CA1189079A - Perfluorotricyclic amine compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A perfluorotricyclic amine compound which is usable as an oxygen carrier in an artificial blood, represented by the general formula

Description

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).

~ 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 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 ~ ~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 ,,, ~ F C2 F 1~CF\ ¦ / -CF 2 -CF3 ~L~I 3907~

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Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A perfluorotricyclic amine compound represented by the general formula (I) wherein R denotes a perfluoroalkyl group having 1 to 4 carbon atoms; the ring A denotes a five- or six-membered ring, the ring B denotes a five-, six- or seven-membered ring, the ring C denotes a five or six-membered ring any one of the rings A, B and C optionally being substituted by one or more lower per-flouroalkyl group in addition to the above-mentioned substi-tuent R; and further f, g, h, i, j and k denote integers ap-propriately selected to construct the above-mentioned size of rings A, B and C.

2. A process for producing a perfluorotricyclic amine compound represented by the formula, (I) wherein R denotes a perfluoroalkyl group having 1 -4 carbon atoms; the ring A denotes a five- or six-membered ring, the ring B denotes a five-, six-or seven-membered ring, the ring C denotes a five-or six-membered ring any one of the rings A, B and C optionary being substituted by one or more lower perfluoroalkyl group in addition to the above-mentioned substituent R; and further f, g, h, i, j and k denote integers appropriately selected to construct the above-mentioned size of rings A, B
and C, which comprises reacting a perhydro-compound of the formula, (II) wherein R' is an alkyl group having 1 - 4 carbon atoms, f, g, h, i, j and the rings A, B and C are same as above, with fluorine.

3. A compound according to claim 1, wherein f is 1, 2, 3 or 4; g is 0, 1 or 2; h is 0 or 1 and i, j and k are each 0, 1, 2 or 3.

4. A compound according to claim 3, wherein R is per-fluoromethyl or perfluoroethyl.

5. A compound according to claim 3, wherein none of the rings A, B and C is substituted by a perfluoroalkyl group or one of the rings A, B and C is substituted by a perfluoromethyl group in addition to the perfluoroalkyl group R.

6. A compound according to claim 2, 3 or 5, wherein the total number of the carbon atoms in the compound is 8 to 12.

7. A compound according to claim 1, which has the fol-lowing formula:

wherein rings A, B and C are as defined in claim 1; f + g + h + i + j + k + ? + m + n = 5 or 6; f is 1, 2 3, or 4; g is 0, 1 or 2; h, ?, m and n are each 0 or 1; and i, j and k are each 0, 1, 2 or 3.

8. Perfluoro-4-methyl-4-azatricyclo[5,2,1,0,2,6]decane.

9. A process according to claim 2, wherein the reaction is performed by mixing anhydrous hydrogen fluoride and the starting perhydro-compound in an electrolytic cell and subjec-ting the resulting solution to electrolysis.

10. A process according to claim 2, wherein a suitable starting perhydro-compound is chosen so as to produce a per-fluoro-compound as defined in claim 7.

11. A process according to claim 2 or 9, wherein the total number of carbon atoms in the compounds of formulae (I) and (II) is 8 to 12.

12. A process for producing perfluoro-4-methyl-4-azatri-cyclo[5,2,1,0,2,6]decane, which process comprises fluorinating 4-methyl-4-azatricyclo[5,2,1,0,2,6]decane.

13. A process according to claim 12, wherein the fluori-nation is performed by first mixing anhydrous hydrogen fluoride and the starting material in an electric cell and then subjec-ting the resulting solution to electrolysis.

14. A process according to claim 9, which further com-prises (i) isolating the product perfluoro-compound, (ii) mixing the perfluoro-compound with (a) a physiologically acceptable aqueous medium and (b) a nonionic surfactant or a phospholipid as an emulsifer, the amounts of the perfluoro-compound and the emulsifier being 5 to 50% (W.V) and 1 to 5% (W/V), respectively, and finally (iii) homogenizing the mixture thereby forming an emulsion until the particle diameter becomes 0.05 to 0.3 µm.