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Description  |
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel fluorohydrocarbons, to their
synthesis and use.
2. Description of the Prior Art
Fluorocarbon compounds due to their inertness have found use as electronic
coolant or leak testing fluids. Other compounds having good solubility for
oxygen have been investigated as artificial blood substitutes. However,
the present fluorocarbons are unduly expensive due to the high content of
fluorine and the method of synthesis. Furthermore, the principal
industrial processes employed in their synthesis, namely electrochemical
fluorination or cobalt trifluoride fluorination do not result in pure
substances but mixtures of compounds containing impurities and
incompletely fluorinated compounds. Pure substances of known structure are
desired for clinical applications.
Another problem with fluorocarbon materials is that the excellent inertness
of these materials prevents their active excretion through metabolic
processes so that there appears to be no mechanism for their elimination
from the body, other than by diffusion to and evaporation through the skin
or lungs. Even though these chemicals are inert there is a risk in
allowing them to remain indefinitely in body tissues.
It has recently been proposed that by choosing fluorochemicals of
sufficiently high vapor pressure their eventual elimination via the lungs
and skin can be assured. While such an approach has merit it appears
likely that in large animals such as dogs and probably man enough of these
chemicals will be absorbed in depot fat or in brain or spinal cord lipids
from which their subsequent clearance will be very slow indeed. Since many
"inert" fluorochemicals have anesthetic properties, subtle behavioral
changes in higher mammals might result from such incorporation.
SUMMARY OF THE INVENTION
Novel fluorocarbon hybrid materials with hydrocarbon fragments are provided
in accordance with the invention. The hybrid compounds are made by a
synthetic route assuring production of pure substances in high yield and
at low cost from readily available materials. The hybrid compounds have
good oxygen and carbon dioxide solubility, exhibit high vapor pressure and
will cost less than available electronic fluids or proposed blood
substitute compounds.
The problem of accumulating fluorocarbon compounds within body tissue is
obviated by attachment of a metabolically reactive hydrocarbon handle to
the larger fluorocarbon unit so that the physical properties responsible
for good oxygen solubility are retained, yet a reactive site is available
in the molecule on which the body's general-purpose detoxifying enzymes
can operate and attach solubilizing conjugating groups such as taurine,
glycine, glutamate, sulfate or glucuronate, permitting gradual renal or
hepatic excretion via known pathways. It is not required that all or even
most of the hybrid compounds be excreted by this active mode since the
vapor pressure of the hybrids is controlled so that a large fraction of
the elimination takes place via the passive evaporative route. The hybrid
compounds of the invention are unique in providing the additional
metabolic mechanism of excretion to permit more rapid or more complete
final clearance of the foreign compound from the body.
The metabolism of the foreign chemical can be adjusted to a half-life of
days or weeks so that the blood substitute will not be eliminated before
it has served its purpose and so that the detoxifying enzymes will not be
overloaded. A further advantage of the hybrid compounds is that the
hydrocarbon portion could also serve as the location of a .sup.13 C,
.sup.14 C, .sup.2 H or .sup.3 H label, simplifying synthesis of labelled
blood substitutes for research or as the site for attachment of a
hydrophilic unit to create a highly fluorochemical-compatible surfactant
for forming very stable emulsions.
The hydrocarbon moiety can be selected based on metabolic considerations.
Alkanes provide a reactive site for slow enzymatic attack via .alpha.,
.beta., or .omega.-hydroxylation in the liver microsomes. Thus, the alkyl
side chains of barbituates and BHT, the antioxidant, are extensively
hydroxylated and the compounds subsequently excreted as the more water
soluble oxidized compounds or as the sulfate or glucuronide conjugates
even though the R--CH.sub.3 groups attacked are unactivated in any
chemical sense. Saturated n-alkanes are known to be oxidized readily to
fatty acids in the rat. Both primary and secondary C-H bonds can be
attacked. Oxidized higher hydrocarbons at a higher oxidation state, e.g.,
ethers such as --CH.sub.2 OCH.sub.3, alcohols such as --CH.sub.2 OH, or
esters such as --CH.sub.2 CO.sub.2 R and the like, might speed up the
conjugation and excretion of the fluorochemical in case the alkane group
is oxidized too slowly; on the other hand, an iso- or neo-alkyl side chain
would probably be attacked more slowly.
In order to minimize toxicity or possible toxicity it is necessary that the
connection between the fluoroalkyl moiety and the hydrocarbon portion of
the molecule be designed to minimize the possibility of enzymatic or
non-enzymatic degradation reactions proceeding past the linkage and
breaking down the fluoroalkyl unit, liberating fluoride ion or toxic
fluoroolefins. Such degradation is prevented in the hybrid compounds of
the invention by terminating the fluoroalkyl unit in a tertiary carbon
connected to a methylene atom which links the unit to the hydrocarbon
portion of the hybrid molecule. Thus, as long as the connecting bond
remains intact, there will be no labile fluorine atoms situated .alpha. to
a hydrogen atom. The chemical lability of such C--F bonds is well known
and probably accounts for the toxicity of partly fluorinated
straight-chained compounds. Elimination of HF from such compounds would
yield fluoroolefins, members of a class of compounds which is generally
quite toxic and which includes the most toxic fluorochemicals outside of
the nerve gases.
The novel hybrid compounds of the invention will find use as electronic
test fluids, electronic cooling fluids and other fields where oxygen
absorption is required such as enriched air for coal gasification. The
hybrid compounds will find biologic use as a liquid/liquid extracorporeal
oxygenator that carries oxygen from a gas source of bubbles to blood in a
liquid/liquid interface oxygenator designed to minimize blood damage. The
hybrids will also find use in liquid breathing. Fluorochemical blood
substitutes have been utilized in organ perfusions to maintain the
viability and function of organs or brain tissue in a fluorocarbon
oxygen-carrying perfusate. Artifical blood preparations could have many
applications including use as an emergency oxygen-carrying plasma expander
in cases of bleeding in shock, exchange transfusion of newborns with
erythroblastosis fetalis, patients in sickle-cell crisis, patients in
various toxic states and patients suffering from drug overdoses and carbon
monoxide poisoning; transfusion of patients whose religious convictions
preclude the use of blood; major surgery requiring large amounts of blood;
and priming of heart-lung and dialysis machines as well as such
extracirculatory uses as lung lavage in cases of smoke inhalation and
other pulmonary diseases, and topical application in skin ulcers, burns
and the like.
These and many other features and attendant advantages of the invention
will become apparent as the invention becomes better understood by
reference to the following detailed description.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The hybrid compounds of the invention have the following essential
structure:
##STR1##
and R.sub.f =C.sub.n F.sub.2n+1
R.sub.f '=C.sub.n' F.sub.2n'+1
R.sub.f "=C.sub.n" F.sub.2n"+1
and n, n', n" are integers from 1 to 11 and Z is the metabolically active
hydrocarbon moiety. The hybrid compound can have from 6 to 15 carbon atoms
in the case of electronic fluids or other uses but for clinical blood
substitutes the hybrid compound should contain from 9 to 13 carbon atoms
and the vapor pressure of the compound should be <50 mm Hg at body
temperature, 37.degree. C. to 39.degree. C., and the oxygen solubility
should be at least 30 volume percent at 37.5.degree. C.
The Z group should contain at least 2 hydrogen atoms and is preferably
without unsaturation. Representative hydrocarbon groups are:
--CH.sub.2 --(CH.sub.2).sub.m --H
--CH.sub.2 --(CH.sub.2).sub.m --O--R
--CH.sub.2 --(CH.sub.2).sub.m --OH
--CH.sub.2 --(CH.sub.2).sub.m --CO.sub.2 R
where m is an integer from 0 to 8 and R is an alkyl or substituted alkyl
group containing non-interfacing, non-toxic groups such as hydrophilic
groups. Straight chain alkyls are preferred from metabolic considerations.
The hybrids are synthesized by addition of a fluoride ion, F.sup.-, to a
perfluoroolefin to form an intermediate tertiary fluorocarbanion according
to the following general reaction:
##STR2##
The tertiary fluorocarbon can in turn undergo alkylation or reaction with
an electrophilic reagent to form a hybrid compound as follows:
##STR3##
where X is an electrophilic group such as iodide or bromide.
A variety of fluoroolefins are available from anionic oliogomerization of
tetrafluorethylene (TFE); hexafluoropropene (HFP), and octafluoro-2-methyl
propene (perfluoroisobutene, PFIB). Representative perfluorinated
compounds are shown below:
##STR4##
Compound I is a dimer of HFP, II is the co-dimer of HFP and PFIB, III-V are
trimers of HFP and VI is a pentamer of TFE. The mechanisms of these
oliogomerizations are described in R. D. Chambers, "Fluorine in Organic
Chemistry," Wiley, N.Y. 1973.
The fluoride ion is present in at least a stoichiometric amount usually as
a Group I metal salt such as KF, CsF, AgF or CuF. The reaction is usually
conducted in a polar solvent such as dimethylformamide.
Examples of practice follow:
EXAMPLE 1
##STR5##
102 Grams (0.34 mol) of 1,3-diiodopropane, 41 grams (0.71 mol) of dry
potassium fluoride and 200 ml. of dry dimethylformamide were placed in a
500 ml. round bottomed three necked flask equipped with a cold finger, gas
inlet tube, septum and magnetic stirring. 189 Grams (0.94 mol) of
perfluoroisobutene was distilled into the pot. After 6 hours of stirring
with the cold finer charged, the pot contents were placed in a separatory
funnel with water and the lower fluorocarbon layer removed. The crude
mixture was separated on a 3/8 inch.times.10 foot 20% FFAP G.C. column at
150.degree. C. with a He flow of 150 ml/min. The first of two peaks was
1,3-bis(perfluoro-tert-butyl) propane which solidified at room
temperature. Sublimation of the product yielded 49 grams (0.102 mol) of
material melting at 32.degree.-33.degree. C. This was 30% of the
theoretical yield based upon starting 1,3-diiodopropane.
EXAMPLE 2
##STR6##
74 Grams (0.24 mol) of 1,4-diiodobutane, 40 grams (0.69 mol) of dry
potassium fluoride and 200 ml. of dry dimethylformamide were placed in a
500 ml. round bottomed three necked flask equipped with a cold finger, gas
inlet tube, septum and magnetic stirring. 130 grams (0.65 mol) of
perfluoroisobutene was distilled into the pot. After 6 hours of stirring
with the cold finger charged, the pot contents were placed into a
separatory funnel with water and the lower fluorocarbon layer removed. The
crude mixture was cooled to 0.degree. C. and the solid collected by
filtration. The crude 1,4-bis(perfluoro-t-butyl) butane was recrystallized
twice from methanol yielding 38.4 grams (0.080 mol) of solid subliming in
an open capillary at 130.degree. C. This was a 32% yield based upon
starting 1,4-diiodobutane.
EXAMPLE 3
##STR7##
49.6 Grams (0.232 mol) of 1,4-dibromo-2-butene, 31.2 grams (0.537 mol) of
dry potassium fluoride and 150 grams of dry dimethylformamide were placed
in a 500 ml. round bottomed three necked flask equipped with a cold
finger, gas inlet tube, septum, and magnetic stirring. 113 Grams (0.563
mol) of perfluoroisobutene was distilled into the pot. After 6 hours of
stirring with the cold finger charged, the pot contents were placed in a
separatory funnel with water and the lower fluorocarbon layer removed. The
crude mixture was then cooled to 0.degree. C. and the
1,4-bis(perfluoro-t-butyl)-2-butene crystallized out. The solid was
separated by filtration and recrystallized from methanol. A 70% yield
based upon 1,4-dibromo-2-butene was obtained, melting at
.beta..degree..fwdarw.75.degree. C. A second recrystallization from
methanol yields pure material melting at 78.5.degree.-79.5.degree. C.
EXAMPLE 4
Synthesis of CF.sub.3 --CF.sub.2 --CF.sub.2 --C(CF.sub.3).sub.2 --CH.sub.2
--CH.dbd.CH.sub.2
##STR8##
30 Grams (0.10 mol) of perfluoro-2-methyl-2-pentene, 13 grams (0.11 mol)
of allyl bromide and 9 grams (0.16 mol) of dry potassium fluoride placed
in a 100 ml. round bottomed single necked flask fitted with a dry tube and
stirred magnetically for 4 days. The pot contents are then washed with
water in a separatory funnel with water and the lower fluorocarbon layer
separated. The crude product is dissolved in anhydrous ether and dried
with MgSO.sub.4. The product is filtered and fractionally distilled. 18
Grams (0.05 mol) of product was collected boiling at 119.degree. C. This
was 50% of the theoretical yield based on starting fluoroolefin.
EXAMPLE 5
Synthesis of (CF.sub.3).sub.3 C--CF.dbd.CFCF.sub.3
##STR9##
Octafluorocyclobutane is pyrolysed in a furnace with a nickel tube
measuring 12 inches in length and 1 foot in diameter at 750.degree. C.
with a gas flow of 2.fwdarw.3 ml/min. The effluent gases, which are
principally perfluoroisobutene and hexafluoropropene, are condensed with a
dry irc-acetone cold finger into dry dimethylformamide containing dry
potassium fluoride. A lower fluoroolefin layer forms from which the
product can be distilled, bp=71.degree.-72.degree. C.
The above synthesis provides a novel perfluoroolefin suitable for forming
hybrids. The compound is readily synthesized from available materials.
Oxygen solubilities were measured at 25.degree. C. and 760 mm O.sub.2
pressure for representative hybrid, fluoroolefin and prior art compounds
by means of a gas chromatograph having a thermal conductivity detector and
calculated from molar volume and .DELTA.H(vap) by the method of Fedors
(Polymer, Engr. Sci. 14 147 (1974). Good agreement was obtained as shown
in the following table:
__________________________________________________________________________
Calculated O.sub.2
Measured
Fluorochemical Material
Solubility
Solubility Literature Values
(FC) cc O.sub.2 /100 cc FC
cc O.sub.2 /100 cc FC
or other data
__________________________________________________________________________
(CF.sub.3).sub.3 C(CH.sub.2).sub.3 CH.sub.3
43.2 41.2 D = 1.393 g/cc
V = 198.3 cc/mole
.delta. =5.98 Hb
BP = 101.5.degree. C./750mm
##STR10## 34.6 34.4 D = 1.4895 V = 205.5 .delta. = 7.39
BP = 53.degree. C./36mm
(CF.sub.3).sub.3 CCH.sub.2 CHCH.sub.2
44.1 48 D = 1.442
V = 180.31
.delta. = 6.0
BP = 76.degree. C./735mm
##STR11## 40.9 39.5 D = 1.820 V = 219.8 .delta. = 6.4 BP
= 110.degree. C./735mm
(n-C.sub.4 F.sub.9).sub.3 N(FC-43)
38.9 36.8 3M solubility data
38.9 cc O.sub.2 /100ccFC
__________________________________________________________________________
Fluorochemicals are not soluble in water and spontaneously forming
emulsions are the exception. Mechanical or ultrasonic mixing in the
presence of surfactants reduces the particles or droplets of
fluorochemical to an extremely small size--beyond phase microscopy,
probably to 0.2 .mu.m or less in diameter and possibly to a true colloidal
dispersion or microemulsion--and are dispersed sufficiently to remain
stable in a "solubilized" form. In order to be useful in O.sub.2 and
CO.sub.2 transport, the emulsions should contain stable dispersions of the
fluorochemical hybrids in a concentration of at least 15-20% by volume.
The pH, electrolyte concentration, osmotic and oncotic pressures are
adjusted to within physiologic range.
Heat, surface coating, absorption, and the presence of air containing
O.sub.2 and N.sub.2 all seem to alter the natural and biologic action of
emulsions of fluorochemicals. It seems that carbon dioxide, itself
extremely soluble in fluorochemicals, is protective to the fluorochemical,
and if all steps in the preparation of the product for biologic use are
carried out in a CO.sub.2 atmosphere, the finished product is more
acceptable biologically, is more stable, formation of fluoride ion is
inhibited and the sonication into small particle sizes is facilitated. By
appropriate filtration such as through a 0.2 micron membrane filter, of
the emulsified product, particle sizes large enough to be biologically
harmful can be removed, the solution can be sterilized (at least
bacteriologically), and foreign materials removed.
The surfactant is present in the emulsion in an amount of 1 to 10% by
weight usually, about 3 to 6% by weight. Suitable surfactants are egg yolk
phospholipid, oxygelatin or nonionic ethylene oxide-propylene oxide
polymers such as Pluronic F.68. Electrolyte can be provided by a
pharmaceutically acceptable saline such as Ringer's solution.
For perfusion and blood substitute uses the emulsion preparation contains
sufficient isooncotic agent, typically 3% by weight to 10% by weight to
make the emulsion isooncotic and a mixture of salts and bicarbonate to
give the proper ionic strength and pH.
It is to be realized that only preferred embodiments of the invention have
been described and that numerous substitutions, modifications and
alterations are permissible without departing from the spirit and scope of
the invention as defined in the following claims.
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Description |
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