Preparation of fluoro compounds

Fluoro compounds are made by reaction of an activated oxy-acid ester or cyclic ether starting material with hydrogen fluoride in the presence of an organometallic compound.

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: 
EQU MY.sub.m Z.sub.n (I) 
where M is a 4-, 6- or 8- coordinated metal selected from magnesium, zinc, 
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 
EQU R.sub.1 R.sub.2 CHOX (II) 
into a fluoride of formula: 
EQU R.sub.1 R.sub.2 CHF (III) 
wherein X is a sulphonic acid residue and R.sub.1 and R.sub.2 are each 
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, optionally 
linked to form a 4- to 7-membered ring, and unsubstituted or substituted 
by alkyl, aryl or aralkyl substituents. 
The starting material may be, for example, cyclohexene oxide: 
##STR7## 
or propylene oxide 
##STR8## 
or a sugar epoxide, e.g. 
##STR9## 
an intermediate for tetracyclines derivative as mentioned in Japanese 
Patent 63-141992 (1988)!. 
The process of the invention 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 organometallic compound of formula I may be any suitable derivative of 
magnesium, zinc, zirconium, cerium, titanium or iron which is at least 
partially soluble in the reaction medium. The ligand Y is preferably 
halogen (e.g. fluorine or chlorine), alkoxy of 1 to 4 carbon atoms which 
may be halogenated (e.g. methoxy, ethoxy, isopropoxy or 
2,2,2-trifluoroethoxy), or phenoxy which may optionally be substituted by 
alkyl of 1 to 4 carbon atoms, halogen (e.g. chlorine), or nitro. The 
ligand Z is preferably a carboxylato radical derived from an alkanoic acid 
of up to 12 (preferably 1 to 6) carbon atoms which may be halogenated 
(e.g. acetic acid) or benzoic acid which may optionally be substituted by 
alkyl of 1 to 4 carbon atoms, halogen (e.g. chlorine) or nitro. Z may also 
be derived from an alkanesulphonic acid of 1 to 12 (preferably 1 to 4) 
carbon atoms. Alternatively, the ligand Z may be .beta.-diketo residue of 
a compound of formula R'--COCH.sub.2 CO-R" where R' is alkyl or haloalkyl 
(including perfluoroalkyl) of 1 to 4 carbon atoms (e.g. methyl) and R" is 
hydrogen, hydroxy, alkyl or haloalkyl (including perfluoroalkyl) of 1 to 4 
carbon atoms, or alkoxy of 1 to 4 carbon atoms, and more especially methyl 
or ethoxy. Z may also be a cyclopentadienyl hydrocarbon ligand or 
alkyl-substituted derivative thereof (in which the alkyl has 1 to 4 carbon 
atoms); e.g. the organometallic compound may be bis(cyclopentadienyl) 
titanium dichloride, or bis(cyclopentadienyl) zirconium dichloride. 
Preferred organometallic compounds for use in the present invention contain 
iron (III), in which case m is preferably zero, n is preferably 3, and Z 
is preferably a .beta.-diketo residue, e.g. acetylacetonato. The use of 
iron (III) acetylacetonate is especially preferred. 
The proportions of the starting materials and organometallic compound are 
not critical. An excess of the hydrogen fluoride, e.g. from 2 to 20 moles 
per mole of starting material, is generally used. 
The proportion of the organometallic compound is generally approximately 
equimolar with the starting material, e.g. 0.5 to 2.0 moles of the 
organometallic compound (on the basis of its metal content) per mole of 
starting material. The reaction is conveniently carried out with moderate 
heating, e.g. to 50.degree. to 150.degree. C. For higher temperatures 
within this range, the reaction vessel is preferably closed so that the 
reaction is carried out under autogenous pressure. This makes possible the 
use of reaction temperatures greater than the boiling point at atmospheric 
pressure of the solvent used. 
Because of the high activity of the organometallic compounds used in the 
process of the present invention, the reaction times required are usually 
less than those necessary when an organo-aluminium compound is used. A 
reaction time of 0.5 to 4 hours is generally satisfactory. 
The reaction mixture may be worked up in conventional manner. The excess 
hydrogen fluoride is preferably first removed, e.g. by reaction with 
calcium carbonate to give insoluble calcium fluoride or by reaction with 
potassium fluoride. The thus-insolubilized fluorine compounds are removed, 
e.g. by filtration, and dilution of the separated reaction medium with 
water causes the desired product to precipitate. It may then be separated, 
e.g. by filtration and purified in the usual way, but very often it is 
sufficiently pure for use in the next stage without additional 
purification.

The following Examples illustrate the invention. 
EXAMPLE 1 
Preparation of 
2-Deoxy-2-fluoro-1,3,5-tri-O-benzoyl-.alpha.-D-arabinofuranose 
COMATIVE EXAMPLE 
(Using procedure described in the literature) 
##STR10## 
A mixture of 8.2 g of 
2-O-(imidazolylsulfonyl)-1,3,5-tri-O-benzoyl-.alpha.-D-ribofuranose (see 
J. Org. Chem., 50, (1985) p.3646) and 4.3 g of KHF.sub.2 is added to 41 ml 
of 2,3-butanediol and 2.0 ml of 50% aqueous HF in a flask vented under 
nitrogen to a scrubber (scrubbed with 5% NaOH). Heat to 120.degree. C. 
during 4 hours and follow reaction by HPLC. (Additional heating time will 
result in product decomposition). Cool to 75.degree. C. and add 40 ml of 
ethyl acetate and cool to room temperature. Add 60 ml of saturated sodium 
carbonate solution (significant CO.sub.2 evolution). Separate the bottom 
aqueous layer. Wash organic layer with 60 ml 5% NaCl solution and 
separate. Perform an azeotropic solvent exchange under vacuum into 
methanol at 20.degree.-250.degree. C. with approximately 30 ml of methanol 
at the final stage. Crystallization of the product occurred. Cool to 
0.degree.-5.degree. C. and stir two hours to complete the crystallization, 
filter the crystals and wash with q.s. cold methanol giving 4.03 g (yield 
62%, mp=80.degree. C.) of the desired fluoro compound (B). 
Process of Invention 
A mixture of 8.2 g of the same starting material (A) and 4.88 g (1 mole 
equivalent) of ferric acetylacetonate is added (under nitrogen) to 50 ml 
of dioxane and anhydrous hydrogen fluoride (2.2 g, 0.11 moles) was then 
transferred under nitrogen into the dioxane with continuous stirring. The 
reaction mixture was then heated to 90.degree. C. over 30 minutes. The 
reaction mixture was sampled as previously described over the 2 hour 
reaction period. After 1 hour the compound (B) constituted 85% w/w of the 
product and the remaining starting material was less than 1%. The reaction 
mixture was cooled, and the coloured solid present was filtered off. 
Deionised water (200 ml) was then added to the filtrate, which 
precipitated out the product. The off-white solid was filtered off, and 
washed with ice-cold methanol and then dried in a vacuum oven to give an 
off-white solid (about 5.44 g (yield 85%), mp=81.degree. C., Purity 
(HPLC).about.95.2%). 
This demonstrates an improved yield with a short time reaction and low 
reaction temperature. 
EXAMPLE 2 
Methyl-5-O-benzyl-2-deoxy-2-fluoro-.alpha.-D-arabinofuranoside 
COMATIVE EXAMPLE 
(Using procedure as described in the literature: J.O.C, 1969, 2634) 
##STR11## 
A solution of 7 g of starting material (C) and 15 g of KHF.sub.2 in 
ethylene glycol (140 ml) was refluxed gently for 1 hr. 30 min. 
(190.degree.-200.degree. C.). The cooled mixture was poured into saturated 
NaHCO.sub.3 (500 ml) and extracted with CHCl.sub.3 (3.times.200 ml). 
Evaporation gave a syrupy residue where HPLC analysis indicated 3.5 g of 
the desired product (D) with 1.3 g of still unreacted starting material 
(C) (81% conversion and 46% yield, i.e. 57% selectivity). 
Process of the invention: 
A solution of 8 g of (C) (34 mmoles) and 11.97 g of Fe(acac).sub.3 in 
dioxane (100 ml) with anhydrous hydrogen fluoride (4.7 g, 8 equivalents), 
under nitrogen was heated to gentle reflux (100.degree. C.) over 1 hr. The 
cooled mixture was filtered to remove the solid. Dionised water (300 ml) 
was then added to the filtrate, which precipitated out the product. The 
off-white solid was filtered off, washed with ice-cold methanol and then 
dried in a vacuum oven to give an off-white solid: .about.5.1 g (69% 
yield. Total conversion). 
EXAMPLE 3 
Cyclohexene oxide (15.2 g 155 m.moles) and Fe(acac).sub.3 (54.7 g 155 
m.moles) were stirred with a 9.5% w/w solution of HF/dioxane in an 
autoclave at 20.degree. C. Disappearance of the substrate could be 
monitored by GC analysis. The reaction mixture was filtered and the filter 
cake washed with further dioxane. The filtrate was then poured into water 
(160 g) and neutralised with calcium carbonate (56 g). Filtration and 
washing of the filter cake gave a filtrate containing 2-fluorocyclohexanol 
(11.2 g), equivalent to a yield of 60.8%. (Determined by GC using 
cyclohexanol as an internal standard. The crude product could be extracted 
into a suitable solvent and recovered by distillation under reduced 
pressure. The product identity was confirmed by gc/ms.) 
The same procedure without the use of Fe(acac).sub.3 gave only a 16.8% 
yield of 2-fluorocyclohexanol.