Process for the preparation of guanine

A process for the preparation of guanine, by reacting 2,4-diamino-5-formylamino-6-hydroxypyrimidine (DAFHP) with formic acid, in the absence of formalize. The process may be conducted with the addition of water and at reflux temperature.

BACKGROUND OF THE INVENTION
 1. Field of the Invention
 The present invention relates to a process for the preparation of guanine
 (2-amino-1,9-dihydropurin-6-one), starting from
 2,4-diamino-5-formylamino-6-hydroxypyrimidine (DAFHP).
 2. Discussion of the Background
 As an important intermediate for the synthesis of pharmacologically active
 compounds, in particular of antiviral active compounds, the nucleic acid
 base guanine is of great importance. Guanine is needed, for example, as a
 precursor for acyclovir, which according to DE-A-35 44 461, incorporated
 herein by reference, is suitable for the therapy of viral infections.
 The reaction of 4,5-diaminopyrimidine sulfates with formamide to give the
 corresponding purines is well-known (Robins et al., J. Am. Chem. Soc. 75
 (1953) 263). 2,4,5-Triamino-6-hydroxypyrimidine sulfate (TAHP sulfate) is
 employed for the synthesis of guanine. According to DE-A-37 29 471,
 guanine can be obtained by heating a suspension of TAHP sulfate in
 formamide to up to 200.degree. C. with removal by distillation of the
 water of reaction formed. A disadvantage in this process is that formamide
 partially decomposes at the high temperatures needed, which in addition to
 the formation of carbon monoxide and ammonia, results in colored guanine
 crude products which necessitate a high expenditure on purification. The
 necessity to employ the TAHP, which is unstable in free form, in the form
 of its sulfate causes a high salt load, which is a further disadvantage.
 According to EP-A-0 415 028, guanine is obtained by reaction of TAHP
 sulfate with alkali metal formate and formic acid. Although this process
 avoids the disadvantages associated with the use of formamide, it also
 leads, however, to production of an economically and ecologically
 unfavorable high unavoidable salt load in the form of alkali metal sulfate
 in the reaction mixture.
 In the process based on TAHP sulfate described above,
 2,4-diamino-5-formylamino-6-hydroxypyrimidine (referred to as DAFHP below)
 is passed through as an intermediate, which is reacted in situ to produce
 guanine.
 According to DE-A-41 36 114, guanine can also be obtained starting from
 isolated DAFHP by heating in formamide to at least 140.degree. C. The
 ratio of DAFHP to formamide is 1:2 to 1:3. Up to 10% of formic acid can be
 added to the reaction mixture. The DAFHP employed here is obtained, for
 example, by a process according to EP-A-0 -267 594, in which
 2,4-diamino-6-hydroxy-5-nitrosopyrimidine is catalytically hydrogenated
 and reacted to give TAHP sulfate. After the hydrogenation, the reaction
 mixture is treated with formic acid, if appropriate with addition of a
 mineral acid, in order to obtain DAFHP quantitatively. Although the
 process described in DE-A-41 36 114 is salt-free, it has, however, the
 already mentioned disadvantages which accompany the use of formamide (such
 as decomposition, and expensive purification of the final product). The
 guanine according to DE-A-41 36 114 is obtained with a purity (HPLC) of
 less than 98.0%. After purification, losses in yield therefore occur.
 Accordingly, there remains a need for a process for producing guanine which
 overcomes the disadvantages discussed above.
 SUMMARY OF THE INVENTION
 It is an object of the present invention to provide a process for producing
 guanine.
 It is also an object of the present invention to provide a process for
 producing guanine which does not have the mentioned disadvantages the
 known processes described above, and in which guanine may be obtained in
 high space-time yield and purity.
 The objects of the invention, and others, may be accomplished with a
 process for the preparation of guanine starting from
 2,4-diamino-5-formylamino-6-hydroxypyrimidine (DAFHP), which comprises
 reacting isolated DAFHP in the absence of formamide in formic acid, with
 or without addition of water under reflux conditions, to produce guanine.
 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.
 DETAILED DESCRIPTION OF THE INVENTION
 The starting material for the inventive process may be isolated DAFHP.
 Isolated DAFHP may be obtained, for example, by the process described in
 EP-A-0267594, incorporated herein by reference.
 Based on DAFHP, preferably up to 2 equivalents, particularly preferably 0.5
 to 1.5 equivalents, of water may be added during the reaction. The use of
 more than 2 equivalents of water causes an increased expenditure on
 purification of the resulting guanine and is therefore not preferred. The
 reaction may be carried out at normal pressure and at a temperature which
 is established when water containing formic acid boils under reflux.
 It has surprisingly and unforeseeably been shown that the inventive process
 permits the use of high molar DAFHP concentrations, which is a particular
 advantage of the present invention. In the embodiment without addition of
 water, the molality (based on DAFHP) is up to 2.5, preferably 1.80 to
 2.25. The reaction time is 12 to 24 hours, preferably 15 to 18 hours.
 Longer reaction times are possible in principle, but lead to no
 significant improvement; moreover longer reaction times contradict the aim
 according to the invention of a high space-time yield. Shorter reaction
 times result in marked losses in yield due to unreacted DAFHP. However, it
 has turned out to be particularly surprising that the preferred embodiment
 with addition of water not only allows a second marked increase in the
 molar DAFHP concentration, but moreover also a marked reduction in the
 reaction time. The molality in this embodiment is up to 5.0, preferably
 3.2 to 4.2. The reaction time is 9 to 15 hours, preferably 10 to 12 hours.
 More than a four-fold space-time yield is achieved here in comparison with
 EP-A-0415028 (0.9 molal based on TAHP sulfate).
 In the process according to the invention, after the reaction is complete
 formic acid and water may be removed by distillation, which is preferably
 carried out under reduced pressure. The water-containing formic acid thus
 recovered is very pure and can be employed in other processes. In
 particular, the recovered water-containing formic acid can be used in the
 preparation of the starting substance DAFHP, which is a further advantage
 of the present invention.
 The guanine obtained may be purified using well-known methods. For example,
 the crude product can be dissolved in aqueous alkali metal hydroxide and
 treated with active carbon. Guanine may then be isolated by precipitation,
 preferably by precipitation by hydrolysis, as described in DE-A-37 23 874,
 incorporated herein by reference. The process according to the invention
 provides guanine in very good yields of, for example, 98% of theory as a
 crude product. After purification, guanine can be obtained in good yields
 of customarily 92% of theory and more as a final product. The pure guanine
 obtained by this process has a purity (HPLC) of more than 99.5%.
 The guanine prepared by the process according to the invention can be used
 as an intermediate for the synthesis of pharmacologically active
 compounds. In a particularly preferred embodiment, the pharmacologically
 active compound is an anti-viral agent. A preferred anti-viral agent is
 acyclovir. Acyclovir may be obtained from the guanine produced by the
 present process as described in, for example, DE-A-35 44 461, incorporated
 herein by reference.
 Having generally described this invention, a further understanding can be
 obtained by reference to certain specific examples which are provided
 herein for purposes of illustration only and are not intended to be
 limiting unless otherwise specified.

EXAMPLES
 Example 1
 67.6 g (0.4 mol) of DAFHP are introduced into 222.2 g of formic acid
 (98-100% strength) in portions with stirring (the molality is 1.8 based on
 DAFHP)The mixture is heated to boiling, and the readily stirrable
 suspension is then kept under reflux for 18 hours. Formic acid and water
 are then almost completely removed by distillation in a water-jet vacuum.
 The crude guanine obtained is purified in a known manner by dissolving it
 in aqueous alkali metal hydroxide, treating with active carbon (15% by
 weight) and subsequent precipitation by hydrolysis. Starting from 10 g of
 crude product (aliquot part), after a single use of this purification
 process 9.61 g (95.9% of theory) of guanine having a purity (HPLC) of
 99.8% are thus obtained.
 Example 2
 First 7.2 g (0.4 mol) of water and then 67.6 g (0.4 mol) of DAFHP are added
 t-o 111.1 g of formic acid (98-100% strength) in portions with stirring
 (the molality is 3.4 based on DAFHP). The mixture is heated to boiling,
 and the readily stirrable suspension is then kept under reflux for 12
 hours. Formic acid and water are then almost completely removed by
 distillation in a waterjet vacuum. Purification is carried analogously to
 Example 1. Guanine having a purity (HPLC) of 99.9% is thus obtained in a
 yield of 91.8% of theory.
 Comparative Example
 (According to EP-A-0415028)
 The TAHP sulfate concentration in the reaction mixture is twice as high in
 this comparison example as in EP-A-0 415 028.
 A mixture of 111.1 g of formic acid (98-100% strength), 47.8 g (0.2 mol) of
 TAHP sulfate and 28.6 g (0.42 mol) of sodium formate is heated to boiling.
 After reaching the reflux temperature, the reaction mixture becomes
 unstirrable. The stirrability improves gradually in the course of several
 hours. Only after approximately 5 hours is a stirrable suspension present.
 The reaction mixture is kept under reflux for a total of 18 hours. The
 crude product obtained after distillation of water and formic acid in a
 water-jet vacuum contains, in addition to 84.2% of guanine, 14.3% of the
 unreacted intermediate DAFHP according to HPLC.
 Obviously, numerous modifications and variations of the present invention
 are possible in light of the above teachings. It is therefore to be
 understood that within the scope of the appended claims, the invention may
 be practiced otherwise than as specifically described herein.
 This Application is based on German Patent Application Serial No. 198
 39013.0, filed on Aug. 27, 1998, and incorporated herein by reference.