Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2002-08-16
2004-02-17
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06693195
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority to German Patent Application 10140269.4, filed Aug. 16, 2001, which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
1. Field of the Invention
A process for preparing 4,6-dihydroxypyrimidine (“DHP”, “4,6-DHP”, also known as 1-H-pyrimidine-4,6-dione in its tautomeric form) from malonic ester, formamide and alkali metal alkoxide. DHP has the following structure:
DHP is a useful intermediate for the syntheses of active ingredients. For instance, DHP, 4,6-dihydroxypyrimidine be used to prepare the corresponding dichloropyrimidine which, in turn, may be processed to give novel, highly active fungicides (EP-A-0 382 375, 0 393 861, 0 468 684 and 0 468 695).
2. Description of Related Art
Most of the known processes for the preparation of 4,6-dihydroxypyrimidine start from malonamide and react this with ethyl formate, see, for example, R. Hull, J. Chem. Soc., 1951, 2214 and C. Hennart and E. Merlin, Bull. Soc. Chem., 1959, 741. Reaction of malonamide with formamide also provides a known route to DHP, see D. J. Brown, J. Chem. Soc., 1956, 2312-2314 and A. Sömmer, DE-A-12 00 308, or V. A. Zasonov, Khim.-Farm. Zh., Vol. 8, No. 12, 28-31. In Zasonov, the malonamide is formed before the cyclocondensation reaction between malonic ester and ammonia. The amide is isolated before further use.
The common disadvantage of all processes starting from malonamide is that the amide cannot be commercially obtained and that nitrogen sources are not used efficiently in multistep preparation processes for DHP, because losses occur in the individual steps. This criticism extends to the process described by EP-A 0 852 580 (Lonza AG), which discloses an elegant route to malonamide and malonic monoamide monoester, but the above-recited disadvantages apply to their further reaction with formamide.
EP-A-0 816 345 teaches that DHP can be synthesised by reacting the malonic ester, formamide and the alkoxide with each other in one step under increased temperature and autogenous pressure, which gives DHP in good yields, very good space-time yields and high degrees of utilisation of the nitrogen source formamide. Therefore, the process described in EP-A-0 816 345 constitutes a distinct advance in the art. In particular, the integrated dissolution of the alkali metal salt of DHP obtained as an intermediate and the isolation of the solid which only takes place in the last step make the process additionally advantageous.
However, the process described by EP-A-0 816 345 also has certain disadvantages, including the need for long addition and post-reaction times and poor product yields when commercially available alkoxides, such as NM30, are used. For instance, the yields achievable using the commercially available 30% solution of sodium methoxide in methanol (NM30) are up to 9% lower than those achievable by using more highly concentrated methoxide solutions according to the examples of EP-A-0 816 345. Therefore, from the perspective of obtaining a more efficient and economical process, it would be advantageous to shorten the addition and reaction times, as well as improve yields of the process when using commercially available reactants.
BRIEF DESCRIPTION OF THE INVENTION
One object of the present invention is to provide a process for the preparation of 4,6-dihydroxpyrimidine without the above-described disadvantages. Thus, the invention provides a process for the preparation of 4,6-dihydroxypyrimidine (DHP) from malonic ester, formamide and alkali metal alkoxide. This process was surprisingly found to give a significant increase in the yield compared to the above-described prior art processes.
The invention also provides a process that reduces cyanide content produced by the reaction, and thus reduces entrainment of cyanide in waste water and reduces environmental and occupational risks as cyanides and hydrocyanic acid formed by acidification are highly toxic.
DETAILED DESCRIPTION OF THE INVENTION
In the inventive process, the temperature is held in the range from 102 to <120° C. from 10 to <60 minutes after mixture or proportioning of the substrates. Any subrange or intermediate temperature within this range may also be used, such as 102-104° C., 104-106° C., 106-108°C., 108-110° C., 110-112° C., 112-114° C., 114-116°C., 116-118° C. or 118 to <120° C. Similarly any intermediate period between 10 and <60 minutes may be used, such as 10-20, 20-30, 30-40, 40-50 or 50 to <60 minutes may be used. The exact holding time depends on the particular temperature employed after completion of the mixture or the metered addition of substrate(s). A metered addition can be carried out, provided heat is removed sufficiently well, in preferably 10-50 minutes, in particular from 10 to 30 minutes and more preferably in about 20 minutes
Moreover, a surprising strong correlation between holding time, temperature, reaction time and yield achieved was found. For instance, a comparative investigation at the temperatures 90° C., 105° C. and 120° C. and a reaction time of 30 minutes gave a virtually inverse parabolic function for the yield with a maximum at about 105° C. Thus, it has been found that the metered addition or proportioning of substrates, as well as the holding time and temperature after metered addition or proportioning, provided by processes of the invention are important variables for obtaining superior yields.
Production standards for 4,6-DHP require that certain specifications be met and that particular secondary components be kept below a particular maximum permitted concentration. The process of the present invention facilitates production of “on-spec” product, and in high yields.
An “on-spec” product may meet one or all of the following requirements:
Determination of concentration by potentiometric titration (pH electrode) with potassium hydroxide solution (internal method). Requirement >96%.
Product purity by reverse-phase HPLC (RP 18), gradient elution (aqueous ammonium acetate solution/acetonitrile) with UV detection (300 nm) (internal method). Requirement <0.8% total impurities.
Malonic acid diamide by GC with FID (internal method). Requirement <0.45%.
For instance, a comparative process for the production of 4,6-DHP, that operates at a reaction temperature of 90° C. and a reaction time of 1 hour provides only an 82% yield of on-spec product—see Comparative Example 1. This product is characterised by the DHP content determined by potentiometric titration being ≧96%, and the quantity of the component 2,4,6-trihydroxynicotinamide determined by a stipulated HPLC method being given by a certain relative peak area.
On the other hand, the process of the invention eliminates the described disadvantages in such a way that at a temperature of from 102 to <120° C., preferably from 103 to 115° C. and more preferably from 103 to 107° C., and a holding time of from 10 to <60 minutes, preferably from 20 to 40 minutes and more preferably from about 25 to 35 minutes (operating point of 30 minutes) a product is obtained in increased yield that is additionally impeccable with regard to described specifications and that is obtained in a considerably shorter total cycle time compared to the standard process—see Example 1. It was surprisingly found that the time after completion of the metered addition (holding time) in the given temperature range must absolutely be adhered to.
Preferable alkali metal alkoxides are sodium or potassium alkoxides, in particular sodium alkoxides. The alcoholic radical in the alkoxide contains from 1 to 4, preferably from 1 to 2, more preferably 1 carbon atom, i.e. preferably the methyl or ethyl group. The use of sodium methoxide is most preferred.
An additional condition to be considered is that the amount of cyanide, which can be formed by decomposition of formamide, should be as low as possible in the alkaline phase before precipitation, in order to avoid entrainment of hydrogen cyanide (HCN) into the wastewater and/or sections of the plant for the precipitation, filtrat
Hunds Artur
Kuever Andreas
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