Preparation of fluoro compounds

Details Preparation of fluoro compounds Preparation of fluoro compounds

1995-12-12

1998-01-06

Geist, Gary

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

Organic compounds

Oxygen containing

568677, 568842, C07C 2200

Patent

active

057057133

DESCRIPTION:

BRIEF SUMMARY
This is the U.S. National Stage Application of PCT/GB94/01023 filed May 12, 1994 now WO94/26756 published Nov. 24, 1994.
This invention relates to the preparation of fluoro-compounds, and more particularly to the preparation of fluoro-sugars (fluorinated carbohydrates).
Interest in organofluorine compounds partly derives from the fact that replacement of hydrogen by fluorine in naturally occurring compounds alters their biological properties dramatically. For example 9.alpha.-fluoro-hydrocortisone exhibits enhanced corticoid activity compared with the corresponding 9.alpha.-hydroxy compound. The selective introduction of fluorine into naturally occurring compounds and organic compounds having functional groups has, in general, presented the synthetic chemist with a continuous challenge.
For a review of methods for making fluorinated carbohydrates, for example, see A. A. E. PENGLIS, Advances in Carbohydrate Chemistry and Biochemistry, 38, 195 to 285 (1981), or for making fluorinated nucleosides, see D. M. HURYN and M. OKAE, Chem. Rev., 1992, 92, 1745 to 1768, and for recent advances in the selective formation of the C-F Bond, see J. A. WILKINSON, Chem. Rev. 1992, 92, 505 to 519.
Disclosures of using HF as source of fluorine in presence of a catalyst are very limited and only a few examples are described in the literature.
European Specification EP-A-0470355 describes a process for the preparation of 2'- and 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'-dideoxy-uridine 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 progress 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 permit direct use of cheap hydrogen fluoride as the source of fluorine and give a more rapid reaction and/or a higher yield of the desired product, compared with existing techniques.
It has now been found that certain organo-metal compounds are highly effective in promoting the preparation of fluoro-compounds by reaction of a reactive oxy-acid ester or a reactive cyclic ether (other than an anhydrouridine) with hydrogen fluoride. In accordance with the present invention this reaction is carried out under anhydrous condition in the presence of an organometallic compound of formula: zirconium, cerium, titanium and iron, Y is a monodentate ligand, Z is a bidentate ligand or a cyclopentadienyl ligand, and m and n are each zero or positive integers such that (m+2 n)=4, 6 or 8.
In one embodiment of the invention the new process may be used to convert a reactive oxy-acid ester of formula hydrogen or alkyl of 1 to 6 carbon atoms, the said alkyl radicals being optionally linked to form a 4 to 7 membered ring and being unsubstituted or substituted by phenyl, halogen, hydroxy or alkoxy of 1 to 6 carbon atoms.
X may be, for example ##STR1## (where R=alkyl with 1 to 4 carbon atoms) ##STR2##
One example of a reaction of this kind is the transformation ##STR3## The product is an intermediate for drugs used to the treatment of AIDS (C. H. TANN et al, J. Org. Chem, 1985, 50, 3644). Another example is the displacement of a primary sulfonyloxy group by fluorine as in: ##STR4##
Another example is the displacement of secondary sulfonyloxy groups, as in: ##STR5##
The process of the invention may also be applied to epoxides as in the reaction: ##STR6## wherein R.sub.5, R.sub.6, R.sub.7, R.sub.8 may be the same or different, and each represents hydrogen, alkyl of 1 to 12 carbon atoms, optional

REFERENCES:
Chemical Abstracts vol. 91:#140295b; Feiring et al., 1979.
Kirk-Othmer;Encycl.Chemical Technology;vol. 10;pp. 871-874, 1980.
Belluci et al;J.Chem.Soc.;Perkin Trans. II; vol. 10; pp. 1336-1340, 1981.
Tann et al; J.Org.Chem.50(19) pp. 3644-3647, 1985.
Journal of Medicinal Chemistry, vol. 32, No. 8, Aug. 1989, Washington U.S. 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'-Dideoxynucleoside Analogues".
Chemical Reviews, vol. 92, No. 4, Jun. 1992, pp. 505-519, J.A. Wilkinson, "Recent Advances in the Selective Fluorination of the C-F Bond".
Chemical Reviews, vol. 92, No. 8, Dec. 1992, pp. 1745-1768, D.M. Huryn et al, "AIDS-Driven Nucleoside Chemistry", p. 1751, col. 2, line 6--p. 1752, col. 1, line 6, p. 1755, col. 2, line 15--p. 1756, col. 2, line 21.

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