Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-02-14
1998-02-10
Kight, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 282, 536 2853, 514 50, C07H 1906
Patent
active
057170860
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the preparation of 2',3'-dideoxy-3'-fluorouridine, and intermediates for use therein.
Certain substituted 2',3'-dideoxy ribonucleosides are known inhibitors of reverse transcriptase activity and are of potential importance in the treatment of diseases caused by retroviruses, including HIV. 3'-Fluoro-2',3'-dideoxyuridine is an intermediate in the preparation of therapeutically useful 2',3'-dideoxy-ribonucleosides, disclosed in, for example, EP-A-305117 and 356166 (The Wellcome Foundation Limited).
European Specification EP-A-0470355 describes inter alia a process for the preparation of 3'-fluoro-2',3'-dideoxy -nucleosides by reaction of a corresponding anhydro dideoxy-nucleoside with hydrogen fluoride in the presence of an aluminium-containing catalyst. The catalyst may be, for example, aluminium acetylacetonate.
East German Specification 103241 describes the preparation of 3'-fluoro-2',3'-dideoxyuridine by reaction of the corresponding 5-O-mesyl-anhydronucleoside with hydrogen fluoride in the presence of an aluminium fluoride catalyst, followed by removal of the mesyl group.
The use of aluminium-containing compounds in the preparation of drugs has attracted unfavourable criticism because of the possible involvement of aluminium in the etiology of Alzheimer's disease. It is therefore desirable to provide catalysts for the aforesaid reaction which do not contain aluminium. There is also a general need for catalysts which give a more rapid reaction and/or a higher yield of the desired product.
It has now been found that certain iron compounds are highly effective catalysts in the aforesaid reaction and give more particularly a higher reaction yield and/or a shorter reaction time than the corresponding aluminium compound.
The present invention accordingly provides a process for the preparation of a nucleoside of formula: ##STR1## where P is hydrogen or a hydroxy-protecting group, which comprises reacting an anhydronucleoside of formula: ##STR2## where P is as hereinbefore defined, with hydrogen fluoride under anhydrous conditions in the presence of an organo-iron (III) compound of formula: each zero or positive integers such that (m+2n)=6, and optionally replacing a hydroxy-protecting group P by hydrogen.
In the starting material of formula II the 5'-hydroxyl radical may be unprotected (i.e. P may be hydrogen), but preferably it is protected by a radical which can be readily removed after the reaction to liberate the hydroxyl radical. A variety of suitable radicals are available for this purpose and their introduction into the starting material and subsequent removal after the reaction are well known to those of ordinary skill in this art. P may be, for example, an acyl group such as C.sub.1-6 alkanoyl, e.g. acetyl or pivaloyl, or an aroyl group optionally substituted by C.sub.1-4 alkoxy or nitro, e.g. benzoyl, 2-naphthoyl, 4-methoxybenzoyl, 4-nitrobenzoyl, or 3,5-dinitrobenzoyl, an ether group such as tri-C.sub.1-6 alkylsilyl, e.g. trimethylsilyl, an aralkyl group, e.g. benzyl or triphenylmethyl, or methanesulphonyl. The use of a 4-methoxybenzoyl radical is preferred.
The compounds of formulae (I) and (II) in which P is a branched chain alkanoyl of 4 to 6 carbon atoms, e.g. pivaloyl, benzoyl substituted by alkoxy of 1 to 4 carbon atoms or byl or 2 nitro radicals, e.g. 4-methoxybenzoyl, 4-nitrobenzoyl, or 3,5-dinitrobenzoyl, or 1- or 2-naphthoyl are new compounds and as such within the scope of the present invention. 2,3'-Anhydro-5'-(4-methoxybenzoyl)-2'-deoxyuridine and 2'3'-dideoxy-3'-fluoro-5'-(4-methyoxybenzoyl)uridine are especially valuable.
The reaction is carried out under anhydrous conditions and preferably in the presence of an inert organic solvent, preferably an aprotic solvent, e.g. 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, or bis(2-methoxyethyl)ether. The use of 1,4-dioxane is preferred.
The organoiron compound of formula III may be any suitable derivative of iron which is at least partially soluble in the reaction medium. The ligand Y is preferably halogen (e.g
REFERENCES:
patent: 5153180 (1992-10-01), Matthes et al.
patent: 5157114 (1992-10-01), Rahim et al.
patent: 5223263 (1993-06-01), Hostetler et al.
patent: 5376644 (1994-12-01), Selway et al.
patent: 5449664 (1995-09-01), Verheyden et al.
patent: 5574149 (1996-11-01), Van Tuttle et al.
Morisawa et al., "3-Deoxy-3-fluoro-5-substituted-D-ribofuranoside Derivative as Antitumor Agents and Virucide," Japanese Kokai Tokkyo Koho 743, Abstr. No. 115,782a 1990); only abstract supplied.
Szabolcs et al., "Preparation of (5-Substituted) 3'-azido-2',3'-dideoxyribonucleosides," Hungarian Patent Document HU 48,901, published 29 Jul. 1989; Chem. Abstr., 112(25), p. 670, Abstr. No. 235776c (1990); only abstract supplied.
Kowollik et al., "Nucleosides of Fluorinated Sugars. XII. Synthesis of 1-(2,3-Dideoxy-3-fluoro-.beta.-D-ribofuranosyl)pyrimidines," J. Prakt. Chem., 315(5), 895-900 (1973); Chem. Abstr., 80(9), p. 392, Abstr. No. 48302d (1974); only abstract supplied.
Joecks et al., "NMR Spectroscopic Studies of the Conformational Behavior of Some 2'-and 3'-Halogen-substituted Pyrimidine Nucleosides," J. Prakt. Chem., 325(6), 881-892 (1983); Chem. Abstract., 100(25), p. 644, Abstr. No. 210313p (1984); only abstract supplied.
Ueda, "Synthesis and Reaction of Pyrimidine Nucleosides," Ch. 1 in Chejmistry of Nucleosides and Nucleotides, vol. 1, Townsend (ed.), Plenum Press, New York, NY, 1988, pp. 1-112, only pp. 1, 53, 61-62 and 105-106 supplied.
Journal of Medicinal Chemistry, vol. 32, No. 8, Aug. 1989, pp. 1743-1749, A. Van Aerschot et al., "'3'-Fluoro-2', 3'-dideoxy-5-chlorouridine: Most Selective Anti-HIV-1 Agent Among a Series of New 2'- and 3'-Fluorinated 2', 3'-Dideoxyucleoside Analogues".
Chemical Abstracts, vol. 113, No. 13, Sep. 24, 1990, Y. Morisawa et al, "'3-Deoxy-3-fluoro-5-substituted-D-ribofuranoside Derivatives as Antitumour Agents and Virucides", p. 743, col. 1, Apr. 1990.
Chemical Abstracts, vol. 112, No. 25, Sep. 18, 1990, Szabolcs et al., "Preparation of (5-Substituted) 3'-Azido-2', 3'-Dideoxyribonucleosides", p. 670, col. 2.
Chemical Abstracts, vol. 80, No. 9, Mar. 4, 1974, Kowollik et al, "Nucleosides of Fluorinated Sugars. XII. Synthesis of 1-(2,3-Dideoxy-3-Fluoro-beta-D-ribofuranosyl) Pyrimidines", p. 392, col. 2.
Chemical Abstracts, vol. 100, No. 25, Jun. 18, 1984, Joecks et al, "'NMR Spectroscopic Studies of the Conformational Behavior of Some 2'- and 3'-Halogen Substituted Pyrimidine Nucleosides", p. 644, col. 1.
Journal of Medicinal Chemistry, vol. 33, No. 2, Feb. 1990, pp. 845-848, Hiebl et al, "Synthesis, Antiretrvirus Effects and Phosphorylation Kinetics of 3'-Isocyano-3'-Deoxythymidine and 3'-Isocyano-2', 3'-Dideoxyuridine".
Chambers Owen Ross
Germain Andrew Lawrence
Youmans Patrick Charles
Crane L. Eric
Kight John
Rhone-Poulenc Chemicals Limited
The Wellcome Foundation Limited
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