Fluorinating reagents and method of fluorination

Fluorinating reagents expressed in a general formula; ##STR1## (In the general formula, R is an alkyl group having 1 to 5 carbons or a dialkylamino group in which each alkyl group has 1 to 3 carbons.), and a fluorinating method to fluorinate an alcoholic hydroxyl group by using the reagent. Raw materials of the aforesaid fluorinating reagents can be easily converted to object products and are less poisonous and corrosive. Their procurement and preparation are also easy. Further, it is easy to fluorinate compounds containing an alcoholic hydroxyl group by using this fluorinating reagents.

This invention relates to fluorinating reagents needed for producing 
compounds containing fluorine which are important as medicines and their 
intermediates and to the method of fluorination which uses the 
fluorinating reagent. 
PRIOR ART 
As reagents and methods of fluorinating an alcoholic hydroxyl group, 
following methods shown in (1) to (5) have been known so far. 
(1) A method of fluorinating a hydroxyl group in secondary alcohol or 
tertiary alcohol by using HF or HF/pyridine solution (M. Hudlioky, 
"Chemistry of Organic Fluorine Compounds", 2nd ed., Ellis Hotwood Ltd. 
1976, page 689: G. A. Olah et al., Synthesis, 1973, page 786). 
(2) A method in which after a hydroxyl group in alcohol is converted to an 
ester of sulfonio acid, the ester is fluorinated by making it react with 
alkalimetal fluoride including KF (M. Hudlicky, "Chemistry of Organic 
Fluorine Compounds", 2nd ed., Ellis Horwood Ltd. 1976, page 689). 
(3) A method of fluorinating a hydroxyl group by using fluoroalkylamine as 
a fluorinating reagent which is obtained from the reaction of secondary 
amine with ohlorotrifluoroethylene or hexafluoropropene (E. D. Bergmann et 
al., Isr. J. Chem., Vol. 8, page 925, 1970: Ishikawa et al., "Chemistry of 
Organic Synthesis", Vol. 37, No.7, page 607, 1979). 
(4) A method of fluorinating a hydroxyl group by using diethylamino sulfur 
trifluoride (DAST) as a fluorinating reagent (W. J. Middleton et al., 
"Org. Synthesis", Vol. 57, page 50, 1977). 
(5) A method of fluorinating a hydroxyl group by using as a fluorinating 
reagent difluorotriphenyl-phosphorane from the reaction of 
triphenylphosphine with sulfur tetrafluoride (Kobayashi et al., "Chem. 
Pharm. Bull." (Tokyo), Vol. 16, page 1009, 1968). 
The inventor of this invention studied new fluorinating reagents, 
especially those containing phosphorus, in place of the above-mentioned 
well-known fluorinating reagents.

It is not easy to prepare the fluorinating reagent described in the above 
(5), because very poisonous and corrosive sulfur tetra-fluoride must be 
used as a raw material. 
OBJECTS OF THE INVENTION 
The object of this invention is to offer fluorinating reagents containing 
phosphorus which can be easily and safely synthesized. 
Another object of this invention is to offer a method of efficiently 
fluorinating an alcoholic hydroxyl group by using the fluorinating reagent 
containing phosphorus. 
THE CONSTITUTION OF THE INVENTION 
As a result of eagerly repeating searches and studies of the 
above-mentioned fluorinating reagents which contain phosphorus and are 
easy to prepare, the inventor found that 
fluoro-(1-pentafluoro-1-propenyl)-tributyl phosphorane (hereinafter 
abbreviated FPTBP) obtained from the reaction of hexafluoropropene 
(hereinafter abbreviated HFP) with tributyl phosphine (hereinafter 
abbreviated TBP) could be used as a fluorinating reagent to fluorinate an 
alcoholic hydroxyl group, having reached the success of completing this 
invention. 
That is, this invention relates to fluorinating reagents (e.g. FPTBP) 
expressed in a general formula; 
##STR2## 
(In the general formula, R is an alkyl group having 1 to 5 carbons or a 
dialkyl-amino group in which each alkyl group has 1 to 3 carbons.) 
This invention also offers a fluorinating method that is characteristic of 
substituting fluorine for the above-mentioned alcoholic hydroxyl group by 
the reaction of the fluorinating reagent and an organic compound 
containing an alcoholic hydroxyl group. 
A fluorinating reagent in this invention, FPTBP, for example, is easily 
produced by the reaction of TBP and HFP in such a solvent as methylene 
ohioride, diethyl ether, and diethylene glycol dimethyl ether (See D. J. 
Burton et al., "J. Fluorine Chem." Vol 44 page 167, 1989). 
In this case, several ways can be taken, such as a way in which HFP is 
blown into TBP dissolved in a solvent to make them react, a reaction under 
normal pressure in which HFP is put into after being condensated by 
cooling and is made react with TBP, and a way that after putting a solvent 
and TBP into an autoclave HFP is introduced under pressure to make it 
react with TBP. 
When synthesis of fluorinating reagents is carried out with the method of 
this invention, besides the above-mentioned TBP, trialkylphosphines, 
including trimethylphosphine, triethylphosphine, and tripropylphosphine, 
or tris (dialkyl-amino) phosphines, including tris (dimethylamino) 
phosphine and tris (diethyl-amino) phosphine, can also be used. 
Such various kinds of raw materials can be easily converted to object 
products and are less poisonous and corrosive. And they are easily 
prepared. Moreover, as TBP and its above-mentioned substitutes, and HFP 
are all easily available, those materials being on sale can be used as 
they are. 
By using one of the aforementioned phosphines, a fluorinating reagent, its 
R in the above-mentioned general formula is corresponding to that of the 
used phosphine, can be obtained. 
A compound containing an alcoholic hydroxyl group to be fluorinated is 
added in a fluorinating reagent such as FPTBP solution obtained in this 
way. 
The mixture is kept at the reaction temperature of -10.degree.-100.degree. 
C., preferablly at 0.degree.-80.degree. C. and stirred, then a compound 
with substituted fluorine for its hydroxyl group and 
1,1,1,2,3-pentafluoropropene are produced. The products can be separated 
from the reaction mixture by distillation under normal or reduced 
pressure. The amount of FPTBP is preferable to be more than the equivalent 
to a hydroxyl group to be fluorinated. 
As compounds having an alcoholic hydroxyl group which can be fluorinated by 
using fluorinating reagents in this invention, though they are not 
particularly limited, alcohols such as methanol, ethanol, propanol, 
isopropanol and octyl alcohol, and compounds having asteroid structure 
with a hydroxyl group (various compounds except those having OH group of 
oarboxylic acid) are considered. 
THE POSSIBILITY OF UTILIZING THE INVENTION IN INDUSTRY 
Since fluorinating reagents in this invention are those compounds expressed 
in the above-mentioned general formula, raw materials of the reagents can 
be easily converted to object products and are less poisonous and 
corrosive. Their procurement and preparation are also easy. Further, it is 
easy to fluorinate compounds containing an alcoholic hydroxyl group by 
using this fluorinating reagents. 
EXAMPLE 
The invention will be explained in detail in the following examples. 
EXAMPLE 1 
Twenty ml of diethyleneglycol dimethyl ether and 20.3 g of TBP were put in 
a 100 ml glass reaction vessel equipped with a gas introduction tube and a 
condenser cooled by dry ice. With the mixture cooled at 
5.degree.-10.degree. C., HFP was introduced through the gas introduction 
tube. HFP introduction rate was controlled so that inner temperature 
didn't rise over 10.degree. C. After 15 g of HFP had been introduced, the 
mixture was further stirred for 1 hour at 5.degree.-10.degree. C. 
Then, after replacing the gas introduction tube with a dropping funnel, 4.6 
g of ethyl alcohol was dropped while keeping the reaction temperature at 
5.degree.-10.degree. C. After the end of dropping, the reaction mixture 
was returned to room temperature and stirred continuously. In the first 
place, 1,1,1,2,3-pentafluoropropene was produced. Then, monofluoroethane 
began to be produced when the reaction mixture was heated to 
50.degree.-55.degree. C. and continuously stirred. After 5 hrs. heating 
and stirring, products were collected in a cold trap cooled at -70.degree. 
C. The weight of the collected liquid was 17.5 g. Gas ohromatographio 
analysis showed that the liquid was composed of 74.3 wt % of 
1,1,1,2,3-pentafluoropropene and 25.7 wt % of monofluoroethane. According 
to the result, the yield of monofluoroethane was 94%. 
Furthermore, a fluorinating reagent FPTBP produced by the above-mentioned 
reaction of TBP and HFP; fluoro-(1-pentafluoro-1-propenyl)-tributyl 
phosphorane was identified by .sup.19 F-NMR and .sup.31 P-NMR analysis. 
Monofluoroethane produced in the fluorinating reaction was also identified 
by .sup.19 F-NMR and .sup.1 H-NMR analysis, and by Mass analysis. All the 
analysis data showed the same values as those reported in literatures. 
EXAMPLE 2 
Instead of ethanol, 6 g of isopropanol was used in the same reaction as 
Example 1. As the result, the amount of the collected liquid was 17.2 g. 
Gas chromatographic analysis showed that the liquid was composed of 69.2 
wt % of 1,1,1,2,3-pentafluoropropene and 30.8 wt % of 2-fluoropropane. 
According to the result, the yield of 2fluoropropane was 85%.