WO2004007418A1

WO2004007418A1 - A process for the preparation of 2-acetoxymethyl-4 halo-but-1-yl acetates

Info

Publication number: WO2004007418A1
Application number: PCT/EP2003/007237
Authority: WO
Inventors: Raffaele Saladino; Umberto Ciambecchini; Daniele Mancinetti; Fausto Bonifacio; Cristina Crescenzi
Original assignee: Recordati S.A.
Priority date: 2002-07-12
Filing date: 2003-07-07
Publication date: 2004-01-22
Also published as: ITMI20021533A1; AU2003249964A1

Abstract

A process for the preparation of 2- acetoxymethyl-4-halo-but-l-yl acetates (I) in which X is chlorine or bromine, which are useful intermediates for the preparation of antiviral medicaments such as Penciclovir and Famciclovir, comprising the opening of 3-hydroxymethyl-tetrahydrofuran (V) in the presence of an acylating agent and a Lewis acid selected from magnesium bromide and samarium triiodide.

Description

A PROCESS FOR THE PREPARATION OF 2-ACETOXYMETHYL-4- HALO-BUT-1-YL ACETATES

FIELD OF THE INVENTION

The present invention relates to purine antiviral drugs, in particular to the synthesis of intermediates for the preparation of Penciclovir and Famciclovir.

TECHNOLOGICAL BACKGROUND

Penciclovir (II) and Famciclovir (III) are compounds having antiviral activity disclosed in EP 0141927 and EP 0182024, respectively.

The preparation thereof comprises the reaction of 2-amino-6-chloro- purine (IV)

(IV) with a compound of formula (I)

(I) in which X is a leaving group. The compound of formula (I) is prepared (Scheme 1) by condensing diethyl malonate with benzyl-2-bromoethyl-ether (in turn prepared from bromomethylbenzene and ethylenecarbonate) to give ethyl 4-benzyloxy-2- ethoxycarbonylbutanoate, which is reduced to the corresponding diol with lithium aluminium hydride. 4-Benzyloxy-2-hydroxymethylbutan-l-ol is acetylated and debenzylated by hydrogenolysis to give 2-acetoxymethyl-4- hydroxy-but-1-yl acetate. Substitution of the hydroxyl with a suitable leaving group affords intermediate of formula (I).

(EtOOC)₂CH₂

EtONa

LiAlr

Scheme 1

This process is, however, disadvantageous from the industrial point of view, in that it provides rather low overall yields and involves a number of steps and the use of difficult-to-handle, costly reagents, such as lithium aluminium hydride and palladium on charcoal.

Compounds of formula (I) in which X is iodine can also be obtained by ring opening of either 3-hydroxymethyl-tetrahydrofuran (V)

(V)

or 3-acetoxymethyl-tetrahydrofuran (Via)

(Via)

with acetyl chloride and sodium iodide as described by Mimero and coll. in Synthetic Communications, 25(5), 613-627 (1995). Advantageously, said method starts from a commercially available product and only consists of a single step. However, in addition to the desired 2-acetoxymethyl-4-iodo-but- l- yl acetate, the 2-iodomethyl-4-acetoxy-but-l-yl acetate isomer is also obtained and, when the substrate is 3-hydroxymethyl-tetrahydrofuran, the bis- halogenation product, namely 2-iodomethyl-4-iodo-but-l-yl acetate, is also obtained (Scheme 2):

Scheme 2

Said two by-products are hardly separated from the main product, which is a remarkable drawback for the subsequent step to obtain Penciclovir and Famciclovir; they also alkylate purines causing in turn further by-products to form, thereby decreasing yields.

A number of methods for the preparation of guanine or purine derivatives involve the use of protected guanines or other purines as starting material, in place of guanine which has low solubility as well as many possible substitution sites (N-l, N-2, N-3, 0-6, N-7 and N-9). 2-Amino-6- chloropurine, although rather difficult to prepare (K. K. Ogilvie et al. Can. J. Chem. 1982, 60, 3005), is widely used as precursor in the synthesis of N-9 substituted guanines. Kjellberg et al. (Nucleoside & Nucleotides 1989, 8, 225) studied the ratio of N-9 to N-7 products formed by alkylation of 2-amino-6- chloropurine with various alkyl halides in dimethylformamide in basic conditions (LiH, NaH, K₂C0₃). The N-9/N-7 ratio can vary between 4 and 8, but very low yields can also be obtained. The highest yields and the most advantageous products ratio are obtained when using potassium carbonate as the base and dimethylformamide (M. R. Harvest et al. J. Med. Chem. 1987, 30, 1636; Tetrahedron Lett. 1985, 26, 4265) or dimethylsulfoxide (J. Zemlicka Nucleoside & Nucleotides 1984, 3, 245) as the solvent.

A solution to problem of the formation of bis-halogenation products in the synthesis of compounds of formula (I) has been suggested by Yu and coll. [Synthetic Communications, 23(14), 1973-1977, 1993], which have described the synthesis of 4-iodo-butan- l-ol esters by opening tetrahydrofuran with samarium triiodide and an acid chloride.

One the other hand, the problem of isomers formation is still unsolved, as far as we know. Goldsmith and coll. (J. Org. Chem. Vol. 40, No. 24, 1975) disclosed the opening of cyclic ethers with magnesium bromide and acetic anhydride. The Authors observed that treatment of 2- and 3-methyl- tetrahydrofuran under said conditions afforded isomeric mixtures deriving from the attack of the nucleophile at the 2- and 5- positions. More particularly, 3-methyl-tetrahydrofuran afforded a mixture of 3-methyl and 2-methyl-4- bromobutyl acetate in a 2.7: 1 ratio.

A procedure for opening 3-hydroxymethyl-tetrahydrofuran, which does not involve the formation of bis-halogenation products and takes place with complete regioselectivity, would be therefore be advantageous. DISCLOSURE OF THE INVENTION

The present invention relates to a process for the preparation of 2- acetoxymethyl-4-halo-but-l-yl acetates (I)

(I) in which X is bromine or iodine, comprising the opening of 3-hydroxymethyl-tetrahydrofuran (V)

(V) in the presence of an acylating agent and a Lewis acid selected from magnesium bromide and samarium triiodide.

"Acylating agent " herein means an anhydride, preferably acetic anhydride, or an acid chloride RCOC1, in which R represents: a straight or branched, saturated or unsaturated, Cι-C₁₉ chain, optionally substituted with one or more chlorine or fluorine atoms, or cyclohexyl, phenyl, benzyl or 1-naphthyl.

According to a preferred aspect of the invention, the straight or branched, saturated or unsaturated, CrC₁₉ chain is methyl, chloromethyl, propyl, isopropyl, t-butyl, vinyl, propen-1-yl, heptafluoropropyl.

Particularly preferred acylating agents are acetic anhydride and acetyl chloride. Preferably, when the acylating agent is acetyl chloride, the Lewis acid is samarium triiodide, whereas when the acylating agent is acetic anhydride the Lewis acid is magnesium bromide.

In more detail, the reaction can be carried out either in a single step, or isolating a 3-acyloxymethyltetrahydrofuran (VI) intermediate

(VI)

wherein R has the meanings defined above.

In the first case, 3-hydroxymethyl-tetrahydrofuran (V) is reacted with the acylating agent, preferably acetic anhydride or acetyl chloride, and with the Lewis acid as defined above. When using acylating agents other than acetic anhydride or acetyl chloride, the acyl groups will be replaced with acetyl groups after completion of the reaction. The molar ratio of 3- hydroxymethyl-tetrahydrofuran to acylating agent ranges from 4.5 to 2.0, and the molar ratio of 3-hydroxymethyl-tetrahydrofuran to Lewis acid ranges from 2.5 to 2.0. The reaction is carried out in organic aliphatic solvents, preferably acetonitrile, at a temperature ranging from 25 to 80°C, preferably from 60 to 80°C. The reaction is usually complete in a time from 18 to 48 hours.

In the second case, 3-hydroxymethyl-tetrahydrofuran (V) is previously acylated with an acylating agent as defined above in the presence of a base, preferably dimethylamino pyridine, in organic aliphatic or aromatic solvents, preferably dichloromethane, at a temperature ranging from 0 to 50°C, preferably from 0 to 25°C. The molar ratio of 3-hydroxymethyl- tetrahydrofuran to acylating agent ranges from 1.1 to 1.0. The reaction is complete in a time ranging from 0.5 to 2 hours.

The resulting 3-acyloxymethyl-tetrahydrofuran (VI) is reacted again with the acylating agent, preferably acetic anhydride or acetyl chloride, and with the Lewis acid as defined above. When using acylating agents other than acetic anhydride or acetyl chloride, the acyl groups will be replaced with acetyl groups after completion of the reaction. The molar ratio of 3- acyloxymethyl-tetrahydrofuran to acylating agent ranges from 2.5 to 1.0 and the molar ratio of 3 -acyloxymethyl-tetrahydrofuran to Lewis acid ranges from 1.1 to 1.0. The reaction is carried out in organic aliphatic solvents, preferably acetonitrile, at a temperature ranging from 25 to 80°C, preferably from 60 to 80°C, and is usually complete in a time ranging from 9 to 48 hours. When the acylating agent is acetic anhydride or acetyl chloride, the reaction product consists for at least 90% of the compound of formula (I), and for 10% of the 2-halomethyl-4-acetoxy-but-l-yl-acetate isomer. No formation of the bis-halogenation products is observed. Furthermore, the isomeric ratio obtained even when the reaction is carried out with isolation of the intermediate 3-acetoxymethyltetrahydrofuran, allows to directly prepare Penciclovir and Famciclovir, with no need for purification of compound (I) by fractional distillation.

The mixture consisting of 2-acetoxymethyl-4-iodo-butyl acetate and 2- acetoxymethyl-4-bromo-butyl acetate has been added to 2-amino-6- chloropurine (IV) in the presence of potassium carbonate and afforded the same results as those described in literature (Kjellberg et al., M. R. Harvest et al.): the main product is always the N9-alkylated purine (N9), while the (N7) isomer forms only in low yields as a by-product, which can be easily separated by chromatography (Scheme 3):

N9 (56%) N7 (7%) N9 (58%) N7 (8%)

Scheme 3

9-(4-Acetoxy-3-acetoxymethyl-but-l-yl)-2-amino-chloropurine (N9), once separated from its (N7) isomer, is transformed into Famciclovir by H₂ transfer catalytic reduction with ammonium formate (Scheme 4).

Scheme 4 The invention will be further illustrated by the following examples.

Examples

Example 1 - Preparation of 2-acetoxymethyl-4-bromo-butyl-l -acetate.

Method 1

A suspension of magnesium bromide (2 eq/mole, 108.17 g) in acetonitrile (300 ml) is added, at 0°C, with acetic anhydride (4 eq/mole,

119.95 g). The mixture is left under stirring for 15 minutes at 0°C, then 3- hydroxymethyl tetrahydrofuran (30 g, 293 mmoles) is added. The mixture is kept at the reflux temperature until complete disappearance of the substrate (18 h), then is added with 300 ml of a sodium bicarbonate saturated solution and left under stirring at room temperature for 30 minutes. The mixture is extracted with ethyl acetate (3x100 ml), the organic phase is dried over anhydrous sodium sulfate, filtered and the solvent is evaporated off to a residue. The reaction conversion is quantitative. 59.02 g (yield: 75%) of a colourless oil are obtained. The gas-chromatographic and nuclear magnetic resonance analysis of the residue show the presence of a mixture consisting of 2-acetoxymethyl-4-bromo-butyl-l -acetate and its 2-bromomethyl-4-acetoxy- butyl- 1 -acetate isomer in a yield of 90% (53.12 g) and 10% (5.902 g), respectively. This mixture can be used directly in the subsequent reaction for the alkylation of 2-aminochloropurine (IV) as no addition products due to the presence of the minor isomer are formed. (The two isomers can anyway be separated, if necessary, by fractional distillation). 2-Acetoxymethyl-4-bromo-butyl-l -acetate:

1H-NMR (δ, ppm): 1.83 (q, 2H, CH₂) 1.98 (s, 6H, 2(CH₃) 2.07-2.13 (m, 1H, CH) 3.45 (t, 2H, CH₂Br) 4.04 (d, 4H, 2(CH₂0).

¹³C-NMR (δ, ppm): 21.33 (CH₂Br) 31.03(2(CH₃) 32.01 (CH₂) 36.55 (CH) 64.00 (2(CH₂0) 171.37 (2(CO). 2-Bromomethyl-4-acetoxy-butyl- 1 -acetate:

1H-NMR (δ, ppm): 1.63 (m, 2H, CH₂) 1.88 (s, 3H, CH₃) 1.90 (s, 3H, CH₃) 1.99 (m, 1H, CH) 3.37 (d, 2H, CH₂Br) 4.01 (d, 2H, CH₂0) 4.13 (t, 2H, CH₂0).

¹³C-NMR (δ, ppm): 20.55 (CH₃) 21.03 (CH₃) 28.37 (CH) 34.49 (CH₂Br) 36.03 (CH₂) 61.25 (OCH₂) 66.26 (OCH₂) 170.39 (CO) 170.42 (CO). Method 2 a) A mixture of 3 -hydroxy methyl tetrahydrofuran (30 g, 293.74 mmoles), triethylamine (2 eq/mole, 59.44 g), dimethylaminopyridine (0,1 eq/mole, 3.58 g) and dichloromethane (300 ml) is added, at 0°C, with acetic anhydride (1 eq/mole, 29.98 g). The reaction is left at room temperature until complete disappearance of the substrate. A sodium bicarbonate saturated solution (300 ml) is added and the mixture is left under stirring for 15 minutes, then extracted with ethyl acetate (3x100 ml). The organic phase is washed with 2 N hydrochloric acid (100 ml), dried over anhydrous sodium sulfate and the solvent is evaporated off to a residue. 33.83 g of 3- acetoxymethyl tetrahydrofuran are obtained, in an 80% yield.

1H-NMR (δ, ppm): 1.53 (m, IH, CH) 1.92 (m, IH, CH) 2.01 (s, 3H, CH₃) 2.44 (m, IH, CH) 3.55 (dd, IH, CH) 3.63 (m, 3H, CH and CH₂) 3.78 (m, 2H, CH₂).

¹³C-NMR (δ, ppm): 20.54 (CH₃) 28.65 (CH₂) 37.92 (CH) 65.60 (CH₂) 67.37 (CH₂) 70.22 (CH₂) 170.64 (CO). b) A mixture of 3 -acetoxy methyl tetrahydrofuran (33 g, 229.16 mmoles) in acetonitrile (300 ml) is added at 0°C with magnesium bromide (1 eq/mole, 42.19 g), then, at 0°C, with acetic anhydride (2 eq/mole, 46.79 g) and is refluxed until complete disappearance of the substrate (9 h). 300 ml of a sodium bicarbonate saturated solution are added and the mixture is left under stirring at room temperature for 30 minutes, then extracted with ethyl acetate (3x100 ml). The organic phase is dried over anhydrous sodium sulfate, then filtered and the solvent is evaporated off to a residue. The reaction conversion is quantitative. 45.43 g (yield: 73.5%) of a mixture consisting of 2- acetoxymethyl-4-bromo-butyl-l -acetate and its 2-bromomethyl-4-acetoxy- butyl- 1 -acetate isomer are obtained, in a yield of 90% (40.88 g) and 10% (4.543 g), respectively.

2- Acetoxy methy 1-4-bromo-buty 1- 1 -acetate :

1H-NMR (δ, ppm): 1.83 (q, 2H, CH₂) 1.98 (s, 6H, 2(CH₃) 2.07-2.13 (m, IH, CH) 3.45 (t, 2H, CH₂Br) 4.04 (d, 4H, 2(CH₂0). ¹³C-NMR (δ, ppm): 21.33 (CH₂Br) 31.03 (2(CH₃) 32.01 (CH₂) 36.55 (CH) 64.00 (2(CH₂0) 171.37 (2(CO).

2-Bromomethyl-4-acetoxy-butyl-l -acetate:

1H-NMR (δ, ppm): 1.63 (m, 2H, CH₂) 1.88 (s, 3H, CH₃) 1.90 (s, 3H, CH₃) 1.99 (m, IH, CH) 3.37 (d, 2H, CH₂Br) 4.01 (d, 2H, CH₂0) 4.13 (t, 2H, CH₂0).

¹³C-NMR (δ, ppm): 20.55 (CH₃) 21.03 (CH₃) 28.37 (CH) 34.49 (CH₂Br) 36.03 (CH₂) 61.25 (OCH₂) 66.26 (OCH₂) 170.39 (CO) 170.42 (CO). Example 2 - Preparation of 2-acetoxymethyl-4-iodo-butyl-l -acetate. Method 1

Samarium powder (0.8 eq/mole, 35.33 g) is placed in a thoroughly dried round-bottom flask, equipped with magnetic stirrer, under inert atmosphere. A solution of 3-hydroxymethyl tetrahydrofuran (30 g, 293 mmoles), iodine (1 eq/mole, 74.55 g), acetyl chloride (2 eq/mole, 46.1 1 g) in acetonitrile (500 ml) is added, at room temperature, and the resulting mixture is kept under stirring at room temperature for 48 h, then added with 2 N hydrochloric acid (100 ml) and extracted with ethyl ether (3(100 ml). The combined organic phases are washed with a sodium thiosulfate aqueous solution (3x50 ml), dried over anhydrous sodium sulfate and the solvent is evaporated off. The crude residue is purified by chromatography (eluent hexane/ethyl acetate 9: 1) to give 50.72 g of 2-acetoxymethyl-4-iodo-butyl- l -acetate in a 55% yield.

Η-NMR (δ, ppm): 1.88 (q, 2H, CH₂) 2.00 (s, 6H, 2(CH₃) 2.03-2.10 (m, IH, CH) 3.21 (t, 2H, CH₂I) 4.02 (d, 4H, 2(CH₂0).

¹³C-NMR (δ, ppm): 2.64 (CH₂I) 20.54 (2(CH₃) 32.10 (CH₂) 37.94 (CH) 63.05 (2(CH₂0) 170.55 (2(CO). Method 2 a) A mixture of 3-hydroxymethyl tetrahydrofuran (30 g, 293.74 mmoles), triethylamine (2 eq/mole, 59.44 g), dimethylaminopyridine (0.1 eq/mole, 3.58 g) and dichloromethane (300 ml) is added, at 0°C, with acetic anhydride (1 eq/mole, 29.98 g). The reaction is left at room temperature until complete disappearance of the substrate. A sodium bicarbonate saturated solution (300 ml) is added and the mixture is left under stirring for 15 minutes, then extracted with ethyl acetate (3(100 ml). The organic phase is washed with 2 N hydrochloric acid (100 ml), dried over anhydrous sodium sulfate and the solvent is evaporated off. 33.83 g of 3-acetoxymethyl tetrahydrofuran are obtained in an 80% yield.

¹³C-NMR (δ, ppm): 20.54 (CH₃) 28.65 (CH₂) 37.92 (CH) 65.60 (CH₂) 67.37 (CH₂) 70.22 (CH₂) 170.64 (CO). b) Samarium powder (0.4 eq/mole, 13.78 g) is placed in a thoroughly dried round-bottom flask, equipped with magnetic stirrer, under inert atmosphere, and a solution of 3-acetoxymethyl tetrahydrofuran (33 g, 229.16 mmoles), iodine (0.5 eq/mole, 29.08 g), acetyl chloride (1 eq/mole, 17.98 g) in acetonitrile (500 ml) is added, at room temperature. The resulting mixture is kept under stirring at room temperature for 48 h, then added with 2 N hydrochloric acid (100 ml) and extracted with ethyl ether (3(100 ml). The combined organic phases are washed with a sodium thiosulfate aqueous solution (3x50 ml), dried over anhydrous sodium sulfate and the solvent is evaporated off. The crude residue is purified by chromatography (eluent hexane/ethyl acetate 9: 1) to give 41.80 g of 2-acetoxymethyl-4-iodo-butyl-l- acetate in a 58% yield.

1H-NMR (δ, ppm): 1.88 (q, 2H, CH₂) 2.00 (s, 6H, 2(CH₃) 2.03-2.10 (m, IH, CH) 3.21 (t, 2H, CH₂I) 4.02 (d, 4H, 2(CH₂0).

¹³C-NMR (δ, ppm): 2.64 (CH₂I) 20.54 (2(CH₃) 32.10 (CH₂) 37.94 (CH) 63.05 (2(CH₂0) 170.55 (2(CO).

Comparative example - Preparation of 2-acetoxymethyl-4-iodo-butyl-l- acetate. Method 1 A mixture of 3-hydroxymethyl tetrahydrofuran (30 g, 293.74 mmoles), sodium iodide (2 eq/mole, 88.05 g) and acetonitrile (300 ml) is added, at 0°C, with acetyl chloride (2 eq/mole, 46.1 1 g). The reaction is left at room temperature until complete disappearance of the substrate, then added with a sodium bicarbonate saturated solution (300 ml). The resulting mixture is left under stirring for 15 minutes, then extracted with ethyl ether (3x100 ml). The organic phase is washed with a sodium chloride saturated solution (100 ml), decolourised with a sodium thiosulfate aqueous solution and then dried over anhydrous sodium sulfate. The solvent is evaporated off to a residue and the crude is purified by column chromatography (eluent hexane/ethyl acetate 9: 1). 2-Acetoxymethyl-4-iodo-butyl-l -acetate (50.14 g) is obtained in a 55% yield. 1H-NMR (δ, ppm): 1.88 (q, 2H, CH₂) 2.00 (s, 6H, 2(CH₃) 2.03-2.10 (m, IH, CH) 3.21 (t, 2H, CH₂I) 4.02 (d, 4H, 2(CH₂0).

¹³C-NMR (δ, ppm): 2.64 (CH₂I) 20.54 (2(CH₃) 32.10 (CH₂) 37.94 (CH) 63.05 (2(CH₂0) 170.55 (2(CO). Method 2 a) A mixture of 3-hydroxymethyl tetrahydrofuran (30 g, 293.74 mmoles), triethylamine (2 eq/mole, 59.44 g), dimethylaminopyridine (0.1 eq/mole, 3.58 g) and dichloromethane (300 ml) is added, at 0°C, with acetic anhydride (1 eq/mole, 29.98 g). The reaction is left at room temperature until complete disappearance of the substrate, then added with a sodium bicarbonate saturated solution (300 ml). The resulting mixture is left under stirring for 15 minutes, then extracted with ethyl acetate (3(100 ml). The organic phase is washed with 2 N hydrochloric acid (100 ml), dried over anhydrous sodium sulfate and the solvent is evaporated off to a residue. 33.83 g of 3-acetoxymethyl tetrahydrofuran are obtained in an 80% yield.

Η-NMR (δ, ppm): 1.53 (m, IH, CH) 1.92 (m, IH, CH) 2.01 (s, 3H, CH₃) 2.44 (m, IH, CH) 3.55 (dd, IH, CH) 3.63 (m, 3H, CH and CH₂) 3.78 (m, 2H, CH₂).

¹³C-NMR (δ, ppm): 20.54 (CH₃) 28.65 (CH₂) 37.92 (CH) 65.60 (CH₂) 67.37 (CH₂) 70.22 (CH₂) 170.64 (CO). b) A mixture of 3-acetoxymethyl tetrahydrofuran (33 g, 229.16 mmoles), sodium iodide (1 eq/mole, 34.34 g) and acetonitrile (300 ml) is added, at 0°C, with acetyl chloride (1 eq/mole, 17.98 g). The reaction is left at room temperature until complete disappearance of the substrate, then added with a sodium bicarbonate saturated solution (300 ml). The resulting mixture is left under stirring for 15 minutes, then extracted with ethyl ether (3x100 ml). The organic phase is washed with a sodium chloride saturated solution (100 ml), decolourised with a sodium thiosulfate aqueous solution and dried over anhydrous sodium sulfate. The solvent is evaporated off to a residue and the crude is purified by column chromatography (eluent hexane/ethyl acetate

9: 1). 2-Acetoxymethyl-4-iodo-butyl- l -acetate (38.85 g) is obtained in a 54% yield. 1H-NMR (δ, ppm): 1.88 (q, 2H, CH₂) 2.00 (s, 6H, 2(CH₃) 2.03-2.10 (m,

IH, CH) 3.21 (t, 2H, CH₂I) 4.02 (d, 4H, 2(CH₂0).

¹³C-NMR (δ, ppm): 2.64 (CH₂I) 20.54 (2(CH₃) 32.10 (CH₂) 37.94 (CH) 63.05 (2(CH₂0) 170.55 (2(CO). Example 3 - Preparation of 9-r4-acetoxy-3-(acetoxymethyl)butyl]-2-amino-6- chloropurine and 7-r4-acetoxy-3-(acetoxymethyl)butyl1-2-amino-6- chloropurine.

A mixture of 2-amino-6-chloropurine (58.9 mmoles, 10 g) and anhydrous potassium carbonate (1.5 eq/mole, 12.22 g) in anhydrous dimethylformamide (240 ml) is added with 2-acetoxymethyl-4-iodo-butyl-l- acetate (58.9 mmol, 18.49 g), prepared according to Example 2. The mixture is stirred at room temperature for 18 h, then water is added (150 ml) and the products are extracted with dichloromethane (3 * 100 ml). The combined organic phases are washed with a sodium chloride saturated solution (3 x 100 ml), dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is fractioned by column chromatography (eluent dichloromethane/methanol 97/3) to give two white solids: 9-[4-acetoxy-3- (acetoxymethyl)butyl]-2-amino-6-chloropurine (11.7 g) and 7-[4-acetoxy-3- (acetoxymethyl)butyl]-2-amino-6-chloropurine (1.46 g) in yields of 56% and 7%, respectively.

9-[4-Acetoxy-3-(acetoxymethyl)butyl]-2-amino-6-chloropurine: 1H-NMR (CDC1₃) (δ, ppm): 1.80-2.05 (m, 3H, CH and CH₂) 2.02 (s, 6H, 2^χCH₃) 4.08 (d, 4H, 2^χCH₂0) 4.16 (t, 2H, CH₂N) 5.32 (br, 2H, NH₂) 7.76 (s, IH, CH).

¹³C-NMR (CDC1₃) (δ, ppm): 21.43 (2^χCH₃) 29.44 (CH₂) 35.54 (CH) 41.95 (CH₂N) 64.22 (2^χOCH₂) 123.43 (C) 142.66 (C) 151.95 (CH) 154.02 (C) 159.78 (C) 171.47 (2^χCO). EI-MS: 355 m/z (M+).

7-[4-Acetoxy-3-(acetoxymethyl)butyl]-2-amino-6-chloropurine: 1H-NMR (CDCI₃) (δ, ppm): 1.88-2.03 (m, 3H, CH and CH₂) 2.02 (s, 6H, 2^χCH₃) 4.09 (d, 4H, 2^χCH₂0) 4.41 (t, 2H, CH₂N) 5.28 (br, 2H, NH₂) 7.99 (s, IH, CH).

¹³C-NMR (CDCI₃) (δ, ppm): 20.76 (2^χCH₃) 30.76 (CH₂) 35.26 (CH) 44.98 (CH₂N) 63.62 (2^χOCH₂) 1 14.45 (C) 142.06 (C) 148.38 (C) 159.43 (CH) 164.46 (C) 171.47 (2^χCO). EI-MS: 355 m/z (M+). Example 4 - Preparation of 9-F4-acetoxy-3-(acetoxymethvObutyl^~l-2-amino-6- chloropurine and 7-[4-acetoxy-3-(acetoxymethvQbutyl1-2-amino-6- chloropurine.

A mixture of 2-amino-6-chloropurine (58.9 mmol, 10 g) and anhydrous potassium carbonate (1.5 eq/mole, 12.22 g) in anhydrous dimethylformamide

(240 ml) is added with 2-acetoxymethyl-4-bromo-butyl- l -acetate (58.9 mmoles, 15.78 g), prepared according to Example 1. After completion of the addition, the mixture is stirred at room temperature for 18 h, then water is added (150 ml) and the products are extracted with dichloromethane (3 x 100 ml). The combined organic phases are washed with a sodium chloride saturated solution (3 x 100 ml), dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is fractioned by column chromatography (eluent dichloromethane/methanol 97/3) to give two white solids: 9-[4-acetoxy-3-(acetoxymethyl)butyl]-2-amino-6-chloropurine (12.1 g) and 7-[4-acetoxy-3-(acetoxymethyl)butyl]-2-amino-6-chloropurine (1.67 g) in yields of 58% and 8%, respectively.

^,3C-NMR (CDCI₃) (δ, ppm): 21.43 (2^χCH₃) 29.44 (CH₂) 35.54 (CH) 41.95 (CH₂N) 64.22 (2^χOCH₂) 123.43 (C) 142.66 (C) 151.95 (CH) 154.02 (C) 159.78 (C) 171.47 (2^χCO). EI-MS: 355 m/z (M+).

7-[4-Acetoxy-3-(acetoxymethyl)butyl]-2-amino-6-chloropurine: 1H-NMR (CDCI₃) (δ, ppm): 1.88-2.03 (m, 3H, CH and CH₂) 2.02 (s,

6H, 2^χCH₃) 4.09 (d, 4H, 2^χCH₂0) 4.41 (t, 2H, CH₂N) 5.28 (br, 2H, NH₂) 7.99 (s, IH, CH).

¹³C-NMR (CDCI₃) (δ, ppm): 20.76 (2^χCH₃) 30.76 (CH₂) 35.26 (CH) 44.98 (CH₂N) 63.62 (2^χOCH₂) 1 14.45 (C) 142.06 (C) 148.38 (C) 159.43 (CH) 164.46 (C) 171.47 (2^χCO). EI-MS: 355 m/z (M+).

Example 5 - Preparation of 9-|^"4-acetoxy-3-(acetoxymethyl)butyl^~l-2- aminopurine (Famciclovir) A mixture of 9-[4-acetoxy-3-(acetoxymethyl)butyl]-2-amino-6-chloro- purine (28.1 mmoles, 10 g), prepared according to Example 3 or 4, 10% palladium on charcoal (0.833 g) and ammonium formate (4 eq/mole, 7.08 g) in methanol (270 ml) is refluxed for 2 h under stirring. The mixture is cooled to room temperature and filtered and the filtrate is evaporated under reduced pressure to give a thick, colourless oil. The residue is then taken up into water (150 ml) and extracted with chloroform (2x 100 ml). The combined organic phases are dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude is purified by crystallization from ethyl acetate/hexane to afford 9-[4-acetoxy-3-(acetoxymethyl)butyl]-2-aminopurine (8.19 g) in a 90% yield.

1H-NMR (CDC1₃) (δ, ppm): 1.87-1.95 (m, 3H, CH and CH₂) 2.00 (s, 6H, 2^χCH₃) 4.07 (d, 4H, 2^χCH₂0) 4.18 (t, 2H, CH₂N) 5.17 (br, 2H, NH₂) 7.72 (s, IH, CH) 8.63 (s, IH, CH).

¹³C-NMR (CDCI₃) (δ, ppm): 20.82 (2^χCH₃) 28.83 (CH₂) 34.95 (CH) 40.79 (CH₂N) 63.65 (2^χOCH₂) 128.21(C) 142.16 (C) 149.90 (CH) 153.20 (C) 159.95 (C) 170.70 (2^χCO). EI-MS: 321 m/z (M+).

Claims

1. A process for the preparation of 2-acetoxymethyl-4-halo-but-l-yl acetates (I)

ω

in which X is bromine or iodine, which process comprises the opening of 3- hydroxymethyl-tetrahydrofuran (V)

(V)

in the presence of an acylating agent and a Lewis acid selected from magnesium bromide and samarium tribromide.

2. A process as claimed in claim 1 wherein the acylating agent is selected from an anhydride, or an acid chloride RCOC1, in which R is: a straight or branched, saturated or unsaturated, C1-C₁₉ chain optionally substituted with one or more chlorine or fluorine atoms; or ciclohexyl, phenyl, benzyl or 1-naphthyl.

3. A process as claimed in claim 2 in which R is selected from methyl, chloromethyl, propyl, isopropyl, t-butyl, vinyl, propen-1-yl, heptafluoropropy 1.

4. A process as claimed in claims 2 or 3 in which, when using acylating agents other than acetic anhydride or acetyl chloride, the acyl groups are replaced with acetyl groups after completion of the reaction.

5. A process according to any one of claims 1 - 3 in which the acylating agent is acetyl chloride or acetic anhydride.

6. A process as claimed in claim 5 in which the acylating agent is acetyl chloride and the Lewis acid is samarium triiodide.

7. A process as claimed in claim 5 in which the acylating agent is acetic anhydride and the Lewis acid is magnesium bromide.