Fluorocyanoacrylates

PATENT SPECIFICATION N0 DRAWINGS (W 1211172 '-‘.2 1211172 10 15' 20 25 30 35 40 (21) Application No. 56847/ 68 (3 1) Convention Application No. 687111 (33) United States of America (US) (45) Complete Specification published 4 Nov. 1970 (51) International Classification C 07 c 121 / 30 A 61 k 9 / O0 (52) Index at acceptance czc 1Q11E 1Q11G 1Q2 1Q6A1 1Q6-A2 1Q8A 1Q9D1 1Q9E ASB 351 352 35Y 39X (22) Filed 29 Nov. 1968 (32) Filed 1 Dec. 1967 in B5N l7Y 184 195 22Y 234 245 250 252X 27OX 273X 2.74X 407 493 498 4-99 546 55Y 56X 669 C3P 8A 8D1B 8K11 8K8 8P1D 8P1X 8P2B 8P3 8P5 8P6X (72) Inventors JERRY EARL ROBERTSON JOSEPH KENNETH HARRINGTON and ELDEN HARRIS BANITT (54) FLUOROCYANOACRYLATES (71) We, MINNESOTA MINING AND MANUFACTURING COMPANY, a corporation of the State of Delaware, United States o-f America, of 2501 Hudson Road, Saint Paul, Known non-fiuorinated alkyl 2 - cyano- acrylates, particularly the methyl, isobutyl and n — butyl 2 - cyanoacrylates, have been investigated for use as biological adhesives, Minnesota 55101, United States of America, see, e_g. Medical World News, 8 (20), 41 45 do hereby declare the invention, for which (1967); Mfg. Chemist, 38 (8), 94 (1967); We pray that a patent may be granted to Technical Report 6618, Walter Reed Army us and the method by which it is to be Medical Center, Dec., 1966. While the un- performed, to be particularly described in substituted alkyl monomers appear to possess and by the following statement:— the requisite bonding and hemostatic pro- 50 This invention relates to compositions parties when applied to damaged mammalian which polymerize to form coatings and ad- tissues, these materials appear to fail to have hesives. More particularly, the invention re- the required properties of low toxicity and lates to fluorine-containing cyanoacrylate adequate absorption by the tissues. Methyl monomers which polymerize rapidly upon 2. - cyanoacrylate, for example gives rise to 55 Contact with basic materials or materials a severe inflammatory tissue response at the supplying hydroxyl ions, e.g. moisture in the site of application. The n - butyl and iso- air, to- form polymers which are suitable for butyl 2. - cyanoacrylate monomers are not biological application, i.e. to bond or coat absorbed well (if at all) by the tissues and living mammalian tissues. polymeric residue of the adhesive has been 60 The fluorinated 2 - cyanoacrylates of this observed by histologic examination of the invention are useful in adhesive compositions site of application as much as twelve months and are particularly useful as biological ad— atfter surgery, see, e.g. Medical World News, hesives and hemostatic agents. Thus, new 8 (29), 27 (1967). approaches to- the joining together of This invention aims to provide new mono— 6'5 mammalian tissues, as well as for arresting mers which are suitable for use in b-iological the escape of blood therethrough, are possible adhesive compositions and which form ad- by the use of these novel monomers. For hesive bonds which do not significantly inter- example, satisfactory hemostasis of splenic fere with natural healing of injured mam- and liver wounds, heretofore to a great ex— malian tissues, are readily assimilated by the 70 tent unrepairable by conventional methods, is body with minimal toxic elfects, and are obtained by the application and polymeriza- autopolymerizable in the presence of blood tion of a thin fihn of fluorinated 2 — cyano- and other body fluids. aczylate monomer on the injured surface. The The present invention also contemplates bonding strength, absorbability by the tissues, providing new monomeric adhesives which 75 hemostatic capability and low degree of local can be used alone, or in co-njunction with inflammation resulting when these monomers each other or in conjunction with unsub- are applied in vivo, are properties which stituted alkyl 2 - cyanoacrylates in the bond- make them especially valuable for biological ing of damaged mammalian tissue or in pre- applications. venting the escape of blood or other fluids 80 [ Price _i_______________________________________.__ 10 15 20 25 30 35 45 1,211,172 therethrough and which are autopolymeriz- able in thin film on said tissue. Comonomer compositions are of interest for specific uses because they may provide advantageous com- binations of properties not completely em- bodied in individual monomers. Further contemplated by the invention is the provision of new monomeric adhesives which can be used either alone or as co- monomers in the bonding of similar or dis- similar materials without the use of heat or catalyst during the bonding operation. The present invention is based on the dis- covery that the replacement of hydrogen atoms in the alcoholic residue of 2 - cyano- acrylate esters with fluorine atoms unex- pectedly renders these monomers substanti- ally better tolerated by living tissue than are the hydrocarbon monomers. The class of monomeric 2 - cyanoacrylate esters which comprises this invention is re- presented by the structural formula CN R I I CH,=C—CO2—CH—CF,R’ wherein R is hydrogen, methyl or ethyl and R’ is fluorine, —-(CF2),,H or CF, and n is an integer from 1 to 3. These new fluorinated monomers when employed in biological ad- hesive compositions, individually or as co- monomers, exhibit excellent skin wound ad- hesion and hemostasis; they are well assimil- ated by the tissues at an acceptable rate, and their use, particularly in the case of the monomers in which the R I -CH—CF2R’ radical is ——~CHz(CF,),H, —CH-_.C.F,CF3, —-CH2(CF2)2H and —CH(CH,)C.F3, produces minimal local tissue inflammation in mammals. The —CH2CF, group-contain- ing monomer, 2,2,2 - trifluoroethyl cyano- acrylate, while exhibiting a relatively higher degree of inflammatory tissue response in sub- cutaneous tissues of mice, was completely biodegraded by the exposed surface of parti- ally excised rat livers within sixteen weeks after application of the monomer. The degree of local inflammation caused by the latter monomer, however, is still less than that caused by methyl 2 — cyanoacrylate as deter- mined by gross and microscopic examina- tions. In most bonding applications employing monomers of the invention, polymerization is catalyzed by small amounts of moisture on the surface of the adherends. Thus a drop of monomer can b-e placed on the surface of e.g. one of two metal or glass pieces which are to be adhered and the other piece brought into contact therewith. A strong bond is soon formed by polymerization. Similarly, desired bonding of tissues or hemostasis proceeds well in the presence of blood and other body fluids. The bonds formed: are of adequate flexibility and strength to withstand normal movement of tissue. In addition, bond strength is main- tained as natural wound healing proceeds concurrently with polymer assimilation. Compositions of the invention are steriliz- able by conventional methods such as dis- tillation under aseptic conditions. The method of repairing injured tissues with compositions of this invention (for ex- ample, to control bleeding) comprises, in general, sponging and subsequent application to the tissue of an adhesive composition con- taining a monomer of the invention which polymerizes to a thin film of polymer while in Contact with said tissue surfaces. For bonding separate surfaces of body tissues, the monomer would be applied to at least one of such surfaces, and the surfaces brought quickly together while the monomer poly- merizes in contact with both of the surfaces. The monomers of the invention are effec- tive in adhesive formulations with the fluoro- alkyl 2 — cyanoacrylates as the major active constituent. Thus, the cyanoacrylate may be combined in admixture with a polymeriza- tion inhibitor (e.g. sulfur dioxide). One or more adiuvant substances, such as thicken- ing agents or plasticizers to improve the surgical utility of the monomer, can also be present. Depending on the particular requirements of the user, these adhesive compositions can be applied by known means such as with a glass stirring rod, sterile brush or medicinal dropper; however, in many situations a pres- surized aerosol dispensing package is pre- fened in which the adhesive composition is in solution with a compatible anhydrous pro- pellant. The monomers are readily polymerized to addition-type polymers and copolymers, which are generally optically clear (as films) and are thermoplastic and moldable at tem- peratures below their decomposition temp- erature. They can be shaped at temperatures in the range of 100° to 150°C. The polymers have a 55 60 65 70 75 80 85 95 100 105 110 -3’ 10 15 20 25 30 35 T40 45 50 55 1,211,172 wherein R and R’ are as defined above and x is a number from 5 to 500. Polymerization occurs by free radical in- itiation, exposure to small amounts of base, e.g. triethylamine, or water. The liquid mono- mer can be spread on e.g. a polyethylene surface and exposed to triethylamine to bring about polymerization to a coating which can be peeled from the polyethylene as a self- supporting, optically clear film. The monomers of the invention can be co- polymerized with other acrylates or epoxides for example, with an unsubstituted mono- meric alkyl 2 - cyano-acrylate containing from 1 to 8 carbon atoms. The preferred method for preparing high purity (95 percent or greater) fluoroalkyl 2 - cyanacrylates comprises catalytizing the con- densation of formaldehyde with esters of cyanoacetic acid by means of a mixture of an acid and the acidic salt of an alkyl primary or secondary amine. With particular reference to the prepara- tion of the fluoroalkyl 2 — cyanoacrylate esters of the present invention, the preferred method of preparation employs the cyano- acetates corresponding to the desired cyano- acrylates (e.g. 2,2,2 - trifluoroethyl cyano- acetate for 2,2,2 — trifluoroethyl 2 - cyano- acrylate). The cyanoacetate is reacted with formaldehyde or polymers thereof such as paraformaldehyde, excepting aqueous solu- tions of formaldehyde as typified by formalin. The reaction medium may be any suitable inert organic solvent capable of forming an azeotrope with water. The essential feature of the synthesis is the particular combination of catalytic materials employed. Any acid salt of an alkyl primary or secondary amine and any free acid may be utilized as components of the catalytic mixture, provided they establish the neces- -sary pH value as described in detail below. All phases o-f the synthetic sequence are carried out under acidic conditions. A criterion for utility of the catalytic mix- ture selected is that it have a corrected pH value of not over pH 5. This pH value can be determined as follows. The exact amounts of amine acid salt and free acid to be used in the condensation step are dissolved in 25 ml. of water, and the pH of the solution is measured. If the result- ing pH value is 5 or less, the mixture will adequately catalyze the condensation reaction. When the mixture is soluble in water, this is the “corrected pH value”. Catalytic mixtures comprising organic acids which are not readily soluble in water may be dissolved in 25 ml. of an ethanol- water mixture; however, the measured pH must then be corrected as described by B. Gutbezehl and E. Grunwald in I. Am. Chem. Soc., 75, 565 (1953). Both primary or secondary amine salt and free acid are always present. Glacial acetic or strong mineral acids such as hydrochloric acid or sulfuric acid are preferred. The amount of catalyst employed is not critical and may be varied. Ordinarily a small amount, e.g. 0.5 to 0.1 percent by weight, based on the weight of cyanoacetic ester, is adequate. Other than employing the amine acid salt and free acid, the condensation of cyano- acetic esters with formaldehyde and the sub- sequent depolymerization process are carried out by methods similar to prior art methods. The following examples illustrate the in- vention and its practical applications. It will be understood, however, that the examples are included merely for the purposes of illus- tration and are not intended to limit the scope of the invention, unless otherwise speci- fically indicated. All parts are by weight un- less otherwise specified, and the pressures are shown in millimeters of mercury. EXAMPLE 1 Fluoroalkyl cyanoacetates Fluoroalkyl cyanoacetates required as starting materials in the synthesis of fluoro- alkyl 2 - cyanocrylates described in this in- vention are not available by simple esteri- fication of cyanoacetic acid. A general pro- cedure fo-r the special preparation of these materials from cyanoacetyl chloride on a large scale is given below. A 5-1 three-necked, round-bottomed flask equipped with an efficient mechanical stirrer, large addition funnel and reflux condenser topped with a gas exit tube was charged with 1000 ml. of diethyl ether and 1042.5 g. of phosphorus pentachloride. This suspension was stirred and cooled in an ice bath. In a separate container, a solution of 425.5 g. (5.0 moles) of cyanoacetic acid in 1750 ml. -of diethyl ether was dried over magnesium sulfate and filtered to remove drying agent. It was then added over a period of 3 to 7 minutes with good stirring to the cold sus- pension. (The exothermic reaction which occurs can be controlled by adjusting the rate of addition but a rapid rate is essential for optimum yield). The condenser was im- mediately replaced with a short head and condenser. Ether and phosphorus oxychloride were then distilled off under reduced pres- 5 sure (aspirator) to afford crude cyanoacetyl chloride as an orange—red, mobile liquid. During this operation, the internal pot tem- perature was not allowed to exceed 55°C. 60 65 70 75 80 85 90 95 100 105 110 115 120 10 30 40 45 50 55 60 65 1,211,172 This step is critical since higher temperatures will cause degradation of cyanoacetyl chloride and may induce exothermic and uncontrol- lable polymerization. Samples of cyanoacetyl chloride should be used directly after pre- paration and should not be stored. The distillation apparatus was then re- moved from the flask and replaced with a reflux condenser topped with a gas exit tube. The selected fluoroalcohol was placed in the funnel and about one-third added to the crude cyanoacetyl chloride. If the reaction did not begin spontaneously as evidenced by evolution of hydrogen chloride, the mixture was heated to 55°—65°C; the remaining fluoroalcohol was then added slowly to main- tain a smooth reaction. After completion of addition, the mixture was stirred at 55°- 65°C. until no more hydrogen chloride was evolved. The acidic product was transferred to a smaller flask and crudely distilled to afford fluoroalkyl cyanoacetate. Fractional redistillation provided pure fluoroalkyl cyano- acetate with yields in the range of 75-85 percent. TABLE I Fluoroalkyl Cyanoacetates, NCCHZCOZR R —~CH2CF3 ‘—'CH2CF2OF3 —CI-I2(-CF2)-2H CH3 —CH \ CFs EXAMPLE 2 2,2,2-Trifluoroethyl 2-cyanoacrylate Six hundred milliliters of benzene, 167.1 g. (1.0 mole of 2,2,2 - trifluoroethyl cyano- acetate, 36.0 g. (1.2 moles) of powdered paraformaldehyde, 1.0 g. of piperidine hydro- chloride and 0.2 ml. of glacial acetic acid were combined in a 1-1 two-necked, round bottomed flask equipped with mechanical stirrer, Dean-Stark water trap and reflux condenser. The heterogeneous mixture was stirred and heated under gentle reflux until all water fonned during the reaction had been azeotropically removed and collected in the Dean-Stark trap. Only a portion of the poly- (trifluoroethyl 2 - cyanoacrylate) formed in the reaction separated; the remainder was precipitated by cooling the flask in an ice bath. After the cold benzene had been decanted, 300 ml. of anhydrous acetone were added and warmed to dissolve polymer. The clear polymer solution was filtered (to remove piperidine hydrochloride and any unreacted paraformaldehyde) into a clean 1-l two- necked, roimd bottomed flask equipped with mechanical stirrer, and 100 g. of tricresyl phosphate were added to aid in fluidizing the mixture. Acetone was then removed by dis- tillation. Pressure in the system was gradu- ally reduced to 15-20 mm. Hg, and the bath temperature slowly raised to 110°-- 120°C. Last traces of acetone were elimin- ated by stirring the yellow, viscous mixture vigorously for 30 minutes under these condi- l'.lOI1.S. b.p (°C.) 93/9 mm. 83—85°C/6 mm. 71/0.25 mm. 105—106/0.9 96/13 mm. nD25° 1.3692 1.3546 1.3785 1.3585 1.3724 At this point, 6-10 g. of polyphosphoric acid and 0.5 g. of pyrogallol were added to serve as inhibitors, and the flask was equipped with a short take-off head fitted with a gas inlet tube mounted in the thermo- meter Well. Thermal depolymerization was effected by heating this mixture under re- duced pressure with good stirring while sul- fur dioxide was bled into the system. Collec- tion of monomeric 2,2,2 - trifluoroethyl 2 - cyanoacrylate in a Dry Ice-cooled receiver was begun when the bath temperature/ system pressure reached 155°C./20 mm. and continued up to a maximum of 200°C/10 mm. Clear, colorless monomer obtained in this fashion is sufliciently pure for most ad- hesive applications; yield, 95 g. (53 percent based on 2,2,2 - trifluoroethyl cyanocetate). Greater purity may be achieved by re- distillation from a amount of phos- phorus pentoxide using a short Vigreux column. A sulfur dioxide bleed to serve as inhibitor and prevent anionic polymerization: is essential during any such redistillation. On redistillation, the distillation cut boiling at 83°—84°»C./13 mm. weighed 71 g. and was shown to be 85.8 percent pure 2,2,2 - tri- fluoroethyl 2 - cyanoacrylate. Monomer purity was established by gas chromatography using a chromatograph equipped with a 6’X 1/4" nitrile-containing silicone column packed on diatomaceous earth (of the type commercially available under the trade name “60/70 Anakrom ABS”) and operated at column temperatures of 150-190°C. Monomer samples were in- 15 20 25 70 75 80 85 90 95 100 110 §_j...j_ 10 15 20 25 30 35 40 45 50 55 60 1,211,172 jected as 10 percent solutions in spectrograde nitromethane. Polymeric 2,2,2 - trifluoroethyl cyano- acrylate was formed by pouring the monomer into a large excess of rapidly stirred 1: 1 methanol-water solution. The polymer pre- cipitated in finely divided form and was re- moved by filtration, Washed with methanol and dried. This was molded into disks at about 100°—125°C. which have useful di- electric properties. These disks can be machined and used as insulating washers. The polymer is soluble in acetone and films o-r coatings can be made from these solu- tions in the usual manner. These also have useful electrical insulating properties. EXAMPLE 3 2—(1,1,1-Trifluoro)propyl 2-cyanoacrylate A 2-1 three-necked flask equipped with a mechanical stirrer and Dean-Stark water trap was charged with 438 g. (2.42 moles) 2 - (1,1,1 - trifluoro)propyl cyanoacetate, 96.0 g. (3.2 moles) powdered parafo-rmalde- hyde, 3.0 g. piperidine hydrochloride, 0.5 ml. glacial acetic acid and 900 ml. benzene. The mixture was stirred and slowly brought to reflux over a period of 3 hours. Heating under reflux was continued until no more water separated in the trap. The cooled solu- tion of low molecular weight polymer was then filtered into a. round-bottomed flask con- taining 240 .g. tricresylphosphate. Benzene was then removed by distillation. Last traces of solvent were eliminated by stirring the mixture of 110°C. 0.3 mm. The distillation head was removed and replaced with a clean, dry one-piece head and condenser fitted with a gas inlet tube in the thermometer well. About 10 g. poly- phosphoric acid were added to the orange syrupy mixture. Thermal depolymerization was affected by heating this mixture under reduced pressure while sulfur dioxide was bled into the system. Collection of crude monomeric 2 — (1,1,1 - trifluoro)propyl 2 - cyanocrylate in a Dry Ice—cooled receiver was begun when the bath tiemperatiire/{system pressure reached 150°-C./20 mm. and con- tinued up to a maximum of 190°C./0.45 mm.; yield, 251 g. On redistillation of crude monomer from a small amount of phosphorus pentoxide as described in Example 1, the fraction boiling at 83°—85°C./ 17 mm. was shown to be at least 98 percent pure 2 — (1,1,1 - trifluoro)propyl cyanoacrylate. The monomer is converted to polymer by the pro- cedure described in Example 1. Examples of other 2-cyanoacrylates Other cyanoacrylates which have been pre- pared in a manner similar to that described in Examples 1 and 2 are collected in Table II. TABLE II CN Fluoroalkyl 2-cyanoacrylates, CH2=C - \ CO2R R b.p. -—CH2(CF2)2H 89—90/0.3 mm. —CH2(CF2).,H 91——95/0.2-0.4 mm. -—CH2-CFZCF3 98—-100°/ 15 mm. These monomers can be polymerized in the same manner as described in Examples 1 and 2. EXAMPLE 4 Hemostasis in Vascular Organs (Excised Cat Spleen) A male cat was anesthetized intravenously with pento-b-arbital—sodium and prepared for aseptic surgery. Prior to surgery 25 milli- grams of heparin sodium USP were intra- venously administered. The spleen was ex- teriorized through a ventral midline incision, and a disk-shaped portion of splenic tissue 1 to 2 centimeters in diameter and 3 to 5 millimeters deep was excised. Resulting pro- fuse hemorrhage from the wound was con- trolled by occluding the blood supply to- the spleen with soft clamps and gauze spong- ing. A thin layer of 2,2,2 - trifluoroethyl 2 - cyanoacrylate adhesive monomer was applied to the wound surface immediately thereafter by spraying with an aerosol at a distance of from 4 to 8 centimeters from the wound surface. After allowing suflicient time for polymerization of the monomer, the organ was replaced in the peritoneal cavity. The ventral midline incision was closed using con- ventional sutures. 1’-ost—operative antibiotics and vitamins were routinely administered. Adhesive and hemostatic properties were re- corded at the time of application. The cat, except for depression during the first few post-operative days, made an un- eventful recovery and remained healthy until sacrified six weeks after surgery. Adhesions between the spleen and surrounding tissue, and expected sequela following surgery of this nature, and mild inflammation of the splenic capsule were the only gross tissue changes observed at necropsy. None of the adhesive was grossly visible and normal heal- ing appeared to be in progress. WHAT WE CLAIM IS:— 1. Compounds having the formula CN R I I CH2=C—CO2——C.H——CF2R1 wherein R is hydrogen, methyl or ethyl; R1 is fluorine, —(CF2),,H or -—CF3; and n is an integer of from 1 to 3. 5 65 70 75 80 85 90 95 100 105 110 115 6 3 Mn: .=nl. E 10 15 20 1,211,172 2. A compound of claim 1 wherein R is hydrogen and R1 is fluorine. 3. A compound of claim 1 wherein R is hydrogen and R1 is ——(GF2)3H. 4. A compound of claim 1 wherein R is hydrogen and R1 is —CF,,. 5. A compound of claim 1 wherein R is hydrogen and R1 is CF21-I. 6. A compound of claim 1 wherein R is —(I’.I-I3 and R1 is fluorine. 7. A compound according to any of the preceding claims in sterile form. 8. An adhesive composition which is auto- polymerizable comprising a monomeric 2 - cyanoacrylate having the formula CN R I I CH,=C—CO2—CH—CF,R1 wherein R is hydrogen, methyl or ethyl; R1 is fluorine, —(CF2),,H or —CF,,; and n is an integer of from 1 to 3, said adhesive com- position containing an amount of polymeriza- tion inhibitor as a stabilizer therefor. 9. An adhesive composition according to claim 8 containing one or more of the com- pounds according to claims 2—6. Printed for Her Ma.jesty’s Stationery Office, Published by The Patent Oflice, 25 Southampton 10. A composition according to claim 8 in which the polymerization inhibitor is sul- fur dioxide. 11. An adhesive composition which is auto- polymerizable comprising a mixture of at least two of the compounds of any of claims 1—7 containing an amount of polymerization inhibitor as a stabilizer therefor. 12. An adhesive composition according to claim 8 which is autopolymerizable in thin film, containing in admixture unsubstituted monomeric alkyl 2 — cyanoacrylate contain- ing from 1 to 8 carbon atoms. 13. A composition according to claim 8 containing an adiuvant material. 14. A cyanoacrylate compound according to any one of the examples 2 or 3. 15. A thermoplastic addition polymer of 211 monomer according to any one of claims —-7. 16. A thermoplastic addition polymer of a monomer according to any one of examples Zor 3. REDDIE & GROSE, Agents for the Applicants, 6 Bream’s Buildings, London, E.C.4. by the Courier Press, Leamington Spa, 1970. Buildinfis, London, WC2A IAY, from which copies may be obtains 6 25 35 45