Process for preparing uracil derivatives

Details Process for preparing uracil derivatives Process for preparing uracil derivatives

1992-08-21

1994-02-15

Ford, John M.

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

Organic compounds

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

544314, 544313, C07D23954, C07D239545

Patent

active

052868613

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a novel process for preparing uracil derivatives useful as intermediates in the synthesis uridines having antiviral or antitumor activity or useful as coadjuvants in antiviral therapy. In particular they are, for instance, useful in the synthesis of 5-benzylacyclouridine (BAU) according to the following scheme: ##STR2## It is known that these uracils may be prepared by cyclisation of a suitable intermediate (see Merck Index, XI Edition, compound 9332 and references cited therein) or by transformation of an uracil derivative, e.g. as described in JP 63 63668. These known methods of preparation require the use of expensive reagents or the use of strong, hazardous base, such as, for instance NaH, which are hardly suitable for industrial preparations.
The present invention provides a simple, low-cost process for the preparation of unsubstituted or 5-halogen, 5-alkyl, aryl or aralkyl substituted uracil derivatives of the formula (I): ##STR3## wherein: R.sub.1 represents hydrogen or halogen atom, or an optionally substituted alkyl, aryl or aralkyl group, which process comprises converting a compound of the formula II ##STR4## wherein R.sub.1 is as defined above, or a salt thereof, into a mesylate derivative of the formula III ##STR5## wherein R is as defined above, and then reducing this compound of the formula III to give the desired compound of the formula I.
Indeed DE-1250829 discloses a process in which 6-Cl substituted uracil derivatives, prepared from the corresponding barbituric acid by the use of phosphorus chlorinating agents, are converted to uracil by reduction. But such process is only limited to removal of halogen, particularly chlorine, as is well known in scientific literature (see J. March, Advanced organic Chemistry, 3th ed., pp 389-392). Moreover the preparation of such chlorine derivatives unfortunately requires the use of severe reaction conditions, i.e. the use of the highly corrosive and toxic phosphorous oxyhalides (POCl.sub.3 +1% H.sub.3 PO.sub.4) as solvent at reflux temperature, which greatly limits the applicability of this process to large scale preparations. The process of the present invention takes advantage of the discovery that, due to the inherent symmetry and to the different pK.sub.A of barbituric acid of the formula (II) above defined, the preparation of the monomesylate of formula (III) above defined is possible in one step.
This reaction, in fact, allows the preparation of compounds of formula (III) without affecting the carbonyl group in the 2 position and thus avoiding a protection/deprotection sequence. Quite surprisingly (see e.g. Advantages in Heterocyclic Chemistry, 38, Recent Progress in Barbituric Acid Chemistry, pp 269-273 and particularly section III.B page 269 and page 271) dimesylated product, N-substituted products, and products arising from scrambling of the mesyl group between the various functionalities were observed only in trace amounts.
Moreover the preparation of the aforementioned mesylate (III) involves the use of very mild reaction conditions, i.e. room temperature in a solvent such as dimethylformamide, and of a reagent-quantity amount of methansulphonyl derivatives.
The present invention also comprises the surprisingly easy reduction of mesylate (III); in fact no precedent is reported in the scientific literature about the reduction of such enol mesylates to the corresponding ene functionality, this kind of reaction being hardly known at all.
This process offers the distinct advantage of the preparation of expensive 5-substituted uracils starting from inexpensive barbituric acid derivatives. This process should be also particularly advantageous from an industrial point of view for the accessibility and low cost of reagents and for the easy and mild reaction conditions. Moreover this methodology avoids the use of hazardous materials allowing greater scale and safer preparation.
In particular, the process of the present invention typically comprises reacting an organic or inorganic salt of as compound of formula (II) a

REFERENCES:
patent: 4618604 (1986-09-01), Chu et al.
Candiani et al, Heterocycles, vol. 24, pp. 875-879 (1992).

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