JPS60112724A - Purification of fluorocarbons - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to the purification of fluorocarbon compounds to remove hydrogen-containing substances and/or to render the fluorocarbons less toxic to living organisms.

BACKGROUND OF THE INVENTION Biological applications of fluorocarbon compounds have expanded in recent years, requiring greater care in the purification of the compounds to obtain pharmaceutical grade materials. As an example of such an application, the use of perfluorinated cyclic hydrocarbons as substitute thin liquid and blood flow media is described in Clark, US Pat. has been done. The latter patent describes the preparation of 1N perfluoropolycyclic hydrocarbon mixtures by refluxing with a 10% aqueous KOH solution. By rapid flow for several hours with a 4N aqueous KOH solution to remove partially fluorinated hydrogen combination by-products.
It is also known that fluorocarbons can be prepared prior to biological evaluation.

However, a fairly concentrated KOH solution (approximately 30 m
Known treatments only reduce the hydrogen content by a factor of about (9) to 50, even when several treatments are carried out at - to %), e.g.
from about 1000 pl) m in the quality to about 500 pl) m in the product
70 (only 1 ppm, and in other types from about 100 ppm of starting material to about 50 ppm in product)
It can only be reduced until now. (ppm of hydrogen in this morning
(means the weight of hydrogen atoms relative to the total weight of the fluorocarbon compound as measured by melt infrared spectroscopy). 7 for biological applications, especially for the treatment of human medical conditions.
Currently, the hydrogen content of fluorocarbons is approximately z
ppm, preferably less than about 5 ppm, so that conventional KOH purification procedures, when supplemented by certain toxicological testing procedures, do not effectively purify KOH. Even if they appear to reduce or eliminate toxicity in purified products, they appear to be unsuitable.

The reason for this inadequacy is the lack of substantial testing of perfluorocarbons in humans. Therefore, and since toxicity is actually a function of both the nature of the hydrogen-containing deity and the hydrogen content, what levels of these hydrogen contents can be considered non-electrostatic? I don't know for sure. We also don't know for sure if the hydrogen content is low, and even if it's highly toxic, we don't know if it will react in the body to form something toxic.

Due to lack of knowledge about human toxicity, and
1) Due to the great danger involved, the best solution is to remove as much hydrogen as possible and, based on the amount of any residual hydrogen present, It is the evaluation of products on the basis of toxicity tests. In this regard, the present method is more effective than existing methods in producing less toxic products.

"Purification" or similar method as used in this 4111 V (removal of acute toxicity and/or (2) hydrogen content, as determined by IIL cell test, in vitro test, or in vivo LD5o test) or a substantial decrease.

In U.S. Pat. No. 3,696,156 (Weeks), KOH or other base deposited on alumina 41
low molecular weight fluoro containing from 1'i to 6 carbon atoms,
Disclosed is the treatment of Q-halocarbons.

This patent discloses dissolving an alkali metal hydroxide compound in just enough water to moisten the surface of the alumina and driving off most of the water by gentle heating, and then dissolving the alkali metal hydroxide in just enough water to
Discloses the treatment of saturated fluoro, e-no-rocarbons with reagents prepared by heating in a stream of nitrogen at 00"C. The purpose of the treatment is to remove toxic unsaturated substances such as octafluorobutene. The process involves removing impurities such that the fluorocarbon product is non-toxic enough to be used as an aerosol propellant. There is no disclosure that it is effective in solving the toxicity problem.

In the present invention, compared to the 5 to 30 bottle sweep KOH solution of the prior art sulfurfluorocarbons purification technology, the compound
By reaction with strong radicals and strong nucleophilic compounds containing not more than 100% of water, berrocarbons can be made into the water required for biological use. In the purification process, hydrogen-containing molecules and/or other substances are reacted with a basic compound, and the reaction product is separated from the perfluorocarbon molecules.Motokawa All.
The term perfluorocarbons used in IJ refers to fluorinated organic compounds that contain hydrogen in their molecules.

On the other hand, fluorocarbons include, in addition to perfluorocarbons, fluorinated organic compounds containing a water system in the molecule. The expression below is the same as perfluoro.

The main advantage of the purification technique of the present invention is that it requires essentially a single reaction with base (for fluorocarbons containing about 1-200 Tlpm), compared to multiple reactants and extractions in prior methods. The ability to achieve greater sieve purity than those obtained by IrO. The reaction may also involve adjustment of process conditions such as temperature, leak-up procedures, and repeating the reaction - or more in the case of fluorocarbons containing higher amounts, e.g., greater than 200 ppm hydrogen. These and other advances are discussed in the following description.

According to the invention, perfluorocarbons are purified by contact with strongly basic alkali metal and/or alkaline earth metal compounds (periodic groups I and II&). Suitable bases have a logarithmic basicity constant (pKb) of at least 12
Or, it is the one that shoulders 13 to 14. It is believed that the base has strong nucleophilic activity sufficient to attack hydrogen-containing molecules further below. Preference is given to compounds 1a1 of lithium, sodium, potassium, magnesium, calcium, barium and strontium. Suitable compounds include hydroxide, trap + / substance r right l bulk γ de pavement Ii #
41' @Naru) Other compounds with reasonable basicity are present.

Representative metal aqueous compounds are sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, and barium hydroxide. Potassium hydroxide is particularly preferred. The organic base oxide is represented by the formula M(OR)x, where M is gold, 1R is alkyl or aryl (referring to aralkyl and alkaryl), and X is the valence of the metal M (1 or 2
). The organic whole oxide has l-added carbon atoms in each R group, preferably from 4 to 10. The larger the number of carbon atoms, the more difficult the extraction after the reaction residue will be, as shown below. R groups can independently include straight-headed or branched button chains, cycloaliphatic or aromatic, and combinations of aliphatic, cycloaliphatic, and aromatic groups, and include groups containing petero atoms (e.g., halogens). However, such a substituent Ie impairs the essential properties of the compound of the present invention, and the condition is f. Typical R groups are C1% C8 alkyls such as methyl, ethyl and propyl; cycloalkyls such as cyclohegycyl and cycloethyl; Fluoro, chloro, and bromo or nitro substituted. A variety of a1)-oxides and alkoxides useful in the present invention are known. Some of these are described and described in technical literature such as Kirk Kosmer, Encyclopedia Dare of Chemical Technology, 2nd edition (1963) 1,839. and methoxides, ethoxides, and phenoxides of lithium, sodium, 1" rum, and magnesium.

The strong base compound used according to the invention is about (9)W
*It can be said that the tl of water does not exceed %. In the case of metal hydroxides, it should not be sticky, syrupy or otherwise liquid, which may be somewhat viscous or exhibit pasty consistency. In the case of metal hydroxides, the waterscape is generally a little smaller than, for example, about 5 shiploads;
This 5Nt will substantially hydrate the oxide. The compounds can be used in sterile form, but other forms such as powders or flakes are also useful. Compounds are prepared in non-aqueous solvents (e.g. alcohols, ethers or ketones)
The solvent can be used by dispersing or dissolving in the reaction mixture to improve contact between the fluorocarbon and the base phase, provided, of course, that the solvent substantially enhances the strong basicity and strong nucleating properties of the base, e.g. It is believed that the superior purification achieved by fluorocarbons and/or other interactions with fluorocarbons is likely to be obtained by the following stepwise process, but the present invention is not limited by the theory. do not have.

In the first step, the fluorocarbon is attacked by a base capable of removing the most strongly bound hydrogen atoms in an otherwise highly fluorinated molecule. Removal of hydrogen produces unstable, negatively charged fluorions.

It therefore undergoes molecular transfer. The binding results in the removal of the fluoride ion and the stabilization of the molecule as a fluoroolefin. In the second step, the hydroxide or alkoxide ion of the base, which acts as a strong a nucleating agent, attacks the 9-chain olefin of the 21 bonds, adds hydroxyl or other functional groups to the molecule, and re-opens the molecule. The destabilizing force changes the ions into negative ions, which are then rearranged to form other olefins. In the special case where the attacking base is a metal hydroxide and the hydroxyl function is a carbon soil that also has fluorine attached to it, hydrogen fluoride is the one most likely to be removed and pre-ketones. to be accomplished. In stage 3, the olefin formed in stage 2 is attacked again by hydroxyl ions, and the process continues as described above until the fluorine is mostly removed from the carbon skeleton to the base metal.

The resulting citron is highly alcoholized, resulting in a residual purified fluorocarbon after partitioning into the aqueous phase and from the fluorocarbon phase in a subsequent extraction step.

Compounds, such as those of the present invention, which are not strongly basic and which are not used in a substantially dry state are unable to react with all the different potential hydrogen positions in the molecule. If hydrogen is not removed, the chain reaction will not occur and no purification will be achieved. Moreover, if the anion of the metal hydroxide or organo-gold iA oxide is strongly nucleophilic, it will intensify the main reaction by attacking the first/fin formed during the first transition. . Without nucleophilic addition to this double bond, perfluoroolefins cannot be removed from the remaining saturated perfluorocarbon. It is through the addition of the hydroxyl, alkoxide or aryloxyto ion of this strong base that the final reaction product is selectively extracted with water or a specific solvent.

The fluorocarbon feedstock for the process of the present invention is the reaction product from the fluorination of carbon compounds, usually hydrocarbons, which products include strongly basic and strongly basic compounds and other fluorinated It contains perfluorinated molecules that are not exposed to attack by molecules or other hydrogen-containing substances and are therefore subject to such attack. These are impure f(d-fluorocarbons), but if some aqueous component is present, they are sometimes referred to as difluorocarbons, although this description is strictly accurate.

The return water compounds are aliphatic (cyclic or acyclic) hydrocarbons and/or
or aliphatic carbon atoms containing heteroatoms, these are
Fully fluorinated except for residual hydrogen and/or toxic compounds. The compounds or mixtures μm may be in vapor or liquid form at ambient temperature and pressure. Solid compounds can be purified according to the invention by dispersing or dissolving in a liquid medium, by melting, or by evaporation.

The present invention is disclosed in U.S. Pat. No. 3,911,138 and U.S. Pat.
The fluorinated cyclic hydrocarbon sheath'
Although this technology has special emphasis on the application of other fluorinated compounds such as U.S. Pat. No. 3,823,091.
It can also be applied to those described in No. 39 and No. 4325972.

Preferred perfluorocarbons for treatment according to the present invention are those having 7 to 18 carbon atoms in the molecule, and more preferably those having 9 to 18 carbon atoms, because of the ability of the perfluorocarbons to This is because it is suitable for use in scientific applications. Typical compounds are chemically inert monocyclic perfluorinated conductors such as isopropylcyclopentane or inpropylcyclohexane, and C9-C1B polycyclic compounds such as bicyclononane (e.g. bicyclo[3,3,1] Nonane, 2,6-dimethylpicyclo(3,3,1]nonane,
3-Methylbicyclo[3,3,1')nonane, and trimethylbicyclo[3,3,1]nonane; adamantane and alkyl (C1-C6)adamantanes such as methyl and dimethyladamantane, ethyl and diethyladamantane, trimethyladamantane, Ethylmethyladamantane, ethyldimethyladamantane, and triethyladamantane, methyldiadamantane and triethyladamantane, methyl and dimethylbicyclooctanes,
Tetrahydronorbinol-8, pinane, camphane, decalin and alkyl decalins such as 1-methyldecalin and 1,4,6,9-dimethanodecalin, bicyclo[
4゜3.2]Undecane, BicycloC5,3,0]decane, Bicyclo[2,2,1]octane, Tricyclo[5
,2,1,02・6]decane, methyltricyclo[5,
2, 1, 02, 6] decane, and others, or mixtures thereof. Peter atom perfluoro compounds are ethers such as y-2-butyltetrahydrofuran, F-2-butyl7, F-hydrofuran, F'-(2,5,8-)dimethyl-3,6,9- )
1.2.2.2-tetrafluoromethyl ether of lioxer (1-dodecanol) and (J F -n -/tylmorpholine).Acyclic aliphatic compounds include B
+ Includes n-heptane and congeners.

Some of the fluorine atoms of the above-mentioned materials may be replaced, for example by other halogen atoms such as bromine, as in perfluorobromo compounds.

Examples of these compounds include monobrominated compounds such as 1-bromopentadecafluoro-4-isoparavircyclohexane, 1-bromotridecafluorohexane, 1-bromo-ntadecafluorooctane and I -Promomentadecafluoro-3-isopropylcyclopentane, and hiberfluoro-1-bromobutyl isopropyl ether or polybrominated US thereof
It is a class of bodies.

As indicated above, the present invention is applicable to liquid or vapor fluorocarbons. However, solid compounds can be treated according to the invention by dissolving them in suitable solvents or by melting or evaporating them.

Typical of such solid compounds are beroadamantane and perfluorodimethyladamantane, which have relatively low levels of hydrogen contamination. These compounds can be dissolved in liquid perfluorocarbons (or other solvents), their purification is convenient, and the resulting solution is then processed. Liquid fluorocarbons suitable as solvents are:
F-decalin, F-) linkro [: 5.2.1.0”
-6]-decalin, F-methane, 1-1-methyldecalin and F-alkyl adamantane, and also mixtures of these.

In the process of the invention, a mixture of perfluorocarbons and other fluorocarbons containing hydrogen in the molecule is treated with an alkaline or alkaline earth base. The base contains more than about 100% water by weight and reacts with such other compounds to convert the latter to a reaction product which is then removed from the unreacted perfluorocarbons. Separated. The presence of toxic and/or hydrogen-containing compounds is reduced.

The process of the invention involves adding a base to the fluorocarbon to be purified in a reaction vessel (preferably glass or glass lined) equipped with a stirrer, and adding the base to the fluorocarbon mixture while stirring. This is conveniently carried out by heating the pan to a temperature sufficient to react with the ingredients. The favorable temperature is approximately 165°C ~ 2
The range is 50°C. At temperatures of 250°C or higher, some decomposition of the fluorocarbons may occur, especially in all-pole reactors, and such temperatures are therefore undesirable. The reaction is maintained at the selected temperature for several minutes to several hours, such as about 1 to 5 hours.

Typical temperatures are about 170-180'C and typical reaction times are 1-2 hours at this temperature. However, both temperature and reaction time depend on the particular fluorocarbon and strong base. Fluorocarbons used for intravenous applications have relatively low vapor pressures and boiling points, so reflux temperatures are often sufficient.

Low boiling fluorocarbons can be similarly purified by heating the reaction mixture under pressure. Pressure reactors are also useful when processing fluorocarbons in the vapor state, and pressure can be used to increase the boiling point of the oil body, thereby allowing higher reaction temperatures.

The above reaction conditions are based on a strong base such as KOH containing about 15 weight percent water, and a fluorocarbon containing about 951) Pm or less hydrogen. of such bases. Higher 11 degrees of bases such as KOH can be used for the purification of such fluorocarbons without any appreciable benefit. As indicated, the reaction conditions can of course be modified to accommodate other fluorocarbons, bases containing other amounts of water, or other solvents or other reactant ratios. A person skilled in the art can make such changes to L7 without requiring much effort. Generally, more aggressive reaction conditions and/or higher base to fluorocarbon ratios are used if the fluorocarbon to be purified has a higher proportion of hydrogen-containing material, or the reaction can be repeated. Elevated temperatures are commonly used to obtain the desired rate and extent of reaction.

During the reaction, the treated PFC from the reaction mixture is separated in the following manner and then the PFCO color is tested against diethylamine (DEA) or from the infrared for hydrogen or for olefins. By,
Refining can be tracked.

Perfluorocarbons are colorless in the presence of DEA, but when hydrogen is present K is dark yellow, brown or black.

At the end of the anti-Ltp, the mixture is cooled and water is added to dissolve any unreacted base, fluoride, and highly oxygenated carbon negative residue that normally forms during the reaction. The addition of water causes the reaction mixture to form an uppermost aqueous phase containing reaction products such as all-polar fluorides and decomposition products, and a fluorocarbon bottom phase containing substantially purified fluorocarbons. These phases can be separated by any suitable liquid-liquid separation method, such as decanting or the use of a separating funnel.

For medical applications, further purification of the fluorocarbohydrate is desirable in order to remove any traces of reaction products. Such traces sometimes give a cloudy appearance to the product, but are detected anyway by the above analysis.

In the case of treatment with organic rye oxides, these traces of reaction products are removed by washing the fluorocarbon with an f#+ medium such as a lower alkanol, ether or ketone, followed by washing out any traces of solvent with water. It can be extracted by This solvent extraction is more effective when each R group of the inorganic total polar oxide used contains about 4 to 1 or more carbon atoms, which makes such ranges preferred. This is the reason why Wit K was described as a good example.

When KOH or other inorganic oxides are used, a typical additional #8 preparation step is to remove residual impurities in the fluorocarbon with ketones (e.g., acetone), organic acids (e.g., C1-C1),
O monocarboxylic acids, such as acetic acid). From the resulting two-phase system, the PF'C phase is separated from the organic phase and then acidified with the various organic acids listed above (water miscibility 01-C
8 alkanol (e.g. methanol, ethanol). An rlI/alkanol ratio of approximately 1:9 in quantity is suitable, but other ratios can also be used, e.g.
The ratio is 1:1. A final wash of 7°C in water is used to remove traces of acid and alkanol remaining in the purified fluorocarbon.

The materials resulting from the above-mentioned P refining process are those in which the starting PFC material contains less than about 2 (approximately 2.") ppm of hydrogen in the infrared if it is of no more than 1 (l T'T'm) hydrogen. according to the present invention, usually less than 5, and is essentially non-toxic as determined by the in vivo tractability test (eg, the LM follicle test described below) and/or the conventional mouse intravenous LD5o test.

The following examples are intended to be illustrative of the invention and are not intended to limit the scope of the invention other than as described in the appended claims.

Example I Part A 2N'+Ik of DMA on cobalt trifluoride
Reaction mixture 4o00 containing primary perfluorodimethyladamintane (F-DMA) and perfluorotrimethylbicyclononane (F-TMBCN) obtained by fluorination and containing 95 PI)m of hydrogen.
m, the unit is placed in a 5 t glass reaction flask equipped with a stirrer and a condenser vented to atmosphere. F-TM
It is obtained as a result of the ring cleavage reaction during BCN fluorination.

85% KOH (15 pieces w/1000 units in thread form)
w H2O) is then added to the flask and stirring begins. Heat is applied to raise the temperature of the reaction mixture to M stream.

This method takes approximately 1 hour to reach a final humidity of 170-175°C. During this heating stage the contents of the flask change in appearance. That is, the pellets break down as the reaction proceeds and the color of the slurry changes from clear with white solids to amber and then dark brown or black. Some water is also produced as droplets in the condenser. The mixture is held at these conditions for 2 hours after reaching reflux, at which point the heat is removed and the mixture is cooled to approximately 'l1l(+'c).

2000 units of water are then slowly added to the flask, causing the temperature of the mixture to rise. The temperature increase is due to the heat of dilution of unreacted KOH. After the water addition is complete, the mixture is stirred with a trowel in order to sufficiently dissolve the solids that accumulate in the wall of the reaction vessel. Separation of the aqueous phase containing substantially all the reaction products from the fluorocarbon (PF'C) phase is accomplished in a separatory funnel. The two phases separate within about 1 hour. The fluorocarbon was then discharged from the bottom of the separatory funnel and was found to contain less than 5 pT)m of hydrogen (the limit of detection with the IR equipment used) by infrared analysis.

By Earl Pigeier, his US National Institutes of Health Contract N[lN
OI-HB-6-2926 original 6/1976
June 21, 1978 His report to Canada and Japan (Ha1
-1 to Vl-6) Stock Littlefield strain - Mouse #1! L using fibroblasts
In cell assays, the fluorocarbon product was used as a media control (0'
6.7 cm of cell growth (ICG) compared to I
). The medium control or assay control is the medium plus cells/l that have been dosed with an equal amount of additional medium to the fluorocarbon in the test medium.

Theoretically, the inhibition of cell survival is 0 (not 1~) to 100.
% (all fatalities), but 6.7% is generally considered insufficient for a product intended for humans.

Part B The fluorocarbon recovered in Part A above has a slightly cloudy appearance due to the presence of only one trace of the reaction product. The cloudiness can be removed by conventional paper filtration (Z), but contact with paper may cause toxicity in the L cell assay described in Part A above (32,
6ch ICG). Instead, the reaction products that give rise to the makeup are removed by treating the fluorocarbon phase in the following manner. 950 units of acetone are shaken in a separatory funnel for 5 minutes with approximately 3800 units of the product recovered from Part A. The fluorocarbon separated from the acetone loses its cloudy appearance and any additional residual acetone is subsequently removed by washing with 950 units of acetic acid solution in methanol (1:9 (by weight)). The trace level of methanol remaining at the end is 9
Removed by treatment with 50 units of water. Both of these image treatments are performed in a similar manner to the acetone treatment described above. The final fluorocarbon product is clear and infrared analysis shows that it contains slightly less than Fl ppm hydrogen at 751rj. (limit of detection).

Example 2 In this example, a fluorocarbon material was obtained as in Example 10, except that in Example 2 the fluorinated product was distilled to obtain a center distillate mixture enriched with F-DMA; The N amount ratio is F-TMBCN] [compared to approximately 3.5F
-DMA. Furthermore, the cytotoxicity test was performed using the L cell suspension culture assay protocol A745 (Hazelton Laboratories America, Inc., Vienna Perlinia) as described below. In this test procedure, the assay controls are cell culture medium and fluorocarbon-free media, and the negative control is a purified fluorocarbon material as described in Example Parts IA and B, which is the first established in this assay. As such, the positive control is an untreated sample of fluorocarbon with a known high dissemination rate.

L-Cell Test Procedure Cells are tested according to the W, R, Arpv (J, National C
ancer engineering n5 titute.

4:165.1.943) is derived from the parental lineage established by K. The source is American Type Culture Collection ATCCL-929. The cells are kept as frozen stock in liquid q-chloride. Working stock is) Wymouse 1AB which has been improved due to cloudy face.
752/1 Medium Complete (Wymouth+x
n 752/1 of 10 ox blood palpitations, 1% glutamine,
0.5 Polyglutamicin, 0.1% Fluroex, 0.
031 methylcellulose and 0.05qb goo/Z y
(Darvan) is shimmering) 3
It was kept in 5φ Co2@d and air at 7°C and passed once between 1-Ni. Test compounds were tested undissolved in one dosing water form, negative and positive controls were tested along with assay controls in both the jild format (cell culture media and media, no fluorocarbons). Test compounds and control substances were tested 41 times.

For dosing, test and control substances were injected into 50 d conical tubes. Approximately 1-1.2
Add at 5 me f1j'' and mix gently. Tighten key Y knob and place tube in roller drum to allow complete rotation of tube. Rotate for 3 days in tube N'37'C. .

After 3 days of culture, a portion of the cell culture vessel was diluted and stained with trypan blue. Cells were counted under a microscope using a hemacytometer to determine whether they were sweet or alive. Recording is by average cell count from each of the four replicate sets.

Cell growth factors are determined from these results. Calculate the cellularity and capture of the test compound compared to the assay control. Cell growth inhibition/resistance (CG%) within 5 units of the negative control value indicates greater efficacy compared to the negative control.

Cell growth inhibition staff (Engineering CG) ICG Section = 100 - Growth Section I'll go.

As in Example 1, the fluorocarbon test material after siliconization in Part A was contacted with paper to yield 51% XCa. The product was then treated as in Part B resulting in 18% ICG (actual increase in cell growth). Apparently the paper was contaminated with a damaging substance that either transferred to the sample or the cellulose in the paper reacted and removed in some way. These and other results are set forth in Table 1 below and show that the test substance was essentially free of cytotoxic properties in the negative and test control samples. (Negative CG was not assigned significance) Table I Test Control 1.5*r O Negative Control 1.5 mJ −5 Positive Control 0.75 w1 100 Test Material 1.5 mg −8 Test Control = Fluorocarbon l− Cell culture medium and medium Negative control = Cell culture medium and medium with pre-purified fluorocarbons as in Example IA and Part B Bodicip control = Cell culture medium and medium with untreated sample of fluorocarbon Test material 1 Example 2 Human part and Cell Culture Media and Media with Purified Fluorocarbons as in Part B Example 3 '5)', Example 1. Fluorocarbon substances (PFCs) purified and then emulsified as in Parts A and B were tested in different ways for sexual toxicity in mice (LD6°Pio Atsuse Systems Corporation, Massachusetts Boston) and are listed in Table ■. I got the result. The fluorocarbon material was obtained analogously to the material of Example 2. It is observed that the Japanese perfluorocarbons from the samples from Compositions C and D do not contribute to strength.

Table ■ (AI NaC7O, 9J229 (BI NaC7O, 9138-229 glycerol
1.0 (C) NaCtO,9118,4 Glycerol 1.0 Zoluronic F-68 Surfactant 3) 3.5 (DI H
aCL O,9118,4 Glycerol CO Zorronik 1'-68 Surfactant 3.5PFC20
,0 1) Sterile water 2) 95% purity level, as practiced by Bioassay Systems Corporation, Boston Massachusetts 3) Polyoxyethylene-polyoxypropylene co-conjugate, molecular weight approximately 8200 Example 4 (Comparative example) ) A 7-combination of F-trimethylbicyclononane and F-dimethyladamantane obtained as in Example 1, except that instead of the fluorination of the two, one of the 7e and y was used. 26.7 cm (w/w) of water containing relatively small residual hydrogen (more than 100 ppm)
Treated with KOH for 10 nights at 105-108"C,
and then 10utItI in 51% KOH solution at room temperature.
I did A.

This is a prior art procedure. The table below gives L cytotoxicity results (as in Fruitful Example 2),
where negativeteb and voditip and assay controls are the same as before (Table I). Advance′! 26. which is representative of v4 technology.
Even with multiple treatments with 7-poly KOH, the toxic substances (55
96ICG), whereas the substance treated according to the invention (negative control) shows no cytotoxicity.

Table 11 Paw control 1.5mg O Negative control 1.9ttl 1 Positive control 0.75ml! 94 Trial material 1.5 m/55 Assay control = Cell culture medium and medium without fluorocarbon Negative control = Example 1, Part A and B Cell culture medium and medium using tRi made fluorocarbon Positive control = Untreated fluorocarbon Cell Culture Media and Media with Sample Material = Actual Mu Cell Culture Media and Media with Purified Fluorotubes as in Example 4 Example 5 The method of Example 1, Part A was repeated in essentially all respects. However, the perfluorodimethyladamantane and perfluorotrimethylbicyclononane were refluxed for 15 minutes instead of 2 hours. The product hydrogen level is 8 to ppm. Examples 1 and 2 show that the best results can be obtained by extending the treatment for about 1 to 2 hours as in Part A of Example 1.

Example The example is another illustration of a higher hydrogen content material.

(AI I) MA: TMBCN violet ratio approximately 2.6
: 100 units of a 1-perfluorodimethyladamantane/perfluorotrimethylbicyclononane mixture containing 401 plums of hydrogen are mixed with 6 units of each in order to prevent the reaction from becoming thermally uncontrollable. 851KOH (A
! treated with (lett). The first 25 units of KOH are added to the fluorocarbon and the temperature of the mixture is gradually increased to 131°C. A second 5 unit portion of 85% KOH was then added to the reaction mixture and the mixture was brought to reflux at 155°C.

The intermediate product (I) of the reaction contained approximately about too ppm hydrogen.

1B) 75 units of intermediate (T3) were treated with 37 units of 85% KOH (pellets) for 2 hours at reflux (174"C). The intermediate product (n) of the reaction was 46 pT) m of hydrogen. Contains.

(C) 67 units of intermediate product (IT) as unit of H5
% KOH (pellets) for 2 hours at reflux (174°C).

The final product obtained was treated as in Example 1, part B, and s
It was found that it contained less than ppm hydrogen.

Example 7 This example illustrates and illustrates the effect of varying the KOH concentration. distilled a mixture of perfluorodimethyladamantane and perfluorotrimethylbicyclononane to obtain a center distillate mixture enriched with Alfluorodimethyladamantane. (To perfluorotrimethylbicyclononane?jL, perfluorodimethyladamantane 3.5:
1). The center cut contained a hydrogen of 52 I) Tlm. 1 portion (50 heavy cap units) of this material 17.
6 units of slightly sterile +7) KOH (7Q e
I) KOH (balance water) for 2 hours between 196°C and 204°C in a pressurized reactor with a Teflon liner. The product contained between 8 and 101)1) m of hydrogen. Sprinkle the center cut of the second part (50 units) with 5 units of syrupy KOH (01 (50 units)
, remaining water) for 2 hours at 196-202"C in a four-lined pressure vessel.

The scale level of the latter product actually increased, reaching approximately 76
ppm. This means at least about 76% KO
It shows that H intensity is required for efficient hydrogen removal.

Example 8 A crude mixture of pyrfluorodimethyladamantane and perfluorotrimethylbicyclononane as in Example 1 containing 64 ppm hydrogen was
Example 1: With pellets of aOH (98, 7* it #), in three fruit M (50 sweet potato, 25 i sweet and pellet grade based on 12.5 wt% crude fluorocarbon mixture) Treated essentially as described in No. 1 AK. However, the reflux temperature was about 165°C. After adding water to the reaction mixture, the fluorocarbon phase was separated. The product of each experiment was found to contain less than 5 Tl1)In,E (limit of detection).

HJ 18 people Sanchik Incorporated agent Benkoishi Yataro Sasai (and 1 other person)

Claims (1)

[Claims] 1. A mixture of fluorocarbons and other fluorocarbons is brought into contact with an essentially alkali metal and a sufficient atmosphere for the other fluorocarbon to react with the queen base, thereby A process for fabricating fluorocarbon mixtures, characterized in that the fluorocarbons are converted into reaction products and the reaction products are separated from unreacted fluorocarbons.2. 3. The method according to claim 1, comprising a mixture of sulfur fluorocarbons containing hydrogen in the molecule and other fluorocarbons containing hydrogen in the molecule. The method according to either claim 194 or 2fj4, in which the base is potassium hydroxide.
The method described in section. 5. The method of claim 4, wherein the potassium hydroxide is in pellet form and the amount of potassium hydroxide in pellet form is at least 15% based on fluorocarbon. 6. The method according to claim 4, characterized in that said potassium hydroxide is slurried in said fluorocarbon-poor mixture. 7. The method according to any one of claims 1 to 6, wherein the fluorocarbon is in a liquid state. 8. The method according to any one of claims 1 to 7, wherein the contacting is carried out at a temperature in the range of 165 to 250°C. 9. A patent or claim characterized in that the reaction product is separated by adding water to dissolve the unreacted base and any metal fluoride formed, and separating the two phases formed into a fluorocarbon phase and an aqueous phase. Small hundred, box 1-8
The method described in any of the following. 10. The fluorocarbon phase is further purified by reaction with an organic carbonylation compound followed by washing with an organic solvent and the resulting product is separated from the organic solvent mixture; 2. The product is dehydrated. 9. The method according to claim 9, characterized in that the solvent is removed by removing the solvent. 11. The method according to claim 10, wherein the carbonyl compound is acetone and the organic solvent is an acetic acid solution in methanol.