Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1 This invention relates to a novel perfluoro-
tricyclic amine compound useful as an oxygen carrier
in ';an artificial blood or in an infusion fluid.
More particularly, it relates to perfluoro-
tricyclic amine compounds represented by the general
formula
--~ ~ (CF2) j
~ CF CF
(CF2)f A (CF2)g B (CF2)i C N-R (I)
~ ~ (CF ) ~ ~ (CF ) ~
wherein R denotes a perfluoroalkyl group having
from 1 to 4 carbon atoms, the xing A denotes a
five- or six-membered ring, the ring B denotes a
five-, six- or seven-membexed ring, the ring C
denotes a five- or six-membered ring, and f, g, h, i,
j and k denote integers appxopriately selected to
construct the above-mentioned size of rinys A, B and
C. In that case, the compound may be substituted
by one or more lower perfluoroalkyl group(s) in
addition to -the above-mentioned substituent R.
Regarding the general formula (I), as
, -- 1 --
~i~
1 mentioned above, f, g, h, i, j and k are integers
appropriately selected to constru~t a five- or
six-membered ring A, a five-, six- or seven-membered
ring B and a five- or six-membered ring C, respec-
tively. Individually, each of the int:egers isappropriately selected, for example, from:
1, 2, 3 and 4 for f; O, 1 and 2 for g; O and 1 for h;
and 0, 1, 2 and 3 for each of i, j and k.
In the general formula (I), the lower
perfluoroalkyl group denoted by R may be either of
straight chain or of branched chain. Examples
thereof include those having l to 4, preferably l
to 2, carbon atoms, such as perfluoromethyl ~roup,
perfluoroethyl yroup, perfluoro-n-propyl group,
perfluoroisopropyl group, perfluoro-n-butyl group,
perfluoroisobutyl group, perfluoro-sec-butyl group
and perfluoro-tert-butyl group.
Rings A, B and C, especially rings A and
C may be substituted at any position thereof by one
or more than one, preferably one or two, lower
perfluoroalkyl group(s) in addition to the above-
mentioned substituent denoted by R. Examples of the
lower perfluoroalkyl groups suitable as such
substituents are similar to those which are described
above referring to R. Perfluoromethyl group is
especially preferred. In case where two or more of
su~stituents are present, they may be different
from each other.
The total number of carbon atoms present in the com-
pound of formula (I) is generally from 8 to 12, preferably 10
or 11.
As an embodimen-t of -the compound of formula (I),
mention may be made of a compound represen-ted by the general
formula
( 3 m ( 3)n
\ (I')
/--1 ,~ (CF'2 ) j
~ CF CF
(CF2)f A (CF2)g B ~I 2)i C J -(CF2)Q(CF3)
CF \ / CF
\ (CF2)h ~ (CF2)k
wherein rings A, B and C are as defined above; f -~ g -~ h + i -
~j + k + Q + m + n = 5 or 6, f denotes, 1, 2, 3 or 4; g de-
notes 0, 1 or 2; h, Q, m and n clenote each O or l; and i, jand k denote each 0, 1, 2 or 3.
The compound of formula (I) can be prepared by
fluorinating a perhydro-compound (II) corresponding to the
compound of formula (I).
- 3 -
~ CH ~ / (CH2)j (II)
(CH2)f A (CH2)g ~ (t H2)i C N-R'
~ CH CH
wherein R' is an alkyl group having 1 - 4 carbon stoms, f, g,
h, i, j and the rings A, B and C are the same as above, with
fluorine.
The methods of :Eluorination include, :Eor example, a
direct fluorination, a fluorination by use of cobalt trifluoride,
and an electro chemical Eluorination.
The preparation of the compound of formula (I)
- 3a -
1 of this invention is preferably performed by the
electrochemical fluorination method. This is
performed, for example, by mixing anhydrous hydrogen
fluoride and a perhydro-compound used as the starting
compound in an electrolytic cell and subjecting the
resulting solution to electrolysis. The voltage,
the current density at the anode, and the temperature
of electrolytic solution are normally 3-9 V, 0.2 -
3.0 A/dm2 and 4-10C, respectively.
The compound o formula (I) thus formed
was drained from the bottom of the cell, being
insoluble in anhydrous hydrogen fluoride.
The isolation and purification of the
compound from the drained product are carried out,
for example, by adding a mixture of equal volumes
of an aqueous alkaline solution and an amine compound
to the drained product, refluxing, then separating
the lowermost layer containing the desired compound
of formula ~I) (the partially fluorinated compounds
decomposed in this process), washing the former
layer with an aqueous acetone solution containing a
suitable amount of potassium iodide to remove
perfluoroalkyl nitrogen fluorides, and by subsequent
fractional distillation to obtain the fraction of
the desired compound of formula (I).
Since the compound of the formula (I) of
this invention can dissolve a large amount of oxygen,
chemically and biologically inert, and can be excreted
-- 4
1 rapidly from the body, it can form, for example,
an aqueous emulsion containing 5 to 50, preferably
10-40, ~(W/V) of the compound of formula II) to be
used as an oxygen carrier in an artificial blood
or in an infusion liquid for men and other mam~als
such as dogs, cats, cattle, mice, rats and guinea
pigs.
The symbol "%~W/V)" referrecL to herein
mean the amount of the material by weight (gram) based
on 100 ml of the resulting emulsion.
In the preparation of the emulsion mentioned
above, there used, as an emulsifier, a nonionic
surfactant or phospholipids in an added amount of
1 to 5~ (W/V).
As the medium for the emulsion, a
physiologically acceptable aqueous solution is
employed. If necessary, there may be added thereto
such materials as inorganic salts to provide the
desired isotonicity, and such plasma expanders
as HES or dextran to regulate the osmotic pressure
of the emulsion.
The emulsion can be prepared by mixing
the above-mentioned ingredients and homogenizing
the mixture by means of, for example, a high-
pressure iet type homogenizer until the particlediameters become 0.05 to 0.3 ~m, preferably less
than 0.2 ~m.
The perhydro-compounds (starting compounds)
~89~9
1 corresponding to the compounds of ~ormula (I) are
substantially known already.
Example
The e~uipment employed in the fluorination
was a Monel reaction cell, through which coolant
could be circulated for temperature control. Power
was supplied to the cell pack by a 0 - 50 amp, 0 - 50
V-DC power supply. The cell pack consisted of 13
nickel plates (more than 99.6% purity) separated
with Teflon spacers, and arranged alternately so
that the seven odd numbered plates were cathodes
and the six even numbered plates were anodes.
The spacing between plates was 1.7 - 2.0 mm.
The cell was equipped with a copper condenser,
through which coolant was circulated by a refrigera-
tion unit. The progress of an electrolysis was
monitered by a voltage-current recorder. In the
electrolytic cell, was placed 1.2 liter of hydrogen
fluoride, and trace amounts of impurities present
in the system (moisture or sulfuric acid) were
removed by preliminary electrolysis. Then, 0.675 mol
(102 g) of 4-methyl-4-azatricyclo[5,2,1,02'6]decane
was introduced into the cell, and the electrolysis
was continued, while introducing nitrogen gas from
the bottom of the cell at a rate of lOQ ml/min.,
under the conditions of anode current density of
O.4 - 2.0 A/dm2, voltage of 5 - 7 V and solution
-- 6
~ ~39~79
1 temperature of 7 - 12C, until the ampere-hours
amounted to 730. Fresh anhydrous hydrogen fluoride
(300 ml) was added every 24 hours during the
electrolysis. No attempt was made to collect
volatile products ormed by a bond breaking reaction.
~fter completion of the electrolysis, fluorocarbons
in the lower layer in the cell was drained through
the bottom of the cell, weighed 260 g (57~ yield).
To the fluorocarbons thus separated, were
added equal volumes of 70% aqueous potassium hydroxide
solution and diisobutylamine, and the resulting
mixture was refluxed for about five days. The
reaction mi~ture was then cooled in an ice bath.
The perfluoro-compounds sedimented in the lowermost
layer were separated in a separatory funneL, washed
successively with water, concentrated sulfuric acid,
saturated aqueous sodium hydrogen carbonate solution
and 9~ aqueous acetone solution containing 3% of
potassium iodide, and finally several times with
water to yield 162.0 g of perfluoro-compounds contain-
ing no protons. This was distilled on a fractional
distillation apparatus equipped with a spinnin~
band column to afford 39.2 g (8.6~ yield) of the
desired product boiling at 143 - 152C. This product
was purified, then analyzed by infrared absorption
spectrometry, 19F-nuclear magnetic resonance spectro-
metory and mass spectrometory, and was confirmed to
be the objective compound, perfluoro-4-methyl 4-
azatricyclo[5,2,1,02'5]decane.
A series of other perfluorotricyclicamine compounds were synthesized and purified in the
same manner as that described above and each product
was conirmed to be the objective compound upon
analysis by infrared absorption spectrometory, 19F-
- nuclear magnetic resonance spect~ometory and mass
spectrometory.
The structural formula and the boiling point
of each of the objective compounds is shown in the
Table. The symbol "F-" in the structural formula
indicates that the compound is perfluorinated. For
example, the formula
indicates in its exact meaning the formula
CF2
,,, ~ F C2
F 1~CF\ ¦ / -CF 2 -CF3
F 2
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