PROCESS FOR THE PREPARATION OF ESTERS OF 2-CYANOACRYLIC ACID AND USE OF THE ESTERS SO PREPARED AS ADHESIVES

WORLD INTELLECTUAL PROPETY ORGANIZATION . Intemational Bureau INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PC'I') WO 94/15907 21 July 1994 (2l.07.94) (51) International Patent Classification 5 : C07C 253/30, 255/23, C08F 22/32 (11) International Publication Number: (43) International Publication Date: PCI‘/[E94/00002 (81) Designated States: AU, BG, BR, CA, CZ, FI, I-IU, JP, KR, NO, NZ, PL, RO, RU, US, European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE). (21) International Application Number: (22) International Filing Date: 10 January 1994 (10.0l.94) Published With imernational search report. With amended claims. (30) Priority Data: 93001196 930599 11 January 1993 (1101.93) RU 10 August 1993 (10.08.93) IE (71) Applicant (for all designated States except US): EUROTAX LIMITED [IE/IE]; Molyneux House, Bride Street, Dublin 8 (IE)- (72) Inventors; and (75) Inventors/Applicants (for US only): DYATIDV, Valery Alexandrovich [RU/RU]; Malyl Levshinskyl per., 12-6, Moscow, 119034 (RU). KA'I'Z, Georgy Arkadievich [RU/RU]; Shenkyrsky proezd., 12a-141, Moscow, 127349 (RU). (74) Agent: ANNE RYAN & CO.; 60 Northumberland Road, Ballsbridge, Dublin 4 (IE). (54) Title: PROCESS FOR THE PREPARATION OF ESTERS OF 2-CYANOACRYLIC ACID AND USE OF THE ESTERS SO PREPARED AS ADHESIVES (57) Abstract A process for the preparation of esters, including non-distillable esters, of 2-cyanoacrylic acid comprises reacting 2-cyanoacrylic acid or an acid halide thereof with an alcohol, including a diol or polyol, or a phenol in the presence of an inert organic solvent under polymerisation inhibiting conditions and, additionally, in the presence of an acid catalyst when 2-cyanoacrylic acid is a reactant, continually removing the water or hydrohalic acid produced and recovering the ester. The esters thereby prepared and many of which are novel compounds include substituted or unsubstituted long chain alkyl cyanoacrylates and multifunctional cyanoacrylates, including bis cyanoacrylates. Such esters have a wide range of applications. For example, they can be grafted onto polymer backbones to improve properties of said polymers such as thermal resistance. FOR THE PURPOSES OF INFORMATION ONLY Codes used to identify States party to the PCI‘ on the front pages of pamphlets publishing international applications under the PCI‘. AT Austria AU Australia Barbados Belgium Burkina Faso Bulgaria Benin Brazil Belarus Canada Central African Republic Congo Switzerland Cote d'Ivoire United lfingdom Georgia Guinea Portugal Romania Russian Fedaation Demoaatic People's Republic Sudan of Korea Swedm Republic of Korea Slovenia Kazakhstan _ Slovakia Liechtenstein Senegal Sri Lanka Chad Luxembourg Togo Latvia Tajikistan Monaco Trinidad and Tobago Republic of Moldova Ukraine United States of America Uzbekistan Viet Nam GB GE GN GR HU IE IT JP KE KG KP KR KZ LI LK LU LV MC MD MG ML MN 9:'ri-'-WEEESQQQQE W0 94/ 15907 _ PCT/IE94/00002 Description Process for the preparation of esters of 2-cyanoacrylic acid and use of the esters so prepared as adhesives Technical Field 5 This invention relates to a process for the preparation of esters of 2-cyanoacrylic acid, including long chain esters, and the use of the esters so prepared. Many of these esters are novel compounds. Background Art Cyanoacrylate esters are the main constituent of instant or rapid 10 bonding adhesives, commonly known as 'superglues'. Bonding in the case of such adhesives results from the conversion of a low viscosity liquid to a solid polymer by anionic polymerisation. Cyanoacrylate esters are also used for the manufacture of polyalkylcyanoacrylate nanoparticles and nanocapsules used as drug and other active agent 15 carrier systems. Until now, the only commercial route for the preparation of Cyanoacrylate esters was the Knoevenagel Condensation Method (H. Lee. (Ed.) (1981) Cyanoacrylic Resins - The Instant Adhesives, _. Pasadena Technology Press, Pasadena, U.S.A.). According to the 20 Knoevenagel method a cyanoacetate ester and formaldehyde are reacted together in the presence of an amine to give oligomers of polyalkylcyanoacrylates. The free Cyanoacrylate monomer is generated by thermally cracking the oligomer under vacuum and distilling onto anionic acid stabiliser under vacuum. Following the distillation step, a 25 free radical stabiliser, such as methylhydroquinone, may be added to inhibit free radical polymerisation during storage. Free radical polymerisation can be initiated, for example, by exposure to light. The Knoevenagel method is limited to the preparation of alkyl cyanoacrylates which have an alkyl moiety with no more than ten W0 94/ 15907 10 15 20 25 30 PCT/IE94/00002 carbon atoms. Above ten carbon atoms, the monomers cease to be distillable at temperatures below their respective thermal destruction temperatures. In fact, n—octyl cyanoacrylate is the monomer with the greatest number of carbon atoms that has been reported in the literature to have been prepared by the Knoevenagel method and has been used in the preparation of a medical adhesive (Kublin, K.S. and Miguel, F.M., (1970) J. Amer. Vet. Med. Ass. Vol. 156, No. 3, p.313- 8 and Alco, J .J . and DeRenzis, F.A., (1971) J. Pharmacol. Ther. Dent. Vol. 1, No. 3, p.129-32). Short chain (less than ten carbon atoms) alkyl cyanoacrylates with polar groups such as hydroxyl, carboxyl and ester groups and aryl cyanoacrylates cannot generally be prepared by the Knoevenagel Condensation Method because of their high boiling points. Additionally, multifunctional cyanoacrylates, such as bis cyanoacrylates, cannot be synthesised because they are non—disti1lable below their thermal destruction temperatures. A method for the preparation of bis cyanoacrylates, which are indicated to be useful as thermally and moisture resistant acrylate additives are the subject of U.S. Patent No. 3,903,055. The method can involve essentially three or five steps. In the five-step method, ethyl or isobutyl cyanoacrylate is reacted with anthracene to form its stable Diels-Alder anthracene adduct. Basic hydrolysis of the adduct gives the corresponding acid salt from which the corresponding acid is obtained upon acidification. The carboxylic acid is then converted to its acid chloride with thionyl chloride and then reacted with diol to give the bis anthracene diester. Displacement of the adduct by the stronger dienophile maleic anhydride gives bis cyanoacrylates in good yield. However, this mu1ti—step method is purely a laboratory method and scaling up to a commercially viable level has not proved practicable. To date, the method of U.S. Patent No. 3,903,055 supra has remained the only feasible. method of producing bis, multifunctional or long chain non-distillable cyanoacrylates. WO 94/15907 10 15 20 25 30 PCT/IE94/00002 L Patent Publication DE 34 15 181 Al describes the preparation for the first time of on-cyanoacrylic acid which can be considered as the obvious precursor for alkylcyanoacrylates. The cyanoacrylic acid is prepared from a cyanoacrylic acid alkyl ester, in which the alkyl group contains from 2-18 carbon atoms, or the Diels-Alder adduct thereof by pyrolysis. The pyrolysis is preferably carried out on silicate-type surfaces such as quartz surfaces. The cyanoacrylic acid so prepared is indicated to be useful for stabilising or regulating the curing time of adhesives based on monomeric cyanoacrylic acid esters. It is also indicated that the cyanoacrylic acid so prepared can be used to prepare the diol esters of the acid. However, there is no indication in the specification as to how this can be accomplished. Patent Publication JP 91 065340 describes a versatile route to pyruvic acid cyanohydrin and its esters as intermediates for the preparation of ot-cyanoacrylate esters. Patent Publication JP 91 075538 describes ot-acetoxy-ot- cyanopropionic acid esters which can be thermally converted to cyanoacrylate esters by elimination of a molecule of acetic acid. Kandror I.I. et al. ((1990) Zh. Obsch. Khemii., Vol. 60, No. 9, p.2l60-8) successfully converted ot-cyanoacrylic acid (prepared according to Patent Publication DE 34 15 181 A1) to its acid chloride by the use of phosphorus pentachloride. Other chlorinating agents, such as thionyl chloride, were found not to be suitable. The product was obtained as a solution in o-xylene/toluene. Any attempts to isolate the pure product resulted in its decomposition. However, Kandror er al. successfully converted the acid chloride in solution to its thioester which spontaneously polymerised upon isolation. Kandror et al. have also successfully converted ot-cyanoacrylic acid to its very unstable trialkylsilyl esters. To date there have been no reports in the literature concerning the conversion of cyanoacrylic acid or its chloride to its alkyl ester monomers, whether short chain, long chain, bis or multifunctional W0 94/ 15907 10 15 20 25 30 PCT/IE94/00002 cyanoacrylates, more particularly by a method which can be canied out on a commercial scale. The preparation of a long chain cyanoacrylate (a thioester) by the strictly laboratory method of U.S. Patent No. 3,903,055 supra was synthesised by S.J. Harris ((1981) J. Polym. Sci. Polym. Chem. Ed. Vol. 19, No. 10, p.2655-6). The n-dodecylthio cyanoacrylate so prepared conferred improved moisture resistance when used as an additive in an ethyl cyanoacrylate adhesive. Cyanoacrylate adhesive monomers, such as the most commonly used ethyl ester, can have their physical properties improved by the addition of linear organic polymers. Thus, non-reactive rubbers can be dissolved in such monomers to give adhesive compositions with much improved toughness/impact resistance when cured in the final adhesive bond. However, to date improvement in thermal/moisture resistance of rapid bonding cyanoacrylates has only been modest. An improvement in adhesion, as well as toughness, would be expected if the non-reactive rubbers additionally contained chemically bound multi-cyanoacrylate functionality. Furthermore, it would be expected that any resulting increased cross-linked density could well provide significantly improved thermal moisture resistance to the final cyanoacrylate bond, relative to that of compositions containing only non-reactive rubbers. J .P. Kennedy et al. ((1990) Am. Chem. Soc. Div. Polym. Chem. 31(2) p.255-6) prepared a cyanoacrylate-capped polyisobutylene by esterification of a hydroxy—terrninated polyisobutylene. The method of U.S. Patent No. 3,903,055 supra was used to generate a multifunctional cyanoacrylate ester monomer which can be used as a glue which resulted in a copolymer being formed. Such copolymers have desirable properties for the reasons stated in the preceding paragraph. However, such multifunctional cyanoacrylate monomers cannot be used as improving additives because of their insolubility in cyanoacrylates. W0 94/15907 10 15 20 25 PCT/[E94/00002 Linear polymers such as poly(methyl methacrylate) are used as thickeners for cyanoacrylate monomers, so that the viscosity of the adhesive can be increased to a desirable level for a particular application. The use of cyanoacrylate-capped poly(alky1 methacrylates) as reactive thickeners would be expected to provide improved thermal/moisture resistance to the final joint and also improve the gap- filling ability of the adhesive. Accordingly, for the above reasons, a method for generating cyanoacrylate esters on a practical and commercial scale is sought. Disclosure of Invention The invention provides a process for the preparation of esters of 2—cyanoacrylic acid, which process comprises reacting 2—cyanoacrylic acid or an acid halide thereof with an alcohol or a phenol in the presence of an inert organic solvent under polymerisation inhibiting conditions and, additionally, in the presence of an acid catalyst when 2- cyanoacrylic acid is a reactant, continually removing the water or hydrohalic acid produced and recovering the ester. The process according to the invention can be used to prepare a wide range of cyanoacrylate esters, including substituted or unsubstituted long chain alkyl cyanoacrylates and multifunctional cyanoacrylates, including bis cyanoacrylates. The process according to the invention can be carried out in a simple, rapid and facile, effectively one step process with the attendant advantages. Thus, the process according to the invention is a ‘one pot‘ process in contrast with the prior art methods described above with their inherent limitations. The term alcohol as used herein includes diols and polyols. The preferred acid halide is the acid chloride. W0 94/ 15907 . PCT/IE94/00002 The following reaction scheme depicts the reactions involving a) the acid and b) the acid chloride. CNO CNO II a) CH =C—C——OH + ROH ———> CH =C—C—OR +H2O CNO CNO II b) CH=C—C—Cl + ROH ———» cH=c—c—oR +HCl 5 When 2—cyanoacry1ic acid is used as a reactant, the acid catalyst is a non-volatile acid stabiliser. Preferably, the acid catalyst is an anionic non-volatile acid stabiliser such as, for example, an aliphatic sulphonic acid, an aromatic sulphonic acid or a sultone. An essential characteristic of the acid 10 catalyst is that it does not react with the alcohol or phenol. Especially suitable acid catalysts are methane sulphonic acid and p-toluene sulphonic acid. Preferably, the process is carried out under anionic polymerisation inhibiting conditions. Such anionic polymerisation 15 inhibiting conditions can involve the use of an excess of 2—cyanoacry1ic acid, where cyanoacrylic acid is a reactant. Alternatively, the anionic polymerisation inhibiting conditions can involve the use of a weak acid. An especially suitable weak acid is sulphur dioxide, more 20 especially gaseous sulphur dioxide which is bubbled into the reaction mixture, as further demonstrated below. Further, preferably, when sulphur dioxide is used as an anionic polymerisation inhibitor, gaseous sulphur dioxide is bubbled into the reaction mixture as a continuous stream of sulphur dioxide. W0 94/ 15907 10 15 20 25 PCT/IE94/00002 Other anionic polymerisation inhibitors include aliphatic sulphonic acids, aromatic sulphonic acids, sultones, carbon dioxide and boron trifluoride. Further, preferably, the process is carried out in the presence of a free radical polymerisation inhibitor. A suitable free radical polymerisation inhibitor is benzoquinone, hydroquinone, methylhydroquinone or naphthoquinone. The inert organic solvent can be any inert solvent which does not cause anionic polymerisation of cyanoacrylic acid or its esters. Suitable inert solvents include benzene, hexane, toluene, xylene and chlorinated hydrocarbons. In the case of acid - catalysed esterification nitroalkanes can be used. The process according to the invention can be carried out at a temperature in the range 20-200°C, more especially 80-100°C. When 2-cyanoacrylic acid is a starting compound, the esterification reaction is carried out under the conditions hereinabove specified with continual removal of water by azeotropic distillation. Preferably, the total volume of the reaction solvent is kept constant. Also preferably there is a gradual addition of alcohol or phenol into the reaction mixture. When secondary alcohols or phenols are being esterified in accordance with the invention, irrespective of whether 2-cyanoacrylic acid or an acid halide thereof is used, the reaction should preferably be carried out in the presence of sulphur dioxide to optimize conditions, because of the tendency of the cyanoacrylate monomers produced to polymerise under the reaction conditions. W0 94/ 15907 10 15 20 25 PCT/IE94/00002 When a cyanoacryolyl halide is a starting compound, an acid catalyst is not required as indicated above. In one embodiment the method of Kandror, I.I. (1990) supra can be used so that the cyanoacryolyl halide is reacted with the alcohol or phenol in sulphur dioxide saturated solvent under a dry inert gas such as argon. Other suitable inert gases include xenon, helium and nitrogen. The alcohol or phenol is added to the acid halide solution in sulphur dioxide - saturated solvent and the hydrohalic acid is removed as solvent is distilled off preferably under a stream of sulphur dioxide and argon. As an alternative to sulphur dioxide in the above embodiment, there can be used boron trifluoride. In each case, the removal of water or hydrohalic acid, as appropriate, forces the reaction to go to completion, more particularly under boiling solvent conditions and stirring. The invention also provides a novel method for the preparation of 2-cyanoacryloyl chloride, which comprises reacting 2—cyanoacrylic acid with phosphorus trichloride. Many of the esters which can be prepared by the process according to the invention are novel compounds. Thus, in a further aspect of the invention there is provided esters of 2—cyanoacrylic acid of the general formula I: CN / O v \. ll HZC = (I) wherein R is i) C11 or C13 or higher saturated, optionally mono- or polysubstituted, linear-, branched- or cyc1o—a1kyl; ii) C7—C1g saturated, optionally mono- or polysubstituted, branched alkyl; W0 94/ 15907 10 15 20 25 PCT/IE94/00002 iii) C7—C10, optionally mono- or polysubstituted, cycloalkyl; iv) C12 saturated, optionally mono- or polysubstituted, branched- or cyclo-alkyl; v) C5 or higher unsaturated, substituted or unsubstituted, linear-, branched- or cyc1o—alkenyl or - alkynyl; vi) C2-C1; substituted alkyl where the or each substituent is a functional group which is not a free hydroxyl group, a hydroxyl group esterified by 2- cyanoacrylic acid, or an ether group; vii) C2—C1_9_ substituted alkyl where the alkyl group is substituted by more than one ether group; viii) C13 or higher substituted alkyl where the or each substituent is a functional group; ix) C3 or higher substituted alkyl where the or each substituent is a hydroxyl group; x) C5 or higher substituted alkyl where the or each substituent is a simple or compound ether group; xi) a mono- or polysubstituted phenyl group; xii) a mono- or polysubstituted biphenyl, naphthyl, anthracyl, phenanthryl or other cyclic or polycyclic aromatic or heteroaromatic group; or xiii) a hydroxy-terminated or a hydroxy-substituted oligomer or polymer. Substituents can include heteroelements. It will be appreciated that the main chain of any ester herein described can contain a heteroelement or ether function. Functional groups which are representative of those which would 30 normally be used to substitute an R group as hereinabove defined include, for example, halogen, carboxyl, nitrile, acyl-amino, unsaturated and heteroelement-containing groups. W0 94/ 15907 10 15 20 25 30 PCT/IE94/040002 1 O In a still further aspect of the invention there is provided the mono— or bis(2-cyanoacrylate) esters of di—, tri-, tetra-, penta-, hexa- and poly-ethylene glycols or derivatives thereof. As indicated above, the process according to the invention can be used to prepare previously unobtainable, non-distillable cyanoacrylate monomers for a wide variety of uses. Cyanoacrylates prepared in accordance with the invention can be grafted onto polymer backbones to improve properties of said polymers such as thermal resistance. For example, aryl cyanoacrylates prepared in accordance with the invention would inherently be expected to give more thermally resistant bonds on account of their aromaticity and would also be expected to be low viscosity monomers similar to the methyl - and ethyl esters. As indicated above, to date improvement in thermal resistance of rapid bonding cyanoacrylates has been only modest. For example, the monomers can be prepared with a high number of ether linkages or multifunctional hydroxyl groups for the preparation of biodegradable drug or other active agent—containing nanocapsules or nanoparticles, more especially nanocapsules. Furthermore, drugs and other active agents can be chemically bound to such cyanoacrylates so as to achieve controlled release/absorption of the active agents with time. Other uses for the cyanoacrylate monomers prepared in accordance with the invention include use in the preparation of a wide range of adhesives, including rapidly biodegradable medical adhesives or adhesives for temporary bonding. Further specific examples of the uses of the cyanoacrylate esters prepared in accordance with the invention are indicated below. U.S. Patent No. 3,903,055, supra describes bis cyanoacrylates as thermally resistant cyanoacrylate additives which are prepared from ' their respective anthracene adducts by displacement with maleic anhydride. However, as indicated above the bis cyanoacrylates so prepared are difficult to purify by this method. W0 94/ 15907 _ PCT/IE94/00002 11 The process according to the invention is versatile and can be used to produce a wide variety of bis cyanoacrylates according to the following general reaction scheme, wherein "R" can have a multiplicity of values as hereinabove described: - CH H CN CN H / \ / \ / HZC : C :—--> C 3 C C 3 C \ / \ / \ CO2H H EOROEIS H 5 o o In the same way tri and tetrafunctional cyanoacrylates can be prepared in accordance with the invention, for example from pentaerythritol O C\ C = CH / 2 CN 4 10 The quantities of tetrafunctional additive needed to provide significant improvements in cross—1ink density for thermal resistance improvement would be less than for bis cyanoacrylates. Polyfunctional cyanoacrylates can be readily synthesised in accordance with the invention from polyvinylalcohol as follows: (C|IH— CH2)n (CH— CH2)n OH O + I H CN C\= O ‘T \C 2 C / /C -7- CH2 H/ \ CO2H 15 CN' W0 94/ 15907 10 15 PCT/IE94/00002 12 It is also postulated that further improvement can be rendered by attachment of cyanoacrylate units to a thermally resistant backbone containing OH functionality in the following manner: 0 o n /u\ H/ _ \ R_1\I/\R'—R—R' N-R COZH \/ I \/ J) O=