Preparation of fluorinated compounds

Details Preparation of fluorinated compounds Preparation of fluorinated compounds

2000-03-20

2001-07-03

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Phosphorus esters

C558S161000, C558S167000, C558S178000, C558S203000

Reexamination Certificate

active

06255518

ABSTRACT:

This invention relates to the preparation of fluorinated compounds and, in particular, to the preparation of fluorophosphonates.
Trialkylphosphonoacetates and related phosphonates are valuable intermediates in organic syntheses. The corresponding monofluorinated compounds have the potential to be equally valuable and the chemistry of one of them, (EtO)
2
PO.CHF.COOEt, has been developed extensively by H. Machleit and R. Westenden (
Lieb. Amr. Chem,
1964, 674, 1), D. J. Burton et. al. (
J. Org. Chem.,
1990, 55, 2311;
J. Org. Chem.,
1990, 55, 4639;
J. Org. Chem.,
1991, 56,273,
J. Org. Chem.,
1994, 59, 7085;
Phosphorus, Sulphur and silicon,
1995, 105, 205;
J. Fluorine Chem.,
1996, 77, 45), R. S. H. Lui et. at. (
J. Am Chem. Soc.
1981, 103, 7195) and P. W. Collins et. al. (
J. Med. Chem.,
1987, 30, 1952).
Most of the material used in these investigations has been prepared by reaction between a trialkylphosphate and ethyl bromofluoroacetate (Arbutzov Reaction and modifications thereof), but while the Arbutzov reaction itself can be carried out in high yield, the preparation of ethyl bromofluoroacetate is a multi-step synthesis. Further, the bromo compounds required to make other fluorinated phosphonates are not readily available. More recently, the lithium salt derived from triethylphosphonoacetate has been treated with the electrophilic fluorinating agent, N-fluoro-o-benzene-disulphonimide (F. A. Davis, W. Han and C. K. Murphy,
J. Org. Chem.
1995, 60, 4730) to produce the monofluoro derivative. However, the fluorinating agent is expensive to prepare and is not readily available.
Additionally, the use of electrophilic fluorinating agents such as N-fluoro-1,4-diazabicyclo[2.2.2]octane in the selective fluorination of various methylenephosphonate and methylenephosphorane derivates is discussed in U.S. Pat. No. 5,442,084 but, again, fluorinating agents of this type are generally not readily available.
A more convenient and economical technique for the fluorination of organic compounds is via the use of elemental fluorine. However, reactions of this type can be difficult to control in view of the high reactivity of elemental fluorine, although some applications have been successful. Thus PCT Application No WO97/00848 discloses the preparation of certain fluorinated esters from the corresponding hydrogenated esters by reaction with elemental fluorine, and a similar technique is applied to various 1,3-diketones and 1,3-ketoesters to obtain the corresponding fluorinated derivatives in PCT Application No WO95/14646. Such procedures are, however, rarely satisfactory and generally, lead to unspecific multiple substitution of the starting material, carbon-carbon bond cleavage and oxidation.
Surprisingly in the light of the prior art, the present inventors have now disclosed that fluorinated phosphonates can be prepared by treating a salt derived from the parent phosphonate, or by treating the parent phosphonate in the presence of a base, with elemental flurorine.
According to the present invention there is provided a method for the preparation of a fluorinated phosphonate having the formula (RO)
2
PO.CFR′.R″ comprises treating a phosphonate of the formula (RO)
2
PO.CHR′R″, or a metal salt thereof, with fluorine, where R is an alkyl group, R′ is hydrogen or alkyl and R″ is hydrogen, alkyl or another group.
Preferably the metal salt is prepared by treatment of (RO)
2
PO.CHR′R″ with an alkali metal hydride or an alkali metal alkoxide. Preferably the phosphonate of formula (RO)
2
PO.CHR′R″ is treated with fluorine in the presence of a base.
It is preferred that the group R has from 1-6 carbon atoms and that in the case where R′ is alkyl, it has from 1-6 carbon atoms. Where R″ is a group other than hydrogen, it is preferably —PO(OR)
2
, —COOR, —COOR, —CO.R or —CN.
Preferably the metal salt has the formula (RO)
2
PO.C
−
R′R″.M
+
where M is lithium, sodium or potassium.
Preferably, the fluorine is diluted with an inert gas such as nitrogen, helium or argon. The concentration of fluorine is preferably in the range 1-50% v/v, more preferably from 2-25% v/v and most preferably from 5-15% v/v.
Preferably, the fluorination is carried out in a solvent which is substantially inert to fluorine, such as acetonitrile or propionitrile.
Preferably, the alkali metal salts are formed in acetonitrile but they may also be formed in a solvent such as diethyl ether, tetrahydrofurane or dimethoxyethane. If solvents such as these are used in the formation of the metal salts, it is necessary for acetonitrile or propionitrile to be added and the ether to be removed by distillation before the fluorination is undertaken.
Where fluorination is carried out by passing a stream of diluted fluorine into a solution of the phosphonate in the presence of a base, the solvent is preferably dry acetonitrile and the base is anhydrous potassium fluoride or anhydrous caesium fluoride.
Preferably, the concentration of phosphonate in the solvent is from 0.1 molar to 10 molar, although higher concentrations may be used.
Preferably, the reaction is carried out at a temperature in the range −60° C. to +150° C., more preferably from −20° C. to +50° C. and most preferably from −10° C. to +15° C.
The following examples serve to illustrate the present invention. Except where indicated otherwise,
1
H,
19
F and
31
P NMR spectra were recorded on a Bruker AC250 spectrometer operating at 250 MHz for hydrogen, 235 MHz for fluorine or 101 MHz for phosphorus.
13
C NMR spectra were measured on a Varian VXR 400 spectrometer operating at 100 MHz or a Varian Gemini 200 spectrometer operating at 50 MHz. Chemical shifts are recorded in ppm from tetramethyl silane, fluorotrichloromethane and phosphoric acid, and coupling constants are in Hz. Mass spectra were measured on a Fisons Trio 1000 mass spectrometer coupled to a Hewlett Packard 5890 II gas chromatograph fitted with a silicone elastomer coated column (SE 30; 25 m., 0.2 mm. i.d.).


REFERENCES:
patent: 4478763 (1984-10-01), McKenna
patent: 4757127 (1988-07-01), Tessier et al.
patent: 5142085 (1992-08-01), Barry et al.
patent: 5442084 (1995-08-01), Lai
patent: WO95/14646 (1995-06-01), None
patent: WO97/00848 (1997-01-01), None
F.A. Davis et al.; Selective, Electrophilic Fluorinations Using N-Fluoro-o-benzenedisulfonimide,J. Org. Chem. 60:4730-4737 (1995).
Collins et al.; “Synthesis and Gastrointestinal Pharmacology of the 4-Fluoro Analogue of Enisoprost,”J. Med. Chem.30:11 1952-1955 (1987).
Davis et al.; “Selective, Electrophilic Fluorinations Using N-Fluoro-o-benzenedisulfonimide,”J. Org. Chem.60:15 4730-4737 (1995).
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Thenappan et al.; “Alkylation of (Fluorocarbethoxymethylene)tri-n-butylyphosphorane: A Facile Entry to-Fluoroalkanoates,”J. Org. Chem.55:8 2311-2317 (1990).
Thenappan et al.; “Reduction-Olefination of Esters: A New and Efficient Synthesis of -Fluoro , -Unsaturated Esters, ”J. Org. Chem.55:15 4639-4642 (1990).
Thenappan et al.; “Acylation of Fluorocarbethoxy-Substituted Ylids: A Simple and General Route to -Fluoro -Keto Esters,”J. Org. Chem.56:1 273-277 (1991).
Thenappan et al.; “Preparation of -fluoro--per (poly) fluoroalkyl-substituted enol ethers,”Journal of Fluorine Chemistry77:45-50 (1996).
Tsai et al.; “A Novel Intramolecular Horner-Wadsworth-Emmons Reaction: A Simple and General Route to -Fluoro-, -unsaturated Diesters,”J. Org. Chem.59:23 7085-7091 (1994).
Tsai et al.; “A One-Pot Synthesis of Unsymmetrical and Symmetrical Tetrasubstituted -Fluoro-, -unsaturated Esters,”Phosporus, Sulfur, and Silicon105:205-212 (1995).

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