Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1990-05-04
1992-03-31
Shen, Cecilia
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C07H 19073
Patent
active
051010232
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the synthesis of 3'-azido-3'-deoxythymidine (azidothymidine, AZT, zidovudine) and of related compounds used in combating AIDS.
A marketing authorization has recently been granted to the Wellcome Firm for the marketing of a product based on azidothymidine. The therapeutic application of this product is described in Patent DE-3,608,606.
Different syntheses of AZT have been described to date; they have the common feature of starting from thymidine and of comprising a rather large number of stages, between five and seven, except for one synthesis which requires the use of an expensive base.
These syntheses are summarized, for example, in the paper in Drugs of the Future, vol. 11, No. 12 (1986); the conversion yields are very low in all cases.
A paper published in 1984 (V. E. Zaitseva et al., Bioorg. Khim., 10, 670 (1984)) described a synthesis of AZT employing three stages; it appears, nevertheless, that this process has not been developed.
In effect, the second stage of the process requires the preparation of lithium p-methylbenzoate, and the isolation of the AZT obtained in the final stage is carried out by column chromatography.
The subject of the present invention is a process for preparing AZT and related compounds which employs only two stages and which, in addition, has the enormous advantage of being able to be performed in a single reaction vessel, if necessary.
More especially, the subject of the invention is a process for preparing a compound of formula (I): ##STR4## in which R.sub.1 is H, an alkyl radical or an alkoxy, hydroxyalkyl or halogen radical, and R.sub.3 is N.sub.3 or a CN radical, characterized in that a compound of formula (II): ##STR5## is reacted with a phosphine or phosphite derivative and an azodicarboxylic acid diester and a carboxylic acid R.sub.2 --COOH in a solvent compatible with the reaction conditions, to form the compound of formula (III): ##STR6## which, after separation if required, is opened in the presence of an azide or a cyanide in a solvent compatible with the reaction conditions, and the compound of formula (I) is then isolated from the reaction medium after deprotection of the 5'-position.
The preparation of a compound of formula III with R.sub.1 denoting a methyl group and R.sub.2 a phenyl group has been mentioned in the literature (Kimura et al., Bull. of the Chem. Soc. of Japan Vol. 52 (4), 1979, p. 1191), but the process in question is not satisfactory since it requires two stages and leads to a low yield, of the order of 35%.
Naturally, among the compounds of formula (I), AZT, that is to say the compound in which R.sub.1 is equal to CH.sub.3 and R.sub.3 is equal to N.sub.3, must be mentioned more especially, nevertheless, at the present time, other AZT derivatives are being developed, these comprising, in particular, derivatives in which R is equal to a lower alkyl radical or a lower alkoxy or lower hydroxyalkyl radical, containing from 1 to 5 carbon atoms, for example methyl or ethyl radicals.
In the process according to the present invention, the starting material, in particular for preparing AZT, is thymidine, a compound which is industrially available and which must preferably, for the requirements of the process, be in general dehydrated since the presence of water considerably impairs the yield of the process.
Among the other reactants used for the preparation of a compound of formula III, although it is possible to use different types of phosphine or phosphite, the preferred phosphine is triphenylphosphine since it is a product which is readily available at the industrial level. Similarly, the azodicarboxylic acid diesters can be alkyl or aryl esters, especially lower alkyl esters such as diethyl azodicarboxylate (DEAD) or preferably diisopropyl azodicarboxylate (DIAD). This compound DIAD is, in effect, a compound which is inexpensive and which enables yields to be obtained which are equal or sometimes even greater than those obtained with other diesters.
Finally, in the choice of carboxylic acid, R.sub.2 --C
REFERENCES:
patent: 4681933 (1987-07-01), Chu
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K. A. Watanabe et al.: "2,5'-Anhydrouridine and 2,5'-Anhydro-5-Fluorouridine, One-Step Conversion of Uridine and 5-Fluorouridine into their Corresponding 2,5'-Anhyronucleosides", & Nucl. Acid. Chem. 1978, 1, 343-346.
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Yamamoto et al. "One-Step Synthesis of 5'-Azido-Nucleosides", Journal of Chemical Society, Perkin Transactions I, (London, GB), (1980), pp. 306-310.
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Czernecki Stanislas
Valery Jean-Marc
Ville Guy
Shen Cecilia
Universite Pierre Et Marie Curie (Paris VI)
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