Process for preparing substituted pyrimidine derivatives

Details Process for preparing substituted pyrimidine derivatives Process for preparing substituted pyrimidine derivatives

1999-12-17

2000-09-05

Ford, John M.

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C07D23902

Patent

active

061145270

DESCRIPTION:

BRIEF SUMMARY
The invention relates to a novel way of obtaining substituted pyrimidine derivatives of the general formula ##STR1## in which Y and R are as defined below. Said compounds have a very broad application spectrum, e.g. as intermediates for pharmaceutical or agrochemical active ingredients.
It is known to obtain compounds of the general formula I by reaction of tris-formaminomethane with CH acidic carboxamides (Brederbeck et al. Chem. Ber. 1965, 98, 3883-3887). The reaction mentioned by way of example is that of tris-formaminomethane with malonic acid ethyl ester amide in a yield of 11% to give the corresponding ethyl 4-hydroxypyrimidine-5-carboxylate (4-hydroxy-5-ethoxycarbonylpyrimidine).
Also known is the reaction of triazine for example with diethyl malonate in a yield of 42% to give ethyl 4-hydroxypyrimidine-5-carboxylate (Huffmann et al. J. Org. Chem. 1962, 27, 551-558).
These syntheses have the disadvantage that they firstly produce relatively poor yields, and secondly use starting compounds which are not readily available and are relatively expensive, thus making them uneconomical.
Consequently, the object of the invention was to develop a novel economic way of obtaining the compounds of the general formula I which does not have the said disadvantages.
The object was achieved with the process of the invention according to claim 1 or 5.
In the general formula I, Y is an oxygen atom or a sulphur atom. R is cyano or a group ##STR2## in which R.sup.2 is optionally substituted alkyl, alkoxy, hydroxyl, amino, alkylamino, dialkylamino, phenyl or benzyl.
Alkyl expediently has the meaning of C.sub.1-6 -alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl and its isomers or hexyl and its isomers, preferably C.sub.1-4 -alkyl. This definition of alkyl includes the alkyl radicals of alkoxy, alkylamino or dialkylamino. In addition, said radicals can be mono- or polysubstituted, by, for example, alkyl, alkoxy, amino or halogen. Halogen is customarily fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
The starting material in the process of the invention according to the variant as in claim 1 is [3-(dimethylamino)-2-azaprop-2-en-1-ylidene]dimethylammonium halide of the general formula ##STR3## in which X is a halogen atom. This compound is known in the form of its chloride as "Gold's reagent". Gold's reagent is prepared in a known manner by reacting cyanuric chloride with N,N-dimethylformamide as in H. Gold, Angew. Chem. 1960, 72, 956-959.
Alternatively, as in claim 5, the Gold's reagent or another halide of the general formula II can be formed in situ and used for the subsequent stage without isolation.
A preferred [3-(dimethylamino)-2-azaprop-2-en-1-ylidene]dimethylammonium halide of the general formula II is "Gold's reagent" or [3-(dimethylamino)-2-azaprop-2-en-1-ylidene]dimethylammonium chloride.
The reaction of the invention with the compound of the general formula II is carried out with a compound of the general formula ##STR4## in which Y and R are as defined above.
Suitable compounds of the general formula III are the substituted acetamides in which Y is oxygen, and R is ##STR5##
Consequently, particular preference is given to malonamide or malonic acid C.sub.1-6 -alkyl ester manoamides, in particular malonic acid C.sub.1-4 -alkyl ester monoamides.
Other suitable compounds of the general formula III are cyanoacetamide and 2-cyanothioacetamide where R is cyano and Y is oxygen or sulphur, respectively.
Gold's reagent or another halide of the general formula II can usually be used in stoichiometric amounts, but is preferably used in a slight excess relative to the compound of the general formula III.
The reaction proceeds in the presence of a base.
Preference is given to using a customary alkali metal alkoxide such as, for example, Na or K methoxide, ethoxide or tert-butoxide.
The reaction expediently takes place in the presence of an organic solvent such as, for example, dimethoxyethane, dioxane, tetrahydrofuran or methanol. The reaction temperature is usu

REFERENCES:
Gold, Angew. Chem, vol. 72, Ab. 24 (1960) pp 956-959.
Hoffman et al, J. of Organic Chemistry vol. 27, pp 551-8 (1962).
Bredereck et al, Chemische Berichte vol. 98, pp 3883-7 (1965).

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