ITMI952151A1 - FORMILGUANINE PREPARATION PROCESS - Google Patents

Abstract

The present invention relates to a method for the preparation of formylguanine by degradative cleavage of glyoxalguanine.

Description

"PROCESS FOR THE PREPARATION OF FORMILGUANIN"

The present invention relates to a method for the preparation of formylguanine by degradative cleavage of glyoxalguanine.

Formylguanine, of formula (I)

(THE)

it is an important synthetic intermediate that can be used, among other things, for the preparation of the well-known antiviriil compound Acyclovir.

Patent application n <*> WO 95/07281 in the name of the Applicant describes the transformation of glyoxalguanine of formula (II)

from)

in formylguanine by sodium periodate.

This reagent, traditionally used for the degradative cleavage of 1,2-diols, however, has drawbacks from an environmental point of view and a high economic impact on the final cost of acyclovir.

Other known methods of degradative oxidation of 1,2-diols, such as described for example in J.Org. Chem. 1986, 51,1599, J.Am. Chem. Soc.

1954, 76, 6345; Tetrahedr. Lett. 1982, 23, 3135; Synthesis 1989, 765; Angew. Chem. Int. Ed. 1973, 12, 401, were not effective in the transformation of glyoxalguanine into formylguanine.

Lead tetraacetate would be active, but obviously poses even more serious environmental problems than that of sodium periodate.

It has now been found that the use of organic iodine derivatives (III) allows the selective and almost quantitative transformation of glyoxalguanine to formylguanine, according to the following scheme:

Scheme

The reaction is typically carried out using a protic solvent such as acetic acid, methanol, water or their mixtures at a temperature between 0 and 100 ° C, preferably at 40-60 ° C, using quantities of oxidant between 1-3 equivalents per equivalent. of glyoxalguanine. The product is generally isolated at the end of the reaction by simple filtration from the reaction mixture.

The organic derivatives of iodine (III) usable according to the present invention can be represented by the formula RIX2 in which:

R can be equal to or different from X; when it is different it can be a

aryl group also substituted or condensed and in particular phenyl, naphthyl, o-iodophenyl, o-hydroxyphenyl, p-methoxyphenyl, etc. ;

X is generally a halogen, preferably chlorine, or a carboxylate group R'-COO- where R'can be:

a C1-C4 alkyl group also substituted and in particular acetyl, trifluoroacetyl, propionyl, etc .; an aryl group also substituted or condensed and in particular with the same meanings as R; or an alkyl or aryl residue bearing a second carboxylate function; in this case the second function, if placed at a suitable distance, can replace the second ligand X to give cyclic derivatives, as in the specific case of phthalic and succinic acid derivatives;

still two X ligands can be replaced by an oxygen atom bonded to iodine by means of a formal double bond.

Specific examples of iodine derivatives (III) which can be advantageously used in the process of the invention are the compounds whose formulas are indicated below

The use of iodobenzene diacetate is particularly preferred

Phl (000013) 2 or of iodobenzene ditrifluoroacetate PhI (OCOCF3) 2 in acetic acid.

If iodobenzene diacetate is used, the addition of trifluoroacetic acid (1-2 equivalents) has proved to be advantageous.

At the end of the reaction, the oxidant is found as iodobenzene in the mother liquor from the filtration of the product. The iodobenzene can thus be recovered and reoxidized, according to the conventional procedures, to iodobenzene diacetate. It is possible to use catalytic quantities of iodobenzene diacetate, re-oxidizing the iodobenzene with peracids, peranhydrides or perborates in the same reaction environment.

The following examples further illustrate the invention.

Example 1

To a mixture of glyoxalguanine (20.9 g, 100 amoles) and acetic acid (80 ml), iodobenzene diacetate (64.4 g, 200 nmoles) is added at 20 ° C and under stirring. The reaction mixture is heated and maintained at 60 ° C for 5 hours, cooled to 20 ° C and then filtered. The filtered product is washed with methanol and dried under vacuum at 60 ° C to give formylguanine (24.6 g, 95 nmoles, yield 95%, HPLC purity> 95%).

Example 2

To a mixture of glyoxalguanine (20.9 g, 100 nmoles) and methanol (80 ml) is added, at 20 ° C and under stirring, iodobenzene diacetate (64.4 g, 200 nmoles). 20 * C until completeness and then filtered. The filtered product is washed with methanol and dried under vacuum at 60 <*> C to give formylguanine (12.9 g, 72 mmol, yield 72%, HPLC purity> 95%).

Example 3

To a mixture of glyoxalguanine (20.9 g, 100 mmoles) and methanol (80 ml) is added, at 20 "C and under stirring, with 1/3 equivalent of iodobenzene diacetate. The mixture is then brought to the reflux temperature for 2 hours. The addition of 1/3 of equivalents of iodobenzene diacetate is repeated every 2 hours for a further 5 times up to a total of 2 total equivalents (64.4 g, 200 mmol) while maintaining the reflux temperature. The mixture is cooled to 20 ° C and filtered. The filtered product is washed with methanol and dried under vacuum at 60 ° C to give formylguanine (11.5 g 64 mmoles, HPLC purity> 95%).

Claims (9)

CLAIMS 1. Process for the preparation of formylcjuanine I (THE) which includes the degradative cleavage of glyoxalguanine II (II) by means of organic derivatives of iodine (III). 2. Process according to claim 1, in which the iodine derivatives (III) are those selected from compounds of formula RIX2 in which: R can be equal to or different from X; when it is different it can be an aryl group also substituted or condensed and in particular phenyl, naphthyl, o-iodophenyl, o-hydroxyphenyl, p-methoxifernia, etc .; X is generally a halogen, preferably chlorine, or a carboxylate group R'-COO- where R'can be: a C ^ -C ^ alkyl group also substituted and in particular acetyl, trifluoroacetyl, propionyl, etc .; an aryl group also substituted or condensed and in particular with the same meanings as R; or an alkyl or aryl residue bearing a second carboxylate function; in this case the second function, if placed at a suitable distance, can replace the second ligand X to give cyclic derivatives, as in the specific case of phthalic and succinic acid derivatives; still two X ligands can be replaced by an oxygen atom bonded to iodine by means of a double bond form. 3. Process according to claim 2, in which iodobenzene diacetate or ditrifluoroacetate are used. 4. Process according to claim 3 in which iodobenzene diacetate is used in the presence of trifluoroacetic acid. Process according to one of claims 1 to 4, wherein the reaction is carried out in a practical solvent selected from acetic acid, methanol or water at a temperature of 0 to 100 ° C. 6. Process according to claim 5, wherein the solvent is acetic acid. Process according to one of claims 1 to 6, in which 1 to 3 equivalents of iodine derivative (III) are used per equivalent of glyoxalguanine. Process according to one of claims 1 to 7, wherein the reaction is carried out at a temperature ranging from 40 to 60 ° C. Process according to one of claims 1 to 7, wherein the reduced iodine-organic derivative is reoxidized in the course of the reaction to iodine derivative (III) by means of peracids, peranhydrides or perborates.