Process for the preparation of 3,7-dialkylxanthines

Details Process for the preparation of 3,7-dialkylxanthines Process for the preparation of 3,7-dialkylxanthines

1992-03-02

1993-05-11

Rizzo, Nicholas S.

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

Organic compounds

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

544267, C07D47310

Patent

active

052101924

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

The present invention relates to a novel process for the preparation of 3,7-dialkylxanthines of the general formula I ##STR3## in which R.sup.1 and R.sup.2 denote C.sub.1 -C.sub.4 -alkyl.
Hitherto, 3,7-dialkylxanthines have only been obtainable by expensive total synthese or by isolation from vegetable products such as cocoa beans or tea waste products. An exception is the partial snythesis of theobromine (3,7-dimethylxanthine) proposed by H. Biltz et al., [Chem. Ber. (1931), Vol. 64, page 1970], in which hydrogen chloride is passed, at 160.degree. C., through a melt of caffeidine and methyl or ethyl urea. This process suffers from the drawbacks that the highly corrosive melt is difficult to handle and purification of the theobromine is an expensive procedure. A further disclosure from the work of H. Biltz et al., [Chem. Ber. (1928). Vol. 61, 1409] is the reaction of caffeidine with potassium cyanate in aqueous solution to produce caffeine. According to the experimental data, this reaction takes place in a weakly acid to neutral medium at a pH of from 5.5 to 7.5.
It is an object of the present invention to provide novel processes for the preparation of 3,7-dialkylxanthines.
Accordingly, we have found a process for the preparation of 3,7-dialkylxanthines of the general formula I ##STR4## in which R.sup.1 and R.sup.2 denote C.sub.1 -C.sub.4 -alkyl, wherein a 1-alkyl-4-alkylamino-5-alkylaminocarbonylimidazole of the general formula II ##STR5## in which R.sup.3 denotes C.sub.1 -C.sub.4 -alkyl, is reacted with an alkali metal cyanate in aqueous solution at a pH of from 3 to 5, and the resulting urea derivative is subjected to cyclization at a pH of from 8 to 14 to form the corresponding 3,7-dialkylxanthines (I).
The fact that this reaction effects cleavage of the amine R.sup.3 --NH.sub.2 must, in view of the paper by H. Blitz et al. on caffeine synthesis (loc. cit.), be regarded as a surprising feature.
The starting materials II, of which caffeidine (R.sup.1, R.sup.2 and R.sup.3 denote methyl) is the most significant, are known or can be prepared by known methods. They are preferably prepared by alkaline hydrolysis of the corresponding 1,3,7-trialkylxanthines III ##STR6##
Other important starting materials are those in which R.sup.1 and R.sup.2 denote ethyl or isopropyl groups.
In the process of the invention, the aqueous solutions of the compounds II are adjusted to a pH of from 3 to 5 with an acid.
Examples of suitable acids are mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, or organic acids such as acetic acid, formic acid and oxalic acid, and since the reaction is pH-sensitive, buffer systems may be used to maintain specific pH's, examples being sodium acetate/acetic acid or sodium dihydrogen phosphate/disodium hydrogen phosphate.
In the preparation of theobromine, yields of more than 60% are obtained in a pH range of from 4.3 to 4.7. When using a caffeidine homologue as starting material, the optimum pH range can be readily determined by carrying out preliminary tests.
Preferredalkali metal cyanates are sodium cyanate and potassium cyanate used in a concentration of from 1 to 4 moles and preferably from 1 to 2 moles, per mole of II. A greater excess of alkali metal cyantate is possible, but not necessary. The concentration of compound II in the aqueous solution is not critical and is usually in the range of from 0.2 to 4 moles per liter. When preparing theobromine, the best results are obtained at a caffeidine concentration of from 0.5 to 2 moles per liter. The reaction proceeds satisfactorily at from 0.degree. to 50.degree. C. The use of higher temperatures is possible, but this leads to an increased consumption of alkali metal cyanate.
The resulting urea derivative IV ##STR7## can be isolated or converted to 3,7-dialkylxanthines in situ. Cyclization to compounds I is effected in an alkaline medium at elevated temperature. A pH ranging from 11 to 13 is particularly preferred, whilst a value of from 11.6 to 12.0 is to be partically recommended for the preparation o

REFERENCES:
Berichte Der Deutschen Chemischen Gesellschaft, Verlag Chemie 1982-pp. 1409-1422, H. Biltz et al. vol. 61.
H. Biltz et al., Chem Ber. 1931, vol. 64, p. 1970.

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