SI20022A - Alkyl substituted purine derivatives and their preparation - Google Patents

Abstract

The invention refers to a new procedure of preparation of alkyl substituted purine derivatives, specifically N7 and N9 alkyl purine derivatives, and to new compounds such as N7 alkyl derivatives exhibiting a potential biological, e.g. antiviral or antitumor activity. The new procedure enables a regionally selective attachment of a certain alkyl group to the site 7 or site 9 of purine and after having removed the protective group on a second nitrogen atom of the imidazole part of the molecule, a desired compound is obtained in a regionally selective way. According to this procedure, 9-benzyl guanine was successfully prepared from 7-benzyl guanine too. A new procedure is also described for preparation of famciclovir via intermediate penciclovir, which has been prepared according to the said procedure from 7-benzyl guanine.

Description

Alkyl substituted purine derivatives and their preparation

The invention relates to a new process for the preparation of alkyl substituted purine derivatives, specifically N7 or N9 alkyl purine derivatives, and to novel compounds, namely N7 alkyl purine derivatives with a potential biological, e.g. antiviral or antitumor efficacy. The new process allows regioselective coupling of a particular alkyl group at site 7 or site 9 of purine.

Purine derivatives, mostly substituted at site 9, represent a number of important antiviral active ingredients, among which are acyclovir, ganciclovir and famciclovir, and the like that are still under development. Recently, the promising biological results of N7-substituted 2-amino purine with an acyclic component characteristic of ganciclovir (EP-A 448 006, EP-A 452 680) have enriched the range of interesting substances. Purine derivatives are usually prepared by attaching a side chain to a basic purine base. The basic problem and challenge, therefore, is the sensible choice of an output base (feedstock) to which it is possible to selectively introduce the selected side chain to the desired N7 or N9 site.

Regioselective alkylation of guanine is, of course, not a trivial problem. The NI and N3 sites need to be protected or deactivated first, attachment to the N7 site is a kinetically controlled process, while N9-substituted derivatives are thermodynamically more stable. The final ratio of the two products also depends specifically on the substituent at the C6 site (Nucleosides & Nucleotides, 8, 225,1989). If we emphasize that for commercial reasons, when concentrating on the starting material, we will concentrate on cheap naturally derived derivatives that can be industrially obtained by fermentation, namely guanosine and guanosine through it, we face a serious problem. Martin et al. as early as 1983, a mixture of N7 and N9-substituted compounds was isolated using diacetyl guanine (J. Med. Chem., 26, 559, 1983). The same happens with the synthesis of penciclovia (Chinese J. Chem; 9, 536, 1991).

It may be mentioned here that most academic work in the search for new purine derivatives has been done on 2-amino-6-chloropurine. Through various approaches, they were able to improve the efficiency ratio of individual N9 to N7 derivatives to 40: 1, but the condensation was not selective. At the same time, it should be emphasized that 2-amino-6-chloro purine is a mutagenic compound at a high price and has been deliberately avoided. (Tetrahedron Lett .; 33,469,1992).

Last but not least, the remarkable biological activity of purine analogues with an acyclic component bound at the N7 site was surprisingly found (EP-A 448 006, 542 680). This fact particularly motivates the search for general solutions for selective coupling at the desired N7 or N9 sites. The first successful results were achieved using the N-triacetyl glyoxal guanine derivative (US Pat. 4 701 526; Acta Chem. Scan. B, 41, 564, 1987), where the alkyl chain was selectively attached to site 7 (J. Het Chem. 23, 625, 1986), but with poor efficiency.

Therefore, the use of alkyl chains for purine substitution has shown the need for a new process.

The object of the present invention is a novel, regioselective process for the preparation of alkyl substituted purine derivatives, specifically N7 or N9 alkyl purine derivatives, derived from 7- or 9benzylguanine.

A further object of the invention is N7 alkyl purine derivatives, which are novel compounds with potentially biological, e.g. antiviral or antitumor efficacy.

To solve the above problems, the inventors have chosen a synthesis route for protecting the imidazole moiety of a guanine molecule with a benzyl group at site 7 or site 9, depending on the purpose to which the substituent is desired. The benzyl group can be easily introduced at site 7 via a natural nucleoside (guanosine) prepared by fermentation. (P. Brookes et al. J. Chem. Soc. (C) 2026, 1968 and P.K. Bridson et al; Synthetic Commun; 20, 2459, 1990). Of course, the protection of a particular site implies the possibility of selective condensation to the remaining active sites 7 and 9, respectively.

In the further reaction, removal of the protecting group on the second nitrogen atom of the imidazole moiety yields the desired compound via a regioselective pathway. In this way, we were also able to prepare 9-benzyl guanine from 7-benzyl guanine, which was further investigated. We also describe a process for the preparation of famciclovium via an intermediate penciclovig prepared by the subject process of 7-benzyl guanine.

According to the present invention, compounds of formula 4 or 5 are prepared:

5 in which:

Ac represents acetyl,

R ₂ represents a CrCi ₂ long straight or branched, saturated or unsaturated alkyl group which may contain a 3-7 membered ring in the molecule as well as an ether, thioether, acetal, thioacetal, lactone, thiolactone, mono or diacyl group, phosphorylmethoxy, phosphorylethoxy and phosphate group,

R ₃ represents a substituted p-methoxy, p-nitro, p-methyl benzyl group on the ring, X represents a chlorine, bromine, iodine, p-toluenesulfone group or mesyloxy group such that the compound represented by formula 1 or 2

in which R1 represents hydrogen, a C1-C6 alkyl group, a C1-C8 alkoxy group, a hydroxy group, a nitro group, an amino group, fluorine, chlorine, bromine or iodine, is reacted with a compound representing the desired substituent (chain) with a reactive leaving group represented by of the formula 3 r ₂ x in which X and R _{2 have} the above meanings.

According to the invention, the 9- and 7-substituted purine derivatives of formula 6 and 7 are prepared,

in which R _{2 has} the above meaning by hydrogenation of the above compounds of formulas 4 and 5.

The present invention provides a preferred example of penciclovium synthesis

and its N7 isomer of formula 10

In the preparation of the above compounds, the chain R ₂ X is represented by the formula 9 (R <) A »(R.) A <

wherein R 4 represents a C 1 -C 5 acyl group, a C ₁ -C 10 alkyl group, or a C ₇ -C ₂₂ arylalkyl group.

The process of the present invention comprises the deoxygenation of compounds 6 and 7 which is carried out via

O6-sulfonylated intermediates 11 and 12

OAc

Ac

> Ac

OAc where

A C represents acetyl,

Ar represents 2,4,6- ^ 3 (3 ^ 2-, 2,4,6-Me3C $ H ₂ -, 4-MeC6H4-, 4-FC6H4-, in famciclovir of formula 14 and its isomer of formula 13

OAc> Ac

OAc where Ac has the upper meaning.

The starting compounds used in the invention, that is, substituted N7-benzyl derivatives, can be prepared from purine nucleosides and then converted to 9-benzyl guanine via an intermediate of formula 4 (R ₃ = benzyl).

The compound of formula 3 of the present invention has a prominent group such as chlorine, bromine, iodine, tosyl or mesyl group on a straight or branched chain, mentioned above. The alkyl group of the present invention represents a side chain characteristic of potential biologically active nucleoside agents and is attached to a purine ring. The product thus assembled has antiviral or antitumor properties. The reaction is preferably characterized by the following substituents, but by no means limited thereto.

In the formulas below, R, R 'and R' represent acetyl, benzoyl, benzyl or other standard protecting groups, and X initially has the meaning given to formulas 4 and 5.

RO

OR '

EtOOC

BOOC

The above-mentioned compounds as N-substituted derivatives are known active ingredients, while N7-substituted derivatives are new compounds.

The condensation reaction takes place in organic solvents such as DMF, DMSO, l-methyl-2-pyrrolidone, preferably in l-methyl-2-pyrrolidone, at a temperature of 80 to 120 ° C and is completed within a few hours. Side chain excess (20 to 50%) is required to improve efficiency.

The compounds of formulas 4 and 5 are novel compounds except in the case of the compounds described in EP-A 728757 A.

Compounds 4 and 5, prepared by the above procedure, typically form salts. If the salt does not precipitate, it is possible to carry out the debenzylation (hydrogenation) reaction on the crude product. Removal of the benzyl group yields the desired intermediates 6 and 7. General methods, such as reduction in the presence of palladium catalyzate under hydrogen, or with formic acid or ammonium formate in standard solvents are used.

In this way, the invention represents and enables the regioselective preparation of alkylated purine derivatives directly from guanosine with substituents at site 9. 9-Substituted derivatives are useful as medicaments. New 7-substituted isomers, especially after deoxygenation into 2 amino- 7 -alkyl compounds, represent a new type of compound with potential biological activity, e.g. antiviral or antitumor efficacy.

The above invention is exemplified by the following Examples and is by no means limited thereto.

THE EXPERIMENTAL PART

1. Synthesis:

Example 1

7-benzylguanine

Guanosine (56.6 g, 0.2 mol) was suspended by stirring in DMSO (150 ml) and benzyl bromide (13 ml, 0.11 mol) was added after 20 minutes of stirring. The mixture was stirred at room temperature for 24 hours. Transfer the solution to the beaker, add 10% HCl (250 ml) and heat for 2 hours at 70 ° C. A precipitate was removed from the reaction mixture, which was cooled and drained. The precipitate was washed with water (approximately 100 ml), suspended in water and neutralized with 6 M NaOH. The precipitate was filtered off and dried in a vacuum gun at 100 ° C. White powder (35.0 g and 5.5 g from the second treatment, 85% in total) was obtained.

1 H NMR (DMSO-d 6) δ 8.07 (1H, s, H-8), 7.27-7.36 (5H, m, Ph), 6.13 (2H, broad s, NH 2, 5.41 (2H, s, CHjPh) .

N -acetyl-7-benzylguanine

7-Benzylguanine (9.65 g, 0.04 mol) was suspended in 1-methyl-2-pyrrolidone (40 ml), Ac ₂ O (5.7 ml, 0.06 mol) was added and heated at 150 ° C for 1 hour. The solvent was distilled off under reduced pressure, the residue was suspended in EtOAc (50 ml) and filtered off. The precipitate was washed with acetone (10 ml). A white powdery product (10.5 g, 93%) was obtained.

1 H NMR (DMSO-d ₆ ) δ 12.11 (1H, rs, NHAc), 11.58 (1H, s, H1), 8.35 (1H, s, H-8), 7.31-7.35 (5H, m, Ph). 5.51 (2H, s, CH2 Ph), 2.15 (3H, s, CH2 CO).

J

7,9-Dibenzyl-N-acetylguanine bromide

Benzyl bromide (3.3 ml, 0.030 mol) was added to a suspension of 7V ² -acetyl-7-benzylguanine (5.6 g, 0.020 mol) in 1-methyl-2-pyrrolidone. The mixture was heated at 120 ° C for 2 hours, then poured hot into EtOAc (150 ml) and stirred for one hour. The peripheral was drained and washed with acetone (10 ml). After drying, 7,9-dibenzyl-N-acetylguanamine bromide (8.Ig, 90%) was obtained.

1 H NMR (DMSO-d ₆ ) δ 12.61 (1H, rs, NHAc), 12.14 (1H, s, H1), 9.83 (1H, s, H-8), 7.38-7.52 (10H, m, 2 Ph) , 5.71 (2H, s, 7N- CHjPh), 5:50 (2H, s, 9N-CH _of Ph \ 2.22 (3H, s, CH ₃ CO).

9-Benzylguanine

A mixture of 7,9-dibenzyl-A ² -acetylguanine bromide (11.5 g, 0.025 mol) and ammonium formate (4.4 g, 0.07 mol) was prepared in methanol (230 ml) and 10% Pd / C (1.2 g) was added. The reaction mixture was heated with stirring at boiling point for 4 hours, filtered hot and washed with hot methanol. The aqueous solution of ammonium aka (20 ml) was added to the filtrate and heated at boiling point for 1 hour.

The solvent was distilled off under reduced pressure and the residue was recrystallized from DMF. A mixture of 7-benzylguanine and 9-benzylguanine was obtained in a ratio of 1 to 7 (determined from NMR, H-8 and / or NH ₂ ) (4.85 g, 0.02 mol, 80%).

The mixture (0.5 g) was transferred to Celite and washed with MeOH (500 - 700 ml). Concentrate the solution to remove the precipitated precipitate. 9-Benzylguanine (0.4 g, 91%) was obtained. 1 H NMR (DMSO-d ₆ ) δ 10.63 (1H, broad s, Hl), 7.76 (1H, s, H-8), 7,207.37 (5H, m, Ph), 6.45 (2H, broad s) , NH ₂ ), 5.18 (2H, s, CH _with Ph).

7V ² -acetyl-9-benzylguanine

To a suspension of 9-benzylguanine (3.7 g, 0.015 mol) in 1-methyl-2-pyrrolidone (25 ml) was added AC ₂ O (2.9 ml, 0.031 mol). The reaction mixture was heated at 150 ° C for 4 hours, then distilled off to dryness under reduced pressure. Fresh l-methyl-2-pyrrolidone (5-10 ml) was added and ether (50 ml) was added with vigorous stirring. Cool and let stand overnight. The crystals were filtered off, washed with THF and dried (1.95 g, 46%).

Ή NMR (DMSO) δ 12.03 (1H, broad s, NHAc), 11.65 (1H, broad s, H1), 8.09 (1H, s, H-8), 7.2-7.3 (5H, m, Ph). 5.32 (2H, s, CH, Ph), 2.16 (3H, s, CH3CO).

7- [4-hydroxy-3- (hydroxymethyl) but-1-yl] guanine

N ² -acetyl-9-benzylguanine (0.50 g, 0.0018 mol) was suspended in 1-methyl-2-pyrrolidone (5 ml), 4-acetoxy-3-acetoxymethyl-1-butyl tosylate (0.76 g, 0.0021 mol) was added and was heated for 2 hours at 120 ° C, then 4-acetoxy-3-acetoxymethyl-1-butyl tosylate (0.28 g, 0.0008 mol) was gradually added and continued heating at 120 ° C for a further 18 hours. Cool and pour into Et ₂ O (20 ml). After 1 hour, the solvent was decanted, washed with Et ₂ O (10 ml) and the residue dissolved in MeOH (25 ml). Activated charcoal is added, boiled and hot filtered. The ammonium formate (0.4 g), 10% Pd on activated carbon (0.15 g) was added to the filtrate and heated at boiling point for 4 hours. The mixture was filtered and the filtrate was washed with MeOH (10 ml). The solvent was evaporated under reduced pressure. The residue was dissolved in 1 M NaOH solution (10 ml) and heated to steam for half an hour. Cooled and neutralized with concentrated HCl. Let stand for 3 hours until the precipitate is removed. The precipitate was washed with cold water and dried in a vacuum gun (60 ° C). White crystals (132 mg, 29%) were obtained.

^! H NMR (DMSO-d ₆ ) δ 10.74 (1H, broad s, Hl), 7.93 (1H, s, H-8), 6.12 (2H, broad s, NH ₂ ), 4.41 (2H, broad s , 2x OH), 4.23 (2H, t, NCH ₂ ), under water (CH ₂ O), 1.74 (2H, m, CH ₂ CH), 1.4 (1H, m, CH).

9- [4-hydroxy-3- (hydroxymethyl) but-1-ylguanine

N -acetyl-7-benzylguanine (1.42 g, 0.005 mol) was suspended in 1-methyl-2-pyrrolidone (10 ml), 4-acetoxy-3-acetoxymethyl-1-butyl tosylate (2.15 g, 0.006 mol) was added and heated 2 hours at 120 ° C, then 4-acetoxy-3-acetoxymethyl-1-butyl tosylate (0.36 g, 0.001 mol) was added again and continued heating at 120 ° C for a further 2 hours. Cool and pour into Et ₂ O (50 ml). After 1 hour, the solvent was decanted, washed with Et ₂ O (10 ml) and the residue dissolved in MeOH (25 ml). Activated charcoal is added, boiled and hot filtered. The ammonium formate (0.9 g), 10% Pd on activated carbon (0.3 g) was added to the filtrate and heated at boiling point for 4 hours. The mixture was filtered and the filtrate was washed with MeOH (10 ml). The solvent was evaporated under reduced pressure. The residue was dissolved in 1 M NaOH solution (15 ml) and heated to steam for half an hour. Cooled and neutralized with concentrated HCl. Let stand for 3 hours until the precipitate is removed. The precipitate was washed with cold water and dried in a vacuum gun (60 ° C). White crystals (0.6 g, 47%) were obtained.

&Lt; 1 &gt; H NMR (DMSO-do) δ 10.51 (1H, broad s, H1), 7.68 (1H, s, H-8), 6.41 (2H, broad s, NH ₂ ), 4.44 (2H, broad s , 2x OH), 3.99 (2H, t, NCH ₂ ), under water (CH ₂ O), 1.70 (2H, m, CH 2 CH), 1.45 (1H, m, CH).

N ² -acetyl-9- [4-hydroxy-3- (hydroxymethyl) but-1-yl] guanine

To a suspension of 9- [4-hydroxy-3- (hydroxymethyl) but-1-yl] guanine (1.4 g, 0.006 mol) in 1-methyl2-pyrrolidone (10 ml) was added Ac ₂ O (2.4 ml, 0.025 mol) and heated at 150 ° C for 5 hours. The solvent was distilled off under reduced pressure and the residue dissolved in water methanol (50: 50), activated charcoal added and hot filtered. Upon cooling (refrigerator, clock), the crystals which are weaned fall out. Drying gave N -acetyl-9- [4hydroxy-3- (hydroxymethyl) but-1-yl] guanine crystals (1.65 g and 0.1 g from other treatments, 83%).

^! H NMR (DMSO-d ₆ ) δ 12.02 (1H, broad s, NHAc), 11.70 (1H, broad s, Hl), 8.03 (1H, s, H-8), 4.17 (2H, t, NCH ₂ ), 4.03 (4H, d, CH ₂ O), 2.20 (3H, s, NHCOCH 3), 1.84-2.02 (9H, m, CH ₂ CHiCH, OCOCH ₃ ) _? ).

9- [4-hydroxy-3- (hydroxymethyl) but-1-yl] -2-acetylamino-6- (2 ', 4', 6 'triisopropylbenzenesulfonyloxy) -977-purine

Mixture of N ² -acetyl-9- [4-hydroxy-3- (hydroxymethyl) but-1-yl] -guanine (1.3 g, 0.0034 mol), 4-dimethylaminopyridine (0.021 g, 0.0017 mol), triethylamine (1.9 ml, 0.0014 mol ), anhydrous dichloromethane (35 ml) and 2,4,6-triisopropylbenzenesulfonyl chloride (2.08 g, 0.0069 mol) were stirred at room temperature until complete clarification (2.5 hours). The solvent was evaporated under reduced pressure and the product was isolated by flash chromatography (mobile phase: dichloromethane followed by ethyl acetate). 9- [4-Hydroxy-3- (hydroxymethyl) but-1-yl] -213 acetylamino-6- (2 ', 4', 6'-triisopropylbenzenesulfonyloxy) -9H-purine (2.21 g, 99.9%) is obtained like yellow foam that slowly crystallizes.

9- [4-hydroxy-3- (hydroxymethyl) but-1-yl] -2-aminopurine

9- [4-hydroxy-3- (hydroxymethyl) but-1-yl] -2-acetylamino-6- (2 ', 4', 6'-triisopropylbenzenesulfonyloxy) -9H-purine (8.5 g, 0.0132 mol) , dissolved in absolute ethanol (140 ml) and 10% Pd / C (1.4 g) and triethylamine (19.8 ml, 0.140 mol) were added. Hydrogenate in a Parr hydrogenator at 80 - 85 ° C and at a pressure of 3 bar for 8 hours. The charcoal is filtered off and washed with hot ethanol. Upon cooling, acetylated deoxy product (3.1 g, 60%) was obtained, which was dissolved (2.65 g) in water (20 ml) and in 40% aqueous methylamine (9 ml). The solution was then stirred for 15 minutes at room temperature and evaporated. The evaporation is repeated several times with 10 ml of water each to expel methylamine. The residue was recrystallized from abs. ethanol. 9- [4-Hydroxy-3- (hydroxymethyl) but-1-yl] -2-aminopurine (1.7 g, 99%) was obtained.

1 H NMR (DMSO-d ₆ ) δ 8.55 (1H, s, H-6), 8.07 (1H, s, H-8), 6.49 (2H, s, NH ₂ ), 4.44 (2H, t, 2x OH ), 4.11 (2H, t, NCH ₂ ), 3.1 - 3.5 (4H, m, 2x, CH ₂ O), 1.76 (2H, q, CH _Z CH), 1.45 (1H, m, CH).

9- [4-acetoxy- (acetoxymethyl) but-1-yl] -2-aminopurine

A mixture of 9- [4-hydroxy-3- (hydroxymethyl) but-1-yl] -2-aminopurine (1.75 g, 0.0074 mol), Ac ₂ O (1.7 ml) in pyridine (1.8 ml), DMAP (90 mg, 0.0074 mol) in anhydrous THF (30 ml) was stirred for 3 hours at room temperature. The solvent was distilled off under reduced pressure and the residue dissolved in water (25 ml). This mixture was extracted with dichloromethane (3 x 40 ml). The extracts were dried with Na ₂ SO ₄ and evaporated to dryness. The white powder was treated with Et ₂ O and filtered. Famciclovir (2.3 g, 97%) was obtained.

1 H NMR (DMSO-d ₆ ) δ 8.56 (1H, s, H-6), 8.9 (1H, s, H-8), 6.49 (2H, s, NH ₂ ), 4.13 (2H, t, NCH ₂ ), 4.02 (4H, d, 2x CH ₂ O), 1.99 (6H, s, 2x CH ₃ ), 1.87 (3H, m, CH ₂ CH).

N -acetyl-7-benzyl-9- (4-acetoxybut-1-yl) guanine bromide

To a suspension of N -acetyl-7-benzylguanine (14.1 g, 0.05 mol) in 1-methyl-2-pyrrolidone (35 ml) was added 4-bromobut-1-yl acetate (10.7 g, 0.055 mol) and heated for 2 hours at temperature

120 ° C. The reaction mixture was then cooled and poured into EtOAc (500 ml). After 1 hour, the precipitate was filtered off and washed with acetone. After drying, N -acetyl-7-benzyl-9- (4acetoxybut-1-yl) guanine bromide was obtained as a white salt (21 g, 88%), which was used in the next step without prior purification.

Ή NMR (DMSO-de) δ 12.60 (1H, broad s, NHAc), 12.17 (1H, s, H1), 9.83 (1H, s, H-8), 7.4 - 7.5 (5H, m, Ph). 5.72 (2H, s, CH ₂ Ph), 4.29 (2H, t, NCH ₂ ), 4.04 (2H, t, OCH ₂ ), 2.23 (3H, s, NHCOCH ₃ ), 2.01 (3H, s, OCOCH ₃ ) ,

1.85 (2H, m, NCHCH?), 1.67 (2H, m, CH ₂ CH ₂ O).

9- (4-Acetoxybut-1-yl) guanine

A mixture of N -acetyl-7-benzyl-9- (4-acetoxybutyl-lyl) guaninium bromide (21 g, 0.044 mol) and ammonium formate (7 g, 0.11 mol) was prepared in methanol (400 ml) and 10% Pd / was added. C (2.7 g). The reaction mixture was heated with stirring at boiling point for 4 hours, filtered hot and washed with hot water (50 ml). The filtrate is heated at the boiling temperature for a further 1 hour, then the solvent is distilled off under reduced pressure. The residue was recrystallized from water to give pure 9- (4-acetoxybut-1-yl) guanine (7.7 g, 66%).

'H NMR (DMSO-d ₆₎ δ 10:54 (IH, s, Hl), 7.70 (IH, s, H-8), 6:44 (2H, cheese. S., NH _2), 3.97 (4H, m, OCH ₂ and NCH ₂ ), 1.99 (3H, s, CH ₃ ), 1.77 (2H, m, Ci ^ CH ₂ N), 1.52 (2H, m, CH ₂ CH, O).

N ² -acetyl-9- (4-acetoxybut-1-yl) guanine

To a suspension of 9- (4-acetoxybut-1-yl) guanine (3.0 g, 0.01 mol) in 1-methyl-2-pyrrolidone (10 ml) was added Ac ₂ O (2.1 ml, 0.02 mol) and heated at boiling point 5 ur. The reaction mixture was cooled and concentrated to about 8 ml. With stirring, Et ₂ O (50 ml) was added and cooled to remove crystals which were drained and washed with Et ₂ O. After drying, N acetyl-9- (4-acetoxybut-1-yl) guanine (3.16 g, 91%) was obtained, which can be used in the next step without prior purification.

Ή NMR (DMSO-de) δ 12.03 (1H, broad s, NHAc), 11.71 (1H, broad s, Hl), 8.01 (1H, s, H-8), 4.09 (2H, t, NCH ₂ ) , 4.01 (2H, t, OCH ₂ ), 2.18 (3H, s, NHCOCH3), 2.00 (3H, s, OCOCH3), 1.83 (2H, m, CH ₂ CH ₂ N), 1.55 (2H, m, CH2CH ₂ O).

N ² -acetyl-9-benzyl-7- (4-acetoxybut-1-yl) guanine bromide

To a suspension of 9-benzylguanine (2.4 g, 0.01 mol) in 1-methyl-2-pyrrolidone (20 ml) was added 4bromobut-1-yl acetate (2.9 g, 0.015 mol) and heated for 2 hours at 120 ° C. The reaction mixture was then cooled and poured into Et ₂ O (200 ml). After 1 hour the solvent was decanted from a dark colored rubber residue treated with ethyl acetate to salt. The precipitate was filtered off and washed with EtOAc. After drying, N -acetyl-9-benzyl-7- (4acetoxybut-1-yl) guanine bromide (4.3 g, 99%) was obtained, which was used in the next step without prior purification.

1 H NMR (DMSO-d 6) δ 11.70 (1H, s, H1), 9.44 (1H, s, H-8), 7.41 (5H, m, Ph), 7.25 (2H, broad s, NH ₂ ) , 5.38 (2H, s, CH ₂ Ph), 4.40 (2H, t, NCH ₂ ), 4.02 (2H, t, OCH ₂ ), 1.90 (2H, m, NCHCH,). 1.62 (2H, m, CH ₂ CH ₂ O).

7- (4-Acetoxybut-1-yl) guanine

A mixture of 9-benzyl-7- (4-acetoxybut-1-yl) guanine bromide (4.3g, 0.010 mol) and ammonium formate (1.9 g, 0.03 mol) was added in methanol (80 ml) and 10% Pd / C ( 0.4 g). The reaction mixture was heated with stirring at reflux for 4 hours, filtered hot and distilled off under reduced pressure to dryness. The catalyst was washed with hot 2M NaOH solution (30 ml) and added to the dry residue. The solution thus obtained is heated over steam for 20 minutes and then neutralized with conc. HCI. In one hour, crystals fall out, which is filtered off and washed with water. After drying, 7- (4-acetoxybut-1-yl) guanine (1.55 g, 71%) was obtained.

&Lt; 1 &gt; H NMR (DMSO-ds) δ 10.76 (1H, broad s, hl), 7.91 (1H, s, H-8), 6.12 (2H, broad s, NH ₂ ), 4.44 (1H, t , OH), 4.18 (2H, t, NCH ₂ ), 3.37 (2H, t, CH ₂ O), 1.99 (3H, s, CH ₃ ), 1.78 Γ2Η. m. CH, CH, N). 1.35 i2H. m. CH ₂ CH, O).

and N ² -acetyl-7 (4-acetoxybut-1-yl) guanine

To a suspension of 7- (4-acetoxybut-1-yl) guanine (1 g, 0.004 mol) in 1-methyl-2-pyrrolidone (10 ml) was added Ac ₂ O (1.1 ml, 0.011 mol) and heated at boiling point 10 ur. The solvent was distilled off under reduced pressure, suspended in EtOAc (5 ml) and filtered off. Wash with acetone. After drying, TV ² -acetyl-7- (4-acetoxybut-1-yl) guanine (1.05 g, 90%) was obtained.

^] H NMR (DMSO-d $) δ 12.05 (1H, broad s, NHAc), 11.58 (1H, broad s, H1), 8.19 (1H, s, H-8), 4.30 (2H, t, NCH ₂ ), 4.00 (2H, t, CH ₂ O), 2.16 (3H, s, NHCOCHA, 1.98 (3H, s, OCOCH ₃ ), 1.85 (2H, m, NC ^ CH 2), 1.51 (2H, m. CH ₂ CH ₂ OAc).

7- (4-Acetoxybut-1-yl) -2-acetylamino-6- (2 ', 4', 6 '-triisopropylbenzenesulfonyloxy) -7 // - purine

Mixture A ^? -acetyl-7 (4-acetoxybut-1-yl) guanine (0.5 g, 0.0016 mol), 4-dimethylaminopyridine (10 mg, 0.0001 mol), triethylamine (0.9 ml, 0.0064 mol), anhydrous dichloromethane (20 ml) and 2 ', 4', 6'-triisopropyl-benzenesulfonyl chloride (1.0 g, 0.0033 mol) was stirred at room temperature until clarification and filtered. Wash with 2 x 15 ml of water, combine the aqueous phase and wash with 20 ml of dichloromethane. The combined organic phases were washed with brine ("juniper", sodium chloride solution) (2 x 25 ml) and dried with Na ₂ SO4. The solvent was distilled off under reduced pressure and the product was isolated by flash chromatography (mobile phase; CH ₂ Cl ₂ (300 ml) followed by EtOAc (600 ml). 7- (4-Acetoxybut-1-yl) -2-acetylamino-6 (2 ', 4', 6'-triisopropylbenzene-sulfonyloxy) -7H-purine (0.9 g, 96%) was obtained as a yellow foam, which gave slowly crystallizes.

1 H NMR (DMSO-d ₆ ) δ 8.14 (1H, s, NH), 7.62 (1H, s, H-8), 7.27 (2H, s, 3'5 'Ar), 4.42 (2H, t, NCH ₂ ), 4.14 (2H, t, CH ₂ O), 4.06 (2H, m, 2'-CH, 6'-CH),

2.97 (1H, m, 4'-CH), 2.12 (3H, s, NHCOCH 2), 2.07 (3H, s, OCOCH ₃ ), 1.73 (2H, m, NCH, CHA 1.63 (2H, m, -CH ₂ ) , 1.30 (6H, d, p-CHfCH2), 1.25 (12H, d, o-CH (CHA?) ·

7- (4-Acetoxybut-1-yl) -2-acetylamino-777-purine

7- (4-Acetoxybut-1-yl) -2-acetylamino-6- (2 ', 4', 6 '-triisopropylbenzenesulfonyloxy) -7H-purine (0.55 g, 0.001 mol) was dissolved in absolute ethanol (25 ml ), 10% Pd / C (0.2 g) and triethylamine (0.15 ml, 0.0011 mol) were added. Hydrogenate in a Parr hydrogenator at 75 ° C and at a pressure of 3 bar for 6 hours. The charcoal is filtered off and washed with hot ethanol. After cooling, a mixture of N-acetyl-7 (4-acetoxybut-1-yl) guanine and 7- (4-acetoxybut-1-yl) 2-acetylamino-7/7-purine is obtained. They were separated by flash chromatography (mobile phase: CH2Cl2: MeOH = 20: 1 (400 ml), 10: 1 (400 ml) to give 7- (4-acetoxybut-1-yl) -2-acetylamino777-purine ( 0.14 g, 50%) as a white precipitate.

Ή NMR (DMSO-de) δ 10.42 (1H, broad s, NHAc), 9.10 (1Η, s, H-6), 8.62 (1H, s, H-8), 4.35 (2H, t, NCH ₂ ) , 4.01 (2H, t, CH ₂ O), 2.18 (3H, s, NHCOCH 3), 1.98 (3H, s, OCOCH3), 1.89 (2H, m, NCH, CH _Z L 1.54 (2H, m, CH ₂ CH) ₂ OA _c) .

Claims (10)

1. A process for the preparation of compounds of formula 4 or 5: 4 5 in which: Ac represents acetyl, R ₂ represents a C 1 -C 8 long straight or branched, saturated or unsaturated alkyl group which may contain a 3-7 membered ring in the molecule and also an ether, thioether, acetal, thioacetal, lactone, thiolactone, mono or diacyl group, phosphorylmethoxy, phosphorylethoxy and phosphate group, R ₃ represents a substituted p-methoxy, p-nitro, p-methyl benzyl group on the ring, X represents a chlorine, bromine, iodine, p-toluenesulfone group or mesyloxy group, characterized in that the compound represented by formula 1 or 2 u «M? in which R1 represents hydrogen, a C1-C8 alkyl group, a C1-C6 alkoxy group, a hydroxy group, a nitro group, an amino group, fluorine, chlorine, bromine or iodine, is reacted with a compound representing the desired substituent (chain) with a reactive leaving group represented by Formula 3 R ₂ X in which X and R _{2 have the} meanings indicated above. 2. Compounds of Formula 6 O wherein R _{2 is as defined} in claim 1. A process for the preparation of 9 and 7 substituted purine derivatives of formula 6 and 7 in which R 2 has the stated meaning in claim 1, by hydrogenation of the compounds of formula 4 and 5 in which Ac, X, R 2 and R 3 have the indicated meaning. Compounds of formula 4 in which Ac, X, R2 and R3 have the meaning indicated in claim 1. Compounds of formula 5 in which Ac, X, R ₂ and R 3 have the meaning indicated in claim 1. A process according to claim 3, characterized in that penciclovir of the formula is obtained in which R ₂ has the meaning indicated in claim 1 and its N7 isomer of formula 10 OH Process according to claim 1,3,6, characterized in that the chain R ₂ X is represented by formula 9 (R.) A '(M Ai OTs where R4 represents a C 1 -C 8 acyl group, a C 1 -C 10 alkyl group, or a C 7 -C 22 arylalkyl group. A process for the deoxygenation of compounds 6 and 7 of claim 3, which is carried out via O6-sulfonylated intermediates 11 and 12 wherein Ac represents acetyl, and Ar represents 2,4,6-'Pr3C6H ₂ -, 2,4,6-Me3C6H ₂ -, 4-MeCgH4-, 4-FC6H4-, in famciclovir of formula 14 and its isomer of formula 13 wherein Ac has the above meaning. Compounds of formula 12 wherein Ac is as defined in claim 1 and Ar is as defined in claim 8. A compound of formula 13 {7- [4-acetoxy-3- (acetoxymethyl) but-1-yl] -2-amino-7H-purine} wherein Ac is as defined in claim 1.