmHg / 25 ° C) for 18 hours to give the title compound as a white powder (975 mg, 92%), mp > 300 ° C with decomposition; mass spectrum (CI / CH,): 266 (M + 1); 1 H NMR (DMS0-d &) 5: 8.18 (s, 1 H, purine CH), 7.2-6.7 '(sa, NH2, OH superimposed by water), 6.20 and 5.90 (both m, 1 H each one, CH = CH), 5.48 (m, 1 H, NCH), 3.47 (d, J = 5.7 Hz, 2 H, CH20), 2.90 (m, 1 H, CH), 2.75-2.55 and 1.75-1.60 ( both m, 1 H each, CH2). • Calculated Analysis for Cj ^ H- ^ NgOCl. HCl: C, 43.73; H, 4.34; N, 23.18; Cl, 23.48. Found: C, 43.62; H, 4.43; N, 23.07; Cl, 23.53. Example 9 (1S, 4R) -4- [2-Amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol (IXa) A solution of (1S, 4R) -4 -chloro-5-formamido-6- [[(4-hydroxymethyl) -2-cyclopenten-1-yl Jamino} pyrimidine (Example 8, 250 mg, 0.883 mmol) was subjected to gentle reflux (in an oil bath maintained at 130 ° C) in n-butanol (dried on molecular sieves of 4 A, 5 ml) under nitrogen with cyclopropylamine (Aldrich, 0.30 ml, 4.4 mmol) for 16 hours. A second portion of cyclopropylamine (0.15 ml) was added, and reflux was continued for an additional 5 hours. The volatiles were removed, and the residual oil was redissolved in ethanol-water (1: 1) with 1 N sodium hydroxide (0.5 ml). The volatiles were removed again, and the residue was chromatographed on a flash column of silica gel (2.54 cm x 25.4 cm [1 x 10 inches]). (1S, 4R) - [(2,5-diamino-6-chloro-4-pyrimidinyl) -amino] -2-cyclopenten-1-methanol (Villa, 35 mg, 16%) eluted with 5% methanol- ethyl acetate. Elution continued with 10% methanol-ethyl acetate gave (1S, 4R) -4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-ethanol (IXa ) as a solid foam of pale bronzed color (160 mg, 60%); NMR of H (DMS0-d6) S: 7.58 (s, 1 H, purine CH), 7.25 (d, J - 4.5 Hz, 1 H, NH), 6.10 (m, 1 H, = CH), 5.80- 5.75 (m, 3 H, = CH and NH2), 5.40 (, 1 H, NCH), 4.72 (m, 1 H, OH), 3.45 (m, 2 H, 0CH2), 3.0 (ma, 1 H, CH cyclopropyl), 2.80 (m, 1 H, CH), 2.70-2.50 (m superimposed on solvent, CH), 1.50-1.05 (m, 1 H, CH), 0.70-0.50 (m, 4 H, 2 CH2 of cyclopropyl). Analysis Calculated for C 14 H 18 N 60.20 H 20.0.40 'CH 3 OH: C, 57.32; H, 6.35; N, 27.85. Found: C, 57.59; H, 6.48; N, 27.70. Example 10 (1S, 4R) -4- [2-Amino-6- (cyclo-ropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol (IXa) was refluxed in ethanol ( 1S, 4R) -4- (2-Amino-6-chloro-9H-purin-9-yl) -2-cyclopenten-1-methanol (US Patent No. 5,206,435) or the hydrochloride salt thereof (Example 1). * pio 8) with 10 molar equivalents of cyclopropylamine for 2 hours. The resulting solution was cooled to room temperature, and 1 N sodium hydroxide (1 or 2 molar equivalents, depending on whether the starting material was Vlla or the Vlla hydrochloride salt) was added. The volatiles were evaporated in vacuo. The (1S, 4R) -4- [2-araino-6- (cyclopropyl-amino) -9H-purin-9-yl] -2-cyclopenten-l-methanol (IXa) was washed from a pad of silica gel eluted with 5% methanol-chloroform or 10% methanol-ethyl acetate, and isolated as a white solid foam (80%); the spectra were identical to those of the product of Example 9. Example 11 (1, S, 3> S, 4, S) -2-Amino-1, 9-dihydro-9- (3, 4-dihydroxy-3) hydroxymethyl-1-cyclopentyl) -6H-purin-6-one a) (4R) -4 - [(2-Amino-6-chloro-5-formamido-4-pyrimidinyl) amino] -1-cyclopenten-1 -methanol By the method of Example 7, N- (2-amino-4,6-dichloro-5-pyrimidinyl) formamide was reacted (Example 3, 2.56 g, 52.4 mmole) with (4R) -4-amino -l-cyclopenten-l-methanol 0 (1.4 g, 52.4 mmol), available from (-) -2-azabicyclo- [2.2.1] hept-5-en-3-one (Chiroscience) by the methods described in Examples 1-4 and 42 of U.S. Patent No. 5,049,671. Crystallization from ethyl acetate-methanol gave the title compound as white crystals, m.p. 148-150 ° C; mass spectrum (CI / CH4): 286, 284 (M + 1), 190, 188 (B + H); NMR of H (DMSO-dg) $: 8.97 and 8.55 (syd with J = 11.3 Hz, total 1 H, NHCHO), 8.12 and 7.80 (syd with J = 11.5 Hz, total 1 H, CHO), 7.00 and 7.78 ( arabos d, J - 7.4 Hz, total 1 H, NH), 6.60 and 6.40 (both d, total 2 H, NH2), 5.48 (s, 1 H, = CH), 4.74 (t, J = 5.5 Hz, 1 H, OH), 4.74-4.60 (m, 1 H, NCH), 4.0-3.90 (m, 2 H, CH20), 2.75-2.55 and 2.40-2. 15 (both m, 2 H each, 2CH2); [°] 2 -.0fig = -4 .4 °, M 52 ° 78 -60 .4 ° (c 0.25, methanol). Analysis Calculated for C,, H, 4N_02C1: C, 46.57; H, 4.97; N, 24.69; Cl, 12.50. Found: C, 46.64; H, 5.01; N, 24.60; Cl, 12.45. b) (4R) -4- (2-Amino-6-chloro-9H-purin-9-yl) -l-cyclopenten-l-methanol A mixture of (4R) -4- [(2-amino-6- chloro-5-formamido-4-pyrimidinyl) amino] -1-cyclopenten-1-methanol (Part a, 1.60 g, 5.65 mmol) and triethylorthoformate (29 ml) was stirred while concentrated hydrochloric acid was added in one portion ( 37%, 2.0 mi). The resulting clear and colorless solution was stirred under nitrogen. After 5 hours, the resulting precipitate was filtered and washed with t-butyl methyl ether (3 x 10 ml, and dried to give a white powder (1.25 g) This powder was dissolved in water, and the pH was adjusted The solution was heated at 60 ° C for 4 hours, cooled, neutralized, and evaporated to a solid, which was subjected to chromatography on silica gel. The title compound was eluted with 5% methanol-chloro-form, and crystallized from ethanol-ethyl acetate to give white crystals, mp 145-147 ° C, mass spectrum (CI / CH4): 268, 266 (M + 1), 172, 170 (B + H); H NMR (DMS0-d & S): 8.09 (s, 1 H, purine CH), 6.9 (sa, 2 H, NH2), 5.64 (m, 1 H, = CH), 5.2-5.0 (, 1 H, NCH), 4.87 (t, J - 5.5 Hz, 1 H, OH), 4.05 (m, 2 H, CH20), 3.0-2.5 (m, 4 H, 2CH2) Analysis Calculated for C-1 H.2N_.0C1: C, 49.06; H, 4.64; N, 26.01; Cl, 13.16, Found: C, 49.18; H, 4.63; N, 26.11; Cl, 13.19. (1S, 2S, 4R) -4- (2-Amino-6-chloro-9H-purin-9-yl) -2- (hydroxy-methyl-1,2-cyclopentanediol) were heated (4R) - 4- (2-amino-6-chloro-9H-purin-9-yl) -l-cyclopenten-1-methanol (Part b, 501 mg, 1.89 mmol), N-methylmorpholine N-oxide (60% aqueous solution) %, Aldrich, 0.33 ml, 1.89 mmol), osmium tetroxide (2.5% in t-butyl alcohol, Aldrich, 0.47 ml), and t-butyl alcohol (12 ml) at 60 ° C for 1.5 hours. The volatiles were evaporated, and the residual solids were subjected to chromatography on silica gel. The title compound was eluted with 10% methanol-chloroform as a tan solid (210 mg) and re-solidified from absolute ethanol to give a white powder, m.p. 217-219 ° C; mass spectrum (CI / CH,): 302, 300 (M + 1), 172, 170 (B + H); 1 B NMR (DMS0-d) S: 8.29 (s, 1 H, purine CH), 6.9 (br s, 2 H, NH2), 5.15-4.90 (m, 1 H, NCH), 4.80 (d, J = 3.9 Hz) overlapping 4.78 (t, J = 3.5 Hz, total 2 H, 20H), 4.30 (s) overriding 4.3- 4.2 (m, total 2 H, OH and 0CH), 3.45-3.35 (m, which is superimposed on water, CH.-0H),. 2.25-2.05 (m, 4 H, 2 CH2). Analysis Calculated for C .. H.Nr-0 Cl: C, 44.08; H, 4.71; N, 23.37; Cl, 11.83. Found: C, 43.89; H, 4.80; N, 23.16; Cl, 11.73. d) (1 'S, 3'S, 4'S) -2-Amino-l, 9-dihydro-9- (3,4-dihydroxy-3-hydroxymethyl-1-cyclopentyl) -6H-purin-6-one Was subjected to reflux (1S, 2S, 4R) -4- (2-amino-6-chloro-9H-purin-9-yl) -2- (hydroxymethyl) -1,2-cyclopentanediol (Part c, 90 mg, 0.27 mmol) in 1 N hydrochloric acid (2.7 ml) for 45 minutes. The volatiles were evaporated in vacuo. Portions of water were evaporated, and the residue was redissolved in water. The pH was adjusted to 5 with hydrochloric acid, and the resulting mixture was cooled, filtered, and the precipitate was dried to give the title compound as an off-white powder (51 mg, 68%), m.p. > 300 ° C with decomposition; mass spectrum (CI / CH4): 283 (M + 1); 1U NMR (DMSO-dg) identical to that described in U.S. Patent No. 5,233,041. Example 12 N- (2,4-Diamino-6-chloro-5-pyrimidinyl) formamide. They were stirred in a Parr autoclave at 50 ° C for 18 hours N- (2-amino-4,6-dichloro-5-pyrimidinyl) ) formamide (Example 3, 500 mg, 2.14 mmol) and ammonia (150 ml). The ammonia was evaporated, and the residual solid was triturated with water (10 ml). The solid was dried to give the title compound as a red powder (400 ra, 89%), p.f. * >; 300 ° C; mass spectrum (CI / CH): 190, 188 (M + 1); 1 H NMR (DMS0-d6) S: 9.05 and 8.60 (both sa, total 1 H, NHCHO), 8.1 and 7.8 (both sa, total 1 H, NHCHO), 6.80-6.20 (4 sa, total 4 H, 2NH2). Analysis Calculated for C, -H, N-.0C1: C, 32.01; H, 3.22; N, 37.34; Cl, 18.90. Found: C, 31.97; H, 3.23; N, 37.26; Cl, 19.00.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims

CLAIMS 1. A compound of formula (I)

1 2 characterized in that R and R, which may be the same or different, are selected from alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, and optionally substituted aryl.
2. A compound of formula (I) according to claim 1, characterized in that R1 and R2 are both alkyl of 1 to 8 carbon atoms.
3. A compound of formula (II)

characterized in that R 1 and R 2 are as defined in claims 1 or 2.
4. A compound of formula (III)

A compound of formula (VI)

characterized in that R can be hydrogen or any group that is not linked by a glycosidic linkage. 6. A compound according to claim 3, characterized in that R is a carbocyclic group of 3 to 7 carbon atoms, hydrocarbyl of 2 to 8 carbon atoms, or heterocyclic of 4 to 7 carbon atoms, with the proviso that that such groups are not linked by a glycosidic bond. 7. A compound of formula (VI) according to claim 3, characterized in that R is a group selected from:

HO ^ ^

b. H;

d. (AcOCH2) 2 HCH2CH2-;

e.HOCH2CH2CHCH2"; CHjOH

twenty

8. A compound of formula (VI), characterized in that

R3 is

25

9. A process for the preparation of a compound of formula (VII)

wherein R is as defined in claims 5, 6, 7, or 8, the process is characterized in that it comprises ring closure of a compound of formula (VI) defined in claim 5, in the presence of an acid. 10. A process for the preparation of a compound of formula (VI)

wherein R is as defined in claims 5, 6, 7, or 8, the process is characterized in that it comprises reacting a compound of formula (II) defined in claim 3 with an amine of formula R NH2 in presence of a base. 11. A process for the preparation of a compound of formula (I), defined in claim 1, the process is characterized in that it comprises reacting 2,5-diamino-, 6-dihydroxypyrimidine with a compound of formula (V)

wherein R 1 and R 2 are as defined in the claims

1 or 2. 12. A process for the preparation of a compound of formula (II)

1 2 - wherein R and R are defined in claims 1 or

2; the process is characterized in that it comprises hydrolyzing a compound of formula (I). 13. A process for the preparation of a compound of formula (III) I)

characterized in that a compound of formula (I) or (II) is hydrolyzed. 14. A process for the preparation of a compound of formula (VI)

wherein R is as defined in claims 5, 6, 7, or 8; the process is characterized in that it comprises reacting a compound of formula (II) defined in claim 3 with an amine of formula R NH ". 15. A process for the preparation of 2,5-diamino-4,6-dichloropyrimidine, characterized in that a compound of formula (I), (II), or (III) is hydrolyzed. 16. A process for the preparation of 2, 6-diaminopurines in which the 6-amino group is substituted by R 4 and R 5, which may be the same or different, and are selected from hydrogen, alkyl from 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl, the process is characterized by the reaction of a compound of formula (VI) defined in claims 5, 6 or 7 with an excess of amine HNR 4R5 in a refluxing solvent. 17. A process for the preparation of (1S, 4R) -4- [2-ami-no-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol, the process is characterized by the reaction of a compound of formula (VI) defined in claim 8 with an excess of cyclopropylamine in a refluxing solvent.