Process for preparing guanine under superatmospheric pressure

Details Process for preparing guanine under superatmospheric pressure Process for preparing guanine under superatmospheric pressure

1999-12-16

2001-04-10

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen bonded directly to ring carbon of the purine ring...

Reexamination Certificate

active

06214993

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing guanine (2-amino-1,9-dihydropurin-6-one) from 2,4-diamino-5-formylamino-6-hydroxypyrimidine (DAFHP) under pressure.
2. Description of the Background
The nucleic acid base guanine is of great importance as an intermediate for the synthesis of pharmacologically active compounds, in particular antiviral compounds. Guanine is required, for example, as a precursor for acyclovir which, according to DE 35 44 461, incorporated herein by reference, is suitable for treating viral infections.
The reaction of 4,5-diaminopyrimidine sulfates with formamide to give the corresponding purines is known from the literature (Robins et al., J. Am. Chem. Soc. 75 (1953) 263). Guanine is synthesized using 2,4,5-triamino-6-hydroxypyrimidine sulfate (TAHP sulfate).
According to DE 37 29 471, guanine can be obtained by heating a suspension of TAHP sulfate in formamide at up to 200° C. while distilling off the water of reaction formed.
A disadvantage is the partial decomposition of formamide at the high temperatures required, which results not only in formation of carbon monoxide and ammonia but also discolored crude guanine products which require costly purification. The need to use the TAHP, which is unstable in free form, in the form of its sulfate causes the formation of a large amount of inorganic salts, which represents a further disadvantage.
According to EP 0 415 028, guanine is obtained by reacting TAHP sulfate with alkali metal formate and formic acid. Although this process avoids the disadvantages associated with the use of formamide, it likewise leads to an economically and ecologically unfavorable formation of large amounts of unavoidable salts in the form of alkali metal sulfate in the reaction mixture.
The abovementioned processes based on TAHP sulfate proceed via the intermediate 2,4-diamino-5-formylamino-6-hydroxypyrimidine (hereinafter referred to as DAFHP) which is converted in situ into guanine.
According to DE 41 36 114, guanine can also be obtained starting from isolated DAFHP by heating in formamide to at least 140° C. The ratio of DAFHP to formamide is from 1:2-1:3. Up to 10% of formic acid can be added to the reaction mixture. The DAFHP used here is obtained, for example, by a process as described in EP 0 267 594, in which 2,4-diamino-6-hydroxy-5-nitrosopyrimidine is catalytically hydrogenated and converted into TAHP sulfate. After the hydrogenation, the reaction mixture is treated with formic acid, if desired with addition of a mineral acid, in order to obtain DAFHP in high yields. Although the process described in DE 41 36 114 is salt-free, it has the abovementioned disadvantages associated with the use of formamide (for example decomposition, costly purification of the end product). The guanine obtained as described in DE 41 36 114 has an assay purity (HPLC) of less than 98.0%. Losses in yield, therefore, occur as a result of purification.
According to German Application No. 198 39 013.0, guanine can also be prepared starting from isolated DAFHP by heating in boiling formic acid which may, if desired, be diluted by addition of small amounts of water. This process requires long reaction times of up to 20 hours.
All the above-mentioned processes have in common not only the process engineering disadvantages described but also the fact that they result in products which, even after being reprecipitated one or more times in the presence of activated carbon, sometimes contain considerable concentrations of a secondary component which fluoresces at 366 nm and can be detected by thin layer chromatography. Accordingly, there remains a need for a process for producing guanine which overcomes these disadvantages.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an industrial process for preparing guanine which does not have the disadvantages of the processes described above and which may provide guanine in a high space-time yield and in extremely high purity.
It is another object of the present invention to convert the guanine produced by the inventive to process to other compounds which may have pharmacological activities, e.g., antiviral agents.
The objects of the invention of the invention, and others, may be achieved with a process for preparing guanine starting from 2,4-diamino-5-formylamino-6-hydroxypyrimidine (DAFHP), in which isolated DAFHP in concentrated formic acid is subjected to a cyclocondensation under superatmospheric pressure at temperatures above the boiling point of the formic acid. The reaction may be conducted, optionally, in the presence of catalytic amounts of an additive(s) which acts as a reducing agent.
Accordingly, the objects of the invention may be accomplished with a process for preparing guanine, comprising reacting 2,4-diamino-5-formylamino-6-hydroxypyrimidine in formic acid at superatmospheric pressure.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description.


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Roland K. Robins, et al., “Purines. II. The Synthesis of Certain Purines and the Cyclization of Several Substituted 4,5-diaminopyrimidines”, J. Am. Chem. Soc., Vo. 75, pp. 263-266, Jan. 20, 1953.

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