Process for preparing pyrimidinetrione derivatives

Details Process for preparing pyrimidinetrione derivatives Process for preparing pyrimidinetrione derivatives

1991-10-30

1993-11-16

Tsang, Cecilia

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

514270, 544243, 544299, 544301, 544302, A61K 31675, A61K 31515, C07D23902, C07F 902

Patent

active

052624021

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a process for preparing pyrimidinetrione derivatives. It also relates to novel N-dihydroxyphosphoryl pyrimidinetrione derivatives which may be useful as water-soluble prodrugs of certain pyrimidinetrione compounds.
The compound, 1-(3-n-butoxy-2-carbamoyloxypropyl)-5-ethyl-5-phenyl-(1H,3H,5H) pyrimidine-2,4,6-trione known as and hereinafter called febarbamate has previously been prepared and described--see for example Helvetica Chimica Acta, XLIV, pp. 105-113, 1960, and British Patent Specifications No. 1 581 834 and No. 2 137 999. These publications also describe related compounds and their preparation. The method of preparation has always involved the alkylation of a 5,5-disubstituted pyrimidinetrione by forming the sodium salt of the appropriate malonyl urea derivative and reacting this with an alkylating agent corresponding to the compound it is desired to prepare--generally a 1-halo-2-carbamoyloxy-3-alkoxy propane, and usually the chloro-compound. Such a process always provides a mixture of unchanged starting material, the N'-monosubstituted 5,5-disubstituted pyrimidinetrione derivative and the N,N'-disubstituted 5,5-disubstituted pyrimidinetrione derivative.
Such derivatives are described in the British Patent Specification No. 1 193 438. The reaction, being carried out in a heterogenous, highly viscous mass, is however difficult to handle and a considerable amount of the starting material 1-halo-2-carbamoyloxy-3-alkoxy propane is consumed in the unavoidable formation of unwanted N,N'-disubstituted derivative. This starting material is not easy to obtain, is time-consuming and difficult to prepare, and even despite rigorous purification always contains about 2% of the isomeric 1-halo-2-alkoxy-3-carbamoyloxy propane.
We have now devised an alternative process which enables the production of a substantially uncontaminated product. In addition our new procedures provide significant improvements in economy and ease of manipulation in the production of febarbamate and its derivatives.
According to one aspect of the invention we provide a process for the preparation of a compound of a formula (I) ##STR1## wherein R.sub.1 and R.sub.2, which may be the same or different, represent aliphatic, araliphatic or aryl groups, and R represents a group --CH.sub.2 CH(OCONH.sub.2)--C.sub.2 OX in which X is a C.sub.1-5 alkyl group, which comprises reacting a compound of formula (II) ##STR2## wherein R.sub.1 and R.sub.2 and X are as defined above with a dihalophosphinyl or halosulphonyl isocyanate to obtain a compound of formula (III) ##STR3## wherein R.sub.1 and R.sub.2 and X are as defined above and Z is a group of formula --SO.sub.2 Y or --POY.sub.2 wherein Y is a halogen atom, followed by hydrolysis of the compound of formula (III).
The intermediate compounds of formula (III) are believed novel, comprise a further feature of the invention, and may either be isolated, or may be hydrolysed in situ to provide compounds of formula (I) as defined above. Preferably, Y is a chlorine atom.
The reaction of the compounds of the formula (II) with a dihalophosphinyl or a halosulphonyl isocyanate may be carried out in solution, preferably in an anhydrous organic solvent, desirably an aromatic hydrocarbon such as toluene or a halogenated hydrocarbon such as methylene chloride, using substantially equimolar amounts of the reactants at a temperature between -10.degree. to 50.degree.. The complete reaction generally requires 1 to 5 hours, typically 1 hour at room temperature.
In the case of N-dihalophosphinyl derivatives the hydrolysis reaction may conveniently be conducted in a mixture of solvents, preferably an organic hydrocarbon solvent, such as toluene or cyclohexane, and water at pH 4 to 6 and at a temperature in the range 40.degree. C. to 110.degree. C., typically at about 70.degree. C. The reaction time varies strongly depending on the conditions used from 1 to 24 hours, but typically about 6 hours at a pH of about 5.5 and at about 70.degree. C. are required.
In the case of N-halosulphonyl derivatives

REFERENCES:
patent: 814496 (1906-03-01), Wolfes
patent: 2051846 (1936-08-01), Holbig et al.
patent: 2161212 (1939-06-01), Whitmore
patent: 2876225 (1959-03-01), Donnison

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